Opioid-sparing effect of cannabinoids for analgesia: an updated systematic review and meta-analysis of preclinical and clinical studies
Monash Addiction Research Centre, Eastern Health Clinical School, Monash University, Frankston, VIC Australia
National Drug and Alcohol Research Centre, UNSW, Sydney, NSW Australia
Discipline of Addiction Medicine, Faculty of Medicine and Health, University of Sydney, Sydney, NSW Australia
Pain Management Research Institute, University of Sydney and Royal North Shore Hospital, Sydney, NSW Australia
Translational Addiction Research Laboratory, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Toronto, ON Canada
The Australian Centre for Cannabinoid Clinical and Research Excellence (ACRE), Newcastle, NSW Australia
Centre Centre for Drug Repurposing and Medicines Research, School of Medicine and Public Health, The University of Newcastle, Newcastle, NSW Australia
School of Health and Behavioural Sciences, University of the Sunshine Coast, Maroochydore, QLD Australia
Drug and Alcohol Services, South Eastern Sydney Local Health District, Surry Hills, NSW Australia
School of Public Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW Australia
Medicine and Health, UNSW, Kensington, NSW Australia
Department of Pain Management, Prince of Wales Hospital, Randwick, NSW Australia
The University of Queensland Diamantina Institute, The University of Queensland, Dermatology Research Centre, Brisbane, QLD Australia
Departments of Pharmacology and Toxicology, Psychiatry, Family and Community Medicine, University of Toronto, Toronto, ON Canada
Abstract
Cannabinoid co-administration may enable reduced opioid doses for analgesia. 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 (ED50) of morphine administered with delta-9-tetrahydrocannabinol was 3.5 times lower (95% CI 2.04, 6.03) than the ED50 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 −3.8 mg, 95% CI −10.97, 3.37) or percentage change in pain scores (mean difference 1.84, 95% CI −2.05, 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, I2 95.5%, eight studies), and 85% reported reduction (95% CI 0.64, 0.99, I2 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.
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Subject terms: Preclinical research, Translational research
Article notes
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Received 2021 Dec 14; Revised 2022 Feb 10; Accepted 2022 Mar 31; Issue date 2022 Jun.
Introduction
Opioids are widely prescribed for chronic pain, but due to concerns related to harms, recommendations have been made to reduce reliance on higher doses [1]. One strategy to reduce opioid dose requirements has been through use of opioid-sparing medicines. Opioid-sparing medicines can (1) delay or prevent the initiation of treatment with opioid analgesics (2) decrease the duration of opioid treatment (3) reduce the total dosages of opioid used or (4) reduce opioid-related adverse outcomes, without causing an unacceptable increase in pain [2].
There is substantial interest in the opioid-sparing potential of cannabinoids in the context of pain management. Preclinical data have consistently demonstrated opioid-sparing effects [3]. Interest from policy makers has been further driven by ecological and epidemiological research [4]; however, highly publicized findings have recently been questioned [5].
The overlapping neuroanatomical distribution of opioid and cannabinoid receptors in the central and peripheral nervous system in areas involved with anti-nociception support potential opioid-sparing effects. Opioids and cannabinoids have comparable neurobiological properties with significant degree of functional interaction [6]. Opioid and cannabinoid receptors are Gi/o-protein-coupled receptors with similar intracellular signaling mechanisms, including: inhibition of the adenylate cyclase activity, reduced activity of voltage-dependent calcium channels, activation of inwardly-rectifying potassium channels, and stimulation of the MAP kinase cascade. Cannabinoid type-1 (CB1) and mu receptors can interact directly as functional heterodimers when co-expressed in the same neuron [7] and cannabinoid administration may stimulate the synthesis and release of endogenous opioid peptides centrally and peripherally [8]. Each of these properties would predict a synergistic interaction between opioids and cannabinoids, yet further complexity is afforded by the pharmacological profile of the drug. For example, in the case of protean agonists the level of activation of cannabinoid receptors (both constitutive and stimulated) impacts upon the observed pharmacological effect [9, 10], whilst partial agonists such as the endocannabinoid anandamide could act as an antagonist in the presence of a more efficacious agonist [11].
Our previous systematic review and meta-analysis found robust preclinical evidence supporting the opioid-sparing potential of delta-9-tetrahydrocannabinol (THC), but limited clinical research testing the opioid-sparing effects of cannabinoids [3]. With the proliferation of research in the past five years, this review aims to provide an updated synthesis of preclinical and clinical studies on the opioid-sparing effects of cannabinoids.
Materials and methods
Search
We conducted an updated systematic literature search in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations [12]. The initial searches conducted on October 29, 2015, had no date limits and the findings have been reported earlier, along with the methods (in lieu of a published/registered protocol) [3]. The updated searches were conducted on December 20, 2020 within Scopus, Cochrane Central Registry of Controlled Trials, Medline, and Embase databases and results were combined with the earlier search. A combination of search terms relating to opioids (e.g., analgesics, opioid*, opiate), cannabinoids (e.g., cannabis, sativex, nabiximol, cannabidiol, tetrahydrocannabinol) and outcomes of interest (e.g., pain, opioid sparing, opioid dose, antinociceptive) were used, consistent with the initial search (Appendix 1). Additional targeted searches of reference lists from identified studies and review articles were conducted to find additional studies not identified by the main searches.
Study eligibility
Eligible studies included: (i) human or animal studies; (ii) for human studies, controlled clinical and preclinical studies where cannabinoids were administered within a medical or clinical therapeutic framework and the study outlined details of cannabinoid administration; (iii) documented concurrent administration of opioids and cannabinoids; (iv) an outcome of either pain/analgesia (including acute, chronic, cancer and non-cancer and experimental pain studies) or opioid requirements/opioid-sparing.
Studies were excluded based on the following criteria: (i) wrong intervention (e.g., cannabinoid use not defined, no cannabinoid administered, non-concurrent opioid and cannabinoid use, non-therapeutic opioid use); (ii) wrong study design (e.g., case reports, epidemiological studies, reviews, letters without empirical data, commentary or news article); (iii) no outcome measure of interest (i.e., pain/analgesia or opioid dose); (iv) full text unavailable; (v) duplicate manuscript; (vi) abstract where full paper published; (vii) unable to confirm eligibility details, or access required data from authors (Appendix 2).
Titles and abstracts, and full texts were screened independently by two authors (SN, LMP, JM, BM, GC, MG, LP and K-EK) using Covidence software [13]. Where inconsistencies were identified, the authors were able to reach consensus on each occasion.
Data extraction and outcomes
The same data extraction forms used in the initial review were used. All data were extracted by one of the authors (SN, LMP and BW, BM) and checked by a second author (SN, LP, BM, JM, MG or K-EK). These same authors reviewed and resolved any inconsistencies. For abstracts without a full text, and missing data, attempts were made to contact authors for additional information.
Outcome measures
For preclinical studies, the primary outcome was the dose of opioid required to give an equivalent antinociceptive effect in the presence and absence of cannabinoids.
Analysis
Preclinical studies
Data were extracted and, where studies that were sufficiently similar in design and outcome measures, meta-analysis was undertaken. For the residual studies, a narrative review was conducted.
To prepare the data for the meta-analysis, the ED50 and either confidence limits or standard error were extracted from the relevant literature. ED50 is calculated on the log10 scale. Therefore, to meet the assumption of normality, the must be used in the meta-analysis. The log10 of the confidence limits must also be determined to calculate the standard deviation (SD) of the :
where UL is the upper confidence limit.
When only standard error was reported, the confidence limits were calculated using the method of Litchfield and Wilcoxon [14] and the above procedure was repeated to calculate the standard deviation. This method also allowed for the inclusion of studies that did not report exact sample sizes for all treatment groups, as sample size was not required for the calculation of standard deviation.
Data for the meta-analysis were analyzed using Review Manager 5.4 (Cochrane Collaboration, Oxford, UK). When calculating the continuous outcome of an equally effective opioid dose (e.g., the log10ED50 for morphine when administered alone versus when administered with a cannabinoid), the inverse variance statistical method and random effects model were used to compensate for study heterogeneity.
No statistical difference was found in outcomes between the studies that used different rodent species or nociceptive assays. Therefore, the mean difference of and the corresponding 95% confidence intervals were calculated. Due to the nature of log calculations, the mean difference—when back-transformed to the original units—represents the response ratio. For easier interpretation, we present the reciprocal of the response rate.
Clinical studies
The outcomes of interest in clinical studies were: (1) reduction in total opioid doses, (2) reductions in pain through the addition of a cannabinoid, (3) adverse events, and (4) evidence of abuse liability. A broad range of study designs were considered. Where studies used sufficiently similar methods and outcome measures, meta-analyses were conducted.
Clinical trials
Observational studies
For observational studies, meta-analyses on proportions reporting changes in opioid dose outcomes were conducted using a random effect model in Stata (metaprop, code available on request). A pooled prevalence was calculated with 95% confidence intervals for each of the identified outcomes that were comparable; (i) reduced opioid use, (ii) ceased opioid use. For remaining outcomes, a narrative synthesis was conducted.
Clinical studies were scored for quality using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria [17]. Quality ratings were not applied to preclinical studies. As all meta-analyses had less than ten studies funnel plots were not used to assess bias [18].
Results
Ninety eligible publications representing data from 92 studies were identified; 29 in the initial searches and 63 in the updated searches. Forty preclinical (21 since 2016) and 37 clinical studies (controlled trials n = 20 [12 since 2016] and observational n = 17 [13 since 2016]) were identified for inclusion (see Appendix 3). Fifteen registered clinical trials, where data were not yet available were also identified.
Summary of preclinical studies
Forty preclinical studies were identified in which the analgesic effect of opioid and cannabinoid co-administration was examined [19–58]. Sixteen of these studies examined delta-9-THC, while smaller numbers of studies examined 20 other cannabinoids, including agonists mixed CB1/CB2 agonists (CP55,940, WIN55,212-2, HU-210), CB1 agonists (ACEA, ACPA), CB2 agonists (beta-caryophyllene, JWH-015, JWH-133, LY2828360), antagonists/inverse agonists at the CB1 (AM-251) and CB2 receptor (JTE-907) and other cannabinoids (AM1241, cannabinol, cannabidiol [CBD], CP 56,667, delta-8-THC, 11-hydroxy-delta-9-THC, dextronantradol, levonantradol and GP1a) (Table 1 and Appendix 4). Opioids examined included morphine, codeine, and other agonists at the mu, delta or kappa opioid receptor including buprenorphine, etorphine, fentanyl, heroin, oxycodone, hydromorphone, methadone, LAAM, meperidine, pentazocine, spiradoline, tramadol, and SNC80. Most studies used rodents; however, three used rhesus monkeys and one used guinea pigs. The most common antinociceptive assays were of thermal nociception although assays of mechanical and chemical nociception were also utilized.
| Cannabinoid type | Potential synergism/opioid-sparing effects | Opioid-sparing effect not clearly observeda or tested |
|---|---|---|
| Mixed CB1/CB2 agonists | ||
| CP55,940 (mixed CB1/CB2 agonist) | Evidence of opioid-sparing effect:Alsalem et al. 2019 (morphine “potential synergy” mechanical nociception)Maguire and France 2018 (morphine, thermal nociception);Maguire 2013 (Rhesus monkey, morphine, thermal nociception) | Evidence of synergy/opioid-sparing not found:Alsalem et al. 2019 (tramadol, mechanical nociception)Welch 1992 (morphine, thermal nociception);Maguire and France 2016 (spiradoline, thermal nociception)Maguire and France 2018 (etorphine, thermal nociception);Minervini 2017 (spiradoline, thermal nociception) |
| Delta-9-THC (partial agonist CB1/CB2) | Evidence of opioid-sparing effect:Cox 2007 (morphine, mechanical nociception)Cichewicz 2005 (guinea pigs, fentanyl and buprenorphine, mechanical nociception)Maguire and France 2018 (morphine, thermal nociception)Nguyen 2019 (oxycodone “possibly synergistic, thermal nociception)Nilges 2020 (Rhesus monkeys, heroin, thermal nociception))Cichewicz 1999 (range of opioid agonists, thermal nociception)Cichewicz 2003 (morphine and codeine, thermal nociception)Li 2008 (Rhesus monkey, morphine, thermal nociception))Pugh 1996 (morphine, thermal nociception)Smith 1998 (morphine, thermal nociception)Smith 2007(morphine, thermal nociception)Welch 1992(morphine, thermal nociception)Williams 2006 (codeine and morphine, thermal nociception)Williams 2008 (morphine, thermal nociception) | Evidence of synergy/opioid-sparing not found:Maguire and France 2018 (etorphine, thermal nociception)Opioid-sparing/synergism not directly tested:Wakley 2011—synergism not tested, (mechanical nociception)Reche 1996—only one dose of morphine examined (thermal nociception) |
| HU-210 (mixed CB1/CB2 agonist) | Evidence of potential opioid-sparing effect:Sierra 2019 (SNC80 [delta opioid agonist] mechanical nociception with neuropathic pain model) | Evidence of synergy/opioid-sparing not found:Alsalem et al. 2020 morphine and tramadol, mechanical nociception)Wilson 2008 (morphine, thermal nociception) |
| WIN55,212–2 (mixed CB1/CB2 agonist) | Evidence of opioid-sparing effect:Alsalem et al. 2020 (tramadol mechanical nociception);Chen et al. 2019 (morphine, thermal nociception and formalin)Yesilurt 2003 (morphine, thermal nociception) | Evidence of synergy/opioid-sparing not found:Alsalem et al. 2020 (not morphine, mechanical nociception) |
| CB1 selective agonist | ||
| ACEA | Evidence of synergy/opioid-sparing not found:Altun 2015 (morphine, thermal nociception) | |
| ACPA | Evidence of synergy/opioid-sparing not found:Auh et al. 2016 (DAMGO, mechanical nociception) | |
| CB1 antagonist/inverse agonist | ||
| AM-251 (also has agonist activity at GPR55) | Evidence of synergy/opioid-sparing not found:Altun 2015 (morphine, thermal nociception) | |
| CB2 selective agonist | ||
| JWH-015 | Evidence of opioid-sparing effect:Grenald et al. 2017 (morphine, mechanical and thermal nociception, formalin pain assay) | Evidence of synergy/opioid-sparing not found:Altun 2015 (morphine, thermal nociception) |
| Beta-caryophyllene | Evidence of synergy/opioid-sparing not found:Katsuyama 2013 (morphine, capsaicin pain assay) | |
| JWH-133 | Evidence of synergy/opioid-sparing not found:Yuill 2017 (morphine, noxious stimuli) | |
| LY2828360 | Evidence of opioid-sparing effect:Iyer 2020 (morphine, mechanical nociception) | |
| CB2 complex | ||
| AM1241 (Protean agonist CB2) | Evidence of potential synergy:Zhang 2018 (morphine, thermal and mechanical nociception) | Evidence of synergy/opioid-sparing not found:Stachtari 2016 (tramadol, thermal nociception)Zhang 2017 (morphine, thermal nociception);Zhang 2016 (morphine, thermal and mechanical nociception) |
| GP1a (CB2 agonist/inverse agonist) | Evidence of potential opioid-sparing effect:Chen et al. 2019 (morphine, thermal nociception) | Evidence of synergy/opioid-sparing not found:Chen et al. 2019 (morphine, formalin pain assay) |
| CB2 antagonist | ||
| JTE-907 (CB2 antagonist) | Evidence of synergy/opioid-sparing not found:Altun 2015 (morphine, thermal nociception) | |
| Complex | ||
| CBD (inverse agonist/NAM CB1, partial agonist CB2) | Evidence of synergy/opioid-sparing not found:Neelakantan 2015 (morphine, thermal and chemical nociception) | |
| Cannabinol (partial CB1 inverse agonist or agonist at CB2) | Evidence of synergy/opioid-sparing not found:Nilges 2020 (heroin, thermal nociception) | |
| Less characterized cannabinoids | ||
| CP 56,667 | Evidence of synergy/opioid-sparing not found:Welch 1992 (morphine, thermal nociception) | |
| Delta-8-THC | Evidence of opioid-sparing effect:Welch 1992 (morphine, thermal nociception) | |
| 11-hydroxy-delta-9-THC | Evidence of opioid-sparing effect:Welch 1992 (morphine, thermal nociception) | |
| Dextronantradol | Evidence of synergy/opioid-sparing not found:Welch 1992 (morphine, thermal nociception) | |
| Levonantradol | Evidence of opioid-sparing effect:Welch 1992 (morphine, thermal nociception] | |
Evidence of opioid-sparing effects or synergism were found for all mixed CB1/CB2 agonists (CP55,940, delta-9-THC, HU-210, WIN55,212–2). Morphine-induced analgesia increased with the CB1 selective agonist ACEA, though the effect was additive as opposed to synergistic [40]. In contrast, the CB1 selective agonist ACPA, and DAMGO (selective mu agonist) appeared to act antagonistically when administered together in a model of mechanical hyperalgesia [41]. The CB1 antagonist/inverse agonist AM-251 reduced the analgesic effect of morphine [40]. Conflicting outcomes were seen for CB2 selective agonists (some evidence of opioid-sparing effects for GP1a, JWH-015, LY2828360, but not for beta-caryophyllene or JWH-133). JTE-907 (a CB2 antagonist) and cannabinoids with more complex pharmacology (CBD and cannabinol) did not demonstrate opioid-sparing effects. Three less well characterized phytocannabinoids, including delta-9-THC metabolites, also showed evidence of synergy or opioid-sparing effects (delta-8-THC, 11-hydroxy-delta-9-THC and levonantradol), while no opioid-sparing effects were seen for other less well characterized cannabinoids (CP, 56,667 and dextronantradol).
Measures of abuse liability
Six studies reported on measures of abuse liability including intracranial self-stimulation (ICSS) [38], conditioned place preference [43, 44], oxycodone self-administration [50], and drug discrimination [32, 33]. None provided evidence that cannabinoids increased abuse liability. CP55,940 had no effect on ICSS with morphine or tramadol [38], JWH105 when co-administered with morphine reduced conditioned place preference, and LY2828360 when administered with morphine blocked condition place preference [43, 44]. THC reduced oxycodone self-administration [50], and attenuated the discriminative stimulus effect of morphine and heroin in nondependent monkeys, but not in dependent monkeys [33]. CP55,940 and WIN55,212 reduced the discriminative stimulus effect of morphine and decreased heroin self-administration, both effects were reversed by the CB1 receptor inverse agonist rimonabant [32].
Meta-analysis of preclinical studies
Seven studies used sufficiently similar approaches to enable a meta-analysis [19–24, 47] (Fig. 1). All studies included in the meta-analysis used rodents and reported comparable antinociceptive doses of morphine alone and morphine co-administered with delta-9-THC.
Meta-analysis identified an opioid-sparing effect with morphine and delta-9-THC co-administration with one study [47] added to the previous meta-analysis, Z = 4.46, p < 0.001 (mean difference in log10ED50 = –0.54 [–0.78, –0.31]). As there was significant heterogeneity in the data (I2 = 99%), a random effects model was used. When back-transformed to the original units, the response ratio was 3.5 (95% CI 2.04, 6.03) indicating that the median effective dose (ED50) of morphine was 3.5 times lower when administered with delta-9-THC compared to when administered alone.
Results from clinical studies
Thirty-five eligible publications representing 37 clinical studies with 5180 participants provided data relevant to the research question (Table 2).
| Study reference | Study design | Population | Observation period | Opioid used | Cannabinoid Used | Comparator | Effect of cannabinoid on opioid dose | Outcome on analgesia observed | GRADE evidence rating and other notes |
|---|---|---|---|---|---|---|---|---|---|
| a. Experimental pain studies | |||||||||
| Babalonis 2019 | Within-subject crossover, randomized, double-blind placebo-controlled design. Analgesia assessed with cold pressor, pressure algometer, hot thermode, cold hyperalgesia | Healthy volunteers (n=10), aged 18–50 years, without acute or chronic pain conditions and no recent opioid or cannabinoid use. Six female, mean age of 26.3 years | Nine outpatient experimental sessions (8.5 h/session) with a minimum of 48 h separating each session, dronabinol administered 1 h before oxycodone, pain measures up to 6 h after dronabinol administration | Oxycodone 0, 5, 10 mg (oral) | Dronabinol l 0, 2.5, 5 mg (oral) | Placebo dronabinol capsules and placebo oxycodone tablets | Cold pressor test: 2.5 mg dronabinol + 5 mg oxycodone decreased tolerance (17.9 [±2.4] s), compared with the 5 mg oxycodone dose alone (34.3 [±17.7] s) | Pressure algometer: Dronabinol a 2.5 mg dose decreased the analgesic effects of 10 mg oxycodone (no effect from 5 mg dronabinol). No effect on other pain measures (pressure algometer, cold pressor test and hot thermode) | GRADE rating “moderate”, placebo-controlled blinded study, indirect evidence as use of experimental pain.Dronabinol increased abuse liability ratings of oxycodone |
| Cooper 2018 | Within-subject, randomized, placebo-controlled, double-blind study Analgesia was assessed with cold pressor test | Healthy volunteers (n = 18) 21–45 years, with who current cannabis use. Six (33%) female, mean age 29.9 years | 6 outpatient experimental sessions. Placebo or oxycodone was administered 45 min before cannabis. Observations for 5 h after cannabis administration; repeated pain assessments until 3 h. 72 h washout between sessions | Oxycodone 0, 2.5 or 5.0 mg (oral) | Cannabis cigarettes (0.0 or 5.6% THC content); Participants smoked 70% of an 800 mg cannabis cigarette (CBD content not stated) | Placebo cannabis cigarettes (0% THC); Placebo oxycodone capsules | Cannabis and low dose of oxycodone (2.5 mg) did not elicit analgesia on their own; when administered together, pain (with cold pressor test) was significantly reduced, pointing to the opioid-sparing effects | Cannabis and 2.5 mg and 5 mg oxycodone increased pain threshold on cold pressor test compared to the cannabis alone (p < 0.05). Mean reductions from pain (McGill Pain Questionnaire) Placebo 2.2 ± 0.5; THC alone 1.5 ± 0.5; 2.5 mg OXY 2.0 ± 0.5; 2.5 mg OXY + THC; 0.7 ± 0.6; 5 mg OXY 1.7 ± 0.4; 5 mg OXY + THC 1.2 ± 0.4. Pain Intensity and bothersomeness Scales did not differ between cannabis, oxycodone, the combination or placebo | GRADE rating “moderate”, placebo-controlled blinded study, indirect evidence as use of experimental painSmoked cannabis increased subjective abuse liability measures for oxycodone |
| Dunn 2021 | Double-blind, within-subject randomized, placebo-controlled, human laboratory study using quantitative sensory testing measures of acute (thermal, pressure pain; thermal, punctate probe temporal summation; cold pressor; conditioned pain modulation) and chronic pain (capsaicin 10% topical cream with thermal rekindling) | Healthy adults (n = 29) with no history of drug use disorder, 52% female, mean 30.4 years | Five outpatient laboratory sessions (min. 7 days apart). Sessions lasted 8 h. Study drugs co-administered at with hourly pain assessments for 4 h | Hydromorphone 4 mg (oral) | Dronabinol 2.5, 5.0, 10 mg; (oral) | Placebo hydromorphone (no placebo dronabinol condition) | Opioid dose held constant across all sessions | Limited evidence of dronabinol enhancement of hydromorphone on pain measures. Dronabinol 2.5 mg had a significant effect of thermal threshold and tolerance. Most pain measures did not show a significant difference between dronabinol+ hydromorphone and hydromorphone alone. No dose effect with dronabinol | GRADE rating “moderate”, indirect evidence as use of experimental pain.Higher doses of dronabinol (5 mg and 10 mg) also showed greater evidence of potential for abuse and adverse effects |
| Naef 2003 | Experimental heat, cold, pressure, single and repeated transcutaneous electrical stimulation pain, randomized, placebo-controlled, double-blind, within-subject study | Healthy cannabis naïve volunteers (n = 12), 6 female, mean age 25 years | Four study sessions with at least seven days washout between sessions. Study medications co-administered, with pain measurements hourly for up to 8 h | Morphine 30 mg (oral) | Dronabinol 20 mg (oral) | Matched placebo capsule compared with THC alone, morphine alone or THC-morphine combination | No significant analgesic effect of dronabinol or morphine-dronabinol combination on heat, pressure and cold tests. Additive effect of morphine on transcutaneous electrical stimulation test | Potentiation of analgesia not observed in this experimental pain study, potential hyperalgesic effect of cannabinoids noted which may reduce analgesic effects of morphine | GRADE rating “moderate”, indirect evidence as use of experimental pain |
| Roberts 2006 | Experimental thermal pain. Double-blind, four treatment within-subject design | Healthy volunteers (n = 13) with no recent opioid or cannabinoid use. Six female, aged 18–49 years | Four lab sessions; Dronabinol administered, 90 min later morphine administered, thermal pain measured 15 min after morphine administration | Morphine 0.02 mg/kg intravenous (1.4 mg dose for 70 mg adult) (i.e., sub- analgesic) | Dronabinol 5 mg (oral) | Placebo dronabinol capsule and placebo morphine injection (normal saline) | Not applicable (opioid dose held constant) | Combination of dronabinol and morphine did not have effect on pain intensity. The combination was reported to have a synergistic effect on affective response to pain (unpleasantness) compared with either drug alone (p = 0.012) | GRADE rating “moderate”, placebo-controlled blinded study, indirect evidence as use of experimental pain.Noted difficulties with extrapolation to clinical practice |
| b. Controlled trials acute pain | |||||||||
| Bebee 2021 | Randomized, double-blind, placebo-controlled clinical trial (ACTRN12618000487213) | Adults with acute (<30 days duration) non-traumatic lower back pain (n=100). Median age 47 years, 44% female | 48 h | Oxycodone (5 mg every 6 h, with additional rescue dosing as required) | CBD 400 mg (oral) | Color matched placebo prepared (medium chain triglyceride oil) | 31/50 patients in the CBD group and 27/50 in the placebo group required oxycodone. Total oxycodone dose in the CBD group was 230 mg compared with 215 mg in the placebo group | Mean pain scores at 2 h were similar for the CBD (6.2 points; 95% CI, 5.5–6.9 points) and placebo groups (5.8 points; 95% CI: 5.1,6.6 points; absolute difference, –0.3 points; 95% CI, –1.3–0.6 points) | GRADE rating “high” |
| Levin 2017 | Single-center randomized double-blind controlled trial (NCT02115529) | Patients scheduled for elective surgery under general anesthesia who had a preoperative risk of post-operative nausea or vomiting (n = 340). Mean age 49.8 years, 100% female | 300 min or until discharge from post-anesthesia care unit | Specific opioid not reported, converted into OMEDD | Nabilone 0.5 mg (oral) | Matched placebo capsule | Morphine equivalents (mg) given in operating room: Nabilone 21.3 (SD 15.2) vs placebo 20.0 (SD 13.4), p = 0.40Morphine equivalents (mg) post-surgery: Nabilone 5.8 (SD9.2) vs placebo 5.4 (SD 6.9) p = 0.62 | No differences in pain score (out of a possible 10) between groups; Maximum pain score (at rest) Nabilone 3.17 (SD 3.15) vs placebo 3.68 (SD 3.25), p = 0.43Maximum pain score (with movement) Nabilone 3.34 (SD 3.30) vs placebo 4.0 (SD 3.33), p = 0.92 | GRADE rating “high” |
| Seeling 2006 | Randomized double-blind controlled trial (two groups) | Prostate cancer patients <70 years, (all male) undergoing surgery (n = 105). 53 in intervention and 52 in control groups | From the day prior to surgery to 2 days post-operation | Pitrimide | Eight doses of Dronabinol 5 mg (oral) over 48 h (perioperatively) | Placebo dronabinol capsules | Median dose of pitrimide alone was 74 mg (IQR = 44–90 mg) compared with 54 mg (IQR = 46–88 mg) when administered with dronabinol | The median of the resting pain was not different between the groups (p > 0.1) | GRADE rating “high”, patients administered their own opioid doses |
| c. Controlled trials cancer pain | |||||||||
| Fallon 2017aa | Study 1: multisite (patients at 101 centers in 12 different countries) randomized, double-blind, placebo-controlled trial (NCT01361607) | Adults (n = 399) with advanced incurable cancer, unalleviated by an optimized opioid therapy. Mean age 59.8 years, 49% female | 49 days (2 weeks after medication ceased) | Reported as OMEDD Patients were recruited on “stable opioid therapy”, not more than 500 mg OMEDD | 1:1 nabiximols (Sativex®) oral mucosal spray (THC 27 mg/mL: CBD 25 mg/mL) or matching placebo. 14-day titration (3–10 spray/day to max tolerated dose), 35 days of medication provided in total | Placebo oral mucosal spray | No effect of nabiximols on; total OMEDD −9.35, 95% CI-18.81–0.012 (p =0 .053); maintenance OMEDD −3.63, 95% CI −10.80, 3.55 (p = 0.321); breakthrough OMEDD −4.17, 95% CI −8.76, 0.42 (p = 0.075). (note patients instructed to continue pain medication) | No differences in median percent improvement from baseline average pain NRS score: nabiximols 7.2% vs placebo 9.5% (median difference=−1.84%; confidence interval (CI): −6.19%, 1.50%; p = 0.274)Median treatment effect −0.02; 95% CI: −0.42, 0.38; p = 0.917) | GRADE rating “high”Significant effect of nabiximols on Subject Global Impression of Change, Patient Satisfaction Questionnaire and Physician Global Impression of Change |
| Fallon 2017ba | Study 2: 2-part enriched enrollment with randomized withdrawal design (“responders” randomized). Single-blind titration for 10 days followed by double-blind randomization to Sativex or placebo (NCT01424566) | Adults (n = 406 entered and 206 randomized) with advanced incurable cancer, unalleviated by an optimized opioid therapy, mean age 61.5 years, 43% female | 49 days (2 weeks after medication ceased) | Reported as OMEDD. Patients were recruited on “table opioid therapy”, not more than 500 mg of OMEDD | Nabiximols (Sativex®) oral mucosal spray (THC 27 mg/mL: CBD 25 mg/mL). 10-day titration, “Responders” (15% pain score improvement) randomized. Treatment for 5 weeks | Placebo oral mucosal spray | No effect of nabiximols on: total OMEDD −7.1, 95% CI:23.9,9.7 (p = 0.405); maintenance OMEDD −8.9, 95% CI:19.7, 1.8 (p = 0.104); Breakthrough OMEDD 1.8, 95% CI:10.3, 14.0 (p = 0.769). (note patients instructed to continue pain medication) | Mean average pain scores increased from 3.2 to 3.7 in the nabiximols group and 3.1 to 3.6 in the placebo group, i.e., a worsening of equal severity in both treatment groups (estimated treatment effect −0.02; 95% CI: −0.42, 0.38; p = 0.917) | GRADE rating “moderate”, selection bias introduced through enrichment design |
| Johnson 2010a | Multicenter, randomized, double-blind, placebo-controlled, parallel-group trial. (NCT00674609) | Adults with cancer pain (n = 177), with inadequate analgesia despite chronic opioid dosing. Mean age 60.2 years, 56% female | 2 weeks | Varied opioids reported as mg OMEDD (IQR) | Placebo oral mucosal spray (Baseline OMEDD for placebo group 120 (40–240)) | Patients allowed to use breakthrough medication as needed; no change in median amount of breakthrough opioid medication in any group. Mean change in opioid dose from baseline Placebo −41.4 (SD 201.27), THC: 36.8 (SD 152.00); THC:CBD −3.5 (SD 108.44). Median change in all groups 0 mg | Change in pain score (out of 10) in favor of THC:CBD compared with placebo (−1.37 (p = 0.014)); the THC group change was not significant (−1.01 (p = 0.245)). The proportion of patients achieving a 30% reduction in pain was 43% (23/48) in the THC:CBD group, 23% in the THC group (12/45) and 21% in the placebo group (12/51) | GRADE rating “high”, placebo-controlled and randomized.No significant group differences were found in sleep quality or nausea scores or the pain control assessment | |
| 120 (50–213) | THC 2.7 mg spray; mean of 8.47 sprays day | ||||||||
| 80 (30–180) | THC 2.7 mg:CBD 2.5 mg per spray; mean sprays 9.26/day | ||||||||
| Lichtman 2018a | Randomized, multisite double-blind, placebo-controlled study (12 countries) (NCT01262651) | Adults (n = 397) with advanced cancer-related chronic pain unalleviated by optimized opioid therapy. Mean age 59.9 years, 46% female | 50 days if not entering extension study | Specific opioids not stated. Mean total daily opioid use at baseline 192.9 (SD 130.7) in the nabiximols group and 186.1 (SD 131.0) in the placebo group | Nabiximols (Sativex®) (THC 27 mg/mL: CBD 25 mg/mL), titration 14 days, maintenance 21 days. Max 10 sprays per day | Placebo oral mucosal spray | Nabiximols did not impact maintenance OMEDD (Estimated treatment difference [ETD] 1.46, 95% CI: −4.67, 7.60, p = 0.64), breakthrough OMEDD (ETD −1.84, 95% CI: −6.33, 2.66, p = 0.42) or total OMEDD (ETD −0.34, 95% CI: −8.26, 7.28, p = 0.93). Protocol stated that medications including opioids, should have been continued at stable doses if possible | Average pain score from baseline to end of treatment (primary endpoint): non-significant: 10.7% median improvement with nabiximols compared to 4.5% with placebo (p = 0.08). Nabiximols did not improve average pain NRS (p = 0.25) or worst pain NRS score (p = 0.68). Prespecified per-protocol analysis favored nabiximols over placebo (p = 0.04) | GRADE rating “moderate”, unclear blinding and randomization.Nabiximols was also associated with greater improvements than placebo in score on the Subject Global Impression of Change, Physician Global Impression of Change, and Patient Satisfaction Questionnaire |
| Lissoni 2014 | Two groups (not randomized): cannabinoid tincture or melatonin (clinical trial registration not reported) | Adults (n = 26) with untreatable metastatic solid tumor (age and gender not stated) | Not stated | Oxycodone, median dose of 30 mg (10–60 mg), twice /day | Cannabis flos (19% THC) was given as infusion 100 ml (500 mg/L water) three times a day | Melatonin 20–100 mg | 5/12 (42%) achieved control of pain without opioid dose increase compared to the control group where 2/14 (14%) achieved pain control | The number that achieved pain control was not significantly different between groups (5/12 in cannabis group and 2/5 in melatonin) | GRADE rating “low”, no-randomization, no allocation concealment described, greater disease progression in the cannabis group |
| Portenoy 2012a | Randomized, 4-arm double-blind, placebo-controlled, graded-dose study (NCT00530764) | Adults (n = 360) with advanced cancer and opioid-refractory pain, mean age 58 years, 48% female | 5 weeks of medication administration | Median OMEDD 120 | Nabiximols 1–4 Sprays | Placebo oral mucosal spray (Median OMEDD 120 mg) | No change in median amount of breakthrough opioid medication in any group. Note that patients were instructed to keep opioid dose constant so opioid-sparing effect on opioid dose could not be observed | OR 1.87 (p = 0.038) compared with placebo | GRADE rating “high”. Opioid composite measure showed better improvements in low dose group. Lower tolerability of THC:CBD in higher dose groups |
| Median OMEDD 120 | Nabiximols 6–10 Sprays | OR 1.70 (p = 0.079) compared with placebo | |||||||
| Median OMEDD 180 | Nabiximols 11–16 Sprays | OR 1.16 (p = 0.622) compared with placebo | |||||||
| Zylla 2021 | Pilot randomized controlled trial comparing early cannabis (EC) to delayed start cannabis (DC) | Adults (n = 30) with stage IV cancer requiring opioids Patients in the EC group were similar to DC group with respect to mean age (57 (SD = 9) years vs 55 (SD = 13) years) and percentage female (47% vs 53%), respectively | 3 months | Opioid type not specified. OMEDD measured using daily diary | Maintenance dose of 30–40 mg of THC and 30–40 mg of CBD per day, titrating up over 2–4 weeks | Early versus late start cannabis | EC group had stable opioid use; 3/9 in EC group and 4/9 in DC group increased OMEDD by ≥20%. Three patients in the EC group decreased their daily OMEDD by ≥20% | Mean pain scores remained similar between the two groups | GRADE rating “low” small sample with high attrition. Also examined dosing patterns: THC per patient each month was nearly twice that of CBD (average 34.3 mg THC vs 16.6 mg CBD) |
| d. Controlled trials: chronic non-cancer pain | |||||||||
| Abrams 2011 | Clinical laboratory study of self-reported pain under observed conditions (also measured pharmacokinetic effects of concurrent administration) (NCT00308555) | Adults (n = 24) receiving chronic opioid treatment (mixed pain conditions). Mean age 45.1 years, 48% female | 5 days | Morphine (mean dose 62 mg, n = 13) or oxycodone (mean dose 53 mg, n = 11) | Vaporized cannabis dose of 0.9 g of 3.56% delta-9-THC or as much as they could tolerate, administered three times a day | No comparator (single-arm study) | NA (opioid dose held constant) | Pain score: reduction from 34.8 (95% CI: 29.4, 40.1) on baseline to 24.1 (95% CI: 18.8, 29.4) on day 5 with morphine; and from 43.8 (95% CI: 38.6, 49.1) on baseline to 33.6 (95% CI: 28.5, 38.6) on day 5 with oxycodone. Significant reduction overall | GRADE rating “low”. No control arm, placebo effects cannot be excluded. No pharmacokinetic interaction observed. Cannabis inhalation produced a subjective “high” |
| Abrams 2020 | Randomized double-blind, two group crossover design (NCT01771731) | Adults with sickle cell disease with chronic pain (n = 23), 21 of whom were using opioids. Mean age, 37.6 years; 56% female | 5 inpatient days with 30-day washout followed by another 5 inpatient days | Hydromorphone, oxycodone, hydrocodone, morphine sulfate, fentanyl, methadone and oxymorphone | Cannabis plant material containing 4.4% THC and 4.9% CBD which were vaporized and inhaled 3 times per day | Vaporized placebo cannabis | The mean (SD) difference in log OMEDD dose between the cannabis and placebo periods in this value was not significant (2.05 [0.21] vs 2.09 [0.22]; p = 0.20) | The mean (SD) difference in pain rating assessment using the VAS data between the active and placebo groups were not significant on any day | GRADE rating “low”; small sample size and unclear blinding procedures and crossover design |
| De Vries 2016 | Randomized, single-dose, double-blind, placebo-controlled, two-way crossover study (NCT01318369) | Adults aged 18 and above with chronic abdominal pain from chronic pancreatitis (n = 24, 12 of whom were taking opioids). Mean age of sample 52 years, 9 of 24 patients were female | 6 h | Pethidine; tramadol and codeine (patients’ usual analgesic medication) | Dronabinol 8 mg | Diazepam 10 mg | The pharmacokinetic parameters of THC were similar between opioid and non-opioid users. Opioid dose requirements were not an outcome of the single-dose study | Primary analysis showed no treatment effect of THC. When only patients on opioids were considered, the mean VAS pain score at 2 h was similar for patients on in THC arm (2.917, SD 2.205) and the diazepam (active placebo) arm (2.53, SD 1.702) | GRADE rating “moderate” downgraded due to small sample size and crossover design.Additional data provided by authors |
| De Vries 2017 | Randomized, single-dose, double-blind, placebo-controlled, two-way crossover study (NCT01562483 and NCT01551511) | Two clinical trials where the samples were combined: (1) Adults with painful chronic pancreatitis (CP) n = 23, and (2) adults with chronic postsurgical abdominal pain (PSP), n = 27, mean age 52.9 years, 50% female | 61 days | Codeine, tramadol, oxycontin, fentanyl, and morphine (patients usual medicines) | Dronabinol tablet, increased to 8 mg three times a day over 10 days, with the option to reduce to 5 mg if 8 mg is not tolerated. Those not tolerating 5 mg three times a day were withdrawn | Matched dronabinol placebo tablet | Not reported. Patients were asked to continue taking their medications (including analgesics) according to prescription | Primary analysis (all patients) VAS mean scores did not differ between THC and placebo. For patients on opioids: (1) CP group (n = 20) mean VAS on day 49 was 2.05, SD 2.65) with THC compared with 2.94, SD 2.10 for placebo (p = 0.4). (2) PSP (n = 17), mean VAS on day 49 for placebo was higher (5.51, SD 2.27) compared with THC (2.9, SD 2.35), p = 0.03 | GRADE rating “moderate”, small sample size and high attrition in the active arm for the CP group.Additional data provided by authors |
| Narang 2008 | Phase 1: randomized, single-dose, double-blind, placebo-controlled, crossover trial. Primary outcome measure Total Pain Relief score (Phase 2 extension study in Table 2b) (NCT00153192) | Adults taking opioids for chronic pain; BPI ≥ 4 (n = 30). Pain diagnosis: neuropathic (N = 7), nociceptive (N = 7), mixed neuropathic and nociceptive (N = 11), and uncategorized (N = 5). Mean age 43.3 years, 53% female | Phase 1: Three, 8-h lab sessions with three days washout. | OMEDD mean 68.1 mg (SD: 57.2, range 7.5–228) (mix of oxycodone, morphine, methadone hydrocodone, hydromorphone) | Dronabinol 10 and 20 mg | Matched placebo dronabinol capsule | One subject took rescue pain medication in all 3 conditions (placebo, dronabinol 10 mg, and dronabinol 20 mg), one subject on both placebo and 10 mg condition, 6 subjects during their placebo condition only | In single-dose studies 10 and 20 mg dronabinol significantly increased the amount of analgesic relief reported. Total pain relief: 31.1 in placebo: 39.7 with dronabinol 10 mg: 41.7 with dronabinol 20 mg | GRADE rating “moderate”, randomized and placebo-controlled, small sample |
| e. Observational studies | |||||||||
| Aviram 2020 | Prospective observational cohort study | Adults with any form of chronic non-cancer–related pain (n = 829, 66% retained at 12 months). Average age 47 years, 43% female | 12 months following treatment initiation | Not specified, mixture of weak (n = 118) and strong (n = 56) opioids at baseline | Varied products (74% THC dominant). Overall reported monthly MC dose increased from 20 ± 20–20 g at T1 to 30 ± 20–30 at T12 (χ2 (4) = 1250.32, p < 0.001). | NA | 42% reduction [27 mg OMEDD (95% CI: −34.89, 18.56) reduction (p < 0.001)). Opioid cessation at 12-month follow-up: 24% using weak and 20% using strong opioids; χ2 (5) = 27.3, p < 0.001; χ2 (5) = 21.9; p < 0.001, respectively | Not reported by opioid status | GRADE rating “low” large observational cohort.In the same cohort, of those not taking opioids at baseline 9% started weak opioids and 10% started strong opioids |
| Bellnier 2018 | Observational pre-post study | Adults (n = 29) with chronic pain (n = 3 cancer-related, n = 26 non-cancer pain, 20 with spinal cord injury with spasticity). Average age was 61 years (±10 years), and 65% of the sample were female | 3 months | Not specified, calculated at OMEDD | 10 mg capsules of 1:1 THC and CBD taken orally every 8–12 h. Vapor pen inhaler of THC/CBD (20:1, 2 mg THC per 0.1 mg CBD) 1 to 5 puffs every 15 min until relief was achieved and use every 4–6 h as needed | Pre-post- | Opioid consumption was reduced from 79.94 (range 0–450) to 19.65 (range 0–150) morphine equivalents per day (p < 0.05). Most (n = 26) completely discontinued opioid use, and the remaining patients reduced their doses by approximately 75% | Paroxysmal pain decreased from 6.76 to 2.04 (p < 0.0001); surface from 4.20 to 1.30 (p < 0.0001); deep from 5.87 to 2.03 (p < 0.0001); and unpleasant rating declined from “miserable” to “annoying” after 3 months therapy | GRADE rating “low” observational data Quality of life EQ-5D scores (range 0 to 100) improved from 36.08 ± 19.85 at baseline to 64.43 + 19.15 after 3 months treatment (p < 0.0001) |
| Capano 2020 | Prospective, observational cohort study | Adults (n = 113) with mod-severe chronic pain for at least 3 years, and stable opioids for at least 1 year (n = 113, 74% retained at 8 weeks, aged 30–65 years (mean 56.1 years), 68% female | 4 and 8 weeks | Not stated, requirement to be taking at least 50 mg OMEDD for 12 months prior to enrollment | 15.7 mg CBD, 0.5 mg THC, 0.3 mg cannabidivarin (CBDV), 0.9 mg cannabidiolic acid (CBDA), 0.8 mg cannabichrome (CBC), and >1% botanical terpene blend | NA | OMEDD not captured. Fifty of the 94 (53.2%) participants using the CBD hemp extract were able to reduce opioid medications at week 8. Of the fifty who reduced, two ceased completely | Baseline pain (PEG) scale at (6.5 [95% CI: 6.16–6.81], 4 weeks 5.9 [95% CI: 5.55–6.25] and 8 weeks,5.7 [95% CI: 5.31–6.12], p =0.006) (12% reduction in pain, [30% reduction considered clinically significant]) | GRADE rating “low” observational data with no control |
| Habib 2018 | Retrospective cohort study | Adults aged 18 and above with fibromyalgia (n = 26), 19 female patients (73%), mean 37.8 ± 7.6 years | Median cannabis duration 3 months | Codeine, tramadol, oxycodone, fentanyl or buprenorphine. Varied doses | The mean dose of medical cannabis was 26 ± 8.3 g per month | NA | 4/4 patients on weak opioids at baseline, ceased while taking cannabinoids (p = 0.055); 15/20 patients on strong opioids ceased while taking medical cannabinoids (p = 0.000) | Not reported by opioid status | GRADE rating “very low”, small retrospective cohort with no control group, short follow-up |
| Haroutounian 2016 | Prospective, observational cohort study | Adults (n = 73/274) 18 years + above 18 with chronic pain, 73 prescribed opioids. Mean age 51.2 years, 62% female | 6 months | Morphine, oxycodone, fentanyl, hydromorphone, buprenorphine, methadone and tramadol. | Smoked (THC 6–14%, CBD 0.2–3.8%) and oral (THC 11–19%, CBD 0.5–5.5%). The mean (SD) monthly prescribed amount of cannabis was 43.2 (17.9) g (any formulation) | NA | 32/73(44%) ceased opioids, (p < 0.001). Median OMEDD among participants receiving opioids at follow-up (n = 41) decreased from 60 mg (95% CI: 45–90) to 45 mg (95% CI: 30-,90); (p = 0.19, Mann–Whitney) | Pain outcomes not available for the subsample on opioids | GRADE rating “low”, non-randomized single-arm open-label study |
| Hickernell 2018 | Retrospective cohort study | Adults (n = 243) who had total knee or hip arthroplasty. Mean age 62.3 years, 64% female | Mean length of stay 2–3 days | Oral oxycodone 10 mg up to three doses mg plus immediate release oxycodone 5–10 mg mg as required | Dronabinol 5 mg twice a day during hospital stay (n = 81) | Patients who did not receive dronabinol (n = 162) over the same time period | No significant difference in OMEDD or total OME dose/length of stay. Significantly lower total OME consumption during stay: Dronabinol group 252.5 mg ± 131.5 mg, control group 313.3 mg ± 185.4 mg. p = 0088 | No significant difference on pain scores between the groups on any day post-surgery | GRADE rating “low” non-randomized retrospective study. Mean length of stay lower for the dronabinol group compared with control (2.3 ± 0.9 vs 3.0 ± 1.2 days, p = 0.02) |
| Hoggart 2015 | Open-label extension study from 2 clinical trials across 66 study sites (38 centers in six countries) | Adults (n = 380) with peripheral neuropathic pain, mean age 57.8 years, 47% female | 38 weeks | Strong and weak opioids | THC/CBD oral mucosal spray (2.7 mg of THC and 2.5 mg of CBD per spray) max 24 sprays per day | NA | No change in the proportion of the whole sample taking strong opioids (56/380 at baseline and 57/380 at follow-up) or other opioids (118/380 at baseline to 123/380 at follow-up) following cannabinoid use | Data on other outcomes not provided by opioid use status | GRADE rating “moderate”, non-randomized sample. Rigorous data collection |
| Lynch 2002 | Observational case series | Adults with pain conditions (n = 3) (peripheral neuropathy, multiple sclerosis, lower back pain), Aged 35–47 years, 33% female | 1–9 month observation period | Morphine (varied doses) | Smoked cannabis plant, unknown content | NA | Mean baseline morphine dose 195 mg (SD 147 mg) compared with mean 35 mg (SD 31 mg) after commencing smoked cannabis. Opioid dose reduction or cessation in each case | Improved pain control described with patients either reducing or ceasing morphine dose | GRADE rating “very low“, unblinded observational study |
| Maida 2008 | Prospective observational study | Adults with advanced cancer (n = 112), 47 of whom were treated with nabilone (mean age 67 years, 38% female) | 30 days | Nabilone group baseline OMEDD 60.3 mg (SD 64.6); comparison group OMEDD 67.3 mg (SD 101.0) | Nabilone, mean of 1.79 mg daily | People with advanced cancer who were not treated with nabilone | Log OMEDD in nabilone group 3.8 mg compared with 4.3 mg in the untreated group (p = 0.016), remained significant after adjusting for baseline symptom level and propensity score | Pain score in nabilone group 3.7 compared with 5.0 in the untreated group (p = 0.003); remained significant after adjusting for baseline symptom level and propensity score with pain score of 3.0 in the nabilone group and 5.5 in the comparison group (p < 0.001) | GRADE rating ”low”. Nabilone prescribing based on symptom-related distress on the initial consultation, leading to selection bias, but managed with propensity scoring |
| Maida 2017 | Observational case series | Adults with pyoderma gangrenosum (n = 2) on opioids. Female (50 years) and male (76 years) | 6–25 days | Opioid analgesic type not specified | Topical cannabinoid oil THC:CBD 5:6 mg/mL or THC:CBD 7:9 mg/mL | NA | Mean Baseline OMEDD 26.7 mg (SD 0.9), Mean follow-up 6.4 mg (SD 8.7) | Mean pain at baseline 8.6, mean pain at follow-up was 2.6 (70% reduction, i.e., clinically meaningful reduction) | GRADE rating “very low”, very small case series |
| Maida 2020 | Observational case series | Two adults (aged 86 and 69, both female), with painful and non-healing leg ulcers, of greater than 6 months duration | 57–68 days | Case 1: Codeine (with acetaminophen), Case 2 188 mg oral morphine equivalents (opioid type not stated) | Topical cannabinoid product THC < 1 mg/mL, CBD 3.75 mg/mL | NA | Both patients ceased opioids | Not reported, opioid requirements used as proxy for pain | GRADE rating “very low”, very small case series |
| Narang 2008 | Open-label extension following randomized, single-dose, double-blind, crossover trial (Table 2d) | Patients on opioids for chronic pain; BPI ≥ 4 (n = 28). (see Table 2d for participant characteristics) | Four weeks | OMEDD mean 68.1 mg (SD 57.2, range 7.5–228) (mix of oxycodone, morphine, methadone hydrocodone, hydromorphone) | Flexible dose schedule; dronabinol 5 mg daily − 20 mg three times a day. | NA | Opioid dose not reported | Mean baseline NRS of 6.9 compared with mean NRS of 5.2 after 4 weeks of dronabinol (24% reduction in pain). Statistically significant reduction, but does not meet the 30% reduction in pain to be clinically significant | GRADE rating “low”. Improvements (p < 0.05) in sleep, energy, pain relief, and social functioning. Lack of placebo control means effects may be non-specific/placebo |
| Rod 2019 | Open-label prospective opioid taper study | Patients with chronic pain (n = 600), on opioid doses of 90–240 mg (age and gender not reported) | Six months | Mean OMEDD 120 mg (Range 90–240 mg) | CBD and THC (4–6%). Doses related directly to the opioid taper: 0.5 g/day for each 10% reduction in opioid dose, as needed by sublingual, oral or inhalation by vaporization | NA | 156 patients (26%) ceased opioids, and a further 329patients (55%) reduced opioid use by an average of 30%. Cannabis use among these patients ranged from 1–3 g/day | Pain not quantified. One patient increased opioid intake; all other patients expressed satisfaction with their pain control, sleep and quality of life | GRADE rating “low”, evidence-based online psychological support provided (e.g., cognitive behavioral therapy and mindfulness) |
| Safakish 2020 | Prospective observational cohort study | 82/751 chronic pain patients, who were using opioids. Mean age of 49.6 years, 57% female | 12 months | Mixed opioids, converted to oral morphine equivalent doses | 7% to 29% THC and/or CBD. | NA | Baseline (n = 82) OMEDD 26.2 (SD 48.1), Month 1 (N = 67) 12.1 (SD 44.7), month 3 (N = 26) 3.3 (SD 8.6), month 6 (n = 9) 3.0 (SD 6.5) month 12 (n = 4) 1.4 (SD 0.1). p < 0.001 | Not reported by opioid status | GRADE rating “very low”, open-label single harm study with high attrition |
| Schneider-Smith 2020 | Retrospective matched cohort study | Adults with traumatic injury: 33 cases (mean age 39.9 years, 76% male) and 33 matched controls (mean age 30.0 years, 30% female) | 48–96 h after admission | Not stated, opioid use reported in OMEDD | Dronabinol (usually 5–10 mg twice a day) | Usual care without dronabinol | OMEDD reduction in group dronabinol (−79 mg (SD20), p < 0.001), OMEDD for controls unchanged from baseline (−9 (18) mg, p = 0.63) | Adjunctive dronabinol reduce pain scores. Average change in pain scores (NRS) were similar between cases and controls (−0.4 vs −0.6, p = 0.78) | GRADE rating “low”, non-randomized retrospective study |
| Takakuwa 2020 | Retrospective cohort study | Adults with low back pain (n = 61) who were prescribed opioids. Mean age 50.1 years, (range = 49–86), 38% female | Data extracted from 1997–2019 from a database of more than 3000 patients | Median OMEDD 21 mg/day (range = 1.1–500). | Variable products reported in grams per day. Median cannabis use 1.45 g/day (range = 0.01–18.7 g). Most smoked (44/61 (72%)). | NA | 31/61 ceased, 9 reduced and 15 increased their opioids. Median OMMED reduction 9.0 mg (IQR = 24–6), sign test: p = 0.004, Wilcoxon sign rank test: p = 0.09). Subgroup analysis: chronic use (median = 21, IQR = 90–5) intermittent opioid use (median = 5.8, IQR = 12–6) | Not reported | GRADE rating “very low”, small retrospective cohort study |
| Yassin 2019 | Prospective observational crossover study | Adult (n = 31) with low back pain and fibromyalgia already treated with oxycodone and duloxetine. Mean age 33.5 years., 90% female | 6 months | Oxycodone 5 mg/Naloxone 2.5 mg twice a day (minimum 12 months of standard analgesic therapy prior to trialing medical cannabinoids) | Medical cannabinoids (smoked or vaporized) 1:4 THC to CBD. The THC levels were less than 5%. The dose of cannabinoid was 20 grams per month for 3 months, with the option to increase to 30 g/month thereafter | Baseline status on standard analgesic therapy | Not reported | Mean VAS score at baseline 8.1(SD 1.4); 3 months: 5.3 (SD 1.3); 6 month: 3.3 (SD 2.2) p < 0.0001. 60% reduction in pain at 3 months, i.e., clinically meaningful reduction | GRADE rating “very low”, small sample, open-label single-arm study; selection bias as only those that did not respond to standard therapy included |
Clinical trials—experimental pain
Five laboratory-based studies in healthy volunteers (n = 82) examined pain responses with co-administered opioids and cannabinoids using double-blind within-patient study designs (Table 2a). Four studies examined oral dronabinol (2.5–20 mg) [59–62] and one examined smoked cannabis [63]. Inconsistent outcomes were observed; two studies found evidence of increased pain, two found some measures of decreased pain, and one study found effects of cannabinoids on pain “unpleasantness” but not pain ratings. One study found low dose dronabinol (2.5 mg) decreased the analgesic effects of oxycodone as measured with a pressure algometer with no effect of 5 or 10 mg dronabinol on analgesic outcomes [61]. Another study noted potentially hyperalgesic effects of cannabinoids [59]. This was in contrast to the analgesic effect observed on pain threshold and tolerance with a cold pressor test when smoked cannabis was administered with 5 mg oxycodone compared oxycodone or cannabis alone, although effects were not found on measure of outcomes of pain intensity or bothersomeness [63]. Dunn et al. [62] demonstrated analgesic effects from dronabinol 2.5 mg when co-administered with hydromorphone on thermal pain measures, but not with higher doses of dronabinol, or on other measures of pain. Roberts et al. [60] found that the co-administration of dronabinol and morphine resulted in reduced pain “unpleasantness” compared to either drug alone. Three experimental studies included measures of abuse liability, and found that smoked cannabis and dronabinol may increase the abuse liability ratings of oxycodone and hydromorphone using measures such as ratings of feeling high and drug liking [61–63].
Clinical trials—acute pain
Three double-blind randomized controlled trials (n = 545) examined the opioid-sparing effects of CBD in acute pain [64–66]. Nabilone and dronabinol were examined in acute post-operative pain and CBD in acute low back pain (<30 days duration). No benefit on opioid dose requirements or analgesic outcomes was identified (Table 2b).
Clinical trials—cancer pain
Seven controlled trials (1795 participants) investigated the opioid-sparing effect of cannabinoids in patients with different forms of cancer pain. One small, non-randomized study found a non-significant effect of cannabis on pain control [67], and a second pilot found no effect of medical cannabis on pain, but an increase in opioid dose in a group that received delayed cannabis [68] (Table 2c). The remaining studies were all larger single or double-blind randomized trials. Five randomized controlled trials (reported in four publications) examined THC and nabiximols compared to placebo in patients with cancer pain who were taking opioids [69–72]. Two studies found improved analgesia with nabiximols compared to the placebo. Johnson et al. [69] found no effect of nabiximols on breakthrough opioid dose requirements. Portenoy et al. [70] conducted a dose-ranging study, and a significant analgesic effect was only found in the lowest dose group, with poorer tolerability observed for higher doses. The remaining three studies found no benefit of adding cannabinoids on their primary outcome of analgesia. Although Lichtman et al. [72] did not find a significant effect of cannabinoids on pain in an intention to treat analysis, the per-protocol analysis did find a significant effect (Table 2c). Four of seven studies required maintenance opioid doses to be kept stable [70–72]; five studies measured breakthrough opioid doses requirements as an outcome with no evidence of a difference found [69–72]. No cancer pain studies included measures of abuse liability.
Meta-analyses were possible on the outcomes of change in mean total oral morphine equivalent daily dose (OMEDD) from baseline (n = 4 studies), percent change in pain score from baseline (n = 4 studies) and adverse events (n = 5 studies). Meta-analysis of four studies (n = 1119 participants) found no effect of nabiximols on change in OMEDD (Mean difference −3.8 mg, 95% CI −10.97, 3.37, I2 = 23%) (Fig. 2a). Four studies (1109 participants) found no effect of nabiximols on percentage change in pain scores (mean difference 1.84, 95% CI −2.05, 5.72, I2 = 58%) (Fig. 2b). Five studies (1536 participants) examined serious adverse events and found no difference in events with cannabinoids compared with placebo (risk ratio [RR] 1.23, 95% CI 0.89, 1.70, I2 = 58%) (Fig. 2c). Five studies (1,536 participants) examined adverse events other than serious adverse events and found more non-serious adverse events with cannabinoids compared with placebo (RR 1.13, 95% CI 1.03, 1.24, I2 = 0%) (Fig. 2d).
Clinical trials—chronic non-cancer pain
Five clinical trials (139 participants, Table 2d) examined the effects of dronabinol [73–75] and smoked cannabis [76, 77] in patients with chronic non-cancer pain. Most studies had short observation periods (5 h to 5 days) [74–77], and used crossover designs [73–76]. Opioid dose was an outcome in one study, with no difference between smoked cannabis and placebo [76]. All five studies reported on analgesic outcomes with conflicting findings. A single-arm open-label study (with no comparison group) recruited people with mixed types of chronic non-cancer pain (n = 24) who were prescribed opioids, and found significant overall reductions from baseline pain ratings following co-administration of cannabinoids [77]. In contrast, a double-blind crossover study in sickle cell patients found no significant differences analgesia effects between placebo and vaporized cannabis [76]. Two studies recruited patients with chronic pancreatitis and found no effect of dronabinol on pain measures compared with placebo [73, 74]. A sub-analysis in patients with chronic postsurgical abdominal pain found lower pain among those who received dronabinol compared with placebo [73]. A single-dose study in patients with mixed-chronic pain conditions, found dronabinol 10 and 20 mg was associated increased analgesia compared with placebo [75]. These studies did not include measures of abuse liability.
Clinical studies—observational
Seventeen observational studies (n = 2674) examined the opioid-sparing effects of cannabinoids; three small retrospective case series of two to three patients each [78–80], two retrospective cohort studies [81, 82], two retrospective matched cohort studies [83, 84], and ten prospective observational cohort studies [85–93], including two open-label extension studies [75, 93] (see Table 2e). Two retrospective matched cohort studies examined acute analgesia with traumatic injury [83] and joint arthroplasty [84]. Both found no difference in pain scores, but reduced opioid consumption on at least one measure. For pain management following joint arthroplasty, there was no change in daily opioid dose with dronabinol administration, but a reduced total opioid consumption due to significantly shorter hospital stays in the dronabinol group [84]. One study compared those prescribed nabilone with those that had not received it, using propensity scoring to adjust for the greater severity of the nabilone prescribed group [89]. The remaining observational studies did not have control conditions and examined opioid use in patients with a range of different types of chronic non-cancer pain. Seven studies reported on the outcome of OMEDD after commencing medical cannabinoids, with reductions from 9 to 140 mg OMEDD reported (Table 2b). Four studies quantified the reduction in pain scores, which ranged from 12% to 70%, with two studies exceeding the minimum threshold of a 30% reduction in pain to be clinically meaningful. Meta-analysis was possible for studies that reported the proportion of patients who reported opioid reduction or cessation; eight studies reported the proportion of patients who ceased opioids (range 2–100%), with a pooled prevalence of 0.39 (95% CI 0.15, 0.64, I2 = 95.47%) (Appendix 5a). Seven studies reported on the proportion of patients reducing opioid use (range 44–100%) with a pooled prevalence of 0.85 (95% CI 0.64, 0.99, I2 = 92.82%) (Appendix 5b). Statistically significant heterogeneity was identified in both meta-analyses.
Discussion
The current update represents the largest synthesis of studies examining the opioid-sparing effects of cannabinoids, with double the number of preclinical studies, four times as many clinical studies and more than six times the number of participants (>5000) compared to our earlier review [3], reflecting the rapid growth of clinical research in this area.
Most preclinical studies found synergistic effects with opioids and cannabinoids co-administration, predominantly with mixed CB1/CB2 agonists such as delta-9-THC, though effects varied with different cannabinoids, opioids and pain assays. Meta-analyses (with one addition preclinical study since 2015) demonstrated that morphine dose required to produce an equivalent analgesic effect was 3.5 times lower when co-administered with delta-9-THC, consistent with the previous review [3]. This effect would be clinically meaningful if replicated in well-controlled clinical studies. However, preclinical studies often have larger effect sizes, attributed to the reduced heterogeneity compared to clinical populations [94]. This body of preclinical research may help to identify specific cannabinoids and mechanisms that underlie an opioid-sparing effect, with the most consistent effects observed with mixed CB1/CB2 agonists, and evidence of potential antagonistic effects between CB1 agonist and mu receptor agonists in models of mechanical hyperalgesia.
A rapidly growing number of clinical studies have measured opioid-sparing endpoints, though findings were inconsistent. The highest quality studies were conducted in patients with cancer pain, where meta-analysis of four studies did not find significant effects on opioid dose or analgesia. Conflicting findings were found in studies of experimental pain, and in patients with chronic non-cancer pain. Further studies are needed to clarify the results found here given the small number of studies.
A limited number of controlled studies demonstrated benefits of combining cannabinoids with opioids for analgesia. Experimental pain studies found cannabinoids improved [62, 63] and worsened [61] analgesia. These effects were not dose dependent, with significant effects seen with lower but not higher doses of delta-9-THC. Opioid-sparing effects were not seen in well-conducted RCTs with acute pain, or in meta-analyses of RCTs in cancer pain, and studies that did find positive effects have important limitations such as no control group [77], small sample sizes [67, 75], and the mixed quality of the study design. Furthermore, some RCTs instructed patients to continue their pain medication in the same doses, which may preclude identifying a change in opioid dose [70–73, 77], although changes in breakthrough opioid requirements were a secondary outcome in six studies [69–72, 75]. Some clinical studies demonstrated beneficial effects of opioid and cannabinoid co-administration on other outcomes such as sleep, and functioning in chronic pain patients [75, 77]. Conflicting results were found between preclinical studies and clinical trials on measure of abuse liability. Evidence of reduced abuse liability was found in some animal models, which contrasted directly with evidence of increased drug liking and subjective effects in human studies.
Finally, observational studies had methodological concerns including small sample sizes (several observational studies included in meta-analysis had two to three patients), no control groups or blinding, selection bias, and were likely to have been impacted by expectancy effects.
Although our review is much broader, we have drawn similar conclusions to earlier reviews. For example, a review of cross-sectional surveys and cohort studies, representing lower quality evidence, found large reductions in opioid doses, though study designs prevented the drawing of causal conclusions [95]. A later review with five randomized trials with patients with chronic pain and 12 observational studies further concluded that there was uncertainty in the evidence [96], although this review considered a substantially smaller number of clinical trials than we consider. Future studies may benefit from focusing on populations with higher opioid tolerance, or higher motivation to reduce opioid doses, where clinical benefits may be greatest [97]. Standardization of outcomes for opioid-sparing research may assist with harmonization of outcome measures and support meta-analysis with future clinical trials [2].
Despite the inclusion of a larger number of studies, and the increased size and quality of clinical trials in recent years, our conclusions have not changed substantially from our earlier review. Nevertheless, we did identify 15 registered clinical trials indicating that this continues to be an active area of research in which the science is likely to continue to evolve.
In conclusion, preclinical studies support the opioid-sparing effect of delta-9-THC and other mixed CB1/CB2 agonists. Observational studies support the opioid-sparing potential of cannabinoids. However, findings from clinical trials provide conflicting results that may highlight important areas for future research. These include identifying optimal doses and populations who may experience benefits with cannabinoids. With numerous clinical trials currently underway, we will update our review, as higher-quality data may enable stronger conclusions to be made.
Supplementary information
Untitled section
Funding
SN is supported by a NHMRC Research Fellowship (#1163961). Open Access funding enabled and organized by CAUL and its Member Institutions.
Competing interests
SN, NL and MF have been investigators on an untied education grant from Indivior for unrelated work. SN has received untied research grants from Seqirus to study prescription opioid overdose. BLF 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’s 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.
Footnotes
Footnote Group
Supplementary information
The online version contains supplementary material available at 10.1038/s41386-022-01322-4.
References
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References
- 1.Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. JAMA. 2016;315:1624–45. doi: 10.1001/jama.2016.1464.
- 2.Gewandter JS, Smith SM, Dworkin RH, Turk DC, Gan TJ, Gilron I, et al. Research approaches for evaluating opioid sparing in clinical trials of acute and chronic pain treatments: Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials recommendations. Pain. 2021;162:2669–81. doi: 10.1097/j.pain.0000000000002283.
- 3.Nielsen S, Sabioni P, Trigo JM, Ware MA, Betz-Stablein BD, Murnion B, et al. Opioid-sparing effect of cannabinoids: a systematic review and meta-analysis. Neuropsychopharmacology. 2017;42:1752–65.. doi: 10.1038/npp.2017.51.
- 4.Campbell G, Hall W, Nielsen S. What does the ecological and epidemiological evidence indicate about the potential for cannabinoids to reduce opioid use and harms? A comprehensive review. Int Rev Psychiatry. 2018;30:91–106. doi: 10.1080/09540261.2018.1509842.
- 5.Shover CL, Davis CS, Gordon SC, Humphreys K. Association between medical cannabis laws and opioid overdose mortality has reversed over time. Proc Natl Acad Sci USA. 2019;116:12624. doi: 10.1073/pnas.1903434116.
- 6.Desroches J, Beaulieu P. Opioids and cannabinoids interactions: involvement in pain management. Curr Drug Targets. 2010;11:462–73. doi: 10.2174/138945010790980303.
- 7.Hojo M, Sudo Y, Ando Y, Minami K, Takada M, Matsubara T, et al. mu-Opioid receptor forms a functional heterodimer with cannabinoid CB1 receptor: electrophysiological and FRET assay analysis. J Pharm Sci. 2008;108:308–19. doi: 10.1254/jphs.08244FP.
- 8.Babalonis S, Walsh SL. Therapeutic potential of opioid/cannabinoid combinations in humans: review of the evidence. Eur Neuropsychopharmacol. 2020;36:206–16. doi: 10.1016/j.euroneuro.2020.03.002.
- 9.An D, Peigneur S, Hendrickx LA, Tytgat J. Targeting cannabinoid receptors: current status and prospects of natural products. Int J Mol Sci. 2020;21:5064. doi: 10.3390/ijms21145064.
- 10.Yao BB, Mukherjee S, Fan Y, Garrison TR, Daza AV, Grayson GK, et al. In vitro pharmacological characterization of AM1241: a protean agonist at the cannabinoid CB2 receptor? Br J Pharmacol. 2006;149:145–54. doi: 10.1038/sj.bjp.0706838.
- 11.Lu H-C, Mackie K. An introduction to the endogenous cannabinoid system. Biol Psychiatry. 2016;79:516–25.. doi: 10.1016/j.biopsych.2015.07.028.
- 12.Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med. 2009;6:e1000097. doi: 10.1371/journal.pmed.1000097.
- 13.Covidence systematic review software. covidence.org. Veritas Health Innovation: Melbourne, Australia; 2019.
- 14.Litchfield JA, Wilcoxon F. A simplified method of evaluating dose-effect experiments. J Pharmacol Exp Ther. 1949;96:99–113.
- 15.Luo D, Wan X, Liu J, Tong T. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res. 2016;27:1785–805. doi: 10.1177/0962280216669183.
- 16.Wan X, Wang W, Liu J, Tong T. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol. 2014;14:135. doi: 10.1186/1471-2288-14-135.
- 17.Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. Br Med J. 2008;336:924–6. doi: 10.1136/bmj.39489.470347.AD.
- 18.Sterne JAC, Sutton AJ, Ioannidis JPA, Terrin N, Jones DR, Lau J, et al. Recommendations for examining and interpreting funnel plot asymmetry in meta-analyses of randomised controlled trials. BMJ. 2011;343:d4002. doi: 10.1136/bmj.d4002.
- 19.Cichewicz DL, Martin ZL, Smith FL, Welch SP. Enhancement mu opioid antinociception by oral delta9-tetrahydrocannabinol: dose-response analysis and receptor identification. J Pharmacol Exp Ther. 1999;289:859–67.
- 20.Cichewicz DL, McCarthy EA. Antinociceptive synergy between delta(9)-tetrahydrocannabinol and opioids after oral administration. J Pharmacol Exp Ther. 2003;304:1010–5. doi: 10.1124/jpet.102.045575.
- 21.Cox ML, Haller VL, Welch SP. Synergy between delta9-tetrahydrocannabinol and morphine in the arthritic rat. Eur J Pharmacol. 2007;567:125–30.. doi: 10.1016/j.ejphar.2007.04.010.
- 22.Smith FL, Cichewicz D, Martin ZL, Welch SP. The enhancement of morphine antinociception in mice by delta9-tetrahydrocannabinol. Pharmacology Biochem Behav. 1998;60:559–66. doi: 10.1016/S0091-3057(98)00012-4.
- 23.Williams J, Haller VL, Stevens DL, Welch SP. Decreased basal endogenous opioid levels in diabetic rodents: effects on morphine and delta-9-tetrahydrocannabinoid-induced antinociception. Eur J Pharmacol. 2008;584:78–86. doi: 10.1016/j.ejphar.2007.12.035.
- 24.Welch SP, Stevens DL. Antinociceptive activity of intrathecally administered cannabinoids alone, and in combination with morphine, in mice. J Pharmacol Exp Ther. 1992;262:10–8.
- 25.Wakley AA, Craft RM. THC-methadone and THC-naltrexone interactions on discrimination, antinociception, and locomotion in rats. Behavioural Pharmacol. 2011;22:489–97. doi: 10.1097/FBP.0b013e328348ed22.
- 26.Wilson AR, Maher L, Morgan MM. Repeated cannabinoid injections into the rat periaqueductal gray enhance subsequent morphine antinociception. Neuropharmacology. 2008;55:1219–25. doi: 10.1016/j.neuropharm.2008.07.038.
- 27.Yesilyurt O, Dogrul A, Gul H, Seyrek M, Kusmez O, Ozkan Y, et al. Topical cannabinoid enhances topical morphine antinociception. Pain. 2003;105:303–8. doi: 10.1016/S0304-3959(03)00245-8.
- 28.Tham SM, Angus JA, Tudor EM, Wright CE. Synergistic and additive interactions of the cannabinoid agonist CP55,940 with mu opioid receptor and alpha2-adrenoceptor agonists in acute pain models in mice. Br J Pharmacol. 2005;144:875–84. doi: 10.1038/sj.bjp.0706045.
- 29.Smith PA, Selley DE, Sim-Selley LJ, Welch SP. Low dose combination of morphine and delta9-tetrahydrocannabinol circumvents antinociceptive tolerance and apparent desensitization of receptors. Eur J Pharmacol. 2007;571:129–37. doi: 10.1016/j.ejphar.2007.06.001.
- 30.Reche I, Fuentes JA, Ruiz-Gayo M. Potentiation of delta 9-tetrahydrocannabinol-induced analgesia by morphine in mice: involvement of mu- and kappa-opioid receptors. Eur J Pharmacol. 1996;318:11–6. doi: 10.1016/S0014-2999(96)00752-2.
- 31.Pugh G, Jr, Smith PB, Dombrowski DS, Welch SP. The role of endogenous opioids in enhancing the antinociception produced by the combination of DELTA9-tetrahydrocannabinol and morphine in the spinal cord. J Pharmacol Exp Ther. 1996;279:608–16.
- 32.Maguire DR, Yang W, France CP. Interactions between mu-opioid receptor agonists and cannabinoid receptor agonists in rhesus monkeys: antinociception, drug discrimination, and drug self-administration. [Erratum appears in J Pharmacol Exp Ther. 2014 Mar;348(3):490-1 Note: Dosage error in article text] J Pharmacol Exp Ther. 2013;345:354–62. doi: 10.1124/jpet.113.204099.
- 33.Li JX, McMahon LR, Gerak LR, Becker GL, France CP. Interactions between Delta(9)-tetrahydrocannabinol and mu opioid receptor agonists in rhesus monkeys: discrimination and antinociception. Psychopharmacology. 2008;199:199–208. doi: 10.1007/s00213-008-1157-0.
- 34.Katsuyama S, Mizoguchi H, Kuwahata H, Komatsu T, Nagaoka K, Nakamura H, et al. Involvement of peripheral cannabinoid and opioid receptors in beta-caryophyllene-induced antinociception. Eur J Pain. 2013;17:664–75. doi: 10.1002/j.1532-2149.2012.00242.x.
- 35.Finn DP, Beckett SR, Roe CH, Madjd A, Fone KC, Kendall DA, et al. Effects of coadministration of cannabinoids and morphine on nociceptive behaviour, brain monoamines and HPA axis activity in a rat model of persistent pain. Eur J Neurosci. 2004;19:678–86.. doi: 10.1111/j.0953-816X.2004.03177.x.
- 36.Cichewicz DL, Welch SP, Smith FL. Enhancement of transdermal fentanyl and buprenorphine antinociception by transdermal delta9-tetrahydrocannabinol. Eur J Pharmacol. 2005;525:74–82. doi: 10.1016/j.ejphar.2005.09.039.
- 37.Williams IJ, Edwards S, Rubo A, Haller VL, Stevens DL, Welch SP. Time course of the enhancement and restoration of the analgesic efficacy of codeine and morphine by delta9-tetrahydrocannabinol. Eur J Pharmacol. 2006;539:57–63. doi: 10.1016/j.ejphar.2006.04.003.
- 38.Alsalem M, Altarifi A, Haddad M, Aldossary SA, Kalbouneh H, Aldaoud N, et al. Antinociceptive and abuse potential effects of cannabinoid/opioid combinations in a chronic pain model in rats. Brain Sci. 2019;9:328.
- 39.Alsalem M, Altarifi A, Haddad M, Azab B, Kalbouneh H, Imraish A, et al. Analgesic effects and impairment in locomotor activity induced by cannabinoid/opioid combinations in rat models of chronic pain. Brain Sci. 2020;10:1–18.. doi: 10.3390/brainsci10080523.
- 40.Altun A, Yildirim K, Ozdemir E, Bagcivan I, Gursoy S, Durmus N. Attenuation of morphine antinociceptive tolerance by cannabinoid CB1 and CB2 receptor antagonists. J Physiological Sci. 2015;65:407–15. doi: 10.1007/s12576-015-0379-2.
- 41.Auh QS, Chun YH, Melemedjian OK, Zhang Y, Ro JY. Peripheral interactions between cannabinoid and opioid receptor agonists in a model of inflammatory mechanical hyperalgesia. Brain Res Bull. 2016;125:211–17.. doi: 10.1016/j.brainresbull.2016.07.009.
- 42.Chen X, Cowan A, Inan S, Geller EB, Meissler JJ, Rawls SM, et al. Opioid-sparing effects of cannabinoids on morphine analgesia: participation of CB1 and CB2 receptors. Br J Pharmacol. 2019;176:3378–89. doi: 10.1111/bph.14769.
- 43.Grenald SA, Young MA, Wang Y, Ossipov MH, Ibrahim MM, Largent-Milnes TM, et al. Synergistic attenuation of chronic pain using mu opioid and cannabinoid receptor 2 agonists. Neuropharmacology. 2017;116:59–70. doi: 10.1016/j.neuropharm.2016.12.008.
- 44.Iyer V, Slivicki RA, Thomaz AC, Crystal JD, Mackie K, Hohmann AG. The cannabinoid CB2 receptor agonist LY2828360 synergizes with morphine to suppress neuropathic nociception and attenuates morphine reward and physical dependence. Eur J Pharmacol. 2020;886:173544.
- 45.Kazantzis NP, Casey SL, Seow PW, Mitchell VA, Vaughan CW. Opioid and cannabinoid synergy in a mouse neuropathic pain model. Br J Pharmacol. 2016;173:2521–31.
- 46.Maguire DR, France CP. Additive antinociceptive effects of mixtures of the kappa-opioid receptor agonist spiradoline and the cannabinoid receptor agonist CP55940 in rats. Behavioural Pharmacol. 2016;27:69–72. doi: 10.1097/FBP.0000000000000184.
- 47.Maguire DR, France CP. Antinociceptive effects of mixtures of mu opioid receptor agonists and cannabinoid receptor agonists in rats: impact of drug and fixed-dose ratio. Eur J Pharmacol. 2018;819:217–24.. doi: 10.1016/j.ejphar.2017.11.038.
- 48.Minervini V, Dahal S, France CP. Behavioral characterization of κ opioid receptor agonist spiradoline and cannabinoid receptor agonist CP55940 mixtures in rats. J Pharmacol Exp Ther. 2017;360:280–87.. doi: 10.1124/jpet.116.235630.
- 49.Neelakantan H, Tallarida RJ, Reichenbach ZW, Tuma RF, Ward SJ, Walker EA. Distinct interactions of cannabidiol and morphine in three nociceptive behavioral models in mice. Behavioural Pharmacol. 2015;26:304–14. doi: 10.1097/FBP.0000000000000119.
- 50.Nguyen JD, Grant Y, Creehan KM, Hwang CS, Vandewater SA, Janda KD, et al. Δ 9 -tetrahydrocannabinol attenuates oxycodone self-administration under extended access conditions. Neuropharmacology. 2019;151:127–35.. doi: 10.1016/j.neuropharm.2019.04.010.
- 51.Nilges MR, Bondy ZB, Grace JA, Winsauer PJ. Opioid-enhancing antinociceptive effects of delta-9-tetrahydrocannabinol and amitriptyline in rhesus macaques. Exp Clin Psychopharmacol. 2020;28:355–64.. doi: 10.1037/pha0000313.
- 52.Rodríguez-Muñoz M, Onetti Y, Cortés-Montero E, Garzón J, Sánchez-Blázquez P. Cannabidiol enhances morphine antinociception, diminishes NMDA-mediated seizures and reduces stroke damage via the sigma 1 receptor. Mol Brain. 2018;11:51.
- 53.Sierra S, Gupta A, Gomes I, Fowkes M, Ram A, Bobeck EN, et al. Targeting cannabinoid 1 and delta opioid receptor heteromers alleviates chemotherapy-induced neuropathic pain. ACS Pharmacol Transl Sci. 2019;2:219–29.. doi: 10.1021/acsptsci.9b00008.
- 54.Yuill MB, Hale DE, Guindon J, Morgan DJ. Anti-nociceptive interactions between opioids and a cannabinoid receptor 2 agonist in inflammatory pain. Mol Pain. 2017;13(no pagination).
- 55.Zhang M, Chi M, Zou H, Tian S, Zhang Z, Wang G. Effects of coadministration of low dose cannabinoid type 2 receptor agonist and morphine on vanilloid receptor 1 expression in a rat model of cancer pain. Mol Med Rep. 2017;16:7025–31. doi: 10.3892/mmr.2017.7479.
- 56.Zhang M, Dong L, Zou H, Li J, Li Q, Wang G, et al. Effects of cannabinoid type 2 receptor agonist AM1241 on morphine-induced antinociception, acute and chronic tolerance, and dependence in mice. J Pain. 2018;19:1113–29. doi: 10.1016/j.jpain.2018.04.009.
- 57.Zhang M, Wang K, Ma M, Tian S, Wei N, Wang G. Low-dose cannabinoid type 2 receptor agonist attenuates tolerance to repeated morphine administration via regulating mu-opioid receptor expression in walker 256 tumor-bearing rats. Anesthesia Analgesia. 2016;122:1031–37. doi: 10.1213/ANE.0000000000001129.
- 58.Stachtari CC, Thomareis ON, Tsaousi GG, Karakoulas KA, Chatzimanoli FI, Chatzopoulos SA, et al. Interaction of a cannabinoid-2 agonist with tramadol on nociceptive thresholds and immune responses in a rat model of incisional pain. Am J Therapeutics. 2016;23:e1484–e92.. doi: 10.1097/MJT.0000000000000131.
- 59.Naef M, Curatolo M, Petersen-Felix S, Arendt-Nielsen L, Zbinden A, Brenneisen R. The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions. Pain. 2003;105:79–88. doi: 10.1016/S0304-3959(03)00163-5.
- 60.Roberts JD, Gennings C, Shih M. Synergistic affective analgesic interaction between delta-9- tetrahydrocannabinol and morphine. Eur J Pharmacol. 2006;530:54–58. doi: 10.1016/j.ejphar.2005.11.036.
- 61.Babalonis S, Lofwall MR, Sloan PA, Nuzzo PA, Fanucchi LC, Walsh SL. Cannabinoid modulation of opioid analgesia and subjective drug effects in healthy humans. Psychopharmacology. 2019;236:3341–52.. doi: 10.1007/s00213-019-05293-1.
- 62.Dunn KE, Bergeria CL, Huhn AS, Speed TJ, Mun CJ, Vandrey R, et al. Within-subject, double-blinded, randomized, and placebo-controlled evaluation of the combined effects of the cannabinoid dronabinol and the opioid hydromorphone in a human laboratory pain model. Neuropsychopharmacology. 2021;46:1451–59.. doi: 10.1038/s41386-021-01007-4.
- 63.Cooper ZD, Bedi G, Ramesh D, Balter R, Comer SD, Haney M. Impact of co-administration of oxycodone and smoked cannabis on analgesia and abuse liability. Neuropsychopharmacology. 2018;43:2046–55.. doi: 10.1038/s41386-018-0011-2.
- 64.Seeling W, Kneer L, Buchele B, Gschwend J, Maier L, Nett C, et al. DELTA9-tetrahydrocannabinol and the opioid receptor agonist piritramide do not act synergistically in postoperative pain. [German] Keine synergistische wirkung der kombination von DELTA9-tetrahydrocannabinol und piritramid bei postoperativen schmerzen. Anaesthesist. 2006;55:391–400. doi: 10.1007/s00101-005-0963-6.
- 65.Levin DN, Dulberg Z, Chan AW, Hare GM, Mazer CD, Hong A. A randomized-controlled trial of nabilone for the prevention of acute postoperative nausea and vomiting in elective surgery. Can J Anaesth. 2017;64:385–95.. doi: 10.1007/s12630-017-0814-3.
- 66.Bebee B, Taylor DM, Bourke E, Pollack K, Foster L, Ching M, et al. The CANBACK trial: a randomised, controlled clinical trial of oral cannabidiol for people presenting to the emergency department with acute low back pain. Med J Aust. 2021;214:370–75.. doi: 10.5694/mja2.51014.
- 67.Lissoni P, Porro G, Messina G, Porta E, Rovelli F, Roselli MG, et al. Morphine, melatonin, Marijuana, Magnolia and MYRRH as the “five m” schedule in the treatment of cancer pain and the possible dose-dependency of the antitumor and analgesic effects of the pineal hormone melatonin. Anticancer Res. 2014;34:6033–34.
- 68.Zylla DM, Eklund J, Gilmore G, Gavenda A, Guggisberg J, VazquezBenitez G, et al. A randomized trial of medical cannabis in patients with stage IV cancers to assess feasibility, dose requirements, impact on pain and opioid use, safety, and overall patient satisfaction. Supportive Care Cancer. 2021;29:7471–78.. doi: 10.1007/s00520-021-06301-x.
- 69.Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, Fallon MT. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manag. 2010;39:167–79. doi: 10.1016/j.jpainsymman.2009.06.008.
- 70.Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, et al. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012;13:438–49. doi: 10.1016/j.jpain.2012.01.003.
- 71.Fallon MT, Albert Lux E, McQuade R, Rossetti S, Sanchez R, Sun W, et al. Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: two double-blind, randomized, placebo-controlled phase 3 studies. Br J Pain. 2017;11:119–33.. doi: 10.1177/2049463717710042.
- 72.Lichtman AH, Lux EA, McQuade R, Rossetti S, Sanchez R, Sun W, et al. Results of a double-blind, randomized, placebo-controlled study of nabiximols oromucosal spray as an adjunctive therapy in advanced cancer patients with chronic uncontrolled pain. J Pain Symptom Manag. 2018;55:179–88.e1. doi: 10.1016/j.jpainsymman.2017.09.001.
- 73.de Vries M, van Rijckevorsel DCM, Vissers KCP, Wilder-Smith OHG, van Goor H. Tetrahydrocannabinol does not reduce pain in patients with chronic abdominal pain in a phase 2 placebo-controlled study. Clin Gastroenterol Hepatol. 2017;15:1079–86.e4. doi: 10.1016/j.cgh.2016.09.147.
- 74.De Vries M, Van Rijckevorsel DCM, Vissers KCP, Wilder-Smith OHG, Van Goor H. Single dose delta-9-tetrahydrocannabinol in chronic pancreatitis patients: analgesic efficacy, pharmacokinetics and tolerability. Br J Clin Pharmacol. 2016;81:525–37. doi: 10.1111/bcp.12811.
- 75.Narang S, Gibson D, Wasan AD, Ross EL, Michna E, Nedeljkovic SS, et al. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J Pain. 2008;9:254–64. doi: 10.1016/j.jpain.2007.10.018.
- 76.Abrams DI, Couey P, Dixit N, Sagi V, Hagar W, Vichinsky E, et al. Effect of inhaled cannabis for pain in adults with sickle cell disease: a randomized clinical trial. JAMA Network Open. 2020;3:e2010874.
- 77.Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL. Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Therapeutics. 2011;90:844–51. doi: 10.1038/clpt.2011.188.
- 78.Lynch ME, Clark AJ. Cannabis reduces opioid dose in the treatment of chronic non-cancer pain. J Pain Symptom Manag. 2003;25:496–8. doi: 10.1016/S0885-3924(03)00142-8.
- 79.Maida V, Corban J. Topical medical cannabis: a new treatment for wound pain—three cases of pyoderma gangrenosum. J Pain Symptom Manag. 2017;54:732–36.. doi: 10.1016/j.jpainsymman.2017.06.005.
- 80.Maida V, Shi RB, Fazzari FGT, Zomparelli L. Topical cannabis-based medicines – a novel paradigm and treatment for non-uremic calciphylaxis leg ulcers: an open label trial. Int Wound J. 2020;17:1508–16. doi: 10.1111/iwj.13484.
- 81.Habib G, Artul S. Medical cannabis for the treatment of fibromyalgia. J Clin Rheumatol. 2018;24:255–58.. doi: 10.1097/RHU.0000000000000702.
- 82.Takakuwa KM, Hergenrather JY, Shofer FS, Schears RM. The impact of medical cannabis on intermittent and chronic opioid users with back pain: how cannabis diminished prescription opioid usage. Cannabis Cannabinoid Res. 2020;5:263–70.. doi: 10.1089/can.2019.0039.
- 83.Schneider-Smith E, Salottolo K, Swartwood C, Melvin C, Madayag RM, Bar-Or D. Matched pilot study examining cannabis-based dronabinol for acute pain following traumatic injury. Trauma Surg Acute Care Open. 2020;5:e000391.
- 84.Hickernell TR, Lakra A, Berg A, Cooper HJ, Geller JA, Shah RP. Should cannabinoids be added to multimodal pain regimens after total hip and knee arthroplasty? J Arthroplast. 2018;33:3637–41.. doi: 10.1016/j.arth.2018.07.027.
- 85.Aviram J, Pud D, Gershoni T, Schiff-Keren B, Ogintz M, Vulfsons S, et al. Medical cannabis treatment for chronic pain: outcomes and prediction of response. Eur J Pain. 2021;25:359–74.
- 86.Capano A, Weaver R, Burkman E. Evaluation of the effects of CBD hemp extract on opioid use and quality of life indicators in chronic pain patients: a prospective cohort study. Postgrad Med. 2020;132:56–61. doi: 10.1080/00325481.2019.1685298.
- 87.Haroutounian S, Ratz Y, Ginosar Y, Furmanov K, Saifi F, Meidan R, et al. The effect of medicinal cannabis on pain and quality-of-life outcomes in chronic pain: a prospective open-label study. Clin J Pain. 2016;32:1036–43.. doi: 10.1097/AJP.0000000000000364.
- 88.Safakish R, Ko G, Salimpour V, Hendin B, Sohanpal I, Loheswaran G, et al. Medical cannabis for the management of pain and quality of life in chronic pain patients: a prospective observational study. Pain Med. 2020;18:3073–86.
- 89.Maida V, Ennis M, Irani S, Corbo M, Dolzhykov M. Adjunctive nabilone in cancer pain and symptom management: a prospective observational study using propensity scoring. J Support Oncol. 2008;6:119–24.
- 90.Bellnier T, Brown GW, Ortega TR. Preliminary evaluation of the efficacy, safety, and costs associated with the treatment of chronic pain with medical cannabis. Ment Health Clin. 2018;8:110–15.. doi: 10.9740/mhc.2018.05.110.
- 91.Rod K. A pilot study of a medical cannabis – opioid reduction program. Am J Psychiatry Neurosci. 2019;7:74–7.
- 92.Yassin M, Oron A, Robinson D. Effect of adding medical cannabis to analgesic treatment in patients with low back pain related to fibromyalgia: an observational cross-over single centre study. Clin Exp Rheumatol. 2019;37(Suppl 116):13–20.
- 93.Hoggart B, Ratcliffe S, Ehler E, Simpson KH, Hovorka J, Lejčko J, et al. A multicentre, open-label, follow-on study to assess the long-term maintenance of effect, tolerance and safety of THC/CBD oromucosal spray in the management of neuropathic pain. J Neurol. 2015;262:27–40. doi: 10.1007/s00415-014-7502-9.
- 94.Berge O-G. Predictive validity of behavioural animal models for chronic pain. Br J Pharmacol. 2011;164:1195–206.. doi: 10.1111/j.1476-5381.2011.01300.x.
- 95.Okusanya BO, Asaolu IO, Ehiri JE, Kimaru LJ, Okechukwu A, Rosales C. Medical cannabis for the reduction of opioid dosage in the treatment of non-cancer chronic pain: a systematic review. Syst Rev. 2020;9:167. doi: 10.1186/s13643-020-01425-3.
- 96.Noori A, Miroshnychenko A, Shergill Y, Ashoorion V, Rehman Y, Couban RJ, et al. Opioid-sparing effects of medical cannabis or cannabinoids for chronic pain: a systematic review and meta-analysis of randomised and observational studies. BMJ Open. 2021;11:e047717. doi: 10.1136/bmjopen-2020-047717.
- 97.Le Foll B. Opioid-sparing effects of cannabinoids: myth or reality? Prog Neuropsychopharmacol Biol Psychiatry. 2021;106:110065. doi: 10.1016/j.pnpbp.2020.110065.