Neuropathic Pain

Guideline on the evidence assessment of pharmacological treatments for neuropathic pain; several medications (TCA, pregabalin, gabapentin, tramadol, opioids, duloxetine, venlafaxine, topical lidocaine, capsaicin patch) show Level A evidence in various indications.

EFNS guideline 2010 on the pharmacological treatment of neuropathic pain; Level A evidence for tricyclic antidepressants, pregabalin, gabapentin, tramadol and opioids (for various etiologies including diabetic polyneuropathy, post-herpetic neuralgia). Combination therapy TCA-gabapentin and gabapentin-opioids Level A.

DGS PraxisLeitlinie cannabis in pain medicine v2.0; recommends cannabinoids as a treatment option for chronic neuropathic pain after failure of conventional therapies; evidence grade B based on several RCTs; emphasizes individualized dosing and monitoring.

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 SR of k=25 RCTs (n=2303, 64% neuropathic pain), 1–6 months; oromucosal THC/CBD comparable ratio probably slightly reduced pain intensity (pooled difference -0.54 points, 0–10 NRS), oral synthetic high-THC possibly slightly (-0.78 points); nabilone moderately effective (pooled difference -1.59 points), dronabinol not (-0.23 points); moderately to strongly increased rates of dizziness, sedation and nausea.

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 SR of k=16 RCTs (n=1.750) on cannabis-based medicines in chronic neuropathic pain vs. placebo. NNTB=20 for ≥30% pain reduction, NNTB=24 for ≥50% pain reduction, NNTH=25 for treatment discontinuation due to side effects. Moderate quality of evidence.

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.

Comprehensive SR of k=27 chronic pain trials plus 11 SRs and 32 primary studies on harms. Low-strength evidence that cannabis relieves neuropathic pain; insufficient evidence for other pain populations. Harms in the general population: increased risk of motor vehicle accidents, psychotic symptoms, short-term cognitive impairment.

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 (incl. neuropathic pain) and MS spasticity, weak evidence for sleep disorders and nausea; cannabinoids vs. placebo: OR=1.41 (95% CI 0.99–2.00) for ≥30% pain reduction.

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 on cannabis-based medicines for chronic neuropathic pain; 6 new studies with n=450 participants included (total number of included studies and pooled n not stated in the abstract). Primary outcomes: ≥50% pain reduction, PGIC 'much/very much improved', serious adverse events, treatment discontinuations. Evidence assessment using GRADE; meta-analysis with random-effects model.

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 on cannabis in chronic pain; k=25 studies (18 RCTs n=1.740, 7 cohort studies n=13.095), study duration 1–6 months, 56% neuropathic pain. Synthetic products with high THC:CBD ratio (>98% THC): moderate pain improvement and ≥30% response, increased risk for sedation and dizziness. Sublingual spray (THC:CBD 1,1:1): small improvement in pain intensity and overall function, large risk for dizziness and sedation, moderate risk for nausea.

Cannabinoids show only minimal pain reduction (3 mm on a 100-mm scale) compared with placebo with a high rate of harm; benefit-harm ratio unfavourable (NNT 24 vs. NNH 6).

Systematic review + meta-analysis on cannabinoids in chronic non-cancer pain; k=104 studies (47 RCTs + 57 observational studies, n=9.958), of which 48 studies on neuropathic pain. RCT-pooled event rate for ≥30% pain reduction: 29,0% (cannabinoids) vs. 25,9% (placebo), significant; NNT=24 (95% CI 15-61). For ≥50% reduction: 18,2% vs. 14,4%, not significant. Pain intensity reduction: SMD=-0,14 (95% CI -0,20 to -0,08), equivalent to 3 mm on 100 mm VAS. Adverse event rate: 81,2% vs. 66,2%; NNH=6 (95% CI 5-8).

Cannabis and cannabinoids via certain routes of administration (oromucosal, oral, inhalation) reduced various pain types (neuropathic, nociceptive, cancer pain), but significantly increased the risk of euphoria.

Systematic review + network meta-analysis across k=25 RCTs (n=2270) on cannabis/cannabinoids in pain; THC/CBD oromucosal reduced neuropathic pain (SMD -0.41, 95% CI -0.7 bis -0.1), THC oromucosal (SMD -0.61, 95% CI -1.2 bis -0.02), inhaled cannabis (SMD -0.77, 95% CI -1.4 bis -0.2); increased risk of euphoria with THC-containing products.

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.

SR + MA across k=15 RCTs (n=1.619) on cannabinoids for chronic neuropathic pain, study duration 2–15 weeks. Cannabinoids superior vs. placebo: mean pain intensity SMD=-0.10 (95% CI: -0.20 to -0.00, p=0.05, k=13, n=1.565); ≥30% pain reduction RD=0.10 (95% CI: 0.03–0.16, p=0.004, k=9, n=1.346, NNT=10). Preparations: 10 studies THC/CBD oromucosal spray, 3 synthetic cannabinoids (2 nabilone, 1 dronabinol), 2 medical cannabis.

Meta-analysis shows limited evidence for pain reduction with cannabis-based medicines vs. placebo (especially with inhalation), but clinical significance is uncertain, as the majority of individual studies showed no effect.

SR of k=43 RCTs (n=2.437 total, k=24 RCTs with n=1.334 in the meta-analysis) on cannabis-based medicines in chronic and postoperative pain; meta-analysis showed limited evidence for pain reduction in chronic pain Hedges's g=-0,61 (95% CI -0,78 to -0,43, p<0,0001), particularly with inhalation g=-0,93 (95% CI -1,51 to -0,35, p=0,001) vs. placebo. Clinical significance of the findings uncertain.

Nabiximols showed statistically significant superiority over placebo in reducing chronic neuropathic pain with a small effect size (MD -0,40 to -0,44 points on an 11-point scale).

Meta-analysis of k=9 double-blind placebo-controlled RCTs (n=1.289) on nabiximols for chronic neuropathic pain; mean difference (MD) −0,40 (95% CI −0,59 to −0,21; p<0,0001) on the 11-point NRS vs. placebo; SMD −0,21 (small effect, FE model). GRADE quality of evidence: moderate.

THC and THC/CBD significantly reduce neuropathic pain intensity versus placebo; CBD, CBDV and CT-3 show no significant effect.

SR+MA of k=17 RCTs (n=861) on cannabis-based medicines vs. placebo in chronic neuropathic pain; THC/CBD reduced pain intensity by -6,6 units (P<0,001), THC by -8,7 units (P<0,001) on 0-100 scale; patients on THC/CBD were 1,76-fold more likely to achieve ≥30% pain reduction (P=0,008). Quality of evidence moderate to low.

Cannabinoids (in particular cannabidiol/THC spray, cannabidiol and dronabinol) showed a statistically significant pain reduction of on average 1,6 points (p < 0,001) and were superior to placebo by 0,8 points (p = 0,029), although the evidence base was small.

Meta-analysis of 7 RCTs (n=298; 222 treated, 76 placebo) on cannabinoids for neuropathic and MS-related pain; pooled pain reduction 1,6±0,4 points (p<0,001); cannabinoids superior to placebo by 0,8±0,3 points (p=0,029). Sativex (CBD/THC spray), cannabidiol and dronabinol individually all significantly effective.

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

IPD meta-analysis across k=5 RCTs (n=178, 405 observed responses) on inhaled cannabis for chronic neuropathic pain; NNT=5,6 (95% Bayesian Credible Interval 3,4-14) for short-term pain reduction. Bayes factor=332, posterior probability of an effect=99,7%. Follow-up only days to weeks.

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

SR of k=18 RCTs on cannabinoids in chronic non-cancer pain (neuropathic pain, fibromyalgia, rheumatoid arthritis, mixed chronic pain). 15 of 18 studies showed significant analgesic effect vs. placebo; several reported significant sleep improvements. Cannabinoids safe and moderately effective for neuropathic pain, preliminary evidence for fibromyalgia and rheumatoid arthritis. No serious adverse effects; discontinuation rates due to adverse effects low.

Only smoked cannabis, capsaicin 8% and rhNGF proved more effective than placebo for painful HIV-SN; the majority of the substances tested showed no superiority.

Systematic review + meta-analysis (k=14 RCTs) on the pharmacological treatment of painful HIV-associated sensory neuropathy; smoked cannabis showed NNT=3.38 [95% CI 1.38–4.10] for ≥30% pain reduction vs. placebo — higher efficacy than amitriptyline, gabapentin and pregabalin, all of which failed to achieve superiority over placebo.

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/cannabinoids in chronic non-malignant neuropathic pain; k=13 RCTs included (of 24 identified studies). Evaluation using the Jadad scale; finding: cannabinoids can provide effective analgesia in treatment-refractory chronic neuropathic pain conditions.

Limited evidence for benefit of THC/CBD spray in neuropathic pain; insufficient evidence for cannabinoids in cancer, rheumatic or gastrointestinal pain; associated with CNS and psychiatric adverse effects.

Umbrella review of k=11 systematic reviews (3 of high, 8 of moderate methodological quality) on cannabinoids in pain therapy and palliative care. For neuropathic pain: limited evidence for THC/CBD spray; insufficient evidence for other cannabinoids (dronabinol, nabilone, medical cannabis) in cancer pain, rheumatic/gastrointestinal pain or anorexia.

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.

SR + MA of k=8 RCTs on cannabinoids in neuropathic pain. Significant improvement in sleep quality (SMD=0.40, 95% CI: 0.19–0.61, p=0.002, I²=55.26%, GRADE: moderate certainty). Significant pain reduction (SMD=-0.55, 95% CI: -0.69 bis -0.19, p=0.003, I²=82.49%, GRADE: moderate certainty). Side effects: daytime sleepiness, nausea, dizziness.

Cannabinoids showed a statistically significant reduction in neuropathic pain with a mean difference of -0,67 on a 0-10 pain scale compared to placebo.

Systematic review on cannabinoids in peripheral neuropathy; k=14 RCTs identified. 13/14 studies (79%) showed statistically significant pain reduction. Meta-analysis across 7 studies: mean difference -0.67 [95% CI -0.89, -0.45] on 0-10 scale vs. placebo (p<0.001). Additional improvements in sleep, sensory symptoms and quality of life.

Three of four RCTs showed statistically significant pain reduction with cannabinoids vs. placebo, however one study showed no superiority.

Systematic review on medical cannabis in diabetic peripheral neuropathy; k=4 RCTs included. 3 of 4 studies showed statistically significant pain reduction vs. placebo; THC doses ~16–18 mg/day (vaporized/sublingual) were associated with clinically relevant pain relief. Side effects (dizziness, cognitive symptoms) mostly mild-moderate.

15 of 22 RCTs showed significant pain reductions, 7 RCTs showed no significant benefit versus placebo.

Systematic review of k=22 RCTs (January 2003–December 2024) on cannabis-based medicines (CT-3, Δ⁹-THC, CBD, THC:CBD combinations, cannabidivarin) for neuropathic pain. 15 studies reported significant pain reduction in MS, spinal cord injury, diabetic neuropathy, postherpetic neuralgia, HIV-associated sensory neuropathy, peripheral neuropathic pain, CRPS, chronic radicular neuropathic pain, and peripheral neuropathy of the lower extremities (often with personalized dosing strategies). 7 RCTs showed no significant pain relief vs. placebo. Limitations: small sample sizes, high placebo response rates, trial unblinding due to psychoactive effects.

High evidence for cannabis benefit in MS spasticity and pain; low evidence for small effect in neuropathic pain; unclear evidence for nausea/vomiting in chemotherapy patients.

Systematic review on cannabis in MS, neuropathic pain and chemotherapy-induced nausea; k=41 RCTs (n=4.550), of which 12 studies on chronic neuropathic pain. Evidence for pain reduction in neuropathic pain; detailed effect sizes not stated in the abstract.

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

Rapid systematic review on cannabis for chronic pain; k=13 RCTs (n=1.352). 5 of 13 studies showed moderate analgesic effects, 8 no significant differences vs. control. Moderate pain reduction particularly in neuropathic pain conditions; relatively safe with few serious adverse events.

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.

SR + MA of k=11 RCTs (n=1.219; 614 cannabinoid group, 605 control) on selective cannabinoids (dronabinol, nabilone, nabiximols) for chronic neuropathic pain. Significant but clinically small pain reduction on NRS (0–10): -0.65 points (95% CI: -1.06 to -0.23, p=0.002, I²=60%, GRADE: weak recommendation, moderate quality of evidence). Improvements in quality of life and sleep, no serious adverse effects.

Double-blind, placebo-controlled crossover RCT with 38 patients with central and peripheral neuropathic pain. Smoked cannabis (high-dose 7%, low-dose 3,5% or placebo) showed a significant analgesic effect on pain intensity in the mixed linear model; no effect on evoked pain. Psychoactive side effects minimal and well tolerated, with acute cognitive effects (especially memory) at the higher dose. Caveat: small case number, acute short-term study.

Pregabalin showed efficacy against neuropathic pain, lidocaine effective in 2 of 3 studies, ketamine showed effectiveness (poor quality), cannabinoids ineffective; adverse effects were a frequent cause of discontinuation.

Systematic review + meta-analysis on pharmacotherapy of chronic spinal cord injury pain; k=21 studies for efficacy analysis, k=17 for adverse effects/discontinuation rates. Pregabalin effective for neuropathic pain (3/3 studies); cannabinoids ineffective for neuropathic pain (1 study, 28,6% discontinuation rate). Pregabalin: increased risk for somnolence (RR 3,15, 95% CI 2,00–4,98) and dizziness (RR 2,9, 95% CI 1,58–5,30).

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 on cannabis in chronic pain; inconsistent findings on efficacy for neuropathic pain (4 SRs with contradictory results) and painful spasms in multiple sclerosis (1 SR); insufficient evidence for rheumatic diseases (3 SRs) and tumor pain (2 SRs); inconsistent tolerability and safety data.

Gabapentin, duloxetine and tricyclic antidepressants are recommended as first-line treatment; specific efficacy values are not reported.

Brazilian Academy of Neurology consensus guideline on central neuropathic pain (CNP); based on SR/meta-analysis of 44 studies (20 analysed qualitatively, 15 quantitatively). Cannabidiol/delta-9-THC recommended as third-line therapy for refractory CNP (in combination with first-/second-line medications).

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; neuropathic pain was one of the primarily evaluated pain entities; nabilone achieved small but significant pain reductions; guidelines classify nabilone as third-line therapy.

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 (2007–2019); 92% are based on SR + expert consensus. All publications support cannabis as third-/fourth-line therapy for neuropathic pain, HIV-associated chronic pain and chronic abdominal pain — exclusively weak recommendations with detailed patient education on benefit-risk assessment.

THC/CBD spray showed statistically significant advantages in the 30% responder rate and in sleep quality as well as SGIC, but not in the primary endpoint of mean pain reduction on the NRS scale.

n=246 peripheral neuropathic pain with allodynia, THC/CBD spray vs. placebo over 15 weeks; 30% responder rate significantly increased (p=0.034, 95% CI 1.05–3.70), sleep quality improved (p=0.0072), mean NRS reduction numerically higher but not significant.

CBD, THC and their combination showed no significant pain reduction versus placebo in peripheral neuropathic pain.

n=115 (ITT) peripheral neuropathic pain patients (polyneuropathy, post-herpetic neuralgia, peripheral nerve injury), randomised to CBD (5–50 mg), THC (2.5–25 mg), CBD/THC combination or placebo over 8 weeks. None of the cannabinoid arms reduced pain vs. placebo (p=0.04–0.60); effect sizes week 8: CBD +1.14 NRS points (95% CI 0.11–2.19), THC +0.38 (-0.65 to 1.4), CBD/THC -0.12 (-1.13 to 0.89).

Transdermal THC:CBD:CBN reduces neuropathic pain in DPN significantly more than placebo (NPSI-T p<0,001).

n=100 diabetic peripheral neuropathy (DPN) of the lower extremities, 12-week study with transdermal cannabis formulation (THC:CBD:CBN) vs. placebo; mean NPSI-T scores decreased from 25.60 to 5.57 (intervention) vs. 25.24 to 22.85 (placebo), statistically significant at weeks 4, 8 and 12 (p<0.001). Only 10% mild side effects, comparable to placebo.

Dronabinol reduced pain intensity by 1,92 points, placebo by 1,81 points with no significant difference (p = 0,676).

Phase III RCT on dronabinol in MS-associated neuropathic pain (n=240); 16 weeks placebo-controlled + 32 weeks open-label (100 patients up to 119 weeks). Pain reduction dronabinol vs. placebo: -1,92 vs. -1,81 points (NRS-11), no significant difference (p=0.676). Adverse event rate dronabinol vs. placebo: 50,0% vs. 25,9%; decreased to 26% with long-term use. No substance abuse, one possible case of dependency.

Cannabis-based medicine was superior to placebo in reducing pain intensity (p = 0,005) and sleep disturbance (p = 0,003) in MS patients with central neuropathic pain.

n=66 MS patients with central neuropathic pain; THC:CBD oromucosal spray (CBM) vs. placebo over 4 weeks. Pain reduction: CBM −2,7 points (95% CI −3,4 to −2,0) vs. placebo −1,4 (p=0,005); reduction in sleep disturbance: CBM −2,5 vs. placebo −0,8 (p=0,003). CBM well tolerated; more frequent adverse effects: dizziness, dry mouth, somnolence.

Dronabinol showed a statistically significant reduction in spontaneous pain intensity versus placebo (median 4.0 vs. 5.0, P=0.02) with a clinically relevant analgesic effect, but with more frequent adverse effects.

n=24 MS patients with central neuropathic pain, dronabinol (max. 10 mg/day) vs. placebo over 3 weeks; median pain intensity significantly lower under dronabinol (NRS 4.0 vs. 5.0, p=0.02), median pain relief score higher (3.0 vs. 0, p=0.035), NNT=3.5 (95% CI 1.9–24.8) for 50% pain reduction. Adverse effects (particularly dizziness) more frequent in week 1 of treatment.

THC, CBD and their combination did not significantly reduce neuropathic pain or spasticity compared with placebo.

Randomised, double-blind, placebo-controlled 4-arm study (n=134; MS n=119, SCI n=15): THC, CBD, THC+CBD vs. placebo over 6 weeks in central neuropathic pain and/or spasticity. No significant difference in mean pain intensity score (THC: Δ0,42 [95% CI −0,54 to 1,38]; CBD: Δ0,45 [−0,47 to 1,38]; THC+CBD: Δ0,16 [−0,75 to 1,08]) compared with placebo. No effect could be demonstrated for spasticity and secondary outcomes either.

THC/CBD spray sustainably reduced neuropathic pain intensity and was well tolerated over 38 weeks without a tendency toward dose escalation.

n=380 patients with peripheral neuropathic nociception (diabetic neuropathy or allodynia), THC/CBD oromucosal spray as add-on, 38-week open-label extension study; pain NRS decreased from mean 6,9 (baseline of the parent studies) to 4,2 (study end); ≥30% pain reduction in >50% of all patients at all measurement time points; sleep quality NRS and EQ-5D improved; no new safety signals with 38-week treatment.

Smoked cannabis reduced daily pain by 34% vs. 17% with placebo (p=0,03) and showed greater pain reduction of >30% in 52% vs. 24% of the placebo group (p=0,04).

n=50 HIV-associated sensory neuropathy, smoked cannabis (3,56% THC) vs. placebo, significant pain reduction on 0-100 scale (mean difference -3.3 points, p=0.03), 52% responders with ≥30% pain reduction vs. 24% placebo, well tolerated.

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

n=48 patients with central neuropathic pain (brachial plexus avulsion), Sativex (THC:CBD 1:1) and THC extract vs. placebo (3×2-week crossover); primary endpoint (pain reduction >2 points) not achieved, however pain severity and sleep parameters showed statistically significant improvement under cannabinoid vs. placebo (p<0.05). Negative primary main hypothesis with positive secondary outcomes.

Vaporized cannabis showed significant analgesic effect for neuropathic pain after spinal cord injury, independent of psychoactive side effects.

n=42 neuropathic pain in spinal cord injury/disease, vaporized cannabis 2,9%/6,7% THC vs. placebo in 8-hour experiments; significant analgesic response in mixed-effects model (p<0,0004), pain reduction remained significant even after adjustment for psychoactive effects. No significant difference between the two active doses, lower dose offers better risk-benefit ratio.

Vaporized cannabis at low dose led to significant pain reduction in neuropathic pain with an NNT of 3,2 and minimal psychoactive effect.

n=39 central and peripheral neuropathic pain, vaporized cannabis 1,29%/3,53% THC vs. placebo; NNT=3,2 (placebo vs. low-dose) and NNT=2,9 (placebo vs. medium-dose) for 30% pain reduction, no significant difference between active doses (p>0,7). Psychoactive effects minimal and well tolerated, neuropsychological effects reversible within 1-2 hours.

Statistically significant reduction in intense pain, sharp pain, and cold and itching sensations in the CBD group compared to the placebo group.

n=29 peripheral neuropathy of the lower extremities, topical CBD oil 250mg/3fl.oz vs. placebo over 4 weeks; statistically significant reduction in intense pain, sharp pain, cold and itching sensations in the CBD group vs. placebo (p<0.05, exact values not given). No adverse events.

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 neuropathic pain after traumatic 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 of 2 points; sleep quality (VAS) significantly improved, mean difference +1,5 (99% CI 0,7–2,4; p<0,001); no significant difference in neuropathic pain (DN4, OR=1 [99% CI 0,07–14,1]; p>0,99). Study advises against addition to standard medication.

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

n=27 patients with neuropathic pain/CRPS; THC inhalation (0.5 mg, 1 mg) vs. placebo; dose-dependent, significant VAS pain reduction with both verum doses vs. baseline; 1-mg dose significant vs. placebo (p<0.05); Cmax THC 14.3 and 33.8 ng/ml; no cognitive impairment; adverse events mild.

Nabilone 1–4 mg/day reduced neuropathic pain in DPN responders significantly more than placebo (p=0,02).

n=26 randomized patients with refractory diabetic peripheral neuropathic pain (DPN; responder enrichment from n=37 run-in); nabilone 1–4 mg/day vs. placebo; mean pain reduction: −1,27 (95% CI −2,29 to −0,25, p=0,02); global improvement: 100% vs. 31% (p<0,05); sleep, anxiety (HADS) and quality of life (EQ-5D) also improved (each p<0,05).

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.

n=21 post-traumatic/postoperative neuropathic pain, smoked cannabis 9,4% THC vs. 0% (placebo) over 4×14-day cycles (cross-over). Primary endpoint: NRS difference 9,4% vs. 0% = 0,7 (95% CI 0,02–1,4, significant). Improved sleep (p<0,001 for faster falling asleep, p=0,01 for fewer nocturnal awakenings). Most common adverse effects: headache, dry eyes, dizziness, cough.

CT-3 significantly reduced chronic neuropathic pain compared to placebo (VAS, p=0,02).

n=21 patients with chronic neuropathic pain (≥6 months); CT-3 (synthetic cannabinoid, 40–80 mg/d) vs. placebo crossover. VAS difference 3 h after intake: CT-3/placebo sequence −11,54 vs. +9,86 (p=0,02). No serious adverse effects; transient dry mouth and fatigue more frequent under CT-3 (p=0,02). No dose-response effect observed.

AJA produced a significant reduction in pain on the VAS versus placebo without relevant psychotropic side effects.

n=21 patients with chronic neuropathic pain; Ajulemic Acid (synthetic cannabinoid) 40/80 mg vs. placebo, 7-day periods; VAS pain reduction significant (p<0.05); NNT for 30% pain reduction=2,14 (first treatment group), NNT=5,29 (second group); no significant reduction in mechanical hypersensitivity (p=0.052); side effects (dry mouth, fatigue, dizziness) without dose-escalation effect.

Inhaled THC significantly reduces diabetic neuropathy pain dose-dependently versus placebo, with cognitive impairment at high dose.

n=16 diabetic peripheral neuropathy, vaporized cannabis (1%/4%/7% THC vs. placebo), significant dose-dependent pain reduction on NRS at 4% THC (mean difference -1.60, p0.01) and 7% THC (mean difference -2.10, p0.01), no severe adverse effects.

Nabilone as add-on therapy to gabapentin showed a statistically significantly greater reduction in pain intensity (VASpain) and impact on daily activities (VASimpact) compared to placebo (both P < 0,01).

n=15 MS patients with neuropathic pain on gabapentin (≥1.800 mg/day), nabilone (1 mg 2×/day) as add-on vs. placebo over 9 weeks (4 weeks titration + 5 weeks maintenance); significantly greater decrease in VASpain (p<0.01) and VASimpact (p<0.01) with nabilone after adjustment for covariates. Nabilone well tolerated, most common side effects dizziness/drowsiness.

THC significantly reduced pain in patients with chronic neuropathic pain compared to placebo.

n=15 chronic radicular neuropathic pain, randomized double-blind placebo-controlled, sublingual THC. THC significantly reduced pain vs. placebo. fMRI analyses: THC analgesia correlated with reduced functional connectivity between ACC and sensorimotor cortex; graph theory analyses show reduced network connectivity in the DLPFC, correlated with individual pain reduction. Baseline connectivity predictive of THC responders.

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

n=12 male patients with chronic radicular neuropathic pain, oral THC 0,2 mg/kg sublingual vs. placebo; THC significantly reduced LF/HF ratio (F(1,11)=20,5; p<0,005) and improved CPM response (F(1,9)=5,2; p=0,048); THC-induced reduction of the LF/HF ratio correlated with increased functional connectivity between rostral ventrolateral medulla and dorsolateral prefrontal cortex (T(10)=6,4, cluster p-FDR<0,005).

Cannabis significantly worsened several endpoints compared to placebo: higher neuropathy ratings, lower functional wellbeing scores and worsened sleep and pain interference ratings.

Pilot RCT (n=12 women, 51±6 years) of oral cannabis (100 mg CBD : 5 mg THC, TID) vs. placebo in taxane-induced peripheral neuropathy (TIPN); 8 weeks, all participants completed. Pain, pain interference and sleep improved in both groups (p<0.03), but the cannabis group showed significantly higher neuropathy ratings (p<0.035), lower functional wellbeing in weeks 6–8 (p<0.02) and worsened sleep/pain interference ratings vs. placebo (p<0.05). No efficacy signal for cannabis.

Sativex led to a significantly greater reduction in pain intensity (−1,48 vs. −0,52 points, p=0,004) and improvements in allodynia, sleep and functionality compared to placebo.

RCT on oro-mucosal Sativex (THC:CBD) in peripheral neuropathic pain, n=125 (63 Sativex, 62 placebo), 5 weeks parallel design. Primary outcome: mean pain reduction (NRS 0-10) -1,48 points (Sativex) vs. -0,52 points (placebo), p=0,004 (95% CI: -1,59 to -0,32). Significant improvements also in Neuropathic Pain Scale (p=0,007), sleep NRS (p=0,001), dynamic allodynia (p=0,042), punctate allodynia (p=0,021) and Pain Disability Index (p=0,003). 18% discontinuation rate Sativex vs. 3% placebo. Open-label extension showed maintenance of pain relief over 52 weeks without dose increase.

Smoked cannabis reduced neuropathic pain in HIV patients significantly more than placebo.

Phase II crossover RCT on smoked cannabis in HIV-associated neuropathic pain (DSPN), n=28 completers (of 34 enrolled). Cannabis 1-8% THC vs. placebo, 4×daily for 5 days. Primary outcome (DDS pain intensity): median difference 3,3 points in favor of cannabis (effect size=0,60; p=0,016). 46% of the cannabis group achieved ≥30% pain reduction vs. 18% placebo (95% CI: 0,28-0,65 vs. 0,03-0,32). Two participants with treatment-limiting toxicity.

Nabilone was inferior to dihydrocodeine: the pain score was 6,0 mm higher under nabilone (worse pain relief), and nabilone caused more side effects.

n=96, double-blind crossover RCT (14 weeks, 3 UK centres); nabilone (max. 2 mg/d) vs. dihydrocodeine (max. 240 mg/d) in chronic neuropathic pain; mean VAS score 6,0 mm higher under nabilone (95% CI 1,4–10,5 mm; n=73 available-case); per-protocol analysis (n=64): 5,6 mm (95% CI 0,8–10,3 mm) — dihydrocodeine superior; side effects more frequent under nabilone.

Topical CBD cream showed no improvement in CIPN symptoms compared to placebo.

Pilot RCT (n=40, double-blind, crossover), topical CBD vs. placebo cream in established chemotherapy-related peripheral neuropathy (CIPN), 2×2 weeks: EORTC-CIPN20 scores comparable between CBD and placebo (no significant difference). Toxicity scores also similar. Negative result — topical CBD isolate did not improve CIPN symptoms; good tolerability.

CBDV led to no significant pain reduction and was not effective for HIV-associated neuropathic pain.

n=32 HIV-associated neuropathy patients, CBDV 400 mg/day vs. placebo (double-blind, crossover, 4 weeks each); primary endpoint pain intensity (NRS 0–10): CBDV 0,62 points higher than placebo (p=0,16, 95% CI −0,27 to 1,51); no significant effect on rescue medication, pain character or quality of life. Safety profile comparable under both treatments; no serious unexpected reactions. CBDV safe, but without clinically meaningful pain reduction.

Sativex showed no significantly greater pain reduction than placebo in diabetic neuropathy.

n=30 patients with painful diabetic peripheral neuropathy (DPN), Sativex vs. placebo (adjuvant, daily); improvement in pain scores in both groups, but no significant difference between groups (p>0.05). Negative finding: Sativex not more effective than placebo in DPN; depression identified as a significant confounder.

No significant overall effect, but clinically relevant pain reduction in a subset of responders (NNT=5).

n=16 patients with chemotherapy-induced neuropathic pain, nabiximols (oral mucosal spray) vs. placebo (crossover); primary endpoint (NRS-PI group difference) not significant; responder analysis: NNT=5, mean NRS-PI reduction −2,6 points under nabiximols vs. −0,6 under placebo; 5 of 16 participants with ≥2-point reduction.

Dronabinol showed no significantly greater pain relief than diphenhydramine in neuropathic pain after spinal cord injury.

n=7 patients with neuropathic pain below a spinal cord injury, dronabinol vs. diphenhydramine (active control), crossover design; no significant difference in pain reduction (dronabinol: +0,20 ± 0,84 VAS; diphenhydramine: -1,80 ± 2,49; Wilcoxon p=0,102). Negative finding with a very small sample.

Open-label, non-randomized comparative study of the cannabinoid nabilone (as monotherapy or add-on therapy) versus gabapentin in peripheral neuropathic pain. Over 6 months all treatment groups showed significant improvements in pain VAS as well as improvements in sleep, quality of life and pain parameters. Due to the open-label, non-randomized design, the evidential value is limited.

Nabiximols was significantly superior to dronabinol with regard to aggregated symptom reduction and tolerability in severe neuropathic pain disease.

German Pain e-Registry: n=674 patients with severe neuropathy (337 nabiximols vs. 337 dronabinol, propensity-matched); ASR-9 total score improvement 55.4% (NBX) vs. 40.5% (DRO), difference 14.0 (95% CI 12.6–15.4, p<0.001); ADR rate 21.1% vs. 35% (p<0.001); more NBX patients discontinued concomitant opioid medication (p<0.001) — NBX both non-inferior and superior to DRO.

Descriptive characterization: cannabis users (27% of the sample) were younger and reported higher pain intensity, higher pain interference and higher neuropathic pain scores than non-users; no intervention effect measured.

Observational study in n=242 MS patients with chronic pain; 27% (n=65) used cannabis for pain treatment. Most common form of administration: oil/tincture (42%), followed by vaping (22%) and edibles (17%). Cannabis users showed higher median pain intensity (6,0 vs. 5,0, p=0,022), higher pain interference (5,9 vs. 5,4, p=0,027) and more pronounced neuropathic pain (20,0 vs. 16,0, p=0,001) than non-users.

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.

JAMA Clinical Review on medical cannabis; k=6 RCTs (n=396) on neuropathic pain with positive results. High-quality evidence for efficacy in neuropathic pain, chronic pain and MS spasticity.

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.