Preclinically strong synergistic opioid sparing by cannabinoids, however clinical evidence mixed and of very low quality.
Summary
SR+MA: k=28 studies (19 preclinical, 9 clinical). Preclinical meta-analysis (n=6 studies): ED50 of morphine in combination with THC 3,6× lower (95% CI 1.95–6.76); ED50 of codeine+THC 9,5× lower (95% CI 1.6–57.5). Clinical evidence very weak: 1 case series (n=3) with very low quality; larger controlled studies show mixed results, opioid dose changes rarely reported. Robust preclinical synergy data; clinical opioid-sparing evidence remains insufficient.
P
PopulationPreclinical and clinical studies on opioid-cannabinoid co-medication; preclinical n=6 (morphine+THC meta-analysis) or n=2 (codeine+THC); clinical 9 studies
I
InterventionCannabinoids (mainly delta-9-THC) in combination with opioids (morphine, codeine, among others)
C
ControlOpioids as monotherapy
O
OutcomePreclinical: ED50 of morphine+THC 3,6-fold lower than morphine alone (95% CI 1,95–6,76); ED50 of codeine+THC 9,5-fold lower (95% CI 1,6–57,5); clinical: predominantly mixed findings, only one case series (n=3) with very low quality of evidence showed opioid sparing
Confidence in the evidence
Very lowLowModerateHigh
High
The highest of four GRADE levels, the effect estimate is very reliable.
Cannabinoids, when co-administered with opioids, may enable reduced opioid doses without loss of analgesic efficacy (ie, an opioid-sparing effect). The aim of this study was to conduct a systematic review to determine the opioid-sparing potential of cannabinoids. Eligible studies included pre-clinical and clinical studies for which the outcome was either analgesia or opioid dose requirements. Clinical studies included controlled studies and case series. We searched Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase. Nineteen pre-clinical and nine clinical studies met the search criteria. Seventeen of the 19 pre-clinical studies provided evidence of synergistic effects from opioid and cannabinoid co-administration. Our meta-analysis of pre-clinical studies indicated that the median effective dose (ED<sub>50</sub>) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9-THC) is 3.6 times lower (95% confidence interval (CI) 1.95, 6.76; n=6) than the ED<sub>50</sub> of morphine alone. In addition, the ED<sub>50</sub> for codeine administered in combination with delta-9-THC was 9.5 times lower (95% CI 1.6, 57.5, n=2) than the ED<sub>50</sub> of codeine alone. One case series (n=3) provided very-low-quality evidence of a reduction in opioid requirements with cannabinoid co-administration. Larger controlled clinical studies showed some clinical benefits of cannabinoids; however, opioid dose changes were rarely reported and mixed findings were observed for analgesia. In summary, pre-clinical studies provide robust evidence of the opioid-sparing effect of cannabinoids, whereas one of the nine clinical studies identified provided very-low-quality evidence of such an effect. Prospective high-quality-controlled clinical trials are required to determine the opioid-sparing effect of cannabinoids.