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Daily Triptan Use, Observations On Safety Issues
L. Robbins, M.D.
Posted July 2003
Department of Neurology, Rush Medical College,
Chicago, IL, USA


Abstract and Key Words

Objective:  This study examines the safety of daily or near-daily triptan use over extended periods of time. For a small group of refractory migraine plus chronic daily headache patients, the triptans are effective.

Methods:  This retrospective study primarily evaluated the cardiac safety of daily triptans in 118 patients and, in addition, hematologic tests were assessed. Each patient had utilized a triptan for a minimum of 4 days/week, for at least 6 months. Patients suffering from rebound had been withdrawn off of the triptans. The majority (97/118) averaged 1 tablet daily; most would occasionally go for several days without the triptan. Forty patients had utilized the triptans for 6 months to 2 years, 37 patients from 2 to 4 years, and 41 for 4 or more years.

Results:  Routine hematologic tests were performed periodically on all patients, and no abnormalities were attributable to the triptans. Almost all patients had an ECG, and no abnormal ECG’s were felt to be related to the triptans. 57/118 patients had a cardiac echocardiography. The 10 abnormal echocardiograms were not due to triptans. All 20 cardiac stress tests performed were normal. Adverse events were minimal; 9 patients described fatigue due to triptans, and 5 had mild chest tightness.

Conclusions:  This 118 patient long-term study indicates that frequent triptan use may be relatively safe.

Key Words:  Triptan, Chronic Daily Headache, Migraine.

Abbreviations:  ECG - Electrocardiogram IHS - International Headache Society

Many patients with migraine and chronic daily headache (cdh) are refractory to the usual preventative medications. One previous study of patients with cdh indicated that, over the long-term, only 46% would respond to preventatives (1). The usual preventatives include antidepressants, anticonvulsants, beta-adrenergic blocking agents, calcium channel antagonists, and muscle relaxants (2). For those who continue to experience moderate or severe headache on a frequent basis, medication choices are limited. These include (among others) opioids (3), monoamine oxidase inhibitors (4), botulinum toxin injections (5), or a combination of preventatives.

A group of patients respond only to triptan medications (sumatriptan, naratriptan, rizatriptan, almotriptan, zolmitriptan, frovatriptan, eletriptan). The patients in this study were never instructed to utilize triptans on a daily basis. They ‘self-discovered’ that a dose of the triptan would alleviate the headache for most or all of the day. The vast majority of patients in this study had a history of many years of headache, refractory to the usual medications. They finally had found a medication (the triptan) that alleviated the headache for some period of time.

One goal of this retrospective study was to evaluate the cardiac safety of the triptans in this large group of patients. A secondary objective was to assess the hematologic tests that were done in these patients.

Subjects and Methods

Subjects:  One-hundred eighteen subjects (27 males and 91 females), ages 27 to 73 years (average age 52 years), were evaluated. Inclusion criteria were: 1. The patient had utilized a triptan medication for a minimum of 4 days weekly, for at least 6 months. 2. The triptan use had to be consistent. All of the patients would occasionally go days without the triptan. Exclusion criteria included: 1. Patients who were felt to be suffering from rebound (they were withdrawn off of the triptan prior to 6 months), and 2. Patients who were not utilizing the triptan at least 4 days weekly, on a consistent basis.

Previous Medications:  The patients were all long-term patients at the Robbins Headache Clinic. Each patient had been refractory to at least 3 of the usual preventative medications. These included beta-adrenergic blocking agents, calcium channel antagonists, antidepressants, anticonvulsants, methysergide, non-steroidal anti-inflammatories (nsaids), and muscle relaxants. The majority of patients had been refractory to 5 or more daily preventatives. During the study, besides the triptan, most patients did continue on at least one preventative medication, the most common of which were antidepressants. In addition, many were also utilizing other abortive medications, besides the triptan. These included nsaids, and other analgesics.

Rebound:  The patients were carefully screened for the presence of rebound headache. If the history was possibly consistent with rebound, the patient was withdrawn off of the triptan.

Patient Assessment:  The interviews and chart reviews were done by the treating neurologist at the Robbins Headache Clinic. Hematologic, electrocardiographic and echocardiographic findings were assessed via retrospective chart reviews. In patients on daily triptans, as a matter of routine (at this Clinic) hematologic tests were regularly done, as were electrocardiographs. Cardiac echocardiography with doppler flow studies were accomplished on 57 (almost half) of the patients.

Type of Headache:  Headache classification was based on International Headache Society (IHS) revisions proposed by Silberstein et al (6). The diagnosis was migraine plus chronic daily headache in 107/118 patients, cdh alone in 2, and chronic cluster in 9.

Type of Triptan:  During the course of therapy, most patients switched from one triptan to another, and often reverted back to the original one. Reasons for this included tolerance and insurance issues.

For the following, the patients had taken the stated triptan for at least 2 months: 85 patients used sumatriptan, 68 naratriptan, 37 rizatriptan, 30 zolmitriptan, and 6 almotriptan.

Amount of Triptan:  For most of the course of their therapy, the vast majority (97/118) of patients averaged 1 tablet daily (50 mg sumatriptan, 2.5 mg naratriptan, 10 mg rizatriptan, 5 mg zolmitriptan). 8 patients used only ˝ tablet daily, while 8 used 1.5 tablets on a daily basis. Five patients consumed 2 tablets daily. 90 of the patients used the triptan every day, while 28 patients averaged 4 to 5 days per week. All of the patients would occasionally go for several days without the medication (or occasionally take weeks off from the triptan).

Table 1: Duration of Triptan Use

Number of Months on Triptan Number of Patients (Percentage of Total)
6-12 18 (15%)
13-18 9 (8%)
19-24 13 (11%)
25-30 9 (8%)
31-36 11 (9%)
37-42 11 (9%)
42-47 6 (5%)
48-53 10 (8%)
54-60 9 (8%)
61-66 3 (3%)
67-72 7 (6%)
73-78 12 (10%)


From 6 months to 2 years, there were 40 patients, from 2 to 4 years there were 37 patients, from 4 to 6 years there were 28, and 13 patients took the triptans for more than 6 years. 41 of the patients had utilized the daily triptans for 4 or more years.

Results

Laboratory (Hematologic) Tests: Routine blood tests were performed regularly on all patients, usually every 6 to 9 months. These included complete blood counts and complete chemistries including liver and kidney functions, as well as cholesterol. 32 patients had an increased cholesterol, 12 patients had increased liver enzymes, and 3 had anemia. 2 patients had an increased blood urea nitrogen, and one had a decrease in platelets. None of the laboratory abnormalities was felt to be due to the triptans.

Electrocardiograms (ECG): 103 patients were administered an ECG, of which 95 were normal. The ECG’s were done after prolonged triptan use by the patient, a minimum of 6 months after the onset of daily triptan therapy. Most patients had an ECG during the calendar years 2001 or 2002, which was toward the end of this study time period. ECG’s were evaluated by a cardiologist. No abnormalities were felt to be related to the triptans. The following were the abnormal ECG findings (8 patients): atrial fibrillation, 1 patient; tachycardia, 2 patients; bradycardia, 1 patient. In addition, inverted t waves, 1 patient; non-specific st-t wave changes, 2 patients; and rare premature atrial contractions, 1 patient.

Echocardiogram with Doppler: (See Table 2) Fifty-seven patients were administered an echocardiogram with Doppler Flow Studies. The echocardiograms were done after prolonged use of triptans by the patient, a minimum of nine months after the onset of daily triptan therapy. Most patients had an echocardiogram during the last 1.5 years of this study.

Table 2: Echocardiograms (done on 57/118 patients)

Number of Patients Results of Echocardiogram
47 Normal
6 Mitral Valve Prolapse
1 Mitral Regurgitation
1 Enlarged Aorta
1 Mild Right Ventric. Enlargement
1 Aortic Regurgitation

For those 10 patients with an abnormality on the echocardiogram, the patient had an evaluation by the attending cardiologist or internist. None of the abnormalities found on echocardiography was felt to be due to the use of the triptans.

Cardiac Stress Tests: 20 patients had cardiac stress tests; all were normal. The stress tests were done for various reasons, unrelated to the triptans. One patient had a cardiac catheterization which was normal.

Adverse Events: 9 patients felt that the triptans contributed to fatigue. 5 patients had mild chest tightness, at times, possibly due to the triptans. Cardiac disease was ruled out in these patients. 3 patients felt that the triptans contributed to nausea.

Because this was a group of patients who decided on their own to utilize the triptans on a daily basis, adverse events would be expected to be low. If patients were not tolerating the medication well, or were having significant adverse effects, they would not choose to continue the triptan on a frequent basis.

Comments

In this current study, there were no adverse consequences discovered from the utilization of frequent triptans over a prolonged period of time. 118 patients (primarily with migraine and cdh) had ‘self-selected’ triptans as the only beneficial therapy for their daily headaches. These patients had been refractory to the usual chronic daily headache and migraine preventatives.

Examinations utilized in this study included ECG’s, echocardiography with doppler, and laboratory blood tests. There may be adverse consequences of daily triptan use that were not detected in this study.

Our previous study assessed 59 patients with migraine plus cdh (7). As in the current study, the patients had taken a daily (or near-daily) dose of a triptan for a minimum of 6 months. These patients had selected daily triptans because, after years of failing various preventative regimens, they had finally found medications that were beneficial.

In the previous study (7), twenty-three patients (39%) had been on triptans for 6 to 12 months, while 36 (61%) were on them for more than one year. The patients had previously failed multiple first and second line preventive medications. Forty-one patients (69%) were currently on preventive medications; the most common preventives were sodium valproate and antidepressants. Forty-five patients (76%) used abortive medications, in addition to the daily triptans. While 39 patients (66%) had previously overused abortives, they were not overusing them since being on daily triptans. Side effects were minimal in this patient population. However, as in the current study, since the patients self selected the daily triptan use, side effects would be expected to be low in this population. Rebound headache due to triptans was not encountered in this study, primarily because those with rebound did not continue on the daily triptans. Blood tests were done on all patients. Results were normal in 47 of the 59 patients, whereas 12 were abnormal. None of the abnormal test results were felt to be due to the triptans. Electrocardiograms were normal in 19 of the 23 patients who had this procedure, while four were abnormal. The abnormal ECG results were not felt to be due to the triptans. Echocardiography was done on five patients and all were normal (7).

Short-lasting adverse events are often encountered with the use of triptans. These include paresthesias, fatigue, chest heaviness, jaw or neck discomfort, etc. (8, 9). The chest symptoms are, with rare exceptions, not of cardiovascular origin. Cardiac ischemia due to triptan use is rare (10,11). The triptans do constrict coronary vessels, but this is a mild and short-lived effect. Despite widespread triptan use, the number of adverse cardiac events has been limited (12). Echocardiography and electrocardiography have generally been normal after triptan use, even in the presence of chest symptoms (13,14).

The primary issue with frequent triptan use, assuming rebound headache is not present, is long-term adverse events. The most likely system for possible long-term sequelae would be cardiovascular. Chronic ischemic changes, valvular abnormalities, or fibrosis are theoretical considerations. There is no evidence to date that long-term use of frequent triptans does produce any of these adverse events. However, this has not been systematically studied. The number of patients throughout the world who have utilized near-daily triptans is unknown. Until studies on these patients have been done, it is reasonable and prudent to do cardiac monitoring, as well as hematologic tests, on these patients.

While adverse effects from long-term triptan use are unknown, the alternatives have potential problems. Many patients with cdh are overusing analgesics, which have well-known adverse events (15). These include liver dysfunction, GI bleeding, renal insufficiency, and addiction.

There are many headache patients who have been refractory to daily preventative medications. The use of daily triptans offers a small number of these patients an improved quality of life. We will need further studies to evaluate safety of frequent triptan use.

References

  1. Robbins L., Maides J. Efficacy of Preventive Medications for Chronic Daily Headache American Journal of Pain Management, October 1999, Vol. 9, No. 4, pp. 130-33.
  2. Robbins L. Tension Headache Preventive Medication. In: Robbins L. Management of Headache and Headache Medications; Second edition, New York: Springer, 2000:109-113.
  3. Robbins L. Daily Opioids (Methadone) for refractory chronic daily headache. Headache Quarterly 1996; 7(1):39-42.
  4. Diamond S. Tension-Type Headaches. In: Dalessio DJ, Silberstein SD, eds. Wolff’s Headache and other head pain. Sixth Edition, New York, N.Y.: Oxford University Press;1993:249.
  5. Gokani T, Robbins L Botulinum Toxin: Efficacy in Migraine, Tension-Type and Cluster Headache. American Journal of Pain Management July 2002; Vol. 12 No. 3:98-103.
  6. Silberstein SD, Lipton SR, Solomon S, Mathew NT. Classification of daily and near daily headaches: proposed revisions to the IHS classification. Headache 1994; 34:17.
  7. Robbins L, Maides J Long-Term Daily Triptan Use: 59 patients. Headache Quarterly 2000 Vol.11 No. 4:275-77.
  8. Lloyd K. The clinical profile of sumatriptan: safety and tolerability. Eur Neurol. 1994;34 Suppl2:40-43.
  9. Visser WH, de Vriend RH, Jaspers MW, Ferrari MD. Sumatriptan in clinical practice: a 2-year review of 453 migraine patients. Neurology. 1996;47:46-51.
  10. Dahlof CGH, Mathew NT. Cardiovascular safety of 5HT 1B1D agonists - Is there cause for concern? Cephalalgia 1998;18:539-545.
  11. Stricker BH, Ottervanger JP. [Chest pain due to sumatriptan (see comments)]. Ned Tijdschr Geneeskd. 1992;136:1774-76.
  12. Smith T. Cardiovascular and Safety Concerns in Using Triptans in Migraine Patients. Headache Quarterly 2001; 12(supplement 1):25-28.
  13. Hillis WS, Macintrye PD. Sumatriptan and chest pain [Letter :comment]. Lancet. 1993;342:683.
  14. Dahlof CGH, Falk L, Risenfors M, Lewis C. Safety trial with the 5HT 1B/1D agonist avitriptan (BMS-180048) in patients with migraine who have experienced pressure, tightness, and/or pain in the chest, neck, and/or throat following sumatriptan. Cephalagia 1998; 18:546-51.
  15. Mathew NT, Kurman R, Perez F. Drug induced refractory headache - Clinical features and management. Headache 1990; 30:634-38.