Therapeutic potential of opioid/cannabinoid combinations in humans: Review of the evidence

The endogenous opioid and cannabinoid receptor systems are widely distributed and co-localized throughout central and peripheral nervous system regions. A large body of preclinical evidence suggests that there are functional interactions between these two systems that may be leveraged to address various health conditions. Numerous animal studies have shown that cannabinoid agonists (e.g., delta-9-tetrahydrocannabinol [Δ⁹-THC]) enhance the analgesic effects of µ-opioid analgesics as evidenced by decreasing the opioid dose required for analgesia (i.e., opioid sparing) and extending the duration of the opioid analgesia. In contrast, controlled human laboratory studies and clinical trials have not demonstrated robust analgesic or opioid-sparing effects from opioid-cannabinoid combinations. Meta-analyses of the literature (clinical trials, controlled laboratory studies; some non-controlled studies/case reports) have examined the effects of cannabis/cannabinoids for pain relief in those taking a wide variety of analgesics, including prescription opioid medications. These data do not strongly support the use of cannabinoids for chronic pain nor do prospective studies demonstrate significant cannabinoid-mediated opioid-sparing effects. Preclinical studies have also suggested a role for cannabinoids for the treatment of opioid withdrawal. Controlled laboratory and clinical studies suggest that there may be a modest signal for Δ⁹-THC to suppress some opioid signs and symptoms but they are not completely ameliorated and there may also be concerns around safety of Δ⁹-THC administration in a state of heightened autonomic arousal as occurs with opioid withdrawal. Despite anecdotal and correlational reports suggesting a benefit of cannabis on reducing opioid overdose, there is no strong data supporting this contention and emerging reports have conflicting results. In summary, there is a groundswell of public advocacy supporting the use of cannabis and cannabinoids to replace opioid analgesics or to reduce opioid use; however, the extant controlled clinical data do not support the role of cannabinoids for opioid replacement or opioid-sparing effects when treating opioid use disorder or chronic pain.