Category Archives: Neuropathic Pain

Moroccan Cannabis sativa essential oil attenuates peripheral neuropathic pain induced by chronic sciatic nerve constriction injury in mice

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“Ethnopharmacological relevance: Cannabis sativa has been widely used in traditional medicine for its therapeutic properties. However, in Morocco, the ethnobotanical applications of Cannabis sativa, especially its essential oils, are underexplored. This study investigates, for the first time, the effects of Moroccan Cannabis sativa essential oil on peripheral neuropathic pain.

Materials and methods: Peripheral neuropathic pain was induced in mice through sciatic nerve injury. The mice were treated daily with cannabis essential oil for 21 days. Behavioral tests were conducted on days 1, 7, 14, and 21 to evaluate thermal, mechanical, and cold sensitivity. The essential oil’s chemical composition was analyzed using gas chromatography-mass spectrometry (GC/MS).

Results: The main constituents of the essential oil were (E)-caryophyllene (41.59%) and α-humulene (14%). Daily treatment with the essential oil significantly reduced pain sensitivity and improved functional and histological recovery over time. These effects are linked to the activity of the dominant terpenoids in the oil.

Conclusion: Moroccan Cannabis sativa essential oil shows significant therapeutic potential for managing peripheral neuropathic pain. By enhancing recovery and alleviating pain symptoms, it offers a promising alternative for treating chronic pain caused by nerve injuries.”

https://pubmed.ncbi.nlm.nih.gov/39947371/

“A multitude of recent studies have explored the broad biological properties of cannabis. Extracts from Cannabis sativa have demonstrated antimicrobial, anti-inflammatory, antinociceptive, and potent antioxidant activities.”

“This study examined the analgesic effects of terpenes found in Cannabis sativa essential oil on neuropathy. The results showed that chronic administration of these bioactive terpenes, specifically β-caryophyllene, α-humulene, and caryophyllene oxide, significantly increased pain sensitivity and response time in mice with neuropathy. Although morphine and THC-based treatments are commonly used to relieve neuropathic pain, these terpenes may offer a promising alternative with limited side effects. Clinical research has demonstrated the efficacy of cannabis-based treatments, leading several pain societies to recommend them for neuropathy management. “

https://www.sciencedirect.com/science/article/pii/S0378874125001692?via%3Dihub

The cannabinoid CB2 receptor mediates the analgesic effects of Cannabis sativa extract in a rat model of neuropathic pain

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“Neuropathic pain (NP) is a complex and debilitating condition that is often refractory to currently available analgesic medications.

Cannabis sativa extract (CSE) has been reported to exhibit analgesic properties across various pain models; however, the underlying mechanisms of action are not fully understood.

This study aimed to investigate the involvement of the cannabinoid CB2 receptor in mediating the analgesic effects of CSE in a rat model of NP, where NP was induced in male Wistar rats through chronic constriction injury (CCI) of the sciatic nerve.

Rats were randomly allocated into four groups: (1) Sham + vehicle, (2) CCI + vehicle, (3) CCI + CSE, and (4) CCI + CSE + AM630 (a CB2 receptor antagonist). CSE was administered intraperitoneally at a dosage of 30mg/kg once daily for 7 days, starting from day 7 to day 13 post-CCI surgery. To assess the involvement of the CB2 receptor, 7µg of AM630 was administered intrathecally to the rats in group 4, 30minutes before the CSE injections. Mechanical allodynia and thermal hyperalgesia were assessed using the von Frey filament and hot plate tests, respectively, at baseline (day 0) and on days 3, 7, 10, and 14 after surgery. Additionally, at the end of the study period (day 14), the expression level of Iba1 and GFAP genes was quantified in the lumbar enlargement tissues using real-time PCR.

The results demonstrated that CCI surgery induced mechanical allodynia and thermal hyperalgesia, along with the upregulation of Iba1 and GFAP genes in the vehicle-treated CCI group. Treatment with CSE significantly mitigated both allodynia and hyperalgesia and downregulated the expression of Iba1 and GFAP genes compared to the CCI + vehicle group. Furthermore, the administration of the CB2 receptor antagonist AM630 not only robustly blocked the antinociceptive effects of CSE but also reversed the significant downregulation of Iba1 and GFAP gene expression in the lumbar enlargement tissues.

These findings highlight the novel role of the CB2 receptor in mediating the analgesic effects of CSE, providing new insights into the potential therapeutic mechanisms of CSE in neuropathic pain management.”

https://pubmed.ncbi.nlm.nih.gov/39947333/

“In summary, this study provides evidence that CSE exerts analgesic and anti-inflammatory effects in NP through CB2 receptor activation. These findings contribute to the growing body of research supporting cannabinoids as potential therapeutic agents for NP management.”

https://www.sciencedirect.com/science/article/abs/pii/S0166432825000683?via%3Dihub

Efficacy and Safety of Transdermal Medical Cannabis (THC:CBD:CBN formula) to Treat Painful Diabetic Peripheral Neuropathy of Lower Extremities

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“Introduction: Diabetic peripheral neuropathy (DPN) represents a prevalent neurological complication affecting millions of patients globally. This clinical investigation evaluated the therapeutic efficacy and safety profile of a novel transdermal medical cannabis formulation (THC:CBD:CBN) in treating painful DPN of the lower extremities.

Methods: This phase III, double-blind, placebo-controlled, randomized clinical trial was conducted at Don Chan Hospital, Thailand, enrolling 100 participants over a 12-week intervention period. Using a computer-generated randomization sequence, participants were allocated to receive either the standardized cannabis formulation or a matched placebo. The primary outcome measure comprised pain intensity assessment using the validated Thai version of the Neuropathic Pain Symptom Inventory (NPSI-T). Secondary outcomes encompassed treatment-emergent adverse events and dermatological manifestations. Statistical analyses were performed using SPSS Version 28.0, incorporating generalized estimating equation (GEE) modeling and Analysis of Covariance (ANCOVA). The study protocol received approval from the Institutional Review Board of Khon Kaen University and the Kalasin Provincial Public Health Office Ethics Committee, with trial registration in the Thai Clinical Trials Registry.

Results: The intervention group demonstrated statistically significant reductions in NPSI-T scores across all measured dimensions (p < 0.001). Mean total NPSI-T scores decreased markedly from 25.60 to 5.57 in the treatment cohort, contrasting with minimal reduction from 25.24 to 22.85 in the placebo group. GEE analysis revealed significant pain amelioration at weeks 4, 8, and 12 (p < 0.001). The cannabis formulation exhibited an excellent safety profile, with only 10% of participants reporting mild adverse events, comparable to placebo group outcomes.

Conclusion: This novel transdermal medical cannabis formulation (THC:CBD:CBN) demonstrated significant therapeutic efficacy in ameliorating painful DPN symptoms while maintaining a favorable safety profile. These findings provide robust clinical evidence supporting its potential as an innovative therapeutic option for managing painful DPN.”

https://pubmed.ncbi.nlm.nih.gov/39720705/

“This randomized controlled trial provides robust evidence supporting the therapeutic efficacy and safety profile of transdermal THC:CBD:CBN formulation in the management of painful DPN. The demonstrated significant reduction in multidimensional pain scores, combined with the pharmacokinetic advantages of transdermal delivery and favorable safety outcomes, suggests substantial clinical potential for this therapeutic approach. As the evidence base continues to expand, cannabinoid-based interventions may emerge as a valuable therapeutic option in addressing the complex challenges of neuropathic pain management.”

https://karger.com/mca/article/8/1/1/916069/Efficacy-and-Safety-of-Transdermal-Medical

The Use of Cannabinoids in the Treatment of Peripheral Neuropathy and Neuropathic Pain: A Systematic Review

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“Purpose: Peripheral neuropathies are commonly occurring conditions that are chronic and debilitating for patients. Established nonsurgical treatments have yielded mixed and patient-dependent results. Although cannabinoids have demonstrated efficacy as a treatment for central neuropathic pain, the therapeutic potential of cannabis-based medications for the management of peripheral neuropathic pain caused by nerve injury, trauma, and other noncompressive etiologies has yet to be definitively established. This study aims to determine whether cannabinoids are a potentially effective treatment for pain and symptoms associated with peripheral neuropathy.

Methods: A systematic search was conducted by two independent reviewers across PubMed, Cochrane, Ovid Medline, and CINAHL to identify studies in accordance with the predetermined inclusion/exclusion criteria. Information regarding study design, medication, dosage, effect on neuropathic pain, and other related outcomes was extracted. Meta-analysis of pain scores was performed for seven studies, and descriptive statistics were used to summarize other study findings as appropriate.

Results: Of the 927 studies identified, 14 randomized controlled trials were included. Thirteen of 14 studies (79%) observed a statistically significant decrease in neuropathic pain score following treatment with a cannabinoid. Meta-analysis yielded a mean difference of -0.67 [-0.89, -0.45]) on a 0-10 scale compared with placebo. Improvements in secondary outcomes such as sleep, sensory symptoms, and quality of life were observed.

Conclusions: Our analysis of the literature shows that cannabis-based medicines may be effective in treating the pain and symptoms of peripheral neuropathy. These findings suggest the applicability of cannabis-based medicines for peripheral neuropathy.”

https://pubmed.ncbi.nlm.nih.gov/39570218/

https://www.jhandsurg.org/article/S0363-5023(24)00474-X/abstract

Efficiency of cannabis and cannabidiol in managing chronic pain syndromes: A comprehensive narrative review

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“Chronic pain affects up to 40% of adults, contributing to high medical expenses, the loss of productivity, reduced quality of life (QoL), and disability. Chronic pain requires detailed diagnostic assessment, treatment and rehabilitation, yet approx. 80% of patients report inadequate pain management.

As new treatment options are needed, we aimed to explore the effectiveness of medical cannabis-based products in managing chronic pain, with a particular focus on treatment patterns.

We searched the PubMed, Scopus and Web of Science databases using keywords related to cannabinoids and chronic pain syndromes. In total, 3,954 articles were identified, and 74 studies involving 12,562 patients were included. The effectiveness of cannabis-based products varied across studies.

Cannabinoids were most effective in treating chronic secondary headache and orofacial pain, chronic secondary musculoskeletal pain, chronic secondary visceral pain, and chronic neuropathic pain. Properly qualifying patients is the first crucial step in managing chronic pain, considering pain characteristics, comorbidities and other treatment options.

Treatment should start with low doses of cannabinoids, which are then increased to achieve the desired therapeutic effect while minimizing adverse effects.This narrative review revealed significant gaps in the evidence regarding precise treatment patterns, particularly for the long-term maintenance treatment needed by patients with chronic pain.

Medical cannabis can be considered an option for carefully selected patients with chronic pain syndromes when other treatment options fail to achieve an adequate response, and when the potential benefits outweigh the risks. However, there is still a need for well-designed clinical research to establish the long-term efficacy and safety of cannabinoids.”

https://pubmed.ncbi.nlm.nih.gov/39499191/

“Medical cannabis can be considered an option in carefully selected patients with chronic pain syndrome for the management of chronic pain when other treatment options fail to achieve an adequate response, and when potential benefits outweigh the risks. Patients with chronic secondary headache and orofacial pain, chronic secondary visceral pain, chronic secondary musculoskeletal pain, and chronic neuropathic pain can benefit more than other groups of patients experiencing chronic pain.”

https://dmp.umw.edu.pl/en/article/2024/61/5/765/

Identification of the TRPA1 Cannabinoid-Binding Site

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“Chronic pain accounts for nearly two-thirds of conditions eligible for medical cannabis licenses, yet the mechanisms underlying cannabis-induced analgesia remain poorly understood.

The principal phytocannabinoids, the psychoactive Δ9-tetrahydrocannabinol (THC) and non-psychoactive cannabidiol (CBD), exhibit comparable efficacy in pain management. Notably, THC functions as an agonist of cannabinoid receptor 1 (CB1), whereas CBD shows minimal activity on CB1 and CB2 receptors.

Elucidating the molecular targets through which phytocannabinoids modulate the pain system is required for advancing our understanding of the pain pathway and optimizing medical cannabis therapies.

Transient receptor potential ankyrin 1 (TRPA1), a pivotal chemosensor in the pain pathway, has been identified as a phytocannabinoid target. Unlike most TRPA1 activators, phytocannabinoid activation is not mediated through the electrophilic binding site, suggesting an alternative mechanism. Here, we identified the human TRPA1 channel cannabinoid-binding site (CBS) and demonstrated that mutations at residue Y840 abolished responses to both THC and CBD at saturating concentrations, indicating a shared primary binding site. Molecular modeling revealed distinct interactions of THC and CBD with the Y840 residue within the CBS. Additionally, CBD binds to the adjacent general anesthetic binding site at oversaturating concentrations.

Our findings define the CBS of TRPA1 as overlapping with and adjacent to binding sites for other allosteric activators, suggesting that TRPA1 possesses a highly adaptable domain for binding non-electrophilic activators. This underscores its unique role as a chemosensor in the pain pathway. Furthermore, our results provide new insights into the molecular mechanisms of cannabinoid-induced analgesia and identify novel targets for pain management therapies.”

https://pubmed.ncbi.nlm.nih.gov/39368566/

https://www.sciencedirect.com/science/article/pii/S104366182400389X?via%3Dihub

Cannabis sativa L. Extract Alleviates Neuropathic Pain and Modulates CB1 and CB2 Receptor Expression in Rat

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“Introduction: Cannabis sativa L. (CSL) extract has pain-relieving potential due to its cannabinoid content, so the effects of two CSL extracts on alleviating neuropathic pain were investigated in vivo. Methods and groups: Male Wistar rats (n = 130) were divided into groups and received vincristine (0.1 mg/kg) and gabapentin (60 mg/kg) to induce and relieve neuropathic pain or CSL extracts (D and B). The mRNA and protein expression of the cannabinoid receptors type 1 and 2 (CB1R, CB2R) were evaluated in the cerebral cortex, hippocampus, and lymphocytes. Behavioural tests (Tail-Flick and von Frey) were performed on all animals.

Results: VK-induced neuropathic pain was accompanied by decreased CB1R protein level and CB2R mRNA expression in the cortex. Gabapentin relieved pain and increased CB1R protein levels in the hippocampus compared to the vincristine group. Hippocampus CB1R protein expression increased with the administration of extract D (10 mg/kg, 40 mg/kg) and extract B (7.5 mg/kg, 10 mg/kg) compared to VK group. In the cerebral cortex CSL decreased CB1R protein expression (10 mg/kg, 20 mg/kg, 40 mg/kg of extract B) and mRNA level (5 mg/kg, 7.5 mg/kg of extract B; 20 mg/kg of extract D) compared to the VK-group.CB2R protein expression increased in the hippocampus after treatment with extract B (7.5 mg/kg) compared to the VK-group. In the cerebral cortex extract B (10 mg/kg, 20 mg/kg) increased CB2R protein expression compared to VK-group.

Conclusion: Alterations in cannabinoid receptor expression do not fully account for the observed behavioural changes in rats. Therefore, additional signalling pathways may contribute to the initiation and transmission of neuropathic pain. The Cannabis extracts tested demonstrated antinociceptive effects comparable to gabapentin, highlighting the antinociceptive properties of Cannabis extracts for human use.”

https://pubmed.ncbi.nlm.nih.gov/39334832/

“Furthermore, both tested Cannabis sativa L. extracts demonstrated antinociceptive effects comparable to gabapentin, highlighting the potential medical value of Cannabis extracts for human use.”

https://www.mdpi.com/2218-273X/14/9/1065

Cannabinoids as a Natural Alternative for the Management of Neuropathic Pain: A Systematic Review of Randomized Placebo-Controlled Trials

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“Dysfunction or damage to the nervous system may develop into and result in a chronic pain condition known as neuropathic pain. Neuropathic pain is defined as the structural and functional alteration of the somatosensory component of the nervous system. The treatment of neuropathic pain is a complex endeavor, which often requires specialist care and intensive drug therapy. Recently, cannabinoids have emerged as an alternative and natural option for the treatment of chronic pain, with tetrahydrocannabinol (THC) and cannabidiol (CBD) being the most extensively studied neuroactive components. The therapeutic potential of cannabis remains largely underexplored, primarily due to its social stigma and the restrictions that are in place on its cultivation. The primary aim of this systematic review was to explore the therapeutic value of cannabinoids in the management of chronic pain and thus achieve an improved quality of life for those patients.

A systematic review of the literature published over the last two decades was performed using the following databases: PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Turning research into practice (Trip), and Google Scholar. Studies that were completed and published between January 01, 2000 and August 31, 2024, in English language, were extracted and appraised. A combination of keywords and Boolean operators Cannabis OR Chronic Pain OR End of life OR Pain Management AND Drug therapy was employed for data extraction. The Cochrane risk-of-bias tool for randomized trials (RoB 2) was used for risk-of-bias assessment. The initial search resulted in 125282 articles; 86,781 of the articles were identified as duplicates and were removed from the primary analysis, and 38,501 abstracts were thus screened. Abstracts, case studies, reports, editorials, viewpoints, cross-sectional studies, cohort studies, case-control studies, case series, and letters to the editor/correspondence manuscripts (n =38,492) were furthermore excluded. Nine full-text articles were critically assessed and tested against the inclusion and exclusion criteria, and a further four articles were excluded with a total of five placebo-controlled randomized control studies being ultimately included in the final systematic review.

Compared to placebo, cannabinoids provided significant relief from chronic pain (33% vs 15%) as measured by the visual analog scale. The transdermal application of CBD led to a more pronounced reduction in sharp pain, according to the neuropathic pain scale. Minimal to no side effects were recorded, further highlighting the potential benefits of cannabinoids. 

The potential benefit of cannabinoids is that they are naturally derived drugs that have already been shown to have the potential to effectively decrease chronic pain with minimal side effects as compared to the standard drugs being used. The ability of cannabinoids to provide pain relief with minimal side effects and concurrently be a naturally derived product may potentially be a life-changing alternative that the pharmaceutical market is in dire need of.”

https://www.cureus.com/articles/297124-cannabinoids-as-a-natural-alternative-for-the-management-of-neuropathic-pain-a-systematic-review-of-randomized-placebo-controlled-trials#!/

The endocannabinoid system as a therapeutic target in neuropathic pain: a review

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“Introduction: This review highlights the critical role of the endocannabinoid system (ECS) in regulating neuropathic pain and explores the therapeutic potential of cannabinoids. Understanding the mechanisms of the ECS, including its receptors, endogenous ligands, and enzymatic routes, can lead to innovative treatments for chronic pain, offering more effective therapies for neuropathic conditions. This review bridges the gap between preclinical studies and clinical applications by emphasizing ECS modulation for better pain management outcomes.

Areas covered: A review mapped the existing literature on neuropathic pain and the effects of modulating the ECS using natural and synthetic cannabinoids. This analysis examined ECS components and their alterations in neuropathic pain, highlighting the peripheral, spinal, and supraspinal mechanisms. This review aimed to provide a thorough understanding of the therapeutic potential of cannabinoids in the management of neuropathic pain.

Expert opinion: Advances in cannabinoid research have shown significant potential for the management of chronic neuropathic pain. The study emphasizes the need for high-quality clinical trials and collaborative efforts among researchers, clinicians, and regulatory bodies to ensure safe and effective integration of cannabinoids into pain management protocols. Understanding the mechanisms and optimizing cannabinoid formulations and delivery methods are crucial for enhancing therapeutic outcomes.”

https://pubmed.ncbi.nlm.nih.gov/39317147/

“Research on the modulation of the endocannabinoid system in nervous tissue related to neuropathic pain reveals complex mechanisms of pain modulation. Dysregulation of the endocannabinoid system, microglial activation, and interactions between various signaling pathways contribute to the onset and persistence of neuropathic pain. Understanding these molecular and cellular processes is crucial for developing targeted therapies that leverage the endocannabinoid system to alleviate neuropathic pain.”

https://www.tandfonline.com/doi/full/10.1080/14728222.2024.2407824

“Smoked Cannabis Proven Effective In Treating Neuropathic Pain”

https://www.sciencedaily.com/releases/2007/10/071024141745.htm

Neuromolecular and behavioral effects of Cannabidiol on depressive-associated behaviors and neuropathic pain conditions in mice

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“Background and aims: Neuropathic pain (NP) has a high incidence in the general population, is closely related to anxiety disorders, and has a negative impact on the quality of life. Cannabidiol (CBD), as a natural product, has been extensively studied for its potential therapeutic effects on symptoms such as pain and depression (DP). However, the mechanism of CBD in improving NP with depression is not fully understood.

Methods: First, we used bioinformatics tools to deeply mine the intersection genes associated with NP, DP, and CBD. Secondly, the core targets were screened by Protein-protein interaction network, Gene Ontology, Kyoto Encyclopedia of Genes and Genomes analysis, molecular docking and molecular dynamics simulation. Next, the effects of CBD intervention on pain and depressive behaviors in the spinal nerve ligation (SNL) mouse model were evaluated using behavioral tests, and dose-response curves were plotted. After the optimal intervention dose was determined, the core targets were verified by Western blot (WB) and Quantitative Polymerase Chain Reaction (qPCR). Finally, we investigated the potential mechanism of CBD by Nissl staining, Immunofluorescence (IF) and Transmission Electron Microscopy (TEM).

Results: A total of five core genes of CBD most associated with NP and DP were screened by bioinformatics analysis, including PTGS2, GPR55, SOD1, CYP1A2 and NQO1. Behavioral test results showed that CBD by intraperitoneal administration 5mg/kg can significantly improve the pain behavior and depressive state of SNL mice. WB, qPCR, IF, and TEM experiments further confirmed the regulatory effects of CBD on key molecules.

Conclusion: In this study, we found five targets of CBD in the treatment of NP with DP. These findings provide further theoretical and experimental basis for CBD as a potential therapeutic agent.”

https://pubmed.ncbi.nlm.nih.gov/39245142/

“We identified five core genes associated with comorbid NP and DP targeted by CBD. CBD intervention can improve NP and depressive-associated behavior in mice.”

https://www.sciencedirect.com/science/article/abs/pii/S0028390824003228?via%3Dihub