Elsevier

Drug and Alcohol Dependence

Volume 154, 1 September 2015, Pages 38-45
Drug and Alcohol Dependence

The effects of dronabinol during detoxification and the initiation of treatment with extended release naltrexone

https://doi.org/10.1016/j.drugalcdep.2015.05.013Get rights and content

Highlights

  • We examined effects of THC in opioid dependent individuals treated with naltrexone.

  • Oral THC decreased the severity of opioid withdrawal severity at treatment outset.

  • Oral THC did not improve retention in treatment with injectable naltrexone.

  • Naturalistic marijuana smoking was associated with improved retention in treatment.

Abstract

Background

Evidence suggests that the cannabinoid system is involved in the maintenance of opioid dependence. We examined whether dronabinol, a cannabinoid receptor type 1 partial agonist, reduces opioid withdrawal and increases retention in treatment with extended release naltrexone (XR-naltrexone).

Methods

Opioid dependent participants were randomized to receive dronabinol 30 mg/d (n = 40) or placebo (n = 20), under double-blind conditions, while they underwent inpatient detoxification and naltrexone induction. Before discharge all participants received an injection of XR-naltrexone, with an additional dose given four weeks later. Dronabinol or placebo was given while inpatient and for 5 weeks afterwards. The primary outcomes were the severity of opioid withdrawal, measured with the Subjective Opioid Withdrawal Scale, and retention in treatment at the end of the inpatient phase and at the end of the 8-week trial.

Results

The severity of opioid withdrawal during inpatient phase was lower in the dronabinol group relative to placebo group (p = 0.006). Rates of successful induction onto XR-naltrexone (dronabinol 66%, placebo 55%) and completion of treatment (dronabinol 35%, placebo 35%) were not significantly different. Post hoc analysis showed that the 32% of participants who smoked marijuana regularly during the outpatient phase had significantly lower ratings of insomnia and anxiety and were more likely to complete the 8-week trial.

Conclusion

Dronabinol reduced the severity of opiate withdrawal during acute detoxification but had no effect on rates of XR-naltrexone treatment induction and retention. Participants who elected to smoke marijuana during the trial were more likely to complete treatment regardless of treatment group assignment.

Introduction

Rates of prescription opioid and heroin use and related morbidity and mortality continue to grow at an alarming rate (SAMHSA, 2013) with a parallel increase in unintentional overdose deaths (CDC, 2012). Treatment with opioid agonists, methadone and buprenorphine is a time-honored and effective approach to manage opioid dependence, however, agonists are not effective for all patients. Approximately 50% of individuals continue using opioids or other drugs, or drop out during the first 6 months of treatment (Mattick et al., 2008, Soyka et al., 2008). Treatment with the opioid receptor antagonist is an alternative treatment approach that has the potential to address some of the limitations of agonists and attract and retain more patients in stable long-term recovery (SAMHSA, 2012). In patients who are able to initiate treatment with extended-release naltrexone, the overall effectiveness of treatment is comparable with agonists with regard to treatment retention (50–70%) with lower rates of ongoing opioid use (Bisaga et al., 2014, Brooks et al., 2010, Comer et al., 2006, Krupitsky et al., 2011).

Initiation of naltrexone treatment is best accomplished while the patient is completing residential treatment. For patients who are opioid dependent, initiation of naltrexone during detoxification is associated with significant withdrawal symptoms. An alternative approach, to wait for 7–10 days post-detoxification before administering naltrexone, results in high rates of relapse. Strategies for easing the rapid transition from agonist to antagonist generally involve a brief course of buprenorphine, followed by use of non-opioid medications to attenuate withdrawal symptoms (Sigmon et al., 2012). Nonetheless withdrawal symptoms can still be substantial, reducing success rates of naltrexone induction. Further, patients who start naltrexone frequently experience protracted withdrawal symptoms that persist for 2–3 weeks and may further limit naltrexone's acceptability and adherence. Approximately 30–40% of individuals who start detoxification leave treatment prior to receiving the first injection of XR-naltrexone and another 30–40% will drop out during the first 2 months of outpatient treatment (Bisaga et al., 2014, Comer et al., 2006, Nunes et al., 2006).

Ascertaining an adjunctive medication to alleviate acute and protracted withdrawal symptoms could have a significant impact on improving effectiveness of naltrexone and help with its widespread implementation. Observational data from several independent studies, and clinical experience, suggest that patients who use marijuana following induction onto naltrexone have better retention in treatment as compared to individuals who do not use marijuana (Church et al., 2001, Raby et al., 2009). This finding suggests marijuana may help alleviate withdrawal symptoms early in the course of naltrexone treatment and points to the role of the endocannabinoid system in preventing opioid dependence relapse.

The endocannabinoid system is involved in the maintenance of drug addiction, and targeting this system has been proposed as an approach to treatment (Panlilio et al., 2013, Scavone et al., 2013a, Serrano and Parsons, 2011). The cross-regulation between cannabinoid and opioidergic pathways has been well documented in preclinical studies (Robledo et al., 2008). Chronic exposure to opioids produces profound changes in the endocannabinoid system (Lopez-Moreno et al., 2008, Parolaro et al., 2010), possibly contributing to behavioral abnormalities emerging during early abstinence. Preclinical studies show that cannabinoid agonists reduce the severity of precipitated opioid withdrawal (Frederickson et al., 1976, Lichtman et al., 2001, Vela et al., 1995, Yamaguchi et al., 2001) possibly by modulating opioid signaling in noradrenergic cells of coeruleo-cortical pathways (Scavone et al., 2013a). Therefore, targeting cannabinoid systems may be a viable therapeutic strategy in opioid dependence.

We conducted a double blind, placebo-controlled trial of dronabinol in combination with XR-naltrexone among opioid-dependent patients. Dronabinol is oral synthetic Δ9tetrahydrocannabinol, the primary psychoactive cannabinoid in marijuana and a cannabinoid receptor type 1 partial agonist (Pertwee, 2009). We hypothesized that administering dronabinol during detoxification and the first weeks of treatment with XR-naltrexone would diminish the severity of opioid withdrawal and, as a result, improve treatment retention and reduce rates of opioid use as compared to treatment with placebo.

Section snippets

Participants

Opioid-dependent individuals seeking treatment were evaluated at an outpatient research clinic using the Structured Clinical Interview for DSM-IV (First et al., 1995) and a clinical interview assessing substance abuse severity. Medical evaluation included history, laboratory tests, electrocardiogram together with physical and psychiatric exam. The Institutional Review Board of the New York State Psychiatric Institute approved the study.

Eligible individuals were between 18 and 60 years old who

Sample characteristic

Participants were on average 38 years of age (SD 11.3), mostly male (85%), and primarily White (58%) or Hispanic (30%). Participants reported using an average of 10 bags of heroin per day (SD 7.6), 50% were injecting heroin and 16% were using prescription opioids (Table 1). Eleven participants (18%) were regular smokers of marijuana (smoked at least once weekly by self-report confirmed with THC positive urine toxicology) prior to study enrollment. Those who smoked marijuana prior to study

Discussion

In this double-blind and placebo controlled clinical trial of a cannabinoid agonist for opioid-dependent patients undergoing treatment with XR-naltrexone, dronabinol (30 mg per day) reduced opioid withdrawal symptoms during the acute inpatient phase of withdrawal and naltrexone initiation. This beneficial effect of dronabinol appeared (based on inspection of the observed data, Fig. 2) to occur mainly during the first few days of opioid detoxification, before oral naltrexone began to be

Role of funding source

Funding for this study was provided by NIDA grant R01 DA027124 (Dr. Bisaga) and K24 DA022412 (Dr. Nunes). The funding sources had no involvement in study design, in the collection, analysis and interpretation of data, in the writing of the report, or in the decision to submit the article for publication.

Contributors

AB, MAS, EVN, MH, and WNR conceived the study design. AB and MAS wrote the protocol, supervised the study and were responsible for patient care. WNR, FRL, KMC, and JJM participated in data collection and provided patient care. AB and KM were responsible for data collection and management. AG and MP were responsible for data analysis and wrote the Results section of the manuscript. AB wrote the first draft of the manuscript. All authors contributed to the interpretation of the results. All

Disclosures

Dr. Bisaga received honoraria, consultation fees and travel reimbursement for training, medical editing and market research from UN Office on Drugs and Crime, The Colombo Plan, Motive Medical Intelligence, Healthcare Research Consulting Group, GLG Research Group, and Guidepoint Global, and he received medication, extended-release naltrexone, for NIH funded research studies from Alkermes. Dr. Sullivan has recently transitioned to become an employee of Alkermes. Dr. Haney received consulting fees

Acknowledgements

We wish to thank Nabil Khan, Daniel Brooks and the staff of STARS treatment program as well as the pharmacy staff and the staff of the inpatient unit for their contribution to this project. Special thanks go to the patients participating in the study.

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