Amitriptyline vs divalproate in migraine prophylaxis: a randomized controlled trial

Objective

This study compares efficacy and safety of divalproate extended release (DVA‐ER) and amitriptyline (AMT) in migraine .

Materials and methods

Three hundred migraineurs having >4 attacks monthly were randomized into DVA‐ER or AMT. The primary end points were >50% reduction in frequency, ≥1 grade improvement in the severity, and >50% improvement in a visual analogue scale (VAS). Secondary end points were functional disability, rescue medication, and adverse events.

Results

The median age was 32 years, and 241 were women. 150 patients each received DVA‐ER and AMT. At 3 months, 74.7% in DVA‐ER and 62% patients in AMT group improved in headache frequency (P = 0.02) and at 6 months, 65.3% and 54%, respectively (P = 0.90). At 3 months, the VAS score improved by >50% in 80.7% in DVA‐ER and 64% in AMT (P = 0.005). At 6 months, there was no significant difference between the two groups in VAS score (69.3% vs 56%; P = 0.47) and other outcome parameters. The composite side effects were also not different between the two groups (68% vs 81%); however, hair fall, menstrual irregularity, polycystic ovary, and weight gain were commoner in DVA‐ER group.

Conclusion

Divalproate extended release is more effective at 3 months than AMT; however, at 6 months, both are equally effective in migraine prophylaxis.     

Amitriptyline in migraine prophylaxis

In a controlled trial of amitriptyline hydrochloride in migraine prophylaxis, 100 patients received placebo for a four-week baseline period and then were randomized in double-blind fashion to therapy with amitriptyline (47 subjects) or placebo (53 subjects) for another four to eight weeks. Subjects received up to four 25-mg tablets of amitriptyline hydrochloride or identical placebo per day. Comparing the first and second four-week periods for each patient, the conditions of 55.3% of amitriptyline subjects as opposed to 34.0% of placebo subjects were greater than or equal to 50% improved and the difference between amitriptyline and placebo response rates was significant (P less than .05). Nondepressed subjects with severe migraine and depressed subjects with less severe migraine responded best to amitriptyline, whereas depressed subjects with severe migraine had little headache relief. Amitritryline is an effective antimigraine agent and the antimigraine effect seems relatively independent of antidepressant activity.     

Efficacy of acupuncture for the prophylaxis of migraine: a multicentre randomised controlled clinical trial

BACKGROUND: Our aim was to assess the efficacy of a part-standardised verum acupuncture procedure, in accordance with the rules of traditional Chinese medicine, compared with that of part-standardised sham acupuncture and standard migraine prophylaxis with beta blockers, calcium-channel blockers, or antiepileptic drugs in the reduction of migraine days 26 weeks after the start of treatment. METHODS: This study was a prospective, randomised, multicentre, double-blind, parallel-group, controlled, clinical trial, undertaken between April 2002 and July 2005. Patients who had two to six migraine attacks per month were randomly assigned verum acupuncture (n=313), sham acupuncture (n=339), or standard therapy (n=308). Patients received ten sessions of acupuncture treatment in 6 weeks or continuous prophylaxis with drugs. Primary outcome was the difference in migraine days between 4 weeks before randomisation and weeks 23-26 after randomisation. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN52683557. FINDINGS: Of 1295 patients screened, 960 were randomly assigned to a treatment group. Immediately after randomisation, 125 patients (106 from the standard group) withdrew their consent to study participation. 794 patients were analysed in the intention-to-treat popoulation and 443 in the per-protocol population. The primary outcome showed a mean reduction of 2 .3 days (95% CI 1.9-2.7) in the verum acupuncture group, 1.5 days (1.1-2.0) in the sham acupuncture group, and 2.1 days (1.5-2.7) in the standard therapy group. These differences were statistically significant compared with baseline (p<0.0001), but not across the treatment groups (p=0.09). The proportion of responders, defined as patients with a reduction of migraine days by at least 50%, 26 weeks after randomisation, was 47% in the verum group, 39% in the sham acupuncture group, and 40% in the standard group (p=0.133). INTERPRETATION: Treatment outcomes for migraine do not differ between patients treated with sham acupuncture, verum acupuncture, or standard therapy.     

Efficacy of coenzyme Q10 in migraine prophylaxis: a randomized controlled trial

Riboflavin, which improves energy metabolism similarly to coenzyme Q10 (CoQ10), is effective in migraine prophylaxis. We compared CoQ10 (3 x 100 mg/day) and placebo in 42 migraine patients in a double-blind, randomized, placebo-controlled trial. CoQ10 was superior to placebo for attack-frequency, headache-days and days-with-nausea in the third treatment month and well tolerated; 50%-responder-rate for attack frequency was 14.4% for placebo and 47.6% for CoQ10 (number-needed-to-treat: 3). CoQ10 is efficacious and well tolerated.     

Topiramate in the prophylaxis of pediatric migraine: a double-blind placebo-controlled trial

Several large, randomized controlled trials have demonstrated the efficacy of topiramate in migraine prophylaxis in adults. However, there are limited data about the use of topiramate in migraine prophylaxis in children. We conducted this single-center, double-blind, placebo-controlled trial to evaluate the efficacy and safety of topiramate in the prophylaxis of migraine in children. A total of 44 children with migraine were randomized using random number tables to receive topiramate (n = 22) or placebo (n = 22). The total duration of treatment was 4 months, including a baseline period of 1 month during which topiramate was titrated weekly in 25-mg increments to 100 mg/d in 2 divided doses or to the maximum tolerated dose. The titration was followed by a 12-week maintenance phase during which topiramate was given in 2 divided doses. The primary outcome measures were the reduction in the mean migraine frequency and severity of headache. Secondary outcome measures included the number of times analgesics were required for a month for acute attacks and functional disability. Functional disability was measured by comparing school absenteeism and Pediatric Migraine Disability Assessment Scale (PedMIDAS). The decrease in mean (+/-SD) monthly migraine frequency from 16.14 (+/-9.35) at baseline to 4.27 (+/-1.95) at the end of the study in the topiramate group was significantly greater as compared with a decrease from 13.38 (+/-7.78) to 7.48 (+/-5.94) at the end of the study in the placebo group (P = .025). The difference in number of rescue medications used for topiramate and placebo was not statistically significant (P = .059). There was a statistically significant decrease in the PedMIDAS score from 50.66 (+/-32.1) to 10.42 (+/-6.39) at the end of the study in the topiramate group compared with a decrease from 42.66 (+/-27.5) to 23.7 (+/-19.1) at the end of 4 months in the placebo group (P = .003). The decrease in school absenteeism was significant with topiramate compared with placebo (P = .002). Weight loss, decreased concentration in school, sedation, and parasthesias were important side effects with topiramate. Most of these side effects were mild to moderate and were not significant enough to cause dropout from the study.     

Changes in regional cerebral blood flow during the course of classic migraine attacks

Regional cerebral blood flow (rCBF) following carotid arteriography was studied in thirteen patients with classic migraine. Using the 133xenon intraarterial injection method, rCBF was measured in 254 areas in one hemisphere. Nine patients developed a characteristic attack following arteriography and were examined by a series of rCBF studies, spaced by intervals of 5 to 10 minutes. A wave of reduced blood flow originating in the posterior part of the brain and progressing anteriorly was observed in eight of the nine patients. The oligemia advanced at a speed of 2 mm per minute over the hemisphere, progressing anteriorly but not crossing the rolandic or sylvian sulcus. Typically, the spreading oligemia reached the primary sensorimotor area after symptoms from that area had begun and persisted there long after the focal symptoms had disappeared. The observed time course suggests that the focal symptoms are not secondary to the oligemia. We suggest that focal symptoms and blood flow changes may be secondary to spreading depression of Leao.     

Topiramate in migraine prevention: results of a large controlled trial

BACKGROUND: Open-label trials and small controlled studies report topiramate's efficacy in migraine prevention. OBJECTIVE: To assess the efficacy and safety of topiramate as a migraine-preventive therapy. DESIGN: A 26-week, randomized, double-blind, placebo-controlled study. SETTING: Outpatient treatment at 49 US clinical centers.Patients Patients were aged 12 to 65 years, had a 6-month International Headache Society migraine history, and experienced 3 to 12 migraines per month, but had 15 or fewer headache days per month during the 28-day baseline period. INTERVENTIONS: Participants were randomized to placebo or topiramate, 50, 100, or 200 mg/d, titrated by 25 mg/wk to the assigned dose or as tolerated in 8 weeks; maintenance therapy continued for 18 weeks. MAIN OUTCOME MEASURES: The primary efficacy assessment was a reduction in mean monthly migraine frequency across the 6-month treatment phase. Secondary end points were responder rate, time to onset of action, mean change in migraine days per month, and mean change in rescue medication days per month. RESULTS: Four hundred eighty-seven patients were randomized, and 469 composed the intent-to-treat population. The mean +/- SD monthly migraine frequency decreased significantly for the 100-mg/d group (from 5.4 +/- 2.2 to 3.3 +/- 2.9; P <.001) and the 200-mg/d group (from 5.6 +/- 2.6 to 3.3 +/- 2.9; P <.001) vs the placebo group (from 5.6 +/- 2.3 to 4.6 +/- 3.0); improvements occurred within the first treatment month. Significantly more topiramate-treated patients (50 mg/d, 35.9% [P =.04]; 100 mg/d, 54.0% [P <.001]; and 200 mg/d, 52.3% [P <.001]) exhibited a 50% or more reduction in monthly migraine frequency than placebo-treated patients (22.6%). Adverse events included paresthesia, fatigue, nausea, anorexia, and taste per version. CONCLUSION: Topiramate, 100 or 200 mg/d, was effective as a preventive therapy for patients with migraine.     

5-Hydroxytryptophan versus methysergide in the prophylaxis of migraine. Randomized clinical trial

One hundred and twenty-four migraineurs were treated randomly with 5-hydroxytryptophan (5-HTP) or with methysergide (M). The two groups were homogeneous without significant statistical differences with respect to age, sex, pill use, type of migraine and frequency of attacks before entry. A significant improvement was observed in 75% of the patients treated with M and in 71% of the cases treated with 5-HTP. The most beneficial effect of 5-HTP appears to be felt with regard to the intensity and duration rather than the frequency of the attacks. Side effects were more frequent in the M group than in the 5-HTP group. These results suggest that 5-HTP could be a treatment of choice in the prophylaxis of migraine.     

Two different doses of Amitriptyline ER in the prophylaxis of migraine: long-term results and predictive factors

Background and purpose:  The rationale for our study was to examine the prophylactic benefit of two doses of amitriptyline over a 6-month observational period in patients with migraine. We aimed at evaluating whether 50 mg of amitryptiline extended release was more effective than 25 mg in reducing the number of migraine days.
Methods:  Primary outcome measure was the reduction of migraine days in time course (i.e., 3 and 6 months after patient enrolment). As secondary analyses, predictors of treatment response were evaluated. Treatment response was defined as reduction of ≥30% and ≥50% in migraine headache days in time course.
Results:  The intent-to-treat population comprised 132 patients (female 96; male 36) with migraine. Median migraine days per month were reduced from 7 days (range: 6–15) at baseline, to 6 days (range: 4–12; P  < 0.001) at 3 months, and to 6 days (range: 3–12; P  < 0.001) at 6 months, respectively. However, no statistically significant difference in the number of migraine days was seen between the two treatment groups at 3 and 6 months. As a result of secondary analyses, the number of migraine days per month at baseline was the only independent predictor of response to amitriptyline treatment (for both definitions of treatment response, i.e., response rate ≥30% and response rate ≥50%) at 6 months.
Conclusions:  The prophylactic effect of amitriptyline seen in our study was rather weak and did not differ between the two treatment groups. The results of this 6-month, prospective, open-label clinical observation are therefore not encouraging.     

The serotonergic agent m-chlorophenylpiperazine induces migraine attacks: A controlled study

In a double-blind study versus placebo, the serotonergic agent m-chlorophenylpiperazine (mCPP) was administered to 20 healthy control subjects and 19 migraineurs to investigate the ability of mCPP (0.5 mg/kg) to induce typical migraine attacks. In the following 24 hours there were more migraines after mCPP than after placebo in both groups. These findings are consistent with involvement of 5HT2B,2C,1A receptor subtypes in the pathophysiology of migraine.     

Timolol vs propranolol vs placebo in common migraine prophylaxis: a double-blind multicenter trial

Common migraine sufferers (25 males, 71 females) with a history of 2-6 attacks per month participated in a 4-centre trial comparing the prophylactic effect of timolol (10 mg b.i.d.) and propranolol (80 mg b.i.d.) to placebo. After a pretreatment period of 4 weeks they entered a double-blind 3-way cross-over trial with 3 treatment periods of 12 weeks each. 83 patients received all 3 treatments. The mean frequency of attacks per 28 days was 3.35 on timolol, 3.69 on propranolol and 4.83 on placebo. Mean severity of attacks (0-3) was 1.75 on timolol, 1.83 on propranolol, and 1.93 on placebo. Mean duration of attacks was 7.41 h on timolol, 7.38 on propranolol and 7.95 on placebo. The headache index (frequency times severity) was 5.71 on timolol, 6.66 on propranolol and 9.03 on placebo (P less than 0.05, P less than 0.01 compared to placebo). The difference between propranolol and timolol was non-significant: frequency of attacks 0.34 (95% confidence limits - 0.26; 0.89). Headache index 0.95 propranolol and 23 patients on placebo experienced side effects (P less than 0.05). It is concluded that timolol and propranolol are equally effective in the used doses (1:8) for common migraine prophylaxis.     

Smoking reduction during inpatient alcohol detoxification: a controlled clinical pilot trial

Health care professionals tend to advise alcohol dependent patients to quit tobacco consumption only after longer periods of alcohol abstinence. This recommendation reflects concerns that smoking intervention programs may adversely interfere with the outcome of ongoing alcohol detoxification and rehabilitation treatment. However, the issue of appropriate time windows for initiating changes of smoking behaviour in alcoholic patients is still in need of empirical evaluation. Thus the aim of the present study is to investigate whether alcohol dependent smokers may be able to reduce cigarette consumption very early during alcohol detoxification and rehabilitation treatment. We performed a non-randomized controlled clinical pilot trial with 56 female and male alcohol dependent smokers in an inpatient setting providing a 3-weeks alcohol detoxification program. 28 individuals received a smoking reduction program consisting of a 6-sessions approach in a group format following behavioural principles. For the control group of 28 individuals the program was not available. Tobacco consumption was assessed daily by staff members. Alcohol dependent patients participating in the smoking reduction program reduced their daily cigarette consumption rates significantly, whereas the control group showed a tendency to increase tobacco consumption. According to the tentative findings of this pilot study early smoking interventions already during alcohol detoxification appear to be a feasible approach.     

Valproate: a new drug in migraine prophylaxis

22 patients with severe migraine resistant to previous prophylactic treatments participated in a prospective open trial of valproate in migraine prophylaxis; 17 had common and 5 classic migraine. The attack frequency was from 4 to 16(30)/month (1 patient suffered from attacks every day). The dose of valproate was 600 mg twice a day from start of treatment, successively adjusted to a serum level about 700 mumol/l. Follow-up was from 3 to 12 months; 11 patients were free from migraine attacks, 6 had a significant reduction of the frequency; in one patient there was no effect; 4 dropped out because of lack of cooperation; 3 who had been free from migraine for 3 months, participated in a withdrawal experiment during which they all experienced relapse. After reinstitution of valproate the attacks disappeared again. How valproate acts in migraine prophylaxis is not known, but this prospective open trial demonstrates that valproate has an appreciable prophylactic effect in patients suffering from severe migraine, and calls for controlled clinical trials.