ISSN 0017-8748 doi: 10.1111/head.12275 Published by Wiley Periodicals, Inc.
Headache © 2013 American Headache Society
Expert Opinion Daily Triptan Use for Intractable Migraine Egilius L.H. Spierings, MD, PhD
INTRODUCTION Daily headache affects an estimated 3-6% of the general population and affects women 2-3 times more frequently than men.1 The vast majority of daily headache is non-paroxysmal, which is also referred to as chronic daily headache, subdivided into chronic tension-type headache and chronic migraine. In the general population, the distribution of chronic tension-type headache and chronic migraine is fairly equal, but in medical practice chronic migraine accounts for the vast majority of patients with chronic daily headache. The first step in the management of chronic daily headache, whether it concerns chronic tension-type headache or chronic migraine, is to identify the potential overuse of analgesic and/or vasoconstrictor medications. Once medication overuse, if present, is dealt with, preventive treatment is initiated with medications and/or non-pharmacological strategies. Chronic migraine patients who are refractory to or do not tolerate those treatments, however, may end up taking a triptan frequently, if not daily. This is illustrated by the following case history, which in turn is followed by questions regarding the safety of daily or almost-daily triptan use in the context of medication-overuse headache and cardiovascular
safety concerns. These issues will be addressed in this expert opinion article. Daily triptan use for chronic migraine is probably not all that rare. A retrospective audit was carried out in 9 general-medicine practices in the United Kingdom and Ireland,2 examining all patients 18 years and older who had a recorded diagnosis of migraine and had been prescribed a triptan during a 1-year period. A total of 77,715 patients were registered with the 9 participating practices, of whom 3672 (4.7%) had a recorded diagnosis of migraine and 360 met the audit inclusion criteria. Of these 360 patients, 7.4% had received prescriptions for at least 150 tablets during the year of the audit, which, if 1 tablet is taken daily, means an average triptan use of every other day at a minimum. A French, population-based, observational study of a regional health care insurance database covering medication use of 5.3 million people, that is, 8% of the population, revealed that over a period of 18 months, 0.04% of the population or 2.4% of all triptan users obtained 60 daily triptan doses per 3 months, averaging a daily triptan dose every 11/2 day.3 If the British and French data presented above can be generalized, they suggest that roughly 5% of all triptan-using migraineurs take a triptan, on average, at least 15 days per month, this is, for abortive treatment of chronic migraine. Clinical History.—This 50-year-old woman has a history of migraine without aura since her teens. The headaches gradually increased in frequency over time and have been daily or almost daily for the last 5 years.
From Craniofacial Pain Center, Tufts University School of Dental Medicine; Headache & Face Pain Program, Department of Neurology, Tufts Medical Center; Department of Neurology, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USA. Address all correspondence to E.L.H. Spierings, MD, PhD, Craniofacial Pain Center, Tufts University School of Dental Medicine, One Kneeland Street, Boston, MA 02111, USA.
Case history by: Randolph W. Evans, MD, Department of Neurology, Baylor College of Medicine, 1200 Binz #1370, Houston, TX 77004, USA. Email: [email protected]
Accepted for publication October 24, 2013.
155
156 She tried multiple preventive medications, including topiramate, amitriptyline, propranolol, onabotulinumtoxinA, divalproex sodium, gabapentin, zonisamide, and memantine, either alone or in combination, without benefit or side effects. She also had a 5-day inpatient course of intravenous dihydroergotamine with only temporary improvement; bilateral greater occipital, auriculotemporal, and supraorbital nerve blocks neither provided relief. She takes sumatriptan 100 mg once daily, occasionally twice, with relief of the headaches within 2 hours. Once or twice per month, the headaches last all day, and diclofenac powder either decreases the intensity of the pain or relieves the pain altogether. She was off sumatriptan for 2 weeks without improvement of the headaches. She has hypertension, which is well controlled on lisinopril. A nuclear cardiac stress test was normal. She does not drink caffeinated beverages. Questions.—Is there evidence to support the use of daily triptans for chronic, refractory, or intractable migraine? How might you distinguish triptan-overuse headache from chronic migraine? What are the indications for daily or near-daily triptan use? Is there long-term safety information? How does the longterm use of daily triptans compare with chronic opioids or butalbital combinations for intractable migraine? Expert Opinions.—Daily Triptan Use vs Opioid or Butalbital Combinations.—I will start off with the last question comparing daily triptan use with daily use of an opioid or butalbital combination for the treatment of intractable migraine because I happen to have conducted research on the daily triptan vs daily opioid comparison. The butalbital combinations also contain caffeine, and I will address their daily use vs daily triptan use when addressing the question about distinguishing triptan-overuse headache from chronic migraine. The research on the daily triptan vs daily opioid comparison I carried out in my headache practice with the help of Kamila Piekos, PharmD.1 Dr. Piekos contacted by telephone patients who had daily headaches from chronic migraine and were taking a triptan or (long-acting) opioid daily. Daily triptan use was operationally defined as treatment with a triptan for headache at least 5 days per week. The patients had to have been stable on their (triptan or opioid)
January 2014 headache treatment for at least 4 weeks prior to the interview. Ineligible patients were those who were taking a (long-acting) opioid in addition to a triptan daily, which excluded 3 patients. Two patients in the daily triptan group could not be reached and were consequently also excluded from the study. Information was collected using the Migraine Treatment Satisfaction Questionnaire,4 Headache Impact Test-6,5 and a series of additional questions, which included a numerical, 11-point headache pain intensity score. The patients were informed of the purpose of the interview and provided their consent verbally. One patient in each group chose not to participate; these 2 patients were assigned the lowest possible response scores. Statistical significance was assessed using the chi-square test; a P value of .05 or less was considered statistically significant. A total of 53 patients were included in the study, consisting of 28 patients (53%) in the opioid group and 25 patients (47%) in the triptan group (Table 1). The average age of the patients in the opioid and triptan groups were 48.7 ± 7.2 (standard deviation [SD]) years and 55.1 ± 9.6 years, respectively, with similar age ranges. The majority of patients in both groups were women, who comprised 68% of the opioid group and 88% of the triptan group.The scores for the Migraine Treatment Satisfaction Questionnaire and Headache Impact Test-6 are listed in Tables 2 and 3, respectively; the results for the supplemental questions are presented in Table 4. In the Migraine Treatment Satisfaction Questionnaire (Table 2), the only question that reached statistical significance refers to the effect of medication on migraine symptoms. Based on the scoring rubric with a lower score being more favorable, the scores of 2.0 ± 0.2 (standard error of the mean [SEM]) for the triptan group and 2.8 ± 0.2 for the opioid group suggest that triptans relieve migraine symptoms more effectively than opioids (P = .05). The triptans were specifically developed to provide acute migraine relief, targeting migraine mechanisms, whereas the opioids target pain in general. It is, therefore, to be expected that triptans outperform opioids in relieving migraine symptoms. According to the scoring rubric for the Headache Impact Test-6 (Table 3), lower scores indicate a
Headache
157
Table 1.—Characteristics of the Long-Acting Opioid and Daily Triptan Groups (Reproduced From Reference 1)
Opioid Group (n = 28)
Age (years) Mean ± standard deviation Range Gender Men Women Average headache duration (years) Average daily-headache duration (years) Average treatment duration (years) Opioids Oxycodone CR Morphine CR Fentanyl transdermal [morphine ER (Kadian®)] Morphine ER (Avinza®) Triptans Sumatriptan Zolmitriptan Rizatriptan Eletriptan Almotriptan Naratriptan Frovatriptan
Triptan Group (n = 25)
48.7 ± 7.2 35–65
55.1 ± 9.6 32–72
9 (32%) 19 (68%) 26.1 13.4 3.0
3 (12%) 22 (88%) 34.7 17.8 8.4
5 (18%) 2 (7%) 16 (46%) [6 (21%)] 2 (7%)
— — — —
— — — — — — —
11 (48%) 6 (22%) 3 (11%) 1 (4%) 3 (11%) 1 (4%) 0 (0%)
CR = controlled release; ER = extended release.
Table 2.—Results of the Migraine Treatment Satisfaction Questionnaire (Mean ± SEM) (Reproduced From Reference 1)
Migraine Treatment Satisfaction Questions†
Opioid Group
Triptan Group
P value‡
Scoring Rubric
2.7 ± 0.2 2.8 ± 0.2 3.0 ± 0.2
2.0 ± 0.2 2.0 ± 0.2 2.8 ± 0.3
.20 .05 .41
1→5: Excellent→Poor 1→5: Completely gone→Much worse 1→6: Extremely pleased→Extremely displeased 1→4: Not at all→A lot 1→5: Strongly agree→Strongly disagree 1→5: Strongly agree→Strongly disagree 1→5: Strongly agree→Strongly disagree 1→5: Strongly agree→Strongly disagree
Ability of medication to improve migraine symptoms Effect of medication on migraine symptoms Pleased with how quickly migraine symptoms improve How much patient benefits from medication Migraine symptoms are much better than before Benefits of medication outweigh side effects Medication works well to control migraine symptoms Patient loses a lot of time in daily activities due to migraine Pleased with medication convenience
3.4 ± 0.2 2.3 ± 0.1 1.7 ± 0.2 1.9 ± 0.3 2.2 ± 0.3
3.6 ± 0.2 2.5 ± 0.3 1.2 ± 0.2 1.6 ± 0.2 2.8 ± 0.3
.70 .96 .18 .72 .73
2.1 ± 0.2
2.4 ± 0.3
.19
Willingness to continue medication in the future Would recommend medication to family/friend
2.0 ± 0.2 1.8 ± 0.2
1.4 ± 0.2 1.2 ± 0.2
.32 .17
Overall satisfaction with current medication
2.1 ± 0.3
1.8 ± 0.2
.71
†Covering the past 4 weeks; ‡chi-square test. SEM = standard error of the mean.
1→6: Extremely pleased→Extremely displeased 1→4: Extremely willing→Not willing 1→5: Definitely recommend→Definitely not 1→6: Extremely satisfied→Extremely dissatisfied
158
January 2014 Table 3.—Results of the Headache Impact Test-6 (Mean ± SEM) (Reproduced From Reference 1)
Headache Impact Questions†‡
How often headache pain is severe How often headache limits usual daily activities How often patient wishes to lie down during headache How often patient felt too tired to do work/daily activities How often patient felt fed up or irritated because of headache How often headache limits ability to concentrate on work
Opioid Group
Triptan Group
P Value§
3.8 ± 0.2 3.6 ± 0.2 3.9 ± 0.2 3.2 ± 0.2 3.0 ± 0.3 3.3 ± 0.2
3.6 ± 0.2 3.0 ± 0.2 3.7 ± 0.2 2.9 ± 0.2 3.5 ± 0.2 3.3 ± 0.2
.87 .08 .44 .80 .35 .99
†Covering the past 4 weeks. ‡Scoring rubric = 1→5: never→always. §Chi-square test. SEM = standard error of the mean.
favorable impact. For the question pertaining to whether headaches often limit usual, daily activities (question 2), the opioids produced a score of 3.6 ± 0.2 (SEM) while the triptans produced a score of 3.0 ± 0.2. The difference almost reached the level of statistical significance (P = .08), suggesting again that triptans outperform opioids for migraine relief. The average headache pain intensity in the opioid group (5.1 ± 2.0 [SD]) was also higher than in the triptan group (3.0 ± 2.0). Although the difference is not statistically significant (P = .16), it again suggests that triptans provide more profound pain relief than opioids. The supplemental questions also reveal that more patients in the opioid group (36%) experienced a decline in efficacy than those in the triptan group (20%). A possible explanation for this observation is
the development of tolerance that is characteristic of opioid analgesics. As a result, 36% of patients in the opioid group had increased the dose of the medication since initiating treatment, compared with 28% of those in the triptan group. The scores on the Migraine Treatment Satisfaction Questionnaire were low overall for both groups,suggesting that the patients in both groups were generally pleased with their treatment. One question produced relatively high scores (question 4), but this question’s scoring rubric is reversed,with a score of 4 being the most favorable.The scores on the Headache Impact Test-6 are consistently higher than the scoring rubric mean of 2.5, suggesting that despite being relatively pleased with the treatment,chronic migraine patients clearly continued to experience the impact of their headaches.
Table 4.—Results of the Supplemental Questions (Reproduced From Reference 1)
Change in Efficacy Opioid group Triptan group
No Change 15 (54%) 20 (80%)
Better 3 (11%) 0 (0%)
Worse 10 (36%) 5 (20%)
Change in dose Opioid group Triptan group
No change 14 (50%) 16 (64%)
Increased 10 (36%) 7 (28%)
Decreased 4 (14%) 2 (8%)
Opioid group (mean ± SD) 5.1 ± 2.0
Triptan group (mean ± SD) 3.0 ± 2.0
P value‡ .16
Question† On a scale of 1-10, with 10 as worst: How does patient rate average headache intensity (with medication)? †Covering the past 4 weeks. ‡Chi-square test. SD = standard deviation.
Headache Long-Term Safety.—The long-term safety aspect of daily triptan use was examined in 2 studies by Robbins and Maides.6,7 The first study concerned a retrospective evaluation of 59 patients who had used a triptan, that is, sumatriptan or naratriptan, on a daily basis for a minimum of 6 months. In the second study, they revisited the safety aspect of frequent triptan use with a retrospective study of 118 patients, 27 men and 91 women, age 27-73 years (mean: 52 years). The study probably included all or most of the patients from the first study.The patients were not deliberately placed on a daily triptan but rather discovered, on their own, that the triptan was highly effective for their daily headaches. Attempts by the physician to limit triptan use failed because the patients reported significant improvement on their quality of life, usually after years of suffering. These patients were not suffering from rebound (medication-overuse) headache as a result of triptan use. All of the patients had chronic daily headache, either chronic tensiontype headache or transformed (chronic) migraine, with the exception of 4 patients who had chronic cluster headache. Each patient in the first study,6 as evaluated by interview and visual analog scale, felt that the triptan improved the intensity and/or frequency of the headaches by at least 50%. Tolerance was noted in 15 patients (25%). Four patients became tolerant to sumatriptan 50 mg and subsequently increased the dose. Another 8 patients stated that they had become somewhat tolerant, with less effect from the same dose over time, but did not increase the amount of sumatriptan. In addition, due to tolerance, 3 patients were switched to naratriptan or had naratriptan added on alternate days. In terms of side effects, 7 patients felt that fatigue was related to the triptans, while 3 patients experienced paresthesias for 20-60 minutes post-dosing. Three patients experienced mild chest or throat pressure/discomfort for 20-100 minutes post-dose. There were no cases of new-onset cardiac problems during the course of the treatment, which was longer than 1 year for 36 of the patients (61%). Of the 118 patients in the second study,7 90 (76%) used a triptan every day while 28 patients averaged a triptan 4 or 5 days per week; most (82%) took 1 tablet
159 daily while the others took 0.5 tablet per day or 2 tablets per day. One third of the patients had taken a triptan for 6 months to 2 years, and the remaining two-thirds had taken a triptan for longer than 2 years, with 35% of the patients taking a triptan daily for 4 or more years. The patients were carefully screened for the presence of rebound, and if the history was possibly consistent with rebound headache, the patient was withdrawn from the triptan. All patients were withdrawn from the triptan for a period of time to help exclude the possibility of rebound (medicationoveruse) headache. A total of 103 patients (87%) had electrocardiograms performed after a minimum of 6 months of daily triptan use, of which 95 (80%) were considered normal by the cardiologist. The following abnormal electrocardiogram findings were apparent in 8 patients: atrial fibrillation (1), tachycardia (2), bradycardia (1), inverted T waves (1), non-specific ST–T wave changes (2), and rare premature atrial contractions (1). Fifty-seven patients (48%) underwent echocardiography with Doppler flow studies a minimum of 9 months after the onset of daily triptan use. The echocardiogram was abnormal in 10 patients (18%), but none of the abnormalities were considered related to the use of triptans. Of these patients, 6 (10%) had mitral valve prolapse; the other abnormalities were mitral regurgitation, enlarged aorta, mild right ventricular enlargement, and aortic regurgitation, each occurring in 1 patient. Twenty patients (17%) had cardiac stress tests performed for various reasons, unrelated to the triptan usage, and all were normal. One patient had a cardiac catheterization, which was also normal. By comparison, there are a number of serious safety concerns with daily or almost daily use of opioids, opioid combinations,8 or butalbital combinations.9 In addition, the combinations may contain acetaminophen, which is the leading cause of death from over-the-counter medications, and over a period of a decade resulted in 1567 deaths from liver failure due to accidental overdoses.10 Indications for Daily for Near-Daily Triptan Use.—With regard to the indications for daily or neardaily triptan use, it is not an established treatment and, therefore, there are no specific indications. In addition, as Robbins and Maides6 observed and what
160 confirms my own experience, patients are not deliberately placed on daily triptan but rather discover, on their own, that the triptan is highly effective for the treatment of their daily headaches. Under those circumstances, it is hard to argue against the daily or almost-daily use of triptans, particularly if there are no indications of medication-overuse headache or safety concerns. The safety issue is addressed above, and that of medication-overuse headache still needs to be addressed. Specifically related to triptans, medicationoveruse headache is defined by the International Headache Society as triptan use on 10 or more days per month for more than 3 months.11 Of course, this definition is too simplistic to be true, is entirely arbitrary, and lacks appreciation of the complexity of what medication-overuse headache is all about. As I recently wrote in an opinion article in Headache,12 the consideration of the clinical picture seems to have disappeared from the scene, not only for the diagnosis of medication-overuse headache but also, for example, for that of hemicrania continua, a condition I described with Ottar Sjaastad in 1984.13 In medication-overuse headache, the clinical picture is that of the patient suffering from daily or almostdaily headaches, often tremendously, despite excessive use of abortive medications, a paradox that patients and physicians alike often still have a hard time comprehending. In contrast, the clinical picture of hemicrania continua is that of the patient with daily and continuous headache, unilateral and sidelocked, who manages the headache quite well with daily use of non-steroidal anti-inflammatory drugs (NSAIDs) abortively, essentially the opposite of what you see with medication-overuse headache. It was this glaring difference in clinical presentation that prompted me to prescribe indomethacin preventively to my patient with hemicrania continua, as opposed to considering him as having medicationoveruse headache and discontinuing his use of aspirin, which he took abortively on a daily basis, several times per day. Medication Overuse.—Medication overuse represents the intake of analgesic and/or vasoconstrictor medications at a frequency that is detrimental rather than beneficial to the headache condition. Their
January 2014 intake may provide some temporary headache relief short term, but in the long run promotes the occurrence of headaches. The mechanisms involved include neglect of underlying headache pathophysiology and creation of a vascular rebound cycle, respectively. The latter occurs with the use of vasoconstrictor medications at intervals that allow them to accumulate in the system, causing rebound vasodilation and headache whenever their effects wear off. Medication overuse is a common accompaniment of chronic daily headache, simply because of the frequency of headache occurrence. The vasoconstrictor agent most commonly involved in medication-overuse headache is caffeine, either in caffeinated beverages or in combination products, such as the butalbital combinations. It is often not realized that caffeine’s plasma elimination is quite variable, and its half-life can be as long as 10 hours.14 It takes up to 5 times the half-life for a medication to be eliminated from the system, which for caffeine means potentially up to 50 hours or a little over 2 days. In order to avoid accumulation in the system and, hence, rebound or medication-overuse headache, caffeine should not be taken for headache more often than 2 or 3 times per week. This precludes the use of caffeine-containing medications, such as the butalbital combinations, for the treatment of chronic migraine with its occurrence of headache on a daily or almost daily basis. Interestingly, a study of 116 episodic migraineurs with regular caffeine intake found that complete cessation of caffeine intake produced a greater than 50% reduction in headache frequency, compared with 9.9% who reduced intake by 50% or more and 0% in those who made no change in their caffeine intake (P < .001).15 In the studies reviewed above conducted by Robbins,7 Robbins and Maides,6 and Piekos and Spierings,1 and as mentioned, the patients were not deliberately placed on daily triptan but rather discovered, on their own, that the triptan is highly effective for the treatment of their daily headaches. However, in a recently published study, patients with chronic migraine were treated with the combination of 85 mg sumatriptan and 500 mg naproxen sodium daily for headache prevention or with 500 mg naproxen sodium alone in a randomized, double-blinded,
Headache parallel-group, comparative, pilot trial.16 They were treated with these preventive regimens for 1 month, after which they were instructed to use the medications abortively only for the subsequent 2 months, up to 14 days per month. In total, 28 patients were randomized, 16 to the sumatriptan/naproxen treatment, and 12 to the naproxen treatment. Already 8 of the 28 patients (29%) discontinued treatment during the first month of the study, 3 in the sumatriptan/ naproxen group (19%), and 7 in the naproxen group (58%), leaving only 15 and 5 patients, respectively, in the groups. Unfortunately, especially considering the extent of the dropouts, the efficacy analysis of the study was not conducted on the intent-to-treat population but on the completer population, greatly invalidating the results obtained. Although most of the dropouts in naproxen group, that is, 5 of 7, dropped out because of lack of efficacy, the reported results claim a high degree of efficacy in that group, with a reduction in migraine headache days per month from 16.4 ± 1.9 (SD) at baseline to 6.2 ± 4.0 in month 1, a highly statistically significant change (P = .0074). The comparable change in the sumatriptan/naproxen group was from 18.9 ± 5.1 days at baseline to 14.4 ± 7.9 days in month 1, a much smaller change that was nevertheless statistically significant (P = .0112). It is difficult to interpret the results, especially when it comes to the efficacy reported for the naproxen group, considering that the analyzed group only consisted of 5 patients and the same number discontinued treatment because of lack of efficacy. Regarding the sumatriptan/naproxen group, although the change in migraine headache days per month from baseline was statistically significant during the month of daily, preventive use, numerically it was not impressive and amounted to no more than roughly a quarter. It certainly does not suggest that regular preventive use of a triptan in chronic migraine is particularly effective, and the difference with the patients in the studies conducted by Robbins,7 Robbins and Maides,6 and Piekos and Spierings1 is that they were using the triptan daily or almost daily abortively and not preventively. NSAIDs have been shown in randomized, double-blinded, placebocontrolled studies to be effective in the preventive
161 treatment of episodic migraine, and the quality of the study reviewed above is not such that this claim can be extended to chronic migraine prevention. In a large, 5-year, longitudinal, population-based study, referred to as the American Migraine Prevalence and Prevention (AMPP), it was found that triptan use in episodic migraine is associated with an increased risk of the development of chronic migraine that increases with days of medication use.17 Interestingly, the combined use of a triptan and an NSAID was not associated with a statistically significant increase in the risk of chronic migraine development. In addition, the daily or almost-daily, long-term use of NSAIDs is generally not well tolerated from a gastrointestinal perspective, not necessarily limited to the stomach because it also seems to be a risk factor for inflammatory bowel disease, but also seems to have its impact on the cardiovascular system, from coronary events to heart failure. In a meta-analysis, although all NSAIDs increase the risk of heart failure and upper gastrointestinal complications, high-dose naproxen is apparently associated with less vascular risk than other NSAIDs.18
REFERENCES 1. Piekos K, Spierings ELH. Management of daily headache unresponsive to preventive treatment: Daily triptans versus daily opioids. Rev Neurol Dis. 2009;6:E121-E130. 2. Williams D, Cahill T, Dowson A, et al. Usage of triptans among migraine patients: An audit of nine GP practices. Curr Med Res Opin. 2002;18:1-9. 3. Donnet A, Braunstein D, Micallef J, et al. Triptan use and overuse in the French general population: A regional pharmaco-epidemiology database analysis in 5.3 million people. Cephalalgia. 2013;33(Suppl. 8):127-128 (abstract). 4. Atkinson MJ, Sinha A, Hass SL, et al. Validation of a general measure of treatment satisfaction, the treatment satisfaction questionnaire for medication (TSQM), using a national panel study of chronic disease. Health Qual Life Outcomes. 2004;2:1-12. 5. Kosinski M, Bayliss MS, Bjorner JB, et al. A six-item short-form survey of measuring headache impact: The HIT-6. Qual Life Res. 2003;12:963-974. 6. Robbins R, Maides JF. Long-term daily triptan use: 59 patients. Headache Quarterly. 2000;11:127-131.
162 7. Robbins L. Frequent triptan use: Observations on safety issues. Headache. 2004;44:178-182. 8. Saper JR, Lake AE, Bain PA, et al. A practice guide for continuous opioid therapy for refractory daily headache: Patient selection, physician requirements, and treatment monitoring. Headache. 2010;50:11751193. 9. Evans RW, Baskin SM. Why do migraineurs abuse butalbital-containing combination analgesics? Headache. 2010;50:1194-1197. 10. Gerth J, Miller TC. Use only as directed. 2013. Available at: http://www.propublica.org/article/tylenolmcneil-fda-use-only-as-directed. (accessed October 5, 2013). 11. Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders. Cephalalgia. 2013; 33:629-808. 12. Spierings ELH. Hemicrania continua should NOT be classified as a trigeminal autonomic cephalalgia. Headache. 2013;53:869-870. 13. Sjaastad O, Spierings ELH. “Hemicrania continua”: Another headache absolutely responsive to indomethacin. Cephalalgia. 1984;4:65-70.
January 2014 14. Magkos F, Kavouras SA. Caffeine use in sports, pharmacokinetics in man, and cellular mechanisms of action. Crit Rev Food Sci Nutr. 2005;45:535562. 15. Lee C-B, Chung C-S. Role of caffeine cessation in migraine management. Cephalalgia. 2013;33(Suppl. 8):248-249. 16. Cady R, Nett R, Dexter K, Freitag F, Beach ME, Manley HR. Treatment of chronic migraine: A 3-month comparator study of naproxen sodium vs sumaRT/Nap. Headache. 2013; doi: 10.1111/ head.12210. Epub ahead of print. 17. Lipton RB, Serrano D, Nicholson RA, Buse DC, Runken MC, Reed ML. Impact of NSAID and triptan use on developing chronic migraine: Results from the American Migraine Prevalence and Prevention (AMPP) study. Headache. 2013; doi: 10.1111/head.12201. Epub ahead of print. 18. Coxib and Traditional NSAID Trialists’ (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: Meta-analyses of individual participant data from randomised trials. Lancet. 2013;382:769-779.
Headache © 2013 American Headache Society
Expert Opinion Daily Triptan Use for Intractable Migraine Egilius L.H. Spierings, MD, PhD
INTRODUCTION Daily headache affects an estimated 3-6% of the general population and affects women 2-3 times more frequently than men.1 The vast majority of daily headache is non-paroxysmal, which is also referred to as chronic daily headache, subdivided into chronic tension-type headache and chronic migraine. In the general population, the distribution of chronic tension-type headache and chronic migraine is fairly equal, but in medical practice chronic migraine accounts for the vast majority of patients with chronic daily headache. The first step in the management of chronic daily headache, whether it concerns chronic tension-type headache or chronic migraine, is to identify the potential overuse of analgesic and/or vasoconstrictor medications. Once medication overuse, if present, is dealt with, preventive treatment is initiated with medications and/or non-pharmacological strategies. Chronic migraine patients who are refractory to or do not tolerate those treatments, however, may end up taking a triptan frequently, if not daily. This is illustrated by the following case history, which in turn is followed by questions regarding the safety of daily or almost-daily triptan use in the context of medication-overuse headache and cardiovascular
safety concerns. These issues will be addressed in this expert opinion article. Daily triptan use for chronic migraine is probably not all that rare. A retrospective audit was carried out in 9 general-medicine practices in the United Kingdom and Ireland,2 examining all patients 18 years and older who had a recorded diagnosis of migraine and had been prescribed a triptan during a 1-year period. A total of 77,715 patients were registered with the 9 participating practices, of whom 3672 (4.7%) had a recorded diagnosis of migraine and 360 met the audit inclusion criteria. Of these 360 patients, 7.4% had received prescriptions for at least 150 tablets during the year of the audit, which, if 1 tablet is taken daily, means an average triptan use of every other day at a minimum. A French, population-based, observational study of a regional health care insurance database covering medication use of 5.3 million people, that is, 8% of the population, revealed that over a period of 18 months, 0.04% of the population or 2.4% of all triptan users obtained 60 daily triptan doses per 3 months, averaging a daily triptan dose every 11/2 day.3 If the British and French data presented above can be generalized, they suggest that roughly 5% of all triptan-using migraineurs take a triptan, on average, at least 15 days per month, this is, for abortive treatment of chronic migraine. Clinical History.—This 50-year-old woman has a history of migraine without aura since her teens. The headaches gradually increased in frequency over time and have been daily or almost daily for the last 5 years.
From Craniofacial Pain Center, Tufts University School of Dental Medicine; Headache & Face Pain Program, Department of Neurology, Tufts Medical Center; Department of Neurology, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USA. Address all correspondence to E.L.H. Spierings, MD, PhD, Craniofacial Pain Center, Tufts University School of Dental Medicine, One Kneeland Street, Boston, MA 02111, USA.
Case history by: Randolph W. Evans, MD, Department of Neurology, Baylor College of Medicine, 1200 Binz #1370, Houston, TX 77004, USA. Email: [email protected]
Accepted for publication October 24, 2013.
155
156 She tried multiple preventive medications, including topiramate, amitriptyline, propranolol, onabotulinumtoxinA, divalproex sodium, gabapentin, zonisamide, and memantine, either alone or in combination, without benefit or side effects. She also had a 5-day inpatient course of intravenous dihydroergotamine with only temporary improvement; bilateral greater occipital, auriculotemporal, and supraorbital nerve blocks neither provided relief. She takes sumatriptan 100 mg once daily, occasionally twice, with relief of the headaches within 2 hours. Once or twice per month, the headaches last all day, and diclofenac powder either decreases the intensity of the pain or relieves the pain altogether. She was off sumatriptan for 2 weeks without improvement of the headaches. She has hypertension, which is well controlled on lisinopril. A nuclear cardiac stress test was normal. She does not drink caffeinated beverages. Questions.—Is there evidence to support the use of daily triptans for chronic, refractory, or intractable migraine? How might you distinguish triptan-overuse headache from chronic migraine? What are the indications for daily or near-daily triptan use? Is there long-term safety information? How does the longterm use of daily triptans compare with chronic opioids or butalbital combinations for intractable migraine? Expert Opinions.—Daily Triptan Use vs Opioid or Butalbital Combinations.—I will start off with the last question comparing daily triptan use with daily use of an opioid or butalbital combination for the treatment of intractable migraine because I happen to have conducted research on the daily triptan vs daily opioid comparison. The butalbital combinations also contain caffeine, and I will address their daily use vs daily triptan use when addressing the question about distinguishing triptan-overuse headache from chronic migraine. The research on the daily triptan vs daily opioid comparison I carried out in my headache practice with the help of Kamila Piekos, PharmD.1 Dr. Piekos contacted by telephone patients who had daily headaches from chronic migraine and were taking a triptan or (long-acting) opioid daily. Daily triptan use was operationally defined as treatment with a triptan for headache at least 5 days per week. The patients had to have been stable on their (triptan or opioid)
January 2014 headache treatment for at least 4 weeks prior to the interview. Ineligible patients were those who were taking a (long-acting) opioid in addition to a triptan daily, which excluded 3 patients. Two patients in the daily triptan group could not be reached and were consequently also excluded from the study. Information was collected using the Migraine Treatment Satisfaction Questionnaire,4 Headache Impact Test-6,5 and a series of additional questions, which included a numerical, 11-point headache pain intensity score. The patients were informed of the purpose of the interview and provided their consent verbally. One patient in each group chose not to participate; these 2 patients were assigned the lowest possible response scores. Statistical significance was assessed using the chi-square test; a P value of .05 or less was considered statistically significant. A total of 53 patients were included in the study, consisting of 28 patients (53%) in the opioid group and 25 patients (47%) in the triptan group (Table 1). The average age of the patients in the opioid and triptan groups were 48.7 ± 7.2 (standard deviation [SD]) years and 55.1 ± 9.6 years, respectively, with similar age ranges. The majority of patients in both groups were women, who comprised 68% of the opioid group and 88% of the triptan group.The scores for the Migraine Treatment Satisfaction Questionnaire and Headache Impact Test-6 are listed in Tables 2 and 3, respectively; the results for the supplemental questions are presented in Table 4. In the Migraine Treatment Satisfaction Questionnaire (Table 2), the only question that reached statistical significance refers to the effect of medication on migraine symptoms. Based on the scoring rubric with a lower score being more favorable, the scores of 2.0 ± 0.2 (standard error of the mean [SEM]) for the triptan group and 2.8 ± 0.2 for the opioid group suggest that triptans relieve migraine symptoms more effectively than opioids (P = .05). The triptans were specifically developed to provide acute migraine relief, targeting migraine mechanisms, whereas the opioids target pain in general. It is, therefore, to be expected that triptans outperform opioids in relieving migraine symptoms. According to the scoring rubric for the Headache Impact Test-6 (Table 3), lower scores indicate a
Headache
157
Table 1.—Characteristics of the Long-Acting Opioid and Daily Triptan Groups (Reproduced From Reference 1)
Opioid Group (n = 28)
Age (years) Mean ± standard deviation Range Gender Men Women Average headache duration (years) Average daily-headache duration (years) Average treatment duration (years) Opioids Oxycodone CR Morphine CR Fentanyl transdermal [morphine ER (Kadian®)] Morphine ER (Avinza®) Triptans Sumatriptan Zolmitriptan Rizatriptan Eletriptan Almotriptan Naratriptan Frovatriptan
Triptan Group (n = 25)
48.7 ± 7.2 35–65
55.1 ± 9.6 32–72
9 (32%) 19 (68%) 26.1 13.4 3.0
3 (12%) 22 (88%) 34.7 17.8 8.4
5 (18%) 2 (7%) 16 (46%) [6 (21%)] 2 (7%)
— — — —
— — — — — — —
11 (48%) 6 (22%) 3 (11%) 1 (4%) 3 (11%) 1 (4%) 0 (0%)
CR = controlled release; ER = extended release.
Table 2.—Results of the Migraine Treatment Satisfaction Questionnaire (Mean ± SEM) (Reproduced From Reference 1)
Migraine Treatment Satisfaction Questions†
Opioid Group
Triptan Group
P value‡
Scoring Rubric
2.7 ± 0.2 2.8 ± 0.2 3.0 ± 0.2
2.0 ± 0.2 2.0 ± 0.2 2.8 ± 0.3
.20 .05 .41
1→5: Excellent→Poor 1→5: Completely gone→Much worse 1→6: Extremely pleased→Extremely displeased 1→4: Not at all→A lot 1→5: Strongly agree→Strongly disagree 1→5: Strongly agree→Strongly disagree 1→5: Strongly agree→Strongly disagree 1→5: Strongly agree→Strongly disagree
Ability of medication to improve migraine symptoms Effect of medication on migraine symptoms Pleased with how quickly migraine symptoms improve How much patient benefits from medication Migraine symptoms are much better than before Benefits of medication outweigh side effects Medication works well to control migraine symptoms Patient loses a lot of time in daily activities due to migraine Pleased with medication convenience
3.4 ± 0.2 2.3 ± 0.1 1.7 ± 0.2 1.9 ± 0.3 2.2 ± 0.3
3.6 ± 0.2 2.5 ± 0.3 1.2 ± 0.2 1.6 ± 0.2 2.8 ± 0.3
.70 .96 .18 .72 .73
2.1 ± 0.2
2.4 ± 0.3
.19
Willingness to continue medication in the future Would recommend medication to family/friend
2.0 ± 0.2 1.8 ± 0.2
1.4 ± 0.2 1.2 ± 0.2
.32 .17
Overall satisfaction with current medication
2.1 ± 0.3
1.8 ± 0.2
.71
†Covering the past 4 weeks; ‡chi-square test. SEM = standard error of the mean.
1→6: Extremely pleased→Extremely displeased 1→4: Extremely willing→Not willing 1→5: Definitely recommend→Definitely not 1→6: Extremely satisfied→Extremely dissatisfied
158
January 2014 Table 3.—Results of the Headache Impact Test-6 (Mean ± SEM) (Reproduced From Reference 1)
Headache Impact Questions†‡
How often headache pain is severe How often headache limits usual daily activities How often patient wishes to lie down during headache How often patient felt too tired to do work/daily activities How often patient felt fed up or irritated because of headache How often headache limits ability to concentrate on work
Opioid Group
Triptan Group
P Value§
3.8 ± 0.2 3.6 ± 0.2 3.9 ± 0.2 3.2 ± 0.2 3.0 ± 0.3 3.3 ± 0.2
3.6 ± 0.2 3.0 ± 0.2 3.7 ± 0.2 2.9 ± 0.2 3.5 ± 0.2 3.3 ± 0.2
.87 .08 .44 .80 .35 .99
†Covering the past 4 weeks. ‡Scoring rubric = 1→5: never→always. §Chi-square test. SEM = standard error of the mean.
favorable impact. For the question pertaining to whether headaches often limit usual, daily activities (question 2), the opioids produced a score of 3.6 ± 0.2 (SEM) while the triptans produced a score of 3.0 ± 0.2. The difference almost reached the level of statistical significance (P = .08), suggesting again that triptans outperform opioids for migraine relief. The average headache pain intensity in the opioid group (5.1 ± 2.0 [SD]) was also higher than in the triptan group (3.0 ± 2.0). Although the difference is not statistically significant (P = .16), it again suggests that triptans provide more profound pain relief than opioids. The supplemental questions also reveal that more patients in the opioid group (36%) experienced a decline in efficacy than those in the triptan group (20%). A possible explanation for this observation is
the development of tolerance that is characteristic of opioid analgesics. As a result, 36% of patients in the opioid group had increased the dose of the medication since initiating treatment, compared with 28% of those in the triptan group. The scores on the Migraine Treatment Satisfaction Questionnaire were low overall for both groups,suggesting that the patients in both groups were generally pleased with their treatment. One question produced relatively high scores (question 4), but this question’s scoring rubric is reversed,with a score of 4 being the most favorable.The scores on the Headache Impact Test-6 are consistently higher than the scoring rubric mean of 2.5, suggesting that despite being relatively pleased with the treatment,chronic migraine patients clearly continued to experience the impact of their headaches.
Table 4.—Results of the Supplemental Questions (Reproduced From Reference 1)
Change in Efficacy Opioid group Triptan group
No Change 15 (54%) 20 (80%)
Better 3 (11%) 0 (0%)
Worse 10 (36%) 5 (20%)
Change in dose Opioid group Triptan group
No change 14 (50%) 16 (64%)
Increased 10 (36%) 7 (28%)
Decreased 4 (14%) 2 (8%)
Opioid group (mean ± SD) 5.1 ± 2.0
Triptan group (mean ± SD) 3.0 ± 2.0
P value‡ .16
Question† On a scale of 1-10, with 10 as worst: How does patient rate average headache intensity (with medication)? †Covering the past 4 weeks. ‡Chi-square test. SD = standard deviation.
Headache Long-Term Safety.—The long-term safety aspect of daily triptan use was examined in 2 studies by Robbins and Maides.6,7 The first study concerned a retrospective evaluation of 59 patients who had used a triptan, that is, sumatriptan or naratriptan, on a daily basis for a minimum of 6 months. In the second study, they revisited the safety aspect of frequent triptan use with a retrospective study of 118 patients, 27 men and 91 women, age 27-73 years (mean: 52 years). The study probably included all or most of the patients from the first study.The patients were not deliberately placed on a daily triptan but rather discovered, on their own, that the triptan was highly effective for their daily headaches. Attempts by the physician to limit triptan use failed because the patients reported significant improvement on their quality of life, usually after years of suffering. These patients were not suffering from rebound (medication-overuse) headache as a result of triptan use. All of the patients had chronic daily headache, either chronic tensiontype headache or transformed (chronic) migraine, with the exception of 4 patients who had chronic cluster headache. Each patient in the first study,6 as evaluated by interview and visual analog scale, felt that the triptan improved the intensity and/or frequency of the headaches by at least 50%. Tolerance was noted in 15 patients (25%). Four patients became tolerant to sumatriptan 50 mg and subsequently increased the dose. Another 8 patients stated that they had become somewhat tolerant, with less effect from the same dose over time, but did not increase the amount of sumatriptan. In addition, due to tolerance, 3 patients were switched to naratriptan or had naratriptan added on alternate days. In terms of side effects, 7 patients felt that fatigue was related to the triptans, while 3 patients experienced paresthesias for 20-60 minutes post-dosing. Three patients experienced mild chest or throat pressure/discomfort for 20-100 minutes post-dose. There were no cases of new-onset cardiac problems during the course of the treatment, which was longer than 1 year for 36 of the patients (61%). Of the 118 patients in the second study,7 90 (76%) used a triptan every day while 28 patients averaged a triptan 4 or 5 days per week; most (82%) took 1 tablet
159 daily while the others took 0.5 tablet per day or 2 tablets per day. One third of the patients had taken a triptan for 6 months to 2 years, and the remaining two-thirds had taken a triptan for longer than 2 years, with 35% of the patients taking a triptan daily for 4 or more years. The patients were carefully screened for the presence of rebound, and if the history was possibly consistent with rebound headache, the patient was withdrawn from the triptan. All patients were withdrawn from the triptan for a period of time to help exclude the possibility of rebound (medicationoveruse) headache. A total of 103 patients (87%) had electrocardiograms performed after a minimum of 6 months of daily triptan use, of which 95 (80%) were considered normal by the cardiologist. The following abnormal electrocardiogram findings were apparent in 8 patients: atrial fibrillation (1), tachycardia (2), bradycardia (1), inverted T waves (1), non-specific ST–T wave changes (2), and rare premature atrial contractions (1). Fifty-seven patients (48%) underwent echocardiography with Doppler flow studies a minimum of 9 months after the onset of daily triptan use. The echocardiogram was abnormal in 10 patients (18%), but none of the abnormalities were considered related to the use of triptans. Of these patients, 6 (10%) had mitral valve prolapse; the other abnormalities were mitral regurgitation, enlarged aorta, mild right ventricular enlargement, and aortic regurgitation, each occurring in 1 patient. Twenty patients (17%) had cardiac stress tests performed for various reasons, unrelated to the triptan usage, and all were normal. One patient had a cardiac catheterization, which was also normal. By comparison, there are a number of serious safety concerns with daily or almost daily use of opioids, opioid combinations,8 or butalbital combinations.9 In addition, the combinations may contain acetaminophen, which is the leading cause of death from over-the-counter medications, and over a period of a decade resulted in 1567 deaths from liver failure due to accidental overdoses.10 Indications for Daily for Near-Daily Triptan Use.—With regard to the indications for daily or neardaily triptan use, it is not an established treatment and, therefore, there are no specific indications. In addition, as Robbins and Maides6 observed and what
160 confirms my own experience, patients are not deliberately placed on daily triptan but rather discover, on their own, that the triptan is highly effective for the treatment of their daily headaches. Under those circumstances, it is hard to argue against the daily or almost-daily use of triptans, particularly if there are no indications of medication-overuse headache or safety concerns. The safety issue is addressed above, and that of medication-overuse headache still needs to be addressed. Specifically related to triptans, medicationoveruse headache is defined by the International Headache Society as triptan use on 10 or more days per month for more than 3 months.11 Of course, this definition is too simplistic to be true, is entirely arbitrary, and lacks appreciation of the complexity of what medication-overuse headache is all about. As I recently wrote in an opinion article in Headache,12 the consideration of the clinical picture seems to have disappeared from the scene, not only for the diagnosis of medication-overuse headache but also, for example, for that of hemicrania continua, a condition I described with Ottar Sjaastad in 1984.13 In medication-overuse headache, the clinical picture is that of the patient suffering from daily or almostdaily headaches, often tremendously, despite excessive use of abortive medications, a paradox that patients and physicians alike often still have a hard time comprehending. In contrast, the clinical picture of hemicrania continua is that of the patient with daily and continuous headache, unilateral and sidelocked, who manages the headache quite well with daily use of non-steroidal anti-inflammatory drugs (NSAIDs) abortively, essentially the opposite of what you see with medication-overuse headache. It was this glaring difference in clinical presentation that prompted me to prescribe indomethacin preventively to my patient with hemicrania continua, as opposed to considering him as having medicationoveruse headache and discontinuing his use of aspirin, which he took abortively on a daily basis, several times per day. Medication Overuse.—Medication overuse represents the intake of analgesic and/or vasoconstrictor medications at a frequency that is detrimental rather than beneficial to the headache condition. Their
January 2014 intake may provide some temporary headache relief short term, but in the long run promotes the occurrence of headaches. The mechanisms involved include neglect of underlying headache pathophysiology and creation of a vascular rebound cycle, respectively. The latter occurs with the use of vasoconstrictor medications at intervals that allow them to accumulate in the system, causing rebound vasodilation and headache whenever their effects wear off. Medication overuse is a common accompaniment of chronic daily headache, simply because of the frequency of headache occurrence. The vasoconstrictor agent most commonly involved in medication-overuse headache is caffeine, either in caffeinated beverages or in combination products, such as the butalbital combinations. It is often not realized that caffeine’s plasma elimination is quite variable, and its half-life can be as long as 10 hours.14 It takes up to 5 times the half-life for a medication to be eliminated from the system, which for caffeine means potentially up to 50 hours or a little over 2 days. In order to avoid accumulation in the system and, hence, rebound or medication-overuse headache, caffeine should not be taken for headache more often than 2 or 3 times per week. This precludes the use of caffeine-containing medications, such as the butalbital combinations, for the treatment of chronic migraine with its occurrence of headache on a daily or almost daily basis. Interestingly, a study of 116 episodic migraineurs with regular caffeine intake found that complete cessation of caffeine intake produced a greater than 50% reduction in headache frequency, compared with 9.9% who reduced intake by 50% or more and 0% in those who made no change in their caffeine intake (P < .001).15 In the studies reviewed above conducted by Robbins,7 Robbins and Maides,6 and Piekos and Spierings,1 and as mentioned, the patients were not deliberately placed on daily triptan but rather discovered, on their own, that the triptan is highly effective for the treatment of their daily headaches. However, in a recently published study, patients with chronic migraine were treated with the combination of 85 mg sumatriptan and 500 mg naproxen sodium daily for headache prevention or with 500 mg naproxen sodium alone in a randomized, double-blinded,
Headache parallel-group, comparative, pilot trial.16 They were treated with these preventive regimens for 1 month, after which they were instructed to use the medications abortively only for the subsequent 2 months, up to 14 days per month. In total, 28 patients were randomized, 16 to the sumatriptan/naproxen treatment, and 12 to the naproxen treatment. Already 8 of the 28 patients (29%) discontinued treatment during the first month of the study, 3 in the sumatriptan/ naproxen group (19%), and 7 in the naproxen group (58%), leaving only 15 and 5 patients, respectively, in the groups. Unfortunately, especially considering the extent of the dropouts, the efficacy analysis of the study was not conducted on the intent-to-treat population but on the completer population, greatly invalidating the results obtained. Although most of the dropouts in naproxen group, that is, 5 of 7, dropped out because of lack of efficacy, the reported results claim a high degree of efficacy in that group, with a reduction in migraine headache days per month from 16.4 ± 1.9 (SD) at baseline to 6.2 ± 4.0 in month 1, a highly statistically significant change (P = .0074). The comparable change in the sumatriptan/naproxen group was from 18.9 ± 5.1 days at baseline to 14.4 ± 7.9 days in month 1, a much smaller change that was nevertheless statistically significant (P = .0112). It is difficult to interpret the results, especially when it comes to the efficacy reported for the naproxen group, considering that the analyzed group only consisted of 5 patients and the same number discontinued treatment because of lack of efficacy. Regarding the sumatriptan/naproxen group, although the change in migraine headache days per month from baseline was statistically significant during the month of daily, preventive use, numerically it was not impressive and amounted to no more than roughly a quarter. It certainly does not suggest that regular preventive use of a triptan in chronic migraine is particularly effective, and the difference with the patients in the studies conducted by Robbins,7 Robbins and Maides,6 and Piekos and Spierings1 is that they were using the triptan daily or almost daily abortively and not preventively. NSAIDs have been shown in randomized, double-blinded, placebocontrolled studies to be effective in the preventive
161 treatment of episodic migraine, and the quality of the study reviewed above is not such that this claim can be extended to chronic migraine prevention. In a large, 5-year, longitudinal, population-based study, referred to as the American Migraine Prevalence and Prevention (AMPP), it was found that triptan use in episodic migraine is associated with an increased risk of the development of chronic migraine that increases with days of medication use.17 Interestingly, the combined use of a triptan and an NSAID was not associated with a statistically significant increase in the risk of chronic migraine development. In addition, the daily or almost-daily, long-term use of NSAIDs is generally not well tolerated from a gastrointestinal perspective, not necessarily limited to the stomach because it also seems to be a risk factor for inflammatory bowel disease, but also seems to have its impact on the cardiovascular system, from coronary events to heart failure. In a meta-analysis, although all NSAIDs increase the risk of heart failure and upper gastrointestinal complications, high-dose naproxen is apparently associated with less vascular risk than other NSAIDs.18
REFERENCES 1. Piekos K, Spierings ELH. Management of daily headache unresponsive to preventive treatment: Daily triptans versus daily opioids. Rev Neurol Dis. 2009;6:E121-E130. 2. Williams D, Cahill T, Dowson A, et al. Usage of triptans among migraine patients: An audit of nine GP practices. Curr Med Res Opin. 2002;18:1-9. 3. Donnet A, Braunstein D, Micallef J, et al. Triptan use and overuse in the French general population: A regional pharmaco-epidemiology database analysis in 5.3 million people. Cephalalgia. 2013;33(Suppl. 8):127-128 (abstract). 4. Atkinson MJ, Sinha A, Hass SL, et al. Validation of a general measure of treatment satisfaction, the treatment satisfaction questionnaire for medication (TSQM), using a national panel study of chronic disease. Health Qual Life Outcomes. 2004;2:1-12. 5. Kosinski M, Bayliss MS, Bjorner JB, et al. A six-item short-form survey of measuring headache impact: The HIT-6. Qual Life Res. 2003;12:963-974. 6. Robbins R, Maides JF. Long-term daily triptan use: 59 patients. Headache Quarterly. 2000;11:127-131.
162 7. Robbins L. Frequent triptan use: Observations on safety issues. Headache. 2004;44:178-182. 8. Saper JR, Lake AE, Bain PA, et al. A practice guide for continuous opioid therapy for refractory daily headache: Patient selection, physician requirements, and treatment monitoring. Headache. 2010;50:11751193. 9. Evans RW, Baskin SM. Why do migraineurs abuse butalbital-containing combination analgesics? Headache. 2010;50:1194-1197. 10. Gerth J, Miller TC. Use only as directed. 2013. Available at: http://www.propublica.org/article/tylenolmcneil-fda-use-only-as-directed. (accessed October 5, 2013). 11. Headache Classification Subcommittee of the International Headache Society. The international classification of headache disorders. Cephalalgia. 2013; 33:629-808. 12. Spierings ELH. Hemicrania continua should NOT be classified as a trigeminal autonomic cephalalgia. Headache. 2013;53:869-870. 13. Sjaastad O, Spierings ELH. “Hemicrania continua”: Another headache absolutely responsive to indomethacin. Cephalalgia. 1984;4:65-70.
January 2014 14. Magkos F, Kavouras SA. Caffeine use in sports, pharmacokinetics in man, and cellular mechanisms of action. Crit Rev Food Sci Nutr. 2005;45:535562. 15. Lee C-B, Chung C-S. Role of caffeine cessation in migraine management. Cephalalgia. 2013;33(Suppl. 8):248-249. 16. Cady R, Nett R, Dexter K, Freitag F, Beach ME, Manley HR. Treatment of chronic migraine: A 3-month comparator study of naproxen sodium vs sumaRT/Nap. Headache. 2013; doi: 10.1111/ head.12210. Epub ahead of print. 17. Lipton RB, Serrano D, Nicholson RA, Buse DC, Runken MC, Reed ML. Impact of NSAID and triptan use on developing chronic migraine: Results from the American Migraine Prevalence and Prevention (AMPP) study. Headache. 2013; doi: 10.1111/head.12201. Epub ahead of print. 18. Coxib and Traditional NSAID Trialists’ (CNT) Collaboration. Vascular and upper gastrointestinal effects of non-steroidal anti-inflammatory drugs: Meta-analyses of individual participant data from randomised trials. Lancet. 2013;382:769-779.
