Trazodone and valproate in patients discontinuing long-term benzodiazepine therapy: effects on withdrawal symptoms and taper outcome

Abstract

Recent uncontrolled research suggested that trazodone and sodium valproate may be helpful in benzodiazepine (BZ) discontinuation. We therefore undertook a double-blind study to assess whether trazodone and valproate, as compared to placebo, would attenuate withdrawal and facilitate discontinuation in BZ-dependent patients with a minimum of 1 year daily BZ use. Seventy-eight patients, taking a mean dose of 19+/-17 mg/day of diazepam (or its equivalent), were stabilized for several weeks on their BZ (16 diazepam, 25 lorazepam, 37 alprazolam) and then for 1-2 weeks, pretreated with trazodone, sodium valproate or placebo before being tapered at 25% per week. All treatments were continued for 5 weeks post-taper. BZ-free status was assessed after 5 and 12 weeks post-taper. Neither trazodone nor valproate had any significant effect on withdrawal severity. Peak physician withdrawal checklist change from baseline to peak severity was 16.4 for trazodone, 18.04 sodium valproate and 18.24 placebo (F = 0.10; NS). Taper success rates were significantly effected by both active agents at the 5-week, but not 12-week, assessment. At 5 weeks post-taper, 79% of sodium valproate and 67% of trazodone, but only 31% of placebo patients were BZ-free (chi2 = 7.34; df 2; P<0.03). Major adverse events for trazodone were sedation and dry mouth, and for valproate, diarrhea, nausea and headaches.

Discriminative Stimulus Effects of Positive GABAAModulators and Other Anxiolytics, Sedatives, and Anticonvulsants in Untreated and Diazepam-Treated Monkeys

“…Valproic acid enhances the anesthetic effects of ethanol and a barbiturate (Hoffman and Habib, 1994), suggesting that valproic acid can modulate effects of some positive GABA A modulators. The ability of valproic acid to attenuate the flumazenil discriminative stimulus in diazepam-treated monkeys is consistent with some (Harris et al, 2000) and not other (Rickels et al, 1999) results obtained in benzodiazepine-dependent subjects.…”

BAP updated guidelines: evidence-based guidelines for the pharmacological management of substance abuse, harmful use, addiction and comorbidity: recommendations from BAP

“…Garfinkel et al (1999) (IIb) reported discontinuation rates of 77% with the addition of melatonin compared with 25% with gradual dose reduction alone. Rickels et al (1999) (Ib) added sodium valproate, trazodone or placebo to a benzodiazepine taper. At 5 weeks post-taper, 79% of sodium valproate and 67% of trazodone, but only 31% of placebo patients were benzodiazepine free.…”

Anticonvulsant Agents for the Management of Benzodiazepine Dependence

“…Classic AC, such as Carbamazepine (CBZ) and Valproate (VPA), especially CBZ, have been widely studied for the treatment of BD and BWS [17,30]. However, because of their drug-to-drug interactions, the need of careful monitoring of serum drug levels, and hepatic and hematologic toxicity, their use is limited [31].…”

“…Taper success did not remain significant at 12-week follow-up. Major adverse events for VPA were diarrhea, nausea and headache [17].…”

“…A great variety of agents have been used as adjuvant medication in BWS with varying degrees of success. Such agents include antidepressants such as mirtazapine [14], paroxetine [15], trazodone [16,17], dothiepin [18] and imipramine…”