A RANDOMIZED SINGLE-BLIND SYMPTOM-REGULATED CONTROLLED TRIAL OF THE EFFICACY AND SAFETY OF PREGABALIN IN THE TREATMENT OF OPIOID WITHDRAWAL SYNDROME
Introduction. Existing detoxification protocols (treatment of opioid withdrawal syndrome, OWS) are poorly tolerated resulting in that many patients do not complete treatment. Hyperalgesia, sleep disturbances and anxiety are the main symptoms of OWS. Pregabalin is an effective analgesic, anxiolytic and hypnotic medication. This study tested the hypothesis that pregabalin can be a safe and effective adjunct to opioid detoxification therapy. The interim outcomes of this trial were encouraging and here we present the final results. Methods. Study design: a randomized single-blind symptom-regulated trial with an active control. 100 patients with OWS admitted to an inpatient addiction treatment program were randomly assigned to one of two groups. The first group of patients (n=51) received pregabalin in a dose of up to 600 mg/day for 6-7 days in combination with symptomatic therapy, that was divided into basic treatment that was given to all patients (doxylamine, 30 mg/day) and additional medications based on patients' needs as determined by a psychiatrist with the use of the Opioid Withdrawal Scale; the latter therapy included ketorolac, loperamide, metoclopramide, naphazoline and phenazepam. Patients in the second group (n=49) received clonidine (up to 600 mcg/day) as the main treatment along with the same basic and symptomatic regimen. Opiate withdrawal severity, craving, sleep disturbances, anxiety and depression, as well as general clinical impressions and side effects were assessed daily using internationally validated quantitative psychometric instruments by psychiatrists who were blind to patients' group assignment. Results. At baseline, the two patient groups did not differ significantly by their demographic and clinical characteristics and OWS severity. In the pregabalin group, 38 of 51 patients completed treatment (74.5%) compared to 22 of 49 patients (44.9%) in the clonidine group (p=0.01; Fisher's exact test). Kaplan-Meier survival analysis also confirmed better retention in treatment in the pregabalin group (p=0,003; Log Rank (Mantel-Cox) criterion). Pregabalin was superior to clonidine on self-rated and physician-rated OWS severity scales (reduction of the severity of OWS), Clinical Global Impression Scale (Severity subscale - CGI-S), Hospital Anxiety Depression Scale (both Depression and Anxiety subscales), and the Visual Analog Scales of Pain. An average symptom-triggered ketorolac dose was significantly lower in the pregabalin group: 34.36 (SD=35.30) mg vs. 44.94 (SD=37.76) mg in the clonidine group (p=0.001). There were no significant differences in the frequency of side effects (adverse events) between the groups, however, the frequency of manifestations of fatigue and central depriming effect of the therapy in the pregabalin group was lower than in the clonidine group (17.6% vs. 46%, p=0.02). There was a tendency close to statistical significance in lower craving for opioids in the pregabalin group compared to the clonidine group. Reduced craving, fatigue and analgesic requirements in patients of the pregabalin group indicated that they tolerated opioid withdrawal better than the clonidine comparison group, and this could lead to a higher percentage of patients who completed detoxification in this group. Conclusions. These findings indicate that pregabalin-based opioid withdrawal (detoxification) protocol is likely to be safe and effective and results in better outcomes than the usual clonidine-based protocol. The mechanism underlying this effect is likely to be related to a reduction in glutamate release from hyper-excited glutamatergic neurons which might have a modulating effect on the functioning of the system of endogenous opioid neuropeptides.