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

Abstract

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.

Fig. 1

Cold Pressor Task pain threshold (top panels) and tolerance (bottom panels) as calculated by percent baseline latency (seconds) to report pain and withdraw the hand from cold water. Data are presented as mean values +/- SEM according to cannabis strength, oxycodone dose (2.5 mg, left panels; 5.0 mg, right panels), and time. Placebo oxycodone + inactive cannabis condition = PBO; placebo oxycodone + active cannabis condition = CAN; 2.5 mg oxycodone + inactive cannabis condition = 2.5 Oxy; 2.5 mg oxycodone + active cannabis condition = 2.5 O + C; 5.0 mg oxycodone + inactive cannabis condition = 5.0 Oxy; 5.0 mg oxycodone + active cannabis condition = 5.0 O + C. Baseline response is shown as BSL on the x-axis; response after oxycodone is indicated by C on the x-axis. Significant differences from placebo are indicated by *p ≤ 0.05 and **p ≤ 0.01; significant differences from active cannabis alone are indicated with ^#p ≤ 0.05

Fig. 2

Subjective ratings of representative abuse-related subjective effects (‘Strength,’ ‘Liking’) as measured by the Cannabis Rating Form and intoxication (‘High’) as a function of time, cannabis strength, and oxycodone dose. Data are presented as mean ratings +/- SEM. Significant differences from placebo are indicated by ***p ≤ 0.0001

Fig. 3

Puffs of cannabis self-administered and money ($) spent as a function of cannabis strength (inactive cannabis, left side; active cannabis, right side) and oxycodone dose (white bars = placebo oxycodone, grey bars = 2.5 mg oxycodone, black bars = 5.0 mg oxycodone). Each puff cost $1. Significant differences from the placebo oxycodone + inactive cannabis condition are indicated by **p ≤ 0.01 and ***p ≤ 0.0001

Fig. 4

Pupillary (top panel; diameter measured in cm) and cardiovascular (bottom panel; beats per minute) effects as a function of cannabis strength (inactive cannabis, left side; active cannabis, right side) and oxycodone dose (white bars = placebo oxycodone, grey bars = 2.5 mg oxycodone, black bars = 5.0 mg oxycodone). Values represent means across post-smoking time points. Significant differences from the placebo oxycodone + inactive cannabis condition are indicated by *p ≤ 0.05 and **p ≤ 0.01; significant differences from active cannabis alone are indicated with ^##p ≤ 0.01