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Headache after frequent triptan use
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Baclioglu A, Wurtman RJ. Effects of fenfluramine and phentermine (fen-phen) on dopamine and serotonin release in rat striatum: a microdialysis study in conscious animals. Brain Res 1998; 813: 67–72. 3 Nurse D. Woman sounding a warning on medication combination. Atlanta Journal Constitution 1998, Sept 22. 4 Wee CC, Phillips RS, Aurigemma G, et al. Risk for valvular disease among users of fenfluramine and dexfenfluramine who underwent echocardiography before use of medication. Ann Intern Med 1998; 129: 870–74. 5 Abenhaim L, Moride Y, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996; 335: 609–15.
Headache after frequent triptan use Sir—Volker Limmroth and colleagues (Jan 30, p 378)1 report, from a tertiary referral centre, a series of 11 patients who had an increase in migraine frequency or development of chronic headache after long-term use of the 5-HT1B/1D agonists (triptans) for the treatment of migraine. These effects have previously been documented for sumatriptan2,3 and other commonly used acute antimigraine therapies.4 Four of the 11 patients had previously developed daily tension-type headache after use of non-steroidal antiinflammatory drugs, ergot derivatives, and sumatriptan and these same patients again developed chronic daily headache after use of triptan. This finding may suggest that patientdependent factors may be more important than specific treatments; there have been reports of an increased incidence of neuroticism in patients with chronic daily headache compared with migraine.5 A l s o , patients with chronic daily headache have been shown to have a tendency to misuse sumatriptan.2 Limmroth and co-workers state that their patients’ migraines were responsive to triptans, but that their daily headaches substantially improved after discontinuation of triptan. They do not elaborate on the subsequent treatment of these patients or the frequency with which these events occur within their clinical practice. Druginduced chronic daily headache may be more common in specialised headache clinics than in general practice. As with any condition, should a patient require acute treatment frequently, clinical reassessment with regards to diagnosis and management is appropriate. N Minton, J Sawyer Z eneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TF, UK
THE LANCET • Vol 353 • April 17, 1999
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Limmroth V, Kazaeawa Z, Fritsche G, Diener H-C. Headache after frequent use of serotonin agonists zolmitriptan and naratriptan. Lancet 1999; 3 5 3 : 378. 2 Kaube H, May A, Pfaffenrath V, Diener HC. Sumatriptan misuse in daily chronic headache. BMJ 1994; 3 0 8 : 1573. 3 Gaist D, Tsirpoulus I, Sindrup SH, et al. Inappropriate use of sumatriptan: population based register and interview study. BMJ 1998; 3 1 6 : 1352–53. 4 Antonacci F. Drug abuse headache: recognition and management. Cephalalgia 1998; 18 (suppl 22): 47–55. 5 Mathew N T. Transformed migraine, analgesic rebound, and other chronic daily headaches. Neurolo Clin 1997; 1 5 : 167–86.
A uthors’ reply Sir—N Minton and J Sawyer point out that patient-dependent factors such as an “increased incidence of neuroticism” may be more important in the development of drug-induced chronic daily headache than specific treatment. We agree with Minton and Sawyer that such factors may be important in certain cases. The new and important finding in our report, however, was not only the fact that second-generation triptans can also cause drug-induced headache, but rather that drug-induced chronic daily headache evolves faster and at lower dosages (7·5 mg, three tablets weekly) with these drugs than with ergotamine derivatives2 or sumatriptan.3 This effect was observed not only in patients who switched from ergotamine to triptan treatment or from triptan A to triptan B, but also in patients who had never taken ergotamine derivatives or triptans before. Thus, patientdependent factors were not likely to have the key role in these cases. Investigations are needed to find out whether these side-effects are caused by the specific properties of drugs, such as higher affinity to 5HT1 subreceptors, higher intrinsic activity at the receptor site, or by the enhanced central effects of these new drugs, particularly zolmitriptan. The answer to this question will not only improve the quality and safety of headache treatment but might be crucial in the development of further antimigraine drugs. Volker Limmroth, Z aza Kazaraw a, Günther Fritsche, *Hans-Christoph Diener Department of Neurology, School of Medicine, University of Essen, 45122 Essen, Ger many 1
Limmroth V, Kazarawa S, Fritsche G, Diener HC. Headache after frequent use of serotonin agonists zolmitriptan and naratriptan. Lancet 1999; 353: 378. 2 Diener HC, Wilkinson M. Drug-induced headache. Berlin: Springer-Verlag, 1988. 3 Kaube H, May A, Pfaffenrath V, Diener HC. Sumatriptan misuse in daily chronic headache. BMJ 1994; 308: 1573.
Sir—Volker Limmroth and colleagues1 ask whether drug-induced headache with triptans is a class effect. They report that of 11 patients who had increased frequency of headaches after the use of zolmitriptan or naratriptan, nine benefited from withdrawal of treatment. Rebound headache has previously been described for s u m a t r i p t a n . 2,3 The importance of Limmroth and colleagues’1 study is difficult to assess without data on the frequency of the event. Clinical experience at the Houston Headache Clinic (Houston, Texas, USA) suggests that the frequency of triptan-induced rebound headache is actually very low. Of more than 1000 patients given triptans in the past 5 years, about 2% reported headaches that were related to or worsened with triptan use. These symptoms usually occurred in patients who had habitually long-lasting migraine or frequent interictal tension-type headache in addition to their migraines. Psychological comorbidity such as depression, anxiety, and neuroticism were also associated with the tendency to use more triptans. However, the investigators raise a relevant issue. Although triptans provide great benefit for most people with migraine, there is a subpopulation of patients who respond differently to treatment. These patients can be a challenge to treat, and the most difficult to manage are those who have headache triggered by pain medication. About a third of the patients Limmroth and colleagues describe reported daily tension-type headache that was treated with non-steroidals and ergot derivatives, as well as triptans.1 In our experience, patients who have a tendency for multiple recurrences after triptans should be treated with adequate prophylactic medications rather than repeating the triptans. We do not know whether drug-induced headache indicates a neuronal or vascular mechanism, a threshold or sensitivity effect, or even an allergic or immunological response. Do these patients also get headache with non-analgesic medications? Rather than focusing on drug-induced rebound headache as a class effect of triptans, perhaps we can better serve the interests of our patients by defining the characteristics of those who respond inappropriately to treatment. Patient factors are probably more important than the drug used in the occurrence of drug-induced rebound headache. Weighing the benefits and risks of the triptans show that these drugs are still the best
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Baclioglu A, Wurtman RJ. Effects of fenfluramine and phentermine (fen-phen) on dopamine and serotonin release in rat striatum: a microdialysis study in conscious animals. Brain Res 1998; 813: 67–72. 3 Nurse D. Woman sounding a warning on medication combination. Atlanta Journal Constitution 1998, Sept 22. 4 Wee CC, Phillips RS, Aurigemma G, et al. Risk for valvular disease among users of fenfluramine and dexfenfluramine who underwent echocardiography before use of medication. Ann Intern Med 1998; 129: 870–74. 5 Abenhaim L, Moride Y, Brenot F, et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N Engl J Med 1996; 335: 609–15.
Headache after frequent triptan use Sir—Volker Limmroth and colleagues (Jan 30, p 378)1 report, from a tertiary referral centre, a series of 11 patients who had an increase in migraine frequency or development of chronic headache after long-term use of the 5-HT1B/1D agonists (triptans) for the treatment of migraine. These effects have previously been documented for sumatriptan2,3 and other commonly used acute antimigraine therapies.4 Four of the 11 patients had previously developed daily tension-type headache after use of non-steroidal antiinflammatory drugs, ergot derivatives, and sumatriptan and these same patients again developed chronic daily headache after use of triptan. This finding may suggest that patientdependent factors may be more important than specific treatments; there have been reports of an increased incidence of neuroticism in patients with chronic daily headache compared with migraine.5 A l s o , patients with chronic daily headache have been shown to have a tendency to misuse sumatriptan.2 Limmroth and co-workers state that their patients’ migraines were responsive to triptans, but that their daily headaches substantially improved after discontinuation of triptan. They do not elaborate on the subsequent treatment of these patients or the frequency with which these events occur within their clinical practice. Druginduced chronic daily headache may be more common in specialised headache clinics than in general practice. As with any condition, should a patient require acute treatment frequently, clinical reassessment with regards to diagnosis and management is appropriate. N Minton, J Sawyer Z eneca Pharmaceuticals, Alderley Park, Macclesfield, Cheshire SK10 4TF, UK
THE LANCET • Vol 353 • April 17, 1999
1
Limmroth V, Kazaeawa Z, Fritsche G, Diener H-C. Headache after frequent use of serotonin agonists zolmitriptan and naratriptan. Lancet 1999; 3 5 3 : 378. 2 Kaube H, May A, Pfaffenrath V, Diener HC. Sumatriptan misuse in daily chronic headache. BMJ 1994; 3 0 8 : 1573. 3 Gaist D, Tsirpoulus I, Sindrup SH, et al. Inappropriate use of sumatriptan: population based register and interview study. BMJ 1998; 3 1 6 : 1352–53. 4 Antonacci F. Drug abuse headache: recognition and management. Cephalalgia 1998; 18 (suppl 22): 47–55. 5 Mathew N T. Transformed migraine, analgesic rebound, and other chronic daily headaches. Neurolo Clin 1997; 1 5 : 167–86.
A uthors’ reply Sir—N Minton and J Sawyer point out that patient-dependent factors such as an “increased incidence of neuroticism” may be more important in the development of drug-induced chronic daily headache than specific treatment. We agree with Minton and Sawyer that such factors may be important in certain cases. The new and important finding in our report, however, was not only the fact that second-generation triptans can also cause drug-induced headache, but rather that drug-induced chronic daily headache evolves faster and at lower dosages (7·5 mg, three tablets weekly) with these drugs than with ergotamine derivatives2 or sumatriptan.3 This effect was observed not only in patients who switched from ergotamine to triptan treatment or from triptan A to triptan B, but also in patients who had never taken ergotamine derivatives or triptans before. Thus, patientdependent factors were not likely to have the key role in these cases. Investigations are needed to find out whether these side-effects are caused by the specific properties of drugs, such as higher affinity to 5HT1 subreceptors, higher intrinsic activity at the receptor site, or by the enhanced central effects of these new drugs, particularly zolmitriptan. The answer to this question will not only improve the quality and safety of headache treatment but might be crucial in the development of further antimigraine drugs. Volker Limmroth, Z aza Kazaraw a, Günther Fritsche, *Hans-Christoph Diener Department of Neurology, School of Medicine, University of Essen, 45122 Essen, Ger many 1
Limmroth V, Kazarawa S, Fritsche G, Diener HC. Headache after frequent use of serotonin agonists zolmitriptan and naratriptan. Lancet 1999; 353: 378. 2 Diener HC, Wilkinson M. Drug-induced headache. Berlin: Springer-Verlag, 1988. 3 Kaube H, May A, Pfaffenrath V, Diener HC. Sumatriptan misuse in daily chronic headache. BMJ 1994; 308: 1573.
Sir—Volker Limmroth and colleagues1 ask whether drug-induced headache with triptans is a class effect. They report that of 11 patients who had increased frequency of headaches after the use of zolmitriptan or naratriptan, nine benefited from withdrawal of treatment. Rebound headache has previously been described for s u m a t r i p t a n . 2,3 The importance of Limmroth and colleagues’1 study is difficult to assess without data on the frequency of the event. Clinical experience at the Houston Headache Clinic (Houston, Texas, USA) suggests that the frequency of triptan-induced rebound headache is actually very low. Of more than 1000 patients given triptans in the past 5 years, about 2% reported headaches that were related to or worsened with triptan use. These symptoms usually occurred in patients who had habitually long-lasting migraine or frequent interictal tension-type headache in addition to their migraines. Psychological comorbidity such as depression, anxiety, and neuroticism were also associated with the tendency to use more triptans. However, the investigators raise a relevant issue. Although triptans provide great benefit for most people with migraine, there is a subpopulation of patients who respond differently to treatment. These patients can be a challenge to treat, and the most difficult to manage are those who have headache triggered by pain medication. About a third of the patients Limmroth and colleagues describe reported daily tension-type headache that was treated with non-steroidals and ergot derivatives, as well as triptans.1 In our experience, patients who have a tendency for multiple recurrences after triptans should be treated with adequate prophylactic medications rather than repeating the triptans. We do not know whether drug-induced headache indicates a neuronal or vascular mechanism, a threshold or sensitivity effect, or even an allergic or immunological response. Do these patients also get headache with non-analgesic medications? Rather than focusing on drug-induced rebound headache as a class effect of triptans, perhaps we can better serve the interests of our patients by defining the characteristics of those who respond inappropriately to treatment. Patient factors are probably more important than the drug used in the occurrence of drug-induced rebound headache. Weighing the benefits and risks of the triptans show that these drugs are still the best
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