Current Treatment Options in Neurology

, Volume 13, Issue 1, pp 15–27

Symptomatic Treatment of Migraine: When to Use NSAIDs, Triptans, or Opiates

Authors

    • Park Nicollet Headache Center
  • Robert G. Kaniecki
    • The Headache Center, Department of Neurology, University of Pittsburgh
Headache

DOI: 10.1007/s11940-010-0107-4

Cite this article as:
Taylor, F.R. & Kaniecki, R.G. Curr Treat Options Neurol (2011) 13: 15. doi:10.1007/s11940-010-0107-4

Opinion statement

Migraine is a biologic disorder of the brain characterized by a heterogeneous array of symptoms and episodes of disabling headache. By definition, such attacks last between 4 and 72 h without treatment, with the disability arising from a variety of factors including severe pain, gastrointestinal symptoms such as nausea or vomiting, and sensory sensitivities to light, noise, or odor. All these features may be exacerbated by stimulation, motion, or activity, often rendering the patient completely immobile. Although retreat and rest, coupled with local application of ice, may provide some measure of comfort, most of those with migraine hunt for therapeutic solutions. In designing acute headache treatment strategies, it is imperative for clinicians to recognize the variability between individuals in the frequency, intensity, and duration of attacks. Certain patients require more aggressive options. It is also crucial to identify the significant intra-individual variability of migraine; most patients describe an assortment of headaches of different intensities and time to disability. Less intense episodes, which patients often term sinus, tension, or regular headaches, usually represent milder versions of migraine, simplifying both diagnostic and therapeutic approaches. Evidence-based guidelines and clinical experience support the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in the management of mild to moderate migraine attacks. Recommend migraine-specific agents (triptans and dihydroergotamine) when the attacks are more severe or have consistently failed to respond to the use of NSAIDs in the past. Encourage those with less frequent episodic migraine to use their acute agents at the earliest signs of headache. Advise those with frequent headache (>10 days per month) to limit acute treatments to only the most disabling episodes in order to avoid the “medication overuse” phenomenon. Consider rescue or back-up therapy. Do not use compounds containing butalbital or opiates (or place extreme limits on them), out of concern for progression to chronic migraine.

Introduction

Migraine has been described and treated since ancient times, yet a more complete understanding required standardized classification and scientifically rigorous research available primarily over the past 25 years. Historical accounts reveal a fascinating array of unusual therapies administered to migraine patients over the centuries, from blood-letting to swallowing of toxins, from trepanation to bandaging the head with a clay crocodile. Migraine therapies became more “modern” with the introduction of ergot (a product of the fungus Claviceps purpurea) by Edward Woakes in 1868. Because the true physiology was unknown, most patients were treated with symptomatic therapies either addressing the pain with analgesics or addressing the gastrointestinal complaints with antiemetics. Major advances in understanding migraine mechanisms and treatment eventually required a standardized definition of the condition. The publication in 1988 of the International Classification of Headache Disorders (ICHD-I) provided the initial specific clinical criteria. Subsequent research using this and its revision in 2004 (ICHD-II) has led to significant insights into the pathophysiology of migraine, expanding the tools and strategies available for its management.

To understand basic migraine neurobiology is to understand the rationale for current treatment options. In considering the basic neurobiology of migraine, it is important to begin with the concept of migraine as not merely a headache, but rather a heterogeneous array of episodic symptoms [1•, Class IV]. In many cases, migraine is heritable, a genetically influenced disorder of central nervous system sensory and pain processing predisposed to headache attacks [2,3; Class IV]. Migraine attacks involve activation of trigeminovascular afferents and the release of calcitonin gene-related peptide (CGRP) and other inflammatory substances leading to significant vasodilatation and increased dural blood flow [4, Class IV]. Activation of meningeal nociceptors by serotonin (5-HT), prostaglandins, and, to a lesser extent, histamine promotes a robust sensitization and activation of meningeal nociceptors [5, Class IV]. If not terminated, peripheral trigeminal nerve activity provokes central (trigeminal nucleus caudalis) neuronal sensitization. Recruitment of the latter during the process of migraine renders the condition more refractory to management [6•, Class IV]. The migraine-specific triptans are felt to have an impact on migraine pathophysiology by blocking neurotransmission presynaptically in the dorsal-horn trigeminal nerve terminals and by reversing vasodilatation of dural vessels. The importance of the latter effect is uncertain, based on CGRP receptor efficacy [7, Class I]. Nonsteroidal anti-inflammatory drugs (NSAIDs) are likely to work by blocking cyclooxygenase in the inflammatory cascade. Both sets of medications are more effective when administered early in the attack, before allodynia and central sensitization become established [6•, Class IV].

Treatment

  • Because of the variable frequency and presentation of migraine, a good history is required to determine appropriate acute treatment. Decisions on preventive and acute approaches demand adequate profiling of headache frequency, including 1) the average number of total headache days per month; 2) the number of days those headaches are severe, limiting work, school, social, or family activities; 3) the number of days per month that acute medication of any type is used; and 4) details of amounts and frequency of dosing of all acute headache medications used, including analgesics, decongestants, caffeine-containing compounds, or muscle relaxants [8,9; Class IV]. The responses to these questions may determine the likelihood of treatment success, the treatment most likely to be prescribed, and the ability to optimize the critical treatment paradigm of “Treat early at mild, but not too often.” Early administration of migraine therapies enhances efficacy [10, Class IV]. If treatment is not early at mild, then treat before severe headache pain, presence of photophobia/phonophobia, and presence of nausea [11, Class I]. Most migraineurs experience and treat headache fewer than 10 days per month, and in the absence of contraindications they may use NSAIDs or triptans/dihydroergotamine at appropriate doses to treat the earliest signs of headache [12, Class IV]. Individuals experiencing headache more frequently are at risk for medication overuse, which perpetuates migraine and frequently renders other medications less effective or ineffective. These patients must ration their acute therapies, aiming to truncate the most disabling 10 headache days each month.

  • An adequate profile of acute treatment also requires questioning beyond the numbers of headaches and treatment frequency. Gastrointestinal complaints often complicate acute attacks, so agents with non-oral routes of administration are frequently necessary for those with significant nausea or vomiting. Adjunctive antiemetics are useful in this population. Patients who awaken with migraine, who describe some headaches that escalate quickly, or who have required emergency department treatment in the past are best managed with parenteral treatment options.

  • As previously mentioned, many patients have variable migraine occurrences. The most effective way of managing this variability is to provide a “toolbox” of two or three acute options: tablets for routine migraines, injections for “wake up/throw up/back up” attacks, and nasal or rectal options for rarer circumstances.

Pharmacologic Treatment

  • According to evidence-based guidelines, NSAIDs and triptans are the most effective acute therapies for attacks of migraine in adults [12,13; Class I]. Although listed as first-line therapy, NSAIDs have often been tried and have failed prior to the patient’s initial clinical consultation, but timing and dosing must be considered before confirming the failure of the entire class. Seven triptans are approved by the US Food and Drug Administration (FDA) and currently marketed for the acute treatment of migraine. All are approved for adults; only almotriptan has received approval for adolescent migraine. No triptans are yet approved for children. The triptan class is preferred to alternatives because of its favorable side-effect profile and neurovascular-specific mechanism of action [14•, Class IV]. Although the triptans are pharmacologically diverse, it has been difficult to establish that differences between them translate into predictable distinctions in clinical efficacy, consistency, tolerability, or safety [15, Class IV].

  • The choice of a migraine-specific medication begins with formulation considerations, as the options in nasal or parenteral forms are limited. Specific tablet selection may then raise considerations of formulary coverage and cost, and prior medication experiences should be reviewed [16•, Class IV]. The aims of acute migraine management are to reverse the entire symptom complex and restore normal function. The goal is to have the patient comfortable with the treatment, returning to a pain-free state within 1–2 h without significant adverse effects and without recurrence of the attack within 24 h. A successful medication achieves such an outcome in well over 50% of treatments, with the majority of remaining episodes responding to a second dose.

Triptans

  • Triptans are serotonin receptor agonists with high affinity for 5-HT1B and 5-HT1D receptors and variable affinity for 5-HT1F receptors. The proposed mechanism of action involves binding postsynaptic 5-HT1B receptors on the smooth-muscle cells of blood vessels and presynaptic 5-HT1D receptors on trigeminal nerve terminals and dorsal horn neurons [17, Class IV]. Triptans may also facilitate descending pain inhibitory systems [18,19; Class IV].

  • The most common adverse effects seen with triptans are commonly termed “triptan” sensations. These include pressure or tightness in the chest, throat, or jaw; limb heaviness; myalgias; and fatigue. Flushing, paresthesias, dizziness, asthenia, and mental cloudiness are also occasionally noted. Skin sensitivity and sinus burning or stuffiness are uncommon. The adverse event profile for the subcutaneous form of sumatriptan also lists local site reactions, whereas the triptan nasal sprays may be associated with an unpleasant taste. Although the adverse effects of triptans are fairly common, these tolerability issues must not be confused with true safety concerns. Triptans are safe [20, Class I]. Serious vascular adverse events are extraordinarily rare.

  • The contraindications of triptans as a class are history, symptoms, or signs of ischemic cardiac, cerebrovascular, or peripheral vascular syndromes. Because these agents may increase blood pressure, they should not be given to patients with uncontrolled hypertension. The package insert says not to administer triptans within 24 h of another triptan or an ergot-type medication (like ergotamine, dihydroergotamine, bromocriptine, pergolide, cabergoline, methysergide, and others). Triptans are FDA-labeled as contraindicated in hemiplegic or basilar migraine, and their use should be avoided by patients with hypersensitivity to specific components or with severe hepatic impairment.

  • Given the common thread of impact on serotonin mechanisms, some controversy has surrounded the “serotonin syndrome,” associated with co-prescription of triptans with antidepressant agents. The FDA contraindicates certain triptans with concomitant use of monoamine oxidase inhibitors. With only Class IV evidence available in the literature and through the FDA registration of adverse events, inadequate data are available to determine the risk of serotonin syndrome with triptan monotherapy or with the addition of a triptan to selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) [21••, Class IV].

Sumatriptan

Standard dosage

Reusable autoinjector with injection cartridges (Statdose): 6 and 4 mg. Disposable autoinjector prefilled device (Alsuma): 6 mg. Single-dose vial for subcutaneous injection: 6 mg/0.5 mL of solution. Needle-free air-powered injector for subcutaneous injection (Sumavel Dosepro): 6 mg. Nasal spray: 20 mg, 5 mg. Tablets: 100, 50, and 25 mg. Fixed-dose combination tablet: 85 mg of sumatriptan with 500 mg of naproxen sodium.

Contraindications

Injection should not be given intravenously because of its potential to cause coronary vasospasm.

Main drug interactions

Avoid use within 2 weeks of monoamine oxidase inhibitors (MAOIs)

Special points

Most flexible dosing: the only triptan with available injection and combination therapies.

Cost

Brand name: very expensive; generics available: expensive.

Eletriptan

Standard dosage

Tablet: 40 mg and 20 mg; 80 mg available in select European countries.

Contraindications

Patients with significant renal failure, arrhythmias, or heart failure.

Main drug interactions

Metabolized by CYP3A4 enzyme; not for use within 3 days after potent CYP3A4 inhibitor, such as ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, or nelfinavir. No MAOI drug interaction.

Special points

Product contains lactose and sunset yellow dye. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucose-galactose malabsorption should not take this medicine. Dye may cause allergic reactions.

Cost

Very expensive; generics not available.

Naratriptan

Standard dosage

Tablet: 2.5 mg and 1 mg.

Contraindications

Contraindicated in severe renal impairment (creatine clearance <15 mL/min), with caution warning for any renal impairment.

Main drug interactions

No MAOI drug or known P450 enzyme interactions.

Special points

Naratriptan contains a sulfonamide component; therefore, there is a theoretical risk of a hypersensitivity reaction with known sulfonamide hypersensitivity. The highest approved dose per 24 h is 5 mg.

Cost

Very expensive; generics available.

Zolmitriptan

Standard dosage

Tablet: 5 mg and 2.5 mg. Wafer: 5 mg and 2.5 mg, orally dispersible. Nasal spray: 5 mg.

Main drug interactions

Should not be taken within 2 weeks of an MAOI drug. In Europe, a maximum intake of 5 mg is recommended following administration of MAO-A inhibitors.

Special points

The wafer formulation contains phenylalanine, and patients with phenylketonuria should be informed. Each 5-mg orally dispersible tablet contains 5.62 mg of phenylalanine.

Cost

Very expensive; generics not available.

Rizatriptan

Standard dosage

Tablet: 10 mg and 5 mg. Wafer: 10 mg and 5 mg orally dispersible.

Main drug interactions

Dose reduction to 5 mg recommended in patients taking propranolol; should not be used within 2 weeks after MAOI.

Special points

Patients should not take more than 3 tablets in a 24-hour period. The wafer form also contains phenylalanine and patients with phenyl-ketonuria should be informed.

Cost

Very expensive; generics not available.

Frovatriptan

Standard dosage

Tablet: 2.5 mg.

Contraindications

Use of ketoconazole, itraconazole, ritonavir, or erythromycin in the past 3 days.

Main drug interactions

As above, in Contraindications.

Special points

Longest half-life of all triptans, at 26 h. Patients should not take more than 3 tablets in a 24-hour period.

Cost

Very expensive; generics not available.

Almotriptan

Standard dosage

Tablet: 12.5 mg and 6.25 mg.

Contraindications

Sulfonamide allergy, due to a sulfa group. Concomitant administration of almotriptan and lithium should be avoided.

Main drug interactions

Dose reduction to 6.25 mg suggested when used with potent CYP3A4 inhibitor, such as ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, or nelfinavir.

Special points

No MAOI drug interaction. Highest 24-hour total dose approved is 25 mg.

Cost

Very expensive; generics not available.

Anti-inflammatories

  • The NSAIDs have been used since the time of Hippocrates. Over half of diagnosed migraineurs in the United States use over-the-counter analgesics, which are effective in up to 60% of cases. [22,23; Class IV]. Most single-agent NSAID studies were performed about 10 years ago or earlier. Among the NSAIDs, aspirin, ibuprofen, naproxen sodium, tolfenamic acid, diclofenac, ketoprofen, piroxicam, and the combination of acetaminophen and aspirin plus caffeine have been reviewed as demonstrating the most consistent evidence of efficacy for acute migraine [23,24; Class IV]. The data are strongest for ibuprofen, naproxen, aspirin, aspirin-acetaminophen-caffeine, and the dissolvable version of diclofenac [25, Class I].

  • The mechanism of action, inhibiting prostaglandin synthesis, was discovered in the 1970s [26, Class IV]. Aspirin acts as an irreversible inhibitor of cyclooxygenase (COX) 1 and 2, whereas NSAIDs are reversible inhibitors of these enzymes. Celecoxib is a selective inhibitor of COX-2. NSAIDs that inhibit prostaglandin E2 synthesis are effective in treating acute migraine attacks [27, Class I].

  • The most common adverse effects of NSAIDs are largely gastrointestinal, with dyspepsia, abdominal burning or discomfort, and diarrhea noted by occasional patients. Infrequent complaints include easy bruising, pruritus, or rash, and some asthmatics experience a hypersensitivity response. More serious adverse events include gastritis or esophagitis, gastrointestinal bleeding, renal failure, hepatic impairment, and in some cases of continuous use, increased risk of cardiovascular events.

  • Perhaps the only absolute contraindications are for those with prior NSAID hypersensitivity reaction and in the perioperative period of coronary artery bypass graft surgery. NSAIDs carry warnings for those with significant cardiovascular disease, renal insufficiency, gastrointestinal erosive disorders, and bleeding diatheses. Patients taking warfarin should avoid NSAIDs. Dose reduction and short duration of therapy is warranted in anyone with impaired renal, hepatic, or cardiac function. As a class, all the NSAIDs warrant special precautions in the elderly, children less than 12 years of age, or patients with infections, asthma, allergic disorders, or hypertension. By consensus, only aspirin and naproxen sodium are non-cardiotoxic in long-term use. Children and adolescents should avoid using aspirin because of the risk of Reye syndrome.

Aspirin

In a study of acute, moderate to severe migraine, 52% of patients taking 1000-mg aspirin caplets experienced pain relief at 2 h, versus 34% of those taking placebo; the pain-free rate was 20% for the aspirin group versus 6% with placebo [28, Class I]. In a meta-analysis of the efficacy of 1000-mg effervescent aspirin, the response rates were 51.5% for headache relief at 2 h, 27.1% pain-free at 2 h, and 23.5% sustained pain-free up to 24 h. The corresponding rates for placebo were 33.9%, 15.1%, and 14.6%, respectively [29, Class I].
Standard dosage

Tablet: 325 mg, 500 mg, 400 mg effervescent.

Special points

Aspirin, the paradigm for NSAIDs, has been shown to be superior to placebo in clinical trials at doses from 500 mg to 1,000 mg. In its tablet form, aspirin is as effective as acetaminophen or acetaminophen plus codeine [30, Class I]. It appears that aspirin is most efficacious in its effervescent form and in combination with other medications such as the antiemetic metoclopramide [31, Class I; 32, Class IV]. Comparing meta-analysis data for aspirin with separate meta-analysis data for naproxen, effervescent aspirin appears superior when not considering intolerance.

Cost

Extremely inexpensive.

Naproxen Sodium

A meta-analysis of over-the-counter naproxen sodium reported that the available evidence suggests that it is more effective than placebo in the acute treatment of moderate to severe migraine. It is effective in reducing headache intensity, resolving pain completely at 2 h, and improving migraine-associated symptoms. However, its effectiveness relative to other active comparators needs to be better defined by appropriate head-to-head clinical trials [27, Class I].
Standard dosage

Tablets: 220 mg, 275 mg, 500 mg, 550 mg.

Special points

The recommended adult dosage of naproxen sodium for acute pain is 550–1100 mg per day in divided doses. If necessary, the dosage can be increased up to 1650 mg per day for a short period, but the adverse effects may also be increased with a higher dose.

Cost

Extremely inexpensive.

Ibuprofen

In a systematic review and meta-analysis, the available evidence suggests that ibuprofen (200 and 400 mg) is effective in reducing headache intensity and rendering patients pain-free at 2 h [33,34; Class I]. For the 200-mg dose, the number needed to treat was 8 (95% CI, 5–20) for headache relief and 13 (95% CI, 8–50) for pain-free status. The risk ratio for ibuprofen (400 mg) was 1.89 (95% CI, 1.45–2.46; P < 0.0001) for headache relief and 2.15 (95% CI, 1.24–3.73; P = 0.0063) for pain-free status. The 24-hour sustained pain-free outcome with ibuprofen was no better than with placebo. Ibuprofen (400 mg) increased the chance of relief of photophobia by 30% (95% CI, 8%–57%; P < 0.01) and of phonophobia by 49% (95% CI, 23%–81%; P < 0.0001). Because of the limited data and the shortcomings of the available evidence, further studies are needed [33, Class IV].
Standard dosage

Tablet: 200, 400, 600, 800 mg.

Special points

The half-life is 2 h, leading to nonsignificant effects of ibuprofen in sustained pain-free trial results when compared with naproxen sodium, which has a longer half-life (12–15 h).

Cost

Extremely inexpensive.

Tolfenamic Acid

A randomized controlled trial of rapid-release tolfenamic acid (200 mg) versus 100 mg of sumatriptan and placebo studied 141 patients experiencing 269 migraine attacks. No significant difference was found between the active treatments (P = 0.85; 95% CI, −22%–18%), but both active treatments were significantly better than placebo [35, Class I].

In an earlier study of 49 patients, 200 mg of tolfenamic acid was effective in treating acute migraine, but caffeine and metoclopramide alone did not differ from placebo. Tolfenamic acid with metoclopramide was better than tolfenamic acid alone, as judged by the smaller dose needed and the intensity of the attack. There were no significant differences between tolfenamic acid alone and its caffeine combination [36, Class I].
Standard dosage

Tablet: 200 mg.

Special points

Preclinical data suggest that tolfenamic acid has the potential to increase the response of pancreatic adenocarcinoma to radiation therapy [37, Class IV].

Cost

Inexpensive.

Diclofenac (Potassium and Sodium)

Compared with placebo and the reference therapy, 100 mg of sumatriptan, diclofenac potassium is an effective, fast-acting, and well-tolerated acute oral therapy for migraine attacks at either 50 or 100 mg; it has advantages over oral sumatriptan in terms of onset of analgesic effect, reduction of accompanying symptoms, and tolerability profile [38, Class I]. A novel water-soluble powder formulation of diclofenac potassium (50 mg for oral solution) is effective in reducing pain intensity within 30 min, with 25% pain-free response at 2 h, compared with 10% for placebo (P < 0.001) [25, Class I]. In a Visual Analog Scale randomized placebo-controlled trial, the 100-mg dose of diclofenac potassium was only marginally more effective than the 50 mg dose [39, Class II].

Diclofenac sodium alone (100-mg softgel formulated with ProSorb technology) did not differ significantly from placebo, but the addition of 100 mg of caffeine produced a statistically significant difference in benefit at 60 min [40, Class II].
Standard dosage

Tablet: 50 mg.

Special points

Enteric-coated sodium ion preparations (25, 50, 75 mg) have not been tested in migraine and would not be expected to be appropriate therapy. The mean time to peak plasma concentration is shorter for diclofenac potassium (20–60 min) than for oral sumatriptan (2.5 h).

Cost

Inexpensive in tablet form; very expensive in water-soluble buffered powder formulation.

Piroxicam

In a single-blind study with only 40 participants, a single sublingual dose of a “Fast Dissolving Dosage Form” of piroxicam (40 mg) had striking efficacy versus placebo in the acute treatment of migraine. The treatment was of quick onset, long duration, and good tolerability [41, Class II].
Standard dosage

Capsules: 10 mg, 20 mg.

Special points

The tested formulation (double the strength of currently available capsules and in a rapid dissolving sublingual form) is not known to be available.

Cost

Inexpensive.

Ketoprofen

Oral ketoprofen (75 mg or 150 mg) in a dual-release formulation is an effective and well-tolerated drug for the acute treatment of migraine attacks [42, Class I]. Both doses compared favorably with zolmitriptan.
Standard dosage

Tablet: 75, 150 mg dual release; 12.5, 50, 75 mg regular release. Extended-release capsule: 200 mg. Topical gel: 20%.

Special points

The dual-release preparation was tested in France and is not widely available. Other formulations, available elsewhere, have not been tested in migraine.

Cost

Inexpensive.

Ketorolac Tromethamine

Ketorolac is frequently given by intravenous or intramuscular routes in emergency departments and is administered at home by the intramuscular route, but no placebo-controlled studies exist. The intravenous route is supported by a small study that showed intravenous ketorolac to be superior to 20 mg of nasal sumatriptan [43, Class II]. The self-administered paradigm is supported by significant improvement in 64% of headaches in a study of 16 patients studied by Turkewitz and colleagues. These patients self-administered 61 injections of 60 mg ketorolac [44, Class III]. Although they had required frequent emergency room visits, only 13% of all injections failed to prevent the need for emergency room treatment.
Standard dosage

Parenteral dosing: 30–60 mg per dose, intramuscular and intravenous.

Special points

No evidence supports the use of tablets. In an in-office study of acute treatment failure of migraine, 60 mg of intramuscular ketorolac was compared with 1.0 mg intravenous dihydroergotamine (DHE) and 5 mg metoclopramide. Eight of nine patients experienced moderate relief with better pain and disability score improvement with the intravenous combination of DHE and metoclopramide, compared with six of nine treated with ketorolac [45, Class II]. In the Turkewitz study [44, Class III], intramuscular dihydroergotamine treatment had failed in 13 of the 16 patients.

Ketorolac compares favorably with narcotics in the relief of postoperative pain. Its advantages include lack of sedation and no known addiction potential.
Cost/cost-effectiveness

The injectable preparation is relatively expensive, but over a 90-day study period in 16 patients self-administering 60 mg of ketorolac, an estimated $15,900 savings was attained as a result of the 53 emergency room visits prevented [44, Class III].

Compounds Containing Butalbital and Opiates

  • Developed 50 years ago, butalbital-containing compounds may have some efficacy in acute migraine, although placebo-controlled studies were never performed [46, Class IV]. Butalbital has a duration of action of 3 to 6 hours and a plasma half-life of 19 to 88 hours, with a proven anxiolytic effect and limited evidence for analgesia independent of the agents with which it is compounded (acetaminophen, aspirin, caffeine). The risks for physical and psychological dependency are clinically evident and have led to bans on butalbital compounds around the globe and cries for a similar ban in the United States [47, Class II].

  • The role of opiates in acute migraine treatment remains controversial. Most certified headache medicine specialists believe they should be used rarely and sparingly, if at all. Nonetheless, opiates remain the most prescribed analgesic class for acute and rescue therapy in migraine. There is no evidence of superiority versus triptans and NSAIDs, and there is much information surrounding opiates to render them suspect as acute migraine therapies. As a class, these agents are vasodilatory and proinflammatory via degranulation of mast cells. They may be pronociceptive in some patients and lead to decreased efficacy of other migraine abortives. Data in animal models links their administration with activation of brainstem inflammatory mechanisms mediated by glial cells [48, Class IV]. In a study of the efficacy of triptans and NSAIDs in migraineurs with evidence of allodynia and central sensitization, opiate use at a level of 3 days per month was enough to render a small group of subjects refractory [48, Class II]. Three small, clinic-based studies (cross-section, case-control, and longitudinal) associate opiate use with progression of episodic migraine to chronic migraine [49••, Class III]. Opiates may contribute to medication overuse headache with frequency of use as few as 8 days per month [50, Class IV]. Earlier guidelines indicate opiate use should be restricted to pregnancy or when indicated drugs are contraindicated or have failed [12,51; Class IV]. The authors of a 2009 review restrict opiate use outside of pregnancy to carefully selected patients with documented poor response, contraindications to triptans and NSAIDS, or validated failure of first-line acute therapies. When opiate use is warranted, use migraine preventive medications liberally and more aggressively and follow these patients closely to monitor for the development of transformed or chronic migraine [49••, Class IV]. Consider opiate contracts for those using such agents as primary or rescue therapies in migraine [23, Class IV].

  • Chronic opiate use by patients with refractory migraine has also been a matter of debate. Issues of concern with chronic opiate administration go beyond dependence and abuse and include medication-overuse headache with reduced responsiveness to migraine-specific acute and preventive therapies, opiate-induced hyperalgesia, aggravation of comorbid psychiatric conditions, and adverse effects from the opiate class, such as sedation, constipation, and respiratory depression. It appears that only 10% to 20% of a selected group of patients with refractory headache meeting strict criteria respond with evidence of convincing headache reduction and functional improvement. [52, Class IV]. Recent guidelines for continuous opiate therapy for refractory daily headache have been published [53, Class III].

Disclosure

Conflicts of Interest: F. Taylor: Board member, Merck Human Health; Consultant for AGA Medical, Inc., Medtronics, Inc., and Merck Scientific Advisory Committee; Member of Merck Speakers Bureau; Grants for Merck Telcagepant study and study for Allergan, Inc.; Royalties from UpToDate, Inc. for authorship of Tension-type Headache in Adults: Pathophysiology, Clinical Features, and Diagnosis. R. Kaniecki: Speaker’s honoraria from Merck, Zogenix, GlaxoSmithKline.

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© Springer Science+Business Media, LLC 2010