Alan Metz

Effect of early intervention with sumatriptan on migraine pain: Retrospective analyses of data from three clinical trials

OBJECTIVE This study assessed the efficacy of sumatriptan 50- and 100-mg tablets in the treatment of migraine attacks while the pain is mild rather than moderate/severe. BACKGROUND Results from The Spectrum Study suggested that early treatment of migraine attacks with sumatriptan 50-mg tablets while the pain is mild might enhance pain-free response and reduce headache recurrence. METHODS Retrospective analyses of headaches treated during mild pain were performed using data from 3 studies of sumatriptan tablets (protocols S2CM09, S2BT25, and S2BT26). Our primary interest was pain-free response 2 and 4 hours after dosing; secondary interests were use of a second dose of medication, clinical disability (as measured on a 4-point disability scale), migraine-associated symptoms, meaningful pain relief (patient defined), time to meaningful relief, sustained pain-free response, and proportion of attacks in which pain had worsened 2 and 4 hours after dosing, all of which were compared in headaches treated during mild versus moderate/severe pain. RESULTS In S2CM09, 92 patients treated 118 headaches during mild pain. Rates of pain-free response were higher 2 hours after dosing with sumatriptan 50 mg (51%) or 100 mg (67%; P < 0.05) compared with placebo (28%), and were higher with early treatment of mild pain compared with treatment of moderate/severe pain at 2 hours (sumatriptan 50 mg: mild pain, 51%; moderate/severe pain, 31%; P < 0.05; sumatriptan 100 mg: mild pain, 67%; moderate/severe pain, 36%) and 4 hours (50 mg: 75% vs 56%; 100 mg: 90% vs 61%; P < 0.05). Early intervention also resulted in less redosing than when moderate/severe pain was treated (50 mg: 21% vs 32%; 100 mg: 20% vs 29%). More attacks treated early with sumatriptan 50 or 100 mg were associated with normal function 4 hours after dosing compared with placebo (70% and 93% vs 46%, respectively). Sustained pain-free response rates 2 to 24 hours after early dosing with sumatriptan 50 or 100 mg were also higher (34% and 53%, respectively) compared with treatment of moderate/severe pain (19% and 24%, respectively). Early treatment with sumatriptan 100 mg produced significantly higher pain-free rates at 2 hours after dosing (P < 0.001) than did ergotamine plus caffeine (S2BT25: 69% vs 34%, respectively) or aspirin plus metoclopramide (S2BT26: 73% vs 25%, respectively). CONCLUSIONS Sumatriptan 50- and 100-mg tablets are effective whether pain is mild or moderate/severe. However, treatment with sumatriptan while pain is mild provides high pain-free response rates while reducing the need for redosing, benefits not seen with ergotamine plus caffeine or aspirin plus metoclopramide.

Bupropion SR as an aid to smoking cessation in smokers treated previously with bupropion: a randomized placebo-controlled study.

Many persons who attempt to quit smoking have made previous unsuccessful attempts to quit with pharmacologic aids. An understanding of the impact of these previous attempts to quit is vital for selecting medications that may be more successful in a future attempt to quit. In particular, the effect of repeated use of bupropion SR (Zyban; INN, amfebutamone) on abstinence rates has not been studied previously.

Bupropion sustained release (SR) for the treatment of hypoactive sexual desire disorder (HSDD) in nondepressed women.

This article describes the results of the first report of bupropion sustained release (SR) in nondepressed females with hypoactive sexual desire disorder (HSDD). Eligible females entered a 4-week, single-blind, placebo baseline phase. Subjects, all of whom did not respond to placebo, continued in a single-blind active treatment phase where they received bupropion SR for up to 8 additional weeks. We assessed HSDD by using investigator ratings of sexual desire and sexual functioning. Of the 51 evaluable subjects who entered the active treatment phase, 29% responded to treatment with bupropion SR. Bupropion SR was generally well tolerated. Pending the results of further study, bupropion SR may offer a treatment option for women with HSDD.This article describes the results of the first report of bupropion sustained release (SR) in nondepressed females with hypoactive sexual desire disorder (HSDD). Eligible females entered a 4-week, single-blind, placebo baseline phase . Subjects, all of whom did not respond to placebo, continued in a single-blind active treatment phase where they received bupropion SR for up to 8 additional weeks. We assessed HSDD by using investigator ratings of sexual desire and sexual functioning. Of the 51 evaluable subjects who entered the active treatment phase, 29% responded to treatment with bupropion SR. Bupropion SR was generally well tolerated. Pending the results of further study, bupropion SR may offer a treatment option for women with HSDD.

Seasonal affective disorder and its prevention by anticipatory treatment with bupropion XL.

BACKGROUND Seasonal affective disorder (SAD) can cause significant distress and impairment. No antidepressant studies have previously attempted to prevent the onset of autumn-winter depression. METHODS Three prospective, randomized, placebo-controlled prevention trials were conducted on 1042 SAD patients, enrolled in autumn and treated while still well, across the northern US and Canada. Patients received either bupropion XL 150-300 mg or placebo daily by mouth from enrollment until spring and were then followed off medications for 8 additional weeks. Primary efficacy variables were end-of-treatment depression-free rates and survival distributions of depressive recurrence. RESULTS Despite a reported average of 13 previous seasonal depressive episodes, almost 60% of patients had never previously been treated for depression. Major depression recurrence rates during the three studies for bupropion XL and placebo groups were 19% versus 30% (p = 0.026), 13% versus 21% (p = 0.049), and 16% versus 31%; yielding a relative risk reduction across the three studies of 44% for patients taking bupropion XL. Survival analyses for depression onset also favored bupropion XL over placebo (p = .081, .057, and <.001). CONCLUSIONS It is possible to prevent recurrence of seasonal major depressive episodes by beginning bupropion treatment early in the season while patients are still well.

Effect on body weight of bupropion sustained-release in patients with major depression treated for 52 weeks

BACKGROUND Short-term studies have demonstrated a modest weight-reducing to weight-neutral effect among patients receiving bupropion sustained-release (SR) for the treatment of depression. OBJECTIVE This study was conducted to evaluate the long-term effects of bupropion SR on body weight in patients with depression. METHODS This analysis was conducted within a long-term relapse-prevention study in patients with major depression. Those whose depression had responded to open-label treatment with bupropion SR were randomized to 44 weeks of double-blind treatment with bupropion SR 300 mg/d or placebo. Patients were categorized by body mass index (BMI) as follows: BMI < 22, BMI 22 to 26, BMI > or = 27, and BMI > or = 30. RESULTS Four hundred twenty-three patients were enrolled in the double-blind phase of the study, 210 receiving bupropion SR and 213 receiving placebo. At the end of the open-label phase, the following mean weight losses were seen in the 4 BMI groups: BMI < 22, 0.5 kg; BMI 22 to 26, 1.1 kg; and BMI > or = 27 and BMI > or = 30, 1.8 kg each. At the end of double-blind treatment, mean change-from-baseline weights were as follows: BMI < 22, -0.1 kg; BMI 22 to 26, -0.6 kg; BMI > or = 27, -1.4 kg; and BMI > or = 30, -2.4 kg. The rate of change in body weight during the double-blind phase was statistically significant compared with baseline BMI (P < 0.001, analysis of covariance). CONCLUSIONS Modest mean weight losses that increased with increasing baseline body weight were observed with long-term bupropion SR treatment. The findings of this analysis suggest that bupropion SR may be an appropriate therapeutic option in normal-weight or overweight patients with depression who are concerned about weight gain.

Response in Relation to Baseline Anxiety Levels in Major Depressive Disorder Treated with Bupropion Sustained Release or Sertraline

Our objective was to determine if pretreatment anxiety levels were associated with preferential response to bupropion sustained release (n = 122) or sertraline (n = 126) during a 16-week randomized acute phase treatment study. Both agents had comparable antidepressant activity, and comparable anxiolytic effects using the intent-to-treat sample. Baseline anxiety levels were not related to antidepressant efficacy, and they did not differentiate responders to each agent. Time to clinically significant anxiolysis did not differentiate between treatment groups or between responders to each agent. These results contradict the commonly held, but unsubstantiated, belief that in clinically depressed anxious patients, serotonergic antidepressants are especially anxiolytic and that such patients preferentially benefit from the antidepressant or anxiolytic effects of selective serotonin reuptake inhibitors. Thus, the clinical decision to select between these two agents when treating depressed outpatients cannot rest on either levels of pretreatment anxiety or on anticipation of more rapid or more complete anxiolysis.

Continuation phase treatment with bupropion SR effectively decreases the risk for relapse of depression

BACKGROUND This was the first controlled continuation phase study (up to 1-year total treatment) to evaluate the safety and efficacy of bupropion SR for decreasing the risk for relapse of depression in patients who responded to bupropion SR. METHODS Patients with recurrent major depression were treated with bupropion SR 300 mg/day during an 8-week open-label phase. Responders (based on Clinical Global Impressions Scale for Improvement of Illness scores) entered a randomized, double-blind phase where they received bupropion SR 300 mg/day or placebo for up to 44 weeks. After randomization, relapse was defined as the point at which the investigator intervened by withdrawing the patient from the study to treat depression. RESULTS Four hundred twenty-three patients were randomized. A statistically significant difference in favor of bupropion SR over placebo was seen in the time to treatment intervention for depression when survival curves were compared (log-rank test, p =.003). Statistically significant separation between bupropion SR and placebo began at double-blind week 12 (p <.05). Adverse events in bupropion SR-treated patients accounted for 9% and 4% of discontinuations from the open-label and double-blind phases, respectively. CONCLUSIONS Bupropion SR was shown to be effective and well tolerated in decreasing the risk for relapse of depression for up to 44 weeks.

Effects of encapsulation on absorption of sumatriptan tablets: data from healthy volunteers and patients during a migraine☆

BACKGROUND Some comparative trials of selective serotonin 1B/ID-agonists in migraine have reported -15% lower efficacy for sumatriptan tablets than that reported in placebo-controlled trials. OBJECTIVE This study was designed to test the hypothesis that the encapsulation methods used to mask active drug may delay absorption of sumatriptan from dosing to 2 hours after dosing (the traditional end point in clinical trials of migraine treatment), an effect that may be enhanced by migraine-associated gastric stasis. METHODS Two randomized, open-label, 2-way crossover trials were conducted to evaluate the absorption and bioequivalence of conventional 50-mg sumatriptan tablets and encapsulated 50-mg sumatriptan tablets in supine, fasted, healthy volunteers (Glaxo Wellcome protocol SUM40270) and supine patients experiencing a migraine (Glaxo Wellcome protocol SUM40268). Absorption was assessed by calculating the area under the plasma concentration-time curve from dosing to 2 hours after dosing (AUC2) and the times to first measurable plasma concentration, 10 ng/mL, 20 ng/mL, and maximum plasma concentration. Data for the AUC from time zero to infinity and maximum plasma concentration were used to assess standard bioequivalence, which is considered to occur when the 90% CIs for the geometric mean treatment ratios (test/reference) fall between 0.8 and 1.25. RESULTS Study 1 included 26 healthy subjects (73% men, 27% women; mean age, 39.1 years), and study 2 included 30 patients with migraine (67% women, 33% men; mean age, 42.7 years). Sumatriptan absorption was delayed with the encapsulated tablet compared with the conventional tablet 0 to 2 hours after dosing, particularly during a migraine. AUC2 values with encapsulated sumatriptan compared with the conventional tablet were 21% lower in healthy volunteers (ratio of capsule/tablet, 0.79; 90% CI, 0.588-1.050) and 27% lower in patients experiencing a migraine (ratio of capsule/tablet, 0.73; 90% CI, 0.519-1.023). Standard bioequivalence was demonstrated in both healthy volunteers and patients experiencing a migraine. CONCLUSIONS Encapsulation delayed absorption of sumatriptan 0 to 2 hours after dosing, particularly during a migraine. This delay in absorption of the encapsulated form may account for the lower efficacy of sumatriptan in some comparative studies.

Cognitive performance on the Alzheimer's disease assessment scale : effect of education

The cognitive subscale of the Alzheimers Disease Assessment Scale (ADAS-Cog) is used to monitor disease progression and treatment efficacy in clinical trials of Alzheimers disease (AD). Using data from a 12-week drug trial, we retrospectively studied the effect of education on ADAS-Cog performance in a group of 444 patients with AD. The effect of education was statistically significant on baseline ADAS-Cog total scores. This effect remained statistically significant after controlling for age, gender, and dementia severity. Education effects were also statistically significant at week 12 for ADAS-Cog total and 10 of 11 subitem scores in 138 AD patients in the placebo arm of the trial. Post hoc analysis showed that non-high school graduates performed worse than those with greater educational levels across a broad range of cognitive domains. Our results, in conjunction with reports linking lower educational level with a higher risk for AD, suggest that educational level of patients be given consideration in the design and interpretation of cognitive tests in AD drug trials.

NSAIDs and cognition in Alzheimer's disease

To the Editor: Recent studies have suggested a neuroprotective influence for nonsteroidal anti-inflammatory drugs (NSAIDs). [1-4] The Rotterdam Study, [1] the Canadian Study of Health and Aging, [2] and a co-twin control study [3] found that anti-inflammatory treatments were associated with a reduced risk of Alzheimers disease (AD). The Honolulu Heart Program study found that concurrent aspirin use was associated with superior cognitive scores in nondemented subjects. [4] We studied 444 AD subjects selected for a multicenter clinical trial to test the hypothesis that concurrent NSAID …