Opioid Reduction

DGS PraxisLeitlinie v2.0 on cannabis in pain medicine; contains recommendations on opioid-sparing strategies and cannabis as a co-analgesic in chronic pain, based on current evidence and expert consensus.

Preclinical and observational studies show potential opioid-sparing effects of cannabinoids, while higher-quality RCTs show no evidence for opioid-sparing effects.

Comprehensive SR+MA on opioid-sparing effects of cannabinoids (k=92 studies including 15 ongoing trials). Preclinical: ED50 of morphine+THC 3.5-fold lower than morphine alone (95% CI 2.04-6.03). Clinical-acute: 3 RCTs found no opioid sparing in acute pain. Cancer pain: k=4 RCTs, no reduction in opioid dose (MD -3.8 mg, 95% CI -10.97 to 3.37) or pain scores (MD 1.84, 95% CI -2.05 to 5.72); more adverse events vs. placebo (RR 1.13, 95% CI 1.03-1.24). Chronic non-cancer pain: 3 RCTs without dronabinol effect. Observational studies: 39% reported opioid discontinuation (95% CI 0.15-0.64), 85% reduction (95% CI 0.64-0.99). Preclinical/observational data suggesting potential, RCT evidence contradictory.

Nine studies showed a 64-75% reduction in opioid dosage in combination with medical cannabis, but all studies had high risk of bias and a causal statement is not possible; the authors warn against generalizations.

Systematic review on medical cannabis as adjuvant for opioid dose reduction in non-oncological chronic pain; k=9 studies (n=7.222). Opioid dose reduction 64–75% with combination with MC; 32–59,3% of patients used MC for opioid substitution. Slight reduction in hospital admissions (p=0,53) and emergency department visits (p=0,39). High risk of bias in all included studies.

The literature suggests that medical cannabis laws might be associated with reduced opioid use, fewer opioid-related hospitalizations and lower overdose rates, but the available evidence is limited and has substantial limitations.

Systematic review on medical cannabis and opioid reduction (k=10 studies from 11.513 hits); 4 cross-sectional surveys on MC substitution for POMs, 6 secondary data analyses on opioid overdose deaths and hospitalizations. MC laws associated with reduced POM use, fewer POM-related hospital admissions, lower opioid overdose rates and reduced healthcare costs. Literature sparse with methodological limitations.

The majority of studies found no significant association between cannabis use and treatment outcomes; individual studies suggested supportive or harmful effects, but cannabis use likely does not independently threaten treatment outcomes.

Systematic review on cannabis use during medication-assisted opioid therapy (MOUD); k=41 studies (23 methadone, 7 buprenorphine, 6 naltrexone, 5 mixed). Majority of studies found NO statistically significant association between cannabis use and opioid outcomes (opioid use, treatment adherence, retention). No naltrexone study showed worsened outcomes in cannabis users. Cannabis use unlikely to be an independent threat to treatment success.

Systematic review on cannabis legalization and opioid outcomes; k=43 studies (18 MCL, 11 RCL, 14 both). Mixed findings on opioid prescriptions. No study found a reduction in non-medical opioid use after MCL; only 1 study after RCL. No studies found a reduction in opioid use disorder. MCL associated with lower opioid overdose mortality in earlier, but NOT in more recent studies; RCL findings on overdose deaths inconsistent. Conclusion: Cannabis legalization should NOT be regarded as an effective policy to curb the opioid epidemic.

Cannabis use showed no significant effect on non-medical opioid use in patients under pharmacotherapies for opioid disorders (OR: 1,00, 95% CI: 0,97–1,04).

Systematic review and meta-analysis of k=10 longitudinal studies (n=8.367, 38% female) on the effect of cannabis use on non-medical opioid use during OUD pharmacotherapy (76,3% methadone, 21,3% buprenorphine, 2,4% naltrexone). Average follow-up 9,7 months (range 4–15). Pooled odds ratio showed NO significant association between cannabis use and non-medical opioid use (OR=1.00, 95% CI 0.97–1.04, p=0.98). Moderate heterogeneity present.

Preclinically strong synergistic opioid sparing by cannabinoids, however clinical evidence mixed and of very low quality.

SR+MA: k=28 studies (19 preclinical, 9 clinical). Preclinical meta-analysis (n=6 studies): ED50 of morphine in combination with THC 3,6× lower (95% CI 1.95–6.76); ED50 of codeine+THC 9,5× lower (95% CI 1.6–57.5). Clinical evidence very weak: 1 case series (n=3) with very low quality; larger controlled studies show mixed results, opioid dose changes rarely reported. Robust preclinical synergy data; clinical opioid-sparing evidence remains insufficient.

Primary objective (30% responder rate) not significant; however secondary analyses showed significant improvement in average pain, worst pain and sleep disturbance in the low and medium dose groups compared with placebo, with dose-dependent side effects.

RCT in cancer patients with opioid-refractory pain (n=360); nabiximols as add-on to existing opioid therapy. Primary endpoint (30% responder) not significant (p=0.59), but secondary continuous analysis showed greater analgesia proportion vs. placebo (p=0.035), specifically at low dose (p=0.008) and medium dose (p=0.039). Low-dose group: average pain p=0.006, worst pain p=0.011, sleep disturbance p=0.003. Side effects dose-dependent.

Dronabinol showed no significant reduction in postoperative opioid consumption compared to placebo and no synergistic analgesic effect with piritramide.

RCT (n=100) after radical prostatectomy; oral dronabinol 5 mg vs. placebo perioperatively + patient-controlled piritramide analgesia. Piritramide consumption: placebo 74 mg median (IQR 44–90) vs. dronabinol 54 mg median (IQR 46–88) — no significant difference (p>0.05). No opioid-sparing effect of THC in this acute setting; plasma THC measurable (median 1.3–1.9 ng/ml). Negative result.

Intermittent cannabis use was associated with markedly improved retention in naltrexone treatment.

n=63 opioid-dependent patients under naltrexone therapy; intermittent cannabis users showed significantly better treatment retention (median stay 133 vs. 35 days for abstinent patients; log-rank p=0.002); effect maintained in Cox model after adjustment for baseline heroin and cocaine use; higher naltrexone adherence with intermittent cannabis use.

Dronabinol significantly reduced the severity of opioid withdrawal during inpatient detoxification (p=0.006), but had no effect on the induction rate for XR-naltrexone or treatment compliance.

n=60 opioid-dependent patients, dronabinol 30mg/d vs. placebo during detoxification and extended-release naltrexone induction. Dronabinol reduced withdrawal severity (SOWS, p=0,006), but no effect on XR-naltrexone induction rate (66% vs. 55%) or treatment completion (35% vs. 35%). Post-hoc: 32% with regular cannabis use had lower insomnia/anxiety scores and higher completion rate.

Dronabinol showed modest signals of withdrawal suppression at higher doses (20-30mg), but was not rated better than placebo and was associated with side effects such as sedation, tachycardia and cognitive impairment.

n=12 opioid-dependent adults, 5-week inpatient proof-of-concept study; dronabinol 5/10/20/30mg vs. placebo during oxycodone withdrawal (21h placebo substitution). Dronabinol 20–30mg showed moderate withdrawal suppression, but dose-dependent tachycardia, sedation and cognitive impairment. Dronabinol 5–10mg equivalent in effect to placebo. Duration of effect limited; no higher liking than placebo.

The combination of vaporized cannabis and opioids significantly reduced chronic pain by 27%, without substantially altering opioid pharmacokinetics.

Open-label pharmacokinetic/efficacy study (inpatient, 5 days) in 21 patients with chronic pain under long-term therapy with extended-release morphine or oxycodone: after addition of vaporized cannabis, pain intensity decreased on average by 27% (95% CI 9-46), without significant change in opioid plasma levels. Suggests additive/synergistic analgesia that could allow lower opioid doses. Substantial limitation: very small sample size, no control group, not blinded.

Daily cannabis use was associated with significantly lower odds for daily illegalized opioid use (adjusted OR 0,50, 95% CI 0,34-0,74, p < 0,001).

Longitudinal analysis of two prospective cohorts of PWUD with chronic pain (n=1.152, Vancouver 2014-2017). 40% reported daily illicit opioid use, 36% daily cannabis use. After adjustment for demographic/substance/health factors, daily cannabis use was associated with significantly lower odds for daily illicit opioid use (aOR 0.50, 95% CI 0.34-0.74, p<0.001). Main reasons for cannabis: pain (36%), sleep (35%), stress (31%).

Medical cannabis laws are associated with significantly lower opioid-related overdose mortality at the state level.

States with medical cannabis laws (n=13 states, 1999–2010) had on average 24,8% lower opioid overdose mortality (95% CI −37,5% to −9,5%; p=0,003) vs. states without such laws; effect strengthened over time (year 6: −33,3%, 95% CI −44,7% to −19,6%; p<0,001).

MCLs were associated with significantly lower daily opioid prescription volumes, particularly in states with dispensaries.

Longitudinal analysis (2010-2015) of daily opioid doses in Medicare Part D vs. state medical cannabis laws (MCL). States with active dispensaries: 3,742 million fewer daily opioid doses/year (95% CI -6,289 to -1,194). Hydrocodone decrease: -2,320 million daily doses (-17,4%) with dispensary-MCL (p=0.002); morphine decrease: -0,361 million daily doses (-20,7%) (p=0.047). Limitation: ecological analysis at state level, no causality at patient level.

The large majority of respondents reported being able to reduce opioid use through cannabis and perceiving cannabis as sole therapy to be more effective.

n=2.897 medical cannabis patients; 34% used opioid-based pain medication in the past 6 months; 97% agreed they could reduce opioid dose while using cannabis concurrently; 81% reported cannabis alone more effective than cannabis+opioids. Self-report data without controlled comparison.

Most patients reduced opioids as well as anti-anxiety, migraine and sleep medication after starting medical cannabis use, while antidepressants and alcohol were substituted less frequently.

Cross-sectional survey among members of a New England dispensary (n=1.513) on the substitution of MC for pharmaceutical agents. Of regular opioid users, 76.7% reported reduction since MC initiation (significantly greater than antidepressants 37.6% or alcohol 42.0%, p<0.0001). About two-thirds reduced anti-anxiety medication (71.8%), migraine medication (66.7%) and sleep medication (65.2%) after MC initiation (p<0.0001 vs. antidepressants/alcohol).

Medical cannabis was associated with a marked reduction in opioid use (−78% of mean daily dose) and significant improvement in quality of life.

Prospective observational study of n=1.145 medical cannabis patients across 21 Canadian clinics; 6-month follow-up. Baseline opioid use in 28% of participants, reduction to 11% after 6 months. Daily opioid dose decreased from 152 mg MME (morphine milligram equivalent) to 32,2 mg MME — a 78% reduction. Significant improvements in all four WHOQOL-BREF domains (quality of life).

Dronabinol was associated with shorter length of stay and lower opioid consumption, but showed no significant effect on pain scores or nausea.

Retrospective cohort study (n=81 dronabinol + n=162 matched controls after total joint replacement); total morphine equivalents significantly reduced (252,5 ± 131,5 vs. 313,3 ± 185,4 mg, p=0,0088) with shorter length of stay (2,3 vs. 3,0 days, p=0,02); no dronabinol side effects reported.

Cannabinoids significantly reduced opioid consumption by 50 % (24 mg morphine equivalents/day) in comedicated patients.

Retrospective analysis of n=178 pain patients (median 72 years, range 26-96) over a median of 366 days of cannabinoid therapy (dronabinol, nabiximols, extracts); 115 patients (65%) received opioids in parallel (median 65 mg/day morphine equivalent). Significant opioid reduction by 24 mg/day or 50% (p<0.05), independent of cannabinoid dose, age and sex. Discontinuation rate due to adverse effects only 2.8% (n=5).

Cannabis use does not negatively affect opioid outcomes, productivity and quality of life in buprenorphine patients.

n=100 male opioid-dependent patients under buprenorphine maintenance therapy (Ø 96 months); 35% current cannabis use. Cannabis users received lower buprenorphine doses (7,9 mg vs. 8,9 mg; p=0.04), but NO significant differences in opioid use, withdrawal symptoms, craving, compliance (86,92±9,58 days/90 days), productivity or WHO-QOL scores between cannabis users and non-users. Cannabis use does not negatively affect opioid outcomes.

Medical cannabis laws significantly reduced prescription volumes and costs in Medicare Part D.

State medical cannabis laws (MML) significantly reduced prescriptions for medications for which cannabis is considered a clinical alternative; estimated annual savings for the Medicare program: $165,2 million (2013). Analysis of all Medicare Part D prescriptions 2010–2013 in MML vs. non-MML states.

Adjunctive dronabinol significantly reduced opioid consumption after trauma by ~79 MME compared to a non-significant change in controls.

Matched cohort study (n=66, 33 cases/33 controls) in trauma patients; adjunctive dronabinol (THC) reduced opioid consumption by -79 MME (p<0,001) vs. -9 MME in controls (p=0,63); 9-fold greater reduction in the dronabinol group (between-group difference p=0,02).

Medical cannabis significantly reduced daily opioid dose and improved pain as well as quality of life in osteoarthritis patients.

n=40 osteoarthritis patients with chronic pain, medical cannabis certification. Opioid consumption (MME/day) decreased from 18.2 to 9.8 mg (p<0.05), 37.5% of patients achieved 0 MME/day. VAS pain scores and Global Physical Health significantly improved after 3 and 6 months.

Almost half of respondents substituted prescription medications with cannabis, particularly opioids, regardless of the legal status of medical cannabis.

n=2.774 cannabis users; 1.248 (46%) reported using cannabis as a substitute for prescription medications. Most common substitutions: narcotics/opioids (35,8%), anxiolytics/benzodiazepines (13,6%), antidepressants (12,7%). Medical cannabis users had 4,59× higher odds of substitution vs. recreational users (95% CI 3.87–5.43). Self-selected convenience sample, no evidence of actual opioid dose reduction; real-world indication of substitution behaviour.

Patients reported improvements in the domains of bodily pain, physical functioning and social functioning after initiation of medical cannabis; 79% showed reduction or cessation of opioid medication.

Survey of medical cannabis patients on self-reported improvements in health functions and opioid reduction; real-world data, but without controlled design or objective measurement of opioid consumption.

Medical cannabis patients predominantly report a self-perceived reduction or complete substitution of opioids, alcohol and other substances.

Cross-sectional survey (n=2032 Canadian medical cannabis patients): 69,1% reported substitution of prescription medications; opioids accounted for 35,3% of all medication substitutions (n=610 opioid mentions); 59,3% of these reported complete cessation of opioid use. Antidepressants were the second most frequent substitution (21,5%).

Users subjectively report strong symptom relief, however medical supervision and scientific evidence for many reported indications are lacking.

Cross-sectional survey n=1.429 medical cannabis users; 59,8% reported using cannabis as a substitute for prescribed pharmaceuticals (including opioids); 86% average symptom reduction self-reported (no control arm, no objective opioid consumption data).

Cannabis enabled complete discontinuation of opioids in a good half of patients, in some cases with no effect or with an increase in opioid use.

Retrospective cohort study (n=61 opioid users with back pain): 50,8% stopped all opioid intake after cannabis recommendation (median time 6,4 years, IQR 1,75-11); 31% of remaining users reduced dose; higher cannabis dosage was the only significant predictor for opioid cessation.

Medical cannabis significantly improved quality of life and pain intensity compared to baseline and reduced opioid consumption as well as treatment costs.

Retrospective mirror-image study in n=29 patients with chronic pain (medical cannabis in New York State); 3-month follow-up. Improvement in quality of life measured by EQ-5D (pre 36 → post 64, p<0.0001). Reduction in opioid consumption as well as cost savings in analgesic prescriptions. Adverse effects in 10% of participants.