Curr Treat Options Neurol (2015) 17:27 DOI 10.1007/s11940-015-0353-6
Headache (JR Couch, Section Editor)
Treatment of Headache Following Triptan Failure After Successful Triptan Therapy Marc E. P. Lenaerts, MD, FAHS1,2,* James R. Couch Jr, MD, PhD3 Address 1 Department of Neurology, University of California, Davis, CA, USA *,2 4860, Y St, Suite #100, Sacramento, CA 95817, USA Email: [email protected] 3 Department of Neurology, University of Oklahoma, Norman, OK, USA
* Springer Science+Business Media New York 2015
This article is part of the Topical Collection on Headache Keywords Headache I Triptans I Triptan Failure I Ergot derivatives I Non-steroids I Opioid analgesics I Neurostimulation
Opinion statement Triptans should remain the first choice in migraine abortive treatment. They are not always effective or adequate for specific patients. Before declaring a triptan in appropriate for a given patient, the provider ought to be analytical about the rationale and especially the use of objective efficacy outcome measures and ensure that treatment is prescribed and used appropriately. Other ergot derivatives, especially dihydroergotamine, may on one hand share common contraindications of triptans but on the other hand can be quite effective where triptans failed. Non-steroids are simple, readily available, and overall safe, and evidence for their efficacy in migraine is plentiful. Opioid analgesics are blatantly overprescribed especially in non-complicated migraine patients. These should be used with great care and restraint and closely monitored. Frequent opioid usage often leads to tolerance, dependence, and medication overuse headache. Neurostimulation is gaining momentum in the armamentarium of migraine management but at the present time remains primarily focused on prophylaxis, yet abortive use is expected to grow.
Introduction Until the advent of triptans in the early 1990s, ergot derivatives such as ergotamine, with or without caffeine, and dihydroergotamine were frequently used. They are less specific in their receptor targets and laden with more side effects, but are still available options. Since 1990 when triptans were first introduced in Europe, their
usefulness and tolerability have been widely known. Triptans currently are the mainstay of migraine modern abortive therapy [1••]. They are very effective against head pain, but also against several other symptoms of the migraine attack such as nausea, vomiting, photophobia, and phonophobia. Yet when they are given
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orally, not uncommonly, they are not adequately and timely absorbed by the gastrointestinal tract especially in case the gastroparesis of migraine is severe. Thus, paradoxically, they are unable to treat those very gastrointestinal symptoms. Efficacy of oral triptans overall can be summarized as approximately 2/3 patients getting at least 50 % relief at 2 h. Consequently, the patient should try a triptan at least three times before making the determination whether it is ineffective or not. There are seven triptans on the market. There is idiosyncratic variability in response to them. Some patients respond to all triptans, and some respond to only one or none. Likewise, there may be relative responses to different triptans in a given patient. Thus, it is logical to try several triptans in a given patient before giving up on this medication class. Even in patients who have failed to respond to oral triptans, the nasal form of zolmitriptan or the nasal, the subcutaneous, and soon the iontophoretic forms of sumatriptan can be considered. Additionally, early administration of the triptan (early therapy) enhances efficacy, as opposed to treating only when the pain has lingered for a while when central sensitization to pain may occur. In patients who have several types of headaches, especially if frequent, early therapy is particularly suitable for those who can reliably distinguish between a migraine attack and a headache of other origin. If the distinction is not easy, the risk for medication overuse is significant. Another aspect of migraine to consider is the fact that it is a syndrome, with more than the classic with and without aura types currently posited. This is conceivably equally important for the treatment of migraine as it is for that of other neurologic conditions such as multiple sclerosis or parkinsonism. Against this background, a medication class, such as triptans, which gives 2/3 chance of relief, appears acceptable. There is no definite evidence that the use of triptans concomitantly with serotonin-specific reuptake inhibitors causes a high risk of serotonin syndrome. Thus, although cautious observation is advised, the mere presence of such antidepressant should be no reason to discontinue the use of triptans [2]. Where a triptan alone may fail, a synergistic combination of triptan and non-steroidal anti-inflammatory drug can still be beneficial [3]. It is paramount to understand failure of a triptan after initial therapeutic success. The expectation that any triptan will effectively relieve every attack of migraine in a given patient is unreasonable. Overall triptans tend to be effective in approximately two out
Curr Treat Options Neurol (2015) 17:27 of three uses. Medication overuse can be a major culprit for the cessation of efficacy of these drugs, just as any other migraine relief treatment. By consensus, the IHS recommends limiting the use of triptans to 10 days per month. Usage above this level can give rise to medication overuse headache (MOH). Regardless of the medication overuse issue, there is a natural tendency for tachyphylaxis to triptans, which of course is not unique to that medication class. In the authors’ experience, this can happen after as early as 6 months of usage. This is manifested by patient using an increasing amount of triptans (higher doses and/or more frequent intakes especially). Switching to another triptan may help for a while, but eventually, a tendency to tachyphylaxis to all triptans may occur. Again in the authors’ experience, once tachyphylaxis occurs, the patient typically does not regain responsiveness to the concerned triptan later. It is paramount to address prophylaxis for patients with over three attacks of migraine per month average. Indeed, besides reduction in headache frequency, it can enhance the efficacy of abortive therapy. In case of failure of triptans to relieve the headache, a careful review of the patient’s diagnosis is paramount, as is a cautious assessment of compliance and aggravating factors such as possible sleep apnea syndrome, etc. Finally, one must remain mindful of the gastroparesis which frequently occurs during a migraine attack and consider alternatives to the oral route before considering the triptan class ineffective [4]. Sumatriptan or zolmitriptan by intranasal administration are valid alternatives if the gastrointestinal absorption is the critical factor. The more recently FDA-approved iontophoretic transdermal formulation is also to be considered, with efficacy numbers as follows: pain freedom at 2 h was achieved in 18 % patients versus 9 % for placebo, and pain relief in 53 and 29 % at 2 h for the verum and placebo, respectively, in a double-blind randomized parallel trial of 530 migraineurs [5]. The variability in symptoms from attack to attack can justify doing both oral and non-oral prescriptions in the same patient. Another aspect of triptan failure is the occurrence of side effects or adverse reactions. With subcutaneous sumatriptan and its rapid onset, worsening of the headache, and chest and neck pain have been reported. The former is likely due to initial activation of the first-order trigeminal neuron before the emergence of synaptic inhibition
Curr Treat Options Neurol (2015) 17:27 and peripheral sensitization reduction, and the latter likely due to the presence of serotonin receptors in the upper trunk muscles. There were initial reports of myocardial infarction with subcutaneous sumatriptan, but with proper out-screening of patients with symptomatic
Page 3 of 7 27 or severe atherosclerosis (especially coronary), there has been no report of vascular ischemia in a very long time. In non-symptomatic patients who are suspicious of severe atherosclerosis, and have limited alternative to triptans, cardiology clearance may be considered.
Alternatives to triptans Dihydroergotamine (DHE) DHE can be very useful in some patients with triptan-resistant headaches. DHE has the same potency at the serotonin B and D receptors as the triptans, but also activates other amine receptors at a low level. Introduced in Sweden in 1945, DHE was used occasionally in Emergency Departments as a subcutaneous injection with overall modest efficacy. The use of intravenous DHE was popularized by Raskin following his use of this medication as an alternative to opioids in the San Francisco area in the early 1980s. He employed intravenous DHE in status migrainosus and MOH with good success. Silberstein et al. later presented a series on this use. There are many variations in the use of DHE in these patients; however, the usual protocols involve using premedication with a dopamine antagonist and, then, after 5–10 min administering 1 mg DHE intravenously slowly or in divided doses over 5– 20 min. The intravenous use of DHE in migraine was first reported from an open-label series by Raskin in 1986 [6], but a randomized placebo-controlled trial failed to demonstrate efficacy [7]. Yet the drug is still used intravenously frequently in status migrainosus. DHE can also be used as a self-administered subcutaneous or intramuscular injection by patients with intermittent severe migraine for whom triptans do not work [8, 9]. Subcutaneous injections of DHE can be performed, but the evidence of efficacy remains limited [10]. There is controversy regarding the innocuousness of this drug vis-à-vis medication overuse headache risk [11, 12]. Despite a far greater propensity of the older ergotamine tartrate to cause this syndrome, dihydroergotamine has been associated with it in occasional reports. It is recommended to limit its use to 2 days per week at the exception of the repeated IV administration over three consecutive days in the Raskin protocol. Intranasal DHE has been used for about 25 years and may abort migraine effectively. Efficacy against placebo in several randomized, controlled trials was statistically achieved as early as 1 h (2 mg) and with pain relief in 70 % at 4 h (3 mg) [13, 14]. Orally inhaled DHE has been shown to be effective in several trials. In a multicentric, randomized controlled trial of 903 patients, 59 % patients experienced pain relief and 38 % pain freedom, at 2 h, and tolerance was very good [15]. The drug is not commercially available at this time, and it has been submitted for FDA approval.
Non-steroidal anti-inflammatory drugs (NSAIDs) Ibuprofen and naproxen have been submitted to numerous controlled trials whose details lie out of the scope of this brief review. Although
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Curr Treat Options Neurol (2015) 17:27 naproxen succeeds in relieving migraine pain, in a meta-analysis of six randomized controlled trials, the overall clinical efficacy level remains debatable: 45 % pain relief at 2 h overall versus 30 % for placebo, and sustained 24 h relief 30 and 18 %, respectively [16]. Ideal dosage for naproxen is 400–1000 mg per day and for ibuprofen 400–1200 mg per day. Caution with NSAIDs is advised against the risk of gastrointestinal ulcers and renal insufficiency. Alternatively, celecoxib, COX-2 inhibitor, has a safer gastrointestinal profile but has been subjected to only limited study in migraine. In a randomized yet open-label study, celecoxib 400 mg performed comparatively to naproxen 550 mg with a reduction in visual analog scale of about 2 points at 1 h and 4 points at 2 h [17]. Recommended dose is 400 mg per day as needed. Diclofenac potassium powdered formulation achieved pain freedom at 2 h in 25 % patients versus 10 % for placebo, in a randomized placebo-controlled parallel study of 690 patients. Sustained pain free at 24 h was respectively 19 and 7 % [18]. Of note, nausea and vomiting also benefited despite the drug being gastro-irritant, and so did photo- and phonophobias. In an older comparative randomized crossover trial, diclofenac compared favorably to sumatriptan, even in regard to nausea relief [19]. Ketorolac is a potent NSAID which, albeit not FDA approved specifically for migraine, can be considered for use as rescue therapy. A small randomized controlled trial in migraine compared IV ketorolac favorably to nasal sumatriptan [20]. A randomized investigation of a mixture of nasal ketorolac 31.5 mg and lidocaine 6 % did not statistically meet its primary end point of pain freedom at 2 h but did show a clear delay in patients’ use for additional relief medication [21]. Intravenous or intramuscular administration of 30 or 60 mg, maximum 120 mg in a day, or intranasal administration of 31.5 mg (one spray of 15.75 mg in each nostril, max 126 mg in a day) can be used. It is recommended to not use more than 5 days for gastrointestinal safety reasons, yet the evidence for a relation between the number of uses and the incidence of such adverse events remains limited.
Others Isometheptene/dichloralphenazone/acetaminophen oral combination has been long shown moderately effective in migraine abortive treatment, with initial studies being performed with different standards; yet a more recent comparative trial indicated efficacy relatively similar to that of sumatriptan [22, 23]. Typical dosage is 1–2 capsules as needed followed by an additional capsule as needed every hour thereafter to a maximum of five capsules in 12 h. Combination analgesics acetaminophen/acetylsalicylate/caffeine can be used, but to our knowledge, there is no randomized controlled trial. Typically, one tablet as needed every 6 h maximum four per day can be used. Dopamine receptor blockers such as metoclopramide and chlorpromazine are strongly effective antiemetics moderately effective migraine pain relievers, but the scientific evidence remains limited and more anecdotal (class III). Opioids are effective in relieving the pain of migraine, but they are highly associated with the phenomenon of medication overuse headache and are not recommended for routine use. Cautious occasional use with close monitoring
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of headache frequency can be justified in circumstances where above options are not adequate. Butalbital-containing medications are not FDA approved for the treatment of migraine, are not recommended by the author, and are even banned from sale in Germany. They are often associated with aggravation of the migraine syndrome by medication overuse headache. For additional review of alternative options, see Marmura et al. [24••]. Despite initial hopes, intravenous meta-analysis of the effect of intravenous magnesium in the abortive treatment of migraine cannot be recommended, based on lack of efficacy [25]. Intravenous valproate has limited evidence but is a valid alternative [26, 27].
Repetitive transcranial magnetic stimulation (rTMS) In 2013, FDA approved a device that delivers repetitive magnetic pulses externally onto the occipital cortex to prevent, as well as abort, migraine attacks. It putatively alters the physiology of the aura and of cortical hyperexcitability in migraine. It has been shown to abort a migraine attack with efficacy similar to that of triptans [28]. In another case control series of 123 patients, 74 % patients had pain reduction and 63 % had improvement of associated symptoms [29]. These results have to be taken with caution but deserve consideration in the treatment of otherwise intractable migraineurs.
Transcutaneous supraorbital nerve stimulation device (Cefaly) Although the use of low-frequency transcutaneous electrical supraorbital nerve stimulation has been proven to reduce migraine frequency as preventive treatment [30] and the device Cefaly® has been approved by FDA as such in 2013, there is anecdotal evidence that high-frequency stimulation with the device helps abort the ongoing attack (class III). The overall tolerance of the device is excellent with only 4 % of mild side effects including local irritation and insomnia [31].
Vagus nerve stimulation Stimulation of the afferent vagal fibers could potentially modulate the activity of the pathway of trigeminal nerve-mediated pain [32]. An open-label trial of external vagus nerve stimulation to abort migraine attacks in 27 subjects gave pain freedom in 21 % at 2 h [33]. This is not FDA-approved at the time of publication.
Spheno-palatine ganglion stimulation and chemical blockade Stimulation of the spheno-palatine ganglion has been demonstrated effective in the abortive treatment of cluster headache. Migraine is not uncommonly observed to exhibit symptoms of ipsilateral parasympathetic cranial activation. Stimulation of the ganglion could have inhibitory effect in the trigeminal nucleus caudalis. Taken together the above led to a trial of spheno-palatine ganglion stimulation in the abortive treatment of migraine. The trial, led by S Tepper, is now completed, and results are awaited and promising. Within the same concept, a double-blind, randomized, placebo-controlled application of 0.3 cm3 of bupivacaine 0.5 % on the ganglion with the local
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catheter device tx360 gave clinically modest yet statistically significant reduction in pain as early as 15 min [34].
Summary Effectiveness of abortive therapy has to be assessed objectively (judicious use, realistic expectations, ad hoc routes of administration…). Triptans remain the mainstay of migraine abortive therapy but can fail to perform, either primarily or secondarily after some period of effectiveness (tachyphylaxis). Response to one given triptan does not necessarily preclude that to another. There are many valid alternatives to triptans, and knowledge of the armamentarium leads to individual and optimal care. Prophylaxis cannot entirely be teased out of abortive treatment: it can interact pharmacologically, and it can enhance its effectiveness. While there has been limited progress in pharmacotherapeutic breakthroughs in the last two decades since the advent of triptans, neurostimulation could take an increasingly hard abortive management.
Compliance with Ethics Guidelines Conflict of Interest Marc E. P. Lenaerts and James R. Couch declare no conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by the author.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: •• Of major importance 1.••
Loder E. Triptan therapy in migraine. N Engl J Med. 2010;363:63–70. Class I, Excellent review and reference in the field. 2. Evans RW, Tepper SJ, Shapiro RE, Sun-Edelstein C, Tietjen GE. The FDA alert on serotonin syndrome with use of triptans combined with selective serotonin reuptake inhibitors or selective serotonin-norepinephrine reuptake inhibitors: American headache society position paper. Headache. 2010;50:1089–99. Class III. 3. Blumenfeld A, Gennings C, Cady R. Pharmacological synergy: the next frontier on therapeutic advancement for migraine. Headache. 2012;52:636–47. Class IV. 4. Newman LC. Why triptan treatment can fail: focus on gastrointestinal manifestations of migraine. Headache. 2013;53:S11–6. Class IV.
5. 6. 7.
8.
9.
Goldstein J, Smith TR, Pugash N, et al. A Sumatriptan iontophoretic transdermal system for the acute treatment of migraine. Headache. 2012;52:1402–10. Class I. Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology. 1986;36:995–7. Class III. Callaham M, Raskin N. A controlled study of dihydroergotamine in the treatment of acute migraine headache. Headache. 1986;26:168–71. Class I. Saadah H. Abortive headache therapy with intramuscular dihydroergotamine. Headache. 1992;32:18–20. Class III. Weisz MA1, el-Raheb M, Blumenthal HJ. Home administration of intramuscular DHE for the treatment of acute migraine headache. Headache. 1994;34:371–3. Class II.
Curr Treat Options Neurol (2015) 17:27 10. 11. 12. 13.
14.
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20. 21.
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Becker WJ, Riess CM, Hoag G. Efficacy of subcutaneous dihydroergotamine by home injections in migraine. Headache. 1996;36:144–8. Class III. Saper JR, Silberstein S. Pharmacology of dihydroergotamine and evidence for efficacy and safety in migraine. Headache. 2006;46:S171–81. Class IV. Tfelt-Hansen P, Diener HC. Use of dihydroergotamine (DHE) should be restricted to no more than twice a week. Headache. 2014. Class IV. Ziegler D, Ford R, Kriegler J, Gallagher RM, Peroutka S, Hammerstad J, et al. Dihydroergotamine nasal spray for the acute treatment of migraine. Neurology. 1994;44:447–53. Class I. Ghallager GM. Acute treatment of migraine with dihydroergotamine nasal spray. Dihydroergotamine Working Group. Arch Neurol. 1996;53(12):1285–91. Class I. Aurora SK, Silberstein SD, Kori SH, Tepper SJ, Borland SW, Wang M, et al. MAP0004, orally inhaled DHE: a randomized, controlled study in the acute treatment of migraine. Headache. 2011;51(4):507–17. Class I. Law S, Derry S, Moore RA. Naproxen with or without an antiemetic for acute migraine headaches in adults. Cochrane Database Syst Rev. 2013;20:10. Class I. Loo CY, Tan HJ, Tay HS, Raymond AA. Randomized, open label, controlled trial of celecoxib in the treatment of acute migraine. Singapore Med J. 2007;48:834–9. Class II. Lipton RB, Grosberg B, Singer RP, et al. Efficacy and tolerability of a new powdered formulation of diclofenac potassium for oral solution for the acute treatment of migraine: results from the International Migraine Pain Assessment Clinical Trial (IMPACT). Cephalalgia. 2010;30:1336–45. Class I. The Diclofenac-K/Sumatriptan Migraine Study Group. Acute treatment of migraine attacks: efficacy and safety of a non-steroidal anti-inflammatory drug, diclofenacpotassium, in comparison to oral sumatriptan and placebo. Cephalalgia. 1999;19:232–40. Class I. Meredith JT, Wait S, Brewer KL. A prospective doubleblind study of nasal sumatriptan versus IV ketorolac in migraine. Am J Emerg Med. 2003;21:173–5. Class I. Pfaffenrath V, Fenzl E, Bergman D, et al. Intranasal ketorolac tromethamine (SPRIX®) containing 6% of lidocaine (ROX-828) for acute treatment of migraine: safety and efficacy data from a phase II clinical trial. Cephalalgia. 2012;32:766–77. Class I. Diamond S. Treatment of migraine with isometheptene, acetaminophen, and dichloralphenazone combination: a double-blind, crossover trial. Headache. 1976;15(4):282–7. Class II. Freitag FG, Cady R, DiSerio F, Elkind A, Gallagher RM, Goldstein J, et al. Comparative study of a combination of isometheptene mucate, dichloralphenazone with acetaminophen and sumatriptan succinate in the
Page 7 of 7 27 treatment of migraine. Headache. 2001;41(4):391–8. Class I. 24.•• Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: the American Headache Society evidence assessment of migraine pharmacotherapies. Headache. 2015;55(1):3–20. Class I, A critical appraisal of current headache care practice in the US. 25. Choi H, Parmar N. The use of intravenous magnesium sulphate for acute migraine: meta-analysis of randomized controlled trials. Eur J Emerg Med. 2014;21(1):2–9. Class I. 26. Edwards KR, Norton J, Behnke M. Comparison of intravenous valproate versus intramuscular dihydroergotamine and metoclopramide for acute treatment of migraine headache. Headache. 2001;41(10):976–80. Class II. 27. Mathew NT, Kailasam J, Meadors L, Chernyschev O, Gentry P. Intravenous valproate sodium (depacon) aborts migraine rapidly: a preliminary report. Headache. 2000;40(9):720–3. Class II. 28. Starling AJ, Dodick DW, Chiacchierini RP (2011) Comparison of effect size between active and placebo for single pulse transcranial magnetic stimulation (spTMS) versus triptans for the acute treatment of migraine. Poster, AAN Proceedings, Honolulu, USA, Class III 29. Bhola R, Kinsella E, Goadsby PJ (2013) Update of the UK post market pilot programme with single pulse transcranial magnetic stimulation (sTMS) for acute treatment of migraine: SpringTMS use in migraine. Poster, International Headache Congress, Boston, USA, Class III 30. Schoenen J, Vandersmissen B, Jeangette S, Herroelen L, Vandenheede M, Gerard P, et al. Migraine prevention with a supraorbital transcutaneous stimulator: a randomized controlled trial. Neurology. 2013;80(8):697– 704. Class I. 31. Magis D, Sava S, d’Elia Sasso T, Baschi R, Schoenen J. Safety and patients’ satisfaction of transcutaneous supraorbital neurostimulation (tSNS) with the Cefaly® device in headache treatment: a survey of 2,313 headache sufferers in the general population. J Headache Pain. 2013;14:95. Class II. 32. Lenaerts ME, Oommen KJ, Couch JR, Skaggs V. Can vagus nerve stimulation help migraine? Cephalalgia. 2008;28:392–5. Class III. 33. Goadsby PJ, Grosberg BM, Mauskop A, Cady R, Simmons KA. Effect of non-invasive vagus nerve stimulation on acute migraine: an open-label pilot study. Cephalalgia. 2014;34:986–93. Class III. 34. Cady R, Saper J, Dexter K, Manley HR. A double-blind, placebo-controlled study of repetitive transnasal spheno-palatine ganglion blockade with tx360 as acute treatment for chronic migraine. Headache. 2015;55(1):101–16. Class I.
Headache (JR Couch, Section Editor)
Treatment of Headache Following Triptan Failure After Successful Triptan Therapy Marc E. P. Lenaerts, MD, FAHS1,2,* James R. Couch Jr, MD, PhD3 Address 1 Department of Neurology, University of California, Davis, CA, USA *,2 4860, Y St, Suite #100, Sacramento, CA 95817, USA Email: [email protected] 3 Department of Neurology, University of Oklahoma, Norman, OK, USA
* Springer Science+Business Media New York 2015
This article is part of the Topical Collection on Headache Keywords Headache I Triptans I Triptan Failure I Ergot derivatives I Non-steroids I Opioid analgesics I Neurostimulation
Opinion statement Triptans should remain the first choice in migraine abortive treatment. They are not always effective or adequate for specific patients. Before declaring a triptan in appropriate for a given patient, the provider ought to be analytical about the rationale and especially the use of objective efficacy outcome measures and ensure that treatment is prescribed and used appropriately. Other ergot derivatives, especially dihydroergotamine, may on one hand share common contraindications of triptans but on the other hand can be quite effective where triptans failed. Non-steroids are simple, readily available, and overall safe, and evidence for their efficacy in migraine is plentiful. Opioid analgesics are blatantly overprescribed especially in non-complicated migraine patients. These should be used with great care and restraint and closely monitored. Frequent opioid usage often leads to tolerance, dependence, and medication overuse headache. Neurostimulation is gaining momentum in the armamentarium of migraine management but at the present time remains primarily focused on prophylaxis, yet abortive use is expected to grow.
Introduction Until the advent of triptans in the early 1990s, ergot derivatives such as ergotamine, with or without caffeine, and dihydroergotamine were frequently used. They are less specific in their receptor targets and laden with more side effects, but are still available options. Since 1990 when triptans were first introduced in Europe, their
usefulness and tolerability have been widely known. Triptans currently are the mainstay of migraine modern abortive therapy [1••]. They are very effective against head pain, but also against several other symptoms of the migraine attack such as nausea, vomiting, photophobia, and phonophobia. Yet when they are given
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orally, not uncommonly, they are not adequately and timely absorbed by the gastrointestinal tract especially in case the gastroparesis of migraine is severe. Thus, paradoxically, they are unable to treat those very gastrointestinal symptoms. Efficacy of oral triptans overall can be summarized as approximately 2/3 patients getting at least 50 % relief at 2 h. Consequently, the patient should try a triptan at least three times before making the determination whether it is ineffective or not. There are seven triptans on the market. There is idiosyncratic variability in response to them. Some patients respond to all triptans, and some respond to only one or none. Likewise, there may be relative responses to different triptans in a given patient. Thus, it is logical to try several triptans in a given patient before giving up on this medication class. Even in patients who have failed to respond to oral triptans, the nasal form of zolmitriptan or the nasal, the subcutaneous, and soon the iontophoretic forms of sumatriptan can be considered. Additionally, early administration of the triptan (early therapy) enhances efficacy, as opposed to treating only when the pain has lingered for a while when central sensitization to pain may occur. In patients who have several types of headaches, especially if frequent, early therapy is particularly suitable for those who can reliably distinguish between a migraine attack and a headache of other origin. If the distinction is not easy, the risk for medication overuse is significant. Another aspect of migraine to consider is the fact that it is a syndrome, with more than the classic with and without aura types currently posited. This is conceivably equally important for the treatment of migraine as it is for that of other neurologic conditions such as multiple sclerosis or parkinsonism. Against this background, a medication class, such as triptans, which gives 2/3 chance of relief, appears acceptable. There is no definite evidence that the use of triptans concomitantly with serotonin-specific reuptake inhibitors causes a high risk of serotonin syndrome. Thus, although cautious observation is advised, the mere presence of such antidepressant should be no reason to discontinue the use of triptans [2]. Where a triptan alone may fail, a synergistic combination of triptan and non-steroidal anti-inflammatory drug can still be beneficial [3]. It is paramount to understand failure of a triptan after initial therapeutic success. The expectation that any triptan will effectively relieve every attack of migraine in a given patient is unreasonable. Overall triptans tend to be effective in approximately two out
Curr Treat Options Neurol (2015) 17:27 of three uses. Medication overuse can be a major culprit for the cessation of efficacy of these drugs, just as any other migraine relief treatment. By consensus, the IHS recommends limiting the use of triptans to 10 days per month. Usage above this level can give rise to medication overuse headache (MOH). Regardless of the medication overuse issue, there is a natural tendency for tachyphylaxis to triptans, which of course is not unique to that medication class. In the authors’ experience, this can happen after as early as 6 months of usage. This is manifested by patient using an increasing amount of triptans (higher doses and/or more frequent intakes especially). Switching to another triptan may help for a while, but eventually, a tendency to tachyphylaxis to all triptans may occur. Again in the authors’ experience, once tachyphylaxis occurs, the patient typically does not regain responsiveness to the concerned triptan later. It is paramount to address prophylaxis for patients with over three attacks of migraine per month average. Indeed, besides reduction in headache frequency, it can enhance the efficacy of abortive therapy. In case of failure of triptans to relieve the headache, a careful review of the patient’s diagnosis is paramount, as is a cautious assessment of compliance and aggravating factors such as possible sleep apnea syndrome, etc. Finally, one must remain mindful of the gastroparesis which frequently occurs during a migraine attack and consider alternatives to the oral route before considering the triptan class ineffective [4]. Sumatriptan or zolmitriptan by intranasal administration are valid alternatives if the gastrointestinal absorption is the critical factor. The more recently FDA-approved iontophoretic transdermal formulation is also to be considered, with efficacy numbers as follows: pain freedom at 2 h was achieved in 18 % patients versus 9 % for placebo, and pain relief in 53 and 29 % at 2 h for the verum and placebo, respectively, in a double-blind randomized parallel trial of 530 migraineurs [5]. The variability in symptoms from attack to attack can justify doing both oral and non-oral prescriptions in the same patient. Another aspect of triptan failure is the occurrence of side effects or adverse reactions. With subcutaneous sumatriptan and its rapid onset, worsening of the headache, and chest and neck pain have been reported. The former is likely due to initial activation of the first-order trigeminal neuron before the emergence of synaptic inhibition
Curr Treat Options Neurol (2015) 17:27 and peripheral sensitization reduction, and the latter likely due to the presence of serotonin receptors in the upper trunk muscles. There were initial reports of myocardial infarction with subcutaneous sumatriptan, but with proper out-screening of patients with symptomatic
Page 3 of 7 27 or severe atherosclerosis (especially coronary), there has been no report of vascular ischemia in a very long time. In non-symptomatic patients who are suspicious of severe atherosclerosis, and have limited alternative to triptans, cardiology clearance may be considered.
Alternatives to triptans Dihydroergotamine (DHE) DHE can be very useful in some patients with triptan-resistant headaches. DHE has the same potency at the serotonin B and D receptors as the triptans, but also activates other amine receptors at a low level. Introduced in Sweden in 1945, DHE was used occasionally in Emergency Departments as a subcutaneous injection with overall modest efficacy. The use of intravenous DHE was popularized by Raskin following his use of this medication as an alternative to opioids in the San Francisco area in the early 1980s. He employed intravenous DHE in status migrainosus and MOH with good success. Silberstein et al. later presented a series on this use. There are many variations in the use of DHE in these patients; however, the usual protocols involve using premedication with a dopamine antagonist and, then, after 5–10 min administering 1 mg DHE intravenously slowly or in divided doses over 5– 20 min. The intravenous use of DHE in migraine was first reported from an open-label series by Raskin in 1986 [6], but a randomized placebo-controlled trial failed to demonstrate efficacy [7]. Yet the drug is still used intravenously frequently in status migrainosus. DHE can also be used as a self-administered subcutaneous or intramuscular injection by patients with intermittent severe migraine for whom triptans do not work [8, 9]. Subcutaneous injections of DHE can be performed, but the evidence of efficacy remains limited [10]. There is controversy regarding the innocuousness of this drug vis-à-vis medication overuse headache risk [11, 12]. Despite a far greater propensity of the older ergotamine tartrate to cause this syndrome, dihydroergotamine has been associated with it in occasional reports. It is recommended to limit its use to 2 days per week at the exception of the repeated IV administration over three consecutive days in the Raskin protocol. Intranasal DHE has been used for about 25 years and may abort migraine effectively. Efficacy against placebo in several randomized, controlled trials was statistically achieved as early as 1 h (2 mg) and with pain relief in 70 % at 4 h (3 mg) [13, 14]. Orally inhaled DHE has been shown to be effective in several trials. In a multicentric, randomized controlled trial of 903 patients, 59 % patients experienced pain relief and 38 % pain freedom, at 2 h, and tolerance was very good [15]. The drug is not commercially available at this time, and it has been submitted for FDA approval.
Non-steroidal anti-inflammatory drugs (NSAIDs) Ibuprofen and naproxen have been submitted to numerous controlled trials whose details lie out of the scope of this brief review. Although
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Curr Treat Options Neurol (2015) 17:27 naproxen succeeds in relieving migraine pain, in a meta-analysis of six randomized controlled trials, the overall clinical efficacy level remains debatable: 45 % pain relief at 2 h overall versus 30 % for placebo, and sustained 24 h relief 30 and 18 %, respectively [16]. Ideal dosage for naproxen is 400–1000 mg per day and for ibuprofen 400–1200 mg per day. Caution with NSAIDs is advised against the risk of gastrointestinal ulcers and renal insufficiency. Alternatively, celecoxib, COX-2 inhibitor, has a safer gastrointestinal profile but has been subjected to only limited study in migraine. In a randomized yet open-label study, celecoxib 400 mg performed comparatively to naproxen 550 mg with a reduction in visual analog scale of about 2 points at 1 h and 4 points at 2 h [17]. Recommended dose is 400 mg per day as needed. Diclofenac potassium powdered formulation achieved pain freedom at 2 h in 25 % patients versus 10 % for placebo, in a randomized placebo-controlled parallel study of 690 patients. Sustained pain free at 24 h was respectively 19 and 7 % [18]. Of note, nausea and vomiting also benefited despite the drug being gastro-irritant, and so did photo- and phonophobias. In an older comparative randomized crossover trial, diclofenac compared favorably to sumatriptan, even in regard to nausea relief [19]. Ketorolac is a potent NSAID which, albeit not FDA approved specifically for migraine, can be considered for use as rescue therapy. A small randomized controlled trial in migraine compared IV ketorolac favorably to nasal sumatriptan [20]. A randomized investigation of a mixture of nasal ketorolac 31.5 mg and lidocaine 6 % did not statistically meet its primary end point of pain freedom at 2 h but did show a clear delay in patients’ use for additional relief medication [21]. Intravenous or intramuscular administration of 30 or 60 mg, maximum 120 mg in a day, or intranasal administration of 31.5 mg (one spray of 15.75 mg in each nostril, max 126 mg in a day) can be used. It is recommended to not use more than 5 days for gastrointestinal safety reasons, yet the evidence for a relation between the number of uses and the incidence of such adverse events remains limited.
Others Isometheptene/dichloralphenazone/acetaminophen oral combination has been long shown moderately effective in migraine abortive treatment, with initial studies being performed with different standards; yet a more recent comparative trial indicated efficacy relatively similar to that of sumatriptan [22, 23]. Typical dosage is 1–2 capsules as needed followed by an additional capsule as needed every hour thereafter to a maximum of five capsules in 12 h. Combination analgesics acetaminophen/acetylsalicylate/caffeine can be used, but to our knowledge, there is no randomized controlled trial. Typically, one tablet as needed every 6 h maximum four per day can be used. Dopamine receptor blockers such as metoclopramide and chlorpromazine are strongly effective antiemetics moderately effective migraine pain relievers, but the scientific evidence remains limited and more anecdotal (class III). Opioids are effective in relieving the pain of migraine, but they are highly associated with the phenomenon of medication overuse headache and are not recommended for routine use. Cautious occasional use with close monitoring
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of headache frequency can be justified in circumstances where above options are not adequate. Butalbital-containing medications are not FDA approved for the treatment of migraine, are not recommended by the author, and are even banned from sale in Germany. They are often associated with aggravation of the migraine syndrome by medication overuse headache. For additional review of alternative options, see Marmura et al. [24••]. Despite initial hopes, intravenous meta-analysis of the effect of intravenous magnesium in the abortive treatment of migraine cannot be recommended, based on lack of efficacy [25]. Intravenous valproate has limited evidence but is a valid alternative [26, 27].
Repetitive transcranial magnetic stimulation (rTMS) In 2013, FDA approved a device that delivers repetitive magnetic pulses externally onto the occipital cortex to prevent, as well as abort, migraine attacks. It putatively alters the physiology of the aura and of cortical hyperexcitability in migraine. It has been shown to abort a migraine attack with efficacy similar to that of triptans [28]. In another case control series of 123 patients, 74 % patients had pain reduction and 63 % had improvement of associated symptoms [29]. These results have to be taken with caution but deserve consideration in the treatment of otherwise intractable migraineurs.
Transcutaneous supraorbital nerve stimulation device (Cefaly) Although the use of low-frequency transcutaneous electrical supraorbital nerve stimulation has been proven to reduce migraine frequency as preventive treatment [30] and the device Cefaly® has been approved by FDA as such in 2013, there is anecdotal evidence that high-frequency stimulation with the device helps abort the ongoing attack (class III). The overall tolerance of the device is excellent with only 4 % of mild side effects including local irritation and insomnia [31].
Vagus nerve stimulation Stimulation of the afferent vagal fibers could potentially modulate the activity of the pathway of trigeminal nerve-mediated pain [32]. An open-label trial of external vagus nerve stimulation to abort migraine attacks in 27 subjects gave pain freedom in 21 % at 2 h [33]. This is not FDA-approved at the time of publication.
Spheno-palatine ganglion stimulation and chemical blockade Stimulation of the spheno-palatine ganglion has been demonstrated effective in the abortive treatment of cluster headache. Migraine is not uncommonly observed to exhibit symptoms of ipsilateral parasympathetic cranial activation. Stimulation of the ganglion could have inhibitory effect in the trigeminal nucleus caudalis. Taken together the above led to a trial of spheno-palatine ganglion stimulation in the abortive treatment of migraine. The trial, led by S Tepper, is now completed, and results are awaited and promising. Within the same concept, a double-blind, randomized, placebo-controlled application of 0.3 cm3 of bupivacaine 0.5 % on the ganglion with the local
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catheter device tx360 gave clinically modest yet statistically significant reduction in pain as early as 15 min [34].
Summary Effectiveness of abortive therapy has to be assessed objectively (judicious use, realistic expectations, ad hoc routes of administration…). Triptans remain the mainstay of migraine abortive therapy but can fail to perform, either primarily or secondarily after some period of effectiveness (tachyphylaxis). Response to one given triptan does not necessarily preclude that to another. There are many valid alternatives to triptans, and knowledge of the armamentarium leads to individual and optimal care. Prophylaxis cannot entirely be teased out of abortive treatment: it can interact pharmacologically, and it can enhance its effectiveness. While there has been limited progress in pharmacotherapeutic breakthroughs in the last two decades since the advent of triptans, neurostimulation could take an increasingly hard abortive management.
Compliance with Ethics Guidelines Conflict of Interest Marc E. P. Lenaerts and James R. Couch declare no conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by the author.
References and Recommended Reading Papers of particular interest, published recently, have been highlighted as: •• Of major importance 1.••
Loder E. Triptan therapy in migraine. N Engl J Med. 2010;363:63–70. Class I, Excellent review and reference in the field. 2. Evans RW, Tepper SJ, Shapiro RE, Sun-Edelstein C, Tietjen GE. The FDA alert on serotonin syndrome with use of triptans combined with selective serotonin reuptake inhibitors or selective serotonin-norepinephrine reuptake inhibitors: American headache society position paper. Headache. 2010;50:1089–99. Class III. 3. Blumenfeld A, Gennings C, Cady R. Pharmacological synergy: the next frontier on therapeutic advancement for migraine. Headache. 2012;52:636–47. Class IV. 4. Newman LC. Why triptan treatment can fail: focus on gastrointestinal manifestations of migraine. Headache. 2013;53:S11–6. Class IV.
5. 6. 7.
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Goldstein J, Smith TR, Pugash N, et al. A Sumatriptan iontophoretic transdermal system for the acute treatment of migraine. Headache. 2012;52:1402–10. Class I. Raskin NH. Repetitive intravenous dihydroergotamine as therapy for intractable migraine. Neurology. 1986;36:995–7. Class III. Callaham M, Raskin N. A controlled study of dihydroergotamine in the treatment of acute migraine headache. Headache. 1986;26:168–71. Class I. Saadah H. Abortive headache therapy with intramuscular dihydroergotamine. Headache. 1992;32:18–20. Class III. Weisz MA1, el-Raheb M, Blumenthal HJ. Home administration of intramuscular DHE for the treatment of acute migraine headache. Headache. 1994;34:371–3. Class II.
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Page 7 of 7 27 treatment of migraine. Headache. 2001;41(4):391–8. Class I. 24.•• Marmura MJ, Silberstein SD, Schwedt TJ. The acute treatment of migraine in adults: the American Headache Society evidence assessment of migraine pharmacotherapies. Headache. 2015;55(1):3–20. Class I, A critical appraisal of current headache care practice in the US. 25. Choi H, Parmar N. The use of intravenous magnesium sulphate for acute migraine: meta-analysis of randomized controlled trials. Eur J Emerg Med. 2014;21(1):2–9. Class I. 26. Edwards KR, Norton J, Behnke M. Comparison of intravenous valproate versus intramuscular dihydroergotamine and metoclopramide for acute treatment of migraine headache. Headache. 2001;41(10):976–80. Class II. 27. Mathew NT, Kailasam J, Meadors L, Chernyschev O, Gentry P. Intravenous valproate sodium (depacon) aborts migraine rapidly: a preliminary report. Headache. 2000;40(9):720–3. Class II. 28. Starling AJ, Dodick DW, Chiacchierini RP (2011) Comparison of effect size between active and placebo for single pulse transcranial magnetic stimulation (spTMS) versus triptans for the acute treatment of migraine. Poster, AAN Proceedings, Honolulu, USA, Class III 29. Bhola R, Kinsella E, Goadsby PJ (2013) Update of the UK post market pilot programme with single pulse transcranial magnetic stimulation (sTMS) for acute treatment of migraine: SpringTMS use in migraine. Poster, International Headache Congress, Boston, USA, Class III 30. Schoenen J, Vandersmissen B, Jeangette S, Herroelen L, Vandenheede M, Gerard P, et al. Migraine prevention with a supraorbital transcutaneous stimulator: a randomized controlled trial. Neurology. 2013;80(8):697– 704. Class I. 31. Magis D, Sava S, d’Elia Sasso T, Baschi R, Schoenen J. Safety and patients’ satisfaction of transcutaneous supraorbital neurostimulation (tSNS) with the Cefaly® device in headache treatment: a survey of 2,313 headache sufferers in the general population. J Headache Pain. 2013;14:95. Class II. 32. Lenaerts ME, Oommen KJ, Couch JR, Skaggs V. Can vagus nerve stimulation help migraine? Cephalalgia. 2008;28:392–5. Class III. 33. Goadsby PJ, Grosberg BM, Mauskop A, Cady R, Simmons KA. Effect of non-invasive vagus nerve stimulation on acute migraine: an open-label pilot study. Cephalalgia. 2014;34:986–93. Class III. 34. Cady R, Saper J, Dexter K, Manley HR. A double-blind, placebo-controlled study of repetitive transnasal spheno-palatine ganglion blockade with tx360 as acute treatment for chronic migraine. Headache. 2015;55(1):101–16. Class I.
