Category Archives: Chronic Inflammatory and Neuropathic Pain

Emerging trends in cannabis administration for women with chronic pain

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“Cannabis use among women who experience chronic pain is on the rise in the United States. However, little is known about women’s motives and preferences for cannabis administration. The purpose of this study was to characterize cannabis use among women with chronic pain.

This study examined self-reported forms of cannabis administration and preferred source of cannabis, frequency and quantity of use, and self-reported side effects, and type, level, and intensity of chronic pain among adult women in the United States. This study also compared women who use cannabis for chronic pain and those who do not across the level of chronic pain, length of chronic pain, and the number of types of chronic pain experienced.

Participants showed a significant preference (60%) for using recreational cannabis to treat chronic pain but reported that medical cannabis was more effective. For participants who preferred medical cannabis 24.3% reported daily use, as compared to only 7.8% of recreational cannabis users. Smoking was the most common form of administration (62.1%), followed by edibles (25.3%), vaporizing in any form (7.4%), tinctures and concentrates (3.2%), and topicals (2.1%). Participants reported using 1-6 different forms of cannabis administration. Those who preferred smoking were significantly likely to use all other forms of administration. However, those who preferred alternatives to smoking were significantly likely to use all forms of administration except for smoking. Medical cannabis users preferred to obtain cannabis from a dispensary, while recreational users preferred to obtain cannabis from unlicensed sources.

Additionally, participants who used cannabis for chronic pain reported a 74% reduction in past 30-day opioid use.

Future research is needed to investigate the health effects associated with single and combined forms of cannabis administration for women with chronic pain. Results can inform educational and intervention programs, treatment development, content regulation of products, policy formation, women’s health research, and public health guidelines.”

https://pubmed.ncbi.nlm.nih.gov/39816373/

https://onlinelibrary.wiley.com/doi/10.1002/mhs2.88

Safety and effectiveness of cannabinoids to Danish patients with treatment refractory chronic pain-A retrospective observational real-world study

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“Background: Cannabinoids are considered a therapeutic option to patients suffering from treatment refractory chronic pain (TRCP) insufficiently relieved by conventional analgesics or experiencing intolerable adverse events (AEs) from those. This study aimed to explore safety and effectiveness of oral cannabinoids among patients with TRCP.

Methods: A retrospective study was conducted among Danish patients with TRCP being prescribed oral cannabinoids. Data on AEs and changes in pain intensity by numeric rating scale (NRS) before and after initiation of oral cannabinoid therapy were analysed.

Results: Among 826 eligible patients ≥18 years old, 529 (64%) were included for data analysis at first follow-up (F/U1) (median 56 days from baseline) and 214 (26%) for second follow-up (F/U2) (median 126 days from F/U1). Mean age was 60 ± 15.9 years and 70% were females. AEs were in general reported mild to moderate by 42% of patients at F/U1 and 34% at F/U2. AEs were mainly related to gastrointestinal (F/U1: 17% and F/U2: 13%) and nervous system disorders (F/U1: 14% and F/U2: 11%). Reduction in NRS was significantly different at both follow-up consultations compared with baseline (<0.0001). Clinically relevant pain reduction (NRS ≥30%) was reported by 17% at F/U1 and 10% of patients at F/U2 in intention-to-treat analysis whereas the figures were 32% and 45% respectively, in per-protocol analysis.

Conclusion: Oral cannabinoid therapy seems to be safe and mildly effective in patients with TRCP. Randomized controlled trials with focus on comparable pain characteristics in diagnostical homogenous patient subgroups are needed for further improvement of evidence level for relief of chronic pain using oral cannabinoids.

Significance: The findings in this retrospective study conducted in a real-world clinical setting suggest a favourable safety profile of cannabinoids. Moreover, one-sixth (intention-to-treat) and one-third (per-protocol) of patients with chronic pain refractory to conventional analgesics, or experiencing intolerable adverse effects, benefited significantly from therapy with oral cannabinoid regimens. Combination of THC and CBD seems overall more effective than cannabinoid monotherapy. Conduction of randomized controlled trials investigating safety and efficacy of cannabinoid therapy to diagnosis specific patient subgroups with comparable clinical and pathophysiological chronic pain characteristics is warranted, hence contributing further to the process of clinical evidence clarification currently in progress.”

https://pubmed.ncbi.nlm.nih.gov/36394124/

“In conclusion, oral cannabinoid therapy in general appears to be safe and effective for relief of chronic pain in some patients, including a subset of patients with cancer-related pain (9%), not responding adequately to conventional treatment regimens or experiencing intolerable AEs. Moreover, beneficial effects on sleep and QoL were reported by the patients receiving oral cannabinoid therapy, although the assessment was not performed in a validated manner. Hence, our study confirms previously reported findings related to patients with chronic pain receiving oral cannabinoid therapy and in that way the study contributes further to the evidence pyramid at the level of observational studies. “

https://onlinelibrary.wiley.com/doi/10.1002/ejp.2054

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

UK medical cannabis registry: A clinical outcome analysis of medical cannabis therapy in chronic pain patients with and without co-morbid sleep impairment

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“Introduction: Chronic pain (CP) affects 35.0%-51.3% of the UK population, with 67%-88% reporting sleep disturbances. Cannabis-based medicinal products (CBMPs) have shown therapeutic potential in managing CP. Evidence suggests poor sleep worsens pain perception; therefore, this study aimed to assess patient-reported outcome measures (PROMs) following CBMP treatment in CP patients with and without co-morbid sleep impairment.

Methods: A prospective cohort study of CP patients from the UK Medical Cannabis Registry was conducted. Participants were separated by baseline single-item sleep quality scale (SQS) score into sleep impaired (SQS ≤3) and unimpaired (SQS ≥4) cohorts. The primary outcome assessed changes in PROMs from baseline to 1-, 3-, 6-, and 12-months. Participants completed the following: SQS, General Anxiety Disorder-7, EQ-5D-5L, Brief Pain Inventory (BPI), and Short-Form McGill Pain Questionnaire-2. Significance was defined as p < 0.050.

Results: 1139 participants met the inclusion criteria (sleep impaired: n = 517, 45.4%; sleep unimpaired: n = 622, 54.61%). The sleep impaired cohort showed improvements in all PROMs at each follow-up (p < 0.010). The sleep unimpaired cohort showed similar results (p < 0.050), except in SQS and ED-5Q-5L: self-care and anxiety/depression scores (p > 0.050). However, the sleep impaired cohort observed greater improvements in BPI pain severity (p < 0.050) and SQS (p < 0.001) than the sleep unimpaired cohort at all follow-ups. 2817 adverse events were self-reported between both cohorts (p = 0.197).

Discussion: These findings align with literature that shows associated improvements in pain outcomes following CBMP administration. Sleep impaired individuals were more likely to experience greater pain severity improvements. However, this was not confirmed on multivariate logistic regression analysis and instead may be confounded by baseline pain severity.

Conclusion: Whilst these results show promise for the effects of CBMPs on CP, they must be examined within the limitations of the study design. These findings provide further evidence to support the design of subsequent randomized controlled trials to verify causality between CBMPs and pain outcomes.”

https://pubmed.ncbi.nlm.nih.gov/39545361/

“The results of this observational cohort study suggest an association between CBMP treatment and improvement in pain-specific and HRQoL PROMs in CP patients with and without co-morbid sleep impairment. Notably, those with co-morbid sleep impairment were associated with greater improvements in BPI pain severity, SQS, and PGIC than those without. However, this finding was not confirmed on multivariate analysis. Reported sleep quality did improve across the cohort from baseline, and when present was also associated with improvements in pain severity, suggesting that the effects of CBMPs on sleep may provide additional benefits for individuals with chronic pain beyond affecting the transmission of nociceptive signals. At the onset of treatment, however, other variables may be better prognostic markers for response to CBMP treatment, such as severe pain or anxiety at baseline. With respect to clinical significance, 44.10% report an improvement in the sleep impaired cohort at 1-months, declining to 24.56% at 12-months. Despite being limited by its observational design, the present study can be used to inform future RCTs, in addition to current clinical practice.”

https://onlinelibrary.wiley.com/doi/10.1111/papr.13438

Changes in Pain and Mental Health Symptoms Associated with Prescribed Medicinal Cannabis Use: A One-Year Longitudinal Study

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“Chronic pain and mental health issues like depression and anxiety significantly contribute to disease burden in Western countries.

While cannabinoids are suggested to have analgesic, anxiolytic and antidepressant properties, evidence, especially for long-term use, is inconclusive. This 12-month observational study evaluated the effects of prescribed medicinal cannabis for 96 patients suffering from pain, as well as sleep disturbances, depression and anxiety. Treatment outcomes for pain, depression, anxiety and sleep problems were assessed at 3, 6, and 12 months using validated instruments.

Significant reductions were observed in pain scores and the interference of pain on daily functions, alongside improvements in mental health and sleep. Many patients reported notable improvements in pain severity and reduced use of pain medications in the first 6 months, with a decline at 12 months. Additionally, sustained improvements in depression, anxiety, stress and sleep were observed, with about half reporting substantial improvement. Adverse effects were common but mostly mild or moderate, most commonly dry mouth and sleepiness.

These results show that prescribed medicinal cannabis treatment is associated with improvements in chronic pain and mental health symptoms, such as depression, anxiety and stress. However, findings also suggest reduced effectiveness with longer-term use, emphasizing the need for additional research.”

https://pubmed.ncbi.nlm.nih.gov/39432717/

“Cannabis is a plant that has been used for thousands of years as a traditional medicine to treat various medical ailments, including pain.

Overall, we found that the use of medicinal cannabis was associated with reduced pain during the first 6 months and improved mental well-being over 12 months. Patients reported not only less pain but also experienced reduced interference from pain in their daily functions. Furthermore, they reported decreased use of pain medications and a large proportion felt that their pain symptoms had significantly improved, as reflected in their reported changes in the severity of pain.”

https://www.tandfonline.com/doi/full/10.1080/15360288.2024.2414898

An early economic analysis of medical cannabis for the treatment of chronic pain

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“Background: Cannabis-based medicinal products (CBMPs) are increasingly demonstrating effectiveness in treating a wide range of conditions, with a relatively high safety profile in clinical usage compared to other prescription pain medications and few contraindications. Consultation and other prescription-related costs are, at present, higher for CBMPs than for some other treatment options, leading to some concern around wider prescribing.

Research design and methods: An early cost-effectiveness model was developed to estimate the impact of prescribing CBMPs alone and/or in addition to analgesics, physiotherapy, and cognitive behavioral therapy for chronic pain in the UK for 1 year.

Results: Due to their comparative effectiveness, CBMPs were found to be cost saving. Various scenarios were model tested; in all scenarios where CBMPs decrease pain-level states, less resource use is required. Increased efficacy of 5% was conservatively assumed based on current Real-World Evidence. In this scenario, CBMPs were significantly more cost-effective, and as costs relating to the prescribing of these continue to fall, relative savings are predicted to increase.

Conclusion: These findings highlight the substantial cost saving that CBMPs may represent for the treatment of chronic pain patients, and the benefits for healthcare providers as a treatment for this often hard-to-treat population.”

https://pubmed.ncbi.nlm.nih.gov/39415537/

https://www.tandfonline.com/doi/full/10.1080/14737167.2024.2412248

Cannabinoids shift the basal ganglia miRNA m6A methylation profile towards an anti-inflammatory phenotype in SIV-infected Rhesus macaques

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“Epitranscriptomic modifications modulate diverse biological processes, such as regulation of gene expression, abundance, location and function. In particular, N6-methyladenosine (m6A) methylation has been shown to regulate various disease processes, including cancer and inflammation. While there is evidence that m6A modification is functionally relevant in neural development and differentiation, the role of m6A modification in HIV neuropathogenesis is unknown.

Here, we identified direct m6A modifications in miRNAs from BG tissues of Rhesus Monkeys (RMs) that were either vehicle-treated uninfected (VEH), SIV-infected combination anti-retroviral therapy (cART) treated (VEH/SIV/cART), or THC:CBD treated VEH/SIV/cART (THC:CBD/SIV/cART) RMs.

We detected m6A modifications across all BG tissues. SIV infection promoted an overall hypomethylated m6A profile. While the overall hypomethylated m6A profile was not significantly impacted by THC:CBD treatment, specific miRNAs, particularly those predicted to target proinflammatory genes showed markedly reduced m6A methylation levels compared to the VEH treated RMs. Additionally, we found that specific BG tissue miRNAs bearing m6A epi-transcriptomic marks were also transferred to BG-derived extracellular vesicles (EVs). Mechanistically, we identified the DRACH motif of the seed region of miR-194-5p to be significantly m6A hypomethylated, which was predicted to directly target STAT1, an important interferon-activated transcription factor known to drive neuroinflammation, in diseases ranging from Alzheimer to Parkinson and Huntington disease.

Notably, THC:CBD treatments significantly reduced m6A methylation of 43 miRNA species directly involved in regulating CNS network genes, thus providing a possible mechanist explanation on the beneficial effects of THC:CBD treatments noted in several disease involving neuroinflammation.

Our findings also underscore the need for investigating the qualitative, posttranscriptional modification changes in the RNA profiles along with the more traditional, qualitative alterations in pathological conditions or after various treatment regimens.”

https://pubmed.ncbi.nlm.nih.gov/39416016/

https://www.biorxiv.org/content/10.1101/2024.10.11.614514v1

Edible cannabis for chronic low back pain: associations with pain, mood, and intoxication

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“Introduction: Cannabis, commonly known for both therapeutic and intoxicating effects, is gaining accessibility on legal markets and traction as a potential alternative therapy for pain mediation, particularly in those suffering from chronic low back pain. However, the effectiveness in this population of legal market forms of cannabis, particularly commonly used edibles, is unknown.

Methods: Therefore, this study utilized a naturalistic prospective design where participants with chronic low back pain with intentions to initiate cannabis use for treatment were recruited and self-selected edible cannabis products containing varying amounts of delta- 9 tetrahydrocannabinol (THC) and cannabidiol (CBD). Products were categorized as CBD-dominant, THC-dominant, or combined THC and CBD (THC + CBD).

Results: 249 participants [140 female (56.62%), mean (SD) age of 46.30 (16.02), 90% White] were tracked over 2 weeks of ad libitum use and assessed during a naturalistic acute cannabis administration session on changes in pain, mood, and subjective drug effects. During acute administration, a significant correlation between THC dose and short-term pain relief was found, suggesting that higher THC doses were associated with greater pain reduction (p < .05). In addition, THC was associated with higher levels of subjective cannabis drug effects (p < .001), regardless of whether CBD was also in the edible product. Acute CBD dose was primarily associated with short-term tension relief (p < .05); however, there were no associations between CBD dose and acute pain. Over the 2-week ad libitum administration period results suggested pain reductions across participants using all forms of cannabis. However, trends suggested that more frequent use of CBD-dominant edible cannabis may be associated with greater reductions in perceived pain over the 2-week observation period (p = .07).

Discussion: These findings support the short-term analgesic effects of THC and anxiolytic effects of CBD and further suggest that orally-administered THC and CBD should continue to be evaluated for the potential to provide both acute and extended relief from chronic low back pain.”

https://pubmed.ncbi.nlm.nih.gov/39380911/

“In this naturalistic observational study, it was found that the use of edible cannabinoid products significantly reduced chronic pain in extended and acute use models. More specifically, THC dose was associated with the greatest decrease in pain during the acute use session. Further, there was signal that more frequent use of a CBD-dominant product may provide stronger relief over a 2-week ad libitum use period.

These results indicate that edible cannabis may be a safe and suitable alternative pain therapy for those looking to substitute more traditional pain medications.”

https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2024.1464005/full

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