1. health and fitness
2. disease
3. headaches and migraines

Headache
© 2008 the Authors
Journal compilation © 2008 American Headache Society
ISSN 0017-8748
doi: 10.1111/j.1526-4610.2008.01142.x
Published by Wiley Periodicals, Inc.
Refractory Migraine
Rational Combination Therapy in Refractory Migraine
B. Lee Peterlin, DO; Anne H. Calhoun, MD; Sherry Siegel, MD; Ninan T. Mathew, MD
Refractory migraine (RM) headaches pose important treatment challenges to the patients who live with them and the
clinicians who try to treat them. Defined based on the lack of response to acute, preventive, and nonpharmacologic treatment,
RM is often treated with a combination of treatments. Although combination therapy for RM has not been systematically
studied in randomized trials, clinical experience suggests that a rational approach to RM treatment, utilizing a combination of
treatments, may be effective where monotherapy has failed. In this article we briefly identify patient populations appropriate
for more aggressive migraine prevention with combination therapy. We then discuss modifiable risk factors and comorbidities
in migraine and then focus on the use of rational combination therapy, as well as the duration migraine preventatives should be
considered for use. Future research is needed to evaluate the full potential of rational combination treatment as a strategy for
treating and ultimately preventing RM.
Key words: refractory migraine, chronic migraine, headache, migraine, rational combination therapy, migraine prevention
(Headache 2008;48:805-819)
ology of RM and refractory chronic migraine are
reviewed elsewhere in this series of articles [Schulman
et al, 2008; Lipton and Bigal, in this issue]).
Although data suggest that effective acute treatment of migraine is associated with improved
responses and decreased disability, the potential
disease-modifying effects of migraine preventives
have not been studied.6,7 It is plausible that migraine
preventives may possess such effects, as several neurological disorders with pathophysiological similarities to migraine (including multiple sclerosis and
epilepsy) have data suggesting preventative therapy
limits disease burden, ie, results in “disease
modification.”8-10 Ultimately, our goal should be to
prevent the development of RM. However, RM is
defined by a poor response to both pharmacologic and
nonpharmacologic treatment. Thus, in RM sufferers it
is natural to consider combination preventive treatment for this group of patients. And herein, we will
focus on the treatment of developed refractory
disease.
Migraine is estimated to affect approximately
more than 30 million people in the United States
alone.1 While the prognosis for the majority of patients
is good, approximately 3-14% of episodic migraineurs
will progress to chronic daily headache.2,3 And unfortunately, it has been estimated that only 14% of
chronic daily headache sufferers will remit to less than
one headache per week over one year.2 Thus, while
migraine itself confers substantial personal and societal burden, refractory migraine (RM) may extract an
even greater toll.1,4,5 (The definitions and the epidemiFrom the Department of Neurology, and Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, USA (B.L. Peterlin); Department
of Neurology, University of North Carolina, Chapel
Hill, NC, USA (A.H. Calhoun); King Pharmaceuticals, Inc.,
Houston, TX, USA (S. Siegel); Houston Headache Clinic,
Houston, TX, USA (N.T. Mathew).
Address all correspondence to B.L. Peterlin, Drexel University
College of Medicine, DUCOM Headache Clinic, 245 N. 15th
Street, MS 423, Philadelphia, PA 19102, USA.
Accepted for publication March 25, 2008.
Conflict of Interest: None
805
806
In this article, we will first briefly identify patient
populations that may be appropriate to consider for
combination preventative therapy. We will then
focus on potentially modifiable factors in migraine
and discuss the use of rational combination therapy
for migraine prevention – with the caveat that none
of these combinations are approved by the Food
and Drug Administration. Finally, we will briefly
discuss the appropriate duration for preventive
therapy.
It should be noted that where possible the combination of preventatives that are reviewed are based
on the available data utilizing polytherapy in
migraine. However, as research in migraine polytherapy is in its infancy, most of the suggestions are
based on the evidence of randomized controlled trials
of medications showing efficacy for migraine prevention as monotherapy, combined with anecdotal evidence and the authors’ personal experience. It should
also be recognized that many other effective combinations exist which are not reviewed here. However, a
review of every potential combination therapy that
can be utilized for migraine prevention is beyond the
scope of this article.
WHEN TO CONSIDER COMBINATION
THERAPY
Concurrent risk factors and/or comorbidities frequently guide preventive choices and may warrant
consideration of combination therapy. Several psychiatric disorders (including depression, anxiety, and
bipolar disorder) and medical disorders (including
stroke, epilepsy, asthma, and cardiovascular disease)
are comorbid with migraine.11,12 Additionally, other
factors are associated with migraine chronification.
While some of these risk factors, including age and
gender, are not modifiable, others such as obesity and
medication overuse are.13,14 And although we recognize that monotherapy may be preferred for preventive therapy, clinically this may not always be
attainable.
A clinic-based study by Oates et al found that
69% of headache patients were on one or more medication that was not intended for headache prevention.15 Many of these non-headache prescriptions
were substances that impacted preventative therapy
June 2008
such as hormones, antidepressants, and antihistamines. This emphasizes the importance of obtaining a
complete medication history (along with the indications for these drugs). It may be possible to utilize one
drug for dual therapeutic purposes, and medications
which could thwart successful headache management
may be identified.
Migraine preventives are predominantly from
one of 3 drug classes: antiepileptic, antidepressant,
and antihypertensive agents.16-18 However, other
classes have data supporting efficacy in migraine
prevention, including antihistamines, hormonal
agents, dopamine antagonists, nonsteroidal antiinflammatory agents, and some vitamins or
supplements.16-23 Choice of preventives may be
based on the presence or absence of comorbidities
or risk factors. However, in the absence of prospective longitudinal data, migraine-specific combination
therapy is largely anecdotal and based on clinical
experience. And though unproven, factors including
a strong family history and an earlier age of onset
may warrant consideration for migraine-specific
combination therapy.4,5 In consideration of the proposed criteria for RM by the Refractory Headache
Special Interest Section (RHSIS) of the American
Headache Society (Table 1), we suggest consideration of combination therapy based on: (1) disability
and (2) history of repetitive failure of previous
preventives.
The proposed RHSIS RM criteria include failure
of at least 2 preventive medications from 2 different
classes; these patients warrant consideration of preventive polytherapy, a suggestion that is supported by
2 studies.24,25 The first was an open-label study of 52
RM patients, evaluating the effectiveness of either a
b-blocker, or valproic acid alone as compared with
the 2 drugs in combination.24 The majority (75%) of
participants had previously failed a trial with amitriptyline or flunarazine. Participants were then given a
2-month trial with a b-blocker alone. In subjects who
showed no response to the b-blocker, a 2-month trial
of valproic acid alone was given. Participants who still
failed to respond were then treated with combination
therapy. Over half (56%) of the patients showed a
>50% reduction in migraine headache days while
only 29% showed no response; 15% stopped therapy
Headache
Table 1.—Refractory Migraine – Criteria and Definitions
Primary diagnosis—ICHD-II migraine or chronic migraine
Refractory = Headache syndrome causes significant
interference with function or quality of life despite
modification of triggers, lifestyle factors, and adequate trial
of medicines with established efficacy.
1. Failed adequate trials of preventive medicines, alone or in
combination, from 2 of 4 treatment classes:
a. b-blockers
b. Anticonvulsants
c. Tricyclic antidepressants
d. Calcium channel blockers
2. Failed adequate trials of abortive medicines from 2 of 3
treatment classes:
a. Both, unless contraindicated:
1. Triptans, and
2. DHE intranasal formulation
b. Either, unless contraindicated:
1. Non-steroidal anti-inflammatory drugs, or
2. Combination analgesics
Adequate trial = Period of time during which an appropriate
dose of medicine is administered, typically 2 months at
optimal dose or maximum-tolerated dose, unless
terminated early due to adverse effects.
Modifiers = 1. With or without medication overuse, as defined
by ICHD-II
2. With disability (MIDAS score ⱖ 11)
DHE = dihydroergotamine; ICHD-II = International Classification of Headache Disorders, 2nd edition; MIDAS = migraine
disability score.
secondary to adverse events. These results are
notable, as over three-quarters of participants had
failed monotherapy with 3 pharmacological agents
from 3 different classes before successful migraine
prevention was achieved with polypharmacy.
More recently, Pascual et al evaluated the use of a
b-blocker plus topiramate in RM patients.25 Participants had previously failed monotherapy with each
medication. Of the 58 patients evaluated, approximately 60% of participants showed >50% reduction
in headache frequency, while 17% did not tolerate the
combination. In addition, among responders, 44%
showed an excellent (>75%) response. These studies
suggest that combination therapy may benefit a subgroup of patients who would be classified as refractory migraineurs by the RHSIS RM criteria. Further
research is warranted to confirm these results and
identify potential populations in which combination
therapy may be appropriate.
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RATIONAL COMBINATION THERAPY:
PREVENTIVE COMBINATIONS
TO CONSIDER
Guidelines do not currently exist for combination
therapy in migraine. Nevertheless, logic suggests that
certain combinations may be useful, particularly in
RM. And although a review of every combination
that may be appropriately used in migraine prevention is beyond the scope of this article, we will review
some options for consideration. It should be noted
that where possible these options will be based on the
available clinical studies utilizing polytherapy for
migraine prevention. However, due to the extreme
paucity of research in this area to date, the following
combinations are largely based on monotherapy
randomized controlled studies showing efficacy for
migraine prevention, anecdotal evidence, and the
authors’ personal experience (Table 2).
b-Blockers.—Mechanism of Action.—The mechanism by which b-blockers benefit migraine is not
entirely known; and the known actions vary significantly among different b-blockers. Some, like propranolol, have membrane stabilizing activity, possess
affinity for 5-HT sites in the brain, and inhibit cytokines; yet efficacy in migraine prevention has been
shown with b-blockers (such as timolol), which do not
share these properties.26,27 Given their varied mechanisms, the only identified common property of bblockers that are successful in migraine prevention is
their lack of partial agonist or intrinsic sympathomimetic activity.26
When to Consider b-Blockers for Combination
Therapy.—In patients who inadequately respond to
monotherapy with another class of preventive – such
as an antiepileptic or antidepressant – the addition
of a b-blocker may be considered. There is evidence
that the combination of a b-blocker and an antiepileptic (either valproic acid or topiramate) is effective
in RM – even in the absence of response to the
b-blocker alone (as reviewed above).24,25 Additionally,
in hypertensive migraineurs or those with performance anxiety or aggressive behavior, the addition
of propranolol may be considered.28,29 Although
b-blockers are first-line choices for hypertensive
patients with angina, they are not first-line therapy for
coronary artery disease prevention (Table 3).30
Primary indications
Adverse events
Antidepressants
Antidepressants may increase the risk of suicidal thoughts or actions in children, teenagers, and young adults. However, depression and certain other mental problems
Amitriptyline
Depression; social phobia;
Fatigue, dry mouth and other anticholinergic
Heart block and significant arrhythmia,
anxiety and panic disorders;
effects, arrhythmias, weight gain
concomitant MAOIs, glaucoma, hypotension
enuresis
Nortriptyline
Depression
Dizziness; drowsiness; dry mouth; headache;
Concurrently concomitant with a MAOI
impotence; nausea; sensitivity to sunlight;
sweating; weight loss or gain
Protriptyline
Depression
Anxiety, confusion, dizziness, flushing,
Acute recovery phase of MI; co-administration
headache, impotence, insomnia, low blood
with cisapride; use with caution in history of
pressure, rapid heartbeat, rash, seizures, GI
seizure, urinary retention
symptoms
Venlafaxine
Depression, GAD, social
Increased blood pressure, abnormal
Gradual taper when discontinuing, nausea, dry
anxiety disorder; panic
ejaculation/orgasm, anxiety, blurred vision,
mouth, anorexia, dizziness, sweating
disorder
constipation, dizziness, dry mouth,
somnolence, abnormal ejaculation,
impotence, insomnia, nausea, nervousness,
impotence in men, anorgasmia in women,
sedation, sweating, tremor, weakness, weight
decreased libido, insomnia, nervousness,
loss constipation, headache, insomnia,
tremor, hypertension, yawning
nausea, sweating
Duloxetine
Diabetic peripheral
Cough, diarrhea, dizziness, dry mouth,
Uncontrolled narrow-angle glaucoma; with
neuropathic pain;
frequent urination, headache, loss of
MAOI; hypersensitivity
generalized anxiety disorder;
appetite, muscle aches, nausea, drowsiness,
major depressive disorder
sleeplessness, sweating
Buspirone
Anxiety disorders
Dizziness, nausea, headache, lightheadedness,
Hypersensitivity
agitation, insomnia
Calcium Channel Blockers
Verapamil, flunarazine (not
Angina, arrhythmias,
Constipation, hypotension, AV block, edema,
Severe LVD, hypotension (systolic
available in the United
hypertension
nausea
pressure < 90 mmHg) cardiogenic shock,
States)
sick sinus syndrome (exception: ventricular
pacemaker), second- or third-degree AV
block (exception: ventricular pacemaker),
atrial flutter or fibrillation and accessory
bypass tract (eg, Wolff–Parkinson–White,
Lown–Ganong–Levine syndromes)
b-Blockers
Propranolol Timolol; Nadolol;
Hypertension, angina, migraine
Fatigue, heart failure/block, lightheadedness,
Sinus bradycardia and greater than
others
prophylaxis, hypertrophic
hypotension, cold extremities, depression,
first-degree block; cardiogenic shock;
subaortic stenosis
bronchospasm, impotence, weight gain,
congestive heart failure, asthma and
masking of hypoglycemia
obstructive pulmonary disease;
bronchospasm, diabetes & hypoglycemia,
thyrotoxicosis, Wolff–Parkinson–White;
peripheral vascular disease, headache with
focal neurological symptoms
Drug
Selected contraindications
and precautions
Table 2.—Review of Drug Combinations That May Be Considered for RM
- Mitral valve prolapse, hypertension,
angina, performance anxiety,
aggressive behavior
+ Valproic acid
+ Topiramate
Note: Duloxetine + propranolol may
cause increased b-blockade
- Hypertension, hemiplegic migraine
+ Vitamin B2
+ CoenzymeQ10
+ Topiramate
+ Aspirin
+ Amitriptyline
+ Magnesium
- Anxiety
+ b-blocker
- Diabetic neuropathic pain
- Obesity
- PMS/PMDD
Anorexia, neuropathic pain
+ Nadolol
+ Anticonvulsant
- Obesity, europathic pain, fatigue
may also increase the risk of suicide.
- Anorexia, neuropathic pain,
insomnia
Relative indications
(based on comorbidities
& risk factors)
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June 2008
Epilepsy; post-herpetic
neuralgia
Epilepsy
Epilepsy bipolar disorder
Gabapentin
Levetiracetam
Lamotrigine
Depression, anxiety disorders,
psychiatric disorders
None
Bloating irritability, depression, breast
tenderness, sexual dysfunction
Bloating irritability, depression, breast
tenderness, sexual dysfunction
Potentially severe rash; severe blistering,
peeling, chest pain; easy bruising or
bleeding;
nausea, stomach pain, increased liver enzymes
dizziness drowsiness; blurred vision; nausea,
vomiting, diarrhea, headache; weight loss;
anxiety, insomnia, unusual dreams
Nausea, sedation, cognitive dysfunction, ataxia
Pancreatitis, increased liver enzymes, hepatitis,
neural tube defects, agranulocytosis, GI
symptoms, asthenia, sedation tremor, hair
loss, weight gain
Sedation, dizziness, unsteady gait, fatigue
Weight loss, nephrolithiasis, glaucoma,
sedation cognitive dysfunction, paresthesias
None
Smoking, prothrombophilias, venous
thromboembolism, cholecystitis, diabetes,
hypertension, estrogen-dependant cancer
Smoking, prothrombophilias, venous
thromboembolism, aura, diabetes,
hypertension
Unusual thoughts or behavior; anxiety,
hallucinations; agitation; chills, flu
symptoms; weakness, dizziness; drowsiness;
Depressed mood
Hypersensitivity
Hypersensitivity
Agranulocytosis, liver disease, pregnancy or
risk of pregnancy, urea cycle disorders
Anorexia
Depression, history of abuse, PTSD
+ Any category of drug therapy
Acne, menstrual-related migraine,
PMDD, PMS, endometriosis,
dysmenorrhea, dysfunctional uterine
bleeding, polycystic ovarian
Vasomotor symptoms, night sweats,
sleep disorders, osteoporosis, vaginal
atrophy
+ Bipolar disorder
+ Antihypertensive or magnesium,
antidepressant, other antiepileptic
for status aura.
NOTE: There is evidence that the
inclusion of valproate in a
multi-drug regimen increases the
risk of serious, potentially
life-threatening rash in adults
+ Venlafaxine or protriptyline in
patient with nephrolithiasis,
depression, obesity
+ Antihypertensive or anticonvulsant
for bipolar disorder
+ Venlafaxine or protriptyline in
patient with nephrolithiasis,
depression, obesity
- Neuropathic pain; borderline
personality disorder
+ TCA in diabetes
+ Lithium for bipolar disorder
- Bipolar disorder
GAD = general anxiety disorder; GI = gastrointestinal; LVD = left ventricular dysfunction; MAOI = monoamine oxidase inhibitor; MI= myocardial infarction; PMDD = premenstrual dysphoric disorder;
PMS = premenstrual syndrome; PTSD = post-traumatic stress disorder.
Cognitive Behavioral Therapy
Cognitive behavioral therapy
Hormone replacement
therapy (estradiol)
Contraception, dysmenorrhea,
moderate acne
(drospirenone & ethinyl
estradiol)
Menopausal symptoms
Epilepsy
Valproic acid
Hormones
Contraceptive therapy
Epilepsy
Anticonvulsants
Topiramate
Headache
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Table 3.—Summary of the Recommendations From the American Heart Association Council for High Blood Pressure (BP)30
Area of concern
BP target
Lifestyle
(mmHg) modification†
General CAD
prevention
High CAD risk§
<140/90
Yes
<130/80
Yes
Stable angina
<130/80
Yes
UA/NSTEMI
<130/80
Yes
STEMI
<130/80
Yes
LVD
<120/80
Yes
Specific drug indications
Any effective antihypertensive
drug or combination‡
ACEI or ARB or CCB or
thiazide diuretic or
combination
b-blocker and ACEI or ARB
Comments
If SBP ⱖ 160 mmHg or DBP ⱖ 100 mmHg,
then start with 2 drugs
If SBP ⱖ 160 mmHg or DBP ⱖ 100 mmHg,
then start with 2 drugs
If b-blocker contraindicated, or if side effects
occur, can substitute diltiazem or verapamil
(but not if bradycardia or LVD is present)
Can add dihydropyridine CCB (not diltiazem or
verapamil) to b-blocker
A thiazide diuretic can be added for BP control
b-blocker (if patient is
If b-blocker contraindicated, or if side effects
hemodynamically stable) and
occur, can substitute diltiazem or verapamil
ACEI or ARB¶
(but not if bradycardia or LVD is present)
Can add dihydropyridine CCB (not diltiazem or
verapamil) to b-blocker
A thiazide diuretic can be added for BP
control
b-blocker (if patient is
If b-blocker contraindicated, or if side effects
hemodynamically stable) and
occur, can substitute diltiazem or verapamil
ACEI or ARB§
(but not if bradycardia or LVD is present)
Can add dihydropyridine CCB (not diltiazem or
verapamil) to b-blocker
A thiazide diuretic can be added for BP control
ACEI or ARB and b-blocker
Contraindicated: verapamil, diltiazem, clonidine,
and aldosterone antagonist††
moxonidine, a-blockers
and thiazide or loop
diuretic and hydralazine/
isosorbide dinitrate (blacks)
Before making any management decisions, you are strongly urged to read the full text of the relevant section of the scientific
statement.
†Weight loss if appropriate, healthy diet (including sodium restriction), exercise, smoking cessation, and alcohol moderation.
‡Evidence supports ACEI (or ARB), CCB, or thiazide diuretic as first-line therapy.
§Diabetes mellitus, chronic kidney disease, known CAD or CAD equivalent (carotid artery disease, peripheral arterial disease,
abdominal aortic aneurysm), or 10-year Framingham risk score ⱖ 10% (see Appendix).
¶If anterior MI is present, if hypertension persists, if LV dysfunction or HF is present, or if the patient has diabetes mellitus.
††If severe HF is present (New York Heart Association class III or IV, or LVEF < 40% and clinical HF). See text.
ACEI = ACE inhibitor;ARB = angiotensin II receptor blockade; CAD = caronary artery disease; CCB = calcium-channel blockers;
DBP = diastolic blood pressure; LVD = LV dysfunction; NSTEMI = non-ST elevated myocardial infarction; SBP = systolic blood
pressure; UA = unstable angina.
Adverse Effects.—Common side effects include
fatigue, decreased exercise tolerance, cold extremities, diarrhea, constipation, and dizziness. b-blockers
can worsen or trigger depression. Vivid dreams,
insomnia, impotence, and memory disturbances are
also possible adverse events.26
Contraindications.—Contraindications include
asthma, chronic obstructive pulmonary disease, dia-
betes, congestive heart failure, atrioventricular conduction defects, and peripheral vascular disease.
Caution is advised for the combination of propranolol with duloxetine; via a 2D6 mechanism, this
combination can produce elevated b-blockade with
hypotension, bradycardia, and AV block.26
Calcium Channel Blockers.—Mechanism of
Action.—Calcium channel antagonists block the
Headache
transmembrane influx of Ca2+ across cell membranes
through slow, voltage-dependent channels.31 Several
properties of these agents may mediate their effectiveness in migraine prophylaxis. Initially, it was thought
that vasodilatory effects on cerebral vessels and inhibition of vasospasm were key mechanisms in their
preventive role. However, nimodipine has little use in
migraine prophylaxis and yet has vasodilatory properties on cerebral vessels. And one of the most effective
calcium channel antagonists in migraine prevention,
flunarazine (not available in the United States), exerts
minimal effect on cerebral vessels in therapeutic doses,
yet protects against excessive Ca2+ influx and release
during cerebral ischemia. Flunarazine also inhibits
synthesis and release of nitric oxide, a substance implicated in migraine pain. However, as the brain contains
a high density of calcium channel binding sites – and
evidence suggests that calcium channel antagonists
affect neurotransmission – interaction with central
nervous system (CNS) transmission may be the
primary mechanism for their effectiveness in
migraine.31
When to Consider Calcium Channel Antagonists
for Combination Therapy.—Calcium channel antagonists may be considered for polytherapy in
migraineurs without contraindications to their use.
They could be used in combination with antiepileptics
(such as topiramate) or antidepressants (such as amitriptyline). Calcium channel antagonists may have a
significant role in patients with hemiplegic migraine, a
disorder associated with calcium channel mutations.32
As mitochondrial dysfunction has been implicated in
migraine pathophysiology, vitamin B2 or CoEnzyme
Q 10 may be effectively combined with a calcium
channel antagonist in this subgroup of migraineurs.33-35
Calcium channel antagonists could also be combined with low-dose aspirin for hemiplegic migraine
or in RM with aura, as there is evidence that aspirin is
an effective mild migraine preventive.36 In addition,
aspirin has also been shown to decrease cerebrovascular and cardiovascular risks, which are increased in
migraineurs with aura.36,37 One caution with this combination is that it may result in prolonged bleeding
times.
Calcium channel antagonists could also be combined with magnesium, a supplement which can be
811
useful in menstrual migraine as well as migraine with
aura.38,39 In addition, as calcium channel blocker use is
often associated with constipation, magnesium may
help limit this adverse effect, as magnesium shortens
gastrointestinal transit time, causing looser stools.31
In RM patients with hypertension, calcium
channel antagonists could be used in conjunction with
another preventive such as an antiepileptic or antidepressant, with the final choice based on associated
comorbidities and other medical problems.
Adverse Effects.—Common side effects include
constipation, hypotension, atrioventricular block,
edema, and nausea.31
Contraindications.—Contraindications include
bradycardia, second- and third-degree heart block,
use of b-blockers, and sick sinus syndrome.31
Antidepressants.—Only tricyclic antidepressants
(TCAs) and dual serotonin norepinephrine reuptake
inhibitors (SNRIs) have shown efficacy in migraine,
although selective serotonin reuptake inhibitors
(SSRIs) may be effective for headaches associated
with premenstrual syndrome (PMS) or premenstrual
dysphoric disorder (PMDD).40-42
Mechanism of Action.—As with antihypertensives, multiple actions are responsible for the utility of
antidepressants in migraine prophylaxis. The analgesic effect seems unrelated to their antidepressant
action and is not attributed to inhibition of serotonin
reuptake. TCAs also block alpha-adrenergic, histaminic, and muscarinic receptors. It is likely that their
benefit involves effects on central pain pathways (via
inhibition of serotonin and norepinephrine reuptake
and attenuation of central sensitization via N-methylD-aspartate (NMDA) receptor agonism). Peripheral
analgesic actions may also play a role.43 Noradrenergic agonist activity in the locus ceruleus is associated
with gating attention to stimuli, including nociceptive
stimuli; this may explain the relatively better performance in pain management of antidepressants that
augment norepinephrine.
Adverse Effects.—Common side effects of TCAs
include dry mouth, constipation, and sedation. They
may also cause slowing of atrioventricular conduction
and orthostatic hypotension. Common side effects
of SSRIs and SNRIs include nausea, insomnia, and
sexual dysfunction; dry mouth, constipation, and
812
sedation are less significant with these agents than
with TCAs. Antidepressants, particularly the SSRIs,
should be used with caution in bipolar disorder as
they may unmask mania.11,40-43 In addition, antidepressants whether used as monotherapy or in combination with other agents that result in an increased
availability of serotonin can precipitate the serotonin
syndrome. While clinically relevant evidence of the
serotonin syndrome is believed to be rare, the true
prevalence of serotonin syndrome with antidepressants is unknown. And although a full review of the
serotonin syndrome with use of serotonin modulating
medications is beyond the scope of this article,
it should be noted that in at least one small case
series study, over 73% of patients diagnosed with
serotonin syndrome presented within 24 hours of
initiation, change, or overdosage of antidepressant
medications.44
When to Consider Antidepressants for Combination Therapy.—As depression, anxiety, and panic disorder are comorbid with migraine, antidepressants
are a logical choice in their presence. In particular,
a TCA such as amitriptyline or nortriptyline can be
helpful in RM when weight loss is not desirable.
These agents may be used in conjunction with an
antiepileptic such as neurontin or valproic acid.45,46
Alternatively, in an obese depressed patient, protriptyline in conjunction with topirimate or zonisamide
may be useful (Table 4).46 In this setting, antihypertensives such as verapamil and propranolol may be
undesirable due to their potential for prolongation of
the PR interval and QTc interval, respectively, as well
as their potential for weight gain and decreased exercise tolerance.47 It should be noted, however, that
TCA doses required for management of depression
are greater than those needed for migraine prevention and may not be as well tolerated.41-44 TCAs may
also be considered in migraineurs who suffer from
fibromyalgia; in this setting, the combination of a
TCA and gabapentin or pregabalin could benefit
both disorders.48-51
Although SSRIs are not effective for migraine
prevention, they are indicated for PMS/PMDD. In
migraineurs with these disorders, SSRIs are effective.
If migraines are also present throughout the cycle,
the combination of an SSRI with an antiepileptic or
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Table 4.—Weight Gain Associated With Migraine
Prophylaxis (Adapted from Young & Rozen45)
Drug class/drug
Antidepressants
Amitriptyline
Fluoxetine
Nortriptyline
Paroxetine
Protriptyline
Venlafaxine
Anticonvulsants
Divalproex sodium
Lamotrigine
Gabapentin
Topiramate
Beta-blockers
Serotonin (5HT) antagonists
Methysergide
Cyproheptadine
Calcium channel blockers
Flunarizine
Verapamil
Weight gain
↑↑↑
↑↑
↑↑
↑↑↑
↓
↔/↓
↑↑↑
↔
↑
↓↓
↑
↑↑↑
↑↑↑
↑↑↑
↔
↑ = weight increase; ↓ = weight decrease; ↔ = no effect on
weight.
antihypertensive may be beneficial. Alternatively,
venlafexine is effective for both PMS/PMDD and
migraine. It could be used alone or in combination
with hormonal manipulation, antiepileptic medications, or calcium channel blockers for RM sufferers
with PMS/PMDD.42
Antiepileptics.—Topiramate and valproic acid are
the only FDA-approved antiepileptics for migraine,
although others have shown efficacy.52
Mechanism of Action.—Several relevant mechanisms of actions for antiepileptics in migraine prophylaxis have been demonstrated. Both topiramate and
valproic acid block sodium channels, as do phenytoin,
lamotrigine, carbamazepine, and oxcarbazepine.
However, both topiramate and valproic acid also
modulate gamma-aminobutyric acid (GABA), as do
phenobarbital and gabapentin.52
Adverse Effects.—For a complete review of
adverse effects of antiepileptics, each drug should be
reviewed individually in the Physician Desk Reference. Topiramate has been associated with sedation,
cognitive dysfunction, paresthesias, weight loss, nephrolithiasis, and acute closed angle glaucoma. Valproic
Headache
acid has been associated with encephalopathy,
tremor, hair loss, weight gain, sedation, gastrointestinal symptoms, elevation of liver enzymes, hepatitis,
agranulocytosis, and neural tube defects.52
When to Consider Antiepileptics for Use in Combination Therapy.—Antiepileptics can be successfully
combined with antidepressants to treat RM. Topiramate can be used in combination with a TCA or
SNRI, antihypertensive or another antiepileptic.
When obesity or diabetes complicates RM with
depression, topiramate is an especially attractive candidate for polypharmacy with an antidepressant.46,52
When nephrolithiasis complicates RM in a depressed
obese patient, gabapentin or levetiracetam with an
antidepressant such as venlafexine or protriptyline
may be considered.
Antiepileptics can also be utilized in RM with
mood or personality disorders. Topiramate may not
only be helpful for prevention of migraine in patients
with bipolar or borderline personality disorder, but
serve as adjunctive therapy of these psychiatric conditions.53,54 It could alternatively be combined with
an antihypertensive (other than b-blockers which
may augment depression), another antiepileptic or
lithium in these settings. Similarly, gabapentin may
also be used with an antihypertensive (other than bblockers), or another antiepileptic in a RM patient
with bipolar disorder.55 Finally, the use of lamotrigine
in combination with another antiepileptic, an antidepressant, an antihypertensive, or magnesium could be
considered in a migraineur with frequent or status
aura.38,39,56
Hormonal Manipulation.—Sex hormones can have
significant impact on migraine throughout a woman’s
life. There are multiple potential indications for use
of hormones in combination with another pharmacological agent. In particular, for the woman who
requires contraception or hormone replacement, who
has acne, PMS/PMDD, or certain gynecological disorders such as endometriosis or dysmenorrhea, the use
of hormonal agents in conjunction with another preventative should be considered.42,57-59
Hormonal Contraceptives.—WHEN TO CONSIDER HORMONES FOR COMBINATION
THERAPY WITH OTHER PROPHYLACTICS.
—In women with menstrual-related migraine (MRM)
813
who require contraception, the use of extended cycle
contraceptives should be considered in combination
with other preventives.59,60 Examples include commercially available extended cycle 30 mg ethinyl
estradiol (EE) products combined with levonorgestrel; alternatively, traditional 30 mg EE products
with other progestins can be used in extended regimens by eliminating the placebo week for months
at a time. This would also represent logical polypharmacy in RM complicated by endometriosis or
dysmenorrheaas hormonal contraceptives have
FDA indications beyond contraception – including
endometriosis, dysmenorrhea, dysfunctional uterine
bleeding, polycystic ovarian syndrome, and acne.61
Hormonal contraceptives have also been advocated
for women at high risk for endometrial cancer or
ovarian cancer, as substantial reductions in these
malignancies have been attributed to long-term use
of oral contraceptives (OCs).62,63
When using OCs in combination with antiepileptics, it is important to be aware of significant
interactions. Doses of topiramate over 200 mg are
reported to interfere with the efficacy of OCs. It is
of note, however, that efficacy of OCs is primarily
attributed to the progestin component, and none of
the antiepileptic drugs (AEDs) commonly used for
migraine prevention (topiramate, valproic acid,
gabapentin, levetiracetam) decrease progestin concentration. However, the increased rate of metabolism of estrogen in the presence of topiramate can
lead to daily instability of estrogen concentration
with potential adverse effect on migraine.64 Use of
topiramate might argue for changing an OC to a
patch or ring formulation, thereby avoiding the firstpass effect through hepatic circulation.65 Use of an
estrogen containing OC significantly decreases lamotrigine plasma concentrations, often necessitating
higher doses of that drug.66
ADVERSE EVENTS.—Adverse events include
bloating, irritability, depression, breast tenderness,
and sexual dysfunction.67 Most of these effects are
attributed to the progestin component and can be
addressed by switching to a different progestin or to a
lower progestin concentration. More serious adverse
events are rare but include venous thrombosis, pulmonary embolism, stroke, and myocardial infarc-
814
tion.67 Cardiovascular events are minimized with the
lowest-dose contraceptives and proper patient selection. Contraceptives with androgenic progestins (such
as norethindrone) can cause lipid abnormalities and
acne.67 However, non-androgenic progestins such as
desogestrel have a more favorable lipid profile and
may be used as more rational co-therapy in women
with lipid abnormalities; contraceptives containing
norgestimate or drospirenone are indicated for treatment of acne vulgaris.68 Although weight gain has
been seen with some OCs, many are weight neutral,
and drospirenone-containing contraceptives are even
associated with mild weight loss, making them a reasonable choice for obese patients.69 Caution is advised
when combining drospirenone-containing OCs with
angiotensin converting enzyme (ACE) inhibitors for
migraine prevention, since this combination could
result in hyperkalemia.69
CONTRAINDICATIONS .— Contraindications
include smoking (especially over the age of 35), diabetes, hypertension, inherited prothrombophilias
(such as Factor V Leyden), venous thromboembolism, and presence of aura.69,70 Even though MRM is
rarely associated with aura, some women with MRM
may still experience aura at other times of the cycle.
Higher concentrations of estrogen are associated with
an increased incidence of aura, so in RM patients with
MRM and occasional aura, use of the ultra-low-dose
ring contraceptive may be a reasonable option.71
Similar to the 30 or 35 mg OCs, these products often
prevent ovulation. However, unlike the pills, the
much lower concentration of estrogen in the ring – in
the setting of anovulation – results in a lower peak
exposure to estrogen throughout the month than the
native menstrual cycle. The ring is particularly effective at preventing ovulation when used in extended
cycle dosing.72
MECHANISM OF ACTION.—Combined hormonal contraceptives prevent conception by three
mechanisms, all of which are attributed to the progestin component. The efficacy of extended cycle hormonal contraceptives in migraine is thought to be
mediated by one of these mechanisms: inhibition of
ovulation. With prolonged inhibition of ovulation,
women experience relative stability of estrogen
content due to anovulation combined with the stable
June 2008
EE content of the contraceptive. Today’s low-dose
OCs, however, do not always inhibit ovulation when
used in the traditional 21/7 regimens (which allow for
a 7-day placebo week following 21 days of active
pills).73,74
Hormone Therapy (HT).—Postmenopausal HT
utilizes different hormones in different dose ranges
from those in contraceptives; they have attendant differences in indications, adverse events, and mechanism. Whereas the estrogen used in contraceptives is
always a synthetic estrogen (usually EE, but rarely
mestranol), the estrogen in HT is more often a natural
estrogen (bioidentical, conjugated, or esterified).
Whereas most contraceptives utilize supraphysiologic
doses, most HT is in physiologic or subphysiologic
dose ranges.
WHEN TO CONSIDER ADDING HT TO
MIGRAINE PREVENTATIVES.—Perimenopausal
or menopausal women with RM who experience
significant vasomotor symptoms may be good candidates for addition of HT to their migraine preventive. Sleep problems often dominate perimenopausal
symptoms and include night sweats and sleep fragmentation, both of which have been shown to
respond to HT. A 5-fold increase in sleep apnea
(both central and obstructive) has been reported to
occur in perimenopause, but was not seen in current
users of HT.75 It is important to remember when
considering co-therapies that HT is also indicated
for prevention of postmenopausal osteoporosis and
for treatment of vulvovaginal atrophy.76
ADVERSE EVENTS.—Although recent studies
have confused this issue by studying the initiation of
HT in women a decade or more beyond menopause,
certain risks are undoubtedly associated with HT.
They include, most prominently, an increased risk of
venous thrombotic events (HT more than doubles
the risk, although absolute numbers remain low) and
cholecystitis.77 Two studies showed that cardiovascular events are more common in the first year after
initiation of HT (possibly mediated by inherited prothrombophilias),78,79 while a larger longitudinal study
suggests primary prevention of cardiac disease when
HT is begun in perimenopause.80 The Women’s
Health Initiative reported a significant 27% increased
risk of breast cancer diagnosis within 5 years follow-
Headache
ing initiation of combined (estrogen plus progestin)
HT and an insignificant 23% decreased risk with
estrogen alone.81
CONTRAINDICATIONS . — Contraindications
include venous thromboembolism and presence of an
estrogen-dependent cancer.82
Cognitive Behavioral Therapy.—Cognitive behavioral therapy should be strongly considered in RM
patients as well as in migraineurs with a history of
depression, abuse, post-traumatic stress disorder, or
other psychiatric disorder. Behavioral therapy in
addition to pharmacological intervention may be
more effective than either treatment alone.83 An
in-depth discussion of behavioral therapy is presented in a separate article in this supplement.
Greater Occipital Nerve Blocks (GONB) and
Botulinum Toxin.—GON fibers arise from the dorsal
root of C2; and both the trigeminal afferents and the
first 2 upper cervical nerve afferents converge upon
the trigeminal nucleus caudalis, possibly explaining
why GONB decrease head pain and allodynia.84,85 In
one study, GONB were shown to decrease the total
pain index by 50% or more in 23 of 27 patients who
had previously failed several combinations of pharmacological treatment.85 Afridi et al showed significant response to GONB in both migraine and
cluster headache with minimal side effects.23
However, it should be noted that Afridi et al also
demonstrated that the mean duration of complete
response was 20 days, with a median of 7 days. Similarly, the mean duration of partial response was 45
days with a median of 20 days for GONB. Thus, the
benefit in RM could be limited by the need for
repetitive injections. In RM patients who do not
wish to add additional oral medications to their
regimen, GONB may be a viable option and may
help to limit adverse effects from drug interactions.
Adverse events include injection site reactions,
alopecia at the injection site, dizziness, and vasovagal
syncope.23,84,85
As with GONB, botulinum toxin has evidence of
benefit for RM and is an option for those who are
hesitant to add additional medications or seek to
limit the potential for drug–drug interactions. Side
effects include injection site reactions, ptosis, and
lacrimation.21,86-88
815
LENGTH OF PREVENTIVE TREATMENT
UTILIZATION
Data guiding duration of preventive therapy are
limited, although 2 studies have addressed the topic.
In the first, Wober et al followed 64 migraineurs after
discontinuation of successful prophylaxis used up to
6 months.89 Following discontinuation of preventive
medication, 75% of patients experienced a relapse in
migraine, and further attempts at prophylaxis, utilizing the same agents, were less successful than the first.
More recently, Pascual et al evaluated 80
migraineurs who received preventive treatment with
topiramate.90 After 6 months the preventive was
stopped.Topiramate was reintroduced for 6 additional
months if the subject worsened, then again discontinued. Following the second withdrawal, patients whose
headaches again worsened received a third round of
topiramate and were followed up for at least half a
year. After the first withdrawal, headaches worsened
in 50% of patients. In these patients only 5% were able
to stop topiramate without an increase in headache
frequency within 2 months.The authors suggested that
the current practice recommendation of 3-6 months
of preventive treatment may be inadequate for many
patients. Based on these studies we suggest preventative therapy be continued for at least one year.
CONCLUSION
Migraine extracts a substantial personal and
societal burden. Although it is unknown if migraine
preventative therapy confers disease modification,
preventive therapy is frequently associated with pain
relief and reduction in disability. Limited data and
clinical experience suggest that combination therapy
should be considered in migraineurs who present
with disability and a history of repetitive failed preventive regimens in the past (ie, RM). Although there
are very few controlled trials, combination therapy
may also be beneficial for migraineurs with comorbid
disorders, medication-overuse headache, early onset,
and strong family history.
Clinically, headache specialists have used rational
combination therapy to treat RM for years. In this
article we reviewed several logical combinations of
medications for migraine prevention in refractory
migraineurs. Many other combinations and rationales
816
for polytherapy exist. Based on the extreme paucity
of data in regards to combination therapy and RM,
extensive research is sorely needed to guide treatment of this special subpopulation of migraineurs.
One possible way this could be accomplished is for
randomized double-blind studies to be undertaken to
evaluate participants who are all on one standard
preventative medication (similar to Pascual et al’s
open-label study),24 and in one arm of the study participants add a second migraine preventative, whether
it is a traditional migraine preventative, a supplement,
a form of hormonal manipulation, or a behavioral
intervention (R.B. Lipton, verbal communication).
Studies such as these will help allow the development
of evidence-based medicine in RM treatment, and
ultimately and hopefully, provide effective treatment
options for safe and faster relief to refractory
migraineurs.
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