Category Archives: Pain

Offering an Alternative to Persons with Chronic Pain: How Access to Cannabis May Provide an Off-Ramp from Undesired Prescription Opioid Use

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“Background: Chronic pain (CP) is experienced by as many as 50 million Americans and can negatively impact physical and mental health. Prescribing opioids is the most common approach to address moderate to severe CP though these potent analgesics are associated with a significant number of side effects. One alternative some Americans are turning to for CP management is cannabis. In addition to serving as an alternative, many individuals with CP use cannabis in addition to using prescription opioids. This study examined individuals with CP who enrolled in the state of Illinois’ opioid diversion program, the Opioid Alternative Pilot Program (OAPP), which offers individuals aged 21 and older a separate pathway to access medical cannabis if they have or could receive a prescription for opioids as certified by a licensed physician.

Methods: Cross-sectional survey data were collected from 450 participants. We described participants and compared those who use only cannabis with those who use cannabis and opioids.

Results: While 16% of the respondents were cannabis-only users, 84% of the respondents were co-users of opioids and cannabis. Both groups considered opioid use risky (100% cannabis-only, 89% co-users,). The majority (73%) of respondents sought to completely stop or never start using opioids for CP. Cannabis-only users reported lower levels of pain compared to co-users. Co-users (85%) were more likely to have their routine provider as a cannabis certifying physician than cannabis-only users (69%).

Conclusion: With increasing clinical evidence, legalization and acceptance, researchers should continue to examine how cannabis may be a viable alternative to reduce the risk of prescription opioid side effects, misuse, or dependence. Our findings also inform health care providers and state policymakers who increasingly are being asked to consider how cannabis may reduce the potential for harmful outcomes among persons with CP who use prescription opioids.”

https://pubmed.ncbi.nlm.nih.gov/37484046/

https://publications.sciences.ucf.edu/cannabis/index.php/Cannabis/article/view/125

Perceived Effectiveness of Medical Cannabis Among Adults with Chronic Pain: Findings from Interview Data in a Three-Month Pilot Study

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“Objectives: Patient-reported outcomes are critical to evaluate the effectiveness of medical cannabis as an alternative treatment for chronic pain. This study examined the perceived effectiveness of medical cannabis for chronic pain management among middle-aged and older adults newly initiating medical cannabis.

Methods: Interview data from participants in a three-month pilot study were analyzed to assess the perceived effectiveness of medical cannabis on chronic pain and related outcomes. The interview was conducted after approximately one month of usage and responses were analyzed using the RADaR (Rigorous and Accelerated Data Reduction) technique.

Results: 51 adults initiating medical cannabis for chronic pain were interviewed (24 women, 27 men, mean age 54.4, SD = 12.0), with the majority (n=41) identifying as Non-Hispanic White followed by Non-Hispanic Black (n=7), Multi-racial (2), Hispanic White (1). Most study participants (62.7%) reported MC being overall effective. Common benefits included reduced pain intensity, anxiety, and dependency on pain and psychiatric medications. Improvements in physical functioning, sleep quality, and mood were reported. Common challenges included difficulty finding a suitable product or dose, experiencing side effects such as ‘undesired high’, ‘stomach issues’, and a limited ‘threshold of pain’ treatable by the product.

Discussion: Findings suggest most participants perceived medical cannabis to be overall effective for chronic pain management. Participants reported improved physical and mental functioning and reduced use of pain and psychiatric medications. Future research systematically assessing side effects, dosage and mode of consumption is needed to further evaluate the outcomes among adults initiating medical cannabis.”

https://pubmed.ncbi.nlm.nih.gov/37484052/

https://publications.sciences.ucf.edu/cannabis/index.php/Cannabis/article/view/149

Tolerability and Efficacy of a 10:25 Preparation of Δ9-Tetrahydrocannabinol and Cannabidiol for Treatment of Chronic Back or Neck Pain: A Multiple-Dose Escalation Study

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“Introduction: The aim was to demonstrate the safety and tolerability of cannabidiol (CBD) with Δ9-THC in patients with moderate to severe chronic back or neck pain unresponsive to over-the-counter non-opioid analgesics.

Methods: This was a non-randomized, single-arm, open-label study. Participants received escalating doses of an oromucosal-administered combination containing 10 mg/mL of Δ9-THC, 25 mg/mL of CBD. On day 1, patients received once-daily 0.5 mL Cybis® 10:25 (5 mg Δ9-THC plus 12.5 mg CBD daily), escalated at days 8, 15, and 22 to 0.5 mL twice-daily (bd) (10 mg Δ9-THC plus 25 mg CBD daily), 1.0 mL bd (20 mg Δ9-THC plus 50 mg CBD daily), and 1.5 mL bd (30 mg Δ9-THC plus 75 mg CBD daily), respectively. The primary outcome was safety and tolerability, with secondary objectives including pharmacokinetic and efficacy outcomes.

Results: 28 patients were enrolled in the study. Their median age was 63.3 years, and half were female. The median history of neck/back pain was 10 years. The pharmacokinetics following single doses of 0.5 mL were variable; however, there were dose-dependent increases in trough levels of CBD and Δ9-THC. Cybis® 10:25 was well tolerated, with the majority of adverse events of mild severity. The most common adverse events were nausea, vomiting, fatigue, dizziness, headache, paresthesia, and anxiety. There were dose-dependent improvements in numerical pain rating scores (p < 0.001), with clinically significant reductions in pain at 1.0 mL bd and 1.5 mL bd doses (28.8% and 34.1% reductions, respectively, p < 0.001). Depressive symptoms and stress had dose-dependent reductions (p = 0.0182, p < 0.01, respectively).

Conclusion: In patients with chronic neck/back pain, CBD and Δ9-THC are well tolerated and doses of 1.0 mL bd and 1.5 mL bd showed clinically significant reductions in pain compared to baseline pain scores.”

https://pubmed.ncbi.nlm.nih.gov/37465637/

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