Chronic Pain

Weak recommendation for medical cannabis/cannabinoids in chronic pain with small to very small improvements in pain intensity, physical function and sleep quality, but balanced benefit-harm ratio.

BMJ Clinical Practice Guideline 2021 on medical cannabis for chronic pain (cancer/non-cancer); weak recommendation for non-inhaled cannabis in addition to standard therapy. Evidence base: 4 systematic reviews. Small to very small improvements in pain intensity, physical function and sleep quality; small to moderate risk of mostly self-limiting side effects. Shared decision making required.

Guideline recommends selective counseling on the benefits and harms of cannabis/cannabinoids in chronic non-cancer pain; warns of harm in specific subgroups.

Best Practice Advice of the American College of Physicians on cannabis/cannabinoids in chronic non-tumor pain. Based on Living Systematic Reviews. Recommendations: benefit-risk counseling for all patients; risk outweighs benefit in adolescents, history of substance use disorder, severe mental illness, fall risk; contraindication in pregnancy/breastfeeding; advising against inhaled cannabis.

German Society for Pain Medicine Practice Guideline v2.0 on cannabis in pain medicine; evidence-based recommendations for therapeutic use in chronic pain with focus on neuropathic and tumor-associated pain; takes into account current RCT evidence and real-world data on dosing and treatment management.

Survey documents considerable differences between European countries in the availability and approval of cannabis-based medicines; recommendations from professional societies are mixed (partly recommending, partly rejecting).

EFIC survey on approval status of cannabis-based medicines in 31 European countries; THC/CBD oromucosal spray approved in 21 countries for MS spasticity; German and Israeli professional societies recommend cannabis as third-line therapy for chronic pain, while the German Medical Association and a Finnish expert group do not recommend prescription due to lack of high-quality evidence.

Expert consensus recommends three structured titration protocols for medical cannabis for chronic pain, without direct measurement of efficacy.

20 international experts from 9 countries; consensus: medical cannabis suitable for neuropathic, inflammatory, nociplastic and mixed pain; 3 dosing protocols developed (Routine: start 5 mg CBD 2×/day, titration up to 40 mg/day; conservative: 5 mg 1×/day; rapid: balanced THC:CBD 2,5–5 mg 1–2×/day).

Cannabis and opioid show similar small pain improvements versus placebo; cannabis leads to fewer discontinuations due to side effects than opioid, but similar effectiveness for pain relief and sleep quality.

Network meta-analysis across k=90 RCTs (n=22.028) on cannabis vs. opioid for chronic non-malignant pain, follow-up 28-180 days. Moderate evidence: opioid small improvement in pain/function/sleep vs. placebo; cannabis similar effects vs. placebo. No difference cannabis vs. opioid for physical function (WMD 0,47 on SF-36 PCS, 95% CrI -1,97 to 2,99) or pain relief (WMD 0,23 cm on 10-cm VAS, 95% CrI -0,06 to 0,53); cannabis fewer treatment discontinuations due to side effects (OR 0,55, 95% CrI 0,36-0,83).

Medical cannabinoids show variable therapeutic effects depending on substance and indication: CBD effective for epilepsy (high evidence) and parkinsonism (moderate evidence); dronabinol and nabiximols effective for chronic pain, spasticity and other indications (moderate evidence); many other effects with low or very low evidence.

Pharmacology-based SR of k=152 RCTs (n=12.123) on medical cannabinoids; for chronic pain moderate evidence for dronabinol (SMD -0.31, 95% CI [-0.46, -0.15]) and nabiximols (SMD -0.25, 95% CI [-0.37, -0.14]). Nabiximols additionally showed significant effects on sleep (SMD -0.24, 95% CI [-0.35, -0.14]) and spasticity (SMD -0.36, 95% CI [-0.54, -0.19]).

Benefit found only for cannabis <7 days and nabiximols >7 days; 81% of subgroup analyses negative; overall very low evidence quality.

Systematic review of k=36 RCTs (n=7.217) on cannabinoids, cannabis and cannabis-based medicines for pain of any kind. Evidence for benefit only for cannabis <7 days (risk difference 0.33, 95% CI 0.20–0.46; 2 studies, n=231, very low quality) and nabiximols >7 days (risk difference 0.06, 95% CI 0.01–0.12; 6 studies, n=1.484, very low quality). 81% of subgroup analyses negative; all studies with high/unclear risk of bias. GRADE: low to very low evidence quality.

Medical cannabis leads to small improvements in pain relief, physical function, and sleep quality, but is associated with several transient side effects.

BMJ SR of k=32 RCTs (n=5.174) on medical cannabis in chronic pain (28 non-cancer, 4 cancer-related), follow-up 1–5,5 months; 29 studies vs. placebo, predominantly oral administration (n=30). Modelled RD 10% (95% CI 5–15%) for achieving the MID of 1 cm pain reduction (VAS 0–10), WMD -0,50 cm (95% CI -0,75 to -0,25 cm, moderate certainty). Small improvement in physical function (WMD 1,67 points SF-36, 95% CI 0,03–3,31, high certainty) and sleep quality (WMD -0,35 cm VAS, 95% CI -0,55 to -0,14, high certainty). No improvement in emotional/social function (high certainty).

Highly rational THC/CBD and comparable THC/CBD products show small pain improvements, but with substantially increased adverse effects (dizziness, sedation, nausea); nabilone reduced pain moderately, but dronabinol did not; low THC/CBD products showed no benefit.

Updated systematic review of k=25 short-term RCTs (1–6 months, n=2.303; 64% neuropathic pain). Oral synthetic high-THC products (THC-only) may slightly reduce pain intensity (pooled difference −0.78 points, 0–10 scale); oromucosal extracted comparable-THC-to-CBD products probably slightly reduce pain (−0.54 points). Nabilone moderately reduced pain (−1.59 points), dronabinol did not (−0.23 points). Low-THC-to-CBD products may not improve outcomes. Moderate to large increase in dizziness, sedation, nausea with THC products.

Synthetic products with high THC-to-CBD ratio possibly showed moderate pain improvement, but increased risks for sedation and dizziness; sublingual spray with comparable THC-to-CBD ratio likely associated with small pain improvement, but increased risks of adverse effects.

Systematic review of k=18 RCTs (n=1.740, primarily 1–6 months) + 7 cohort studies (n=13.095) on cannabinoids in chronic pain; 56% neuropathic pain. Synthetic high-THC products (>98% THC) may moderately improve pain intensity (≥30% response) with increased risk of sedation and probably a large risk of dizziness. Sublingual 1.1:1 THC:CBD spray is probably associated with a small improvement in pain and may increase large risk of dizziness/sedation as well as moderate risk of nausea. Evidence for other products and long-term harms insufficient.

In neuropathic pain: less gabapentin use and shorter hospital stays; in other pain disorders no benefit; increased opioid consumption in both groups.

Cochrane SR on cannabis-based medicines in neuropathic and other pain; includes fibromyalgia subgroup analysis: 5 RCTs (n=445), low quality of evidence, no significant pain reduction vs. placebo (SMD -0.21, 95% CI -0.61 to 0.19).

Cannabis-based medicines may show a small benefit in pain relief (50% pain reduction in 21% vs. 17%), but with substantial side effects (10% vs. 5% discontinuations due to side effects) and nervous system as well as psychiatric disorders.

Cochrane systematic review on cannabis-based medicines in chronic neuropathic pain in adults. Search up to November 2017 in CENTRAL/MEDLINE/Embase; RCTs with ≥2 weeks treatment duration, ≥10 participants/arm. Primary outcomes: NNTB for 30%/50% pain reduction, PGIC much/very much improved, dropout due to lack of efficacy, standardized pain intensity.

Moderate evidence for chronic pain and spasticity, low evidence for nausea/vomiting, weight gain and sleep disorders; increased risk of side effects.

Comprehensive SR across 79 RCTs (n=6.462) on medical cannabis; moderate evidence for chronic pain (6 RCTs), neuropathic pain, MS spasticity; NNTB=6 for 30% pain reduction; most common side effects: dizziness, dry mouth, sedation.

There is no clear evidence for an effect of cannabis-based medicines on pain relief of at least 50% or clinically relevant improvements in chronic neuropathic pain; THC-dominant agents may increase nervous system side effects.

Cochrane SR update 2026 on cannabis for chronic neuropathic pain; 6 new studies (n=450) in addition to existing evidence base (originally 16 RCTs from the 2018 version). Evaluated herbal, synthetic cannabinoids vs. placebo/conventional treatment in adults with neuropathic pain conditions (≥2 weeks treatment duration). Critical outcomes: ≥50% pain reduction, PGIC improvement, serious adverse events, dropouts.

Adverse events are common (26,0%), especially psychiatric side effects (13,5%), but serious side effects occur in fewer than 1 in 20 patients.

Systematic review on long-term side effects of medical cannabis in chronic pain; k=39 studies, n=12.143 adult patients. Very low evidence certainty: Adverse events common (26,0%; 95% CI 13,2%–41,2%), especially psychiatric events (13,5%; 95% CI 2,6%–30,6%). Serious side effects, discontinuation due to side effects, cognitive impairment and dependence each in <5% of patients. Studies with ≥24 weeks follow-up showed more adverse events than shorter studies (interaction p<0,01).

Some CAM therapies (inhaled cannabis, graded motor imagery, Compound Kushen injection) showed moderate to high effect sizes for chronic pain relief with good tolerability, while for other CAM modalities the evidence remains unclear.

Umbrella review of k=26 systematic reviews (207 clinical studies, n>12.000 participants) on CAM therapies for chronic pain. Inhaled cannabis showed moderate to high effect sizes with low heterogeneity and high adherence (≥80%) for chronic pain reduction. Adverse effects were minor.

Small improvement in sleep quality and sleep disturbance in chronic pain patients, but markedly increased risk of adverse effects such as dizziness (29%), drowsiness, dry mouth, fatigue and nausea (6–10%).

Systematic review on medical cannabis for sleep disturbances; k=39 RCTs (n=5.100), median follow-up 35 days, 33 studies in chronic pain (cancer/non-cancer). Moderate evidence: cannabis probably leads to a small improvement in sleep quality vs. placebo in chronic pain (modeled RD for MID 8%, 95% CI 3–12%). Reduction in sleep disturbance: non-cancer pain RD 19% (95% CI 11–28%), cancer pain WMD -0.19 cm (95% CI -0.36 to -0.03 cm, p=0.03 for interaction). Adverse effects: dizziness RD 29% (95% CI 16–50%) at ≥3 months follow-up, somnolence/dry mouth/fatigue/nausea RD 6%–10%.

Moderate evidence for pain reduction through cannabinoids at 2–8 weeks, with decreasing strength of evidence for longer treatment duration.

SR+MA of 36 RCTs (n=4.006), cannabinoids vs. placebo in chronic non-cancer pain; pooled WMD on 0-10 VAS: -0,68 (95% CI -0,96 to -0,40), p<0,00001 after 2-8 weeks of treatment. Serious adverse events rare and comparable between cannabinoid (3,4%) and placebo group (3,2%).

Cannabis-based medicines showed positive effects on pain, sleep and mood in some chronic pain patients with very low quality of evidence, without achieving large clinically relevant effect sizes.

SR of k=6 prospective observational studies (n=2.686) on cannabis in chronic non-cancer pain, study duration 26–52 weeks, very low certainty of evidence. Mean pain reduction WMD 1,75 (95% CI 0,72–2,78) on 0–10 scale; 20,8% (95% CI 10,2–34,0%) reported ≥50% pain relief. Moderate effect size for sleep problems, low for depression/anxiety. Study completion 53,3% (95% CI 26,8–79,9%), discontinuation due to adverse events 6,8% (95% CI 4,3–9,7%), severe adverse events 3,0% (95% CI 0,02–12,8%), mortality 0,3% (95% CI 0,1–0,6%).

Cannabinoids reduced chronic pain and improved sleep, but with clinically questionable effect sizes; no effect on acute or cancer pain; increased risk of non-serious adverse events.

SR across 20 RCTs (n=1.868) on cannabinoids vs. placebo for pain; pooled effect: standardised mean difference -0.14 (95% CI -0.20 to -0.08, p0.001), clinically small effect; Trial Sequential Analysis shows insufficient information for a definitive conclusion; moderate quality of evidence for neuropathic pain.

Cannabinoids were marginally superior to placebo in reducing pain intensity and achieving 30% pain reduction, but showed higher discontinuation rates and more frequent CNS and psychiatric side effects.

Systematic review on cannabinoids for chronic neuropathic pain; k=15 RCTs (n=1.619), study duration 2-15 weeks. Cannabinoids vs. placebo: pain intensity SMD -0.10 (95% CI -0.20 to -0.00, p=0.05), ≥30% pain reduction RD=0.10 (95% CI 0.03-0.16, p=0.004, NNT=10). Discontinuation rate due to side effects RD=0.04 (95% CI 0.02-0.07, p<0.001, NNH=25).

Cannabinoids are not superior to codeine and cause frequent psychotropic side effects, so that broad clinical use for pain therapy is considered not advisable.

Systematic review of k=9 RCTs (n=222) on cannabinoids in acute, chronic non-malignant and cancer pain; oral THC 5-20 mg, synthetic THC analogue and i.m. levonantradol comparably effective to codeine 50-120 mg; oral benzopyranoperidine worse than codeine 60-120 mg and not better than placebo. Cannabinoids NOT superior to codeine; frequent CNS side effects.

Inhaled cannabis leads to short-term pain reductions in chronic neuropathic pain in 1 of 5-6 treated patients (NNT = 5,6).

Bayesian IPD meta-analysis across k=5 RCTs (n=178, 405 observed responses) on inhaled cannabis for chronic neuropathic pain vs. placebo. Number Needed to Treat=5.6 (Bayesian 95% credible interval 3.4–14) for short-term pain reduction; about 1 of 5–6 patients benefits. Bayes factor=332, posterior probability of effect 99.7%. Limitations: short follow-up duration (days to weeks), small number of studies, inadequate allocation concealment, substantial attrition.

Cannabinoids show safe and modest analgesic efficacy in neuropathic pain, with preliminary indications of efficacy in fibromyalgia and rheumatoid arthritis.

Systematic review on cannabinoids in chronic non-cancer pain; k=18 RCTs included (neuropathic pain, fibromyalgia, rheumatoid arthritis, mixed chronic pain); 15 of 18 studies showed significant analgesic effect vs. placebo, several reported significant sleep improvement; no serious adverse effects, discontinuation rate due to adverse effects low; moderate efficacy for neuropathic pain, preliminary evidence for fibromyalgia and rheumatoid arthritis.

Cannabis showed moderate efficacy against chronic pain, but the benefits may be partially or completely offset by serious adverse effects (perceptual, motor and cognitive deficits).

SR/MA of k=18 double-blind RCTs on cannabinoids vs. placebo for chronic pain; standardized mean difference (VAS) favoring cannabis SMD=-0.61 (95% CI -0.84 to -0.37); NNH for perceptual adverse effects=7, motor impairment NNH=5.

Cannabinoids can be effective analgesics in chronic neuropathic pain that is refractory to other treatments, however further high-quality studies are required.

Systematic review of cannabis in chronic neuropathic pain; k=13 RCTs included (of 24 screened studies), assessed using the Jadad scale. Cannabinoids can provide effective analgesia in treatment-refractory neuropathic pain conditions. Authors call for further high-quality studies on treatment duration and optimal route of administration.

Cannabis showed no clear benefit for opioid sparing or pain relief; randomized studies yielded very low to high levels of evidence for no or minimal effect on opioid reduction and pain relief, while nausea and vomiting were likely increased.

Systematic review on opioid-sparing effects of cannabis in chronic pain; k=17 studies (5 RCTs in cancer pain, 12 observational studies). RCTs: high-certainty evidence for minimal effect on pain relief (WMD -0.18 cm on 10-cm VAS, 95% CI -0.38 to 0.02) and opioid dose (WMD -3.4 MME, 95% CI -12.7 to 5.8). Cannabis increased nausea (RR 1.43, 95% CI 1.04–1.96) and vomiting (RR 1.5, 95% CI 1.01–2.24). Observational studies: opioid reduction -22.5 MME (95% CI -43.06 to -1.97), very low certainty.

Moderate efficacy of cannabinoid-based medications in chronic pain and comorbidities such as sleep problems, anxiety and selected chronic conditions.

Clinical practice guideline for cannabinoid-based medicine (CBM) in chronic pain and comorbidities; based on systematic review (k=70 studies: 19 SRs + 51 original studies, PROSPERO 135886). GRADE recommendations: moderate benefit of CBM in chronic pain management; evidence for efficacy in comorbidities (sleep disorders, anxiety, appetite suppression) and symptoms in HIV, MS, fibromyalgia, arthritis.

The majority of studies showed pain reduction of 42–66 % with CBD alone or CBD with THC, but three studies showed no significant improvement and one had mixed results.

Systematic review on CBD in chronic pain; k=15 studies from 1.516 identified articles. Majority of studies showed pain reduction of 42%–66% with CBD alone or CBD+THC; 3 studies without significant improvement, 1 with mixed findings. Pain assessment mainly via self-report and VAS/VNS.

Cannabinoids showed significant improvements in sleep quality (SMD 0.40, p=0.002) and reduction in pain intensity (SMD -0.55, p=0.003) in chronic neuropathic pain, however with increased side effects such as daytime sleepiness, nausea and dizziness.

Systematic review + meta-analysis on cannabinoids in neuropathic pain; k=8 RCTs (from 3491 screened studies). Sleep quality: SMD=0.40 (95% CI: 0.19–0.61, p=0.002, I²=55%, GRADE: moderate certainty). Pain reduction: SMD=-0.55 (95% CI: -0.69 bis -0.19, p=0.003, I²=82%, GRADE: moderate certainty). Side effects: increased daytime sleepiness, nausea, dizziness.

The opioid-sparing effect of cannabinoids remains uncertain based on the current evidence; some observational studies showed reductions with certain dosages, but the overall evidence is limited.

SR of k=15 studies (7 RCTs, 8 observational studies) on cannabinoid dosage and opioid-sparing effect in acute/chronic pain. In chronic non-cancer pain: significant opioid reduction with THC+CBD combination (Ø 17 mg/15 mg daily) in two observational studies and CBD-rich extract (31,4 mg/day) in one study. In cancer pain: only nabilone (Ø 1,7 mg/day) showed opioid reduction. In acute pain: dronabinol 5–10 mg/day over 4 days in two observational studies. Conclusion: opioid-sparing effect remains uncertain based on current evidence.

The evidence is very low, therefore it is unclear whether cannabinoids reduce pain in chronic non-cancer pain, but they are associated with significant adverse effects.

Systematic review + meta-analysis via Epistemonikos database on cannabinoids in chronic non-cancer pain; k=32 RCTs identified from 37 systematic reviews. GRADE analysis: unclear whether cannabinoids reduce pain — evidence quality very low (very low certainty). Significant adverse effects reported.

All 12 included recommendations support medical cannabis for chronic non-cancer pain, but only as weak recommendations for third- or fourth-line therapy.

Systematic review of k=12 health recommendations on medical cannabis for chronic non-cancer pain (CNCP). Publications 2007–2019, 33% from 2018, Canada leading (n=4). 92% of recommendations are based on systematic reviews + expert consensus. All publications support medical cannabis for CNCP in general and specifically for neuropathic pain, HIV-associated pain, chronic abdominal pain — but only as a weak recommendation (3rd–4th line of therapy) with detailed patient education on benefits/risks.

5 of 13 RCTs showed moderate analgesic effects of cannabis for chronic pain, 8 showed no significant differences to the control group.

Rapid SR of k=13 RCTs (n=1.352) on cannabis for chronic pain. Five studies showed moderate analgesic effects, eight showed no significant pain reductions vs. control. Finding: moderate evidence for neuropathic pain, patient-reported benefit, relatively safe with few serious adverse events. Conclusion: cannabinoids have a potential role in chronic pain management, inconsistent evidence requires larger studies.

Selective cannabinoids showed a statistically significant but clinically small pain reduction (−0,65 points on a 0-10 scale) compared with comparator groups, with improved quality of life and sleep, but high heterogeneity between studies.

Systematic review of k=11 RCTs (n=1.219) on selective cannabinoids (dronabinol, nabilone, nabiximols) for chronic neuropathic pain vs. placebo/conventional therapy. NRS reduction -0.65 points (95% CI -1.06 to -0.23, p=0.002, I²=60%); statistically significant but clinically small. Improvement in quality of life and sleep without serious adverse effects. GRADE: weak recommendation, moderate quality of evidence.

Inconsistent findings on the efficacy of cannabis-based medicines for neuropathic pain and muscle spasms in MS; insufficient evidence for rheumatic diseases and cancer pain.

Umbrella review of k=10 systematic reviews (2009–2017) on cannabis-based medicines in chronic pain; 4 SRs of high and 6 of moderate methodological quality (AMSTAR). Inconsistent findings on efficacy for neuropathic pain (4 SRs) and painful MS spasms (1 SR); insufficient evidence for rheumatic pain (3 SRs) and tumor pain (2 SRs). Inconsistent results regarding tolerability and safety.

Weak evidence of benefit for neuropathic pain, insufficient evidence for other pain types; limited evidence for increased risk of mental health consequences in the general population.

n=757 chronic pain patients with medical cannabis over 12 months (30,4% follow-up at 6 months, 13,7% at 12 months). Time significantly associated with improvement in pain intensity (p<0.001), pain interference (p<0.001), quality of life (p<0.001), and general health symptoms (p<0.001). Opioid use reduced from 40,8% (baseline) to 23,9% (12 months).

The findings on superiority of cannabinoids over controls (placebo, amitriptyline) were inconsistent; currently insufficient evidence for a recommendation.

Systematic review on cannabinoids for chronic pain of rheumatic diseases (fibromyalgia, back pain, osteoarthritis, rheumatoid arthritis). k=4 RCTs identified (2 nabilone studies fibromyalgia n=71, 2–4 weeks; 1 nabilone study back pain n=30, 4 weeks; 1 THC/CBD study rheumatoid arthritis n=58, 5 weeks). No RCTs on osteoarthritis. Superiority of cannabinoids over controls (placebo, amitriptyline) not consistent. Risk of bias high in 3 studies. Cannabinoids generally well tolerated and safe during study duration. Conclusion: insufficient evidence for a recommendation.

As add-on therapy, nabilone causes small but significant pain reductions with an acceptable adverse effect profile.

Systematic review (k=11: 8 RCTs, 2 prospective cohorts, 1 retrospective analysis) on nabilone in various pain types (cancer pain, chronic non-cancer pain, neuropathic pain, fibromyalgia, spasticity pain); nabilone led to small but significant pain reductions; most common adverse effects: euphoria, drowsiness, dizziness.

Placebo showed moderate to large effect size for pain reduction in cannabinoid studies; media attention was high but not associated with clinical outcomes.

Meta-regression across 31 cannabis RCTs: placebo response correlates with media attention (β=0.41, p=0.03); higher placebo effects in pain and psychiatric studies with intensive coverage; methodological implications for cannabis pain trials.

VER-01 significantly reduced pain intensity by 0,6 NRS points more than placebo (p<0,001) and also showed benefits for neuropathic pain (NPSI reduction 7,3 points more than placebo, p=0,017); primary endpoint met.

Phase III RCT, n=820 adults with chronic low back pain (CLBP); VER-01 (cannabis full-spectrum extract) vs. placebo over 12 weeks. Primary endpoint met: mean NRS pain reduction -1,9 points (MD vs. placebo -0,6; 95%-CI -0,9 to -0,3; p<0,001). Key secondary endpoint (neuropathic pain component): NPSI -14,4 points (MD vs. placebo -7,3; 95%-CI -13,2 to -1,3; p=0,017). Effects maintained in 6-month open-label extension (NRS -2,9); no signal of dependence.

No increased risk for serious adverse effects, but increased risk for non-serious adverse effects (mostly mild to moderate) under cannabis compared to the control group.

Prospective cohort study (COMPASS) over 1 year, n=431 (215 cannabis users with chronic non-cancer-related pain, 216 controls). Median daily dose 2.5 g standardised cannabis (12.5% THC). No difference in serious adverse events (adjusted IRR=1.08, 95% CI 0.57–2.04); increased risk for non-serious adverse effects (adjusted IRR=1.73, 95% CI 1.41–2.13), predominantly mild to moderate. No differences in secondary safety parameters (lung function, neurocognition, laboratory).

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.

n=360 cancer patients with opioid-refractory tumour pain, nabiximols (Sativex) vs. placebo in three dose levels (low/medium/high); primary endpoint (30% responder rate) not significant (p=0,59); secondary continuous responder analysis significant in favour of nabiximols overall (p=0,035) as well as in the low- (p=0,008) and medium-dose group (p=0,039); mean daily pain (p=0,006), worst pain (p=0,011) and sleep disturbance (p=0,003) significantly improved in the low-dose arm; side effects dose-dependent, high-dose group less favourable compared with placebo.

Vaporized cannabis did not significantly reduce chronic pain in sickle cell disease, but showed a significant effect on mood impairment.

Pilot RCT (crossover design, n=23 adult sickle cell disease patients with chronic pain) on inhaled vaporized cannabis (4.4% THC / 4.9% CBD) vs. placebo, 3× daily over 5 days each. Primary endpoint: daily pain via VAS and Brief Pain Inventory. Mean pain reduction between cannabis and placebo groups statistically evaluated (details of numerical difference not fully given in abstract; full-text extraction required for exact effect size). Study completed June 2019.

Statistically significant reduction in pain intensity, pain disability as well as anxiety and depression symptoms after 12 months of cannabis therapy as an adjuvant.

Prospective single-arm study (n=338) on cannabis flos 19% decoction as add-on therapy for various chronic pain diagnoses over 12 months; statistically significant reduction in pain intensity from baseline to 12 months (χ²=61.375; p<0.001), improvements also in pain disability (χ²=39.423; p<0.001) as well as anxiety (χ²=30.362; p<0.001) and depression symptoms (χ²=27.786; p<0.001). Cannabis as an adjuvant to traditional analgesia effective for functional and psychological dimensions of chronic pain.

53% of patients reduced or eliminated opioid use within 8 weeks; 94% reported improvements in quality of life; significant improvements in sleep quality and pain intensity.

n=97 chronic pain patients with prior opioid treatment over 8 weeks CBD-rich hemp extract. 53% reduced or eliminated opioids within 8 weeks, 94% reported quality of life improvements. Significant relationship between CBD and Pittsburgh Sleep Quality Index (p=0.003) as well as Pain Intensity/Interference (p=0.006).

Transdermal CBD lowered masseter activity and myofascial pain considerably more than placebo.

RCT (n=60, double-blind, parallel, TMD myofascial pain); transdermal CBD vs. placebo over 14 days; VAS pain intensity reduced by >70,2% in the CBD group vs. 9,81% in the placebo group; sEMG masseter activity significantly decreased (11% right, 12,6% left in the CBD group vs. <0,3–3,3% placebo).

Statistically significant improvement in pain and sleep, but without reaching the clinically relevant minimum reduction.

n=48 patients with treatment-refractory chronic neuropathic pain (brachial plexus avulsion), Sativex vs. THC vs. placebo (2-week treatment periods); pain severity scores showed statistically significant improvement despite the primary endpoint (reduction >2 points) not being reached. Cannabis extracts well tolerated; AEs mild to moderate.

Nabilone significantly reduced pain intensity compared to placebo and was clearly preferred by patients.

n=30 patients with treatment-resistant chronic skeletal/musculoskeletal pain; nabilone (0,25–1 mg/d) add-on treatment vs. placebo crossover. Current spinal pain VAS decrease: nabilone 0,6 vs. placebo 0,0 (p=0,006); quality of life increase (ΔQOL score): 5,0 vs. 2,0. During the switch period, >4× more patients preferred nabilone over placebo (89% vs. 11% of all medication days, p=0,003).

Dronabinol showed dose-dependent psychoactive effects comparable to smoking cannabis.

n=30 chronic non-cancer pain patients under opioid therapy, randomised-controlled crossover study of placebo vs. 10 mg vs. 20 mg oral dronabinol. Both doses showed significantly increased ARCI scores (Addiction Research Center Inventory) across 4/5 subscales vs. placebo (p<0.05). Peak effects after 2h comparable to smoked cannabis after 30 min (p=0.80).

Cannabis significantly improved sleep quality but failed to achieve a clinically relevant pain reduction, so addition to standard therapy is not recommended.

Triple-blind crossover RCT (n=28) in chronic neuropathic pain following brachial plexus injury; cannabis medicine vs. placebo: VAS pain reduction mean difference 1,0 (99% CI -0,03–2,1; p=0,01), below the clinically relevant minimum threshold (MCID=2 points); sleep quality improved (mean difference +1,5; p<0,001). Study reaches a negative efficacy judgement for pain reduction in this population.

Dose-dependent pain reduction under THC inhalation versus placebo in chronic pain without relevant cognitive impairment.

n=27, chronic neuropathic pain/CRPS; inhaled THC 0.5 mg and 1 mg vs. placebo; both THC doses reduced pain intensity (VAS) significantly versus baseline (p<0.05); the 1-mg dose showed significant pain reduction vs. placebo; effect stable over 150 min; adverse events mostly mild and self-limiting.

Nabilone reduced pain intensity, analgesic consumption and medication dependence significantly more than ibuprofen.

n=26 patients with chronic intractable medication overuse headache (MOH), nabilone 0,5 mg/day vs. ibuprofen 400 mg/day, 8-week crossover; nabilone significantly superior for pain intensity (p<0,05) and daily analgesic consumption (p<0,05). Only nabilone reduced degree of medication dependence (−41%, p<0,01) and improved quality of life (p<0,05). First RCT on cannabinoids in MOH.

CBD-rich cannabis oil significantly improved spasticity, dystonia, sleep, pain and quality of life in children with complex movement disorders.

n=25 children (1–17 y.) with complex movement disorder, CBD-rich cannabis oil over 5 months; significant improvement in pain intensity in the overall cohort regardless of formulation group; accompanying improvements in quality of life and sleep also reported.

Cannabis with 9,4% THC significantly reduced pain intensity by 0,7 points (5,4 vs. 6,1) and improved sleep quality and sleep onset time, but was associated with headache and other adverse effects.

Crossover RCT, n=23 (21 completers) with post-traumatic or postoperative neuropathic pain. Inhaled cannabis (0%, 2.5%, 6%, 9.4% THC) over four 14-day cycles (3×25 mg/day for 5 days, 9-day washout). Primary contrast 9.4% vs. 0% THC: mean pain intensity (11-point scale) 5.4 vs. 6.1 (difference=0.7, 95% CI 0.02–1.4, p<0.05). Improved sleep (easier falling asleep p=0.001, faster p<0.001, fewer wake periods p=0.01). Most common adverse effects with 9.4% THC: headache, dry eyes, burning, dizziness.

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

n=21 patients with chronic pain under morphine/oxycodone, 5-day inpatient cannabis inhalation. Pain reduction averaging 27% (95% CI 9–46) after cannabis addition without significant change in opioid plasma levels. Indication of synergistic analgesia without pharmacokinetic interaction.

THC significantly reduced the LF/HF ratio (increased parasympathetic activity) and significantly improved conditioned pain modulation compared to placebo.

Cross-over RCT in n=12 male patients with chronic radicular neuropathic pain; oral THC 0.2 mg/kg vs. placebo. THC significantly reduced the LF/HF HRV ratio (parasympathetic activation, F(1,11)=20.5, p<0.005) and improved conditioned pain modulation (CPM response, F(1,9)=5.2, p=0.048). THC-induced LF/HF reduction correlated with increased functional connectivity between rostral ventrolateral medulla and dorsolateral prefrontal cortex (T(10)=6.4, cluster p-FDR<0.005).

Dronabinol led to decreased pain intensity, increased patient satisfaction, and significant pain relief as adjuvant therapy in opioid-treated chronic pain patients.

n=30 chronic pain patients under opioid therapy, dronabinol 10–20 mg/d adjuvant vs. placebo; no significant difference in the primary endpoint (BPI pain intensity p=0.59), trend towards improved sleep quality.

Medical cannabis card led to improved self-reported insomnia symptoms, but to higher incidence and severity of cannabis use disorder and no significant improvement in pain, anxiety or depressive symptoms.

n=269 medical cannabis card holders (Massachusetts) over 12 months: no significant improvement in pain (β=-0.24, p=0.45), insomnia or affective symptoms vs. baseline; higher risk of cannabis use disorder (OR 2.5, p0.05).

CBD 20–30 mg/day did not significantly reduce pain intensity compared with placebo.

RCT (n=129) on synthetic CBD 20–30 mg/day vs. placebo over 12 weeks in hand osteoarthritis and psoriatic arthritis; group difference in pain intensity after 12 weeks: 0,23 mm (95%-CI −9,41 to 9,90; p=0,96) — no clinically or statistically significant pain effect. 22% CBD vs. 21% placebo group achieved >30 mm pain reduction.

Oral THC did not reduce chronic abdominal pain more than placebo.

n=65 patients with chronic abdominal pain (postoperative or chronic pancreatitis), oral THC tablet (up to 8 mg 3×/day) vs. placebo over 50–52 days. Primary endpoint VAS pain not different (F=0,016; p=0,901): THC group –1,6 points (40%), placebo group –1,9 points (37%). No significant difference in secondary outcomes. Negative finding: THC with no advantage over placebo for chronic abdominal pain.

Benzopyranoperidine showed no analgesic effect versus placebo and was inferior to codeine; both doses tended to increase pain perception.

n=35 cancer pain patients, benzopyranoperidine (THC analogue) 2 mg / 4 mg vs. codeine 60 mg / 120 mg vs. placebo (5-way crossover); no significant difference between placebo and benzopyranoperidine; codeine 120 mg showed clinically relevant pain reduction. THC analogue not more effective than placebo; pain perception tended to be increased under both doses.

Δ9-THC did not significantly reduce chronic abdominal pain in pancreatitis compared to active placebo.

n=24 patients with chronic abdominal pain in chronic pancreatitis, Δ9-THC 8 mg oral vs. diazepam 5/10 mg (active control), crossover design; no treatment effect on VAS pain delta (p not significant). Negative finding; anxiety symptoms and heart rate significantly increased after THC vs. diazepam.

Oral THC led to adequate pain relief in only a portion of patients, while the majority did not respond sufficiently.

Open-label study (n=13) of oral delta-9-THC in chronic non-malignant pain (CNMP) without response to standard therapy; 5 of 13 patients (38%) reported adequate response, 8 of 13 (62%) inadequate or no response; 6 patients with adverse events, 2 study discontinuations. Oral THC therapy in selected therapy-refractory CNMP patients possibly an option.

Early exploratory investigation (34 'N-of-1' trials, predominantly neuropathic chronic pain) with sublingual cannabis extracts (THC, CBD, 1:1) over 12 weeks, randomised after an open-label phase, double-blind, placebo-controlled in a crossover design. THC-containing extracts showed the best symptom control across a broad dose range. Side effects were frequent but mostly acceptable and comparable to other psychotropic drugs. Caveat: very small, heterogeneous pilot data without quantitative effect sizes, only indicative for later studies.

Cannabis medicines show typical side effects (fatigue, dizziness, nausea, dry mouth) with all preparations; potentially serious side effects (depression, suicidal ideation, hallucinations) were reported in >0,1% of cases each; efficacy not quantified in this interim analysis.

n≈21.000 (3-year analysis of the German cannabis accompanying survey), fibromyalgia as third most common indication; in fibromyalgia patients improvement of pain and quality of life in 60% of cases.

Oral medical cannabis significantly improved all measured clinical outcomes over 2 years (p<0,001) with an acceptable safety profile.

Prospective Australian registry study (n=3.961, 71,9% chronic pain, 2 years follow-up), oral medical cannabis; pain interference (BPI) improved by 26,1%, pain severity by 22,2% (p<0,001); 37,3% mild to moderate adverse events, serious events <2% (n=23).

On average, symptoms improved by 3,5 points on an 11-point scale; higher THC contents were associated with stronger relief but also more side effects, while CBD content showed no clear effect.

n=3.341 medical cannabis patients, 19.910 self-administration sessions (ReleafApp); average symptom improvement 3,5 points (SD=2,6) on an 11-point scale; higher THC content independently associated with greater symptom relief (p<0.05); dried cannabis flower most common product form with greatest symptom reduction; CBD potency not significantly associated.

Clinically meaningful and statistically significant improvements in health-related quality of life, fatigue and sleep disturbance were maintained over 12 months; anxiety, depression, insomnia and pain also improved for patients with corresponding conditions.

QUEST Initiative: n=2353 Australian patients with chronic conditions (38,1% musculoskeletal pain, 23,2% neuropathic pain) over 12 months of medicinal cannabis. Clinically meaningful improvements in HRQL (EQ-5D-5L d=0.52, QLQ-C30 d=0.91), pain (QLQ-C30 pain d=0.5, PROMIS pain intensity d=0.76, pain interference d=0.76), fatigue (d=0.51), sleep disturbance (d=0.76), anxiety (DASS d=0.69) and depression (DASS d=0.65). Follow-up rate fell to 38% at 12 months.

Statistically significant, clinically meaningful improvements in quality of life, fatigue, anxiety and depression over 3 months; clinically meaningful pain reduction in chronic pain; no change in sleep disturbances.

QUEST Initiative: Prospective multicentre real-world study in patients with chronic conditions under newly prescribed medical cannabis (n=2.327 with baseline + follow-up, Australia 2020–2021). Primary population: chronic pain (68,7%), insomnia (22,9%), anxiety (21,5%). Clinically meaningful improvement in quality of life from baseline to mean follow-up: EQ-5D-5L d=0,54 (95% CI 0,47–0,59), QLQ-C30 summary d=0,64 (95% CI 0,58–0,70), fatigue d=0,54 (95% CI 0,48–0,59). In chronic pain, clinically meaningful pain reduction d=0,65 (95% CI 0,57– [abstract truncation]).

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).

Prospective cohort study in drug users with chronic pain (n=1.152, Vancouver 2014–2017). 40% reported daily illegal opioid use, 36% daily cannabis use. Most common therapeutic reasons for cannabis: pain (36%), sleep (35%), stress (31%). After adjustment, daily cannabis use was associated with significantly lower odds for daily illegal opioid use (aOR=0,50; 95% CI 0,34–0,74; p<0,001).

Significant reduction in pain intensity, but only 17% (ITT) or 32% (per-protocol) showed clinically relevant pain reduction ≥30% at first follow-up; mild to moderate side effects in 42% of patients.

n=826 Danish patients with treatment-refractory chronic pain (TRCP), retrospective real-world study on oral cannabinoids. NRS reduction significant at follow-up 1 (median 56 days) and follow-up 2 (median 126 days) vs. baseline (p<0.0001). Clinically relevant pain reduction (NRS ≥30%) in 17% (F/U1) or 10% (F/U2) in intention-to-treat analysis; 32% or 45% in per-protocol analysis. Side effects mild-moderate in 42% (F/U1) and 34% (F/U2), mainly gastrointestinal (17%/13%) and CNS (14%/11%).

Medical cannabis was associated with significant improvements in pain intensity, pain interference and quality of life over 12 months; opioid use was reduced.

n=751 chronic pain patients over 12 months, medical cannabis associated with significant reduction in pain intensity and interference (p<0.001) from month 1, improvement in SF-12 physical and mental health domains from month 3 (p<0.002). Significant reduction in oral morphine equivalent doses in baseline opioid users (p<0.0001).

Medical cannabis led after 12 months to an average reduction in pain intensity of 20% and improvement of all other parameters by 10-30%; at the same time a reduction of the opioid-equivalent dose by 42%.

n=279 patients with chronic pain under medical cannabis, mixed etiologies (incl. fibromyalgia n~50); significant pain reduction (NRS -2,5 points, p0.001), 18% response rate for ≥30% reduction after 6 months.

Delta-9-THC significantly reduced pain intensity and improved psychometric parameters, with an acceptable side effect profile in the majority of patients.

Multicentre retrospective telephone survey: n=172 patients with central neuropathic pain and fibromyalgia received on average 7,5 mg Delta-9-THC over 7 months; n=124 evaluable (48 premature discontinuation). Psychometric parameters (PDI, SF-12, QLIP, HADS) as well as pain intensity (NRS) improved significantly; opioid doses were reduced. ~25% of patients did not tolerate the treatment.

THC:CBD spray showed an improvement in symptoms of on average 39,0% (ASR-9) after 12 weeks, with a particularly pronounced effect in neuropathic pain (54,9% improvement) and good tolerability.

Real-world registry analysis from the German Pain e-Registry 2017, n=800 patients with severe chronic pain under THC:CBD oromucosal spray as add-on. ASR-9 improvement (9-factor symptom relief) after 12 weeks: 39,0±26,5% (95% CI 36,9–41,1, median 42%, range -41 to +85). Complete ASR-9 response (≥50% improvement in all 9 factors) in 15,4% (n=123); ≥50% improvement in ≥5/9 factors in 56,0% (n=488). Subgroup analysis: neuropathic pain (n=497, 62,1%) significantly better (ASR-9: 54,9±17,2%, median 56%) vs. mixed pain (n=249, 31,1%; ASR-9: 18,2±12,0%, median 19%, p<0,001) and nociceptive pain (n=54, 6,8%; ASR-9: -11,9±10,5%, median -11%, p<0,001). Adverse events in 19,9% (n=159), mostly mild (81,6%); most common TEAEs: increased appetite (6,3%, n=50), dysgeusia (2,9%, n=23). Discontinuations due to TEAEs: 4,0% (n=32); due to insufficient pain relief: 14,1% (n=113), predominantly in nociceptive pain (74,1%, n=40 of 54), rarely in neuropathic pain (0,2%, n=1, p<0,001).

CBMPs were associated with significant improvements in pain intensity and health-related quality of life over 6 months.

UK Medical Cannabis Registry, n=190 patients with chronic pain; significant improvements in BPI, SF-MPQ-2, VAS pain, GAD-7, SQS and EQ-5D-5L at all measurement time points (1, 3, 6 months; p<0,050); adverse events in 39,47% (mild 19,47%, moderate 12,11%, severe 7,37%); most common AE nausea (n=11; 5,8%).

Pain intensity and pain interference decreased in both groups, physical and mental health improved, high satisfaction reported.

Prospective observational study (n=64) on Cannamedical® Hybrid Cannabis Extract THC25:CBD25 in chronic pain patients over 4 visits; NRS pain intensity decreased from 5.46±1.73 (V1) to 3.37±2.43 (V4) in the ITT population; in cannabis-naive patients (n=35) reduction from 5.92±1.34 to 2.37±1.69. Pain Interference Subscore improved from 5.39±1.92 to 3.38±2.46 (ITT) and from 5.68±1.46 to 2.54±1.99 (cannabis-naive), respectively. SF-12 showed improvements in physical and mental health; high patient and physician satisfaction.

CaM is frequently used as a substitute for prescription medications (particularly opioids), with predominantly positive self-assessment regarding efficacy and side effects.

Online survey (n=2.841 cannabis-as-medicine users); 54,6% used cannabis as a substitute for prescription medications; pain medications were the most common substitution target (67,2%). Among substitution users, 38,1% reported complete discontinuation and 45,9% substantial reduction of prescription medications; >65% perceived CaM as more effective than the replaced medication.

16% of participants used cannabis for pain relief; users reported more severe pain and greater impairment, but also greater pain relief in combination with opioids compared with opioid monotherapy.

POINT study with n=1.514 Australian patients under opioid therapy for chronic non-cancer pain; 16% had used cannabis for pain relief (6% in the last month), 25% would use it if they had access. Cannabis users reported higher pain intensity, higher opioid doses, and better pain relief in combination with opioids than with opioids alone. 43% lifetime cannabis use (recreational), 12% met ICD-10 criteria for a cannabis use disorder.

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 in Washington State; 61,2% used cannabis primarily for pain; average 86% symptom reduction (self-reported); 59,8% used cannabis as a substitute for pharmaceuticals (no control arm, purely observational).

About 80% of participants reported substituting cannabis for traditional pain medications (53% for opioids, 22% for benzodiazepines), citing fewer side effects and better symptom control as reasons.

n=1.321 medical cannabis users with chronic pain (59% female, 54% ≥50 years); 80% reported cannabis substitution for traditional pain medications (53% for opioids, 22% for benzodiazepines), reasoning: fewer side effects and better symptom management. Experienced users (≥1 year) vs. novices (<1 year): more often no concomitant medication (43% vs. 30%) and improved health (74% vs. 67%, p=0.004).

In 84% of participants, quality of life improved markedly under cannabis medicine therapy according to subjective assessment.

Real-world registry on cannabis therapy in chronically ill patients in Germany (n=1.030); pain was the most common symptom (71%), followed by sleep disturbances (64%). Subjective quality of life improvement in 84% of patients. Symptom matrix (SMX) of 6 core symptoms identified.

Respondents currently taking cannabinoids more often report large pain improvements and fewer side effects; however, clinical trials show mixed and often inconclusive results.

Web-based cross-sectional survey among n=969 patients with chronic pain (46% currently taking cannabinoids, 22% formerly, 32% never). Current users report large pain improvement more often (incl. difficult-to-treat chronic overlapping pain syndromes such as pelvic pain), improved comorbidities (sleep), lower side-effect burden. Never-users cite lack of physician recommendation (40%), illegality (25%), lack of FDA approval (19%) as reasons.

Medical cannabis use was associated with a 64% reduction in opioid use, decreased medication side effects, and improved quality of life (45%).

Retrospective survey of n=244 medical cannabis patients with chronic pain (Michigan 2013–2015); cannabis use associated with 64% reduction in opioid use (n=118), improved quality of life (45%) and fewer medication side effects.

Cannabis was used by a significant proportion of pain patients to relieve pain, sleep and mood, with dose and frequency varying widely.

Cross-sectional survey, n=209 chronic non-cancer pain patients; 15% used cannabis for pain relief; pain users significantly younger (p=0.001) and more often smokers (p=0.0001); pain, sleep and mood most frequently reported as improved.

The majority of patients reported high therapeutic satisfaction, with certain subjective effects differing between cannabis varieties with different THC/CBD content.

Cross-sectional study (n=102) in Dutch patients with pharmaceutically-qualified cannabis; chronic pain most common indication (53%; n=54); 86% reported (almost) always therapeutic satisfaction with use; subjective pain relief as main outcome; no control group, no effect size calculation.

Patients reported significant improvements in all 8 domains of quality of life (SF-36) following cannabis treatment, which mostly persist over time, with improvements ranging from 6,60 to 18,31 points depending on domain (all p < 0,001).

n=2.762 medical cannabis patients (Australia, QUEST initiative) over 3 months: improvement in health-related quality of life (EQ-5D-5L index +0.06, p0.001) and pain dimension (−0.11, p0.001); real-world data without placebo control.

Medicinal Cannabis led to significant improvement in pain scores (S-TOPS: 83,3 → 75,0; p<0,001), pain severity and pain interference, as well as a 44% reduction in opioid consumption.

Prospective open-label study with n=206 (ITT) patients with treatment-refractory chronic pain; after 6 months of medical cannabis the S-TOPS pain score improved from 83,3 (95% CI 79,2–87,5) to 75,0 (95% CI 70,8–79,2, p<0,001), pain severity score from 7,50 to 6,25 (p<0,001), pain interference score from 8,14 to 6,71 (p<0,001). Opioid consumption decreased by 44% (p<0,001). Serious adverse events led to treatment discontinuation in 2 participants.

MCP patients showed significantly higher odds of opioid discontinuation (OR 17,27) and dose reduction (OR 5,12) with a 47-percentage-point reduction in daily opioid dosing as well as improvements in pain reduction and quality of life.

Historical cohort study on Medical Cannabis Program (MCP) enrollment in New Mexico, n=37 chronic pain patients with habitual opioid use (MCP group) vs. n=29 non-enrolled (control), observation over 21 months. MCP enrollment associated with 17,27-fold higher adjusted odds of opioid prescription cessation (95% CI 1,89–157,36, p=0,012), 5,12-fold higher odds of dose reduction (95% CI 1,56–16,88, p=0,007) and 47 percentage points lower daily opioid dose vs. +10,4 percentage points increase in control (95% CI -90,68 to -3,59, p=0,034). Monthly trend in MCP group: -0,64mg IV morphine equivalent (95% CI -1,10 to -0,18, p=0,008), control: +0,18mg (95% CI -0,02 to +0,39, p=0,081). Patient-reported outcomes after 1 year: improvements in pain reduction, quality of life, social activity, concentration (all p<0,001); few side effects.

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; of the remaining 29 patients, 31% reduced opioid dose; higher cannabis dose was the only predictor for opioid cessation.

52,5% of patients achieved pain relief of more than 30%, 10% of more than 50%; approximately four symptoms or side effects from previous treatment were positively affected.

Retrospective data analysis on dronabinol in geriatric pain and palliative care patients; real-world data on tolerability and clinical use in a vulnerable population; exploratory-descriptive evidence for chronic pain syndromes in older age.

Sativex improved subjective sleep parameters across multiple pain syndromes without development of tolerance over up to four years.

Narrative review on Sativex (THC/CBD 1:1) in pain disorders; n=2000 patients, 1000 patient-years of exposure in phase I-III studies. 40-50% of patients achieved good to very good sleep quality; pronounced subjective pain improvement in MS, peripheral neuropathic pain disorder, cancer pain and rheumatoid arthritis without dose escalation over up to 4 years.

71% of the 38 surveyed RCTs showed statistically significant pain-relieving effects of cannabinoids, 29% showed no effects; adverse effects predominantly mild and well tolerated.

Narrative review on cannabinergic pain medicine with PubMed survey of k=38 RCTs; 71% (n=27) showed statistically significant pain-relieving effects, 29% (n=11) did not. CB1 receptors 10-fold more common than μ-opioid receptors in the CNS. Adverse effects mostly non-serious and well tolerated.

High-quality evidence supports the use of marihuana/cannabinoids for chronic pain, neuropathic pain and spasticity in multiple sclerosis; many other indications are not evidence-supported.

Narrative review on medical cannabis for chronic pain and psychiatric indications; discusses the evidence situation and risks, no systematic data extraction.

Moderate evidence for analgesic effect of cannabis/cannabinoids especially in neuropathic pain, but with considerable limitations (short treatment duration, small patient numbers, heterogeneous populations, modest measurable effects).

Narrative review on cannabinoids and pain; discusses preclinical mechanisms (neurotransmitter inhibition, postsynaptic modulation, descending inhibition, reduction of neuroinflammation). Refers to meta-analyses with moderate evidence for cannabis/cannabinoids in chronic pain, particularly neuropathic pain. Limitations: short treatment duration, small sample sizes, heterogeneous populations, differing cannabinoids/doses, modest effects. Short-term side effects mild to moderate, well tolerated, transient; long-term safety data scarce. Calls for larger, longer-duration RCTs on long-term efficacy and safety.

Narrative review reports on the safety and efficacy of cannabinoids in clinical trials for neuropathic pain, rheumatoid arthritis and cancer pain, without stating specific quantitative results.

Narrative review on cannabinoid analgesia in difficult-to-treat pain; Sativex (THC/CBD oromucosal spray) approved in Canada in 2005 for MS-associated neuropathic pain, in 2007 for refractory cancer pain; numerous RCTs showed safety and efficacy in central/peripheral neuropathic pain, rheumatoid arthritis and cancer pain; good tolerability profile in clinical trials.

Narrative review without own clinical data; it is reported that full-spectrum cannabis products might show improved efficacy or tolerability, but definitive clinical studies are still needed.

Narrative review on cannabis and pain, discusses entourage effects and synergistic mechanisms between cannabinoids and terpenes; mainly mechanistic hypotheses, limited clinical evidence for neuropathy; no meta-analysis or systematic data extraction.

Narrative clinical review (PubMed literature search) on cannabis/cannabinoids in pain therapy. The authors refer to a recent meta-analysis of clinical studies that found moderate evidence for the benefit of cannabinoid-based pharmacotherapy for pain; initial epidemiological indications also suggest a possible reduction in opioid requirement. Limitation: subjective pain relief does not necessarily correspond with objective analgesia measurements, narrow therapeutic window, no own systematic evaluation.