Delta-9-tetrahydrocannabinol modulates pain sensitivity among persons receiving opioid agonist therapy for opioid use disorder: A within-subject, randomized, placebo-controlled laboratory study

Abstract

The opioid and cannabinoid receptor systems are inextricably linked-overlapping at the anatomical, functional and behavioural levels. Preclinical studies have reported that cannabinoid and opioid agonists produce synergistic antinociceptive effects. Still, there are no experimental data on the effects of cannabinoid agonists among humans who receive opioid agonist therapies for opioid use disorder (OUD). We conducted an experimental study to investigate the acute effects of the delta-9-tetrahydrocannabinol (THC) among persons receiving methadone therapy for OUD. Using a within-subject, crossover, human laboratory design, 25 persons on methadone therapy for OUD (24% women) were randomly assigned to receive single oral doses of THC (10 or 20 mg, administered as dronabinol) or placebo, during three separate 5-h test sessions. Measures of experimental and self-reported pain sensitivity, abuse potential, cognitive performance and physiological effects were collected. Mixed-effects models examined the main effects of THC dose and interactions between THC (10 and 20 mg) and methadone doses (low-dose methadone defined as <90 mg/day; high dose defined as >90 mg/day). Results demonstrated that, for self-reported rather than experimental pain sensitivity measures, 10 mg THC provided greater relief than 20 mg THC, with no substantial evidence of abuse potential, and inconsistent dose-dependent cognitive adverse effects. There was no indication of any interaction between THC and methadone doses. Collectively, these results provide valuable insights for future studies aiming to evaluate the risk-benefit profile of cannabinoids to relieve pain among individuals receiving opioid agonist therapy for OUD, a timely endeavour amidst the opioid crisis.

Keywords: cannabis; nociception; opioid addiction; opioid-sparing effects.

Figure 1.. Effects of Delta-9-tetrahydocannabinol (THC) on Pain Sensitivity Indexed by The Cold Pressor Test (CPT).

Mean scores for (A) pain threshold and (B) pain tolerance of the CPT, at 90 minutes and 180 minutes, in response to oral THC (10 mg, 20 mg) and placebo. The maximum duration of the CPT is of 180 seconds. For details, please see section 5.2 of the manuscript.

Figure 2.. Effects of Delta-9-tetrahydocannabinol (THC) on Pain Sensitivity Indexed by the McGill Pain Questionnaire (MPQ).

Mean scores for (A) total pain (B) sensory pain, and (C) affective pain, at 90 minutes and 180 minutes, indexed by the MPQ, in response to oral THC (10 mg, 20 mg) and placebo. The MPQ total pain scores range from 0 to 45. The MPQ sensory items range from 0 to 33 and the affective items range from 0 to 12. For details, please see section 5.2 of the manuscript. *p< .05 for pairwise comparisons of the THC conditions with the placebo condition.

Figure 3.. Subjective Effects of Delta-9-tetrahydocannabinol (THC).

Mean scores for (A) stimulatory effects (B) pleasurable effects, and (C) aversive effects, indexed by the Drug Effects Questionnaire (DEQ); and (D) opioid withdrawal severity, indexed by the Subjective Opioid Withdrawal Scale (SOWS), in response to oral THC (10 mg, 20 mg) and placebo. The DEQ measures range from 0 to 100 mm, and the SOWS scores range from 0 to 64. Error bars reflect standard error of the mean. For details, please see section 5.3 of the manuscript. *p< 0.05 for pairwise comparisons of the THC conditions with the placebo condition.

Figure 4.. Effects of Delta-9-tetrahydocannabinol (THC) on Cognitive Performance.

Mean scores for (A and B) sustained attention, indexed by the Continuous Performance Test (ContPT) throughput score and percent correct responses, respectively; and (C and D) verbal learning, indexed by the Hopkins Verbal Learning Test (HVLT) total/immediate and delayed recall, respectively, in response to oral THC (10 mg, 20 mg) and placebo. The continuous performance test throughput scores range from 0 to 100. The HVLT immediate recall scores range from 0 to 46 and the HVLT delayed recalls scores range from 0 to 12. For details, please see section 5.4 of the manuscript. *p< 0.05 for pairwise comparisons of the THC conditions with the placebo condition.