UNIVERSITY OF MEDICINE AND PHARMACY

"CAROL DAVILA" BUCHAREST

FACULTY OF GENERAL MEDICINE

MEDICAL LICENSE THESIS

Scientific Coordinator
Universitary Lecturer Dr. Gabriela Mihăilescu

Graduate
RIVKA HUBER
 UNIVERSITY OF MEDICINE AND PHARMACY

"CAROL DAVILA" BUCHAREST

FACULTY OF GENERAL MEDICINE

MEDICAL LICENSE THESIS

“Medication Overuse Headache Evaluation, Management and Quality Of Life “

Scientific Coordinator
Universitary Lecturer Dr. Gabriela Mihăilescu

Graduate
RIVKA HUBER
BUCHAREST 2017
I would like to express the deepest gratitude to Professor Doctor Bogdan Ovidiu Popescu for
permitting me to perform this thesis study during period of 2016-2017 in Neurology
department Colentina Hospital.
I would like to extend my warmest appreciation to University Lecturer Dr. Gabriela
Mihăilescu for being a great adviser to me. I will be graduating this academic year thanks in
part to your good mentoring and guidance in conducting and finishing my thesis. Your input
and comments about my thesis were all helpful in making it a significant thesis.
Table of Contents
I. General Part ............................................................................................................................................ 9

1.1 Introduction .................................................................................................................................... 10

1.2 Types Of Headache ........................................................................................................................ 12

1.2.1 Primary Headache Disorders ................................................................................................... 12

1.2.2 Secondary Headache Disorders ............................................................................................... 15

1.3 Definition of Medication Overuse Headache ................................................................................. 19

1.4. Epidemiology and Risk Factors for Medication Overuse Headache ............................................. 20

1.4.1 Risk Factors for Medication Overuse Headache ..................................................................... 21

1.5 Drug Induced Headache and Medication ....................................................................................... 23

1.5.1 ICHD-II Classification and Clinical Features .......................................................................... 24

1.6 Pathogenesis of Medication Overuse Headache ............................................................................. 25

1.6.1 Genetic Predisposition ............................................................................................................. 25

1.6.2 Central Sensitization ................................................................................................................ 26

1.6.3 Bio-Behavioral Factors ............................................................................................................ 28

1.7 Clinical Manifestations ................................................................................................................... 29

1.8 Comorbidities ................................................................................................................................. 30

1.9 Clinical Diagnosis Criteria ............................................................................................................. 31

1.10 Paraclinical Diagnosis .................................................................................................................. 33

1.11 Differential Diagnosis .................................................................................................................. 34

1.12 Treatment ...................................................................................................................................... 35

1.12.1 Management in primary care ................................................................................................. 37

1.13 Evolution and Follow Up ............................................................................................................. 41

1.14 Prognosis ...................................................................................................................................... 42

II. Special Part .......................................................................................................................................... 43

2.1 Introduction .................................................................................................................................... 44

2.2 Material and Method ...................................................................................................................... 45

2.2.1 Details of data collection ......................................................................................................... 46

2.2.2 Method ..................................................................................................................................... 46

2.2.3 The limitations of my study ..................................................................................................... 46

2.3 Results ............................................................................................................................................ 47

2.3.1 Conclusions .............................................................................................................................. 65

III. Annexes .............................................................................................................................................. 68

3.1 Annex 1 specially created questionnaire ........................................................................................ 69

3.1.1 Headache diary......................................................................................................................... 70

3.1.3 Anxiety score (HAM-A) .......................................................................................................... 70

3.1.4 Depression score (HAM-D) ..................................................................................................... 70

3.1.5 Headache and assessment of response to treatment ................................................................. 70

3.1.6 Visual analogue scale (VAS) ................................................................................................... 70

3.1.7 Severity of dependence scale ................................................................................................... 70

3.2 Annex 2 Headache diary ................................................................................................................ 71

3.3 Annex 3 RAND 36-Item Health Survey v1.0 Questionnaire Items ............................................... 72

3.4 Annex 4 Hamilton Anxiety Scale HAM-A .................................................................................... 76

3.5 Annex 5 Hamilton Depression Scale HAM-D ............................................................................... 77

3.6 Annex 6 Headache and Assessment of Response to treatment ...................................................... 81

3.7 Annex 7 Visual Analogue Scale .................................................................................................... 84

3.8 Annex 8 Severity of Dependence Scale SDS ................................................................................. 85

IV. References .......................................................................................................................................... 86

List of abbreviation

1) 18-FDG PET – 18 Fludeoxyglucose Positron Emission Tomography

2) 5-HTR- 5-hydroxytryptamine receptors
3) a.s.o- and so on
4) CDH – chronic daily headache
5) CGRP- calcitonin gene-related peptide
6) CSD – cortical spreading depression
7) CSD- cortical spreading depression
8) CSF - cerebral spinal fluid
9) CT – computerized tomography
10) CTA- computed tomography angiography
11) CTTH- chronic tension type headache
12) DHE – dihydroergotamine
13) DNICs – diffuse noxious inhibitory controls
14) DNICs- diffuse noxious inhibitory controls
15) DSM - diagnostic and statistical manual of mental disorders
16) EFNS – european federation of neurological societies
17) fMRI – functional magnetic resonance imaging
18) GI- gastrointestinal
19) GMV – gray matter volume
20) HAM-A – hamilton anxiety scale
21) HAM-D – hamilton depression scale
22) HTN-hypertension
23) mmol/L-millimoles per litre
24) MOH-medication overuse headache
25) MRI – magnetic resonance imaging
26) NSAID’S non-steroidal anti-inflammatory drugs
27) OCD - obsessive compulsive disorder
28) OCT- over the counter
29) ONS – occipital nerve stimulation
30) QoL – quality of life
31) RAND- research and development
32) SCID-CV- structured clinical interview for DSM clinician version
33) SCID-II structured clinical interview for DSM IV TR Personality Disorders
34) SDS - severity of dependence scale
35) SONS supraorbital transcutaneous stimulation
36) SSRIs – selective serotonin reuptake inhibitors
37) SUNCT - short-lasting, unilateral, neuralgiform headache attacks with conjunctival injection
and tearing
38) TMS – transcranial magnetic stimulation
39) TN-trigeminal neuralgia
40) TTH- tension type headache
41) VAS – visual analogue scale
42) vs-versus
I. General Part

9
1.1 Introduction

Of all the difficult states that harass people, headache is without a doubt the most regular and
adversary’s spinal pain as the most well-known explanation behind looking for therapeutic offer
assistance. In fact, there are so many cases of headache that special headache clinics have been
established in many medical centers. In addition to its frequency in general practice, many headaches
are caused by rather general medical than neurological diseases, and the subject is the legitimate
concern of the general physician. Yet there is always the question of intracranial disease, so that it is
difficult to approach the subject without knowledge of neurology.
The face and the scalp are more richly supplied with pain receptors than many other parts of the body,
perhaps to protect the precious contents of the skull. Also, the nasal and oral passages, the eye, and the
ear, the sinuses - all delicate and highly sensitive structures - reside here and must be protected; when
affected by a disease, each is capable of inducing pain in its own way. Finally, there is greater concern
about what happens to the head than to other parts of the body, since the skull houses the brain, and
headache frequently raises the specter of brain tumor, intracranial hypertension, subdural hematoma or
other severe cerebral diseases. Semantically, the term headache encompasses all aches and pains
located in the head, but in practice, its application is restricted to discomfort in the region of the cranial
vault [1].
Headache is one of the most common medical complaints of civilized humans, yet severe and
chronic headaches are only infrequently caused by organic disease. In the United States, in 1 year, most
of the population will have a headache and over 5% will seek medical aid; over 1% of physicians’
office visits and emergency department visits are primarily for headache. .
Most recurrent headaches are symptoms of a chronic primary headache disorder but ophthalmological
problems, otitis, sinusitis, dental disorders, high blood pressure, infection, brain tumor, cerebral
hemorrhage, meningitis and encephalitis may all present with headache. Headache, as pain of benign
origin, may be intense; headache, as a pain of malignant origin, may be mild.
Many patients fear that their headache is secondary to a serious medical problem and seek not
only pain relief but also reassurance that they do not have a brain tumor or another life-threatening
problem. For these reasons, every physician must be knowledgeable in the diagnosis and treatment of
headache.

10
 Before 1988, the taxonomy of headache was not uniform and diagnostic criteria were rarely
based on operational rules. In 1988, the International Headache Society (II-IS) instituted a classification
system for headache, that has become the standard for headache diagnosis and clinical research. The
international headache society (IHS) classification of headache provides operational definitions for all
headache types. It divides headaches into two broad categories: the primary headache disorders
(categories 1-4), which include migraine, tension type headache, cluster headache and miscellaneous
headaches unassociated with a structural lesion and the secondary headache disorders (categories 5-12).
The IHS classification system diagnoses headache attacks, not disorders. If a patient has more than one
type of headache, each type should be diagnosed separately.
For primary headaches, physical examination and laboratory investigations serve to exclude
secondary disorders, or they may provide evidence to support the diagnosis of a secondary headache.
Thus, the diagnosis of a primary headache disorder is based on the patient's report of symptoms of
previous attacks, and accurate diagnosis requires explicit rules about the required symptom features.
Each major category of primary headache has sub-types, which are differentiated, based on the
symptom profile (migraine with aura vs. migraine without aura), the temporal profile, or the attack
frequency (episodic vs. chronic tension-type headache, episodic vs. chronic cluster headache).
Alternatively, a secondary headache disorder may be present if the onset of the primary and that of the
secondary disorders are separated in time. Migraine with aura formerly classic migraine is also
precisely defined, particularly with respect to the time of the onset and duration of the aura.
Types of aura include (1) homonymous visual disturbance, (2) unilateral paresthesia’s and/or
numbness, (3) unilateral weakness, and (4) aphasia or un-classifiable speech difficulty. Most common
is the visual aura [2].

11
1.2 Types Of Headache

1.2.1 Primary Headache Disorders

1. Migraine
1.1.Migraine without aura
This episodic headache is used to be called common migraine and is typically unilateral associated with
nausea and vomiting, photophobia and phonophobia [3].
1.2.Migraine with aura
Migrainous headaches preceded by neurological symptoms were termed 'classic' or `classical' migraine
in the past but the IHS Committee considered that, to avoid any possibility of confusion, 'migraine with
aura' was preferable. The aura is commonly a visual disturbance that may affect both visual fields
simultaneously, such as blurring, rippling, spots or flashes, but in some cases moves slowly over one or
both fields of vision as a zigzag pattern, leaving areas of impaired vision.
These auras are known as fortification spectra or scintillating scotomas. Varieties of 'migraine with
aura' include familial hemiplegic migraine, basilar migraine (when aura symptoms arise from the
brainstem and occipital lobes) and episodes consisting solely of the aura without any headache
('migraine equivalents') [3].
1.3.Ophthalmoplegic migraine
A rare condition in which paresis of one or more of the ocular motor nerves (third, fourth or sixth
cranial nerves) accompanies migrainous headache. This diagnosis can only be made after other causes
of compression of these nerves have been excluded [3].
1.4.Retinal migraine
In retinal migraine, the visual disturbance is confined to one eye and the headache then develops behind
that eye. This variety is very uncommon and a structural ocular lesion must be ruled out [3].
1.5.Childhood periodic syndromes
The IHS Committee recognized that certain recurrent symptoms in childhood could be associated with
migraine or be precursors of migraine in later life. Those nominated were 'benign paroxysmal vertigo'
and 'alternating hemiplegia of childhood'. The authors would delete the latter which is a progressive
disorder leading to a dystonic state and would add abdominal pain or vomiting, recurring without an
organic explanation (abdominal migraine, bilious attacks) [3].
1.6.Complications of migraine
Prolonged migrainous headache, continuing for days or weeks (status migrainosus) and permanent
ischemic damage to the nervous system (migrainous infarction) are listed as complications [3].

12
2.Tension-type headache (TTH)
2.1.Episodic
Recurrent attacks of a tight, pressing sensation in the head, usually bilaterally. The episodes are usually
precipitated by physical or mental stress and a subvariety is associated with excessive muscle
contraction and muscle tenderness [3].
2.2.Chronic
Chronic tension-type headache recurs during 15 or more days in a month, commonly every day. It has
the same heavy or tight quality as the episodic variety and may or may not be associated with over
activity of the jaw and facial muscles. Other forms of chronic daily headache may develop from
episodic migraine attacks (`transformed migraine') or start suddenly for no apparent reason ('new daily
persistent headache') [3].
3. Cluster headache and paroxysmal hemicrania
3.1.Cluster headache
Attacks of unilateral pain, centered on the orbital or periorbital region, usually lasting 15-180 minutes
and recurring up to eight times a day. The pain is usually severe and is accompanied by redness and
lacrimation of the eye and nasal congestion on the affected side.
The disorder characteristically recurs in bouts lasting weeks or months, separated by a period of
freedom for months or years (episodic cluster headache). If attacks continue for a year or more without
remission, the condition is known as chronic cluster headache [3].
3.2.Chronic paroxysmal hemicranias (CPH)
CPH has the same characteristics as cluster headache but recurs as brief episodes, usually lasting 5-20
minutes, from five to 30 times in each 24-hour period. It is said to respond specifically to indomethacin.
An episodic form has also been described. Short-lasting unilateral neuralgiform headache attacks with
conjunctival injection, tearing, sweating and rhinorrhea (SUNCT syndrome) may be a variation of
cluster headache [3].

4. Miscellaneous headaches unassociated with a structural lesion

4.1. Idiopathic stabbing headache
Transient stabs of pain in the head (`icepick pains') that occur spontaneously in the absence of organic
disease of underlying structures [3].
4.2. External compression headache
Resulting from continued stimulation of peripheral nerves by pressure from a hat or tight band such as
the goggles worn during swimming training [3].
4.3. Cold stimulus headache
Headache caused by exposure of the unprotected head to a low environmental temperature, for
example, subzero weather or diving into cold water. Headache caused by the ingestion of cold
substances (`ice-cream headache') [3].

13
4.4. Benign cough headache
Headache precipitated by coughing in the absence of intracranial disorders [3].
4.5. Benign exertional headache
Headache brought on by exercise. Some varieties have been given specific names such as 'weightlifter's
headache' [3].
4.6. Headache associated with sexual activity
Headache arising during sexual intercourse or masturbation, often as a dull ache increasing with sexual
excitement, becoming intense with orgasm, but sometimes as an explosive headache at the time of
orgasm without warning [3].

Figure 1. Sites of Head and Facial Pain [3]

14
1.2.2 Secondary Headache Disorders

5. Headache associated with head trauma

5.1. Acute posttraumatic headache
Headache occurring less than 14 days after head injury and ceasing within 8 weeks of trauma [3].
5.2. Chronic posttraumatic headache
Headache persisting for more than 8 weeks after head injury [3].

6. Headache associated with vascular disorders

6.1. Acute ischemic cerebrovascular disease
Headaches accompanying transient ischemic attacks or thromboembolic stroke [3].
6.2. Intracranial hematomas
Headaches with intracranial, subdural or extradural hematomas [3].
6.3. Subarachnoid hemorrhages
A severe headache of sudden onset, usually associated with neck stiffness, caused by rupture of an
intracranial aneurysm or arteriovenous malformation [3].
6.4. Ruptures vascular malformation
Headache caused by enlargement of an intracranial aneurysm [3].
6.5. Arteritis
Giant cell arteritis (temporal arteritis, Horton's disease) causes headache by inflammation of the scalp
arteries. It is often associated with polymyalgia rheumathica [3].
6.6. Carotid or vertebral artery pain
Dissection of the carotid or vertebral arteries gives rise to ipsilateral pain in the neck and headache,
often associated with neurological signs of ischemia in the affected arterial territory [3].
6.7. Venous thrombosis
Headache associated with thrombosis of one of the major intracranial veins or venous sinuses, is often
accompanied by raised intracranial pressure, focal neurological deficits or seizures [3].
6.8. Arterial hypertension
Acute pressor responses may be caused by phaeochromocytoma, acute nephritis, malignant
hypertension, eclampsia or medication. Moderate chronic hypertension does not cause headache [3].

15
7. Headache associated with non-vascular intracranial disorders
7.1. High cerebrospinal fluid pressure
Headache is a feature of communicating and non-communicating hydrocephalus with high
cerebrospinal fluid (CSF) pressure. In the absence of any obstruction to the CSF pathways, the
condition is called 'benign intracranial hypertension' [3].
7.2. Low cerebrospinal fluid pressure
A postural headache, worse on standing and relieved by lying, may develop after lumbar puncture or
result from other causes of a CSF leak [3].
7.3. Intracranial infection
Meningitis and encephalitis are associated with headache from meningeal irritation [3].
7.4. Intracranial sarcoidosis and other non-infectious inflammatory diseases [3]
7.5. Headache associated with intrathecal injections
An example is the headache following the insertion of air into the CSF in the now out-mode technique
of pneumo encephalography [3].
7.6. Intracranial neoplasms
Cerebral tumors may cause headache by displacing blood vessels or obstructing the flow of the CSF
[3].

8. Headache associated with substances or their withdrawal

8.1. Headache induced by acute substance use or exposure
Examples are the headaches induced by vasodilator agents, such as nitrates, nitrites or calcium channel
blockers, and the inhalation of volatile hydrocarbons used in dry cleaning and similar processes [3].
8.2. Headache induced by chronic substance use or exposure
The daily ingestion of ergotamine tartrate or analgesics may induce headache [3].
8.3. Headache from substance withdrawal (acute use)
`Hangover' headache following the excessive consumption of alcohol is cited as example but this may
depend on the action of toxic metabolites rather than the withdrawal of alcohol [3].
8.4. Headache from substance withdrawal (chronic use)
`Rebound' headache following the withdrawal of ergotamine tartrate, caffeine or narcotics [3].
8.5. Headache associated with substances but with uncertain mechanism
Oral contraceptives, for example, may increase the tendency to vascular headaches [3].

9. Headache associated with non-cephalic infections

9.1. Viral infections [3].
9.2. Bacterial infections
Localized or systemic (septicemia) [3].

16
10. Headache associated with metabolic disorder
10.1. Hypoxia
Headaches associated with a PaO2 less than 70 mmHg. This section includes headaches developing at
high altitudes and those following sleep apnea [3].
10.2. Hypercapnia
Headaches associated with a PCO2 above 50 mmHg in the absence of hypoxia [3].
10.3. Mixed hypoxia and hypercapnia [3]
10.4. Hypoglycemia
Headache precipitated by a blood glucose level less than 2.2 mmol/L (40 mg%) [3].
10.5. Dialysis
Headache during or after hemodialysis [3].

11. Headache or facial pain associated with a disorder of neck, cranial or extra cranial structures
11.1. Cranial bones
Diseases of the skull such as osteomyelitis, multiple myeloma and Paget's disease may cause
headache[3].
11.2. Neck
Occipital headache can be referred from the upper cervical spine. A constant pain in the back of the
neck and head, aggravated by bending the neck backwards, has been described as 'retropharyngeal
tendinitis'. Some patients with lax atlanto-axial joints experience a sharp pain in the upper neck on
sudden neck turning, associated with numbness in the occiput and the ipsilateral half of the tongue
('neck—tongue syndrome'). The reason for this is that sensitive fibers from the tongue enter the central
nervous system through the second cervical root, which is compromised by extreme neck rotation [3].
11.3. Eyes
Acute glaucoma may cause pain in the eye and forehead, a red eye, myosis and a tubular visual field.
Refractive errors and disorders of ocular balance may be factors promoting headache [3].
11.4. Ears
Disorders of the middle ear may cause neuralgic pain [3].
11.5. Nose and sinuses
Headache and facial pain may be caused by obstruction of the nasal, frontal, maxillary sinuses [3].
11.6. Teeth, jaws and related structures
Disorders of the teeth usually cause facial pain but are rarely responsible for headache [3].
11.7. Temporomandibular joint disease
Dysfunction of the temporomandibular joint may refer pain to the temple and adjacent areas of the face
(Costen's syndrome) [3].

17
12. Cranial neuralgias, nerve trunk pain and differentiation pain
12.1. Constant pain of cranial nerve origin
Compression or distortion of sensory cranial nerves (trigeminal, nervus intermedius, glossopharyngeal,
and vagus) or the upper three cervical roots may refer pain to the appropriate area. Optic neuritis,
diabetic oculomotor nerve palsy and Tolosa-Hunt syndrome (orbital fissure granuloma) may be
associated with pain in the orbit or frontal region. Herpes zoster infection affecting the first branch of
the trigeminal nerve or the geniculate ganglion refers pain to the forehead or ear respectively and may
be followed by postherpetic neuralgia [3].
12.2. Trigeminal neuralgia
Shock-like pains limited to one or more divisions of the trigeminal nerve. Trigger points and trigger
factors can usually be identified. The condition may be symptomatic of trigeminal nerve compression
by blood vessels or tumors, or of a central lesion, such as multiple sclerosis [3].
12.3. Glossopharyngeal neuralgia
Stabbing pains felt in the ear and base of the tongue, often provoked by swallowing, talking or
coughing. Like trigeminal neuralgia, it may also be symptomatic of a structural lesion [3].
12.4. Nervus intermedius neuralgia
A rare disorder characterized by brief paroxysms of pain felt deeply in the external auditory canal [3].
12.5. Superior laryngeal neuralgia
A rare condition in which paroxysms of severe pain are felt in the lateral aspect of the throat and under
the ear, precipitated by swallowing, shouting or turning the head [3].
12.6. Occipital neuralgia
Jabbing or constant pain, with or without altered sensation, associated with the distribution of one
greater occipital nerve [3].
12.7. Central causes of head and facial pain
Persistent pain may follow lesions of the trigeminal nerve (analgesia dolorosa) or disorder of the central
pain pathways in the Quinto- thalamic tract or thalamus (thalamic pain) [3].
12.8. Facial pain not fulfilling the criteria for groups 11 and 12
Persistent facial pain not associated with physical signs or a demonstrable organic cause (atypical
facial pain) [3].

18
1.3 Definition of Medication Overuse Headache
Medication-overuse headache (MOH) is defined as a chronic headache disorder by the
International Classification of Headache Disorders, characterized by increased frequency and intensity,
occurring in people overusing analgesics, Triptans or other acute pain relief medication (especially for
headaches but sometimes also for other types of pain in patients having a history of headache) on 15
days or more per month for > 3 months, in different doses and combinations, mostly over the counter
(OTC), or opioids, Ergotamine’s or Triptans for more than 10 days per month, for at least 3 months. It
can become a mild to moderate daily headache, may have some attacks similar to the initial migraine,
which can be controlled for some few hours with acute medication and the headache returns and usually
increases like in a vicious cycle, becomes unresponsive, medication becomes inefficient and drug
dependency develop. MOH resolves after the medication overuse is stopped, and even treated, the
relapse rate is high.

Figure 2. International Classification of Headache Disorders, 3rd beta edition (ICHD-IIIß) Criteria for
Medication-Overuse Headache [4]

Medication overuse headache (MOH) was used to be called “Rebound headache”, “Withdrawal
headache”, “Analgesic rebound headache”, “Drug induced headache”, “Medication misuse headache”.

19
1.4. Epidemiology and Risk Factors for Medication Overuse Headache

Medication-overuse headache (MOH) is one of the most common chronic headache disorders
and a public health problem with a population based prevalence of 0.7 –1.7% with a higher
preponderance in women 74 – 95 % than in men 5 - 26%.
Epidemiological data suggest that 4% of the population misuse pain medication. In specialized
headache clinics, MOH patients represent the largest group. Cerebral pain is extremely regular and for
the most part happens ramblingly, however 3–4% of the all-inclusive community have chronic
headache, characterized as 15 or more days of cerebral pain every month.
Cerebral pain is frequently treated, up to 60% of cases in primary care with analgesics, while in
the secondary and tertiary care with analgesics and opioids and it is the most well-known purpose
behind pain relieving use in the community. Over-the-counter (OTC) drugs represent the most common
medication used to treat headache and especially adolescents use this drugs, single or in combinations
without medical prescription. Unseemly utilization of symptomatic prescription for cerebral pains may
incomprehensibly prompt MOH.

MOH is a condition characterized by chronic headache and overuse of different acute headache
medications especially in patients who suffered from migraine or tension type headache as a primary
headache. Rebound headache after excessive intake of Ergotamine was described in the early 1950s and
1960s, and from the 1980s, studies have shown that frequent intake of all symptomatic medication used
to relieve headache may transform episodic headache into frequent or chronic headache. MOH is a
chronic headache with a distinct clinical picture and a clear biological basis, and these patients, like
other chronic headache sufferers, experience a reduced quality of life.

MOH is classified as a secondary chronic headache, but whether MOH is a primary or secondary
headache is still under debate, and the concept of medication overuse in other secondary headaches is
unclear.

20
1.4.1 Risk Factors for Medication Overuse Headache
Many psychosocial and socioeconomically factors are associated with MOH. However, it is
hard to ascertain if these are directly or indirectly associated, as these findings are mainly based on
cross-sectional studies. Thus, many of these factors may merely be markers of a complex situation
since many aspects of life may be affected by having chronic headache, as well as other chronic
conditions. As for other frequent headaches, MOH patients tend to have a low socioeconomic status
with low income, low occupational status and low education, but it is uncertain whether this may be a
cause of or an effect of headache [4].
A high prevalence of smoking, high body mass index and sleeping problems were also found
among MOH patients. Depression and anxiety were more common among MOH patients than among
people with episodic migraine, but the association may be bidirectional and could be more likely an
epiphenomenon related to medication overuse. In another study, this was related to the headache
frequency, rather than to the headache diagnosis. The risk of developing MOH is greater in individuals
with a family history of MOH or other substance abuse (a genetic susceptibility has been postulated).
Data from a population-based longitudinal study suggested that those who used analgesics daily or
weekly at baseline had a higher risk for developing chronic headache 11 years later [5]. This supports
the causative role of medication overuse in generating MOH. A more recent study identified several
risk factors for MOH among people with chronic headache (11 years follow up). Regular use of
tranquilizers, sedative-hypnotics, antihypertensive drugs, medications used for other co-morbidities,
combination of treatments for chronic musculoskeletal and gastrointestinal complaints, and increased
scores at the Hospital Anxiety and Depression Scale, as well as smoking and physical inactivity,
increased the risk for MOH. The study was extensive and included over 25,000 people at risk for
chronic headache and MOH. However, the mentioned risk factors were just found in a minority of all
the MOH patients, and may thus reflect the complex situation for specific subgroups of MOH patients
rather than for the MOH patients in general [6]. Previous primary headache such as migraine and
tension-type headache are also risk factors more than cluster headache, post-traumatic headache or
other secondary headaches and seems to be required for the development of MOH [4].
The adherence to the specific headache treatment – especially Triptans (appears to cause MOH faster
and at lower doses than other drugs) and combined analgesic treatments - are risk factors in developing
MOH.

21
Medication used as acute treatment, in order to obtain a rapid pain relief for migraine, tension type
headache or other acute pains and that can induce MOH is represented by:

• Analgesics: non-steroidal anti-inflammatory drugs (NSAIDs) like Aspirin, Acetaminophen,

Ibuprofen, Naproxen, Diclofenac, Phenazone, Tolfenamic acid, Valdecoxib - alone or in
combinations.
• Caffeine
• Barbiturates (Butalbital)
• 5HT 1B/1D receptor agonists (Triptans): Sumatriptan, Zolmitriptan, Naratriptan, Rizatriptan,
Almotriptan, Eletriptan, Frovatriptan
• Ergot derivatives: Ergotamine Tartrate, Dihydroergotamine (DHE)
• Opiates: Codeine alone or in combination with Paracetamol as Co-codamol (probably the worst
culprits), Morphine.

Frequently patients use more than one single drug of this list, insufficient time or in doses that
are not effective for acute treatment of pain or prophylactic therapy, and consider them as not effective,
so they change the medication, but in the same way, without a medical advice.
The important thing in developing MOH is that the overuse of treatment is both frequently and
regularly, for example two days or more per week. Bunching up of days of treatment with long gaps in
between is much less likely to cause MOH. The amount and frequency of medication use needed to
cause MOH is not clear, it may be different from one patient to another, and there is for sure some
patient susceptibility. On average, these medications should have not be taken for more than 2
days/week.

22
 1.5 Drug Induced Headache and Medication
Table I: Classification of the Medication Overuse Subtypes According to the International
Classification of Headache Disorders, 2nd Edition [7]
ICHD-II CODE Diagnosis
1 Ergotamine overuse headache
2 Triptan overuse headache
3 Analgesic overuse headache
4 Opioid overuse headache
5 Combination analgesic overuse
headache
6 Medication overuse headache
attributed to combination of acute
medications
7 Headache attributed to other
medication overuse
8 Probable medication overuse
headache
23
Amount of medication
Ergotamine intake on >10 days per month
on a regular basis for >3 months
Triptan intake (any formulation)
on >10 days per month on a regular
basis for >3 months
Intake of simple analgesics on >15 days per
month on a regular basis for >3 months
Opioid intake on >10 days per month on a regular
basis for >3 months
Intake of combination analgesic medications on
>10 days per month
on a regular basis for >3 months
Intake of any combination
of ergotamine, triptans, analgesics, and/or opioids
on >10 days per month
on a regular basis for >3 months
without overuse of any single class
Regular overuse for >3 months
of a medication other
than those described above
Medication overuse
has ceased within the last 2 months
but headache has not so far resolved
or has reverted to its previous pattern
1.5.1 ICHD-II Classification and Clinical Features
Medication overuse headache (MOH) is subdivided into seven groups, plus an additional topic
for probable medication overuse headache [8].
According to the ICHD-II, a diagnosis of medication overuse headache is established when three
situations fulfilled: (1) the consumption of acute medication is beyond critical dose. (2) Patients have
headaches on more days in a month than days without headache. (3) Secondary disorders that may
explain the headaches excluded either clinically or through subsidiary paraclinical investigations.
The ICHD-II does not suggest that subsidiary investigation is required in all cases but requires that, at
least clinically, the provider exclude secondary disorders other than medication overuse.
In a study conducted in the authors' center, medication overuse headache ranged from three
tablets per week to 30 per day (mean = 5.2 per day) in another from 10 to 180 drug units per month.
More than 10% of patients consumed more than 10 pills per day, and 4.4% of the patients took more
than 15 pills per day. The majority of patients were overusing one (35.1%) or two (36.8%) substances
other than caffeine, but 31.6% were overusing three or more. Investigators contrasted the medications
involved in overuse, comparing patients whose first visit was more than 5 years before the study
(before 1996) with those whose first visit was between 1996 and 2001. The drugs more frequently
associated with acute care medication overuse, Butalbital, Acetaminophen, and Opioids, remained the
same during both periods. There were statistically significant reduction in NSAIDs (25.1% versus
10.1%, P<.0001), Aspirin (31.7% versus 17.9%, P=.0008), Ergot compounds (19.5% versus 10.5%,
P=.01), and significant increase in the overuse of Sumatriptan (3.0% versus 10.5%, P=.001) over
time.[9] Most patients with chronic daily headache and medication overuse were overusing analgesics
single or combined, barbiturates or other nonnarcotic substances (39.5%), simple analgesics (38.6%),
triptans (11.4%), and Ergotamine (10.5%) [7].
Drug induced headache may be considered also an adverse event of any medication used by the patient,
and it is different from medication overuse headache.

24
1.6 Pathogenesis of Medication Overuse Headache

The pathogenesis of medication overuse headache (MOH) is indistinct. Clinical and preclinical
studies have reliably exhibited expanded excitability of neurons in the cerebral cortex and trigeminal
framework after prescription abuse. Cortical hyper excitability may encourage the development of
cortical spreading depression (CSD), while increased sensitivity of trigeminal neurons may facilitate
the procedure of peripheral and focal sensitization. These changes may be secondary to the
derangement of central, probably endogenous serotonin (5-hydroxitriptamine 5-HT) dependent pain
control system, which may be responsible for MOH and for affective psychiatric disturbances
controlled by subcortical structures and perhaps endocannabinoid-dependent or other modulating
systems. Increased expression of excitatory cortical 5-HT2A receptors may increase the susceptibility
to developing cortical spreading depression, an analog of migraine aura.
A reduction of diffuse noxious inhibitory controls may facilitate the process of central
sensitization, activate the nociceptive facilitating system, or promote similar molecular mechanisms to
those involved in kindling. Low 5-HT levels also increase the expression and release of calcitonin gene-
related peptide from the trigeminal ganglion and sensitize trigeminal nociceptors. Thus, derangement of
central modulation of the trigeminal system because of chronic medication use may increase sensitivity
to pain perception and foster or reinforce medication overuse headache [10].
Available evidence suggests all drugs used for the acute symptomatic treatment of headache can
cause MOH in primary headache disorders, but the mechanisms may differ from one class of overused
medication to another. In the developing countries, analgesics and Ergotamine are mostly misused to
treat migraine, while in the Western Europe, Triptans and in the USA Butalbital, maybe taking into
account also economic reasons. Multiple factors seem to play a role, including genetic predisposition,
central sensitization, and bio -behavioral factors [11].

1.6.1 Genetic Predisposition

Various studies and clinical observations suggest that MOH is restricted to individuals who
already have other headache disorders, such as for example, migraine, a disease, which also has some
genetic predisposition. Furthermore, MOH does not develop de novo in individuals with no previous
headache history. An inherited susceptibility to MOH has been proposed, as the risk of creating MOH
is threefold more prominent in people with a family history of MOH or other substance misuse.
Molecular genetic factors have become a theme of study in MOH pathophysiology.
Val66Met polymorphism in brain-derived neurotrophic factor, found in patients with behavior
disorders, substance abuse and MOH, try to emphasize that MOH is a substance abuse disorder [12].
Allele 10 of the dopamine transporter gene SLC6A3 or DAT1 is significantly under-represented in
MOH patients.

25
A few small-scale studies have found some molecular genetic factors that are possibly associated with
MOH, but these results are from small studies in selected groups and generalizing the findings is
difficult to ascertain [13]–[15].

1.6.2 Central Sensitization

Alteration of cortical neuronal excitability, central sensitization involving the trigeminal
nociceptive system and changes in serotoninergic and dopaminergic expressions and pathways,
including the endocannabinoid system have been suggested to play a part in the pathophysiology of
MOH [13], [15]–[19].
Low serotonin (5-HT) levels with reduction of 5-HT in platelets and upregulation of a pro-
nociceptive 5-HT2A receptor have been demonstrated in MOH [20], [21]. A higher frequency of
cortical spreading depression (CSD) has been found in animals with low 5-HT levels, suggesting an
association with a sensitization processes [22], [23]. Furthermore, chronic, but not acute, Paracetamol
administration, led to an increase in CSD frequency in another rat model which may indicate that
chronic analgesic exposure leads to hyper-excitability in cortical neurons and an increase in CSD [24].
A 5-HT2A receptor antagonist blocked this increased CSD susceptibility in the rats which had been
exposed to chronic Paracetamol [24]. Also chronic use of Aspirin and Paracetamol in rats increased the
cortical excitability, facilitated trigeminal nociception in animal models of headache and also increased
the excitability of neurons in the central nucleus of the amygdala and generated an anxiety like behavior
[25]. Chronic use of opioids and especially the use of Triptans, has been shown to increase calcitonin
gene related peptide (CGRP) levels, peptide which is involved in neurogenic inflammation and
headache [17], [26]. In addition, chronic Morphine infusion may alter the diffuse noxious inhibitory
controls (DNICs) and impaired DNICs are also found in MOH [27].

26
 Figure 3: Presumed Cellular and Molecular Mechanisms Potentially Involved in the Process of
Sensitization in Medication Overuse Headache [28]

In MOH patients, increased levels of orexin-A and corticotrophin-releasing hormone were

found in the cerebrospinal fluid (CSF) compared with patients with chronic migraine and these levels
were correlated to monthly drug intake [29]. Glutamate level in the CSF of MOH patients was higher
than in controls, but higher in other medication overuse than in Triptans abuse.
In endocrine stimulation of MOH patients growth hormone and thyroid stimulating hormone had
reduced responses compared to controls, but adrenocorticotropic hormone and cortisol concentrations
were increased. MOH patients had low levels of 5-HT in platelets compared to controls, maybe due to
suppression of 5-HT uptake induced by medication overuse.

In addition, neuroimaging studies 18-FDG PET suggest changes in the orbitofrontal cortex and
the mesolimbic dopamine circuit and cortical hypo-metabolism in the thalamus, anterior cingulate
gyrus, insula/ventral striatum, inferior parietal lobe which normalized after medication withdrawal [30],
[31].
Some psychological mechanisms may also be considered, as those involved in any other addiction,
patients with MOH dislike medication but cannot live without it, and some of the treatments have
psychotropic effects (Caffeine, Opioids, and Barbiturates). It is clear that many of these phenomena are
similar to and thus may involve mechanisms seen in dependence processes [16], [32] and it is equally
clear that more research in these areas is needed.

27
1.6.3 Bio-Behavioral Factors
A few patients may become addicted, portrayed by compulsive attend to find medications in
spite of negative results, generating or increasing MOH. Some patients may utilize sedatives or
different medications with narcotic or anxiolytic impacts to relief pain and anxiety. Practices that might
be especially imperative in provoking and maintaining the overuse drugs comprise the fright of
headache, expectant tension, obsessional taking medications in and psychologic reliance.
Approximately half of those with headache on more than 15 days per month have MOH [33].
Most headache experts regard the association between overuse of acute medication and development of
MOH as a cause [34] [35]. Improvement for two thirds to three quarters of patients upon removal of
the overused medication supports its causative role in generating or maintaining a chronic headache.
However, it is still a matter of debate whether the overuse is a consequence of living with chronic
headache or the other way round [36], [37]. Furthermore, not all headache patients with medication
overuse develop MOH, and the mechanism how chronic exposure to abortive medication leads to MOH
remains unclear. Virtually all of the acute headache medication may cause MOH and since the different
medications have different pharmacological actions, it is unlikely that MOH is caused by the specific
action of any single agent.
Mechanisms may vary, starting with one class of overused drug then onto the next and diverse
conceivable pathogeneses have been proposed. It is obviously conceivable that there is a common, yet
at the same time obscure, component by which pharmacologically diverse medicines prompt MOH. In
any case, at present it is conceivable just to describe mechanisms
(for the most part from preclinical studies) that seem, by all accounts, to be connected with, or may
incline individuals to be predisposed to MOH. A pre-existent headache disorder seems to be required to
develop MOH [38]. Migraine and tension-type headache have a higher potential for developing MOH
than other primary headaches, but also patients with cluster headache may develop MOH [34], [39],
[40]. However, MOH does not develop in persons without a medical history of headache, when
medication is taken regularly for other conditions such as arthritis, back pain or inflammatory bowel
disease [38], [41]. Along these lines, an association between headache specific pain pathways and
cerebral pain medicine impacts is, by all accounts, a focal component in producing a more chronic pain.

28
1.7 Clinical Manifestations
MOH is a subset of chronic, recurrent, daily headache syndrome, occurring in up to 2% of
adults, 5 women to 1 man, and 1% of children and adolescents as a complication from the overuse of
one or more classes of migraine abortive medication or other analgesics used in a patient with a pre-
existing headache disorder (usually migraine or tension-type headache) [42]. When this condition has
grown, early mediation is critical. The long-term prognosis relies on upon the term of medicine abuse.
The area, character, and seriousness of MOH can differ among people, and not the quality, but rather
the quantity of the headache and the refractoriness to acute or prophylactic treatment for acute
headaches is conducting to the diagnosis.
The headache may vary in severity, type and location and is present daily, typically present after
awakening. It enhances temporarily with analgesics or other specific drugs and returns as the
medication diminished or better stopped. If induced by Triptans overuse it may have characteristics
similar to the migraine attacks for which the treatment was initiated, but may occur on a daily basis and
even present an aura before the headache emerges. Ergot induced MOH is more likely to have a
throbbing component.
Pain can be located on the forehead, in the temporal or occipital regions of the head, unilaterally
or bilaterally, sometimes associating cutaneous allodynia (allodynia means that experiences that are not
painful, such as light, noise, smells, or touch are felt as painful, and this is common in MOH) driving
the patient confuse and making him seek for explanations for this variability. It is responsible for the
majority of referrals to headache specialists. Headaches may be more frequent in the morning,
secondary to nocturnal withdrawal or to sleep problems, this also related to drug withdrawal or to
increased caffeine consumption. Emotional distress may be associated to headache. Patients may
complain of pain in the sinuses area and are frequently treated for sinus infection, or self-medicated
with decongestants or cold medications, worsening MOH.
MOH is a disorder causing decline in the quality of life and causing physical symptoms, such as
daily and incapacitating headaches, insomnia and non-restorative sleep as well as psychological distress
and reduced functioning. Other symptoms that may accompany the headaches are nausea, anxiety,
irritability, asthenia, restlessness, difficulty concentrating, memory problems and depression [43].
It is typically for migraine that individuals have episodic attacks of various symptoms, yet they retreat
to their standard condition of well-being between attacks. MOH, conversely, is a dull steady headache.
MOH is not associated with focal or lateralizing neurological signs. Between headache episodes,
neurological examination should be normal. There is a high incidence of patients waking up with
headache in the morning, or having early morning awaking headache, myofascial syndrome, associated
to inattention, anxiety and depression [44]. Consider that these symptoms should be taken into account
in the diagnosis of MOH, should be followed up and used in the future new classifications of MOH.
Some authors consider two types of MOH, simple and complicated, based on the duration of MOH, the
amount and types of drugs overused, the coexistence of psychiatric disorders, and history of relapse
after withdrawal [45].
29
1.8 Comorbidities

Psychiatric comorbidities: generalized anxiety, panic disorders, mood disorders - dysthymia,

depression, obsessive-compulsive features, and personality disorders, more susceptible to dependence
resembling eating or substance abuse, heavy smoking, sleeping problems, restlessness, irritability.
Certain behaviors and psychological states, such as fear of headache (cephalgiaphobia), anticipatory
anxiety, catastrophizing, low headache-related self-efficacy, obsessional drug taking and psychological
drug dependence may be associated in patients developing MOH. Patients with psychiatric pathology
may have lower pain tolerance, using higher doses of antalgics of any type, more often opioids. There
was also an idea of to classify MOH patients to type I MOH (simple) and type II MOH (complex) [46].
Type I MOH patients using non-opioid and non-barbiturate medication and having no psychiatric
pathology associated and in type II MOH (complex) all the other patients.
Twenty-eight CTTH (Group C) and eighty-nine MOH patients were included into a study. MOH
patients were divided into two groups according to their pre-existing headache types: MOH patients
with pre-existing ETTH (Group E, number = 31), and with pre-existing migraine (Group M, number =
58). All patients were interviewed with a psychiatrist and SCID-CV and SCID-II were applied. Beck
Anxiety Inventory and Beck Depression Inventory scales were also performed [47].
The results of the study showed that eleven patients (39.3%) in-group C, 21 patients (67.7%) in-group
E, and 31 patients (53.7%) in-group M were diagnosed to have comorbid psychiatric disorders. In
Group E, mood disorders were found significantly higher, but the difference between the two groups
with regard to anxiety disorders was insignificant. Mean depression scores were significantly higher in
Group E than Group C. The mostly diagnosed type was obsessive-compulsive personality disorder in
all the three groups, and was statistically significant in Group M than Group C [47].
Often, neck pain increases and autonomic signs such as vasomotor instability occur. The headache may
develop a circadian rhythm [30]. Patients may be awakened from sleep or have onset upon arising.
Comorbidities may be also generated by the medication overused, representing side- effects of
the treatment like: sensory neuropathy, slowing of central cognitive processing, changes in the arterial
vessel wall structure of the cerebral arteries, concentration and attention problems, forgetfulness,
distress (Ergot derivatives), disturbances of the peripheral autonomic nervous system, analgesic
nephropathy, gastritis, gastric ulcerations.

30
1.9 Clinical Diagnosis Criteria

The history is the most important item for diagnosis of MOH as there are no specific diagnostic
tests. Consider MOH as a possible cause in all patients with a daily or second-daily headache, with no
other obvious cause, particularly among those with a prior history of migraine or tension-type
headache. The temporal course of the headache with transformation from intermittent headache to
continuous or frequent (at least second daily) headache is very important.
MOH is thus a diagnosis that should be considered in all chronic headache patients as the very first step
in their management strategy.

 According to the International Classification of Headache Disorders (second edition):

A) Headache present on ≥15 days/month fulfilling criteria C and D

B) Regular overuse for >3 months of one or more drugs that can be taken for acute and/or symptomatic
treatment of headache.
C) Headache has developed or markedly worsened during medication overuse.
D) Headache resolves or reverts to its previous pattern within 2 months after discontinuation of
overused medication.[48]

 According to the European Headache Federation:

A) Is associated with:
• regular use of simple analgesics on ≥ 15 days a month
and/or
• regular use of opioids, ergots or triptans, or any combination
Of these, on ≥10 days a month
B) Occurs daily or near-daily
C) Is present – and often at its worst – on awakening in the morning
D) Is initially aggravated by attempts to withdraw the medication.
Diagnosis of medication-overuse headache is confirmed if symptoms improve within 2 months after
overused medication is withdrawn.[42]

31
The anamnesis and medical history is very important for the diagnosis of MOH. The diagnosis is
clinically greatly essential, since patients seldom react to preventative medications, as long as they are
over using acute medications.

‘Ask-tell-ask’: assess frequency of headache and medication use

“How many headaches do you get each month?”
“How many rescue medications do you take?”
Rephrase patient’s answer for confirmation: “so you have 20 headaches days/month and you take four
acute medications per day-that is about 100 tablets per month?”
Ask open-ended questions to assess medication use
“How has your use of rescue medications changes?”
“Tell me about how your migraines and medications make you feel”.
Ask closed-ended questions to assess the use of headache medications
“Do you use any preventive medications for your headaches?”
“Which medications do you take?”
Figure 4. Techniques for Communicating with Patients [42]

32
1.10 Paraclinical Diagnosis

There are no specific diagnostic tests for MOH. If the patient symptoms have been stable over
months or years, there is no indication for neurological investigation or imaging. Abnormalities on
brain imaging, CT scan CTA or MRI, are most likely to be incidental. Recognizable proof of a high
admission of analgesics is essential since medication overuse headache required particular approach for
treatment. Specifically brain imaging is essential if secondary headache type is associated, if the course
with cerebral pain attacks changes or if persistent neurological or psychopathological variations are
found to be abnormal in the paraclinical investigation and for differential diagnosis.
MRI shows that the gray matter volume (GMV) decreases in the orbitofrontal cortex and left middle
occipital gyrus as well as GMV increases in the left temporal pole/Para hippocampus in MOH patients.
GMV decreases in frontal, temporal, occipital lobes, precuneus, and cerebellum. GMV of the
orbitofrontal cortex was predictive of the response to medication overuse treatments [49].
Functional magnetic resonance imaging (fMRI) data, during the execution of a decision-making under
risk paradigm, found that MOH patients showed dysfunction in the mesocorticolimbic dopamine
circuit, particularly in the ventromedial prefrontal cortex (reversible after withdrawal) and in the
substantia nigra/ventral tegmental complex. Some other studies, on a small number of patients showed,
after beginning of withdrawal in MOH patients, reduced pain related activity across the primary
somatosensory cortex, inferior parietal lobule, supramarginal gyrus and in the region of the lateral
pathway of the pain matrix (containing spinothalamic tract neurons) and normalization of the activity in
this regions 6 months after withdrawal, suggesting that no irreversible changes occur due to medication
overuse. PET show that several areas are less metabolically active in MOH [31].

33
1.11 Differential Diagnosis

Each of the primary headaches may be taken into account for the differential diagnosis to others.
Medication overuse headache (MOH) needs a differential diagnosis to chronic migraine and chronic
tension type headache[42]. Any form of chronic daily headache, whether primary or secondary, needs
to be considered in the differential diagnosis of MOH.
Primary headache subtypes of chronic daily headache include chronic migraine, chronic
tension-type headache, hemicrania continua, and new daily persistent headache[50].
Other primary headache disorders, however, can also present as a chronic daily headache. The list
includes cluster headache, SUNCT, hypnic headache, nummular headache, and chronic paroxysmal
hemicranias[50]. A high recurrence of medication admission does not imply that MOH is the main
cerebral pain issue that is present. Regularly, the patient with MOH has underlying primary headache
disorder, that bit by bit, or unexpectedly, expanded in recurrence, which prompted to an expanded
admission of analgesics and in the end to MOH superimposed upon the primary etiology.
The frequent occipital pain can be misdiagnosed as cervicogenic headache and patients may be
submitted to unnecessary and expensive neck interventions, which are ineffective for MOH.
MOH should be differentiated from headache directly induced by medication such as nitrates and
related compounds.
Drug dependency disrupt patient’s life by drug-seeking behavior and MOH patients are less
likely to have cravings or to escalate the quantity of drug intake.
Neurological signs and symptoms such as eyelid ptosis, pupillary asymmetry, papilloedema, lateralized
weakness or sensory disturbance, asymmetrical tendon reflexes and cerebellar incoordination should be
investigated using cerebral imaging (CT scan or MRI) to exclude brain tumors, stroke or intracranial
hypertension.

34
1.12 Treatment

Medication-overuse headache is an aggravation of a prior primary headache by chronic overuse

of medication taken to treat it, transforming acute pain into a chronic one. Once this condition has
developed, early intervention is important. The long-term prognosis depends on the duration of
medication overuse [42]. MOH is frequent and represents a major problem of treatment in patients with
chronic headache.
The most important way to treat MOH is to prevent from developing. Educating patients about
the relationship between frequent intake of acute headache medication and MOH, with the aim to
reduce intake of acute medication, is mandatory. Initiation of migraine prevention therapy in patients
shows that it is superior to acute medication. The aim is to prevent the medication overuse through
education, which is superior, easier and cheaper than any treatment. The main effective treatment for
MOH is withdrawal of the speculated drugs, but in most cases that is easier said than done. Patients are
aware that they are using too much medication but they do not realize this is the cause of their disease
and that they will need a detoxification programed.
A few patients think that it is exceptionally hard to acknowledge that the pharmaceuticals they
use to treat their headaches are really exacerbating their condition. Prophylactic treatment for migraine
like: Topiramate, Amitriptiline, Propranolol or others like beta blockers, Valproic acid, Calcium
channel antagonists (Flunarizine), Onabotulinumtoxin A or non-pharmacological treatments as greater
occipital nerve block, acupuncture, neuromodulator, transcranial magnetic stimulation (TMS), occipital
nerve stimulation (ONS), supraorbital nerve stimulation (SONS) or noninvasive supraorbital
transcutaneous stimulation (STS) can be started before medication withdrawal.
There are no specific guidelines for the treatment of MOH, as there are not enough double blind
placebo controlled trials; there are trials with no statistical significance or with a too small number of
patients due to trial discontinuation, done in order to establish a specific treatment for MOH. Guidelines
are based on publications with a low level of evidence and on the consensus of the experts EFNS.
Headache prophylactics should be used as treatment in acute migraine as they cause no MOH and can
become effective in MOH before and after medication withdrawal. This information can be utilized to
empower hesitant patients, especially to the individuals who contend that 'only medication X is viable
for my situation'.
Critical co-morbidities, such as obsessive-compulsive disorder, anxiety or depression, are ought
to be recognized and treated associatively. It is necessary to explain to the patient that frequently MOH
can be cured, with proper compliance and withdrawal of the drugs intake, and that a significant
improvement in his quality of life can be achieved.

35
There are four separate objectives in the complete management of MOH:
1. Achieve withdrawal from the overused medication
2. Recovery from MOH with pharmacological and no pharmacological methods
3. Review and reassess the underlying primary headache disorder (migraine or tension-type headache)
4. Prevent relapse [42].

The principle of these objectives is to explain to the patient that the treatment he is taking for his
headache attacks is the cause of his bad condition. Withdrawal is most effectively done. Medication can
be stopped abruptly (analgesics, triptans, ergot derivate) or it can be a tapered withdrawal of medication
(opioids, barbiturates, benzodiazepines) associating a detoxification program. This can be conducted in
an outpatient clinic or after the admission to the hospital, seldom required, associating withdrawal
therapy, having the aim to detoxify the patient, stop the chronic headache and increase the response to
the acute and prophylactic medication.
There are not enough randomized clinical trials showing if the abrupt or gradual withdrawal of
the overused medication is better, but it should be individualized for the treatment that was used in
excess. This way of treatment do not only detoxify the body, but also increases the future
responsiveness to acute or prophylactic therapy.
Withdrawal drives at first to intensifying cerebral pain, can cause a status migrenosus, may
associate nausea, vomiting, arterial hypotension, tachycardia, sleep disturbances and increasing anxiety
and restlessness so ought to be wanted to maintain a strategic distance from stress and life disturbances.
This symptoms may last from 2 to 10 days (for triptans 4 days, for ergot derivate 6,7 days and for
nonsteroidal anti-inflammatory drugs 9,5 days) but sometimes maybe 3-4 weeks to some months, and
after this difficult days for the patient, usually there are signs of improving, recovery proceeds
gradually [51]. The patient should be monitored by the neurologist, headache or pain specialist and
general practitioner, and sometimes a psychologist can be very helpful.
A 1-year randomized multicenter open-label trial study, performed in 2009, intention to treat
analyses performed on 56 patients with MOH showed the importance of prophylactic therapy. These
were randomly assigned to receive prophylactic treatment from the start without detoxification,
undergo a standard outpatient detoxification program without prophylactic treatment from the start, or
no specific treatment (5-month follow-up). The primary outcome measure, change in headache days per
month, did not differ significantly between groups. However, the prophylaxis group had the greatest
decrease in the number of headache days compared with baseline, and also a significantly more
pronounced reduction in total headache index (headache days’/month x headache intensity x headache
hours) at months 3 (P = 0.003) and 12 (P = 0.017) compared with the withdrawal group. At month 12,
53% of patients in the prophylaxis group had  50% reduction in monthly headache days compared
with 25% in the withdrawal group (P = 0.081). Early introduction of preventive treatment without a
previous detoxification program reduced total headache suffering more effectively compared with
abrupt withdrawal [43].
36
1.12.1 Management in primary care
Most medication overuse headache can be managed in primary care.
Reasons for future consultation, by a neurologist or headache specialist are:
 uncertainty of diagnosis
 suspicion of serious secondary headache
 cases where investigation may be necessary to exclude serious pathology [42]
 headache which is new or different to the patients feeling
 comorbidities requiring a specialist consultation
 presence of risk factors

General practitioners with patients, who are motivated and overuse Triptans or other single
antalgic drugs, excluding Barbiturates, Benzodiazepines or Opioids, can undertake drug withdrawal.
However, if the patient has failed a trial of outpatient withdrawal or has severe drug withdrawal
symptoms like nausea or status migrenosus or overuses barbiturates, Benzodiazepines, Opioids or
multiple drugs, and particularly if there is significant anxiety or depression complicating the
presentation, or some other co-morbidities the patient should be treated in a specialized hospital and a
headache specialist or neurological consultation should be considered [52].
In hospitals they can be better hydrated, treated with parenteral antiemetic, prednisone or
prednisolone starting with 60 mg/day and decreasing progressively the dose in 6 days, maybe some
Benzodiazepines and Amitriptyline 50 mg in order to limit the symptoms of drug withdrawal,
Sumatriptan subcutaneously in case of status migrenosus and Naproxen 1000 mg/day - as a bridge, or
transitional therapy, over a medium term, sometimes Lignocaine or an Ergot derivative intravenously
and all this pharmacological treatment associating psychodynamic psychotherapy. The combination of
the pharmacological and non-pharmacological treatment was superior and reduced long term relapses.
Experts say that antalgics are not recommended for withdrawal headache with the only exception of
intravenous administration in very severe cases. Triptans overuse can be treated by greater occipital
nerve block. The prophylactic treatment for the primary headache should be tailored to the patient’s
condition, taking into account also the side effects of every drug, the co-morbidities, the patient’s desire
and the anterior therapeutic experience.[53] The only drug with moderate evidence in the prophylactic
treatment of migraine and MOH is Topiramate up to 200 mg/day. It can be started before reducing and
then stopping antalgics in MOH. If the primary headache is not correctly diagnosed, withdrawal of
treatments should be started in MOH and the patient and the doctor should wait to see what kind of
headache remains, as primary headache, and after a specific diagnosis, prophylactic treatment should be
prescribed.

37
 In some patients the approved prophylactic medication (more than 15 preventive meds including
Beta blockers, Calcium channel blockers, Antidepressants – SSRIs, SSNTIs and Tricyclics, hormone
therapy, Anticonvulsants, Antihistamines, nerve block injections, botulinum toxin A) is not helpful in
reducing the frequency and intensity of the headaches in migraine and had side effects, some quite
significant. So new off label, treatments are tested in clinical trials, taking into account the role of the
GCRP Receptor complex in the pathophysiology of MOH. So, anti CGRP monoclonal antibodies like
Eptinezumab, Galcanezumab, Fremanezumab (all targeting CGRP ligands) and Erenumab (targeting
CGRP receptor) are now tested in randomized, double blind placebo controlled studies or parallel-
group studies for prevention of chronic migraine and showed great promise as a potential preventive
injectable treatment with fewer adverse effects.

Adherence to prophylactic treatment in migraine but also in MOH is relatively low and only
approximately 50% take this type of medication as prescribed.
The treatment in the hospital compared to the treatment, as outpatient is more expensive, but the patient
is strictly monitored, he cannot continue taking his previous medication, he has psychological support
and emergency treatment if needed. The strategy for achieving withdrawal is, at present, based on
expert opinion rather than scientific evidence, partly due to the lack of randomized controlled
studies[43] .A further challenge in the treatment of MOH is the fact that there is no worldwide
consensus for the management of these patients other than that termination of medication overuse is
desirable[43].

Withdrawal drives at first to intensifying cerebral pain, can cause a status migrenosus, may
associate nausea, vomiting, autonomic and vasomotor symptoms such as arterial hypotension,
tachycardia, nasal drainage and congestion, lacrimation, vasomotor instability, gastrointestinal
hypermotility, sleep disturbances, increasing anxiety and restlessness symptoms that will need specific
pharmacological treatment but also ought to be wanted to maintain a strategic distance from stress and
life disturbances. These symptoms may last from two to 10 days but sometimes maybe 3-4 weeks or
some months, and after these difficult days for the patient, usually there are signs of improving,
recovery proceeds gradually. Patients should take their medication only as directed by their physician,
they should have healthy lifestyle habits — such as getting adequate sleep, eating plenty of fruits and
vegetables, and getting regular exercise —and all this can help prevent headaches. Avoid any known
headache triggers.

The patient should be monitored by the headache or pain specialist, neurologist and general
practitioner, and sometimes a psychologist can be very helpful. Psychological cognitive-behavioral
therapy and group therapy can be also effective. Multidisciplinary educational programs for patients in
groups are cost-effective and limit the use of medication.[53]

38
 The duration of withdrawal headaches have been found to vary with different drugs, being
shorter in patients overusing Triptans (~4 days), than in Ergotamine derivate (~7 days) or nonsteroidal
anti-inflammatory drugs (~10 days)[54] There are relapses of MOH in 14-41% of cases in 1 year, more
frequently in some months after stopping the treatment that induced MOH, especially in men, if they
start again taking the medication they have used before or some analgesic combinations. Some non-
standardized studies consider a better prognosis for patients who had migraine as a primary headache
than for those who had tension headache. Patients should be monitored closely and regularly to prevent
relapses.

Non-pharmacological treatments can also be helpful:

Biofeedback
Patients taught to increase awareness and bring involuntary process under
voluntary control.
Includes sympathetic arousal, circulation (finger temperature) and muscle
tension.
Relaxation techniques
Used to minimize physiological responses to stress.
Includes breathing techniques such as diaphragmatic breathing, visual
imagery, medication, prayer, yoga, listening to music, self-hypnosis and
listening to guided relaxation CD’s or tapes.
Cognitive-behavioral therapy
Helps patients build or improve coping skills.
Includes identifying triggers, promoting healthy lifestyle habits and keeping
headaches diaries.

Figure 5: Non pharmacological strategies for MOH treatment [55]

39
 There is still some discussion in the matter of whether or not at first to detoxify MOH patients,
and whether prophylactic medication ought to be started quickly before, with withdrawal or after
finished withdrawal treatment.

Figure 6: Course of Headache Intensity (Top) and Percentage of Patients with Headache (bottom)
During 14 Days of Withdrawal Therapy After Medication Overuse [28]

MOH may be managed first by prophylactic treatment (i.e. Propranolol, Topiramate,

Onabotulinumtoxin A, Amitryptiline, Nortryptiline, a Calcium channel blocker), before stopping the
overuse medication and continuing after stopping it. It can be superior to the detoxification treatment.
Long-term treatment, which also include patient’s education and changes in his daily basis behavior,
may be very helpful to treat MOH. Patients with headache disorders very frequently desire professional
information about their condition, as many of them are reading misdirecting data from the internet.

40
1.13 Evolution and Follow Up

Every patient withdrawing from medication requires follow-up in order to provide support and
observe outcome
• First follow up is recommended following 3 weeks to make certain that withdrawal has been
accomplished.
• Utilization of a schedule, prescribed to record side effects and pharmaceutical use amid withdrawal,
and to record changes of headache pattern if there are any.
• Most patients return to their headache set during 2 months and this will need suitable management.
• Additionally follow-up is imperative to keep away from relapse, and most patients require expanded
support: the relapse rate is around 40% in the range of five years.

Although supporting evidence is limited, behavioral interventions may help prevent headaches.
Examples include relaxation therapy, stress management, meditation, regular aerobic exercise, or
movement disciplines such as Thai chi or yoga. Specific recommendations need to be mindful of
patient preference and likely compliance, as well as local availability [52].

41
1.14 Prognosis

The long-term prognosis depends on the duration of medication overuse, on the type of
medication overused (analgesic combinations have a higher rate of relapses than triptans and ergot
products), and on the type of primary headache, the patients previous suffering from tension type
headache are three times more likely to relapse than those with migraine precursor headaches[56],[57].

The success rate of the detoxifying treatment is of 50-70%. Most relapses happen in the first year after
withdrawal. These points are illustrated by the following reports:

 A meta-analysis of 17 studies and 1101 patients with MOH found that the success rate for
withdrawal therapy at one to six months was 72 percent, where treatment success was defined as
either no headaches or a reduction in headache days of >50 percent [58].
 In a study with prospective data collected from 240 patients with MOH who were treated with
drug withdrawal and preventive therapy, the one-year rate of treatment success was 57 percent.
Independent predictors of unfavorable treatment outcome at one year were a higher frequency
of primary headache, ergotamine overuse, and a greater degree of headache-related disability at
the time of MOH diagnosis [59].
 In a prospective study of 96 patients with MOH, complete data sets at four years were available
for 75 patients. The relapse rate at six months, one year, and four years was 31, 41, and 45
percent, respectively. Patients with underlying migraine headache had a lower relapse rate than
those with tension-type headache or combined migraine and tension-type headache, but small
numbers prevent definitive conclusions [57].
 In a retrospective report that analyzed outcomes for 67 patients with MOH after
multidisciplinary headache treatment at a tertiary center, the reduction in total headache
frequency for those with underlying tension-type headache and those with underlying migraine
was 50 and 72 percent. These findings suggest that patients with background migraine have a
better outcome following withdrawal from MOH than those with underlying tension-type
headache.[60]

SF -36 questionnaire is used to appreciate the quality of life and is a good predictor for the
prognosis. RAND 36 Item Health Survey v1.0 Questionnaire Items can be also used in order to
appreciate the Quality of life. MOH is a common and disabling condition; with a high socioeconomic
impact (work absenteeism, recurrent emergency medical visits, hospital admissions, and unnecessary
diagnostic tests), being one of the most expensive neurological disorders and it should be avoided, early
recognized and efficiently treated. There is still much to do in establishing the pathophysiology, the
underlying genetic or psychological susceptibilities and the specific treatments based on evidence based
medicine.

42
II. Special Part

43
2.1 Introduction
Medication overuse headache (MOH) is a frequent disease due to auto medication and easy
access to over the counter (OTC) medicines, taken frequently in order to relieve headaches and other
types of pain, but it is underdiagnosed and undertreated. Headaches can start as primary headaches:
migraine with or without aura or tension type headache, and less frequent cluster headache,
combination of this three or other types of headache, which increase in frequency and intensity,
occurring on daily basis, turning into chronic daily headache (CDH). Excessive use of medication taken
for symptomatic headache relieve is a well-known phenomenon, becoming more and more frequent due
to the “over the counter” (OTC) used drugs, sold without a medical prescription. This is why MOH has
developed into the third most common type of headache after migraine and tension type headache.
All drugs taken to relieve pain, such as non-steroidal anti-inflammatory drugs (NSAIDs), other
analgesics, Aspirin, Acetaminophen (Paracetamol), Codeine, Caffeine, Drotaverine, Ergotamine
derivate, Triptans and Opioids can induce MOH in susceptible patients, and especially in patients with
history of headache or family history of headache or substance abuse. NSAIDs are very often the cause
although Aspirin is infrequently cited (Paracetamol 38%, Ibuprofen 16% and both in combination 28%,
more frequent Paracetamol combined with Codeine).
The prevalence of MOH is approximately 0.7-1.7% of the world's population (but it can be
more frequent due to missing statistical data). Frequently women of 30-60 years of age are affected,
having a history of more than 10 years of primary headache, taking specific medication for more than 3
times/week and it shows an increasing trend as recent studies reveal a common involvement throughout
the ages, even starting in childhood.
MOH is usually discussed in the context of frequent headache. The CDH is applied to patients
with 15 or more headache days per month for more than 3 months, taking acute medication more than
10-15 days monthly, depending of the overused medication, regardless of the primary headache type.
MOH is often cited as a form of secondary CDH—that is, CDH caused by medication overuse and can
associate many other symptoms, especially psychiatric ones.
It has a significant psychosocial, social and economic impact and affects severely the patient’s
quality of life. It is a cause of dysfunction in daily life, in routine work, in professional work and a
socioeconomic burden. In order to evaluate and then minimize the causes and risk factors which lead to
MOH – a new and frequent pathology in the modern times, and find the best way to diagnose, treat and
monitor this patients, as there are not enough clinical trials and guidelines based on evidences, I decided
to do a prospective study on patients diagnosed with MOH in the time interval 01.02.2016 -01.04.2017
referred to the Neurology Department of the Colentina Clinical Hospital. Due to the small number of
patients referred for hospitalization or who came to the emergency room of the neurologic clinic, as it is
not a headache center – where normally most of this patients can be referred (50-80% of the referred
patients), I extended my study and collaborated with 1 out-patient clinic, the place where most of this
patients are examined and diagnosed. For diagnosis, I used the criteria of the International
Classification of Headache Disorders (ICH disorders).
44
2.2 Material and Method
I performed a prospective study on 23 patients (19 women and 4 men) with mean age of 46
years, diagnosed with medication overuse headache (MOH) based on ICH, who consented after being
carefully informed, to take part in this prospective study. All the patients were the subject of a very
thorough anamnesis and were asked to bring all their medical documents referring to their headache
history. A neurological examination was performed at every visit. The patients consented to answer to a
specially created questionnaire (Annex 1), to perform laboratory tests and at least one cerebral image
diagnostic test (CT scan, angioCT scan or MRI) or some other tests necessary for the differential
diagnosis (i.e. blood pressure measurements or Holter registrations of blood pressure/24 hours, sinus or
cervical column Roentgen imaging tests a.s.o).
The patients were also asked to complete a headache diary (Annex 2) after the first visit (baseline) and
also to write down what do they do when headache begins and complete a medication list at home after
the baseline visit, the RAND 36-Item Health Survey v1.0 Questionnaire Items (Annex 3) representing a
health survey, measuring each of the following eight health concepts: physical functioning, limitations
due to physical health, bodily pain, social functioning, general mental health (psychological distress and
psychological wellbeing), role limitations due to emotional problems, vitality (energy/fatigue), general
health in order to assess the impact of MOH on quality of life.

As anxiety and depression are important co-morbidities in MOH, we used the Hamilton Anxiety
Scale HAM-A (Annex 4) and the Hamilton Depression Scale HAM-D (Annex 5).
A questionnaire regarding Headache and Assessment of Response to Treatment (Annex 6), and the
Visual Analogue Scale - VAS (Annex 7) were used in order to assess the intensity of their headache.
The severity of dependence scale SDS (annex 8) was used in these patients with frequent pain episodes
in order to establish the medication overused and to find the right management of MOH.

45
2.2.1 Details of data collection: Data collection should be conducted at intervals sufficiently frequent
for the management purpose. So the patients were examined at baseline, after a month of completing
the headache diary in order to have for sure the diagnosis criteria for MOH fulfilled and then at 3 weeks
after stopping treatments which had caused MOH and then monthly for the following 3 months (6
visits/patient).
2.2.2 Method: Examination for causes, risk factors, medication overuse type and doses inducing MOH,
diagnosis and outcome after diagnosis, recommending, prophylactic specific headache treatments,
stopping overused treatments with or without withdrawal therapy associated and after withdrawal,
recommend specific treatment for the precise primary headache type and co-morbidities.
2.2.3 The limitations of my study: the small number of patients referred and who consented to take
part in this prospective trial, the short time to follow up, the poor compliance of some of the patients to
be monitored and come to be followed up for 6 visits.

This study allows an analysis of:

1. The influence of epidemiological associations

2. Risk factor impact in population
3. Socioeconomic effects
4. Preventive actions
5. Treatment
6. Quality of life
7. Disability

46
2.3 Results

Figure 7. Distribution of Patients by Gender

Figure 7. Distribution of patients by gender - 17.35% (4 patients) are males and 82.6% (19 patients) are
females.

47
 Figure 8. Distribution of Patients by Years of Age

Figure 8. Distribution of patients by years of age -The manner of selecting the age groups were divided
by five different age intervals represented as: 20-29 years of age (8.6%), 30-39 years of age (17.39%),
40-49 years of age (26%), 50-59 years of age (34.7%), 60-69 years of age (13%).

48
 Figure 9. Distribution of Patients by Gender and Age Groups

Figure 9. Distribution of patients by gender and age groups - Out of a total of 4 male patients, 25% (1
patient) were 20-29 years old group
25% (1 patient) was 30-39 years old group
25% (1 patient) was 40-49 years old group
25% (1 patient) was 50-59 years old group
Zero percentage (no male patients) in-group 60-69
Out of a total of 19 female patients, 5.2% (1 patient) was 20-29 years old
15.7% (3 patients) were 30-39 years old
26.3% (5 patients) were 40-49 years old
36.8% (7 patients) were 50-59 years old
15.7% (3 patients) were 60-69 years old

49
 Figure 10. Analysis Regarding the Medication Overuse Which Induced MOH

Figure 10. Analysis regarding the medication overuse which induced MOH - Out of 23 cases: 9
(39.1%) of them were using Paracetamol. 2 cases (8.6%) using Sumatriptan. 3 cases (13%) using
Valporic acid. 7 cases (30.4%) using other NSAID’s. 5 cases (21.7%) using Quarelin. 5 cases (21.7%)
using Ibuprofen. 1 case (4.34%) used Ketanol. 3 cases (13%) using Aspirin. 1 case (4.34%) used
Barbiturates. 2 cases (8.6%) using Ergot derivatives. 2 cases (8.6%) using Caffeine. 2 cases (8.6%)
using Doreta.1 case (4.34%) used Cafergot. 1 case (4.34%) used Naproxen. 1 case (4.34%) used
Diclofenac. 1 case (4.34%) used Arcoxia. 3 cases (13%) using Indomethacin.

50
 Figure 11. Duration of Drug Administration

Figure 11. Duration of drug administration-all of our patients were taking medication that induced
MOH for years. The minimum duration of drug administration were 5 years, and the maximum were 30
years, with an average of 17 years duration of drug administration.

51
 Figure 12. Associated Comorbidities of MOH

Figure 12. Associated comorbidities of MOH- Our study show that not all 23 patients were presented
with comorbidity. This graph shows how many cases shares the same comorbidity associated with
MOH, in which anxiety (47.8%) were presented in the majority of the cases, together with depression
(34.7%).

52
 Figure 13. Hamilton Anxiety Rating Distribution

Figure 13. The Hamilton Anxiety Rating Scale (HAM-A) - is a psychological questionnaire we used
among our patients to rate the severity of their anxiety. Scored based upon the composite rating of
fourteen individually evaluated criteria. Upon the completion, we compiled a total score based upon the
summation of each of the 14 individually rated items. It has been predetermined that the results of the
evaluation can be interpreted as follows:

>17 = Mild Anxiety

18-24 = Moderate Anxiety

25-30 = Moderate to Severe Anxiety

Out of a total of 19 female patients: 3 patients (15.7%) having moderate to severe anxiety.
7 patients (36.8%) having moderate anxiety.9 patients (47.3%) having mild anxiety.
Out of a total of 4 male patients: 2 patients (50%) having mild anxiety, 2 patients (50%) having
moderate anxiety.

53
 Figure 14. Hamilton Depression Rating Distribution

Figure 14. Hamilton depression rating distribution - is a multiple item questionnaire used to provide an
indication of depression.
The patient is rated by the clinic among 21 dimensions with a score on a 3 or 5 point scale.

It has been predetermined that the results of the evaluation can be interpreted as follows:

0-7 = Normal
8-13 = Mild Depression
14-18 = Moderate Depression
19-22=severe depression
≥ 23 = Very Severe Depression.
Out of a total of 19 female patients: 4 patient (21.05%) normal. 3 patients (15.7%) having mild
depression. 2 patients (10.5%) having moderate depression. 3 patients (15.7%) having severe
depression. 7 patients (36.8%) having very severe depression.
Out of a total of 4 male patients: 1 patients (25%) is normal. 2 patients (50%) having severe depression.
1 patient (25%) having very severe depression.

54
 Figure 15. RAND 36-Item Health Survey Assessment of Quality Of Life in MOH Patients

Figure 15. RAND 36-Item Health Survey v1.0 Questionnaire Items, online calculator representing a
health survey, measuring each of the following 8 health concepts: physical functioning, limitations due
to physical health, bodily pain, social functioning, general mental health (psychological distress and
psychological wellbeing), role limitations due to emotional problems, vitality (energy/fatigue), general
health. Scores are the summation of the questions in each of the eight concepts, and are averaged
together to form a general score range from 0-100. No normative values or cut-off scores are presented,
however, the scoring indicates that 0% is the poorest possible QoL (more disability) and 100%
indicates full QoL (the best possible result, less disability). The higher the scores indicate better QoL.

55
 Figure 16. Intensity of Headache Pain in MOH at Baseline and After 4 Months of Withdrawal
Treatment

Figure 16. Intensity of headache pain in MOH at baseline and after 4 months of withdrawal
treatment- In this graph, we used VAS (Visual Analog Scale) to quantify the intensity of headache pain
in each patient at baseline, reaching the hospital or clinic and after 4 months of withdrawal treatment.
The interpretation is based on scale of 0 to 10, 0 being no pain, 5 Distressing pain and 10
Unbearable Pain.
Our study show that all 23 patients were presented with intensity of pain at baseline, which was high
and decreased after 4 months of withdrawal treatment. 3 patients (number 10,18,21) lost follow up.

56
 Figure 17. Primary Headache Type Before Treated as MOH

Figure 17. Primary headache type before treated as MOH - Our study show that all 23 patients were
presented with primary headache. This graph shows 6 patients (26.09%) with tension type headache
and 17 patients (73.91%) with migraine as primary headache type. Out of the 6 patients with tension
type headache 1 patient is male (16.6%) and 5 patients (83.3%) are females. Out of the 17 patients with
migraine type headache 3 patients are males (17.6%) and 14 patients (82.3%) are females.

57
 Figure 18. Years of Education of Patient with MOH

Figure18- Represents the years of education in MOH patients.

The graph shows four different distributions of education: 10 years (22%), 12 years (39%), 16 years
(17%) and 17 or more years of education (22%). 61% of the MOH patients are with  12 years of
education.

58
 Figure 19. Unemployment Due to MOH

Figure 19. 35% of the patients were eventually unemployment due to MOH and 65% persist their
occupation employed.

Figure 20. Unemployment Causes

Figure 20. Unemployment causes- 4% of patients with no job. 9% pensioners, 22% due to headache
and 65% from other causes.

59
 Figure 21. Headache Family History

Figure 21. Headache family history- out of a total 23 patients, 11 patients (47.8%) have no family
history related to headache, 12 patients (52.2%) have headache family history.

60
 Figure 22. Headache Medical Prescription, Over the Counter, Both

Figure 22. Out of a total of 23 patients, 9% (2 patients) had medical prescription for treating headaches.
39% (9 patients) had over the counter medications and 52% (12 patients) used both.

61
 Figure 23. Severity of Dependence Scales in MOH

Figure 23. Severity of dependence scales in MOH- the severity of dependence scale (SDS) is a 5
elements questionnaire. The score indicating the severity of dependence. Each of the five elements
scored 0-3 and the total score obtained through the summation of the five elements ratings.
Higher score= the higher level of dependence (Maximum 15 points).
Lower score=the lower level of dependence. (Minimum 0 points)
Out of a total of 23 patients, zero patients with minimum zero points. 1 patient with 1 point. 4 patients
with 2 points. 6 patients with 3 points. 4 patients with 4 points. 4 patients with 5 points. 4 patients with
6 points. Conclusion:  4 points in 52.17% of the patients.

62
 Figure 24. Treatment of Withdrawal

Figure 24. Treatment of withdrawal- Our study show that all 23 patients were treated after MOH
diagnosed. Out of a total of 23 patients, 48% (11 patients) stop NSAID’s. 22% (5 patients) treated with
Valporic acid and stop of NSAID’s. 9% (2 patients) treated with anti-hypertensive medications. 4% (1
patient) treated with Topiramate. 4% (1 patient) treated with Naproxen. 13% (3 patients) treated with
other medication combined.

63
 Figure 25. Side Effects of Treatment

Figure 25. Side effects of treatment- Our study show that not all 23 patients were presented with side
effects 26% (6 patients). The majority of the patients had more than one side effect. 9% (2 patients)
gastritis. 13% (3 patients) epigastric pain. 18% (4 patients) insomnia. 4% (1 patient) edema. 9% (2
patients) hypertension. 4% (1 patients) fainting. 13% (3 patients) nausea. 4% (1 patient) visual
disturbances.

64
2.3.1 Conclusions

From the study of the 23 patients diagnosed and treated for medication overuse headache (MOH) that I
studied regarding MOH correlated to the consulted literature I can conclude:

• Medication overuse headache (MOH) is a disease more frequent present than diagnose,
recognized or understood. It has become one of the major challenges in headache
treatment.
• There are no statistical data about the incidence and prevalence of MOH in Romania.
There are no specialized headache departments. Patients are treated by general
neurologists as outdoor - outpatients (the most of them) or indoor patients. Their
compliance to treatment and scheduled visits is relatively poor. Self-administer
treatment is very frequent. These do not require a doctor's prescription to obtain this
medication.
• Most of the patients become MOH patients after being primary headache patients. Most
of the patients develop MOH after being primary headache patients, suffering from
migraine 73.91% or tension type headache 26.09%. (Most of them suffering from
episodic migraine with or without aura and tension type headache in my study, and a few
of them of cluster headache or a combination of the two first as cited in the literature).
• Migraine is a major public health problem. However, what about MOH?
• MOH has a significant psychosocial, social and economic impact if the direct and
indirect costs with healthcare and the lost working days are taken into account. 35%
were unemployed.
• Women are more affected than men (82.6% women)
• Medication: Paracetamol and Non-steroidal anti-inflammatory drugs were more frequent
the cause of MOH (used between 5 and 30 years) in 39% without medical prescription
and in 52 % auto medication associated to medical prescription. Only 9% used medical
prescription only.
• Depression and anxiety are the most frequently associated co-morbidities.
• A family or personal pathological history of headache are risk factors to develop MOH
(52.2%)
• Patients with lower education were more affected, 61% with  12 years of education.
• Risk factors to develop MOH are: history of headache, lower education, excessive use of
drugs in order to cure pain, easy access to over the counter (OTC) medication, excessive
TV advertising for OTC medication, difficult access to the general practitioner or

65
 neurologist (long time to a medical visit), no use or not early use of prophylactic
treatment for episodic or primary headaches
• To avoid MOH patients should use analgesics prescribed by their physician, as
infrequently as possible and on less than 15 days/month and Triptans, Barbiturates or
Opioid drugs less than 10 days/month associated with prophylactic therapy.
• More attention should be given to preventive treatments in migraine in order to avoid
overuse of acute medications for pain relief.
• MOH should be recognized early, using an attentive anamnesis and specific
questionnaires and scales, which should be translated and validated in the local language
and the differential diagnosis with other chronic headaches, should be rapidly done, in
order to enable appropriate treatments to be initiated and induce this disease, which
affects severely the patient’s quality of life.
• There is only a small number of clinical trials that were performed for MOH, and as
there are no double blind, randomized, placebo-controlled multicenter trials, the
treatments used in MOH are conducted more taking into account the opinion of the
experts in headache.
• The treatment of MOH can be done in outpatient clinics or in a hospital. In the hospital
patients are better controlled, a multidisciplinary team can be involved, treatment is
more efficient, but more expensive. The overused medication can be stopped abruptly or
tapered, depending on the used medication. Prophylactic therapy for the primary
headache should be introduced before stopping overused medication. Detoxification
therapy may be useful and maybe Prednisolone, Amitriptiline, Topiramate or Naproxen.
Psychotherapy and behavioral therapy associated are useful, but only a small number of
patients agreed to it. Botulinum toxin A was not used in the patients of the group I
studied.
• A multidisciplinary team consisting of a neurologist, a pain specialist, the general
practitioner and a psychologist can reduce the time until withdrawal headache is cured.
• The rate of rebound of MOH is difficult to establish as the patients are not compliant for
monitoring after withdrawal treatment, but the patients with MOH induced by Triptans
had better results to withdrawal treatment (taking into consideration that Triptans are not
OTC ) than those overusing analgesics, and especially combinations of analgesics.
• RAND 36-Item Health Survey v1.0 Questionnaire Items was a good prognostic
predictor. MOH, a disease that affects severely the patient’s quality of life, 52.17% of
the patients having scores <60% in the Rand 36 item Health survey.
• SDS scores were high in MOH patients  4 points in 52.17% of the patients. The
maximum score in this scale is 15 points, with very high dependence, and 0 point with
no dependence at all.

66
• Patients need more education regarding OTC medication overuse and auto medication,
TV advertising for analgesics should be reduced, patients should go to the physician!
• Prospective controlled studies are needed, focused on different types of preventive
medication and the way to combine withdrawal treatment with pain relief drug
treatments.
• Specialized departments in headache, with neurologists, experts in headache and a
trained multidisciplinary team are necessary, as MOH is frequently present but
underdiagnosed and untreated.

67
III. Annexes

68
Annexes

3.1 Annex 1 specially created questionnaire

• Name (initials)
• Age
• Gender
• City/village
• Education (number of years)
• Employed/ Unemployed
• If Unemployed – why, for how long?
• Occupation
• Smoking
• Using illegal drugs
• Alcohol consumption – what? Doses?
• Family medical history
• Family history of headache: what type of headache?
• Family history of drugs or substance abuse
• Personal medical history
• History of headache – localization, when started? Type, frequency, intensity, triggers, treatment
(which medication and how often?), evolution (are there changes in the last 6 months?)
• Headache at the moment of examination – localization, when started? Type, frequency (number
of days/month), intensity, triggers, treatment, evolution
• Co morbidities – hypertension, depression, anxiety, obsessive-compulsive disorders, mood
disorders, cervical spondylosis, sinusitis, tumor, vascular malformation, TN
• Treatments for headache : what treatment (acute/prophylactic, type of medication), doses, for
how long, how many days/month, single or combination, did they increase the amount or
frequency of taking drugs, what side effects do they have from this drugs, how do they get their
treatment (prescribed or over the counter)
• Associated symptoms

69
3.1.1 Headache diary
3.1.2 RAND 36-Item Health Survey v1.0 Questionnaire Items, online calculator

3.1.3 Anxiety score (HAM-A)

3.1.4 Depression score (HAM-D)

3.1.5 Headache and assessment of response to treatment

3.1.6 Visual analogue scale (VAS)

3.1.7 Severity of dependence scale

Value of blood pressure

Neurological signs and symptoms
CT scan
Changes from one visit to another (Headache diary and Headache and assessment of response to
treatment.
New treatments

70
3.2 Annex 2 Headache diary [61]

71
3.3 Annex 3 RAND 36-Item Health Survey v1.0 Questionnaire Items [62]

72
73
74
75
3.4 Annex 4 Hamilton Anxiety Scale HAM-A [63]

76
3.5 Annex 5 Hamilton Depression Scale HAM-D [64]

77
78
79
80
3.6 Annex 6 Headache and Assessment of Response to treatment [65]

    
On how many days in the
1
last month did you have a headache?

none 1-2 3-5 5-15 16-30

On how many days in the     

last three months did your headaches make
2
it hard to work, study or carry out household
work? none 1-5 6-10 10-20 20+

    
On how many days in the
last three months did your headaches spoil
3
or prevent your family, social or leisure
activities? none 1-5 6-10 10-20 20+

Analysis (these questions establish frequency of all headaches and of disabling headaches under current treatment; ticks
towards the right suggest increasing need for treatment review)

All ticks in white area Headache control is good: no review needed.

Better acute headache management is needed; review Qs 4-8

One or more ticks in lightly-shaded area
for guidance; prophylaxis may not be required.

Headache control is not good; review Qs 4-8 to optimize acute

One or more ticks in middle-shaded area
medication; consider ways of reducing frequency (trigger
avoidance and prophylactic medication).

Disabling headache, poorly treated; possibly chronic daily

One or more ticks in dark-shaded area headache (acute medication should be avoided); review Qs 4-8
and consider ways of reducing frequency.

On how many days in the

4     
last month did you take medication to

81
 relieve a headache? (Do not count
none 1-4 5-9 10-15 16-30
preventative medication.)

    
When you take your headache medication,
5 does one dose get rid of your headache and
keep it away?
always often sometimes rarely never

    
Are you able to take your headache
6 medication without being bothered by side
effects?
always often sometimes rarely never

    
7 Do you feel in control of your headaches?

always often sometimes rarely never

please write your diagnosis here:

What have you been told is your headache
diagnosis?  
8
yes no
Do you feel you understand it?

Analysis (these questions suggest how current management might be improved)

Q4: Response should accord with Q1. When
medication days are >10, there is risk of medication
overuse headache.
Q5: Ticks towards the right increasingly suggest
poor efficacy
Advise patient about the risk and dangers of medication
overuse. Consider ways to reduce frequency (trigger avoidance
and prophylactic medication).
Consider treating earlier, changing medication, dose or route of
administration, or using combination therapy, according to
local guidelines.

Q6: Ticks towards the right increasingly suggest Consider changing medication or dose according to local
poor tolerability. guidelines.

82

Q7: This question relates to self-efficacy and to
satisfaction.
The response should be concordant with previous
responses.
Q8: This question relates to education.
When the response is in the shaded area, look for the reason(s)
in responses to Qs 1-6. If it is not evident, consider co-
morbidities.
When the response is not concordant, consider cognitive
interventions and expectation management.
Always hand out the appropriate information leaflet. When the
diagnosis is wrongly stated, or the answer “no” is given, further
explanation may be necessary.
83
3.7 Annex 7 Visual Analogue Scale: [66]

84
3.8 Annex 8 Severity of Dependence Scale SDS [67]

This questionnaire will assist your GP to identify ways of meeting your needs about a drug,
which may be causing you some concern.

Circle the answer that best applies to how you have felt about your use of
………………… over the last twelve months.

1. Did you ever think your use of …………………..(drug) was out of control?

Never or almost never 0

Sometimes 1
Often 2
Always 3

2. Did the prospect of missing a shot/snort make you very anxious or worried?

Never or almost never 0

Sometimes 1
Often 2
Always 3

3. How much did you worry about your use of the drug?

Not at all 0
A little 1
Often 2
Always or nearly always 3

4. Did you wish you could stop?

Never or almost never 0

Sometimes 1
Often 2
Always 3

5. How difficult would you find it to stop or go without ………….(drug)?

Not difficult at all 0

Quite difficult 1
Very difficult 2
Impossible 3

SCORE____

85
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86
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