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This updated systematic review on the opioid-sparing effects of cannabinoids considered preclinical and clinical studies where the outcome was analgesia or opioid dose requirements. We searched Scopus, Cochrane Central Registry of Controlled Trials, Medline, and Embase (2016 onwards). Ninety-two studies met the search criteria including 15 ongoing trials. Meta-analysis of seven preclinical studies found the median effective dose (ED\n                    <jats:sub>50<\/jats:sub>\n                    ) of morphine administered with delta-9-tetrahydrocannabinol was 3.5 times lower (95% CI 2.04, 6.03) than the ED\n                    <jats:sub>50<\/jats:sub>\n                    of morphine alone. Six preclinical studies found no evidence of increased opioid abuse liability with cannabinoid administration. Of five healthy-volunteer experimental pain studies, two found increased pain, two found decreased pain and one found reduced pain bothersomeness with cannabinoid administration; three demonstrated that cannabinoid co-administration may increase opioid abuse liability. Three randomized controlled trials (RCTs) found no evidence of opioid-sparing effects of cannabinoids in acute pain. Meta-analysis of four RCTs in patients with cancer pain found no effect of cannabinoid administration on opioid dose (mean difference \u22123.8\u2009mg, 95% CI \u221210.97, 3.37) or percentage change in pain scores (mean difference 1.84, 95% CI \u22122.05, 5.72); five studies found more adverse events with cannabinoids compared with placebo (risk ratio 1.13, 95% CI 1.03, 1.24). Of five controlled chronic non-cancer pain trials; one low-quality study with no control arm, and one single-dose study reported reduced pain scores with cannabinoids. Three RCTs found no treatment effect of dronabinol. Meta-analyses of observational studies found 39% reported opioid cessation (95% CI 0.15, 0.64,\n                    <jats:italic>I<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    95.5%, eight studies), and 85% reported reduction (95% CI 0.64, 0.99,\n                    <jats:italic>I<\/jats:italic>\n                    <jats:sup>2<\/jats:sup>\n                    92.8%, seven studies). In summary, preclinical and observational studies demonstrate the potential opioid-sparing effects of cannabinoids in the context of analgesia, in contrast to higher-quality RCTs that did not provide evidence of opioid-sparing effects.\n                  <\/jats:p>","DOI":"10.1038\/s41386-022-01322-4","type":"journal-article","created":{"date-parts":[[2022,4,22]],"date-time":"2022-04-22T11:03:30Z","timestamp":1650625410000},"page":"1315-1330","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":95,"title":["Opioid-sparing effect of cannabinoids for analgesia: an updated systematic review and meta-analysis of preclinical and clinical studies"],"prefix":"10.1038","volume":"47","author":[{"given":"Suzanne","family":"Nielsen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louisa","family":"Picco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bridin","family":"Murnion","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4973-0771","authenticated-orcid":false,"given":"Bryony","family":"Winters","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6248-3704","authenticated-orcid":false,"given":"Justin","family":"Matheson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Myfanwy","family":"Graham","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrielle","family":"Campbell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laila","family":"Parvaresh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kok-Eng","family":"Khor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brigid","family":"Betz-Stablein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Farrell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Lintzeris","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6406-4973","authenticated-orcid":false,"given":"Bernard","family":"Le Foll","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2022,4,22]]},"reference":[{"key":"1322_CR1","doi-asserted-by":"publisher","first-page":"1624","DOI":"10.1001\/jama.2016.1464","volume":"315","author":"D Dowell","year":"2016","unstructured":"Dowell D, Haegerich TM, Chou R. 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SN has received untied research grants from Seqirus to study prescription opioid overdose.\u00a0BLF has received cannabis product from Aurora, Grants from Canopy and Alkermes, participated in an Advisory Board for Indivior (and few other industry related projects not related to the present work). NL has served on Advisory Boards for Chiesi Pharmaceuticals and Indivior, received research funding from Camarus AB. K-EK has previously received a speaker\u2019s honorarium from Pfizer and Mundipharma, in addition to fees from an advisory board and an educational grant from Seqirus. MG is funded through the New South Wales Health Clinical Cannabis Medicines Program. All other authors have nothing to declare.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}