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Cited by 265Cannabis and Cannabinoid ResearchPain Management and Opioid UseAnesthesia and Pain Management

Opioid-Sparing Effect of Cannabinoids: A Systematic Review and Meta-Analysis

Open access
Nielsen, Suzanne, Sabioni, Pamela, Trigo, Jose M, Ware, Mark A, Betz-Stablein, Brigid D, Murnion, Bridin, Lintzeris, Nicholas, Khor, Kok Eng +3 more·2017·Neuropsychopharmacology
DOI 10.1038/npp.2017.51PMC PMC5520783
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Abstract

Cannabinoids, when co-administered with opioids, may enable reduced opioid doses without loss of analgesic efficacy (ie, an opioid-sparing effect). The aim of this study was to conduct a systematic review to determine the opioid-sparing potential of cannabinoids. Eligible studies included pre-clinical and clinical studies for which the outcome was either analgesia or opioid dose requirements. Clinical studies included controlled studies and case series. We searched Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase. Nineteen pre-clinical and nine clinical studies met the search criteria. Seventeen of the 19 pre-clinical studies provided evidence of synergistic effects from opioid and cannabinoid co-administration. Our meta-analysis of pre-clinical studies indicated that the median effective dose (ED 50) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9-THC) is 3.6 times lower (95% confidence interval (CI) 1.95, 6.76; n=6) than the ED 50 of morphine alone. In addition, the ED 50 for codeine administered in combination with delta-9-THC was 9.5 times lower (95% CI 1.6, 57.5, n=2) than the ED 50 of codeine alone. One case series (n=3) provided very-low-quality evidence of a reduction in opioid requirements with cannabinoid co-administration. Larger controlled clinical studies showed some clinical benefits of cannabinoids; however, opioid dose changes were rarely reported and mixed findings were observed for analgesia. In summary, pre-clinical studies provide robust evidence of the opioid-sparing effect of cannabinoids, whereas one of the nine clinical studies identified provided very-low-quality evidence of such an effect. Prospective high-quality-controlled clinical trials are required to determine the opioid-sparing effect of cannabinoids.

AI snapshot

Written from the paper’s full text.

TL;DR

This systematic review and meta-analysis found robust preclinical evidence that cannabinoids, especially delta-9-THC, can reduce opioid doses needed for equivalent antinociception, but clinical evidence for an opioid-sparing effect was very limited and low quality. The authors conclude that high-quality controlled clinical trials are needed.

Key findings

  • Nineteen preclinical and nine clinical studies met inclusion criteria; 17 of 19 preclinical studies provided evidence of synergistic opioid–cannabinoid effects.
  • Meta-analysis of preclinical studies found the median effective dose (ED50) of morphine co-administered with delta-9-THC was 3.6 times lower than morphine alone (95% CI 1.95, 6.76; n = 6), and the ED50 of codeine co-administered with delta-9-THC was 9.5 times lower than codeine alone (95% CI 1.6, 57.5; n = 2).
  • Among clinical studies, one case series (n = 3) provided very low-quality evidence of reduced opioid requirements with cannabinoid co-administration; larger controlled studies rarely reported opioid dose changes and showed mixed findings for analgesia.
  • GRADE ratings of clinical studies were: one very low, three low, two moderate, and three high quality; none of the high-quality studies provided evidence of an opioid-sparing effect.

Methods

  • Systematic review conducted according to PRISMA, searching Scopus, Cochrane Database of Systematic Reviews, Medline, and Embase on October 29, 2015, with no date limits; eligible studies included human or animal studies with outcomes of pain/analgesia or opioid requirements from concurrently administered opioids and cannabinoids, including controlled clinical studies and case series.
  • Preclinical studies were narratively reviewed; six studies with sufficient data were meta-analyzed for morphine and two for codeine, using log10 ED50 values, inverse variance, and a random effects model because of heterogeneity; a funnel plot assessed publication/small study bias.
  • Clinical studies were heterogeneous and not suitable for meta-analysis, so a narrative synthesis was conducted with quality scored using GRADE criteria.

Limitations

  • The paper states that preclinical studies used a range of animal populations, antinociceptive assays, opioids, and cannabinoids, often with small numbers of animals per group, resulting in statistical heterogeneity; funnel plot interpretation was limited because fewer than 10 studies were included.
  • The paper states that no studies examined the opioid-sparing effect of cannabidiol alone, delta-9-THC:CBD outside a 1:1 ratio, or other cannabinoids, and that the lack of high-quality human studies means evidence for opioid-sparing is largely limited to preclinical studies.
  • Clinical limitations stated in the paper include lack of placebo control, difficulty extrapolating from experimental to clinical pain, use of single doses, small sample sizes, mixed study design quality, subtherapeutic morphine doses in one study, fixed cannabinoid dose ranges, and discouraging opioid dose reduction in another study; evident from the text, only one very low-quality clinical study directly showed an opioid-sparing effect.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1038/npp.2017.51

Cites

72 of 72 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

0 of 40 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    One of the nine clinical studies identified provided very low-quality evidence of an opioid-sparing effect of cannabinoids.

    “In summary, pre-clinical studies provide robust evidence of the opioid-sparing effect of cannabinoids, while one of the nine clinical studies identified provided very low-quality evidence of such an effect.”
    • Also stated in: § Discussion · plain
      “An opioid-sparing effect of cannabinoids in chronic pain patients was observed in only one very low-quality clinical study.”
    Quote in the paperSubstantial claim
  • Findingown data

    The median effective dose (ED50) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9-THC) is 3.6 times lower (95% CI 1.95, 6.76; n = 6) than the ED50 of morphine alone.

    “Our meta-analysis of pre-clinical studies indicated that the median effective dose (ED 50 ) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9-THC) is 3.6 times lower (95% CI 1.95, 6.76; n = 6) than the ED 50 of morphine alone.”
    • Also stated in: § Meta-Analysis of Pre-Clinical Studies · hedged
      “When back-transformed to the original units, the response ratio was 3.6 (95% CI 1.95, 6.76), indicating that the median effective dose (ED 50 ) of morphine was 3.6 times lower when given in combination with delta-9-THC compared to when morphine was administered alone.”
    Quote in the paperSubstantial claim
  • Findingown data

    Seventeen of the 19 pre-clinical studies provided evidence of synergistic effects from opioid and cannabinoid co-administration.

    “Seventeen of the 19 pre-clinical studies provided evidence of synergistic effects from opioid and cannabinoid co-administration.”
    • Also stated in: § Summary of Pre-Clinical Studies · boosted
      “Most studies (17 of the 19) demonstrated that combining a cannabinoid with an opioid resulted in a synergistic effect on analgesia compared to the analgesic effects of the individual drugs.”
    Quote in the paperSubstantial claim
  • Findingown data

    Opioid dose changes were rarely reported in larger controlled clinical studies.

    “Larger controlled clinical studies showed some clinical benefits of cannabinoids; however, opioid dose changes were rarely reported and mixed findings were observed for analgesia.”
    Quote in the paperSubstantial claim
  • Findingcitation

    One case series (n = 3) provided very low-quality evidence of a reduction in opioid requirements with cannabinoid co-administration.

    “One case series (n = 3) provided very low-quality evidence of a reduction in opioid requirements with cannabinoid co-administration.”
    • Also stated in: § Discussion · plain
      “One case series provided very low-quality evidence of a reduction in opioid dose requirements with cannabinoid co-administration (Lynch et al, 2003).”
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    • cites Lynch et al, 2003 source

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  • Classified as probably not a substantial claim. 18
  • May combine two claims. 24
  • The quote only partly states this claim. 3

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    Findingnone given

    To date no systematic review has focused on the opioid-sparing effects of cannabinoids.

    “Despite the growing body of relevant literature, to date no systematic review has focused on the opioid-sparing effects of cannabinoids.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingreasoning

    The nine clinical studies identified were heterogeneous in design and outcomes, and therefore not suitable for meta-analysis.

    “The nine clinical studies identified were heterogeneous in design and outcomes, and therefore not suitable for meta-analysis.”
    • Also stated in: § Results from Clinical Studies · plain
      “Nine clinical studies with 750 participants provided data relevant to the research question (Table 2); however, the heterogeneous nature of the studies precluded meta-analysis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    No additional data were identified to enable inclusion of additional studies in the meta-analysis.

    “Authors of the other studies were contacted in an attempt to include additional studies in the meta-analysis; however, no additional data were identified to enable the inclusion of any additional studies.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    The initial searches identified 3019 records after duplicates were removed.

    “The initial searches identified 3019 records after duplicates were removed, with 19 pre-clinical and nine clinical studies identified for inclusion in the final review (see Figure 1 for the PRISMA diagram).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The clinical studies were rated using GRADE criteria: one provided very low-quality evidence, three low-quality, two moderate-quality, and three randomized controlled trials provided high-quality evidence.

    “The clinical studies were rated using the GRADE criteria.One study provided very low-quality evidence, three studies provided low-quality evidence, two studies provided moderate-quality evidence, and three randomized controlled trials provided high-quality evidence.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    All data were extracted by one author and checked by a second author.

    “All data were extracted by one of the authors (SN, PS, or JT) and checked by a second author (SN, PS, or JT).”
    Quote in the paperNot a substantial claim

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    Study design and conductown data

    Titles were screened by two authors, with consensus reached where inconsistencies were identified.

    “Titles were screened by two authors (SN and PS).Where inconsistencies were identified, the authors were able to reach consensus on each occasion.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    Attempts were made to contact authors of published reports to collect additional information when required data were missing.

    “When required data were missing, attempts were made to contact authors of published reports to collect additional information.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductcitation

    The systematic search was conducted in accordance with PRISMA recommendations.

    “We conducted a systematic search of the literature in accordance with recommendations by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) (Moher et al, 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Moher et al, 2009 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductreasoning

    A narrative synthesis was conducted for clinical studies, with all studies scored for quality using GRADE criteria.

    “Thus, a narrative synthesis was conducted instead, with all studies scored for quality using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria (Guyatt et al, 2008).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Guyatt et al, 2008 source

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  • Classified as probably not a substantial claim.

    Study design and conductown data

    The inverse variance statistical method and random effects model were used to compensate for study heterogeneity.

    “When calculating the continuous outcome of an equally effective opioid dose (e.g. the log 10 ED 50 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.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    A funnel plot was produced to examine publication bias and small study effects in the pre-clinical studies included in the meta-analysis.

    “A funnel plot was produced to examine publication bias and small study effects in the pre-clinical studies included in the meta-analysis.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationnone given

    Pre-clinical studies may overrepresent effects.

    “While the outcomes of pre-clinical studies are often consistent with clinical studies, pre-clinical studies may overrepresent effects.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    The findings from clinical trials are inconsistent, with some studies found to have important limitations such as a lack of placebo control.

    “However, the findings from clinical trials are inconsistent, with some studies found to have important limitations such as a lack of placebo control.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Pre-treatment with CP 55,940 resulted in a mean leftward shift of -6.73-fold.

    “Pre-treatment with CP 55,940 resulted in a mean leftward shift to of -6.73-fold.”
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    • cites Pugh 1996 source

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    Premisecitation

    A greater than additive effect was observed, with a clear leftward shift of the graph, for the morphine and delta-9-THC combination.

    “Greater than additive effect observed, clear leftward shift of graph”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Reche 1996 source

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    Premisecitation

    Antinociception from the combination of CP 55,940 and morphine appeared to be achieved without an increase in abuse liability.

    “Antinociception from the combination appeared to be achieved without an increase in abuse liability”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Pugh 1996 source

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    Premisecitation

    Tolerance to morphine alone was rapidly established, but there was no loss of effect with low-dose combinations of morphine plus delta-9-THC.

    “Tolerance to morphine alone rapidly established; no loss of effect with low-dose combinations of morphine + delta-9-THC”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Smith 2007 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    In Smith 1998, the potency ratio for delta-9-THC (4 mg/kg s.c.) with morphine s.c. in the tail-flick test was 8.5.

    “Potency ratio: 8.5”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Smith 1998 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    The rats trained for drug discrimination tasks had received repeated administration of opioids and cannabinoids over many months and may have been tolerant to drug effects at the doses administered.

    “The rats trained for drug discrimination tasks had received repeated administration of opioids and cannabinoids over many months and may have been tolerant to drug effects at the doses administered”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wakley 2011 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisecitation

    In Smith 1998, the potency ratio for delta-9-THC (20 mg/kg p.o.) with morphine p.o. in the tail-flick test was 7.6.

    “Potency ratio: 7.6”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Smith 1998 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In opioid and delta-9-THC naïve rats, methadone 1.0 mg/kg significantly enhanced the antinociceptive effect of delta-9-THC, but this was not observed in rats previously trained for drug discrimination tasks.

    “In opioid and delta-9-THC naïve rats, methadone 1.0 mg/kg significantly enhanced the antinociceptive effect of delta-9-THC, however this was not observed in rats that were previously trained for drug discrimination tasks.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wakley 2011 source

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  • May combine two claims.

    Premisecitation

    In Roberts 2006, the combination of delta-9-THC and morphine did not have an effect on pain intensity; the combination resulted in lower ratings of unpleasantness of pain compared with either drug alone.

    “Combination of delta-9-THC and morphine did not have an effect on pain intensity.The combination resulted in lower ratings of unpleasantness of pain compared with either drug alone”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Roberts 2006 source

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  • May combine two claims.

    Premisecitation

    In Johnson 2010, there was no change in median amount of breakthrough opioid medication in any group; change in pain NRS from baseline was statistically significantly in favor of delta-9-THC:CBD compared with placebo.

    “No change in median amount of breakthrough opioid medication in any group Change in pain NRS (out of 10) from baseline was statistically significantly in favor of delta-9-THC:CBD compared with the placebo”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Johnson 2010 source

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  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    In Narang 2008, in single-dose studies, 10 and 20 mg dronabinol significantly increased the amount of analgesic relief reported compared to placebo; TOTPAR was 31.1 in the placebo group, compared with 39.7 with dronabinol 10 mg and 41.7 with dronabinol 20 mg.

    “In single-dose studies, 10 and 20 mg dronabinol significantly increased the amount of analgesic relief reported compared to placebo”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Narang 2008 source

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  • May combine two claims.

    Premisecitation

    In Study 1, pre-treatment with delta-9-THC did not enhance the fully efficacious dose of morphine but enhanced low-dose morphine and both doses of codeine, in addition to extending the time course.

    “Study 1: Pre-treatment with delta-9-THC did not enhance the fully efficacious dose of morphine but enhanced low-dose morphine and both doses of codeine, in addition to extending the time course.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Williams 2006 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Narang 2008, mean baseline NRS was 6.9 compared with 5.2 after four weeks of dronabinol; this represents a statistically significant reduction.

    “Mean baseline NRS of 6.9 compared with 5.2 after four weeks of dronabinol.This represents a statistically significant reduction”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Narang 2008 source

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    Premisecitation

    No evidence of synergism was found for morphine plus HU-210; the combination showed the greatest increase in hot plate latency (39.9 s ± 1.1 s), but was not significantly different from morphine alone.

    “No evidence of synergism.Morphine + HU-210 showed the greatest increase in hot plate latency (39.9 s ± 1.1 s), but was not significantly different from morphine alone”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Wilson 2008 source

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    Premisecitation

    In Lissoni 2014, 5/12 patients (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 patients (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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lissoni 2014

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  • May combine two claims.

    Premisecitation

    In Naef 2003, there was no significant analgesic effect of dronabinol or morphine-dronabinol combination on heat, pressure or cold tests; there was an additive effect of morphine on the transcutaneous electrical stimulation test; potentiation of analgesia was not observed.

    “No significant analgesic effect of dronabinol or morphine-dronabinol combination on heat, pressure or cold tests.Additive effect of morphine on transcutaneous electrical stimulation test Potentiation of analgesia not observed in this experimental pain study”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Naef 2003 source

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  • May combine two claims.

    Premisecitation

    In Lynch 2003, mean baseline morphine dose was 195 mg (SD 147 mg) compared with 35 mg (SD 31 mg) after commencing smoked cannabis; there was opioid dose reduction or cessation in each case; improved pain control was described.

    “Mean baseline morphine dose of 195 mg (SD 147 mg) compared with 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”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Lynch 2003 source

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  • May combine two claims.

    Premisecitation

    In Abrams 2011, mean pain score reduction was from 34.8 (95% CI 29.4,40.1) at 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) at baseline to 33.6 (95% CI 28.5, 38.6) on day 5 with oxycodone; there was a significant reduction overall.

    “Mean pain score reduction, from 34.8 (95% CI 29.4,40.1) at 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) at baseline to 33.6 (95% CI 28.5, 38.6) on day 5 with oxycodone.Significant reduction overall.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Abrams 2011 source

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  • May combine two claims.

    Premisecitation

    In Portenoy 2012, there was no change in median amount of breakthrough opioid medication in any group; patients were discouraged from reducing their opioid dose, so the opioid-sparing effect could not be observed.

    “No change in median amount of breakthrough opioid medication in any group.Note that patients were discouraged from reducing their opioid dose, so the opioid-sparing effect could not be observed”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Portenoy 2012 source

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  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    In Portenoy 2012, treatment difference (change from baseline pain score) for nabiximols 1-4 sprays was -0.75 points (95% CI -1.28, -0.22, p = 0.06 compared to placebo); for 6-10 sprays -0.36 points (95% CI -.089, 0.18 points, p = 0.19); for 11-16 sprays -0.09 points (95% CI: -0.62, 0.44 points, p = 0.75).

    “Treatment difference (change from baseline pain score): -0.75 points (95% CI -1.28, -0.22, p = 0.06 compared to placebo)”
    Quote in the paperSubstantial claim0 of 1 sources checked
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The systematic review included 28 studies in qualitative synthesis.

    “Studies included in qualitative synthesis (n = 28)”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The meta-analysis of preclinical data for morphine included 6 studies.

    “Studies included in quantitative synthesis (meta-analysis) of preclinical data for morphine (n = 6)”
    Quote in the paperNot a substantial claim

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    In Seeling 2006, median dose of piritramide alone was 74 mg (IQR 44-90) compared with 54 mg (IQR 46-88) when administered with dronabinol; the difference between intervention and control group was not significant; no evidence was found of synergistic antinociceptive interaction between delta-9-THC and piritramide for acute postoperative pain.

    “Median dose of piritramide alone was 74 mg (IQR 44-90) compared with 54 mg (IQR 46-88) when administered with dronabinol.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Seeling 2006 source

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    The meta-analysis of preclinical data for codeine included 2 studies.

    “Studies included in quantitative synthesis (meta-analysis) of preclinical data for codeine (n = 2)”
    Quote in the paperNot a substantial claim
38 of 38

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Cannabinoids produce clear opioid-sparing effects.

    “studies have shown that cannabinoids produce clear opioid-sparing effects 73.”

    From Psychosocial and pharmacological interventions for the treatment of cannabis use disorder (2018) · cites this paper as [73]

    The Discussion reports reduced opioid requirements in most pre-clinical studies, supporting an opioid-sparing effect in those models. But it says clinical findings were mixed, two controlled studies found no reduction in opioid dose requirements, and no randomized controlled study provided evidence of an opioid-sparing effect. The unqualified word “clear” overstates the evidence across settings. Page numbers are not available in the supplied passages. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • A recent meta-analysis reported strong evidence that cannabinoids produce opioid-sparing effects in preclinical studies, but only a single study of nine clinical studies provided evidence of opioid-sparing effects in humans.

    “Indeed, a recent meta-analysis study reported strong evidence that cannabinoids produce opioid-sparing effects in preclinical studies, but only a single study of nine clinical studies provided evidence of opioid-sparing effects in humans (Nielsen et al, 2017).”

    From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Nielsen et al, 2017

Statistics recomputed

Every reported test result, recomputed from its test statistic and degrees of freedom. A result shows as not adding up only once an independent check has confirmed it.

  • Consistentz = 5.59reported p < .001 · recomputed p < .001

    “Z = 5.59, p < .001”

  • Consistentz = 2.49reported p = .01 · recomputed p = .013

    “Z = 2.49, p = .01”

2 of 2

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Morphine meta-analysis Z statistic conflicts with its confidence interval

    Minor

    The reported mean difference of −0.56 and 95% CI of −0.83 to −0.29 imply a Z statistic of approximately 4.07, not 5.59.

  • Wilson hot-plate latency differs between text and table

    Minor

    The text reports 38.9 seconds for morphine combined with HU-210, while Table 1 reports 39.9 seconds for that combination.

2 of 2

Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Lissoni P, Porro G, Messina G, Porta E, Rovelli F, Roselli MG et al (2014). 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 34: 6033–6034.

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Related

Authors
Nielsen, S., Sabioni, P., Trigo, J. M., Ware, M. A., Betz-Stablein, B. D., Murnion, B., Lintzeris, N., Khor, K. E., Farrell, M., Smith, A., & Le Foll, B.
Affiliations
  • UNSW Sydney (AU)
  • Centre for Addiction and Mental Health (CA)
  • McGill University (CA)
  • The University of Sydney (AU)
  • Prince of Wales Hospital (AU)
Corresponding author
Nielsen, Suzanne
ORCID
Venue
Neuropsychopharmacology
Publisher
Springer Science and Business Media LLC
Published
2017-03-22
Volume
42
Issue
9
Pages
1752-1765
ISSN
  • 0893-133X (ISSN-L)
  • 1740-634X
DOI
10.1038/npp.2017.51
PMC
PMC5520783
OpenAlex
W2601973957
Semantic Scholar
425a7d6d3175215eaa53fad85d7035e9be6e755c
Cited by
265
References
72
Citations by year
2026: 19 · 2025: 22 · 2024: 24 · 2023: 25 · 2022: 24 · 2021: 44 · 2020: 35 · 2019: 40 · 2018: 30 · 2017: 2
FWCI
3.71
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Neuropsychopharmacology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • UNSWorks (University of New South Wales, Sydney, Australia) (submittedVersion, cc-by-nc-nd)
  • UNSWorks (UNSW Sydney) (submittedVersion, cc-by-nc-nd)
Topics
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Health Sciences › Medicine › Anesthesiology and Pain Medicine › Pain Management and Opioid Use
  • Health Sciences › Medicine › Surgery › Anesthesia and Pain Management
Keywords
cannabinoids, opioid-sparing effect, opioid dose reduction, delta-9-tetrahydrocannabinol, morphine, codeine, analgesia, ED50, pain management
MeSH terms
Analgesics, Opioid, Animals, Cannabinoids, Drug Synergism, Humans, Pain

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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