Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability, Ziva D. Cooper et al., 2018

Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability

Ziva D. Cooper, Gillinder Bedi, Divya Ramesh, Rebecca Balter, Sandra D. Comer and Margaret Haney

Neuropsychopharmacology, 2018, 0, 1–10

Doi : 10.1038/s41386-018-0011-2


Cannabinoids combined with opioids produce synergistic antinociceptive effects, decreasing the lowest effective antinociceptive opioid dose (i.e., opioid-sparing effects) in laboratory animals. Although pain patients report greater analgesia when cannabis is used with opioids, no placebo-controlled studies have assessed the direct effects of opioids combined with cannabis in humans or the impact of the combination on abuse liability. This double-blind, placebo-controlled, within-subject study determined if cannabis enhances the analgesic effects of low dose oxycodone using a validated experimental model of pain and its effects on abuse liability. Healthy cannabis smokers (N = 18) were administered oxycodone (0, 2.5, and 5.0 mg, PO) with smoked cannabis (0.0, 5.6% Δ9 tetrahydrocannabinol [THC]) and analgesia was assessed using the Cold-Pressor Test (CPT). Participants immersed their hand in cold water (4 °C); times to report pain (pain threshold) and withdraw the hand from the water (pain tolerance) were recorded. Abuse-related effects were measured and effects of oxycodone on cannabis self-administration were determined. Alone, 5.0 mg oxycodone increased pain threshold and tolerance (p ≤ 0.05). Although active cannabis and 2.5 mg oxycodone alone failed to elicit analgesia, combined they increased pain threshold and tolerance (p ≤ 0.05). Oxycodone did not increase subjective ratings associated with cannabis abuse, nor did it increase cannabis self-administration. However, the combination of 2.5 mg oxycodone and active cannabis produced small, yet significant, increases in oxycodone abuse liability (p ≤ 0.05). Cannabis enhances the analgesic effects of sub-threshold oxycodone, suggesting synergy, without increases in cannabis’s abuse liability. These findings support future research into the therapeutic use of opioid-cannabinoid combinations for pain.



In the United States, an estimated 11.2% of the adult population suffers from chronic pain [1] and nearly 20% of patients presenting with acute and chronic non-cancer pain are prescribed opioids [2]. Between 1999 and 2015, opioid prescribing tripled [3] along with the number of deaths attributed to opioid analgesics, with an estimated 17,500 fatalities in 2015 relative to 6160 reported in 1999 [4]. With recent recognition of the significant health risks associated with high doses of opioids including opioid use disorder [5] and overdose [6, 7] physicians are asked to limit the number of prescriptions written, shorten the duration of opioid therapy, and decrease the total daily doses prescribed [8]. As awareness of the risks of prescription opioid use grows, medical cannabis use is also garnering widespread acceptance, with over half of the United States passing medical cannabis laws [9]. Pain is the primary indication for use by patients who are prescribed cannabis [10], and chronic pain is one indication for which strong evidence exists supporting the use of cannabinoids (National Academies of Sciences, Engineering, and Medicine [62, 11]). Yet recent systematic reviews concluded that there is limited or inconclusive evidence supporting the use specifically of cannabisbased products for neuropathic pain and insufficient evidence supporting its use for other types of chronic pain [12, 13]. These findings exemplify the need for more rigorously controlled clinical trials in this area.

With increased access to cannabis and more conservative opioid prescribing, evidence suggests that patients are substituting cannabis for opioids. For example, opioid analgesic prescriptions filled by Medicare Part D enrollees fell significantly in states with medical cannabis laws [14], and patients with chronic pain report over 60% reduction in their opioid use in these states [15]. In lieu of full substitution,  some pain patients report that cannabis increases the analgesic effects of their opioids [16] or decreases the opioid dose needed for therapeutic effect [17]. Moreover, some randomized controlled studies have demonstrated analgesic effects of cannabinoids in patients taking opioids for chronic and cancer pain [18–20]. These data suggest that cannabis may (1) increase the pain-relieving properties of opioids and consequently decrease the total dose used, or (2) provide adequate analgesia on its own thus acting as a substitute. However, there are no data from placebo-controlled studies directly addressing whether cannabis can decrease the effective analgesic doses of opioids. Furthermore, to date, no studies have investigated the impact of opioid-cannabinoid drug combinations on abuse liability, a critical aspect when considering the therapeutic utility of two drugs that have significant abuse liability when administered alone.

Based on animal studies, combining opioids and cannabinoids for pain relief is hypothesized to provide superior clinical therapeutic effectiveness than opioid administration alone by increasing the analgesic potency of the opioid and therefore decreasing its effective analgesic dose (termed opioid-sparing effects). Although this effect has yet to be confirmed in humans, preclinical evidence regarding the pro analgesic effects of coadministration of mu-opioid agonists and cannabinoids abounds, predominantly with Δ9 tetrahydrocannabinol (THC), a partial CB1 and CB2 receptor agonist [21] and the main psychoactive component of cannabis [22]. Combining THC and mu-opioid agonists has been reported to have additive or synergistic effects across a range of routes of administration in rodents (i.e., [23–28]) and non-human primates, depending on the efficacy of the opioid agonist (i.e., [29–31]). Achieving analgesia with lower opioid doses may also decrease adverse effects related to opioid use that diminish their therapeutic utility, including constipation, respiratory depression, and the development of opioid tolerance and dependence [32]. For instance, although chronic administration of a CB1 or mu-opioid receptor agonist alone produces antinociceptive tolerance and physiological dependence, co-administration of the drugs prevents these effects in rodents [33, 34]. In addition to reducing the development of tolerance and dependence, CB1 receptor agonists also reduce the discriminative stimulus and reinforcing effects of opioid agonists in non-human primates [30, 35]. This potential for cannabinoids to decrease the abuse liability of opioids has profound implications for the most significant adverse effects of opioids; that is, the risk of opioid use disorders and associated fatalities [4, 36]. Based on the preclinical literature, coadministration of cannabinoids, specifically CB1 receptor agonists like THC, would potentially decrease the risk of developing an opioid use disorder.

Few controlled clinical studies have sought to identify the opioid-sparing effects of cannabinoids; one assessed the impact of vaporized cannabis on opioid analgesia and pharmacokinetics, however this was under non-placebo controlled conditions. In addition, that study was not designed to assess if cannabis could decrease the effective opioid analgesic dose [37]. Other studies have used various cannabinoid preparations and routes of administration (i.e., oral THC or THC:CBD oromucosal spray) and have either lacked an opioid control (i.e., opioid placebo) or failed to include more than one opioid dose, again making it difficult to conclude whether cannabinoids can decrease the effective opioid dose for analgesia [18–20, 38, 39]. Furthermore, while one study assessed the effects of cannabis and opioid co-administration on subjective intoxication [37], no studies to date have assessed the abuse liability of the drug combination, a critical endpoint when determining if the combination can mitigate risks of abuse associated with opioid administration.

This within-subject, randomized, placebo-controlled, doubleblind study sought to determine the opioid-sparing effects of cannabis by assessing analgesia and abuse liability of subthreshold and lowest-effective doses of oxycodone (2.5 and 5.0 mg, respectively) when administered alone or in combination with smoked cannabis over six experimental sessions in a healthy, cannabis-smoking population. The sub-threshold dose was chosen specifically to assess potential synergistic effects of the drug combination that may not have been apparent with higher doses. Analgesia was assessed using the Cold Pressor Test (CPT) an experimental test of pain that has predictive validity for medications used for chronic pain (opioids [40–42], gabapentin [43], and lamotrigine [44]). Assessing analgesic effects using this elicited pain test in a non-pain population afforded robust experimental control by excluding significant confounding variables that occur when studying a pain population including (1) current use of analgesics and (2) fluctuations in baseline pain across session days.