Selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headaches.

BACKGROUND: Headache is a common medical problem. In view of recent discoveries about the role of serotonin in pain mechanisms, selective serotonin re-uptake inhibitors (SSRIs) have been evaluated for the prevention of migraine and tension-type headaches (TTH). OBJECTIVES: To evaluate the efficacy and tolerability of SSRIs for preventing migraine and TTH. SEARCH STRATEGY: We searched MEDLINE (1966-2004), EMBASE (1994-2003), the Cochrane Central Register of Controlled Trials (Issue 4, 2003), and reference lists of retrieved articles. Headache Quarterly was hand searched from 1990 to 2003. SELECTION CRITERIA: We included randomised controlled trials comparing SSRIs with any type of control intervention in patients of either sex, over 18 years of age, with migraine or TTH. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data (headache frequency, index, severity, and duration; use of symptomatic/analgesic medication; days off work; quality of life; mood improvement; cost-effectiveness; and adverse events) and assessed the methodological quality of trials. MAIN RESULTS: Thirteen studies utilizing five SSRIs met the inclusion criteria (636 participants). Most of the included studies had methodological and/or reporting shortcomings; follow up rarely extended beyond 3 months. After 2 months SSRIs did not significantly lower headache index scores in patients with migraine when compared to placebo (SMD -0.14; 95% CI -0.57 to 0.30). Patients with chronic TTH treated with an SSRI had a significantly higher analgesic intake of 5 more doses per month when compared to patients treated with a tricyclic antidepressant (WMD 4.98; 95% CI 1.12 to 8.84). Tricyclics also significantly reduced headache duration by 1.26 hours per day (WMD 1.26; 95% CI 0.06 to 2.45) and marginally reduced headache indexes (SMD 0.42; 95% CI 0.00 to 0.85) when compared to SSRIs in patients with chronic TTH. When the data on adverse events were considered without regard to headache diagnostic subgroups, there were no significant differences between SSRIs and placebo for withdrawals due to adverse events (Peto OR 1.02; 95% CI 0.31 to 3.34). For minor adverse events, SSRIs were generally more tolerable than tricyclics (OR 0.34; 95% CI 0.13 to 0.92). However, there were no differences in the number of patients withdrawing due to any reason in the SSRI and tricyclic groups (OR 1.01; 95% CI 0.56 to 1.80). AUTHORS' CONCLUSIONS: Over 2 months of treatment, SSRIs are no more efficacious than placebo in patients with migraine. In patients with chronic TTH, SSRIs are less efficacious than tricyclic antidepressants. In comparison with SSRIs, the burden of adverse events in patients receiving tricyclics was greater. These results are based on short-term trials and may not generalise to longer-term treatment.

Plasma concentrations of carbamazepine and carbamazepine 10,11-epoxide during pregnancy and after delivery.

Plasma concentrations of carbamazepine were monitored in 9 pregnant epileptic patients treated with the drug alone at constant doses during pregnancy and for at least 3 months after delivery. In addition, plasma concentrations of the metabolite, carbamazepine 10,11-epoxide were measured in 6 of the 9 patients. Plasma carbamazepine concentrations were fairly stable during pregnancy, and carbamazepine relative plasma clearances were significantly higher in weeks 4 to 24 than in weeks 25 to 32. After the end of the second trimester, there were no variations in plasma carbamazepine 10,11-epoxide concentrations and carbamazepine 10,11-epoxide:carbamazepine ratios. Both parameters were significantly higher in weeks 4 to 24 than in weeks 25 to 32 of pregnancy.

Changes in primidone/phenobarbitone ratio during pregnancy and the puerperium.

Plasma concentrations of primidone and its metabolite phenobarbitone were monitored in 9 pregnant epileptic patients treated with primidone (and in 3 cases other antiepileptic drugs) given at constant doses throughout pregnancy and the puerperium. Phenobarbitone plasma concentrations were monitored in another 6 patients given phenobarbitone itself. A trend towards increasing primidone plasma concentrations during the second quarter of pregnancy was evident in all patients, with a concomitant significant decrease in primidone-derived phenobarbitone plasma concentrations. A trend towards a lowering of plasma concentrations of phenobarbitone administered as such was confirmed. These results suggest the usefulness of a careful monitoring of primidone and primadone-derived phenobarbitone during pregnancy and the puerperium. Discrepancies of findings with primidone and phenobarbitone are discussed in view of the possible mechanism involved.

Change of seizure frequency in pregnant epileptic women.

The effect of pregnancy on seizure frequency was monitored prospectively in 136 pregnancies of 122 epileptic women. Pregnancy did not influence the seizure frequency in 68 pregnancies (50%). In 50 pregnancies (37%) the number of seizures increased during pregnancy or puerperium. The seizure frequency decreased in 18 pregnancies (13%). In 34 out of 50 pregnancies (68%) the increase was associated with non-compliance with the drug regimen or sleep deprivation. In seven out of 18 pregnancies (39%) improvement was related to correction of non-compliance or sleep deprivation during the pregestational nine months. Insufficiently low plasma concentrations of antiepileptic drugs were found in 47% of the women with uncontrolled epilepsy during pregnancy. The course of epilepsy during pregnancy is primarily influenced by non-compliance, sleep deprivation during pregnancy, and inadequate therapy before and during pregnancy. With good medical attention pregnancy itself seems to have only a minimal influence on the course of epilepsy.

Plasma levels of primidone and its metabolite phenobarbital: effect of age and associated therapy.

The effects of age and associated therapy on plasma primidone (PRM) and derived phenobarbital (PB) concentrations, and on plasma concentrations-to-PRM dose ratios (L/D ratio) were evaluated retrospectively from 408 consecutive PRM and derived PB determinations in 238 chronically treated epileptic patients (153 children and adolescents between 5 months and 15 years of age and 85 adults between 16 and 55 years of age). The correlation between PRM administered and both plasma PRM and derived PB levels was significant; the correlation between PRM and PB plasma levels was also significant, but the scatter of values for the linear regressions was such that the relationship had no predictive value. Significant differences in mean plasma PRM and PB L/D ratios were found between patients aged 0-3 years, 4-9 years, 10-15 years, and adults (16-55 years), with higher values in the older groups. The PB/PRM concentration ratios were significantly lower in children than in adolescents and adults. Concomitant treatment with carbamazepine affected PRM disposition and led to increased L/D ratios for PB and decreased L/D ratios for PRM, whereas phenytoin increased the L/D ratios for PB without any significant change in the L/D ratios for PRM. The variability in the results indicates the need for routine monitoring of PRM and derived PB plasma levels, particularly in pediatric populations, in order to tailor the dose to each patient.

Comparison of the effectiveness of several formulations of sodium valproate: tablets, enteric-coated capsules, solutions and rectal capsules.

The effects of an oral enteric-coated preparation (VAL 579 capsules) of sodium valproate (VPA) were compared with those of conventional oral and rectal preparations in 24 epileptic patients. Enteric-coated capsules are useful for avoiding gastric intolerance to VPA. Plasma VPA level peaks after the enteric- coated form were later than after other forms. The bioavailability appeared to be the same for all the forms.

Ethosuximide plasma concentrations: influence of age and associated concomitant therapy.

The relationship between oral dose and plasma concentration of ethosuximide was evaluated retrospectively in 198 epileptic patients aged 2.5 to 34 years. Age appears to be a major factor in determining the ethosuximide plasma level/dose (L/D) ratio. Children younger than 10 years had men L/D ratios significantly lower (p less than 0.0003) than adolescents (10 to 15 years of age) and adults (16 to 34 years of age). Associated antiepileptic therapy reduced the ethosuximide L/D ratio: mean ethosuximide L/D ratios were significantly lower in patients also taking primidone (p less than 0.0005) or valproic acid (p less than 0.02). The correlation between the dose of ethosuximide administered and the plasma concentration was significant in the 3 age groups considered (p less than 0.0004), but the wide scattering of individual plasma concentrations makes it impossible to predict what plasma concentration of ethosuximide will be obtained after a given dose. For this reason, routine monitoring of ethosuximide plasma concentrations still appears to be necessary, especially in children and patients on polytherapy.