Category Archives: Pain

Therapeutic potential of endocannabinoid system activation in opioid use disorder and pain

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“Introduction: Opioid use disorder (OUD) and chronic pain remain major global health challenges. Although opioid-based therapies provide effective analgesia, their long-term use is limited by safety concerns, dependence, and variable efficacy. Modulation of the endocannabinoid system (ECS) has emerged as a promising therapeutic strategy for pain management and opioid-related disorders.

Areas covered: This narrative review summarizes current evidence on ECS-targeted interventions for OUD, chronic non-cancer pain, and cancer-related pain. Relevant literature was identified through PubMed using search terms related to the ECS, cannabinoid receptors (CB1 and CB2), phytocannabinoids (Δ9 -tetrahydrocannabinol [THC] and cannabidiol [CBD]), synthetic cannabinoids, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibitors, and opioid – cannabinoid interactions. Particular emphasis is placed on mechanistic interactions between ECS and opioid signaling pathways, as well as evidence from preclinical and clinical studies evaluating therapeutic efficacy and safety.

Expert opinion: ECS modulation may alleviate pain, reduce opioid withdrawal symptoms, and improve affective outcomes. Interactions between cannabinoid and opioid receptors may produce synergistic analgesic effects while potentially mitigating opioid tolerance and dependence. However, clinical translation remains limited by small sample sizes, heterogeneous study populations, and variability in trial design. Well-controlled clinical trials are needed to establish optimal dosing strategies, evaluate long-term safety, and clarify the therapeutic role of ECS-targeted interventions in OUD and pain management.”

https://pubmed.ncbi.nlm.nih.gov/42295097

“The endocannabinoid system (ECS) represents a promising therapeutic target for opioid use disorder (OUD), chronic non-cancer pain, and cancer-related pain.”

“Cannabinoids (e.g., CBD and Δ9 -THC) exert analgesic and anti-inflammatory effects through CB1-mediated central mechanisms and CB2-mediated peripheral mechanisms.”

https://www.tandfonline.com/doi/full/10.1080/14728222.2026.2690138

Targeting Phantom Limb Pain with Cannabinoids in a Rat Model

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“Introduction: Phantom limb pain (PLP) is a debilitating neuropathic condition arising after limb loss or nerve injury, with limited effective treatments. Cannabinoids, including cannabidiol (CBD), β-caryophyllene (BCP), and Δ9-tetrahydrocannabinol (THC), possess analgesic and anti-inflammatory properties. This study evaluated their combined efficacy as preventive or delayed interventions in a rodent model of PLP.

Methods: To model PLP, a chronic constriction injury was used to mimic pre-amputation pain, followed by formalin-induced localized inflammation and complete sciatic nerve transection to simulate extremity amputation. Cannabinoid treatments (CBD/BCP/THC, CBD/BCP, or THC) or vehicle control were administered either preemptively on the day of axotomy (prevention paradigm) or after the emergence of pain behaviors (reversal paradigm). Progression of pain behaviors were assessed over a 72-day period, and modulation of spinal cytokine levels, glial reactivity, and GABAergic signaling was evaluated.

Results: Preemptive THC or CBD/BCP reduced PLP onset and severity, while the full combination was less effective. In contrast, with delayed treatment, CBD/BCP and the CBD/BCP/THC combination were most effective in mitigating PLP. Pain reduction was correlated with restoration of spinal GABAergic inhibition. All cannabinoid treatments decreased microglial and astrocyte reactivity and shifted cytokines toward an anti-inflammatory state.

Conclusion: Cannabinoid-based interventions demonstrate significant therapeutic promise for PLP, showing efficacy as both early and delayed treatments. Findings suggest that THC may exert greater therapeutic effects when administered pre-emptively, while CBD and BCP may offer greater therapeutic advantages in established pain states. These findings highlight the therapeutic potential of tailored cannabinoid interventions for neuropathic pain and underscore the importance of optimizing dosing strategies for maximal analgesic effect.”

https://pubmed.ncbi.nlm.nih.gov/42267080

“Cannabis contains a complex mixture of cannabinoids, terpenes, and flavonoids that have demonstrated therapeutic potential in a variety of pathologies and conditions. Their anti-inflammatory, analgesic, and antioxidant activities are believed to play a central role in mediating pain relief.”

“Our findings support the therapeutic potential of cannabinoid-based treatments in both preventing and reversing PLP, with efficacy varying by cannabinoid pairing and timing of treatment.

Together, these results underscore the therapeutic promise of cannabinoid-based treatments while highlighting the need to carefully consider how specific compounds and dosing strategies interact in different stages of pain.”

https://karger.com/mca/article/9/1/92/946968/Targeting-Phantom-Limb-Pain-with-Cannabinoids-in-a

High-dose cannabidiol for chronic neuropathic pain associated with spinal cord injury: a randomised clinical trial

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“Background: Chronic neuropathic pain is common after spinal cord injury (SCI), yet current treatments have limited efficacy and significant side effects. Cannabidiol (CBD), a non-intoxicating component of cannabis, has demonstrated efficacy in preclinical neuropathic pain models. Here, we investigated the effect of high-dose (up to 800 mg/day) CBD on chronic neuropathic pain in SCI.

Methods: This randomised, double-blinded, placebo-controlled, crossover clinical trial was conducted at Neuroscience Research Australia. Adults with SCI and neuropathic pain (≥three months duration) were recruited. Participants were randomised to one of two treatment orders by an unblinded investigator who had no participant contact. Participants and all other investigators were blinded. Participants consumed oral CBD and placebo over two six-week treatment periods separated by a four-week washout. Treatment was titrated up to 800 mg/day of CBD over two-weeks. The primary outcome was change in self-reported pain intensity on a zero (no pain) to ten (worst pain imaginable) Visual Analogue Scale. Statistical comparisons included CBD versus placebo treatment, and pre-treatment (inactive phase) versus on-treatment (active phase). Outcomes were analysed by modified intention-to-treat. The study is registered with anzctr.org.au, ACTRN12622000634774 (not recruiting).

Findings: Forty participants were randomised (August 1, 2022 to December 16, 2024) and 38 included in the primary analysis (n = 6 female). A significant treatment by phase interaction effect (p < 0.001) was observed on self-reported pain. Pairwise comparison showed lower pain intensity during the active phase with CBD (mean ± SEM: 3.82 ± 0.23) compared to placebo (mean difference = -0.54, SEM = 0.15, p < 0.001), with a 95% confidence interval for the difference of -0.88 to -0.21. Treatments did not differ during the inactive phase (mean difference <0.01, SEM = 0.17, p = 1.00, 95% CI = -0.38 to 0.38). Adverse events, nearly all minor, were reported by 68.4% of participants during CBD (n = 67 events), and by 52.6% during placebo (n = 51 events) treatment.

Interpretation: In this placebo-controlled trial, CBD significantly reduced the self-reported intensity of neuropathic pain and was generally well-tolerated. While modest in magnitude, the observed effect supports further research into high-dose CBD for chronic neuropathic pain.”

https://pubmed.ncbi.nlm.nih.gov/42256679

“This trial provides evidence that high-dose CBD is safe and effective in treating chronic neuropathic pain following SCI. Additionally, the study provides initial evidence of a subgroup effect, whereby CBD is more effective in some individuals than others: this also warrants further exploration.”

https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(26)00234-8/fulltext

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

Evaluation of Dronabinol to Decrease Opioid Use for Cancer-Induced Bone Pain

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“Background: Bone metastases (BM) from breast cancer cause significant cancer-induced bone pain (CIBP). Management of CIBP is primarily with opioids, which have notable side effects. In preclinical models, cannabinoid receptor (CB)2 and CB1 agonists were shown to decrease CIBP and bone degradation. We hypothesized that the addition of CB2/CB1 agonists would decrease opioid requirements in patients with BM.

Methods: We conducted a single-arm study among breast cancer patients with BM on opioid therapy. Patients were treated with 10 mg dronabinol BID for 8 weeks. Our primary objective was to determine the proportion who decreased their opioid use by ≥ 20%. Participants completed the Brief Pain Inventory and the European Organization for Research and Treatment of Cancer quality of life questionnaires before and after treatment. Pre- and post-treatment blood and urine were collected for analysis of biomarkers of bone remodeling.

Results: We enrolled 14 evaluable patients, and 4 decreased opioid use by ≥ 20%, meeting the primary endpoint. Patients reported significant improvements in pain severity, interference scores, quality of life, and insomnia. There was one grade 3 adverse event (dizziness) related to the study drug. A significant decrease was noted in serum C-terminal telopeptide levels with therapy.

Conclusion: Our pilot study shows that the addition of dronabinol resulted in decreased opioid requirements for CIBP. Patient-reported outcomes also demonstrated improved pain and QOL with addition of dronabinol. Our results are promising and warrant further investigation into novel analgesics for CIBP to decrease opioid use.”

https://pubmed.ncbi.nlm.nih.gov/42050177

https://academic.oup.com/oncolo/advance-article/doi/10.1093/oncolo/oyag163/8664403

“Dronabinol, sold under the brand names Marinol and Syndros, is the generic name for the molecule of (−)-trans-Δ9-tetrahydrocannabinol (THC) in the pharmaceutical context. It has indications as an appetite stimulant and antiemetic and is approved by the US Food and Drug Administration (FDA) as safe and effective for HIV/AIDS-induced anorexia and chemotherapy-induced nausea and vomiting.”