BACKGROUND: Effective pharmacologic treatments for comorbid alcohol use disorder (AUD) and post-traumatic stress disorder (PTSD) are lacking. Kappa (κ) opioid receptor antagonists may address this unmet need. Buprenorphine is a κ-opioid antagonist and a partial agonist of mu (μ) opioid receptors, and naltrexone blocks all μ-mediated effects, thus, yielding a pharmacological net effect of a κ-opioid receptor antagonist. This combination was tested in this proof-of-concept study since no specific κ-opioid receptor antagonist was available.

METHODS: Consenting participants were enrolled in a Phase II, multisite, double-blinded, randomized, placebo-controlled trial to evaluate the effectiveness of sublingual buprenorphine combined with extended-release (XR) injectable naltrexone for the treatment of comorbid AUD and PTSD. Eligible participants (n=75) were randomized (1:1:1) to receive either buprenorphine 2mg/d plus naltrexone-XR (n=35), buprenorphine 8mg/d plus naltrexone-XR (n=6) or sublingual plus injectable placebo (n=34) for 12 weeks. The buprenorphine 8mg/d plus naltrexone-XR arm was dropped early due to the negative impact of COVID-19 on enrollment. A binary primary outcome of response at week 8 was defined as a decrease from baseline of ≥10 points on the past week Clinician-Administered PTSD Scale (CAPS-5) and a reduction of ≥1 of past month alcohol risk level, as defined by World Health Organization (WHO) and measured by the Timeline Follow-Back.

RESULTS: Based on the results of a futility analysis, enrollment was stopped prior to reaching initial goal of 90 participants. At the week 8 primary timepoint, there were no statistically significant differences between buprenorphine plus naltrexone-XR and placebo group for the primary composite outcome, or the subcomponents of the PTSD outcome and AUD outcome. The placebo arm had a significantly higher proportion of participants with ≥1 WHO risk reduction compared to the buprenorphine plus naltrexone-XR arm.

CONCLUSIONS: This is the first study to evaluate the potential of κ-opioid receptor antagonism for the treatment of comorbid AUD and PTSD. The combination of buprenorphine and naltrexone-XR showed no significant improvement over placebo for the composite, PTSD or alcohol measures.