Does pregabalin cause tolerance when treating generalised anxiety disorder (GAD)?/nThe questioner h

Fråga: Does pregabalin cause tolerance when treating generalised anxiety disorder (GAD)?

The questioner has had several patients with anxiety disorders including GAD who have responded well to pregabalin but the effect has declined and not even improved with increasing doses.

Sammanfattning: Relapse is common during treatment of GAD but we have not found any evidence of pregabalin tolerance.

Svar: Pregabalin is chemically a GABA analogue but the main effect of pregabalin is thought to be mediated by binding to a subunit of voltage dependent calcium channels in the central nervous system. Pregabalin inhibits the release of several neurotransmitters including glutamate, noradrenaline and substance P. Pregabalin does not bind to GABAA or GABAB receptors and does not influence reuptake or degradation of GABA. Pregabalin is approved for treatment of epilepsy, peripheral neuropathy and generalised anxiety disorder (1).

The mean pregabalin dose and the pooled VAS scores were stable in a cohort of 517 patients with neuropathic pain treated for at least 420 days. This indicates that pregabalin does not cause tolerance. Only minor changes in pregabalin dose was needed to maintain efficacy in a cohort of epilepsy patients treated for two years (1).

The documentation of long term treatment with pregabalin in patients with GAD is sparse and most studies have investigated the effect for 4-6 weeks. One study has investigated the effect during 24 weeks of treatment. The study had a run in phase were patients were given pregabalin for eight weeks. The patients responding to pregabalin were then randomised to pregabalin or placebo treatment for 24 weeks. About 46 percent of the patients discontinued pregabalin during the run-in period mostly due to adverse events. 168 patients were randomised to pregabalin 450 mg/d and 170 patients were randomised to placebo. The time to relapse was significantly longer in the pregabalin group compared to the placebo group. One fourth of the patients in the placebo group had relapsed by day 14 in the placebo group and by day 23 in the pregabalin group. At study end 65% of the placebo patients had met relapse criteria and 12% had completed the study without relapse. In the pregabalin group 42% met relapse criteria and 21% completed the study without any relapse (2). This study shows that relapse is common during treatment of GAD but it does not answer the question about tolerance development.

In the Swedish Adverse Drug Reactions Register there are two reports of increased tolerance in patients with anxiety. In both cases the patients had a history of substance abuse and they rapidly became tolerant to pregabalin and increased their doses up to 1200 mg/d and 3000 mg/day respectively. There are also several reports of pregabalin abuse in the register (3). 1 Scientific discussion EMEA 2004; pp. 1-42 Feltner D, Wittchen HU, Kavoussi R, Brock J, Baldinetti F, Pande AC. Long-term efficacy of pregabalin in generalized anxiety disorder. Int Clin Psychopharmacol 2008;23(1):18-28 Swedis (cited 2009-11-23)