Category Archives: Chronic Pain

UK Medical Cannabis Registry: an updated analysis of clinical outcomes of medicinal cannabis therapy for hypermobility-associated chronic pain

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“Introduction/objective: The primary aim of this study was to evaluate changes in pain-specific and general health-related quality of life in individuals prescribed cannabis-based medicinal products (CBMPs) for hypermobility-associated chronic pain.

Methods: The case series utilised data from the UK Medical Cannabis Registry. Primary outcomes were changes in Brief Pain Inventory (BPI), Pain Visual Analogue Scale (VAS), Short-Form McGill Pain Questionnaire-2 (SF-MPQ-2), EQ-5D-5L index value, Generalised Anxiety Disorder-7 (GAD-7), and Single-item Sleep Quality Scale (SQS) over 24 months. Repeated measures analysis of variance was used to assess changes over time, with post hoc pairwise comparisons performed for significant findings.

Results: A total of 240 patients were analysed. Changes were observed across all patient-reported outcome measures (PROMs) on repeated measures analysis of variance (p < 0.001). Post hoc pairwise comparisons for the BPI subscales, SF-MPQ-2 and Pain VAS demonstrated improvement from baseline to all subsequent timepoints (p < 0.001). By 24 months, 56.67% (n = 136) and 61.25% (n = 147) of participants reported clinically significant improvements in BPI severity and interference respectively. Clinically significant improvements were also reported for SF-MPQ-2 (47.08%, n = 113) and Pain VAS scores (60.00%, n = 144).

Conclusion: In this real-world cohort, CBMP treatment was associated with sustained improvements in outcomes for individuals with hypermobility-associated chronic pain. These findings support the need for further controlled studies to determine causality.

Key Points • This 24-month real-world study demonstrates sustained improvements in pain, anxiety, and sleep outcomes for patients with hypermobility-associated chronic pain treated with cannabis-based medicinal products, with approximately 60% achieving clinically meaningful pain reductions.

• Cannabis-based medicinal products were associated with reductions in concomitant opioid prescriptions at 12, 18, and 24 months.

• This represents the largest and longest-duration observational study of medical cannabis therapy specifically in hypermobility spectrum disorders and Ehlers-Danlos syndrome, addressing a critical evidence gap in chronic pain management.

• Adverse events were predominantly mild-to-moderate in severity, with poor baseline sleep quality and current cannabis use identified as positive predictors of pain improvement, informing patient selection and treatment optimisation.”

https://pubmed.ncbi.nlm.nih.gov/42217098

“This study provides a 24-month real-world evaluation of CBMPs in patients with hypermobility-associated chronic pain. It demonstrates long-term sustained improvement in pain, anxiety and sleep-related outcomes, underpinning health-related quality of life. Despite its observational design, the study provides important insight into potentially addressing an area of significantly unmet therapeutic need.”

https://link.springer.com/article/10.1007/s10067-026-08166-z

Selective opioid-sparing effects of cannabidiol on opioid analgesia in rats

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“Cannabidiol, a major non-psychoactive constituent of cannabis, has generated interest as a novel therapeutic for managing several pathological conditions including chronic pain and opioid use disorder.

Here, we evaluated the effects of cannabidiol (3.2 or 10.0 mg/kg) on the antinociceptive and the reward-related effects of the opioid analgesic oxycodone (0.56 mg/kg) in rats (male and female Sprague-Dawley) using an operant facial pain assay, locomotor activity monitoring, and the conditioned place preference paradigm.

Cannabidiol enhanced the antinociceptive effect of oxycodone without affecting oxycodone-induced rearing behavior, or the acquisition and expression of oxycodone conditioned place preference under the conditions tested.

Together, these findings suggest that cannabidiol potentiates the analgesic effects of oxycodone without affecting its reward-related properties. These results support the potential of cannabidiol as an adjunctive, opioid-sparing agent in pain management.

PERSPECTIVE: Opioids remain important for treating moderate to severe pain, but adverse effects and misuse liability limit their use. These preclinical findings suggest cannabidiol may enhance oxycodone antinociception under acute painful conditions, without increasing abuse-relevant effects under the conditions tested, supporting further study as an opioid-sparing adjunct.”

https://pubmed.ncbi.nlm.nih.gov/42219047

https://www.jpain.org/article/S1526-5900(26)00156-2/abstract

Endocannabinoid system modulation in acute, chronic, and neuropathic pain: reviewing experimental models, clinical evidence, and nanotechnology delivery

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“Chronic pain is highly prevalent and inadequately managed by current therapeutic strategies, which present significant limitations such as the development of tolerance, dependence, and cognitive impairment. Therefore, searching for new pain management strategies is an ultimate goal.

The endocannabinoid system (ECS), is a broad crucial regulatory network in central nervous system’s development and in modulating various physiological and cognitive functions. It comprises endogenous cannabinoids, cannabinoid receptors, and the enzymes governing cannabinoid production and breakdown.

Recently, cannabinoids, particularly medical cannabis, have garnered renewed interest for their possibilities in treating different medical conditions, including chronic pain.

Although the risk of lethal overdose is negligible, the prevalence of non-serious adverse effects is significant and requires careful clinical consideration. Currently, there is a paucity of sufficient efficacy and long-term safety data to fully support the systematic use of medical cannabis for chronic non-malignant pain conditions.

Further research is crucial to unlock the future potential of these approaches and to delineate essential directions for exploring the ECS and its role in pain management. Advances in nanotechnology have enabled novel delivery platforms that address key limitations of cannabinoid-based therapies.

Nanocarriers, including lipid and polymeric nanoparticles, nanoemulsions, and self-emulsifying systems, can improve cannabinoid solubility, stability, bioavailability, and targeted delivery. Through controlled release and site-specific targeting, these systems hold promise for enhancing the analgesic efficacy and safety of cannabinoid therapeutics.”

https://pubmed.ncbi.nlm.nih.gov/42154330

https://link.springer.com/article/10.1007/s11011-026-01862-4

Medical Cannabis as an Opiate Alternative: A Prospective Observational Cohort Study

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“Opioid use for chronic pain has contributed to an epidemic of overdoses and deaths in the United States.

Some clinical studies suggest that medical cannabis may help alleviate pain and improve quality of life. However, cost can be a barrier to patients accessing medical cannabis.

This is the first prospective observational study evaluating medical cannabis as an alternative to opioids in a setting where cost was removed as a major barrier.

Methods: Twenty-nine patients were recruited from a university-based outpatient chronic pain clinic. Each patient underwent monthly pain assessments using the Numeric Pain Rating Scale (NRS). Daily opioid use, measured in morphine milligram equivalents (MMEs), was recorded and monitored over five months. Pain-related quality of life was assessed using the SF-36 Health Survey at baseline, and again at two and five months.

Results: Daily opioid use decreased from baseline to one month (from 46.8 MMEs to 16.2 MMEs, a 65% reduction), and this reduction was maintained through five months. The mean NRS score decreased by two points from baseline to one month (from 7.03 to 5.07; p < 0.0001), and this improvement was sustained at five months. The SF-36 Physical Functioning score increased from 15.3 at baseline to 21.4 at one month and was maintained at five months (p < 0.03 for both comparisons).

Conclusion: These results suggest that medical cannabis may be a useful adjunct therapy for reducing opioid use, relieving chronic pain, and improving health-related quality of life.”

https://pubmed.ncbi.nlm.nih.gov/42153072

“Opioids are associated with serious adverse events, including death, particularly at higher dosages or when used in combination with benzodiazepines.

In contrast, medical cannabis has not been associated with mortality from overdose. When used under appropriate medical supervision, medical cannabis may represent an effective adjunctive strategy for reducing opioid use among patients receiving long-term opioid therapy.

“Although cannabis has historically been characterized as a potential “gateway drug,” it may also serve as a harm-reduction tool for some patients seeking to reduce reliance on higher-risk opioid medications.”

https://www.cureus.com/articles/432327-medical-cannabis-as-an-opiate-alternative-a-prospective-observational-cohort-study#!

Effect of cannabidiol, cannabinol and tetrahydrocannabivarin in managing inflammatory pain

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“Current medications used to treat the inflammatory pain either have limited effectiveness or may be associated with serious side effects. Non-psychoactive phytocannabinoids may have a better safety profile and could be used as an alternative approach to treat this condition.

The aim of this study was to test the potential of three phytocannabinoids, cannabinol (CBN), tetrahydrocannabivarin (THCV) and cannabidiol (CBD), in treating inflammatory pain.

The inflammatory pain was triggered in male rats by a single intra-articular knee injection of the complete Freund’s adjuvant (CFA). One week later, rats were given four daily administrations of ibuprofen, CBN, THCV or CBD. Our data demonstrated that CFA injection triggered an inflammatory response expressed as damage of the synovial tissue, reduced locomotor activity, increased mechanical and, to a lesser extent, thermal pain sensitivity, and loss of body weight.

All phytocannabinoids reduced mechanical hyperalgesia and had no or a minor effect on locomotor activity.

Treatment with CBN also lowered thermal hypersensitivity. Treatment with CBN and THCV recovered the body weight of CFA-injected rats. However, administration of CBD reduced body weight and elevated blood monocyte and granulocyte levels above those of the CFA-injected control animal group.

We conclude that CBN and THCV may have potential in managing inflammatory pain.”

https://pubmed.ncbi.nlm.nih.gov/42151379

https://www.nature.com/articles/s41598-026-51275-7

Assessing the Efficacy of Cannabinoid Compositions for Treating 3 Classes of Chronic Pain: A Real-World Evidence Study

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“Purpose: Cannabis has been determined to be effective at treating chronic pain, although research on the effects of specific cannabinoids, especially for different mechanisms of chronic pain, is limited. This study examined therapeutic efficacy for combinations of intoxicating and nonintoxicating cannabinoids for symptoms of 3 different types of chronic pain conditions.

Methods: We recruited adult California residents diagnosed with fibromyalgia (n = 64), rheumatoid arthritis (n = 25), and osteoarthritis of the knee and/or hip (n = 75). Participants in each group were randomly assigned to receive a 12-week supply of oral capsules with 3 different cannabinoid compositions: product 1-12.5 mg cannabidiol (CBD) and 12.5 mg tetrahydrocannabinol (n = 45); product 2-10 mg tetrahydrocannabinolic acid, 10 mg cannabidiolic acid (CBDa), 5 mg cannabigerol, and 3 mg cannabichromene (n = 57); and product 3-10 mg CBD and 10 mg CBDa (n = 62). Participants completed validated self-report questionnaires assessing pain characteristics, mental health and cognitive functioning, and physical functioning at baseline and 12-week timepoints.

Findings: Of 276 individuals recruited, 168 (60.9%) completed all survey questionnaires. Four individuals who completed the questionnaires but discontinued study product use were removed from the dataset. Per-protocol analyses identified significant improvements across all symptoms except cognitive function abilities. Effects ranged from small to large; most did not differ in magnitude across product or type of chronic pain. Products differed in effectiveness for sleep disturbance, and participants taking product 2 reported reductions in neuropathic pain intensity.

Implications: These findings suggest that various cannabinoid combinations may have beneficial effects across 3 different types of chronic pain. Nonintoxicating cannabinoids such as CBD and CBDa may provide relief from pain and related symptoms and may be utilized when cannabis intoxication is undesirable or problematic.”

https://pubmed.ncbi.nlm.nih.gov/42140793

“Various cannabinoid combinations may have therapeutic benefits across 3 different types of chronic pain.”

https://www.clinicaltherapeutics.com/article/S0149-2918(26)00136-0/abstract

The greater the pleiotropic effects, the greater the benefits – cannabis as a “biopsychosocial” drug: a mixed-methods study on chronic non-cancer pain

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“Background: Against the background of widely inconsistent data from randomized controlled trials (RCT), the use of cannabis-based medicines (CBM) from the perspective of patients with chronic non-cancer pain (CNCP) was described.

Methods: Based on a purposive/convenient sampling, patients were recruited from the Pain Clinic of Hannover Medical School who had been using CBM prescribed by a doctor for at least 6 months. The patients discussed their experiences with CBM in semi-structured individual interviews. The interview transcripts were coded and analyzed using a modified grounded theory approach with the help of MAXQDA®. In addition, the Treatment Satisfaction Questionnaire with Medication (TSQM) was used.

Results: Theoretical saturation was reached after 32 interviews. Open and selective coding revealed the overarching phenomenon of “subjective pain experience under CBM therapy”, with one of the main themes being the “effect of CBM”. This revealed the categories “effect on pain” and “psychological” and “somatic effect”. The most important concepts were “pain intensity”, “pain management”, “stress management”, “musculoskeletal system”, and “sleep quality.” Constructing a theoretical framework 4 groups of responses to CBM treatment were identified. The focus is either on (I) pain reduction, (II) pain coping, (III) reduced stress or (IV) multidimensional aspects. When this classification was applied to topic of quality of life (QOL), the greatest effectiveness and highest overall satisfaction were found in group (IV). Mixed methods showed a continuous increase in the perceived effectiveness of CBM on pain-centered complaints from group (I) to (IV).

Conclusions: In line with the biopsychosocial understanding of chronic pain, it appears that those CNCP patients who benefit most from CBM are those who show the most far-reaching effects on both a physical and psychological level. The pleiotropic effects of CBM may be responsible for this. Based on these results, interdisciplinary prospective research appears sensible and necessary to further and systematically investigate this clinically relevant topic.”

https://pubmed.ncbi.nlm.nih.gov/42015327

https://link.springer.com/article/10.1186/s42238-026-00440-w

Electrophysiological modulation of pain‑related sodium channels by cannabinoids: a systematic review

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“Voltage-gated sodium channels regulate dorsal root ganglion excitability and are critical for nociceptive transmission. Cannabidiol (CBD) and related phytocannabinoids have been proposed to modulate these channels, offering potential non-opioid analgesic strategies. This systematic review evaluated their in vitro effects on pain-related sodium channels, focusing on electrophysiological and biophysical mechanisms.

Following PRISMA guidelines, Embase®, LILACS®, PubMed®/MEDLINE®, and Scopus® were searched using the SPIDER strategy. Eligible studies evaluated CBD or its derivatives on voltage-gated sodium channels Nav1.3, Nav1.6, Nav1.7, Nav1.8, and Nav1.9 through electrophysiological assays. Data extraction and analysis were conducted independently by two reviewers, with inter-rater agreement assessed by Cohen’s kappa. Seven studies met the inclusion criteria.

CBD consistently inhibited sodium currents with IC₅₀ values in the low micromolar range (2–3.3 µM), reduced action potential firing, induced hyperpolarizing shifts in steady-state inactivation, and delayed recovery from inactivation. Other phytocannabinoids, such as cannabigerol, cannabinol, cannabigerolic acid, and cannabidivarinic acid, also inhibited sodium channels, though with variable potency and distinct effects on channel gating.

Cannabinoids, particularly CBD, act as non-selective inhibitors of voltage-gated sodium channels implicated in pain signaling. Their ability to stabilize inactivated channel states and reduce neuronal excitability supports their therapeutic potential in neuropathic pain. These findings highlight the relevance of phytocannabinoids as promising candidates for the development of non-opioid analgesics.”

https://pubmed.ncbi.nlm.nih.gov/41987259

https://link.springer.com/article/10.1186/s42238-026-00436-6





Peripheral Cannabinoid Receptor Activation Attenuates Frostbite-Induced Chronic Pain via Modulation of TRP Channels, Neuroinflammation, and Autophagy

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“Frostbite injury is a debilitating cold injury encountered in extreme high-altitude and subzero environments, frequently resulting in persistent chronic pain even after tissue healing. Using our previously validated frostbite-induced chronic pain model, we further investigated the contribution of neuroimmune, excitatory mechanisms and evaluated the therapeutic efficacy of peripheral cannabinoid receptor activation.

Frostbite produced significant mechanical allodynia, mechanical hyperalgesia, and cold hypersensitivity, along with increased spontaneous nocifensive behaviors.

Local peripheral administration of CB13, a peripherally acting CB1/CB2 receptor dual agonist, dose-dependently attenuated both mechanical and cold allodynia without impairing locomotor activity, indicating a lack of central nervous system side effects.

At the molecular level, frostbite induced marked peripheral and spinal sensitization, demonstrated by elevated expression of TRPV1, TRPA1, TRPV4, and TRPM8 channels, increased levels of pro-inflammatory cytokines, and enhanced c-Fos expression as an indicator of heightened neuronal activation in pain-relevant regions. These alterations were accompanied by pronounced microglial activation and upregulation of the NLRP3 inflammasome.

CB13 treatment significantly reversed these pathological changes and concurrently restored Beclin-1-associated autophagy signaling, suggesting engagement of both neuroimmune resolution and intracellular homeostasis pathways. Notably, frostbite injury was associated with marked oxidative and nitrosative stress in the sciatic nerve, as evidenced by reduced glutathione depletion and elevated lipid peroxidation and nitrite levels, which were significantly normalized by CB13 treatment.

Collectively, these findings demonstrate that peripheral cannabinoid receptor activation effectively inhibit frostbite induced chronic pain through modulation of nociceptive, neuroinflammatory, redox, and cellular stress pathways.

This work highlights peripherally selective cannabinoid receptor agonists as promising, safer therapeutic strategies for chronic pain associated with cold injuries.”

https://pubmed.ncbi.nlm.nih.gov/41802611

“This study demonstrates that peripheral cannabinoid receptor activation via CB13 effectively alleviates frostbite-induced chronic pain by targeting multiple pathological mechanisms, including nociceptor hyperexcitability, spinal neuronal activation, neuroinflammation, inflammasome signaling, oxidative stress, and impaired autophagy.”

https://www.sciencedirect.com/science/article/abs/pii/S0891584926001565?via%3Dihub

Effect of Δ9-tetrahydrocannabinol and cannabidiol on myofascial pain modulation in patients with temporomandibular disorder: a prospective crossover study

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“Background: Temporomandibular Disorder (TMD) often causes chronic orofacial pain and functional limitations, with conventional treatments providing suboptimal results. Phytocannabinoids such as Δ9-Tetrahydrocannabinol (Δ9-THC) and Cannabidiol (CBD) have analgesic and anti-inflammatory properties, but evidence in TMD is scarce.

Objective: To evaluate the efficacy of Δ9-THC/CBD therapy in reducing pain and improving mandibular function in TMD patients.

Methods: Twenty adults with chronic myofascial pain (DC/TMD diagnosis) participated in a blinded, crossover, non-randomized study. Participants underwent two consecutive 90-day phases: placebo followed by Δ9-THC/CBD therapy (1:1 ratio, starting with a dose of 2 mg/day in the first week, gradually adjusting an increase of 2 mg/week until reaching 10 mg/day in the fifth week, sublingually), without washout. Outcomes included pain intensity (VAS), muscle sensitivity (algometry), mandibular function (mouth opening, protrusion, laterality) and pain sensitivity (allodynia/hyperalgesia). Data were analyzed using linear mixed models for repeated measures.

Results: Δ9-THC/CBD improved all outcomes versus baseline and post-placebo (p < 0.001; Cohen’s d > 0.8). Mouth opening increased from 45.9 mm to 49.9 mm; VAS pain decreased from 7.35 to 3.50. Functional pain dropped by ∼90%, with near elimination of allodynia and hyperalgesia. Placebo effects were minimal.

Conclusion: Δ9-THC/CBD therapy provided substantial analgesic and functional benefits in TMD patients, supporting its potential as a therapeutic alternative. Larger randomized studies are recommended to validate these findings and explore underlying mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/41740529

“Cannabinoid therapy was effective in reducing painful symptoms in TMD patients, associated with relevant functional improvements in mandibular opening, protrusion, and laterality compared to placebo.”

https://www.sciencedirect.com/science/article/pii/S1807593226000268?via%3Dihub