Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Opioid-sparing effect of cannabinoids for analgesia: an updated systematic review and meta-analysis of preclinical and clinical studies

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.

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 \(\log _{10}\;\widehat {ED}_{50}\) 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 \(\log _{10}\;\widehat {ED}_{50}\):

$$SD\left( {{{{{{{{\mathrm{log}}}}}}}}_{10}\;\widehat {ED}_{50}} \right) = \frac{{{{{{{{{\mathrm{log}}}}}}}}_{10}UL - {{{{{{{\mathrm{log}}}}}}}}_{10}\;\widehat {ED}_{50}}}{{1.96}}$$

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 \({{{{{\rm{log}}}}}}_{10}ED_{50}\) 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

Meta-analysis for clinical trials was conducted with Revman 5.4, where medians and interquartile ranges were required to be converted into means and standard deviations to allow inclusion in meta-analyses, we used methods established by Luo et al. [15] and Wan et al. [16].

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 [19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58]. 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.

Table 1 Summary of opioid-sparing outcomes in preclinical studies by cannabinoid type.

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 [19,20,21,22,23,24, 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.

Fig. 1: Forrest plot for meta-analysis examining the opioid-sparing effect of delta-9-THC when co-administered with morphine.
figure 1

Note mean difference and standard deviation values are of log10ED50.

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).

Table 2 Clinical studies.

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) [59,60,61,62] 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 [61,62,63].

Clinical trials—acute pain

Three double-blind randomized controlled trials (n = 545) examined the opioid-sparing effects of CBD in acute pain [64,65,66]. 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 [69,70,71,72]. 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 [70,71,72]; five studies measured breakthrough opioid doses requirements as an outcome with no evidence of a difference found [69,70,71,72]. 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).

Fig. 2: Opioid-sparing outcomes from clinical trials in people with cancer pain.
figure 2

Meta-analysis comparing cannabinoids with placebo on outcomes of a percent improvement in pain score, b change in mean total Oral Morphine Equivalent Daily Dose (OMEDD), c serious adverse events from baseline, and d adverse events excluding serious adverse events, in clinical trials of people with cancer pain.

Clinical trials—chronic non-cancer pain

Five clinical trials (139 participants, Table 2d) examined the effects of dronabinol [73,74,75] and smoked cannabis [76, 77] in patients with chronic non-cancer pain. Most studies had short observation periods (5 h to 5 days) [74,75,76,77], and used crossover designs [73,74,75,76]. 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 [78,79,80], two retrospective cohort studies [81, 82], two retrospective matched cohort studies [83, 84], and ten prospective observational cohort studies [85,86,87,88,89,90,91,92,93], 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.

Quality ratings of clinical studies

The clinical studies were rated using the GRADE criteria. Of the clinical trials, five laboratory studies provided moderate evidence, three clinical trials in acute pain provided high quality evidence, six clinical studies provided low-high quality evidence in cancer pain, and five studies in chronic non-cancer pain were assessed as low-moderate quality. The seventeen observational studies were assessed to be low to very-low-quality evidence (Table 2).

Ongoing clinical trials

We identified 15 registered clinical trials which, based on published protocols and clinical trial registry entries, may provide important data for future updated reviews (Appendix 6).

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 [70,71,72,73, 77], although changes in breakthrough opioid requirements were a secondary outcome in six studies [69,70,71,72, 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.

References

  1. Dowell D, Haegerich TM, Chou R. CDC guideline for prescribing opioids for chronic pain—United States, 2016. JAMA. 2016;315:1624–45.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. Desroches J, Beaulieu P. Opioids and cannabinoids interactions: involvement in pain management. Curr Drug Targets. 2010;11:462–73.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  Article  Google Scholar 

  8. Babalonis S, Walsh SL. Therapeutic potential of opioid/cannabinoid combinations in humans: review of the evidence. Eur Neuropsychopharmacol. 2020;36:206–16.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. Lu H-C, Mackie K. An introduction to the endogenous cannabinoid system. Biol Psychiatry. 2016;79:516–25.

    CAS  PubMed  Article  Google Scholar 

  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.

    PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    PubMed  PubMed Central  Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  20. Cichewicz DL, McCarthy EA. Antinociceptive synergy between delta(9)-tetrahydrocannabinol and opioids after oral administration. J Pharmacol Exp Ther. 2003;304:1010–5.

    CAS  PubMed  Article  Google Scholar 

  21. Cox ML, Haller VL, Welch SP. Synergy between delta9-tetrahydrocannabinol and morphine in the arthritic rat. Eur J Pharmacol. 2007;567:125–30.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  25. Wakley AA, Craft RM. THC-methadone and THC-naltrexone interactions on discrimination, antinociception, and locomotion in rats. Behavioural Pharmacol. 2011;22:489–97.

    CAS  Article  Google Scholar 

  26. Wilson AR, Maher L, Morgan MM. Repeated cannabinoid injections into the rat periaqueductal gray enhance subsequent morphine antinociception. Neuropharmacology. 2008;55:1219–25.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    Article  CAS  Google Scholar 

  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.

    CAS  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  60. Roberts JD, Gennings C, Shih M. Synergistic affective analgesic interaction between delta-9- tetrahydrocannabinol and morphine. Eur J Pharmacol. 2006;530:54–58.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    PubMed  PubMed Central  Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    PubMed  Article  CAS  Google Scholar 

  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.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  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.

    CAS  Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    PubMed  PubMed Central  Article  Google Scholar 

  81. Habib G, Artul S. Medical cannabis for the treatment of fibromyalgia. J Clin Rheumatol. 2018;24:255–58.

    PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    Article  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    PubMed  Article  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    PubMed  PubMed Central  Article  Google Scholar 

  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.

    PubMed  Google Scholar 

  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.

    CAS  PubMed  Article  Google Scholar 

  94. Berge O-G. Predictive validity of behavioural animal models for chronic pain. Br J Pharmacol. 2011;164:1195–206.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  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.

    PubMed  PubMed Central  Article  Google Scholar 

  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.

    PubMed  PubMed Central  Article  Google Scholar 

  97. Le Foll B. Opioid-sparing effects of cannabinoids: myth or reality? Prog Neuropsychopharmacol Biol Psychiatry. 2021;106:110065.

    PubMed  Article  CAS  Google Scholar 

Download references

Funding

SN is supported by a NHMRC Research Fellowship (#1163961). Open Access funding enabled and organized by CAUL and its Member Institutions.

Author information

Authors and Affiliations

Authors

Contributions

SN, BM, NL, K-EK, MF, and BLF were involved in the conceptualization of the work. SN, LMP, BW, BM, JM, GC, MG, LP, and K-EK screened the abstracts and full texts. SN, LMP, BW, JM, GC, LP, MG, and BM extracted the data, and/or checked the extracted data. BB-S transformed the preclinical data, prepared the data for meta-analysis and provided advice on the meta-analysis. SN conducted the meta-analysis and drafted the manuscript with assistance from BM, BW, LMP, LP, and K-EK. All authors revised the manuscript and approved the final version.

Corresponding author

Correspondence to Suzanne Nielsen.

Ethics declarations

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.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Nielsen, S., Picco, L., Murnion, B. et al. Opioid-sparing effect of cannabinoids for analgesia: an updated systematic review and meta-analysis of preclinical and clinical studies. Neuropsychopharmacol. 47, 1315–1330 (2022). https://doi.org/10.1038/s41386-022-01322-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41386-022-01322-4

Search

Quick links