PainChampions

October 16, 2016

WHAT HAPPENS WHEN PAIN GOES UNTREATED?

Not only is it inhumane to tell people with impossible pain to just suck it up as I said
in the previous article: untreated or under-treated pain is more than uncomfortable.
There are profound effects on someone who lives with pain. Many of us living with
pain would respond sarcastically, No. Really?! Yes, many of those changes seem like
common sense, but it helps us know the details.

A 1999 Chinese study of cancer patients showed that, after taking into account the
effects of cancer, the more pain someone had, the worse the effects on their health
and how they functioned. Understandably, the relationship between the severity
of pain and impairment was nonlinear: patients with no pain or only mild pain were
significantly better functioning than those with moderate and severe pain.1

Dr. Forest Tennant has written, Persistent pain, which is also often characterized
as chronic or intractable, has all the ramifications of a disease in that it may have
pre-clinical and overt phases. It may be intermittent or constant, as well as, mild,
moderate, or severe. The most unappreciated clinical feature of persistent pain,
however, is the plethora of complications that may resultparticularly if the pain is
constant and unremitting.2

Our doctors are more likely to listen to us and treat our pain if they can see
evidenceand as people with pain, the more we know about what the consequences
are, the better we can work to prevent them and search out more appropriate tools
for our pain toolbox.

Pain steals the resources we need to get through our days. Lets define some of these
losses by looking at three general areas:

Neural and brain changes;

Physical damage (cardiovascular, respiratory, immune system); and

Social and psychological effects.

PainChampions October 16, 2016 Page 2

NEURAL AND BRAIN CHANGES

Pain is serves as a warning; the feeling of pain triggers a fight-or-flight response,

telling us that were in danger and that we need to fix whatever is causing us injury.
If the pain continues, our body and brain dont understand why, and the sensation of
pain is increased to get our attention and make us fix the problem. This is the neural
change with which most doctors are probably familiar, the adaptation our nervous
systems make when pain persists.

The Societys Pain Management Medical Resource Guide describes it this way: A
cardinal feature of EDS is pain. At first there are just small pains; but acute pains may
accumulate, then become continual and chronic. There may be a major dislocation of
injury to start the cycle; but without adequate treatment, persistent pain can change
the nervous system in a process that is difficult to reverse. By lowering the threshold
for pain signals, chronic pain becomes harder to treat.3

Reduced to one statement: acute pain that is inappropriately managed can result in
neural changes which can progress to chronic pain.4

This is particularly crucial to remember with EDS, because its nearly impossible for us
to prevent acute pain. The connective tissue weaknesses were born with affect the
molecular structures that protect our body tissue from stretching too far. Not only
do our joints dislocate fully or partially which may hurt in themselves; all the tissues
around our joints (and on into the muscles, tendons, and fascia that are connected
to those joints) are stretched beyond the ability of the tissue to hold itself together,
so those tissues are injured in a myriad of microscopic tears. Over and over and over.
Even nerve pathways and neurons can be disrupted when tissue stretches too far,
something else our brains will likely interpret as pain.

We are subject to chronic pain in two forms, not only the normal, burned-into-nerve
pathways type of pain commonly called chronic pain, but also chronic acute pain: we
dont injure the tissue around our joints once, but continually, every time a joint slips,
day in, day out.

Its not just our neural net that changes. It turns out our brains adapt, too, but in ways
not directly associated with pain. In a healthy brain, the various regions maintain
a balance; when one region becomes active, the others calm down. In people with
PainChampions October 16, 2016 Page 3

chronic pain, a front region of the cortex that is mostly

associated with emotion never calms down, staying fully
active all the time. This wears out neurons and alters the
connections between neurons; when neurons fire constantly,
they can even die out from such intense activity, causing
permanent damage.

Dante Chialvo, the lead investigator in an 2008 study5

From Northwestern University:
documenting that activity, said, If you are a chronic pain These images show the brain from
patient, you have pain 24 hours a day, seven days a week, the left side, demonstrating
striking differences between
every minute of your life. That permanent perception of pain healthy subjects and chronic pain
patients. They illustrate with color
in your brain makes these areas in your brain continuously how much activation (red/yellow)
active. This continuous dysfunction in the equilibrium of the or deactivation (dark/light blue)
was found at each location.
brain can change the wiring forever and could hurt the brain.
[The changes] may make it harder for you to make a decision or be in a good mood
to get up in the morning. It could be that pain produces depression and the other
reported abnormalities because it disturbs the balance of the brain as a whole.6

Other studies have seen lower numbers of grey matter nerve cells in the brains of
people with chronic pain.7 Another noted significantly less neocortical grey matter
volume, after correcting for intracranial volume, age, and sex, compared to matched
controls; 1.3 cubic centimeters of grey matter (the part of the brain that processes
information and memory) are lost for every year of chronic pain.8 White matter has
also shown to be decreased, which falls in line with neuronal loss but also suggests the
brain is reorganizing connections.9

These changes result from the constant sensation of pain; they reflect the suffering
of perceiving pain and the ways our bodies try to cope with that suffering. Peripheral
and spinal cord nerve systems reorganize their interactions because theyre constantly
in use. Those systems then affect the cortex itself, and all of them continue to try to
negotiate daily life under the barrage of continual pain.10

By the way, the reorganization of information processing in the brain appears to have
other unexpected effects. One thats been documented is a decreased threshold
(increased sensitivity) to taste.11
PainChampions October 16, 2016 Page 4

PHYSICAL DAMAGE

The stress of pain also affects physical systems. Its been documented that acute
untreated pain after operations increases the risk of lung collapse, respiratory
infection, myocardial ischemia, infarct or cardiac failure, and thromboembolic disease.12
And persistent pain profoundly affects our endocrine, cardiovascular, immune, and
musculoskeletal systems.2,13

When pain is unending, there is an Pain

increase in the level of cortisol, the
primary stress-induced hormone. Some Hypothalamus
cortisol is necessary for the immune
system, but when the level is raised for Corticotropin-Releasing Hormone
long periods, cell function in the immune
system and kidney is compromised and
Pituitary
the immune system doesnt work well,
operating at less than capacity. This
affects overall quality of life, as well as Adrenocorticotropin Hormone
the ability to fight infections and heal.
There is evidence that these immune Adrenal Gland
system effects of chronic pain may
speed up growth of cancer cells.14
Glucocorticoid Excess
In fact, chronic pain may even
reprogram the way genes work in the Adrenal Exhaustion
immune system. A study at McGill
University found that chronic pain
Glucocorticoid Deficiency
changes the way DNA is marked in the
Forest Tennant, MD DrPH
brain and in T-cells, a type of white Complications of Uncontrolled, Persistent Pain

blood cell essential for immunity. DNA www.practicalpainmanagement.com/pain/other/co-morbidities/

complications-uncontrolled-persistent-pain
from brains and white blood cells of
rats was examined using a method that mapped DNA marking by a chemical called a
methyl group. Methyl marks are important for regulating how those genes function.
(Chemical marking like this is part of epigenetics, the study of changes caused by
modification of gene expression rather than alteration of the genetic code itself.)
PainChampions October 16, 2016 Page 5

Moshe Szyf, a professor in the Faculty of Medicine at McGill, said, We were surprised
by the sheer number of genes that were marked by the chronic painhundreds to
thousands of different genes were changed. We can now consider the implications
that chronic pain might have on other systems in the body that we dont normally
associate with pain.15

Compromised homeostatic function of prefrontal cortical-limbic circuitry in major

depressive disorder and chronic pain disrupts autonomic, neuroendrocrine, and
neuroimmune regulation, shown here.

1. Stress, pain, and depression lead to excessive, untimely release of corticotropin-

releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and glucocorticoids.

2. Sympathetic overactivity, combined with diminished parasympathetic tone,

contributes to immune activation and release of proinflammatory cytokines (e.g.,
tumor necrosis factor-alpha [TNF-alpha], interleukin-1 [IL-1], and interleukin-6 [IL-6])
from macrophages and other immune cells.

3. Inflammatory cytokines further interfere with monoaminergic and neurotrophic

signaling. Proinflammatory cytokines also can reduce central glucocorticoid receptor
sensitivity, leading to further disruptions of (1) the hypothalamic-pituitary-adrenal
(HPA) axis and (2) immune system regulation.

4. Disturbances of serotonin (5-HT), norepinephrine (NE), and dopamine (DA)

signaling in major depressive disorder and chronic pain impair the function of
descending pain modulatory pathways. Elevated mediators of the inflammatory
response, combined with excessive sympathetic tone, can further affect dorsal
column processing of pain signals by contributing to activation of microglia and
astroglia.

5. Activated microglia exchange chemical signals with astrocytes and nociceptive

neurons, thus amplifying pain-related transmission of glutamate (Glu), substance P
(SP), adenosine triphosphate (ATP), brain-derived neurotrophic factor (BDNF),
pro-inflammatory cytokines (IL-1, IL-6, interleukin-8, TNF-alpha, nitrogen oxide (NO),
and prostaglandins (PGs).

Ach: acetylcholine; ATP: adenosine triphosphate; CRF: corticotropin releasing factor;

PVN: paraventricular nucleus of hypothalamus
Illustration from Maletic V, Raison CL (2009). Neurobiology of depression, fibromyalgia and neuropathic pain. Front Biosci (Landmark Ed). 2009;14:5291-5338

SOCIAL AND PSYCHOLOGICAL EFFECTS

The fight-or-flight response to pain was a useful evolutionary aid for self-
preservation. But fight-or-flight isnt very useful in the modern world, and next to
useless for chronic pain.

Common consequences of untreated chronic pain can include decreased mobility,

impaired immunity as already discussed, decreased concentration, sleep disturbances,
and anorexia.16,17

As a result, those of us with chronic painwith or without the contributions of Ehlers-

Danlosface social isolation, dependence on care givers, and impaired relationships
PainChampions October 16, 2016 Page 6

with friends and family.18

Were four times more likely than those without pain to have depression or anxiety.17

Absenteeism, loss of income loss, healthcare costs, and workers compensation due to
chronic pain place the same strain on countries as cancer and cardiovascular disease
do.16 The annual cost of untreated pain in the United States alone is reported to be
between US$560$635 billion, and in a larger view, many of the greatest disease
burdens globally, such as depression, trauma from vehicle collisions, and falls, are
caused by acute or chronic pain.18

The following are some of the disorders directly related to pain, and more particularly
pain in Ehlers-Danlos. Please note this does not in any possible way suggests that
Ehlers-Danlos or our pain is psychiatric in nature: instead, it adds to the possible
symptom list for EDS a variety of psychiatric associationsand indirectly suggests
that if our pain were treated adequately, these effects would be at least minimized.

Hershenfeld SA, Wasim S, McNiven V, Parikh M, Majewski P, Faghfoury H and So J

(2016). Psychiatric disorders in EhlersDanlos syndrome are frequent, diverse and
strongly associated with pain. Rheumatol Int 36: 341. doi:10.1007/s00296-015-
3375-1

Abstract

Ehlers-Danlos syndromes (EDS) are a heterogeneous group of hereditary

connective tissue disorders characterized by joint hypermobility, widespread
musculoskeletal pain and tissue fragility. Psychiatric disorders and psychosocial
impairment are common, yet poorly characterized, findings in EDS patients.

We investigated the frequency and types of psychiatric disorders and their

relationship to systemic manifestations in a cohort of 106 classic and hypermobility
type EDS patients. In this retrospective study, extensive medical chart review was
performed for patients referred at two genetics clinics who were diagnosed with
EDS. Statistical analysis was undertaken to determine the frequency of psychiatric
disorders and association with systemic findings.
PainChampions October 16, 2016 Page 7

Psychiatric disorders were found in 42.5% of the EDS cohort, with 22.7% of
patients affected with 2 or more psychiatric diagnoses. Anxiety and depression
were most commonly reported, with frequencies of 23.6 and 25.5%, respectively.

A variety of other psychiatric diagnoses were also identified. Abdominal pain (odds
ratio [OR] 7.38), neuropathic pain (OR 4.07), migraines (OR 5.21), joint pain (OR
2.85) and fatigue (OR 5.55) were significantly associated with the presence of a
psychiatric disorder.

The presence of any pain symptom was significantly associated with having
a psychiatric disorder (OR 9.68). Muscle pain (OR 2.79), abdominal pain (OR
5.78), neuropathic pain (OR 3.91), migraines (OR 2.63) and fatigue (OR 3.78) were
significantly associated with having an anxiety or mood disorder.

Joint hypermobility and the classic dermatological features of EDS showed no

significant association with having a psychiatric disorder.

Our findings demonstrate a high frequency of psychiatric disorders and an

association with pain symptoms in EDS.

Chronic pain changes our behavior. When part of the cortex is firing constantly, not
only our emotions are affected. The cortex also plays a role in memory, attention,
and consciousness, so its as though we are multi-tasking all the time, which can
make concentration difficult. Simple decisions and human interaction become more
complicated.

Chronic pain affects our sleep, not just because we hurt; pain interrupts our usual
wake/sleep cycle. And not getting enough sleep makes pain worse, pain and sleep
cycling around each other.19 Ehlers-Danlos sleep is also disturbed by adrenaline rushes
that result from the physical threats of dysautonomia as well as from shifting pain.

When we dont have control over our pain, our brains become hyper-vigilant and
anticipate future pain. Chronic pain sets up a continual level of anxiety.20

Studies have identified that 3060 percent of chronic pain patients develop
depression.21 The reduced pain control and the complex rewiring in the brain also
contribute to a sense of hopelessness, making treatment of depression more
PainChampions October 16, 2016 Page 8

difficult.20 Functional and structural changes in the amygdala and hippocampus have
been described in major depressive disorder, fibromyalgia, and neuropathic pain.22
Those changes disrupt neuroendocrine, autonomic, and immune function, which
could further contribute to aggravated mood and pain symptomsrelaying us back
to physical changes resulting from pain.22,23

CONCLUSIONS

While it comes as no surprise to so many of us with Ehlers-Danlos, pain clearly

reduces the quality of our lives both physically and mentally. Chronic pain becomes
disabling as the brain changes, trying to manage first the pain, then its own
interactions with peripheral nerves and the spinal cord as they become sensitized. But
these attempts to cope actually further erode our ability to live with pain.

Chronic pain cannot be seen anymore as only being the perception of pain. The
simple pleasures of everyday life are lost to suffering, as well as learning, memory,
and concentration. Even our emotions are influenced, increasing levels of anxiety
and depression in a cycle that makes pain less bearable. Changes in our cortex
also impinge on the limbic system, increasing our suffering by reshaping our basic
emotions and drives.10

Chronic pain causes brain damage, a reorganization of our neural circuitry, affecting
our emotions, decisions, and behavior.

While it would be easy to read all this loss Ive described and feel hopeless, there is
good news. The brain damage doesnt appear to be permanent. Researchers at McGill
University found that chronic pain patients who were eventually treated for their
pain were able to recover. Their brain mass began to increase, the area of the brain
that controls pain repaired itself (cortical thickness increased, and gray matter cells
grewand the ability to perform tasks requiring mental focus returned to normal.24

Pain management in all available forms is crucial for our health. The more we can
manage our pain and suffering, the more able well be to deal with everything else life
and Ehlers-Danlos throw our way.

Mark Martino, The Ehlers-Danlos Society

PainChampions October 16, 2016 Page 9

SOURCES
For an in-depth look at how depression and chronic pain are interlinked, consider a review paper in
Current Psychiatry from February 2016, Chronic pain and depression: Understanding two culprits
in common, authored by Malefic and DeMuri. Its available in full on http://www.mdedge.com/
currentpsychiatry/article/106087/depression/chronic-pain-and-depression-understanding-2-
culprits.
1
Wang XS, Cleeland CS, Mendoza TR, Engstrom MC, Liu S, Xu G, Hao X, Wang Y and Ren XS
(1999). The effects of pain severity on health-related quality of life. Cancer, 86: 18481855.
http://onlinelibrary.wiley.com/doi/10.1002/(SICI)1097-0142(19991101)86:9%3C1848::AID-
CNCR29%3E3.0.CO;2-M/full
2
Tennant F. Complications of Uncontrolled, Persistent Pain. www.practicalpainmanagement.com/
pain/other/co-morbidities/complications-uncontrolled-persistent-pain
3
The Ehlers-Danlos Society. Pain Management Medical Resource Guide. http://ehlers-danlos.com/
wp-content/uploads/MRGPainManagementS.pdf
4
Stephens J, Laskin B, Pashos C, Pena B, Wong J (2003). The burden of acute postoperative pain
and the potential role of the COX-2-specific inhibitors. Rheumatology (Oxford) 42 Suppl 3: iii4052.
doi:10.1093/rheumatology/keg497
5
Baliki MN, Geha PY, Apkarian AV and Chialvo DR (2008). Beyond Feeling: Chronic Pain Hurts the
Brain, Disrupting the Default-Mode Network Dynamics. J Neurosci 28(6): 1398-1403. doi:10.1523/
JNEUROSCI.4123-07.2008.
6
Paul M. Chronic pain harms the brain. February 5, 2008. http://www.northwestern.edu/
newscenter/stories/2008/02/chronicpain.html
7
Robinson ME, Craggs JG, Price DD, Perlstein WM and Staud R (2011). Gray Matter Volumes of Pain
Related Brain Areas are Decreased in Fibromyalgia Syndrome. J Pain. 2011 Apr; 12(4): 436443.
Published online 2010 Dec 13. doi:10.1016/j.jpain.2010.10.003 and https://www.ncbi.nlm.nih.gov/pmc/
articles/PMC3070837/
8
Apkarian AV, Sosa Y, Sonty S, Levy RE, Harden R, Parrish T, Gitelman D (2004). Chronic back pain is
associated with decreased prefrontal and thalamic gray matter density. J Neurosci. 2004;24:10410
10415.
9
Geha PY, Baliki MN, Harden RN, Bauer WR, Parrish TB, Apkarian AV (2008). The brain in chronic
CRPS pain: abnormal gray-white matter interactions in emotional and autonomic regions. Neuron.
2008;60:570581.
10
Apiarian AV. Chapter 15: Human Brain Imaging Studies of Chronic Pain. Kruger L, Light AR, editors
(2010), Translational Pain Research: From Mouse to Man. Boca Raton, FL: CRC Press/Taylor & Francis.
https://www.ncbi.nlm.nih.gov/books/NBK57254/

Small DM, Apkarian AV. Increased taste intensity perception exhibited by patients with chronic
11

back pain. Pain. 2006;120:124130.

PainChampions October 16, 2016 Page 10

12
Stephens J, Laskin B, Pashos C, Pena B, Wong J (2003) The burden of acute postoperative pain and
the potential role of the COX-2-specific inhibitors. Rheumatology (Oxford) 42 Suppl 3: iii4052. doi:
10.1093/rheumatology/keg497

Chapman RC and Gavin J (1999). Suffering: The contributions of persistent pain. Lancet. 1999.
13

353:2233-7.
14
McIlwain, HH. http://www.sharecare.com/question/chronic-pain-affect-immune-system
15
Massart R, Dymov S, Millecamps M, Superman M, Gregoire S, Koenigs K, Alvarado S, Tajerian M,
Stone L and Szyf M (2016). Overlapping signatures of chronic pain in the DNA methylation landscape
of prefrontal cortex and peripheral T cells. S Rep 6:19615. doi:10.1038/srep19615. http://www.nature.
com/articles/srep19615

Lipman AG (2005). Pain as a human right: the 2004 Global Day Against Pain. J Pain Palliat Care
16

Pharmacother 19: 85100. doi: 10.1080/j354v19n03_16

Lohman D, Schleifer R, Amon JJ (2010). Access to pain treatment as a human right. BMC Med 8: 8.
17

doi: 10.1186/1741-7015-8-8
18
International Association for the Study of Pain (2013). Unrelieved pain is a major global healthcare
problem. Washington (D.C.): International Association for the Study of Pain

Optum (2016). The Effect of Sleep on Chronic Pain: Enhancing Sleep Can Lead to Less Pain and
19

Better Outcomes (2016) http://www.helioscomp.com/docs/default-source/White-Paper/insomnia-

whitepaper-and-chart.pdf?sfvrsn=6
20
Strigo IA, Simmons AN, Matthews SC, Craig AD and Paulus MP (2008). Association of Major
Depressive Disorder With Altered Functional Brain Response During Anticipation and Processing of
Heat Pain. Arch Gen Psychiatry 2008;65(11):1275-1284. doi:10.1001/archpsyc.65.11.1275 https://www.
ncbi.nlm.nih.gov/pmc/articles/PMC2702160/
21
Bair MJ, Wu J, Damush TM, et al. (2008). Association of depression and anxiety alone and
in combination with chronic musculoskeletal pain in primary care patients. Psychosom Med.
2008;70(8):890-897
22
Maletic V, Raison CL (2009). Neurobiology of depression, fibromyalgia and neuropathic pain. Front
Biosci (Landmark Ed). 2009;14:5291-5338
23
Gracely RH, Ceko M, Bushnell MC (2011). Fibromyalgia and depression [published online November
19, 2011]. Pain Res Treat. 2012;2012:486590. doi: 10.1155/2012/486590
24
Seminowicz DA, Wideman TH, Naso L, Hatadmi-Khoroushahi Z, Fallatah S, Ware MA, Jarzem P,
Bushnell MC, Shir Y, Ouellet JA and Stone LS (2011). Effective Treatment of Chronic Low Back Pain
in Humans Reverses Abnormal Brain Anatomy and Function. J Neurosci 31(20): 7540-7550; doi:
10.1523/JNEUROSCI.5280-10.2011 and http://www.mcgill.ca/newsroom/channels/news/no-pain-big-
gain-174398