Category Archives: Pain

Cannabis use is associated with decreased opioid prescription fulfillment following single level anterior cervical discectomy and fusion (ACDF)

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“Background: Recently, there has been increasing legalization of marijuana within the United States, however data are mixed with respect to its efficacy in treating acute pain. Our goal was to identify a difference in opioid utilization in patients with known cannabis use before anterior cervical discectomy and fusion (ACDF) compared with those that report no cannabis use.

Methods: This study was a retrospective case-control design using PearlDiver. Patients who underwent a single level ACDF between January 2010 and October 2020, were included. Patients were placed in the study group if they had a previous diagnosis of cannabis use, dependence, or abuse. Patients were excluded if they were under the age of 18 or if they had filled an opioid prescription within 3 months of their procedure. A control group was then created using a propensity score match on age, gender, and Charleston comorbidity index (CCI), and had no diagnosis of cannabis use. The primary outcome was the number of morphine milliequivalents (MME) dispensed per prescription following surgery.

Results: A total of 1,339 patients were included in each group. The number of patients filling prescriptions was lower in the cannabis group than in the control group at 3 days postoperatively (p<.001). The average total MME per day as prescribed was lower in the cannabis group than the control group at 60 days post-op (48.5 vs. 59.4, respectively; p=.018).

Conclusions: Patients who had a previous diagnosis of cannabis use, dependence or abuse filled fewer opioid prescriptions postoperatively (at 3 days postoperatively) and required lower doses (reduced average daily MME, at 60 days postoperatively) when compared with the control group.”

https://pubmed.ncbi.nlm.nih.gov/37440986/

“In summary, patients who were known to use cannabis filled fewer opioid prescriptions following ACDF procedures and were prescribed lower daily doses than the control group, suggesting that cannabis use may reduce opioid requirements in this population.”

https://www.nassopenaccess.org/article/S2666-5484(23)00028-8/fulltext

Anti-allodynic and medullary modulatory effects of a single dose of delta-9-tetrahydrocannabinol (THC) in neuropathic rats tolerant to morphine

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“Neuropathic pain (NP) is often treated with opioids, the prolonged use of which causes tolerance to their analgesic effect and can potentially cause death by overdose. The phytocannabinoid delta-9-tetrahydrocannabinol (THC) may be an effective alternative analgesic to treat NP in morphine-tolerant subjects. Male Wistar rats developed NP after spared nerve injury, and were then treated with increasing doses of THC (1, 1.5, 2, 2.5, and 5 mg/kg, intraperitoneally) which reduced mechanical allodynia at the dose of 2.5 and 5 mg/kg. Another group of NP rats were treated with morphine (5 mg/kg, twice daily for 7 days, subcutaneously), until tolerance developed, and on day 8 received a single dose of THC (2.5 mg/kg), which significantly reduced mechanical allodynia. To evaluate the modulation of THC in the descending pain pathway, in vivo electrophysiological recordings of pronociceptive ON cells and antinociceptive OFF cells in the rostroventral medulla (RVM) were recorded after intra-PAG microinjection of THC (10 μg/μl). NP rats with morphine tolerance, compared to the control one, showed a tonic reduction of the spontaneous firing rate of ON cells by 44%, but the THC was able to further decrease it (a hallmark of many analgesic drugs acting at supraspinal level). On the other hand, the firing rate, of the antinociceptive OFF cells was increased after morphine tolerance by 133%, but the THC failed to further activate it. Altogether, these findings indicate that a single dose of THC produces antiallodynic effect in individuals with NP who are tolerant to morphine, acting mostly on the ON cells of the descending pain pathways, but not on OFF cells.”

https://pubmed.ncbi.nlm.nih.gov/37257771/

https://www.sciencedirect.com/science/article/abs/pii/S027858462300091X?via%3Dihub

Beyond Pain Relief: A Review on Cannabidiol Potential in Medical Therapies

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“The phytocannabinoid cannabidiol (CBD) is receiving increasing attention due to its pharmacological properties. Although CBD is extracted from Cannabis sativa, it lacks the psychoactive effects of Δ9-tetrahydrocannabinol (THC) and has become an attractive compound for pharmacological uses due to its anti-inflammatory, antioxidant, anticonvulsant, and anxiolytic potential. The molecular mechanisms involved in CBD’s biological effects are not limited to its interaction with classical cannabinoid receptors, exerting anti-inflammatory or pain-relief effects. Several pieces of evidence demonstrate that CBD interacts with other receptors and cellular signaling cascades, which further support CBD’s therapeutic potential beyond pain management. In this review, we take a closer look at the molecular mechanisms of CBD and its potential therapeutic application in the context of cancer, neurodegeneration, and autoimmune diseases.”

https://pubmed.ncbi.nlm.nih.gov/37259306/

https://www.mdpi.com/1424-8247/16/2/155

Analgesia by intrathecal delta-9-tetrahydrocannabinol is dependent on Cav3.2 calcium channels

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“Delta-9-tetrahydrocannabinol (Δ9-THC) is known to produce systemic analgesia that involves CB1 and CB2 cannabinoid receptors. However, there is compelling evidence that Δ9-THC can potently inhibit Cav3.2T-type calcium channels which are highly expressed in dorsal root ganglion neurons and in the dorsal horn of the spinal cord. Here, we investigated whether spinal analgesia produced by Δ9-THC involves Cav3.2 channels vis a vis cannabinoid receptors. We show that spinally delivered Δ9-THC produced dose-dependent and long-lasting mechanical anti-hyperalgesia in neuropathic mice, and showed potent analgesic effects in models of inflammatory pain induced by formalin or Complete Freund’s Adjuvant (CFA) injection into the hind paw, with the latter showing no overt sex differences. The Δ9-THC mediated reversal of thermal hyperalgesia in the CFA model was abolished in Cav3.2 null mice, but was unaltered in CB1 and CB2 null animals. Hence, the analgesic effects of spinally delivered Δ9-THC are due to an action on T-type calcium channels, rather than activation of spinal cannabinoid receptors.”

https://pubmed.ncbi.nlm.nih.gov/37231418/

https://molecularbrain.biomedcentral.com/articles/10.1186/s13041-023-01036-8

Medicinal cannabis products for the treatment of acute pain

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“For thousands of years, medicinal cannabis has been used for pain treatment, but its use for pain management is still controversial. Meta-analysis of the literature has shown contrasting results on the addition of cannabinoids to opioids compared with placebo/other active agents to reduce pain. Clinical studies are mainly focused on medicinal cannabis use in chronic pain management, for which the analgesic effect has been proven in many studies. This review focuses on the potential use of medical cannabis for acute pain management in preclinical studies, studies on healthy subjects and the few pioneering studies in the clinical setting.”

https://pubmed.ncbi.nlm.nih.gov/37214578/

https://www.wjgnet.com/2307-8960/full/v11/i12/2670.htm

Cannabidiol alleviates neuroinflammation and attenuates neuropathic pain via targeting FKBP5

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Brain, Behavior, and Immunity

“Microglia is a heterogeneous population that mediates neuroinflammation in the central nervous system (CNS) and plays a crucial role in developing neuropathic pain. FKBP5 facilitates the assembly of the IκB kinase (IKK) complex for the activation of NF-κB, which arises as a novel target for treating neuropathic pain. In this study, cannabidiol (CBD), a main active component of Cannabis, was identified as an antagonist of FKBP5. In vitro protein intrinsic fluorescence titration showed that CBD directly bound to FKBP5. Cellular thermal shift assay (CETSA) indicated that CBD binding increased the FKBP5 stability, which implies that FKBP5 is the endogenous target of CBD. CBD was found to inhibit the assembly of the IKK complex and the activation of NF-κB, therefore blocking LPS-induced NF-κB downstream pro-inflammatory factors NO, IL-1β, IL-6 and TNF-α. Stern-Volmer analysis and protein thermal shift assay revealed that tyrosine 113 (Y113) of FKBP5 was critical for FKBP5 interacting with CBD, which is consistent with in silico molecular docking simulation. FKBP5 Y113 mutation (Y113A) alleviated the effect of CBD inhibiting LPS-induced pro-inflammatory factors overproduction. Furthermore, systemic administration of CBD inhibited chronic constriction injury (CCI)-induced microglia activation and FKBP5 overexpression in lumbar spinal cord dorsal horn. These data imply that FKBP5 is an endogenous target of CBD.”

https://pubmed.ncbi.nlm.nih.gov/37196785/

“Cannabidiol (CBD) is the main active component of cannabis with good BBB permeability (Calapai et al., 2020) and has been gaining great attention for its safety, non-psychoactive effect and several beneficial pharmacological activities (Devinsky et al., 2016, Lucas et al., 2018, Pisanti et al., 2017). CBD has a good anti-neuroinflammatory effect (Atalay et al., 2019) and is used to treat neurological diseases caused by neuroinflammation, such as major depression (Florensa-Zanuy et al., 2021) and Parkinson’s disease (Giuliano et al., 2021) in animal models as well as autism spectrum disorder (Carbone et al., 2021) and multiple sclerosis (Nielsen et al., 2018) in clinical trials. As CBD has a low affinity for cannabinoid receptors (Rosenthaler et al., 2014), it would be worthy to explore the molecular target, which mediates the anti-inflammatory activity of CBD. Herein, FKBP5 was found as an endogenous target of CBD. CBD inhibited the assembly of the IKK complex and the activation of NF-κB, therefore suppressing LPS-induced pro-inflammatory factors. The FKBP5 tyrosine 113 (Y113) mutation abolished FKBP5 interacting with CBD, therefore ameliorating the effect of CBD inhibiting LPS-induced pro-inflammatory factors. Moreover, oral CBD attenuated peripheral nerve injury-induced overexpression of FKBP5 in activated microglia of lumbar spinal cord dorsal horn in vivo. These data implicate that FKBP5 is a direct binding target of CBD.”

https://www.sciencedirect.com/science/article/abs/pii/S0889159123001265?via%3Dihub

Cannabidiol for musculoskeletal regenerative medicine

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“Chronic musculoskeletal (MSK) pain is one of the most prevalent causes, which lead patients to a physician’s office. The most common disorders affecting MSK structures are osteoarthritis, rheumatoid arthritis, back pain, and myofascial pain syndrome, which are all responsible for major pain and physical disability.

Although there are many known management strategies currently in practice, phytotherapeutic compounds have recently begun to rise in the medical community, especially cannabidiol (CBD). This natural, non-intoxicating molecule derived from the cannabis plant has shown interesting results in many preclinical studies and some clinical settings. CBD plays vital roles in human health that go well beyond the classic immunomodulatory, anti-inflammatory, and antinociceptive properties. Recent studies demonstrated that CBD also improves cell proliferation and migration, especially in mesenchymal stem cells (MSCs).

The foremost objective of this review article is to discuss the therapeutic potential of CBD in the context of MSK regenerative medicine. Numerous studies listed in the literature indicate that CBD possesses a significant capacity to modulate mammalian tissue to attenuate and reverse the notorious hallmarks of chronic musculoskeletal disorders (MSDs). The most of the research included in this review report common findings like immunomodulation and stimulation of cell activity associated with tissue regeneration, especially in human MSCs.

CBD is considered safe and well tolerated as no serious adverse effects were reported. CBD promotes many positive effects which can manage detrimental alterations brought on by chronic MSDs. Since the application of CBD for MSK health is still undergoing expansion, additional randomized clinical trials are warranted to further clarify its efficacy and to understand its cellular mechanisms.”

https://pubmed.ncbi.nlm.nih.gov/37158062/

https://journals.sagepub.com/doi/10.1177/15353702231162086

Medical cannabis is effective for cancer-related pain: Quebec Cannabis Registry results

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“Objectives: To evaluate the safety and effectiveness of medical cannabis (MC) in reducing pain and concurrent medications in patients with cancer.

Methods: This study analysed data collected from patients with cancer who were part of the Quebec Cannabis Registry. Brief Pain Inventory (BPI), revised Edmonton Symptom Assessment System (ESAS-r) questionnaires, total medication burden (TMB) and morphine equivalent daily dose (MEDD) recorded at 3-month, 6-month, 9-month and 12-month follow-ups were compared with baseline values. Adverse events were also documented at each follow-up visit.

Results: This study included 358 patients with cancer. Thirteen out of 15 adverse events reported in 11 patients were not serious; 2 serious events (pneumonia and cardiovascular event) were considered unlikely related to MC. Statistically significant decreases were observed at 3-month, 6-month and 9-month follow-up for BPI worst pain (5.5±0.7 baseline, 3.6±0.7, 3.6±0.7, 3.6±0.8; p<0.01), average pain (4.1±0.6 baseline, 2.4±0.6, 2.3±0.6, 2.7±0.7; p<0.01), overall pain severity (3.7±0.5 baseline, 2.3±0.6, 2.3±0.6, 2.4±0.6; p<0.01) and pain interference (4.3±0.6 baseline, 2.4±0.6, 2.2±0.6, 2.4±0.7, p<0.01). ESAS-r pain scores decreased significantly at 3-month, 6-month and 9-month follow-up (3.7±0.6 baseline, 2.5±0.6, 2.2±0.6, 2.0±0.7, p<0.01). THC:CBD balanced strains were associated with better pain relief as compared with THC-dominant and CBD-dominant strains. Decreases in TMB were observed at all follow-ups. Decreases in MEDD were observed at the first three follow-ups.

Conclusions: Real-world data from this large, prospective, multicentre registry indicate that MC is a safe and effective complementary treatment for pain relief in patients with cancer. Our findings should be confirmed through randomised placebo-controlled trials.”

https://pubmed.ncbi.nlm.nih.gov/37130724/

https://spcare.bmj.com/content/early/2023/04/11/spcare-2022-004003

Medicinal cannabis for Australian patients with chronic refractory pain including arthritis

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“Objectives: To examine the tolerability and effectiveness of medicinal cannabis prescribed to patients for chronic, refractory pain, with a subset analysis on arthritis.

Methods: This was an interim analysis of the CA Clinics Observational Study investigating self-reported adverse events (AEs) and changes in health-related quality of life (HRQoL) outcomes over time after commencing medicinal cannabis. Patients were prescribed medicinal cannabis by a medical practitioner, containing various ratios of Δ9-tetrahydrocannabinol (THC) and/or cannabidiol (CBD).

Results: The overall chronic pain cohort, and specifically the balanced CBD:THC products, were associated with significantly reduced pain intensity scores (p = 0.003, p = 0.025), with 22% of patients reporting a clinically meaningful reduction in pain intensity. Patients in the arthritis subset (n = 199) reported significantly reduced pain intensity scores (p = 0.005) overall, and specifically for those taking CBD-only (p = 0.018) and balanced products (p = 0.005). Other HRQoL outcomes, including pain interference and pain impact scores were significantly improved depending on the CBD:THC ratio. Products that contained a balanced ratio of CBD:THC were associated with improvements in the most number of PROMIS-29 domains. Approximately half (n = 364; 51%) of the chronic pain cohort experienced at least one AE, the most common being dry mouth (24%), somnolence (19%) or fatigue (12%). These findings were similar in the arthritis subset.

Discussion: Medicinal cannabis was observed to improve pain intensity scores and HRQoL outcomes in patients with chronic, refractory pain, providing real-world insights into medicinal cannabis’ therapeutic potential.”

https://pubmed.ncbi.nlm.nih.gov/37057257/

https://journals.sagepub.com/doi/10.1177/20494637221147115

Cannabidiol Treatment Shows Therapeutic Efficacy in a Rodent Model of Social Transfer of Pain in Pair-Housed Male Mice

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“Introduction: Prosocial behavior refers to sharing emotions and sensations such as pain. Accumulated data indicate that cannabidiol (CBD), a nonpsychotomimetic component of the Cannabis sativa plant, attenuates hyperalgesia, anxiety, and anhedonic-like behavior. Nevertheless, the role of CBD in the social transfer of pain has never been evaluated. In this study, we investigated the effects of acute systemic administration of CBD in mice that cohabited with a conspecific animal suffering from chronic constriction injury. Furthermore, we assessed whether repeated CBD treatment decreases hypernociception, anxiety-like behavior, and anhedonic-like responses in mice undergoing chronic constriction injury and whether this attenuation would be socially transferred to the partner. 

Materials and Methods: Male Swiss mice were Housed in pairs for 28 days. On the 14th day of living together, animals were then divided into two groups: cagemate nerve constriction (CNC), in which one animal of each partner was subjected to sciatic nerve constriction; and cagemate sham (CS), subjected to the same surgical procedure but without suffering nerve constriction. In Experiments 1, 2, and 3 on day 28 of living together, the cagemates (CNC and CS) animals received a single systemic injection (intraperitoneally) of vehicle or CBD (0.3, 1, 10, or 30 mg/kg). After 30 min, the cagemates were subjected to the elevated plusmaze followed by exposure to the writhing and sucrose splash tests. For chronic treatment (Exp. 4), sham and chronic constriction injury animals received a repeated systemic injection (subcutaneous) of vehicle or CBD (10 mg/kg) for 14 days after the sciatic nerve constriction procedure. On days 28 and 29 sham and chronic constriction injury animals and their cagemates were behaviorally tested. 

Results and Conclusion: Acute CBD administration attenuated anxiety-like behavior, pain hypersensitivity, and anhedonic-like behavior in cagemates that cohabited with a pair in chronic pain. In addition, repeated CBD treatment reversed the anxiety-like behavior induced by chronic pain and enhanced the mechanical withdrawal thresholds in Von Frey filaments and the grooming time in the sucrose splash test. Moreover, repeated CBD treatment effects were socially transferred to the chronic constriction injury cagemates.”

https://pubmed.ncbi.nlm.nih.gov/37074109/

https://www.liebertpub.com/doi/10.1089/can.2022.0300