Naratriptan in the prophylaxis of cluster headache

A 36-year-old man with cluster headache refractory to trials of standard prophylactic treatment and only partially responsive to parenteral sumatriptan and inhaled oxygen was admitted to an inpatient pain unit. The diagnosis of cluster headache was confirmed by direct observation of a typical attack. Despite efforts at prophylaxis, the patient continued to experience three to four severe headaches per day. Attempts to control his headaches with scheduled parenteral dihydroergotamine were successful, but headaches recurred when the medication was tapered, and continuous or intermittent use of parenteral dihydroergotamine was not felt to be a practical option for the patient. Naratriptan 2.5 mg twice daily completely abolished his headaches, which recurred when the medication was discontinued. No electrocardiographic or laboratory abnormalities were observed during treatment, and the patient reported no side effects.     

Naratriptan in the prophylaxis of transformed migraine

We report three patients with transformed migraine, previously refractory to a wide variety of traditional preventive pharmacologic and nonpharmacologic interventions. Naratriptan 2.5 mg given each morning, with a second tablet allowed for breakthrough headache, at least 4 hours later, demonstrated a remarkable reduction in frequency and intensity of daily headache. In addition, a subjective improvement in quality of life and restoration of functioning including a decrease in missed workdays was noted. All three patients had previously experienced good responses to sumatriptan or zolmitriptan, but were limited in frequency of use by the authors. The patients were not experiencing rebound phenomena at the onset of treatment with naratriptan. Clinical responses were noted within 3 to 7 days of initiation of treatment. Traditional risk factor analysis and screening were performed. Naratriptan was extremely well tolerated, with no cardiovascular adverse events reported or observed. Possible mechanisms of action are discussed.     

Tolerability and efficacy of naratriptan tablets with long-term treatment (6 months)

This open-label study was conducted to examine the long-term tolerability and efficacy of the novel 5HT₁ agonist naratriptan tablets 2.5 mg used to treat all migraine attacks for 6 months. Patients could reduce the dose to 1 mg in the event of intolerable adverse events. The results demonstrate that the majority (median 83%) of attacks treated with naratriptan tablets 2.5 mg were not associated with an adverse event. Among attacks treated with naratriptan tablets 2.5 mg (+optional 2.5 mg for headache recurrence), the most frequently reported adverse event was nausea (4% of attacks after a single naratriptan dose). Both the overall incidence of adverse events and the incidences of specific adverse events were no higher during months 4–6 of treatment compared with months 1–3. Only 5 of 414 patients elected to reduce their naratriptan dose to 1 mg. Headache relief 4 h postdose was reported in a mean of 68% of 6770 moderate or severe migraine attacks treated with naratriptan tablets 2.5 mg. The median number of naratriptan tablets used per attack was 1.0 (mean 1.25); patients treated only a median 7% of attacks (mean 13%) with a 2nd naratriptan tablet for headache recurrence. Patients rated naratriptan tablets as good or excellent in 61% of 7566 treated attacks. In summary, the data from this study demonstrate that naratriptan tablets 2.5 mg were very well tolerated and effective for the acute treatment of migraine for 6 months in a situation closely resembling actual clinical use.     

Maximum effect of triptans in migraine? A comment

The efficacy of triptans in the treatment of migraine was recently contested. How high is then the maximum effect of a triptan? After subcutaneous naratriptan 10 mg a 88% pain-free response was observed. This result was obtained despite the fact that more half of the patients had a migraine duration of > 4 h. These results indicate that subcutaneous naratriptan in a high dose can overcome central sensitization that occurs in migraine attacks.     

Prediction of attack frequency in migraine treatment

Usually limited information about the frequency of migraine episodes is derived from acute migraine trials. However, the design of some studies is such that they also provide relevant information about the attack frequency without the bias associated with patient expectations of treatment effect between attacks during prophylaxis trials. Using clinical data from repeated migraine attacks treated with placebo, naratriptan 2.5 mg or sumatriptan 100 mg, we show that attack and interictal periods can be described by a random probability distribution. Based on a gamma distribution, the mean interval between attacks was estimated to be 24 (17–34) days for placebo, 23 (18–29) days for naratriptan 2.5 mg and 22 (17–28) for sumatriptan 100 mg. These findings suggest that the interictal interval is not affected by abortive treatment with triptans. Interpretation of these results may be limited by the study type, yet the method represents a new tool for the evaluation of disease dynamics and treatment effect in the prophylaxis of migraine.     

The Safety of Sumatriptan and Naratriptan in Pregnancy: What Have We Learned?

Objectives.— To monitor for a signal of major teratogenicity by determining the risk of all major defects following in utero exposure to sumatriptan and naratriptan. To monitor for unusual patterns of birth defects that might suggest teratogenicity. Background.— The prevalence of migraine is highest in women of childbearing age. Coupled with the recurrent nature of migraine attacks and the high proportion of unplanned pregnancies, intentional and inadvertent exposure to these drugs in pregnancy is likely. The Sumatriptan and Naratriptan Pregnancy Registry captures data on women exposed to those drugs during pregnancy to monitor for evidence of major teratogenicity. Methods.— Healthcare professionals from anywhere in the world can enroll, on a voluntary basis, women exposed to sumatriptan or naratriptan during their pregnancies in this primarily prospective, observational study. Only pregnancies with unknown outcomes at the time of enrollment were included in the analysis. The percentage of infants or fetuses with major birth defects was calculated as the total number of infants/fetuses with major birth defects divided by the sum of the number of infants/fetuses with major birth defects + the number of live births without defects. The risk of major birth defects was further stratified by earliest trimester of pregnancy exposure. Results.— Data are available on pregnancy outcomes from 599 exposed women. Among 479 first‐trimester exposures to sumatriptan, 20 outcomes with major birth defects were reported (4.6%, 95% confidence interval [CI] 2.9‐7.2%). The risk of major birth defects following exposure to sumatriptan during any trimester was 4.7% (95% CI 3.1‐7.0%). No distinctive pattern of major birth defects among exposed infants was noted. There were 50 first‐trimester exposures to naratriptan with 1 reported birth defect in a fetus with exposure to both sumatriptan and naratriptan. Conclusions.— The risk of all major birth defects following first‐trimester exposure to sumatriptan was 4.6% (95% CI 2.9‐7.2%). This coupled with a consistent failure of additional epidemiological studies to observe a signal for major teratogenicity gives a level of reassurance concerning the safety of sumatriptan in pregnancy. There are too few data on naratriptan to draw definitive conclusions, and the sample size for sumatriptan remains too small to detect any but very large increases in specific birth defects.     

A model-based approach to treatment comparison in acute migraine

AIMS: Currently, direct comparisons between 5-HT(1B/d) receptor agonists are used to assess differences and similarities in antimigraine response. Such comparisons depend on the selected sampling time and do not allow evaluation of entire response profiles. A thorough evaluation of drug properties requires that the time course of the response be taken into account. In this investigation we show the advantages of a model-based approach to compare the efficacy of two triptans (sumatriptan vs. naratriptan). METHODS: A Markov model was used to describe the course of a migraine attack over three clinically identified stages. Drug effects were modelled as concentration-dependent increases in transition rates and were parameterised as potency (EC(50)) and maximum effect (E(max)). Parameters were estimated using headache measurements from efficacy studies. Model estimates were then used to compare the pharmacodynamics of the two drugs in a time-independent manner. RESULTS: Efficacy parameters could be derived, allowing for comparison between compounds. The potency ratio (EC50(suma)/EC50(nara)) for headache relief was 3.3 (0.9, 12). The ratio of maximum effects (Emax(suma)/Emax(nara)) for this endpoint was 0.74 (0.55, 0.97). To interpret these efficacy measures and explore their value for the development of antimigraine drugs, results were evaluated against the reported in vitro potency at 5-HT(1B) and 5-HT(1D) receptors. CONCLUSIONS: Comparison of the effects of two or more drugs based on preset sampling times does not allow proper assessment of the antimigraine properties in vivo. Disease dynamics must be considered to evaluate treatment response adequately and optimise the dosing regimen in migraine.     

Ischemic colitis associated with naratriptan and oral contraceptive use

Ischemic colitis has not been reported in association with naratriptan therapy. We describe the occurrence of ischemic colitis in a patient who was treated with abortive doses of naratriptan for migraine and was also taking long-term oral contraceptives. Concurrent use of naratriptan and oral contraceptives should probably be avoided.     

Efficacy of oral naratriptan in the treatment of menstrually related migraine

The aim of this study was to investigate the efficacy of orally administered 2.5 mg naratriptan in the treatment of menstrually related migraine (MRM). A high percentage of women suffering from migraine report increased frequency of attacks in association with menstruation that may be more severe, of longer duration and more difficult to treat than at other times. This was a phase IIIb, randomized, double-blind, placebo-controlled clinical trial. Subjects were given either 2.5 mg naratriptan or placebo to treat a single MRM episode, defined as starting between days -2 and +4 relative to the start of menstruation. The primary efficacy measure was the percentage of subjects who were free of pain 4 h after treatment, the absence of pain at 30 min, 1 and 2 h being secondary efficacy measures. Other secondary measures were the absence of associated symptoms, sustained headache relief 24 h after a single dose of the study medication, recourse to a second dose of study medication or escape medication, pain intensity 4-24 h after first treatment, the ability to carry out work or daily activities, and patient satisfaction. Adverse events were also monitored. A total of 275 women were enrolled in the trial and 229 (115 naratriptan group, 114 placebo group) provided data on the effects of the study medication on MRM. A higher percentage of subjects in the naratriptan group (58%) reported complete pain relief 4 h after medication than in the placebo group (30%) (P<0.001). Significant differences between the naratriptan and placebo groups and in favor of naratriptan were also found for: total pain relief at 2 h (P=0.004), sustained pain-free response within 4-24 h (P<0.001), absence of all associated symptoms at 2 and 4 h (P=0.004), ability to work and carry out daily activities at 2 h (P=0.036), and patient overall satisfaction (P<0.001). Three adverse events were recorded that might potentially be attributable to naratriptan. Naratriptan given orally at a dose of 2.5 mg is effective in the acute treatment of MRM as early as 2 h after treatment.     

Naratriptan as short-term prophylaxis of menstrually associated migraine: a randomized, double-blind, placebo-controlled study

OBJECTIVE: To determine the efficacy of naratriptan 1-mg and 2.5-mg tablets twice daily compared with placebo as short-term prophylaxis of menstrually associated migraine. BACKGROUND: Approximately 60% of women with migraine report headaches associated with their menstrual cycles. Results from an open-label study suggest that short-term administration of sumatriptan is useful in the prophylaxis of menstrually associated migraine. METHODS: A randomized, double-blind, three-arm, parallel-group, placebo-controlled study was conducted in women aged 18 years or older with a history of migraine with or without aura, as defined by the International Headache Society, of at least 6 months. Two dose strengths of naratriptan (1 mg, 2.5 mg) or identical-appearing placebo tablets (1:1:1) were administered twice daily for 5 days starting 2 days prior to the expected onset of menses across four perimenstrual periods. End points included the number of menstrually associated migraines, total migraine days, peak headache severity, lost work/activity time, migraine-related quality of life, and incidence of adverse events. RESULTS: Overall, the intent-to-treat population comprised 206 women (naratriptan 1 mg, n = 70; naratriptan 2.5 mg, n = 70, and placebo, n = 66); 171 women treated four perimenstrual periods. Significantly more perimenstrual periods per subject treated with naratriptan, 1 mg, were headache-free compared with placebo (50% versus 25%, P =.003). Naratriptan, 1 mg, significantly reduced the number of menstrually associated migraines (2.0 versus 4.0, P <.05) and menstrually associated migraine days (4.2 versus 7.0, P <.01) compared with placebo. More patients treated with naratriptan, 1 mg, were headache-free across all treated perimenstrual periods compared with placebo (23% versus 8%). No difference in headache severity was observed in breakthrough headaches. The incidence and severity of adverse events was similar across treatment groups. Naratriptan, 2.5 mg, was not statistically superior to placebo for any measure. CONCLUSIONS: Naratriptan, 1 mg, with tolerability similar to placebo, is an effective, short-term, prophylactic treatment for menstrually associated migraine.