Drug dependence, including opioid addiction, is among the most challenging issues in many societies. Previous researches suggest that opioid use disorder to be the most common drug dependence in Iran.1
Opioid dependence because of long term drug addiction causes structural changes in the number and sensitivity of opioid receptors and also increases the sensitivity of neurons by various mediators. Abnormal physiological, behavioral, cognitive, and psychosocial signs and symptoms may therefore seem and encourage continued opioid consumption.2
Opioid dependence is a public health concern and patients’ motivation to withdraw from opioids is an important issue. If a patient is willing to discontinue drug dependence, opioid detoxification would be their first step.3 As drug detoxification may be associated with withdrawal symptoms, the method used for its accomplishment should be convenient and adequate, so as to make the withdrawal syndrome more bearable for the patient and enhance their compliance.4
Various methods have been proposed for the management of withdrawal syndrome, including methadone maintenance therapy, synthetic opioid consumption,5 the administration of buprenorphine as a partial opioid agonist,6 and even ɑ2 agonists such as clonidine, which have reported success rates of 10% to 90%.7
New methods are being increasingly proposed for this syndrome. Gabapentin is one of the drugs recommended for the management of opioid withdrawal syndrome.8 This drug is a GABA-stimulator used for drug-resistant seizures as well as postherpetic neuralgia. It has also proved to be a successful regimen for the management of cocaine and alcohol withdrawal syndrome.9,10 Gabapentin selectively inhibits voltage gated Ca2+-channels and entails an increase in GABA-neurotransmission as well as a modulation of excitatory amino acids at NMDA receptor sites, which are increased during the withdrawal period.11,12
Pregabalin is a medication that is similar to gabapentin regarding its mechanism of action; however, the number of studies conducted on the effectiveness of this medication in the treatment of opioid withdrawal symptoms is small and there is very little information available on the medication.11 In addition, pregabalin has a higher half-life compared to gabapentin, which may contribute to the patients’ compliance.13
The present clinical trial was conducted to assess the effects of pregabalin on opioid withdrawal syndrome.
This double-blind, randomized, controlled trial was conducted on noninjection opioid users diagnosed with opioid dependence based on the Diagnostic and Statistical Manual of Mental Disorders V [DSM-V]9 who were referred to the Addiction Treatment Center of Khorshid Hospital in Isfahan, Iran, in 2015 to 2016.
Written informed consent was obtained from the participants and the research was approved by the ethics committee of Isfahan University of Medical Sciences.
The inclusion criteria consisted of (1) meeting the DSM-V criteria for drug dependence, (2) regular/daily consumption of opioid orally or by smoking, (3) using no other medications, including psychiatric drugs and other substances, except for cigarettes, (4) not taking any pain medications, (5) the absence of comorbid psychiatric disorders, (6) no comorbidities necessitating opioid use and prohibiting withdrawal, (7) no contraindications for pregabalin consumption, and (8) not using any medications that could interact with pregabalin.
The exclusion criteria consisted of (1) not consenting to participation in the study or unwillingness to continue participation, (2) any ethical or medical conflicts for continuation, and (3) the incidence of physical/mental complications requiring special interventions.
This study was double-blind and both the patients and the evaluator were blinded.
The patients were divided into 2 groups by decussation based on visiting time. The intervention group received pregabalin and the control group was treated with placebos.
The sample size was 18 per group, and 2 patients in the intervention group and 4 in the control group were excluded from the study because of noncompliance (Fig. 1).
Pregabalin was produced by Sobhan Darou Co. in Tehran, Iran. Its administration began at the dose of 150 mg for the first week and increased to 300 mg for the next week. In the third and fourth weeks, the patients were administered 450 mg of pregabalin and it was then tapered. The placebo drug was also produced in a similar appearance with the assistance of the School of Pharmacy and Pharmaceutical Sciences of Isfahan University of Medical Sciences.
All the patients in both groups were candidates of detoxification with buprenorphine. The buprenorphine dose was adjusted based on the patients’ withdrawal symptoms severity, and all the patients were stabilized (no complain of withdrawal symptoms) on buprenorphine within 3 to 5 days. Buprenorphine tapering began on the seventh day of the study with a similar pattern for all the patients within 2 weeks, and the final dose of buprenorphine was administered on the 21st day.
All the patients completed the Short Opioid Withdrawal Scale (SOWS) the day before beginning their buprenorphine tapering (sixth day) as the baseline for the assessment of withdrawal symptoms. They recompleted the scale 4 times at 1-week interval during the tapering of buprenorphine (2 weeks) and during the follow-up (another 2 weeks).
Table 1 presents the results of the SOWS, which is a 10-item scale for evaluating the severity of opioid withdrawal symptoms based on a Likert scale from 0 (no symptoms) to 3 (severe symptoms). The SOWS is simple to understand and easy to administer and does not have the redundant items of the original scale. The SOWS is proposed as a useful instrument that can be used both in research and clinical practice with opioid addicts.10
Data were analyzed in IBM SPSS-20 (USA). Descriptive data were reported as mean±SD. The analytic data were analyzed using the repeated-measures ANOVA. The level of statistical significance was set at P<0.05.
This study was conducted on 30 patients, including 28 male and 2 female patients. The participants were divided into 2 groups, including 16 patients (2 females) who received pregabalin and 14 patients who were treated with placebo (P=0.49). The mean age of the patients was 41.58±10.09 years in the intervention group and 44±8.87 in the control group (P=0.47).
Table 2 presents the mean scores of each symptom before beginning medication administration (i.e. at baseline), in the first week, the second week, the third week, and the fourth week of medication administration. Figure 2 also presents these findings.
Table 3 presents the side-effects reported by the patients in both groups.
Managing the symptoms of opioid withdrawal syndrome is important because it determines the success of their withdrawal. Various methods have been tested for managing these symptoms, but there is still no unanimously agreed-upon method. The present study assessed the effectiveness of pregabalin in reducing opioid withdrawal symptoms.
Using 450 mg/d of pregabalin did not prove superior to placebo in this study. None of the symptoms evaluated using the SOWS were significantly lower in the intervention group compared with the controls during the 4 weeks of the study. In addition, although pregabalin was well-tolerated, half of those who received this medication complained of headache. Nevertheless, the frequency of this complaint decreased significantly during the assessment period.
Pregabalin affects monoamine release in “hyperexcited” neurons. The binding site of pregabalin is the α2δ subunit of the calcium channels. Previous studies have noted the positive effects of this medication on the withdrawal symptoms of patients with benzodiazepine and alcohol dependence.11
The present study was conducted using the SOWS. An advantage of this scale is that it is objective, since it is filled out by a psychiatrist and its rate of bias is therefore significantly decreased.
This study showed that none of the symptoms assessed in the SOWS reduced significantly in the pregabalin group during the 4 weeks of the study compared with the control group. Krupitsky EM et al compared pregabalin with Clonidine and found that pregabalin results in less craving, depression and anxiety after opioid withdrawal, but the opioid withdrawal syndrome severity was not significantly different between their 2 groups. Their results were confirmed by a psychiatrist. The patients’ self-assessment were in accordance with the psychiatrist’s assessment, as the patients who used pregabalin reported better health during the follow-ups compared to those who received clonidine.12 This disparity of findings may be due to the lower dose of pregabalin administered in the present study.
The side-effects of pregabalin were also assessed during the 4 weeks of this study. The medication proved well-tolerated and the approximate rate of complaints about its side-effects decreased over time. The most frequent side-effect reported by the patients was fatigue, but it subsided during the follow-up; 9 patients complained of fatigue in the first week, but this number reduced to 2 in the fourth week (P=0.008). In general, pregabalin seems to be well tolerated by patients. The other discussed study reported similar results.12
Pregabalin is similar to gabapentin, and gabapentin has been used as a single therapy as well as an add-on therapy for opioid withdrawal syndrome. Perez-Galvez and colleagues found an acceptable tolerability and few side-effects for gabapentin as an add-on therapy for managing the symptoms of opioid withdrawal. It should be noted, however, that their study was conducted on seven subjects only.13 Kheirabadi and colleagues compared gabapentin and placebo and found that a 900-mg/day dose is not significantly superior to placebo medications. Nonetheless, they assessed gabapentin while the present study evaluated pregabalin, and the reason for the lack of a difference between the pregabalin and placebo groups in the present study could well be the dose of pregabalin used.
The administration of 450 mg/d of pregabalin did not prove superior to the administration of placebo for relief from the symptoms associated with opioid withdrawal syndrome, but this medication was well tolerated by the patients. Further studies are recommended on the subject.
Limited number of the participants and outpatient setting of study and poor control on probable self-medication were the main limitations of this study.
The authors thank all participants and the staff of addiction treatment center in Khorshid hospital in Isfahan University of Medical Science as the field of study.
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