Fibromyalgia Treatment

Reviving the
Broken Marionette:
Treatments for CFS/ME
and Fibromyalgia
MAIJA HAAVISTO
Reviving the Broken Marionette: Treatments for CFS/ME and
fibromyalgia. A publication of CFS–verkko. All rights reserved.
© 2008 Maija Haavisto
Cover design: Stephen Caissie

Cover photo: Lauri Koponen
ISBN: 978-1-4092-0335-3
I would like to thank the following
people for their invaluable help:
Lauri Koponen
Pekka Valkonen
Roberto Orsini
Mary Romeo
Margaret Taylor
Murray Gillies
This book is dedicated to the memory of Kathleen Walker.

Preface
I could say that this book happened by accident. I am glad that it
did. The story may seem bleak, but I promise there is a happy ending.
I got sick with CFS/ME on the 28th of August, 2000. Where I live,
in Finland, CFS/ME simply does not exist, outside of a single infection
clinic of a university hospital where it is taken halfway seriously. You
never see it mentioned anywhere. I was lucky in that I had been inte-
rested in medicine for a long time. In 2002 I was able to find why I was
sick. Even before that I already knew I had something that was progres-
sively getting worse.
It was not until 2005 that I got my official diagnosis at the afore-
mentioned infection clinic, a diagnosis that was not worth the paper it
was written on, but at least my observations were finally confirmed.
Most people here—I guess anywhere—are not as lucky. I even got some
treatment that worked for a while. Frustrated that instead of getting
better I was deteriorating, they discharged me.
Even the few that get a diagnosis in this country are usually told
there is nothing that can be done for them. It frustrated me to no end,
because I knew the doctors were wrong, but they refused to listen to me.
In early 2006 I decided to compile a list of CFS/ME treatments for my
Finnish website. I intended it to be a brochure of 20–30 pages that I and
others could print for their doctor.
Some months later it was apparent I was working with a book
manuscript, but I was unsure whether I could finish it. My condition was
declining more rapidly now. I was struggling with severe cognitive
problems and had all but lost my ability to walk. I had been long aware
that I might end up in wheelchair and I could just about deal with it, but
I knew other people could not and I was terrified. I was certain that
medical treatment would help me, but the doctors did not seem to be
interested.
And then, in early 2007, I met my doctor (insert some violin music
and fireworks here). I showed him the manuscript and asked if he could
prescribe me low dose naltrexone. He agreed to, and my condition signi-
ficantly improved. Repeat with a few other medications (a few failed,
but some others made up for that). I am not cured by any means, but I
got my life back, my brain back, and my illness seems to have halted its
progressive course. The Finnish version of this book was finished soon
afterwards.
I cannot guarantee that others will achieve similar results, but I can
say that this book changed at least one person’s life—mine. Other read-
ers have been happy too. Some people bought five copies of the book so
6 Reviving the Broken Marionette
they could give one to all of their doctors. I knew I had to write an Eng-
lish version so that my work could benefit more people. I also wanted to
include fibromyalgia treatments, as I regretted not doing that the Finnish
version (in fact they were included, but did not make it to the cover
because of my foolishness).
This is a true story, which I hope you found interesting. If there is a
moral to this story, it is about hope. Never give up hope. Medicine can
do amazing things. We are broken, but not beyond repair. The best thing
you can do is to try to find a doctor who shares this belief.
If you have a personal story to share about being sick with CFS/ME
or fibromyalgia and getting much better (not necessarily cured), I would
love to read it and share it with others. Please email me at book@broken
marionettebook.com and I will publish your story on the website of this
book. Let me know if your real name can be published or if you want to
use your initials or a pseudonym. Note that I may not publish stories that
appear like an advertisement for a particular product.
Maija Haavisto
Disclaimer
This book has been written for informational purposes only. It has
not been authored by a medical doctor and as such should not be consi-
dered medical advice. It cannot be used to treat, prevent or diagnose any
medical condition and is not intended to substitute or replace professio-
nal medical care.
The author has gone to great lengths to verify all the information
presented in this book. Nonetheless, the sheer volume of reviewed mate-
rial makes it impossible to guarantee complete factual accuracy. All
information is subject to change and some may already be outdated by
the time the book is available in print.
The author or the publishers and distributors of the book cannot
assume responsibility for the accuracy of any of the information cont-
ained herein, or of the consequences of treating the information as medi-
cal advice. All treatment–related decisions and their consequences are
the sole responsibility of the reader and their doctors.
Reports of any errors, omissions or changes to the information
contained in the book can be submitted to the author via electronic mail
to the address book@brokenmarionettebook.com. If verified, the author
will attempt to publish them on the website of the book at http://www.
brokenmarionettebook.com. The author cannot guarantee that all such
information will be received or posted on the website.
CFS, ME and fibromyalgia
It is hard to say anything about CFS/ME and fibromyalgia without
stuttering into the first crucial issue: the terminology. Is it CFS, ME,
CFS/ME, ME/CFS or perhaps ME–CFS? Does ME refer to myalgic
encephalomyelitis, encephalitis or encephalopathy? To confuse things
further there are other alternative names for this condition (or these con-
ditions), such as CFIDS (chronic fatigue and immune dysfunction synd-
rome) and PVFS (post–viral fatigue syndrome).
Another thousand dollar question is whether CFS and ME are the
same thing and whether they are the same thing as fibromyalgia. I can
say that honestly I am not sure about the answer and I doubt I am the
only one. I used to be of the opinion that CFS and ME are the same
thing, but I am leaning towards the view that ME could be defined as a
subset of CFS which may or may not be a single entity,
I do think that fibromyalgia is a different (albeit similar) condition,
but many doctors believe that CFS/ME and fibromyalgia are the same
illness. The ICD–10 is mostly in agreement with me. It considers CFS,
ME and PVFS to be the same neurological illness, but fibromyalgia is
defined elsewhere.
Then there is the issue of deciding what the “E” means in ME.
Again I have ended up agreeing with the ICD–10 and prefer the term
encephalomyelitis as the most accurate term. Since I mostly use the abb-
reviation, you can interpret it to mean any of these names that you pre-
fer. Any one of them is more descriptive than CFS.
I find it unlikely that ME can only be caused by an enterovirus as is
sometimes stated. I know several people who obviously have this illness
(who suffer from profound fatigue and weakness with a myriad of neu-
rological symptoms that started suddenly and postinfectiously) and for
whom there are strong reasons to suspect it is caused by another kind of
virus, such as HHV–6 or even the influenza virus.
I do not subscribe to the belief that fibromyalgia is an autoimmune
disease.. I do think it is a neurological illness like CFS/ME, which may
have some autoimmune components in some cases. Treating fibromy-
algia as an autoimmune condition has led to disappointing results.
This book, however, takes no sides on as to what causes these ill-
nesses (or whether they are one, two or three separate things). It descri-
bes many different kinds of treatments, some of which are firmly con-
nected to a particular theory of origin and others that are used by many
doctors regardless of which “school” they belong to. The only theory I
CFS, ME and fibromyalgia 9
am specifically against is the ridiculous and unfounded idea that

CFS/ME or fibromyalgia are psychiatric conditions.
In the end I settled on the term CFS/ME, because it is neutral and
commonly used. Terms like CFIDS and PVFS are not widely in use. In
addition, my choice does not really take a stance on whether these are
two names for the same illness, an illness and its subset, or two different
conditions. I try to make it clear whether I am referring to CFS/ME or
fibromyalgia (which I sometimes abbreviate as “FM”), but sometimes
my sources are not clear about it.
The reason I included both CFS/ME and fibromyalgia treatments in
the same book—even though I believe they are not one and the same—
is that there are many similarities between them. They share similar
symptoms, they are often comorbid, they share similar comorbidities
and they can be treated with many of the same drugs—virtually all
drugs used to treat fibromyalgia are used to treat CFS/ME as well.
Contents
Disclaimer ...............................................................................................7
CFS, ME and fibromyalgia......................................................................8
Introduction ...........................................................................................12
Chronic fatigue syndrome/myalgic encephalomyelitis .....................12
Fibromyalgia......................................................................................15
Relationship with other illnesses .......................................................17
Treatment...........................................................................................19
CHAPTER 1. Sleep aids, tranquilizers and muscle relaxants ..................24
The “Z drugs” ....................................................................................24
Benzodiazepines ................................................................................26
Other sleep aids .................................................................................30
Muscle relaxants................................................................................32
CHAPTER 2. Painkillers..........................................................................46
Non–specific anti–inflammatory drugs (NSAIDs)............................46
Narcotic painkillers ...........................................................................52
Migraine and headache treatments ....................................................59
Other analgesics.................................................................................63
Topical and intravenous pain treatments ...........................................65
CHAPTER 3. Anticonvulsants .................................................................75
CHAPTER 4. Antimicrobials ..................................................................89
Antibiotics .........................................................................................89
Antivirals ...........................................................................................95
Antifungals ......................................................................................100
CHAPTER 5. Psychiatric drugs .............................................................111
Tricyclic antidepressants (TCAs) ....................................................112
Selective serotonin reuptake inhibitors (SSRI)................................118
Serotonin and norepinephrine reuptake inhibitors (SNRI)..............122
Norepinephrine reuptake inhibitors (NRIs) .....................................125
Monoamine oxidase inhibitors (MAOI) ..........................................127
Other antidepressants.......................................................................131
Neuroleptics and lithium .................................................................137
CHAPTER 6. Stimulants and nootropics ...............................................154
Sympathomimetic and dopaminergic drugs ....................................154
Nootropics .......................................................................................162
CHAPTER 7. Heart and blood pressure drugs .......................................173
Antiadrenergic drugs .......................................................................173
Beta blockers ...................................................................................175
Calcium channel blockers................................................................177
Other cardiovascular medications ...................................................180
CHAPTER 8. Hormones and immunomodulators ................................193
Corticosteroids ................................................................................ 194
Other hormones ............................................................................... 198
Biological immunosuppressants...................................................... 205
Other immunomodulators................................................................ 207
CHAPTER 9. Other medications ........................................................... 232
NMDA receptor antagonists............................................................ 232
Cholinesterase inhibitors ................................................................. 235
Antihistamines................................................................................. 239
Cannabinoids................................................................................... 243
Parenteral supplements.................................................................... 246
Treatments for bladder and bowel dysfunction ............................... 251
Other drugs...................................................................................... 255
CHAPTER 10. Experimental therapies.................................................. 274
APPENDIX A Drug interactions............................................................ 298
Pharmacodynamic interactions........................................................ 298
Metabolic interactions ..................................................................... 298
Interactions with non–pharmaceuticals ........................................... 300
Other problems with polypharmacy ................................................ 303
APPENDIX B. Surgery .......................................................................... 305
APPENDIX C. Vaccinations .................................................................. 308
Glossary............................................................................................... 312
Index.................................................................................................... 321
Introduction
CFS/ME and fibromyalgia are among the most common chronic
illnesses, but also among the most poorly understood and the most mis-
understood ones. Contrary to popular belief, however, they are not
“medically unexplained.” There is still plenty of work ahead before we
completely understand the etiology of these illnesses, but the same goes
for dozens of other chronic conditions.
Chronic fatigue syndrome/myalgic

encephalomyelitis
CFS/ME is a serious neurological illness, which is poorly known

among doctors. There are numerous misconceptions about it, such as
that it is a psychiatric illness or a “psychosocial construct.” Many doc-
tors still refuse to believe that it is a separate disease entity, even though
there are thousands of studies proving this. The WHO has recognized
myalgic encephalomyelitis as a neurological illness since 1969.
CFS/ME is sometimes regarded as a rare disease, but in fact the
current estimates of prevalence are about 0.5–1%, making it about as
common as rheumatoid arthritis and significantly more common than
multiple sclerosis. Although CFS/ME has been pejoratively seen as
“yuppie flu,” recent studies have found that it may be just as (if not
more) common in some developing countries.1
CFS/ME is thought to be more common in females. The onset
usually happens in the middle age, but it can occur at any time of life,
including childhood. Epidemics have been reported in a number of
countries, such as the United States, the United Kingdom and Iceland.2
Some doctors believe that CFS/ME can also affect animals, such as
dogs, cats and horses.3
The spectrum of CFS/ME goes from mild to extremely severe. It
can be chronic, relapsing and remitting or progressive. Some patients
are able to work or study, but some are completely paralyzed and unable
to move or speak. Some severely affected patients even die of the illness
or its complications. In a press conference held by CDC in November
2006 CDC’s William Reeves compared the disability caused by CFS/
ME to multiple sclerosis, AIDS, end stage renal failure and COPD.4
Introduction 13
Symptoms
CFS/ME is often mistaken for chronic fatigue, but it is much more

than that. Many patients have dozens of different, mostly neurological
symptoms. The severely affected often contest that the weakness,
malaise and extreme exhaustion has nothing to do with “fatigue.”
Nothing could be more confusing than labeling an illness as a fatigue
syndrome, considering that fatigue is a symptom of hundreds of diffe-
rent illnesses and conditions. This book is not about "chronic fatigue,"
though some treatments may be helpful for idiopathic fatigue.
What separates CFS/ME and its fatigue component from most
other fatiguing illnesses is the significant and disproportionate post–
exertional malaise, which may not begin until more than 24 hours after
the exertion and can last for days, weeks, months or even years, depend-
ing on the severity of the illness. In some cases the damage may even be
permanent. If you have been diagnosed with CFS/ME and do not suffer
from post–exertional malaise, you should definitely question the validity
of your diagnosis.
One of the most harmful misconceptions about CFS/ME is that
exercise, especially graded exercise, is an effective treatment for it. This
has been “proven” by studies of highly questionable methodology. Most
have in fact not permitted patients with CFS/ME to enter, but have only
included those with idiopathic fatigue. Those who suggest exercise as a
treatment for CFS/ME simply do not understand the nature of the ill-
ness. Doctors should caution about the risks of exercise, not encourage
it.5
The mildly affected may be able to do some exercise. Very careful
exercise may prevent muscle atrophy and prevent deconditioning, but
CFS/ME is not caused by deconditioning. A person with CFS/ME can-
not improve their physical fitness by exercise as a healthy person can.
Those who do want to exercise should do so with extreme caution in
order to avoid relapses. Rest is the best treatment for CFS/ME.
Cognitive problems are another hallmark of CFS/ME. Both con-
centration and memory are usually affected. Again, the spectrum goes
from problems finding words and ADHD–like attention problems to
severe, profound dementia. Those who do not suffer from any cognitive
problems should question their diagnosis of CFS/ME. Cognitive fatiga-
bility is usually just as troublesome and disabling a problem as muscle
fatigability, and in some patients it is even worse than physical exhaus-
tion.
Most patients with CFS/ME suffer from chronic pain. The pain can
include myalgia (muscle pain), arthralgia (joint pain), neuropathic pain
(nerve pain), abdominal pain, sore throat and headaches, including ten-
sion headaches, migraines and other types of headaches. The pain can
be constant and extremely severe. There can also be pain in less com-
mon anatomical locations, such as lymph nodes and the urinary tract.
Many people with CFS/ME also have tender points and trigger points.
Immune dysfunction is an integral part of CFS/ME.6,7 In the United
States the illness is sometimes called CFIDS, for chronic fatigue and
immune dysfunction syndrome. Some patients get all the infections;
others never even catch a cold. Swelling of lymph nodes and fever may
be chronic or intermittent. Allergic symptoms may include food and
chemical allergies and intolerances, chronic rhinitis and urticaria
(hives). Bladder problems and IBS are common.
Most patients have neurological symptoms, which can include par-
esthesias (abnormal sensations), impaired coordination and balance, tre-
mor, tinnitus, photophobia (sensitivity to light), hyperacuity (sensitivity
to noise), vertigo, visual disturbances, nystagmus and epileptic seizures.
Depression and anxiety are often of neurological origin. Sleep disorders
are very prevalent.
Cardiac and circulatory problems such as tachycardia and palpitati-
ons are common. The usual pattern is high pulse combined with a low
blood pressure. Nearly all patients suffer from orthostatic hypotension.
Some cannot even sit up because of this. Other common symptoms
include e.g. nausea, hair loss, dizziness, PMS, dyspnea, muscle tension,
sexual problems, edema, hot and cold intolerance, night sweats, hypo-
glycemia, and rashes.
Etiology
There are dozens if not hundreds of different theories about the

etiology of CFS/ME, though most of them are connected. It is now
widely accepted that most if not all cases of CFS/ME have an infectious
origin, but it is not clear whether this is a chronic infection or a postin-
fectious state (see CHAPTER 5 for more information). Most theories
about the cause of symptoms (such as cardiomyopathy and hypercoagu-
lation) do implicate an infectious agent.
Almost all theories also connect to poor circulation. Postulated cau-
ses include hypovolemia (low blood volume), orthostatic hypotension or
other dysautonomic states, hypercoagulation, poor erythrocyte deforma-
bility and combinations of these. Reduced circulation to brain and other
organs could explain virtually all symptoms. Blood perfusion in the
brain, especially in the brainstem, has been shown to be impaired in
CFS/ME.8
Introduction 15
CFS/ME is not generally considered an autoimmune illness, but

autoimmunity could still contribute to its symptoms. Several autoantibo-
dies have been detected more commonly compared to healthy controls.
These include e.g. gangliosides, phospholipids and serotonin.9 Antinuc-
lear antibodies (ANA) are found in a subset of CFS/ME patients. In one
study over 50% of CFS/ME patients had autoantibodies to muscarinic
cholinergic receptors.10
Mitochondrial dysfunction has also been proposed and muscle bio-
psies have provided evidence of it.11 One theory proposes that CFS/ME
is a channelopathy (an illness caused by abnormal ion channel func-
tion).12 Oxidative stress may also play a part.13 Several toxins have been
associated with CFS/ME, including organophosphates and ciguatera
toxin.14
Fibromyalgia
Fibromyalgia is even more common than CFS/ME. Some

authorities have estimated its prevalence to be as high as 5–10%. Even
with more conservative estimates it is still one of the most common ill-
nesses. It is more common and thought to be more severe in females.
Because of the high prevalence some doctors do not see fibromyalgia as
an illness but as an illness spectrum, similar to autism.
Even though fibromyalgia is generally better known and less cont-
roversial than CFS/ME, it is still viewed by some as a “psychosocial
construct.” For some reason doctors often have trouble perceiving pain
as real, if there is no visible pathology. With symptoms like pain, dep-
ression and poor sleep, it can be very difficult to assess which one
causes which or if they all have a common cause.
FDA approval of the anticonvulsant Lyrica (pregabalin) as a treat-
ment of fibromyalgia certainly boosted the public image of the illness.
Anticipating the huge size of the market several other pharmaceutical
companies have followed suit and are trying to get their products appro-
ved for the treatment of fibromyalgia. On the downside, this may inspire
a belief that fibromyalgia is “created” by pharmaceutical companies,
similar to what restless legs syndrome has been accused of being.
Symptoms
The hallmark symptom of fibromyalgia is pain. According to the

American College of Rheumatology’s diagnostic criteria the pain has to
be present in both sides of the body, above and below the waist and in
the axial skeleton, such as the spine. In addition, at least 11 of 18 com-
mon tender points must be painful (not just tender) on palpation.

CFS/ME can also cause pain and tender points are common, but the pain
in CFS/ME does not supposedly exhibit allodynia (pain in response to
mild stimulation).15
Chest pain, headache and facial pain are also common, but pain is
rarely the only symptom. Others include fatigue, morning stiffness,
insomnia, restless legs, paresthesias (abnormal sensations), cognitive
problems (“fibro fog”), depression and anxiety. Increased urinary fre-
quency, dyspnea, nausea, muscle cramps, light–headedness, problems
with balance and coordination, depression, vision disturbances, photo-
phobia and hyperacuity, skin symptoms, edema, hair loss, irritability
and easy bruising are also reported.
Etiology
There are thought to be several subtypes of fibromyalgia. One com-

mon classification divides the cases into three groups: prima-
ry/idiopathic fibromyalgia (no known cause), secondary fibromyalgia
(in the presence of autoimmune illnesses) and post–traumatic fibromyal-
gia (caused by an injury or other physical trauma). Still, the causes for
all of these subgroups remain elusive. The cause of tender points is not
known, though it has been suggested that they are simply sites that are
the most tender even in healthy population.
Fibromyalgia is commonly thought to be a neurological illness,
even though it is usually treated by rheumatologists. Central sensitiza-
tion is the most common theory to explain the symptoms. Fibromyalgia
has been suggested to be a form of neuropathic pain16,17 or generalized
reflex sympathetic dystrophy.18 There is some evidence of changes in
the muscle19 and the skin.20,21,22 Even so, these signs of inflammation
could have a neurogenic origin.
Sympathomimetic hyperactivity of the autonomic nervous system
is one popular theory of etiology..23,24 The association between fibromy-
algia and short stature has been viewed as evidence of this concept25,
though it could be explained by a growth hormone deficiency caused by
other reasons. Other suggested neurological causes for symptoms
include abnormal circulation in the brain26, accelerated brain aging27 and
hippocampal atrophy due to excitotoxicity.28 Some researchers have
proposed that fibromyalgia has a cardiovascular origin.29
Serotonin or dopamine deficiency and endocrinological deficien-
cies such as vitamin D, growth hormone or thyroid hormone deficiency
may also play a part. It could be that such deficiencies cause a subset of
Introduction 17
fibromyalgia cases. The same goes for suggested infectious causes such
as mycoplasma, which are explored in more detail in CHAPTER 4.
Like CFS/ME, fibromyalgia has been suspected to be an autoim-
mune illness and is sometimes listed as such. Especially the fact that FM
is commonly comorbid with other autoimmune conditions points to this
direction. About half of fibromyalgia patients have antipolymer antibo-
dies and they appear to correlate with illness severity.30
A subset of patients has antinuclear antibodies (ANA) and it has
been suggested that some fibromyalgia patients may have a systemic
connective tissue disorder.31,32 Thyroid autoimmunity is more common
in fibromyalgia. Antibodies to serotonin, gangliosides and phospholi-
pids were found in over half of 100 fibromyalgia patients in one study.33
49% of the patients had all of the three antibodies.
Relationship with other illnesses
Both fibromyalgia and CFS/ME commonly occur together with other

illnesses or conditions. Some of them (like allergies and PMS) could be
viewed as symptoms, others may be risk factors and some may be
complications resulting from these illnesses.
Common comorbidities in CFS/ME
• epilepsy
• fructose intolerance
• seborrheic dermatitis
Common comorbidities in fibromyalgia
• enthesopathies (such as plantar fascitis)

• rheumatoid arthritis
• systemic lupus erythematosus (SLE)
• Sjögren’s syndrome
• osteoarthritis
• hepatitis C
• costochondritis/Tietze’s syndrome
Common comorbidities in both
• premenstrual syndrome (PMS)

• irritable bowel syndrome (IBS)
• migraine
• sleep apnea
• hypothyroidism
• dysmenorrhea
• mitral valve prolapse
• temporomandibular joint disorder (TMD)
• interstitial cystitis, chronic prostatitis
• vulvodynia, vulvar vestibulitis
• restless legs syndrome (RLS)
• joint hypermobility
• Ehlers–Danlos syndrome
• allergies and asthma
• chronic rhinitis/sinusitis
• multiple chemical sensitivity (MCS)
• vestibular disorders
• Sicca syndrome
• esophageal dysmotility
• Raynaud’s phenomenon
• Lyme disease
• silicone breast implant syndrome
• carpal tunnel syndrome
• myofascial pain syndrome (MPS)
• endometriosis
• orthostatic/neurally mediated hypotension
• gluten intolerance
• hypoglycemia, insulin resistance and metabolic syndrome
• sciatica
• bruxism
• post–traumatic stress disorder (PTSD)
Common etiology
Several theories have sprung up to explain why CFS/ME, fibromy-

algia and some other illnesses, especially MCS, IBS, TMD and mig-
raine, so commonly occur in the same population. Dr. Muhammad B.
Yunus proposes a concept called CSS, for central sensitivity syndro-
mes.34 Besides CFS/ME and FM, he includes IBS, migraine, tension
headaches, primary dysmenorrhea, RLS, TMD and myofascial pain. He
suggests they are all caused by central sensitization and other neuro-
endocrine dysfunction.
Introduction 19
Jay Goldstein has written several books based on his theories about
the nature of CFS/ME, fibromyalgia and other illnesses which he calls
neurosomatic. He believes they are disorders of dysfunctional informa-
tion processing in the brain, which can be triggered e.g. by an infectious
agent or genetic vulnerability.35 All other symptoms are secondary to
this problem. He also classifies conditions such as asthma, mitral valve
prolapse, psoriasis, endometriosis and nearly all psychiatric diseases
under the neurosomatic spectrum.
Claudia S. Miller has put forth a concept of TILT, for toxicant–
induced loss of tolerance.36 The concept is similar to multiple chemical
sensitivity, proposing that certain chemical pollutants may cause a
wide–spectrum sensitivity to chemicals that were previously tolerated.
Under this umbrella she includes CFS/ME, FM, MCS, migraine, depres-
sion, asthma, GWS and ADD.
Excessive amounts of nitric oxide and specifically its oxidative
metabolic product peroxynitrite are the culprits in professor Martin
Pall’s theory, known as the “NO/ONOO” theory. He has published
about a dozen papers on this subject, as well as a book. He posits pero-
xynitrite as the cause of the symptoms of e.g. CFS/ME, fibromyalgia,
MCS, GWS, PTSD, IBS, orthostatic intolerance, and tinnitus.37,38,39
Most treatments he recommends are antioxidants, but the NMDA recep-
tors also play a crucial part (see CHAPTER 9 for NMDA antagonists).
Treatment
There are so many theories about the origins of these illnesses that
trying to solve the puzzle seems hopeless. The fact that many of these
theories can be correct at the same time, even in the same patient, just
adds to the confusion. It is worth remembering that we can treat an ill-
ness without knowing what causes it. Even though the cause of CFS/ME
and fibromyalgia is not known, thousands of studies have increased our
understanding of them. Sometimes trial and error has led to discoveries
of effective therapies.
One problem of pharmaceutical treatment is side effects. The fear
of side effects can be an even worse problem. Almost all medications
have potential to cause adverse reactions, but that does not mean that
everyone gets them. Even people who are very sensitive to medications
may not get any side effects or only mild ones, especially when the drug
is introduced in a low dose. Many side effects are transient and often
only last a few days. If they do not, the medication can be discontinued.
Sometimes the side effects are worth the symptom relief. Other
side effects may even be beneficial for some people, such as weight
loss/gain, elevated blood pressure, delayed ejaculation, or sedation in a

drug that is only taken once a day. It is, still, possible to take several
medications in the long term without any harmful effects, but it often
takes patience to find the right combination of drugs. There are risks
with drug treatment, but not treating can also be risky. Good communi-
cation between the doctor and the patient is essential. With patience and
persistence good results can nearly always be achieved.
Treatment of children
Both CFS/ME and fibromyalgia can unfortunately also affect child-

ren. They are thought to have a much better prognosis than adults, but
this should not be taken to mean that they do not need treatment, especi-
ally since some of them can be severely ill and not all will spontane-
ously recover.
Most treatments are appropriate for children, with a few exceptions.
Sex steroids should obviously not be used. The author would also advise
caution with the use of psychiatric drugs, though sometimes their use
may be necessary. The worst problem is probably that even adults may
be so sensitive to medication that they need to cut smallest tablet sizes
to pieces. Children obviously need lower dosages than adults, so liquid
formulations or compounded tablets may be necessary to achieve small
enough doses.
With small children the symptoms are difficult to assess, because
they may not yet know how to express how they feel, especially with
such abstract and complex symptoms as cognitive dysfunction. This
makes it difficult to get a diagnosis and to figure out which particular
symptoms causing the most problems. Particular care should be taken
with potential side effects of medication, as they can sometimes be diffi-
cult to express even for an adult. The parents and the doctors should
take any complaints seriously.
Introduction 21
References
1 Njoku MG, Jason LA, Torres–Harding SR. The prevalence of chronic

fatigue syndrome in Nigeria. J Health Psychol. 2007 May;12(3):461–74.
J Health Psychol. 2007 May;12(3):461–74.
2 Briggs NC, Levine PH. A comparative review of systemic and neuro-
logical symptomatology in 12 outbreaks collectively described as chro-
nic fatigue syndrome, epidemic neuromyasthenia, and myalgic encepha-
lomyelitis. Clin Infect Dis. 1994 Jan;18 Suppl 1:S32–42.
3 Tarello W. Chronic Fatigue Syndrome (CFS) in 15 dogs and cats with
specific biochemical and microbiological anomalies. Comp Immunol
Microbiol Infect Dis. 2001 Jul;24(3):165–85.
4 CDC Media Relations Telebriefing Transcript – November 3, 2006.
http://www.cdc.gov/od/oc/media/transcripts/t061103.htm
5 Ho–Yen DO. Patient management of post–viral fatigue syndrome. Br
J Gen Pract. 1990 Jan;40(330):37–9.
6 Lloyd AR, Wakefield D, Boughton CR, et al. Immunological abnor-
malities in the chronic fatigue syndrome. Med J Aust. 1989 Aug
7;151(3):122–4.
7 Klimas NG, Salvato FR, Morgan R, et al. Immunologic abnormalities
in chronic fatigue syndrome. J Clin Microbiol. 1990 Jun;28(6):1403–10.
8 Costa DC, Tannock C, Brostoff J. Brainstem perfusion is impaired in
chronic fatigue syndrome. QJM. 1995 Nov;88(11):767–73.
9 Klein R, Berg PA. High incidence of antibodies to 5-hydroxy-
tryptamine, gangliosides and phospholipids in patients with chronic fati-
gue and fibromyalgia syndrome and their relatives: evidence for a clini-
cal entity of both disorders. Eur J Med Res. 1995 Oct 16;1(1):21-6.
10 Tanaka S, Kuratsune H, Hidaka Y, et al. Autoantibodies against mus-
carinic cholinergic receptor in chronic fatigue syndrome. Int J Mol Med.
2003 Aug;12(2):225-30.
11 Behan WM, More IA, Behan PO. Mitochondrial abnormalities in the
postviral fatigue syndrome. Acta Neuropathol. 1991;83(1):61–5.
12 Chaudhuri A, Watson WS, Pearn J, et al. The symptoms of chronic
fatigue syndrome are related to abnormal ion channel function. Med
Hypotheses. 2000 Jan;54(1):59–63.
13 Fulle S, Pietrangelo T, Mancinelli R, et al. Specific correlations bet-
ween muscle oxidative stress and chronic fatigue syndrome: a working
hypothesis. J Muscle Res Cell Motil. 2007 Aug;28(6):355–62.
14 Pearn J. Chronic Ciguatera: One Organic Cause of the Chronic Fati-
gue Syndrome. J Chron Fatigue Syn. 1996;2(2/3):29–34.
15 Bradley LA, McKendree–Smith NL, Alarcón GS, et al. Pain comp-

laints in patients with fibromyalgia versus chronic fatigue syndrome.
Curr Rev Pain. 2000;4(2):148–57.
16 Eyigör S, Kirazlı Y. [Fibromyalgia syndrome from the perspective of
neuropathic pain.] Agri. 2008 Jan;20(1):8–12.
17 Pamuk ON, Yeşil Y, Cakir N. Factors that affect the number of ten-
der points in fibromyalgia and chronic widespread pain patients who did
not meet the ACR 1990 criteria for fibromyalgia: are tender points a ref-
lection of neuropathic pain? Semin Arthritis Rheum. 2006 Oct;36(2):
130–4.
18 Martínez–Lavín M. Is fibromyalgia a generalized reflex sympathetic
dystrophy? Clin Exp Rheumatol. 2001 Jan–Feb;19(1):1–3.
19 Bengtsson A, Henriksson KG. The muscle in fibromyalgia—a
review of Swedish studies. J Rheumatol Suppl. 1989 Nov;19:144–9.
20 Kim SH, Kim DH, Oh DH, et al. Characteristic electron microscopic
findings in the skin of patients with fibromyalgia—preliminary study.
Clin Rheumatol. 2008 Mar;27(3):407–11.
21 Eneström S, Bengtson A, Lindström F, et al. Attachment of IgG to
dermal extracellular matrix in patients with fibromyalgia. Clin Exp
Rheumatol. 1990 Mar–Apr;8(2):127–35.
22 Sprott H, Müller A, Heine H. Collagen crosslinks in fibromyalgia.
Arthritis Rheum. 1997 Aug;40(8):1450–4.
23 Martinez–Lavin M. Biology and therapy of fibromyalgia. Stress, the
stress response system, and fibromyalgia. Arthritis Res Ther. 2007;9(4):
216.
24 Cohen H, Neumann L, Shore M, et al. Autonomic dysfunction in
patients with fibromyalgia: application of power spectral analysis of
heart rate variability. Semin Arthritis Rheum. 2000 Feb;29(4):217–27.
25 Carmona L. More evidence on the dysautonomic nature of fibromy-
algia: the association with short stature. Arthritis Rheum. 2002 May;46
(5):1415–6.
26 Mountz JM, Bradley LA, Modell JG, et al. Fibromyalgia in women.
Abnormalities of regional cerebral blood flow in the thalamus and the
caudate nucleus are associated with low pain threshold levels. Arthritis
Rheum. 1995 Jul;38(7):926–38.
27 Kuchinad A, Schweinhardt P, Seminowicz DA, et al. Accelerated
brain gray matter loss in fibromyalgia patients: premature aging of the
brain? J Neurosci. 2007 Apr 11;27(15):4004–7.
28 Wood PB. Fibromyalgia Syndrome: A Central Role for the Hippo-
campus: A Theoretical Construct. J Musculoskelet Pain. 2004;12(1):19-
26.
Introduction 23
29 Félix FH, Fontenele JB. Is fibromyalgia a cardiovascular disease? A

comment on Martinez–Lavin's review 'Stress, the stress response sys-
tem, and fibromyalgia'. Arthritis Res Ther. 2007;9(5):404.
30 Wilson RB, Gluck OS, Tesser JR, et al. Antipolymer antibody reacti-
vity in a subset of patients with fibromyalgia correlates with severity. J
Rheumatol. 1999 Feb;26(2):402–7.
31 Dinerman H, Goldenberg DL, Felson DT. A prospective evaluation
of 118 patients with the fibromyalgia syndrome: prevalence of Ray-
naud's phenomenon, sicca symptoms, ANA, low complement, and Ig
deposition at the dermal–epidermal junction. J Rheumatol. 1986 Apr;13
(2):368–73.
32 Smart PA, Waylonis GW, Hackshaw KV. Immunologic profile of
patients with fibromyalgia. Am J Phys Med Rehabil. 1997 May–Jun;76
(3):231–4.
33 Klein R, Berg PA. High incidence of antibodies to 5–hydroxytrypta-
mine, gangliosides and phospholipids in patients with chronic fatigue
and fibromyalgia syndrome and their relatives: evidence for a clinical
entity of both disorders. Eur J Med Res. 1995 Oct 16;1(1):21–6.
34 Yunus MB. Central sensitivity syndromes: a unified concept for fib-
romyalgia and other similar maladies. JIRA. 2000 Mar;8(1):27–33.
35 Goldstein Jay. Betrayal by the Brain: The Neurologic Basis of Chro-
nic Fatigue Syndrome, Fibromyalgia Syndrome, and Related Neural
Network Disorders. Haworth Medical Press 1996. pp. 1–16.
36 Miller CS. Are we on the threshold of a new theory of disease? Toxi-
cant–induced loss of tolerance and its relationship to addiction and ab-
diction. Toxicol Ind Health. 1999 Apr–Jun;15(3–4):284–94.
37 Pall ML, Satterlee JD. Elevated nitric oxide/peroxynitrite mechanism
for the common etiology of multiple chemical sensitivity, chronic fati-
gue syndrome, and posttraumatic stress disorder. Ann N Y Acad Sci.
2001 Mar;933:323-9.
38 Novel Disease Paradigm Produces Explanations for a Whole Group
of Illnesses. A Common Causal (Etiologic) Mechanism for Chronic
Fatigue Syndrome, Multiple Chemical Sensitivity, Fibromyalgia and
Posttraumatic Stress Disorder. Martin L. Pall, Professor of Biochemistry
and Basic Medical Sciences. http://molecular.biosciences.wsu.edu/
faculty/pall/pall_main.htm
39 Pall ML, Bedient SA. The NO/ONOO– cycle as the etiological
mechanism of tinnitus. Int Tinnitus J. 2007;13(2):99–104.
CHAPTER 1.
Sleep aids, tranquilizers and
muscle relaxants
CFS/ME and fibromyalgia are frequently associated with major

sleep disturbances. This is even a part of the Canadian diagnostic
criteria for CFS/ME.1 Most likely the disordered sleep is not the cause
of the fatigue or other symptoms, but it can often worsen them and
lower quality of life. Even modest sleep deprivation increases the secre-
tion of inflammatory cytokines such as IL–6, which can contribute to
pain, fatigue, malaise and flu–like symptoms.2 IL–6 in particular causes
muscular hyperalgesia (heightened sensitivity to pain).
The sleep problems can include low quality of sleep, sleep apnea,
insomnia, hypersomnia and hypnagogic states. Other related problems
such as nocturia and involuntary movements are also common. Accor-
ding to Dr. Robert Bennett restless legs syndrome is the most common
sleep disorder in fibromyalgia and up to one fifth of the patients suffer
from sleep apnea.3
Patients often experience frequent awakenings during the night and
cannot easily fall asleep again. Thus quick–acting medications may not
always be of much help. The quality of sleep may suffer because of fre-
quent need to urinate. In such cases medication for nocturia should be
considered.
The “Z drugs”
The “Z drugs” are known as such because they all begin with the
letter “Z,” though it could be associated with their mode of action as
well. The drugs in this group are pharmacologically similar, resembling
the benzodiazepines, but with a somewhat smaller risk for tolerance and
dependence. With prolonged use tolerance can still develop.
The most important differences inside of this group lie within the
half–lives, which determine the duration of action of the drug, though
there are also slight differences in the receptor profiles. Jay Goldstein
reports that his CFS/ME and fibromyalgia patients consider zopiclone to
be the best of them and zolpidem also very good, but they have found
zaleplon poor.4 Typical side effects for this group of drugs are drowsi-
ness, dizziness and dry mouth.
Sleep aids, tranquilizers and muscle relaxants 25
zolpidem (Ambien, Stilnoct, Stilnox, Zoldem, Ivadal)
As the half–life of zolpidem is only 2–3 hours, some patients may

wake up at night and cannot fall asleep again. Compared to the other Z
drugs zolpidem appears to be slightly more effective, better tolerated
and less likely to lead to rebound insomnia on discontinuation.5 Jay
Goldstein notes that zolpidem works as an effective analgesic for some
patients and is sometimes activating.6
A small double–blind study concluded that zolpidem improved
sleep and daytime energy levels in patients with fibromyalgia, but other
symptoms such as pain, tender points and morning fatigue did not get
better.7 Patients in the placebo group actually reported more adverse ef-
fects than those getting zolpidem. In a large survey of fibromyalgia pati-
ents zolpidem was ranked as one of the most effective mediations.8 Zol-
pidem may also help nocturia9 and restless legs.10
Paradoxically, in some cases zolpidem is able to arouse people
diagnosed as being in a permanent vegetative state (a deep comatose
state thought to have almost zero hope of awakening).11 This may seem
to bear no relevance to CFS/ME and fibromyalgia, but later the drug has
been shown to help many other neurological conditions as well, such as
Bell’s palsy and Parkinson’s disease.12 It can be hypothesized that zolpi-
dem might be worth a try in severe CFS/ME. Other similar sedative
drugs do not appear be effective in this use.
Carbamazepine, phenytoin, azole antifungals, many different anti-
biotics, nefazodone and verapamil may either decrease or increase the
blood levels of zolpidem.
Zolpidem is available in the United States, the United Kingdom,
Australia and many other countries, but not in Canada. It is very inex-
pensive. A quick acting oral spray formulation is waiting for FDA app-
roval.
zaleplon (Sonata, Starnoc, Zalep, Zaplon, Zerene)
Zaleplon has a very short duration of action: its half–life is only an

hour. Thus it is only useful for problems with falling asleep, but not for
other sleep disorders. Contrary to Goldstein’s opinion, Dr. Michael E.
Rosenbaum considers zaleplon to be a particularly good medication for
treating the sleeping problems associated with CFS/ME.13
Side effects such as morning grogginess are uncommon, because of
the short half–life of the drug, but stomach pain is possible. Cimetidine
causes a major increase in the blood levels of zaleplon.
Zaleplon is available in the United States, the United Kingdom,
Canada and some other countries, but not in Australia. It is somewhat

more expensive than zolpidem.
zopiclone (Imovane, Zimovane, Zileze, Zopiclone)

eszopiclone (Lunesta)
Zopiclone has a longer half–life than zaleplon and zolpidem, about

six hours. Eszopiclone is its active S–enantiomer. Smaller doses can be
used for sleep initiation and larger amounts for sleep maintenance. Two
double–blinded studies have tried zopiclone in fibromyalgia. The first
one demonstrated significant improvement in sleep and tiredness, but no
relief from other symptoms.14 Another study only found zopiclone
slightly more beneficial than placebo for sleep, though some subjective
improvement was reported in the treatment arm.15
Zopiclone often causes an unpleasant, metallic taste in the mouth. It
can interact with the same drugs as zolpidem, as well as NSAIDs and
pioglitazone. Zopiclone has been suspected to be a human carcinogen16,
but there is no clear data available supporting or refuting this claim.
Zopiclone is available in the United Kingdom, Canada, Australia
and some other countries. In the United States it is peculiarly classified
as a Schedule IV drug and not available, but eszopiclone is on the
market. Zopiclone is fairly inexpensive, but eszopiclone costs a bit
more, because it is still covered by patent protection.
Benzodiazepines
Benzodiazepines bind to the so–called benzodiazepine receptor in

the brain, which is actually a subunit of the GABAA receptor. This
receptor is further divided into subunits and different benzodiazepines
have somewhat different effects (sedative, hypnotic, anxiolytic, antiepi-
leptic, muscle relaxant) depending on which subunits they bind to. They
are best known as anxiolytics and sleep aids, but some of them have use
as analgesics, too. They can also be helpful for dyspnea (breathlessness)
which often accompanies CFS/ME and FM.
Benzodiazepines have varying half–lives, which also dictate the cli-
nical use of the drug—a benzodiazepine with a short half–life is good
for initiating sleep or for an acute anxiety attack, but those who tend to
wake up prematurely need a longer–acting drug. Benzodiazepines are
often combined with another drug such as trazodone, or rotated with
other drugs to avoid developing tolerance.
The most common side effect is sedation and benzodiazepines also
potentiate the effect of other sedative drugs, but in some people they can
paradoxically cause irritability, even aggression. Benzodiazepines

should not be used in patients with sleep apnea. Because sleep apnea is
common in CFS/ME and fibromyalgia, a polysomnography (sleep
study) may be warranted.
Benzodiazepines can cause depression, dizziness, muscle weakness
and low blood pressure. Some also have the potential of causing retro-
grade amnesia. Blood changes and severe allergic reactions are very
rare. Benzodiazepines also act as immunomodulators. Interestingly dia-
zepam appears to have a suppressive effect, while alprazolam acts as an
immunostimulant.17
Most doctors consider the addiction potential and development of
tolerance as the most important concern with the benzodiazepines. Res-
ponsible use of small doses usually does not lead to any problems, but
long–term treatment should not be abruptly discontinued. Not taking
benzodiazepines on a daily basis minimizes the risk of dependency.
diazepam (Valium, Stesolid, Diazepam, Apaurin,

Seduxen)
Diazepam has a long duration of action, but a rapid onset as well. It

is the strongest muscle relaxant of all benzodiazepines and is also used
for its anticonvulsive properties. Usually it is only taken occasionally to
maintain the good efficacy. Sarah Myhill has found diazepam in doses
of 2–5 mg helpful for hyperventilation, which she believes to disturb
sleep and cause nightmares in patients with CFS/ME.18 Diazepam may
alleviate bladder problems.
Many drugs such as oral contraceptives, azole antifungals, valpro-
ate, fluvoxamine, propranolol, metoprolol, macrolides and omeprazole
can further prolong the long half–life of diazepam. Carbamazepine and
smoking may speed up the metabolism of the drug.
Diazepam is available everywhere. It is very inexpensive.
alprazolam (Xanax, Alprox, Frontin, Helex, Tafil)
Alprazolam has a fairly short duration of action and is often used

for anxiety. It can be utilized as a sleep aid, if sleep initiation is the
problematic part. It appears not to impair sleep quality as other benzo-
diazepines do. Lucinda Bateman prescribes her CFS/ME patients a dose
of 0.5–1 mg for sleep.19
In a large Internet survey fibromyalgia patients rated alprazolam
among the most helpful medications.20 One study found the combination
of alprazolam and ibuprofen more effective for fibromyalgia than either
drug alone.21 However, a second double–blinded study concluded that

this combination offered very little benefit.22
Alprazolam can relieve pain and aches, including headaches. It may
be helpful for tinnitus.23 Distinct from other benzodiazepines alprazolam
has antidepressant action, but because of the strong potential for depen-
dency it is usually not used for purpose. Interestingly in animal studies
low doses of alprazolam seem to improve cognitive function and act as a
stimulant.24
Alprazolam is widely available. It is very inexpensive.
temazepam (Restoril, Normison, Euhypnos, Remestan,

Levanxol)
Temazepam is the most sedative of all benzodiazepines with a

medium duration of action. Many CFS/ME and fibromyalgia specialists
such as Lucinda Bateman, Sarah Myhill and Richard Podell use it as a
sleep aid. It has also been used to relieve restless legs. It should not be
used continuously for more than a few weeks. Occasional use is fine for
longer periods.
Temazepam is available in the United States, the United Kingdom,
Canada, Australia and some other countries. It is very inexpensive.
clonazepam (Klonopin, Rivotril, Paxam, Clonapam,

Antelepsin)
Clonazepam is a stronger anticonvulsant and muscle relaxant than

most other benzodiazepines. It is probably the most commonly used
benzodiazepine in CFS/ME and fibromyalgia. Usually a small dose of
0.5 mg is prescribed. Paul Cheney, one of the most prominent CFS/ME
specialists, swears by clonazepam. According to him very small doses
during the daytime can improve energy levels.25 He believes this to
because of the inhibitory effect GABA has on the NMDA receptors,
reducing excessive nitric oxide production.
Clonazepam is also recommended by Charles Lapp, another
CFS/ME expert.26 He believes the best sleep aid is a combination of clo-
nazepam to induce sleep and trazodone to maintain sleep. In a fibro-
myalgia newsletter published in 1999 nine experts listed the treatments
they considered the most helpful and clonazepam made it to six lists.27
This opinion is also shared by the fibromyalgia patients, who ranked
clonazepam among the most effective medications in a large survey.28
Because of its muscle relaxant properties clonazepam is often used
to treat pain similar to diazepam. Some patients with CFS/ME note
improvement in both cognitive symptoms and flu–like pains and

aches.29 Clonazepam proved helpful for dysautonomia of CFS/ME in a
small study.30 It often works for restless legs31 and sometimes for skin
tenderness and headaches.32 Dr. David Bell believes clonazepam is
effective for those who feel “tired and wired,” but not for the sleepy–
fatigued type.33
Carbamazepine, phenytoin and St. John’s wort can decrease and
azole antifungals, macrolides, diclofenac, nefazodone and verapamil
increase the blood levels of clonazepam.
Clonazepam is available in the United States, the United Kingdom,
Canada, Australia and many other countries. It is very inexpensive.
lorazepam (Ativan, Merlit, Lorans, Temesta, Lorapam)
Lorazepam has a medium duration of action. It is sometimes used

for anxiety attacks in CFS/ME and fibromyalgia. Jay Goldstein consi-
ders lorazepam nasal spray to be the best treatment for panic attacks
(this formulation is not commercially available and has to be prepared
by a compounding pharmacy).34 Additionally lorazepam has some anti-
emetic action. Valproate may elevate the plasma levels of the drug.
Lorazepam is widely available. It is very inexpensive.
triazolam (Halcion, Trycam)
Triazolam has a very short duration of action. In the treatment of

CFS/ME and fibromyalgia it is mostly used to induce sleep if there are
no nocturnal awakenings, or in combination with other medications. It
can, however, cause withdrawal symptoms after just one dose and as a
result may provoke early–morning insomnia.
Triazolam may be more likely to cause amnesia, confusion and
some other neuropsychiatric symptoms than other benzodiazepines. It
can also cause visual disturbances. Concomitant use with the azole anti-
fungals is not recommended.
Triazolam is available in the United States, Canada, Australia and
some other countries, but not in the United Kingdom. It is very inexpen-
sive.
Other sleep aids
See also:
anticonvulsants (CHAPTER 3), trazodone, mirtazapine,

mianserin, olanzapine, risperidone, quetiapine (CHAPTER 5),
dextromethorphan, cholinesterase inhibitors, hydroxyzine,
diphenhydramine, doxylamine, cannabinoids, parenteral
magnesium, ranitidine/cimetidine, granisetron/tropisetron/
ondansetron (CHAPTER 9), acamprosate (CHAPTER 10)
melatonin (Transzone, Circadin)
Melatonin is a hormone produced by the pineal gland with major

effects on our circadian rhythm. It is a well–known sleep aid and used in
the treatment of jet leg, but also much more than that. Though it can
have side effects, it is one of the few medications that are actually good
for you (in most cases). Some may find that melatonin puts them to
sleep, but keeps them up at night. Different doses, slow–release prepara-
tions or the over–the–counter supplement inositol may help.
According to Dr. Andrew J. Wright over 60% of his patients with
CFS/ME produce undetectable levels of melatonin.35 He prescribes a
low dose of 0.5 mg, though most CFS/ME doctors use more, 3–9 mg. 3
mg is the standard dose, but the requirements appear to be highly indivi-
dual—for some people 3 mg is too much and produces sedation the next
day, yet others need more than that to even feel drowsy. Low doses of
melatonin can sometimes be more effective than higher doses. Lucinda
Bateman recommends a “pulse” treatment.36
For some reason studies of patients with CFS/ME and fibromyalgia
have reported both high and low melatonin levels, but clinical efficacy
has nonetheless been good. In one study melatonin improved the quality
of life and functionality in CFS/ME.37 Another study found improve-
ment in several parameters, including fatigue, using a 5 mg dose.38 A
pilot study of melatonin for fibromyalgia found that melatonin not only
significantly improved sleep but also pain and tender point count.39
Melatonin is a powerful antioxidant, anti–inflammatory and to
some extent an immunostimulant.40 It can be useful in the treatment of
immune system disorders, osteoporosis and even cancer.41 Melatonin
both scavenges peroxynitrite and reduces the production of nitric
oxide.42 It also has anticonvulsant action43 and increases the secretion of
growth hormone.44 Not only is melatonin neuroprotective45,46, it also

protects the mitochondria.47 All of these properties can be beneficial in
CFS/ME and fibromyalgia.
Melatonin has analgesic effects that appear to be mediated by
increased secretion of beta endorphin.48 It can help prevent migraine and
other headaches49 and ameliorate the symptoms of IBS.50 In one study
melatonin helped 40% of patients with tinnitus, and when it was combi-
ned with the neuroleptic sulpiride, as many as 81% of the patients
reported improvement.51
Melatonin does not cause tolerance or dependency. Some people
may experience morning grogginess, which usually subsides with dose
decrease. Tachycardia, tiredness, depression, headaches and orthostatic
hypotension are possible but rare. Combining melatonin with an MAOI
can lead to excessive sedation. Caffeine and fluvoxamine can elevate
melatonin levels. There have been concerns that over–the–counter mela-
tonin products may contain contaminants similar to those that caused the
eosinophilia myalgia syndrome.52
Melatonin is available in most countries. Usually it is a prescription
drug, but in the United States and Canada it is an over–the–counter
supplement. Available dosages vary from 0.1 mg to 5 mg a pill. In some
countries there are also over–the–counter products containing “homeo-
pathic melatonin,” which contain insufficient quantities of the drug to be
effective. Melatonin is generally inexpensive.
ramelteon (Rozerem)
Ramelteon presents a novel mode of action compared to other

pharmaceutical sleep aids, by binding to the melatonin receptor. It has a
very short half–life. It is not known to have any benefits over melatonin
itself, except for being pharmaceutical grade, whereas over–the–counter
melatonin products may contain impurities. Melatonin, however, is mar-
kedly cheaper, and since it does not require a prescription it is often
easier to acquire.
Ramelteon does not bind to the MT3 subtype of the melatonin
receptor. The relevance of this selectivity is not known. MT3 receptors
are mostly present in the gut, so this suggests that ramelteon may lack
the benefits of melatonin in the treatment of IBS. Not all beneficial
effects of melatonin are mediated by its receptors either. In contrast to
melatonin, ramelteon has a few possible drug interactions, particularly
with the azole antifungals and fluvoxamine.
Ramelteon is currently only available in the United States, where it
is the only non–controlled medication approved for the treatment of in-
somnia. It is likely to be more widely available in the near future.
sodium oxybate (Xyrem, Alcover)
Sodium oxybate (gamma–hydroxybutyrate) is an endogenous sub-

stance which has been used as an anesthetic. Unfortunately it has gained
a questionable reputation owing to its use as a recreational and “date
rape” drug. It is only lately that it has been approved for the treatment of
narcolepsy and specifically the cataplexy attacks caused by the condi-
tion.
Sodium oxybate is a highly effective sleep aid and helps many
people whose insomnia is not relieved by other agents. It is a powerful
muscle relaxant and may act as an antidepressant. It increases growth
hormone secretion.53 In studies with FM patients sodium oxybate has
not only improved quality of sleep but fatigue and pain as well.54,55,56,57
Trials of the drug in CFS/ME and several more for fibromyalgia were
running at the time of the writing.
Despite its bad reputation sodium oxybate is a safe, well–tolerated
and non–addictive drug when used according to the instructions. Most
people experience no morning “hangover” of any kind. Side effects can
include nausea, confusion, headache, tremor and dizziness. Sodium oxy-
bate has no known metabolic interactions with other substances, but
taking it with any other sedatives (including alcohol and muscle relax-
ants) is dangerous.
Sodium oxybate is available in the United States, Canada, the
United Kingdom and some other European countries, but not Australia.
It is very expensive and thus most likely inaccessible to patients lacking
insurance or those whose insurance does not cover it.
Muscle relaxants
Muscle relaxants are often helpful in relieving muscle pain and

cramps, which are familiar to almost everyone with CFS/ME and fibro-
myalgia, but they can also help even if there is no muscle tension. They
can improve sleep quality and help in the prevention of migraines and
other headaches.
There are many different modes of action for muscle relaxants, so
even if one does not help a different agent could prove useful. Muscle
relaxants have not been studied much in patients with CFS/ME, but
many studies have been done on people with fibromyalgia. The avail-
ability of the different muscle relaxants varies widely between countries.
See also:
clonazepam, diazepam, sodium oxybate (CHAPTER 1), flupirtine,

thiocolchicoside (CHAPTER 2), gabapentin, pregabalin
(CHAPTER 3), cannabinoids, parenteral magnesium (CHAPTER 9)
tizanidine (Zanaflex, Sirdalud)
Tizanidine is an antagonist of the imidazoline receptors and agonist

of the alpha2 adrenergic receptors. It can be used to relieve and prevent
muscle aches and cramps, muscle weakness and headaches. Tizanidine
is particularly useful in treating the spasticity caused by multiple sclero-
sis, but it also helps many patients with CFS/ME and fibromyalgia. It re-
duces the levels of substance P in patients with FM while improving
sleep, pain and functionality.58
A trial that compared low doses of tizanidine (1–2 mg, when nor-
mally 4 mg is used) to cyclobenzaprine in the treatment of fibromyalgia
found that both drugs helped pain, stiffness, tiredness, anxiety and dep-
ression.59 Tizanidine improved the functionality of the patients even
more than the more commonly used cyclobenzaprine. Another fibromy-
algia study found tizanidine helpful for pain, sleep, fatigue and function-
ality.60 The number of tender points was also markedly reduced.
One study found tizanidine effective in the prevention of chronic
daily headaches.61 It can also help with restless legs and neuropathic
pain.62 Fibromyalgia specialist Richard Podell notes that tizanidine is
useful not only in fibromyalgia, but also for menopausal hot flashes.63
Tizanidine has shown excellent efficacy in the treatment of myofascial
pain.64 89% of the patients with MPS rated it as a good treatment.
In many patients tizanidine causes marked sedation and thus can
only be used at bedtime. On the other hand, some paradoxically experi-
ence insomnia. Dizziness, dry mouth, stomach upset, orthostatic hypo-
tension and muscle weakness are common side effects. Some patients
who suffer from urinary frequency have reported that tizanidine has
worsened the problem for up to a week or two after just one dose.
Tizanidine should not be combined with alcohol and concomitant
use with blood pressure medications or fluvoxamine can cause a major
drop in blood pressure. Oral contraceptives can significantly elevate
blood levels of the drug. Some doctors recommend regular monitoring
of liver enzymes if tizanidine is used in the long term.
Tizanidine is available in the United States, the United Kingdom,
Canada and some other countries, but not in Australia. It is fairly
expensive in continuous use.
orphenadrine (Norflex, Disipal, Biorphen, Relaflex)
Orphenadrine is chemically similar to the antihistamine diphenhyd-

ramine. It has many different modes of action and all of them can be
useful in the treatment of CFS/ME and especially fibromyalgia. It is
classified as a muscle relaxant, but also possesses antihistamine–like, lo-
cal anesthetic and anticholinergic effects. It is a competitive antagonist
of the NMDA receptor.
Orphenadrine can alleviate muscle pain, stiffness and cramps,
headaches (including migraines), neuropathic pain, dizziness and rest-
less legs. Quality of sleep is often improved. Interestingly an old French
study found orphenadrine useful for depression with a very quick onset
of action, but no one has attempted to replicate the findings.65 Conside-
ring the modes of action of the drug, antidepressive effects seem plau-
sible nonetheless.
Orphenadrine is usually well tolerated, but because of the anticho-
linergic properties, larger doses can cause problems, such as dry mouth,
vision impairment, nausea or confusion.
Orphenadrine is available in the United States, the United King-
dom, Canada, Australia and some other countries. It is often sold in
combination products. The price is markedly lower than that of tizani-
dine.
baclofen (Lioresal, Liotec, Baclofen, Clofen)
Baclofen is an agonist of the GABAB receptor. It is used to treat

spasticity in e.g. multiple sclerosis. Baclofen may also help to relieve
aches, cramps and related symptoms of CFS/ME and fibromyalgia, inc-
luding muscle weakness. Like sodium oxybate/GHB, baclofen increases
the secretion of growth hormone66 and this response in CFS/ME does
not differ from that in the healthy persons.67 Baclofen can also help
bladder problems68, GERD (acid reflux)69 and trigeminal neuralgia.70
Dr. Jay Goldstein believes that baclofen is one of the most effective
treatments for CFS/ME (especially for pain, including headache) and he
uses a dose of 10–20 mg three times a day.71 He has found it helpful for
anxiety and sometimes for fatigue too. If baclofen produces adverse
effects, he suggests trying estrogen, oxytocin, mexiletine or reboxetine,
which have somewhat opposite effects.72 Dr. David Bell has found that
baclofen does not work very often, but when it does, the results can be
dramatic.73
Baclofen can lower blood pressure, which may be problematic for

many patients with CFS/ME. Drowsiness, dizziness and nausea are
common side effects. Some people may experience a worsening in
muscle weakness, especially if they also use tricyclic antidepressants.
The treatment should not be discontinued abruptly, as that may lead to
seizures or other withdrawal symptoms.
Baclofen is available in the United States, the United Kingdom,
Canada, Australia and many other countries. It is inexpensive.
carisoprodol (Soma, Carisoma, Somadril)
Carisoprodol is a central muscle relaxant frequently used to treat

CFS/ME and fibromyalgia, especially to improve sleep. It can also alle-
viate muscle tension, aches and headache. Its analgesic action is appa-
rently separate from the muscle relaxation.74 Many patients with fibro-
myalgia report it helps tender points. A double–blind study of Somadril
Comp (which contains acetaminophen/paracetamol and caffeine) for
fibromyalgia found improvement in pain, sleep quality and malaise.75
Carisoprodol may cause dependency and as a result many doctors
do not like prescribing it. Sedation is the most common side effect.
Fluconazole, fluvoxamine and omeprazole may elevate blood levels of
the drug.
Carisoprodol is available in the United States, Canada and some
other countries, but not in the United Kingdom or Australia. Several
combination products are available. In some countries it is only sold in
combination with acetaminophen (paracetamol) and caffeine, which
makes it impractical to use as a sleep aid. It has been recently withdrawn
from sale in several EU countries because of concerns over abuse. In
some U.S. states it is a Schedule IV controlled medication. Carisoprodol
is inexpensive.
cyclobenzaprine (Flexeril, Flexitec, Flexiban)
Cyclobenzaprine is chemically similar to amitriptyline and has

similar anticholinergic and sedative effects. It is also an antagonist of
some of the 5–HT2 serotonin receptors producing muscle relaxation. Its
half–life is about 18 hours, much longer than that of any other muscle
relaxant. Cyclobenzaprine is a common treatment for fibromyalgia, but
seldom used in patients with CFS/ME alone. Because of its mode of
action it can be effective for bladder problems.
A meta–analysis looking at five placebo–controlled trials found
that those taking cyclobenzaprine for fibromyalgia were three times as
likely to report improvement as those treated with placebo.76 Sleep im-

proved the most, pain also to some extent, but fatigue and tender points
were unchanged in most studies. Nonetheless, in one fibromyalgia study
only 12% of the patients taking cyclobenzaprine were improved after
one month, and long–term benefit was not significantly different from
placebo.77
The most common side effects are drowsiness and dry mouth.
Other adverse effects typical to the tricyclics can also occur. One study
compared two different cyclobenzaprine regimes for fibromyalgia: 15
mg at night and 30 mg in three separate doses.78 The efficacy was equal,
but the larger dose caused side effects in 84% of the patients. The smal-
ler dose was much better tolerated with only 27% experiencing adverse
effects. Similar to the tricyclics cyclobenzaprine is contraindicated when
taking e.g. MAOIs.
Cyclobenzaprine is available in the United States, Canada and
some other countries, but not in the United Kingdom or Australia. It is
inexpensive.
chlorzoxazone (Parafon Forte, Paraflex)
Chlorzoxazone is a central muscle relaxant used in the treatment of

painful musculoskeletal conditions, especially mild injuries such as
strains and sprains. In addition, chlorzoxazone inhibits inducible nitric
oxide synthase and thus reduces nitric oxide levels, which has been pro-
posed to be beneficial in both CFS/ME and fibromyalgia.79 It is usually
taken three or four times a day.
Chlorzoxazone may in rare cases cause serious hepatocellular toxi-
city (liver damage), which may be life–threatening. It should not be
used by people with liver problems or elevated liver enzymes.
Monitoring of liver function in long–term use is probably warranted.
The most common side effects include malaise, stomach upset, nausea,
drowsiness, dizziness and weakness.
Chlorzoxazone is available in the United States, Canada and a few
other countries, but not in the United Kingdom or Australia. The Para-
fon Forte preparation also contains acetaminophen (paracetamol). In
Canada this product does not require a prescription. Chlorzoxazone is
inexpensive.
metaxalone (Skelaxin)
Metaxalone acts somewhat similarly to chlorzoxazone, but without

the inhibitory effect on nitric oxide production. It is most commonly
used for back problems. It is normally taken three or four times a day.
The most common side effects are nausea, stomach upset, drowsiness,
dizziness, headache and irritability. Metaxalone can in rare cases cause
liver problems, though this appears to be less common than with chlor-
zoxazone.
Metaxalone is only available in the United States. There is only one
tablet size, 800 mg, which may be too much for many people with
CFS/ME and fibromyalgia. It is much more expensive than chlorzoxa-
zone.
methocarbamol (Robaxin)
Methocarbamol is a central muscle relaxant mainly used to treat

spasms. Structurally it is closely related to guaifenesin, which is also
one of its metabolites. Methocarbamol has some analgesic and anxioly-
tic action. It is sometimes used to treat fibromyalgia. It has a very short
half–life of only a little over an hour and is usually taken four times a
day.
Methocarbamol can cause lethargy, sedation, muscle weakness and
ataxia (impaired coordination). Allergic reactions are possible. Some
patients report increased urinary frequency; others note that
methocarbamol is the only muscle relaxant that does not make them
sleepy.
Methocarbamol is available in the United States, the United
Kingdom, Canada and a few other countries, but not in Australia. It is
often combined with painkillers in products such as Robaxisal, which
contains methocarbamol and aspirin, and Robaxet, with methocarbamol
and acetaminophen. It is fairly inexpensive.
See also:
guaifenesin (CHAPTER 10)
dantrolene (Dantrium, Dantrolen, Dantamacrin)
Dantrolene is the only muscle relaxant that acts directly on the ske-
letal muscle, not centrally (via the brain). It works by binding to the
ryanodine receptor and reducing intracellular calcium concentration.
Dantrolene is used to treat some medical emergencies such as malignant
hyperthermia, neuroleptic malignant syndrome and serotonin syndrome,
occasionally for muscle spasticity. It is not commonly used in CFS/ME
or fibromyalgia.
Besides being a muscle relaxant, dantrolene has some interesting
properties. It inhibits the production of nitric oxide, which has been
implicated as a possible cause of the symptoms of CFS/ME and fibro-
myalgia, and the inflammatory cytokine TNF alpha, while increasing
the production of the anti–inflammatory cytokine IL–10.80 It is also an
antagonist of the glycineB site of the NMDA receptor.81 These properties
could reduce e.g. fatigue, flu–like symptoms, pain and cognitive prob-
lems.
Liver enzymes should be monitored regularly, because dantrolene
can rarely cause liver damage. Possible side effects include drowsiness,
dizziness, muscle weakness, rash, nausea and stomach upset. Dantrolene
should not be combined with calcium channel blockers. Carbamazepine
and phenytoin can decrease the blood levels of the drug and azole anti-
fungals, macrolides, doxycycline, diclofenac, doxycycline and nefazo-
done increase them. Estrogen may increase the risk of hepatotoxicity.
Dantrolene is available in the United States, the United Kingdom,
Canada, Australia and many other countries. It is somewhat expensive.
References
1 Carruthers DM, Jain AK, De Meirleir KL, et al. Myalgic encephalo-

myelitis/chronic fatigue syndrome: Clinical working case definition,
diagnostic and treatment protocols. J Chron Fatigue Syn. 2003;11 (1):7–
115.
2 Vgontzas AN, Zoumakis E, Bixler EO, et al. Adverse effects of
modest sleep restriction on sleepiness, performance, and inflammatory
cytokines. J Clin Endocrinol Metab. 2004 May;89(5):2119–26.
3 Robert Bennett, M.D., on Treatment of Fibromyalgia in Detail. http://
www.immunesupport.com/library/showarticle.cfm/ID/3594/
4 Goldstein Jay. Tuning the Brain: Principles and Practice of Neuroso-
matic Medicine. Haworth Press 2004. p. 163.
5 Tsutsui S; Zolipidem Study Group. A double–blind comparative study
of zolpidem versus zopiclone in the treatment of chronic primary insom-
nia. J Int Med Res. 2001 May–Jun;29(3):163–77.
7 Moldofsky H, Lue FA, Mously C, et al. The effect of zolpidem in pati-
ents with fibromyalgia: a dose ranging, double blind, placebo controlled,
modified crossover study. J Rheumatol. 1996 Mar;23(3):529–33.
8 Bennett RM, Jones J, Turk DC, et al. An internet survey of 2,596
people with fibromyalgia. BMC Musculoskelet Disord. 2007 Mar
9;8:27.
9 Song YS, Ku JH. Zolpidem pharmacotherapy combined with alpha–
blocker therapy for nocturia unresponsive to alpha–blocker monothe-
rapy in men with lower urinary tract symptoms: a preliminary study. Int
Urol Nephrol. 2007;39(4):1147–52.
10 Spolador T, Allis JC, Pondé MP. Treatment of restless legs syndro-
me. Rev Bras Psiquiatr. 2006 Dec;28(4):308–15.
11 Clauss R, Nel W. Drug induced arousal from the permanent vegetati-
ve state. NeuroRehabilitation. 2006;21(1):23–8.
12 Clauss RP, Nel HW. Evidence for Zolpidem efficacy in brain dama-
ge. SA Fam Pract 2005;47(3): 49–50.
13 Michael E. Rosenbaum, M.D., on Treating Chronic Fatigue Syndro-
me and Fibromyalgia. http://www.immunesupport.com/library/show
article.cfm/ID/4337/
14 Drewes AM, Andreasen A, Jennum P, et al. Zopiclone in the treat-
ment of sleep abnormalities in fibromyalgia. Scand J Rheumatol.
1991;20(4):288–93.
15 Grönblad M, Nykänen J, Konttinen Y, et al. Effect of zopiclone on

sleep quality, morning stiffness, widespread tenderness and pain and ge-
neral discomfort in primary fibromyalgia patients. A double–blind ran-
domized trial. Clin Rheumatol. 1993 Jun;12(2):186–91.
16 Stebbing J, Waters L, Davies L, et al. Incidence of cancer in indivi-
duals receiving chronic zopiclone or eszopiclone requires prospective
study. J Clin Oncol. 2005 Nov 1;23(31):8134–6.
17 Covelli V, Maffione AB, Nacci C, et al. Stress, neuropsychiatric dis-
orders and immunological effects exerted by benzodiazepines. Immuno-
pharmacol Immunotoxicol. 1998 May;20(2):199–209.
18 Myhill Sarah. Diagnosing and treating chronic fatigue syndrome.
http://www.drmyhill.co.uk/cfs_book.pdf
19 Cause and Cure Pending: Treat the "Syndrome Subsets" of Chronic
Fatigue Syndrome and Fibromyalgia. Lucinda Bateman, MD. http://
www.offerutah.org/batemanarticle.html
9;8:27.
21 Russell IJ, Fletcher EM, Michalek JE, et al. Treatment of primary
fibrositis/fibromyalgia syndrome with ibuprofen and alprazolam. A
double–blind, placebo–controlled study. Arthritis Rheum. 1991 May;34
(5):552–60.
22 Kravitz HM, Katz RS, Helmke N. Alprazolam and Ibuprofen in the
Treatment of Fibromyalgia–Report of a Double–blind Placebo–Cont-
rolled Study. J Musculoskelet Pain. 1994;2(1):3–27.
23 Johnson RM, Brummett R, Schleuning A. Use of alprazolam for re-
lief of tinnitus. A double–blind study. Arch Otolaryngol Head Neck
Surg. 1993 Aug;119(8):842–5.
24 Bentué–Ferrer D, Reymann JM, Tribut O, et al. Role of dopamin-
ergic and serotonergic systems on behavioral stimulatory effects of low–
dose alprazolam and lorazepam. Eur Neuropsychopharmacol. 2001 Feb;
11(1):41–50.
25 Dr. Paul Cheney Discusses the Benefits of Klonopin. http://www.
immunesupport.com/library/showarticle.cfm/ID/3154/
26 Clinical Care for CFS by Marcia Harmon, Director of Communica-
tions, CFIDS Association of America. http://www.cfids.org/sparkcfs/
clinical-care.pdf

9;8:27.
29 Verrillo Erica F, Gellman Lauren M. Chronic Fatigue Syndrome: A
Treatment Guide. St. Martin's Griffin 1997. p. 170.
30 Siddiqui M, Kadri NN, Hee TT, et al. Clonazepam: an effective treat-
ment of neurally mediated symptoms in patients with chronic fatigue
syndrome. Chest 2000;118:219S.
31 Saletu M, Anderer P, Saletu–Zyhlarz G, et al. Restless legs syndrome
(RLS) and periodic limb movement disorder (PLMD): acute placebo–
controlled sleep laboratory studies with clonazepam. Eur Neuropsycho-
pharmacol. 2001 Apr;11(2):153–61.
32 Berne Katrina. Running on Empty: The Complete Guide to Chronic
Fatigue Syndrome. Hunter House 1995. pp. 200–201.
33 David S Bell, MD | Lyndonville News, Vol. 4 No. 3. http://www.
davidsbell.com/LynNewsV4N3.htm
35 Chronic Fatigue Syndrome/ME and Fibromyalgia plus Associated
Syndromes. Evidence for their organic basis: A summary of the sugges-
ted underlying pathophysiologies and treatment approaches by Dr.
Andrew J Wright. http://web.archive.org/web/20031231214020/http://
www.cfsresearch.org/cfs/research/treatment/drandrew.pdf
Fatigue Syndrome and Fibromyalgia. Lucinda Bateman, MD.
http://www.offerutah.org/batemanarticle.html
37 Smits MG, Van Rooy R, Nagtegaal JE. Influence of melatonin on
quality of life in patients with chronic fatigue and late melatonin onset. J
Chron Fatigue Syn. 2002;10(3/4):25–32.
38 van Heukelom RO, Prins JB, Smits MG, et al. Influence of melatonin
on fatigue severity in patients with chronic fatigue syndrome and late
melatonin secretion. Eur J Neurol. 2006 Jan;13(1):55–60.
39 Citera G, Arias MA, Maldonado–Cocco JA, et al. The effect of mela-
tonin in patients with fibromyalgia: a pilot study. Clin Rheumatol.
2000;19(1):9–13.
40 Maestroni GJ. The immunotherapeutic potential of melatonin. Expert
Opin Investig Drugs. 2001 Mar;10(3):467–76.
41 Witt–Enderby PA, Radio NM, Doctor JS, et al. Therapeutic treat-
ments potentially mediated by melatonin receptors: potential clinical
uses in the prevention of osteoporosis, cancer and as an adjuvant thera-
py. J Pineal Res. 2006 Nov;41(4):297–305.
42 Aydogan S, Yerer MB, Goktas A. Melatonin and nitric oxide. J

Endocrinol Invest. 2006 Mar;29(3):281–7.
43 Fauteck J, Schmidt H, Lerchl A, et al. Melatonin in epilepsy: first re-
sults of replacement therapy and first clinical results. Biol Signals Re-
cept. 1999 Jan–Apr;8(1–2):105–10.
44 Valcavi R, Zini M, Maestroni GJ, et al. Melatonin stimulates growth
hormone secretion through pathways other than the growth hormone–
releasing hormone. Clin Endocrinol (Oxf). 1993 Aug;39(2):193–9.
45 Gupta M, Gupta YK, Agarwal S, et al. A randomized, double–blind,
placebo controlled trial of melatonin add–on therapy in epileptic child-
ren on valproate monotherapy: effect on glutathione peroxidase and glu-
tathione reductase enzymes. Br J Clin Pharmacol. 2004 Nov;58(5):542–
7.
46 Lahiri DK, Chen DM, Lahiri P, et al. Amyloid, cholinesterase, mela-
tonin, and metals and their roles in aging and neurodegenerative dis-
eases. Ann N Y Acad Sci. 2005 Nov;1056:430–49.
47 Leon J, Acuña–Castroviejo D, Sainz RM, et al. Melatonin and mito-
chondrial function. Life Sci. 2004 Jul 2;75(7):765–90.
48 Shavali S, Ho B, Govitrapong P, et al. Melatonin exerts its analgesic
actions not by binding to opioid receptor subtypes but by increasing the
release of beta–endorphin an endogenous opioid. Brain Res Bull. 2005
Jan 30;64(6):471–9.
49 Peres MF, Masruha MR, Zukerman E, et al. Potential therapeutic use
of melatonin in migraine and other headache disorders. Expert Opin
Investig Drugs. 2006 Apr;15(4):367–75.
50 Saha L, Malhotra S, Rana S, et al. A preliminary study of melatonin
in irritable bowel syndrome. J Clin Gastroenterol. 2007 Jan;41(1):29–
32.
51 Lopez–Gonzalez MA, Santiago AM, Esteban–Ortega F. Sulpiride
and melatonin decrease tinnitus perception modulating the auditolimbic
dopaminergic pathway. J Otolaryngol. 2007 Aug;36(4):213–9.
52 Williamson BL, Tomlinson AJ, Mishra PK, et al. Structural characte-
rization of contaminants found in commercial preparations of melatonin:
similarities to case–related compounds from L–tryptophan associated
with eosinophilia–myalgia syndrome. Chem Res Toxicol. 1998 Mar;11
(3):234–40.
53 Van Cauter E, Plat L, Scharf MB, et al. Simultaneous stimulation of
slow–wave sleep and growth hormone secretion by gamma–hydroxybu-
tyrate in normal young Men. J Clin Invest. 1997 Aug 1;100(3):745–53.
54 Scharf MB, Hauck M, Stover R, et al. Effect of gamma–hydroxybu-

tyrate on pain, fatigue, and the alpha sleep anomaly in patients with fib-
romyalgia. Preliminary report. J Rheumatol. 1998 Oct;25(10):1986–90.
55 Scharf MB, Baumann M, Berkowitz DV, et al. The effects of sodium
oxybate on clinical symptoms and sleep patterns in patients with fibro-
myalgia. J Rheumatol. 2003 May;30(5):1070–4.
56 Wood PB. A randomized, double–blind, placebo–controlled, paral-
lel–group, multi–center trial comparing the effects of orally adminis-
tered Xyrem (sodium oxybate) with placebo for the treatment of fibro-
myalgia [abstract]. Pain Med. 2006;7:181.
57 Russell IJ, Bennett RM, Michalek JE, Oxybate for FMS Study
Group: Sodium oxybate relieves pain and improves sleep in fibromyal-
gia syndrome [FMS]: A randomized, double–blind, placebo–controlled,
multi–center clinical trial. Presented at: The 69th Annual Meeting of the
American College of Rheumatology. San Diego, CA, U.S. Nov 12–17,
2005.
58 Russell IJ, Michalek JE, Xiao Y, et al. Therapy with a central alpha
2–adrenergic agonist (tizanidine) decreases cerebrospinal fluid sub-
stance P, and may reduce serum hyaluronic acid as it improves the clini-
cal symptoms of the fibromyalgia syndrome. Arthritis Rheum.
2002;46(9): S614.
59 Katz RS, Daly NH, Shott S.. Low Dose Muscle Relaxant Trial in
Fibromyalgia Patients. http://www.abstractsonline.com/viewer/view
Abstract.asp?CKey=%7bF5DF28B2-5F53-4888-96CF0198E4D5636E
%7d&MKey=%7bF5B9F43A-15A0-467D-8458-5DF32518B4E3%7d
60 McLain D. An open label dose finding trial of Tizanidine for treat-
ment of fibromyalgia. J Musculoskelet Pain 2002;10(4):7–18.
61 Saper JR, Lake AE 3rd, Cantrell DT, et al. Chronic daily headache
prophylaxis with tizanidine: a double–blind, placebo–controlled, multi-
center outcome study. Headache. 2002 Jun;42(6):470–82.
62 Semenchuk MR, Sherman S. Effectiveness of tizanidine in neuropat-
hic pain: an open–label study. J Pain. 2000 Winter;1(4):285–92.
63 How We Approach Fibromyalgia Treatments (FMS) by Richard
Podell, MD. http://drpodell.org/fibromyalgia_treatments.shtml
64 Malanga GA, Gwynn MW, Smith R, et al. Tizanidine is effective in
the treatment of myofascial pain syndrome. Pain Physician. 2002 Oct;5
(4):422–32.
65 Gisselmann A, Marin A, Simon P. [Pilot study on the effects of an
antiparkinson anticholinergic agent during depressive conditions]. Ence-
phale. 1975;1(4):363–6.
66 Davis LL, Trivedi M, Kramer GL, et al. Growth hormone response to

baclofen: a comparison of 10–mg and 20–mg doses in healthy men.
Psychiatry Res. 1996 Feb 28;60(1):41–7.
67 Majeed T, Dinan TG, Behan PO. Baclofen–induced growth hormone
release: does the GABA play any role in the pathophysiology of chronic
fatigue syndrome? J Chron Fatigue Syn. 1996;2(2/3):119–20.
68 Taylor MC, Bates CP. A double–blind crossover trial of baclofen—a
new treatment for the unstable bladder syndrome. Br J Urol. 1979 Dec;
51(6):504–5.
69 Wise J, Conklin JL. Gastroesophageal reflux disease and baclofen: is
there a light at the end of the tunnel? Curr Gastroenterol Rep. 2004
Jun;6(3):213–9.
70 Parmar BS, Shah KH, Gandhi IC. Baclofen in trigeminal neuralgia—
a clinical trial. Indian J Dent Res. 1989 Oct–Dec;1(4):109–13.
Network Disorders. Haworth Medical Press 1996. pp.135–137.
73 David S. Bell, MD, on Medications for Chronic Fatigue Syndrome
and Chronic Pain Control. http://www.immunesupport.com/library/
showarticle.cfm/ID/3343/
74 Margolin S. Pharmacologic demonstration in man of increased thres-
holds to tooth pain following carisoprodol and other analgesics. Proc
Soc Exp Biol Med. 1960 Dec;105:531–3.
75 Vaeroy H, Abrahamsen A, Forre O, et al. Treatment of fibromyalgia:
a parallel double blind trial with carisoprodol, paracetamol, and caffeine
verssus placebo. Clin Rheumatol. 1989;8:245–50.
76 Tofferi JK, Jackson JL, O'Malley PG. Treatment of fibromyalgia
with cyclobenzaprine: A meta–analysis. Arthritis Rheum. 2004 Feb 15;
51(1):9–13.
77 Carette S, Bell MJ, Reynolds WJ, et al. Comparison of amitriptyline,
cyclobenzaprine, and placebo in the treatment of fibromyalgia. A rando-
mized, double–blind clinical trial. Arthritis Rheum. 1994 Jan;37(1):32–
40.
78 Santandrea S, Montrone F, Sarzi–Puttini P, et al. A double–blind
crossover study of two cyclobenzaprine regimens in primary fibromyal-
gia syndrome. J Int Med Res. 1993 Mar–Apr;21(2):74–80.
79 Grant SK, Green BG, Wang R, et al. Characterization of inducible
nitric–oxide synthase by cytochrome P–450 substrates and inhibitors.
Inhibition by chlorzoxazone. J Biol Chem. 1997 Jan 10;272(2):977–83.
80 Haskó G, Szabó C, Németh ZH, et al. Modulation by dantrolene of

endotoxin–induced interleukin–10, tumour necrosis factor–alpha and
nitric oxide production in vivo and in vitro. Br J Pharmacol. 1998
Jul;124(6):1099–106.
81 Salinska E, Sobczuk A, Lazarewicz JW. Dantrolene antagonizes the
glycine(B) site of the NMDA receptor. Neurosci Lett. 2008 Feb 20;432
(2):137–40.
CHAPTER 2.
Painkillers
Non–specific anti–inflammatory drugs

(NSAIDs)
NSAIDs are generally not that effective for the pain caused by
CFS/ME and fibromyalgia, but often they provide enough relief to be
worthwhile. Some patients have noted NSAIDs to help with chronic
fever, but they are not always helpful. Sometimes one NSAID may be
next to useless, but another one proves effective. Trying several diffe-
rent ones is a good idea. Often when NSAIDs alone are not enough to
provide pain relief, they are used in combination with other analgesics.
For many people NSAIDs are sufficient to treat migraine attacks
and provide a cheaper alternative to migraine drugs. Using them too
often for this purpose, however, may lead to medication rebound head-
ache, as with other headache medications. NSAIDs can be useful for
costochondritis, which is common in fibromyalgia. For osteoarthritis
acetaminophen (paracetamol) is usually the drug of choice.
NSAIDs can also be used to treat orthostatic hypotension because
they raise blood pressure. They may also have general immunomodula-
tory action by on suppressing cytokine production. Aspirin has been
found to be the most effective in reducing TNF alpha induced NF–
kappa B activation, followed by ibuprofen and sulindac.1 In animal tests
NSAIDs have demonstrated ability to repair increased blood–brain bar-
rier permeability.2
In chronic use NSAIDs unfortunately pose significant risks. The
risk of peptic ulcers is well known, but many are not aware that it is pos-
sible to develop an ulcer without any warning signs or symptoms.
Several other drugs such as corticosteroids and even SSRIs3 further in-
crease this risk. Some people cannot tolerate even occasional doses of
NSAIDs, as they experience severe stomach upset. In chronic use sto-
mach–protecting medications should be considered.
“Traditional” NSAIDs inhibit both COX–1 and COX–2. The
COX–2 inhibitors (coxibs) are mostly selective for COX–2. Only inhibi-
tion of COX–2 relieves pain, but COX–1 inhibition is associated with
the gastrointestinal risk. Meloxicam and etodolac are sometimes consi-
dered COX–2 inhibitors because of their selectivity. Several of the co-
Painkillers 47
xibs have been withdrawn from market for safety reasons, including
rofecoxib, valdecoxib and lumiracoxib, but there is no evidence that all
coxibs are problematic.
Renal problems are another significant but less well–known risk of
chronic NSAID use. Edema and weight gain could indicate the develop-
ment of renal or cardiac problems. People with asthma are at risk for a
severe allergic reaction to NSAIDs. Many people find large doses of
NSAIDs sedative, but they can also disturb stage 4 sleep, perhaps
because they decrease plasma melatonin.4 Of course, untreated pain can
also cause sleep disturbances. Rarely NSAIDs may cause photosensiti-
vity.
NSAIDs can be used topically with negligible systemic side effects.
Usually they are formulated into a gel or cream, but there are also sprays
and mousses. The absorption varies greatly, so one could try several dif-
ferent products. Ketoprofen was shown to have the best penetration in
one study whereas piroxicam hardly demonstrated any.5 Microemulsi-
ons appear to have the best penetration and gels the second best, with
creams performing the worst.6
See also:
flavocoxid (CHAPTER 10)
aspirin (Aspirin, Bayer Aspirin, Aspro, Aspirina,

Disprin)
Aspirin (acetylsalicylic acid) is one of the oldest medications still

in use. It is quite prone to causing gastric upset. Besides fever and pain
relief, it is also used for its antiplatelet (“blood thinning”) effects in the
prevention of stroke. This effect may also be useful in CFS/ME, but on
the other hand it increases bleeding in case an ulcer develops. Aspirin
has some antioxidant activity.7 It inhibits the growth of Chlamydia
pneumoniae, a pathogen which has been connected to CFS/ME.8
Aspirin should not be combined with other blood–thinning medica-
tions or herbs without doctor’s supervision. It can also interact with phe-
nytoin, valproic acid, probenecid, acetazolamide, corticosteroids, spiro-
nolactone and vitamin C.
Aspirin is available everywhere and is very inexpensive. It is sold
as tablets, caplets, gelcaps and in some countries also as chewing gum
and oral dissolving powder. A controlled release formulation is
available in some markets.
ibuprofen (Advil, Motril, Brufen, Nurofen, Ibutop)
Ibuprofen is a popular NSAID almost everyone has used. Not many

know, however, that it also has some anti–inflammatory action mediated
by PPARgamma. 9 The short–term use of ibuprofen in fibromyalgia was
evaluated in a double–blind study in the 1980s, but no significant thera-
peutic effect was found compared to placebo.10
In another FM study the combination of ibuprofen and the muscle
relaxant cyclobenzaprine was compared to cyclobenzaprine alone. There
were no other differences, but morning stiffness was more effectively
alleviated by the combination.11 Ibuprofen may increase the blood levels
of fluoxetine, sertraline, phenytoin, pioglitazone and rosiglitazone.
Ibuprofen is available everywhere. It is sold as capsules, tablets,
gelcaps, liquid formulations and in some markets also topical formulati-
ons. Depending on the country, 200 mg or 400 mg is usually the largest
dose which is available without prescription. It is inexpensive and much
more so on prescription, because only small packets are usually avail-
able over–the–counter.
See also:
pioglitazone/rosiglitazone (CHAPTER 10)
naproxen (Aleve, Anaprox, Naprosyn, Proxen, Apranax)
Naproxen is one of the most commonly used NSAIDs. It is used to

treat many different kinds of inflammatory conditions and dysmenor-
rhea, as well as in migraine treatment and prophylaxis. Its benefits
include a longer duration of action than ibuprofen, which makes it more
useful for chronic pain.
There is disagreement about the cardiovascular risk caused by nap-
roxen, but the FDA recommends caution.12 In either case naproxen cau-
ses a fairly large increase in blood pressure compared to other NSAIDs,
which makes it useful for treating orthostatic hypotension.13
Naproxen is widely available. Available forms include tablets,
capsules, caplets, modified release formulations and oral suspension. In
United States, Australia and some other countries it is available over the
counter, but in Canada and the United Kingdom it is a prescription drug.
Naproxen is inexpensive, but again cheaper on prescription.
Painkillers 49
indometacin (Indocin, Indocid, Elmetacin, Indocollyre,

Indogesic)
Indometacin is highly selective for COX–1. It is much more prone

to causing gastrointestinal upset and ulcers than most other NSAIDs. It
is usually only used for severe pain or acute fever. It has PPARgamma–
mediated anti–inflammatory action similar to ibuprofen.14 It is the
NSAID of choice for orthostatic hypotension.
Indometacin causes a headache in up to 10–20% of treated patients.
The headache may be associated with dizziness and other symptoms.
Confusion and muscle weakness are also possible. Indometacin is not
recommended for people with epilepsy. This is not an absolute contrain-
dication, but as there are many other NSAIDs, those who have epilepsy
should probably choose a different drug. Indometacin can also increase
the blood levels of e.g. fluoxetine, sertraline, phenytoin, pioglitazone
and rosiglitazone.
Indometacin is widely available in a variety of formulations, such
as tablets, capsules, suppositories, modified release capsules, syrup, gel
and patches. It is inexpensive.
piroxicam (Feldene, Candyl, Piroxicam, Felden,

Artrilase)
Piroxicam only needs to be taken once a day, which makes it sui-

table for chronic use. On the other hand it is fairly selective for COX–1
and thus associated with a significant risk of stomach ulcer and hemor-
rhage. It is another good drug for elevating blood pressure.
Dizziness is the most common side effect. Piroxicam may rarely
cause photosensitivity and different kinds of skin eruptions. It has inter-
actions with the same drugs as indometacin.
Piroxicam is widely available, usually as capsules and a topical gel.
In some countries the gel is available without prescription. It is very
inexpensive.
meloxicam (Mobic, Movalis)
Once a day dosing is sufficient for meloxicam as well. Despite the

similar name it differs from piroxicam by being more selective for
COX–2 than COX–1 and thus relatively stomach friendly as far as
NSAIDs go. Almost all of those with NSAID hypersensitivity can tole-
rate meloxicam, but this should be tested for before initiating use.15 Still
meloxicam seems much more prone to causing side effects than most
other NSAIDs.16 Meloxicam has no specific drug interactions.

Meloxicam is available in the United States, the United Kingdom,
Canada and some other countries, but not in Australia. It is inexpensive.
etodolac (Lodine, Elderin)
Etodolac is selective for COX–2 and poses a low risk of peptic

ulcer compared to other traditional NSAIDs. In general it is well tolera-
ted with a low risk of the adverse effects associated with the NSAIDs.17
It is normally dosed twice a day, but sometimes one dose is enough.
Etodolac is available in the United States, the United Kingdom,
Canada and a few other countries, but not in Australia. A modified–
release formulation is available. It is inexpensive.
nabumetone (Relafen, Relifex, Nabugesic, Naburen)
Nabumetone differs from other NSAIDs in that it is absorbed in the

gut instead of the stomach, which lowers the risk of peptic ulcer. As a
significant part of the bleeding risk is mediated systemically and not
locally, it is not completely eliminated, but nabumetone is also fairly
selective for COX–2. It is usually taken once, sometimes twice a day.
Nabumetone is available in the United States, the United Kingdom,
Canada and a few other countries, but not in Australia. It is inexpensive.
diclofenac (Voltaren, Cataflam, Almiral, Diclac,

Diclogesic)
Diclofenac is well tolerated and because of its selectivity for COX–

2 it has a lower risk for gastrointestinal complications than most other
NSAIDs. It is usually taken 2–3 times a day. It is believed to have anti–
inflammatory modes of action that other NSAIDs do not have.
Diclofenac has been shown to increase plasma levels of beta endor-
phin.18 This may be helpful for both pain and other symptoms. One
study found diclofenac effective against E. coli bacteria and suggested it
as a treatment for urinary tract infections.19 Headache, dizziness and
itchiness are fairly common side effects. The risk of liver toxicity may
be higher with diclofenac compared to other NSAIDs.
Diclofenac is available virtually everywhere. Many different prepa-
rations exist, including immediate release and modified release tablets,
gels, creams, suppositories, sprays and patches. Oral forms are inexpen-
sive. Diclofenac is available over–the–counter in Germany, Australia
and New Zealand, but is usually prescription–only. Topical creams and
Painkillers 51
gels are often available over the counter. In Arthrotec diclofenac is com-
bined with misoprostol (see CHAPTER 10). In some European countries a
combination of diclofenac and codeine is sold as Combaren.
flurbiprofen (Ansaid, Froben, Flugalin)
Flurbiprofen is a propionic acid derivative similar to ibuprofen and

naproxen, but it possesses some interesting and unique properties as an
NSAID. Its right stereoisomer R–flurbiprofen which is almost devoid of
COX inhibiting activity has antitumor effects and may be a potential
treatment for Alzheimer’s disease20. R–flurbiprofen also has some anal-
gesic activity, despite not being anti–inflammatory.21 Thus flurbiprofen
may have advantages compared to other NSAIDs.
Flurbiprofen may increase the blood levels of e.g. fluoxetine, sert-
raline, phenytoin, pioglitazone and rosiglitazone. It is also extremely
selective for COX–1, creating a major risk for gastrointestinal side ef-
fects.
Flurbiprofen is available in the United States, the United Kingdom,
Canada and some other countries, but oral formulations are not sold in
Australia. Both immediate release and slow release formulations are
available. In some markets it is also available as poultices. Flurbiprofen
is inexpensive.
celecoxib (Celebrex, Celebra)
Celecoxib is a popular pain reliever which is usually taken twice a

day. Some patients have reported that celecoxib also alleviates their
brainfog and fatigue. This may be explained by the finding that celeco-
xib is also a carbonic anhydrase inhibitor like acetazolamide.22 Signifi-
cantly slower metabolism of the drug has been noted in black people,
who may require smaller doses than patients of other ethnicities.
Celecoxib is contraindicated in people who have had an allergic
reaction to the sulfa drugs. Celecoxib can elevate the blood levels of e.g.
dextromethorphan, many antidepressants and neuroleptics. When using
fluconazole the celecoxib dose usually needs to be reduced by half.
Celecoxib is available in the United States, the United Kingdom,
Canada, Australia and many other countries. It is more expensive than
the NSAIDs.
etoricoxib (Arcoxia, Tauxib)
Etoricoxib is more selective for COX–2 than celecoxib. It has a

very long half–life and one dosing a day is sufficient. It does not inter-
fere with the metabolism of other drugs. Unlike celecoxib, etoricoxib is
not a sulfa drug.
Etoricoxib is available in the United Kingdom and some other, pri-
marily Asian and European countries, but not in the United States,
Canada or Australia. It is somewhat more expensive than celecoxib.
Narcotic painkillers
Many people with CFS/ME and virtually everyone with fibromyal-

gia suffer from constant pain. For some of them the pain can be at a
constant 10/10 level. Some do benefit from NSAIDs, acetaminophen
(paracetamol) and other medications with analgesic properties, but for
many these drugs do not provide enough relief. Opioids are also a safer
alternative to NSAIDs in chronic use, as they do not cause ulcers, renal
problems or increased cardiovascular mortality. Opioids can also help
restless legs syndrome.
There are many different kinds of opioids with different receptor
profiles and different half–lives. Some also have other modes of action
not mediated through the opioid receptors. As with NSAIDs, some opi-
oids work better for some patients, producing better analgesia and/or
fewer side effects. Often two different opioid formulations are combi-
ned: a long–lasting product for maintenance and a short–lasting one for
breakthrough pain. Sometimes different opioid painkillers are rotated, as
that may afford the use of lower doses.
There are many unjustified prejudices associated with opioid treat-
ment. There is no reason to categorically avoid them, as they are safe
and effective. The risk of addiction when using opioids in the treatment
of chronic pain has been shown to be extremely low, especially when
therapy is based on long–acting drugs.23 Appropriate treatment of pain
significantly improves quality of life and often reduces other symptoms
(such as fatigue, depression and sleep disturbances) as well.
Side effects are more likely to pose problems than addiction or tole-
rance. Opioids can cause neuropsychiatric symptoms, itching, constipa-
tion and nausea. Often the nausea gets better after the first days of use,
but on the other hand some people only begin to experience nausea after
opioids have been used for a long time. Opioids have traditionally been
associated with fatigue, but for some people they are activating. Accord-
ing to Dr. Jay Goldstein this happens particularly often in people with
fibromyalgia.24
Constipation can be a serious problem, especially if the patient is
bedbound (and often also dehydrated). Another medication or other stra-
Painkillers 53
tegies may be needed to alleviate this symptom. On the other hand some
people with CFS/ME suffer from chronic diarrhea. Opioids can also
cause urinary retention, which can be either beneficial or problematic
depending on the patient.
Other central nervous system depressants increase the sedative
effects of opioids. In some cases combinations with benzodiazepines or
barbiturates have even led to death. Opioids should not be combined
with MAO inhibitors or beta blockers. Strong opioids should not be pre-
scribed to patients with severe asthma or another serious pulmonary ill-
ness. Opioids also decrease bone density25,26 and cause hormonal defici-
encies in long–term use.27 Unlike NSAIDs, however, they are extremely
unlikely to cause life–threatening side effects.
codeine (Tricodein, Codicaps)
Codeine is a pro–drug that undergoes a conversion into morphine

in the liver. It is used to treat chronic pain of mild to moderate severity
and may also be useful for IBS. The duration of action is nonetheless
short and the efficacy only increases to a certain point (60 mg), after
which increasing the dose confers no benefit (ceiling effect). According
to Dr. Mark Pellegrino many people with fibromyalgia are sensitive to
codeine and may also react to tramadol.28
Paroxetine, fluoxetine and some other drugs inhibit the conversion
of codeine to morphine and thus make the drug all but ineffective. Up to
10% of Caucasians cannot perform this metabolic step in the first place,
and are thus resistant to the effects of codeine.
Codeine is widely available in tablets and liquid formulations,
though in most countries it is only available in combination products
with other analgesics and sometimes caffeine. In the United Kingdom,
Canada and some other countries such preparations containing low
doses of codeine may be dispensed without prescription. In the United
States codeine is a Schedule II, III or IV drug depending on the formula-
tion.
Codeine cough syrups are commonly sold over the counter in many
places (including the United States), but they should not be used for the
relief of chronic pain. Modified release preparations of codeine are
available in some countries, but not in the United States. Codeine is
inexpensive.
oxycodone (OxyContin, Roxicodone, Proladone,

Oxynorm)
Oxycodone is used to treat moderate and severe chronic pain. Some

of its analgesic qualities appear to be mediated through the kappa opioid
receptor, as opposed to most other opioids which usually act only
through the mu opioid receptor.29 The modified release drug Oxycontin
is one of the drugs preferred by doctors to treat the pain caused by
CFS/ME and fibromyalgia. It only needs to be taken every 12 hours.
Some SSRIs and some other drugs may elevate the plasma levels of
oxycodone. The efficacy of oxycodone is poor in the same people who
cannot convert codeine to morphine.
Oxycodone is available in the United States, the United Kingdom,
Canada, Australia and some other countries. Tablets, capsules, oral solu-
tion, suppositories and different extended release forms are available
depending on the country. Some formulations also contain acetamino-
phen (paracetamol) or NSAIDs. In the United States oxycodone is a
Schedule II drug, but in most countries it is in the strictest schedule.
Oxycodone is fairly expensive.
hydrocodone (Vicodin, Lortab)
Hydrocodone is a drug used to treat moderate and severe pain as

well as cough. It is also available in combination with guaifenesin as a
cough syrup, which may be a good analgesic for those who benefit from
guaifenesin. It has a short half–life, which is why it is mostly used for
breakthrough pain.
Hydrocodone requires the same metabolic step as codeine and oxy-
codone and as a result does not work for everyone. Fluoxetine, paroxe-
tine and some other medications lower the efficacy of hydrocodone.
Hydrocodone is available in the United States, Canada and a few
other countries, but not in the United Kingdom or Australia. In the
United States and most other countries it is only available in combina-
tion products (e.g. with an NSAID, acetaminophen/paracetamol or an
antihistamine). These products are Schedule III in the United States.
Hydrocodone is fairly expensive.
hydromorphone (Dilaudid, Palladone, Palladon, Opidol)
Hydromorphone is a one of the metabolites of hydrocodone. It is

used for moderate to severe pain. It is faster acting than morphine and
thus more suitable for breakthrough pain, but also lower on side effects,
Painkillers 55
especially nausea and pruritus (itching).

Hydromorphone is available in the United States, the United King-
dom, Canada, Australia and a few other countries. In the United States it
is a Schedule II drug. It is available as tablets, modified–release capsu-
les, liquid formulations (including an oral liquid, which is absorbed
from the mouth) and suppositories. The modified–release capsules are
not available in the United States. Large doses tend to become expen-
sive.
morphine (Avinza, Kadian, Kapanol, Skenan,

Oramorph)
Morphine is the “prototype” of narcotic drugs. It is used for mode-

rate to severe pain, severe chronic diarrhea and severe cough. Other nar-
cotic painkillers have largely replaced it, because they have better tole-
rability or other beneficial properties. Morphine also has a fairly low
bioavailability when taken orally.
Morphine is available in the United States, the United Kingdom,
Canada, Australia and many other countries. It is classified a Schedule
II drug in the United States. It is available as capsules, tablets, liquid
formulations, modified release preparations and suppositories. Most pre-
parations contain no other analgesics. In refractory cases morphine can
also be used intrathecally (administered into the spinal cord with a pain
pump). Most formulations are very inexpensive.
fentanyl (Duragesic, Durogesic, Actiq, Fentanyl,

Sublimaze)
Fentanyl is a highly potent opioid which is usually only used for

cancer pain. Because of its potency it can only be used in patients who
already have tolerance to narcotics. Some patients with CFS/ME and
fibromyalgia may need pain relief of this caliber. For chronic pain the
72–hour duration of the fentanyl patches is a clear benefit. For severe
breakthrough pain there is a lollipop–like lozenge called Actiq, which
also works well for refractory migraines.30
Fentanyl is less sedative than other opioids and less likely to cause
constipation. It may be useful for some patients who cannot tolerate
morphine. Elevated intracranial pressure is a rare side effect. Large
doses may bring about hallucinations. The patches frequently produce
skin irritation and the glue can cause allergic symptoms. Azole antifun-
gals, macrolide antibiotics, diclofenac, nefazodone and verapamil can
dangerously elevate blood levels of fentanyl. St. John’s wort has the
opposite effect.
Fentanyl is widely available in tablets, liquid formulations, patches
and lozenges. It is quite expensive, especially in lozenge form. It is a
Schedule II drug in the United States.
methadone (Dolophine, Methadose, Physeptone,

Metadon, Metadol)
Methadone is better known from its role in the treatment of addic-

tion, but it is also used for severe chronic pain and sometimes cough.
Besides the mu opioid receptor it acts on the delta opioid receptor. It is
also an NMDA antagonist with some SSRI–like action. These properties
have made it the favorite opiate prescribed by Jay Goldstein.31 Metha-
done has a long half–life, but its analgesic action has a short duration
and the drug needs to be taken several times a day.
Like fentanyl, methadone can elevate intracranial pressure. It may
prolong the QT interval and should not be combined with other drugs
that do this. Orthostatic hypotension is common. Carbamazepine and
phenytoin decrease the blood levels of methadone. Methadone can ele-
vate the blood levels of amphetamines, lidocaine, dextromethorphan,
some beta blockers, many antidepressants and risperidone.
Methadone is available in the United States, the United Kingdom,
Canada, Australia and some other countries. In the United States it is a
Schedule II drug. Available forms include tablets, dispersible tablets and
oral solution.
pethidine/meperidine (Demerol, Dolantina)
Pethidine is an opioid with anticholinergic and local anesthetic acti-

on. It inhibits the reuptake of serotonin and dopamine and as a result is
somewhat stimulating. It is indicated for moderate to severe pain. It has
a rapid onset of action, but also a short duration of just 2–3 hours. Be-
cause of this it should only be used for breakthrough pain, but it is also
occasionally used as a maintenance drug for chronic pain.
Pethidine used to be a popular drug and was thought to be less
addictive than other opioids and more effective in some conditions, but
both have been shown to be false. In fact pethidine is appears to be less
effective, more addictive and more likely to cause some side effects
(cognitive impairment and hallucinations) than most other opioids. It
can also cause seizures. Pethidine should never be combined with
MAOIs. It is hard to justify the use of this drug when there are better
alternatives.
Painkillers 57
Pethidine is available in the United States, the United Kingdom,

Canada and a few other countries, but not in Australia. It is a Schedule
II drug in the United States. Tablets and oral solution are available.
buprenorphine (Buprenex, Subutex, Temgesic,

Transtec, Butrans)
Buprenorphine is used for moderate to severe pain. It has a fairly

long half–life. It differs from most narcotic painkillers by being a partial
agonist (both an agonist and antagonist) of the opioid receptors. It also
blocks the kappa opioid receptor. These properties make tolerance less
likely to develop, but buprenorphine can trigger withdrawal symptoms
in patients who already have opioid tolerance. It also has a ceiling dose
similar to codeine. One study found buprenorphine effective and quick
acting in the treatment of refractory major depression.32
Buprenorphine has poor bioavailability when administered orally,
but in chronic use it can be utilized in the form of patches or sublingual
tablets. A new patch formulation delivers the drug continuously for a
week. In the United States buprenorphine is a Schedule III drug.
dextropropoxyphene/propoxyphene (Darvon, Doloxene,

Depronal, Abalgin)
Dextropropoxyphene/propoxyphene is a relatively mild opioid

generally only used for mild chronic pain and cough. It has some
NMDA antagonist activity similar to methadone and also acts as a sodi-
um channel blocker. Nonetheless its efficacy is considered poor.
CFS/ME specialist David Bell believes dextropropoxyphene to be infe-
rior compared to other opioids, because it has high addiction potential
yet offers “wimpy” pain relief.33 It should be kept in mind that the
effects of every drug can depend on the individual.
Dextropropoxyphene is available in the United States, Canada,
Australia and some other countries, but not in the United Kingdom. In
most markets it is only available in combination products also contain-
ing other analgesics or other ingredients, such as muscle relaxants. Dex-
tropropoxyphene is classified into Schedule IV in the United States,
making it less strictly controlled than most other opioids. Similar rules
apply to many other markets. Dextropropoxyphene is somewhat expen-
sive.
tramadol (Ultram, Zydol, Tramal, Zytrim, Tradonal)
Tramadol is a painkiller with some opioid action, but also sero-

tonergic, noradrenergic and GABAergic properties. Lesser known are its
effects on the muscarinic acetylcholine receptor and ion channels.34 Tra-
madol is quick–acting, but its efficacy greatly increases in regular use.
For many patients with CFS/ME tramadol is the most effective painkil-
ler and can also relieve sleeping problems and fatigue.35 Some patients
find the drug energizing and have to take it early to avoid insomnia.36
Several studies have tried tramadol or tramadol in combination
with acetaminophen for fibromyalgia. Two found the drug effective37,38
and one moderately effective.39 The combination of tramadol and aceta-
minophen works well for migraines.40 For many patients with CFS/ME
and fibromyalgia the common dosing regime of 50 mg twice a day
causes intolerable adverse effects, but 25 mg two or three times a day is
better tolerated.41
Tramadol is not recommended for use in people with epilepsy or
who take other drugs that lower the seizure threshold. Because of the
serotonergic effects combining it with most antidepressants, especially
the MAOIs, can be dangerous. 5–HT3 receptor antagonists like ondan-
setron may block the analgesic effects of tramadol.
Tramadol is available in most countries. In some, such as Canada,
it is only available in products also containing acetaminophen (paraceta-
mol). These combination products are usually called Tramacet or
Ultracet. Even though tramadol is a narcotic painkiller, it is not a cont-
rolled substance in most countries, including the United States. In a few
markets tramadol is even available without prescription.
pentazocine (Talwin NX, Fortral, Fortal)
Pentazocine is an atypical opioid, which only has weak affinity for

the mu opioid receptor, but acts as an agonist of the kappa opioid recep-
tor and the sigma1 receptor. It is rarely prescribed and its primary use is
the treatment of mild to moderate pain. It is less prone to causing seda-
tion, nausea and hypotension compared to typical opioids. Sigma1 ago-
nists may be useful in the treatment of depression and cognitive prob-
lems.42 Pentazocine has also demonstrated anticonvulsive action.43
Jay Goldstein lists many different possibly beneficial mechanisms
for pentazocine in the treatment of CFS/ME and fibromyalgia, not as a
painkiller but for general symptom relief.44 According to him it works
for some patients for whom all other treatment has failed. He includes
Painkillers 59
two case reports of seriously ill patients refractory to other treatments,

whose symptoms were greatly relieved after just one pill of pentazocine
and naloxone.
Pentazocine is more likely than other opioids to cause hallucina-
tions and other psychiatric side effects. It has been suspected to cause
adverse effects when combined with the muscle relaxant orphenadrine.
Smoking may reduce blood levels of the drug.
Pentazocine is available in the United States, the United Kingdom,
Canada, Australia and some other countries. In the United States penta-
zocine is only sold in combination with naloxone, an opioid antagonist.
Because naloxone is not absorbed from the stomach, this does not affect
the efficacy of the drug, but prevents intravenous administration. In
spite of this, pentazocine is a Schedule IV drug in the United States.
Migraine and headache treatments
These drugs are used in the treatment and/or prevention of head-

aches/migraines. Some of them are only used for prevention, some only
for migraine attacks and some can be used for both. Excessive use of
migraine attack drugs (and other analgesics to treat migraines) can lead
to rebound headaches, also known as drug–induced headaches, which
can usually only be relieved by discontinuing medication.
There are numerous combination drugs to treat migraine attacks.
These drugs usually require a prescription and may contain acetamino-
phen (paracetamol), NSAIDs, opioids, sedatives (e.g. barbiturates), anti-
emetics (e.g. metoclopramide), and vasoconstrictors (e.g. caffeine, ergo-
tamine and isomethepene). There are hundreds of different combi-
nations available and the formulations vary from country to country.
See also:
melatonin, muscle relaxants (CHAPTER 1), NSAIDs, acetamino-

phen (paracetamol), narcotic painkillers, botulinum toxin, Sara-
pin (CHAPTER 2), anticonvulsants (CHAPTER 3), tricyclic anti-
depressants, moclobemide, phenelzine, buspirone, L–trypto-
phan/5–hydroxytryptophan, lithium (CHAPTER 5), clonidine,
beta blockers, calcium channel blockers (CHAPTER 6), nicergo-
line, ergoloid (CHAPTER 7), DHEA, naltrexone (CHAPTER 8),
NMDA antagonists, cholinesterase inhibitors, cinnarizine, can-
nabinoids, parenteral magnesium, acetazolamide (CHAPTER 9),
montelukast, telmisartan, captopril (CHAPTER 10)
pizotifen (Sandomigran, Sanomigran, Mosegor,

Pizotifen)
Pizotifen is a serotonin antagonist primarily acting on the 5–HT1,

5–HT2A and 5–HT2C receptors, with some antihistamine activity as well.
It is used in the prevention of migraine and other vascular headaches.
The anti–migraine action of pizotifen may actually stem from calcium
channel antagonism.45 Some studies have found pizotifen helpful for
anxiety and depression, though with fairly large doses of the drug (3–10
mg a day).46,47 The normal daily dosage is 1.5 mg taken in one or three
doses.
Pizotifen can cause drowsiness, dizziness, fatigue, nausea, head-
ache, weakness, weight gain and dry mouth. The efficacy may also de-
crease over time. As with other serotonergic drugs, pizotifen should not
be combined with MAO inhibitors and preferably not with SSRIs. The
treatment should not be abruptly discontinued.
Pizotifen is available in the United Kingdom, Canada, Australia
and some other markets, but not in the United States. In some markets it
is available as both tablets and suspension. It is somewhat costly, but on
the other hand if it reduces the amount of triptan drugs one has to take
for migraine attacks, it quickly pays itself back.
cyproheptadine (Periactin, Peritol, Viternum)
Cyproheptadine is an antiserotonergic and antihistaminic agent

similar to pizotifen. It is used as an antihistamine and migraine preven-
tative, though not as commonly as pizotifen. Cyproheptadine also has
some activity as a calcium channel blocker.48 Side effects and contrain-
dications are similar to pizotifen.
Cyproheptadine may have use as a sleep aid, as it appears to enhan-
ce sleep quality.49 In animal studies cyproheptadine has shown analge-
sic, antipyretic (fever lowering) and anti–inflammatory properties.50,51 In
animals it also reduces spasticity (muscle rigidity from neurological
causes).52
Cyproheptadine is available in the United States, the United King-
dom, Canada, Australia and some other countries. Both tablets and
syrup are usually available. It is quite a bit cheaper than pizotifen.
Painkillers 61
sumatriptan (Imigran, Imitrex, Imigrane)

naratriptan (Amerge, Naramig)
The triptans are effective abortive drugs for migraine attacks and
cluster headaches, but they can also help other kinds of headaches. They
most likely act by binding to the 5–HT1B and 5–HT1D receptors. This
causes vasoconstriction of the cranial blood vessels, which are thought
to be excessively dilated in migraine. The triptans have two actions that
can be beneficial in both fibromyalgia and CFS/ME: they increase
growth hormone secretion53 and inhibit release of substance P.54
Sumatriptan is sometimes used to treat CFS/ME symptoms in gene-
ral. It can alleviate muscle pain55 and trigeminal neuralgia.56 Jay Gold-
stein usually prefers naratriptan, because it is the most potent 5–HT1B
agonist and has the longest duration of action, but he thinks it may be
worthwhile to try all of the triptans.57 He notes that they are often help-
ful for patients who get side effects from all SSRIs and he also uses
them for IBS pain.58
Possible side effects include chest pain, dizziness, fatigue, drowsi-
ness, worsening of the headache, nausea and psychiatric symptoms.
Sumatriptan should not used in patients who are allergic to sulfa drugs.
The triptans should be used with caution in patients with epilepsy and
those with cardiovascular disease. They should never be combined with
ergot derivatives or MAO inhibitors. SSRI drugs and St. John’s wort
also cause problems.
Sumatriptan is available in the United States, the United Kingdom,
Canada, Australia and many other countries. Naratriptan is available in
the United States, the United Kingdom, Canada, Australia and a few
other countries.
Sumatriptan is available as tablets, intranasal spray and subcutane-
ous injection, but naratriptan is only sold in tablet form. Sumatriptan
tablets are available over–the–counter in the United Kingdom. The trip-
tans are extremely expensive even in the oral form and often insurance
companies only reimburse a few doses a month.
ergotamine (Ergomar, Migril)

dihydroergotamine (Migranal, Dihydergot, Seglor)
Ergotamine and dihydroergotamine are ergot alkaloids which act as

vasoconstrictors. They have affinity for several serotonin, dopamine and
adrenergic receptors, but especially the 5–HT1B and 5–HT1D receptors,
similar to the triptans. They are used for early abortion of migraines and
cluster headaches, in migraine prevention and sometimes for orthostatic
hypotension.
Possible side effects include nausea, paresthesias and chest pain.
Ergotamines are contraindicated in many cardiac and vascular conditi-
ons. They should never be combined with triptans, azole antifungals,
MAO inhibitors and some macrolide antibiotics. Concomitant use with
beta blockers and antidepressants should be done with caution. Ergota-
mine and dihydroergotamine may cause cardiac and pulmonary fibrosis
in long–term use, but this is highly unlikely if they are only used occa-
sionally in acute migraine attacks.
Ergotamine and dihydroergotamine are available in the United
States, the United Kingdom, Canada, Australia and some other count-
ries. Ergotamine is available as tablets, sublingual tablets, inhalable
aerosol and suppositories. Dihydroergotamine is available as tablets,
nasal spray and injections. Not all forms are available in every market.
Most ergotamine products also contain caffeine and/or other ingre-
dients, such as analgesics, sedatives and antiemetics. Some dihydroergo-
tamine products are formulated for migraine, others may contain sym-
pathomimetics like etilefrine.
intranasal lidocaine (Altaseptic, Xylocaine)
Intranasal lidocaine spray can be used as an abortive treatment for

migraine headaches. Some studies have not found it effective, but most
have demonstrated efficacy in about half of the patients.59,60 Lidocaine
not only relieves the pain, but nausea and photophobia (light sensitivity)
as well. In some patients, however, the efficacy is short–lived and the
headache comes back. Local stinging and swelling is a common adverse
reaction. Nausea, dizziness and sedation are also possible.
Lidocaine sprays are widely available. They are meant for numbing
the mouth and the throat, but they can be used intranasally. It is inex-
pensive.
Painkillers 63
Other analgesics
See also:
zolpidem, muscle relaxants (CHAPTER 1), anticonvulsants

(CHAPTER 3), neomycin (CHAPTER 4), tricyclic antidepressants,
venlafaxine, milnacipran, duloxetine, SAM–e, olanzapine
(CHAPTER 5), clonidine, moxonidine (CHAPTER 7), oxytocin, nal-
trexone (CHAPTER 8), NMDA antagonists, cholinesterase inhibi-
tors, cannabinoids, granisetron/tropisetron/ ondansetron, sibu-
tramine, misoprostol (CHAPTER 9), calcitonin, ibudilast, neuro-
tropin, ACE inhibitors (CHAPTER 10)
acetaminophen/paracetamol (Tylenol, Panadol, Calpol,

Perfalgan, Tempra)
Acetaminophen (paracetamol) is a fairly effective painkiller which

is sometimes listed as a NSAID, but it is only an analgesic and antipyre-
tic (fever lowering drug), with negligible anti–inflammatory activity. Its
mode of action is not well understood, but it seems to act by several dif-
ferent routes, such as the endocannabinoid system and by blockage of
sodium channels, perhaps even by serotonergic mechanisms.
Acetaminophen rarely causes any side effects. It does not raise
blood pressure, renal problems are unlikely and the risk of ulcers is neg-
ligible. Because of potential for hepatotoxicity in large doses, more than
4,000 mg should never be taken in a period of 24 hours. When taking
combination painkillers, this must be kept in mind, as many combina-
tion products contain large amounts of paracetamol. Acetylcysteine
reduces the risk of hepatotoxicity.
Acetaminophen is available everywhere, usually over–the–counter.
It is available as tablets, chewable tablets, liquid formulations and
suppositories, in some markets also as oral dissolving powder. It is also
included in numerous combination painkillers with e.g. opioids. It is
very inexpensive.
nefopam (Acupan)
Nefopam is a non–NSAID non–narcotic analgesic derived from

diphenhydramine and orphenadrine. It is thought to be more effective
than NSAIDs. It can be used to treat both chronic and acute pain. There
are several possible modes of action. Nefopam inhibits the reuptake of
serotonin and norepinephrine.61 It is an NMDA antagonist and blocks

voltage–sensitive sodium channels.62 Even the H3 histamine receptors
may be involved.63
Nausea and dry mouth are the most common side effects. Dizzi-
ness, nervousness, tachycardia, urine retention, sedation, headache and
insomnia are also possible. People with epilepsy should not take nefo-
pam. It should not be combined with MAO inhibitors. Anticholinergic
drugs may increase the side effects.
Nefopam is available in the United Kingdom and some other, most-
ly European countries, as well as South Africa and New Zealand. It is
fairly inexpensive.
flupirtine (Katadolon)
Flupirtine is a non–narcotic, non–NSAID analgesic drug with some

muscle relaxant activity. It is used especially for chronic lower back
pain. It has also shown efficacy in the treatment of headaches and mig-
raines, cancer pain, dysmenorrhea and neuropathic pain.64 In Germany
flupirtine is sometimes used for fibromyalgia. One case series has been
published about this use.65
Flupirtine is much more than just a painkiller though; it has several
properties that have been used to treat neurodegenerative illnesses such
as Alzheimer’s, CJD and some congenital diseases. It is thought to be an
NMDA antagonist and a KPNQ potassium channel opener with some
alpha2 adrenergic action. It would thus likely work well for CFS/ME,
too. A patent has been filed about the use of flupirtine for overactive
bladder.66
Flupirtine is usually well–tolerated. Dizziness, drowsiness, dry
mouth, pruritus (itching) and stomach upset are the most common side
effects. There can also be nausea, headache and sleep disturbances. No
drug interactions are known. The only real downside is the short half–
life—usually flupirtine is administered 3–4 times a day. There are cur-
rently no slow–release formulations, but perhaps one will be developed
in the future.
Flupirtine is available in some European countries, such as Germa-
ny, Portugal and Italy, as well as Brazil. It is being developed as a fibro-
myalgia drug under the brand name Effirma by a U.S. company, with a
phase II study expected soon. Thus in a few years flupirtine could be
available in the United States and many other countries, but currently
most patients would need to order it from abroad, as many people with
neurological conditions already do. In long–term use it gets somewhat
costly.
Painkillers 65
thiocolchicoside (Coltramyl, Miorel, Muscoril, Miotens,

Coltrax)
Thiocolchicoside is a derivative of the gout drug colchinine, with

muscle relaxant, anti–inflammatory and analgesic properties. It is
thought to act at GABA and glycine receptors. It can be used both orally
and topically. Usually thiocolchicoside is used for back pain, especially
low back pain, but also for other painful conditions such as temporo-
mandibular pain. It may be useful for fibromyalgia pain.
Thiocolchicoside is a proconvulsant, which means it can cause sei-
zures in a predisposed individual. People with a history of seizures
should not use oral or intramuscular thiocolchicoside, but topical appli-
cation is probably fine. Topical thiocolchicoside can sometimes cause
contact allergy, photosensitivity or skin atrophy, but usually it is well
tolerated.
Thiocolchicoside is available in some European countries, such as
France, Italy, Portugal and the Czech Republic, as well as in some parts
of Asia and South America. Usually a prescription is required. It is fair-
ly inexpensive. Many different formulations are available, including
capsules, nasal spray, intramuscular injection, ointments and creams and
a skin foam.
Topical and intravenous pain treatments
See also:
ketamine, parenteral magnesium (CHAPTER 9)
botulinum toxin A (Botox, Dysport)

botulinum toxin B (NeuroBloc, Myobloc)
Botulinum toxin is a neurotoxin produced by the bacteria Clostri-

dium botulinum, which can cause severe food poisoning. It is perhaps
best known for its use as a cosmetic treatment, but because it blocks
neuromuscular transmission it is also used locally to treat e.g. pain,
muscle spasms, migraines, incontinence and hyperhidrosis (excessive
sweating). An injection makes the muscle unable to contract (paralyzed)
for 3–6 months, after which function is regained.
Botulinum toxin has been used to treat several different kinds of
pain, such as temporomandibular joint disorders (TMJ), chronic muscu-
loskeletal pain and diabetic neuropathy. The efficacy in preventing mig-
raines and chronic headaches is still disputed. Botulinum toxin A may

work for myofascial pain, though not all trials have found it
effective.67,68 It seems to be less effective than lidocaine injections.69 In
fibromyalgia botulinum toxin A injections have been both helpful70 and
unhelpful.71
Potential adverse effects include local bruising, paralysis of unwan-
ted areas and allergic reactions. Botulinum toxin B appears to be much
more likely than type A to cause systemic autonomic symptoms. Thus
people with autonomic dysfunction should probably not be treated with
botulinum toxin B.72 In long–term use the body may produce antibodies
to the toxin, leading to decreased efficacy, but this is rare.
Botulinum toxin type A is widely available. Type B is available in
the United States, the United Kingdom and a few other countries. The
injections are very expensive, but on the other hand they can last for
several months.
Sarapin (Sarracenia purpurea distillate)
Sarapin is a preparation of Sarracenia purpurea (pitcher plant). It is

used as local injections for some types of pain, especially myofascial
pain and neuralgia. It may also be effective for migraine and other head-
aches when injected into trigger points on the temples or the neck. The
mode of action is unknown. Even though Sarapin has been used for
decades, there is little scientific data available to support its efficacy.
Sarapin is claimed to be free of side effects. Even though it is a
plant extract it supposedly does not cause allergic reactions. Many
people describe the injection as unpleasant, often heavy, sometimes as
burning.
Sarapin is available in the United States, Canada and some count-
ries in Europe and South America. It is not particularly expensive, but
the injections cost more.
lidocaine/procaine/buvicaine injections
Injections of lidocaine or similar local anesthetics into trigger

points are a common treatment of myofascial pain. Usually the injection
consists of 1–10 ml of 1% lidocaine, sometimes only 0.5%. Some doc-
tors add a steroid such as triamcilone, but this is generally not recom-
mended, because steroids have side effects and may not contribute to the
pain relieving effects. Some doctors believe lidocaine to be more effec-
tive and better tolerated than other local anesthetics.73
Trigger point injections are commonly listed as a fibromyalgia
Painkillers 67
treatment, which can be confusing, as FM features tender points, not

trigger points (though it is possible to have both). Nevertheless, similar
injections appear to be useful for treating tender points. In one study 39
of 40 FM patients benefited from these injections.74 On average the pain
relief lasted for 13 weeks. A study of trigger point injections for myo-
fascial pain found that those who also had fibromyalgia did benefit, but
less than those without FM.75
The injections should be avoided by those who are taking anticoa-
gulants. In persons who are allergic to lidocaine and its derivatives,
plain water or glucose solution is sometimes used, though obviously the
efficacy is not equal.
topical lidocaine (Lidoderm)

topical lidocaine and prilocaine (Emla)
Lidocaine can also be used topically in the form of creams, gels,

sprays or patches. Lidocaine patches have been used to treat myofascial
pain, though only a subset notes major benefit.76 They can also help
other kinds of neuropathic and non–neuropathic pain.77 Topical lido-
caine alone is usually not an optimal treatment for widespread pain, but
it can be used as an adjunct to other medications for the most painful
areas. The patches should only be worn for at most 12 hours a day. Side
effects other than local reactions are uncommon.
Lidocaine patches and gel are widely available. In some countries
topical lidocaine preparations are available without prescription in small
packet sizes, but tend to get costly when purchased in that fashion.
intravenous lidocaine
Lidocaine is also used intravenously for severe, intractable pain. It

is often very effective for fibromyalgia. Dr. Jacob Teitelbaum gives 40–
50 mg at first, which may be increased up to 300–400 mg per session if
no serious side effects occur. 78 He notes lidocaine to be particularly
helpful when given concomitantly with Myers’ cocktails.
In a small double–blinded pilot study lidocaine was much more
helpful than conventional treatment alone for pain, but global improve-
ment did not reach significance.79 A more recent and much larger study
found that intravenous lidocaine provided most fibromyalgia patients
with good pain relief lasting for several weeks.80
According to Jay Goldstein this treatment helps up to 50% of the
patients who have not benefited from oral medication.81 He even consi-
ders intravenous lidocaine to be the most effective treatment for
CFS/ME and fibromyalgia. Besides pain, other symptoms such as fati-

gue, cognitive problems and gut spasms often improve, as well.
Possible side effects include dizziness, tinnitus and orthostatic
hypotension. Allergic reactions may occasionally occur. Goldstein stres-
ses that the infusion has to be given very slowly, because otherwise
there can be adverse reactions and afterwards the patient will never res-
pond to lidocaine again.82
Lidocaine is available everywhere, though the availability and cost
of this treatment in practice may vary.
See also:
mexiletine (CHAPTER 7)
capsaicin (Zostrix, Axsain)
Capsaicin is the ingredient that creates the hotness of chili peppers,

which technically is a sensation, not a taste. It has been used as a topical
treatment (patches or cream) for severe pain. It works for both neuro-
pathic pain and musculoskeletal pain, but appears to be more effective
for the former. A pilot study showed topical capsaicin to be effective for
fibromyalgia back in 1994.83 Further studies have not been published.
As could be expected, capsaicin can cause an uncomfortable burn-
ing sensation on the skin and at first pain may get worse. In repeated use
the sensation—and the pain—usually goes away, so capsaicin is meant
for regular application, not for use as needed. At least four weeks are
needed to evaluate efficacy. The cream is usually applied three to four
times a day. Systemic side effects are rare, but coughing can sometimes
occur. Some people may be allergic to capsaicin.
Capsaicin is available on prescription in the United States, the
United Kingdom, Canada, Australia and some other countries. It may be
available as both a prescription drug and an over–the–counter product.
Often the latter contain smaller quantities of the drug.
Painkillers 69
References
1 Takada Y, Bhardwaj A, Potdar P, et al. Nonsteroidal anti–inflamma-

tory agents differ in their ability to suppress NF–kappaB activation,
inhibition of expression of cyclooxygenase–2 and cyclin D1, and abro-
gation of tumor cell proliferation. Oncogene. 2004 Dec 9;23(57):9247–
58.
2 Candelario–Jalil E, Taheri S, Yang Y, et al. Cyclooxygenase inhibi-
tion limits blood–brain barrier disruption following intracerebral injec-
tion of tumor necrosis factor–alpha in the rat. J Pharmacol Exp Ther.
2007 Nov;323(2):488–98.
3 de Abajo FJ, Rodríguez LA, Montero D. Association between selec-
tive serotonin reuptake inhibitors and upper gastrointestinal bleeding:
population based case–control study. BMJ. 1999 Oct 23;319(7217):
1106–9.
4 Murphy PJ, Myers BL, Badia P. Nonsteroidal anti–inflammatory
drugs alter body temperature and suppress melatonin in humans. Physiol
Behav. 1996 Jan;59(1):133–9.
5 Montastier P, Poiraud T, Poelman MC. Etude de la cinetique de diffu-
sion in vitro de quatre AINS destins la voile percutane. Med du Sport.
1994;68:40–2.
6 Paolino D, Ventura CA, Nisticò S, et al. Lecithin microemulsions for
the topical administration of ketoprofen: percutaneous adsorption
through human skin and in vivo human skin tolerability. Int J Pharm.
2002 Sep 5;244(1–2):21–31.
7 Shi X, Ding M, Dong Z, et al. Antioxidant properties of aspirin: cha-
racterization of the ability of aspirin to inhibit silica–induced lipid pero-
xidation, DNA damage, NF–kappaB activation, and TNF–alpha produc-
tion. Mol Cell Biochem. 1999 Sep;199(1–2):93–102.
8 Yoneda H, Miura K, Matsushima H, et al. Aspirin inhibits Chlamydia
pneumoniae–induced NF–kappa B activation, cyclo–oxygenase–2
expression and prostaglandin E2 synthesis and attenuates chlamydial
growth. J Med Microbiol. 2003 May;52(Pt 5):409–15.
9 Mrak RE, Landreth GE. PPARgamma, neuroinflammation, and dis-
ease. J Neuroinflammation. 2004 May 14;1(1):5.
10 Yunus MB, Masi AT, Aldag JC. Short term effects of ibuprofen in
primary fibromyalgia syndrome: a double blind, placebo controlled trial.
J Rheumatol. 1989 Apr;16(4):527–32.
11 Fossaluzza V, De Vita S. Combined therapy with cyclobenzaprine
and ibuprofen in primary fibromyalgia syndrome. Int J Clin Pharmacol
Res. 1992;12(2):99–102.
12 FDA Statement on Naproxen. http://www.fda.gov/bbs/topics/news/

2004/new01148.html
13 Forster HS. Naproxen reversal of nortriptyline–induced orthostatic
hypotension. J Clin Psychiatry. 1989 Sep;50(9):356.
15 Domingo MV, Marchuet MJ, et al. Meloxicam tolerance in hyper-
sensitivity to nonsteroidal anti–inflammatory drugs. J Investig Allergol
Clin Immunol. 2006;16(6):364–6.
16 Gehling M, Niebergall H. [Non–opioid analgesics and co–analgesics
in therapy of chronic pain]. Z Arztl Fortbild Qualitatssich. 1998 Jan;92
(1):41–6.
17 Jones RA. Etodolac: An overview of a selective COX–2 inhibitor.
Inflammopharmacology. 1999;7(3):269–75.
18 Martini A, Bondiolotti GP, Sacerdote P, et al. Diclofenac increases
beta–endorphin plasma concentrations. J Int Med Res. 1984;12(2):92–5.
19 Mazumdar K, Dutta NK, Dastidar SG, et al. Diclofenac in the mana-
gement of E. coli urinary tract infections. In Vivo. 2006 Sep–Oct;20(5):
613–9.
20 Eriksen JL, Sagi SA, Smith TE, et al. NSAIDs and enantiomers of
flurbiprofen target gamma–secretase and lower Abeta 42 in vivo. J Clin
Invest. 2003 Aug;112(3):440–9.
21 Geisslinger G, Schaible HG. New insights into the site and mode of
antinociceptive action of flurbiprofen enantiomers. J Clin Pharmacol.
1996 Jun;36(6):513–20.
22 Knudsen JF, Carlsson U, Hammarström P, et al. The cyclooxygen-
ase–2 inhibitor celecoxib is a potent inhibitor of human carbonic anhyd-
rase II. Inflammation. 2004 Oct;28(5):285–90.
23 Adriaensen H, Vissers K, Noorduin H, et al. Opioid tolerance and
dependence: an inevitable consequence of chronic treatment? Acta
Anesthesiol Belg. 2003;54(1):37–47.
25 Porter J, Jick H. Addiction rare in patients treated with narcotics. N
Engl J Med. 1980 Jan 10;302(2):123.
26 Kinjo M, Setoguchi S, Schneeweiss S, et al. Bone mineral density in
subjects using central nervous system–active medications. Am J Med.
2005 Dec;118(12):1414.
27 Abs R, Verhelst J, Maeyaert J, et al. Endocrine consequences of
long–term intrathecal administration of opioids. J Clin Endocrinol
Metab. 2000 Jun;85(6):2215–22.
Painkillers 71
28 Prescribed Medications for Fibromyalgia: By Mark Pellegrino, M.D.

– 2007 Update. http://www.immunesupport.com/library/showarticle.
cfm/ID/3308/
29 Ross FB, Smith MT. The intrinsic antinociceptive effects of oxyco-
done appear to be kappa–opioid receptor mediated. Pain. 1997 Nov;73
(2):151–7.
30 Landy SH. Oral transmucosal fentanyl citrate for the treatment of
migraine headache pain in outpatients: a case series. Headache. 2004
Sep;44(8):762–6.
32 Bodkin JA, Zornberg GL, Lukas SE, et al. Buprenorphine treatment
of refractory depression. J Clin Psychopharmacol. 1995 Feb;15(1):49–
57.
34 Minami K, Uezono Y, Ueta Y. Pharmacological aspects of the
effects of tramadol on G–protein coupled receptors. J Pharmacol Sci.
2007 Mar;103(3):253–60.
36 Michael E. Rosenbaum, M.D., on Treating Chronic Fatigue
Syndrome and Fibromyalgia. http://www.immunesupport.com/library/
37 Bennett RM, Kamin M, Karim R, et al. Tramadol and acetaminophen
combination tablets in the treatment of fibromyalgia pain: a double–
blind, randomized, placebo–controlled study. Am J Med. 2003 May;114
(7):537–45.
38 Russell J, Kamin M, Bennett RM, et al. Efficacy of tramadol in treat-
ment of pain in fibromyalgia. J Clin Rheumatol 2000;6:250–7.
39 Biasi G, Manca S, Manganelli S, et al. Tramadol in the fibromyalgia
syndrome: a controlled clinical trial versus placebo. Int J Clin Pharma-
col Res. 1998;18(1):13–9.
40 Silberstein SD, Freitag FG, Rozen TD, et al. Tramadol/acetamino-
phen for the treatment of acute migraine pain: findings of a randomized,
placebo–controlled trial. Headache. 2005 Nov–Dec;45(10):1317–27.
41 Treatment of CFS and FMS. http://www.wfprofessional.com/treat
ment.htm
42 Hayashi T, Su TP. Sigma–1 receptor ligands: potential in the treat-
ment of neuropsychiatric disorders. CNS Drugs. 2004;18(5):269–84.
43 Khanna N, Khosla R, Kohli J. Opioid receptor mediated anticonvul-

sant effect of pentazocine. Indian J Med Sci. 1998 Jan;52(1):1–7.
45 Peroutka SJ, Banghart SB, Allen GS. Calcium channel antagonism
by pizotifen. J Neurol Neurosurg Psychiatry. 1985 Apr;48(4):381–3.
46 Banki CM. Clinical observations with pizotifene (Sandomigran) in
the treatment of nonmigrainous depressed women. Arch Psychiatr
Nervenkr. 1978 Mar 7;225(1):67–72
47 Standal JE. Pizotifen as an antidepressant. Acta Psychiatr Scand.
1977 Oct;56(4):276–9.
48 Peroutka SJ, Allen GS. The calcium antagonist properties of cypro-
heptadine: implications for antimigraine action. Neurology. 1984 Mar;
34(3):304–9.
49 Tokunaga S, Takeda Y, Shinomiya K Effects of some H1–antago-
nists on the sleep–wake cycle in sleep– disturbed rats. J Pharmacol Sci.
2007 Feb;103(2):201–6.
50 Tan JQ, Fan CK, Cui J, et al. [Analgesic and antipyretic effects of
cyproheptadine]. Zhongguo Yao Li Xue Bao. 1990 May;11(3):204–7.
51 Tan JQ, Xu KY, Shen FM, et al. [Anti–inflammatory effect of cypro-
heptadine] Zhongguo Yao Li Xue Bao. 1989 Jul;10(4):357–9.
52 Nance PW. A comparison of clonidine, cyproheptadine and baclofen
in spastic spinal cord injured patients. J Am Paraplegia Soc. 1994 Jul;17
(3):150–6.
53 Boeles S, Williams C, Campling GM, et al. Sumatriptan decreases
food intake and increases plasma growth hormone in healthy women.
Psychopharmacology (Berl). 1997 Jan;129(2):179–82.
54 Arvieu L, Mauborgne A, Bourgoin S, et al. Sumatriptan inhibits the
release of CGRP and substance P from the rat spinal cord. Neuroreport.
1996 Aug 12;7(12):1973–6.
Fatigue Syndrome. Hunter House 1995. p. 201.
56 Kanai A, Suzuki A, Osawa S, et al. Sumatriptan alleviates pain in
patients with trigeminal neuralgia. Clin J Pain. 2006 Oct;22(8):677–80.
59 Maizels M, Geiger AM. Intranasal lidocaine for migraine: a randomi-
zed trial and open–label follow–up. Headache. 1999 Sep;39(8):543–51.
Painkillers 73
60 Maizels M, Scott B, Cohen W, et al. Intranasal lidocaine for treat-

ment of migraine: a randomized, double–blind, controlled trial. JAMA.
1996 Jul 24–31;276(4):319–21.
61 Fuller RW, Snoddy HD. Evaluation of nefopam as a monoamine up-
take inhibitor in vivo in mice. Neuropharmacology. 1993 Oct;32(10):
995–9.
62 Verleye M, André N, Heulard I, et al. Nefopam blocks voltage–sen-
sitive sodium channels and modulates glutamatergic transmission in ro-
dents. Brain Res. 2004 Jul 9;1013(2):249–55.
63 Girard P, Pansart Y, Coppé MC, et al. Role of the histamine system
in nefopam–induced antinociception in mice. Eur J Pharmacol. 2004
Oct 25;503(1–3):63–9.
64 Friedel HA, Fitton A. Flupirtine. A review of its pharmacological
properties, and therapeutic efficacy in pain states. Drugs. 1993 Apr;45
(4):548–69.
65 Stoll AL. Fibromyalgia symptoms relieved by flupirtine: an open–
label case series. Psychosomatics. 2000 Jul–Aug;41(4):371–2.
66 Use of the non–opiate analgesic drug flupirtine for the treatment of
overactive bladder and associated diseases including urge incontinence,
urinary flow problems as a result of prostate hyperplasia and irritable
bowel syndrome. United States Patent 7309713. http://www.freepatents
online.com/7309713.html
67 De Andrés J, Cerda–Olmedo G, Valía JC, et al. Use of botulinum
toxin in the treatment of chronic myofascial pain. Clin J Pain. 2003 Jul–
Aug;19(4):269–75.
68 Lang AM. A preliminary comparison of the efficacy and tolerability
of botulinum toxin serotypes A and B in the treatment of myofascial
pain syndrome: a retrospective, open–label chart review. Clin Ther.
2003 Aug;25(8):2268–78.
69 Kamanli A, Kaya A, Ardicoglu O, et al. Comparison of lidocaine in-
jection, botulinum toxin injection, and dry needling to trigger points in
myofascial pain syndrome. Rheumatol Int. 2005 Oct;25(8):604–11.
70 Ko GD, Whitmore S, Huang D, et al. Effective Pain Palliation in Fib-
romyalgia Syndrome Patients with Botulinum Toxin Type–A: Case
Series of 25. J Musculoskelet Pain. 2007 Aug;15(4):55–66.
71 Paulson GW, Gill W. Botulinum toxin is unsatisfactory therapy for
fibromyalgia. Mov Disord. 1996 Jul;11(4):459.
72 Dressler D, Benecke R. Autonomic side effects of botulinum toxin
type B treatment of cervical dystonia and hyperhidrosis. Eur Neurol.
2003;49(1):34–8.
73 eMedicine – Fibromyalgia : Article by Regina P Gilliland, MD.

http://www.emedicine.com/PMR/topic47.htm
74 Reddy SS, Yunus MB, Inanici F, et al. Tender point injections are
beneficial in fibromyalgia syndrome: a descriptive, open study. J
Musculoskelet Pain. 2000;8(4):7–18.
75 Hong CZ, Hsueh TC. Difference in pain relief after trigger point in-
jections in myofascial pain patients with and without fibromyalgia. Arch
Phys Med Rehabil. 1996 Nov;77(11):1161–6.
76 Dalpiaz AS, Lordon SP, Lipman AG. Topical lidocaine patch thera-
py for myofascial pain. J Pain Palliat Care Pharmacother. 2004;18(3):
15–34.
77 Argoff CE. Conclusions: chronic pain studies of lidocaine patch 5%
using the Neuropathic Pain Scale. Curr Med Res Opin. 2004;20 Suppl 2:
S29–31.
78 Teitelbaum Jacob. From Fatigued to Fantastic!: A Proven Program to
Regain Vibrant Health, Based on a New Scientific Study Showing
Effective Treatment for Chronic Fatigue and Fibromyalgia. Avery 2001.
pp. 139–140.
79 Posner IA, Oduber HE. Treatment of Fibromyalgia Syndrome with
Intravenous Lidocaine: A Prospective, Randomized Pilot Study. J Mus-
culoskelet Pain. 1995;2(4):55–65.
80 Raphael JH, Southall JL, Treharne GJ, et al. Efficacy and adverse ef-
fects of intravenous lignocaine therapy in fibromyalgia syndrome. BMC
Musculoskelet Disord. 2002 Sep 8;3:21.
83 McCarty DJ, Csuka M, McCarthy G, et al. Treatment of pain due to
fibromyalgia with topical capsaicin: A pilot study. Semin Arth Rheum.
1994;23:41–7.
CHAPTER 3.
Anticonvulsants
Anticonvulsants (also known as antiepileptic drugs) are used in the

prevention of epileptic seizures, which can sometimes accompany
CFS/ME. They have many possible modes of action, often several diffe-
rent ones in a single drug, and their ability to prevent different types of
seizures (partial seizures, complex seizures and absence seizures) varies.
Some anticonvulsants can even worsen some types of seizures.
Despite their different modes of action, almost all anticonvulsants
can be used to treat chronic pain, bipolar disorder and for migraine pro-
phylaxis. Many of them are effective for depression, anxiety and sleep
problems. Anticonvulsants can also relieve fatigue, flu–like symptoms,
cognitive problems, neurological symptoms, IBS, bladder problems and
muscle tension. They are one of the most important classes of medica-
tions in the treatment of CFS/ME and fibromyalgia.
Different anticonvulsants have completely different side effect pro-
files. Almost all can cause sedation and dizziness and rarely “freaky”
side effects (strange cognitive and neurological reactions), but some of
them can also cause life–threatening adverse reactions. Many older anti-
convulsants adversely affect bone strength. Carbamazepine, oxcarbaze-
pine and valproate can also impair male fertility.1
See also:
diazepam, clonazepam, melatonin (CHAPTER 1), pentazocine

(CHAPTER 2), selegiline (CHAPTER 5), vinpocetine (CHAPTER 6),
calcium channel blockers (CHAPTER 7), riluzole, cannabinoids
(CHAPTER 10)
carbamazepine (Tegretol, Teril, Finlepsin, Neurotop,

Timonil)
Carbamazepine is thought to work by blocking sodium channels.

Besides epilepsy, it is mostly used to for bipolar disorder, but also dia-
betic neuropathy. It has also been used to treat CFS/ME, even though
newer anticonvulsants have largely replaced it because of fewer side
effects.
The dose used in CFS/ME varies from 100 mg twice a day up to

1,200 mg a day.2 In this use carbamazepine can relieve cognitive prob-
lems, headache and other pains3, especially neuropathic pain and the
associated paresthesias.4 Carbamazepine is particularly useful for sharp
and stabbing neuropathic pain. It can also be used in the treatment of
depression, migraine prophylaxis and restless legs syndrome.5 Other
possible indications include anxiety and PTSD.6
There are, however, serious adverse reactions, such as blood chan-
ges, Stevens–Johnson syndrome and liver damage. Other side effects
include e.g. dizziness, headache, drowsiness, nausea, weight gain and
rashes. Carbamazepine can deplete the body of several nutrients, such as
biotin, folic acid and vitamin D. It can interact with benzodiazepines,
corticosteroids, tricyclic antidepressants, calcium channel blockers, anti-
psychotics and oral contraceptives. Many drugs can also alter the plas-
ma levels of carbamazepine.
Carbamazepine is available everywhere. It is usually sold as tablets,
oral suspension and extended release formulations. Even in the largest
doses carbamazepine is very inexpensive.
oxcarbazepine (Trileptal, Oxcarbatol, Apydan)
Oxcarbazepine is a derivative of carbamazepine. It is less prone to

causing liver problems and some other serious side effects of carbama-
zepine, which is particularly important when treating CFS/ME patients
who often have problems with liver function. On the other hand it may
be more likely to cause some hormonal problems. Other than that its
effects and indications for usage are similar to carbamazepine. Jacob
Teitelbaum prescribes oxcarbazepine in doses of 150–300 mg twice a
day for neuropathic pain.7
Oxcarbazepine is available in the United States, the United King-
dom, Canada, Australia and many other countries. It is more expensive
than carbamazepine, but still very affordable.
valproate (Depacon, Deprakine, Epilim, Valpakine)

valproic acid (Depakene, Depakine, Convulex)
divalproex (Depakote, Epival)
The mode of action of valproate is not well understood, but appears

to be mediated by increased amounts of GABA in the brain. Sodium
channel blockage and inhibition of glutamate release may also be invol-
ved. Valproate is provided in several different forms, which metabolize
to the same drug in body. Divalproex is a combination of valproate and
Anticonvulsants 77
valproic acid. The effects are supposedly the same with all of the three,
but in practice this may not be true, because of differences in bioavail-
ability.
Valproate is not usually used to treat CFS/ME or fibromyalgia, but
it can be tried for pain, mood and sleep problems. Occasionally it is
used to treat the anxiety and panic disorder sometimes present in
CFS/ME. Valproate is also approved for the treatment of migraines. It
may be helpful in PTSD.8 It has some anti–inflammatory action, as it
inhibits the activation of NF–kappa B.9
Valproate is fairly low on side effects, though in rare cases it can
precipitate serious side effects such as pancreatitis and polycystic ovary
syndrome. About 10% of patients experience thinning and curling of
hair. Stomach upset is common, but usually mild and transient. Weight
gain is possible. Valproate may increase the replication of cytomegalo-
virus and impair the efficacy of antiherpesviral therapies.10
Valproate can lower the blood levels of carnitine and folic acid,
probably warranting supplementation, as these nutrients are important in
CFS/ME. It can potentiate the effects of antidepressants, neuroleptics,
benzodiazepines and carbamazepine, and elevate the levels of e.g. nimo-
dipine and lamotrigine. Aspirin and erythromycin may elevate valproate
levels. Valproate should not be combined with potentially hepatotoxic
medications. Regular bloodwork is recommended.
Valproate is available everywhere. It is sold as capsules, modified
release capsules and liquid formulations. It is very inexpensive.
gabapentin (Neurontin, Gabaran, Gabax)
As it name suggests gabapentin was designed to be a GABA analo-

gue, but has been found to possess relatively little GABAergic action.
Its main mode of action is thought to be the modulation of the alpha2-
delta subunit of voltage–gated calcium channel. Besides epilepsy it is
widely prescribed for neuropathic pain, depression, panic disorder,
PTSD and bipolar disorder. It works especially well for neuropathic
pain if the pain is burning or resembles electric shocks.
Gabapentin is one of the most commonly used drugs to treat
CFS/ME. Jay Goldstein prescribes his CFS/ME patients a small dose of
100–300 mg three times a day, which he has found to relieve fatigue
even after just one tablet.11 Usually the dose used for CFS/ME is larger,
900–1,800 mg a day.12 Dr. Jay W. Seastrunk uses an even larger dose,
up to 3,200 mg, but starts low at 100–400 mg.13 In some people even
100 mg a day can be helpful.
Gabapentin is helpful for many different kinds of ailments. A doub-
le–blinded study found it beneficial in fibromyalgia in a fairly large

dose of 1,200–2,400 mg.14 It appears to be effective in relieving muscle
cramps15 and improving sleep quality.16 This is why many doctors use it
as a sleep aid for their CFS/ME patients.17 At least in animals gabapen-
tin also improves memory, an effect that may be mediated through mus-
carinic cholinergic receptors.18
Gabapentin has been shown to relieve the hot flashes associated
with menopause and other hormonal disturbances.19 Some doctors think
it may help to stabilize body temperature in other conditions, as well. It
can be helpful for interstitial cystitis20, as well as overactive bladder and
nocturia.21 It may be useful for restless legs syndrome, if dopamine ago-
nists have not been of help.22
Most patients tolerate the drug well. Some may experience signifi-
cant side effects, but they are usually transient. Sedation, increased fati-
gue and dizziness are the most common adverse effects. Gabapentin can
also cause weight gain, edema, vision disturbances and rarely migraines.
In contrast to most anticonvulsants it has few drug interactions. Morph-
ine and some other narcotic painkillers may affect gabapentin metabo-
lism. Antacids should be taken at a different time of the day.
Gabapentin is available in the United States, the United Kingdom,
Canada, Australia and many other countries. The smallest 100 mg cap-
sules are not available in every market. A compounding pharmacy can
formulate gabapentin into a cream for use as a topical pain reliever.
Price depends largely on the dose.
pregabalin (Lyrica)
The mode of action and effects of pregabalin are similar to gaba-

pentin. It is often used to treat neuropathic pain. In 2007 pregabalin be-
came the first FDA–approved treatment for fibromyalgia after several
studies vouched for its efficacy. There is no data, however, showing that
pregabalin is more effective (or better tolerated) than gabapentin in this
use. Similar to gabapentin, the dosages used for CFS/ME and FM vary
widely from 25 mg to 600 mg or more.
Pregabalin has been shown to be effective for both anxiety and dep-
ression. In one double–blinded study 600 mg daily dose of pregabalin
relieved anxiety nearly as well as alprazolam and 150 mg dose was
almost as effective.23 Unlike benzodiazepines pregabalin is not habit–
forming and does not build tolerance. As could be expected it also
improves sleep and reduces the number of nocturnal awakenings.24 It
can also work well for IBS.25
The side effects of pregabalin are similar to gabapentin. It may be
Anticonvulsants 79
better tolerated, but some patients who cannot tolerate pregabalin can
take gabapentin. Dizziness and drowsiness are the most common side
effects. Pregabalin can also cause weight gain. It is not known whether
pregabalin can interact with the same drugs as gabapentin.
Pregabalin is available in the United States, the United Kingdom,
Canada, Australia and many other countries. It is somewhat more
expensive than gabapentin.
vigabatrin (Sabril, Sabrilex)
Vigabatrin works by slowing the breakdown of GABA. It has been

used to treat e.g. neuropathic pain, anxiety and PTSD. It is occasionally
prescribed for CFS/ME and fibromyalgia, though agents with better
tolerability are usually preferred in all of these uses. According to ani-
mal studies vigabatrin may be helpful for tinnitus.26
Sleepiness, fatigue and vision disturbances are by far the most
common side effects. Headache, weight gain, dizziness, nervousness,
depression and memory problems occur less commonly. Jay Goldstein
notes that vigabatrin has made all of his patients who have taken it dep-
ressed.27 Vigabatrin can reduce the visual field permanently, so regular
ophthalmologic exams are recommended. It can lower the blood levels
of carbamazepine and phenytoin.
Vigabatrin is available in the United Kingdom, Canada, Australia
and some other countries. It is not yet available in the United States, but
this may change in 2008. It is somewhat expensive.
tiagabine (Gabitril)
Tiagabine is a GABA reuptake inhibitor. It is used to treat chronic

pain and small doses improve sleep quality. According to one study the
pain relieving effect was similar to gabapentin, but sleep improved
much more on tiagabine.28 Additionally it can help anxiety.29 Despite
this, in a fairly large double–blinded study it was not found useful for
PTSD.30 Tiagabine might work as an acute therapy for migraine.31
A preliminary study concluded that tiagabine may be helpful in fib-
romyalgia.32 Lucinda Bateman prescribes her CFS/ME patients a small
dose of 2–12 mg33 and Jacob Teitelbaum uses a bit more, 5–24 mg.34 Dr.
Jay Goldstein has not found the drug helpful for CFS/ME and
fibromyalgia.35
Tiagabine can sometimes paradoxically cause seizures in people
with no history of epilepsy. Similar to other GABA derivatives it can
cause sedation and dizziness especially when beginning treatment. Nau-
sea and psychiatric side effects such as depression and nervousness are
common, but small doses in the range of a few milligrams only rarely
cause marked side effects.
Tiagabine is available in the United States, the United Kingdom,
Canada, Australia and a few other, mostly European countries. It is
somewhat expensive.
lamotrigine (Lamictal, Elmendos)
Lamotrigine primarily works by binding to voltage–sensitive sodi-

um channels and blocking excess glutamate release. It also binds to the
sigma receptors to some extent and weakly antagonizes the 5–HT3 sero-
tonin receptors. It is a common treatment for bipolar disorder, especially
if depression predominates. It can be used to treat chronic pain, especi-
ally neuropathic pain, and may be useful in some refractory cases.
Lamotrigine improves the quality of sleep, especially by increasing the
amount of REM sleep.36
Perhaps owing to these multiple modes of action lamotrigine is a
medication that improves the condition of many CFS/ME patients. At
best the patient can reach almost full remission. The dose used to treat
CFS/ME varies from the 25–50 mg used by Jay Goldstein up to 300–
400 mg a day. Jacob Teitelbaum feels that doses below 200 mg a day
are not effective.37 Lamotrigine may be useful in PTSD38 and migraine,
especially migraine with aura.39 It also has some antiviral action against
HHV–6.40
When using lamotrigine it is important to consider the possibility of
life–threatening rash (Stevens–Johnson syndrome) and begin the treat-
ment with a very low dose which is slowly titrated up. One problem is
that up to 1/10 of patients get some kind of a rash from lamotrigine,
which is usually a harmless one without fever and other symptoms, but
often the medication is discontinued anyway. Most patients can continue
taking the drug if it stopped until the rash has healed and then reintrodu-
ced even more slowly.
Headache, dizziness and vision impairment are common side
effects when using larger doses. Nervousness, nausea, stomach upset,
drowsiness, insomnia, muscle aches and tremor are also seen fairly
often. Many other drugs can markedly either slow down or speed up the
metabolism of lamotrigine so one has to be careful when trying new
drugs, especially other anticonvulsants, when on lamotrigine. Acetami-
nophen (paracetamol) should not be used with lamotrigine.
Lamotrigine is widely available and the smallest tablets only con-
tain 5 mg of the drug. Different “starting kits” are also available.
Anticonvulsants 81
Lamotrigine is fairly inexpensive.
topiramate (Topamax, Topimax)
Topiramate has a variety of different antiepileptic actions. It is one

of the most common agents used for migraine prophylaxis. Double–
blinded studies have shown efficacy in PTSD.41 Lucinda Bateman pre-
scribes topiramate in doses of 12.5–150 mg to treat CFS/ME.42 Jay
Goldstein has found topiramate to combine well with gabapentin in the
treatment of CFS/ME and fibromyalgia.43
Topiramate is another good though less commonly used drug for
the treatment of neuropathic pain.44 According to Dr. Jacob Teitelbaum
topiramate is helpful for many patients refractory to other treatments.45
He recommends a daily dose of 200–300 mg for this purpose.
Possible side effects include paresthesias, cognitive problems and
weight loss. Topiramate is even used as a diet aid, though this use is
controversial. Metabolic acidosis is a common adverse effect. There
may be nausea, but it is usually transient. The cognitive problems can be
quite severe, and some patients have complained of losing the ability to
perform even simple tasks. Studies have confirmed the possibility of se-
vere impairment.46
Topiramate is widely available, with price depending largely on the
dose. Small doses are quite affordable, but larger doses may not be fit
for all patients' budget.
zonisamide (Zonegran, Excegran)
Zonisamide has a different structure and mode of action from most

anticonvulsants. It blocks sodium and calcium channels and has some
dopaminergic and serotonergic action as well. It can be used for neuro-
pathic pain.47 Dr. Jacob Teitelbaum prescribes it for this purpose, start-
ing at 100 mg a day for the first two weeks and then increasing the dose
to 200 mg.48 Dr. Lucinda Bateman uses a daily dose of 100–200 mg to
facilitate sleep.49
Zonisamide has been tried with good results in a variety of diffe-
rent uses, such as a supportive medication in weight loss50 and in Par-
kinson’s disease.51 It is sometimes used in migraine prophylaxis, even
though not all studies have got statistically significant results in this
use.52 A clinical trial is currently running to evaluate the efficacy of
zonisamide in patients with fibromyalgia and migraine.53
Zonisamide is normally well tolerated, though it can cause drowsi-
ness, dizziness, irritability and lack of appetite. Weight loss is more
common than weight gain. Zonisamide may interact with carbamaze-

pine, valproate and acetazolamide. Patients are recommended to drink
plenty of fluids to prevent the formation of kidney stones. The drug
should not be used if there are other risk factors predisposing to kidney
stones. Those with sulfa allergy should not use zonisamide.
Zonisamide is available in the United States, the United Kingdom,
Canada, Australia and some other countries. It is somewhat expensive.
levetiracetam (Keppra)
Levetiracetam belongs to the racetams, a group of nootropic and

anticonvulsant drugs. Its mode of action is not well understood. As most
antiepileptics, levetiracetam has been used to treat neuropathic pain.54 In
one study conducted on healthy persons the drug improved the quality
and quantity of sleep and reduced the number of nocturnal awakenings,
without inducing daytime sleepiness.55
Levetiracetam can also be helpful for restless legs symptoms.56
Like other anticonvulsants it is suited for migraine prophylaxis. In one
particularly impressive study it helped half of the patients suffering from
migraines with aura reach a full remission.57 Jacob Teitelbaum notes
that levetiracetam sometimes relieves pain in otherwise refractory
cases.58 Levetiracetam has been reported to be helpful in most cases of
treatment–refractory PTSD.59
Compared to most other anticonvulsants levetiracetam is well tole-
rated and not thought to have drug interactions. Psychiatric and neurolo-
gical side effects are still possible, most common ones being drowsiness
and asthenia (weakness). Vitamin B6 appears to significantly reduce
these side effects.60
Levetiracetam is available in the United States, the United King-
dom, Canada, Australia and many other countries, but especially larger
doses can become costly.
See also
piracetam, aniracetam (CHAPTER 6)
felbamate (Felbatol, Taloxa)
Felbamate is primarily an NMDA antagonist. Jay Goldstein descri-

bes beneficial effects using it in many CFS/ME patients.61 Felbamate
has analgesic properties and he also finds it useful in mood disorder.
Anticonvulsants 83
According to Goldstein some CFS/ME patients experience a decrease in

all symptoms. He also recommends it for fibromyalgia. He has noticed
synergistic effects with felbamate and gabapentin.
Felbamate poses a small (yet compared to baseline greatly increa-
sed) risk of aplastic anemia and acute liver failure. Both of these condi-
tions are life threatening with significant mortality. Because of this risk
the patient should have monthly tests for blood counts and liver funct-
ion. Some sources even recommend testing once a week.
Because of these complications felbamate has been withdrawn
from market in many countries. In the United States usage requires the
patient to sign an informed consent form. In the United Kingdom it is
only available on a limited named–patient basis. Felbamate is available
in many European countries. An oral solution form is also available.
Felbamate is quite expensive.
phenytoin (Dilantin, Hydantin, Phenytek, Epanutin)
Phenytoin is believed to act by modulating glutamatergic transmis-

sion. It has been in clinical use as an anticonvulsant for over 50 years,
but it is also an antiarrhythmic similar to lidocaine and mexiletine. It has
analgesic, anxiolytic and mood stabilizing properties. Jay Goldstein has
used it to treat CFS/ME and fibromyalgia in a low dose of 100 mg a
day.62 He reports synergistic effects from combining it with gabapentin.
Phenytoin may also help tinnitus.63
Phenytoin is generally thought to have adverse effects on cognition,
but this may only apply to the large doses used to treat epilepsy. Smaller
doses have even been shown to positively influence cognition.64 In one
study phenytoin was found to cause a significant increase in right brain
volume in patients with PTSD.65
The most common side effects include tiredness, nausea, ataxia
(impaired coordination), nystagmus, dizziness and tremor. Phenytoin
may reduce the blood levels of folic acid, biotin, calcium, vitamins B1
and B12, vitamin D, vitamin K and carnitine, but folate also decreases
blood levels of the drug. Phenytoin can also interact with a number of
different medications, including many antibiotics, anticoagulants, azo-
les, opiates, benzodiazepines, other anticonvulsants and oral contracep-
tives.
Phenytoin is available virtually everywhere and it is very inexpen-
sive. It can be used topically as an analgesic, but this form is not com-
mercially available and must be compounded.
References
1 Isojärvi JI, Löfgren E, Juntunen KS. Effect of epilepsy and antiepilep-

tic drugs on male reproductive health. Neurology. 2004 Jan 27;62(2):
247–53.
Fatigue Syndrome. Hunter House 1995. pp. 194,199–201.
4 Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). Out-
line for development of services for CFS/ME in Scotland. Report of the
Scottish short life working group. http://www.sehd.scot.nhs.uk/mels/
HDL2003_02report.pdf
5 The Management of Chronic Fatigue Syndrome, a summary of a talk
given by Dr. Michael Oldmeadow. http://home.vicnet.net.au/~mecfs/
general/oldmeadow.html
6 Keck PE Jr, McElroy SL, Friedman LM. Valproate and carbamaze-
pine in the treatment of panic and posttraumatic stress disorders, with-
drawal states, and behavioral dyscontrol syndromes. J Clin Psychophar-
macol. 1992 Feb;12(1 Suppl):36S–41S.
7 Teitelbaum Jacob. Pain Free 1–2–3. McGraw–Hill 2005. p. 211.
8 Adamou M, Puchalska S, Plummer W, et al. Valproate in the treat-
ment of PTSD: systematic review and meta analysis. Curr Med Res
Opin. 2007;23(6):1285–91.
9 Ichiyama T, Okada K, Lipton JM, et al. Sodium valproate inhibits pro-
duction of TNF–alpha and IL–6 and activation of NF–kappaB. Brain
Res. 2000 Feb 28;857(1–2):246–51.
10 Michaelis M, Ha TA, Doerr HW, et al. Valproic acid interferes with
antiviral treatment in human cytomegalovirus–infected endothelial cells.
Cardiovasc Res. 2008 Feb 1;77(3):544–50.
Network Disorders. Haworth Medical Press 1996. p. 144.
12 Prescribed Medications for Fibromyalgia: By Mark Pellegrino, M.D.
– 2007 Update. http://www.immunesupport.com/library/showarticle.
cfm/ID/3308/
13 Neurontin and brain injury treatment By Gail Kansky and Mike Rey-
nolds. http://www.ncf-net.org/forum/neurontin98.htm
Anticonvulsants 85
14 Arnold LM, Goldenberg DL, Stanford SB, et al. Gabapentin in the

treatment of fibromyalgia: a randomized, double–blind, placebo–cont-
rolled, multicenter trial. Arthritis Rheum. 2007 Apr;56(4):1336–44.
15 Serrao M, Rossi P, Cardinali P, et al. Gabapentin treatment for musc-
le cramps: an open–label trial. Clin Neuropharmacol. 2000 Jan–Feb;23
(1):45–9.
16 Placidi F, Diomedi M, Scalise A, et al. Effect of anticonvulsants on
nocturnal sleep in epilepsy. Neurology. 2000;54(5 Suppl 1):S25–32.
17 CFS Experts Discuss Diagnosis and Treatment. http://www.co-cure.
org/experts.htm
18 Boccia MM, Acosta GB, Baratti CM. Memory improving actions of
gabapentin in mice: possible involvement of central muscarinic cholin-
ergic mechanism. Neurosci Lett. 2001 Oct 5;311(3):153–6.
19 Reddy SY, Warner H, Guttuso T Jr., et al. Gabapentin, estrogen, and
placebo for treating hot flushes: a randomized controlled trial. Obstet
Gynecol. 2006 Jul;108(1):41–8.
20 Sasaki K, Smith CP, Chuang YC, et al. Oral gabapentin (neurontin)
treatment of refractory genitourinary tract pain. Tech Urol. 2001 Mar;7
(1):47–9.
21 Carbone A, Palleschi G, Conte A, et al. Gabapentin treatment of neu-
rogenic overactive bladder. Clin Neuropharmacol. 2006 Jul–Aug;29(4):
206–14.
22 Winkelman JW, Allen RP, Tenzer P, et al. Restless legs syndrome:
nonpharmacologic and pharmacologic treatments. Geriatrics. 2007 Oct;
62(10):13–6.
23 Pande AC, Crockatt JG, Feltner DE, et al. Pregabalin in generalized
anxiety disorder: a placebo–controlled trial. Am J Psychiatry. 2003 Mar;
160(3):533–40.
24 Hindmarch I, Dawson J, Stanley N. A double–blind study in healthy
volunteers to assess the effects on sleep of pregabalin compared with
alprazolam and placebo. Sleep. 2005 Feb 1;28(2):187–93.
25 Houghton LA, Fell C, Whorwell PJ. Effect of a second–generation
alpha2delta ligand (pregabalin) on visceral sensation in hypersensitive
patients with irritable bowel syndrome. Gut. 2007 Sep;56(9):1218–25.
26 Brozoski TJ, Spires TJ, Bauer CA, et al. Vigabatrin, a GABA trans-
aminase inhibitor, reversibly eliminates tinnitus in an animal model. J
Assoc Res Otolaryngol. 2007 Mar;8(1):105–18.
atic Medicine. Haworth Press 2004. p. 128.
28 Todorov AA, Kolchev CB, Todorov AB. Tiagabine and gabapentin

for the management of chronic pain. Clin J Pain. 2005 Jul–Aug;21(4):
358–61.
29 Schwartz TL, Azhar N, Husain J, et al. An open–label study of tiaga-
bine as augmentation therapy for anxiety. Ann Clin Psychiatry. 2005
Jul–Sep;17(3):167–72.
30 Davidson JR, Brady K, Mellman TA, et al. The efficacy and tolerabi-
lity of tiagabine in adult patients with post–traumatic stress disorder. J
Clin Psychopharmacol. 2007 Feb;27(1):85–8.
31 Leniger T, Wiemann M, Bingmann D, et al. Different effects of GA-
BAergic anticonvulsants on 4–aminopyridine–induced spontaneous GA-
BAergic hyperpolarizations of hippocampal pyramidal cells—implica-
tion for their potency in migraine therapy. Cephalalgia. 2000 Jul;20(6):
533–7.
32 Jenson M, Sorensen R. An Open–label Trial of Tiagabine in Patients
with Primary Fibromyalgia Syndrome. Poster presented at: 21st Annual
meeting of the American Academy of Pain Medicine. Palm Springs,
CA, U.S. Feb 23–26, 2005.
36 Placidi F, Diomedi M, Scalise A, et al. Effect of anticonvulsants on
nocturnal sleep in epilepsy. Neurology. 2000;54(5 Suppl 1):S25–32.
38 Hertzberg MA, Butterfield MI, Feldman ME, et al. A preliminary
study of lamotrigine for the treatment of posttraumatic stress disorder.
Biol Psychiatry. 1999 May 1;45(9):1226–9.
39 D'Andrea G, Granella F, Cadaldini M, et al. Effectiveness of lamotri-
gine in the prophylaxis of migraine with aura: an open pilot study.
Cephalalgia. 1999 Jan;19(1):64–6.
40 Naesens L, Bonnafous P, Agut H, et al. Antiviral activity of diverse
classes of broad–acting agents and natural compounds in HHV–6–infec-
ted lymphoblasts. J Clin Virol. 2006 Dec;37 Suppl 1:S69–75.
41 Tucker P, Trautman RP, Wyatt DB, et al. Efficacy and safety of topi-
ramate monotherapy in civilian posttraumatic stress disorder: a randomi-
zed, double–blind, placebo–controlled study. J Clin Psychiatry. 2007
Feb;68(2):201–6.
Anticonvulsants 87

44 Guay DR. Oxcarbazepine, topiramate, zonisamide, and levetirace-
tam: potential use in neuropathic pain. Am J Geriatr Pharmacother. 2003
Sep;1(1):18–37.
46 Salinsky MC, Storzbach D, Spencer DC, et al. Effects of topiramate
and gabapentin on cognitive abilities in healthy volunteers. Neurology.
2005 Mar 8;64(5):792–8.
47 Krusz JC. Treatment of chronic pain with zonisamide. Pain Pract.
2003 Dec;3(4):317–20.
50 Gadde KM, Franciscy DM, Wagner HR 2nd, et al. Zonisamide for
weight loss in obese adults: a randomized controlled trial. JAMA. 2003
Apr 9;289(14):1820–5.
51 Murata M, Horiuchi E, Kanazawa I. Zonisamide has beneficial ef-
fects on Parkinson's disease patients. Neurosci Res. 2001 Dec;41(4):
397–9.
52 Drake ME Jr, Greathouse NI, Renner JB, et al. Open–label zonisa-
mide for refractory migraine. Clin Neuropharmacol. 2004 Nov–Dec;27
(6):278–80.
53 Zonisamide for Fibromyalgia & Migraine. http://clinicaltrials.gov/ct/
show/NCT00259636
54 Price MJ. Levetiracetam in the treatment of neuropathic pain: three
case studies. Clin J Pain. 2004 Jan–Feb;20(1):33–6.
55 Cicolin A, Magliola U, Giordano A, et al. Effects of levetiracetam on
nocturnal sleep and daytime vigilance in healthy volunteers. Epilepsia.
2006 Jan;47(1):82–5.
56 Della Marca G, Vollono C, Mariotti P, et al. Levetiracetam can be
effective in the treatment of restless legs syndrome with periodic limb
movements in sleep: report of two cases. J Neurol Neurosurg Psychi-
atry. 2006 Apr;77(4):566–7.
57 Brighina F, Palermo A, Aloisio A, et al. Levetiracetam in the prophy-
laxis of migraine with aura: a 6–month open–label study. Clin Neuro-
pharmacol. 2006 Nov–Dec;29(6):338–42.

59 Kinrys G, Wygant LE, Pardo TB, et al. Levetiracetam for treatment–
refractory posttraumatic stress disorder. J Clin Psychiatry. 2006 Feb;67
(2):211–4.
60 Miller GS. Pyridoxine ameliorates adverse behavioral effects of leve-
tiracetam in children. Epilepsia. 2002;43(Suppl. 7):S62
63 Tatemoto K. [Clinical and electrophysiological investigations of the
influence of phenytoin natrium on tinnitus] Nippon Jibiinkoka Gakkai
Kaiho. 1990 Feb;93(2):256–67.
64 Smith WL, Lowrey JB. Effects of diphenylhydantoin on mental abili-
ties in the elderly. J Am Geriatr Soc. 1975 May;23(5):207–11.
65 Bremner JD, Mletzko T, Welter S, et al. Effects of phenytoin on me-
mory, cognition and brain structure in post–traumatic stress disorder: a
pilot study. J Psychopharmacol. 2005 Mar;19(2):159–65.
CHAPTER 4.
Antimicrobials
Antibiotics
Antibiotics can be helpful, even curative, in the treatment of

CFS/ME if a chronic bacterial infection is either a causative agent or an
opportunistic infection that worsens the symptoms. Especially the role
of mycoplasma appears strong.1,2,3 Chlamydia pneumoniae4, Coxiella
burnetii (Q fever)5, Toxoplasma gondii6, Staphylococci7 and rickettsiae8
have also been implicated. There is still confusion whether chronic
Lyme disease/post–Lyme syndrome can be considered a subset of CFS/
ME or whether it is a separate illness.
Fibromyalgia has not been associated with chronic bacterial infecti-
ons nearly as often as CFS/ME, but Garth Nicolson’s research group has
connected mycoplasma with both CFS/ME and fibromyalgia.9 A letter
published in the journal Rheumatology in 1997 reported findings of anti-
bodies to Chlamydia pneumoniae and Chlamydia trachomatis in patients
with fibromyalgia.10
Many of the implicated bacterial infections are intracellular or
otherwise hard to detect with standard blood tests. Especially antibody
tests are very unreliable and PCR testing should be used instead. An
infection cannot always be reliably excluded and some doctors recom-
mend a trial of antibiotics just in case. Besides their antimicrobial
effects, many antibiotics (especially tetracyclines and macrolides, the
two groups most commonly utilized) have immunomodulatory and neu-
romodulatory properties.
Almost all available antibiotics have been tried for CFS/ME and it
would be impossible to include them all here, so this list only covers the
most commonly used ones. Fluoroquinolones have been excluded,
because they can cause significant neurotoxicity and the author believes
they should never be used unless absolutely necessary. They can some-
times even cause/trigger CFS/ME or a similar illness. Co–trimoxazole/
trimethoprim has also been implicated as a cause/trigger for CFS/ME.11
Many different protocols are in use, depending on both the doctor
and the suspected pathogen. Usually the treatment is continuous, but
some doctors utilize a pulse–like approach. Usually just one antibiotic is
used, but some doctors argue that multiple agents should be used at once
to avoid resistance. Sometimes the antibiotic is regularly switched in-

stead. Even with different protocols, it is clear that the treatment has to
last long enough, sometimes a year or more.
The so–called Marshall protocol was initially developed to treat
sarcoidosis, but has been used in CFS/ME and FM as well. It is based on
the theory that these illnesses are caused by nanobacteria (extremely
small bacteria), which are “hiding” from the immune system and can
only be eradicated with minocycline, olmesartan and the avoidance of
vitamin D. No studies have proven the efficacy of this treatment in any
illness (or even the existence of nanobacteria). Some patients report
good results with MP, but it carries significant risks.12,13
In the beginning of any antibiotic treatment the symptoms can wor-
sen even significantly and new symptoms can appear as a result of bac-
terial die–off (often called “herx,” for Jarisch–Herxheimer reaction), but
with time the illness should start to clear up if bacteria have been impli-
cated. If there is no response after several months of therapy, it should
probably be discontinued. If there is evidence or strong suspicion of a
chronic bacterial infection, switching to a different antibiotic (or several
at once) should be considered.
See also:
cholestyramine, pioglitazone/rosiglitazone, erdosteine, probene-

cid, fibrinolytic enzymes (CHAPTER 10)
doxycycline (Vibramycin, Vibramicina, Doryx, Dotur,

Unidox)
Tetracyclines are wide–spectrum antibiotics with activity against

most kinds of bacteria, including mycoplasma and borrelia. Doxycycline
is a popular candidate for treating persistent bacterial infections. Unlike
tetracycline it permeates the blood–brain barrier well. E.g. the CFS/ME
expert David Bell prefers doxycycline.14 Tetracyclines have anti–inflam-
matory properties, which have been utilized in the treatment of non–
infectious conditions and may be helpful in CFS/ME as well.15
In one study doxycycline was tried in CFS/ME patients positive for
the bacteria Coxiella burnetii.16 The infection apparently cleared but
without symptom relief. A large double–blinded study tried doxycycline
in Gulf War syndrome, but no benefit was noted.17 Some CFS/ME doc-
tors report that doxycycline can give the patients more energy. Often the
used dose is fairly large, 200–300 mg a day.18
Antimicrobials 91
Nausea and vomiting are the most likely adverse effects. Photosen-
sitivity and yeast infections are also common. Benign increase in intra-
cranial pressure is a rarer occurrence. E.g. carbamazepine and St. John’s
wort speed up the elimination of doxycycline, reducing its therapeutic
efficacy. Doxycycline may increase the efficacy of anticoagulants. Like
other antibiotics it may reduce the effect of oral contraceptives, though
this has been disputed. Doxycycline should not be given to young child-
ren.
Doxycycline is available everywhere. It is sold in capsules, tablets
and different liquid formulations. It is somewhat expensive.
minocycline (Minocin, Minomycin, Arestin, Cyclomin,

Minotab)
Minocycline has an even broader spectrum than other tetracyclines.

Its long half–life and good penetration through the blood–brain barrier
are definite benefits. It is often used to treat mycoplasma, borrelia and
other chronic infections. In Marshall protocol minocycline is combined
with olmesartan and vitamin D avoidance with the aim of a permanent
cure.19 Minocycline has also shown efficacy in “post Q fever fatigue
syndrome.”20
Minocycline exerts stronger anti–inflammatory activity than other
tetracyclines or other types of antibiotics and has neuroprotective pro-
perties as well. It suppresses the secretion of IL–6, a major inflamma-
tory cytokine.21 It has been successfully tried as a treatment for e.g. mul-
tiple sclerosis22, Alzheimer’s disease23, rheumatoid arthritis24 and even
schizophrenia.25 In animal studies minocycline also shows analgesic
action.26
The side effects and drug interactions are similar to doxycycline,
but minocycline is more likely to cause the rare side effect of increased
intracranial pressure. Dizziness is a common side effect. Minocycline
can sometimes cause skin discoloration. Despite its efficacy in several
autoimmune diseases, several cases of minocycline–induced autoim-
mune hepatitis and systemic lupus erythematosus–like syndrome have
been reported.27
Minocycline is available in the United States, the United Kingdom,
Canada, Australia and some other countries. It is fairly expensive in
most places.
azithromycin (Zithromax, Zitromax, Aziwok, Aruzilina,

Sumamed)
The macrolide antibiotics are effective against most of the bacteria

that have been implicated in CFS/ME. In addition they too have some
anti–inflammatory properties and they have been tried in the treatment
of e.g. cystic fibrosis.28 The dose used in CFS/ME is usually 500 mg
three times a day, though Charles Wheldon prescribes his patients only
250 mg three times a week.29
Fairly impressive results were achieved in a CFS/ME study using
azithromycin: 58 out of the 99 patients improved on the drug, though
none recovered fully.30 The lack of total recovery and the fact that those
with low plasma acetylcarnitine levels were more likely to respond sug-
gests that the benefits were possibly because of the immunomodulatory
properties of the drug.
Azithromycin is a safe and well–tolerated drug, though it can
sometimes cause stomach upset. Taking it with food markedly hinders
the absorption and it should be taken two hours before and after a meal.
This can cause problems with hypoglycemic patients who have to eat
often. Azithromycin may increase the effects of oral anticoagulants. It
should not be used with ergotamine.
Azithromycin is widely available. It is quite expensive, though the
price varies widely between different markets.
clarithromycin (Biaxin, Klacid, Klaribac, Klaricid,

Fromilid)
Clarithromycin is not as effective as azithromycin against some

species of Gram–negative bacteria, but overall its antibacterial efficacy
and anti–inflammatory properties are similar to azithromycin. In the
treatment of CFS/ME it is usually used in the maximum daily dose of
1,000 mg.
The side effects are similar to azithromycin, but clarithromycin has
more drug interactions. It should not be combined with statins or astemi-
zole. It can increase the plasma levels of e.g. carbamazepine, theophyl-
line, omeprazole and some benzodiazepines. Interactions with other
drugs such as phenytoin, valproate, bromocriptine and disopyramide are
possible.
The price and availability of clarithromycin are similar to those of
azithromycin.
Antimicrobials 93
metronidazole (Flagyl, Metronidazol, Metronidazole,

Metrogyl, Klion)
Metronidazole is a nitroimidazole derivative, which has activity

against most anaerobic bacteria. It has good permeability in all kinds of
tissue and penetrates the blood–brain barrier well. It has been used to
treat chronic Lyme disease and many doctors believe it is the best drug
for this purpose, especially when combined with other antibiotics.31
Metronidazole also works against the parasite Giardia lamblia, which
has been controversially associated with IBS and chronic fatigue by
some doctors.32,33
Dr. Charles Wheldon combines metronidazole pulses with continu-
ous administration of doxycycline and macrolides to treat chronic Chla-
mydia pneumoniae infection.34 Metronidazole can also be used to treat
dysbiosis of the gut and to eradicate Helicobacter pylori, which is
usually associated with stomach ulcers, but can colonize other parts of
the body as well.35
Stomach upset is the most common side effect of metronidazole.
Other adverse effects can include nausea and vomiting, skin eruptions
and neurological and psychiatric problems. Metronidazole can cause
peripheral neuropathy. In long term use monitoring of bloodwork is
recommended. Metronidazole can potentiate the effects of oral anticoa-
gulants. There may be other interactions with phenytoin, cimetidine and
lithium.
Metronidazole is widely available and is very inexpensive.
rifaximin (Xifaxan, Normix, Zaxine, Spiraxin, Rifacol)
Rifaximin is used for gastrointestinal infections, especially trave-

ler’s diarrhea. It is not absorbed into the body. It has been used to treat
IBS based on the theory that the condition is caused by small intestinal
bacterial overgrowth (SIBO). A paper reviewing several small studies
about this use concluded that it seems to be effective in some cases.36
In one study 96 out of 123 fibromyalgia patients were diagnosed as
suffering from SIBO.37 After treatment with antibiotics, improvement
was reported not only in gastrointestinal symptoms, but in joint pain and
fatigue as well. A patent has been filed titled “Method of diagnosing fib-
romyalgia caused by small intestinal bacterial overgrowth.”38 This treat-
ment has reportedly greatly improved some cases of RLS39 and intersti-
tial cystitis40 that have been purportedly caused by SIBO.
Rifaximin is usually free of side effects, because of the lack of sys-
temic absorption. It can rarely cause allergic reactions. Because of its li-
mited spectrum of action, it is not likely to cause fungal infections.

Rifaximin is available in the United States and some other, mostly
European countries, but not in the United Kingdom, Canada or Austra-
lia. It is somewhat expensive, especially in the U.S.
neomycin (Neo–Rx, Mycitracin)
Neomycin is an antibiotic of the aminoglycoside class. It is usually

only used in topical preparations. Given orally it can be used to treat
small intestinal bacterial overgrowth similar to rifaximin. Neomycin is
also an N–type calcium channel blocker, which may make it a highly
potent analgesic. There is some evidence of this, though more studies
are needed.41,42,43 Still, as a topical preparation neomycin is so safe and
convenient compared to many other treatments that it is worth trying at
least for severe intractable pain.
Neomycin can cause allergic reactions. When taken orally there is
negligible systemic absorption, but because neomycin is highly nephro-
toxic, it may still cause kidney damage in some cases. Ototoxicity
(damage to the ears) is also possible. Neither of these problems is likely
to occur in external application, because the doses are so low, milli-
grams versus grams used in oral therapy.
Neomycin is available in the United States, the United Kingdom,
Canada, Australia and many other countries. Topical preparations often
contain other ingredients, but this usually does not matter, unless corti-
costeroids are included. In some markets neomycin cream is available
over the counter. The cost of the cream depends on the size of the
treated area, but it is not very expensive.
cycloserine (Seromycin, Cycloserine, Closina)
Cycloserine primarily has activity against mycobacteria (not to be

confused with mycoplasma), and is mostly used to treat tuberculosis.
Jay Goldstein sometimes tries small doses in otherwise treatment–resis-
tant cases of CFS/ME and fibromyalgia, not because of its antibiotic
properties, but because it has neuropharmacological effects that may be
helpful to some treatment–resistant patients.44 Most importantly it is a
partial agonist at the glycine coagonist site of the NMDA receptor,
making it similar to NMDA antagonists.
Goldstein is not the first one who has used the drug for such off–
label indications. Cycloserine has been studied for phobias and traumas
in particular, often with success.45 Some studies have demonstrated
benefit in using the drug for Alzheimer’s disease.46 In animal tests cyc-
Antimicrobials 95
loserine has shown efficacy in neuropathic pain.47 Usually the doses

used for neurological and psychiatric conditions are smaller than those
prescribed for tuberculosis.
Cycloserine can cause neuropsychological side effects such as
drowsiness, dizziness, depression, anxiety, headache, irritability and
convulsions. Pyridoxine (vitamin B6) may ameliorate these side effects.
Cycloserine affects the metabolism of phenytoin and may also deplete
vitamin B12 and folic acid.
Cycloserine is available in the United States, the United Kingdom,
Australia and a few other countries, but not in Canada. In most markets
only capsules of 250 mg are available, which makes it difficult to use
smaller doses (usually 50 mg).
Antivirals
In the 1980s CFS/ME was thought to be caused by Epstein–Barr

virus, the herpesvirus behind most cases of glandular fever, spawning
names such as chronic mononucleosis and chronic Epstein–Barr virus
syndrome.48 Now we know that at least most cases are not caused by
EBV, but it is widely accepted that CFS/ME is caused by a viral infec-
tion either always or in a subset of cases. Some doctors consider it the
sequela of a past viral infection and others think it is a chronic active
viral infection.
Successful trials with antiviral agents suggest that there must be a
chronic viral infection present in at least a subset of patients. Some
cases may be a combination of both: first one virus injures the immune
system and even though this infection is cleared, the body succumbs to
another virus. This “new” infection does not have to be something
newly caught—herpesviruses and many other viruses stay dormant in
the body and may become reactivated.
Which virus or viruses are guilty is a trickier question which nume-
rous researchers have attempted to answer. Even if EBV or the other
herpesviruses are not the cause of CFS/ME, they have been shown to be
reactivated in a number of cases. Besides EBV and cytomegalovirus
(CMV), human herpesvirus 6 (HHV–6) has been strongly connected
with CFS/ME.49,50 HHV–7 may also be implicated.51 Infectious disease
specialist Martin Lerner believes CFS/ME is caused by a herpesvirus
infection of the heart.52
Enteroviruses, a group of viruses including e.g. polioviruses and
Coxsackie viruses, have been connected with CFS/ME epidemics for
decades. Several research groups have established the connection bet-
ween enterovirus antibodies and CFS/ME.53,54,55,56 Other studies have
found evidence of enteroviral RNA in the muscle.57,58,59 Enteroviruses

have also been connected to fibromyalgia.60,61 Contrary to some report-
ing, enteroviruses are not really “stomach viruses”—they infect the CNS
as well, as is evident from polio.
Other reported viruses include Borna virus (in CFS/ME62), parvovi-
rus B19 (in CFS/ME63 and fibromyalgia64) and retrovirus (in CFS/
ME65,66), though all of these findings have later been disputed. The Nati-
onal CFIDS Association has even reported finding parainfluenza virus 5
(PIV–5) in CFS/ME.67 Fibromyalgia has been associated with just about
every chronic viral infection from HIV to hepatitis C and even
influenza68, but they are usually thought to be triggers instead of causes.
The antiherpesvirals have some problematic downsides. Almost all
of them are prohibitively expensive. Some of them require intravenous
administration. They have potential for toxicity, though usually patients
with CFS/ME tolerate them surprisingly well. In contrast to other anti-
microbials, antiviral drugs usually cannot eradicate the infection comp-
letely. In a subset of cases, however, they seem be capable of suppres-
sing it in the long term, as some studies have achieved lasting results in
the treatment of CFS/ME.
See also:
immunomodulators (CHAPTER 8), amantadine (CHAPTER 9),

probenecid (CHAPTER 10)
aciclovir (Zovirax)
Aciclovir is mostly used against herpes simplex and varicella zoster

viruses, but it has some activity against cytomegalovirus and Epstein–
Barr virus. It was first tried as a CFS/ME treatment in the 1980s. A
fairly small double–blinded study from 1988 did not get any significant
results using aciclovir in patients with CFS/ME with evidence of EBV
infection, even though some participants did report feeling better.69 The
results have been criticized to have been skewed.70
There are apparently no newer studies, but aciclovir is still occasio-
nally used to treat CFS/ME. At least the shingles that often arises as a
complication of CFS/ME warrants aciclovir treatment. In oral use the
medication is usually dosed as many as 3–5 times a day. Headache and
stomach upset are the most common side effects. Drowsiness and neuro-
logical symptoms are possible. Allergic reactions and blood changes
occur rarely.
Antimicrobials 97
Aciclovir is available virtually everywhere. Although expensive, it

is more affordable than other antiherpesvirals.
valaciclovir (Valtrex, Valavir)
Valaciclovir has better oral absorption compared to aciclovir and

does not require as frequent administration. In a six–month trial valacic-
lovir was given to 16 CFS/ME patients who had evidence of a persistent
EBV infection and they got better.71 Nine other patients in the trial had
both EBV and CMV and they failed to improve. Later a double–blinded
study with three–year follow–up showed that valaciclovir was more
effective than placebo for CFS/ME patients with EBV.72
Another small study tried both valaciclovir and ganciclovir on 11
patients who suffered from concomitant EBV and CMV infection. All
the participants improved and none suffered major adverse effects.73 In
general valaciclovir is fairly well tolerated. Valaciclovir has also been
tried in fibromyalgia in a double–blind study, but it did not result in any
benefit.74
Valaciclovir is available in most countries. It is more expensive
than aciclovir, but because of the better absorption and less frequent
administration the real cost is quite similar.
ganciclovir (Cytovene, Cymevene)
Ganciclovir is chemically very similar to aciclovir, but is much

more effective against cytomegalovirus. It has activity against Epstein–
Barr, HHV–6 and HHV–8 as well. In a small study 13 out of 18 CFS/
ME patients significantly improved after 30 days on ganciclovir.75 It has
been successfully given together with aciclovir.76
In oral use ganciclovir is poorly absorbed and calls for intravenous
administration, at least five days a week. Diarrhea and blood changes
are the most common side effects. Others include bone marrow depres-
sion, malaise, skin problems, aches and neurological symptoms.
Ganciclovir is available in the United States, the United Kingdom,
Canada, Australia and some other countries. It is extremely expensive.
valganciclovir (Valcyte, Valixa)
Valganciclovir is converted to ganciclovir in the body, so the

effects and adverse effects are similar to those of ganciclovir, but val-
aciclovir is absorbed better and can be taken orally. A study conducted
in the Stanford university got good results with valganciclovir.77 As
many as 21 out of 25 CFS/ME patients reported major benefit from the

drug. They also published a scientific paper based on a smaller number
of patients.78
It is interesting to note that in these studies the effect lasted even
after the drug was discontinued after several months of therapy. Appa-
rently the treatment was the most helpful for those patients whose ill-
ness had a sudden onset with flu–like symptoms. Stanford university has
the funding for a double–blind study of valaciclovir. Dr. Dale Guyer
also reports getting good results by using the drug on his CFS/ME pati-
ents.79
Valganciclovir is available in the United States, the United King-
dom, Canada and Australia. It is extremely expensive. A single tablet
can cost as much as 100 tablets of aciclovir.
famciclovir (Famvir)
Famciclovir has good oral absorption. It is used primarily in herpes

simplex and varicella zoster infections, but it also has activity against
other herpesviruses, as well as the hepatitis B virus and even the retrovi-
ruses. It may be effective against some herpesvirus strains which are
resistant to other medication.
Famciclovir does not usually cause blood changes or other serious
adverse effects. Nausea and headache are the most common side effects.
There may rarely be drowsiness, rashes, sedation, stomach upset or
fever.
Famciclovir is available in the United States, the United Kingdom,
Canada, Australia and some other countries. It tends to be more expen-
sive than valaciclovir but cheaper than foscarnet and valganciclovir.
foscarnet (Foscavir)
Foscarnet is mainly used to treat cytomegalovirus infections, some-

times herpes simplex and HHV–6. It can be effective against virus
strains that are resistant to aciclovir and ganciclovir. It is sometimes
used in combination with other antiherpesvirals. Famciclovir is also the
most effective drug against HHV–6A, which is the subtype often found
in CFS/ME. It can only be administered intravenously.
Dan Peterson, a prominent CFS/ME expert, has reported that some
of his patients with evidence of viral infection in their cerebrospinal
fluid were improved on foscarnet, even though trials with valaciclovir
and ganciclovir were of no help.80 Four out of the 29 subjects were even
able to return to work.
Antimicrobials 99
Foscarnet is available in the United States, the United Kingdom,

Australia and many other countries, but not in Canada. It is one of the
most expensive antiherpesvirals, but does not reach to the magnitude of
valganciclovir.
cidofovir (Vistide)
Cidofovir is indicated in the treatment of cytomegalovirus infec-

tion, but it is also effective against HHV–6 and some non–herpesviru-
ses. There are reports from CFS/ME doctors who have found it useful
for some patients with HHV–6A.81 Cidofovir cannot be administered
orally, but in maintenance therapy it is often given only twice a month.
The most serious risk with cidofovir is the possibility of severe,
irreversible kidney damage. To protect the kidneys patients must be pro-
perly hydrated. Other possible side effects include e.g. nausea, fever,
weakness, headache, dyspnea and hair loss. Because of the risk of kid-
ney damage cidofovir should never be combined with other drugs that
are toxic to the kidneys, including the NSAIDs.
Cidofovir is available in the United States, the United Kingdom
and Australia, but not in Canada. In general it does not enjoy availability
as good as that of the older antiherpesvirals. Even in countries where it
is licensed it may only be available to patients with CMV retinitis. It is
highly expensive.
ribavirin (Copegus, Rebetol)
Ribavirin is effective against a myriad of different viruses from

herpesviruses to influenza viruses, though it is mostly used against
hepatitis C. It also works against enteroviruses and the paramyxoviruses
(which includes PIV–5). The research team of John and Andrew Chia
found improvement in symptoms in CFS/ME patients with enteroviral
infection treated with the combination of ribavirin and interferon alfa.82
At least in mice ribavirin also possesses analgesic action.83
The most serious side effect is hemolytic anemia. Muscle aches,
bradycardia (slow heartbeat), stomach upset, tiredness, gout, rashes and
hair loss can occur. Some of these side effects are possibly caused by
magnesium depletion, so magnesium supplements may help. Ribavirin
can be teratogenic to both females and the female partners of male pati-
ents for up to six months after therapy has been discontinued.
Ribavirin is available in most countries. It is even sold over the
counter as an influenza treatment in Mexico. In some markets it is only
sold in combination with interferon alfa with the name Rebetron. Riba-
virin is expensive, but not nearly as expensive as some of the antiher-

pesvirals.
Antifungals
Candida (a species of yeast, but usually specifically Candida albi-

cans) is a controversial subject in medicine. It is a normal part of the
human flora and it is a well–known fact that it can sometimes colonize
the bodies of immunosuppressed patients and cause even life–threaten-
ing fungal infections. The concept of candida colonization in otherwise
healthy people is still disputed.
Chronic intestinal candidiasis was proposed as a cause of CFS/ME
in an article published in the Medical Hypotheses journal.84 Arnold
Mervyn Levin has also published a similar theory.85 In the early 1990s
Dr. Carol Jessop reported that over 80% of the CFS/ME patients she
tested were positive for candida.86 Some recent studies have found evi-
dence of candidiasis in CFS/ME either immunologically or in stool
samples.87,88
To the author it seems improbable that candida would cause CFS/
ME as some holistic doctors also claim, but because of the immune dys-
function caused by the illness candida may be an opportunistic infec-
tion—a result, not the cause. The use of steroids (including oral contra-
ceptives) and antibiotics can increase the risk of candida infection. An
association between candida and autoimmune disease has been
speculated.89
Candidiasis is purported to cause many different kinds of symp-
toms, such as fatigue, muscle weakness, stomach problems, headaches,
sore throat, cognitive problems, dizziness, poor coordination, chemical
sensitivity, low libido, PMS, urinary frequency, skin problems, irritabi-
lity and anxiety. It has even been connected to depression90 and mitral
valve prolapse91, though especially the latter is highly controversial.
Most of these symptoms are similar to those of CFS/ME, which in
some cases may make it hard to figure out whether the patient has can-
didiasis, CFS/ME or both with candidiasis as an opportunistic infection.
Many CFS/ME specialists prescribe antifungal drugs, because they
believe that candida may indeed be a factor in causing the symptoms.
Especially Dr. Majid Ali has reportedly got good results with antifun-
gals in CFS/ME, but his findings have never been properly published.
In a large survey conducted on patients with multiple chemical sen-
sitivity, nystatin and fluconazole were rated the second and third most
effective prescription treatments, respectively.92 For some reason keto-
Antimicrobials 101
conazole only scored as marginally more beneficial than harmful, even

though hundreds of patients rated all of the three medications.
Like bacteria, fungi can also develop a resistance to antimicrobial
therapies. This is why some doctors recommend using several antifungal
drugs at once. Often holistic practitioners also recommend a specific
“candida diet,” which is low on carbohydrates and especially sugar,
because they believe that sugar feeds candida (whether in the intestine
or in the blood).
nystatin (Mycostatin)
Nystatin is an antifungal which is only used topically for fungal

infections of the gastrointestinal tract (including the mouth), as it is not
absorbed into the body. It is a popular medication in the treatment of
CFS/ME and a large number of patients report having been helped by
it.93 Andrew J. Wright prescribes his patients 1–2 tablets four times a
day to be used for 2–6 weeks.94
In a double–blinded study nystatin was found helpful for “poly-
symptomatic patients” (people with many different symptoms in diffe-
rent organ systems).95 The most striking effect was found for mental,
abdominal and urogenital symptoms. Those who also followed a sugar
and yeast free diet in addition to nystatin got the most benefit.
Nystatin is low on side effects because of the lack of systemic
absorption, but in rare cases it can cause stomach upset and allergic
reactions. According to Dr. Jacob Teitelbaum the yeast die–off may pro-
voke unpleasant symptoms, which is why he prescribes pioglitazone as
needed.96 There are no known drug interactions or contraindications
(except for allergy to the product).
Nystatin is available in virtually all countries, though the availabi-
lity of different forms (e.g. suspension, pastilles, tablets, ointments)
varies widely. Usually pure powder form is recommended.
ketoconazole (Nizoral, Fungoral, Oronazol, Ketazol)

fluconazole (Diflucan, Fungata, Mycosyst, Flucomicon,
Baten)
itroconazole (Sporanox, Orungal, Isox)
These antifungal drugs belong to a group called azoles (other drugs

whose names end –azole such as omeprazole or aripiprazole are not
azoles). Unlike nystatin, they can be used for fungal infections situated
anywhere in the body. Itroconazole and fluconazole have a broader
spectrum of action than ketoconazole, which is mostly used against
candida. Fluconazole is the most commonly used of these three, especi-

ally in CFS/ME.97 A commonly prescribed regime is 100–200 mg a day
for 3–6 weeks.
Relief in symptoms can apparently be experienced in a matter of a
few days. Jacob Teitelbaum treats patients with interstitial cystitis for
candida with a three–month course of fluconazole 98 He also uses it for
chronic sinusitis. Devin Starlanyl sometimes tries it for fibromyalgia
patients whose cognitive problems, depression, IBS or sleep disturban-
ces she suspects to be caused by yeast.99
Stomach upset and pruritus (itching) are the most common side
effects of the azoles. Some patients have reported worsening of fatigue
from fluconazole, which may persist for a while after the medication has
been discontinued. Ketoconazole reduces the production of testosterone
and glucocorticoids. Fluconazole may prolong the QT interval. All of
the azoles can cause hepatotoxicity, so liver monitoring may be war-
ranted.
Azoles can interact with many other drugs, such as macrolides, car-
bamazepine, buspirone, reboxetine, calcium channel blockers and many
benzodiazepines. Drugs that reduce stomach acidity (such as H2
blockers and proton pump inhibitors) may reduce the absorption of keto-
conazole and itroconazole. Ketoconazole and magnesium should be
taken at different times of the day.
Itroconazole is available in the United States, the United Kingdom,
Canada, Australia and many other countries. Fluconazole and ketocona-
zole are sold virtually everywhere. The azoles are available as capsu-
les/tablets and oral solution. Ketoconazole is also sold in many topical
formulations such as shampoo. All of these drugs are fairly expensive
especially in long term use, but ketoconazole is quite a bit cheaper than
the others.
Antimicrobials 103
References
1 Nicolson GL, Gan R, Haier J. Multiple co–infections (Mycoplasma,

Chlamydia, human herpes virus–6) in blood of chronic fatigue
syndrome patients: association with signs and symptoms. APMIS. 2003
May;111(5):557–66.
2 Nijs J, Nicolson GL, De Becker P, et al. High prevalence of Myco-
plasma infections among European chronic fatigue syndrome patients.
Examination of four Mycoplasma species in blood of chronic fatigue
syndrome patients. FEMS Immunol Med Microbiol. 2002 Nov 15;34(3):
209–14.
3 Vojdani A, Choppa PC, Tagle C, et al. Detection of Mycoplasma
genus and Mycoplasma fermentans by PCR in patients with Chronic
Fatigue Syndrome. FEMS Immunol Med Microbiol. 1998 Dec;22(4):
355–65.
4 Chia JK, Chia LY. Chronic Chlamydia pneumoniae infection: a treat-
able cause of chronic fatigue syndrome. Clin Infect Dis. 1999 Aug;29
(2):452–3.
5 Ayres JG, Flint N, Smith EG, et al. Post–infection fatigue syndrome
following Q fever. QJM. 1998 Feb;91(2):105–23.
6 Pamphlett R, O'Donoghue P. Antibodies against Sarcocystis and
Toxoplasma in humans with the chronic fatigue syndrome. N Z J Med.
1992 Jun;22(3):307–8.
7 Tarello W. Chronic fatigue syndrome (CFS) associated with Staphylo-
coccus spp. bacteremia, responsive to potassium arsenite 0.5% in a vete-
rinary surgeon and his coworking wife, handling with CFS animal cases.
Comp Immunol Microbiol Infect Dis. 2001 Oct;24(4):233–46.
8 Jadin CL. Common Clinical and Biological Windows on CFS and
Rickettsial Diseases. J Chron Fatigue Syn. 2000;6(3/4):133–45.
9 Nasralla M, Haier J, Nicolson GL. Multiple Mycoplasmal Infections
Detected in Blood of Chronic Fatigue Syndrome and Fibromyalgia
Syndrome Patients. Eur J Clin Microbiol Infect Dis. 1999;18:859–65.
10 Machtey I. Chlamydia pneumoniae antibodies in myalgia of un-
known cause (including fibromyalgia). Br J Rheumatol. 1997 Oct;36
(10):1134.
11 Jones DM. Co–Trimoxazole/Trimethoprim ME Cases. Presented at:
First world congress on chronic fatigue syndrome and related disorders.
Brussels, Belgium. Nov 9–11, 1995.
12 Lassesen K. Alternative Explanation of one aspect of MarshallProto-
col.com Treatment for CFIDS/FM/RA. Co–Cure discussion list, Jan 25
2005. Available at: http://listserv.nodak.edu/cgi-bin/wa.exe?A2=ind

0501D&L=CO–CURE&P=R1568
13 Dr. Paul Cheney: CFS & Cardiac Issues, Part 2a. http://www.
dfwcfids.org/medical/cheney/Cheney.CFS-Cardiac.Part2a.pdf
14 Are there antibiotics that CFS patients should avoid? By David S.
Bell, MD, FAAP. http://www.pediatricnetwork.org/medical/q+a/bell/
antibiotics.htm
15 Sapadin AN, Fleischmajer R. Tetracyclines: nonantibiotic properties
and their clinical implications. J Am Acad Dermatol. 2006 Feb;54(2):
258–65.
16 Iwakami E, Arashima Y, Kato K, et al. Treatment of chronic fatigue
syndrome with antibiotics: pilot study assessing the involvement of
Coxiella burnetii infection. Intern Med. 2005 Dec;44(12):1258–63.
17 Donta ST, Engel CC Jr, Collins JF, et al. Benefits and harms of
doxycycline treatment for Gulf War veterans' illnesses: a randomized,
double–blind, placebo–controlled trial. Ann Intern Med. 2004 Jul
20;141(2):85–94.
Fatigue Syndrome. Hunter House 1995. pp. 198.
19 Is the MP Treatment for Sarcoidosis also Helpful for other Chronic
Diseases? Exploring the claims and theories of the MP. http://stuff.mit.
edu/people/london/universe.htm
20 Arashima Y, Kato K, Komiya T. Improvement of chronic
nonspecific symptoms by long–term minocycline treatment in Japanese
patients with Coxiella burnetii infection considered to have post–Q
fever fatigue syndrome. Intern Med. 2004 Jan;43(1):49–54.
21 Zanjani TM, Sabetkasaei M, Mosaffa N, et al. Suppression of inter-
leukin–6 by minocycline in a rat model of neuropathic pain. Eur J Phar-
macol. 2006 May 24;538(1–3):66–72.
22 Zabad RK, Metz LM, Todoruk TR, et al. The clinical response to
minocycline in multiple sclerosis is accompanied by beneficial immune
changes: a pilot study. Mult Scler. 2007 May;13(4):517–26.
23 Choi Y, Kim HS, Shin KY, et al. Minocycline attenuates neuronal
cell death and improves cognitive impairment in Alzheimer's disease
models. Neuropsychopharmacology. 2007 Nov;32(11):2393–404.
24 Langevitz P, Livneh A, Bank I, et al. Benefits and risks of minocyc-
line in rheumatoid arthritis. Drug Saf. 2000 May;22(5):405–14.
25 Miyaoka T, Yasukawa R, Yasuda H, et al. Possible antipsychotic ef-
fects of minocycline in patients with schizophrenia. Prog Neuropsycho-
pharmacol Biol Psychiatry. 2007 Jan 30;31(1):304–7.
Antimicrobials 105
26 Mika J, Osikowicz M, Makuch W, et al. Minocycline and pentoxifyl-

line attenuate allodynia and hyperalgesia and potentiate the effects of
morphine in rat and mouse models of neuropathic pain. Eur J Pharma-
col. 2007 Apr 10;560(2–3):142–9.
27 Gough A, Chapman S, Wagstaff K, et al. Minocycline induced auto-
immune hepatitis and systemic lupus erythematosus–like syndrome.
BMJ. 1996 Jan 20;312(7024):169–72.
28 Ianaro A, Ialenti A, Maffia P, et al. Anti–inflammatory activity of
macrolide antibiotics. J Pharmacol Exp Ther. 2000 Jan;292(1):156–63.
29 David Wheldon MB CHB, FRCPath (Fellow of the Royal College of
Pathology) Cpn Protocol. http://www.cpnhelp.org/wheldon
30 Vermeulen RC, Scholte HR. Azithromycin in Chronic Fatigue Synd-
rome (CFS), an analysis of clinical data. V J Transl Med. 2006 Aug 15;4
(1):34.
31 Brorson O, Brorson SH. An in vitro study of the susceptibility of mo-
bile and cystic forms of Borrelia burgdorferi to metronidazole. APMIS.
1999 Jun;107(6):566–76.
32 Intestinal parasites, bacterial dysbiosis and leaky gut by Leo Galland,
M.D. http://www.mdheal.org/parasites.htm
33 Grazioli B, Matera G, Laratta C, et al. Giardia lamblia infection in
patients with irritable bowel syndrome and dyspepsia: a prospective stu-
dy. World J Gastroenterol. 2006 Mar 28;12(12):1941–4.
34 David Wheldon MB CHB, FRCPath (Fellow of the Royal College of
Pathology) Cpn Protocol. http://www.cpnhelp.org/wheldon
35 Morinaka S, Ichimiya M, Nakamura H. Detection of Helicobacter
pylori in nasal and maxillary sinus specimens from patients with chronic
sinusitis. Laryngoscope. 2003 Sep;113(9):1557–63.
36 Fumi AL, Trexler K. Rifaximin Treatment for Symptoms of Irritable
Bowel Syndrome. Ann Pharmacother. 2008;42(3):408–12.
37 Pimentel M, Chow EJ, Hallegua D, et al. Small intestinal bacterial
overgrowth: a possible association with fibromyalgia. J Musculoskelet
Pain. 2001;9(3):107–13.
38 Method of diagnosing fibromyalgia caused by small intestinal bacte-
rial overgrowth. United States Patent 7056686. http://www.freepatents
online.com/7056686.html
39 Weinstock LB, Fern SE, Duntley SP. Restless Legs Syndrome in
Patients with Irritable Bowel Syndrome: Response to Small Intestinal
Bacterial Overgrowth Therapy. Dig Dis Sci. In press.
40 Weinstock LB, Klutke CG, Lin HC. Small Intestinal Bacterial Over-
growth in Patients with Interstitial Cystitis and Gastrointestinal Symp-
toms. Dig Dis Sci. In press.
41 Ocaña M, Baeyens JM. Analgesic effects of centrally administered

aminoglycoside antibiotics in mice. Neurosci Lett. 1991 May 13;126(1):
67–70.
42 Blenk KH, Häbler HJ, Jänig W. Neomycin and gadolinium applied to
an L5 spinal nerve lesion prevent mechanical allodynia–like behaviour
in rats. Pain. 1997 Apr;70(2–3):155–65.
43 Prado WA, Machado Filho EB. Antinociceptive potency of amino-
glycoside antibiotics and magnesium chloride: a comparative study on
models of phasic and incisional pain in rats. Braz J Med Biol Res. 2002
Mar;35(3):395–403.
45 Ressler KJ, Rothbaum BO, Tannenbaum L, et al. Cognitive enhan-
cers as adjuncts to psychotherapy: use of D–cycloserine in phobic
individuals to facilitate extinction of fear. Arch Gen Psychiatry. 2004
Nov;61(11):1136–44.
46 Tsai GE, Falk WE, Gunther J, et al. Improved cognition in Alzhei-
mer's disease with short–term D–cycloserine treatment. Am J
Psychiatry. 1999 Mar;156(3):467–9.
47 Millecamps M, Centeno MV, Berra HH, et al. D–cycloserine reduces
neuropathic pain behavior through limbic NMDA–mediated circuitry.
Pain. 2007 Nov;132(1–2):108–23.
48 Holmes GP, Kaplan JE, Stewart JA, et al. A cluster of patients with a
chronic mononucleosis–like syndrome. Is Epstein–Barr virus the cause?
JAMA. 1987 May 1;257(17):2297–302.
49 Ablashi DV, Salahuddin SZ, Josephs SF, et al. Human herpesvirus–6
(HHV–6) (short review). In Vivo. 1991 May–Jun;5(3):193–9.
50 Komaroff AL. Is human herpesvirus–6 a trigger for chronic fatigue
syndrome? J Clin Virol. 2006 Dec;37 Suppl 1:S39–46.
51 Chapenko S, Krumina A, Kozireva S, et al. Activation of human her-
pesviruses 6 and 7 in patients with chronic fatigue syndrome. J Clin
Virol. 2006 Dec;37 Suppl 1:S47–51.
52 Lerner AM, Zervos M, Dworkin HJ, et al. A unified theory of the
cause of chronic fatigue syndrome. Infect Dis Clin Pract. 1997;6:230–
43.
53 Bell EJ, McCartney RA, Riding MH. Coxsackie B viruses and myal-
gic encephalomyelitis. J R Soc Med. 1988 Jun;81(6):329–31.
54 Dowsett EG, Ramsay AM, McCartney RA, et al. Myalgic encephalo-
myelitis—a persistent enteroviral infection? Postgrad Med J. 1990
Jul;66(777):526–30.
Antimicrobials 107
55 Yousef GE, Bell EJ, Mann GF, et al. Chronic enterovirus infection in
patients with postviral fatigue syndrome. Lancet. 1988 Jan 23;1(8578):
146–50.
56 Chia JK, Chia AY. Chronic fatigue syndrome is associated with
chronic enterovirus infection of the stomach. J Clin Pathol. 2008 Jan;61
(1):43–8.
57 Archard LC, Bowles NE, Behan PO, et al. Postviral fatigue syndro-
me: persistence of enterovirus RNA in muscle and elevated creatine ki-
nase. J R Soc Med. 1988 Jun;81(6):326–9.
58 Gow JW, Behan WM, Clements GB, et al. Enteroviral RNA sequen-
ces detected by polymerase chain reaction in muscle of patients with
postviral fatigue syndrome. BMJ. 1991 Mar 23;302(6778):692–6.
59 Cunningham L, Bowles NE, Lane RJ, et al. Persistence of enteroviral
RNA in chronic fatigue syndrome is associated with the abnormal pro-
duction of equal amounts of positive and negative strands of enteroviral
RNA. J Gen Virol. 1990 Jun;71(6):1399–402.
60 Wittrup IH, Jensen B, Bliddal H, et al. Comparison of viral antibo-
dies in 2 groups of patients with fibromyalgia. J Rheumatol. 2001 Mar;
28(3):601–3.
61 Nash P, Chard M, Hazleman B. Chronic coxsackie B infection
mimicking primary fibromyalgia. J Rheumatol. 1989 Nov;16(11):1506–
8.
62 Nakaya T, Takahashi H, Nakamur Y, et al. Borna disease virus infec-
tion in two family clusters of patients with chronic fatigue syndrome.
Microbiol Immunol. 1999;43(7):679–89.
63 Kerr JR, Bracewell J, Laing I, et al. Chronic fatigue syndrome and
arthralgia following parvovirus B19 infection. J Rheumatol. 2002 Mar;
29(3):595–602.
64 Leventhal LJ, Naides SJ, Freundlich B. Fibromyalgia and parvovirus
infection. Arthritis Rheum. 1991 Oct;34(10):1319–24.
65 Holmes MJ, Diack DS, Easingwood RA, et al. Electron microscopic
immunocytological profiles in chronic fatigue syndrome. J Psychiatr
Res. 1997 Jan–Feb;31(1):115–22.
66 Holmes MJ. A Retroviral Aetiology for CFS? In the book: Hyde B,
(ed.) The Clinical and Scientific Basis of Myalgic Encephalomyeli-
tis/Chronic Fatigue Syndrome. The Nightingale Research Foundation
1992. pp. 319–323.
67 Press Releases from The National CFIDS Foundation: Potential Ani-
mal (Zoonotic) Virus Identified in Patients with Chronic Fatigue Synd-
rome, Multiple Sclerosis and Epilepsy. http://www.ncf-net.org/Press
Releases.htm
68 Tyler AN. Influenza A Virus: A Possible Precipitating Factor in Fib-

romyalgia? Alt Med Rev. 1997;2(2):82–6.
69 Straus SE, Dale JK, Tobi M, et al. Acyclovir treatment of the chronic
fatigue syndrome. Lack of efficacy in a placebo–controlled trial. N Engl
J Med. 1988 Dec 29;319(26):1692–8.
Treatment Guide. St. Martin's Griffin 1997. pp. 167–168.
71 Lerner AM, Beqaj SH, Deeter RG, et al. A six–month trial of val-
acyclovir in the Epstein–Barr virus subset of chronic fatigue syndrome:
improvement in left ventricular function. Drugs Today (Barc). 2002
Aug;38(8):549–61.
72 Lerner AM, Beqaj SH, Deeter RG, et al. Valacyclovir treatment in
Epstein–Barr virus subset chronic fatigue syndrome: thirty–six months
follow–up. In Vivo. 2007 Sep–Oct;21(5):707–13.
73 Lerner AM, Zervos M, Chang CH, et al. A small, randomized, place-
bo–controlled trial of the use of antiviral therapy for patients with chro-
nic fatigue syndrome. Clin Infect Dis. 2001;32(11):1657–8.
74 Kendall SA, Schaadt ML, Graff LB, et al. No effect of antiviral (val-
acyclovir) treatment in fibromyalgia: a double blind, randomized study.
J Rheumatol. 2004 Apr;31(4):783–4.
75 Lerner AM, Zervos M, Dworkin HJ, et al. New cardiomyopathy: A
pilot study of intravenous ganciclovir in a subset of the chronic fatigue
syndrome. Infect Dis Clin Pract. 1997;6:110–117.
76 Lerner AM, Zervos M, Chang CH, et al. A small, randomized, place-
bo–controlled trial of the use of antiviral therapy for patients with chro-
nic fatigue syndrome. Clin Infect Dis. 2001;32(11):1657–8.
77 1/8/07 News Release. New therapy for chronic fatigue syndrome to
be tested at Stanford. http://mednews.stanford.edu/releases/2007/
january/montoya.html
78 Kogelnik AM, Loomis K, Hoegh–Petersen M, et al. Use of
valganciclovir in patients with elevated antibody titers against Human
Herpesvirus–6 (HHV–6) and Epstein–Barr Virus (EBV) who were
experiencing central nervous system dysfunction including long–
standing fatigue. J Clin Virol. 2006 Dec;37 Suppl 1:S33–8.
79 Dale Guyer, MD, Discusses the Integrative and Molecular Treatment
of Chronic Fatigue Syndrome and Fibromyalgia. http://www.immune
support.com/library/showarticle.cfm/ID/3725/
80 Peterson DL. Role of the Brain in the Pathogenesis of Medically
Unexplained Symptoms. Presented at: American Association for Chro-
nic Fatigue Syndrome (AACFS) 6th International Conference on Chro-
Antimicrobials 109
nic Fatigue Syndrome, Fibromyalgia and Related Illnesses. Chantilly,

VA, U.S. Jan 31–Feb 2, 2003.
81 The Pathogens in Chronic Fatigue Syndrome (ME/CFS) I: The Her-
pesviruses – Human Herpes Virus 6 (HHV–6) By Cort Johnson http://
phoenix-cfs.org/HHV-6.htm
82 Chia JK, Chia AY. Ribavirin and interferon–alpha for the treatment
of patients with chronic fatigue syndrome associated with chronic cox-
sackievirus B infection: a preliminary observation. J Appl Research
2004;4(2):286–92.
83 Abdel–Salam OM. Antinociceptive and behavioral effects of ribavi-
rin in mice. Pharmacol Biochem Behav. 2006 Feb;83(2):230–8.
84 Cater RE 2nd. Chronic intestinal candidiasis as a possible etiological
factor in the chronic fatigue syndrome. Med Hypotheses. 1995 Jun;44
(6):507–15.
85 Levin AM. Chronic Fatigue Syndrome: The Yeast Concept. J Chron
Fatigue Syn. 2001;8(2):71–6.
86 Jessop C. Clinical features and possible etiology of CFIDS. CFIDS
Chronicle. 1991 Spring;70–3.
87 Cozon GJ. In vivo and in vitro abnormal cellular reactivity to Candi-
da albicans in patients with CFS. Abstract presented at: American Asso-
ciation for Chronic Fatigue Syndrome (AACFS) 6th International Con-
ference on Chronic Fatigue Syndrome, Fibromyalgia and Related Illnes-
ses. Chantilly, VA, U.S. Jan 31–Feb 2, 2003.
88 Evengard B. Comparison of the composition of the intestinal micro-
flora of CFS patients when in the acute phase of illness. Poster presen-
ted at: International Association for Chronic Fatigue Syndrome (IACFS)
8th International Conference on Chronic Fatigue Syndrome, Fibromyal-
gia and Related Illnesses. Fort Lauderdale, FL, U.S. Jan 12–Jan 14,
2007.
89 Vojdani A, Rahimian P, Kalhor H, et al. Immunological cross reacti-
vity between Candida albicans and human tissue. J Clin Lab Immunol.
1996;48(1):1-15.
90 Crook WG. Depression associated with Candida albicans infections.
JAMA. 1984 Jun 8;251(22):2928–9.
91 Crook WG. Mitral valve prolapse and candidiasis. Nurse Pract. 1985
Nov;10(11):67–8.
92 Gibson PR, Elms AN, Ruding LA. Perceived treatment efficacy for
conventional and alternative therapies reported by persons with multiple
chemical sensitivity. Environ Health Perspect. 2003 Sep;111(12):1498–
504.

95 Santelmann H, Laerum E, Roennevig J, et al. Effectiveness of nysta-
tin in polysymptomatic patients. A randomized, double–blind trial with
nystatin versus placebo in general practice. Fam Pract. 2001 Jun;18(3):
258–65.
99 Devin Starlanyl On Medications For Fibromyalgia. http://www.
CHAPTER 5.
Psychiatric drugs
Antidepressants are among the medications most frequently used to

treat both CFS/ME and fibromyalgia and also the ones most frowned
upon by the patients—often for a reason. It is commonly assumed that
antidepressants are used to treat these conditions because they are
believed to be psychosomatic or psychiatric in origin. This may be true
in many cases, but these medications do have valid uses.
Serotonin is much more than just a neurotransmitter that regulates
mood. It could be called one of the “master commanders” of the body,
as it plays a role in a wide variety of biological functions. Dopamine and
norepinephrine (noradrenaline) are important for vigilance and alertness.
Antidepressants can be used as immunomodulators, to ameliorate fati-
gue, to improve sleep and to alleviate chronic pain. Especially the newer
antidepressants can also relieve cognitive problems.
Antidepressants have many pharmacological properties that are not
widely known. One study found that antidepressants of three different
classes downregulated the nitric oxide pathway by inhibiting the NMDA
receptor.1 Some opioidergic action has also been demonstrated.2 These
effects may explain some of the antidepressant and analgesic properties
of the drugs.
There are several practical benefits to antidepressants and some
other psychiatric drugs. Excluding some of the newest ones, most of
them are very inexpensive. The majority of doctors are familiar with
psychiatric drugs and almost any physician agrees to prescribe them—
something that cannot be said about all CFS/ME and FM treatments.
They are not the most effective therapy and probably not the first–line
choice in most cases, but sometimes they prove invaluable.
Of course, many people with CFS/ME and FM do suffer from dep-
ression or anxiety. Sometimes antidepressants can help these symptoms,
even if the more physical ones are untouched. Nonetheless the depres-
sion in most cases is secondary to the burden of the illness and thus it is
more useful to treat the person as a whole. Pain and disordered sleep can
be the root causes for depression and anxiety. Treating them effectively
may provide full relief from psychiatric comorbidities.
One must be careful when prescribing psychiatric medications, as
they frequently cause problems for people with these illnesses, especi-
ally CFS/ME. Some patients get severe adverse reactions from every
single kind of antidepressant. If a few different medications have provo-

ked serious side effects, it often means that the rest would also do more
harm than good. Usage should always begin with tiny doses, often doses
that would be completely ineffective for the majority of healthy people.
Most psychiatric medications also have the potential to cause signi-
ficant drug–to–drug interactions, particularly some of the tricyclic anti-
depressants and SSRIs. Generally the serotonergic drugs (drugs that
affect serotonin levels, which includes almost all antidepressants)
should not be combined with sibutramine, dextromethorphan, tramadol,
many migraine drugs and St. John’s wort without physician’s approval.
This chapter also details the use of some other psychotropic medi-
cations, such as neuroleptics and lithium. These drugs carry even more
of a stigma than antidepressants, but they may have similar beneficial
effects and should not be ignored because of prejudice.
See also:
benzodiazepines, orphenadrine (CHAPTER 1), anticonvulsants

(CHAPTER 3), cycloserine (CHAPTER 4), piracetam/aniracetam
(CHAPTER 6), ketamine, cannabinoids (CHAPTER 9), scopola-
mine, aprepitant, losartan, ACE inhibitors, naphazoline
(CHAPTER 10)
Tricyclic antidepressants (TCAs)
Tricyclic antidepressants (TCAs) are very nonselective compared

to newer antidepressants and affect a wide range of different receptors.
Unlike newer antidepressants they also act as sodium channel blockers.
Because of this lack of selectivity the tricyclics often cause bothersome
side effects even in small doses, but on the other hand they may provide
relief from many different kinds of symptoms with just one pill. They
are also extremely inexpensive.
Because of their sleep–improving and analgesic qualities the TCAs
are one of the most commonly used drug classes used in the treatment
CFS/ME and especially fibromyalgia. The doses tend to be significantly
lower than would be used for depression. Even then the dosage may
vary greatly from person to person, as even the same dose can result in
different blood levels because of individual differences.
The TCAs can help with the prevention of migraine and chronic
tension headache. They are often helpful for IBS, especially the pain
associated with it.3,4 The anticholinergic effect may be useful in patients
Psychiatric drugs 113
with nocturia or interstitial cystitis.5 Several of the drugs have antihista-

mine–like properties which can reduce allergic symptoms and possibly
even inhibit the secretion of certain inflammatory cytokines in
CFS/ME.6 Many of them also block the H2 histamine receptor, an effect
that reduces the secretion of stomach acid.
Tachycardia, cardiac arrhythmias, orthostatic hypotension, dry
mouth, daytime sedation and weight gain are common side effects of the
tricyclics. They lower the seizure threshold and may cause photosensiti-
vity. According to one review article up to 40% of patients with
CFS/ME cannot tolerate tricyclics at all7, which is hardly surprising con-
sidering how poorly this population tolerates drugs in general. Even
when the tricyclics do work, they often lose their efficacy over time.
All tricyclic antidepressants may have metabolic interactions with
e.g. diphenhydramine, bupropion, celecoxib, cimetidine, ropinirole,
dexamethasone, risperidone, many opiates and grapefruit juice. There
may also be other kinds of interactions with methylphenidate, clonidine,
hypoglycemic agents (including insulin), levodopa, lithium, carbamaze-
pine, fluoroquinolone antibiotics, ephedrine and valproate. Tricyclic
antidepressants may deplete the body of coenzyme Q10 and vitamin B2
amitriptyline (Elavil, Endep, Tryptanol, Tryptizol,

Saroten)
Amitriptyline is one of the most popular treatments for CFS/ME

and especially fibromyalgia. It is highly sedative and has strong anticho-
linergic action. Amitriptyline is particularly effective in the treatment of
pain and sleep disorders. Additionally it can help stomach upset, diffe-
rent kinds of headaches and interstitial cystitis.8 According to doctor
Derek Enlander amitriptyline can give CFS/ME and fibromyalgia pati-
ents more energy.9
There have been no trials of amitriptyline for CFS/ME, but several
have been done on fibromyalgia, the earliest one dating back to 1981.
Most studies have found significant10 or at least moderate11 benefit. In
one study amitriptyline demonstrated better efficacy than moclobe-
mide.12 Another one found it slightly better than the similar cyclobenza-
prine.13
Compared to other tricyclics amitriptyline is more prone to causing
muscle weakness, orthostatic hypotension and weight gain. If it leads to
excessive morning sedation, it is best taken earlier in the evening. The
dose used to treat CFS/ME and fibromyalgia varies between 5 and 75
milligrams, much less than the dose that would work as an antidepres-
sant. Amitriptyline has also been tried topically for pain relief, but it was
not better than placebo.14

Amitriptyline is widely available in many different formulations,
including suspension and products combining the drug with e.g. a ben-
zodiazepine. It is very inexpensive.
See also:
cyclobenzaprine (CHAPTER 1)
nortriptyline (Pamelor, Allegron, Noritren, Nortrilen,

Aventyl)
Nortriptyline is a metabolite of amitriptyline. Compared to amitrip-

tyline it has more effect on norepinephrine than serotonin. Because of its
overall higher selectivity it is better tolerated. CFS/ME expert Dr. David
Bell considers nortriptyline to have a stronger analgesic effect than ami-
triptyline.15 There is one published case study about the use of nortripty-
line in the treatment of CFS/ME.16 A study on fibromyalgia, however,
did not find the drug more helpful than placebo.17
Nortriptyline is less prone to causing orthostatic hypotension or
weight gain than other TCAs. Although not as sedative as amitriptyline
it can still be used as a sleep aid, but some patients find it energizing and
have to take it in the morning. It appears to be less likely to cause car-
diac problems compared to most other TCAs, but the noradrenergic
action can cause urinary hesitancy.
Nortriptyline is available in the United States, the United Kingdom,
Canada, Australia and many other countries. The generic formulations
are very inexpensive.
protriptyline (Vivactil, Triptil, Concordin)
Protriptyline is almost entirely noradrenergic in action and has a

very long half–life. It is often considered the most energizing of the tri-
cyclic antidepressants. Its antidepressant effect tends to have a rapid on-
set, even shorter than a week. Because of its stimulating nature protrip-
tyline has sometimes been used treat ADHD, narcolepsy and hypersom-
nia.
Protriptyline is only available in the United States. It is inexpen-
sive.
clomipramine (Anafranil, Clomipramine, Clofranil,

Placil, Hydiphen)
Out of the TCAs clomipramine has the most pronounced effect on

serotonin reuptake. As a result it is sometimes even grouped as a SSRI,
even though it also has noradrenergic action. Like other drugs in the
class it has a wide range of action on other receptors. It is less sedative
than most other tricyclics. Clomipramine has been used to treat many
conditions, such as narcolepsy, OCD and a variety of pain syndromes.
Even though clomipramine is fairly well tolerated, cardiac adverse
effects may be more common than with most other tricyclic antidepres-
sants and the risk of seizures may be increased more. The strong seroto-
nergic properties of the drug often cause sexual dysfunction. Azole anti-
fungals, phenytoin and omeprazole may interact with the metabolism of
clomipramine.
Clomipramine is widely available. Unlike most TCAs it is also
available as a modified release tablets. It is very inexpensive.
imipramine (Tofranil, Melipramin, Iramil, Imiprex)
Imipramine inhibits the reuptake of both serotonin and norepine-

phrine to a similar extent. It also has activity on the D1 and D2 dopamine
receptors. Imipramine is a highly effective antidepressant and thus fre-
quently used for depression refractory to other treatments. It is also a
common treatment for enuresis (bed wetting) and other presentations of
overactive bladder. This effect may be at least partially mediated by
increased secretion of antidiuretic hormone.18
Imipramine was tried for fibromyalgia in a small study in 1985
with disappointing results.19 Out of 20 participants 19 quit the trial pre-
maturely, most of them because of lack of efficacy. Only two improved
and one of them still dropped out because of adverse effects. Still, pain
specialist Jacob Teitelbaum believes imipramine may be more effective
than amitriptyline for pain.20 In general imipramine is among the most
poorly tolerated tricyclics, which is why its metabolite desipramine is
often preferred.
Imipramine is available in most markets, including the United
States, the United Kingdom, Canada and Australia. An oral suspension
is also available. The drug is very inexpensive.
desipramine (Norpramin, Pertofran)
Desipramine is a metabolite of imipramine. Unlike imipramine it

only affects norepinephrine and is in fact one of the most selectively

noradrenergic medications. As a result it is the least sedative of the tri-
cyclics and often the best tolerated one, with very little anticholinergic
action. It has been shown to be an effective treatment for chronic pain21
and ADHD.22 One study concluded that low–dose desipramine actually
worked better for chronic back pain than higher doses.23
Desipramine is by far the cheapest noradrenergic drug. It has been
discontinued in most markets, including the United Kingdom and Aust-
ralia. It is still available in the United States, Canada and some other
countries. It is very inexpensive.
trimipramine (Surmontil, Rhotrimine, Tripress,

Sapilent)
Trimipramine is somewhat different in action from most tricyclic

antidepressants. In spite of what its name may suggest, it is not closely
related to imipramine. It only moderately inhibits the reuptake of nor-
epinephrine and weakly that of serotonin and dopamine. Its antidepres-
sant action is thought to primarily stem from the blockage of the 5–HT2
serotonin receptor. Trimipramine also blocks muscarinic cholinergic re-
ceptors, both H1 and H2 histamine receptors, alpha1 receptors and even
the D2 dopaminergic receptor.
Being highly sedative, trimipramine works well as a sleep aid.
Unlike the other tricyclic agents it does not adversely affect the amount
of REM sleep, but may even increase it.24 It is sometimes used to treat
chronic pain. One study found low dose trimipramine effective for the
pain symptoms of rheumatoid arthritis, but not for any associated dep-
ression.25 It was also found to be effective and well–tolerated in IBS.26
Trimipramine is better tolerated than most other tricyclics. The D2
blockage may cause tardive dyskinesia similar to neuroleptics, though
this effect has not been apparent in studies and the risk when using low
doses is negligible. Trimipramine is highly sensitive to drug interac-
tions. E.g. many other antidepressants, phenytoin, omeprazole, diclofe-
nac, clarithromycin, doxycycline, azole antifungals, verapamil and
cimetidine can affect its metabolism.
Trimipramine is available in the United States, the United King-
dom, Canada, Australia and some other markets. It is very inexpensive.
dosulepin/dothiepin (Prothiaden, Dothapax, Dothep,

Thaden)
Dosulepin (formerly known as dothiepin) has similar potency in

inhibiting the uptake of serotonin and norepinephrine. Besides blocking
the receptors typical to the TCAs it also antagonizes the 5–HT2 seroto-
nin receptors, which may contribute to its good efficacy as an anxioly-
tic. Dosulepin is highly sedative, but studies have shown it superior in
tolerability to both doxepin27 and clomipramine.28
There has been one double–blind study on dosulepin in fibromyal-
gia back in the 1980s.29 It concluded that the drug improved all the stu-
died clinical variables compared to placebo and patients only experien-
ced mild and transient side effects. The use of dosulepin as an analgesic
was also studied in rheumatoid arthritis with comorbid depression.30 The
drug was found effective for both pain and morning stiffness, though
depression scores did not differ between the treatment and placebo
groups.
Dosulepin is no longer widely available because of its high toxicity
in overdose. It is still on market in the United Kingdom, but not in many
other countries. It is also sold as a suspension, making dosing easier as
tablets are usually formulated for fairly large doses. It is very inexpen-
sive.
doxepin (Sinequan, Sinquan, Zonalon, Deptran, Xepin)
Doxepin is a popular medication in the treatment of CFS/ME and

fibromyalgia. It is very sedative, though possibly slightly less so than
amitriptyline. It is often helpful for improving sleep quality and relie-
ving chronic pain. Strong antagonism on both H1 and H2 types of hista-
mine receptors makes it an effective antihistamine. It may also have
other antiallergic and immunomodulatory properties. Some CFS/ME
patients report that doxepin gives them more energy.31
A common dose is 2–10 mg at bedtime, though some patients take
considerably larger doses. CFS/ME expert Nancy Klimas recommends
doxepin, starting with a dose of 5 mg and titrating it up to a maximum
of 20–25 mg.32 Paul Cheney believes that the dose should not be larger
than 5–10 mg and recommends starting with only two drops of the sus-
pension.33 He often uses doxepin in combination with clonazepam for
synergistic effects.
Doxepin is available in the United States, the United Kingdom,

Canada, Australia and many other countries. A suspension form is avail-
able in most of them. It is very inexpensive.
Selective serotonin reuptake inhibitors

(SSRI)
The selective serotonin reuptake inhibitors (commonly known as

SSRI) are currently by far the most commonly prescribed antidepres-
sants. They are frequently used in the treatment of CFS/ME, even
though the benefits appear questionable. There is more evidence to sup-
port their use in fibromyalgia, but even then other classes of antidepres-
sants (especially the serotonin and norepinephrine reuptake inhibitors)
tend to be more effective. Nonetheless, some patients experience
remarkable improvement on the SSRIs.
Compared to the tricyclics SSRIs have better tolerability, but des-
pite this CFS/ME patients often tolerate them poorly. According to
Canadian psychiatrist Eleanor Stein patients with CFS/ME generally
tend to react badly to fluoxetine and paroxetine.34 Instead she recom-
mends low doses of citalopram or venlafaxine for depression and sertra-
line or citalopram for anxiety. In general the starting doses should
always be tiny.
SSRIs may sometimes relieve fatigue and tiredness, but often the
effects are the opposite. The same goes for orthostatic hypotension and
even interstitial cystitis—the condition can improve or get worse on the
SSRIs. The effects may not only depend on the individual but also the
particular drug. An exacerbation in fatigue may go away with time,
though that may not be of much comfort to a patient who is even more
disabled than usual.
Interestingly SSRI antidepressants have some immunomodulatory,
particularly immunostimulatory properties.35 They also appear to have
specific antibacterial36 and antifungal37 activity, though the former was
mostly against Gram–positive bacteria, which have rarely been implica-
ted in chronic infections. The clinical relevance of these findings is
uncertain, but the SSRIs are clearly more than just mood enhancers.
The most common side effect is nausea. The likelihood depends on
the drug, but may be as much as 40%. Sexual side effects such as erec-
tile dysfunction and difficulty reaching orgasm are common. Additio-
nally the SSRIs can cause e.g. insomnia, nervousness, tremor, loss of
appetite, dry mouth, weight gain, headache, dizziness, sweating, sto-
mach upset and rarely even epileptic seizures.
Abrupt discontinuation of an SSRI can cause marked “withdrawal”

symptoms, especially with fluvoxamine and paroxetine which have
short half–lives. The SSRIs should never be combined with MAO inhi-
bitors. Combinations with tricyclics, dextromethorphan, tramadol and
the triptans are usually not recommended.
See also:
methadone, buprenorphine (CHAPTER 2), dextromethorphan,

diphenhydramine, chlorphenamine (CHAPTER 9)
fluoxetine (Prozac, Sarafem, Portal, Fontex, Lovan)
Besides inhibiting serotonin reuptake, fluoxetine is an antagonist of

the 5–HT2C serotonin receptor, but the clinical effects of this are unclear.
Fluoxetine has a significantly longer half–life than any other SSRI, up to
a week. This minimizes withdrawal symptoms upon discontinuation, but
any side effects will also persist for longer, as well as the effects on the
metabolism of other drugs. Often the doses used to treat CFS/ME are
very low, only 2–10 mg a day.
Fluoxetine is normally considered the most energizing SSRI, but its
use in CFS/ME has mostly been disappointing. A fairly large study
found no benefit at all.38 Even the depression that some of the patients
suffered from did not improve. According to a 1990 study in CFS/ME
patients fluoxetine can act as an immunomodulator.39 Interestingly the
effects were more pronounced in patients with little or no depression. It
can take up to 3–4 months before the effects are noticeable.
The results from studies on fibromyalgia have been more impres-
sive, though still conflicting. One study found fluoxetine effective and
well–tolerated.40 Another trial declared the benefit “mediocre” with 43%
getting adverse effects41, and a third one even found the drug ineffec-
tive.42 Fluoxetine has also been compared with amitriptyline and found
more efficacious.43 A second trial with these two antidepressants conc-
luded that they work the best in combination.44 Fluoxetine may also be
helpful for IBS symptoms.45
Fluoxetine may be the SSRI least likely to cause sexual dysfunc-
tion, but anxiety and weight gain are relatively common. It can speed up
the elimination of some benzodiazepines as well as slow down the meta-
bolism of tricyclic antidepressants, some anticonvulsants and neurolep-
tics. The efficacy of some narcotic painkillers may be reduced. Fluoxe-
tine should not be combined with lovastatin or simvastatin. There are
many other interactions, making the drug disagreeable for patients with
several medications.
Fluoxetine is available virtually everywhere and is very inexpen-
sive. Usually the smallest tablet size is 10 mg. Oral suspension form is
available in some markets, making it easier to try small doses. In some
countries there is also a Prozac Weekly formulation, which contains 90
mg of fluoxetine.
fluvoxamine (Luvox, Fevarin, Faverin, Dumirox,

Floxyfral)
Fluvoxamine is prescribed for OCD more often than for depression.

It has a shorter half–life than other SSRIs and as a result it is usually
taken twice a day instead of just once. It appears to have pain–relieving
action.46 A study of low dose fluvoxamine in fibromyalgia reported
benefit in 41% of the patients.47 The drug was well tolerated, nausea
being by far the most common adverse effect. Another study tried the
drug for fatigue caused by a severe liver disorder, but did not find it
helpful.48
Fluvoxamine is one of the most sedative SSRIs, but it still causes
insomnia often compared to the others. Nausea and constipation are also
more common than with other SSRIs. Fluvoxamine has plenty of poten-
tial interactions with other drugs, including tricyclic antidepressants,
olanzapine, mexiletine, propranolol, ropinirole, carbamazepine, diaze-
pam and alprazolam. It also strongly potentiates the effects of caffeine.
Fluvoxamine is available in the United States, the United Kingdom,
Canada, Australia and many other markets. It is very inexpensive. There
is no suspension form and the smallest 25 mg tablets are not available in
all markets, so patients may have to split pills for small doses.
sertraline (Zoloft, Lustral, Gladem, Serlain, Altruline)
Besides depression, sertraline is often used for anxiety, OCD and

PTSD. In a small study done in 1994 sertraline proved somewhat help-
ful in CFS/ME.49 Another study compared the drug to a combination of
ultrasound therapy and physiotherapy in patients with fibromyalgia and
found it far superior in efficacy.50 Pain, sleep and morning stiffness all
improved and 83% of the study participants evaluated sertraline as a
good treatment.
Dr. Charles Shepherd recommends initiating the treatment in
CFS/ME with a 25 mg dose, which may be increased if it does not cause
major side effects.51 According to him a subset of patients gets good
results, but some cannot tolerate the medication at all. Charles Lapp is
another CFS/ME doctor who makes use of sertraline.52
Sertraline is more likely to cause sexual dysfunction than other
SSRIs. Because of minimal interactions it is a good choice for patients
with many medications.
Sertraline is available virtually everywhere, usually both as tablets
and as suspension. It is very inexpensive.
paroxetine (Paxil, Seroxat, Aropax, Paroxat, Deroxat)
Paroxetine has the strongest effect of the SSRIs on norepinephrine

reuptake. Besides depression it is used to treat e.g. anxiety, OCD and
PTSD. Paroxetine is not commonly used in CFS/ME or fibromyalgia,
but e.g. Jay Goldstein sometimes prescribes it to his patients in doses of
10–20 mg a day.53 According to him it can take between one hour and
eight weeks to start working.
Paroxetine inhibits nitric oxide synthesis, which may be important
in CFS/ME and fibromyalgia.54 Martin Pall, the researcher behind the
“NO/ONOO” theory which postulates excessive nitric oxide as the
cause of the symptoms in these illnesses, recommends paroxetine for
this reason 55 A study about controlled release paroxetine for fibromyal-
gia found it useful for other symptoms, but not so much for pain.56 Paro-
xetine can also be quite helpful for vasovagal syncope, a form of ortho-
static intolerance that causes fainting.57
Paroxetine often brings out insomnia, but it is also quite prone to
causing drowsiness and fatigue compared to other SSRIs. It can elevate
the blood levels of e.g. some TCAs, neuroleptics, beta blockers and
amphetamines and potentiate the effect of anticoagulants. Some drugs
such as ropinirole can elevate the blood levels of paroxetine.
Paroxetine is available virtually everywhere and is very inexpen-
sive.
citalopram (Celexa, Cipramil, Seropram, Cipram,

Citalon)
escitalopram (Lexapro, Cipralex, Seroplex)
Citalopram is a highly selective SSRI with barely any effect on the

reuptake of norepinephrine and dopamine. It is a popular antidepressant,
but it is not that commonly used to treat CFS/ME. Escitalopram is the
active stereoisomer of the racemic citalopram and even more selective.
It may have a lower incidence of side effects with similar efficacy. It
should be kept in mind that escitalopram dosages correspond to at least
twice as much citalopram, because the drug is much more potent.

A small study recently tried escitalopram for CFS/ME with comor-
bid depression and found improvement in post–exertional malaise,
headaches, sleep, cognitive problems as well as depressive symptoms.58
There was no placebo group, however. Two double–blind studies have
tried citalopram in fibromyalgia. One found no benefit at all59, the other
concluded that there was slightly more improvement in the citalopram
group.60 Generally citalopram is a weak analgesic, but escitalopram is
not.61
Citalopram may be helpful in the treatment of orthostatic hypoten-
sion, if the therapy is initiated with a very low dose, which is slowly tit-
rated up.62 It has also been found beneficial for some cases of IBS and
improvement was not connected with reduction in anxiety or depres-
sion.63 One study found citalopram useful for idiopathic chronic fatigue
and the aches associated with this condition.64 In low doses it may also
alleviate cognitive problems.65
The most common side effects are nausea, dry mouth, somnolence
and insomnia. Generally citalopram causes no change in weight, but
unlucky patients may experience even severe weight gain. Citalopram
may have interactions with metoprolol and cimetidine, but in general it
is unlikely to cause problems when combined with other drugs.
Citalopram is available virtually everywhere. Escitalopram is avail-
able in the United States, the United Kingdom, Canada, Australia and
some other markets. Besides tablets, oral drops are often available. Cita-
lopram is very inexpensive, but escitalopram is more costly.
Serotonin and norepinephrine reuptake

inhibitors (SNRI)
Inhibiting the reuptake of both serotonin and norepinephrine some-

times offers superior antidepressant and anxiolytic efficacy. Increasing
the levels of norepinephrine may alleviate fatigue and the SNRIs are
often helpful for those who do not suffer from any psychiatric problems.
It has been noted that medications which affect the reuptake of both
serotonin and norepinephrine are more effective in treating fibromyalgia
pain than ones that only affect either neurotransmitter.66
See also:
pethidine/meperidine, tramadol, nefopam (CHAPTER 2), sibutra-

mine (CHAPTER 10)
venlafaxine (Effexor, Efexor, Efectin, Vandral)

desvenlafaxine (Pristiq)
Venlafaxine has a much stronger inhibitory effect on serotonin than

norepinephrine. Large doses may also affect dopamine reuptake. Smal-
ler dosages are often considered to only have serotonergic action. In any
case for many patients venlafaxine is more helpful than the SSRIs and it
sometimes helps depression refractory to all the other treatments. It can
also be used to treat many different kinds of chronic pain.67 Desvenlafa-
xine is a metabolite of venlafaxine, which is only taken once a day.
Venlafaxine is fairly commonly used in both fibromyalgia and
CFS/ME. Jay Goldstein uses a small dose of 37.5–75 mg twice a day,
starting out with only 18.5 mg.68 He recommends trying SSRIs and bup-
ropion first and venlafaxine only if these agents fail. According to him
venlafaxine often works well in combination with risperidone, though
this may carry the risk of serotonin syndrome.
One open and one double–blinded study have tried venlafaxine for
fibromyalgia with promising results, but both were small and the results
cannot be considered conclusive. Nonetheless both studies found signi-
ficant improvement with venlafaxine.69,70 In the first one the improve-
ment was found to be correlated with depression and anxiety; in the lat-
ter no such connection was found.
Venlafaxine can cause tachycardia and raise blood pressure, the
latter of which could be beneficial for some. Nausea is more common
than with the SSRIs. Other common side effects include e.g. psychiatric
symptoms, sweating, hot flashes and visual disturbances. According to
psychiatrist Eleanor Stein many CFS/ME patients tolerate the drug bet-
ter if taken in small, frequent doses instead of slow release formulati-
ons.71
The treatment should never be discontinued abruptly, as venlafa-
xine is highly prone to causing withdrawal symptoms. Sometimes wean-
ing off long–term use of the drug has to be done extremely slowly, over
the course of several months. Venlafaxine has potential interactions with
the same drugs as paroxetine. Azoles, macrolides and verapamil may
elevate the blood levels of venlafaxine. Desvenlafaxine only potentially
interacts with azoles.
Venlafaxine is available in the United States, the United Kingdom,

Canada, Australia and many other markets. It is slightly more expensive
than the SSRI drugs. In some countries normal tablets are no longer
sold, only extended release formulations. Desvenlafaxine is only avail-
able in the United States and is more costly.
duloxetine (Cymbalta, Yentreve)
Duloxetine inhibits the reuptake of serotonin and norepinephrine,

to some extent also dopamine. It is more potent than venlafaxine. It is
frequently used to treat neuropathic pain, especially diabetic neuropathy
and is gaining popularity as a fibromyalgia treatment. Three double–
blinded studies have got good results using it for fibromyalgia.72,73,74
Duloxetine has been predicted as the next FDA–approved fibromyalgia
treatment.
Duloxetine is considered a promising candidate for the treatment of
CFS/ME as well, with a clinical trial currently underway.75 It is fre-
quently used for urinary incontinence and some studies have found it
useful for overactive bladder as well.76 Most such trials have been done
in women and the drug may not be as effective for men.
Common side effects include nausea, dry mouth, headache, drowsi-
ness, dizziness, urinary hesitancy and sexual problems. All but the last
two usually go away with time. Some people may experience orthostatic
hypotension and fainting, but duloxetine can also raise blood pressure.
A subset of patients gain weight, others experience reduced appetite and
weight loss. E.g. ropinirole, azoles and fluoroquinolone antibiotics may
elevate the blood levels of duloxetine.
Duloxetine is available in the United States, the United Kingdom,
Australia, Canada and some other countries, but its international avail-
ability is still limited. The price is similar to most other SNRIs and
NRIs.
milnacipran (Ixel)
Milnacipran inhibits the reuptake of serotonin and norepinephrine

with a much greater effect on the latter. The mode of action is similar to
tricyclic antidepressants, but milnacipran is much more selective and
thus better tolerated. Milnacipran can be effective for both fatigue and
pain. One study also found it effective for the cognitive dysfunction
associated with post–stroke depression.77
Two double–blind studies have evaluated the use of milnacipran in
fibromyalgia with good results. In the first study 75% of patients in the
treatment group reported improvement, compared with only 38% in the

placebo arm.78 Pain, fatigue, mood and sleep were all improved.
Another study got similar results and actually found the drug more
effective in the group of non–depressed patients.79
Milnacipran is one of the best–tolerated antidepressants. Possible
side effects include dizziness, sweating, itching, nausea, anxiety, hot
flashes and painful urination. Milnacipran can also worsen orthostatic
hypotension, even though like venlafaxine it can sometimes elevate
blood pressure.
Milnacipran is currently available in some European countries. It
will probably be available in the United States and Canada in the near
future. It is one of the least expensive noradrenergic drugs.
Norepinephrine reuptake inhibitors (NRIs)
Norepinephrine reuptake inhibitors tend to be highly energizing,

sometimes bringing out insomnia and restlessness. They primarily help
with fatigue and cognitive problems. They are not as effective as pain
relievers as the SNRIs, but usually work better for this purpose than
purely serotonergic drugs. The NRIs may be tolerated by patients who
cannot take serotonergic medications.
The NRIs cannot cause serotonin syndrome in combination with
other drugs (although excessive noradrenergic stimulation can cause
adverse effects, there is no such thing as “norepinephrine syndrome”).
Still they should be not combined with MAOIs and they cancel out the
effect of clonidine. The NRIs do not usually cause tiredness, weight
gain or sexual problems, though they have their own characteristic side
effects, such as overstimulation, urinary hesitancy and palpitations.
See also:
protriptyline, desipramine (CHAPTER 5)
reboxetine (Edronax, Vestra, Norebox, Solvex, Prolift)
Reboxetine is a highly selective norepinephrine reuptake inhibitor.

It has barely any effect on serotonin reuptake. The antidepressant action
tends have a quicker onset than with most other drugs, often just ten
days or less. Reboxetine is stimulating and energizing compared to most
other antidepressants. It has been successfully used to treat narcolepsy.80
It is also an effective anxiolytic.
Reboxetine can also help the fatigue caused by fibromyalgia and

CFS/ME. There is even a patent filed of its use for this purpose.81 The
pain relieving qualities of the drug are another good reason to use it for
these illnesses. A case series got good results by using reboxetine for
fibromyalgia and chronic low back pain.82
Dizziness, excessive sweating, dry mouth, headache, nausea, tachy-
cardia and erectile and urinary difficulties are possible adverse effects of
reboxetine. Sexual side effects are nonetheless far less common than
with SSRIs. Reboxetine may lower seizure threshold. It should not be
combined with azoles, macrolides or fluvoxamine.
Reboxetine is available in the United Kingdom, Australia and many
other countries, but not in the United States or Canada. The price is
similar to venlafaxine.
atomoxetine (Strattera, Attentin)
Atomoxetine increases the levels of norepinephrine and dopamine

in the brain. It is most often used to treat ADHD. For some reason it has
not been studied for fibromyalgia. Atomoxetine has also been shown to
increase the levels of acetylcholine in some parts of the brain, an effect
which can improve cognitive function.83 Other cholinergic drugs have
sometimes yielded good results in the treatment of CFS/ME.
Headache, dry mouth, insomnia, stomach upset, loss of appetite,
nausea and vomiting are common side effects of atomoxetine. It may
also cause cardiac problems and dysmenorrhea (painful periods). A few
cases of severe liver injury associated with the treatment have been
reported. Weight loss is fairly common. E.g. fluoxetine, paroxetine and
ropinirole may increase the blood levels of atomoxetine.
Atomoxetine is available in the United States, the United Kingdom,
Canada, Australia and many other markets. It is more expensive than
most other antidepressants. The Strattera formulation is similarly priced
per dose regardless of strength, but unfortunately for the patients it is
sold in capsules, which makes it difficult to divide them.
bupropion (Wellbutrin, Zyban, Quomem)
Bupropion is often claimed to be an SSRI, but in reality it inhibits

the reuptake of norepinephrine and dopamine with barely any effect on
serotonin. It also has some action on the nicotinic cholinergic receptors.
It is used as an antidepressant (Wellbutrin) and as a smoking cessation
aid (Zyban), though both of these formulations contain the same active
ingredient and can be used interchangeably. It is considered a good anti-
depressant for bipolar disorder, especially for rapid cycling.84

Bupropion has been used to relieve many different kinds of fatigue
and tiredness, e.g. in cancer patients. Besides the noradrenergic and
dopaminergic effects, it suppresses the inflammatory cytokine TNF
alpha85, which may be pertinent in reducing fatigue and other symptoms
of CFS/ME and fibromyalgia. Studies have demonstrated efficacy in the
treatment of neuropathic pain86 and restless legs syndrome.87
One small study about the successful use of the drug in CFS/ME88
as well as one case report, which describes the use of bupropion in com-
bination with paroxetine89, have been published. Lucinda Bateman pre-
scribes her CFS/ME patients slow release tablets with the dosage 100–
300 mg a day.90 Others suggest doses from 75 mg once a day to 150 mg
three times a day.91 The CFS/ME study used 300 mg a day, which is
probably suitable for FM as well.
Bupropion lacks most of the side effects of SSRIs except for dry
mouth. Instead of weight gain it tends to cause weight loss. Sexual side
effects are rare—in fact it can help with sexual problems caused by
SSRIs or other reasons. Because of its stimulating nature bupropion can
cause insomnia. Other common side effects include fever, tremor,
impaired concentration, headache, dizziness, stomach upset and altered
taste.
Bupropion increases the risk of seizures. This risk is generally neg-
ligible without other precipitating factors, but it means the drug cannot
be used in patients with epilepsy or a history of seizures. Fluoxetine,
orphenadrine, carbamazepine, valproate, cimetidine and oral contracep-
tives can affect the metabolism of the drug. Levodopa and amantadine
may worsen the side effects of bupropion.
Bupropion is available in the United States, the United Kingdom,
Canada, Australia and some other markets. In some countries it is only
approved for smoking cessation. It is more expensive than the SSRIs,
but cheaper than most other noradrenergic drugs. There are different
modified release formulations available depending on the country. Some
need to be taken twice a day, but Wellbutrin XL is only taken once.
Monoamine oxidase inhibitors (MAOI)
Monoamine oxidase inhibitors (MAO inhibitors or MAOIs for

short) work by inhibiting the activity of monoamine oxidase, an enzyme
which breaks down neurotransmitters such as serotonin, epinephrine,
norepinephrine and dopamine. MAOIs are generally effective antidep-
ressants, but with some highly inconvenient properties. They have large-
ly fallen out of fashion in favor of SSRIs and are mostly used for atypi-
cal and treatment–resistant depression.

MAOIs can be either reversible or irreversible and selective or
non–selective. Older ones are irreversible, which means they perma-
nently deactivate MAO and even if the drug is discontinued it can take
two weeks for the body to replace the enzyme. The selectivity refers to
whether the medication inhibits mostly just MAO–A, MAO–B or both
types.
Because of their mode of action MAOIs require strict dietary
restrictions. Foods containing the amino acids tyramine or tyrosine must
be either completely avoided or only consumed in moderation, depend-
ing on the food. This includes e.g. aged cheese, wine, coffee, chocolate,
avocados, bananas and most fermented and pickled products (such as
yoghurt, sauerkraut and soy sauce). Especially with the older MAOIs
consumption of the forbidden foods can have deadly consequences.
The interactions do not stop here. MAOIs should never be combi-
ned with most psychotropic medications and supplements, including
SSRIs, tricyclics, cyclobenzaprine, St. John’s wort and tryptophan/5–
HTP. Other medications to avoid include carbamazepine, some opiates
and dextromethorphan. They may also interact with e.g. anticholinergic
drugs, antihistamines, levodopa, lithium and alcohol. Individual MAOIs
can also have metabolic interactions with other drugs.
MAOIs are not commonly used to treat CFS/ME or fibromyalgia,
though Jay Goldstein has found them useful for some refractory cases.92
They are often poorly tolerated especially by CFS/ME patients, but may
sometimes be useful, especially if the patient also suffers from severe
depression and/or anxiety. Usually they are only tried when other agents
have not proven effective. If the patient cannot tolerate other types of
antidepressants, MAOIs usually cause even worse adverse effects.
moclobemide (Manerix, Aurorix)
Moclobemide is a reversible MAOI which selectively inhibits

MAO–A. As a result diet restrictions are not as crucial as with other
MAOIs. A Finnish study tried the drug for fibromyalgia, but failed to
get statistically significant results compared to placebo.93 The drug did
offer some pain relief, but fared poorly in regard to sleep. On the other
hand a study using pirlindole, a similar reversible MAO–A inhibitor
which is no longer available, found it helpful for fibromyalgia.94
Moclobemide may be helpful in increasing energy levels and
improving concentration in CFS/ME. There have been two trials about
this use showing limited efficacy. The first study included 49 CFS/ME
patients, of whom 14 suffered from depression.95 Other patients did not
benefit from moclobemide, but half of the depressed ones got relief.
The other study was a double–blind placebo controlled one. Of the
treatment group 51% believed moclobemide helped them— though on
the other hand 33% of the placebo arm also reported improvement.96
According to the study moclobemide was particularly helpful for those
patients with impaired cell–mediated immunity. One trial got very pro-
mising results using moclobemide in migraine and tension headache
prophylaxis.97
Compared to many other psychiatric drugs moclobemide is not par-
ticularly sedative, but that comes at a price; it frequently causes insom-
nia and other sleep disturbances. Headache, stomach upset and dizziness
are also common. Many CFS/ME patients get severe adverse reactions
from this drug, so it should be started with a very low dose (if at all),
especially if the patient has tolerated other antidepressants poorly.
Moclobemide is not available in the United States, but it is sold in
the United Kingdom, Canada, Australia and a host of other countries. It
is very inexpensive.
phenelzine (Nardil)
Phenelzine is an irreversible and non–selective MAO inhibitor. In

addition it increases the levels of GABA in some parts of the brain,
which may explain why it is a powerful anxiolytic that provides relief
even in some otherwise refractory cases. Phenelzine has shown efficacy
in migraine prophylaxis.98 It is sometimes used to treat CFS/ME, with
one study from 1996 supporting its efficacy for this use, though many
patients dropped out prematurely because of side effects.99
The commonly recommended dosing regime of phenelzine differs
from other antidepressants. It is initially started with 15 mg three times a
day and titrated up to 60–90 mg a day. This dosage is maintained for at
least four weeks, after which it can be dropped as low as 15 mg, every
day or even every other day. These instructions may not be appropriate
for people with CFS/ME. The aforementioned study only used at most
15 mg a day.
The most common side effects are dizziness, drowsiness, sleep dis-
turbances (both insomnia and hypersomnia), fatigue, weakness, weight
gain, orthostatic hypotension, constipation, dry mouth and stomach
upset. Sexual problems are possible. The side effects usually markedly
abate with time. Abrupt withdrawal of the drug can cause nausea,
vomiting and malaise. Phenelzine can also reduce the blood levels of
vitamin B6.
Phenelzine is available in the United States, United Kingdom,
Canada, Australia and a few European countries. The price is quite

affordable.
tranylcypromine (Parnate)
Tranylcypromine is an irreversible MAO inhibitor with some anti-

cholinergic action. Besides depression it is sometimes used to treat
PTSD and occasionally also CFS/ME. Tranylcypromine is more energi-
zing than phenelzine, but as a result it is more likely to cause insomnia.
It may be less prone to lowering blood pressure compared to phenelzine.
Tranylcypromine is not recommended for those with a history of
headache (migraine or other kinds). Weakness, drowsiness, dizziness,
dry mouth, vision disturbances, loss of appetite, weight loss, nausea,
diarrhea and stomach upset are common side effects. Tranylcypromine
increases the blood levels of many drugs, such as mexiletine, ropinirole,
diazepam and phenytoin. It may lower the efficacy of many opiates.
Tranylcypromine is available in the United States, Canada, Austra-
lia and a few other countries, but not in the United Kingdom. It is
affordable but more costly than moclobemide and phenelzine.
selegiline (Eldepryl, Deprenyl, Jumex, Niar, Emsam)
Selegiline is an irreversible inhibitor of MAO–B (though large

doses also inhibit MAO–A), so it mostly affects dopamine. It also has
some effect on dopamine reuptake independent of the MAO inhibition.
Because of its dopaminergic mode of action selegiline was originally
approved as a treatment for Parkinson’s disease. More recently a trans-
dermal selegiline patch (Emsam) has been approved in the treatment of
clinical depression.
Selegiline is stimulating and energizing and is sometimes used to
treat narcolepsy. It is widely considered a nootropic and is purported to
be a “life extension” drug used in tiny doses. It has some anticonvulsant
action as well.100 One small study compared oral selegiline to placebo
on 25 CFS/ME patients.101 It concluded that selegiline had a “small but
significant” therapeutic effect in CFS/ME, though it was not found to
act as an antidepressant.
In most patients selegiline is well tolerated. It is not as strict with
dietary restrictions as other MAOIs and with the lowest dose of the
Emsam patch no such restrictions are considered necessary. Dry mouth,
orthostatic hypotension and insomnia are possible adverse effects. The
patch may cause skin irritation.
Oral forms of selegiline are available almost everywhere. The
Emsam patch is not yet available outside of the United States. It is also
highly expensive, most likely being the most expensive antidepressant at
the moment. Oral selegiline in contrast is very inexpensive.
rasagiline (Azilect, Agilect)
Rasagiline is a MAO–B inhibitor similar to selegiline. One of the

main differences is that selegiline metabolizes partly to L–methamphe-
tamine, a stereoisomer of methamphetamine, but rasagiline does not.
Although this isomer is not considered psychoactive, it is not known
whether it can cause problems to some patients. It does show up as
amphetamine in drug tests.
The effects and contraindications of rasagiline are similar to the
ones of selegiline, but it has not been studied as extensively. Side effects
can include joint pain and indigestion. Rasagiline has potential drug
interactions with e.g. cimetidine, modafinil, carbamazepine, omeprazole
and ciprofloxacin.
Rasagiline has limited availability compared to selegiline and is
more expensive. It is available in the United States, Canada and some
European countries.
Other antidepressants
trazodone (Desyrel, Molipaxin, Trazolan, Trazone,
Trittico)
Trazodone is an antagonist of the 5–HT2 serotonin receptors with

some effect on serotonin reuptake. As an antidepressant it generally
starts working faster than most, usually within two weeks. It is very
sedative and its effects resemble those of the tricyclic antidepressants. In
CFS/ME and fibromyalgia it is primarily utilized as a sleep aid.
A few studies have found trazodone useful for some kinds of chro-
nic pain102, but most have shown no benefit.103,104 Nonetheless improved
sleep may indirectly improve pain, especially in fibromyalgia. Trazo-
done is particularly good for those who tend to constantly wake up
during the night. CFS/ME doctor Charles Lapp prefers a combination
where clonazepam helps the patient fall asleep and trazodone aids in
maintaining sleep.105
Based on the experience of Dr. Roseanne Armitage, nefazodone is
more useful for women in the treatment of CFS/ME, but trazodone
works better for men.106 The dosage used varies greatly between 25 and
450 mg. Some patients benefit from small doses, but larger ones often
cause orthostatic hypotension.107 The website eMedicine which is aimed

at medical professionals recommends starting with 25 mg in the treat-
ment of fibromyalgia.108
The sedative action may cause daytime sleepiness. Other common
side effects of trazodone (neurological symptoms, nausea, headache,
nasal congestion) can be confused with the symptoms of CFS/ME and
FM as well. Nonetheless, compared to tricyclics the drug is well tolera-
ted and has much fewer cardiac effects. The blood levels of trazodone
can be affected by ketoconazole and carbamazepine. Grapefruit juice
should only be consumed in moderation.
Trazodone is available in the United States, the United Kingdom,
Canada and many other markets, but not in Australia. It is very inexpen-
sive.
nefazodone (Serzone, Dutonin, Nefadar)
As the name suggests, nefazodone is closely related to trazodone,

though it is also somewhat noradrenergic and as such less sedative than
trazodone. It is not considered a particularly effective antidepressant,
but it works for some people who are not helped by other medications or
cannot tolerate them. Nefazodone appears to not only be analgesic on its
own but also potentiate morphine analgesia.109
A small study tried nefazodone on 10 patients with CFS/ME, with
eight getting some relief from fatigue and four of them reporting mode-
rate to major relief.110 Sleep disturbance was improved in eight of the
patients. Seven out of these ten had previously failed to respond to other
antidepressants. A case series published as a letter in the American Jour-
nal of Psychiatry describes three CFS/ME patients who benefited from
nefazodone.111
The side effects are typical of both SSRI and SNRI antidepressants
including e.g. nausea, dizziness, weakness, dry mouth, urinary prob-
lems, constipation, insomnia and sleepiness. Some people may experi-
ence hypoglycemia. Sexual problems are infrequent. Nefazodone can
have life–threatening interactions with astemizole and may also greatly
elevate the blood levels of some benzodiazepines. Combinations with
carbamazepine and some of the statin drugs are not recommended.
Nefazodone has been withdrawn from many markets because of the
risk of liver failure. This risk is extremely low (estimated to be 1 in
250,000–300,000 patient years), so many other medications can be con-
sidered to have similar or worse risks. Nefazodone is still available e.g.
in the United States. In the UK it can be prescribed on a named patient
basis. The risk of liver damage can most likely be minimized by supple-
menting with sources of glutathione such as whey protein or the drug

acetylcysteine (see CHAPTER 9).
mirtazapine (Remeron, Zispin)
Mirtazapine is a tetracyclic, mostly noradrenergic antidepressant

with a variety of actions. It blocks 5–HT2 serotonin receptors, H1 hista-
mine receptors and alpha2 adrenergic receptors, but not cholinergic
receptors. It is also an antagonist of the 5–HT3 receptor, a mechanism
that relieves nausea and is often helpful in the treatment of CFS/ME and
fibromyalgia. It is sometimes used to treat IBS.
Mirtazapine has been tried in fibromyalgia in one open–label trial
in which 38% of the participants benefited from the drug.112 Dr. Charles
Lapp utilizes mirtazapine as a sleep aid in his CFS/ME patients.113 Espe-
cially smaller doses improve sleep quality. Depending on dose mirtaza-
pine can be either stimulating or sedating. It may help in tension head-
ache.114
Sleepiness and weight gain are the most common side effects. Both
can improve with dose reduction—or sometimes even with an increase
in dose. Mirtazapine lacks most of the side effects of SSRI drugs. It can
sometimes cause orthostatic hypotension, akathisia (motor restlessness)
and restless legs syndrome. Interactions with e.g. azoles, carbamazepine
and macrolides are possible.
Mirtazapine is available in the United States, the United Kingdom,
Canada, Australia and many other markets. It is inexpensive.
mianserin (Tolvon, Bolvidon, Norval, Lerivon)
Mianserin is quite similar in action to mirtazapine, though it has a

more pronounced effect on serotonin. Like mirtazapine it blocks alpha2
receptors and H1 receptors, but has barely any anticholinergic action. It
can be used similarly as a sleep aid. Mianserin has some analgesic pro-
perties115, probably mediated by the opioid receptors.116 A Russian study
found it effective for reducing pain and improving sleep and mood
symptoms in fibromyalgia.117
Mianserin is quite sedative and can cause drowsiness especially
during the first days of the treatment. It can potentiate the sedative
effects of other sedative drugs. Some metabolic drug interactions may
exist, but have not been properly evaluated. Like mirtazapine mianserin
can cause restless legs syndrome. Agranulocytosis and aplastic anemia
are rare but serious side effects.
Mianserin is available in many European countries (including the

United Kingdom) and Australia, but not e.g. in the United States and
Canada. In many markets it has been replaced by mirtazapine. Mianse-
rin is very inexpensive.
buspirone (Buspar, Anxiron, Spitomin, Buspiron)
Buspirone is more of an anxiolytic than antidepressant. It is not

related to the benzodiazepines, but acts through serotonergic and norad-
renergic mechanisms and may also be a dopamine antagonist.118 It is
sometimes used as an adjunct for SSRIs for both depression and anxiety
and may be useful for PTSD. Buspirone has some analgesic action119,
but it may also decrease the analgesia of both opioids and NSAIDs.120 It
can be used to reverse SSRI–induced sexual problems in most cases.121
Buspirone may be helpful for chronic tension headache122 and
appears to be particularly effective in migraine prophylaxis.123 Devin
Starlanyl has found buspirone useful for fibromyalgia, reporting that it
may improve memory, reduce anxiety and regulate body temperature.124
Buspirone also increases growth hormone secretion125, which can be
beneficial in both CFS/ME and fibromyalgia.
Dr. Peter O. Behan believes that buspirone may be helpful for CFS/
ME because it targets the 5–HT1A serotonin receptor.126 According to
him the drug may significantly worsen the symptoms for a week or two,
but after that they begin to get better. Dr. H. Hooshmand notes that
buspirone relieves the fatigue associated with multiple sclerosis.127
Buspirone is usually not sedative. The most common side effects
are vertigo, agitation, headache, nervousness and nausea. It is not
recommended for people with a history of epileptic seizures. Several
drugs (e.g. azoles, macrolides and verapamil) and grapefruit juice can
significantly elevate the blood levels of buspirone and they should not
be used concomitantly. Dexamethasone and carbamazepine decrease the
efficacy of the drug.
Buspirone is available in the United States, the United Kingdom,
Canada, Australia and many other countries. It is very inexpensive.
tianeptine (Stablon, Coaxil)
Tianeptine has a novel action as an antidepressant. It enhances the

reuptake of serotonin, so it essentially works the opposite from SSRI
drugs. It is an effective antidepressant and anxiolytic lacking most of the
side effects of other antidepressants. It has also been used for various
off–label indications, such as erectile dysfunction128, asthma129, and
ADHD130, making it an intriguing treatment choice for those patients

with many comorbid conditions.
Tianeptine appears to be generally neuroprotective, though it does
not protect against glutamate excitotoxicity.131 It stabilizes the HPA
axis132 and acts as an analgesic.133 A clinical trial is currently trying it
for fibromyalgia.134 There is a U.S. patent that proposes tianeptine as a
treatment for a myriad of neurological conditions, including “chronic
fatigue syndrome, [and] myalgic encephalomyelitis post–viral fatigue
syndrome.”135 Another patented use is that of IBS and dyspepsia.136
Insomnia, nightmares and headache are fairly common side effects.
Nausea, constipation, drowsiness, dizziness and dry mouth can occur,
but are less frequent than with most other antidepressants. There are no
known drug interactions. Tianeptine is taken more frequently than most
antidepressants, usually three times a day. Abrupt discontinuation can
cause insomnia, nausea and other symptoms.
Tianeptine is currently available in France and some other Euro-
pean countries and in parts of Asia and South America, but not in the
United States, United Kingdom, Canada or Australia. It no longer
enjoys patent protection, which makes it very inexpensive, but unlikely
to be licensed to new markets.
S–adenosylmethionine/ademetionine (Transmetil)
S–adenosylmethionine, better known as SAM–e or SAMe, is a

molecule naturally found in almost all body tissues, which acts as a
methyl donor. It is most commonly used as an antidepressant and is
thought to have multiple modes of action. It may act through increasing
levels of brain neurotransmitters, creatine and the important antioxidant
glutathione. It is also involved in the formation of myelin.
Besides lifting mood, SAM–e can relieve fatigue and cognitive
problems. In some countries it is approved for the treatment of osteo-
arthritis and liver problems. Many studies have shown it just as effective
as other antidepressants, and it usually has a quicker onset.137 The
recommended dosage varies from 50 mg to 1,600 mg a day, usually
being 200–400 mg.
As many as four double–blinded studies have evaluated the use of
SAM–e in fibromyalgia. One tried intravenous administration of the
drug, but did not find it useful.138 In contrast intramuscular injections of
SAM–e proved helpful for pain and depression in another trial.139 Both
of the studies administering the drug orally produced positive
results.140,141 The precise outcome differed between the studies—one
found benefit in tender point score and depression, others did not.
SAM–e has better tolerability compared to traditional antidepres-

sants. Side effects are rarely experienced, but stomach upset seems to be
the most common. Some people have reported nausea, anxiety, irritabi-
lity, dizziness, insomnia or lowered libido. SAM–e may raise the levels
of homocysteine, which has been considered a risk factor for cardiovas-
cular disease, but the causal relationship is unclear. As a result it is
recommended to take SAM–e with some B complex vitamins (B6, B12
and folic acid).
SAM–e is available over–the–counter in the United States and
many other countries. In some, mostly European countries (such as Ger-
many, Italy and Spain) it is a prescription medication. The problem with
it lies in the price, as in most countries it is very expensive in larger
doses. Small doses should still be affordable.
L–tryptophan (Tryptan, Optimax)

5–hydroxytryptophan (Levotonine, Cincofarm)
L–tryptophan or just tryptophan is an essential amino acid, that is,

we must obtain sufficient quantities of it from our diet to subsist. One of
its functions in the body is acting as a serotonin precursor. 5–hydroxy-
tryptophan (better known as 5–HTP, sometimes called oxitriptan) is
another precursor, which is the intermediate step from L–tryptophan to
5–hydroxytryptamine, or serotonin. Besides depression the tryptophans
often help insomnia.
An open trial of 5–HTP in fibromyalgia found improvement in all
studied parameters142 and a second, double–blinded, trial corroborated
these findings.143 Another fibromyalgia study found the combination of
a MAOI and 5–HTP much more effective than other antidepressant regi-
mes (amitriptyline, 5–HTP or MAOI alone).144 Several studies have
tried the tryptophans for chronic headaches (including migraines), but
the results have been mixed. In some countries 5–HTP is approved as an
adjunct treatment for myoclonus and other neurological disorders.
Tryptophan is better tolerated than SSRI drugs, but not without side
effects. 5–HTP is more bioavailable than L–tryptophan and may thus be
more effective, but it can also cause stomach problems, as it is able to
convert to serotonin already in the intestine, which contains plenty of
serotonin receptors. Both can cause nausea, sedation and sexual prob-
lems.
In the 1980s L–tryptophan was associated with a serious and some-
times deadly condition called eosinophilia myalgia syndrome, caused by
impurities in some manufacturers’ products. Monitoring has been much
stricter since and no further cases have been reported. A more important
reason for caution is the risk of serotonin syndrome when either of the
tryptophans are combined with other antidepressants, so this should
never be done without physician’s approval.
As a result of the eosinophilia myalgia syndrome scandal L–trypto-
phan used to be banned in many countries. Now both are usually avail-
able over the counter. In Canada and Germany L–tryptophan requires a
prescription. 5–HTP is a prescription drug in e.g. France, Italy and
Spain. In the United Kingdom L–tryptophan is available both on pre-
scription and as a supplement. In some countries 5–HTP is only legally
available in herbal products as a constituent of the plant Griffonia simp-
licifolia (also known as Bandeiraea simplicifolia).
Neuroleptics and lithium
Neuroleptics (also known as antipsychotics) are primarily used to

treat psychosis and as adjuncts in the treatment of bipolar disorder,
sometimes depression as well. They are divided into typical antipsycho-
tics, which block dopamine receptors, and atypical ones, which also
antagonize 5–HT2 serotonin receptors and are usually lower in side
effects. All of the drugs reviewed here are atypical ones. Lithium is
sometimes classified as a neuroleptic agent, though it is usually consi-
dered a mood stabilizer.
Neuroleptics are mainly used in the treatment of CFS/ME and fib-
romyalgia to relieve pain and as sleep aids. They and lithium both have
the potential to cause significant adverse effects. Neuroleptics may
cause tardive dyskinesia (involuntary movements) and the extremely
rare neuroleptic malignant syndrome, which is a medical emergency.
Weight gain is common and sometimes drastic. Thus with a few excep-
tions these agents should only be reserved for severe, refractory symp-
toms.
olanzapine (Zyprexa)
Olanzapine blocks a large variety of different receptors, including

several types of dopamine and serotonin receptors, muscarinic receptors,
alpha1 receptors and H1 type histamine receptors. It is less well known
that it also antagonizes 5–HT3 receptors, which can is often beneficial in
CFS/ME and fibromyalgia. It is mostly used to treat schizophrenia, but
has also been prescribed for depression, nausea, PTSD, chronic head-
ache and other chronic pain syndromes.
Several papers have been published about the use of olanzapine for
fibromyalgia. The earliest one described two cases refractory to other
treatment who had done well on olanzapine.145 A case series reviewed

the charts of 51 fibromyalgia patients treated with the drug and found
significant improvement on most scales.146 Another case series found
olanzapine helpful for 43% of study completers—though almost half of
the original participants dropped out because of side effects.147
Olanzapine has been used as a sleep aid owing to its sedative and
sleep improving qualities. Lucinda Bateman uses a dose of 2.5–10 mg
on her CFS/ME patients.148 David Bell prescribes a dose of 2.5 mg.149
Because of the significant side effects even low doses should probably
be reserved for those patients who do not respond to other treatments.
Daytime sedation is a common, but the most bothersome side effect
of olanzapine is weight gain, which is often marked. A study tried the
anticonvulsant topiramate for reducing the weight gain with good
results, also improving quality of life and health of the patients.150 H2
antagonists may be effective for the same purpose.151 Olanzapine has
been associated with an increased risk of diabetes. Fluvoxamine and
ketoconazole increase the blood levels of the drug and carbamazepine
can reduce its efficacy.
Olanzapine is available virtually everywhere, though the smallest
2.5 mg tablets are not available on every market. This is not a major
problem as the 5 mg tablets can be split and doses smaller than 2.5 mg
are hardly ever used. Larger doses tend to become expensive compared
to most psychiatric drugs.
risperidone (Risperdal, Rispolept, Belivon)
Risperidone has high affinity for the 5–HT2 serotonin receptors and
only moderate affinity for the D2 dopamine receptor. It also blocks
many other receptors similar to the tricyclic antidepressants, but has no
effect on cholinergic receptors. Low doses are sometimes prescribed for
anxiety, depression and PTSD. Dr. Jacob Teitelbaum uses risperidone to
treat pain, anxiety and sleep.152 He recommends starting out with only
0.25 mg, which is titrated up by 0.25 mg every six weeks to a maximum
of 1.5 mg.
Jay Goldstein uses risperidone in low doses (0.25–0.5 mg) to treat
CFS/ME and fibromyalgia and notes that in these doses it may actually
increase serotonin and dopamine levels in the brain.153 He reports occa-
sional good results with a combination of risperidone with venlafa-
xine154, but there are reports of serotonin syndrome arising from similar
combinations.
The most common side effects are insomnia, agitation, anxiety and
headache. Weight gain is possible, but usually less pronounced compa-
red to other neuroleptics. Risperidone can cause orthostatic hypotension,

but this is unlikely with the proposed low dosages. Carbamazepine may
lower the blood levels of the drug.
Risperidone is available in the United States, the United Kingdom,
Canada, Australia and many other markets. The 0.25 mg tablets are not
available everywhere, but the 0.5 mg tablets are scored and thus easy to
split. Risperidone is fairly inexpensive.
amisulpride (Solian)
sulpiride (Dolmatil, Sulpor, Meresa, Sulpitil, Dogmatil)
Like other antipsychotics, amisulpride and sulpiride block the

dopamine receptors. In small doses these drugs actually lead to an
increase in dopaminergic transmission, which can have stimulating and
antidepressive effects. In some European countries amisulpride and sul-
piride are approved for the treatment of dysthymia (chronic “low–
grade” depression). The antidepressant action often has a very rapid
onset.
One study found amisulpride as effective as fluoxetine for depres-
sion and more effective for anxiety with the drugs having similar tolera-
bility.155 Low doses of sulpiride are also used to treat vertigo and tinni-
tus. In one study it benefited 56% of patients with tinnitus.156 When it
was combined with melatonin, as many as 81% were improved.
Both drugs can cause orthostatic hypotension, nausea and weight
gain, though the latter tends to be mild. Sedation is possible, but usually
the small doses are more prone to causing overstimulation and thus the
medication should be taken early in the day. Both drugs may lower the
seizure threshold. Rarely they may prolong the QT interval, which may
result in dangerous cardiac arrhythmias.
Amisulpride and sulpiride are available in many European and
Asian countries (including the United Kingdom) and amisulpride also in
Australia, but they are not approved in the United States and Canada.
Besides tablets an oral suspension form is usually available. Both drugs
are very inexpensive.
ziprasidone (Geodon, Zeldox)
Ziprasidone is the most potent agonist of the 5–HT1A serotonin

receptor in clinical use. Like other atypical neuroleptics it also blocks
dopamine receptors and 5–HT2 receptors, with some affinity for hista-
mine and alpha1 receptors. It is used to treat schizophrenia and bipolar
disorder. Jay Goldstein has found it the most useful atypical neuroleptic
[in the treatment of CFS/ME and fibromyalgia], noting that it has few
adverse reactions, causes no weight gain and may even be effective
from the first dose.157
Common side effects include insomnia, sedation and orthostatic
hypotension, though ziprasidone is not as sedative as many other anti-
psychotic drugs. It can increase the QT interval and should not be com-
bined with other drugs with similar action. Carbamazepine can decrease
and azoles increase the blood levels of ziprasidone.
Ziprasidone is available in the United States, Canada, Australia and
some other countries all over the world, but not in the United Kingdom.
It is somewhat expensive.
quetiapine (Seroquel)
Quetiapine is indicated in the treatment of schizophrenia and mania

and used for a variety of off–label indications. One study found it effec-
tive for the fatigue and stiffness associated with fibromyalgia, but not
for pain.158 A second fibromyalgia trial augmented it with pregabalin
with good results, though a fairly large proportion of participants with-
drew from the study.159
Because of its extreme sedative qualities quetiapine is commonly
utilized as a sleep aid. As one person using it as described, “it is not a
sleeping pill but an elephant tranquilizer.” It is often used by people
with CFS/ME for this purpose, but they usually require very small doses
to avoid excessive daytime sedation and “feeling like a zombie.”
Other side effects include constipation, headache and weight gain,
though it is less pronounced than with many other antipsychotics and
weight loss is also possible. Quetiapine may lower seizure threshold.
Animal studies have found that in long–term use quetiapine can cause
cataracts. It is not known whether this is applicable to humans, but in
prolonged use eye examinations are recommended.
Quetiapine is available in the United States, the United Kingdom,
Canada, Australia and some other markets. Even in the smallest 25 mg
dose it is somewhat expensive compared to most other sleep inducing
agents.
lithium (Eskalith, Carbolith, Camcolit, Priadel,

Neurolithium)
For over 50 years it has been known that many lithium salts act as
mood stabilizers, even though the mode of action is not fully under-
stood. Lithium is commonly used to treat bipolar disorder and is effec-
tive against both depression and mania. It may be prescribed for mig-
raine prophylaxis, for chronic headaches or to augment the efficacy of
antidepressants. Lithium also has immunomodulatory and antiviral, par-
ticularly antiherpesviral properties.160
Lithium is sometimes used to treat fibromyalgia. A case series
describes three patients who improved markedly on lithium with a dose
of 300 mg administered 3–4 times a day.161 One of them could not tole-
rate the dose that produced complete pain relief, but in others the drug
was well tolerated. One patient even remained pain free after lithium
was discontinued. Jacob Teitelbaum prescribes lithium in doses of 200–
600 mg a day for both CFS/ME and FM.162
Before initiating lithium treatment the patient needs some blood-
work for e.g. renal and thyroid function, which should be monitored
every 3–6 months. Lithium concentrations also need monitoring,
because its therapeutic width is very narrow (that is, toxic levels are not
far from therapeutic levels). Electrolyte imbalances may increase the
risk of toxicity. It is important to try to eat a moderate and fairly cons-
tant amount of salt.
Common side effects include ataxia, tremor, muscle weakness, nau-
sea, loss of appetite, stomach upset and dry mouth. Hair loss is possible.
Lithium frequently causes increased thirst and urination. Diuretics, ACE
inhibitors, metronidazole, tetracyclines and some NSAIDs may elevate
lithium levels and thus induce lithium toxicity. SSRIs, verapamil, baclo-
fen, neuroleptics, carbamazepine and phenytoin may exacerbate the neu-
rological side effects of lithium.
Lithium is available virtually everywhere. It is very inexpensive. In
some countries certain lithium preparations are sold over–the–counter
and are purported to have antidepressant and mood stabilizing proper-
ties, but in reality most of these preparations contain “homeopathic”
doses (often only micrograms) of lithium, not nearly enough to have real
therapeutic effects.
References
1 Li YF, Zhang YZ, Liu YQ, et al. Inhibition of N–methyl–D–aspartate

receptor function appears to be one of the common actions for anti-
depressants. J Psychopharmacol. 2006 Sep;20(5):629–35.
2 Gray AM, Spencer PS, Sewell RD. The involvement of the opioider-
gic system in the antinociceptive mechanism of action of antidepressant
compounds. Br J Pharmacol. 1998 Jun;124(4):669–74.
3 Halpert A, Dalton CB, Diamant NE, et al. Clinical response to
tricyclic antidepressants in functional bowel disorders is not related to
dosage. Am J Gastroenterol. 2005 Mar;100(3):664–71.
4 Morgan V, Pickens D, Gautam S, et al. Amitriptyline reduces rectal
pain related activation of the anterior cingulate cortex in patients with
irritable bowel syndrome. Gut. 2005 May;54(5):601–7.
5 Nickel JC. Interstitial cystitis. Etiology, diagnosis, and treatment. Can
Fam Physician. 2000 Dec;46:2430–4, 2437–40.
6 Theoharides TC, Papaliodis D, Tagen M, et al. Chronic fatigue
syndrome, mast cells, and tricyclic antidepressants. J Clin Psychophar-
macol. 2005 Dec;25(6):515–20.
7 O’Malley PG, Jackson JL, Santoro, et al. Antidepressant therapy for
unexplained symptoms and symptom syndromes. J Fam Pract. 1999
Dec;48(12):980–90.
9 Derek Enlander, M.D., on the Treatment of Chronic Fatigue
Syndrome and Fibromyalgia. http://www.immunesupport.com/library/
10 Scudds RA, McCain GA, Rollman GB, et al. Improvements in pain
responsiveness in patients with fibrositis after successful treatment with
amitriptyline. J Rheumatol Suppl. 1989 Nov;19:98–103.
11 Carette S, McCain GA, Bell DA, et al. Evaluation of amitriptyline in
primary fibrositis. A double–blind, placebo–controlled study. Arthritis
Rheum. 1986 May;29(5):655–9.
12 Hannonen P, Malminiemi K, Yli–Kerttula U, et al. A randomized,
double–blind, placebo–controlled study of moclobemide and amitripty-
line in the treatment of fibromyalgia in females without psychiatric
disorder. Br J Rheumatol. 1998 Dec;37(12):1279–86.
13 Carette S, Bell MJ, Reynolds WJ, et al. Comparison of amitriptyline,
cyclobenzaprine, and placebo in the treatment of fibromyalgia. A rando-
mized, double–blind clinical trial. Arthritis Rheum. 1994 Jan;37(1):32–
40.
14 Ho KY, Huh BK, White WD, et al. Topical amitriptyline versus lido-
caine in the treatment of neuropathic pain. Clin J Pain. 2008 Jan;24(1):
51–5.
15 David S Bell, MD | Lyndonville News | Vol. 2 No. 1. http://www.
16 Gracious B, Wisner KL. Nortriptyline in chronic fatigue syndrome: a
double blind, placebo–controlled single case study. Biol Psychiatry.
1991 Aug 15;30(4):405–8.
17 Heymann RE, Helfenstein M, Feldman D. A double–blind, rando-
mized, controlled study of amitriptyline, nortriptyline and placebo in
patients with fibromyalgia. An analysis of outcome measures. Clin Exp
Rheumatol. 2001 Nov–Dec;19(6):697–702.
18 Tomasi PA, Siracusano S, Monni AM. Decreased nocturnal urinary
antidiuretic hormone excretion in enuresis is increased by imipramine.
BJU Int. 2001 Dec;88(9):932–7.
19 Wysenbeek AJ, Mor F, Lurie Y, et al. Imipramine for the treatment
of fibrositis: a therapeutic trial. Ann Rheum Dis. 1985 Nov;44(11):752–
3.
21 Max MB, Kishore–Kumar R, Schafer SC, et al. Efficacy of desipra-
mine in painful diabetic neuropathy: a placebo–controlled trial. Pain.
1991 Apr;45(1):3–9.
22 Wilens TE, Biederman J, Prince J, et al. Six–week, double–blind,
placebo–controlled study of desipramine for adult attention deficit
hyperactivity disorder. Am J Psychiatry. 1996 Sep;153(9):1147–53.
23 Atkinson JH, Slater MA, Capparelli EV, et al. Efficacy of noradre-
nergic and serotonergic antidepressants in chronic back pain: a prelimi-
nary concentration–controlled trial. J Clin Psychopharmacol. 2007 Apr;
27(2):135–42.
24 Berger M, Gastpar M. Trimipramine: a challenge to current concepts
on antidepressives. Eur Arch Psychiatry Clin Neurosci. 1996;246(5):
235–9.
25 Macfarlane JG, Jalali S, Grace EM. Trimipramine in rheumatoid
arthritis: a randomized double–blind trial in relieving pain and joint ten-
derness. Curr Med Res Opin. 1986;10(2):89–93.
26 Myren J, Lövland B, Larssen SE, et al. Psychopharmacologic drugs
in the treatment of the irritable bowel syndrome. A double blind study
of the effect of trimipramine. Ann Gastroenterol Hepatol (Paris). 1984
May–Jun;20(3):117–23.
27 Ferguson JM, Mendels J, Manowitz NR. Dothiepin versus doxepin in
major depression: results of a multicenter, placebo–controlled trial. Pro-
thiaden Collaborative Study Group. J Clin Psychiatry. 1994 Jun;55(6):

258–63.
28 Welch CP, Tweed JA, Smithers A, et al. A double–blind,
comparative study of dothiepin and clomipramine in the treatment of
major depressive illness. Int J Clin Pract. 1997 Sep;51(6):360–3.
29 Caruso I, Sarzi Puttini PC, Boccassini L et al. Double–blind study of
dothiepin versus placebo in the treatment of primary fibromyalgia synd-
rome. J Int Med Res. 1987 May–Jun;15(3):154–9.
30 Ash G, Dickens CM, Creed FH, et al. The effects of dothiepin on
subjects with rheumatoid arthritis and depression. Rheumatology
(Oxford). 1999 Oct;38(10):959–67.
org/experts.htm
34 How to differentiate CFS from Psychiatric Disorder by Eleanor
Stein, MD FRCP(C). http://www.ahmf.org/medpolstein.htm
35 Lieb J. The immunostimulating and antimicrobial properties of lithi-
um and antidepressants. J Infect. 2004 Aug;49(2):88–93.
36 Munoz–Bellido JL, Munoz–Criado S, Garcìa–Rodrìguez JA.
Antimicrobial activity of psychotropic drugs: selective serotonin
reuptake inhibitors. Int J Antimicrob Agents. 2000 Apr;14(3):177–80.
37 Lass–Flörl C, Dierich MP, Fuchs D, et al. Antifungal properties of
selective serotonin reuptake inhibitors against Aspergillus species in vit-
ro. J Antimicrob Chemother. 2001 Dec;48(6):775–9.
38 Vercoulen JH, Swanink CM, Zitman FG, et al. Randomised, double–
blind, placebo–controlled study of fluoxetine in chronic fatigue syndro-
me. Lancet. 1996 Mar 30;347(9005):858–61.
39 Klimas Nancy G, Morgan Robert, Van Riel Flavia, Fletcher Mary
Ann. Observations Regarding the Use of an Antidepressant, Fluoxetine,
in Chronic Fatigue Syndrome. In the book: Goodnick Paul J, Klimas
Nancy G. Chronic Fatigue and Related Immune Deficiency Syndromes.
American Psychiatric Publishing 1993. pp. 95–108.
40 Arnold LM, Hess EV, Hudson JI, et al. A randomized, placebo–cont-
rolled, double–blind, flexible–dose study of fluoxetine in the treatment
of women with fibromyalgia. Am J Med. 2002 Feb 15;112(3):191–7.
41 Cortet B, Houvenagel E, Forzy G, et al. [Evaluation of the effective-
ness of serotonin (fluoxetine hydrochloride) treatment. Open study in
fibromyalgia]. Rev Rhum Mal Osteoartic. 1992 Jul–Sep;59(7–8):497–

500.
42 Wolfe F, Cathey MA, Hawley DJ. A double–blind placebo
controlled trial of fluoxetine in fibromyalgia. Scand J Rheumatol.
1994;23(5):255–9.
43 Ozerbil O, Okudan N, Gökbel H, et al. Comparison of the effects of
two antidepressants on exercise performance of the female patients with
fibromyalgia. Clin Rheumatol. 2006 Jul;25(4):495–7.
44 Goldenberg D, Mayskiy M, Mossey C, et al. A randomized, double–
blind crossover trial of fluoxetine and amitriptyline in the treatment of
fibromyalgia. Arthritis Rheum. 1996 Nov;39(11):1852–9.
45 Vahedi H, Merat S, Rashidioon A, et al. The effect of fluoxetine in
patients with pain and constipation–predominant irritable bowel syndro-
me: a double–blind randomized–controlled study. Aliment Pharmacol
Ther. 2005 Sep 1;22(5):381–5.
46 Schreiber S, Pick CG. From selective to highly selective SSRIs: a
comparison of the antinociceptive properties of fluoxetine, fluvoxamine,
citalopram and escitalopram. Eur Neuropsychopharmacol. 2006 Aug;16
(6):464–8
47 Nishikai M, Akiya K. Fluvoxamine therapy for fibromyalgia. J
Rheumatol. 2003 May;30(5):1124.
48 ter Borg PC, van Os E, van den Broek WW, et al. Fluvoxamine for
fatigue in primary biliary cirrhosis and primary sclerosing cholangitis: a
randomised controlled trial [ISRCTN88246634]. BMC Gastroenterol.
2004 Jul 13;4:13.
49 Behan PO, Haniffah BAG, Doogan DP, et al. A pilot study of sertra-
line for the treatment of chronic fatigue syndrome. Clin Infect Dis.
1994;18 Suppl 1:S111.
50 González–Viejo MA, Avellanet M, Hernández–Morcuende MI. [A
comparative study of fibromyalgia treatment: ultrasonography and
physiotherapy versus sertraline treatment]. Ann Readapt Med Phys.
2005 Nov;48(8):610–5.
51 The ME Association – Treatment – Lustral/setraline in ME/CFS.
http://web.archive.org/web/20061221131218/http://www.meassociation.
org.uk/sertraline.htm
52 Stepwise Approach to Fibromyalgia and Chronic Fatigue Syndrome
By Charles Lapp, M.D. http://www.immunesupport.com/library/show
53 Goldstein Jay. Betrayal by the Brain: The Neurologic Basis of
Chronic Fatigue Syndrome, Fibromyalgia Syndrome, and Related
Neural Network Disorders. Haworth Medical Press 1996. p. 17.
54 Finkel MS, Laghrissi–Thode F, Pollock BG, et al. Paroxetine is a

novel nitric oxide synthase inhibitor. Psychopharmacol Bull. 1996;32
(4):653–8.
55 Pall ML. Nitric oxide synthase partial uncoupling as a key switching
mechanism for the NO/ONOO– cycle. Med Hypotheses. 2007;69(4):
821–5
56 Patkar AA, Masand PS, Krulewicz S, et al. A randomized,
controlled, trial of controlled release paroxetine in fibromyalgia. Am J
Med. 2007 May;120(5):448–54.
57 Di Girolamo E, Di Iorio C, Sabatini P, et al. Effects of paroxetine
hydrochloride, a selective serotonin reuptake inhibitor, on refractory
vasovagal syncope: a randomized, double–blind, placebo–controlled
study. J Am Coll Cardiol. 1999 Apr;33(5):1227–30.
58 Amsterdam JD, Shults J, Rutherford N. Open–label study of s–citalo-
pram therapy of chronic fatigue syndrome and co–morbid major depres-
sive disorder. Prog Neuropsychopharmacol Biol Psychiatry. 2008 Jan
1;32(1):100–6.
59 Nørregaard J, Volkmann H, Danneskiold–Samsøe B. A randomized
controlled trial of citalopram in the treatment of fibromyalgia. Pain.
1995 Jun;61(3):445–9.
60 Anderberg UM, Marteinsdottir I, von Knorring L. Citalopram in pati-
ents with fibromyalgia—a randomized, double–blind, placebo–control-
led study. Eur J Pain. 2000;4(1):27–35.
61 Schreiber S, Pick CG. From selective to highly selective SSRIs: a
comparison of the antinociceptive properties of fluoxetine, fluvoxamine,
citalopram and escitalopram. Eur Neuropsychopharmacol. 2006 Aug;16
(6):464–8.
62 Postural Orthostatic Tachycardia Syndrome. http://home.att.net/~pots
web/POTS.html
63 Tack J, Broekaert D, Fischler B, et al. A controlled crossover study
of the selective serotonin reuptake inhibitor citalopram in irritable bowel
syndrome. Gut. 2006 Aug;55(8):1095–103
64 Hartz AJ, Bentler SE, Brake KA, et al. The effectiveness of citalo-
pram for idiopathic chronic fatigue. J Clin Psychiatry. 2003 Aug;64(8):
927–35.
65 Egashira N, Matsumoto Y, Mishima K, et al. Low dose citalopram
reverses memory impairment and electroconvulsive shock–induced
immobilization. Pharmacol Biochem Behav. 2006 Jan;83(1):161–7.
66 Littlejohn GO, Guymer EK. Fibromyalgia syndrome: which antidep-
ressant drug should we choose. Curr Pharm Des. 2006;12(1):3–9.
67 Grothe DR, Scheckner B, Albano D. Treatment of pain syndromes

with venlafaxine. Pharmacotherapy. 2004 May;24(5):621–9.
69 Dwight MM, Arnold LM, O'Brien H, et al. An open clinical trial of
venlafaxine treatment of fibromyalgia. Psychosomatics. 1998 Jan–Feb;
39(1):14–7.
70 Sayar K, Aksu G, Ak I, Tosun M. Venlafaxine treatment of fibromy-
algia. Ann Pharmacother. 2003 Nov;37(11):1561–5.
71 How to differentiate CFS from Psychiatric Disorder by Eleanor
Stein, MD FRCP(C). http://www.ahmf.org/medpolstein.htm
72 Arnold LM, Rosen A, Pritchett YL, et al. A randomized, double–
blind, placebo–controlled trial of duloxetine in the treatment of women
with fibromyalgia with or without major depressive disorder. Pain. 2005
Dec 15;119(1–3):5–15.
73 Arnold LM, Lu Y, Crofford LJ, et al. A double–blind, multicenter
trial comparing duloxetine with placebo in the treatment of fibromyalgia
patients with or without major depressive disorder. Arthritis Rheum.
2004 Sep;50(9):2974–84.
74 Russell IJ, Mease PJ, Smith TR, et al. Efficacy and safety of duloxe-
tine for treatment of fibromyalgia in patients with or without major dep-
ressive disorder: Results from a 6-month, randomized, double-blind,
placebo-controlled, fixed-dose trial. Pain. In press.
75 Double Blind Trial of Duloxetine in Chronic Fatigue Syndrome.
http://www.clinicaltrials.gov/ct2/show/NCT00375973
76 Steers WD, Herschorn S, Kreder KJ. Duloxetine compared with pla-
cebo for treating women with symptoms of overactive bladder. BJU Int.
2007 Aug;100(2):337–45.
77 Sato S, Yamakawa Y, Terashima Y, et al. Efficacy of milnacipran on
cognitive dysfunction with post–stroke depression: preliminary open–
label study. Psychiatry Clin Neurosci. 2006 Oct;60(5):584–9.
78 Vitton O, Gendreau M, Gendreau J, et al. A double–blind placebo–
controlled trial of milnacipran in the treatment of fibromyalgia. Hum
Psychopharmacol. 2004 Oct;19 Suppl 1:S27–35.
79 Gendreau RM, Thorn MD, Gendreau JF, et al. Efficacy of milnacip-
ran in patients with fibromyalgia. J Rheumatol. 2005 Oct;32(10):1975–
85.
80 Larrosa O, de la Llave Y, Bario S, et al. Stimulant and anticataplectic
effects of reboxetine in patients with narcolepsy: a pilot study. Sleep.
2001 May 1;24(3):282–5.
81 Method of treating chronic fatigue syndrome. United States Patent

20060128705. http://www.freepatentsonline.com/20060128705.html
82 Krell HV, Leuchter AF, Cook IA, et al. Evaluation of reboxetine, a
noradrenergic antidepressant, for the treatment of fibromyalgia and
chronic low back pain. Psychosomatics. 2005 Sep–Oct;46(5):379–84.
83 Tzavara ET, Bymaster FP, Overshiner CD, et al. Procholinergic and
memory enhancing properties of the selective norepinephrine uptake
inhibitor atomoxetine. Mol Psychiatry. 2006 Feb;11(2):187–95.
84 Calabrese JR, Shelton MD, Rapport DJ, et al. Current research on
rapid cycling bipolar disorder and its treatment. J Affect Disord. 2001
Dec;67(1–3):241–55.
85 Brustolim D, Ribeiro–dos–Santos R, Kast RE, et al. A new chapter
opens in anti–inflammatory treatments: the antidepressant bupropion
lowers production of tumor necrosis factor–alpha and interferon–gamma
in mice. Int Immunopharmacol. 2006 Jun;6(6):903–7.
86 Semenchuk MR, Sherman S, Davis B, et al. Double–blind, randomi-
zed trial of bupropion SR for the treatment of neuropathic pain.
Neurology. 2001 Nov 13;57(9):1583–8.
87 Kim SW, Shin IS, Kim JM, et al. Bupropion may improve restless
legs syndrome: a report of three cases. Clin Neuropharmacol. 2005
Nov–Dec;28(6):298–301.
88 Goodnick PJ, Sandoval R, Brickman A, et al. Bupropion treatment of
fluoxetine–resistant chronic fatigue syndrome. Biol Psychiatry. 1992
Nov 1;32(9):834–8.
89 Schonfeldt–Lecuona C, Connemann BJ, Wolf RC, et al. Bupropion
augmentation in the treatment of chronic fatigue syndrome with coexis-
tent major depression episode. Pharmacopsychiatry. 2006
Jul;39(4):152–4.
91 Chronic fatigue syndrome: A Primer For Physicians and Allied
Health Professional. http://www.masscfids.org/publications/CFS_
Primer/med.htm
93 Hannonen P, Malminiemi K, Yli–Kerttula U, et al. A randomized,
double–blind, placebo–controlled study of moclobemide and amitripty-
line in the treatment of fibromyalgia in females without psychiatric
disorder. Br J Rheumatol. 1998 Dec;37(12):1279–86.
94 Ginsberg F, Joos E, Géczy J, et al. A pilot randomized placebo–

controlled study of pirlindole in the treatment of primary fibromyalgia. J
Musculoskelet Pain. 1998;6(2):5–17.
95 White P, Cleary K. An open study of the efficacy and adverse effects
of moclobemide in patients with chronic fatigue syndrome. Int Clin
Psychopharmacol. 1997;12(1):47–52.
96 Hickie I, Wilson A, Wright M, et al. A randomized, double–blind
placebo–controlled trial of moclobemide in patients with chronic fatigue
syndrome. J Clin Psychiatry. 2000;61(9):643– 648
97 Meienberg O, Amsler F. [Preventive treatment of migraine and chro-
nic tension headache with moclobemide]. Schweiz Rundsch Med Prax.
1997 Jul 2;86(27–28):1107–12.
98 Merikangas KR, Merikangas JR. Combination monoamine oxidase
inhibitor and beta–blocker treatment of migraine, with anxiety and dep-
ression. Biol Psychiatry. 1995 Nov 1;38(9):603–10.
99 Natelson BH, Cheu J, Pareja J, et al. Randomized, double blind,
controlled placebo–phase in trial of low dose phenelzine in the chronic
fatigue syndrome. Psychopharmacology (Berl). 1996 Apr;124(3):226–
30.
100 Gupta M, Kulkarni SK. Studies on anticonvulsant actions of L–dep-
renyl. Indian J Exp Biol. 2000 Apr;38(4):332–7.
101 Natelson B, Cheu J, Hill N, et al. Single–blind, placebo phase–in
trial of two escalating doses of selegiline in the chronic fatigue syndro-
me. Neuropsychobiology. 1998;37(3):150–154.
102 Wilson RC. The use of low–dose trazodone in the treatment of
painful diabetic neuropathy. J Am Podiatr Med Assoc. 1999
Sep;89(9):468–71.
103 Davidoff G, Guarracini M, Roth E, et al. Trazodone hydrochloride
in the treatment of dysesthetic pain in traumatic myelopathy: a randomi-
zed, double–blind, placebo–controlled study. Pain. 1987
May;29(2):151–61.
104 Tammiala–Salonen T, Forssell H. Trazodone in burning mouth
pain: a placebo–controlled, double–blind study. J Orofac Pain. 1999
Spring;13(2):83–8.
clinical-care.pdf
106 Report from the Chronic Fatigue Syndrome – State of the Science
Conference. http://www.immunesupport.com/library/showarticle.cfm/
ID/2886/

108 eMedicine – Fibromyalgia: Article by Regina P Gilliland, MD.
http://www.emedicine.com/PMR/topic47.htm
109 Pick CG, Paul D, Eison MS, et al. Potentiation of opioid analgesia
by the antidepressant nefazodone. Eur J Pharmacol. 1992 Feb 18;211
(3):375–81.
110 Hickie I. Nefazodone for patients with chronic fatigue syndrome.
Aust N Z J Psychiatry. 1999 Apr;33(2):278–80.
111 Goodnick PJ, Jorge CM. Treatment of chronic fatigue syndrome
with nefazodone. Am J Psychiatry. 1999 May;156(5):797–8.
112 Samborski W, Lezanska–Szpera M, Rybakowski JK. Open trial of
mirtazapine in patients with fibromyalgia. Pharmacopsychiatry. 2004
Jul;37(4):168–70.
clinical-care.pdf
114 Bendtsen L, Jensen R. Mirtazapine is effective in the prophylactic
treatment of chronic tension–type headache. Neurology. 2004 May 25;
62(10):1706–11.
115 Pakulska W, Czarnecka E. Influence of mianserin on the antinoci-
ceptive effect of morphine, metamizol and indomethacin in mice. Phar-
macol Res. 2002 Nov;46(5):415–23.
116 Schreiber S, Backer MM, Kaufman JP, et al. Interaction between
the tetracyclic antidepressant mianserin HCl and opioid receptors. Eur
Neuropsychopharmacol. 1998 Dec;8(4):297–302.
117 Tabeeva GR, Levin IaI, Korotkova SB, et al. [Treatment of fibro-
myalgia]. Zh Nevrol Psikhiatr Im S S Korsakova. 1998;98(4):40–3.
118 McMillen BA, Matthews RT, Sanghera MK, et al. Dopamine
receptor antagonism by the novel antianxiety drug, buspirone. J
Neurosci. 1983 Apr;3(4):733–8.
119 Giordano J, Rogers L. Antinociceptive effects of the novel anxioly-
tic buspirone in three pain tests in rats. Pain. 1989 Oct;39(1):109–13.
120 Pakulska W, Czarnecka E. Effect of citalopram and buspirone on
the antinociceptive action of analgesic drugs. Acta Pol Pharm. 2001 Jul–
Aug;58(4):299–305.
121 Gitlin MJ. Effects of depression and antidepressants on sexual func-
tioning. Bull Menninger Clin. 1995 Spring;59(2):232–48.
122 Mitsikostas DD, Gatzonis S, Thomas A, et al. Buspirone vs amitrip-
tyline in the treatment of chronic tension–type headache. Acta Neurol
Scand. 1997 Oct;96(4):247–51.
123 Pascual J, Berciano J. An open trial of buspirone in migraine prop-

hylaxis. Preliminary report. Clin Neuropharmacol. 1991 Jun;14(3):245–
50.
125 Meltzer HY, Flemming R, Robertson A. The effect of buspirone on
prolactin and growth hormone secretion in man. Arch Gen Psychiatry.
1983 Oct;40(10):1099–102.
126 Behan PO. Post–Viral Fatigue Syndrome Research in Glasgow (a
review of lectures given by professor Peter O. Behan). In the book:
Hyde B, (ed.) The Clinical and Scientific Basis of Myalgic Encephalo-
myelitis/Chronic Fatigue Syndrome. The Nightingale Research Founda-
tion 1992. pp. 235–243.
127 H. Hooshman, M.D. Multiple Sclerosis (MS). http://www.rsdrx.
com/Multiple%20Sclerosis.htm
128 El–Shafey H, Atteya A, el–Magd SA, et al. Tianeptine can be effec-
tive in men with depression and erectile dysfunction. J Sex Med. 2006
Sep;3(5):910–7.
129 Lechin F, van der Dijs B, Lechin AE. Treatment of bronchial asth-
ma with tianeptine. Methods Find Exp Clin Pharmacol. 2004 Nov;26(9):
697–701.
130 Niederhofer H. Tianeptine as a slightly effective therapeutic option
for attention–deficit hyperactivity disorder. Neuropsychobiology. 2004;
49(3):130–3.
131 Plaisant F, Dommergues MA, Spedding M, et al. Neuroprotective
properties of tianeptine: interactions with cytokines. Neuropharmaco-
logy. 2003 May;44(6):801–9.
132 Delbende C, Contesse V, Mocaër E, et al. The novel antidepressant,
tianeptine, reduces stress– evoked stimulation of the hypothalamo–pitui-
tary–adrenal axis. Eur J Pharmacol. 1991 Sep 24;202(3):391–6.
133 Uzbay IT, Cinar MG, Aytemir M, et al. Analgesic effect of tianep-
tine in mice. Life Sci. 1999;64(15):1313–9.
134 Tianeptine for the treatment of fibromyalgia: a prospective double–
blind, randomised, single–centre, placebo–controlled, parallel group
study. http://www.controlled-trials.com/ISRCTN16400909/
135 Use of tianeptine in the production of medicaments to treat neuro-
degenerative pathologies. United States Patent 6599896. http://www.
freepatentsonline.com/6599896.html
136 Compositions and methods for treatment of irritable bowel syndro-
me and nonulcer dyspepsia. United States Patent 6683072. http://www.
freepatentsonline.com/6683072.html
137 Papakostas GI, Alpert JE, Fava M. S–adenosyl–methionine in

depression: a comprehensive review of the literature. Curr Psychiatry
Rep. 2003 Dec;5(6):460–6.
138 Volkmann H, Nørregaard J, Jacobsen S, et al. Double–blind, place-
bo–controlled cross–over study of intravenous S–adenosyl–L–
methionine in patients with fibromyalgia. Scand J Rheumatol.
1997;26(3):206–11.
139 Tavoni A, Vitali C, Bombardieri S, et al. Evaluation of S–adenosyl-
methionine in primary fibromyalgia. A double–blind crossover study.
Am J Med. 1987 Nov 20;83(5A):107–10.
140 Tavoni A, Jeracitano G, Cirigliano G. Evaluation of S–adenosyl-
methionine in secondary fibromyalgia: a double–blind study. Clin Exp
Rheumatol. 1998 Jan–Feb;16(1):106–7.
141 Jacobsen S, Danneskiold–Samsøe B, Andersen RB. Oral S–adeno-
sylmethionine in primary fibromyalgia. Double–blind clinical evalua-
tion. Scand J Rheumatol. 1991;20(4):294–302.
142 Sarzi Puttini P, Caruso I. Primary fibromyalgia syndrome and 5–
hydroxy–L–tryptophan: a 90–day open study. J Int Med Res. 1992 Apr;
20(2):182–9.
143 Caruso I, Sarzi Puttini P, Cazzola M, et al. Double–blind study of
5–hydroxytryptophan versus placebo in the treatment of primary
fibromyalgia syndrome. J Int Med Res. 1990 May–Jun;18(3):201–9.
144 Nicolodi M, Sicuteri F. Fibromyalgia and migraine, two faces of the
same mechanism. Serotonin as the common clue for pathogenesis and
therapy. Adv Exp Med Biol. 1996;398:373–9.
145 Kiser RS, Cohen HM, Freedenfeld RN, et al. Olanzapine for the
treatment of fibromyalgia symptoms. J Pain Symptom Manage. 2001
Aug;22(2):704–8.
146 Freedenfeld RN, Murray M, Fuchs PN, et al. Decreased pain and
improved quality of life in fibromyalgia patients treated with olanza-
pine, an atypical neuroleptic. Pain Pract. 2006 Jun;6(2):112–8.
147 Rico–Villademoros F, Hidalgo J, Dominguez I, et al. Atypical anti-
psychotics in the treatment of fibromyalgia: a case series with olanza-
pine. Prog Neuropsychopharmacol Biol Psychiatry. 2005
Jan;29(1):161–4.
149 David S Bell, MD | Lyndonville News | Vol. 2 No. 1. http://www.
150 Nickel MK, Nickel C, Muehlbacher M, et al. Influence of topira-

mate on olanzapine–related adiposity in women: a random, double–
blind, placebo–controlled study. J Clin Psychopharmacol. 2005
Jun;25(3):211–7.
151 Pae CU, Kim JJ, Lee KU, et al. Effect of nizatidine on olanzapine–
associated weight gain in schizophrenic patients in Korea: a pilot study.
Hum Psychopharmacol. 2003 Aug;18(6):453–6.
Chronic Fatigue Syndrome, Fibromyalgia Syndrome, and Related Neu-
ral Network Disorders. Haworth Medical Press 1996. pp. 167–169.
ral Network Disorders. Haworth Medical Press 1996. p. 177.
155 Smeraldi E. Amisulpride versus fluoxetine in patients with dysthy-
mia or major depression in partial remission: a double–blind, compara-
tive study. J Affect Disord. 1998 Feb;48(1):47–56.
156 Lopez–Gonzalez MA, Santiago AM, Esteban–Ortega F. Sulpiride
and melatonin decrease tinnitus perception modulating the auditolimbic
dopaminergic pathway. J Otolaryngol. 2007 Aug;36(4):213–9.
157 Goldstein Jay. Tuning the Brain: Principles and Practice of Neuro-
somatic Medicine. Haworth Press 2004. p. 380.
158 Hidalgo J, Rico–Villademoros F, Calandre EP. An open–label study
of quetiapine in the treatment of fibromyalgia. Prog Neuropsychophar-
macol Biol Psychiatry. 2007 Jan 30;31(1):71–7.
159 Calandre EP, Morillas–Arques P, Rodriguez–Lopez CM, et al. Pre-
gabalin augmentation of quetiapine therapy in the treatment of fibro-
myalgia: an open–label, prospective trial. Pharmacopsychiatry. 2007
Mar;40(2):68–71.
160 Rybakowski JK. Antiviral and immunomodulatory effect of lithium.
Pharmacopsychiatry. 2000 Sep;33(5):159–64.
161 Tyber MA. Lithium carbonate augmentation therapy in fibromyal-
gia. CMAJ. 1990 Nov 1;143(9):902–4.
162 Teitelbaum Jacob. From Fatigued to Fantastic!: A Proven Program
to Regain Vibrant Health, Based on a New Scientific Study Showing
p. 81.
CHAPTER 6.
Stimulants and nootropics
Sympathomimetic and dopaminergic drugs
Sympathomimetic drugs stimulate the sympathetic nervous system,

similar to our endogenous sympathomimetic amines, epinephrine (adre-
naline) and norepinephrine (noradrenaline). They are usually activating.
Dopaminergic drugs can be very stimulating or sedative, depending on
which dopamine receptors are affected and also on individual differen-
ces. Some sympathomimetic drugs such as amphetamines also release
dopamine in the brain. Fibromyalgia and some related conditions have
been suggested to be deficiencies of sympathomimetic amines.1
Dopamine is a neurotransmitter which is important for e.g. vigi-
lance and cognition. It is also associated with feelings of pleasure—
almost all recreational drugs increase dopamine levels in the brain. The
symptoms of Parkinson’s disease are caused by a lack of dopamine.
Low dopamine has also been implicated in ADHD and depression. Ex-
cess dopamine is thought to cause psychosis. All current antipsychotics
(CHAPTER 5) are antagonists (or partial agonists) of dopamine receptors.
A deficiency of dopamine has been postulated in CFS/ME and
especially fibromyalgia. A study using PET imaging showed that people
with fibromyalgia do not experience a similar release of dopamine in the
brain as healthy people do.2 Another PET study demonstrated reduced
presynaptic dopamine activity in patients with FM.3 The main author of
these studies has suggested stress as a cause for this dopaminergic dys-
function.4
High levels of prolactin have been found in post–polio syndrome.
As excessive prolactin signifies dopamine deficiency, it has been sug-
gested that the symptoms of PPS and other “post–viral fatigue syndro-
mes” are caused by dopamine depletion, which could be treated with
dopaminergic drugs.5 A study found that the majority of women with
hyperprolactinemia have fibromyalgia.6
Dr. Jay Goldstein believes that dopamine plays an important part in
the pathophysiology of CFS/ME and fibromyalgia. He thinks the dys-
function may be located at the dopamine receptors, but that dopamine
secretion might also be impaired.7 In animal studies dopaminergic drugs
reduce the production of nitric oxide and TNF alpha in peripheral neut-
Stimulants and nootropics 155
rophils.8 This anti–inflammatory effect might explain the benefits of

dopaminergic drugs in CFS/ME and fibromyalgia.
All kinds of stimulants can cause restlessness, overstimulation and
insomnia. Some people cannot tolerate them at all. On the other hand
some dopaminergic drugs can cause narcolepsy–like sleeping attacks.
They also have other peculiar but very rare side effects, such as patholo-
gical gambling and other forms of obsessive behavior. Ergot alkaloids
may cause cardiac fibrosis (thickening of the heart valves). Sympatho-
mimetic drugs are contraindicated when using MAO inhibitors.
See also:
protriptyline, desipramine, norepinephrine reuptake inhibitors,

selegiline (CHAPTER 5), amantadine (CHAPTER 9), naphazoline
(CHAPTER 10)
methylphenidate (Ritalin, Concerta, Rubifen, Equasym,

Ritalina)
Methylphenidate is a sympathomimetic drug used to treat ADHD,

sometimes narcolepsy and even depression. It may be employed to com-
bat fatigue and cognitive problems in CFS/ME and fibromyalgia. A
double–blinded study achieved fairly good results in a subset of CFS/
ME patients.9
Lucinda Bateman prescribes methylphenidate for her CFS/ME pati-
ents in dose of 5–20 mg 2–3 times a day.10 Dr. Charles Lapp also
recommends methylphenidate for CFS/ME.11 The drug often works well
initially, but tolerance may develop with time. Methylphenidate potenti-
ates opioid analgesia and reduces opioid–induced sedation.12
Insomnia, restlessness, headache, tachycardia and arrhythmias are
common side effects. In some cases there can even be hallucinations.
Methylphenidate should not be used with venlafaxine or tricyclic anti-
depressants. E.g. fluoxetine, paroxetine, carbamazepine and ropinirole
can influence blood levels of the drug. It should be used with caution in
epilepsy and bipolar disorder.
Methylphenidate is widely available. It is available as immediate
release capsules and tablets, several modified release formulations and
as a transdermal patch (Daytrana). It is affordable.
amphetamine salts (Adderall)

dexamphetamine/dextroamphetamine (Dexedrine)
lisdexamphetamine (Vyvanse)
Amphetamines have a reputation as drugs of abuse, but as with

many other drugs, the problem is not the substance but the reckless use
for recreational purposes. Amphetamines are used as a treatment for
ADHD and can help other kinds of cognitive problems as well. They are
often effective for narcolepsy and severe chronic fatigue. In a placebo–
controlled pilot study dexamphetamine helped 9 out of the 10 patients
with CFS/ME.13
Amphetamines also have some interesting, non–intuitive uses.
There is a case report of two women with refractory interstitial cystitis
whose illness remitted in a matter of week with 20 mg of dexampheta-
mine a day.14 Another case report describes a woman whose intractable
pain from rheumatoid arthritis was alleviated by 10 mg dexampheta-
mine.15
There is a hypothesis that increased capillary permeability is an
etiologic factor in fibromyalgia and that amphetamines would help it, as
well as headaches, carpal tunnel syndrome and chronic urticaria.16 It has
been suggested that the weight loss properties of amphetamines are in
fact caused by the reduction of excessive vascular permeability, which
leads to reduced water retention (edema).17 Like methylphenidate,
amphetamines potentiate opioid analgesia and reduce the sedation
caused by opiates.18
The effects of amphetamines are significantly longer lasting than
those of methylphenidate. Dexamphetamine has a slightly shorter dura-
tion of action than amphetamine salts, but lisdexamphetamine lasts
longer than either of them. Jay Goldstein has found amphetamine salts
to be the stimulant of choice for people with CFS/ME or fibromyalgia,
and superior to other amphetamines.19 Amphetamines may be more like-
ly than methylphenidate to cause insomnia and loss of appetite.
Amphetamine salts are available in the United States, Canada and a
few other countries. Dexamphetamine is available in the United States,
the United Kingdom, Canada, Australia and some European countries.
Lisdexamphetamine is currently only available in the United States.
With the exception of lisdexamphetamine, the amphetamines are not
particularly expensive.
midodrine (ProAmatine, Amatine, Gutron)
Midodrine is an alpha–sympathomimetic drug (not an alpha block-

er, as some sources mistakenly list it, but the exact opposite) used to
treat orthostatic hypotension. It acts a vasoconstrictor and may improve
cerebral circulation, which may in turn improve attention.20 Midodrine
has a fairly short half–life and needs to be taken three times a day. It is
not recommended for use before bedtime or before lying down.
Mark Alexander reports improvement from midodrine in adoles-
cents with orthostatic intolerance and CFS/ME.21 He reports serious side
effects to be uncommon. One case report22 and one small study23 on the
use of midodrine in CFS/ME have been published, providing very
encouraging results. Dr. Jay Goldstein believes that the positive effects
of midodrine are not a result of the raised blood pressure, but due to the
stimulation of oxytocin release.24
Side effects may include tingling, itching and other sensations of
skin, cardiac symptoms and problems urinating. There can be drug inter-
actions with e.g. other sympathomimetics, heart medications, cimeti-
dine, ranitidine, metformin and ergotamine derivatives. Midodrine
should not be used in persons with hypertension. It can elevate blood
pressure too much even in hypotensive persons. Concomitant use of
fludrocortisone increases this risk.
Midodrine is available e.g. in the United States, Canada and some
other countries, but not in the United Kingdom or Australia. The high
price no doubt limits its availability to many patients.
etilefrine (Effortil)
Etilefrine is a sympathomimetic similar to midodrine, but it also

has some beta agonist activity. It is used for orthostatic hypotension, in
some countries also for nasal congestion and enuresis (bed wetting) in
children. It is usually taken in doses of 5–10 mg three times a day, but
people who are sensitive to medications may have to start at 1/4 of a
tablet (1.25 mg). Side effects are similar to midodrine.
Etilefrine is available in some countries in Europe, South America,
Asia and Africa, but not in the United States, the United Kingdom,
Canada or Australia. It is inexpensive.
ephedrine (Efedrin)
Ephedrine is an alpha/beta adrenergic sympathomimetic drug with

a fairly short half–life. It is used as a stimulant, cardiac stimulant, hyper-
tensive, decongestant and appetite suppressant, sometimes also for
asthma and cough. It is not considered a particularly good stimulant,
taking into account its efficacy and side effect profile, but occasionally
it has been prescribed for patients with CFS/ME.

The most common side effects are tachycardia, restlessness, insom-
nia and anxiety. Tremor, dry mouth, poor circulation in the extremities
and arrhythmias are also possible.
Ephedrine is available (in oral formulations) in the United States,
the United Kingdom and some other countries, but not in Canada or
Australia. It is mostly sold in combination products which may contain
other useful ingredients, such as guaifenesin, dextromethorphan or ace-
taminophen (paracetamol). It is usually inexpensive.
In the United States the sales of ephedrine are monitored, not
because it is considered particularly harmful or addictive, but because it
can be used in the manufacturing of amphetamines. In some countries
ephedrine is a prescription drug, but herbal ephedra products (which
contain ephedrine) are available over the counter. These products have
often been associated with possibly harmful impurities and contami-
nants.
phentermine (Ionamin, Adipex–P, Adipex, Duromine)
Phentermine is a sympathomimetic mostly used as an appetite

suppressant, but it is also a powerful stimulant which may help fatigue
and cognitive problems. Not all people lose weight on it, even if they
are overweight. It is similar to amphetamines and methylphenidate, but
some people with CFS/ME or fibromyalgia who have not benefited
from other stimulants (or have not been able to tolerate them) have
found phentermine very useful. The efficacy tends to decrease unless
there are frequent “drug holidays.”
Because phentermine has a long half–life, it often causes insomnia.
Other common side effects include cardiac symptoms, dizziness, head-
ache, restlessness, mood changes, nausea, tremor and dry mouth. The
contraindications are similar to amphetamines.
Phentermine is available in the United States, Canada, Australia
and some other countries, but not in the United Kingdom and most parts
of Europe. It is inexpensive.
levodopa and carbidopa (Sinemet)
Levodopa (L–dopa) is a precursor of dopamine which is used to

treat Parkinson’s disease. It is usually combined with carbidopa, which
slows down the breakdown of dopamine. It is sometimes used to treat
CFS/ME and fibromyalgia, particularly if the patient suffers from restl-
ess legs. Levodopa may also relieve neuropathic pain.25 Carbidopa by
itself can be used to increase the efficacy of 5–HTP.

The drug is available in several different versions with the ratio of
levodopa to carbidopa varying between 1:4 and 1:10. Dr. Richard Podell
mentions in the CFIDS Chronicle that he considers the best formulation
for RLS to be the 25/100 tablet (25 mg levodopa/100 mg of carbi-
dopa).26 Dr. Jacob Teitelbaum recommends either 10/100 or 25/100, but
only if zolpidem and clonazepam have already been tried.27 In studies
the doses used to treat RLS have been as high as 100/400 mg.28
The drug can cause involuntary movements, psychiatric symptoms,
nausea and dizziness. Caution should be used if the patient has a serious
cardiac, pulmonary or endocrinological condition or has suffered from
peptic ulcer or epileptic seizures. Some drugs can also impair the effi-
cacy of the treatment and vitamin B6 supplementation should be avoid-
ed. In long–term therapy monitoring of liver, kidney and other blood-
work is recommended. Treatment should not be abruptly discontinued.
The levodopa/carbidopa combination is available everywhere. It is
available as tablets, orally disintegrating tablets and modified release
tablets. It is inexpensive.
pramipexole (Mirapex, Mirapexin, Sifrol)
Pramipexole is a dopamine agonist used in the treatment of Parkin-

son’s disease and RLS, sometimes also for cluster headaches, bipolar
disorder and sexual side effects of SSRIs. Besides the D2 receptor, it
also binds to the D3 receptor, which provides neuroprotection.29 Prami-
pexole has shown significant benefit in fibromyalgia in a double–blind-
ed trial.30 Pain, fatigue and functionality were improved with 4.5 mg
dose. Many other variables also showed a trend for improvement, but
did not reach statistical significance.
Pramipexole may also be useful in CFS/ME. Dr. Lucinda Bateman
uses a low dose of 0.125–1.5 mg in the evening to treat sleep problems
in her patients.31 A patient has given an anecdotal account about reco-
vering from CFS/ME after 15 years of severe illness with the drug.32
There are also anecdotal reports of significant relief of myofascial pain.
Pramipexole can also help depression and anxiety.33 Usually the drug is
taken three times a day.
Pramipexole can cause sleep disturbances, sedation (even suddenly
falling asleep), nausea and stomach upset. In the aforementioned fibro-
myalgia study the most common side effects were anxiety and weight
loss. No patient discontinued the study because of side effects and
serious adverse reactions were actually reported more frequently in the
placebo arm. Amantadine and cimetidine may affect the plasma levels
of pramipexole.
Pramipexole is available in the United States, the United Kingdom,
Canada, Australia and many other countries. In low doses it is inexpen-
sive, but higher doses can get costly.
ropinirole (Requip, Repreve, Adartrel)
Ropinirole is a dopamine agonist that acts mainly at the D3 receptor

similar to pramipexole, also having some affinity for opioid receptors. It
is used for Parkinson’s disease and RLS, normally taken three times a
day. It has been used to treat the cognitive problems in CFS/ME and one
preliminary report has described good results in fibromyalgia.34 Side
effects are similar to pramipexole.
Ropinirole is available in the United States, the United Kingdom,
Canada, Australia and many other countries. Low doses are not
particularly expensive.
rotigotine (Neupro)
Rotigotine is an agonist of the D1, D2, and D3 dopamine receptors.

It is indicated for Parkinson’s disease. It has also been successfully tried
in restless legs syndrome35 and is in clinical trials for the treatment of
fibromyalgia.36 It is the only dopaminergic drug (aside from the MAO–
B inhibitor selegiline) available as a transdermal patch. Besides local
reactions at the patch site, side effects are similar to other dopamine
agonists. There are no known drug interactions.
Rotigotine is available in the United States, the United Kingdom,
Canada, Australia and some other, mostly European countries. It is only
available as 24–hour transdermal patches, in several different strengths.
The price is similar to ropinirole.
bromocriptine (Parlodel, Apo–Bromocriptine,

Bromergon, Serocryptin, Pravidel)
Bromocriptine is an ergot derived dopamine agonist, which is used

to treat Parkinson’s disease, menstrual problems and some pituitary con-
ditions, sometimes also RLS. It may have antidepressive properties.
Owing to its immunomodulatory properties it can be useful in e.g. SLE
and rheumatoid arthritis.37 It also acts as a free radical scavenger (anti-
oxidant).38
In CFS/ME bromocriptine has been reported to be potentially help-
ful in relieving fatigue, anxiety and cognitive symptoms. It increases
growth hormone secretion in people with normal growth hormone

levels, so it may also increase them in patients with CFS/ME and fibro-
myalgia. A study found bromocriptine very helpful for fatigue and cog-
nitive problems caused by post–polio syndrome.39 Bromocriptine impro-
ves glycemic control and glucose tolerance in patients with type II dia-
betes, so it could also work as a preventative.40
Side effects can include orthostatic hypotension, congestion, cons-
tipation, headache and sleepiness, sometimes also falling asleep. Bro-
mocriptine should not be used in patients with cardiovascular disease,
severe psychiatric problems, Raynaud’s phenomenon or peptic ulcers.
Azoles and some macrolides are contraindicated. Concomitant use with
other ergot derivatives, MAO inhibitors or SSRIs is not recommended.
Bromocriptine is available in the United States, the United King-
dom, Canada, Australia and many other countries. It is inexpensive.
modafinil (Provigil, Modasomil, Modiodal, Alertec)

armodafinil (Nuvigil)
adrafinil (Olmifon)
Modafinil has wakefulness–promoting effects, but differs from

classic stimulants in several ways. The exact mode of action is unclear,
but modafinil appears to inhibit the reuptake of dopamine and norepi-
nephrine as well as having glutamatergic action. Armodafinil is the R–
isomer of racemic modafinil, which has a longer duration of action than
the S–isomer. Adrafinil is a prodrug that metabolizes to modafinil in the
body.
Modafinil is approved for the treatment of narcolepsy and in some
countries also for hypersomnia. It has been used to augment the efficacy
of SSRI antidepressants.41 Many people with chronic fatigue, depression
and ADHD find it helpful. Sometimes modafinil is regarded as a nootro-
pic instead of a stimulant, because it enhances cognition.42 Patients with
multiple sclerosis often report reduced fatigue. For some reason in mul-
tiple sclerosis small doses have proven more effective than larger ones.43
Three studies have evaluated modafinil for CFS/ME. Two smaller
ones got encouraging results44,45, but the third one was not quite as pro-
mising.46 A few papers have published preliminary results about the suc-
cessful use of modafinil to treat fatigue in fibromyalgia.47,48 Lucinda
Bateman uses modafinil in a dose of 50–400 mg in CFS/ME.49 Nonethe-
less CFS/ME expert Paul Cheney is concerned that modafinil is harmful
in the long term, because it activates the NMDA receptor.50
Generally the drugs are well tolerated, but CFS/ME patients are
prone to headache and restlessness. Dizziness, visual disturbances, nau-
sea, loss of appetite, anxiety and insomnia can occur. Modafinil can de-
crease the efficacy of oral contraceptives and elevate the blood levels of
e.g. triazolam, diazepam and propranolol. Concurrent use with tricyclic
antidepressants or MAO inhibitors is not recommended. With adrafinil
regular bloodwork is warranted to monitor liver enzymes.
Modafinil is available in the United States, the United Kingdom,
Canada, Australia and some other countries. In some countries it requi-
res a special permit. In the United States it is classified as a Schedule IV
substance. Armodafinil is only available in the United States and a few
other countries. Both of the drugs are very expensive. Adrafinil is avail-
able in France and carries a much cheaper price tag. It is not regulated in
the United States.
Nootropics
The word nootropic comes from the Greek words “noos” (mind)
and “tropein” (to bend). They are also known as “smart drugs,” but of
course they do not make anyone intelligent as such. They can be useful
for enhancing cognition (memory, concentration and performance
speed). Most nootropics are effective for both healthy people and those
suffering from a neurological condition, such as dementia or brain da-
mage caused by accident or stroke.
Nootropics are not the same things as stimulants and the majority
of them cannot be considered to be “psychiatric drugs,” but there are se-
veral possible modes of action. Most nootropics are either cholinergic
(increase the amount of acetylcholine in the brain) or improve cerebral
circulation (which can be done by several different ways), often both.
Sometimes other mechanisms are also involved.
There are nonetheless clear differences among different nootropics.
Some work better for memory (especially cholinergic drugs) and others
improve concentration. Some tend to improve word recall and others
facilitate learning of new things. The effects are also highly individual.
What feels too speedy to one person may be wonderfully calming for
someone else. Some people find they need to take multiple tablets of a
nootropic to get any effect, yet others may get a profound boost just
from taking a little piece of a tablet.
Nootropics are potentially a highly useful class of medication in the
treatment of CFS/ME and fibromyalgia, but they tend to be poorly
known to doctors in the United States, as they are mostly used in Europe
to treat conditions like Alzheimer’s disease, stroke and ADHD. One of
the good things about them is that they are usually both very safe and
well tolerated. Long–term use usually has more benefits than risks—
some nootropics are even used for the purpose of “life extension.”
In addition to cognitive impairment, nootropics often help neurolo-
gical symptoms such as vertigo, tinnitus, tremor, vision disturbances,
photophobia (light sensitivity), hyperacuity (noise sensitivity) and some
headaches. Depression, anxiety and mood swings often respond. Most
nootropics can also alleviate fatigue, because when our brain function
improves, our bodies tend to feel less sluggish, too. A few of them may
also help pain.
Besides being well–tolerated, nootropics are unlikely to cause
problems with other drugs. None of the drugs listed here have any meta-
bolic interactions. Some do not have any interactions at all. One note-
worthy thing is that almost all nootropics work synergistically together
and usually the dose has to be reduced—sometimes to a fraction of what
would be needed when using a single drug. The cholinergic drugs may
also work better if cholinergic supplements (such as choline or acetyl–
L–carnitine) are taken.
See also:
alprazolam, clonazepam (CHAPTER 1), atomoxetine, selegiline

(CHAPTER 5), modafinil/armodafinil/adrafinil (CHAPTER 6), pin-
dolol, nimodipine (CHAPTER 7), desmopressin, estrogen
(CHAPTER 8), NMDA antagonists, cholinesterase inhibitors, cin-
narizine (CHAPTER 9)
piracetam (Nootropil, Nootrop, Cerebryl)

aniracetam (Ampamet)
Piracetam and aniracetam are derivatives of GABA, but are not

thought to have GABAergic effects. They are cholinergic and may pos-
sibly act at NMDA receptors and ion channels. Additionally piracetam
decreases the viscosity of blood and reduces platelet aggregation. Anira-
cetam also modulates AMPA receptors and may have dopaminergic act-
ion.
The racetams have neuroprotective and anticonvulsive properties.
They are used to treat a variety of cognitive and neurological problems,
such as stroke, dyslexia, dementia and vertigo. Both drugs but especially
aniracetam are thought to have antidepressant and anxiolytic effects. In
animal studies aniracetam has also improved neurogenic bladder overac-
tivity.51 Piracetam appears to work well for Raynaud’s phenomenon.52
CFS/ME patients have reported decreased cognitive fatigability and

improved cognition, especially in verbal areas like word recall. The
racetams can also alleviate physical fatigue. In one study the combi-
nation of piracetam and the antihistamine cinnarizine produced good
results in the treatment of chronic fatigue.53 Piracetam has shown effi-
cacy in “soft tissue rheumatism,” an old term which includes fibromy-
algia.54
The racetams do not normally have any adverse effects. Drug
monographs may list plenty of side effects for piracetam, but they are
applicable for use in myoclonus, which requires very large doses (up to
20 grams a day). In nootropic use the dose is usually 800–4,800 mg a
day in 2–3 doses, sometimes less. Normal dose for aniracetam is 500–
1,500 mg a day in 1–2 doses. Too large doses may cause headache, rest-
lessness and insomnia, sometimes sedation. There are no known drug
interactions.
Piracetam is considered an over–the–counter supplement in many
countries, but a prescription drug in e.g. Australia, and many European
and Asian countries. It is also sold in combination products with ergo-
loid, other nootropics and cinnarizine. In the United States it can be pre-
pared by a compounding pharmacy. Aniracetam is a prescription drug in
Italy, Greece and Argentina. They are fairly inexpensive.
See also:
levetiracetam (CHAPTER 4)
ergoloid (Hydergin, Hydergine, Gerimal, Niloric,

Redergin)
Ergoloid (also known with several other names such as co–dergo-

crine, dihydroergotoxine and hydergine) is a combination of three ergot
alkaloids with cholinergic, serotonergic and dopaminergic effects on
brain function. It is also a strong antioxidant. Ergoloid is mostly used to
treat senile dementia and sometimes migraine. It improves brain oxy-
genation and metabolism and can be beneficial for a wide range of neu-
rological problems from stroke to tinnitus. It may be particularly helpful
with piracetam.
Ergoloid also benefits physical endurance. Jay Goldstein believes
that ergoloid is helpful for the fatigue experienced by CFS/ME and FM
patients. He normally prescribes a dose in the magnitude of 9 mg a day,
but one patient of his got significant relief with just 1 mg three times a
day.55 Ergoloid may help restless legs syndrome. It also has a beneficial
effect on cholesterol.56
Like most nootropics, ergoloid is normally well tolerated. In case
of nausea or stomach upset, the drug should be taken with food. Ortho-
static hypotension and nasal congestion may occur. People with a histo-
ry of psychosis should not take ergoloid. Ergoloid may potentiate the
effects of hypotensive drugs and lower the efficacy of hypertensive
treatments. It should not be combined with azole antifungals, macrolide
antibiotics or triptans. The most important concern is nonetheless the
possibility of valvular damage.
Ergoloid is available in the United States, Canada, United Kingdom
and many other primarily European countries, but not in Australia. It is
available as tablets, sublingual tablets and oral solution, sometimes also
as capsules. It is very inexpensive in Europe, but tends to cost more
elsewhere.
nicergoline (Sermion, Cebran, Ergotop, Varson)
Nicergoline is an ergot derivative used similar to ergoloid, but with

a different mode of action. It is thought to primarily be an alpha blocker
and to some extent a calcium channel blocker which induces cerebral
vasodilation. It inhibits platelet aggregation, making blood “thinner.”
Increased levels of dopamine and norepinephrine in the brain may also
contribute to its effects. Nicergoline is used for dementia, Raynaud’s
phenomenon, migraines, vertigo, tinnitus and some eye disorders.
Possible side effects include stomach upset, nausea, tachycardia,
headache, insomnia, nasal congestion and flushing. Because of its mode
of action nicergoline can cause orthostatic hypotension. Nicergoline
should not be combined with modafinil, as the drugs have opposite
effects on the alpha1 receptor and would cancel out each other’s effects.
Combinations with beta or alpha blockers are also not recommended.
Nicergoline can be purchased without a prescription in many count-
ries. It is a prescription drug in some parts of Europe, such as France,
Germany, Portugal, Italy and Spain, as well as Japan.
vinpocetine (Cavinton)
Vinpocetine is an inhibitor of phosphodiesterase type 1 (PDE1) and

to some extent also PDE4. It also blocks sodium channels and lowers
the viscosity of blood. It improves cerebral microcirculation and
increases the production of ATP in cells. It also has significant anticon-
vulsant action.57 Vinpocetine is a popular “smart drug” and is sometimes
prescribed to reduce the damage caused by a stroke. It is also used for

Alzheimer’s disease, cerebrovascular disease, menopausal symptoms
and motion sickness.
Vinpocetine can help with such neurological symptoms as aphasia
(problems with expression and understanding of language), apraxia (ina-
bility to conduct voluntary movements despite normal muscle function),
motor disorders, tinnitus, dizziness and headaches. It improves memory
in healthy subjects as well. Physical endurance may also be increased.
Vinpocetine is not commonly prescribed in CFS/ME or fibromyalgia,
but there is no reason not to use it. It has a short half–life, so it is usually
taken three times a day.
Vinpocetine is usually well tolerated. Sometimes there may be sto-
mach upset, constipation, nausea, facial flushing, sleep disturbances,
headache, dry mouth, hypotension, tachycardia and skin rashes. Some
recommend to begin use with a very low dose in case of hypersensiti-
vity—which is probably always a good idea when trying out new drugs
for CFS/ME. There are no known drug interactions, though vinpocetine
may affect blood pressure and coagulation.
Vinpocetine is a prescription drug in many European countries,
such as Germany and Hungary, as well as Japan. It can be purchased
over the counter in the United States and Canada.
sulbutiamine (Arcalion)
Sulbutiamine is a derivative of thiamine (vitamin B1). It is used to

treat asthenia (fatigue and weakness), but is also considered a nootropic.
The mode of action is thought to be cholinergic, but because some peop-
le find sulbutiamine extremely stimulating, other mechanisms may be
involved as well. Doses used vary from 200 mg to over 1,000 mg. A
French study tried doses of 400 mg and 600 mg for “chronic postinfect-
ious fatigue”, but the results were inconclusive as to whether it was
effective.58
Sulbutiamine is a very safe drug, but its effects vary widely
depending on the individual. Some people consider it too stimulating yet
others find its effects sedative. Despite possible stimulation sulbutia-
mine is not thought to cause insomnia. Depression and anxiety have
been reported occasionally. Large doses can cause headaches. No drug
interactions or contraindications are known, but it has been suggested
that people with bipolar disorder should not use sulbutiamine.
Sulbutiamine is an over–the–counter drug in many areas, but requi-
res a prescription in some parts of Europe, Asia and South America.
pyritinol (Enerbol, Encephabol)
Pyritinol is a derivative of pyridoxine (vitamin B6). It is a strong

antioxidant with nootropic properties. In a small double–blinded study
done in healthy people it improved performance speed, but did not have
any effect on memory.59 In addition to the cognition–enhancing effects
pyritinol has immunomodulatory properties and has been used to treat
e.g. rheumatoid arthritis. In one study it demonstrated superior efficacy
to auranofin (gold), though the drop–out rate was greater in the pyritinol
group.60
In general pyritinol is well tolerated, but a few cases of severe
adverse reactions have been reported, notably some cases of severe
cholestatic hepatitis.61 Because of this possible side effect patients
taking pyritinol should have their liver enzymes monitored at least in the
beginning of the treatment.
Pyritinol is a prescription drug in many European countries such as
France, Germany and Spain, as well as some Asian and South American
countries.
meclofenoxate (Helfergin, Cerutil, Cetrexin)
Meclofenoxate (also known as centrophenoxine) is used to treat

Alzheimer’s disease and sometimes ADHD. It can also relieve fatigue.
It works by a cholinergic mechanism and reduces the levels of lipofus-
cin, a pigment which accumulates in the brain with aging. Because of
this meclofenoxate is often considered an anti–aging substance.62
Recommended dosages vary from 250 to 3,000 mg a day, given in two
doses. Effects should be noticeable very quickly.
Meclofenoxate is very safe and low on side effects. It can rarely
cause insomnia, dizziness, restlessness, tremor, depression, nausea,
muscle tension and headache, which usually indicates the dosage is too
large. It is not recommended for people with a history of seizures,
severe hypertension or Parkinson’s disease. Exacerbation of major dep-
ression or bipolar mania is also possible. There are no known drug inter-
actions, but the dose should be reduced when used with other choliner-
gic drugs.
Meclofenoxate is generally considered a supplement, but in some
European countries such as Germany, Hungary and Austria as well as in
Japan it is a prescription drug. In Australia a prescription is also requi-
red, but meclofenoxate can only be purchased from abroad.
References
1 Check JH, Katsoff D, Kaplan H, et al. A disorder of sympathomimetic

amines leading to increased vascular permeability may be the etiologic
factor in various treatment refractory health problems in women. Med
Hypotheses. 2008;70(3):671–7.
2 Wood PB, Schweinhardt P, Jaeger E, et al. Fibromyalgia patients
show an abnormal dopamine response to pain. Eur J Neurosci. 2007
Jun;25(12):3576–82.
3 Wood PB, Patterson JC 2nd, Sunderland JJ, et al. Reduced presynaptic
dopamine activity in fibromyalgia syndrome demonstrated with positron
emission tomography: a pilot study. J Pain. 2007 Jan;8(1):51–8.
4 Wood PB. Stress and dopamine: implications for the pathophysiology
of chronic widespread pain. Med Hypotheses. 2004;62(3):420–4.
5 Bruno RL, Creange SJ, Frick NM. Parallels between post–polio fati-
gue and chronic fatigue syndrome: a common pathophysiology? Am J
Med. 1998 Sep 28;105(3A):66S–73S.
6 Buskila D, Fefer P, Harman–Boehm I, et al. Assessment of nonarticu-
lar tenderness and prevalence of fibromyalgia in hyperprolactinemic
women. J Rheumatol. 1993 Dec;20(12):2112–5.
7 Goldstein Jay. Tuning the Brain: Principles and Practice of Neuroso–
matic Medicine. Haworth Press 2004. pp. 439–440.
8 Meli R, Raso GM, Gualillo O, et al. Prolactin modulation of nitric oxi-
de and TNF–alpha production by peripheral neutrophils in rats. Life Sci.
1997;61(14):1395–403.
9 Blockmans D, Persoons P, Van Houdenhove B, et al. Does methyl-
phenidate reduce the symptoms of chronic fatigue syndrome? Am J
Med. 2006 Feb;119(2):167.e23–30.
11 The Treatment of Chronic Fatigue Syndrome and Fibromyalgia by
Dr. Charles Lapp. http://www.immunesupport.com/library/showarticle.
cfm/ID/2926/
12 Dalal S, Melzack R. Potentiation of opioid analgesia by psychosti-
mulant drugs: a review. J Pain Symptom Manage. 1998 Oct;16(4):245–
53.
13 Olson LG, Ambrogetti A, Sutherland DC. A pilot randomized cont-
rolled trial of dexamphetamine in patients with chronic fatigue syndro-
me. Psychosomatics. 2003 Jan–Feb;44(1):38–43.
14 Check JH, Katsoff B, Citerone T, et al. A novel highly effective

treatment of interstitial cystitis causing chronic pelvic pain of bladder
origin: case reports. Clin Exp Obstet Gynecol. 2005;32(4):247–9.
15 Boimel P, Check JH. Marked improvement of intractable arthritic
pain in a woman with rheumatoid arthritis with sympathomimetic amine
treatment despite previous failure with standard therapy and possible
implications for last trimester unexplained fetal demise—case report.
Clin Exp Obstet Gynecol. 2007;34(4):254–6.
16 Check JH, Katsoff D, Kaplan H, et al. A disorder of sympathomime-
tic amines leading to increased vascular permeability may be the etiolo-
gic factor in various treatment refractory health problems in women.
Med Hypotheses. 2008;70(3):671–7.
17 Check JH, Shanis BS, Shapse D, et al. A randomized comparison of
the effect of two diuretics, a converting enzyme inhibitor, and a sympat-
homimetic amine on weight loss in diet–refractory patients. Endocr
Pract. 1995 Sep–Oct;1(5):323–6.
18 Dalal S, Melzack R. Potentiation of opioid analgesia by psychosti-
mulant drugs: a review. J Pain Symptom Manage. 1998 Oct;16(4):245–
53.
20 Duschek S, Hadjamu M, Schandry R. Enhancement of cerebral blood
flow and cognitive performance following pharmacological blood pres-
sure elevation in chronic hypotension. Psychophysiology. 2007 Jan;44
(1):145–53.
21 AACFS conference January 2001. Report by Dr. Rosamund Val-
lings. http://www.cfs-news.org/aacfs-01.htm
22 Naschitz J, Dreyfuss D, Yeshurun D, et al. Midodrine treatment for
chronic fatigue syndrome. Postgrad Med J. 2004 Apr;80(942):230–2.
23 Naschitz JE, Rosner I, Rozenbaum M, et al. Successful treatment of
chronic fatigue syndrome with midodrine: a pilot study. Clin Exp Rheu-
matol. 2003 May–Jun;21(3):416–7.
25 Ertas M, Sagduyu A, Arac N, et al. Use of levodopa to relieve pain
from painful symmetrical diabetic polyneuropathy. Pain. 1998 Apr;75
(2–3):257–9.
26 Sleep Dysfunction in CFS By Richard Podell, MD, MPH. http://
www.cfids.org/archives/2002rr/2002-rr4-article01.asp
27 Teitelbaum Jacob. From Fatigued to Fantastic!: A Proven Program to
Regain Vibrant Health, Based on a New Scientific Study Showing

p. 129.
28 Garcia–Borreguero D, Serrano C, Larrosa O, et al. Circadian effects
of dopaminergic treatment in restless legs syndrome. Sleep Med. 2004
Jul;5(4):413–20.
29 Du F, Li R, Huang Y, et al. Dopamine D3 receptor–preferring ago-
nists induce neurotrophic effects on mesencephalic dopamine neurons.
Eur J Neurosci. 2005 Nov;22(10):2422–30.
30 Holman AJ, Myers RR. A randomized, double–blind, placebo–cont-
rolled trial of pramipexole, a dopamine agonist, in patients with fibro-
myalgia receiving concomitant medications. Arthritis Rheum. 2005
Aug;52(8):2495–505.
32 Mirapex for Chronic fatigue syndrome (CFS; CFIDS; M.E.): Com-
munity ratings. http://www.revolutionhealth.com/drugs-treatments/
rating/mirapex-for-chronic-fatigue-syndrome-cfs-cfids-me
33 Lemke MR. [Antidepressant effects of dopamine agonists : Experi-
mental and clinical findings.] Nervenarzt. 2007 Jan;78(1):31–8.
34 Holman AJ. Ropinirole, open preliminary observations of a dopami-
ne agonist for refractory fibromyalgia. J Clin Rheumatol. 2003 Aug;9
(4):277–9.
35 Oertel WH, Benes H, Garcia–Borreguero D, et al. Efficacy of rotigo-
tine transdermal system in severe restless legs syndrome: A randomized,
double–blind, placebo–controlled, six–week dose–finding trial in Euro-
pe. Sleep Med. 2008 Mar;9(3):228–239.
36 A Double–blind Multicenter Proof of Concept Trial to Assess the
Efficacy and Safety of Rotigotine in Subjects With Fibromyalgia Synd-
rome (SP888). http://www.clinicaltrials.gov/ct2/show/NCT00464737
37 Chuang E, Molitch ME. Prolactin and autoimmune diseases in
humans. Acta Biomed. 2007;78 Suppl 1:255–61.
38 Yoshikawa T, Minamiyama Y, Naito Y, et al. Antioxidant properties
of bromocriptine, a dopamine agonist. J Neurochem. 1994 Mar;62(3):
1034–8.
39 Bruno RL, Zimmerman JR, Creange SJ, et al. Bromocriptine in the
treatment of post–polio fatigue: a pilot study with implications for the
pathophysiology of fatigue. Am J Phys Med Rehabil. 1996 Sep–Oct;75
(5):340–7.
40 Pijl H, Ohashi S, Matsuda M, et al. Bromocriptine: a novel approach

to the treatment of type 2 diabetes. Diabetes Care. 2000 Aug;23(8):
1154–61.
41 Fava M, Thase ME, DeBattista C, et al. Modafinil augmentation of
selective serotonin reuptake inhibitor therapy in MDD partial responders
with persistent fatigue and sleepiness. Ann Clin Psychiatry. 2007 Jul–
Sep;19(3):153–9.
42 Turner DC, Robbins TW, Clark L, et al. Cognitive enhancing effects
of modafinil in healthy volunteers. Psychopharmacology (Berl). 2003
Jan;165(3):260–9.
43 Rammohan KW, Rosenberg JH, Lynn DJ, et al. Efficacy and safety
of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis:
a two centre phase 2 study. J Neurol Neurosurg Psychiatry. 2002 Feb;72
(2):179–83.
44 Turkington D, Hedwat D, Rider I, et al. Recovery from chronic fati-
gue syndrome with modafinil. Hum Psychopharmacol. 2004;19(1):63–
64.
45 Garcia–Fructuoso F, Fernández–Solá J, Poca–Dias V, et al. Effect of
Modafinil on Daytime Hypersomnia in Patients with Chronic Fatigue
Syndrome. Presented at: International Association for Chronic Fatigue
Syndrome (IACFS) 8th International Conference on Chronic Fatigue
Syndrome, Fibromyalgia and Related Illnesses. Fort Lauderdale, FL,
U.S. Jan 12–Jan 14, 2007.
46 Randall DC, Cafferty FH, Shneerson JM, et al. Chronic treatment
with modafinil may not be beneficial in patients with chronic fatigue
syndrome. J Psychopharmacol. 2005 Nov;19(6):647–60.
47 Schaller JL, Behar D. Modafinil in fibromyalgia treatment. J Neuro-
psychiatry Clin Neurosci. 2001 Fall;13(4):530–1.
48 Pachas WN. Modafinil for the treatment of fatigue of fibromyalgia. J
Clin Rheumatol. 2003 Aug;9(4):282–5.
50 The Heart of the Matter: Dr. Cheney on Chronic Fatigue Syndrome
& Cardiac Issues. http://www.immunesupport.com/library/showarticle.
cfm/ID/6679/
51 Nakada Y, Yokoyama O, Komatsu K, et al. Effects of aniracetam on
bladder overactivity in rats with cerebral infarction. J Pharmacol Exp
Ther. 2000 Jun;293(3):921–8.
52 Moriau M, Lavenne–Pardonge E, Crasborn L, et al. Treatment of the

Raynaud's phenomenon with piracetam. Arzneimittelforschung 1993
May;43(5):526–35.
53 Boiko AN, Batysheva TT, Matvievskaya OV, et al. Characteristics of
the formation of chronic fatigue syndrome and approaches to its treat-
ment in young patients with focal brain damage. Neurosci Behav
Physiol. 2007 Mar;37(3):221–8
54 Glas–Schottl R. Piracetam in the treatment of soft tissue rheumatism.
Fortschr Med 1989 Apr 30;107(13):298–302
56 Spiegel R, Huber F, Köberle S. A controlled long–term study with
ergoloid mesylates (Hydergine) in healthy, elderly volunteers: results
after three years. J Am Geriatr Soc. 1983 Sep;31(9):549–55.
57 Dutov AA, Tolpyshev BA, Petrov AP, et al. [Use of cavinton in epi-
lepsy] Zh Nevropatol Psikhiatr Im S S Korsakova. 1986;86(6):850–5.
58 Tiev KP, Cabane J, Imbert JC. [Treatment of chronic postinfectious
fatigue: randomized double–blind study of two doses of sulbutiamine
(400–600 mg/day) versus placebo]. Rev Med Interne. 1999 Oct;20(10):
912–8.
59 Hindmarch I, Coleston DM, Kerr JS. Psychopharmacological effects
of pyritinol in normal volunteers. Neuropsychobiology. 1990–1991;24
(3):159–64.
60 Lemmel EM. Comparison of pyritinol and auranofin in the treatment
of rheumatoid arthritis. The European Multicentre Study Group. Br J
Rheumatol. 1993 May;32(5):375–82.
61 Maria V, Albuquerque A, Loureiro A, et al. Severe cholestatic hepa-
titis induced by pyritinol. BMJ. 2004 Mar 6;328(7439):572–4.
62 Rodemann HP, Bayreuther K. [Prolongation of the mitotic life span
of diploid human glia cells in a quantitative cell culture system by cent-
rophenoxine (author's transl)] Arzneimittelforschung. 1979;29(1):124–9.
CHAPTER 7.
Heart and blood pressure drugs
Antiadrenergic drugs
The antiadrenergic drugs listed here include two kinds of drugs

with action on the alpha adrenergic receptors: alpha2/imidazoline ago-
nists and alpha1 antagonists (also known as alpha blockers). Because the
alpha1 and alpha2 receptors have mostly opposite action, both classes
have a similar effect of reducing adrenergic tone. Tizanidine is also an
alpha2 agonist, but it is a muscle relaxant and thus listed in CHAPTER 1.
Both types of drugs are most commonly used to treat hypertension
(high blood pressure), but similarly to many antihypertensive agents
they can also act to stabilize labile blood pressure in orthostatic hypo-
tension. They can improve sleep and reduce nightmares. Some newer
and more selective alpha1 antagonists are not used for hypertension but
only for urinary problems stemming from enlarged prostate. Alpha2
agonists are also effective analgesics.
clonidine (Catapres, Catapresan, Dixarit, Isoglaucon,

Aruclonin)
Clonidine is a centrally acting alpha2 agonist with plenty of off–

label uses, such as restless legs, PTSD, smoking cessation, dysmenor-
rhea (painful periods) and ADHD. It is often helpful for neuropathic
pain and other types of pain, apparently through several different
mechanisms.1 In CFS/ME clonidine is used to treat e.g. tachycardia and
orthostatic hypotension.2 One study found it useful for the cognitive
problems associated with CFS/ME.3
Clonidine has been tried for diarrhea–predominant IBS with good
results.4 It can also be helpful for migraine and overactive bladder.5 Clo-
nidine increases growth hormone secretion6 and inhibits the release of
substance P7, two potentially very beneficial mechanisms particularly in
fibromyalgia. It also has some antihistamine–like action.8 Sometimes
clonidine is utilized as a sleep aid. Small doses appear to increase the
amount of REM sleep and larger doses reduce it.9
Sedation, dizziness and dry mouth are the most common side
effects. The patch is much better tolerated than the tablets. Clonidine
should not be combined with tricyclic antidepressants, mirtazapine or

neuroleptic drugs with alpha antagonistic action. It will antagonize the
effects of methylphenidate and modafinil and may potentiate the effects
of other sedative drugs. The treatment should not be discontinued
abruptly, but tapered down over several days.
Clonidine is available in the United States, the United Kingdom,
Canada, Australia and many other countries. It is available as tablets and
a once–weekly patch in several different strengths. The oral forms are
very inexpensive. The patches are much more costly, but on the other
hand only four patches a month are needed.
moxonidine (Physiotens, Fisiotens, Normatens, Moxon)
Moxonidine is a centrally acting agonist of the I1 imidazoline

receptor and partial agonist of the alpha2A receptor used in the treatment
of hypertension. It improves insulin sensitivity and like clonidine it has
analgesic properties.10 It also appears to synergize with opioids.11 A
double–blinded study on the use of moxonidine in fibromyalgia was
completed in 2006, but the results were never published, which suggests
limited efficacy.12
Usually moxonidine is fairly well tolerated. The side effects can
include dry mouth, headache, weakness, dizziness, nausea and sleep dis-
turbances. Concomitant use with alcohol, benzodiazepines and tricyclic
antidepressants can lead to excessive sedation. Use in patients with Ray-
naud’s phenomenon, depression or epilepsy is not recommended.
Moxonidine is available in the United Kingdom, Australia and
some other countries, but not in the United States or Canada. It is very
inexpensive.
prazosin (Minipress, Minipres, Apo–Prazo, Pratsiol,

Pressin)
Prazosin is an antagonist of the alpha1 receptor. Besides hyperten-

sion it is used to treat Raynaud’s phenomenon as well as urination prob-
lems caused by prostate hypertrophy. It has sometimes been employed
to treat interstitial cystitis and bladder problems in CFS/ME. Prazosin
has also shown efficacy in PTSD and the associated sleep disturban-
ces.13
Nasal congestion and orthostatic hypotension (sometimes even
fainting) are possible side effects. Sudden changes in posture should be
avoided in the beginning of the treatment. Sedation, nausea and tachy-
cardia are possible. Usually side effects are at their worst after the first
Heart and blood pressure drugs 175
dose and get better after that. They can often be avoided when the treat-
ment is initiated with a very small dose.
Prazosin is available in the United States, the United Kingdom,
tamsulosin (Flomax, Flomaxtra, Omnic, Secotex, Alna)
Tamsulosin is an antagonist of the alpha1 receptor. It is fairly selec-

tive for the alpha1A receptor subtype, which is mostly found in the pros-
tate and the urinary tract. It is usually only used to treat prostrate hyper-
trophy, but may sometimes be prescribed for urinary problems in wo-
men. A large trial did not find it effective for overactive bladder in wo-
men14, but it was found helpful for female lower urinary tract symptoms
in another study.15
Professor and sleep researcher Olli Polo has tried tamsulosin in
many of his patients who suffer from chronic fatigue or CFS/ME, noting
that it can improve sleep, circulatory problems and urinary frequency.16
Some of his patients have even described it as a stimulant, which he
believes may result from improved sleep quality. He prescribes 0.4 mg
for either daily use or to be taken every other day (tamsulosin has a long
half–life).
Tamsulosin is the least prone of the alpha blockers to causing
orthostatic hypotension, sedation and reflex tachycardia, but these are
still possible side effects. Nasal congestion is fairly common. Men can
experience problems with sexual function, especially ejaculation. Tam-
sulosin should not be used by those allergic to sulfa drugs. Many other
drugs, such as some SSRI antidepressants, ropinirole, azole antifungals,
macrolide antibiotics, diclofenac, verapamil and doxycycline can affect
blood levels of tamsulosin.
Tamsulosin is available in the United States, the United Kingdom,
Canada, Australia and some other countries. It is only available as 0.4
mg extended release capsules. It is very inexpensive.
Beta blockers
Beta blockers are antagonists of the beta adrenergic receptors. They

are best known for their use in hypertension and anxiety (especially per-
formance anxiety). They are fairly commonly used to treat CFS/ME,
because they are antiarrhythmic and can help orthostatic hypotension.
Another common use is for migraine prophylaxis
Unlike calcium channel blockers and some antiadrenergic drugs,
beta blockers are not considered to have analgesic properties, but they
can reduce excessive urinary frequency. They appear to increase the

secretion of cortisol and DHEA (probably by reducing sympathetic
hyperactivity), which may be beneficial in CFS/ME and fibromyalgia.17
Beta blockers are normally well–tolerated, but some people with
CFS/ME cannot tolerate them at all. Because they lower blood pressure,
they may worsen orthostatic hypotension. They can cause hypoglycemia
and even hypothyroidism. Beta blockers are either cardioselective or
nonselective. The non–selective ones should not be given to patients
with asthma and even the selective ones can cause problems. Some beta
blockers also have sympathomimetic activity.
Especially propranolol and to some extent metoprolol inhibit coen-
zyme Q10, which can paradoxically cause adverse cardiac effects.18
Beta blockers decrease melatonin release, which might explain why they
often cause sleep disturbances.19 They may have beneficial metabolic
effects as well; studies show they may reduce the risk of bone frac-
tures.20
propranolol (Inderal, Dociton, Detensol, Novopranol)
Besides blocking the beta receptor, propranolol also has some local
anesthetic/membrane stabilizing activity. A downside is its short half–
life, which means it has to be taken several times a day. Propranolol is
non–selective and thus should not be used in patients with asthma.
Propranolol is available in the United States, the United Kingdom,
Canada, Australia and many other countries. It is available as tablets,
capsules, oral solution and extended release formulations. It is very
inexpensive.
atenolol (Tenormin, Blokium, Atenolol, Atehexal,

Vascoten)
Atenolol is a commonly used cardioselective beta blocker. It is

taken once a day. It is not as effective in migraine prophylaxis as e.g.
propranolol. It may have fewer psychiatric side effects than other beta
blockers.
Atenolol is available virtually everywhere. It is very inexpensive.
metoprolol (Lopressor, Lopresor, Betaloc, Beloc,

Seloken)
Metoprolol is another cardioselective beta blocker. It is usually

taken twice a day. Fluoxetine, paroxetine and ropinirole may increase
blood levels of the drug.

Metoprolol is available virtually everywhere. It is available as both
normal tablets and extended release formulations. It is very inexpensive.
pindolol (Visken, Apo–Pindol, Barbloc)
Pindolol is a less commonly used beta blocker with significant

sympathomimetic activity. A small open trial tried pindolol for fibromy-
algia with encouraging results.21 Especially tender point scores impro-
ved and scores in FIQ (fibromyalgia impact questionnaire, which mostly
measures functionality) also significantly increased.
Dr. Jay Goldstein prescribes pindolol in doses of 5 mg 2–3 times a
day for cognitive impairment, especially memory problems. Apparently
the effect is mediated by pindolol’s blockage of the 5–HT1A serotonin
receptor and not antiadrenergic action. Because of this receptor antago-
nism pindolol can be used to augment the antidepressive effect of SSRI
drugs and speed up their onset of action.22
Pindolol is available in the United States, the United Kingdom,
Calcium channel blockers
Calcium channel blockers (also called calcium antagonists) prevent

the influx of calcium into cells. They are used to treat hypertension and
also have antiarrhythmic properties. A paper published in the Medical
Hypotheses journal proposed that CFS/ME and FM are caused by viral
injury to the calcium channels, which leads to an excessive amount of
calcium entering striated muscle cells, and thus calcium channel
blockers would make an effective therapy.23 Whether the theory is true
or not, calcium channel blockers are frequently used in CFS/ME.
Calcium channel blockers can prevent migraine and chronic head-
aches as well as alleviating chronic pain in general. They have anticon-
vulsant properties. The vasodilatory and NMDA receptor antagonizing
effects can help with e.g. cognitive problems. Like beta blockers they
can also relieve bladder problems. One reason why the calcium channel
blockers help fibromyalgia and CFS/ME may be because of their anta-
gonism of the 5–HT3 serotonin receptor.24
Calcium channel blockers are stronger vasodilators than beta
blockers, so they are more likely to provoke orthostatic hypotension.
Nasal congestion and facial flushing are also possible. Opposite to the
action of beta blockers they dilate lung bronchioles, so they are a good
choice for those with asthma. Calcium channel blockers may adversely
affect the positive effect of exercise on bone formation—obviously not a

concern for those who cannot exercise, but might be of importance for
those who are recovering from CFS/ME.25
See also:
cyproheptadine, pizotifen (CHAPTER 2), neomycin (CHAPTER 4),

nicergoline (CHAPTER 6), dextromethorphan, cinnarizine,
parenteral magnesium, flavoxate (CHAPTER 9)
verapamil (Calan, Isoptin, Verpamil, Cordilox,

Verahexal)
Verapamil is mostly used to treat hypertension, arrhythmias and

angina pectoris, sometimes also for headaches, migraines and bipolar
mania. It may have use in endometriosis.26 Verapamil is occasionally
used to treat CFS/ME. There is one study of this use, which tried vera-
pamil on 25 CFS/ME patients for six months.27 The drug was helpful for
the immune system, memory problems and muscle pain. Fatigue was
also alleviated. A common dose is 60–120 mg at bedtime.
The most common side effect of verapamil is constipation. It may
also cause hypotension. Edema, dizziness, nausea, facial flushing, skin
reactions, headaches and fatigue are less common side effects. Verapa-
mil has plenty of interactions with other drugs, especially beta blockers,
antibiotics, psychiatric drugs and anticonvulsants.
Verapamil is widely available. It is sold as tablets and capsules,
including extended release formulations. It is very inexpensive.
nimodipine (Nimotop, Tropocer, Brainal, Nemotan,

Eugerial)
Nimodipine mainly has a vasodilatory effect on the cerebral arte-

ries. It is indicated for the treatment of post–stroke cerebral vasospasm
in very large doses, up to 12 tablets a day. It is a promising treatment for
CFS/ME with relatively few side effects. Jay Goldstein believes that
nimodipine is one of the most useful treatments for CFS/ME and fibro-
myalgia.28 About 40% of his patients have experienced increased ener-
gy, exercise tolerance and mental clarity as well as decreased tender
point sensitivity.
Andrew J. Wright prescribes nimodipine to treat orthostatic hypo-
tension in CFS/ME. He starts with a very low dose of 7.5 mg which is
slowly titrated up.29 The usual maintenance dose is 30 mg twice a day.

Dr. Mason Brown recommends starting with a much lower dose—as
little as 1/8 or 1/16 of a tablet every 3–4 days, if the patient has severe
CFS/ME.30
Nimodipine is a good migraine prophylactic. One study found its
efficacy comparable to the common prophylactic agent pizotifen, but it
was better tolerated.31 It has sometimes been used for psychiatric prob-
lems and seems to be helpful for bipolar disorder, especially the trouble-
some and hard–to–treat ultra rapid cycling.32 It may be effective in
refractory panic disorder.33 Nimodipine also greatly helps a minority of
people with tinnitus.34
Unlike verapamil, nimodipine can be taken in the morning, as it is
not so prone to causing lightheadedness. Even small doses can nonethe-
less cause headache. Nimodipine has potential interactions with many
other medications. Especially concurrent use of azole antifungals and
many psychiatric drugs and anticonvulsants can affect the blood levels
of either or both drugs. In general use with anticonvulsants is not recom-
mended. Grapefruit juice can dangerously elevate blood levels of nimo-
dipine.
Nimodipine is widely available. Unfortunately it is quite expensive
to extremely expensive, depending on the country. Usually 30 mg is the
only available size, and in some markets the only available form is cap-
sules, making it difficult to administer smaller doses. Tablets are usually
not scored, but still easy to split.
nifedipine (Adalat, Nifelat, Nifecard, Nifedin, Nifehexal)
Nifedipine is the “prototypical” dihydropyridine calcium channel

blocker. Compared to nimodipine it has less effect on the cerebral arte-
ries and more peripheral action. Thus it is more prone to causing ortho-
static hypotension and dizziness, but also more likely to help muscle cir-
culation and Raynaud’s phenomenon. One case study has been pub-
lished about the successful use of nifedipine to treat CFS/ME.35 Nifedi-
pine inhibits activation of NF–kappa B much more potently than other
calcium channel blockers.36
The drug interactions are similar to nimodipine, but nifedipine can
also affect the metabolism of fluvoxamine, mexiletine, mirtazapine,
ropinirole and theophylline.
Nifedipine is available everywhere. It is very inexpensive.
nilvadipine (Escor, Nivadil)
Nilvadipine has a strong effect on the cerebral arteries similar to

nimodipine. It is used for both hypertension and problems in cerebral
circulation. It has anti–inflammatory effects37,38 and improves lipid
profile (cholesterol and triglycerides).39 As could be expected, it is also
efficacious in migraine prophylaxis.40 In one animal study nilvadipine
elevated dopamine levels in the striatum of the brain, but amlodipine did
not.41 In another study it prevented glutamate neurotoxicity although
nifedipine did not.42
Nilvadipine has a longer half–life than most other calcium channel
blockers and only needs to be taken once a day. Side effects are similar
to nimodipine and nifedipine, though nilvadipine is thought to be better
tolerated than nifedipine. Interactions are also similar, but may be of
less importance.
Nilvadipine is available in many European countries (but not in the
United Kingdom) and Japan. The only available size is usually 8 mg
depot capsules, which may be a bit too much for CFS/ME patients. Nil-
vadipine is a bit more expensive than nifedipine, but less so than nimo-
dipine.
Other cardiovascular medications
See also:
phenytoin (CHAPTER 3), tadalafil, theophylline, statins,

angiotensin II receptor blockers, ACE inhibitors, isoxsuprine,
buphenine, epoetin (CHAPTER 10)
glyceryl trinitrate (Minitran, Deponit, Nitro–Dur,

Nitroderm, Nitrolingual)
Glyceryl trinitrate is often known as nitroglycerine, nitro or nitrate.

It is used for angina pectoris (chest pain of cardiac origin), because it
causes nitric oxide mediated vasodilation in the coronary arteries and
other blood vessels. As excess NO has been implicated as a cause of
CFS/ME and fibromyalgia, this approach may not be appropriate for all
patients, but many specialists do prescribe glyceryl trinitrate.
Nitrates are especially helpful for pain and patients with fibromyal-
gia appear to benefit more than those who only have CFS/ME. It has
been suggested that pain in fibromyalgia stems from muscle hypoperfu-

sion (impaired circulation) which would explain the efficacy of vasodi-
latory treatments.43 On the other hand, nitrates have also been found
helpful for painful diabetic neuropathy.44 Jorge Flechas notes that pati-
ents who benefit often have cold hands and feet and are pale (signifying
poor circulation).45
Nitrates can also alleviate a variety of other symptoms, such as
headache, sore throat, IBS, dyspnea and visual disturbances, but also
fatigue, cognitive problems and mood.46,47 For some patients nitrates
provide better pain relief than anything else, sometimes in a matter of
minutes. Unfortunately tolerance can develop quickly, sometimes after
just a few doses.
Possible side effects include headache, nausea, flushing, tachycar-
dia, (orthostatic) hypotension and dizziness. These may be greatly
potentiated if glyceryl trinitrate is combined with other drugs that cause
vasodilation or otherwise lower blood pressure. Tadalafil is contraindi-
cated. Patches may cause local reactions.
Glyceryl trinitrate is available virtually everywhere. Available
forms include tablets, depot tablets, patches and sublingual tablets and
sprays. It is very inexpensive.
disopyramide (Norpace, Rythmodan, Disomet)
Disopyramide is used to treat heart arrhythmias, which are common

in CFS/ME patients. The primary indication in CFS/ME, however, is the
treatment of orthostatic hypotension, a use which has been studied in
one small trial along with other medications.48 Charles Lapp recom-
mends using disopyramide in combination with fludrocortisone.49
Anticholinergic side effects are common, but cardiac symptoms are
also possible. Disopyramide is contraindicated when using other medi-
cations with cardiac depressant effects, such as beta blockers or calcium
channel blockers. Disopyramide may increase the QT interval and
should be used with caution with e.g. tricyclic antidepressants. Conco-
mitant use with other anticholinergic drugs may increase side effects.
Disopyramide is available in the United States, the United King-
dom, Canada, Australia and a many other countries. It is also available
in extended release formulations. It is very inexpensive.
pentoxifylline/oxpentifylline (Trental, Artal, Pentoxin,

Pentoxil)
Pentoxifylline is a xanthine derivative (remotely similar to caffei-

ne) and a phosphodiesterase–4 (PDE4) inhibitor. It increases the

deformability of red blood cells and is primarily used to improve circu-
lation. People with CFS/ME generally suffer from poor circulation and
SPECT scans have demonstrated hypoperfusion in the brains of the pati-
ents.50 According to doctor Leslie O. Simpson red blood cells are often
deformed in CFS/ME, which impairs the circulation in capillaries.51,52
Simpson has found pentoxifylline helpful in relieving dizziness and cog-
nitive problems in CFS/ME.
In addition pentoxifylline downregulates some major inflammatory
pathways, such as TNF alpha53, IL–254 and NF–kappa B.55 This is
another good rationale for using the drug in CFS/ME. Pentoxifylline
appears to possess some other immunomodulatory and antiviral proper-
ties as well and as a result it is sometimes used as a supportive treatment
for HIV/AIDS.56 It can also reduce the malaise and loss of appetite asso-
ciated with HIV infection.57
Pentoxifylline works for both inflammatory and neuropathic pain.
One study found it helpful in rheumatoid arthritis58 and another one suc-
cessfully combined it with beta interferon in multiple sclerosis.59 Pento-
xifylline may also be of use in the treatment of endometriosis and
aphthous ulcers (mouth ulcers), but the studies of these uses have been
inconclusive.
Pentoxifylline cannot be used in patients who cannot tolerate
stimulants, who have a major risk of hemorrhage or who suffer from a
peptic ulcer. Possible side effects include nausea, stomach upset, pruri-
tus (itching), cardiac arrhythmias, insomnia, headache and dizziness.
Weight loss may occur sometimes. Pentoxifylline may potentiate the
effects of antihypertensive and blood sugar lowering drugs, including
insulin. It also appears to increase the replication of cytomegalovirus.60
Pentoxifylline is available almost everywhere. In some countries it
is even an over–the–counter drug, but most places (including the United
States, the United Kingdom and Australia) require a prescription. In
Australia and some other countries the drug is known as oxpentifylline.
It is inexpensive.
mexiletine (Mexitil, Katen, Ritalmex)
Mexiletine is an antiarrhythmic drug which is essentially an oral

form of lidocaine. Besides arrhythmias it is used to treat neuropathic
pain61, sometimes also headaches, epilepsy62, tinnitus63 and multiple
sclerosis.64 It is usually only tried in refractory cases. Jay Goldstein uses
mexiletine in CFS/ME and fibromyalgia in a small dose of 150 mg and
notes that it has very few significant side effects.65
Tremor, drowsiness, dizziness, problems with coordination, heart-

burn, nausea and paresthesias are fairly common side effects. Mexiletine
can also have pro–arrhythmic effects. The dose usually used in CFS/ME
and FM is very low and thus better tolerated than antiarrhythmic doses.
Many other medications can interact with mexiletine. Usually concomi-
tant use is still possible, but mexiletine dose may need to be adjusted.
Mexiletine may increase the effects of caffeine and local anesthetics.
Mexiletine is available in the United States, the United Kingdom,
Canada, Australia and many other markets. It is inexpensive.
hydralazine (Apresoline, Hydrapres, Alphapress)
Hydralazine causes vasodilation by a mechanism somewhat similar

to nitrates. It is used to treat hypertension, generally only if other agents
have failed. It stimulates the heart and may cause fluid retention, which
is why it is usually combined with beta blockers and a diuretic in this
use. It is not common treatment for CFS/ME or fibromyalgia, but Jay
Goldstein reports getting impressive results in some patients using a
dose of 10–25 mg three times a day.66 Pain is the most likely symptom
to improve.
Adverse effects may include orthostatic hypotension, nausea, sto-
mach upset, lack of appetite, diarrhea, constipation, muscle cramps and
weakness, congestion and dyspnea. Rarely hydralazine can cause drug–
induced lupus syndrome. People with pre–existent lupus should not take
hydralazine. Propranolol may increase blood levels of the drug. Hydra-
lazine should not be combined with MAO inhibitors. Its use may war-
rant supplementation of coenzyme Q10 and vitamin B6.
Hydralazine is available in the United States, the United Kingdom,
Canada, Australia and some other countries. It is inexpensive.
hydrochlorothiazide (Hydrodiuril, Microzide, Apo–

Hydro, Esidrex)
Hydrochlorothiazide is a popular diuretic used in the treatment of

hypertension and congestive heart failure. As many CFS/ME patients
suffer from hypovolemia (low blood volume), it may seem strange to
consider a diuretic as a treatment. The other pharmacologic effects of
this drug are the reason why Jay Goldstein proposes it as a treatment for
CFS/ME and fibromyalgia.67 He is particularly interested in the drug
because it can inhibit rapid glutamate AMPA receptor desensitization
(AMPA receptors are somewhat similar to NMDA receptors).68
Hydrochlorothiazide increases the production of glutamate and
nitric oxide, properties that are usually considered harmful in CFS/ME

and fibromyalgia, but may benefit some patients. It is also a weak inhi-
bitor of carbonic anhydrase similar to acetazolamide. Another possibly
beneficial action that Goldstein does not directly mention is that hydro-
chlorothiazide can elevate the blood levels of uric acid, which has been
suggested to be beneficial in CFS/ME.69
Hydrochlorothiazide can cause electrolyte imbalances, particularly
hypokalemia. Potassium supplementation is often recommended and
CFS/ME and FM patients should probably consider magnesium as well.
It can also elevate blood sugar. Blood tests should be performed perio-
dically to assess kidney function and electrolytes. Those allergic to sulfa
drugs should avoid hydrochlorothiazide. It can also cause flares in
people with SLE.
Besides that hydralazine can cause dizziness, weakness, rash and
impotence. It potentiates the effects of any other medication that lowers
blood pressure. Corticosteroids increase the risk of hypokalemia. Cho-
lestyramine reduces the absorption of the drug. Hydrochlorothiazide
may also increase the side effects of amantadine.
In many markets hydrochlorothiazide is only available in combina-
tion products. Products containing only hydrochlorothiazide as the acti-
ve ingredient are available in the United States, the United Kingdom,
spironolactone (Aldactone, Spirolone, Spiractin, Spirix)
Spironolactone is an antiandrogen and a mineralocorticoid antago-

nist, essentially an antagonist of testosterone and fludrocortisone. As a
potassium–sparing diuretic it is used to treat hypertension (usually in
conjunction with other drugs) and PMS. The mode of action seems
counterintuitive, but Jay Goldstein reports occasional good results with
the drug, and according to him the effects can be assessed in 30 minu-
tes.70 Spironolactone appears to have anti–inflammatory effects.71
Spironolactone may increase the risk of peptic ulcers. It can also
cause irregular periods, testicular atrophy, sedation, ataxia (problems
with coordination), erectile dysfunction and rashes. Potassium supple-
mentation and salt substitutes containing potassium are contraindicated.
On the other hand supplementing with Q10 may be a good idea.
Spironolactone is available in the United States, the United King-
dom, Canada, Australia and many other countries. It is very inexpen-
sive.
heparin (Calciparine, Monoparin, Multiparin, Minihep)

enoxaparin (Lovenox, Clexane, Klexane)
Heparin is an anticoagulant and one of the oldest medications still

in use. It has been theorized that at least some patients with CFS/ME
suffer from a hypercoagulable state similar to the autoimmune disease
antiphospholipid syndrome.72 Based on this theory fibrin collects into
blood vessels and the resulting impairment of circulation causes all or at
least some of the symptoms. Hypercoagulation has also been connected
with Gulf War syndrome.73
The cause of hypercoagulation may be a genetic defect or an immu-
ne reaction to a pathogen. Hypercoagulation has been implicated in
many different viral and bacterial infections, including mycoplasma,
borrelia and HHV–6.74 Genetic factors are possibly involved, too.75 Dr.
David Berg uses heparin as a treatment.76 According to him the majority
of patients treated with it feel almost healthy in just 2–3 days after com-
mencing the treatment.
Dr. Paul Cheney believes that in heparin can be useful for shifting
the Th2 dominant state of immune system into the Th1 side.77 Heparin
also has antiherpesviral effects.78 It is sometimes used to treat interstitial
cystitis. Treatment probably should not be initiated before adequate
bloodwork for coagulation factors is done.
One problem with heparin treatment is the very short half–life of
the drug, especially since it has to be administered either intravenously
or subcutaneously. Smoking may further shorten the half–life. Enoxapa-
rin is a low–molecular weight heparin with a longer duration of action,
only requiring one dosing a day. Unfortunately it too has to be given as
an injection, but it is available in pre–filled syringes.
Heparin use should be avoided before surgical operations and
lumbar puncture. It should not be given to patients who have had a
peptic ulcer. Thrombocytopenia (low platelet count) and bleeding are
possible, albeit rare side effects. There may rarely be irritation in the
injection site, allergic reactions and hair loss. Long–term treatment
increases the risk of osteoporosis. Heparin also suppresses NK cell
activity.79 NSAIDs potentiate the effects of heparin.
The heparins are widely available. Both are expensive, enoxaparin
much more so.
See also:
fibrinolytic enzymes (CHAPTER 10)

References
1 Tryba M, Gehling M. Clonidine – a potent analgesic adjuvant. Curr

Opin Anesthesiol. 2002 Oct;15(5):511–7.
org/experts.htm
3 Morriss RK, Robson MJ, Deakin JF. Neuropsychological performance
and noradrenaline function in chronic fatigue syndrome under conditi-
ons of high arousal. Psychopharmacology (Berl). 2002 Sep;163(2):166–
73.
4 Camilleri M, Kim DY, McKinzie S, et al. A randomized, controlled
exploratory study of clonidine in diarrhea–predominant irritable bowel
syndrome. Clin Gastroenterol Hepatol. 2003 Mar;1(2):111–21.
5 Sandyk R, Gillman MA, Iacono RP, et al. Clonidine in neuropsychiat-
ric disorders: a review. Int J Neurosci. 1987 Aug;35(3–4):205–15.
6 Devesa J, Arce V, Lois N, et al. Alpha 2–adrenergic agonism enhan-
ces the growth hormone (GH) response to GH–releasing hormone
through an inhibition of hypothalamic somatostatin release in normal
men. J Clin Endocrinol Metab. 1990 Dec;71(6):1581–8.
7 Ono H, Mishima A, Ono S, et al. Inhibitory effects of clonidine and
tizanidine on release of substance P from slices of rat spinal cord and
antagonism by alpha–adrenergic receptor antagonists. Neuropharmaco-
logy. 1991 Jun;30(6):585–9.
8 Miadonna A, Tedeschi A, Leggieri E, et al. Clonidine inhibits IgE–
mediated and IgE–independent in vitro histamine release from human
basophil leukocytes. Int J Immunopharmacol. 1989;11(5):473–7.
9 Miyazaki S, Uchida S, Mukai J, et al. Clonidine effects on all–night
human sleep: opposite action of low– and medium–dose clonidine on
human NREM–REM sleep proportion. Psychiatry Clin Neurosci. 2004
Apr;58(2):138–44.
10 Fairbanks CA, Wilcox GL. Moxonidine, a selective alpha2–adrener-
gic and imidazoline receptor agonist, produces spinal antinociception in
mice. J Pharmacol Exp Ther. 1999 Jul;290(1):403–12.
11 Fairbanks CA, Nguyen HO, Grocholski BM, et al. Moxonidine, a se-
lective imidazoline–alpha2 –adrenergic receptor agonist, produces
spinal synergistic antihyperalgesia with morphine in nerve–injured
mice. Anesthesiology. 2000 Sep;93(3):765–73.
12 Moxonidine for the treatment of fibromyalgia: a prospective double–
blind, randomised, single–centre, placebo–controlled, parallel group
study. http://www.controlled-trials.com/ISRCTN70535562
13 Taylor HR, Freeman MK, Cates ME. Prazosin for treatment of night-
mares related to posttraumatic stress disorder. Am J Health Syst Pharm.
2008 Apr 15;65(8):716–22.
14 Robinson D, Cardozo L, Terpstra G, et al. A randomized double–
blind placebo–controlled multicentre study to explore the efficacy and
safety of tamsulosin and tolterodine in women with overactive bladder
syndrome. BJU Int. 2007 Oct;100(4):840–5.
15 Pummangura N, Kochakarn W. Efficacy of tamsulosin in the treat-
ment of lower urinary tract symptoms (LUTS) in women. Asian J Surg.
2007 Apr;30(2):131–7.
16 Polo O. Personal communication. 2007.
17 Kizildere S, Glück T, Zietz B, et al. During a corticotropin–releasing
hormone test in healthy subjects, administration of a beta–adrenergic
antagonist induced secretion of cortisol and dehydroepiandrosterone sul-
fate and inhibited secretion of ACTH. Eur J Endocrinol. 2003 Jan;148
(1):45–53.
18 Kishi T, Watanabe T, Folkers K. Bioenergetics in clinical medicine
XV. Inhibition of coenzyme Q10–enzymes by clinically used adrenergic
blockers of beta–receptors. Res Commun Chem Pathol Pharmacol. 1977
May;17(1):157–64.
19 Stoschitzky K, Sakotnik A, Lercher P, et al. Influence of beta–block-
ers on melatonin release. Eur J Clin Pharmacol. 1999 Apr;55(2):111–5.
20 Schlienger RG, Kraenzlin ME, Jick SS, et al. Use of beta–blockers
and risk of fractures. JAMA. 2004 Sep 15;292(11):1326–32.
21 Wood PB, Kablinger AS, Caldito GS. Open trial of pindolol in the
treatment of fibromyalgia. Ann Pharmacother. 2005 Nov;39(11):1812–
6.
22 Li DL, Simmons RM, Iyengar S. 5HT1A receptor antagonists enhan-
ce the functional activity of fluoxetine in a mouse model of feeding.
Brain Res. 1998 Jan 19;781(1–2):119–26.
23 Lund–Olesen LH, Lund–Olesen K, et al. The etiology and possible
treatment of chronic fatigue syndrome/ fibromyalgia. Med Hypotheses.
1994 Jul;43(1):55–8.
24 Hargreaves AC, Gunthorpe MJ, Taylor CW, et al. Direct inhibition
of 5–hydroxytryptamine3 receptors by antagonists of L–type Ca2+
channels. Mol Pharmacol. 1996 Nov;50(5):1284–94.
25 Li J, Duncan RL, Burr DB, et al. L–type calcium channels mediate
mechanically induced bone formation in vivo. J Bone Miner Res. 2002
Oct;17(10):1795–800.
26 Magri B, Viganò P, Rossi G, et al. Comparative effect of the calcium
antagonist verapamil and the synthetic steroids gestrinone and danazol
on human monocyte phagocytosis in vitro. Gynecol Obstet Invest. 1997;

43(1):6–10.
ment.htm
30 Chronic Fatigue Syndrome Frequently Asked Questions. http://www.
cfs-me.co.uk/faq.html
31 Havanka–Kanniainen H, Hokkanen E, Myllylä VV. Efficacy of
nimodipine in comparison with pizotifen in the prophylaxis of migraine.
Cephalalgia. 1987 Mar;7(1):7–13.
32 Goodnick PJ. The use of nimodipine in the treatment of mood disor-
ders. Bipolar Disord. 2000 Sep;2(3 Pt 1):165–73.
33 Gibbs DM. Hyperventilation–induced cerebral ischemia in panic dis-
order and effect of nimodipine. Am J Psychiatry. 1992 Nov;149(11):
1589–91.
34 Davies E, Knox E, Donaldson I. The usefulness of nimodipine, an L–
calcium channel antagonist, in the treatment of tinnitus. Br J Audiol.
1994 Jun;28(3):125–9.
35 Adolphe AB. Chronic fatigue syndrome: possible effective treatment
with nifedipine. Am J Med. 1988 Dec;85(6):892.
36 Matsumori A, Nunokawa Y, Sasayama S. Nifedipine inhibits activa-
tion of transcription factor NF–kappaB. Life Sci. 2000 Oct 13;67(21):
2655–61.
37 Iwasaki Y, Asai M, Yoshida M, et al. Nilvadipine inhibits nuclear
factor–kappaB–dependent transcription in hepatic cells. Clin Chim
Acta. 2004 Dec;350(1–2):151–7.
38 Kagawa H, Nomura S, Ozaki Y, et al. Effects of nilvadipine on cyto-
kine–levels and soluble factors in collagen disease complicated with
essential hypertension. Clin Exp Hypertens. 1999 Oct;21(7):1177–88.
39 Leonetti G; Italian Study Group on Nilvadipine in Mild to Moderate
Hypertension. Effects of nilvadipine and amlodipine in patients with
mild to moderate essential hypertension: a double blind, prospective,
randomised clinical trial. Curr Med Res Opin. 2005 Jun;21(6):951–8.
40 Kihara M, Takahashi M. The potency of migraine prophylaxis with

nilvadipine: eight cases reported with further consideration. Pathophysi-
ology. 2001 Dec;8(2):129–131.
41 Kurosaki R, Akasaka M, Michimata M, et al. Effects of Ca2+ anta-
gonists on motor activity and the dopaminergic system in aged mice.
Neurobiol Aging. 2003 Mar–Apr;24(2):315–9.
42 Otori Y, Kusaka S, Kawasaki A, et al. Protective effect of nilvadipi-
ne against glutamate neurotoxicity in purified retinal ganglion cells.
Brain Res. 2003 Jan 31;961(2):213–9.
43 Katz DL, Greene L, Ali A, et al. The pain of fibromyalgia syndrome
is due to muscle hypoperfusion induced by regional vasomotor dysregu-
lation. Med Hypotheses. 2007;69(3):517–25.
44 Yuen KC, Baker NR, Rayman G. Treatment of chronic painful dia-
betic neuropathy with isosorbide dinitrate spray: a double–blind place-
bo–controlled cross–over study. Diabetes Care. 2002 Oct;25(10):1699–
703.
45 Pioneering Treatments for Fibromyalgia & Chronic Fatigue Syndro-
me. http://www.immunesupport.com/library/showarticle.cfm/ID/4911/
Fatigue Syndrome. Hunter House 1995. pp. 184–185.
48 Bou–Holaigah I, Rowe PC, Kan J, et al. The relationship between
neurally mediated hypotension and the chronic fatigue syndrome.
JAMA. 1995 Sep 27;274(12):961–7.
cfm/ID/2926/
50 Costa DC, Tannock C, Brostoff J. Brainstem perfusion is impaired in
chronic fatigue syndrome. QJM. 1995 Nov;88(11):767–73.
51 Simpson LO. The Role of Nondiscocytic Erythrocytes in the Patho-
genesis of ME/CFS. In the book: Hyde B, (ed.) The Clinical and Scien-
tific Basis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.
The Nightingale Research Foundation 1992. pp. 597–605.
52 Simpson LO. Nondiscocytic erythrocytes in myalgic encephalomye-
litis. N Z Med J. 1989 Mar 22;102(864):126–7.
53 Baughman RP, Iannuzzi M. Tumour necrosis factor in sarcoidosis
and its potential for targeted therapy. BioDrugs. 2003;17(6):425–31.
54 Thanhäuser A, Reiling N, Böhle A, et al. Pentoxifylline: a potent
inhibitor of IL–2 and IFN–gamma biosynthesis and BCG–induced cyto-
toxicity. Immunology. 1993 Sep;80(1):151–6.
55 Liu J, Feng X, Yu M, et al. Pentoxifylline attenuates the development

of hyperalgesia in a rat model of neuropathic pain. Neurosci Lett. 2007
Feb 2;412(3):268–72.
56 Navarro J, Punzón MC, Pizarro A, et al. Pentoxifylline inhibits acute
HIV–1 replication in human T cells by a mechanism not involving inhi-
bition of tumour necrosis factor synthesis or nuclear factor–kappa B
activation. AIDS. 1996 May;10(5):469–75.
57 Wanchu A, Bhatnagar A, Bambery P, et al. Prevention of opportunis-
tic infections in HIV infection by pentoxiphylline. Indian J Med Res.
2006 Dec;124(6):705–8.
58 Maksymowych WP, Avina–Zubieta A, Luong MH, et al. An open
study of pentoxifylline in the treatment of severe refractory rheumatoid
arthritis. J Rheumatol. 1995 Apr;22(4):625–9.
59 Weber F, Polak T, Günther A, et al. Synergistic immunomodulatory
effects of interferon–beta1b and the phosphodiesterase inhibitor pento-
xifylline in patients with relapsing–remitting multiple sclerosis. Ann
Neurol. 1998 Jul;44(1):27–34.
60 Staak K, Prosch S, Stein J, et al. Pentoxifylline promotes replication
of human cytomegalovirus in vivo and in vitro. Blood. 1997 May 15;89
(10):3682–90.
61 Tremont–Lukats IW, Challapalli V, McNicol ED, et al. Systemic
administration of local anesthetics to relieve neuropathic pain: a syste-
matic review and meta–analysis. Anesth Analg. 2005 Dec;101(6):1738–
49.
62 Kohyama J, Shimohira M, Watanabe S, et al. Mexiletine hydrochlo-
ride in an infant with intractable epilepsy. Brain Dev. 1988;10(4):258–
60.
63 Berninger E, Nordmark J, Alván G, et al. The effect of intravenously
administered mexiletine on tinnitus – a pilot study. Int J Audiol. 2006
Dec;45(12):689–96.
64 Okada S, Kinoshita M, Fujioka T, et al. Two cases of multiple scle-
rosis with painful tonic seizures and dysesthesia ameliorated by the
administration of mexiletine. Jpn J Med. 1991 Jul–Aug;30(4):373–5.

68 Yamada KA, Tang CM. Benzothiadiazides inhibit rapid glutamate
receptor desensitization and enhance glutamatergic synaptic currents. J
Neurosci. 1993 Sep;13(9):3904–15.
69 Dr. Paul Cheney: CFS & Cardiac Issues, Part 2b. http://www.
dfwcfids.org/medical/cheney/Cheney.CFS-Cardiac.Part2b.pdf
71 Miura R, Nakamura K, Miura D, et al. Anti–inflammatory effect of
spironolactone on human peripheral blood mononuclear cells. J Pharma-
col Sci. 2006 Jul;101(3):256–9.
72 Berg D, Berg LH, Couvaras J, et al. Chronic fatigue syndrome and/or
fibromyalgia as a variation of antiphospholipid antibody syndrome.
Blood Coagul Fibrinolysis. 1999;10(7):435–8.
73 Hannan KL, Berg DE, Baumzweiger W, et al. Activation of the coa-
gulation system in Gulf War Illness: a potential pathophysiologic link
with chronic fatigue syndrome A laboratory approach to diagnosis.
Blood Coagul Fibrinolysis. 2000 Oct;11(7):673–8.
74 Brewer JH, Berg D. Hypercoaguable state associated with active
human herpesvirus–6 (HHV–6) viremia in patients with chronic fatigue
syndrome. J Chron Fatigue Syn. 2001;8(3/4):111–16.
75 Procoagulant Genetic Factors in a Pooled Cohort of 582 Chronic
Fatigue Syndrome, Fibromyalgia and Related Chronic Illness Cases Pre-
sented at: American Association for Chronic Fatigue Syndrome
(AACFS) 7th International Conference on Chronic Fatigue Syndrome,
Fibromyalgia and Related Illnesses. Madison, WI, U.S. Oct 8–10, 2004.
76 Berg D, Berg LH, Couvaras J. Is CFS/FM due to an undefined hyper-
coagulable state brought on by immune activation of coagulation? Does
adding anticoagulant therapy improve CFS/FM patient symptoms?
AACFS Proceedings: Cambridge, MA, U.S. Oct 10–12, 1998, p. 62.
77 Dr. Paul Cheney Discusses TH1, TH2, the Immune System and
Chronic Fatigue Syndrome (CFS) – Part 2. http://www.immunesupport.
com/library/showarticle.cfm/ID/2925/
78 Ramos–Kuri M, Barron Romero BL, Aguilar–Setien A. Inhibition of
three alphaherpesviruses (herpes simplex 1 and 2 and pseudorabies
virus) by heparin, heparan and other sulfated polyelectrolytes. Arch
Med Res. 1996 Spring;27(1):43–8.
79 Johann S, Zoller C, Haas S, et al. Sulfated polysaccharide anticoagu-

lants suppress natural killer cell activity in vitro. Thromb Haemost. 1995
Oct;74(4):998–1002.
CHAPTER 8.
Hormones and immuno-
modulators
Several hormonal deficiencies have been associated with CFS/ME

and fibromyalgia. Many of the symptoms can be corrected simply by
fixing the deficiency, providing a justified and safe way to treat the pati-
ent. Occasionally there may be even complete symptom relief. Because
many of these hormones have a profound effect on the immune system,
they can also alleviate the immune dysfunction.
This chapter also includes other immunomodulatory drugs. Almost
all drugs have some effect on the immune system, but immunomodula-
tors are drugs that are primarily used for these effects. Traditionally
immunomodulators have been grouped into immunostimulants (drugs
that upregulate the immune system) and immunosuppressants (drugs
that downregulate the immune system), but all immunomodulators do
not conveniently fit into this scheme and may have both kinds of proper-
ties.
There is no consensus whether CFS/ME and fibromyalgia are cau-
sed by underactive or overactive immune system (if either), or whether
there are different subsets. Both immunostimulants and immunosuppres-
sants have been used to treat CFS/ME and to some extent also FM,
though immunostimulants have been more popular. Immunosuppres-
sants have been traditionally used to treat autoimmunity, but immunosti-
mulants (such as IVIG and LDN, both reviewed later in this chapter)
may offer a safer alternative.
Both kinds of immunomodulators may be able to treat the root
cause of CFS/ME and fibromyalgia, if it is immune dysfunction, and to
stop illness progression which is sometimes present. Immunostimulants
are also very helpful in the treatment of viral infections. Immunostimu-
lants are usually safer, but they can cause fever and other flu–like symp-
toms. Immunosuppressants are often lower on side effects, but they
increase the risk of infections and even cancer.
CFS/ME is generally considered a Th2 illness, which means that
the cellular immune system is overactive and the humoral immune sys-
tem (Th1) side is suppressed. Many of the immunomodulators used to
treat CFS/ME are thought to switch the immune system from excessive
Th2 domination to Th1 side. Th2 domination has generally been asso-
ciated with allergic conditions and Th1 with autoimmunity, though the
latter is increasingly being disputed. As a whole this model is probably
inadequate to explain the full complexity of the immune system.
Corticosteroids
Corticosteroids are steroid hormones produced by the adrenal cor-

tex, hence the name. Severe deficiency of these hormones causes Addi-
son’s disease, which can produce symptoms similar to CFS/ME, such as
fatigue, muscle weakness, joint and muscle pains, stomach pain, head-
ache, anxiety, photophobia and orthostatic hypotension. Addison’s dis-
ease is life–threatening without treatment, but fortunately quite rare.
Because missing this diagnosis would be tragic, people with suspected
CFS/ME and fibromyalgia should have their cortisol levels tested.
Unfortunately one–off tests are unreliable—they can be used to rule
out Addison’s disease and may spot other adrenal problems too, but
even if cortisol input is supposedly adequate, the patient can still suffer
from low–level hypocortisolism. Cortisol production can be adequate at
times yet occasionally dip too low, especially in times of stress. The cir-
cadian rhythm of cortisol secretion may also be disturbed. This is why
24–hour testing should always be done.
Addison’s disease is a form of primary adrenal insufficiency, cau-
sed by dysfunction of the adrenal gland. In CFS/ME and fibromyalgia
the problem is secondary, caused either by reduced production of
ACTH/CRH or diminished responsivity to them. This is called dysfunc-
tion of the HPA (hypothalamic–pituitary–adrenal) axis. Some doctors
believe that CFS/ME and fibromyalgia are caused by HPA dysfunction;
others think it is secondary to something else, such as a chronic infec-
tion.
In an ACTH test the release of cortisol is measured after an injec-
tion of ACTH (adrenocorticotropic hormone, which stimulates the pro-
duction of cortisol in the adrenals). It is commonly used to test for adre-
nal insufficiency, but it is not always reliable, either. Some studies have
speculated that a low dose (1 mcg) ACTH test would be more sensitive
than the normal (250 mcg) one.1 Other researchers have suggested the
sensitivity is not improved and that metyrapone test would be the most
sensitive one.2
Because of the similar symptoms caused by Addison's disease in
comparison to CFS/ME and fibromyalgia, numerous studies have eva-
luated adrenal function in these illnesses. Many studies have reported
lower cortisol values in CFS/ME compared to FM.3 It has been sug-
gested that there are autoantibodies to ACTH in CFS/ME, which would
Hormones and immunomodulators 195
explain low cortisol levels.4 In one study the adrenals of CFS/ME pati-
ents were found to have shrunk by up to 50% compared to healthy cont-
rols.5
Most studies have reported hypocortisolism in fibromyalgia6,7,
though one found high values.8 Low cortisol in fibromyalgia appears to
correlate with fatigue, sleep disturbances and the number of tender
points9, as well as early morning pain.10 In FM the secretion of ACTH is
increased, but the adrenals still produce too little cortisol.11,12,13
People with fibromyalgia appear to lose the diurnal variation in
cortisol secretion.14 In one study patients with FM were noted to have
abnormal circadian cortisol rhythm: half of the patients had elevated late
evening cortisol.15 In this study CFS/ME patients had lowered overnight
cortisol, but it did not reach statistical significance. One study found sig-
nificantly lowered morning cortisol in women with CFS/ME, but male
patients had values similar to healthy men.16
There are two different kinds of corticosteroids: glucocorticoids
and mineralocorticoids. As their name implies, glucocorticoids play a
part in glucose metabolism, but they are also behind the anti–inflamma-
tory and immunosuppressive effects of corticosteroids. Mineralocorti-
coids are primarily responsible for the mineral and fluid balance of the
body. Cortisol is mostly a glucocorticoid and aldosterone a mineralocor-
ticoid. Most synthetic corticosteroids have very little or no mineralocor-
ticoid activity.
Usually the doses used to treat CFS/ME and fibromyalgia are very
small. Larger, anti–inflammatory doses are sometimes used, but their
benefit is questionable. It can be due to the suppression of inflammatory
cytokines, reduction of peroxynitrite production or because of the stimu-
lating effect glucocorticoids have on the central nervous system. Dr.
Kent Holtorf believes that almost all patients with CFS/ME or FM
should have a therapeutic trial of hydrocortisone (15 mg a day or less),
especially if their symptoms point to adrenal insufficiency.17
Treatment with glucocorticoids is notorious for its risks and side
effects. It should be noted that these risks are mostly applicable for high
doses, which are not needed for hormone replacement. It is often
thought that glucocorticoid therapy always causes adrenal suppression,
but this does not apply to low dose steroids. In fact they may improve
HPA axis reactivity in CFS/ME.18 While cortisone treatment is consi-
dered immunosuppressive, adrenal insufficiency causes immune dys-
function as well.
Treatment with low dose corticosteroids has few side effects and,
as always, the risks of treatment should be weighed against the risks of
not treating. Low–level adrenal insufficiency is not life–threatening, but
it does tend to cause problems in the long term. Higher doses of gluco-
corticoids are a different matter. Because they cause adrenal suppres-
sion, they also necessitate a tapering of dose upon discontinuation,
which can take months. “Withdrawal” symptoms similar to the symp-
toms of adrenal insufficiency are common.
Large doses have many different side effects and risks. Immuno-
suppression leads to increased risk of infections and they can be difficult
to recognize, because steroids can mask their characteristic symptoms.
Lowered bone density is very common. Often osteoporosis drugs are
combined with glucocorticoid treatment. Diabetes, osteonecrosis (lite-
rally “death of bone”) and glaucoma can also be precipitated by cortico-
steroids.
Long–term use of large dose glucocorticoids often causes signifi-
cant weight gain. Fat tends to be redistributed to certain areas, especially
the face, neck and waist. Other possible adverse effects include e.g. dep-
ression and other psychiatric symptoms, insomnia, acne, muscle weak-
ness, muscle and joint pain, fluid retention and hirsutism (hair growth in
face and body).
See also:
corticosteroid pulse (CHAPTER 10)
prednisone (Deltasone, Orasone, Meticorten, Panafcort)

prednisolone (Orapred, Prelone, Prednisolon,
Deltacortril)
Prednisone and prednisolone are glucocorticoids with a medium

duration of action and only minor mineralocorticoid properties. They are
the primary drugs used to treat CFS/ME at the infection clinic of Helsin-
ki University, but there is little evidence of their efficacy in this use.
NIH conducted a double–blinded study of prednisone in the early 1990s,
but the results were so disappointing they were never published.
A few CFS/ME patients do improve dramatically on a daily dose of
5–10 mg of prednisone, but the effects are usually short–lasting and it
seems impossible to predict who will benefit. It could be that the drug
merely helps the underlying adrenal insufficiency and thus a small dose
of hydrocortisone would be a better choice.
In fibromyalgia prednisone does not seem very useful either. In a
double–blinded study done in the 1980s no improvement was noted and
most variables even showed a trend towards deterioration.19 On the
other hand in one study five out of six patients with treatment–resistant
major depression and severe fatigue improved on a 7.5 mg daily dose of
prednisone.20
Prednisone and prednisolone are available everywhere. Oral soluti-
ons are available on most markets. They are very inexpensive.
hydrocortisone (Cortef, Hydrocortison, Hydrocortone)
Hydrocortisone is a synthetic version of the endogenous cortisol

which is produced by the adrenals. Whereas prednisone is usually
employed in autoimmune and allergic conditions, hydrocortisone is
primarily used for hypocortisolism. It has a shorter duration of action
than prednisone and has a much greater potency as a mineralocorticoid.
Normally this can be problematic as it causes edema and raises blood
pressure, but it is usually beneficial when treating CFS/ME. Usually the
doses are fairly small. Several double–blinded studies have successfully
tried hydrocortisone in the treatment of CFS/ME.21,22,23
Hydrocortisone is available everywhere as tablets, creams and
liquid forms meant for external use. The creams can be used for rashes
and the liquids for seborrheic dermatitis, a scalp problem common in
CFS/ME. Hydrocortisone is very inexpensive.
fludrocortisone (Florinef, Astonin H)
Fludrocortisone is the synthetic equivalent of aldosterone, the most

important mineralocorticoid in the human body. It only has minor glu-
cocorticoid action. Administration causes fluid retention and thus raises
blood volume. Hypovolemia is very common in CFS/ME24 and patients
appear to have lower aldosterone levels than healthy controls.25 A Japa-
nese case report describes a CFS/ME patient whose illness went into
remission for six years when she suffered from hyperaldosteronism due
to an adrenal adenoma.26
Measuring aldosterone levels is probably not necessary; the symp-
toms are more useful in determining whether a patient might benefit
from fludrocortisone. Most people with CFS/ME suffer from orthostatic
hypotension, sometimes so severe that the patient cannot even stand
upright. Even in milder cases treating the problem can relieve the symp-
toms in general. Other circulation problems may also stem from
hypovolemia.
Not all studies have shown benefit from fludrocortisone in
CFS/ME, but one got very impressive results, even a full remission in
some of the patients using fludrocortisone in combination with other
treatments for orthostatic hypotension.27 The treatment is also endorsed

by the CFS/ME specialists Richard Podell28 and Charles Lapp.29 Dr.
David Bell has found fludrocortisone beneficial for 1/3 to 1/2 of his
patients, noting that it is most helpful for adolescents and the lesser ill.30
Many CFS/ME doctors recommend beginning the treatment with a
very small dose, such as only one fourth of a tablet for the first four
nights and then increasing the dose by one fourth of a tablet every four
days. Andrew J. Wright, however, does not recommend increasing the
dose beyond one fourth of a tablet.31 Some doctors think it is important
to always take the medication at the same time of the day.
Potassium supplementation may be warranted and it is important
that the patient ingests plenty of fluids and an adequate amount of pro-
tein. If the drug causes headache or stomach upset, taking it with a glass
of water may help. Fludrocortisone can cause depression (sometimes
even severe) or an excessive surge in blood pressure. CFS/ME expert
Paul Cheney does not recommend fludrocortisone and believes it can
actually exacerbate the illness in long–term use.32
Fludrocortisone is available in the United States, the United King-
dom, Canada, Australia and some other countries. Like the other corti-
costeroids it is very inexpensive. The potassium supplementation will
likely cost more, though it is by no means expensive either.
Other hormones
See also:
spironolactone (CHAPTER 7), raloxifene (CHAPTER 10)
thyroxine (Synthroid, Eltroxin, Euthyrox, Levothroid,

Thyrax)
liothyronine (Cytomel, Tertroxin)
thyroxine and liothyronine (Thyrolar, Novothyral)
thyroid (Armour thyroid, Westhroid, Thyrar)
Hypothyroidism has sparked significant interest as a possible cause

for CFS/ME and fibromyalgia, as many of the symptoms are strikingly
similar. Even if thyroid problems are not the root cause, they may cont-
ribute to the symptoms. It is sometimes claimed that hypothyroidism
excludes CFS/ME, but this is false. Especially female CFS/ME patients
commonly suffer from hypothyroidism (often autoimmune). Hypothy-
roidism may also be misdiagnosed as CFS/ME or FM.
Many doctors, even some endocrinologists, are not aware that a

person may be hypothyroid despite supposedly normal values of T3 and
T4, though it is becoming better known that T3 supplementation can
help refractory depression without evident hypothyroidism.33 Dr.
Gordon R. Skinner has shown that thyroxine can help “clinically hypo-
thyroid but biochemically euthyroid” patients.34 Doctors should consider
the patient as a whole and not just focus on numbers.
According to one view hypothyroidism, similar to diabetes, can be
divided into two categories based on whether there is a deficiency of the
hormone or a resistance to it (the secretion of the hormone is in normal
limits, but it does not elicit a sufficient response).35 It has been proposed
that those fibromyalgia patients who appear to be euthyroid have a
mutation in the c–erbA beta/alpha 1 gene, resulting in abnormal low–
affinity thyroid receptors which cause this resistance.36
There have been no studies to see whether this mutation really
underlies fibromyalgia, but hypothyroidism has been shown to be com-
mon in patients with FM.37,38,39 Thyroid antibodies are also preva-
lent.40,41 Fibromyalgia patients with thyroid antibodies have been report-
ed to have more symptoms of dry eyes, painful urination, blurred vision
and sore throat.42 Thyroxine has been shown to be an effective therapy
in some cases of fibromyalgia.43
Thyroid medication comes in several different forms. The form
normally used is T4 hormone (thyroxine). Thyrolar contains both the T3
and T4 forms. Natural thyroid is a thyroid extract made from porcine
(pig) thyroid. It contains both T3 and T4 as well as other thyroid hormo-
nes that are missing from other formulations. All forms are susceptible
to big individual differences in absorption, so the dose may not be
directly related to the degree of hypothyroidism.
There is no agreement as to which form is the best. T4 (thyroxine)
is the normally used form, but it may not always be helpful. In one study
patients with hypothyroidism fared better with a combination of T3 and
T4 than T3 alone.44 Kenny De Meirleir recommends treating with only
T3.45 Another CFS/ME and fibromyalgia doctor Kent Holtorf agrees
that T4 is probably not useful and believes that compounded slow–relea-
se T3 is the best form.46 Usually the effects of thyroid supplementation
should be noticeable in a few weeks.
When using the right form of thyroid supplementation in correct
dose, there should be no side effects, though sometimes there are transi-
ent symptoms as the body adjusts. Possible symptoms include fatigue,
hair loss, palpitations, restlessness, skin changes, headache, other aches,
excessive sweating, pruritus (itching), insomnia, nausea and chest pain.
Those allergic to pork should not take Armour thyroid.
Thyroxine is widely available. Liothyronine alone is available in

the United States, the United Kingdom, Canada, Australia and some
other countries. Combinations of the two are available in the United
States and some other countries. They are usually sold in several diffe-
rent dosages, which all contain the same ratio of T3 to T4.
All synthetic forms of thyroid supplementation are very inexpen-
sive. Natural thyroid is available in the United States, the United King-
dom and some other countries. It is available in about a dozen different
strengths and it is more expensive.
estrogen
estrogen and progesterone
The fact that women are much more likely than men to get
CFS/ME and fibromyalgia suggests that female hormones probably play
a part—but it is not clear how. Many doctors believe that a deficiency of
estrogen is a factor. A deficiency can cause many symptoms similar to
those of CFS/ME and fibromyalgia, such as fatigue, memory problems,
insomnia, depression, anxiety, palpitations, muscle and joint pain, hair
loss and skin problems.
The use of estrogen or the combination of estrogen and progeste-
rone in female patients with CFS/ME and fibromyalgia is a controver-
sial issue. Some patients cannot tolerate these hormones and a few doc-
tors recommend against them. Others believe that hormone replacement
is very important, as with replacing e.g. cortisol or thyroid hormone.
Hormone replacement therapy after menopause has been associated
with increased cancer risk, but estrogen also has beneficial effects such
as maintaining bone density and improving sleep. It can relieve depres-
sion and cognitive problems.47,48 Progesterone may aid cognition and
relieve anxiety. It can relieve chronic pain by NMDA antagonism.49
Some patients with severe CFS/ME go into early menopause in their 20s
or even sooner and lose these benefits.
The contraceptive pill is a common way of “hormone replacement
therapy” in premenopausal women with CFS/ME and fibromyalgia. It
can also be used to maintain regular periods. Women with CFS/ME
have a less regular cycle than healthy women.50 The pill can also help
orthostatic hypotension by increasing blood volume.51
Hormone specialist Dr. Elizabeth Lee Vliet believes that gonadal
insufficiency can be a triggering factor for CFS/ME and fibromyalgia.52
According to her all women with CFS/ME and fibromyalgia have low
estrogen levels and up to 75% improve after getting supplemental estro-
gen, testosterone and DHEA for six months. She prefers contraceptive
patches, because they keep hormone levels more stable than the pill.
Premarin, a horse–derived estrogen supplement is commonly used
as hormone replacement therapy, but it is far from identical to human
hormones. It contains much more estrone, which may be the reason for
the increased cancer risk. Synthetic estrogens are usually a better choice.
In general there are major differences between different hormonal pro-
ducts. Different oral contraceptives contain not only different amounts
of the hormones, but also different forms of estrogen and progesterone.
Some people cannot tolerate any female hormone supplementation,
but most experience no adverse reactions or only get minor side effects.
Possible side effects include weight gain, irritability, spotting and mood
changes. Some medications such as carbamazepine and some antibiotics
as well as St. John’s wort can impair the efficacy of oral contraceptives.
Estrogen and estrogen/progesterone products are widely available.
They are sold as tablets, patches, creams, implants and long–acting
injections, but the availability of particular products depends on the
market. Most products are inexpensive.
testosterone
Testosterone is not just a male hormone. Women need it too, just in

smaller quantities. Blood levels decrease with age and this has been
associated with a phenomenon called “andropause” in men. It may also
contribute to menopausal symptoms in women. Low testosterone levels
are common in fibromyalgia53, and likely in CFS/ME as well.
Low testosterone can cause low libido, depression, fatigue, hair
loss, muscle weakness and headaches. It is often thought that moodiness
and aggression stem from testosterone, but in fact low testosterone can
cause such symptoms in men.54,55 In animal studies a deficiency of testo-
sterone significantly reduces the amount of ATP (the primary energy
source) in the muscle in both male and female rats.56
Dr. Elizabeth Lee Vliet stresses that in women with CFS/ME estro-
gen supplementation should be initiated first and testosterone is only
started after that.57 Hillary D. White, a professor in microbiology and
immunology who specializes in sex hormones, believes that testosterone
is one of the best treatments for fibromyalgia and she uses it herself.58
She has also filed a patent about the use of testosterone (or testosterone
and DHEA) in the treatment of CFS/ME and fibromyalgia.59 Jay Gold-
stein recommends transdermal testosterone for the men who respond to
nitrate drugs.60
Testosterone supplementation can be done in several different
ways, including tablets, patches, creams, sublingual troches and depot
injections, even aerosols. There is no consensus as to which method is

the best—some doctors think the levels should be constant and others
prefer administration that mimics the natural circadian rhythm. Gels and
creams have the benefit of allowing for easy dose titration.
Taking too much testosterone can cause acne, sleep apnea, night-
mares, mood swings and hirsutism in women. On the other hand, low
testosterone may be risk factor for e.g. diabetes, osteoporosis, prostrate
cancer, Alzheimer’s disease and cardiovascular disease. Oral testoste-
rone can cause elevation of liver enzymes.
Testosterone is widely available. Most products are fairly inexpen-
sive, injections usually being the cheapest. Because of abuse in athletes,
testosterone is a Schedule III drug in the United States.
DHEA/prasterone
Dehydroepiandrosterone (DHEA) is an important natural steroid

hormone which is e.g. a precursor to testosterone and estrogens. Levels
decline with age and have been associated with the negative effects of
aging. There is conflicting information about the levels of DHEA in
CFS/ME—some studies have concluded there is too little of it61,62, but
one study found elevated levels.63 In fibromyalgia both normal64 and
low65 levels have been reported.
DHEA does not just affect the levels of sex steroids, but aso appe-
ars to have anti–inflammatory, neuroprotective and even anti–cancer
effects. It inhibits the secretion of IL–6, a major inflammatory cytokine,
which has been associated with fibromyalgia pain.66 DHEA has been
successfully used to treat e.g. SLE67 and HIV infection.68 Higher
DHEAS levels have been associated with better cognition in women.69
Two studies have found DHEA effective for CFS/ME.70,71 A doub-
le–blind trial trying 50 mg of DHEA for postmenopausal women with
fibromyalgia found no improvement in any of the studied variables, but
DHEA did cause some side effects typical of the androgens.72 Dr.
Charles Lapp sometimes prescribes intranasal DHEA spray for the mig-
raines experienced by his CFS/ME patients.73
Small doses do not usually cause side effects, but long–term use of
larger, over 50 mg doses may cause acne, cardiac arrhythmias, weight
gain, menstrual problems, hair loss, hirsutism, insulin resistance, other
lipid changes and possibly increase the risk of hormonal cancers. Even
smaller doses can decrease the amount of HDL (good cholesterol).
DHEA is not recommended for those with a history of PTSD, psychosis
or bipolar disorder. Some people think that DHEA may cause CFS/ME
relapses.
DHEA is available in most countries. It is usually a prescription

drug, but in the United States it is available over the counter.
oxytocin (Syntocinon, Pitocin)
Oxytocin is a hormone which is associated with e.g. mood, learn-

ing, sexual arousal and bonding. A deficiency may be present in fibro-
myalgia, especially in patients with depression.74 Anxiety and high
levels of pain also correlated with low oxytocin. Dr. Jorge Flechas belie-
ves that people with CFS/ME suffer from an oxytocin deficiency.75 He
prescribes his patients first a DHEA supplement based on blood levels
and then oxytocin. According to him the positive effects are noticeable
within a week or two.
Dr. Jay Goldstein uses an intramuscular dose of 5–10 units a day in
1–2 doses.76 He has found the effects of oxytocin complex and versatile.
According to him it helps about 1/5 of the patients who are not helped
by other treatments. Fatigue may not be relieved, but cognitive problems
and fibromyalgia pain often markedly abate and diminished libido may
return. Charles Lapp agrees that the benefits of oxytocin can be very
significant.77 Oxytocin also slows the development of opioid tolerance.
Oxytocin is used to initiate labor, so it should never be given to
pregnant patients. Structurally it is very similar to vasopressin and has
similar but milder antidiuretic effects, which can be beneficial for many
patients, but may cause edema and electrolyte imbalances. Oxytocin can
cause hypotension and cardiac arrhythmias. Too large doses tend to
produce anxiety.
Oxytocin is available everywhere. It can be administered intramus-
cularly or as a nasal spray, but the latter is considered inefficient. Tab-
lets are also available in some countries.
growth hormone (Genotropin, Humatrope, Norditropin,

Nutropin, Saizen)
Besides treatment of short stature, growth hormone has success-

fully been used for many other illness states, but this use is controver-
sial. Deficiency of growth hormone can cause symptoms very similar to
CFS/ME and fibromyalgia. Such deficiency has been associated with
CFS/ME78,79 and especially FM.80 It appears not to be present in all pati-
ents, but only a subset of them.
In one study growth hormone was given to 20 CFS/ME patients
and although quality of life did not improve significantly, four of the
patients were able to return to work after a prolonged absence.81 Two
randomized studies have evaluated the use of growth hormone as a

treatment of fibromyalgia with good results.82,83 The quality of life
scores as well as the number of tender points improved and the treat-
ment was well–tolerated. Growth hormone can also improve attention in
patients who are deficient in it.84
According to Dr. Susan Levine treating growth hormone deficiency
in CFS/ME can improve the quality of sleep.85 CFS/ME expert Paul
Cheney is concerned that deficiency may not only impair sleep, but liver
function too.86 He prescribes a small dose of 0.1–1 mg (usually once a
week) and has found it very helpful for some treatment–refractory pati-
ents. Growth hormone has to be given by intramuscular or subcutaneous
injection. Many other pharmaceuticals can be used to increase the secre-
tion of this hormone.
The side effects of growth hormone treatment have probably been
exaggerated, as studies have not found major adverse effects. Edema,
muscle and joint pain and tingling in the extremities are possible. In one
of the fibromyalgia studies there were no other side effects but carpal
tunnel syndrome. Growth hormone can also escalate the growth of any
existing cancer. It should be used with caution in patients with diabetes.
Growth hormone is widely available. It is extremely expensive.
See also:
sodium oxybate, melatonin, baclofen (CHAPTER 1), triptans

(CHAPTER 2), buspirone (CHAPTER 5), bromocriptine (CHAPTER
6), clonidine (CHAPTER 7), pyridostigmine (CHAPTER 9)
desmopressin (DDAVP, Minirin, Octostim, Desmospray,

Desmotabs)
Vasopressin is also known as antidiuretic hormone (ADH). Inade-

quate secretion of this hormone causes excessive urinary frequency,
which is a common symptom of CFS/ME and sometimes FM. There is
evidence of ADH deficiency in CFS/ME.87 Desmopressin is a synthetic
equivalent of vasopressin.
There is one preliminary study about the use of desmopressin in
CFS/ME.88 Desmopressin raises blood pressure and blood volume to
some extent, which may help orthostatic hypotension. It also has nootro-
pic (cognition improving) action.89 Paul Cheney has found that many of
his CFS/ME patients have diabetes insipidus and he treats them with
desmopressin.90 Desmopressin can be taken as a nasal spray or as tab-
lets, but the tablets have a poor bioavailability.

Side effects can include headache, stomach upset, nausea and facial
flushing. The nasal spray can cause local irritation, congestion and nasal
bleeding. Many drugs (especially psychiatric drugs) have interactions
with desmopressin, but usually the problem can be solved by reducing
the desmopressin dose. Not limiting fluid consumption during the treat-
ment can result in fluid retention and hyponatremia.
Desmopressin is available in the United States, the United King-
dom, Canada, Australia and many other countries. It is affordable; the
nasal spray is cheaper than the tablets, as because of the low bioavail-
ability much higher doses are needed with the tablets.
Biological immunosuppressants
Biological drugs are used in the treatment of autoimmune diseases,

some other inflammatory conditions and some cancers. Aside from the
cancer therapies, most of them are immunosuppressants, but they are
more specific in action than e.g. corticosteroids. Most are antibodies to
cytokines or their receptors. For example TNF alpha is a common tar-
get, and it has been shown to often be elevated in CFS/ME.91 The down-
side of these drugs is that they are extremely expensive, need to be
given by injection and the long–term safety remains to be assessed.
infliximab (Remicade)
Infliximab is a mouse–human chimeric antibody against the major

inflammatory cytokine TNF alpha. It has been successfully tried for
many different ailments from ulcerative colitis to prolapsed discs. There
are no studies about its use in CFS/ME yet, but Jonathan Kerr plans to
conduct one as soon as he gets the required funding.92 Andrew J. Wright
proposed infliximab as a CFS/ME treatment back in 2002.93 Professor
Olli Polo has also made a similar proposal.94
Infliximab is given as an infusion in a hospital first every few
weeks, then usually every 4–8 weeks. The method of administration is
not the most convenient one, but on the other hand it does not need to be
done very often. Infliximab does not usually cause major side effects,
though infections are common. There can be flu–like symptoms during
the infusion and rarely allergic symptoms between the treatments.
Infliximab may also increase the risk of lymphoma.
Infliximab is available in the United States, the United Kingdom,
Canada, Australia and many other countries. It is extremely expensive.
etanercept (Enbrel)
Etanercept mediates its anti–inflammatory effect by binding the

cytokine TNF alpha. It is mostly used in the field of rheumatology, but
has been used for other kinds of inflammatory conditions too.95 It has
also been successfully used to reduce the drowsiness associated with
sleep apnea.96
In a small study etanercept was given to six CFS/ME patients for
eight weeks. The patients experienced a significant reduction in fatigue,
muscle pain, headache and lymphodynia (lymph node pain). Exercise
tolerance was also improved.97 A Taiwanese doctor reports having tried
etanercept in fibromyalgia, but without significant benefit.98
Etanercept has to be administered fairly often, depending on the
dose either once or twice a week. It does not require hospitalization, as
the patient can administer the required subcutaneous injection. Treat-
ment can cause infections, in some cases even serious ones. Headaches
are also fairly common.
Etanercept is available in the United States, the United Kingdom,
Canada, Australia and several other countries.
adalimumab (Humira)
Adalimumab is a fully human monoclonal antibody which works

by binding to TNF alpha. It has been approved for treating e.g.
rheumatoid arthritis, ankylosing spondylitis and Crohn’s disease.
Adalimumab was proposed as a CFS/ME treatment in a letter published
in the Journal of Neuropsychiatry in 2007.99
Adalimumab is normally given by a subcutaneous injection which
the patient is usually instructed to administer every other week. The side
effects and risks are thought to be similar to the other TNF alpha
inhibitors. Headache, rash, nausea and infections are the most common
side effects.
Adalimumab is available in the United States, the United Kingdom,
Canada, Australia and some other countries.
omalizumab (Xolair)
Omalizumab is a monoclonal antibody used in the treatment of

asthma and severe allergies. It inhibits receptor binding of immunoglo-
bulin E, which mediates allergic symptoms. It is administered by injec-
tion every 2–4 weeks. Some patients with CFS/ME have reported dra-
matic improvement with omalizumab.100 Although this evidence is only
anecdotal, CFS/ME has been postulated to be a kind of an allergy–like

hypersensitivity, so it would make sense to try omalizumab in patients
with elevated IgE levels.
Omalizumab does not usually cause side effects, but there are a few
reports of serious anaphylactic reactions. Like other monoclonal anti-
bodies it may increase the risk of cancer and some other illnesses.
Because IgE also protects the body from parasites, omalizumab could
increase the risk of parasitic infection, but in most developed countries
this is not an issue.
Omalizumab is available in the United States, the United Kingdom,
anakinra (Kineret)
Anakinra is an antagonist of the IL–1 receptor. It is used in the

treatment of rheumatoid arthritis. CFS/ME and fibromyalgia may also
be associated with excessive levels of IL–1.101,102 Anakinra is given as a
subcutaneous injection, usually every day.
Nausea, diarrhea, headache and infections are the most common
side effects. Most patients experience local reactions at the infection
site, but they are usually transient.
Anakinra is available in the United States, the United Kingdom,
Other immunomodulators
See also:
benzodiazepines, dantrolene (CHAPTER 1), tetracyclines, macro-

lides (CHAPTER 4), SSRIs, lithium (CHAPTER 5), pyritinol
(CHAPTER 6), pentoxifylline (CHAPTER 7), cannabinoids, raniti-
dine/cimetidine (CHAPTER 9), pioglitazone/rosiglitazone, sizofi-
ran, montelukast, angiotensin II receptor blockers, pegademase,
ACE inhibitors, statins (CHAPTER 10)
immunoglobulin (Flebogamma, Gammagard,

Endobulin, Intragam, Beriglobin)
Immunoglobulins are important antibodies. A deficiency of immu-

noglobulin G or its subclasses–especially IgG1 and IgG3, sometimes
also IgG4–is often associated with CFS/ME.103,104,105 Intravenous immu-
noglobulin (or IVIG, sometimes called gamma globulin), a blood

product containing the pooled IgG immunoglobulins from plasma of
more than a thousand donors, has been used as a CFS/ME treatment
since the 1980s. It is usually infused about once a month.
Many patients benefit from IVIG, even if there is no detectable IgG
deficiency, perhaps because of the anti–inflammatory and antiviral
effects of the treatment. Some patients go from severely ill to being able
to work. Some doctors even think that immunoglobulin is the most
effective treatment for CFS/ME.106 Charles Lapp gives it to his sickest
patients if nothing else has helped.107 It may take several months before
the full benefits are apparent, but on the other hand the efficacy may
decrease with time.108
Several, though not all, studies have showed benefit from using
IVIG in CFS/ME. In an Australian double–blinded study of 49 patients
those who got a monthly dose of IVIG were significantly more likely to
improve than those getting placebo.109 An early double–blind study of
IVIG for “chronic mononucleosis syndrome” found improvement in the
treatment group, and several of the patients even experienced a full
relief of symptoms.110 There are reports of curing CFS/ME caused by
parvovirus B19 with an IVIG pulse.111
A recent study showed that a subset of fibromyalgia patients may
also benefit from IVIG, given in small doses for five days. Pain, tender-
ness and muscle strength improved the most.112 In one study of several
chronic pain syndromes, including FM, IVIG helped almost half of the
patients and 20% experienced over 70% pain relief.113
Immunoglobulin is not known to cause crashes or illness exacerba-
tions and most patients can tolerate it, but because of the nature of the
treatment (an immunomodulatory blood product given intravenously) it
does have its risks. Patients should always be monitored during the infu-
sion and for some time afterwards. Some people experience transient
headache, fever, nausea, joint pain and hypotension. There is a very
small risk of anaphylaxis and kidney failure. IVIG is not thought to be
able to transmit infectious agents.
Immunoglobulin is available in most countries, but because of the
nature of the product it is very expensive. Often only patients who can
demonstrate severe immune dysfunction are eligible for treatment, and
IgG deficiencies may not be enough to qualify. In some countries every-
one can get IVIG, if they can afford to pay for it out of pocket.
interferon alfa (Intron A, Pegasys, PegIntron, Roferon–

A, Infergen)
interferon beta (Avonex, Betaseron, Betaferon, Rebif,
Serobif)
interferon gamma (Actimmune, Imukin, Immukin,
Immukine)
Interferons are messengers of the immune system and of particular

importance in fighting viral infection. Different interferons are used to
treat e.g. cancer, hepatitis B and C and multiple sclerosis. Both theories
and research about the relationship of CFS/ME and interferons have
been conflicting. According to some studies the T cells of CFS/ME pati-
ents produce abnormally low amounts of interferon gamma114,115, but
another study concluded the production was actually excessive.116
Interferons would be a logical choice for treatment of CFS/ME if
the illness were caused by a chronic viral infection. On the other hand
many doctors think that the symptoms of CFS/ME could be caused by
excessive production of interferon alfa and/or gamma, as the symptoms
of CFS/ME resemble the side effects of interferon treatment.117,118 All of
the interferons and interferon alfa in particular have been tried as treat-
ments for CFS/ME.
Some CFS/ME doctors believe that interferon alfa can give patients
more energy.119 Two double–blinded studies have evaluated this use as
well. The first one found significant improvement in about 1/3 of the
patients120, but in the second study only a subset of patients with prob-
lems in NK cell function benefited.121 In a large double–blinded study
done on fibromyalgia patients a 50 IU dose of sublingual interferon alfa
produced a significant improvement in functionality and morning stiff-
ness, but not in other symptoms.122
The combination of alfa and gamma interferon has been proposed
as a treatment for the chronic enteroviral infection which may be behind
CFS/ME.123 Interferon beta also has some antiviral properties. HHV–6,
a herpesvirus commonly reactivated in CFS/ME, appears to respond
particularly well to interferon beta.124 Additionally beta interferon may
help repair increased permeability of the blood–brain barrier.125 Blood–
brain barrier permeability has been suggested as a factor in CFS/ME.126
Interferons are usually given intramuscularly or subcutaneously,
once or several times a week. Side effects are common and can include
injection site reactions, muscle and joint pain, fatigue, flu–like symp-
toms, stomach upset, neurological symptoms, skin eruptions and severe
psychiatric symptoms even without any history of psychiatric illness.
Interferons can cause an autoimmune illness or worsen an existing auto-
immune condition. They are usually not used in patients with epilepsy
or a severe psychiatric, cardiac, renal or hepatic condition.
There are several different varieties of each of the interferons.
Interferon alfa and beta are widely available in injectable forms. Oral
(sublingual) interferon alfa is available in Canada and possibly other
countries. Interferon gamma is available in the United States, the United
Kingdom, Australia and some other, primarily European countries, but
not in Canada. All of the interferons are very expensive.
liver derivative complex (Nexavir)
Nexavir is an extract of porcine (pig) liver. It is a popular drug used

to treat CFS/ME and occasionally fibromyalgia. The better–known
drugs Hepapressin and Kutapressin (which are no longer available) were
similar liver extracts. There is little research of Nexavir, but many
CFS/ME experts like Paul Cheney and Derek Enlander recommend it.
In a six–month study of Kutapressin in over a hundred CFS/ME
patients as many as 85% reported major improvement in their
symptoms.127 42% even reported that they were in remission. Minor side
effects were experienced by 16% of patients. Kutapressin was also
shown to have antiviral activity against EBV128 and HHV–6.129
Nexavir is usually given by a subcutaneous or intramuscular
injection. It is recommended that the dose be varied constantly in order
to keep it effective, but sometimes the efficacy still decreases with time.
In that case it can be temporarily stopped and resumed later. It can take
several weeks before the results are apparent and months to get the full
effect. Dr. Kenny De Meirleir believes that sleep often normalizes in 2–
3 days, but it can take a few months before the patient is pain free.130
Nexavir should not be used by people who are allergic to pork.
Others may want to avoid porcine products for ethical reasons, though
most religions accept the use of pork–derived products out of medical
necessity. Because Nexavir contains tyramine, it is contraindicated
when using MAO inhibitors. Tyramine may also provoke migraines in
some people. Phenols are used as preservatives and may cause allergic
reactions. The injections can cause local reactions such as itching.
Nexavir is only available in the United States, though other liver
derivative complexes may be available elsewhere. It should not be
confused with the cancer drug sorafenib which is marketed as Nexavar.
Nexavir is very expensive, but despite the experimental nature many
insurance companies do cover the drug. Compounding pharmacies can
also produce a transdermal gel of the drug, which does not require
prescription.
inosine pranobex (Isoprinosine, Imunovir, Delimmun)
Inosine pranobex (commonly known as isoprinosine) is a synthetic

purine derivative with immunomodulatory and antiviral properties.
Many doctors have used it to treat CFS/ME, especially when there is
evidence of an active herpesvirus infection. Normal inosine, however,
which is available as a nutritional supplement, has been suggested to
have similar efficacy. Inosine pranobex has also been used to promote
physical endurance in healthy persons, but there is no data to support
this use.
A small single–blind study of inosine pranobex published in the
Journal of Chronic Fatigue Syndrome found benefit in 6 of 10 patients
at 28 weeks.131 In those who improved NK cell activity and the number
of CD4+ T helper cells were significantly increased. Dr. Larry Sharp
believes that inosine pranobex is “one of the safest, most cost effective
and helpful drugs at our disposal [for CFS/ME].”132
As with Nexavir, it is thought that the dose should be constantly
varied. Paul Cheney’s traditional protocol has been six tablets on Mon-
day, Wednesday and Friday, two on Tuesday and Thursday and none on
the weekend, done for two months and then a pause for one month.133
Dr. Byron Hyde has used a dosing schedule of six tablets a day Mon-
day–Friday every second week, two tablets a day Monday–Friday the
other week, none on the weekends and again one month off every two
months.
Inosine pranobex is well–tolerated and usually does not cause any
side effects. Possible side effects include dizziness, nausea, headaches,
fatigue, indigestion and itching. It should not be used by people with
gout.
Inosine pranobex is available in Canada, some European countries
(including the United Kingdom, France and Germany) and in some parts
of Asia and South America, but not in the United States or Australia. In
some countries it is quite expensive, but other markets offer more
affordable prices.
thymalfasin (Zadaxin)
Thymalfasin is a synthetic form of the human peptide thymosin

alpha 1. It is an immunomodulator and is currently used as an adjuvant
in the treatment of hepatitis B and hepatitis C, for increasing the effi-
cacy of vaccinations and experimentally in some cancers. It can help
shift the immune system from excessive Th2 domination to a stronger
Th1 response, increasing the production of NK cells. It may be especi-
ally useful in combination with antibiotics or antivirals.

Thymalfasin is given as a subcutaneous injection, usually twice a
week. It is generally very well tolerated. Local adverse reactions at the
injection site are possible, but systemic side effects are rare. There have
been occasional reports of rashes, edema and joint pain.
Thymalfasin is only available in the United States and a few other,
mostly Asian countries, but it will likely be approved in many more
countries in the near future. It is very expensive.
hydroxychloroquine (Plaquenil, Plaquinol)
Hydroxychloroquine is an antimalarial drug which is also used for

some autoimmune and inflammatory conditions. Some doctors have
used hydroxychloroquine to treat CFS/ME, particularly if the patient has
high titers of antinuclear antibodies or other signs of autoimmu-
nity.134,135 It appears to be effective against the cysts of Borrelia burg-
dorferi, which may be important if the patient is suspected to have chro-
nic Lyme disease.136 It also inhibits cholinesterase, increasing acetylcho-
line levels.137
The effects of the drug come on very slowly, often only after seve-
ral months of treatment. Hydroxychloroquine is fairly low on adverse
reactions. Stomach upset and nausea are the most common side effects.
Long–term use may cause alterations in vision, warranting regular oph-
thalmologic examinations. According to one study SLE patients taking
hydroxychloroquine had significantly more fatigue than those on other
medications.138
Hydroxychloroquine is available in the United States, the United
Kingdom, Canada, Australia and some other countries. It is very inex-
pensive.
acetylcysteine (Mucomyst, Parvolex, ACC, Solmucol,

Fluimucil)
Acetylcysteine (often called N–acetylcysteine or NAC) is an amino

acid with two primary indications: as a mucolytic and as an antidote for
acetaminophen (paracetamol) overdose. It is a strong antioxidant with a
wide range of uses as an immunomodulatory and organ–protecting
agent. Acetylcysteine increases intracellular levels of glutathione and
stimulates T cell function. As a result it can have antiviral action and is
often used by HIV patients. It is probably helpful in influenza and
colds.139
Acetylcysteine is also used for “detoxing” of chemicals and is a
common treatment for multiple chemical sensitivity. It is a part of pro-

fessor Martin Pall’s recommended regime for treating CFS/ME and fib-
romyalgia. He notes that low doses should be used and that magnesium
should lessen any sensitivity to the drug.140 Acetylcysteine has also
shown efficacy in the autoimmune condition Sjögren’s syndrome.141 It
may have use in the treatment of neuropathy.142
Nausea and stomach upset are the most common side effects. Other
side effects are rare, but acetylcysteine is claimed to bring out symptoms
caused by detoxification. An unflavored acetylcysteine solution has an
unpleasant, “sweaty” taste.
Acetylcysteine is available almost everywhere. In the United States
and some other countries it is both a prescription drug and a popular
nutritional supplement. Depending on the country available forms may
include tablets, fizzy tablets and liquid suspensions. It is fairly inexpen-
sive.
Staphylococcus toxoid (Staphypan)
Toxoid refers to inactivated bacterial toxin. For example the tetanus

vaccine is a toxoid vaccine; it does not offer protection from Clostrid-
ium tetani, only from its deadly toxin. Staphylococcus toxoid has been
used to treat both CFS/ME and fibromyalgia. Some doctors think its
benefits are due to immunomodulation, whereas others believe that sta-
phylococci may actually be involved in the pathogenesis of the ill-
ness.143,144 The injections are given about once a month.
Several studies have tried staphylococcus toxoid in CFS/ME and
fibromyalgia. In the first trial fatigability improved the most.145 Half of
the participants were able to resume working. In another study 65% of
patients with CFS/ME or FM reported improvement compared to only
18% in the placebo arm.146 The largest trial so far included 160 patients
with fibromyalgia or CFS/ME on long–term treatment with staphylococ-
cus toxoid for one year.147 Of particular importance in that study was the
reduced incidence of infections reported by patients.
Even though vaccinations in general have caused problems in this
population, treatment with the staphylococcus toxoid appears to be
well–tolerated. Local reactions are common but usually mild. Headache
is possible. In the long–term study only 9 out of 160 patients withdrew
from the study because of side effects, two because they developed an
allergy to preservative in the vaccine. Nonetheless, the therapy may not
be appropriate for those who have reacted severely to vaccinations.
Staphylococcus toxoid is currently only available in Switzerland. It
is likely difficult to acquire outside of clinical trials.
Mycobacterium vaccae
Mycobacterium vaccae is a non–pathogenic species of mycobacte-

ria, related to the bacteria that cause tuberculosis. An infusion of the kil-
led bacteria has been used as an immunomodulator in e.g. cancer, asth-
ma and eczema. It should be noted that this is not the same thing as
Bacillus Calmette–Guérin (BCG), the tuberculosis vaccine that has been
used as immunotherapy in some cancers.
Like many other immunomodulators, Mycobacterium vaccae seems
to downregulate the Th2 side of the immune system. It also appears to
increase serotonin metabolism in the brain with possible antidepressant
action.148 Mycobacterium vaccae has been tried in the treatment of
CFS/ME. No studies have been published, but a patent has been filed of
this use. The patent also includes a few short case studies of CFS/ME
patients who experienced major improvement on the therapy.149
The treatment is usually first administered every two weeks, then
once a month. Side effects can include fever, other flu–like symptoms
and nausea. BCG contains live bacteria and can rarely cause severe
infections in immunosuppressed persons, but Mycobacterium vaccae
preparations do not, so it is safe in this regard.
Mycobacterium vaccae is most likely only available in hospitals
with innovative and open–minded researchers who are willing to admi-
nister it to patients with CFS/ME.
naltrexone (Revia, Nalorex, Antaxone, Nemexin)
Naltrexone is an opioid antagonist used in the treatment of drug

and alcohol addiction, sometimes also for other addictions, in doses of
50–300 mg. In low doses of 2–5 mg (usually 4.5 mg) it can be used as
an immunomodulator, because the very short–lived opioid antagonism
stimulates the body to produce more endogenous opioid peptides
(endorphins and enkephalins) which upregulate the immune system.
The low dose naltrexone (LDN) therapy was invented by neurolo-
gist Bernard Bihari as a treatment for HIV/AIDS and multiple sclerosis
back in the 1980s. It has also been used for e.g. SLE and other autoim-
mune diseases, neurodegenerative diseases, autism, IBS and even can-
cer.150 It has been used in CFS/ME since the early 1990s and recently
also for fibromyalgia. A clinical trial for fibromyalgia is currently run-
ning in the United States.151 There are reports that LDN can help chronic
Lyme disease, but may not be as efficacious as in other conditions.
Traditionally autoimmune illnesses have been seen as overactivity
states of the immune system and the use of LDN might seem counterin-
tuitive, but evidence is mounting that they may in fact be immunodefici-

encies. At least LDN has been shown to work extremely well in e.g.
Crohn’s disease.152 It could also be that overactivity and underactivity
are too simplistic concepts for something as complex as the immune
system. This could well apply to CFS/ME and fibromyalgia too.
Beta endorphin levels have been demonstrated to be low in CFS/
ME and fibromyalgia.153,154 Natural killer cell (NK cell) activity is well–
known to be impaired in CFS/ME155 and correlates with illness seve-
rity.156 Beta endorphin has been shown to stimulate NK cell function.157
Low dose naltrexone has also been proposed to work by reducing the
formation of peroxynitrites158, a suggested factor in CFS/ME and fibro-
myalgia.159
LDN can relieve pain, fatigue, depression, muscle weakness, cogni-
tive problems, fever, dyspnea and flu–like symptoms. It may also help
in migraine prevention. It has been reported to significantly reduce CFS/
ME “crashes.” It may take anywhere from a day to a few months before
symptom relief is apparent. LDN is always taken at night between 9 PM
and 3 AM to maximize endorphin production.
Normal doses of naltrexone have plenty of side effects, but in LDN
the action of the drug is opposite. Usually there are no side effects at all.
In the beginning of the treatment there may be sleep disturbances and
sometimes slight nausea, tremor and hunger pangs, but they usually
quickly subside. LDN cannot be used together with any opioids, but
other than that it has no drug interactions. Because of the nature of the
treatment it is probably not effective when used together with immuno-
suppressants.
Naltrexone is available in 50 mg doses in the United States, the
United Kingdom, Canada, Australia and many other countries, but low
doses have to be prepared by a compounding pharmacy. Calcium carbo-
nate should not be used as a filler, as it may interfere with the efficacy.
If for some reason a compounding pharmacy cannot be used, 50 mg
naltrexone tablets can be dissolved in water and measured for the proper
dose. Slow release formulations should never be used. LDN is inexpen-
sive, but the exact price depends on the compounding pharmacy.
polyI:polyC12U (Ampligen)
Ampligen is a mismatched double–stranded RNA drug with antivi-

ral and immunomodulatory properties. It is the only drug so far that has
been primarily focused on CFS/ME, though it has also been used for
HIV/AIDS, hepatitis B, some cancers and in small doses as an adjunct
to the treatment of avian influenza. Because Ampligen is antiviral, it
should work well for those with a confirmed chronic viral infection,
especially HHV–6.160 It has demonstrated activity against the enterovi-
ruses as well.161
Ampligen has been used in CFS/ME since the late 1980s, mostly in
clinical trials. The first phase II trials were done in the early 1990s, but
the development has been slow. Ampligen has been shown to be
efficacious in several trials, including multiple phase III ones.162 The
drug (and especially the company manufacturing it) has been subject to
plenty of controversy in the CFS/ME community. There have been con-
cerns that the company has downplayed the possible risks and side
effects.
Ampligen can help both physical endurance and cognitive prob-
lems. Paul Cheney believes Ampligen is most effective for those in the
first five years of the illness, those who had abrupt onset of illness and
those who have activation of the RNase L pathway.163 The latter can be
tested for, but there are very few laboratories in the world capable of
doing the testing. In contrast to most drugs, Ampligen may also be more
effective for the severely ill.
Ampligen has to be administered intravenously, usually two times a
week. Possible side effects include flushing, flu–like symptoms, diarr-
hea, rashes, cardiac symptoms, dizziness and abdominal pain. The side
effects tend to subside with time. Liver enzymes may be elevated. There
are reports of the drugs actually worsening CFS/ME.164 Usually concur-
rent use with other immunomodulators and antivirals or NSAIDs is not
recommended.
Ampligen is not officially approved in any country, though it may
become FDA–approved in the United States very soon. In the U.S.,
Canada and some European countries patients may be able to try Ampli-
gen, but usually they have to pay for the extremely expensive treatment
out of pocket. Most insurance companies do not cover the treatment. It
is worth noting that in some countries Ampligen is a brand name for
gentamicin, an antibiotic.
mycophenolate (CellCept, Myfortic)
Mycophenolate is an immunosuppressive drug primarily used to

prevent organ transplant rejection. It is also sometimes used in autoim-
mune diseases such as psoriasis and SLE. Curiously it has marked anti-
viral activity (especially in conjunction with other drugs) against many
viruses, such as dengue virus165, HIV166, hepatitis C167 and two kinds of
viruses that have been associated with CFS/ME: herpesviruses168 and
Coxsackie B169 virus. Thus it may have use when treating chronic viral
infection.
Mycophenolate appears to be more specific to lymphocytes and
thus safer than “wide–spectrum” immunosuppressants like corticoste-
roids. Nonetheless, it still increases the risk of infections and some types
of cancer. It is possible that doses that do not cause significant immuno-
suppression could still be effective adjuncts to antiviral medication.
Regular bloodwork is recommended in either case. Cholestyramine may
impair the efficacy of mycophenolate even if it is given at a different
time of the day.
Mycophenolate is widely available. It is fairly expensive.
thalidomide (Thalomid)
Thalidomide has a morbid reputation stemming from its catastro-

phic history. It was introduced as a sedative and antiemetic for morning
sickness in the late 1950s and was later found to have caused about
10,000 children to be born with severe deformities. It is less well known
that thalidomide is still being used to treat some illnesses of the immune
system, including AIDS, autoimmune diseases and some cancers.
Thalidomide has traditionally been considered an immunosuppres-
sant, but it actually seems to be an anti–inflammatory with some immu-
nostimulatory properties.170,171 Immunosuppressants would worsen the
course of tuberculosis, but thalidomide can be used as a tuberculosis
treatment.172 It has also been found helpful for refractory hepatitis C.173
Some of its effects may be mediated by decreased activation of NF–kap-
pa B.174 Thalidomide has been theorized to be potentially helpful in the
treatment of CFS/ME.175
Sedation is the most common side effect. Other possible adverse
effects include allergic reactions, headache, nerve damage, sedation and
orthostatic hypotension. Thalidomide can increase the sedative effects
of other drugs. Women of childbearing age must use two forms of cont-
raception and have regular pregnancy tests. Frequent blood tests
assessing immune function are also recommended.
Thalidomide is only officially available in the United States and a
few other countries, but it can be acquired with a special permit in some
other countries such as Canada. It is very expensive.
References
1 Kirnap M, Colak R, Eser C, et al. A comparison between low–dose (1

microg), standard–dose (250 microg) ACTH stimulation tests and insu-
lin tolerance test in the evaluation of hypothalamo–pituitary–adrenal
axis in primary fibromyalgia syndrome. Clin Endocrinol (Oxf). 2001
Oct;55(4):455–9.
2 Suliman AM, Smith TP, Labib M, et al. The low–dose ACTH test
does not provide a useful assessment of the hypothalamic–pituitary–
adrenal axis in secondary adrenal insufficiency. Clin Endocrinol (Oxf).
2002 Apr;56(4):533–9.
3 Gur A, Cevik R, Nas K, et al. Cortisol and hypothalamic–pituitary–
gonadal axis hormones in follicular–phase women with fibromyalgia
and chronic fatigue syndrome and effect of depressive symptoms on
these hormones. Arthritis Res Ther. 2004;6(3):R232–8.
4 Wheatland R. Chronic ACTH autoantibodies are a significant patholo-
gical factor in the disruption of the hypothalamic–pituitary–adrenal axis
in chronic fatigue syndrome, anorexia nervosa and major depression.
Med Hypotheses. 2005;65(2):287–95.
5 Scott LV, Teh J, Reznek R, et al. Small adrenal glands in chronic fati-
gue syndrome: a preliminary computer tomography study. Psychoneuro-
endocrinology. 1999 Oct;24(7):759–68.
6 Wingenfeld K, Heim C, Schmidt I, et al. HPA axis reactivity and lym-
phocyte glucocorticoid sensitivity in fibromyalgia syndrome and chro-
nic pelvic pain. Psychosom Med. 2008 Jan;70(1):65–72.
7 Calis M, Gökçe C, Ates F, et al. Investigation of the hypothalamo–
pituitary–adrenal axis (HPA) by 1 microg ACTH test and metyrapone
test in patients with primary fibromyalgia syndrome. J Endocrinol
Invest. 2004 Jan;27(1):42–6.
8 Catley D, Kaell AT, Kirschbaum C, et al. A naturalistic evaluation of
cortisol secretion in persons with fibromyalgia and rheumatoid arthritis.
Arthritis Care Res. 2000 Feb;13(1):51–61.
9 Gur A, Cevik R, Sarac AJ, et al. Hypothalamic–pituitary–gonadal axis
and cortisol in young women with primary fibromyalgia: the potential
roles of depression, fatigue, and sleep disturbance in the occurrence of
hypocortisolism. Ann Rheum Dis. 2004 Nov;63(11):1504–6.
10 McLean SA, Williams DA, Harris RE, et al. Momentary relationship
between cortisol secretion and symptoms in patients with fibromyalgia.
Arthritis Rheum. 2005 Nov;52(11):3660–9.
11 Griep EN, Boersma JW, Lentjes EG, et al. Function of the hypothala-
mic–pituitary–adrenal axis in patients with fibromyalgia and low back
pain. J Rheumatol. 1998 Jul;25(7):1374–81.
12 Griep EN, Boersma JW, de Kloet ER. Altered reactivity of the hypo-
thalamic–pituitary–adrenal axis in the primary fibromyalgia syndrome. J
Rheumatol. 1993 Mar;20(3):469–74.
13 Crofford LJ, Pillemer SR, Kalogeras KT, et al. Hypothalamic–pitui-
tary–adrenal axis perturbations in patients with fibromyalgia. Arthritis
Rheum. 1994 Nov;37(11):1583–92.
14 McCain GA, Tilbe KS. Diurnal hormone variation in fibromyalgia
syndrome: a comparison with rheumatoid arthritis. J Rheumatol Suppl.
1989 Nov;19:154–7.
15 Crofford LJ, Young EA, Engleberg NC, et al. Basal circadian and
pulsatile ACTH and cortisol secretion in patients with fibromyalgia
and/or chronic fatigue syndrome. Brain Behav Immun. 2004 Jul;18(4):
314–25.
16 Nater UM, Maloney E, Boneva RS, et al. Attenuated morning sali-
vary cortisol concentrations in a population–based study of persons with
chronic fatigue syndrome and well controls. J Clin Endocrinol Metab.
2008 Mar;93(3):703–9.
17 Holtorf K. Diagnosis and Treatment of Hypothalamic–Pituitary–
Adrenal (HPA) Axis Dysfunction in Patients with Chronic Fatigue
Syndrome (CFS) and Fibromyalgia (FM). J Chron Fatigue Syn. 2008;14
(3):59–88.
18 Cleare AJ, Miell J, Heap E, et al. Hypothalamo–pituitary–adrenal
axis dysfunction in chronic fatigue syndrome, and the effects of low–
dose hydrocortisone therapy. J Clin Endocrinol Metab. 2001 Aug;86(8):
3545–54.
19 Clark S, Tindall E, Bennett RM. A double blind crossover trial of
prednisone versus placebo in the treatment of fibrositis. J Rheumatol.
1985 Oct;12(5):980–3.
20 Bouwer C, Claassen J, Dinan TG, et al. Prednisone augmentation in
treatment–resistant depression with fatigue and hypocortisolaemia: a
case series. Depress Anxiety. 2000;12(1):44–50.
21 Cleare AJ, Miell J, Heap E, et al. Hypothalamo–pituitary–adrenal
axis dysfunction in chronic fatigue syndrome, and the effects of low–
dose hydrocortisone therapy. J Clin Endocrinol Metab. 2001 Aug;86(8):
3545–54.
22 Cleare AJ, Heap E, Malhi GS, et al. Low–dose hydrocortisone for
chronic fatigue syndrome: a randomised crossover trial. Lancet. 1999;
353(9151):455–8.
23 McKenzie R, O'Fallon A, Dale J, et al. Low–dose hydrocortisone for

treatment of chronic fatigue syndrome: a randomized controlled trial.
JAMA. 1998;280(12):1061–6.
24 Streeten DH, Bell DS. Circulating Blood Volume in Chronic Fatigue
Syndrome. J Chron Fatigue Syn. 1998;4(1):3–11.
25 Boneva RS, Decker MJ, Maloney EM, et al. Higher heart rate and re-
duced heart rate variability persist during sleep in chronic fatigue synd-
rome: a population–based study. Auton Neurosci. 2007 Dec 30;137(1–
2):94–101.
26 Kato Y, Kamijima S, Kashiwagi A, et al. [Chronic fatigue syndrome,
a case of high anti–HHV–6 antibody titer and one associated with pri-
mary hyperaldosteronism]. Nippon Rinsho. 1992 Nov;50(11):2673–8.
27 Bou–Holaigah I, Rowe PC, Kan J. The relationship between neurally
mediated hypotension and the chronic fatigue syndrome. JAMA. 1995
Sep 27;274(12):961–7.
28 How We Approach Chronic Fatigue Syndrome by Richard Podell,
MD. http://drpodell.org/chronic_fatigue_syndrome_treatments.shtml
Dr. Charles Lapp, MD. http://www.immunesupport.com/library/show
30 Bell David S. Faces of CFS. MZR Publishing 2000. p. 206.
32 Dr. Cheney's NMH Treatment Protocol. http://www.dfwcfids.org/
medical/nmh.html
33 Cooper–Kazaz R, Lerer B. Efficacy and safety of triiodothyronine
supplementation in patients with major depressive disorder treated with
specific serotonin reuptake inhibitors. Int J Neuropsychopharmacol.
2007 Nov 30;:1–15.
34 Skinner GR, Holmes D, Ahmad A, et al. Clinical response to thyro-
xine sodium in clinically hypothyroid but biochemically euthyroid pati-
ents. J Nutr Environ Med 2000;10:115–24.
35 Garrison RL, Breeding PC. A metabolic basis for fibromyalgia and
its related disorders: the possible role of resistance to thyroid hormone.
Med Hypotheses. 2003 Aug;61(2):182–9.
36 Lowe JC, Cullum ME, Graf LH Jr, et al. Mutations in the c–erbA
beta 1 gene: do they underlie euthyroid fibromyalgia? Med Hypotheses.
1997 Feb;48(2):125–35.
37 Wilke WS, Sheeler LR, Makarowski WS. Hypothyroidism with pre-

senting symptoms of fibrositis. J Rheumatol. 1981 Jul–Aug;8(4):626–
31.
38 Neeck G, Riedel W. Thyroid function in patients with fibromyalgia
syndrome. J Rheumatol. 1992 Jul;19(7):1120–2.
39 Abud–Mendoza C, Magana–Aquino M, Medina R, et al. Hypothala-
mus–hypophysis–thyroid axis dysfunction in patients with refractory
fibromyalgia. Arthritis Rheum Suppl 1997;40(9).
40 Pamuk ON, Cakir N. The frequency of thyroid antibodies in fibro-
myalgia patients and their relationship with symptoms. Clin Rheumatol.
2007 Jan;26(1):55–9
41 Ribeiro LS, Proietti FA. Interrelations between fibromyalgia, thyroid
autoantibodies, and depression. J Rheumatol. 2004 Oct;31(10):2036–40.
42 Bazzichi L, Rossi A, Giuliano T, et al. Association between thyroid
autoimmunity and fibromyalgic disease severity. Clin Rheumatol. 2007
Dec;26(12):2115–20.
43 Lowe JC, Garrison RL, Reichman AJ, et al. Effectiveness and safety
of T3 (triiodothyronine) therapy for euthyroid fibromyalgia: a double–
blind placebo–controlled response–driven crossover study. Clin Bull
Myofascial Ther. 1997;2:(2/3):31–58.
44 Bunevicius R, Kazanavicius G, Zalinkevicius R, et al. Effects of thy-
roxine as compared with thyroxine plus triiodothyronine in patients with
hypothyroidism. N Engl J Med. 1999 Feb 11;340(6):424–9.
45 ME/CFS & Chronic Infection of the Gut – Notes on Dr. Kenny De
Meirleir’s Presentation in Perth. http://www.immunesupport.com/
library/showarticle.cfm/ID/8489/
46 Holtorf Medical Group, Inc – Torrance, CA) Treatment of Chronic
Fatigue Syndrome and Fibromyalgia. http://www.hormoneandlongevity
center.com/cfidsfibromyalgia/
47 Panay N, Studd JW. The psychotherapeutic effects of estrogens.
Gynecol Endocrinol. 1998 Oct;12(5):353–65.
48 Joffe H, Hall JE, Gruber S, et al. Estrogen therapy selectively enhan-
ces prefrontal cognitive processes: a randomized, double–blind, place-
bo–controlled study with functional magnetic resonance imaging in
perimenopausal and recently postmenopausal women. Menopause. 2006
May–Jun;13(3):411–22.
49 Ren K, Wei1 F, Dubner R, et al. Progesterone attenuates persistent
inflammatory hyperalgesia in female rats: involvement of spinal NMDA
receptor mechanisms. Brain Res. 2000 May 26;865(2):272–7.
50 Harlow BL, Signorello LB, Hall JE, et al. Reproductive correlates of
chronic fatigue syndrome. Am J Med. 1998 Sep 28;105(3A):94S–99S.
51 General information brochure on orthostatic intolerance and its treat-

ment. http://www.pediatricnetwork.org/medical/OI/johnshopkins.htm
52 Interview with Elizabeth Vliet, M.D. http://web.archive.org/web/
20070814050451/http://www.endfatigue.com/Newsletter/sample1-inter
view.html
53 Dessein PH, Shipton EA, Joffe BI, et al. Hyposecretion of adrenal
androgens and the relation of serum adrenal steroids, serotonin and insu-
lin–like growth factor–1 to clinical features in women with fibromyal-
gia. Pain. 1999 Nov;83(2):313–9.
54 Burris AS, Banks SM, Carter CS et al. A long–term, prospective stu-
dy of the physiologic and behavioral effects of hormone replacement in
untreated hypogonadal men. J Androl. 1992 Jul–Aug;13(4):297–304.
55 Wang C, Alexander G, Berman N et al. Testosterone replacement
therapy improves mood in hypogonadal men—a clinical research center
study. J Clin Endocrinol Metab. 1996 Oct;81(10):3578–83.
56 Ramamani A, Aruldhas MM, Govindarajulu P. Impact of testoste-
rone and oestradiol on region specificity of skeletal muscle–ATP, crea-
tine phosphokinase and myokinase in male and female Wistar rats. Acta
Physiol Scand. 1999 Jun;166(2):91–7.
57 Interview with Elizabeth Vliet, M.D. http://web.archive.org/web/
20070814050451/http://www.endfatigue.com/Newsletter/sample1-inter
view.html
58 Treating Fibromyalgia with Testosterone. http://www.immune
59 Use of androgen therapy in fibromyalgia and chronic fatigue syndro-
me. United States Patent 5935949. http://www.freepatentsonline.com/
5935949.html
60 Goldstein Jay. Tuning the Brain: Principles and Practice of Neuroso–
61 van Rensburg SJ, Potocnik FC, Kiss T, et al. Serum concentrations of
some metals and steroids in patients with chronic fatigue syndrome with
reference to neurological and cognitive abnormalities. Brain Res Bull.
2001 May 15;55(2):319–25.
62 Kuratsune H, Yamaguti K, Sawada M, et al. Dehydroepiandrosterone
sulfate deficiency in chronic fatigue syndrome. Int J Mol Med. 1998
Jan;1(1):143–6.
63 Cleare AJ, O'Keane V, Miell JP. Levels of DHEA and DHEAS and
responses to CRH stimulation and hydrocortisone treatment in chronic
fatigue syndrome. Psychoneuroendocrinology. 2004 Jul;29(6):724–32.
64 Nilsson E, de la Torre B, Hedman M, et al. Blood dehydroepiandro-
sterone sulphate (DHEAS) levels in polymyalgia rheumatica/giant cell
arteritis and primary fibromyalgia. Clin Exp Rheumatol. 1994 Jul–Aug;

12(4):415–7.
65 Dessein PH, Shipton EA, Joffe BI, et al. Hyposecretion of adrenal
androgens and the relation of serum adrenal steroids, serotonin and insu-
lin–like growth factor–1 to clinical features in women with fibromyal-
gia. Pain. 1999 Nov;83(2):313–9.
66 Straub RH, Konecna L, Hrach S, et al. Serum dehydroepiandroste-
rone (DHEA) and DHEA sulfate are negatively correlated with serum
interleukin–6 (IL–6), and DHEA inhibits IL–6 secretion from mononuc-
lear cells in man in vitro: possible link between endocrinosenescence
and immunosenescence. J Clin Endocrinol Metab. 1998 Jun;83(6):
2012–7.
67 Chang DM, Lan JL, Lin HY, et al. Dehydroepiandrosterone treat-
ment of women with mild–to–moderate systemic lupus erythematosus: a
multicenter randomized, double–blind, placebo–controlled trial. Arthri-
tis Rheum. 2002 Nov;46(11):2924–7.
68 Rabkin JG, Ferrando SJ, Wagner GJ, et al. DHEA treatment for
HIV+ patients: effects on mood, androgenic and anabolic parameters.
Psychoneuroendocrinology. 2000 Jan;25(1):53–68.
69 Davis SR, Shah SM, McKenzie DP, et al. Dehydroepiandrosterone
Sulfate Levels Are Associated with More Favorable Cognitive Function
in Women. J Clin Endocrinol Metab. 2008 Mar;93(3):801-8.
70 McCoy J. Immunomodulatory properties of DHEA as a potential
treatment for CFIDS. The CFIDS Chronicle. Fall 1993.
71 Himmel PB, Seligman TM. A pilot study employing dehydroepiand-
rosterone (DHEA) in the treatment of chronic fatigue syndrome. J Clin
Rheumatol 1999;5:56–9.
72 Finckh A, Berner IC, Aubry–Rozier B, et al. A randomized control-
led trial of dehydroepiandrosterone in postmenopausal women with fib-
romyalgia. J Rheumatol. 2005 Jul;32(7):1336–40.
73 CFIDS Treatment Options by Charles Lapp, MD. http://www.ncf–
net.org/forum/lapp97.htm
74 Anderberg UM, Uvnäs–Moberg K. Plasma oxytocin levels in female
fibromyalgia syndrome patients. Z Rheumatol. 2000 Dec;59(6):373–9.
Network Disorders. Haworth Medical Press 1996. pp. 155–162

cfm/ID/2926/
78 Allain TJ, Bearn JA, Coskeran P, et al. Changes in growth hormone,
insulin, insulinlike growth factors (IGFs), and IGF–binding protein–1 in
chronic fatigue syndrome. Biol Psychiatry. 1997 Mar 1;41(5):567–73.
79 Berwaerts J, Moorkens G, Abs R. Secretion of growth hormone in
patients with chronic fatigue syndrome. Growth Horm IGF Res. 1998
Apr;8 Suppl B:127–9.
80 Bennett RM. Adult growth hormone deficiency in patients with fib-
romyalgia. Curr Rheumatol Rep. 2002 Aug;4(4):306–12.
81 Moorkens G, Wynants H, Abs R. Effect of growth hormone treat-
ment in patients with chronic fatigue syndrome: a preliminary study.
Growth Horm IGF Res. 1998;8(suppl):B131– B133.
82 Cuatrecasas G, Riudavets C, Güell MA, et al. Growth hormone as
concomitant treatment in severe fibromyalgia associated with low IGF–
1 serum levels. A pilot study. BMC Musculoskelet Disord. 2007 Nov
30;8:119.
83 Bennett RM, Clark SC, Walczyk J. A randomized, double–blind, pla-
cebo–controlled study of growth hormone in the treatment of fibromyal-
gia. Am J Med. 1998 Mar;104(3):227–31.
84 Oertel H, Schneider HJ, Stalla GK, et al. The effect of growth hor-
mone substitution on cognitive performance in adult patients with hypo-
pituitarism. Psychoneuroendocrinology. 2004 Aug;29(7):839–50.
85 Clinical Care for CFS by Marcia Harmon, Director of Communicati-
ons, CFIDS Association of America. http://www.cfids.org/sparkcfs/
clinical-care.pdf
86 Dr. Cheney: Advances in CFIDS Treatment. http://www.dfwcfids.
org/medical/advances.html
87 Behan PO, Bakheit AM. Clinical spectrum of postviral fatigue synd-
rome. Br Med Bull. 1991 Oct;47(4):793–808.
88 Scott LV, Medbak S, Dinan TG. Desmopressin augments pituitary–
adrenal responsivity to corticotropin–releasing hormone in subjects with
chronic fatigue syndrome and in healthy volunteers. Biol Psychiatry.
1999;45(11):1447–54.
89 Weingartner H, Gold P, Ballenger JC, et al. Effects of vasopressin on
human memory functions. Science. 1981 Feb 6;211(4482):601–3.
90 Dr. Cheney's NMH Treatment Protocol. http://www.dfwcfids.org/
medical/nmh.html
91 Patarca R, Klimas NG, Lugtendorf S, et al. Dysregulated expression
of tumor necrosis factor in chronic fatigue syndrome: interrelations with
cellular sources and patterns of soluble immune mediator expression.

Clin Infect Dis. 1994 Jan;18 Suppl 1:S147–53.
92 Kerr JR, Christian P, Hodgetts A, et al. Current research priorities in
chronic fatigue syndrome/myalgic encephalomyelitis: disease mecha-
nisms, a diagnostic test and specific treatments. J Clin Pathol. 2007 Feb;
60(2):113–6.
93 Chronic Fatigue Syndrome, Fibromyalgia and Associated Synd-
romes: Evidence for Their Organic Basis by Dr. Andrew J. Wright,
MBChB, DRCOG, MRCGP, DCH, DIHom. http://www.immune
95 Genovese T, Mazzon E, Crisafulli C, et al. Immunomodulatory ef-
fects of etanercept in an experimental model of spinal cord injury. J
Pharmacol Exp Ther. 2006 Mar;316(3):1006–16.
96 Vgontzas AN, Zoumakis E, Lin HM, et al. Marked decrease in slee-
piness in patients with sleep apnea by etanercept, a tumor necrosis fac-
tor–alpha antagonist. Clin Endocrinol Metab. 2004 Sep;89(9):4409–13.
97 Lamprecht K, et al. Pilot study of etanercept treatment in patients
with chronic fatigue syndrome. Presented at: American Association for
Chronic Fatigue Syndrome (AACFS) 5th International Conference on
Chronic Fatigue Syndrome, Fibromyalgia and Related Illnesses. Seattle,
WA, U.S. Jan 25–Jan 29, 2001.
98 Chou CT. The clinical application of etanercept in Chinese patients
with rheumatic diseases. Mod Rheumatol. 2006;16(4):206–13.
99 Hoseini SS, Gharibzadeh S. Potential drugs for improving chronic fa-
tigue syndrome. J Neuropsychiatry Clin Neurosci. 2007 Fall;19(4):472.
100 Xolair for Chronic fatigue syndrome (CFS; CFIDS; M.E.) Commu-
nity Ratings – Revolution Health. http://www.revolutionhealth.com/
drugs-treatments/rating/xolair-for-chronic-fatigue-syndrome-cfs-cfids-
me
101 Cannon JG, Angel JB, Abad LW, et al. Interleukin–1 beta, interleu-
kin–1 receptor antagonist, and soluble interleukin–1 receptor type II sec-
retion in chronic fatigue syndrome. J Clin Immunol. 1997 May;17(3):
253–61.
102 Thompson ME, Barkhuizen A. Fibromyalgia, hepatitis C infection,
and the cytokine connection. Curr Pain Headache Rep. 2003 Oct;7(5):
342–7.
103 Read R, Spickett G, Harvey J, et al. IgG1 subclass deficiency in
patients with chronic fatigue syndrome. Lancet. 1988 Jan 30;1(8579):
241–2.
104 Wakefield D, Lloyd A, Brockman A. Immunoglobulin subclass

abnormalities in patients with chronic fatigue syndrome. Pediatr Infect
Dis J. 1990 Aug;9(8 Suppl):S50–3.
105 Komaroff AL, Geiger AM, Wormsely S. IgG subclass deficiencies
in chronic fatigue syndrome. Lancet. 1988 Jun 4;1(8597):1288–9.
109 Lloyd A, Hickie I, Wakefield D, et al. A double–blind, placebo–
controlled trial of intravenous immunoglobulin therapy in patients with
chronic fatigue syndrome. Am J Med. 1990 Nov;89(5):561–8.
110 DuBois RE. Gamma globulin therapy for chronic mononucleosis
syndrome. AIDS Res. 1986 Dec;2 Suppl 1:S191–5.
111 Kerr JR, Cunniffe VS, Kelleher P, et al. Successful Intravenous
Immunoglobulin Therapy in 3 Cases of Parvovirus B19Associated
Chronic Fatigue Syndrome. Clin Infect Dis. 2003 May 1;36(9):e100–6.
112 Caro XJ, Winter EF, Dumas AJ. A subset of fibromyalgia patients
have findings suggestive of chronic inflammatory demyelinating poly-
neuropathy and appear to respond to IVIg. Rheumatology (Oxford).
2008 Feb;47(2):208–11.
113 Goebel A, Netal S, Schedel R, et al. Human pooled immunoglobu-
lin in the treatment of chronic pain syndromes. Pain Med. 2002 Jun;3
(2):119–27.
114 Visser J, Blauw B, Hinloopen B, et al. CD4 T lymphocytes from
patients with chronic fatigue syndrome have decreased interferon–gam-
ma production and increased sensitivity to dexamethasone. J Infect Dis.
1998 Feb;177(2):451–4.
115 Klimas NG, Salvato FR, Morgan R, et al. Immunologic abnormali-
ties in chronic fatigue syndrome. J Clin Microbiol. 1990 Jun;28(6):
1403–10.
116 Rasmussen AK, Nielsen H, Andersen V, et al. Chronic fatigue
syndrome—a controlled cross sectional study. J Rheumatol. 1994 Aug;
21(8):1527–31.
117 Holmes MJ. A Retroviral Aetiology for CFS? In the book: Hyde B,
(ed.) The Clinical and Scientific Basis of Myalgic Encephalomyeli-
tis/Chronic Fatigue Syndrome. The Nightingale Research Foundation
1992. pp. 319–323.
118 Mowbray JF. Evidence of Chronic Enterovirus Infections in M.E.

In the book: Hyde B, (ed.) The Clinical and Scientific Basis of Myalgic
Encephalomyelitis/Chronic Fatigue Syndrome. The Nightingale Re-
search Foundation 1992. pp. 304–309.
Fatigue Syndrome. Hunter House 1995. pp. 198.
120 Brook MG, Bannister BA, Weir WR. Interferon–alpha therapy for
patients with chronic fatigue syndrome. J Infect Dis. 1993 Sep;168(3):
791–2.
121 See DM, Tilles JG. Alpha–Interferon treatment of patients with
chronic fatigue syndrome. Immunol Invest. 1996;25(1–2):153–64.
122 Russell IJ, Vipraio GA, Michalek JE, et al. Reduction of morning
stiffness and improvement in physical function in fibromyalgia syndro-
me patients treated sublingually with low doses of human interferon–
alpha. J Interferon Cytokine Res. 1999 Aug;19(8):969–78.
123 Chia JK. The role of enterovirus in chronic fatigue syndrome. J Clin
Pathol. 2005 Nov;58(11):1126–32.
124 Hong J, Tejada–Simon MV, Rivera VM, et al. Anti–viral properties
of interferon beta treatment in patients with multiple sclerosis. Mult
Scler. 2002 May;8(3):237–42.
125 Kraus J, Oschmann P. The impact of interferon–beta treatment on
the blood–brain barrier. Drug Discov Today. 2006 Aug;11(15–16):755–
62.
126 Bested AC, Saunders PR, Logan AC. Chronic fatigue syndrome:
neurological findings may be related to blood—brain barrier permeabi-
lity. Med Hypotheses. 2001 Aug;57(2):231–7.
127 Steinbach T, Hermann W, Lawyer C, et al. Subjective reduction in
symptoms of chronic fatigue syndrome following long–term treatment
with a porcine liver extract: a phase 1 trial. Clin Infect Dis. 1994;18:S0–
S114.
128 Rosenfeld E, Salimi B, O'Gorman MR, et al. Potential in vitro acti-
vity of Kutapressin against Epstein–Barr virus. In Vivo. 1996 May–Jun;
10(3):313–8.
129 Ablashi DV, Berneman ZN, Lawyer C, et al. Antiviral activity in
vitro of Kutapressin against human herpesvirus–6. In Vivo. 1994 Jul–
Aug;8(4):581–6.
131 Diaz–Mitoma F, Turgonyi E, Kumar A, et al. Clinical improvement
in chronic fatigue syndrome is associated with enhanced natural killer
cell–mediated cytotoxicity: The results of a pilot study with Isoprino-

sine. J Chron Fatigue Syn. 2003;11(2):71–93.
132 Dr. Larry Sharp – Frequently Asked Questions. http://www.cfids
doctor.com/CFIDSfaqs.asp
133 Dr. Paul Cheney Discusses TH1, TH2, the Immune System and
Chronic Fatigue Syndrome (CFS) – Part 2. http://www.immunesupport.
ment.htm
135 Combining Science, Expertise and Creativity to Treat FMS and
CFS. http://faculty.washington.edu/pmease/combining_science.html
136 Brorson O, Brorson SH. An in vitro study of the susceptibility of
mobile and cystic forms of Borrelia burgdorferi to hydroxychloroquine.
Int Microbiol. 2002 Mar;5(1):25–31.
137 Katewa SD, Katyare SS. Antimalarials inhibit human erythrocyte
membrane acetylcholinesterase. Drug Chem Toxicol. 2005;28(4):467–
82.
138 Tench CM, McCurdie I, White PD, et al. The prevalence and asso-
ciations of fatigue in systemic lupus erythematosus. Rheumatology (Ox-
ford). 2000 Nov;39(11):1249–54.
139 Ungheri D, Pisani C, Sanson G, et al. Protective effect of n–acetyl-
cysteine in a model of influenza infection in mice. Int J Immunopathol
Pharmacol. 2000 Sep–Dec;13(3):123–28.
140 Live Chat with Martin L. Pall, PhD – July 6, 2007: Professor of
Biochemistry Explains Mechanisms of Chronic Fatigue Syndrome and
Fibromyalgia & Suggested Protocol. http://www.immunesupport.com/
141 Walters MT, Rubin CE, Keightley SJ, et al. A double–blind, cross–
over, study of oral N–acetylcysteine in Sjögren's syndrome. Scand J
Rheumatol Suppl. 1986;61:253–8.
142 Head KA. Peripheral neuropathy: pathogenic mechanisms and alter-
native therapies. Altern Med Rev. 2006 Dec;11(4):294–329.
143 Dunstan RH, McGregor NR, Roberts TK, et al. The Development
of Laboratory–Based Tests in Chronic Pain and Fatigue: 1. Muscle
Catabolism and Coagulase Negative Staphylococci Which Produce
Membrane Damaging Toxins. J Chron Fatigue Syn. 1999;7(2):53–7.
144 Dr Whiting Summarises Some of the Latest Research into CFS/ME.
http://home.vicnet.net.au/~mecfs/general/whiting.html
145 Andersson M, Bagby JR, Dyrehag L, et al. Effects of staphylococ-
cus toxoid vaccine on pain and fatigue in patients with fibromyal-
gia/chronic fatigue syndrome. Eur J Pain. 1998;2(2):133–42.
146 Zachrisson O, Regland B, Jahreskog M, et al. Treatment with stap-

hylococcus toxoid in fibromyalgia/chronic fatigue syndrome—a rando-
mised controlled trial. Eur J Pain. 2002;6(6):455–66.
147 Gottfries CG, Hager O, Regland B, et al. Long–term Treatment
with a Staphylococcus Toxoid Vaccine in Patients with Fibromyalgia
and Chronic Fatigue Syndrome. J Chron Fatigue Syn. 2007 Apr;13(4):
29–40.
148 Lowry CA, Hollis JH, de Vries A, et al. Identification of an immu-
ne–responsive mesolimbocortical serotonergic system: potential role in
regulation of emotional behavior. Neuroscience. 2007 May 11;146(2):
756–72.
149 Use of mycobacterium vaccae for treating chronic fatigue syndro-
me. European Patent EP0951289. http://www.freepatentsonline.com/
EP0951289.html
150 Berkson BM, Rubin DM, Berkson AJ. The long–term survival of a
patient with pancreatic cancer with metastases to the liver after treat-
ment with the intravenous alpha–lipoic acid/low–dose naltrexone proto-
col. Integr Cancer Ther. 2006 Mar;5(1):83–9.
151 Effects of Low Dose Naltrexone in Fibromyalgia. http://www.
clinicaltrials.gov/ct2/show/NCT00568555
152 Smith JP, Stock H, Bingaman S, et al. Low–Dose Naltrexone The-
rapy Improves Active Crohn's Disease. Am J Gastroenterol. 2007 Apr;
102(4):820–8.
153 Conti F, Pittoni V, Sacerdote P. Decreased immunoreactive beta–
endorphin in mononuclear leucocytes from patients with chronic fatigue
syndrome. Clin Exp Rheumatol. 1998 Nov–Dec;16(6):729–32.
154 Panerai AE, Vecchiet J, Panzeri P, et al. Peripheral blood mononuc-
lear cell beta–endorphin concentration is decreased in chronic fatigue
syndrome and fibromyalgia but not in depression: preliminary report.
Clin J Pain. 2002 Jul–Aug;18(4):270–3.
155 Whiteside TL, Friberg D. Natural killer cells and natural killer cell
activity in chronic fatigue syndrome. Am J Med. 1998 Sep 28;105(3A):
27S–34S.
156 Ojo–Amaize EA, Conley EJ, Peter JB. Decreased natural killer cell
activity is associated with severity of chronic fatigue immune dysfunc-
tion syndrome. Clin Infect Dis. 1994 Jan;18 Suppl 1:S157–9.
157 Hsueh CM, Chen SF, Ghanta VK, et al. Expression of the conditi-
oned NK cell activity is beta–endorphin dependent. Brain Res. 1995 Apr
24;678(1–2):76–82.
158 Agrawal YP. Low dose naltrexone therapy in multiple sclerosis.
Med Hypotheses. 2005;64(4):721–4.
159 Pall ML. Nitric oxide synthase partial uncoupling as a key switch-
ing mechanism for the NO/ONOO– cycle. Med Hypotheses. 2007;69
(4):821–5.
160 Ablashi DV, Berneman ZN, Williams M, et al. Ampligen inhibits
human herpesvirus–6 in vitro. In Vivo. 1994 Jul–Aug;8(4):587–91.
161 Padalko E, Nuyens D, De Palma A, et al. The interferon inducer
ampligen [poly(I)–poly(C12U)] markedly protects mice against coxsac-
kie B3 virus–induced myocarditis. Antimicrob Agents Chemother. 2004
Jan;48(1):267–74.
162 Mitchell W. Review of Ampligen clinical trials in chronic fatigue
syndrome. J Clin Virol. 2006 Dec;37 Suppl 1:S113.
163 CFS Radio Program February 28th, 1999 Roger G. Mazlen, M.D.,
Host with Dr. Paul Cheney. http://www.co-cure.org/cheney.htm
164 Ampligen in the Pink By Tom Windler. http://www.ncf-net.org/
forum/ampligeninPink.htm
165 Diamond MS, Zachariah M, Harris E. Mycophenolic acid inhibits
dengue virus infection by preventing replication of viral RNA. Viro-
logy. 2002 Dec 20;304(2):211–21.
166 Chapuis AG, Paolo Rizzardi G, D'Agostino C, et al. Effects of
mycophenolic acid on human immunodeficiency virus infection in vitro
and in vivo. Nat Med. 2000 Jul;6(7):762–8.
167 Henry SD, Metselaar HJ, Lonsdale RC, et al. Mycophenolic acid
inhibits hepatitis C virus replication and acts in synergy with cyclospo-
rin A and interferon–alpha. Gastroenterology. 2006 Nov;131(5):1452–
62.
168 Neyts J, De Clercq E. Mycophenolate mofetil strongly potentiates
the anti–herpesvirus activity of acyclovir. Antiviral Res. 1998
Dec;40(1–2):53–6.
169 Padalko E, Verbeken E, Matthys P, et al. Mycophenolate mofetil
inhibits the development of Coxsackie B3–virus–induced myocarditis in
mice. BMC Microbiol. 2003 Dec 21;3:25.
170 Arala–Chaves M, Vilanova M, Ribeiro A, et al. Immunostimulatory
effect of thalidomide in normal C57BL/6 mice is compatible with stimu-
lation of a highly connected central immune system. Scand J Immunol.
1994 Nov;40(5):535–42.
171 Haslett PA, Roche P, Butlin CR, et al. Effective treatment of erythe-
ma nodosum leprosum with thalidomide is associated with immune sti-
mulation. J Infect Dis. 2005 Dec 15;192(12):2045–53.
172 Fu LM, Fu–Liu CS. Thalidomide and tuberculosis. Int J Tuberc
Lung Dis. 2002 Jul;6(7):569–72.
173 Milazzo L, Biasin M, Gatti N, et al. Thalidomide in the treatment of

chronic hepatitis C unresponsive to alfa–interferon and ribavirin. Am J
Gastroenterol. 2006 Feb;101(2):399–402.
174 Keifer JA, Guttridge DC, Ashburner BP, et al. Inhibition of NF–
kappa B activity by thalidomide through suppression of IkappaB kinase
activity. J Biol Chem. 2001 Jun 22;276(25):22382–7.
175 Hoseini SS, Gharibzadeh S. Potential drugs for improving chronic
fatigue syndrome. J Neuropsychiatry Clin Neurosci. 2007 Fall;19(4):
472.
CHAPTER 9.
Other medications
NMDA receptor antagonists
The excitatory NMDA (N–methyl–D–aspartate) receptor may be

one of the most important targets in the treatment of CFS/ME and fibro-
myalgia. Overactivation of the NMDA receptor could lead to central
sensitization, which is theorized as an origin of fibromyalgia.1,2 This is
also a part of Martin Pall’s “NO/ONOO” theory. Excessive activity of
glutamate in the NMDA receptors results in a phenomenon called exci-
totoxicity, which causes brain damage.
Besides chronic pain, the NMDA receptors are thought to play a
part in cognitive function, depression, migraines and many other things.
Normally reducing NMDA function tends to adversely affect memory,
but if the receptor is overactive, blocking it usually has the opposite
effect. Indeed, many people with CFS/ME and fibromyalgia have
reported lessened mental fog with NMDA antagonists. NMDA antago-
nism slows the development of opioid tolerance, as well as potentiating
their analgesic effects.
Some of the NMDA antagonists block the receptor competitively,
others uncompetitively, or they may only affect one subunit or binding
site of the receptor. All of the drugs listed here also have other possibly
useful properties. Generally if one drug works, others will probably
work too, but if there are too many side effects, another NMDA blocker
could be tried. NMDA receptor activity can also be reduced by
GABAergic drugs.
See also:
orphenadrine, dantrolene (CHAPTER 1), methadone, dextropro-

poxyphene/propoxyphene, flupirtine, nefopam (CHAPTER 2),
anticonvulsants (CHAPTER 3), cycloserine (CHAPTER 4), calcium
channel blockers (CHAPTER 7), progesterone (CHAPTER 8),
parenteral magnesium (CHAPTER 9), guaifenesin, acamprosate,
isoxsuprine, buphenine (CHAPTER 10)
Other medications 233
dextromethorphan (Robitussin, DexAlone, Romilar,

Benylin)
Dextromethorphan is a well–known cough suppressant drug. It is

primarily a non–competitive NMDA antagonist, but also has activity as
an agonist of sigma1, sigma2 and nicotinic cholinergic receptors. It is a
serotonin and possibly dopamine reuptake inhibitor. It may also be a
calcium channel blocker.3
Dextromethorphan is effective for neuropathic pain. One meta–ana-
lysis found it to have the lowest NNT value of all evaluated pharmaceu-
tical treatments (NNT refers to the number of patients needed to treat to
get one adequate response).4 In painful diabetic neuropathy dextrome-
thorphan was significantly more effective than memantine.5
Dextromethorphan has shown good efficacy in fibromyalgia.6 The
response to intravenous ketamine appears to strongly predict the res-
ponse to dextromethorphan treatment, which is hardly surprising consi-
dering the similar mode of action.7 Dr. Richard Podell has found dextro-
methorphan to improve sleep in fibromyalgia patients.8
Sedation, dizziness, tachycardia, nausea and stomach upset are the
most common side effects. Skin reactions are possible. Dextromethor-
phan should never be combined with SSRI or MAOI antidepressants.
Dextromethorphan is available in most countries. It may be avail-
able as tablets, gelcaps, lozenges and different liquid formulations.
Especially cough syrups are usually available over the counter, but they
often contain too much sorbitol or other additives to be well suited for
long–term pain relief.. Dextromethorphan is also often sold in combina-
tion products that may contain e.g. antihistamines, decongestants and
guaifenesin.
amantadine (Symmetrel, Symadine, Atarin)
Amantadine has two very different clinical uses: it is used for the
treatment and prevention of type A influenza virus infection as well as
in the treatment of Parkinson’s disease. It is an NMDA antagonist with
dopaminergic and anticholinergic action. Amantadine is sometimes used
to alleviate fatigue caused by CFS/ME and other similar illnesses, such
as multiple sclerosis.9 It may relieve CFS/ME brainfog10 and can be
used to treat restless legs syndrome.11 One study found that amantadine
has antiviral activity against HHV–6.12
Dr. Jay Goldstein considers amantadine to be an excellent drug,
“like ketamine with fewer side effects.”13 He even recommends intrave-
nous administration, but usually tries the drug in the form of a transder-
mal gel. One study compared amantadine against the supplement L–car-
nitine in CFS/ME, but the results were not too impressive—only half of
the 30 patients were even able to tolerate amantadine and none seemed
to benefit from it.14
The most common adverse effects involve the central nervous sys-
tem, including dizziness, insomnia, problems with concentration and
headaches. Anticholinergic side effects such as dry mouth and urinary
hesitancy are also common. Other anticholinergic drugs can exacerbate
the side effects. Abrupt discontinuation of the treatment is not a good
idea, as it may lead to the dangerous neuroleptic malignant syndrome.15
Amantadine is very inexpensive and is available everywhere.
riluzole (Rilutek)
In addition to acting as an antagonist of the NMDA receptor, rilu-

zole blocks sodium channels and voltage–sensitive calcium channels. It
is used in the treatment of amyotrophic lateral sclerosis (ALS), also
known as Lou Gehrig’s disease, though the benefits in this use are
modest at best. In studies it has demonstrated efficacy in major depres-
sion16, generalized anxiety17 and obsessive–compulsive disorder18. It
also has significant anticonvulsive properties.19
Riluzole appears to be well tolerated. Fatigue and nausea are the
most common side effects. It should not be prescribed to patients with
any liver problems or elevated liver enzymes. Regular monitoring of
liver enzymes is recommended. Caffeine, quinolone antibiotics and
many psychiatric drugs can elevate blood levels of riluzole, whereas
smoking, charbroiled meat and omeprazole can lower them. Caution
should be taken when combining riluzole with other drugs that can
affect the liver.
Riluzole is available in the United States, the United Kingdom,
Canada, Australia and some other countries. It is very expensive.
memantine (Namenda, Ebixa, Akatinol, Axura)
Memantine is used to treat Alzheimer’s disease. In contrast to other

Alzheimer’s drugs its primary mode of action is not cholinergic, but the
blockage of the NMDA receptors. It also blocks 5–HT3 serotonin
receptors, which is often beneficial in CFS/ME and fibromyalgia. Both
of these two actions may be of value when treating IBS.20 Memantine
has been proposed as a treatment for e.g. HIV dementia, SLE21, bipolar
disorder22 and migraine.23 It is sometimes used for multiple sclerosis and
increasingly in fibromyalgia.
Memantine appears to be well tolerated. Possible adverse effects
include tiredness, constipation, dizziness and headaches. It can potenti-
ate the the effects of dopaminergic and anticholinergic drugs and lower
the efficacy of barbiturates and neuroleptics. Baclofen and dantrolene
may be affected as well. Smoking elevates blood levels of memantine.
The pH of urine also affects memantine clearance.
Memantine is available in the United States, the United Kingdom,
Canada, Australia and many other countries. It is available as tablets and
drops. It is fairly expensive.
ketamine (Ketalar, Ketanest, Calypsol)

S–ketamine (Ketanest–S)
Ketamine is an anesthetic which is usually given parenterally, but

sometimes orally too, usually in conjunction with other analgesics. Besi-
des its non–competitive NMDA receptor antagonism it blocks sodium
channels and binds to mu opioid receptors and sigma receptors. Ketami-
ne has been shown to work for many refractory cases of major depres-
sion24 and migraine.25 It also has some anti–inflammatory activity by
inhibiting activation of NF–kappa B.26
As could be expected, ketamine has works well in fibromyalgia
(and likely in CFS/ME as well, but clinical trials have not been perfor-
med). Several studies have demonstrated its efficacy.27,28 Jay Goldstein
believes ketamine to be the most useful agent in neurosomatic medicine
(in the treatment of CFS/ME and fibromyalgia).29 If it makes the patient
worse, he thinks topiramate might be a good candidate to try next,
because its mode of action is somewhat opposite.
Ketamine can be administered as either a racemic mixture, or as the
S–enantiomer, S–ketamine or esketamine. The S–form is a stronger
analgesic and less likely to cause hallucinations, but also more prone to
causing drowsiness. Oral ketamine is usually given every day, whereas
intravenous ketamine generally only needs to be administered a few
times a month. One study demonstrated good efficacy in using a topical
cream with 2% ketamine and 1% amitriptyline for neuropathic pain.30
Ketamine is widely available, but the availability of S–ketamine is
more limited. Treatment is usually fairly expensive.
Cholinesterase inhibitors
The role of acetylcholine in CFS/ME and fibromyalgia is not fully

understood and research is often conflicting. What is known is that ace-
tylcholine has an important role on cognitive function (especially

memory) and acetylcholine deficit results in muscle weakness. An
example of the latter is myasthenia gravis, a rare autoimmune disease
where autoantibodies to acetylcholine cause severe muscle weakness.
Some people with CFS/ME may test positive in the Tensilon test used to
diagnose MG.
Acetylcholinesterase, often called just cholinesterase is an enzyme
that breaks down acetylcholine. Inhibiting this enzyme increases the
levels of this important neurotransmitter. Cholinesterase inhibitors can
either function centrally (increasing acetylcholine levels in the brain) or
peripherally (increasing acetylcholine in other parts of the body). The
former are used to treat Alzheimer’s disease and sometimes for milder
cognitive problems, the latter for myasthenia gravis.
Centrally acting cholinesterase inhibitors have been used to treat
ADHD with mixed results. Donepezil appears to be useful for treating
ADHD–like symptoms in young people31,32, but a small trial using
galantamine failed to produce results.33 Cholinesterase inhibitors also
have analgesic properties.34 They have been used to treat sedation
caused by large doses of narcotic painkillers.35 They may even help in
migraine prophylaxis.36
There have been concerns that although some people with CFS/ME
seem to have cholinergic deficits, others may actually have cholinergic
receptor upregulation, low levels of cholinesterase, or may be otherwise
overly sensitive to the effects of acetylcholine.37,38 Similarly, Jay Gold-
stein notes that cholinesterase inhibitors often work (especially for
mental clarity) in patients who get adverse reactions from NMDA anta-
gonists39—but then again most patients benefit from NMDA antago-
nists. Thus caution should be taken with these medications In CFS/ME.
Cholinergic drugs should also be prescribed with caution (if at all)
in patients with a history of asthma, peptic ulcers or bipolar disorder.
Those who get significant adverse effects might benefit from a trial of
the anticholinergic drug scopolamine.
See also:
carbamazepine (CHAPTER 3), atomoxetine (CHAPTER 5), nootro-

pics (CHAPTER 6), hydroxychloroquine (CHAPTER 8)
pyridostigmine (Mestinon, Kalymin)
Pyridostigmine is a peripherally acting cholinesterase inhibitor. It is

used in the treatment of e.g. myasthenia gravis. According to CFS/ME

expert Jay Goldstein pyridostigmine can help with muscle weakness,
muscle aches, fatigue and brainfog.40 Pyridostigmine does not normally
cross the blood–brain barrier, so some of these benefits may be
mediated by the increase in growth hormone secretion effected by the
drug.41 In animal studies pyridostigmine has also elevated brain seroto-
nin and dopamine levels.42
As fibromyalgia patients are often deficient in growth hormone,
pyridostigmine has sparked interest as a treatment. In one study FM
patients were shown to have a significantly reduced growth hormone
response to exercise.43 In 19 out of the 20 patients a 30 mg dose of pyri-
dostigmine normalized the secretion of growth hormone, but the study
did not examine the resulting clinical effects. A later study did not find
pyridostigmine helpful in fibromyalgia, except for anxiety and sleep.44
Pyridostigmine has been shown to significantly raise blood levels
of growth hormone in CFS/ME using a dose of 120 mg, but again clini-
cal effects were not reported.45 A case series has been published on the
successful use of pyridostigmine in CFS/ME in three patients using a
dose of 10–30 mg.46 This is significantly smaller than the dose used to
treat myasthenia gravis, which may be even more than 500 mg.
Pyridostigmine is considered a promising treatment for orthostatic
hypotension and postural orthostatic tachycardia syndrome (POTS).47 It
may also be helpful for cases of chronic Lyme disease with symptoms
of myasthenia (muscle weakness).48
Possible cholinergic side effects include nausea, vomiting, stomach
upset, muscle weakness and increased secretion of saliva, mucus and
tears. Pyridostigmine should be used with caution in patients with
asthma or diabetes. The bromide part of the compound may cause an
allergic rash requiring discontinuation of the drug. People who have pre-
viously experienced a rash with bromide containing drugs should not
use pyridostigmine.
Pyridostigmine is available virtually everywhere and is very
inexpensive.
donepezil (Aricept)
Donepezil is a centrally acting cholinesterase inhibitor which is

used in Alzheimer’s disease. In CFS/ME it is used to treat for pain, fati-
gue and cognitive problems. Donepezil has been shown effective for the
cognitive impairment caused by multiple sclerosis.49,50 A patent has
been filed proposing e.g. donepezil for the treatment of migraine, fibro-
myalgia and other pain syndromes.51 Jacob Teitelbaum recommends it
as a pain treatment, noting that the effects begin within a week.52

Donepezil can cause many side effects similar to the symptoms of
CFS/ME, such as drowsiness, dizziness, headache, nausea and insom-
nia. Cardiac symptoms and peculiar dreams are also possible. The side
effects are usually milder if the dose is slowly titrated up. Azole
antifungals can increase the blood levels of donepezil. Some antiepilep-
tics have the opposite effect.
Donepezil is available the United States, the United Kingdom,
Canada, Australia and most other markets. It is fairly expensive. It is
also available as a suspension.
galantamine (Reminyl, Razadyne, Nivalin)
Galantamine (also spelled galanthamine) is used to treat Alzhei-

mer's disease. Besides being a cholinesterase inhibitor it also has some
direct effect on the nicotinic acetylcholine receptors, which may even be
its primary mode of action as an Alzheimer’s treatment.53 The relevancy
of this in the treatment of CFS/ME or fibromyalgia is not known.
One study got very impressive results using galantamine for CFS/
ME.54 70% of the patients reported at least 30% improvement in fatigue,
pain and sleep. In the placebo group only 10% improvement was noted.
Galantamine seemed to work particularly well for sleeping problems,
with 60% of patients reporting at least 70% improvement in sleep.
Another study found no evidence of benefit, but on the other hand it
used fairly small doses (2.5–10 mg), which may not have been suffici-
ent.55
In the former study the most commonly reported side effect was
nausea. Dizziness, sedation, diarrhea, stomach upset and lack of appetite
are also common. Paroxetine, fluoxetine, fluvoxamine and azole anti-
fungals can elevate blood levels of galantamine.
Galantamine is available the United States, the United Kingdom,
Canada, Australia and most other markets. It is fairly expensive. Exten-
ded release formulation and oral solution are not as widely available as
the normal tablets.
tacrine (Cognex)
Tacrine is an old centrally acting cholinesterase inhibitor. Because

of side effects, the risk of hepatotoxicity and the necessity of dosing
four times a day, it is rarely used any more. Jay Goldstein has used it for
its other pharmacological effects as well, as it e.g. blocks voltage–gated
potassium, sodium and calcium channels.56 He has described a case of a
seriously ill patient who got much better after trying tacrine and the
improvement was sustained.
The most common side effects are nausea, diarrhea, stomach upset,
muscle pain, lack of appetite and ataxia (impaired coordination). Moni-
toring of liver enzymes is recommended biweekly from week 4 to week
16, after which monitoring once every three months is sufficient. Tacri-
ne markedly increases the blood levels of theophylline. Cimetidine and
fluvoxamine can significantly elevate the blood levels of tacrine.
Tacrine has mostly been replaced by newer Alzheimer’s drugs that
are better tolerated. It is still available e.g. in the United States, Australia
and a few other countries, but not in Canada or the United Kingdom.
Antihistamines
Antihistamines are antagonists (technically usually inverse ago-

nists) of the H1 histamine receptor. They are best known as treatments
for allergy, but can also be used for many other problems, such as
insomnia, urinary frequency, interstitial cystitis, IBS, vertigo, motion
sickness, even for anxiety and as adjuncts to painkillers, as they potenti-
ate opioid analgesia.57 One theory posits that hypersensitivity to the
effects of histamine may be a factor in the pathology of CFS/ME.58
Antihistamines are usually well–tolerated even in people who tole-
rate medications poorly. Histamine is also a mediator of awakeness,
which is why antihistamines that cross the blood–brain barrier often
cause sedation. In CFS/ME the integrity of the blood–brain barrier may
be disturbed, which may be the reason why people with CFS/ME often
experience drowsiness even from supposedly non–sedative antihistami-
nes. Usually they can still take some antihistamines, or can take them at
bedtime.
See also:
orphenadrine (CHAPTER 1), pizotifen, cyproheptadine

(CHAPTER 2), doxepin, mirtazapine, mianserin, olanzapine
(CHAPTER 5), ranitidine/cimetidine (CHAPTER 9), montelukast
(CHAPTER 10)
hydroxyzine (Atarax, Vistaril)
Hydroxyzine is a first generation antihistamine which is mostly

uses as a sleep aid and anxiolytic, but also for chronic urticaria and
interstitial cystitis. Besides histamine blockage, the tranquilizing effects

may result from GABAergic action. Hydroxyzine is a good antiemetic.
It also has significant analgesic action.59 CFS/ME expert Paul Cheney
prescribes it for this purpose.60 Hydroxyzine can also help the increased
urinary frequency which is often a part of CFS/ME and fibromyalgia.
Because of its sedative effects, hydroxyzine is usually taken at bed-
time, but there can be morning grogginess. On rare occasion it can cause
seizures and arrhythmias—and paradoxically also urticaria and insom-
nia. Hydroxyzine should be used with caution in conjunction with other
sedative and anticholinergic medications. There may be interactions
with MAO inhibitors.
Hydroxyzine is available in the United States, the United Kingdom,
Canada and some other countries, but not in Australia. It is available as
tablets and syrup. It is very inexpensive.
cetirizine (Zyrtec, Reactine, Virlix, Cidron, Alerid)

levocetirizine (Xyzal, Xyzall)
Cetirizine is a metabolite of hydroxyzine. It is one of the least seda-

tive older antihistamines, but can still produce sedation in some patients.
For some reason many CFS/ME patients who cannot tolerate antihista-
mines because of sedation can take cetirizine without any drowsiness.
Levocetirizine is supposedly lower on side effects, but in most cases
cetirizine works just as well and is cheaper. Cetirizine also has some
anti–inflammatory properties.61
Cetirizine is inexpensive and widely available. It is a prescription
drug in the United States, but in Canada, the United Kingdom and many
other countries it is a popular over the counter remedy. Some products
with the trade name Benadryl contain cetirizine instead of diphenhydra-
mine, the active ingredient in the U.S. Benadryl. Cetirizine is signifi-
cantly less sedative than diphenhydramine. To confuse matters further,
some formulations of Benadryl do not contain either of these, but acri-
vastine instead.
Levocetirizine is available in the United States, the United King-
dom, and some other countries, but not in Canada or Australia. It is
somewhat more expensive.
chlorphenamine/chlorpheniramine (Trimeton, Chlor–

Trimeton, Polaramine, Polaramin, Piriton)
Chlorphenamine is an old, moderately sedative antihistamine. It is

used to treat allergic symptoms. Some people with CFS/ME have
reported significant overall symptom relief from this drug.62 This may
be explained by the fact that chlorphenamine also inhibits serotonin
reuptake, similar to the SSRI antidepressants. It may also activate D1
dopamine receptors and alpha1 receptors.63 Chlorphenamine has a short
half–life, so it is usually taken as many as 3–5 times a day.
Because of its serotonergic effects, chlorpheniramine should not be
combined with MAOIs or dextromethorphan. Combinations with other
psychiatric drugs, tryptophan and St. John’s wort may also cause prob-
lems. Azole antifungals, diclofenac, doxycycline, nefazodone and vera-
pamil may increase the blood levels of chlorphenamine.
Chlorphenamine is available in the United States, the United King-
dom, Canada, Australia and some other countries. It is mostly used in
combination products which usually contain analgesics, antitussives,
and/or decongestants. Because of the short dosing interval it gets more
expensive than other antihistamines.
diphenhydramine (Benadryl, Nytol, Unisom)
Diphenhydramine is a sedative first–generation antihistamine with

significant anticholinergic effects. It also inhibits the reuptake of seroto-
nin and in fact some SSRIs were developed based on diphenhydramine.
It is very effective for allergic symptoms and also works as an antieme-
tic, but it is even more commonly used as a sleep aid. Small 25 mg
doses may be useful for severe pain in patients who have not responded
to other treatments.64
Besides sedation, diphenhydramine can have significant anticholin-
ergic side effects, such as dry mouth, tachycardia, constipation, urinary
retention, confusion, cognitive problems and even hallucinations. Obvi-
ously some of these effects can also be beneficial, but diphenhydramine
should not be combined with other anticholinergic drugs.
Diphenhydramine is available in the United States, the United
Kingdom, Canada, Australia and many other countries. In these four
markets it is available without prescription. A cream is also available on
some markets. The tablet form is very inexpensive.
doxylamine (Unisom SleepTabs, Unisom–2, Dozile)
Doxylamine is a highly effective anti–allergy drug with significant

sedative and anticholinergic effects, similar to diphenhydramine. It is
even more sedative than many prescription tranquilizers. It is used as a
sleep aid, for the treatment of colds, with analgesics for pain (especially
headaches) and in combination with vitamin B6 for morning sickness in
pregnancy.
Side effects are similar to diphenhydramine. In addition doxyla-
mine has some anti–thyroid effects, so it probably should not be used by
people with hypothyroidism.
Doxylamine is available in the United States, the United Kingdom,
Canada, Australia and some other countries. Most preparations also con-
tain other ingredients, such as analgesics and caffeine, pseudoephedrine,
guaifenesin, dextromethorphan or the aforementioned vitamin B6. Many
products are available without prescription.
meclozine/meclizine (Antivert, Bonamine, Postafen,

Agyrax, Sea–legs)
Meclozine is a first generation antihistamine chemically similar to

hydroxyzine. It is frequently used to treat to vertigo, hence the common
brand name. Meclozine is sometimes prescribed to CFS/ME patients for
vertigo, balance problems and nausea.65 It can also help tinnitus and
motion sickness. Like most older antihistamines it is very sedative with
strong anticholinergic properties.
Meclozine is available in the United States, the United Kingdom,
Canada and some other countries, but not in Australia. It is a prescrip-
tion drug in some countries, but in most places it is available over the
counter.
cinnarizine (Stugeron, Mitronal, Cinna)
Cinnarizine is an old antihistamine, which is mainly used to treat

motion sickness and vertigo. It also works as a calcium channel blocker
with most of the vasodilatory effects taking place in the brain, similar to
nimodipine. In addition cinnarizine increases erythrocyte deformability
like piracetam and pentoxifylline, which can further improve circula-
tion. As all of these three drug classes are used to treat CFS/ME, cinna-
rizine could effectively offer the benefits of all of them.
Cinnarizine can be somewhat sedating, but because it improves
cerebral circulation it is sometimes considered a nootropic. In some
countries it is even sold in combination with piracetam. A study done on
this combination found it useful in the treatment of chronic fatigue.66 It
has also shown good efficacy in migraine prophylaxis.67
The most common side effects are drowsiness and impaired con-
centration. These effects may improve after a few days of use. Stomach
upset and anticholinergic side effects such as dry mouth and problems
with urination are possible. The vasodilatory effects may cause head-
aches in some people. The sedative and anticholinergic effects of the

drug can be worsened by other sedatives and anticholinergic drugs and
the latter also by MAOIs.
Cinnarizine is available in the United Kingdom and many other,
primarily European countries, but not in the United States or Canada. It
is often sold over the counter but sometimes only by prescription. In
Australia a special permit is required. The strength of tablets varies
widely from 10 to 75 mg. It is very inexpensive.
Cannabinoids
Cannabis, also known as marijuana, is one of the most controver-

sial pharmaceutical treatments. This is regardless of the fact that it has
been used as a medicine for thousands of years and that cannabis tinc-
ture was a popular patent medicine in the Western world sold by com-
panies like Eli Lilly until politics phased it out in the early 1900s.68,69
Cannabis has demonstrated efficacy in many different conditions. It
has a favorable side effect profile compared to most other medications
used for these maladies, with no known drug interactions. The only
serious risk is the possibility of triggering psychosis in susceptible indi-
viduals. No organ damage has been noted as long as cannabis is not
combined with tobacco.
One of the most important uses of cannabis is the treatment of neu-
ropathic pain, which is notorious for responding poorly even to the
strongest opioids.70 It is also used to treat nausea and low appetite in
AIDS and cancer; tics in Tourette’s syndrome; glaucoma and multiple
sclerosis, but that is not all. Owing to its broad range of effects cannabis
could have been classified in almost any category of this book, such as
painkillers, anticonvulsants, sleep aids, muscle relaxants, immunomodu-
lators and even psychiatric drugs.71
Despite its psychotropic effects cannabis even has neuroprotective
properties. It inhibits nitric oxide production, which may be of import-
ance in CFS/ME and fibromyalgia.72 Cannabidiol (CBD), a constituent
of cannabis, is being investigated as an antipsychotic drug.73 Cannabi-
noids may be potentially helpful in depression, bipolar disorder and
anxiety disorders.74,75,76,77 THC inhibits cholinesterase, increasing the
levels of acetylcholine in the brain.78
In a study of patients with multiple sclerosis or spinal cord or other
severe neurological injury cannabis extracts relieved pain, spasticity,
muscle spasms, bladder symptoms and tremor with only transient side
effects.79 Cannabis has been discovered to be helpful in neurological
conditions including epilepsy80, migraine81 and congenital nystagmus.82
It may also alleviate respiratory conditions such as asthma83 and sleep

apnea.84 Antitumor properties have been reported.85
Cannabinoids are not just something found in the hemp plant. The
human body produces several of them on its own, known as endocanna-
binoids, which explains why we have several types of cannabinoid
receptors in our bodies. Curiously abnormally low levels of endocanna-
binoids have been found in many chronic illnesses (including migraine,
fibromyalgia and IBS) and some researchers have even proposed that
they are caused by an endocannabinoid deficiency.86
Because of its controversial nature cannabis is not frequently men-
tioned by CFS/ME and fibromyalgia doctors, but many patients speak in
favor of it, especially since it can relieve a wide variety of symptoms.
Jay Goldstein’s book Betrayal by the Brain dedicates a few pages to
cannabinoids and their relevance to CFS/ME and fibromyalgia.87 In one
study patients with fibromyalgia reported significant benefit from delta–
9–tetrahydrocannabinol (THC), the main active ingredient in cannabis,
though many discontinued the study prematurely.88
Despite ample evidence displaying the many beneficial effects of
cannabis in many chronic illnesses, in many places cannabis is still con-
sidered nothing but an illegal recreational drug. In some countries even
possession can lead to harsh penalties, even imprisonment. Medical
marijuana is available in some U.S. states, but is still illegal on the fede-
ral level.
The synthetic analogues of THC are generally viewed more favo-
rably, but they are only available in a handful of countries. Even in pla-
ces where medical marijuana is more or less legal, it may only be avail-
able to people with certain diagnoses, such as cancer or multiple sclero-
sis, excluding CFS/ME and fibromyalgia patients. This book is in no
way endorsing the illegal use of cannabis.
The side effects of cannabis can include intoxication, dizziness,
impaired coordination, dry mouth, anxiety, lethargy, depression, hypo-
glycemia, hypotension and drowsiness. Allergic reactions are possible.
Although cannabis is antiemetic, large doses can cause nausea. Canna-
bis is not considered addictive, but as with many medications, sudden
cessation of the drug can cause mild withdrawal symptoms such as slee-
piness and lack of appetite. Psychological addiction is possible, but
rarely noted in medical users.
medical marijuana
Technically the word marijuana refers to the dried flower tops of

the hemp or cannabis plant (Cannabis sativa). In the medical context it
can be used to refer to other products of the cannabis plant, as well. In

places where medical use of cannabis is legal the material can be suppli-
ed by the government, pharmacies, independent “cannabis clubs” and/or
grown by the patient, depending on the exact legislation.
Many patients and researchers believe that marijuana is more effec-
tive than the synthetic products.89,90 This may be because they only con-
tain one or two cannabinoids. The cannabis plant contains over 30 diffe-
rent cannabinoids (most of them non–psychoactive) and possibly other
compounds that may contribute to its therapeutic effects. The constitu-
ents and thus the therapeutic effects largely depend on the cultivar
(“strain”). Medical strains are usually developed to cause little sedation
and intoxication while having strong analgesic properties.
Cannabis is most often smoked, which can cause lung irritation,
even though it has not been shown to cause lung cancer, likely because
of the anticarcinogenic effects of the plant.91 Those who would rather
not smoke can prepare the plant matter into food (which produces a
longer duration of effects) or use a so–called vaporizer to breathe in
vapors, similar to effect in smoking but gentler on the airways and con-
taining much less tar. Smoked marijuana should never be combined
with tobacco, which is harmful and physically addictive.
Medical cannabis is available in some parts of the United States, as
well as Canada, the Netherlands and Belgium. In many countries a small
number of patients have got a special permit to use the drug. In some
other countries either the possession of small amounts of cannabis is
legal, or cannabis has been decriminalized, which means it is technically
illegal, but possession and/or growing of small quantities is not penali-
zed. The cost varies widely.
dronabinol (Marinol)
Dronabinol contains a synthetic form of delta–9–tetrahydrocanna-

binol (THC), the main active ingredient in cannabis. It is an effective
antiemetic and appetite booster, but because it lacks many other canna-
binoids it may not be as effective as a painkiller, muscle relaxant or
sleep aid as other medical marijuana products. Dronabinol is administe-
red in capsule form. An aerosol is in clinical trials.
Dronabinol is approved for use in the United States, Canada and
Denmark. It is classed as a Schedule III drug in the United States. It is
very expensive.
nabilone (Cesamet)
Nabilone is a synthetic cannabinoid similar to THC, but with less

intoxicating effects. It is administered as tablets. It is approved for the
treatment of nausea, anorexia and weight loss in patients with cancer or
AIDS, but is also sometimes used for chronic pain. It has been reported
to be helpful in fibromyalgia.92 A recent double–blind study tried nabi-
lone for this indication with very beneficial results.93
Nabilone is available in the United States, the United Kingdom,
Canada and Australia. It is very expensive.
tetrahydrocannabinol and cannabidiol (Sativex)
Sativex contains the two most important cannabinoids (THC and

CBD) derived from the cannabis plant in 1:1 ratio and thus may be more
effective than dronabinol or nabilone. The ratio of these is nonetheless
quite different from most strains of cannabis, as hemp usually contains
much more THC than CBD. It is used as an antiemetic, but especially as
a treatment for multiple sclerosis. It is formulated as a mouth spray,
which results in a very rapid delivery of the active ingredients.
Sativex is currently only licensed in Canada and Catalonia (Spain),
but it can legally be imported to the United States and some other count-
ries with a doctor’s prescription. In the United Kingdom prescribing is
possible on a named–patient basis. It is very expensive.
Parenteral supplements
parenteral magnesium
Magnesium is a highly important nutrient for e.g. the muscles,

energy production, mood, immune system, and bone formation. It is also
a calcium channel blocker and NMDA antagonist. Even if nutritional
intake is adequate, stress can cause excessive excretion of magnesium in
the urine. A deficiency may even lower magnesium absorption.
Many doctors believe that in CFS/ME and fibromyalgia the intra-
cellular magnesium levels are too low, even though there is enough
magnesium circulating in the blood and thus ordinary bloodwork usual-
ly gives results in the normal range. Studies point to the same.94,95 Mag-
nesium deficiency has even been proposed as the cause of symptoms of
CFS/ME.96
Magnesium deficiency has been associated with decreased melato-
nin levels97, decreased cell–mediated immunity98, increased levels of
inflammatory cytokines99, increased nitric oxide production and loss of

glutathione.100 Such deficiency also increases the levels of substance P,
an inflammatory neuropeptide which has been associated with CFS/ME
and especially fibromyalgia.101
As a result it is not surprising that magnesium is one of the most
popular nutritional supplements used in CFS/ME and fibromyalgia,
often in conjunction with malic acid. Many patients cannot absorb oral
magnesium well and the supplementation should be done parenterally,
usually intramuscularly as magnesium sulfate. A common dose is 1
gram of magnesium sulfate i. m. 1–2 times a week.102 Dr. Jacob Teitel-
baum recommends a larger dose, 2 grams once a week for four weeks.103
A case study published in Japan describes a woman with CFS/ME
whose condition improved significantly after i. m. magnesium given
once a week every six weeks.104 CFS/ME doctor Sarah Myhill believes
that 70% of her patients benefit from magnesium injections, which she
combines with oral magnesium and vitamin B1.105
Magnesium injections can relieve e.g. tiredness, fatigue, sleep dis-
turbances, cognitive symptoms, muscle aches, spasms and stiffness,
anxiety, sensory oversensitivity, headaches, cardiac arrhythmias and
Raynaud’s phenomenon. Both depression106 and bipolar mania107 often
respond. Magnesium is used to treat both myofascial and neuropathic
pain.
Intravenous magnesium can rapidly abort different types of head-
aches, including migraines, tension headaches and cluster headaches.108
Intravenous magnesium is also used in emergency medicine for e.g.
asthma and myocardial infarction (“heart attack”). It was ranked as by
far the most effective treatment in a large survey of patients with multip-
le chemical sensitivity with 63.5% benefiting109, hardly surprising consi-
dering that patients with MCS are usually deficient in magnesium.110
Magnesium injections are usually low in side effects. Transient
visual disturbances have been reported. The actual intramuscular injec-
tion can be quite painful (“pain in the ass” as doctors put it, since it is
usually injected in the buttocks), but the pain can be reduced by warm-
ing the infusion to body or at least room temperature, using lidocaine
and possibly also by administering it together with vitamin B12 and/or
the amino acid taurine. Magnesium injections should not be given to
patients with kidney problems.
Magnesium is available everywhere, but usually the injection
concentrate has to be compounded.
intramuscular vitamin B12
A deficiency of vitamin B12 usually cannot be demonstrated in the

bloodwork of patients with CFS/ME, but elevated levels of homocys-
teine have been found in the cerebrospinal fluid of patients who had
both CFS/ME and fibromyalgia. Elevated homocysteine can be caused
by a deficiency of vitamin B12 and in the study the levels of homocys-
teine correlated significantly with fatigue, with the CSF B12 levels hav-
ing an inverse correlation (higher B12 levels meant less fatigue).111
Intramuscular administration of vitamin B12 is not a very common
treatment for fibromyalgia, but it is one of the most popular CFS/ME
treatments and considered one of the most effective. Oral and sublingual
forms of the vitamin help many, but the absorption is low. B12 injecti-
ons can contain thousands of times the RDA of the vitamin. Opinions
differ as to which is the best form of B12.
CFS/ME specialist Charles Lapp believes there is enough vitamin
in the blood, but it is not properly taken into the cells.112 According to
him as many as 80% of CFS/ME patients benefit from large doses of
B12. He uses a dose of 3 mg, which the patient administers himself 2–3
times a week. The effects are noticeable in a few weeks, often almost
immediately. Kenny De Meirleir recommends a 10 mg injection twice a
week.113
Dr. Sarah Myhill too considers B12 injections to be an essential
part of treatment of CFS/ME.114 She prescribes a weekly dose of 2 mg.
In her experience B12 helps fatigue, muscle weakness and cognitive
problems. Paul Cheney goes as far as prescribing 10–25 mg daily
doses.115 Martin Pall believes that B12 works because it scavenges nitric
oxide.116 Dr. Leslie O. Simpson on the other hand thinks the benefits
result from improved deformability of red blood cells.117
B12 also has some analgesic effects, especially in the treatment of
neuropathic pain.118 It is sometimes used as a treatment of multiple
sclerosis. Many patients with multiple chemical sensitivity benefit from
B12 injections. Even healthy people often note that B12 supplements
ameliorate tiredness and impaired concentration. A study using vitamin
B12 for tiredness in the 1970s found it very helpful.119
B12 is very safe even in massive doses. Side effects are extremely
rare aside from harmless discoloration of the urine. Rarely there may be
an acne–like rash, which usually disappears by lowering the dose. It is
possible to be allergic to B12, but it is very uncommon. Some patients
have reported increased anxiety from B12.
B12 is available everywhere, though doses larger than 1 mg may
have to be compounded. Cost depends on dose and injection frequency.
Myers’ cocktail
The American doctor John Myers used an intravenous nutrient

cocktail to treat his patients starting from the 1950s. After Myers’ death
Alan R. Gaby designed his own version of the preparation and called it
“Myers’ cocktail.”120 It contains magnesium chloride, calcium gluco-
nate, vitamin C and most B complex vitamins in a small amount of
liquid. Because of the nature of the formula it is difficult to determine
which of the ingredients are actually conferring the benefits.
This experimental nutrient infusion is reportedly helpful for many
different conditions, such as asthma, migraine, muscle spasms, fatigue,
depression, cardiovascular disease, respiratory infections, allergic rhini-
tis (hay fever), chronic sinusitis and chronic urticaria. Jacob Teitelbaum
considers it particularly helpful for CFS/ME and fibromyalgia patients
whose main problems are achiness, asthma and migraines.121
The ingredients of Myers’ cocktail are available everywhere and
are very inexpensive. Nonetheless a doctor is needed to agree on the
administration of the cocktail, and many doctors charge a lot for IV
infusions. Insurance is unlikely to cover this treatment for any indica-
tion.
intravenous vitamin C
Vitamin C or ascorbic acid is a powerful antioxidant and a popular

supplement. Although its role in flu treatment and prevention has not
been scientifically established—it is possible that studies have used too
low doses—it is known to increase the levels of glutathione, an impor-
tant antioxidant which is thought to be deficient in CFS/ME. Some
people get severe stomach upset from C vitamin supplements, even if
they have been “buffered” into a neutral salt such as calcium ascorbate.
Vitamin C is necessary for human life, as we are among the few
animals whose bodies lack the ability to synthesize it. The recommen-
ded daily dose to avoid scurvy is about 60 mg. From the amount of vita-
min C produced by some other mammals, it has been estimated that if
humans produced their own vitamin C, it would amount to several
grams a day. This has been one of the arguments used to justify the
administration of very high doses of the vitamin.
In 1971 doctor Frederick R. Klenner published a paper where he
describes the use of parenteral vitamin C in doses of up to 150 grams of
in the treatment of e.g. herpesviral and enteroviral infections.122 It is
interesting to note that Klenner believed coxsackieviruses to be the

cause of multiple sclerosis. Later coxsackieviruses and other enteroviru-
ses have been associated with CFS/ME.
There are other reasons to use intravenous vitamin C. Dr. Majid Ali
has reported that administering 15 grams of vitamin C intravenously
reverses the abnormal shapes of red blood cells in CFS/ME, improving
blood flow.123 Dr. Jay Goldstein believes vitamin C works by acting as a
NMDA antagonist and by modulating dopaminergic neurotransmis-
sion.124 He recommends infusing 25–50 grams of vitamin C together
with some magnesium sulfate and calcium gluconate.
In many parts of the western world intravenous vitamin C is consi-
dered an alternative treatment with no proven value. In Japan it is none-
theless a common treatment, especially in conjunction with DHEA One
paper describes the successful use of this treatment for “interstitial pneu-
monia alias chronic fatigue syndrome.”125 Intravenous vitamin C also
appears to reduce fatigue and improve quality of life in patients with
advanced cancer.126
The therapy is very low on side effects, but as some patients with
CFS/ME tolerate antioxidants poorly, the infusion should be started
slow and discontinued if any adverse effects occur. Goldstein has noted
that some people may experience transient dysphoria (unpleasant emoti-
ons). Intravenous vitamin C should not be given to patients with renal
insufficiency or iron overload (such as hemochromatosis).
Vitamin C is available everywhere and is very inexpensive, but
again some doctors may charge high prices from the infusions.
intravenous saline
Intravenous saline can be used for increasing blood volume, which

is usually low in CFS/ME.127 Many people with CFS/ME have reported
improvement in most or all symptoms after saline infusions and prelimi-
nary research has confirmed good efficacy.128 Unfortunately the effects
are usually short–lived and the saline has to be infused several times a
week, sometimes daily. Occasionally the results may become more last-
ing each time.129
CFS/ME specialist David Bell has been one of the proponents of
intravenous saline. He believes it is the most effective treatment for
severe CFS/ME he has found—and that volume expansion may also
explain the efficacy of other intravenously administered medications.130
He has reported some cases where the patient has recovered from seve-
rely ill to well enough to resume full–time work. Of the 25 patients he
had given the treatment by 2006, 19 (76%) noted improvement.
Salt and water, being normal constituents of the human body, are
safe, but some patients cannot tolerate the treatment. Others require that
the infusion be given at a very slow rate to avoid side effects. Also,
when giving intravenous saline on daily basis, it is usually done via an
indwelling catheter which can become infected. In case of an infection
the catheter has to be removed and the patient is given antibiotics, but
with doctor’s approval the treatment can resume.
Treatments for bladder and bowel

dysfunction
Anticholinergic drugs are also known as antispasmodics or spasmo-

lytics, because they can be used to relieve spasms of the stomach, intes-
tine and bladder. They calm down gastric motility and reduce urinary
frequency. According to fibromyalgia specialist Robert Bennett as many
as 40–60% of FM patients suffer from irritable bladder and he uses anti-
spasmodic drugs as a part of the treatment.131 He even uses them to treat
neurally mediated hypotension. Most of the drugs listed in this section
are anticholinergic.
Anticholinergic drugs are contraindicated in some medical condi-
tions, such as narrow–angle glaucoma and GERD (acid reflux). They
may prolong the QT interval, so they should not be used with other
drugs with this property.
See also:
diazepam, melatonin, baclofen, cyclobenzaprine (CHAPTER 1),

flupirtine, triptans, codeine (CHAPTER 2), anticonvulsants
(CHAPTER 3), metronidazole, rifaximin, antifungals (CHAPTER
4), tricyclic antidepressants, SSRIs, mianserin, mirtazapine, tia-
neptine (CHAPTER 5), midodrine, etilefrine, ephedrine, anira-
cetam (CHAPTER 6), alpha blockers, beta blockers, calcium
channel blockers, nitrates (CHAPTER 7), naltrexone (CHAPTER
8), memantine, hydroxyzine, diphenhydramine, cannabinoids,
ranitidine/cimetidine, misoprostol, granisetron/tropisetron/on-
dansetron (CHAPTER 9), aprepitant, scopolamine (CHAPTER 10)
oxybutynin (Ditropan, Cystrin, Driptane, Lyrinel,

Dridase)
Oxybutynin is the anticholinergic most commonly used in the treat-

ment of urinary problems, even though it is not as well tolerated as the

newer agents. It affects both muscarinic and nicotinic acetylcholine
receptors. Besides the anticholinergic action it also has alpha antagonist,
antihistamine–like and local anesthetic properties. Normal tablets are
usually taken two or three times a day, but the patch is applied twice a
week. It may take several weeks to get the maximum benefit.
Oxybutynin is very prone to causing dry mouth. It can also cause
constipation, visual disturbances, tachycardia, confusion, cognitive
problems, sedation, weight gain and orthostatic hypotension. It should
be started with a low dose once or twice a day to improve tolerability.
The extended release formulation is generally better tolerated and the
patch is much less likely to cause dry mouth.
Oxybutynin is available in the United States, the United Kingdom,
Canada, Australia and many other countries. It is fairly affordable, but
the patches are more expensive. On the other hand the patch is only
changed eight times a month, so the cost is not nearly as high as it may
seem at first.
tolterodine (Detrol, Detrusitol, Unidet)
Tolterodine is another very common treatment for bladder troubles.

It affects both M2 and M3 type muscarinic receptors, so it is not as selec-
tive as the newer agents, but more so than oxybutynin. It is usually
taken two times a day, but an extended release formulation is available.
Tolterodine causes typical anticholinergic side effects, but has been
shown to have tolerability superior to oxybutynin. If it is combined with
macrolide antibiotics, azole antifungals and some SSRI antidepressants
the dose should be decreased, because these drugs can slow down the
metabolism of tolterodine.
Tolterodine is available in the United States, the United Kingdom,
Canada, Australia and some other countries. It is more expensive than
oxybutynin.
trospium (Sanctura, Spasmex, Spasmo–lyt, Trosec,

Regurin)
The anticholinergic action of trospium is mostly selective for the

muscarinic receptors. The drug cannot pass through the blood–brain bar-
rier, which reduces the amount of side effects. One study concluded that
oxybutynin and tolterodine caused minor sleep disturbances, but tros-
pium did not.132 Trospium is normally taken twice a day.
Trospium is available in the United States, the United Kingdom,
Canada, Australia and some other, primarily European countries. The

price is similar to tolterodine.
darifenacin (Enablex, Emselex)
Darifenacin is selective for the M3 type muscarinic receptor, which

is mostly found in the bladder and to some extent the gastrointestinal
tract, so it may have fewer side effects like dry mouth than non–selec-
tive anticholinergic drugs. It is usually taken once a day.
Carbamazepine, phenytoin, azole antifungals, macrolide antibiotics
and some other drugs can affect the blood levels of darifenacin.
Darifenacin is available in the United States, the United Kingdom,
Canada, Australia and some other countries. It is slightly more expen-
sive than trospium and tolterodine.
solifenacin (VESIcare)
Solifenacin is an antagonist of the M3 type muscarinic receptors

similar to darifenacin, but possibly more selective. It is taken once a
day. The adverse effects are similar to darifenacin, but possibly milder.
The potential drug interactions of darifenacin also apply for solifenacin.
Solifenacin is available in the United States, the United Kingdom,
Canada, Australia and some other countries. The price is similar to dari-
fenacin.
flavoxate (Urispas, Bladuril)
Flavoxate is a urinary antispasmodic. It is generally considered an

anticholinergic drug, but also appears to have phosphodiesterase inhibi-
ting and direct smooth muscle relaxant activity, which may contribute to
its effects.133,134 Thus it might help some patients who do not benefit
from the other anticholinergic drugs. Flavoxate is usually taken three or
four times a day.
Flavoxate is available in the United States, the United Kingdom,
Canada, Australia and some other countries. It is a little more costly
than oxybutynin and tolterodine.
dicycloverine/dicyclomine (Bentyl, Antispas, Dibent,

Bentylol, Merbentyl)
Dicycloverine is an anticholinergic drug which is used to treat irri-

table bowel syndrome. It is mostly selective for the M1 muscarinic re-
ceptor. It also has antibacterial activity against both Gram negative and
Gram–positive bacteria.135 Recommended dosages vary from 30 to 160
mg a day, taken in 3–4 doses.
Dicycloverine is available in the United States, the United King-
dom, Canada, Australia and some other countries. It is available as cap-
sules, tablets and syrup. It is also included in many combination pro-
ducts.
hyoscyamine (Anaspaz, Egazil, Levsin)
Hyoscyamine is the L–isomer of atropine. It is a very potent anti-

cholinergic; the dosages used are in the range of hundreds of micro-
grams. It is used for both gastrointestinal and urinary symptoms.
Hyoscyamine is available in the United States, the United King-
dom, Australia and a few other countries, but not in Canada. Modified
release preparations are available in some countries. Several multi–ing-
redient formulations are available, usually containing antihistamines or
barbiturates.
hyoscyamine, atropine, methenamine, methylene blue,

phenyl salicylate and benzoic acid (Urised, Uriseptic)
Urised contains a combination of medications designed to help

bladder problems: an anticholinergic (hyoscyamine), antiseptics (methe-
namine, methylene blue and benzoic acid) and a painkiller (phenyl sali-
cylate, similar to aspirin). It can be used to treat urinary tract infections
and painful conditions of the bladder.
Urised is only available in the United States, but similar products
with a different combination of ingredients are available in many
countries.
phenazopyridine (Uristat, Prodium, Pyridium, Phenazo)
Phenazopyridine is a local anesthetic which is taken orally, but acts

on the bladder. Its exact mode of action is not known. It alleviates pain-
ful urination and is most commonly prescribed as an adjunct to an anti-
biotic in a urinary tract infection. Phenazopyridine can also reduce the
need for excessive urination and is sometimes used for interstitial cys-
titis. It is not recommended for continuous use, only for flare–ups. It is
usually taken three times a day.
Side effects of phenazopyridine can include headaches, stomach
upset and dizziness. It causes a harmless color change in urine, but may
also cause discoloration of the skin and eyes with possible permanent
discoloration of contact lenses and underwear. For some people with
interstitial cystitis phenazopyridine may actually worsen bladder prob-
lems. In animals long–term use has increased the risk of cancer, but
whether this applies to humans is unclear.
Phenazopyridine is available in the United States, Canada and a
few other countries, but not in the United Kingdom, Australia or almost
any European country. Some formulations are available over the coun-
ter. Phenazopyridine is also sold in combination with the anticholinergic
hyoscyamine and the sedative butabarbital.
pentosan polysulfate (Elmiron)
Pentosan polysulfate is a heparin–like drug which is used to treat

interstitial cystitis. It is believed to work by creating a protective coating
on the bladder wall and possibly by mast cell inhibition. Unfortunately
the oral bioavailability is extremely low—only 6% is excreted through
urine. The drug needs to be taken for weeks, three times a day, to be
effective. Alternatively it can be used as a bladder instillation during a
flare of the symptoms.
Pentosan polysulfate has some antiviral action similar to heparin.136
It has been suggested to possess migraine–prophylactic action137 and
neuroprotective properties.138 Pentosan polysulfate can be used to treat
osteoarthritis, but for some reason is only used for this purpose in ani-
mals.139
Pentosan polysulfate is usually well–tolerated. Side effects can inc-
lude headache, hair loss, skin rashes, rectal hemorrhage (bleeding from
the rectum), diarrhea and nausea, but they are all fairly rare. No other
drug interactions are known, but other anticoagulant drugs can increase
the risk of bleeding. Pentosan polysulfate should not be used in patients
with a peptic ulcer.
Pentosan polysulfate is available in the United States, Canada, and
a few other countries, but not in the United Kingdom or Australia. It is
quite expensive.
Other drugs
acetazolamide (Diamox, Sequels, Glaupax, Diuramid)
Acetazolamide is a carbonic anhydrase inhibitor. It has diuretic

properties and changes the pH of tissue. It is mostly used to treat epilep-
sy, mountain sickness, edema and glaucoma. Charles Lapp, Paul Che-
ney and several other experts use acetazolamide to treat CFS/ME. Lapp
recommends using a dose of 125–500 mg once or twice a day.140
Usually any benefits are noticeable very quickly.
In CFS/ME acetazolamide can help cognitive problems, headaches,
problems with balance and sometimes fatigue.141 Some patients report
improvement in vertigo and Cheney prescribes the drug for pain.142 Ace-
tazolamide is generally used for other types of headaches, but studies
show it may also be helpful for migraines.143,144 It acts as a cerebral
vasodilator, which may explain its beneficial effects on cognition and
vascular headaches.145
Different kinds of adverse effects are possible especially in long–
term use, including metabolic acidosis. Common side effects include
sedation, altered taste and numbness and tingling of extremities. Potas-
sium supplementation may reduce the side effects. Weight loss is pos-
sible. People with sulfa allergy should not use the drug. Acetazolamide
may lower lithium levels and elevate phenytoin levels. Salicylates (inc-
luding aspirin) can dangerously elevate the levels of acetazolamide.
Acetazolamide is available in the United States, the United King-
dom, Canada, Australia and some other countries. It is available as tab-
lets and sustained release capsules. It is inexpensive.
sibutramine (Meridia, Reductil)
Sibutramine inhibits the reuptake of serotonin, norepinephrine and

to some extent also dopamine. Despite that it has not been shown to
have antidepressant activity, but instead it is used as a weight loss
treatment. One study with 30 FM patients got excellent results with
sibutramine.146 83% of the participants reported markedly decreased
pain, in some cases from 10/10 to 0–2. All patients reported reduced
fatigue, increased energy levels and better mood and overall functi-
oning. They also found the drug well tolerated.
Sibutramine may raise blood pressure, which, like weight loss, can
be either beneficial or harmful. Blood pressure should be monitored
regularly. The most common side effects are insomnia, dry mouth, cons-
tipation and headache. Paradoxically the drug may cause increased
appetite. Ketoconazole and omeprazole may increase the plasma levels
of sibutramine. Sibutramine should never be combined with MAOIs.
Other serotonergic drugs may also pose the risk of serotonin syndrome.
Sibutramine is available in the United States, the United Kingdom,
Canada, Australia and some other countries. Often it is not covered by
insurance, but the price is still affordable. It is a Schedule IV controlled
substance in the United States.
misoprostol (Cytotec)
Misoprostol is a synthetic prostaglandin analogue, which reduces

the secretion of stomach acid and protects the gastric mucosa with other
mechanisms as well. It is used to reduce the risk of peptic ulcers in
long–term use of NSAIDs. Misoprostol may repair increased intestinal
permeability caused by other factors too, and thus help with the stomach
upset and food intolerances often associated with CFS/ME.147 It can be
used to treat chronic constipation, though usually it is not the drug of
choice for this purpose.
Misoprostol appears to work for two other maladies often comorbid
with CFS/ME and fibromyalgia: trigeminal neuralgia and interstitial
cystitis. Two small studies tried it for refractory trigeminal neuralgia
associated with multiple sclerosis.148,149 It helped most of the patients
and was well tolerated. In a study with refractory interstitial cystitis
about half of the participants benefited from misoprostol.150 Most expe-
rienced some adverse effects, but they were minor. Misoprostol may
also help tinnitus.151
Diarrhea and abdominal pain are the most common adverse effects.
Women may sometimes experience problems with menstruation. Miso-
prostol does not have known interactions with other drugs. It is also
used to induce abortion, so obviously women of childbearing age have
to be using effective contraception.
Misoprostol is available in the United States, the United Kingdom,
Canada, Australia and some other countries. It is also combined with
diclofenac in a product named Arthrotec. Both are fairly inexpensive.
ranitidine (Zantac, Histac, Ranitic, Ranix, Ranitin)

cimetidine (Tagamet, Cimehexal, Histodil, Dyspamet,
Ulcedine)
Ranitidine and cimetidine are antagonists of the H2 histamine

receptor. Because of this they are often called antihistamines, though
their effects are quite different from the antiallergic drugs (which act on
the H1 receptor). They are used to reduce the secretion of stomach acid
in ulcer prevention and treatment, but have largely been surpassed by
the proton pump inhibitors. They may be useful for allergic symptoms
in conjunction with H1 antagonists (“normal” antihistamines).152
Dr. Jay Goldstein discovered in the 1980s that H2 receptor antago-
nists can be very effective against infectious mononucleosis.153 Because
at the time CFS/ME was thought to be a form of chronic mononucleosis,
he also tried them in CFS/ME patients, often with good results. He
believes the effects may result from the cholinergic and NMDA antago-
nist properties of the drugs. Devin Starlanyl notes these drugs may be
useful in fibromyalgia for promoting stage 4 sleep, especially with ami-
triptyline.154
The H2 antagonists have some immunostimulatory properties.155,156
They can be used to treat interstitial cystitis157 and painful bladder dis-
ease.158 There is some evidence H2 antagonists are helpful for weight
loss.159,160 They have shown some efficacy in reducing the weight gain
caused by olanzapine (an antipsychotic).161 This might apply to other
medications that cause weight gain, as well. Additionally they potentiate
opioid analgesia.162
According to Goldstein H2 antagonists may cause restlessness and
overstimulation in patients with CFS/ME and fibromyalgia. Headache is
also possible and rarely may be severe. Occasionally H2 antagonists
cause allergic reactions. People with SLE may experience lupus flares.
The H2 antagonists may also increase the requirements of folic acid,
vitamin B12 and zinc. Cimetidine may interact with phenytoin, carba-
mazepine, lidocaine, opioids, theophylline and tricyclic antidepressants.
Cimetidine and ranitidine are widely available. Low doses of cime-
tidine are available over–the–counter in the United States and some
other countries. Ranitidine is available without prescription in the
United States, the United Kingdom and Australia.
folinic acid/leucovorin (Leucovorin, Lederfoline,

Lederfolin, Rescuvolin)
levofolinic acid/levoleucovorin (Isovorin, Antrex,
Calcifolin)
Folinic acid is the biologically active form of the B group vitamin

folic acid (folate) and levofolinic acid is its active stereoisomer. Both
drugs are used to minimize the toxic effects of the chemotherapeutic
agent methotrexate as well as in the treatment of colorectal cancer to-
gether with 5–fluorouracil. A deficiency of folic acid has been associa-
ted with CFS/ME163 and may also be behind the elevated homocysteine
levels.164 Deficiency can cause restless legs which responds to folate
supplementation.165
Some of the patients who do not respond to folic acid benefit from
folinic acid, if they lack the enzyme that converts folic acid to folinic
acid. Folinic acid is a part of the “methylation treatment” recommended
by researcher Richard van Konynenburg and CFS/ME doctor Sarah
Myhill.166,167 This protocol also includes tetrahydrofolate (another form
of folate), SAM–e, trimethylglycine (betaine), phosphatidylserine and
some other nutrients, most available over–the–counter.

There has been one study about levofolinic acid for CFS/ME.168 As
many as 81% out of the 51 participants felt they improved on the drug in
the dose of 75–100 mg a day. No major adverse effects were reported.
This result, although preliminary, definitely warrants further trials. It is
not known whether these drugs would be helpful in fibromyalgia as
well.
Folinic acid does not usually cause any side effects. Besides some
chemotherapeutic agents it does not have any drug interactions. Vitamin
B12 supplementation is recommended, because large amounts of folate
can mask the symptoms of a B12 deficiency.
The drugs are widely available, but are rather expensive as pre-
scription drugs. In the United States and some other countries folinic
acid is available as an over–the–counter supplement. Folinic acid is
commonly available in oral form, but levofolinic acid is usually sold
only as solution for injection.
granisetron (Kytril)
tropisetron (Navoban)
ondansetron (Zofran, Emeset, Emetron)
The “setrons” block the 5–HT3 serotonin receptor, producing anti-

emetic effects and reducing the levels of the inflammatory neuropeptide
substance P. Normally they are only used to treat very severe nausea
associated with e.g. cancer chemotherapy. They have arisen as potential
treatments for CFS/ME and especially fibromyalgia. They can help pain
(including headaches), fatigue, sleep and IBS. Usually one dose is
enough to establish efficacy.
Many studies have got promising results with the setrons, espe-
cially tropisetron for fibromyalgia, after the first report surfaced in
1994.169 The response rates have varied between 30% and 72% in diffe-
rent studies, depending on the criteria. The largest double–blinded trial
with 418 participants found the response rate to be 39%.170 No study so
far has compared the efficacy of the different setrons in this use. Lack of
depression171 and lower intensity of pain172 seem to be associated with
better response.
German researchers found that a 2 mg IV injection of tropisetron
was more effective than 5 mg of oral tropisetron.173 Some patients who
had not responded to oral therapy improved on the injections. A later
study using 5 mg tropisetron intravenously found that the effects of the
treatment lasted anywhere from one day up to 12 weeks, usually for 1–2
weeks.174 Too large doses may actually be inferior to placebo.175 Local
injections do not seem to work in fibromyalgia176, but can be very effec-

tive for myofascial pain.177
In a preliminary trial tropisetron and ondansetron relieved the fati-
gue caused by CFS/ME.178 Another small study concluded that graniset-
ron was very helpful for fatigue in CFS/ME.179 A German study found
that IV tropisetron markedly improved autonomic cardiac dysfunction in
fibromyalgia180, so it could be predicted to have similar effects in
CFS/ME, as well. Ondansetron may also help sleep apnea.181
Usually the setrons are well tolerated, but headache and constipa-
tion are fairly common. Tiredness and dizziness are also possible. Rare-
ly there can be hypersensitivity reactions manifesting as chest pain, dys-
pnea or skin eruptions. Carbamazepine, phenytoin and St. John’s wort
may decrease the blood levels of ondansetron and tropisetron. Combi-
ning the setrons with opioids can cause significant constipation. The set-
rons also block the analgesic efficacy of acetaminophen (paraceta-
mol).182
Ondansetron and granisetron are available in the United States, the
United Kingdom, Canada, Australia and some other countries with
ondansetron having wider availability. Tropisetron is available in the
United Kingdom, Australia and some other, primarily European count-
ries, but not in the United States or Canada. All of the three are highly
expensive.
See also:
mirtazapine, olanzapine (CHAPTER 4), calcium channel blockers

(CHAPTER 7), memantine (CHAPTER 9)
References
1 DeMaria S Jr., Hassett AL, Sigal LH. N–methyl–D–aspartate recep-

tor–mediated chronic pain: new approaches to fibromyalgia syndrome
etiology and therapy. J Musculoskelet Pain. 2007;15(2):33–9.
2 Sarchielli P, Di Filippo M, Nardi K, et al. Sensitization, glutamate,
and the link between migraine and fibromyalgia. Curr Pain Headache
Rep. 2007 Oct;11(5):343–51.
3 Carpenter CL, Marks SS, Watson DL, et al. Dextromethorphan and
dextrorphan as calcium channel antagonists. Brain Res. 1988 Jan 26;439
(1–2):372–5.
4 Sindrup SH, Jensen TS. Pharmacologic treatment of pain in polyneu-
ropathy. Neurology. 2000 Oct 10;55(7):915–20.
5 Sang CN, Booher S, Gilron I, et al. Dextromethorphan and memantine
in painful diabetic neuropathy and postherpetic neuralgia: efficacy and
dose–response trials. Anesthesiology. 2002 May;96(5):1053–61.
6 Staud R, Vierck CJ, Robinson ME, et al. Effects of the N–methyl–D–
aspartate receptor antagonist dextromethorphan on temporal summation
of pain are similar in fibromyalgia patients and normal control subjects.
J Pain. 2005 May;6(5):323–32.
7 Cohen SP, Verdolin MH, Chang AS, et al. The intravenous ketamine
test predicts subsequent response to an oral dextromethorphan treatment
regimen in fibromyalgia patients. J Pain. 2006 Jun;7(6):391–8.
8 Improving Sleep Quality Despite Fibromyalgia or Chronic Fatigue
Syndrome. http://drpodell.org/improving_sleep_quality.shtml
9 Krupp LB, Coyle PK, Doscher C, et al. Fatigue therapy in multiple
sclerosis: results of a double–blind, randomized, parallel trial of amanta-
dine, pemoline, and placebo. Neurology. 1995 Nov;45(11):1956–61.
11 Evidente VG, Adler CH, Caviness JN, et al. Amantadine is beneficial
in restless legs syndrome. Mov Disord. 2000 Mar;15(2):324–7.
12 Naesens L, Bonnafous P, Agut H, et al. Antiviral activity of diverse
classes of broad–acting agents and natural compounds in HHV–6–infec-
ted lymphoblasts. J Clin Virol. 2006 Dec;37 Suppl 1:S69–75.
14 Plioplys AV, Plioplys S. Amantadine and L–carnitine treatment of
Chronic Fatigue Syndrome. Neuropsychobiology. 1997;35(1):16–23.
15 Ito T, Shibata K, Watanabe A, et al. Neuroleptic malignant syndrome

following withdrawal of amantadine in a patient with influenza A ence-
phalopathy. Eur J Pediatr. 2001 Jun;160(6):401.
16 Zarate CA Jr, Payne JL, Quiroz J, et al. An open–label trial of rilu-
zole in patients with treatment–resistant major depression. Am J Psychi-
atry. 2004 Jan;161(1):171–4.
17 Mathew SJ, Amiel JM, Coplan JD, et al. Open–label trial of riluzole
in generalized anxiety disorder. Am J Psychiatry. 2005 Dec;162(12):
2379–81.
18 Coric V, Taskiran S, Pittenger C, et al. Riluzole augmentation in
treatment–resistant obsessive–compulsive disorder: an open–label trial.
Biol Psychiatry. 2005 Sep 1;58(5):424–8.
19 Borowicz KK, Rwiader M, Drelewska E, et al. Interactions between
riluzole and conventional antiepileptic drugs — a comparison of results
obtained in the subthreshold method and isobolographic analysis. J Neu-
ral Transm. 2004 Dec;111(12):1511–22.
20 Dunphy RC, Verne GN. Drug treatment options for irritable bowel
syndrome: managing for success. Drugs Aging. 2001;18(3):201–11.
21 Kowal C, DeGiorgio LA, Nakaoka T, et al. Cognition and immunity;
antibody impairs memory. Immunity. 2004 Aug;21(2):179–88.
22 Teng CT, Demetrio FN. Memantine may acutely improve cognition
and have a mood stabilizing effect in treatment–resistant bipolar dis-
order. Rev Bras Psiquiatr. 2006 Sep;28(3):252–4.
23 Peeters M, Gunthorpe MJ, Strijbos PJ, et al. Effects of pan– and sub-
type–selective NMDA receptor antagonists on cortical spreading
depression in the rat: therapeutic potential for migraine. J Pharmacol
Exp Ther. 2007 May;321(2):564–72.
24 Zarate CA Jr, Singh JB, Carlson PJ, et al. A randomized trial of an
N–methyl–D–aspartate antagonist in treatment–resistant major depres-
sion. Arch Gen Psychiatry. 2006 Aug;63(8):856–64.
25 Nicolodi M, Sicuteri F. Exploration of NMDA receptors in migraine:
therapeutic and theoretic implications. Int J Clin Pharmacol Res. 1995;
15(5–6):181–9.
26 Sun J, Li F, Chen J, et al. Effect of ketamine on NF–kappa B activity
and TNF–alpha production in endotoxin–treated rats. Ann Clin Lab Sci.
2004 Spring;34(2):181–6.
27 Graven–Nielsen T, Aspegren Kendall S, Henriksson KG, et al. Keta-
mine reduces muscle pain, temporal summation, and referred pain in
fibromyalgia patients. Pain. 2000 Apr;85(3):483–91.
28 Sörensen J, Bengtsson A, Bäckman E, et al. Pain analysis in patients

with fibromyalgia. Effects of intravenous morphine, lidocaine, and keta-
mine. Scand J Rheumatol. 1995;24(6):360–5.
30 Lynch ME, Clark AJ, Sawynok J, et al. Topical amitriptyline and ke-
tamine in neuropathic pain syndromes: an open–label study. J Pain.
2005 Oct;6(10):644–9.
31 Doyle RL, Frazier J, Spencer TJ, et al. Donepezil in the treatment of
ADHD–like symptoms in youths with pervasive developmental dis-
order: a case series. J Atten Disord. 2006 Feb;9(3):543–9.
32 Wilens TE, Biederman J, Wong J, et al. Adjunctive donepezil in at-
tention deficit hyperactivity disorder youth: case series. J Child Adolesc
Psychopharmacol. 2000 Fall;10(3):217–22.
33 Biederman J, Mick E, Faraone S, et al. A double–blind comparison
of galantamine hydrogen bromide and placebo in adults with attention–
deficit/hyperactivity disorder: a pilot study. J Clin Psychopharmacol.
2006 Apr;26(2):163–6.
34 Eisenach JC. Muscarinic–mediated analgesia. Life Sci. 1999;64(6–
7):549–54.
35 Slatkin NE, Rhiner M. Treatment of opiate–related sedation: utility
of the cholinesterase inhibitors. J Support Oncol. 2003 May–
Jun;1(1):53–63.
36 Nicolodi M, Galeotti N, Ghelardini C, et al. Central cholinergic chal-
lenging of migraine by testing second–generation anticholinesterase
drugs. Headache. 2002 Jul–Aug;42(7):596–602.
37 Spence VA, Khan F, Kennedy G, et al. Acetylcholine mediated vaso-
dilatation in the microcirculation of patients with chronic fatigue synd-
rome. Prostaglandins Leukot Essent Fatty Acids. 2004 Apr;70(4):403–7.
38 Chaudhuri A, Majeed T, Dinan T, et al. Chronic Fatigue Syndrome:
A Disorder of Central Cholinergic Transmission. J Chron Fatigue Syn.
1997;3(1):3–16.
41 Massara F, Ghigo E, Demislis K, et al. Cholinergic involvement in
the growth hormone releasing hormone–induced growth hormone re-
lease: studies in normal and acromegalic subjects. Neuroendocrinology.
1986;43(6):670–5.
42 Taysse L, Christin D, Delamanche S, et al. Peripheral ChE inhibition

modulates brain monoamines levels and c–fos oncogene in mice subjec-
ted to a stress situation. Neurochem Res. 2005 Mar;30(3):391–402.
43 Paiva ES, Deodhar A, Jones KD, et al. Impaired growth hormone
secretion in fibromyalgia patients: evidence for augmented hypothala-
mic somatostatin tone. Arthritis Rheum. 2002 May;46(5):1344–50.
44 Jones KD, Burckhardt CS, Deodhar AA, et al. A six–month randomi-
zed controlled trial of exercise and pyridostigmine in the treatment of
fibromyalgia. Arthritis Rheum. 2008 Jan 31;58(2):612–22.
45 Majeed T, Dinan TG, Behan PO. Pyridostigmine–induced growth
hormone responses – evidence for cholinergic supersensitivity in CFS.
Presented at: First world congress on chronic fatigue syndrome and rela-
ted disorders. Brussels, Belgium. Nov 9–11, 1995.
46 Kawamura Y, Kihara M, Nishimoto K, et al. Efficacy of a half dose
of oral pyridostigmine in the treatment of chronic fatigue syndrome:
three case reports. Pathophysiology. 2003 May;9(3):189–94.
47 Gales BJ, Gales MA. Pyridostigmine in the treatment of orthostatic
intolerance. Ann Pharmacother. 2007 Feb;41(2):314–8.
48 Finsterer J. Myasthenia and neuroborreliosis with excessively high
acetylcholine–receptor antibodies. Scand J Infect Dis. 2007;39(2):187–
90.
49 Greene, et al, Tariot PN, Wishart H, et al. A 12–week, open trial of
donepezil hydrochloride in patients with multiple sclerosis and associa-
ted cognitive impairments. J Clin Psychopharmacol. 2000 Jun;20(3):
350–6.
50 Krupp LB, Christodoulou C, Melville P, et al. Donepezil improved
memory in multiple sclerosis in a randomized clinical trial. Neurology.
2004 Nov 9;63(9):1579–85.
51 United States Patent 6608088. Use of donerezil for the treatment of
functional and/or organic pain syndromes. http://www.freepatentsonline.
com/6608088.html
53 Samochocki M, Höffle A, Fehrenbacher A, et al. Galantamine is an
allosterically potentiating ligand of neuronal nicotinic but not of musca-
rinic acetylcholine receptors. J Pharmacol Exp Ther. 2003 Jun;305(3):
1024–36.
54 Snorrason E, Geirsson A, Stefansson K. Trial of a selective acetyl-
cholinesterase inhibitor, galanthamine hydrobromide, in the treatment of
chronic fatigue syndrome. J Chron Fatigue Syn. 1996;2(2/3):35–54.
55 Blacker CV, Greenwood DT, Wesnes KA, et al. Effect of galanta-

mine hydrobromide in chronic fatigue syndrome: a randomized control-
led trial. JAMA. 2004 Sep 8;292(10):1195–204.
57 Bluhm R, Zsigmond EK, Winnie AP. Potentiation of opioid analge-
sia by H1 and H2 antagonists. Life Sci. 1982 Sep 20–27;31(12–13):
1229–32.
58 Dechene L. Chronic fatigue syndrome: influence of histamine, hor-
mones and electrolytes. Med Hypotheses. 1993 Jan;40(1):55–60.
59 Stambaugh JE Jr, Lane C. Analgesic efficacy and pharmacokinetic
evaluation of meperidine and hydroxyzine, alone and in combination.
Cancer Invest. 1983;1(2):111–7.
61 Gelfand EW, Appajosyula S, Meeves S. Anti–inflammatory activity
of H1–receptor antagonists: review of recent experimental research.
Curr Med Res Opin. 2004 Jan;20(1):73–81.
63 Hirano S, Miyata S, Onodera K, et al. Involvement of dopamine D1
receptors and alpha1–adrenoceptors in the antidepressant–like effect of
chlorpheniramine in the mouse tail suspension test. Eur J Pharmacol.
2007 May 7;562(1–2):72–6.
64 Santiago–Palma J, Fischberg D, Kornick C, et al. Diphenhydramine
as an analgesic adjuvant in refractory cancer pain. J Pain Symptom
Manage. 2001 Aug;22(2):699–703.
66 Boiko AN, Batysheva TT, Matvievskaya OV, et al. Characteristics of
the formation of chronic fatigue syndrome and approaches to its treat-
ment in young patients with focal brain damage. Neurosci Behav
Physiol. 2007 Mar;37(3):221–8.
67 Togha M, Ashrafian H, Tajik P. Open–label trial of cinnarizine in
migraine prophylaxis. Headache. 2006 Mar;46(3):498–502.
68 Zuardi AW. History of cannabis as a medicine: a review. Rev Bras
Psiquiatr. 2006 Jun;28(2):153–7.
69 Herer Jack. The Emperor Wears No Clothes: The Authoritative His-
torical Record of Cannabis and the Conspiracy Against Marijuana.
Quick American Archives 1985.
70 Corey S. Recent developments in the therapeutic potential of canna-

binoids. P R Health Sci J. 2005 Mar;24(1):19–26.
71 Grotenhermen F. Pharmacokinetics and pharmacodynamics of can-
nabinoids. Clin Pharmacokinet. 2003;42(4):327–60.
72 Esposito G, De Filippis D, Maiuri MC, et al. Cannabidiol inhibits
inducible nitric oxide synthase protein expression and nitric oxide pro-
duction in beta–amyloid stimulated PC12 neurons through p38 MAP ki-
nase and NF–kappaB involvement. Neurosci Lett. 2006 May 15;399(1–
2):91–5.
73 Zuardi AW, Crippa JA, Hallak JE, et al. Cannabidiol, a Cannabis sa-
tiva constituent, as an antipsychotic drug. Braz J Med Biol Res. 2006
Apr;39(4):421–9
74 Ashton CH, Moore PB, Gallagher P, et al. Cannabinoids in bipolar
affective disorder: a review and discussion of their therapeutic potential.
J Psychopharmacol. 2005 May;19(3):293–300.
75 Bambico FR, Katz N, Debonnel G, et al. Cannabinoids elicit antidep-
ressant–like behavior and activate serotonergic neurons through the
medial prefrontal cortex. J Neurosci. 2007 Oct 24;27(43):11700–11.
76 Serra G, Fratta W. A possible role for the endocannabinoid system in
the neurobiology of depression. Clin Pract Epidemol Ment Health. 2007
Nov 19;3:25.
77 Sethi BB, Trivedi JK, Kumar P, et al. Antianxiety effect of cannabis:
involvement of central benzodiazepine receptors. Biol Psychiatry. 1986
Jan;21(1):3–10.
78 Eubanks LM, Rogers CJ, Beuscher AE 4th, et al. A molecular link
between the active component of marijuana and Alzheimer's disease
pathology. Mol Pharm. 2006 Nov–Dec;3(6):773–7.
79 Wade DT, Robson P, House H, et al. A preliminary controlled study
to determine whether whole–plant cannabis extracts can improve intrac-
table neurogenic symptoms. Clin Rehabil. 2003 Feb;17(1):21–9.
80 Mortati K, Dworetzky B, Devinsky O. Marijuana: an effective anti-
epileptic treatment in partial epilepsy? A case report and review of the
literature. Rev Neurol Dis. 2007 Spring;4(2):103–6.
81 Russo E. Cannabis for migraine treatment: the once and future presc-
ription? An historical and scientific review. Pain. 1998 May;76(1–2):3–
8.
82 Pradeep A, Thomas S, Roberts EO, et al. Reduction of congenital
nystagmus in a patient after smoking cannabis. Strabismus. 2008 Jan–
Mar;16(1):29–32.
83 Alsasua del Valle A. Implication of cannabinoids in neurological dis-
eases. Cell Mol Neurobiol. 2006 Jul–Aug;26(4–6):579–91.
84 Carley DW, Paviovic S, Janelidze M, et al. Functional role for canna-

binoids in respiratory stability during sleep. Sleep. 2002 Jun 15;25(4):
391–8.
85 Guzmán M. Cannabinoids: potential anticancer agents. Nat Rev Can-
cer. 2003 Oct;3(10):745–55.
86 Russo EB. Clinical endocannabinoid deficiency (CECD): can this
concept explain therapeutic benefits of cannabis in migraine, fibromyal-
gia, irritable bowel syndrome and other treatment–resistant conditions?
Neuro Endocrinol Lett. 2004 Feb–Apr;25(1/2):31–9.
88 Schley M, Legler A, Skopp G, et al. Delta–9–THC based monothe-
rapy in fibromyalgia patients on experimentally induced pain, axon ref-
lex flare, and pain relief. Curr Med Res Opin. 2006 Jul;22(7):1269–76.
89 Grinspoon L. On the pharmaceuticalization of marijuana. Int J Drug
Policy. 2001 Nov;12(5–6):377–83.
90 Whittle BA, Geoffrey G, Robson P. Prospects for New Cannabis–
Based Prescription Medicines. J Cannabis Ther. 2001;1(3/4):183–205.
91 Melamede R. Cannabis and tobacco smoke are not equally carcino-
genic. Harm Reduct J. 2005 Oct 18;2:21.
92 Ko GD, Hum A, Weidenfeld H, et al. Case series of fibromyalgia pa-
tients improved with oral cannabinoid Nabilone. Poster presented at:
52nd Annual Meeting of the Canadian Association of Physical Medicine
and Rehabilitation. Charlottetown, PEI, Canada. Jun 16–19, 2004.
93 Skrabek RQ, Galimova L, Ethans K, et al. Nabilone for the Treat-
ment of Pain in Fibromyalgia. J Pain. 2008 Feb;9(2):164–73.
94 Cox IM, Campbell MJ, Dowson D. Red blood cell magnesium and
chronic fatigue syndrome. Lancet. 1991 Mar 30;337(8744):757–60.
95 Magaldi M, Moltoni L, Biasi G, et al. [Changes in intracellular calci-
um and magnesium ions in the physiopathology of the fybromyalgia
syndrome]. Minerva Med. 2000 Jul–Aug;91(7–8):137–40.
96 Seelig M. Review and Hypothesis: Might Patients with the Chronic
Fatigue Syndrome Have Latent Tetany of Magnesium Deficiency. J
Chron Fatigue Syn. 1998;4(2):77–108.
97 Billyard AJ, Eggett DL, Franz KB. Dietary magnesium deficiency
decreases plasma melatonin in rats. Magnes Res. 2006 Sep;19(3):157–
61.
98 Galland L. Magnesium and immune function: an overview. Magne-
sium. 1988;7(5–6):290–9.
99 Weglicki WB, Phillips TM. Pathobiology of magnesium deficiency:

a cytokine/neurogenic inflammation hypothesis. Am J Physiol. 1992
Sep;263(3 Pt 2):R734–7.
100 Mak IT, Komarov AM, Wagner TL, et al. Enhanced NO production
during Mg deficiency and its role in mediating red blood cell glutathi-
one loss. Am J Physiol. 1996 Jul;271(1 Pt 1):C385–90.
101 Chmielinska JJ, Tejero–Taldo MI, Mak IT, et al. Intestinal and car-
diac inflammatory response shows enhanced endotoxin receptor (CD14)
expression in magnesium deficiency. Mol Cell Biochem. 2005 Oct;278
(1–2):53–7.
103 Teitelbaum Jacob. Teitelbaum Jacob. From Fatigued to Fantastic!:
A Proven Program to Regain Vibrant Health, Based on a New Scientific
Study Showing Effective Treatment for Chronic Fatigue and Fibromyal-
gia. Avery 2001. p. 180.
104 Takahashi H, Imai K, Katanuma A, et al. [A case of chronic fatigue
syndrome who showed a beneficial effect by intravenous administration
of magnesium sulphate]. Arerugi. 1992 Nov;41(11):1605–10.
105 Magnesium by injection – the only way to guarantee getting magne-
sium levels up in the body. http://www.drmyhill.co.uk/article.cfm?id=12
106 Eby GA, Eby KL. Rapid recovery from major depression using
magnesium treatment. Med Hypotheses. 2006;67(2):362–70.
107 Heiden A, Frey R, Presslich O, et al. Treatment of severe mania
with intravenous magnesium sulphate as a supplementary therapy. Psy-
chiatry Res. 1999 Dec 27;89(3):239–46.
108 Mauskop A, Altura BT, Cracco RQ, et al. Intravenous magnesium
sulfate rapidly alleviates headaches of various types. Headache. 1996
Mar;36(3):154–60.
109 Gibson PR, Elms AN, Ruding LA. Perceived treatment efficacy for
conventional and alternative therapies reported by persons with multiple
chemical sensitivity. Environ Health Perspect. 2003 Sep;111(12):1498–
504.
110 Rea WJ, Johnson AR, Smiley RE, et al. Magnesium deficiency in
patients with chemical sensitivity. Clin Ecol. 1986;4(1):17–20.
111 Regland B, Andersson M, Abrahamsson L, et al. Increased concent-
rations of homocysteine in the cerebrospinal fluid in patients with fibro-
myalgia and chronic fatigue syndrome. Scand J Rheumatol. 1997;26(4):
301–7.
112 The Treatment of Chronic Fatigue Syndrome (CFS) – the Perspec-
tive of a Private Specialty Practice in Charlotte, NC (Part Two) by Dr.
Charles Lapp. http://www.immunesupport.com/library/showarticle.

cfm/ID/2927/
114 B12 – rationale for using vitamin B12 by Dr Myhill. http://www.
drmyhill.co.uk/article.cfm?id=341
115 Dr. Paul R. Cheney’s Basic Protocol. http://www.dfwcfids.org/
medical/basc2003.html
116 Pall ML. Cobalamin used in chronic fatigue syndrome therapy is a
nitric oxide scavenger. J Chron Fatigue Syn. 2001;8(2):39–44.
117 Simpson LO. Myalgic encephalomyelitis (ME): a haemorheological
disorder manifested as impaired capillary blood flow. J Orthomol Med.
1997;12:69–76.
118 Sun Y, Lai MS, Lu CJ. Effectiveness of vitamin B12 on diabetic
neuropathy: systematic review of clinical controlled trials. Acta Neurol
Taiwan. 2005 Jun;14(2):48-54.
119 Ellis FR, Nasser S. A pilot study of vitamin B12 in the treatment of
tiredness. Br J Nutr. 1973;30:277–83.
120 Gaby AR. Intravenous nutrient therapy: the "Myers' cocktail".
Altern Med Rev. 2002 Oct;7(5):389–403.
121 Teitelbaum Jacob. Teitelbaum Jacob. From Fatigued to Fantastic!:
A Proven Program to Regain Vibrant Health, Based on a New Scientific
Study Showing Effective Treatment for Chronic Fatigue and Fibromyal-
gia. Avery 2001. p. 180.
122 Klenner FR. Observations On the Dose and Administration of As-
corbic Acid When Employed Beyond the Range Of A Vitamin, Human
Pathology. J Appl Nutr. 1971;23(3/4):61–88.
123 Ali M. Ascorbic acid reverses abnormal erythrocyte morphology in
chronic fatigue syndrome. Am J Clin Pathol. 1990;94:515.
ral Network Disorders. Haworth Medical Press 1996. pp. 131–135.
125 Kodama M, Kodama T. The clinical course of interstitial pneumo-
nia alias chronic fatigue syndrome under the control of megadose vita-
min C infusion system with dehydroepiandrosterone–cortisol annex. Int
J Mol Med. 2005 Jan;15(1):109–16.
126 Yeom CH, Jung GC, Song KJ. Changes of terminal cancer patients'
health–related quality of life after high dose vitamin C administration. J
Korean Med Sci. 2007 Feb;22(1):7–11.
127 Streeten DH, Bell DS. Circulating Blood Volume in Chronic

Fatigue Syndrome. J Chron Fatigue Syn. 1998;4(1):3–11.
128 Snell CR, VanNess JM, Stevens SR, et al. Intravenous saline admi-
nistration improves physical functioning in a patient with Chronic Fati-
gue Syndrome. Med Sci Sports Exerc. 2006;38(5).
129 New Treatment for NMH by Gail Kansky. http://www.ncf-
net.org/forum/volumefall.htm
130 David S Bell, MD | Lyndonville News, Vol. 3 No. 2. http://www.
131 Robert Bennett, M.D., on Treatment of Fibromyalgia in Detail.
http://www.immunesupport.com/library/showarticle.cfm/ID/3594/
132 Diefenbach K, Arold G, Wollny A, et al. Effects on sleep of anti-
cholinergics used for overactive bladder treatment in healthy volunteers
aged > or = 50 years. BJU Int. 2005 Feb;95(3):346–9.
133 Cazzulani P, Pietra C, Abbiati GA, et al. Pharmacological activities
of the main metabolite of flavoxate 3–methylflavone–8–carboxylic acid.
Arzneimittelforschung. 1988 Mar;38(3):379–82.
134 Cazzulani P, Panzarasa R, De Stefani C, et al. Mechanism of flavo-
xate antispasmodic activity comparative in vitro studies. Arch Int Phar-
macodyn Ther. 1985 Apr;274(2):189–200.
135 Karak P, Kumar KA, Mazumdar K, et al. Antibacterial potential of
an antispasmodic drug dicyclomine hydrochloride. Indian J Med Res.
2003 Nov;118:192–6.
136 Nyberg K, Ekblad M, Bergström T, et al. The low molecular weight
heparan sulfate–mimetic, PI–88, inhibits cell–to–cell spread of herpes
simplex virus. Antiviral Res. 2004 Jul;63(1):15–24.
137 Russell AL, McCarty MF. Glucosamine for migraine prophylaxis?
Med Hypotheses. 2000 Sep;55(3):195–8.
138 Veszelka S, Pásztói M, Farkas AE, et al. Pentosan polysulfate pro-
tects brain endothelial cells against bacterial lipopolysaccharide–indu-
ced damages. Neurochem Int. 2007 Jan;50(1):219–28.
139 Ghosh P. The pathobiology of osteoarthritis and the rationale for the
use of pentosan polysulfate for its treatment. Semin Arthritis Rheum.
1999 Feb;28(4):211–67.
142 Dr. Cheney On Symptomatic Treatment. http://www.immune
143 De Simone R, Marano E, Di Stasio E, et al. Acetazolamide efficacy

and tolerability in migraine with aura: a pilot study. Headache. 2005
Apr;45(4):385–6.
144 Ambrosini A, Pierelli F, Schoenen J, et al. Acetazolamide acts on
neuromuscular transmission abnormalities found in some migraineurs.
Cephalalgia. 2003 Mar;23(2):75–8.
145 Hauge A, Nicolaysen G, Thoresen M. Acute effects of acetazol-
amide on cerebral blood flow in man. Acta Physiol Scand. 1983 Feb;
117(2):233–9.
146 Palangio M, Flores JA, Joyal SV. Treatment of fibromyalgia with
sibutramine hydrochloride monohydrate: comment on the article by
Goldenberg, et al. Arthritis Rheum. 2002 Sep;46(9):2545–6.
148 DMKG study group. Misoprostol in the treatment of trigeminal
neuralgia associated with multiple sclerosis. J Neurol. 2003 May;250(5):
542–5.
149 Reder AT, Arnason BG. Trigeminal neuralgia in multiple sclerosis
relieved by a prostaglandin E analogue. Neurology. 1995 Jun;45(6):
1097–100.
150 Kelly JD, Young MR, Johnston SR, et al. Clinical response to an
oral prostaglandin analogue in patients with interstitial cystitis. Eur
Urol. 1998;34(1):53–6.
151 Yilmaz I, Akkuzu B, Cakmak O, et al. Misoprostol in the treatment
of tinnitus: a double–blind study. Otolaryngol Head Neck Surg. 2004
May;130(5):604–10.
152 Khosla PP, Saha N, Koul A, et al. Effects of ranitidine alone and in
combination with chlorpheniramine on histamine–induced wheal and
flare and psychomotor performance. Indian J Physiol Pharmacol. 1993
Apr;37(2):132–4.
153 Goldstein JA. Treatment of chronic Epstein–Barr virus disease with
H2 blockers. J Clin Psychiatry.1986;47:572.
155 Brockmeyer NH, Kreuzfelder E, Mertins L, et al. Immunomodula-
tory properties of cimetidine in ARC patients. Clin Immunol Immuno-
pathol. 1988 Jul;48(1):50–60.
156 Kumar A, Pantarotto RE, Kaufman DB. IgG subclasses and IgM in
rats: immunoregulatory effects of cimetidine on serum levels. Comp
Immunol Microbiol Infect Dis. 1990;13(3):147–53.
157 Nickel JC. Interstitial cystitis: characterization and management of

an enigmatic urologic syndrome. Rev Urol. 2002 Summer;4(3):112–21.
158 Haq A, Donaldson PJ, Parry JR. Oral cimetidine gives effective
symptom relief in painful bladder disease: a prospective, randomized,
double–blind placebo–controlled trial. BJU Int. 2001 Sep;88(4):444–5.
159 Støa–Birketvedt G. Effect of cimetidine suspension on appetite and
weight in overweight subjects. BMJ. 1993 Apr 24;306(6885):1091–3.
160 Støa–Birketvedt G, Paus PN, Ganss R, et al. Cimetidine reduces
weight and improves metabolic control in overweight patients with type
2 diabetes. Int J Obes Relat Metab Disord. 1998 Nov;22(11):1041–5.
161 Pae CU, Kim JJ, Lee KU, et al. Effect of nizatidine on olanzapine–
associated weight gain in schizophrenic patients in Korea: a pilot study.
Hum Psychopharmacol. 2003 Aug;18(6):453–6.
162 Bluhm R, Zsigmond EK, Winnie AP. Potentiation of opioid analge-
sia by H1 and H2 antagonists. Life Sci. 1982 Sep 20–27;31(12–13):
1229–32.
163 Jacobson W, Saich T, Borysiewicz LK. Serum folate and chronic
fatigue syndrome. Neurology. 1993 Dec;43(12):2645–7.
164 Regland B, Andersson M, Abrahamsson L, et al. Increased concen-
trations of homocysteine in the cerebrospinal fluid in patients with fibro-
myalgia and chronic fatigue syndrome. Scand J Rheumatol. 1997;26(4):
301–7.
165 Patrick LR. Restless legs syndrome: pathophysiology and the role
of iron and folate. Altern Med Rev. 2007 Jun;12(2):101–12.
166 Simplified Treatment Approach Based on the Glutathione Depleti-
on– Methylation Cycle Block Pathogenesis Hypothesis for Chronic Fati-
gue Syndrome (CFS) by Rich Van Konynenburg, Ph.D. http://phoenix-
cfs.org/GSHMethylTrtPlanJuly07.htm
167 CFS – The Methylation Cycle | Dr Myhill. http://www.drmyhill.co.
uk/article.cfm?id=407
168 Lundell K, Qazi S, Eddy L, et al. Clinical activity of folinic acid in
patients with chronic fatigue syndrome. Arzneimittelforschung. 2006;56
(6):399–404.
169 Stratz T, Schochat T, Hrycaj P, et al. [Therapy of generalized tendo-
myopathy (fibromyalgia) caused by blocking 5–HT3 receptors]. Z
Rheumatol. 1994 Nov–Dec;53(6):335–8.
170 Färber L, Stratz TH, Brückle W, et al. Short–term treatment of pri-
mary fibromyalgia with the 5–HT3–receptor antagonist tropisetron. Re-
sults of a randomized, double–blind, placebo–controlled multicenter
trial in 418 patients. Int J Clin Pharmacol Res. 2001;21(1):1–13.
171 Stratz T, Varga B, Müller W. [The influence of depression on the

effect of Tropisetron in the therapy of fibromyalgia]. Z Rheumatol. 2003
Feb;62(1):42–5.
172 Hrycaj P, Stratz T, Mennet P, et al. Pathogenetic aspects of respon-
siveness to ondansetron (5–hydroxytryptamine type 3 receptor antago-
nist) in patients with primary fibromyalgia syndrome—a preliminary
study. J Rheumatol. 1996 Aug;23(8):1418–23.
173 Müller W, Stratz T. Results of the intravenous administration of tro-
pisetron in fibromyalgia patients. Scand J Rheumatol Suppl. 2000;113:
59–62.
174 Tolk J, Kohnen R, Müller W. Intravenous treatment of fibromyalgia
with the 5–HT3 receptor antagonist tropisetron in a rheumatological
practice. Scand J Rheumatol Suppl. 2004;(119):72–5.
175 Späth M, Stratz T, Färber L, et al. Treatment of fibromyalgia with
tropisetron—dose and efficacy correlations. Scand J Rheumatol Suppl.
2004;(119):63–6.
176 Ernberg M, Lundeberg T, Kopp S. Effects on muscle pain by intra-
muscular injection of granisetron in patients with fibromyalgia. Pain.
2003 Feb;101(3):275–82.
177 Müller W, Stratz T. The use of the 5–HT3 receptor antagonist tropi-
setron in trigger point therapy: A pilot study. J Musculoskelet Pain
2005;13(2):43–8.
178 Spath M, Welzel D, Farber L. Treatment of chronic fatigue syndro-
me with 5–HT3 receptor antagonists—preliminary results. Scand J
Rheumatol Suppl. 2000;113:72–7.
179 The GK, Prins J, Bleijenberg G, et al. The effect of granisetron, a
5–HT3 receptor antagonist, in the treatment of chronic fatigue syndrome
patients—a pilot study. Neth J Med. 2003 Sep;61(9):285–9.
180 Seidel MF, Weinreich GF, Stratz T, et al. 5–HT3 receptor antago-
nists regulate autonomic cardiac dysfunction in primary fibromyalgia
syndrome. Rheumatol Int. 2007 Sep;27(11):1025–30.
181 Veasey SC, Chachkes J, Fenik P, et al. The effects of ondansetron
on sleep–disordered breathing in the English bulldog. Sleep. 2001 Mar
15;24(2):155–60.
182 Pickering G, Loriot MA, Libert F, et al. Analgesic effect of aceta-
minophen in humans: first evidence of a central serotonergic mecha-
nism. Clin Pharmacol Ther. 2006 Apr;79(4):371–8.
CHAPTER 10.
Experimental therapies
cholestyramine (Questran, Prevalite)
Cholestyramine is a cholesterol drug which works by binding to

bile and preventing its reabsorption. The resulting insoluble compound
is excreted in the feces. Cholestyramine itself is not absorbed in the
body. It is typically sold in powder form in sachets containing 4 grams
of the drug. The powder is dissolved in food or liquid and taken 1–4
times a day. Cholestyramine is sometimes used in the treatment of Clos-
tridium difficile, a dangerous infection of the gastrointestinal tract,
because the drug binds the toxin of the bacteria.1
Ritchie C. Shoemaker, MD, and neurotoxicologist H. Kenneth
Hudnell believe that the symptoms of CFS/ME and some other illnesses
are caused by the build–up of neurotoxins in the body.2 According to
their theory it can be caused by e.g. Lyme disease. Ciguatera toxin has
been associated with CFS/ME as well and cholestyramine can possibly
aid in its removal. Some CFS/ME/FM patients with suspected ciguatera
poisoning have reported dramatic benefits from cholestyramine.3
Shoemaker and Hudnell use cholestyramine to remove neurotoxins
from the body and Hudnell has published a study of this use.4 They have
also published a double–blinded study where the combination of choles-
tyramine and atovaquone was used to treat the co–infection of borrelia
and babesia.5 CFS/ME expert Paul Cheney also considers cholestyra-
mine to be a potentially useful treatment.6
Because of its mode of action cholestyramine can interfere with the
absorption of many other drugs, such as oral contraceptives and anticoa-
gulants, tetracyclines, penicillines and thyroid hormones, as well as
many nutrients. These drugs should be taken at least an hour before cho-
lestyramine or 4–6 hours after it. Cholestyramine does not have side
effects besides stomach upset, but according to Shoemaker and Hudnell
it can at first cause an exacerbation of symptoms.
Cholestyramine is available in the United States, the United King-
dom, Canada, Australia and some other countries. It is not particularly
expensive unless used in high doses. Cholestyramine powder usually
contains either sugar or aspartame, but compounding pharmacies may
be able to provide a version without sweeteners.
Experimental therapies 275
pioglitazone (Actos)
rosiglitazone (Avandia)
Pioglitazone and rosiglitazone are diabetes drugs belonging to the

chemical class of thiazolidinediones. They work by improving insulin
sensitivity, but they also have anti–inflammatory action mediated via
PPARgamma. Ritchie C. Shoemaker and H. Kenneth Hudnell use pio-
glitazone to reduce the side effects of antibiotic or cholestyramine trea-
tment caused by the excessive secretion of inflammatory cytokines.7
Thiazolinediones have also been proposed as a treatment for auto-
immune and inflammatory conditions.8,9 Good results have been achie-
ved e.g. in psoriatic arthritis10, multiple sclerosis11 and autism.12 This
group of drugs also blocks nitric oxide synthesis13, which may be bene-
ficial in CFS/ME and fibromyalgia. Dr. Paul Cheney, however, feels
that pioglitazone is not appropriate for patients with CFS/ME, only for
those with chronic Lyme disease.14
Vision disturbances, edema, weight gain and hypoesthesia (decrea-
sed sensitivity to touch) are the most common side effects of pioglita-
zone. The most common adverse reactions to rosiglitazone are reported
to be anemia, hypercholesterolemia, headache and stomach upset.
Women may be at increased risk for fractures from these drugs. Piogli-
tazone has no known interactions, but rosiglitazone may theoretically
have with some drugs. Thiazolidinediones cannot be used by those suf-
fering from type I diabetes.
Both drugs are available in the United States, the United Kingdom,
Canada, Australia and many other countries. They are both fairly afford-
able with very similar prices.
calcitonin (Miacalcin, Miacalcic, Osteocalcin, Calco,

Calsynar)
Calcitonin is a hormone produced in humans by the thyroid gland,

but is not considered to be a thyroid hormone. It acts opposite to para-
thyroid hormone, reducing calcium levels in the blood. Calcitonin is
used, usually as an intranasal spray, to treat osteoporosis and occasio-
nally for some chronic pain conditions, especially bone pain but also
neuropathy. A small double–blind fibromyalgia study did not find any
improvement in any of the studied parameters with subcutaneously
administered calcitonin.15
Intranasal calcitonin can cause damage to the nasal mucus memb-
rane. In cases of severe damage the treatment has to be discontinued.
Allergic reactions have been reported occasionally. Nausea is a common
side effect and in the fibromyalgia trial almost all patients reported nau-
sea. There can also be stomach upset, diarrhea, facial flushing, dizzi-
ness, headache, tiredness and myalgia. In light of the side effects and the
lack of demonstrated efficacy, calcitonin should probably not be used to
treat fibromyalgia.
Calcitonin is available in the United States, the United Kingdom,
Canada, Australia and many other countries. It is quite expensive.
tadalafil (Cialis)
Tadalafil is a phosphodiesterase type 5 (PDE5) inhibitor which is

used to treat erectile dysfunction. It is very similar to sildenafil (Viagra),
but has a significantly longer half–life. One study tried the drug on 30
male patients with CFS/ME and found that it reduced dyspnea and imp-
roved exercise tolerance.16 93% of participants experienced “changes in
erectile behavior.” It should be noted that tadalafil does not cause an
erection in the absence of sexual stimulation.
The most common side effects are headache, hypotension, stomach
upset, back pain, muscle aches, nasal congestion and flushing. Tadalafil
should not be combined with other hypotensive drugs, especially not
with alpha–adrenergic antagonists or nitrates. Azole antifungals, verapa-
mil, macrolide antibiotics, doxycycline and grapefruit juice can lower
the clearance of the drug.
Tadalafil is available in the United States, the United Kingdom,
Canada, Australia and many other countries. It is expensive.
sizofiran (Sonifilan)
Sizofiran (also known as SPG) is a polysaccharide obtained from

the suehirotake mushroom (Schizophyllum commune), also known as
split gill. It is used in cancer treatment. Apparently sizofiran does not
have antitumor effects as such, but acts as an immunostimulant and thus
makes the body able to fight cancer more effectively.
Sizofiran has been studied in CFS/ME with claims that 80% of the
patients completely or partially recovered from the illness.17 Phase II
studies were supposedly carried out several years ago, but there is no
further information to be found about this. A patent has been filed in the
early 1990s about the use of sizofiran for CFS/ME.18 It is unclear
whether there have been any recent developments in this field.
Sizofiran is only available in Japan. The mushroom it is derived
from should be easy to acquire, but the proper dosage would be difficult
to determine.
ibudilast (Ketas)
Ibudilast is a phosphodiesterase inhibitor, mostly selective for the

PDE4 and PDE3 subtypes. It has anti–inflammatory, antioxidant, anti–
allergic, antiplatelet, bronchodilator and vasodilator effects.19 It is pri-
marily used to treat asthma and stroke and also topically for allergic
conjunctivitis. Ibudilast enhances opioid analgesia and reduces the deve-
lopment of tolerance, but also has direct activity against neuropathic
pain.20
Ibudilast has several neuroprotective properties. It suppresses glial
cell activation and reduces production of nitric oxide and the major
inflammatory cytokines TNF alpha, IL–1 beta and IL–6.21 Ibudilast has
shown moderate efficacy in the treatment of multiple sclerosis.22 Based
on these effects it would likely be beneficial in CFS/ME, as well. Ibudi-
last is usually taken three times a day.
Ibudilast is usually well tolerated. Major side effects have not been
reported. There can be stomach upset in the beginning, but it usually
goes away in a few days. Headache and nausea are also possible. As a
result of the vasodilatory action ibudilast may cause hypotension.
Because of the antiplatelet effect, caution should be taken when
combining the drug with anticoagulants or aspirin.
Ibudilast is currently only available in Japan, China, South Korea
and some other Asian countries. Besides oral formulations it is available
as an ophthalmic solution.
montelukast (Singulair)
Montelukast is an antagonist of the leukotriene D4 receptor. It is

used to treat asthma and allergic rhinitis. Because leukotrienes affect
inflammation outside of the respiratory organs as well, montelukast
could have use in many other conditions as well. It inhibits 5–LOX23, an
important pathway of inflammation, as well as NF–kappa B.24
Small trials have shown efficacy in interstitial cystitis25, endometri-
osis and vulvar vestibulitis (a painful condition of the vagina).27 Mon-
26
telukast has been suggested as a possible therapy for migraine prophyla-

xis.28 It is sometimes used clinically for this purpose, but a double–
blinded study did not find it effective.29 A letter published in the medical
journal Chest reported of two patients taking montelukast whose celiac
disease had apparently gone into remission even though they were
eating a normal diet.30
Montelukast is usually well tolerated. The only common side effect
is headache. Fatigue, weakness, dizziness, fever and stomach upset are
possible but rare. Sometimes the drug may cause mood changes and
even suicidal thoughts. Carbamazepine, phenytoin, and St. John’s wort
may decrease the blood levels of the drug.
Montelukast is available in the United States, the United Kingdom,
Canada, Australia and many other countries. It is available as tablets,
chewable tablets and granules. The chewable tablets contain aspartame.
Montelukast is not particularly expensive.
neurotropin
Neurotropin is a non–protein extract of rabbit skin inoculated with

vaccinia virus. It inhibits the formation of bradykinin, a major inflam-
matory peptide. It is commonly used in Japan for chronic pain. It is
being investigated as a treatment for e.g. neuropathic pain, RSD/CRPS,
asthma, chronic urticaria and Alzheimer’s disease. There are case
reports of the use of neurotropin to treat CFS/ME31 and fibromyalgia.32
Neurotropin is currently in clinical trials in the U.S. for fibromyalgia.33
Neurotropin is currently only available in Japan and China outside
of clinical trials.
erdosteine (Vectrine, Flusten, Dostein, Erdomed,

Erdotin)
Erdosteine is a mucolytic which is indicated for chronic bronchitis

and COPD. It has antioxidant activity and it reduces tissue levels of nit-
ric oxide.34 Thus it could be useful in the treatment of CFS/ME and fib-
romyalgia. It also reduces bacterial adhesiveness to the mucus memb-
ranes, which might be useful in the treatment of persistent respiratory
infections.35
Erdosteine is usually very well tolerated. It rarely causes other side
effects besides mild stomach upset. It has no known drug interactions.
Erdosteine is available in some European and South American
countries, such as France, Greece and Italy, but not in the United States,
the United Kingdom, Canada or Australia. It is not particularly expen-
sive.
theophylline (Euphyllin, Nuelin, Theo–Dur, Theolair,

Xanthium)
Theophylline is a xanthine derivative somewhat similar to pentoxi-

fylline. It is found in tea in small, non–therapeutic quantities. It relaxes
bronchial smooth muscle and has mostly been used in asthma and
COPD. It also raises blood pressure and may be helpful in neurally

mediated hypotension in CFS/ME.36 Additionally theophylline has some
anti–inflammatory effects, such as inhibiting NF–kappa B.37
Most common side effects are tremor, tachycardia, headache, nau-
sea, lack of appetite and stomach upset. Many drugs such as cimetidine,
ranitidine, fluoroquinolone and macrolide antibiotics, propranolol, oral
contraceptives, nifedipine, mexiletine, verapamil and influenza vaccina-
tion can elevate the blood levels of theophylline. Carbamazepine,
phenytoin and St. John’s wort can decrease the blood levels of the drug.
Theophylline can lower the blood levels of lithium and should not be
combined with ketamine.
Theophylline is available everywhere. It is sold as tablets, extended
release tablets and several liquid formulations. In the United States and
some other countries it is also available as a combination product to-
gether with guaifenesin, but the amount of guaifenesin is very small.
Theophylline is very inexpensive.
naphazoline (Albalon, Allersol, Naphcon Forte)
Naphazoline is an alpha–adrenergic sympathomimetic drug used in

eye drops and nasal sprays. It induces local vasoconstriction, which re-
duces secretion and irritation of the mucus membrane. Jay Goldstein
uses the eye drops as a treatment for CFS/ME and fibromyalgia. He
theorizes that it can directly modulate brain function through the trige-
minal nerve.38 The effects—if any—should be noticeable immediately.
Sometimes all symptoms improve or even disappear. Goldstein believes
those with severe anxiety are most likely to respond.
The eye drops may cause local reactions such as irritation, dryness,
stinging, mydriasis (pupil dilation) and blurred vision. Occasionally
systemic side effects such as nausea, tachycardia, dizziness, headache
and nervousness occur, but this is rare. Some people experience
overstimulation, which can be avoided by diluting the drops with clean
water. Naphazoline should be used with caution together with tricyclic
antidepressants and MAO inhibitors.
Naphazoline is available in the United States, the United Kingdom,
Canada, Australia and many other countries. In places where it is not
available another similar sympathomimetic (such as tetryzoline) can
likely be substituted. Over the counter formulations of naphazoline are
widely available, but they are usually very dilute (0.1%) compared to
the prescription formulations and according to Goldstein they only help
a minority of the patients. Naphazoline is inexpensive.
raloxifene (Evista, Optruma)
Raloxifene is a selective estrogen receptor modulator (SERM). It is

used in the treatment and prevention of osteoporosis in postmenopausal
women, but it also reduces the incidence of breast cancer. Selective est-
rogen receptor modulation means that the drug acts like estrogen in
some tissue and has the opposite action in other parts of the body.
Besides the prevention of osteoporosis and breast cancer raloxifene
has some powerful anti–inflammatory properties. It decreases the secre-
tion of the major inflammatory cytokines TNF alpha and IL–6.39 It may
also lower blood levels of substance P.40
Hot flashes and leg cramps are the most common side effects.
Others include flushing, malaise, headaches, edema, weight gain, dep-
ression, stomach upset and nausea. Raloxifene is contraindicated in pre-
menopausal women and in persons with past history of thrombosis
(blood clots). Because of the risk of thrombosis it should not be used in
immobile patients. Cholestyramine should not be used with raloxifene.
Raloxifene is available in the United States, the United Kingdom,
scopolamine/hyoscine (Transderm Scop, Scopoderm,

Scopace, Buscopan, Transderm–V)
Scopolamine (hyoscine) is an alkaloid derived from the belladonna

plant with anticholinergic properties. It is a popular antiemetic usually
used in the form of a small transdermal patch attached behind the ear.
Depot patches release the active ingredient for as long as 72 hours. They
can withstand showering and bathing. It should be noted that products
containing scopolamine derivatives such as scopolamine butylbromide
do not readily cross the blood–brain barrier and are not effective for
nausea.
Scopolamine is primarily used to treat motion sickness and seasick-
ness, but can also provide relief from vertigo and other vestibular symp-
toms. Occasionally it is used for IBS. Some patients with severe
CFS/ME have also reported improvement in sensory oversensitivity
when using the patch. A double–blind study trying intravenously admi-
nistered scopolamine for major depression demonstrated a significant
and rapid reduction in the depression and anxiety scores.41 All patients
improved and 10 out of 18 experienced remission.
Scopolamine can cause anticholinergic side effects and potentiate
the anticholinergic side effects of other drugs. Sedation and paradoxi-
cally nausea and vomiting are possible. Sometimes there may be confu-
sion and hallucinations. The patch can cause skin irritation.
Scopolamine is widely available. The patches are somewhat costly,
but it should be kept in mind that most patches are effective for 72
hours, making the price per day more affordable. Only one dosage is
available and the patch should not be cut.
aprepitant (Emend)
Aprepitant is an antagonist of the inflammatory neuropeptide subs-

tance P which acts through the neurokinin1 receptor. It is used to prevent
postoperative nausea and severe nausea associated with cancer chemo-
therapy. Substance P, however, has a variety of different effects in the
body. It has long been known to be elevated in fibromyalgia.42
Aprepitant has been noted to have antidepressive and anxiolytic ac-
43
tion. Later studies have not always confirmed this effect, but similarly
acting drugs are being developed as antidepressants. Aprepitant has also
been successfully tried as a treatment for overactive bladder44 and may
also ameliorate irritable bowel.45 It has demonstrated beneficial immu-
nomodulatory effects in HIV infection.46
Stomach problems, dizziness and skin eruptions are the most com-
mon side effects. Aprepitant may decrease the efficacy of oral contra-
ceptives and anticoagulants. It can also interact with e.g. benzodiazepi-
nes, astemizole, ketoconazole, paroxetine and phenytoin.
Aprepitant is available in a large number of countries including the
United States, the United Kingdom, Canada and Australia, but is extre-
mely expensive. Usually insurance covers it only if the patient is treated
with highly emetogenic chemotherapy.
valsartan (Diovan, Tareg)

losartan (Cozaar, Cormac, Lortaan, Lorista)
telmisartan (Micardis, Pritor, Kinzalmono)
olmesartan (Benicar, Olmetec)
Angiotensin II receptor antagonists (ARBs) are popular antihyper-

tensive drugs. They are anti–inflammatory and as a result are sometimes
used as adjuncts in the treatment of inflammatory conditions. They have
been used to treat e.g. autoimmune heart failure.47 They also protect the
lining of the stomach.48 The anti–inflammatory activity may be further
increased by the concurrent use of statins.
Large doses of olmesartan are a part of the so–called Marshall pro-
tocol, which also includes minocycline and avoidance of vitamin D. The
use of olmesartan is based on its immunomodulatory action.49 The

Marshall protocol was originally designed to treat the autoimmune dis-
ease sarcoidosis, but some people have claimed benefits in CFS/ME as
well. It is even touted as a cure, even though this claim has not been
proven.
Losartan has demonstrated significant benefit in the treatment of
Alzheimer’s disease and may also have antidepressant and anxiolytic
effects.50 David Moskowitz recommends small doses of ARBs at bed-
time as a treatment for CFS/ME and fibromyalgia.51 He explains that ta-
king them like this avoids excessive lowering of blood pressure and that
none of his patients have had to discontinue treatment. Some patients
with CFS/ME have actually reported that the ARB drugs stabilize their
blood pressure and heart rate.
Unlike most other ARBs telmisartan can cross the blood–brain bar-
rier, which may be useful when treating cognitive problems.52 Telmisar-
tan also has a significantly longer half–life than the other ARBs and
usually once a day dosing is sufficient. There is some evidence of the
use of telmisartan in migraine prophylaxis with negligible side effects.53
In addition to the lowered blood pressure, stomach upset, skin erup-
tions and different kinds of pains and aches are common side effects.
ARBs have some interactions with other drugs, mainly because of elect-
rolyte imbalances and possible worsening of orthostatic hypotension.
Estrogens and fluconazole can affect the metabolism of losartan.
Valsartan, losartan and telmisartan are available in the United
States, the United Kingdom, Canada, Australia and many other count-
ries. Olmesartan has a more limited availability. It is sold in the United
States, the United Kingdom, Australia and some other countries, but not
in Canada. They are all in the moderate price range, but in practice
telmisartan is the cheapest, because only one daily dose is needed.
guaifenesin (Humibid, Mucinex)
Guaifenesin is an expectorant, meaning that thins overly thick

mucus in the airways. It is used in the treatment of e.g. asthma, allergies
and coughing, sometimes also for infertility. It can be helpful for chro-
nic sinusitis. Guaifenesin acts as a muscle relaxant and inhibits platelet
aggregation, which may be beneficial in CFS/ME.
Guaifenesin has become a popular treatment for fibromyalgia and
to some extent also CFS/ME in doctor Paul St. Amand’s guaifenesin
protocol, which is based on the theory that FM is caused by accumula-
tion of phosphates in the body and that guaifenesin can remove them.54
The protocol involves progressively increasing doses of guaifenesin and
total avoidance of salicylates (contained in many vegetables, herbs and

cosmetics), which supposedly interfere with the efficacy.
The guaifenesin protocol is claimed to be able to cure fibromyalgia.
There is no evidence that it actually works, let alone cures FM, nor that
there are phosphate deposits involved in fibromyalgia. Many people
have reported improvement on this protocol, but the possibility that this
is caused by the drug’s other effects should not be ignored. The efficacy
of some medical treatments may have nothing to do with the theory be-
hind them.
A year–long double–blinded study done on the guaifenesin
protocol found no benefit whatsoever.55 Paul St. Amand claimed this
was due to salicylate consumption, even though there was no evidence
of this.56 There is no clear scientific rationale about the complete
salicylate avoidance (which goes as far as avoiding hair sprays that
contain salicylates) other than using it as a scapegoat—failure to get
better on the protocol is attributed to accidental consumption of
salicylates.57
Jay Goldstein has found IV guaifenesin an effective treatment for
CFS/ME and fibromyalgia. He completely disregards Paul St. Amand’s
theories and believes the efficacy to stem from NMDA antagonism. In
one animal study guaifenesin was found to increase the analgesic effi-
cacy of acetaminophen (paracetamol), but to be ineffective on its own.58
Guaifenesin is low in side effects and has no known drug interacti-
ons. Large doses may cause nausea and even kidney stones.59 According
to the proponents of this protocol it can exacerbate FM and CFS/ME
even severely before improvement begins. Guaifenesin also lowers
blood levels of uric acid, which is helpful in gout, but CFS/ME experts
such as Paul Cheney report that CFS/ME patients have abnormally low
blood levels of uric acid and should aim to raise them.60
Guaifenesin is widely available. It is commonly sold over the coun-
ter in cough syrups and in some countries this is the only available form.
Many syrups may not be suitable for use in the guaifenesin protocol,
because of the large doses required. The same goes for tablets that con-
tain other ingredients, such as antihistamines, decongestants or dextro-
methorphan. Guaifenesin tablets may be over–the–counter or prescrip-
tion–only, sometimes depending on the dose. The tablets are inexpen-
sive; the syrups may become costly in large doses.
probenecid (Benemid, Benuryl, Probecid, Benemid,

Pro–Cid)
Probenecid is a uricosuric drug, that is it increases the excretion of

uric acid and can be used to treat gout. Because it decreases the renal
excretion of some drugs, it is sometimes used to increase tissue concen-
trations of antibiotics in serious infections. It has the same effect on
some antiherpesvirals as well. Dr. Cecile Jadin uses probenecid to treat
the severe Jarisch–Herxheimer reaction that sometimes occurs when
treating CFS/ME with antibiotics.61
Probenecid was previously used by Dr. Paul St. Amand in fibromy-
algia for the same purpose that he now uses guaifenesin for.62 It may
have use in the treatment for chronic pain, as it increases the brain levels
of kynurenic acid, an endogenous antagonist of excitatory amino acids.63
Kynurenic acid is a NMDA antagonist with neuroprotective, analgesic
and anticonvulsant effects.64
Probenecid may cause nausea, drowsiness, loss of appetite, head-
ache, gum soreness and frequent urination, but usually these side effects
are transient. Aspirin and other salicylates can impair the efficacy of
probenecid. Probenecid should not be used by people with sulfa allergy
or those with schizophrenia.
Probenecid is available in the United States, the United Kingdom,
Canada, Australia and some other countries. It is fairly inexpensive.
flavocoxid (Limbrel)
Flavocoxid is a proprietary formulation of plant–derived flavonoids

(technically considered a “medical food” instead of a drug, but it is for-
mulated into capsules). It is indicated for the treatment of osteoarthritis
and works by inhibiting both COX–1 and COX–2 (similar to NSAIDs),
but also the enzyme 5–LOX, being anti–inflammatory and antioxidant.
Flavocoxid is likely to work well for other painful conditions and some
fibromyalgia patients have reported benefit. It is usually taken twice a
day.
Flavocoxid is better tolerated than NSAIDs. Technically there is a
small risk for ulcers, but no such incidents or other serious adverse
effects have been reported so far. Nausea, diarrhea, heartburn, skin rash
and joint pain are the most common side effects. Flavocoxid may raise
blood sugar levels. Allergic reactions are possible, but unlikely. Flavo-
coxid should not be combined with NSAIDs, but it can be taken with
acetaminophen (paracetamol). No other drug interactions are known or
suspected.
Flavocoxid is only available in the United States and it requires a
prescription. It is quite expensive. Most but not all insurance companies
cover this treatment (some do not cover medical foods).
pegademase (Adagen)
Pegademase is used as an enzyme replacement therapy in one form

of severe combined immunodeficiency (SCID), a severe inherited
immunodeficiency caused by a deficiency of adenosine deaminase
(ADA). As CFS/ME can cause a similar immunodeficiency, idiopathic
CD4 lymphocytopenia or ICL (“HIV negative AIDS”), which may also
be caused by an ADA deficiency, pegademase has also been suggested
as a possible treatment for those patients with CFS/ME who develop
ICL.65,66
Pegademase is given by intramuscular injection, usually once a
week. It can take from a few weeks to six months before the full effects
of the treatment are apparent. Monitoring of adenosine deaminase acti-
vity in the plasma (and possible dose adjustments based on the results)
during treatment are recommended. Other immune parameters should
also be followed to assess the efficacy of the treatment. Pain at the injec-
tion site and headache are possible side effects. Allergic reactions are
rare.
Pegademase is available in the United States, the United Kingdom,
captopril (Capoten, Captopril, Tensiomin, Captohexal,

Lopirin)
enalapril (Vasotec, Renitec, Enap, Ednyt, Enalapril)
Captopril and enalapril are ACE (angiotensin converting enzyme)

inhibitors. They are used to treat e.g. hypertension, congestive heart fai-
lure and diabetic nephropathy. ACE levels have been found to elevated
in the majority of patients of CFS/ME.67 Interestingly gene polymor-
phisms which increase ACE levels have been associated with GWS.68
Dr. David Moskowitz believes that ACE inhibitors can be very useful in
both CFS/ME and fibromyalgia.69
Besides inducing vasodilation ACE inhibitors inhibit some other
enzymes, such as dipeptidyl carboxypeptidase, which breaks down
opioid peptides like beta endorphin. They appear to reduce the secretion
of Th2 cytokines, TGF–beta, NF–kappa B and NO, all of which are
thought to be elevated in CFS/ME and fibromyalgia.70,71
ACE inhibitors can also help orthostatic hypotension.72 They im-

prove cerebral blood flow which may be beneficial in the treatment of
cognitive problems.73 Captopril significantly reduces platelet aggregati-
on (similar to the “blood thinning” effect of aspirin), but enalapril does
not.74
In animal studies captopril has demonstrated analgesic properties.75
It has shown efficacy against migraine and other headaches.76,77 Capto-
pril is sometimes been used to treat chronic pain in CFS/ME in conjunc-
tion with other drugs.78 Jay Goldstein notes captopril and possibly enala-
pril to have antidepressive action.79
Enalapril is taken once a day, captopril 2–3 times a day. Even
healthy people are often recommended to start with just half of the smal-
lest tablet size, so this is especially important in CFS/ME to avoid hypo-
tension. Other side effects include cough, hypoglycemia, skin eruptions
and dizziness. With captopril there should be regular bloodwork to
monitor for neutropenia and agranulocytosis. Both drugs can have inter-
actions with a wide range of medications, but different ones for each.
Both medications are available everywhere. Enalapril is usually
cheaper, but both are very inexpensive.
atorvastatin (Lipitor, Sortis, Torvast, Torvacard,

Zarator)
simvastatin (Zocor, Vasilip, Kavelor, Belmalip, Simvor)
lovastatin (Mevacor, Lovacol, Medostatin, Mevlor,
Nergadan)
fluvastatin (Lescol, Canef, Locol, Vastin, Digaril)
The cholesterol levels in patients with both CFS/ME and fibromy-

algia have been found to be elevated.80,81 This may in some cases war-
rant the use of lipid–lowering drugs, but the statins can also be used for
their anti–inflammatory properties.82 For this reason the statins have
been tried in e.g. multiple sclerosis.83,84 Statins also act as antioxidants
and reduce blood clotting85, the latter of which may be useful for at least
to a subset of CFS/ME patients.
On the downside statins also lower the production of coenzyme
Q10 in the body. Q10 is one of the most highly praised supplements for
CFS/ME, so at least patients with CFS/ME should certainly consider
supplementing with at least 100 mg of Q10. Stomach upset is the most
common side effect of the statins. Allergic reactions, weakness, head-
ache and neurological symptoms can occasionally happen.
The statins may cause muscle pain and weakness, in rare cases
even rhabdomyolysis (acute breakdown of the muscle, which is dan-
gerous). The risk goes up if azoles or macrolides are used concomi-

tantly. Atorvastatin may elevate the hormone levels in blood in women
using oral contraceptives.
Simvastatin is by far the cheapest of the statins and atorvastatin is
currently the most expensive one, though all of them are affordable.
Most of the statins are widely available. Fluvastatin is available in the
United States, the United Kingdom, Canada, Australia and some other
countries.
In the United Kingdom small doses of simvastatin no longer requi-
re prescription for individuals deemed to be at a moderate risk for heart
disease, only an interview with a pharmacist. So far other countries have
not shown interest in adopting a similar practice.
omeprazole (Prilosec, Losec, Ortanol, Ulcuprazol,

Omeprazol)
esomeprazole (Nexium)
lansoprazole (Prevacid, Zoton, Ogastro, Monolitum,
Lanzo)
rabeprazole (Aciphex, Pariet)
The proton pump inhibitors (PPIs) reduce the secretion of stomach

acid. Inadequate stomach acid secretion has been suggested to be com-
mon in CFS/ME and fibromyalgia, but some patients suffer from GERD
(acid reflux) and others may need reduced acidity to be able to take
NSAIDs. In general those on long–term NSAIDs should consider PPIs
for stomach protection. An ulcer can develop without any prior gastric
symptoms. Rabeprazole is the only PPI which also increases gastric
mucus production.86
Another choice for this purpose would be an H2 receptor antagonist
which may have other beneficial effects in CFS/ME, though they are
less effective for reducing stomach acidity. Professor Olli Polo has
noted that proton pump inhibitors relieve fatigue and chronic fever in
some patients, though he is not aware of the mechanism of this action.87
The PPIs are usually well tolerated, headache being the most com-
mon side effect. They impair the absorption of some drugs, such as the
azole antifungals, as well as some nutrients, especially calcium and vita-
min B12. Long–term use of the PPIs in older people increases the inci-
dence of hip fractures. (Es)omeprazole and lansoprazole may interact
with e.g. phenytoin, pioglitazone, rosiglitazone, carbamazepine, diaze-
pam, propranolol, St. John’s wort and some SSRIs.
Omeprazole is widely available as both normal capsules and ex-
tended release capsules, but the latter may not have any real advantage
over the normal capsules. It is available without prescription in the

United States and the United Kingdom. Esomeprazole, lansoprazole and
rabeprazole are available in the United States, the United Kingdom,
acamprosate (Campral)
Acamprosate is a calcium salt of the amino acid taurine, which is

sometimes used as a nutritional supplement. Acamprosate is indicated
for the treatment of alcohol dependence. It is thought to be a GABA
agonist and has some NMDA/glutamate antagonistic effects as well. As
a result it may have analgesic, anxiolytic and sleep–improving effects.
Acamprosate is normally well–tolerated and side effects are
uncommon. Large doses may cause diarrhea. It has been suspected that
acamprosate may increase the risk of kidney problems. Thus it should
probably not be used if NSAIDs are used in the long term, which alrea-
dy increases the risk of renal damage.
Acamprosate is available in the United States, the United Kingdom,
Canada, Australia and some other countries. In some countries its use
requires a special permit.
isoxsuprine (Duvadilan)
buphenine (Arlidin)
Isoxsuprine and buphenine (nylidrin) are beta agonists (the oppo-

site of beta blocker) which act as a vasodilators. They are used to treat
peripheral vascular problems such as Raynaud’s phenomenon and
intermittent claudication, isoxsuprine also to delay premature birth.
They also have several other modes of action. Jay Goldstein sometimes
prescribes them to his CFS/ME and fibromyalgia patients, because of
their ability to block the NR1 and NR2B subunits of the NMDA
receptor, which has analgesic effects.88
Both drugs need to be taken 3–4 times a day. Possible side effects
of isoxsuprine include tachycardia, chest pain, orthostatic hypotension,
dizziness, nausea, weakness and stomach upset. Sometimes it causes a
skin rash and should then be discontinued. Nylidrin can cause nervous-
ness, trembling and less commonly the same side effects as isoxsuprine.
Concomitant use of either drug with other vasodilators is not
recommended.
Isoxsuprine has been discontinued in the United States. It is not
available in the United Kingdom, Canada or Australia either, but is sold
in some countries in Europe, Asia and South America. Nylidrin is avail-
able in Canada, India, Mexico, Switzerland and Austria.
streptokinase (Streptase, Kabikinase)

urokinase (Abbokinase, Ukidan)
alteplase (Activase, Actilyse)
Streptokinase and urokinase are fibrinolytic enzymes. Alteplase is a

tissue plasminogen activator which converts plasminogen to the fibrino-
lytic enzyme plasmin in the body. All of these drugs dissolve blood
clots and inhibit excessive coagulation. They are thus somewhat similar
to heparin. They are normally used to treat acute myocardial infarction
(heart attack).
Fibrinolytic enzymes can also increase the efficacy of antibiotics in
some chronic, treatment–resistant infections. A group of Latvian specia-
lists uses them to treat chlamydial infections in CFS/ME and fibromy-
algia, sometimes in conjunction with heparin.89 They report that some
patients have been completely cured in a matter of a few weeks.
As with heparin, fibrinolytic enzymes are contraindicated in
situations with a risk of hemorrhage, such as peptic ulcers. Hemorrhages
are possible nonetheless. The most common side effects of streptokinase
are fever and chills, flu–like symptoms and back pain. All of the enzy-
mes can in rare instances cause severe allergic reactions. The body may
also form antibodies to the enzymes, making the treatment partially or
completely ineffective.
Streptokinase and alteplase are available in the United States, the
United Kingdom, Canada, Australia and some other countries. Uroki-
nase is available in the United States and some other countries, but has
been discontinued in the United Kingdom, Canada and Australia.
epoetin (Procrit, Eprex, Recormon, NeoRecormon,

Epogen)
Erythropoietin is a hormone that stimulates red blood cell produc-

tion in the bone marrow. Synthetic epoetin is most often used in cancer
patients, who suffer from anemia as a result of chemotherapy. Epoetin
has been tried as a treatment for CFS/ME, even though erythropoietin
levels of the patients appear to be normal.90 It is sometimes used for
orthostatic hypotension.
One study has been done about the use of epoetin in CFS/ME with
57 participants.91 Epoetin was helpful for orthostatic intolerance, but not
other symptoms. Another study found low doses of epoetin useful in
treating those CFS/ME patients with elevated complement component
4A.92 Richard Podell prescribes epoetin for his CFS/ME patients.93 Dr.
Charles Lapp suggests it as a treatment for the pain experienced by
children with CFS/ME.94
Epoetin is given intravenously or subcutaneously, one or more
times a week. Excessive hypertension is a common side effect and may
lead to cardiac problems. Sudden, massive headache can be a sign of a
hypertensive crisis, but milder headaches are common. Fever and flu–
like symptoms are also possible. The treatment can cause iron defici-
ency anemia, so iron supplementation may be in order.
Epoetin is available in the United States, the United Kingdom,
Canada, Australia and many other countries.
corticosteroid pulse
Corticosteroid pulse therapy is mostly used in acute exacerbations

of multiple sclerosis, SLE and some other autoimmune diseases. The
pulse involves a very high dose of glucocorticoids (e.g. 200 mg of dexa-
methasone or 1,000 mg of methylprednisolone i. v.) for one or more
days in hospital. In the treatment of CFS/ME this has only seldom been
tried, so it is unclear whether it would be a viable treatment for CFS/ME
(or fibromyalgia) “flares.”
There are fewer risks to this treatment than could be expected,
especially compared to long–term administration of glucocorticoids.
The most important problem may be that glucocorticoids are activating
and such a massive dose can cause severe insomnia.
References
1 Palace GP, Lazari P, Norton K. Analysis of the physicochemical inter-

actions between Clostridium difficile toxins and cholestyramine using
liquid chromatography with post–column derivatization. Biochim Bio-
phys Acta. 2001 Mar 9;1546(1):171–84.
2 New Theory Links Neurotoxins with Chronic Fatigue Syndrome,
Lyme, MCS and Other Mystery Illnesses. http://www.immunesupport.
3 Cholestyramine for CFIDS/FM. http://cigua.com/index2.php?option=
content&do_pdf=1&id=30
4 Hudnell HK. Chronic biotoxin–associated illness: multiple–system
symptoms, a vision deficit, and effective treatment. Neurotoxicol
Teratol. 2005 Sep–Oct;27(5):733–43.
5 Shoemaker RC, Hudnell HK, House DE, et al. Atovaquone plus
cholestyramine in patients coinfected with Babesia microti and Borrelia
burgdorferi refractory to other treatment. Adv Ther. 2006 Jan–
Feb;23(1):1–11.
6 Response to “Chronic Neurotoxin” Test and Treatment. http://www.
dfwcfids.org/medical/cheney.html
7 Neurotoxins: Diagnosis and Treatment Information for Chronic Fati-
gue Syndrome, Fibromyalgia and other. http://www.immunesupport.
8 Pershadsingh HA. Peroxisome proliferator–activated receptor–
gamma: therapeutic target for diseases beyond diabetes: quo vadis?
Expert Opin Investig Drugs. 2004 Mar;13(3):215–28.
10 Bongartz T, Coras B, Vogt T, et al. Treatment of active psoriatic
arthritis with the PPARgamma ligand pioglitazone: an open–label pilot
study. Rheumatology (Oxford). 2005 Jan;44(1):126–9.
11 Pershadsingh HA, Heneka MT, Saini R, et al. Effect of pioglitazone
treatment in a patient with secondary multiple sclerosis. J Neuroinflam-
mation. 2004 Apr 20;1(1):3.
12 Boris M, Kaiser CC, Goldblatt A, et al. Effect of pioglitazone treat-
ment on behavioral symptoms in autistic children. J Neuroinflammation.
2007 Jan 5;4:3.
13 Storer PD, Xu J, Chavis J, et al. Peroxisome proliferator–activated
receptor–gamma agonists inhibit the activation of microglia and astrocy-
tes: implications for multiple sclerosis. J Neuroimmunol. 2005 Apr;161
(1–2):113–22.
14 Response to “Chronic Neurotoxin” Test and Treatment. http://www.

dfwcfids.org/medical/cheney.html
15 Bessette L, Carette S, Fossel AH, et al. A placebo controlled cross-
over trial of subcutaneous salmon calcitonin in the treatment of patients
with fibromyalgia. Scand J Rheumatol. 1998;27(2):112–6.
16 Shoemaker RC, Maizel MS. Treatment of CFS Patients With Low
Levels of Vasoactive Intestinal Polypeptide (VIP) and Shortness of
Breath with Tadalafil Improves Exercise Tolerance and Pulmonary Ar-
tery Responses to Exercise. Poster presented at: International Associa-
tion for Chronic Fatigue Syndrome (IACFS) 8th International Conferen-
ce on Chronic Fatigue Syndrome, Fibromyalgia and Related Illnesses.
Fort Lauderdale, FL, U.S. Jan 12–Jan 14, 2007.
17 Yun O, Okubo Y, Teshigawara K, et al. Treatment with Perna canali-
culus and D–glucan of CFS patients: restoration of NK activity and
improvement of clinical symptoms.. Presented at: First world congress
on chronic fatigue syndrome and related disorders. Brussels, Belgium.
Nov 9–11, 1995.
18 Agent for treatment of chronic fatigue syndrome. European Patent
EP0561408. http://www.freepatentsonline.com/EP0561408.html
19 Kishi Y, Ohta S, Kasuya N, et al. Ibudilast: a non–selective PDE
inhibitor with multiple actions on blood cells and the vascular wall.
Cardiovasc Drug Rev. 2001 Fall;19(3):215–25.
20 Ledeboer A, Hutchinson MR, Watkins LR, et al. Ibudilast (AV–411).
A new class therapeutic candidate for neuropathic pain and opioid with-
drawal syndromes. Expert Opin Investig Drugs. 2007 Jul;16(7):935–50.
21 Suzumura A, Ito A, Yoshikawa M, et al. Ibudilast suppresses TNF-
alpha production by glial cells functioning mainly as type III phosphodi-
esterase inhibitor in the CNS. Brain Res. 1999 Aug 7;837(1–2):203–12.
22 Feng J, Misu T, Fujihara K, et al. Ibudilast, a nonselective phospho-
diesterase inhibitor, regulates Th1/Th2 balance and NKT cell subset in
multiple sclerosis. Mult Scler. 2004 Oct;10(5):494–8.
23 Ramires R, Caiaffa MF, Tursi A, et al. Novel inhibitory effect on 5–
lipoxygenase activity by the anti–asthma drug montelukast. Biochem
Biophys Res Commun. 2004 Nov 12;324(2):815–21.
24 Maeba S, Ichiyama T, Ueno Y, et al. Effect of montelukast on nuc-
lear factor kappaB activation and proinflammatory molecules. Ann
Allergy Asthma Immunol. 2005 Jun;94(6):670–4.
25 Bouchelouche K, Nordling J, Hald T, et al. The cysteinyl leukotriene
D4 receptor antagonist montelukast for the treatment of interstitial cysti-
tis. J Urol. 2001 Nov;166(5):1734–7.
26 Konno R, Fujiwara H, Suzuki M. Effectiveness of leukotriene recep-

tor antagonists for dysmenorrhea of endometriosis. Fam Med. 2004 Jan;
36(1):8–9.
27 Kamdar N, Fisher L, MacNeill C. Improvement in vulvar vestibulitis
with montelukast. J Reprod Med. 2007 Oct;52(10):912–6.
28 Sheftell F, Rapoport A, Weeks R, et al. Montelukast in the prophyla-
xis of migraine: a potential role for leukotriene modifiers. Headache.
2000 Feb;40(2):158–63.
29 Brandes JL, Visser WH, Farmer MV. Montelukast for migraine
prophylaxis: a randomized, double–blind, placebo–controlled study.
Headache. 2004 Jun;44(6):581–6.
30 Fee WH. Irritable bowel syndrome helped by montelukast. Chest.
2002 Oct;122(4):1497.
31 Toda K, Kimura H. Efficacy of neurotropin in chronic fatigue synd-
rome: a case report. Hiroshima J Med Sci. 2006 Mar;55(1):35–7.
32 Toda K, Tobimatsu Y. Efficacy of Neurotropin in Fibromyalgia: A
Case Report. http://www.blackwell–synergy.com/doi/abs/10.1111/j.
1526-4637.2007.00279.x
33 Neurotropin to Treat Fibromyalgia. http://clinicaltrials.gov/ct/show/
NCT00366535
34 Moretti M, Marchioni CF. An overview of erdosteine antioxidant ac-
tivity in experimental research. Pharmacol Res. 2007 Apr;55(4):249–5.
35 Braga PC, Dal Sasso M, Sala MT, et al. Effects of erdosteine and its
metabolites on bacterial adhesiveness. Arzneimittelforschung. 1999
Apr;49(4):344–50.
36 Dr. Hugh Calkins Lecture of June 6, 1998. http://www.wicfs-me.org/
dr.htm
37 Umeda M, Ichiyama T, Hasegawa S, et al. Theophylline inhibits NF–
kappaB activation in human peripheral blood mononuclear cells. Int
Arch Allergy Immunol. 2002 Jun;128(2):130–5.
39 Gianni W, Ricci A, Gazzaniga P, et al. Raloxifene modulates
interleukin–6 and tumor necrosis factor–alpha synthesis in vivo: results
from a pilot clinical study. J Clin Endocrinol Metab. 2004 Dec;89(12):
s6097–9.
40 Kukuvitis A, Kourtis A, Papaiconomou N, et al. Differential effects
of unopposed versus opposed hormone therapy, tibolone, and raloxifene
on substance p levels. Fertil Steril. 2003 Jul;80(1):96–8.
41 Furey ML, Drevets WC. Antidepressant efficacy of the antimuscari-

nic drug scopolamine: a randomized, placebo–controlled clinical trial.
Arch Gen Psychiatry. 2006 Oct;63(10):1121–9.
42 Russell IJ, Orr MD, Littman B, et al. Elevated cerebrospinal fluid
levels of substance P in patients with the fibromyalgia syndrome.
Arthritis Rheum. 1994 Nov;37(11):1593–601.
43 Ranga K, Krishnan R. Clinical experience with substance P receptor
(NK1) antagonists in depression. J Clin Psychiatry. 2002;63 Suppl 11:
25–9.
44 Green SA, Alon A, Ianus J, et al. Efficacy and safety of a
neurokinin–1 receptor antagonist in postmenopausal women with
overactive bladder with urge urinary incontinence. J Urol. 2006
Dec;176(6 Pt 1):2535–40.
45 Duffy RA. Potential therapeutic targets for neurokinin–1 receptor
antagonists. Expert Opin Emerg Drugs. 2004 May;9(1):9–21.
46 Wang X, Douglas SD, Lai JP, et al. Neurokinin–1 receptor
antagonist (aprepitant) inhibits drug–resistant HIV–1 infection of
macrophages in vitro. J Neuroimmune Pharmacol. 2007 Mar;2(1):42–8.
47 Yuan Z, Nimata M, Okabe TA, et al. Olmesartan, a novel AT1
antagonist, suppresses cytotoxic myocardial injury in autoimmune heart
failure. Am J Physiol Heart Circ Physiol. 2005 Sep;289(3):H1147–52.
48 Laudanno OM, Cesolari JA. [Angiotensin II AT1 receptor antago-
nists as antiinflammatory and gastric protection drugs]. Acta Gastroen-
terol Latinoam. 2006 Jun;36(2):76–80.
49 Marshall TG, Lee RE, Marshall FE. Common angiotensin receptor
blockers may directly modulate the immune system via VDR, PPAR
and CCR2b. Theor Biol Med Model. 2006 Jan 10;3:1.
50 Gard PR. Angiotensin as a target for the treatment of Alzheimer's
disease, anxiety and depression. Expert Opin Ther Targets. 2004 Feb;8
(1):7–14.
51 Treating Chronic Fatigue Syndrome and Fibromyalgia: Interview
with David Moskowitz, M.D. http://www.immunesupport.com/library/
52 Unger T. Blood pressure lowering and renin–angiotensin system
blockade. J Hypertens Suppl. 2003 Jul;21(6):S3–7.
53 Tronvik E, Stovner LJ, Helde G, et al. Prophylactic treatment of mig-
raine with an angiotensin II receptor blocker: a randomized controlled
trial. JAMA. 2003 Jan 1;289(1):65–9.
54 R. Paul St. Amand, M.D. on Guaifenesin Treatment. http://www.
55 Bennett R, De Garmo P, Clark SR. A 1–year double blind placebo

controlled study of guaifenesin in fibromyalgia. Arthritis Rheum. 1996;
39:S212.
56 The Role of Guaifenesin in Fibromyalgia. http://stuff.mit.edu/people/
london/guai.html
57 Consumer Alert – Guaifenesin for Fibromyalgia. http://www.fmnet
news.com/resources-alert-product6.php
58 Dolezal T, Krsiak M. Guaifenesin enhances the analgesic potency of
paracetamol in mice. Naunyn Schmiedebergs Arch Pharmacol. 2002
Dec;366(6):551–4.
59 Pickens CL, Milliron AR, Fussner AL, et al. Abuse of guaifenesin–
containing medications generates an excess of a carboxylate salt of
beta–(2–methoxyphenoxy)–lactic acid, a guaifenesin metabolite, and
results in urolithiasis. Urology. 1999 Jul;54(1):23–7.
60 Dr. Paul Cheney: CFS & Cardiac Issues, Part 2b. http://www.
dfwcfids.org/medical/cheney/Cheney.CFS-Cardiac.Part2b.pdf
61 Jadin C. Rickettsial approach. Sydney CFS conference 1999. http://
www.ahmf.org/99booth.html
62 R. Paul St. Amand, M.D. on Guaifenesin Treatment. http://www.
63 Vécsei L, Miller J, MacGarvey U. Kynurenine and probenecid
inhibit pentylenetetrazol– and NMDLA–induced seizures and increase
kynurenic acid concentrations in the brain. Brain Res Bull. 1992 Feb;28
(2):233–8.
64 Németh H, Toldi J, Vécsei L. Role of kynurenines in the central and
peripheral nervous systems. Curr Neurovasc Res. 2005 Jul;2(3):249–60.
65 Just Ask! An NCF Column for Inquiring Patients. By Prof. Alan
Cocchetto. http://www.ncf-net.org/forum/JustAsk-S07.htm
66 Potential Hope for CFIDS/ME Patients with ICL. by Alan Cocchetto,
NCF Medical Director. http://www.ncf-net.org/forum/HopewithICL-
Fall05.htm
67 Lieberman J, Bell DS. Serum angiotensin–converting enzyme as a
marker for the chronic fatigue–immune dysfunction syndrome: a
comparison to serum angiotensin–converting enzyme in sarcoidosis. Am
J Med. 1993;95:407–12.
68 Vladutiu GD, Natelson BH. Association of medically unexplained
fatigue with ACE insertion/deletion polymorphism in Gulf War vete-
rans. Muscle Nerve. 2004 Jul;30(1):38–43.
69 Treating Chronic Fatigue Syndrome and Fibromyalgia: Interview
with David Moskowitz, M.D. http://www.immunesupport.com/library/
70 De Albuquerque DA, Saxena V, Adams DE, et al. An ACE inhibitor

reduces Th2 cytokines and TGF–beta1 and TGF–beta2 isoforms in
murine lupus nephritis. Kidney Int. 2004 Mar;65(3):846–59.
71 Ilieva I, Ohgami K, Jin XH, et al. Captopril suppresses inflammation
in endotoxin–induced uveitis in rats. Exp Eye Res. 2006 Sep;83(3):651–
7.
72 Slavachevsky I, Rachmani R, Levi Z, et al. Effect of enalapril and
nifedipine on orthostatic hypotension in older hypertensive patients. J
Am Geriatr Soc. 2000 Jul;48(7):807–10.
73 Postiglione A, Bobkiewicz T, Vinholdt–Pedersen E, et al. Cerebro-
vascular effects of angiotensin converting enzyme inhibition involve lar-
ge artery dilatation in rats. Stroke. 1991 Nov;22(11):1363–8.
74 Skowasch D, Viktor A, Schneider–Schmitt M, et al. Differential anti-
platelet effects of angiotensin converting enzyme inhibitors: comparison
of ex vivo platelet aggregation in cardiovascular patients with ramipril,
captopril and enalapril. Clin Res Cardiol. 2006 Apr;95(4):212–6.
75 Motta MA, Vasconcelos Mda S, Catanho MT. Antinociceptive action
of captopril and transcutaneous electric nerve stimulation in Mus mus-
culus mice. Clin Exp Pharmacol Physiol. 2002 May–Jun;29(5–6):464–6.
76 Sicuteri F. Enkephalinase inhibition relieves pain syndromes of cent-
ral dysnociception (migraine and related headache). Cephalalgia. 1981
Dec;1(4):229–32.
77 Paterna S, di Pasquale P, Martino S, et al. [Captopril versus placebo
in the prevention of hemicrania without aura. A randomized double–
blind study]. Clin Ter. 1992 Dec;141(12):475–81.
80 van Rensburg SJ, Potocnik FC, Kiss T, et al. Serum concentrations of
some metals and steroids in patients with chronic fatigue syndrome with
reference to neurological and cognitive abnormalities. Brain Res Bull.
2001 May 15;55(2):319–25.
81 Gurer G, Sendur OF, Ay C. Serum lipid profile in fibromyalgia wo-
men. Clin Rheumatol. 2006 May;25(3):300–3.
82 Tsirpanlis G, Boufidou F, Manganas S, et al. Treatment with fluva-
statin rapidly modulates, via different pathways, and in dependence on
the baseline level, inflammation in hemodialysis patients. Blood Purif.
2004;22(6):518–24.
83 Stuve O, Youssef S, Weber MS, et al. Immunomodulatory synergy

by combination of atorvastatin and glatiramer acetate in treatment of
CNS autoimmunity. J Clin Invest. 2006 Apr;116(4):1037–44.
84 Aktas O, Waiczies S, Smorodchenko A, et al. Treatment of relapsing
paralysis in experimental encephalomyelitis by targeting Th1 cells
through atorvastatin. J Exp Med. 2003 Mar 17;197(6):725–33.
85 Szczeklik A, Undas A, Musial J, et al. Antithrombotic actions of sta-
tins. Med Sci Monit. 2001 Nov–Dec;7(6):1381–5.
86 Skoczylas T, Sarosiek I, Sostarich S, et al. Significant enhancement
of gastric mucin content after rabeprazole administration: its potential
clinical significance in acid–related disorders. Dig Dis Sci. 2003 Feb;48
(2):322–8.
89 Chronic fatigue syndrome, fibromyalgia enzyme therapy with strep-
tokinse, urokinase and tissue plasminogen activator (t–pa) for patients
with antibiotic – resistant systemic chlamydial infections. http://www.
expo.lv/gailes/fibromyalgia.htm
90 Winkler AS, Blair D, Marsden JT, et al. Autonomic function and
serum erythropoietin levels in chronic fatigue syndrome. J Psychosom
Res. 2004 Feb;56(2):179–83.
91 Hurwitz B. Therapeutic Effect of Epoetin Alpha on Red Blood Cell
Volume, Perceived Fatigue and Susceptibility to Syncope in Chronic
Fatigue Syndrome. Presented at: International Association for Chronic
Fatigue Syndrome (IACFS) 8th International Conference on Chronic
Fatigue Syndrome, Fibromyalgia and Related Illnesses. Fort Lauderdale,
FL, U.S. Jan 12–Jan 14, 2007.
92 Shoemaker RC, Maizel MS. Treatment of Elevated C4a in Patients
with CFS Using Low Doses of Erythropoietin Safely Reduces Symp-
toms and Lowers C4a: A Prospective Clinical Trial. Poster presented at:
International Association for Chronic Fatigue Syndrome (IACFS) 8th
International Conference on Chronic Fatigue Syndrome, Fibromyalgia
and Related Illnesses. Fort Lauderdale, FL, U.S. Jan 12–Jan 14, 2007.
93 How We Approach Chronic Fatigue Syndrome by Richard Podell,
MD. http://drpodell.org/chronic_fatigue_syndrome_treatments.shtml
94 Treating kids with Chronic Fatigue Syndrome (CFS). http://www.
APPENDIX A.
Drug interactions
Drug interactions mean that the combination of two drugs (or a

drug and a non–drug substance) either decreases or increases the effica-
cy of either or both drugs, or causes new or worse side effects. Drug
interactions are possible even if the drugs are taken at a different time of
the day.
Pharmacodynamic interactions
Pharmacodynamic interactions sound like something very techni-

cal, but in reality the concept is easy to comprehend. At its simplest it
could mean taking a sedative and a stimulant at the same time. In some
cases such a combination could be useful, but usually it would be just as
counter–intuitive as it seems to, causing unnecessary costs and increa-
sing the risk of side effects, as the medications would mostly cancel out
each other’s effects.
Taking two drugs that act the opposite ways is obviously not wise,
but the same may go for drugs with similar modes of action. People who
suffer from low blood pressure can often take one drug that can cause
hypotension, but if they take two hypotensive drugs at the same time,
blood pressure could drop dangerously low. This does not go just for
blood pressure medications—many psychiatric drugs for example can
lower blood pressure. Combining two drugs that potentially cause
nausea may greatly increase the risk of vomiting, and so on.
Metabolic interactions
Cytochrome P450
Cytochrome P450 (CYP450) is a large group of enzymes involved

in the metabolism of both endogenous and foreign substances, such as
medications. Many drugs either increase (induce) or decrease (inhibit)
the action of one or more of the CYP450 enzymes. Drugs can also act as
substrates for one or several enzymes, which means their metabolism is
affected by substances that induce or inhibit the involved enzymes.
Drug interactions 299
The enzyme inhibition, induction or being a substrate is not an

absolute thing. For example, a drug can be a major substrate of CYP3A4
and a minor substrate of CYP2C19. In that case an inhibitor or inducer
of 2C19 or a minor inhibitor/inducer of 3A4 would probably not alter its
metabolism much, but a major inhibitor of 3A4 would significantly slow
down the clearance of the drug (elevating the blood levels) and a major
inducer of 3A4 would make the clearance of the drug much faster.
Not all drugs are metabolized by this system at all, but many are.
Luckily you do not have to understand how it works nor memorize these
cryptic combinations of letters and numbers, but it is good to be aware
of the underlying mechanics, because they explain why and how two
drugs can interact with each other, even if they act by entirely different
mechanisms.
Often drugs in the same group (e.g. tricyclic antidepressants) affect
the same enzymes, because they are structurally similar, but for example
anticonvulsants are a class containing very different chemicals, so the
metabolic routes also vary. Also, often some drugs in the same group
are much stronger inhibitors or inducers or affect a larger number of
CYP450 enzymes, so they would not be a good choice for someone who
takes many different medications.
Absorption and bioavailability
Drugs can also affect the absorption of other drugs, or the way they
are carried in blood. For example, everything that alters gastrointestinal
motility (how quickly the stomach is emptied) may alter the way drugs
are absorbed. If you speed up the motility, medications may be
incompletely absorbed. If you do the opposite, the absorption usually
does not suffer, but may become slower.
The same also happens if the pH (acidity) of the stomach changes.
Antacids, H2 inhibitors and proton pump inhibitors may also affect the
absorption of drugs. Some drugs like cholestyramine directly bind to
many substances, resulting in insoluble compounds. Many drugs are
bound to the proteins in plasma, a component of blood. If several pro-
tein–bound drugs are taken at the same time, they can displace each
other.
Interactions with non–pharmaceuticals

Herbs and supplements
Medications are not the only thing that cause interactions; herbs
and supplements can do it too. Doctors usually know which drugs are a
no–no to take together, but they often have little to no knowledge about
herbal products. St. John’s wort (also known as hypericum), a com-
monly used herbal antidepressant and antiviral can cause serotonin
syndrome if combined with antidepressants. It also affects several
CYP450 enzymes, interfering with the metabolism of oral contracep-
tives, theophylline, alprazolam and some other drugs.
Piperine (also known as Bioperine) from black pepper can signifi-
cantly increase the absorption of many drugs. This is why it is added to
some supplements (especially Q10 and turmeric), but drugs with a low
therapeutic window should probably be taken at a different time of the
day. Turmeric supplements in themselves may affect the metabolism of
many antidepressants, mexiletine, naproxen, riluzole, theophylline and
tizanidine.
Many herbs and other supplements act as anticoagulants. Brome-
lain, ginkgo, fish oil, garlic, chamomile and large doses of vitamin E are
known to do this, but danshen, capsicum (chili), feverfew, ginger, pas-
sionflower and pau d’arco have also been implicated. Goldenseal, gin-
seng, green tea and coenzyme Q10 may act the opposite, reducing the
efficacy of anticoagulants and platelet inhibitors.
Several herbs can raise blood pressure, including at least St. John’s
wort, pau d’ arco, goldenseal, licorice root, gentian, ephedra (ma huang)
and everything that contains caffeine, such as guarana. On the other
hand, garlic, olive leaf extract, danshen, motherwort, passionflower,
hawthorn (crataegus), maitake mushrooms, coleus forskohlii and mistle-
toe may lower blood pressure. Ginseng and gotu kola have been associa-
ted with both raised and lowered blood pressure.
Calcium may reduce the absorption of many medications. For this
reason it is a good idea not to take medications and calcium supplements
at the same time. Some medications are also affected by iron. Vitamins
(except for vitamin E) usually do not cause interactions, but vitamin B6
and folic acid can impair the efficacy of some drugs. This only goes for
large doses, normal multivitamins are OK. Vitamin K may affect the
efficacy of oral anticoagulants.
Additionally, garlic can lower blood sugar when combined with
diabetes medications, feverfew should not be combined with migraine
drugs, ginkgo may raise blood pressure when combined with some diu-
retics and ginseng should not be combined with phenelzine (and pos-
sibly other MAO inhibitors). The principles of pharmacodynamic inter-
actions also apply to herbs. For example, taking sedative herbs (such as
valerian or passionflower) together with sedative pharmaceuticals can
lead to excessive sedation.
Food and lifestyle
Luckily, even though our activity patterns, such as whether we

exercise or not, affect our energy metabolism, they have lesser effects
on drug metabolism. Excessive exercise can modify the effects of drugs,
but inactivity is not thought to do so. Still, foods may play a role. Milk
can reduce the absorption of some antibiotics and increase the efficacy
of some laxatives. Acidic juices such as citrus juices should not be taken
together with antacids and some antibiotics. Leafy green vegetables may
affect the efficacy of oral anticoagulants.
Grapefruit juice, and of course grapefruit itself, is well–known for
its effects on the CYP450 system. Of course large quantities of grape-
fruit are also counted. It is less well known that the otherwise extremely
healthy pomegranate juice also has potential interactions. It can increase
the blood levels of disopyramide, nifedipine, nimodipine and statins.
Other things that can cause interactions include smoking, charbroi-
led meat, cruciferous vegetables, chamomile tea and beverages contain-
ing caffeine. All of these may either induce or inhibit the metabolism of
many antidepressants, mexiletine, naproxen, riluzole, theophylline and
tizanidine.
Alcohol generally does not affect drug metabolism, but it can have
several negative effects. The effects and side effects of many drugs
(especially ones that cause sedation or nausea) are often potentiated.
Others may become less effective and some cannot be taken with alco-
hol at all. Binge drinking may also have others adverse effects—the
patient may forget to take their drugs (or inadvertently take too many,
because they cannot remember if they have taken them yet) or even
expel them. And of course, getting drunk is not healthy in the first place.
Even individual differences may cause variation in drug absorption
and metabolism. Our age, gender, ethnicity, in some cases even our hair
color may affect it. Old people tend to metabolize drugs slower than the
young. Our genes determine the activity of some CYP enzymes—we
may be slow, normal, rapid or ultra rapid metabolizers. This may some-
times explain why a drug seems to cause unusually nasty side effects, or
why it appears all but ineffective for someone else. In such cases the
blood levels of the medication can be measured.
Avoiding harmful interactions
The worst offenders when it comes to disturbing the metabolism of

other drugs include some anticonvulsants, antidepressants, beta blockers
and calcium channel blockers. Some drugs that are most often affected
by other medications are carbamazepine, valproate, oral anticoagulants
and the heart medication digoxin. If you are taking these drugs, it is
especially important to pay attention to interactions, because the levels
of these drugs should stay as constant as possible.
If you are taking oral contraceptives (the pill) you have to be espe-
cially careful with drug interactions, because they could interfere with
the efficacy of the contraception. This could cause breakthrough bleed-
ing and in the worst case even an unwanted pregnancy. You should
avoid modafinil, carbamazepine or St. John’s wort. When taking anti-
biotics, you should probably use another form of contraception, because
there have been concerns that all antibiotics may affect the absorption of
the pill. Cholestyramine could have the same effect.
Because of limited space, every possible interaction has not been
included in this book, or half of the book would have been spent explor-
ing this topic. Only drugs that are commonly taken by people with
CFS/ME and FM have been included, excluding e.g. HIV/AIDS and
cancer treatments. Almost all the antiretroviral medications have nume-
rous interactions and the same goes for antibiotics used for tuberculosis,
such as rifampicin. If you are being treated for another serious illness,
you should discuss any possible treatment with all of your doctors.
Taking two drugs that interact is usually possible, but may require
dose adjustments. If a new medication is added to your regime and it
slows down the metabolism of another drug you are taking, your doctor
may instruct you reduce the dose of the previous medication. Many
medications do not even require a change of dose, because the changes
in metabolism might not have clinical importance.
Sometimes, however, taking a certain medication presents an abso-
lute contraindication (meaning it is strictly forbidden) to taking another
drug, because the levels of either drug could be dangerously elevated
leading to toxicity, or because the combined effects of the drugs could
cause dangerous symptoms, such as very high or very low blood pres-
sure. It is crucial that your doctor knows about all the drugs and supple-
ments you are taking. Informing your pharmacist is also wise, because
they might notice an interaction the doctor has missed.
Drug interactions are not always harmful. Many drugs work syner-
gistically together, meaning that their combination produces more than
just additive effects—sometimes 1+1=3. The primary use of some drugs
is to increase the absorption or efficacy of another drug. This can be
useful if the absorption or efficacy of the drug is otherwise poor, but
also if the drug is very expensive. Probenecid is used to elevate the
tissue levels of antibiotics and antivirals and carbidopa is used to slow
the breakdown of levodopa.
Other problems with polypharmacy
Drug interactions are not the only problem with polypharmacy

(taking several pharmaceuticals at the same time). Many people with
fibromyalgia and CFS/ME do need several medications, but there is a
risk of overmedication. One may end up taking drugs that do not really
help or have lost their efficacy, or taking several drugs that only help
minimally, even though they could try to find ones that provide more
improvement.
It is not a good idea to keep taking a medication when it is obvious
it does not work, but sometimes one may be afraid of stopping the drug.
There can be several reasons for this, such as thinking that the drug
might be doing something and discontinuing it would cause a relapse, or
fearing possible withdrawal symptoms. Some doctors may encourage
taking drugs with no clear benefit, especially in the case of antidepres-
sants. The patient may be scared of making their doctor upset, but there
is no reason to keep taking useless pills.
With some drugs, all side effects do not occur straight away, but
may be delayed by months or even years. Some side effects only appear
if the drug is used too frequently (such as rebound headache with the
triptans). If that happens, it can be difficult to determine which medica-
tion is the culprit, because numerous drugs can cause side effects like
headache or elevated liver enzyme levels. And of course, we may not
even know if something is a side effect or a part of our illness.
Occasionally people are taking two drugs that contain the same or
similar ingredient, or two drugs that counter each other’s effects. This is
usually caused by several doctors prescribing medications without being
aware of the others, but it can be due to carelessness on part of one
doctor, too. There are some combinations which are not necessarily dan-
gerous, but do not offer any benefit either and should thus be discoura-
ged, such as taking several NSAIDs at the same time.
When taking several medications at the same time, practical consi-
derations also become important. Some drugs need to be taken at night,
some in the morning, some with food and some without food. In that
case one has to consider whether some medications could be disconti-
nued or changed for longer–acting ones, reducing the number of doses
that must be taken. With a large number of medications, even
remembering to take all the pills and to refill the prescriptions may pose
a problem.
APPENDIX B.
Surgery
Because any exertion is prone to causing relapses in CFS/ME and

in some people with fibromyalgia, it is not surprising that surgery can
cause severe and prolonged relapses. If you are told you need surgery it
would be advisable to obtain a second opinion, unless the need for sur-
gery is clear (such as in the case of most cancers) or urgent (such as in
appendicitis).
You should inform the surgeon of your illness, but chances are they
do not know much about CFS/ME or fibromyalgia. The term myalgic
encephalomyelitis is likely taken more seriously than “chronic fatigue
syndrome.” If you have multiple chemical sensitivity, things get even
more complicated. You may have to consider a different hospital, if the
staff does not appear willing to accommodate to your needs.
Informing your family and friends about any potential problems is
a good idea, so that they know what to tell the doctors should you ever
need an emergency operation. A medical bracelet or an information
sheet in your wallet for this purpose would be even better. Include a list
of all medications and supplements you are taking as well as any
allergies you have, not only drug allergies. Some companies sell key
chains and necklaces with a small waterproof case to store the
information in.
Large surgeries are usually done under general anesthesia, which
requires the use of several anesthetic agents. Smaller operations can be
done under local anesthesia, using lidocaine or similar drugs. This is
usually a safe option, but you should request that the anesthesia be done
without epinephrine (adrenaline), as this is the part which is prone to
causing complications. If epinephrine is needed, at least the dose should
be markedly decreased. For some operations regional anesthesia (such
as epidural anesthesia) is a possibility.
Some non–surgical procedures like colonoscopy are often done
under conscious sedation. It means you are technically awake, but given
such a heavy dose of sedatives (usually benzodiazepines) that you are
not aware of the operation and will usually not remember it afterwards.
This is generally safe, as even people who are very sensitive to medica-
tions can usually handle benzodiazepines, but the dosage may have to be
markedly reduced.
Dr. Paul Cheney recommends against possibly hepatotoxic anesthe-

tic gases, noting that many people with CFS/ME have subclinical hepa-
titis and these drugs could provoke fulminant, even fatal hepatitis.1
Charles Lapp believes that histamine–releasing anesthetics and muscle
relaxants such as pentothal and curare derivatives should also be avoid-
ed, because this population is often sensitive to histamine.2 He advises
to use vasodilators with caution. People with CFS/ME may require less
anesthetics but more painkillers than healthy people.3
Both Lapp and Cheney recommend administering magnesium and
potassium supplementation before surgery. Lapp also stresses the
importance of proper hydration. Those who have or are suspected to
have adrenal insufficiency should be given (extra) hydrocortisone before
surgery, especially if they are already on corticosteroids.
Jay Goldstein recommends always using pre–emptive analgesia. He
also recommends the following anesthetic cocktail to be used: 1) isoflu-
rane (or similar), 2) propofol, 3) ketamine, 4) fentanyl and 5) midazo-
lam.4 He believes that although surgery is a risk for relapses, both iso-
flurane and propofol can occasionally put CFS/ME and fibromyalgia in
remission. Dr. Patrick L. Class similarly recommends propofol as the
induction agent, midazolam, fentanyl and droperidol during the anesthe-
tic and nitrous oxide, oxygen and isoflurane for maintenance.5
Before surgery you are usually advised to stop all blood–thinning
medications such as aspirin and heparin. This also goes for herbs with
blood–thinning properties. Some may have to be stopped even several
weeks before surgery, so be sure to mention all medications and supple-
ments you are taking when discussing the upcoming operation. The
American Society of Anesthesiologists even recommends that all herbal
medications be discontinued 2–3 weeks before surgery.6
Many operations require fasting, usually overnight and sometimes
for longer than 24 hours. If you suffer from hypoglycemia or tend to
otherwise not tolerate fasting well, insist that you need to get the earliest
possible appointment to minimize the time you must fast. Juices and
other liquids are often allowed during the fast period, but ask to be sure.
Surgery 307
References

Fatigue Syndrome. Hunter House 1995. pp. 205–206
2 Recommendations for Persons with Chronic Fatigue Syndrome (or
Fibromyalgia) Who Are Anticipating Surgery by Dr. Charles W. Lapp,
MD. http://www.immunesupport.com/library/showarticle.cfm/ID/8592/
3 So you are going to have surgery? (Advice on anaesthetics and pain
control for those with M.E.) by Betty Dowsett. http://www.25megroup.
org/Newsletter/issue%2012.htm
5 Class PL. Ask the Doctor. The CFIDS Chronicle, Summer 1994, p.
82.
6 Ang–Lee MK, Moss J, Yuan C. Herbal medications and perioperative
care. JAMA 2001;286:208–16.
APPENDIX C.
Vaccinations
Whether to vaccinate or not when you have CFS/ME or fibromyal-

gia is a difficult question. Some of us may have originally got sick from
a vaccination. Others have experienced a relapse or even severe deterio-
ration from an immunization. Vaccines that have been associated with
the development of CFS/ME include at least MMR, pneumovax,
influenza, hepatitis B, tetanus, typhoid and polio.1 The anthrax vaccine
has been suspected as a causative factor in GWS.2
There are three different types of vaccinations, which include either
dead viruses/bacteria or particles from these microbes which stimulate
immune response; live but attenuated viruses/bacteria or a toxoid, an
inactivated bacterial toxin. Most vaccinations fall into the first group.
These vaccinations cannot cause the illness they vaccinate against, but
they can still lead to problems by producing an unwanted immune res-
ponse. It has been suggested that the hepatitis B vaccination may cause
CFS/ME through an autoimmune response.3
The live viruses include e.g. the FluMist influenza vaccination,
smallpox, varicella (chickenpox), BCG (tuberculosis), MMR/MMRV
and the oral polio vaccine. Normal polio and influenza vaccinations
contain dead viruses. No one with CFS/ME (or any other serious illness
that affects the immune system) should get a vaccine that contains live
viruses (such as FluMist), as in the worst case they can get sick with the
illness they are supposed to be protected against.
Tetanus vaccination is the most common example of a toxoid vac-
cination. It does not confer immunity against Clostridium tetani, only
the deadly toxin produced by it. This vaccination is generally not recom-
mended in CFS/ME, but those who spend a lot of time gardening should
probably take it, as the tetanus bacteria live in the soil. Most toxoid vac-
cines are not necessarily harmful in CFS/ME, and some can even be
useful—see CHAPTER 8 for the Staphylococcus toxoid.
There is also passive immunization, which does not require the pro-
duction of an immune response, because the antibodies are taken from
another person. Instead of the hepatitis A vaccination one can also take
hepatitis A immunoglobulin, which is probably a safer choice. The con-
ferred immunity is not as lasting, so this is suitable for those who are
planning for a short trip abroad. There is also an immunoglobulin
Vaccinations 309
against hepatitis B, but it is usually only used in conjunction with the

vaccination, or after possible exposure has occurred.
Vaccinations can cause adverse effects even in healthy people.
Usually the side effects are mild and may include fever and aches. There
can be serious neurological reactions, but they are extremely rare. This
is considered an acceptable risk, because vaccines protect us against
many infections that are frequently deadly or leave people with perma-
nent damage. It has been suggested that vaccinating against multiple
things at once (such as in the case of MMR) is more likely to cause
problems than vaccinations against just one disease.
The risks of some vaccines have been exaggerated by the media
and especially some advocacy groups, but in some cases there have been
serious risks and usually the vaccine has been withdrawn as a result.
Vaccines should never be regarded as completely safe, but this does not
mean they are something highly dangerous either. All medications have
side effects and risks. This goes for herbs and nutritional supplements
too. Even peanuts kill people, yet most of us can eat them without a
problem.
One supposed problem with vaccinations is a chemical called thio-
mersal, an organic compound containing mercury which is used as a
preservative. It has been connected to some illnesses, especially autism,
but despite several studies, no positive correlation between vaccinations
and autism has been found—in fact the opposite appears to be true.4 The
same goes for all other illnesses that have been supposedly associated
with thiomersal exposure. Not all mercury compounds are equally toxic
and the amount of thiomersal used in vaccinations is extremely small.
Even though there is no evidence of any problems with thiomersal,
it is being phased out of vaccines in most of the western world. It is pos-
sible that some people are extraordinarily sensitive to even incredibly
tiny doses of mercury and thus could react to thiomersal. It is more like-
ly, however, that a hypersensitivity reaction to a vaccine is due to some
other component—many vaccines contain e.g. the antibiotic neomycin,
which can cause allergic reactions. If there are any concerns about aller-
gies, they can be brought up with a healthcare professional.
There is a theory that some cases of CFS/ME have been caused by
a polio vaccine contaminated with the simian (monkey) virus SV–40
back in the 1950s and 1960s.5 The contamination was possible because
the poliovirus was inoculated in kidney cells from monkeys. Millions of
people did receive contaminated vaccinations, but there is no evidence
of any harmful consequences.6 Thus this theory is regarded as wildly
controversial. Even if it was true, the problem has been long eliminated
with modern screening technology.
The consequences of vaccinations in people with CFS/ME and fib-

romyalgia have not been widely studied. A double–blinded study conc-
luded that influenza vaccination was as safe and effective in CFS/ME
patients as in the general population.7 Only 19 patients were studied,
however. In another small study patients with CFS/ME were found to
differ from healthy controls in their response to OPV.8 Vaccination has
been suggested as a possible co–trigger for fibromyalgia.9
Personally the author would recommend against most vaccinations
in CFS/ME and fibromyalgia unless absolutely necessary, especially
against the following ones: hepatitis B, BCG, polio, pertussis and MMR.
This depends on the severity of the illness though—a mildly ill person
who has never had a reaction to vaccinations may well have no prob-
lems with them, but someone with severe CFS/ME should probably not
try their luck. Healthy people have no reason to avoid immunizations.
Those who have not experienced an adverse reaction to the influen-
za vaccination in the past and who are at risk of catching the flu, should
probably get the vaccination, because influenza is a dangerous illness
for someone who is already seriously ill. Many people end up hospitali-
zed and some even die. This is a very real risk. Those who are mostly or
completely housebound probably do not need the vaccine, but their
family/carers should take it.
Influenza can also be prevented by other means. Washing your
hands and not touching your face in the public are very good ideas,
though they are not as effective for preventing the flu as for preventing
colds, because influenza spreads as an aerosol. One can take amantadine
as a preventative, but it only works against influenza A. On the other
hand the influenza B viruses usually cause a less severe illness. Gin-
seng, eleuthero/Siberian ginseng and the flavonoid quercetin may work
as preventatives.
Vaccinations 311
References
1 Devanur LD, Kerr JR. Chronic fatigue syndrome. J Clin Virol. 2006
Nov;37(3):139–50.
2 Schumm WR, Reppert EJ, Jurich AP, et al. Self–reported changes in
subjective health and anthrax vaccination as reported by over 900 Persi-
an Gulf War era veterans. Psychol Rep. 2002 Apr;90(2):639–53.
3 Hyde B. The clinical investigation of acute onset ME/CFS and MS
following recombinant hepatitis B immunisation. Presented at: Second
world congress on chronic fatigue syndrome and related disorders. Brus-
sels, Belgium. Sep 9–12, 1999.
4 Fombonne E, Zakarian R, Bennett A, Pervasive developmental disor-
ders in Montreal, Quebec, Canada: prevalence and links with immuniza-
tions. Pediatrics. 2006 Jul;118(1):e139–50.
5 Cohen R. Re: CONTAMINATED VACCINES. GENTECH discus-
sion list, Jul 30, 1997. Available at: http://www.gene.ch/gentech/1997/
Jul-Aug/msg00328.html
6 Concerns about Vaccine Contamination. http://web.archive.org/web/
20060621182206/http://www.cdc.gov/nip/vacsafe/concerns/gen/contami
nation.htm
7 Sleigh KM, Danforth DG, Hall RT, et al. Double–blind, randomized
study of the effects of influenza vaccination on the specific antibody
response and clinical course of patients with chronic fatigue syndrome.
Can J Infect Dis. 2000 Sep;11(5):267–73.
8 Vedhara K, Llewelyn MB, Fox JD, et al. Consequences of live polio-
virus vaccine administration in chronic fatigue syndrome. J Neuroim-
munol. 1997 May;75(1–2):183–95.
9 Ablin JN, Shoenfeld Y, Buskila D. Fibromyalgia, infection and vacci-
nation: Two more parts in the etiological puzzle. J Autoimmun. 2006
Nov;27(3):145–52.
Glossary
This is not a comprehensive glossary of the vocabulary used in this
book, but the most important terms that have not been explained in the
text are listed here. If you cannot find the word you are looking for, try
browsing the index, because it is likely explained somewhere else.
agonist
A substance that binds to a receptor and causes a response similar to the
endogenous ligand. For example a serotonin agonist would act similarly
to serotonin.
antagonist
The opposite of agonist: a substance that occupies a receptor and pre-
vents the endogenous ligand from binding there. For example antihista-
mines block the action of histamine.
antiemetic
A drug that relieves or prevents nausea and vomiting (emesis).
autoimmunity
A condition where the immune system produces antibodies against the
body’s own tissue. For example in type I diabetes the body attacks the
islet cells of the pancreas, ultimately resulting in their destruction.
breakthrough pain
An acute worsening of chronic pain that “breaks through” the mainte-
nance pain medication and usually requires a short–acting drug.
case report/study/series
A published account of one (case report/case study) or several patients
(case series). A large case series may be useful in determining the com-
mon effects of a medication, but a case study cannot be generalized to
say something is likely to happen, only that it can happen.
cluster headache
A neurological illness which features extremely painful but very short–
lived headaches which occur periodically in "clusters".
Glossary 313
comorbidity
The concurrent presence of two or more illnesses, usually related to
each other.
costochondritis
An inflammatory condition which causes pain in the costal cartilages
(the cartilage connecting the ribs in the chest). The pain can be confused
with cardiac symptoms.
cytokine
A group of proteins produced by leukocytes (white blood cells) which
act as chemical messengers regulating the activity of the immune sys-
tem. Most cytokines are considered either anti–inflammatory or pro–
inflammatory.
diuretic
A drug that increases diuresis, the rate of urine excretion.
double–blinded study
In a double–blinded study the efficacy of a treatment is compared to
either another treatment or placebo, and neither the patients nor the
researchers know which one the patient is getting until the study is
finished. This is considered more reliable than a single–blinded study
where the patients are “blinded” but the researchers are not.
dysautonomia
A disease or malfunction of the autonomic nervous system, often mani-
festing as the inability to regulate blood pressure.
dyspepsia
Indigestion, pain or discomfort in the upper abdomen.
dyspnea
Shortness of breath, air hunger. The feeling of having difficulty breath-
ing or not being able to get enough air.
Ehlers–Danlos syndrome
A group of rare genetic disorders varying greatly in severity, caused by
a defect in collagen metabolism and typically characterized by joint
hypermobility.
endocrine
Pertaining to the secretion of hormones. An endocrinologist specializes
in disorders of the endocrine system such as hypothyroidism or diabetes.
endogenous
A substance originating from within the body. E.g. endorphin is an
endogenous opioid, whose name was formed from the words “endoge-
nous” and “morphine.”
endometriosis
A medical condition common in women where tissue similar to endo-
metrium (the lining of the uterus) grows outside of the uterus, causing
e.g. pain, stomach upset and often infertility.
ergot alkaloid
Alkaloids produced by ergot (Claviceps spp.), a parasitic fungus that can
contaminate grains, or derivatives of such alkaloids. Ergot derivatives
can produce variety of physiological effects depending on the chemical
structure of the particular substance.
GABA
Gamma–aminobutyric acid, the main inhibitory neurotransmitter in the
central nervous system, whose receptors or metabolism are affected by
e.g. sedative, anxiolytic and anticonvulsant drugs and some herbs.
gout
A condition where uric acid builds up in the body and forms crystal–like
deposits in cartilage, resulting in severe, sudden pain, usually in the
joints (especially the big toe).
Gulf War syndrome (GWS)

A debilitating medical condition of uncertain origin experienced by
veterans of the Persian Gulf War, with symptoms somewhat similar to
CFS/ME. Proposed causes have included vaccinations, bacteria, para-
sites, radiation, toxic chemicals and post–traumatic stress.
half–life
The time it takes for half of the amount of a substance to be either
removed from the body or metabolized. The half–life of medications
varies from seconds to several weeks, usually being between a few
hours and a day. Individual differences, other medications and other
factors can play a major part. Usually the half–life determines how often
Glossary 315
a medication is taken; for example a medication with a 20–hour half–

life would usually be taken once a day and one with a 10–hour half–life
would require 2–3 daily doses. Medications with half–lives in excess of
24 hours are usually still taken every day. The duration of action of
some medications, however, may be much longer than their half–life.
inflammation
A biological response to irritation, infection or injury which is often
characterized by pain, swelling and malaise. Inflammation is important
when fighting infection or healing injuries, but inflammation can also
become chronic even if it no longer serves any function. Persistent
inflammation has been suggested as a possible cause for cancer, cardio-
vascular disease and even depression.
interleukin
A group of important cytokines that modulate the function of the
immune system, abbreviated as IL–<number>.
interstitial cystitis
A bladder disease causing urinary frequency, urgency and pain. Its ori-
gins are commonly thought to be autoimmune or allergic in nature.
ion channel
A membrane protein that allows the passive flow of ions (positively or
negatively charged atoms or molecules) across a cell membrane. Ion
channels include calcium, sodium, potassium and chloride channels all
of which have different subtypes. A defect in the function of these chan-
nels has been suggested as the origin of symptoms in CFS/ME, fibromy-
algia and many other conditions, especially epilepsy. Many sodium and
calcium channel blockers are important treatments for CFS/ME and FM.
homocysteine
A metabolic product of the amino acid methionine. Deficiency of vita-
min B6, B12 or folic acid may elevate blood levels of homocysteine,
which has been associated with increased risk of cardiovascular disease.
hypovolemia
Low blood volume, having too little circulating blood.
metabolite
A chemical product created by the metabolism of another chemical.
Most drugs metabolize to something else before being excreted from the
body. These metabolites may be inactive (having no physiological ef-

fects), similar in effects to the original substance or have somewhat or
completely different effects. Some drugs are inactive before they are
metabolized in the body. They are known as pro–drugs.
mitochondria
Mitochondria are small organelles inside the cell responsible for its
energy production and some other essential functions. A problem with
mitochondrial function could explain many of the symptoms of
CFS/ME, especially lack of energy and easy fatigability.
mitral valve prolapse

A common form of valvular heart disease, in which the mitral valve
does not completely block the flow of blood as it should. Commonly
without symptoms, but can cause palpitations, chest pain and shortness
of breath. Often audible as a slight murmur.
mucolytic
A drug that dissolves thick mucus.
multiple chemical sensitivity (MCS)

As the name suggests, multiple chemical sensitivity is a condition in
which low levels of multiple kinds of chemicals cause symptoms, which
can range from typical allergic reactions to e.g. fatigue and cognitive
dysfunction.
multiple sclerosis (MS)

A neurological illness in which autoimmune processes attack the central
nervous system, resulting in many symptoms very similar to those of
CFS/ME. Infectious agents have been suggested as a possible cause.
myofascial pain syndrome (MPS)

A painful muscular condition associated with trigger points, sensitive
areas between the muscle and the fascia which can refer pain to other
locations. Unlike tender points, trigger points can be felt by palpating.
narcolepsy
A neurological condition in which the main symptom is excessive day-
time sleepiness, including spontaneous attacks of falling asleep
Glossary 317
neuropathic pain
Pain caused by dysfunction of the nervous system. Neuropathic pain can
feel gnawing, stabbing, burning or resemble electric shocks; sometimes
it causes numbness and paresthesias (abnormal sensations), even itch-
ing. Neuropathic pain responds poorly to traditional analgesics and is
usually treated with e.g. anticonvulsants and some antidepressants.
neuroprotective
A substance or mechanism which protects the neurons from degenera-
tion or death caused by e.g. aging, toxic chemicals or lack of oxygen.
NF–kappa B
Nuclear factor–kappa B, a transcription factor which regulates immune
response to infection, but has also been associated with other forms of
inflammation and even cancer.
NK cell
Natural killer cell, a type of a lymphocyte (white blood cell) which is
especially important in fighting viruses and cancer.
nocturia
The need to get up at night to urinate.
orthostatic hypotension
A form of dysautonomia causing hypotension (low blood pressure) that
occurs when standing up, causing dizziness, blurring of vision and even
syncope (fainting). Neurally mediated hypotension (NMH) is very simi-
lar, but occurs with a delay and is associated with a drop in heart rate.
Even a person with hypertension can suffer from these problems.
osteoarthritis
A degenerative form of arthritis (joint inflammation), which causes pain
and stiffness. Osteoarthritis is extremely common, affecting over half of
the population by the age of 65. Several causative factors are involved.
parenteral
A route of systemic administration which bypasses the digestive tract,
such as intravenously (into a vein), intramuscularly (into a muscle) or
subcutaneously (under the skin).
Parkinson’s disease
A degenerative disorder of the central nervous system, which causes
abnormal movements such as tremor. The symptoms are due to a dopa-
mine deficiency in the brain. Other neurological illnesses and some
medications can cause similar symptoms, called Parkinsonism.
phase I/II/III clinical trials

All drugs have to go several phases of trials before they are approved
for use. Phase I trials usually include a small number of healthy volun-
teers. Phase II tests the actual efficacy of a drug for a particular condi-
tion. If a phase II trial is successful, then a phase III trial will be done on
a large number of patients. If efficacy and safety is verified, the drug
can be approved for this condition.
PMS
Premenstrual tension, a collection of physical and psychological symp-
toms experienced during certain parts of the menstrual cycle, usually
before and during the periods. May include e.g. edema, depression,
mood swings, insomnia and fatigue.
precursor
A (usually inactive) substance that can be converted in the body into
another (usually active) one. For example beta carotene converts to vita-
min A in the body and hence is a precursor of vitamin A.
prophylaxis
Preventive treatment.
PTSD
Post–traumatic stress disorder, an anxiety disorder that can develop after
severe trauma, such as violence or sexual abuse, even illness.
QT interval
A measure of the time between the Q and T waves of the electrical cycle
of the heart. QT interval is sometimes written as QTc, where the c
stands for corrected (for heart rate). Prolonged QT interval increases the
risk of some arrhythmias and can even lead to sudden death.
Raynaud’s phenomenon
Discoloration of fingers and sometimes other extremities due to poor
circulation. It can be idiopathic (Raynaud’s disease) or secondary to
other, usually autoimmune causes (Raynaud’s syndrome).
Glossary 319
restless legs syndrome (RLS)

A common condition that causes an irresistible urge to move one’s legs,
usually at rest. It is not a form of compulsive behavior, but the legs feel
very uncomfortable if they are kept still.
refractory
A condition that does not respond to usual treatment, for example dep-
ression that has not responded to a trial of several antidepressants.
rheumatoid arthritis
An inflammatory autoimmune disorder that causes severe pain and
inflammation in the joints, but sometimes also other tissues. An infec-
tious origin has been suspected.
rhinitis
Irritation and inflammation of the nasal passages, which produces a
runny nose.
SLE
Systemic lupus erythematosus, often known as just lupus, though there
are other forms of lupus. An autoimmune disease whose symptoms can
be very similar to CFS/ME.
sleep apnea
A common sleep disorder characterized by pauses in breathing (apneas)
during sleep, often (but not always) associated with snoring.
statistical significance
A statistically significant difference is unlikely to have occurred by
chance, such as when two groups in a study are compared. It is usually
expressed as p value, and if p is less than 0.05, the results are treated as
significant. This means, however, that there is still a 5% chance that the
results occurred by chance. If p is <0.001, there is only smaller than
0.1% chance (1 in 1,000) that the results were due to chance alone.
stereoisomer
Stereoisomers are alternative forms of some molecules, which have the
same structure, but in mirror. Most drugs with stereoisomerism are pro-
vided in racemic form, which contains roughly equal amounts of each.
Often one stereoisomer is inactive, or only causes side effects, which
makes it sensible to produce a version containing only the active isomer.
For example escitalopram (S–citalopram) is the active isomer of citalo-
pram, dexamphetamine (D–amphetamine) is the active isomer of

amphetamine and levodopa (L–dopa) is the active isomer of DOPA.
sublingual
A drug or supplement given under the tongue as a tablet, powder or
liquid. This way most of it is absorbed directly into systemic circulation,
bypassing the gastrointestinal tract, where the drug might be broken
down or not be effectively absorbed.
tachycardia
Rapid heartbeat, usually defined as over 100 beats a minute.
temporomandibular joint disorder (TMD)

A condition of acute or chronic inflammation in the temporomandibular
joint, which connects lower jaw to the skull. Possible symptoms include
pain in the jaw, face or ears, cracking noises when moving the jaw, jaw
locking and headache.
TNF alpha
Tumor necrosis alpha, one of the main inflammatory cytokines. It is
named that way because it has some anti–tumor properties, but it can
also cause very unpleasant symptoms such as fatigue, malaise and fever.
There is also a TNF beta, but it is considered less important.
transdermal
A delivery system where the drug is absorbed through the skin, either
from a patch or from a cream/gel/emulsion/foam/spray.
vasoconstriction
Narrowing of blood vessels. Substances that cause vasoconstriction are
known as vasoconstrictors or vasopressors (or simply pressors). If blood
vessels are excessively dilated, vasoconstriction may improve circula-
tion. Usually it also results in elevated blood pressure.
vasodilation
The opposite of vasoconstriction, relaxation of the smooth muscle in
blood vessels, which causes them to dilate. Vasodilation may improve
circulation, but it can also lower blood pressure.
Advil, 48
aging, 16, 167, 202, 316
Index alcohol, 301
alcoholism, 214, 288
abdominal pain, 14, 101, 194 aldosterone, 195, 197
absence seizures, 75 Alexander, Mark, 157
acamprosate, 288 alfa interferon, 99, 209-210
ACE inhibitor 285-286 allergies
acetaminophen allergic conjunctivitis, 277
by itself, 46, 63 allergic rhinitis, 14, 249
muscle relaxants and, 35-37 food allergies, 14
opiates and, 54, 58 in general, 14, 17-18, 207,
other combinations, 59, 158, 305, 308
283 Th2 and, 193-194
overdose, 212 treatment, 113, 117, 197,
acetazolamide, 255-256 206-207, 239-242, 249,
acetylcarnitine, 92 257, 277, 282
acetylcholine. See muscarinic urticaria, 14, 249
cholinergic receptor; alkaloids, 61-62, 164-165, 280,
nicotinic cholinergic 313
receptor; anticholinergic; allodynia, 16
cholinesterase inhibitors alopecia. See hair loss
acetylcysteine, 212-213 alpha1 agonists, 241
acetylsalicylic acid. See aspirin alpha1 antagonists, 116, 137, 139,
adenosine deaminase deficiency, 165, 173-175
285 alpha2 agonists, 33, 64, 173
acid reflux. See GERD alpha2 antagonist, 133
ACTH, 194-195 alpha2A partial agonist, 174
Actiq, 55-56 alpha2delta subunit, 77
aciclovir, 96-97 alprazolam, 27-28
Adagen, 285 ALS, 234
adalimumab, 206 alteplase, 289
Adderall, 156 altitude sickness. See mountain
addiction, 27, 52, 56, 214, 244 sickness
Addison’s disease, 194 Alzheimer’s disease
ademetionine, 135-136 ARBs and, 282
ADHD, cholinesterase inhibitors and,
antidepressants and, 114, 116, 236-238
126, 135, cycloserine and, 94
nootropics and, 162, 167 flurbiprofen and, 51
stimulants and, 154-156, 161 flupirtine and, 64
other drugs and, 174, 236 memantine and, 134
adrafinil, 161-162 minocycline and, 91
adrenaline. See epinephrine neurotropin and, 278
adrenal insufficiency, 194-197, nootropics and, 162, 166-167
305 testosterone and, 202
amantadine 233-234
Ambien, 25 andropause, 201

amino acids anesthesia, 304-305
acetylcysteine, 212-213 angina pectoris, 178, 180
excitatory, 284 angiotensin
methionine, 314 ACE inhibitors, 285-286
taurine, 247, 288 receptor antagonists, 281-282
tryptophan, 136-137 animals, CFS/ME in, 12
tyramine/tyrosine, 128 aniracetam, 163-164
aminoglycosides, 94 ankylosing spondylitis, 206
amisulpride, 139 anthrax vaccine, 307
amitriptyline, 113-114 antiadrenergic drugs, 173-175
AMPA receptors, 163, 183 antiaging, 167
amphetamines, 154, 156 antiandrogen. 184
Ampligen, 215-216 antibiotics
anaerobic bacteria, 93 as anti–inflammatories, 90-92
analgesic drugs combinations, 89-91, 93
acamprosate as, 288 drug interactions, 301-302
alpha2 agonists as, 173-174 macrolides, 92
antibiotics as, 91, 94 non-absorbed, 93-94
anticonvulsants as, 83 tetracyclines, 90-91
antidepressants as, 111-112, antibodies
114, 117, 122, 132-135, biological drugs, 205-207
antihistamines as, 60, 240- passive immunization, 307-
241 308
benzodiazepines as, 26 to bacteria, 89
cannabinoids as, 243-245 to enteroviruses, 95
captopril as, 285 See also autoantibodies;
cholinesterase inhibitors as, immunoglobulin
236 anticholinergic drugs
combinations, 59, 62, 242 amantadine, 233-234
kynurenic acid as, 284 antidepressants as, 112-113,
NSAIDs, 46-52 130
opiates, 52-59 antihistamines, 240-243
zolpidem as, 25 disopyramide, 181
melatonin as, 31 muscle relaxants as, 34-35
muscle relaxants as, 35, 37 pethidine, 56-57
neuropathic pain and, 316 scopolamine, 280
NMDA antagonists as, spasmolytics, 251-255
232-235, 288 anticoagulants
others, 63-65 drug interactions, 301-302
ribavirin as, 83 heparin, 185
vitamin B12 as, 248 pentosan polysulfate, 255
See also pain herbs as, 300
androgens See also platelet aggregation
DHEA, 202-203 anticonvulsants
testosterone, 201-202 anxiety and, 75-79, 83
antagonist, 184 benzodiazepines as, 27-28
Index 323
anticonvulsants (continued) 316

calcium channel blockers as, pizotifen as, 60
177 scopolamine as, 280
cannabinoids as, 243 SNRIs, 122-125
cognition and, 75-76, 78, 81, sodium oxybate as, 32
83 SSRIs, 118-122
depression and, 75-80 St John’s wort, 300
drug interactions, 299, 301 tricyclics, 112-118
kynurenic acid as, 284 antidiuretic hormone, 115, 203-205
melatonin as, 30 antiemetics
migraine and, 75-77, 79-82, antihistamines as, 240-241
pain and, 75-83, 316 aprepitant, 281
pentazocine as, 58 cannabinoids as, 244-246
racetams, 82, 163-164 definition, 311
restless legs and, 76, 78, 82 lorazepam as, 29
riluzole as, 234 migraine drugs, 59, 62
selegiline as, 130 mirtazapine as, 133
sleep and, 75, 77-82 olanzapine as, 137
vinpocetine as, 165 scopolamine, 280
antidepressants setrons, 259-260
ACE inhibitors as, 286 thalidomide as, 217
alprazolam as, 28 antifungals, 100-102
aniracetam as, 163 antihistamine–like drugs, 34, 60,
anticonvulsants as, 75-80 113, 116-117, 133, 137,
aprepitant as, 281 139, 173, 251, 257,
augmenting efficacy, 141, antihistamines, 239-243
161, 177 anti–inflammatory drugs
bipolar disorder and, 126-127 antibiotics as, 90-92
bromocriptine as, 160 ARB drugs, 281-282
buprenorphine as, 57 biological drugs, 205-207
combinations, 117, 119, 123, cetirizine as, 240
127, 131, 136 corticosteroids, 195
IBS and, 112, 116, 119, 122, dantrolene as, 38
133, 135 DHEA as, 202
as immunomodulators, dopaminergic drugs as, 154-
111, 117-119, 129 155
ketamine as, 235 flavocoxid, 284
losartan as, 282 ibudilast, 277
MAO inhibitors, 127-131 IVIG, 208
migraine and, 112, 129, 134, ketamine as, 235
136 melatonin as, 30
muscle relaxants as, 33-34, cyproheptadine as, 60
Mycobacterium vaccae as, nilvadipine as, 180
214 non–steroidal. See NSAIDs
NRIs, 125-127 pentoxifylline as, 182
pain and, 111-113, 115-117, raloxifene as, 280
120-128, 131, 133, 135, spironolactone as, 184
anti–inflammatory drugs 130, 141, 156-158,

(continued) 162, 183, 238-239, 256,
statins, 286 284
thalidomide as, 217 increasing, 182, 243, 245,
theophylline as, 279 256, 279
thiazolidinediones 275 See also weight
thiocolchicoside, 65 apraxia, 166
valproate as, 77 aprepitant, 281
antimalarials, 212 aphthous ulcers, 182
antioxidants, 19, 30, 47, 135, 160, ARB drugs, 281-282
164, 167, 212, 249-250, Armitage, Roseanne, 131
277-278, 284, 286 armodafinil, 161-162
antiplatelet, 47, 163, 165, 277, 282, Armour thyroid, 198-200
286 arthralgia, 13, 93, 200
antiretroviral drugs, 302 arthritis. See osteoarthritis
antiphospholipid syndrome, 185 aspirin, 46-48
antipolymer antibodies, 17 asthenia, 166
antipsychotic drugs, 137-140 asthma, 18-19, 134, 157, 177, 206,
antipyretic drugs, 46, 60, 63 214, 244, 247, 249, 277-
antiseptic, local, 254 278, 282
antispasmodics, 251-254 atenolol, 176
antitumor, 51, 244, 276 Ativan, 29
antiviral drugs atomoxetine, 126
amantadine, 233-234 atorvastatin, 286-287
antiherpesvirals, 96-99 atovaquone, 274
antiretrovirals, 302, ATP, 165, 201
ribavirin, 99-100 atropine, 254
immunomodulators as, 193, atypical depression, 127-128
208-212, 214-217 atypical antipsychotics, 137-140
anxiety atypical opioids, 58
anticonvulsants and auranofin, 167
antidepressants and, 111, aura. See migraine with aura
117-118, 120-123, 125, autism, 15, 214, 275, 308
128-129, 134 autoantibodies
other drugs and, 27, 33-34, in CFS/ME, 15
60, 138-139, 159-160, in fibromyalgia, 17, 198-199
163, 175, 200, 203, 234, autoimmune diseases
237, 239-240, 243, 247, candida and, 100
280-282, 288 CFS/ME as/and, 15, 185,
symptom, 14, 16, 194, 198, 212, 307
200, 203, 279 definition, 311
See also panic attacks, fibromyalgia as/and, 8, 16-17,
PTSD 199
aphasia, 166 heart failure, 281
appendicitis, 304 as immunodeficiencies, 193-
appetite 194, 214-215
decreasing, 81, 118, 124, 126,
Index 325
autoimmune diseases (continued) Behan, Peter O., 134

treatment, 193, 197, 205-207, belladonna, 280
212-217, 236, 275, 281- Bell, David, 29, 34, 57, 90, 114,
282, 290 138, 198, 250
thyroid autoimmunity, 17, Bell’s palsy, 25
198-199 Benadryl, 240-241
See also celiac disease; Benicar, 90-91, 281-282
multiple sclerosis; benzodiazepines
myasthenia gravis; as anticonvulsants, 26-28
psoriasis, rheumatoid as antidepressants, 28
arthritis; sarcoidosis; derivatives, 24-26
Sjögren’s syndrome; immune system and, 27
SLE; ulcerative colitis as muscle relaxants, 26-28
azithromycin, 92 as sleep aids, 26-29
azole antifungals, 101-102 benzoic acid, 254
Berg, David, 185
beta agonists, 157-158, 288-289
babesia, 274 beta blockers, 175-177, 183, 301
baclofen, 34-35 beta carotene, 317
bacteria beta endorphin, 31, 50, 214-215,
anaerobic, 93 285
and CFS/ME, 89, 92, 185 betaine, 258
and fibromyalgia, 89 beta interferon, 182, 209-210
and GWS, 313 Biaxin, 92
bacterial adhesion, 278 Bihari, Bernard, 214
chronic bacterial infections, biological drugs, 205-207
89-91, 185 Bioperine, 300
Gram–negative, 92, 254, bipolar disorder
Gram–positive, 118, 254 anticonvulsants and 75, 77,
Lyme/borrelia, 93, 185 80
Mycobacterium vaccae, 214 cannabis and, 243
nanobacteria, 90 depression predominant,
respiratory infections, 249, 80
278 lithium and, 140-141
small intestinal bacterial mania, 178, 247
overgrowth, 93-94 memantine and, 235
gastrointestinal infections, 93, neuroleptics and, 137, 139
101, 274 pramipexole and, 159
toxins, 65-66, 213, 274 rapid cycling, 127, 179
urinary tract infection bird flu. See avian influenza
vaccines, 307-309 birth control pill. See oral
balance problems, 14, 16, 242, 256 contraceptives
barbiturates, 53, 59, 254-255, 305 black pepper, 300
Bateman, Lucinda, 27-28, 30, 79, bladder
81, 127, 138, 155, 159, incontinence, 65, 124
161 infection. See urinary tract
BCG, 214, 307, 309 infection
bladder (continued) function, 163-164, 279

overactivity. See overactive imaging, 154, 182
bladder information processing, 19
pain in, 258, 314 right brain volume, 83
problems, 14, 27, 34-35, 75, See also blood-brain
174, 177, 243, 251-255 barrier; neurological
See also interstitial cystitis symptoms; nootropics
blood breakthrough pain, 52, 54-56, 311
coagulation. See bromelain, 300
hypercoagulation bromocriptine, 160-161
clotting, 286, 289 bronchodilators, 177, 277-278
flow. See circulation Brown, Mason, 179
perfusion, 14, 181-182 bruxism, 18
products, 207-208 buphenine, 288
thinning, 47, 165, 305 buprenorphine, 57
viscosity, 163, 165, 182 bupropion, 123, 127-128
volume, 14, 197, 200, 204, buspirone, 134
250, 307 butabarbital, 255
blood–brain barrier, 46, 90-91, 93, buvicaine, 66-67
209, 237, 239, 252, 280,
282
blood pressure caffeine, 35, 59, 242, 300-301
lowering, 27, 33, 35, 173- calcitonin, 275-276
181, 183-184, 281-282, calcium gluconate, 249-250
285-286, 300 calcium channel blockers
raising, 46, 48-49, 123-125, heart drugs, 177-180
156-158, 197-198, 200, antihistamines as, 60, 242
204, 256, 279, 300 dextromethorphan as, 233
stabilizing, 282 drug interactions, 301
body temperature, 78, 134. See magnesium as, 246
also fever neomycin, 94
bone nicergoline, 165
density, 53, 75, 176, 178, cancer
196, 200, 246 causes, 314, 316
pain, 275 fatigue in, 127, 250
See also osteoporosis immunotherapy, 31, 209, 211,
Borna virus, 96 214-215, 217, 276
borrelia. See Lyme disease nausea/weight loss, 243, 246
botulinum toxin, 65-66 pain in, 55, 64
bradykinin, 278 prevention, 202, 280
brain surgery, 304
damage, 162, 232 treatment. See chemotherapy
circulation, 14, 16, 165, 178, candida, 100-102
180, 182, 242, 286 capillaries, 156, 182
aging, 16, 167 capsaicin, 68
fog. See cognitive captopril, 285-286
problems carbamazepine, 75-76
Index 327
carbidopa, 158-159 chlorphenamine, 240-241

carbonic anhydrase inhibitors, 51, chlorzoxazone, 36
184, 255-256 cholesterol, 165, 180
cardiomyopathy, 14 choline, 163
cardiovascular disease cholinesterase inhibitors, 212, 235-
causes, 202, 314 239, 243
fibromyalgia and, 16 chronic fatigue. See fatigue,
treatment, 249 chronic idiopathic
carisoprodol, 35-36 chronic fever, 14, 46, 215, 287
carnitine, 92, 163, 234 chronic headache. See headache,
cataplexy, 32 chronic
CD4 cells, 211, 285 chronic Lyme disease. See Lyme
CDC, 12 chronic mononucleosis, 95, 208,
ceiling dose, 53, 57 257
celecoxib, 51 chronic pain. See pain, chronic
Celexa, 121-122 chronic prostatitis, 18
celiac disease, 277 cidofovir, 99
cell–mediated immunity, 129, 246 cimetidine, 257-258
central sensitivity syndrome, 18 cinnarizine, 242-243
central sensitization, 16, 232 circadian rhythm, 30, 194-195, 202
centrophenoxine, 167 circulation 14, 16, 157, 162, 165,
cetirizine, 240 175, 178-182, 185, 197,
CFIDS (term), 8-9, 14, 242, 250, 286
chamomile, 300-301 citalopram, 118, 121-122
channelopathy, 15 CJD, 64
charbroiled meat, 301 clarithromycin, 92
chemical sensitivity. See multiple Class, Patrick L., 305
chemical sensitivity clomipramine, 115
chemotherapy, 258-259, 281, clonazepam, 28-29
289 clonidine, 173-174
Cheney, Paul Clostridium botulinum, 65
recommends, 28, 117, 185, Clostridium difficile, 274
204, 210-211, 216, 240, Clostridium tetani, 213, 307
248, 256, 274, 305 cluster headaches, 61, 159, 247,
recommends against, 161, 311
198, 275, 283, 305 cobalamin. See vitamin B12
chest pain, 16, 180, 315 codeine, 53
Chia, John and Andrew, 99 coenzyme Q10, 200
chickenpox. See varicella cognitive problems
children, treating, 20, 157, 198, symptom 5, 13, 16, 20
290 treatment. See nootropics
chili peppers, 68, 300 See also dementia
chlamydiae cold (illness), 14, 212, 241, 309
Chlamydia trachomatis, 89 cold intolerance, 14
Chlamydia pneumoniae, 47, cold hands, 181
89, 93 coleus forskohlii, 300
in general, 289 collagen, 312
colonoscopy, 304 acetylcholine, 236

coma. See persistent vegetative adenosine deaminase, 285
state dopamine, 16, 154
complex seizures, 76 endocannabinoids, 244
concentration, 13, 128, 162, 248 glutathione, 249
Concerta, 155 hormones, 16, 193-194, 199-
conscious sedation, 304 201, 203-204, 237
constipation, 257 immunoglobulin, 207-208
contraceptive pill. See oral magnesium, 246-247
contraceptives serotonin, 16
coordination problems, 14, 16, 100 sympathomimetic amines,
COPD, 12, 278-279 154
corticosteroids, 66, 194-198, 290, vitamins 16, 248, 258-259,
305 314
costochondritis, 17, 46, 312 deformability, erythrocytes, 14,
co–trimoxazole, 90 182, 242, 248
cough, 54-57, 157, 233, 282 delta opioid receptor, 56
cough syrups, 53-54, 233, 282 delta–9–THC, 244-245
Coxiella burnetii, 89-90. See also De Meirleir, Kenny, 199, 210, 248
Q fever dementia
COX–1/2, 46-51, 284 Alzheimer’s. See Alzheimer’s
coxsackie viruses disease
CFS/ME and, 95, 216 CFS/ME symptom, 13
multiple sclerosis and, 250 in general, 162-163, 165
crataegus, 300 senile, 164
creatine, 135 dengue virus, 216
Crohn’s disease, 206, 215 depression
CRPS, 278 refractory, 57, 115, 123, 128,
curare derivatives, 305 197, 199, 235
curative treatment, 89-90, 282-283, symptom, 14-16, 19
289 treatment. See antidepressants
cyanocobalamin. See vitamin B12 desipramine, 115-116
cyclobenzaprine, 33, 35-36, 48 desmopressin, 204-205
cycloserine, 94-95 detoxification, 212-213, 274
Cymbalta, 124 dexamethasone, 290
CYP450, 298, 301 dexamphetamine, 156
cystic fibrosis, 92 dextromethorphan, 233
cytomegalovirus, 77, 95, 97-99, dextropropoxyphene, 57
182 DHEA, 176, 200-203
diabetes, 138, 161, 202, 275, 311
diabetes insipidus, 204
danshen, 300 diabetic nephropathy, 285
dantrolene, 37-38 diabetic neuropathy, 65, 75, 124,
darifenacin, 253 181, 233
DDAVP. See desmopressin diagnostic criteria
deconditioning, 14 CFS/ME, 24
deficiency fibromyalgia, 15-16
Index 329
Diamox, 255-256 droperidol, 305

drug interactions, 298-302
dry eyes, 199
diarrhea duloxetine, 124
chronic, 53, 55 dysautonomia, 29, 312. See also
traveler’s, 93 POTS; orthostatic
IBS/D, 173 hypotension; neurally
diazepam, 27 mediated hypotension
diclofenac, 50-51 dysbiosis of the gut. See small
dicycloverine/dicyclomine, 253- intestinal bacterial
254 overgrowth
diet, 101, 128, 277, 301 dyslexia, 163
dieting. See weight, losing dysmenorrhea, 18, 48, 64, 126, 173
Diflucan, 101-102 dyspepsia, 135, 312
digoxin, 302 dyspnea, 14, 16, 26, 181, 215, 276,
dihydroergotamine, 61-62 312
Dilantin, 83 dysthymia, 139
Dilaudid, 54-55
dipeptidyl carboxypeptidase, 285
diphenhydramine, 241 E. coli, 50
disopyramide, 181 eczema, 214
diuretics, 183-184, 255, 312 edema, 14, 16, 156, 255, 317
divalproex, 76-77 Effexor, 123
dizziness, 14, 34, 100, 166, 182, Ehlers–Danlos syndrome, 18, 313
316. See also vertigo Elavil, 113-114
donepezil, 236-238 eleuthero, 300
dopamine eMedicine, 132
agonists, 159-161, 241 emergency
antagonists, 116, 134, 137- surgery, 304
140 situations, 38, 137, 247
CFS/ME and fibromyalgia employment. See work
and, 16, 56, 154 enalapril, 285-286
function as, 111, 154-155 endocannabinoids
other dopaminergic drugs, 81, deficiency, 244
115, 126, 130-131, 155- paracetamol and, 63
156, 163-165, 180, 233, endocrinologal deficiencies. See
237, 250 deficiency
precursor, 158-159 endometriosis, 18-19, 178, 182,
reuptake inhibitors, 116, 123- 277, 313
124, 126-127, 161, 233, endorphins, 31, 50, 214-215, 285
256 end stage renal failure, 12
dosulepin, 117 endurance, 164, 166, 211, 216
dothiepin, 117 Enlander, Derek, 113, 210,
doxepin, 117-118 enoxaparin, 185
doxycycline, 90 enteroviruses, 95-96, 99, 209, 216,
doxylamine, 241 249-250
dronabinol, 245 enthesopathies, 17
enuresis, 115, 157 visual disturbances, 14, 181

enzyme induction/inhibition, 298-
299
enzyme replacement therapy, 285 famciclovir, 98
eosinophilia myalgia syndrome, fasting, 315
31, 136-137 fatigue
ephedra, 158, 300 caused by cancer, 127, 250
ephedrine, 157-158 chronic (idiopathic), 13, 64,
epidemic, of CFS/ME, 12, 95 161, 164, 166, 175, 197,
epilepsy, 17, 182, 243, 255, 314. 242, 247, 287
See also anticonvulsants cytokines and, 24, 38, 127,
epinephrine, 127, 154, 304 319
epoetin, 289-290 hypocortisolism and, 194-195
Epstein–Barr virus, 95-97, 210 caused by liver disorder, 120
erdosteine, 273 caused by multiple
erectile dysfunction, 134, 276 sclerosis, 127, 161, 233
ergot derivatives other causes, 100, 200-201,
bromocriptine, 160-161 248, 315
definition, 313 caused by post-polio
ergoloid (hydergine), 164-165 syndrome, 154, 161
dihydroergotamine, 61-62 in SLE, 212
ergotamine, 59, 61-62 FDA approval, 15, 78, 124, 216
nicergoline, 165-166 felbamate, 82-83
erythrocytes deformability, 14, fentanyl, 55-56, 305
182, 242, 248 fever, 14, 46-47, 49, 60, 63, 215,
erythropoietin, 289-290 287, 319
escitalopram, 121-122 feverfew, 300
esketamine, 235 fibrin, 185
esophageal dysmotility, 18 fibrinolytic enzymes, 289
estrogen, 34, 200-202, 280 fibro fog. See cognitive
eszopiclone, 26, problems
etanercept, 206 Fibromyalgia Impact
etilefrine, 157 Questionnaire, 177
etiology. fish oil, 300
CFS/ME, 14-15 flavocoxid, 284-285
fibromyalgia, 16-17 flavonoids, 284, 309
See also theories flavoxate, 253
etodolac, 46, 50 Flechas, Jorge, 181, 203
etoricoxib, 51-52 flu. See influenza
exercise fluconazole, 100-102
CFS/ME and, 13 fludrocortisone, 181, 184, 197-198
drug metabolism and, 301 fluid retention, 156, 183, 196-
growth hormone and, 237 197, 205
tolerance, 178, 206, 276 flu–like symptoms, 24, 29, 38, 75,
expectorant, 282 98, 215
eyes FluMist, 307
dryness, of, 199 fluoroquinolones, 89
Index 331
fluoxetine, 118-120 GET. See graded exercise

flupirtine, 64 GHB. See sodium oxybate
flurbiprofen, 51 Giardia lamblia, 93
fluvastatin, 286-287 ginger, 300
fluvoxamine, 120 ginkgo, 300
folic acid, 258 ginseng, 300, 309
folinic acid, 258-259 glaucoma, 243, 255
food intolerances, 14, 257 glial cell activation, 277
food poisoning, 65 glucocorticoids, 66, 195-197, 290
foscarnet, 98-99 glucose metabolism, 195
free radical scavenger, 160 glucose tolerance, 161
fructose intolerance, 17 glutathione, 135, 212, 247, 249
functionality, 30, 33, 159, 177, 209 glutamate, 76, 80, 83, 161, 180,
fungal infections, 100-102 183-184, 233, 288
See also NMDA
antagonists
GABA glycemic control, 161
anticonvulsants and, 76-77, glyceryl trinitrate, 180-181
79 glycine, 38, 65, 94
definition, 313 goldenseal, 300
NMDA and, 28, 232 Goldstein, Jay
benzodiazepines and, 26, 28 combinations, 81-83, 123,
GABAB agonist, 34 138, 305
other GABAergic drugs, 58, recommends, 24-25, 29,
65, 129, 240, 288 34, 56, 58-59, 61, 67-
racetams and, 163 68, 78, 80, 82-83, 94,
gabapentin, 77-78 121, 128, 138-140, 156,
Gaby, Alan R., 249 164-165, 177, 178,
galantamine, 236-238 182-184, 201, 203,
gammaglobulin, 207-208 233-239, 244, 250,
gamma–hydroxybutyrate. See 257-258, 279, 283, 286,
sodium oxybate 288, 305
gamma interferon, 209-210 recommends against, 24,
ganciclovir, 97 79
gangliosides, antibodies to, 15 observations, 52, 138, 250
garlic, 300 theories, 19, 154, 157, 250,
gastric motility, 251, 299 257-258, 279, 283
gastrointestinal infections, 93, 101, gonadal insufficiency, 200
274 gotu kola, 300
gastroprotectives, 257-258, 281, gout, 65, 283-284, 313
287-288 graded exercise, 13
general anesthesia, 304 Gram–negative bacteria, 92, 254,
genes, 19, 185, 301 Gram–positive bacteria, 118, 254
gender differences, 12, 15, 124, granisetron, 259-260
131, 175, 195, 200, 301 grapefruit juice, 301
gentian, 300 green tea, 300
GERD, 34, 287 Griffonia simplicifolia, 137
and surgery, 305

growth hormone herpesviruses. See
deficiency, 16, 203-204 antiherpesvirals; CMV;
increasing secretion, 31-32, EBV; herpes simplex;
34, 61, 134, 160-161, 173, HHV–6; HHV–7;
237 varicella zoster
guaifenesin, 37, 282-283 Herxheimer reaction. See
guarana, 300 Jarisch–Herxheimer
Gulf War syndrome, 19, 90, 185 reaction
285, 307, 313 HHV–6
Guyer, Dale, 98 amantadine and, 234
antiherpesvirals and, 97-99
CFS/ME and, 8, 95, 97-99
hair loss, 14, 16, 200-201 hypercoagulation, 185
hawthorn, 300 immunomodulators and, 209-
headache 210, 216
chronic, 33, 134, 136-137, lamotrigine and, 80
141, 177 HHV–7, 95
cluster, 61, 159, 247, 311 hippocampus, 16
general, 28-29, 31, 33-35, 61, histamine
64, 66, 76, 100, 113, 122, antagonists. See
156, 163, 166, 178, 181, antihistamines
183, 194, 201, 206, 241, CFS/ME and, 239
247, 256, 259, 286 H3 receptors, 64
migraine. See migraine histamine-releasing anesthetics,
prevention, 32, 112, 129, 177 305
rebound, 46, 59, 303 HIV/AIDS
symptom, 14, 16, 18 fibromyalgia and, 96
tension, 18, 112, 129, 133- treatment, 182, 202, 212,
134, 247 215- 217, 235, 243, 246,
vascular, 60 281, 302
heart failure, 184, 281, 285 HIV negative AIDS, 285
heat intolerance, 14 hives. See urticaria
Helicobacter pylori, 93 Holtorf, Kent, 195, 199
hemp, 244-246 homocysteine, 136, 248, 258, 314
heparin, 185 hormone replacement, 195, 200-
hepatitis, and CFS/ME, 305 201
hepatitis A vaccine, 307 hot flashes, 33, 78
hepatitis B HPA axis
treatment, 98, 209, 211, 215 corticosteroids and, 194-195
vaccine, 307-309 tianeptine and, 135
hepatitis C Hudnell, H. Kenneth, 274-275
fibromyalgia and, 17, 96 human growth hormone. See
treatment, 99, 209, 211, 216- growth hormone
217 hydergine, 164-165
herbs hydralazine, 183
drug interactions with, 300 hydrochlorothiazide, 183-184
Index 333
hydrocodone, 54 imidazoline receptors, 33, 173-174

hydrocortisone, 195-197, 305 imipramine, 115
hydromorphone, 54-55 immunoglobulins
hydroxychloroquine, 212 IgE, 206
hydroxycobalamin. See vitamin IgG, 207-208
B12 hepatitis A/B, 307-308
hydroxyzine, 239-240 treatment with, 207-208
hyoscine. See scopolamine immunomodulators
hyoscyamine, 254 immunostimulants, 30, 193,
hyperacuity, 14, 16, 163 207-216
hyperalgesia, 24 immunosuppressants, 193-
hypercoagulation, 14, 185 197, 205-207, 216-217
hyperhidrosis, 65 antibiotics as, 89-92
hypericum. See St. John’s wort antidepressants as, 111, 117-
hypermobility, 18, 313 119, 129
hyperprolactinemia, 154 benzodiazepines as, 27
hypersomnia, 24, 115, 161 lithium as, 140
hyperventilation, 27 pentoxifylline as, 182
hypoglycemia, 14, 18, 305 incontinence, 65, 124
hypoperfusion individual differences, 30, 57, 112,
brain, 14, 182 154, 162, 166, 199, 301
muscles, 181 indometacin, 49
hypothyroidism. See thyroid inflammation
hypovolemia, 14, 197, 314 definition, 314
fibromyalgia and, 16
treatment. See anti–
IBS inflammatory drugs
anticonvulsants and, 75, 78 infections
antidepressants and, 112, 116, bacterial. See bacteria
119, 122, 133, 135 viral, 95-100
bacteria and, 93 fungal. See fungal infections
diarrhea–predominant, 173 infliximab, 206
fungi and, 102 influenza
parasites and, 93 avian, 215
relation 14, 17-19, 244 CFS/ME and, 8
other drugs and, 31, 53, 61, fibromyalgia and, 96
173, 181, 214, 234, 239, treatment, 99, 212, 234
259, 280 prevention, 234, 309
ibudilast, 277 vaccination, 307, 309
ibuprofen, 27-28, 46, 48 inosine pranobex, 211
ICD–10, 8 insomnia, 16, 24
idiopathic CD4 insulin resistance, 18
lymphocytopenia, 285 interactions. See drug interactions
IL–1, 207, 277 interferon, 99-100, 182, 209-210
IL–2, 182 intermittent claudication, 288
IL–6, 24, 91, 202, 277, 280 interstitial cystitis
IL–10, 38 anticoagulants and, 185, 255
interstitial cystitis (continued) See also temporomandibular

antidepressants and, 113, 118 pain
antihistamines and, 239-240,
258
definition, 314 kappa opioid receptor, 54, 57-58
fungal infections and, 102 Kerr, Jonathan, 205
other drugs and, 78, 156, 174, ketamine, 233, 235
254-255, 257, 277 ketoconazole, 100-102
relation, 18 ketoprofen, 47
small intestinal Klenner, Frederick R., 249-250
bacterial overgrowth, 93 Klimas, Nancy, 117
interstitial pneumonia, 250 Klonopin, 28-29
intolerances van Konynenburg, Richard, 258
food, 14, 257 KPNQ potassium channels, 64
fructose, 17 Kutapressin, 210
gluten, 18 kynurenic acid, 284
orthostatic, 19, 121, 157, 289
intrathecal administration, 55
ion channels lamotrigine, 80-81
calcium channels. See Lapp, Charles, 28, 121, 131, 133,
calcium channel blockers 155, 181, 198, 202-203,
CFS/ME and, 15 208, 248, 255-256, 290,
definition, 314 305,
other effects, 58, 163 L–carnitine, 163, 234
potassium channel blockers, LDN, 214-215
239 learning, 162
potassium channel openers, leucovorin, 258-259
64 leukotrienes, 277
sodium channels. See levetiracetam, 82
sodium channel blockers Levin, Arnold Mervyn, 100
iron, 300 Levine, Susan, 204
irritability, 16, 100 levocetirizine, 240
isoflurane, 305 levodopa, 158-159, 319
isomethepene, 59 levofolinic acid, 258-259
isoprinosine, 211 levothyroxine. See thyroxine
isoxsuprine, 288-289 Lexapro, 121-122
itroconazole, 101-102 licorice root, 300
IVIG, 207-208 libido, 100, 201, 203
lidocaine, 62, 66-68, 182-183
Jadin, Cecile, 284 lightheadedness. See dizziness,
Jarisch–Herxheimer reaction vertigo
definition, 90 life extension, 130
probenecid and, 284 liothyronine, 198-200
Jessop, Carol, 100 lipofuscin, 167
joints lisdexamphetamine, 156
hypermobility, 18, 312 lithium, 140-141
pain, 13, 93, 194, 200 liver derivative complex, 210
Index 335
liver disorder, 120. See also methylcobalamin. See vitamin

hepatitis B12
liver function, 135, 204 methylene blue, 254
local anesthesia, 304 methylphenidate, 155
local anesthetics, 34, 56, 66-67, methylprednisolone
176, 251, 254 metoclopramide, 59
lorazepam, 39 metoprolol, 176-177
losartan, 281-282 metronidazole, 93
Lou Gehrig’s disease. See ALS metyrapone test, 194
lovastatin, 286-287 mexiletine, 182-183
low dose naltrexone, 5, 214-215 mianserin, 133-134
L–tryptophan, 136-137 microemulsions, 47
lumiracoxib, 47 midazolam, 305
Lunesta, 26 midodrine, 156-157
lupus. See SLE migraine
Lyme disease. 89, 93, 212, 214, prevention, 31-32, 34, 60-61,
237, 274-275 65-66, 75-77, 80-82, 112,
lymph nodes, 14, 206 129, 134, 136, 141, 165,
Lyrica, 15, 78 173, 175-180, 215, 234,
235-237, 242, 244, 249,
255-256, 277, 282, 286
macrolides, 92-93 refractory, 55
malignant hyperthermia, 37 symptom, 14, 18-19, 244
mania, 140-141, 178 treatment, 46, 48, 58-59, 61-
MAO inhibitors, 127-130 62, 64, 79, 165, 202, 235,
Marinol, 246 244, 247, 249
Marshall protocol, 90-91, 281 with aura, 80, 82
mast cells, 255 Miller, Claudia S., 19
meclofenoxate, 167 milk, 301
meclozine, 242 milnacipran, 124-125
medical emergencies. See mineralocorticoids
emergency aldosterone, 195
melatonin, 30-31 synthetic, 197-198
meloxicam, 46, 49-50 antagonist, 184
memantine, 233-235 minocycline, 90-91, 281
memory, 13, 78, 134, 162, 166, Mirapex, 159-160
177-178, 200, 232, 236 mirtazapine, 133-134
menopause. 33, 78, 166, 200-201 misoprostol, 257
menstruation. See periods mistletoe, 300
meperidine, 56-57 mitochondria, 15, 31, 315
mercury, 308 mitral valve prolapse, 18-19, 100,
metaxalone, 36-37 315
methamphetamine, 131 MMR vaccine, 307
methenamine, 254 moclobemide, 128-129
methocarbamol, 37 modafinil, 161-162
methotrexate, 258 monoclonal antibodies, 206
methylation, 258-259 montelukast, 277-278
mood guaifenesin as, 282

improvement, 125, 133, 181, sodium oxybate as, 32
256 surgery and, 305
magnesium and, 246 muscles
serotonin and, 111 ache, 33-35, 237, 247, 249
stabilizers, 77, 82-83, 140- biopsies, 15, 95-96
141 circulation, 179, 181
swings, 163, 317 cramps, 16, 33-34, 78
oxytocin and, 203 exercise and, 13
testosterone and, 201 fatigability, 13
See also depression; bipolar findings in fibromyalgia, 16
disorder pain, 13, 34, 61, 178, 194,
morning stiffness, 16, 48, 117, 200, 206
120, 209 spasms, 65, 243, 247, 249
morphine, 53, 57 spasticity, 33-34, 37, 60, 243
Moskowitz, David, 282, 285 stiffness, 34, 247
motherwort, 300 strength, 208
motion sickness, 166, 239, 242, tension, 14, 35, 75
280 weakness, 33, 100, 194, 201,
mountain sickness, 255 215, 236-237, 248
moxonidine, 174 See also myofascial pain
mucolytic, 212, 278, 315 mushrooms, 276, 300
multiple chemical sensitivity, 18, myalgia. See muscle pain
19, 100-101, 213, 247- myasthenia gravis, 236-237
248, 304 mycobacteria, 94, 214
multiple sclerosis Mycobacterium vaccae, 214
fatigue in, 134, 161, 233 mycophenolate, 216-217
CFS/ME and, 12 mycoplasma, 17, 89-91, 185
cognitive problems in, 237 myelin formation
coxsackieviruses and, 250 Myers’ cocktail, 67, 249
definition, 315 Myhill, Sarah, 27-28, 247-248, 258
spasticity in, 33-34, 243 myoclonus, 136, 164
treatment, 91, 182, 209, 214, myofascial pain, 18, 33, 66-67,
234, 243, 246, 248, 257, 159, 247, 260, 315
275, 277, 286, 290
mu opioid receptor, 54, 56, 58,
235, N–acetylcysteine. See
muscarinic cholinergic receptors acetylcysteine
agonists, 58, 78 nabilone, 246
antagonists, 116, 137, nabumetone, 50
252-254 naloxone, 59
antibodies to, 15 nanobacteria, 90
muscle relaxants naphazoline, 279
analgesics as, 64-65 naproxen, 48
benzodiazepines as naratriptan, 61
cannabinoids as, 243 narcolepsy, 32, 114-115, 125, 130,
class of drugs, 32-38 155-156, 161, 315
Index 337
narcotic painkillers, 52-59 75, 124, 181, 233

nasal sprays, 29, 61-62, 65, 203- CFS/ME/FM and, 13, 16
204, 275-276, muscle relaxants and, 33-
nausea, 14, 16, 62, 133, 137, 243, 35, 64
246, 259, 280, 281, 298 NMDA antagonists and,
nefazodone, 131-133 95, 233, 235
nefopam, 63-64 other drugs and, 158, 173,
neurally mediated hypotension, 18, 182, 213, 247-248, 275,
251, 279, 316 277-278
See also orthostatic local treatments, 65, 67-68,
hypotension 235
neurokinin1 receptor, 281 trigeminal neuralgia, 35, 61,
neuroleptic drugs, 137-140 257
neuroleptic malignant neuroprotective, 31, 91. 135, 159,
syndrome, 37, 137, 234 163, 202, 243, 255, 277,
neurological symptoms 284, 316
aphasia, 166 neurosomatic medicine, 19, 235
apraxia, 166 neurotoxins, 65, 274
cognitive problems. See neutrophils, 154-155
cognitive dysfunction NF–kappa B, 46, 77, 179, 182,
coordination problems. See 217, 235, 277, 279,
coordination 285, 316
dizziness, 14, 34, 100, 166, Nexavir, 210
182, 316 Nexium, 287
in general, 8, 13, 25, 75, 163- nicergoline, 165
166 Nicolson, Garth, 89
nystagmus, 14 nicotinic cholinergic receptors,
paresthesias, 14, 16, 76, 316 126, 233, 238, 252
photophobia, 14, 16, 62, nifedipine 179-180
163, 194 nightmares, 27, 173
seizures. See epilepsy night sweats, 14
spasticity, 33-34, 37, 60, 243 nilvadipine, 180
tinnitus. See tinnitus nimodipine, 178-179
tremor, 14, 163 nitrates, 180-181
vertigo, 14, 139, 163, 165, nitric oxide, 19, 28, 30, 36, 38,
239, 242, 256, 280 111, 121, 154, 180, 183-184,
vision disturbances 243, 247-248, 275, 277-278.
Neurontin, 77-78 See also peroxynitrite
neuropathic pain nitroimidazole, 93
burning or electric, 77 nitrous oxide, 305
sharp and stabbing, 76 NK cells, 185, 209, 211, 215, 316
anticonvulsants and, 75-82 NMDA receptor
antidepressants and, 124, agonists, 162
127 antagonists, 34, 56-57, 64, 82,
cannabinoids and, 243 177, 200, 232-236, 246,
definition, 316 250, 258, 283-284, 288
diabetic neuropathy, 65, GABA and, 28
glycine coagonist site of, 38, receptors, 54, 56-58, 133,

94 160, 235
NR1/NR2B subunits, 288 sedation, 155-156, 236
See also glutamate tolerance, 52, 203, 232
nocturia, 24-25, 78, 112-113, opportunistic infections, 89, 100
316 oral anticoagulants, 300
nocturnal awakenings, 29, 78, 82 oral contraceptives, 200-201, 302
NO/ONOO theory, 19, 121, 232 organophosphates, 15
nootropics organ transplant, 216
cinnarizine as, 242 orphenadrine, 34-35
class of drugs, 162-167 orthostatic hypotension
definition, 162 osteoarthritis, 17, 46, 135, 139,
desmopressin as, 204 284, 316
modafinil as, 161 overactive bladder, 64, 78, 115,
selegiline as, 130 124, 163, 173-174, 251,
noradrenaline. See norepinephrine 255, 281, 314
norepinephrine oxcarbazepine, 76
role, 111, 154 oxidative stress, 15
NRIs, 125-127 oxpentifylline, 181-182
reuptake inhibitors, 112- oxybutynin, 251-252
117, 121, 127-130, 161, oxycodone, 54
256 oxytocin, 34, 157, 203
sympathomimetic drugs, 154-
158
other drugs, 132, 165 pain
See also SNRIs aches, 28-29, 33-35, 122,
nylidrin, 288-289 200, 237, 247
nystagmus, 14, 244 abdominal, 14, 61, 101, 112,
nystatin, 101 194
back, 65, 116
bladder, 258, 314
OCD, 115, 120, 121 breakthrough, 52, 54-56, 311
oedema. See edema bones, 275
olanzapine, 137 cancer, 55, 64
olive leaf, 300 chronic, 52-57, 63, 65, 75,
olmesartan, 90, 91, 281-282 79-80, 111, 115-117, 123,
omalizumab, 206-207 131, 137, 177, 232, 237,
omeprazole, 287-288 245, 275, 278, 284
ondansetron, 259-260 CFS/ME, 13-14, 28-29, 34,
opioids 46, 52, 54, 58, 137, 178,
adjuncting, 155-156, 174, 183, 206, 210, 237-238,
232, 239, 258, 277 256, 259, 286, 290
antagonists, 214 chest, 16, 180, 315
atypical opioids, 58 cytokines and, 24, 37, 202
endogenous opioids, 214, 285 early morning, 195
partial agonists, 57 facial, 16, 319
painkillers, 52-58 fibromyalgia, 15-16, 30, 33,
Index 339
35-36, 47, 54, 58, 64-65, partial seizures, 75

67, 78-79, 117, 122, 126, parvovirus B19, 96, 208
128, 131, 133, 135, 137, passionflower, 300
141, 159, 180-181, 183, patents
202-203, 208, 232, 237, CFS/ME, 126, 135, 201, 214,
246, 256, 259, 275, 284 276
in general, 24, 28, 30, 38, 47, fibromyalgia, 93, 126, 201,
76-77, 113, 115, 120, 237
124-126, 131, 137-138, IBS and dyspepsia, 135
163, 173, 200, 215, 232, overactive bladder, 64
236-238, 243, 246, 259, patent medicine, 243
joints, 13, 93, 194, 200 pau d’arco, 300
low back, 64-65, 126 pegademase, 285
lymph nodes, 206 Pellegrino, Mark, 53
mild to moderate, 53, 57-58 pentazocine, 58-59
muscles. See muscle, pain pentosan polysulfate, 255
myofascial. See myofascial pentothal, 305
pain pentoxifylline, 181-182
neuropathic. See neuropathic performance anxiety, 175
pain performance speed, 162, 167
periods. See dysmenorrhea peptides, 211, 214
pump, 55 periods
refractory, 67-68, 94, 156 pain. See dysmenorrhea
severe, 49, 52, 54-57, 67-68, irregularity of, 200
94, 241 See also: PMS
surgery, 305 peroxynitrite, 19, 30, 195, 215
temporomandibular, 18, 65, See also nitric oxide
319 pertussis vaccine, 309
vulva, 18, 277 Peterson, Dan, 98
See also headaches; pethidine, 56-57
osteoarthritis; PET imaging, 154
painkillers; rheumatoid pH, 255, 299
arthritis; RSD; sore phenazopyridine, 254-255
throat; tender points phenelzine, 129-130
Pall, Martin, 19, 121, 213, 232, phentermine, 158
248 phenyl salicylate, 254
palpitations, 14, 315 phenytoin, 83
panic attacks, 26, 29 phobias, 94
panic disorder, 77, 179 phosphate deposits, 282-283
paracetamol. See acetaminophen phosphatidyl serine, 258
paramyxoviruses, 99 phosphodiesterase inhibitors, 165-
parasites, 93, 207 166, 181-181, 253, 276-
parathyroid hormone, 275 277
paresthesias, 14, 16, 76, 316 phospholipids, antibodies to, 15,
Parkinson’s disease, 25, 81, 130, 17
154, 158-160, 233, 317 photophobia, 14, 16, 62, 163,
paroxetine, 118, 121 194
physiotherapy, 120 primary fibromyalgia, 16

pindolol, 177 Prilosec, 287-288
pioglitazone, 275 ProAmatine, 156-157
piperine, 300 probenecid, 284
piracetam, 163-164 procaine, 66-67
pirlindole, 128 Procrit, 289-290
piroxicam, 47, 49 prognosis, 20
pizotifen, 60 prolactin, 154
plantar fascitis, 17 prolapsed disc, 205
plasmin/plasminogen, 289 propofol, 305
platelet aggregation, 47, 163, 165, propoxyphene, 57
277, 282, 286 propranolol, 176-177
pleasure, 154 prostaglandin analogue, 257
Pneumovax, 307 prostate
Podell, Richard, 28, 33, 159, chronic prostatitis, 18
198, 233, 290 hypertrophy, 173-175
polio proton pump inhibitors, 287-288
vaccine, 307-309 protriptyline, 114
viruses, 95-96 Provigil, 161-162
Polo, Olli, 175, 205, 287 Prozac, 119-120
polyI:polyC12U, 215-216 psoriasis, 19, 216
polysaccharide psoriatic arthritis, 275
polysymptomatic patients, 101 psychiatric drugs. See
pomegranate juice, 301 antidepressants;
post–exertional malaise, 13, 122 antipsychotic drugs
post–Lyme syndrome. See psychosis
Lyme disease antipsychotic drugs, 137-
post–polio syndrome, 154, 161 140
post–traumatic fibromyalgia, 16 schizophrenia, 91
post–traumatic stress disorder. See psychosocial construct, 12, 15
PTSD PTSD
POTS, 237 relationship, 19
PPARgamma, 48-49, 275 anticonvulsants and, 76-
pramipexole, 159-160 77, 79-83
prazosin, 174-175 antidepressants and, 120-
precursors 121, 130, 134
definition, 317 definition, 317
to dopamine, 158-159 other drugs and, 137-138,
to serotonin, 136-137 173-174
to sex hormones, 202 pulse treatment
prednisone/prednisolone, 196-197 antibiotics, 89, 93
pre-emptive analgesia, 305 IVIG, 208
pregabalin, 15, 78-79, 140 corticosteroids, 290
pregnancy, 241-242, 302 melatonin, 30
Premarin, 201 pyridostigmine, 236-237
premature birth, 288 pyritinol, 167
pressor. See vasopressor P450. See CYP450
Index 341
CFS/ME, 80, 197-198, 210,

305
Q fever, 89, 91. See also Coxiella depression, 280
burnetii interstitial cystitis, 155
quality of life, 24, 30, 52, 138, fibromyalgia, 305
203-204, 250 migraine, 82
quercetin, 309 REM sleep, 80, 116, 173
Questran, 274-275 respiratory infections, 249, 278
quetiapine, 140 restless legs syndrome
quinolones. See fluoroquinolones anticonvulsants and, 76, 78,
Q10, 300 82
benzodiazepines and, 28-29
definition, 318
rabeprazole, 287-288 dopaminergic drugs and, 127,
racetams, 82, 163-164 158, 160, 233
raloxifene, 280 folinic acid and, 258
ramelteon, 31-32 muscle relaxants and, 33-34
ranitidine, 257-258 other drugs and, 25, 165, 173
rasagiline, 131 opioids and, 52
rashes, 14, 197. See also urticaria symptom, 15-16, 18, 25
Raynaud’s phenomenon, 18, 163, rheumatoid arthritis, 12, 17, 91,
165, 174, 179, 247, 288, 317 116-117, 156, 160, 167,
rebound headache, 46, 59 182, 206-207, 318
reboxetine, 125-126 rhinitis
red blood cell. See erythrocyte chronic, 14, 18
Reeves, William, 12 allergic, 249, 277
reflex sympathetic dystrophy. See definition, 318
RSD ribavirin, 99-100
refractory rickettsiae, 89
anxiety, 129 rifampicin, 302
definition, 318 rifaximin, 93-94
CFS/ME/FM, 59, 94, 128, riluzole, 234
137-138, 204 risperidone, 138-139
depression, 57, 115, 123, 128, Ritalin, 155
197, 199, 235 RNase L, 236
hepatitis C, 217 rofecoxib, 47
infections, 289 ropinirole, 160
interstitial cystitis, 156 Rosenbaum, Michael E., 25
migraine, 55, 235 rosiglitazone, 275
pain, 67-68, 94, 156 rotigotine, 160
panic disorder, 179 RSD, 278
trigeminal neuralgis, 257 ryanodine receptor, 37
regional anesthesia, 304
relapse, 13, 303, 304-305, 307
Remeron, 133 salicylates, 47, 254, 283
remission saline, 250-251
celiac disease, 277 SAM–e, 135-136
Sarapin, 66 sexual dysfunction

sarcoidosis, 90, 282 caused by illness, 14, 127
sartans, 281-282 caused by SSRIs, 127, 134,
Sativex, 246 159
Schizophyllum commune, 276 Sharp, Larry, 211
schizophrenia, 91, 138-140 Shepherd, Charles, 120-121
sciatica, 18 shingles, 96
SCID, 285 Shoemaker, Ritchie C., 274-275
scopolamine, 280-281 short stature, 16, 203
scurvy, 249 Siberian ginseng
seasickness, 280 sibutramine, 256
Seastrunk, Jay W., 77 sigma receptors, 58, 80, 233,
seborrheic dermatitis, 17, 197 235
secondary fibromyalgia, 16 sildenafil, 276
selective estrogen receptor silicone breast implant
modulator, 280 syndrome, 18
selegiline, 130-131 Simpson, Leslie O., 182, 248
senile dementia, 164 simvastatin, 286-287
sensitivity sinusitis, 18, 102, 249, 282
chemicals. See multiple sizofiran, 276
chemical sensitivity S–ketamine, 235
food, 14, 257 Sjögren’s syndrome, 17, 213
light. See photophobia skin
medications, 19 fibromyalgia and
noise. See hyperacuity penetration of NSAIDs
temperatures, 14 rashes
Seroquel, 140 Skinner, Gordon R., 199
serotonin SLE, 17, 160, 202, 212, 214, 217,
antagonists, 60 234, 290
antibodies to, 15, 17 sleep aids
deficiency, 16 anticonvulsants as, 75, 77-82
immune system and, 111 benzodiazepines as, 26-29
precursors, 137-138 Z drugs, 24-26
receptors. See 5–HT sleep apnea, 18, 24, 206, 244, 260,
receptors 318
reuptake inhibitors, 111-125, small intestinal bacterial
233, 241, 256 overgrowth, 93-94
reuptake enhancer, 135 smallpox vaccine, 307
serotonergic drugs, 35, 56, smart drug. See nootropic
58, 61-64, 81, 127-135, smoking
164, 177, 214, 237 cannabis, 245
serotonin syndrome, 37 cessation, 126-127, 173
sertraline, 118, 120-121 drug interactions, 301
setrons, 259 SNRI drugs
severe CFS/ME, 12, 25, 179, 200, antidepressants, 122-125
208, 216, 250, 280, 309 nefopam, 63-64
sexual arousal, 203 opioids as, 56, 58
Index 343
SNRI drugs (continued) 287

sibutramine, 256 upset, 113, 257, 313
sodium channel blockers, 57, 63- virus, 96
64, 75, 76, 80, 81, 112, See also IBS; dyspepsia;
165, 234-235, 239 gastric motility
sodium oxybate, 32 strains
soft tissue rheumatism, 164 (injuries), 36
solifenacin, 253 (medical cannabis), 245
somatropin. See growth Strattera, 126
hormone streptokinase, 289
sore throat, 14, 100, 181, 199 stroke, 47, 124, 162-164, 166, 178,
spasticity, 33-34, 37, 60, 243 277
SPECT scans, 182 subgroups of fibromyalgia
spironolactone, 184 substance P, 33, 61, 173, 247, 259,
sprains, 36 280-281
stage 4 sleep, 47, 258 sudden onset, of CFS/ME, 98, 216
St. Amand, Paul, 282-284 sulbutiamine, 166
staphylococci, 90, 213 sulpiride, 139
staphylococcus toxoid, 213 sumatriptan, 61-62
Starlanyl, Devin, 102, 134, 258 supplements, 30-31, 137, 163-
Stein, Eleanor, 118, 123 164, 166-167, 211, 213,
steroids 234, 246-251
corticosteroids, 67, 194-198, surveys, 25, 27-28, 100-101, 247
290, 305 SV–40, 308
sex steroids, 200-202 sympathomimetic
stimulants definition, 154
alprazolam as, 28 drugs, 154-158, 177, 279
corticosteroids as, 195 hyperactivity, 16, 176
dopaminergic drugs, 130-131, See also SNRIs,
160-161 noradrenaline reuptake
nootropics as, 166 inhibitors
pethidine as, 56 synergy, 83, 117, 163, 174, 302
psychiatric drugs as as, 114,
125-127, 130-131, 133,
139 tachycardia, 14, 319
sympathomimetics, 154-158, See also POTS
161-162, 279 tacrine, 238-239
tamsulosin as, 175 tadalafil, 276
St. John’s wort, 300 Tagamet, 257-258
stomach tamsulosin, 175
acidity, 113, 257, 287, 299 tardive dyskinesia, 137
pain, 14, 101, 194 taurine, 247, 288
problems, 100 Teitelbaum, Jacob
protection. See pain treatments, 67, 76, 79-
gastroprotectve drugs 82, 115, 138, 141, 237-
spasms, 251 238
ulcer, 46-47, 50, 93, 257-258,
Teitelbaum, Jacob (continued) thyroid, 16-18, 198-200, 275

other treatments, 101-102, tiagabine, 79-80
138, 141, 159, 247, 249 tianeptine, 134-135
telmisartan, 281-282 tics, 243
temazepam, 28 Tietze’s syndrome. See
temperature costochondritis
body temperature, 78, 134 TILT, 19
sensitivity, 14 tinnitus, 14, 19, 28, 31, 79, 83,
temporomandibular pain, 18, 65, 139, 163-167, 179, 182,
319 242, 257
tender points tiredness, 26, 33, 118, 127, 247-
as a symptom, 14, 16 248
etiology, 16, 195 tizanidine, 33-34
injections, 66-67 TMD. See temporomandibular
treatment, 30, 33, 35, 135, pain
177-178, 204 TNF alpha
testosterone antibodies to, 205-206
antagonism, 184 definition, 319
treatment, 200-202 drugs that reduce, 38, 127,
tetanus vaccine, 213, 307 155, 182, 277, 280
tetracyclic antidepressants, 133- tolterodine, 252
134 topiramate, 81
tetracyclines, 90-91 Tourette’s syndrome, 243
tetrahydrocannabinol, 244-246 toxins
tetrahydrofolate, 258 GWS and, 313
Th1/Th2 balance, 185, 193-194 mercury, 308
thalidomide, 217 neurotoxins, 274
THC, 243-246 bacterial toxins, 65-66, 213,
theophylline, 278-279 274, 307
theories ciguatera, 15, 274
CFS/ME, 8-9, 14-15, 18-19, organophosphates, 15
90, 96, 100, 154, 177 185, removing, 212-213, 274
209, 239, 274, 308 toxicant–induced loss of
fibromyalgia, 8-9, 16-19, 90, tolerance, 19
154, 156, 199, 232, 244, toxoids, 213, 307
282 Toxoplasma gondii, 89
GWS, 185, 313 tramadol, 53, 58
IBS, 93, 244 transdermal
interstitial cystitis, 93, 102, definition, 319
156 gels/creams, 210, 234
migraine, 244 patches 130, 155, 160, 289
restless legs, 93 testosterone, 201
thiamine, 166, 247 tranylcypromine, 130
thiazolidinediones, 275 trazodone, 26, 28, 131-132
thiocolchicoside, 65 treatment–resistant. See refractory
thiomersal, 308 triamcilone, 66
thymalfasin, 211-212 triazolam, 29
Index 345
tricyclic antidepressants, 112-118 valdecoxib, 47

trigeminal nerve, 279 valerian, 300
trigeminal neuralgia, 34, 61, 257 valganciclovir, 97-98
trigger points, 14, 66-67, 315 Valium, 27
triglycerides, 180 valproate, 76-77
trimethoprim, 89 valsartan, 281-282
trimethylglycine, 258 varicella zoster
trimipramine, 116 treatment, 96, 98
triptans, 61 vaccination, 307
tropisetron, 259-260 vaporizer, 245
trospium, 252-253 vascular problems. See intermittent
tryptophan, 136-137 claudication; Raynaud’s
tumor necrosis factor. See phenomenon; headache,
TNF alpha vascular
turmeric, 300 vasoconstrictors
Tylenol, 63 definition, 319
typhoid vaccine, 307 migraine and, 59, 61
orthostatic hypotension and,
157
ulcer secretions and, 279
aphthous (mouth), 182 vasodilators
peptic (stomach), 46-47, alpha-adrenergic, 173-175
50, 93, 257-258, 287 beta agonists, 288-289
ulcerative colitis, 205 calcium channel blockers,
Ultram, 58 177-180
ultrasound therapy, 120 definition, 319
uric acid, 184, 283-284, 313 others, 165, 180-181, 183,
urinary frequency, 16, 100, 256, 277, 285-286
175-176, 204, 239, surgery and, 305
251-255, 314 vasopressin, 115, 203-205
See also overactive vasopressors, 157-158
bladder vasospasm, 178
urinary tract vasovagal syncope, 121
incontinence, 124 vegetables, 283, 301
infections, 50, 254 venlafaxine, 118, 123
pain, 14 verapamil, 178
symptoms, 175 vertigo, 14, 139, 163, 165, 239,
urine retention, 53, 64, 241 242, 256, 280
urogenital symptoms, 101 Viagra, 276
urokinase, 289 Vicodin, 54
urticaria, 14, 156, 239, 249, 278 vigabatrin, 79
vigilance, 111, 154
vinpocetine, 165-166
vaccinations visual disturbances, 14, 181
adjuncts to, 211 vitamin B complex, 136, 249
risks and benefits, 307-309 vitamin B1, 166, 247
valaciclovir, 97 vitamin B6, 82, 95, 136, 167, 243,
300, 314
vitamin B12, 136, 247-248, 259,
314 Zadaxin, 211-212
vitamin C, 249-250 zaleplon, 24-26
vitamin D Zanaflex, 33-34
fibromyalgia and, 16 Z drugs, 24-26
Marshall Protocol and, 90, ziprasidone, 139-140
91, 281 Zithromax, 92
vitamin E, 300 Zoloft, 120-121
vitamin K, 300 zolpidem, 24-25
Vliet, Elizabeth Lee, 200-201 zonisamide, 81-82
vulvar vestibulitis, 18, 277 zopiclone, 26
vulvodynia, 18
5–fluorouracil, 258
water retention, 156, 183, 196-197, 5–HT. See serotonin
205 5–HT receptors
weight, gaining 5–HT1, 60
anticonvulsants, 76-79 5–HT1A, 134, 139, 177
hormones, 196, 201-202, 280 5–HT1B/1D, 60-61,
other drugs, 60, 182, 246, 5–HT2, 35, 116-117, 131,
252, 275, 133, 137, 138, 140
psychiatric drugs, 113-114, 5–HT2A, 60
118-119, 122, 124, 129, 5–HT2C, 60, 119
133, 137-140, 5–HT3, 80, 133, 136, 177,
as a symptom, 20, 234, 259
weight, losing, 20, 81-82, 124, 5–HTP, 136-137
126-127, 130, 156, 158- 5–LOX, 277, 284
159, 182, 256, 258
Wellbutrin, 126-127
Wheldon, Charles, 92-93
White, Hillary D., 201
WHO, the, 12
word recall, 162, 164
work, returning to, 98-99, 203,
208, 213, 250
Wright, Andrew J., 30, 101, 178-
179, 198, 205
Xanax, 27-28
Xyrem, 32-33
yeast. See candida

Yunus, Muhammad B., 18
yuppie flu, 12

Fibromyalgia Treatment

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Fibromyalgia Treatment

Uploaded by

Copyright:

Available Formats

Reviving the

© 2008 Maija Haavisto

Cover design: Stephen Caissie

This book is dedicated to the memory of Kathleen Walker.

am specifically against is the ridiculous and unfounded idea that

Chronic fatigue syndrome/myalgic

CFS/ME is a serious neurological illness, which is poorly known

CFS/ME is often mistaken for chronic fatigue, but it is much more

There are dozens if not hundreds of different theories about the

CFS/ME is not generally considered an autoimmune illness, but

Fibromyalgia is even more common than CFS/ME. Some

The hallmark symptom of fibromyalgia is pain. According to the

mon tender points must be painful (not just tender) on palpation.

There are thought to be several subtypes of fibromyalgia. One com-

Relationship with other illnesses

Both fibromyalgia and CFS/ME commonly occur together with other

Common comorbidities in CFS/ME

Common comorbidities in fibromyalgia

• enthesopathies (such as plantar fascitis)

Common comorbidities in both

• premenstrual syndrome (PMS)

Several theories have sprung up to explain why CFS/ME, fibromy-

loss/gain, elevated blood pressure, delayed ejaculation, or sedation in a

Both CFS/ME and fibromyalgia can unfortunately also affect child-

1 Njoku MG, Jason LA, Torres–Harding SR. The prevalence of chronic

15 Bradley LA, McKendree–Smith NL, Alarcón GS, et al. Pain comp-

29 Félix FH, Fontenele JB. Is fibromyalgia a cardiovascular disease? A

CFS/ME and fibromyalgia are frequently associated with major

zolpidem (Ambien, Stilnoct, Stilnox, Zoldem, Ivadal)

As the half–life of zolpidem is only 2–3 hours, some patients may

zaleplon (Sonata, Starnoc, Zalep, Zaplon, Zerene)

Zaleplon has a very short duration of action: its half–life is only an

Canada and some other countries, but not in Australia. It is somewhat

zopiclone (Imovane, Zimovane, Zileze, Zopiclone)

Zopiclone has a longer half–life than zaleplon and zolpidem, about

Benzodiazepines bind to the so–called benzodiazepine receptor in

paradoxically cause irritability, even aggression. Benzodiazepines

diazepam (Valium, Stesolid, Diazepam, Apaurin,

Diazepam has a long duration of action, but a rapid onset as well. It

alprazolam (Xanax, Alprox, Frontin, Helex, Tafil)

Alprazolam has a fairly short duration of action and is often used

drug alone.21 However, a second double–blinded study concluded that

temazepam (Restoril, Normison, Euhypnos, Remestan,

Temazepam is the most sedative of all benzodiazepines with a

clonazepam (Klonopin, Rivotril, Paxam, Clonapam,

Clonazepam is a stronger anticonvulsant and muscle relaxant than

improvement in both cognitive symptoms and flu–like pains and

lorazepam (Ativan, Merlit, Lorans, Temesta, Lorapam)

Lorazepam has a medium duration of action. It is sometimes used

triazolam (Halcion, Trycam)

Triazolam has a very short duration of action. In the treatment of

Other sleep aids

anticonvulsants (CHAPTER 3), trazodone, mirtazapine,

melatonin (Transzone, Circadin)

Melatonin is a hormone produced by the pineal gland with major

growth hormone.44 Not only is melatonin neuroprotective45,46, it also

Ramelteon presents a novel mode of action compared to other

somnia. It is likely to be more widely available in the near future.

sodium oxybate (Xyrem, Alcover)

Sodium oxybate (gamma–hydroxybutyrate) is an endogenous sub-

Muscle relaxants are often helpful in relieving muscle pain and

clonazepam, diazepam, sodium oxybate (CHAPTER 1), flupirtine,

tizanidine (Zanaflex, Sirdalud)