Natural Products Derived from Cannabis sativa for Pain Management

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“Cannabis sativa is one of the oldest medicinal plants in human history. Even ancient physicians from hundreds of years ago used Cannabis sativa to treat several conditions like pain.

In the modern era, the research community, including health-care providers, have witnessed wide-scale changes in cannabis policy, legislation, and marketing, with a parallel increase in patient interest. A simple search in PubMed using “cannabis and pain” as keywords provides more than 2,400 articles, about 80% of which were published in the last 8-10 years. Several advancements have been achieved in understanding the complex chemistry of cannabis along with its multiple pharmacological activities.

Preclinical data have demonstrated evidence for the promising potential of cannabis for pain management, and the continuous rise in the prevalence of pain increases the urgency to translate this into clinical practice. Despite the large body of cannabis literature, researchers still need to find rigorous answers for the questions about the efficacy and safety of cannabis in treatment of certain disorders such as pain. In the current chapter, we seek to present a critical overview about the current knowledge on cannabis with special emphasis on pain-related disorders.”

Classical cannabinoid receptors as target in cancer-induced bone pain: a systematic review, meta-analysis and bioinformatics validation

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“To test the hypothesis that genetic and pharmacological modulation of the classical cannabinoid type 1 (CB1) and 2 (CB2) receptors attenuate cancer-induced bone pain, we searched Medline, Web of Science and Scopus for relevant skeletal and non-skeletal cancer studies from inception to July 28, 2022. We identified 29 animal and 35 human studies. In mice, a meta-analysis of pooled studies showed that treatment of osteolysis-bearing males with the endocannabinoids AEA and 2-AG (mean difference [MD] – 24.83, 95% confidence interval [95%CI] – 34.89, – 14.76, p < 0.00001) or the synthetic cannabinoid (CB) agonists ACPA, WIN55,212-2, CP55,940 (CB1/2-non-selective) and AM1241 (CB2-selective) (MD – 28.73, 95%CI – 45.43, – 12.02, p = 0.0008) are associated with significant reduction in paw withdrawal frequency. Consistently, the synthetic agonists AM1241 and JWH015 (CB2-selective) increased paw withdrawal threshold (MD 0.89, 95%CI 0.79, 0.99, p < 0.00001), and ACEA (CB1-selective), AM1241 and JWH015 (CB2-selective) reduced spontaneous flinches (MD – 4.85, 95%CI – 6.74, – 2.96, p < 0. 00001) in osteolysis-bearing male mice. In rats, significant increase in paw withdrawal threshold is associated with the administration of ACEA and WIN55,212-2 (CB1/2-non-selective), JWH015 and AM1241 (CB2-selective) in osteolysis-bearing females (MD 8.18, 95%CI 6.14, 10.21, p < 0.00001), and treatment with AM1241 (CB2-selective) increased paw withdrawal thermal latency in males (mean difference [MD]: 3.94, 95%CI 2.13, 5.75, p < 0.0001), confirming the analgesic capabilities of CB1/2 ligands in rodents.

In human, treatment of cancer patients with medical cannabis (standardized MD – 0.19, 95%CI – 0.35, – 0.02, p = 0.03) and the plant-derived delta-9-THC (20 mg) (MD 3.29, CI 2.24, 4.33, p < 0.00001) or its synthetic derivative NIB (4 mg) (MD 2.55, 95%CI 1.58, 3.51, p < 0.00001) are associated with reduction in pain intensity.

Bioinformatics validation of KEGG, GO and MPO pathway, function and process enrichment analysis of mouse, rat and human data revealed that CB1 and CB2 receptors are enriched in a cocktail of nociceptive and sensory perception, inflammatory, immune-modulatory, and cancer pathways. Thus, we cautiously conclude that pharmacological modulators of CB1/2 receptors show promise in the treatment of cancer-induced bone pain, however further assessment of their effects on bone pain in genetically engineered animal models and cancer patients is warranted.”

Cannabidiol Alleviates Chronic Prostatitis and Chronic Pelvic Pain Syndrome via CB2 Receptor Activation and TRPV1 Desensitization

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“Purpose: This study elucidates the mechanism of the physiological effect of cannabidiol (CBD) by assessing its impact on lipopolysaccharide (LPS)-induced inflammation in RWPE-1 cells and prostatitis-induced by 17β-estradiol and dihydrotestosterone in a rat model, focusing on its therapeutic potential for chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS).

Materials and methods: RWPE-1 cells were stratified in vitro into three groups: (1) controls, (2) cells with LPS-induced inflammation, and (3) cells with LPS-induced inflammation and treated with CBD. Enzyme-linked immunosorbent assays and western blots were performed on cellular components and supernatants after administration of CBD. Five groups of six Sprague-Dawley male rats were assigned: (1) control, (2) CP/CPPS, (3) CP/CPPS and treated with 50 mg/kg CBD, (4) CP/CPPS and treated with 100 mg/kg CBD, and (5) CP/CPPS and treated with 150 mg/kg CBD. Prostatitis was induced through administration of 17β-estradiol and dihydrotestosterone. After four weeks of CBD treatment, a pain index was evaluated, and prostate tissue was collected for subsequent histologic examination and western blot analysis.

Results: CBD demonstrated efficacy in vivo for CP/CPPS and in vitro for inflammation. It inhibited the toll-like receptor 4 (TLR4)/nuclear factor-kappa B (NF-κB) pathway by activating the CB2 receptor, reducing expression of interleukin-6, tumor necrosis factor-alpha, and cyclooxygenase-2 (COX2) (p<0.01). CBD exhibited analgesic effects by activating and desensitizing the TRPV1 receptor.

Conclusions: CBD inhibits the TLR4/NF-κB pathway by activating the CB2 receptor, desensitizes the TRPV1 receptor, and decreases the release of COX2. This results in relief of inflammation and pain in patients with CP/CPPS, indicating CBD as a potential treatment for CP/CPPS.”

Cannabidiol induces systemic analgesia through activation of the PI3Kγ/nNOS/NO/KATP signaling pathway in neuropathic mice. A KATP channel S-nitrosylation-dependent mechanism

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“Background: Cannabidiol (CBD) is the second most abundant pharmacologically active component present in Cannabis sp. Unlike Δ-9-tetrahydrocannabinol (THC), it has no psychotomimetic effects and has recently received significant interest from the scientific community due to its potential to treat anxiety and epilepsy. CBD has excellent anti-inflammatory potential and can be used to treat some types of inflammatory and neuropathic pain. In this context, the present study aimed to evaluate the analgesic mechanism of cannabidiol administered systemically for the treatment of neuropathic pain and determine the endogenous mechanisms involved with this analgesia.

Methods: Neuropathic pain was induced by sciatic nerve constriction surgery, and the nociceptive threshold was measured using the paw compression test in mice.

Results: CBD produced dose-dependent antinociception after intraperitoneal injection. Selective inhibition of PI3Kγ dose-dependently reversed CBD-induced antinociception. Selective inhibition of nNOS enzymes reversed the antinociception induced by CBD, while selective inhibition of iNOS and eNOS did not alter this antinociception. However, the inhibition of cGMP production by guanylyl cyclase did not alter CBD-mediated antinociception, but selective blockade of ATP-sensitive K+ channels dose-dependently reversed CBD-induced antinociception. Inhibition of S-nitrosylation dose-dependently and completely reversed CBD-mediated antinociception.

Conclusion: Cannabidiol has an antinociceptive effect when administered systemically and this effect is mediated by the activation of PI3Kγ as well as by nitric oxide and subsequent direct S-nitrosylation of KATP channels on peripheral nociceptors.”

“Canabidiol (CBD) induces significant analgesia at 20 mg/kg in neuropathic mice.”

Exploring the therapeutic potential of cannabidiol for sleep deprivation-induced hyperalgesia

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“Hyperalgesia resulting from sleep deprivation (SD) poses a significant a global public health challenge with limited treatment options. The nucleus accumbens (NAc) plays a crucial role in the modulation of pain and sleep, with its activity regulated by two distinct types of medium spiny neurons (MSNs) expressing dopamine 1 or dopamine 2 (D1-or D2) receptors (referred to as D1-MSNs and D2-MSNs, respectively). However, the specific involvement of the NAc in SD-induced hyperalgesia remains uncertain.

Cannabidiol (CBD), a nonpsychoactive phytocannabinoid, has demonstrated analgesic effects in clinical and preclinical studies. Nevertheless, its potentcy in addressing this particular issue remains to be determined.

Here, we report that SD induced a pronounced pronociceptive effect attributed to the heightened intrinsic excitability of D2-MSNs within the NAc in Male C57BL/6N mice. CBD (30 mg/kg, i.p.) exhibited an anti-hyperalgesic effect. CBD significantly improved the thresholds for thermal and mechanical pain and increased wakefulness by reducing delta power. Additionally, CBD inhibited the intrinsic excitability of D2-MSNs both in vitro and in vivo. Bilateral microinjection of the selective D2 receptor antagonist raclopride into the NAc partially reversed the antinociceptive effect of CBD. Thus, these findings strongly suggested that SD activates NAc D2-MSNs, contributing heightened to pain sensitivity.

CBD exhibits antinociceptive effects by activating D2R, thereby inhibiting the excitability of D2-MSNs and promoting wakefulness under SD conditions.”

“CBD could be a candidate for treating sleep deprivation induced hyperalgesia.”

Cannabinoids for Cancer-related Pain Management: An Update on Therapeutic Applications and Future Perspectives

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“Pain is a debilitating phenomenon that dramatically impairs the quality of life of patients. Many chronic conditions, including cancer, are associated with chronic pain. Despite pharmacological efforts that have been conducted, many patients suffering from cancer pain remain without treatment. To date, opioids are considered the preferred therapeutic choice for cancer-related pain management.

Unfortunately, opioid treatment causes side effects and inefficiently relieves patients from pain, therefore alternative therapies have been considered, including Cannabis Sativa and cannabinoids.

Accumulating evidence has highlighted that an increasing number of patients are choosing to use cannabis and cannabinoids for the management of their soothing and non-palliative cancer pain and other cancer-related symptoms. However, their clinical application must be supported by convincing and reproducible clinical trials.

In this review, we provide an update on cannabinoid use for cancer pain management. Moreover, we tried to turn a light on the potential use of cannabis as a possible therapeutic option for cancer-related pain relief.”

Targeting the endocannabinoid system for the management of low back pain

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“Low back pain (LBP) is a major unmet clinical need. The endocannabinoid system (ECS) has emerged as a promising therapeutic target for pain, including LBP. This review examines the evidence for the ECS as a therapeutic target for LBP. While preclinical studies demonstrate the potential of the ECS as a viable therapeutic target, clinical trials have presented conflicting findings. This review underscores the need for innovative LBP treatments and biomarkers and proposes the ECS as a promising avenue for their exploration. A deeper mechanistic understanding of the ECS in LBP could inform the development of new pain management strategies.”

Tetrahydrocannabinol and Cannabidiol for Pain Treatment-An Update on the Evidence

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“In light of the current International Association for the Study of Pain (IASP) clinical practice guidelines (CPGs) and the European Society for Medical Oncology (ESMO) guidelines, the topic of cannabinoids in relation to pain remains controversial, with insufficient research presently available.

Cannabinoids are an attractive pain management option due to their synergistic effects when administered with opioids, thereby also limiting the extent of respiratory depression.

On their own, however, cannabinoids have been shown to have the potential to relieve specific subtypes of chronic pain in adults, although controversies remain. Among these subtypes are neuropathic, musculoskeletal, cancer, and geriatric pain.

Another interesting feature is their effectiveness in chemotherapy-induced peripheral neuropathy (CIPN). Analgesic benefits are hypothesized to extend to HIV-associated neuropathic pain, as well as to lower back pain in the elderly.

The aim of this article is to provide an up-to-date review of the existing preclinical as well as clinical studies, along with relevant systematic reviews addressing the roles of various types of cannabinoids in neuropathic pain settings. The impact of cannabinoids in chronic cancer pain and in non-cancer conditions, such as multiple sclerosis and headaches, are all discussed, as well as novel techniques of administration and relevant mechanisms of action.”

Vaporized Cannabis versus Placebo for Acute Migraine: A Randomized Controlled Trial

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“Preclinical and retrospective studies suggest cannabinoids may be effective in migraine treatment. However, there have been no randomized clinical trials examining the efficacy of cannabinoids for acute migraine.

In this randomized, double-blind, placebo-controlled, crossover trial, adults with migraine treated up to 4 separate migraine attacks, 1 each with vaporized 1) 6% tetrahydrocannabinol (THC-dominant); 2) 11% cannabidiol (CBD-dominant); 3) 6% THC+11% CBD; and 4) placebo cannabis flower in a randomized order. Washout period between treated attack was 1 week. The primary endpoint was pain relief and secondary endpoints were pain freedom and most bothersome symptom (MBS) freedom, all assessed at 2 hours post-vaporization.

Results Ninety-two participants were enrolled and randomized, and 247 migraine attacks were treated. THC+CBD was superior to placebo at achieving pain relief (67.2% vs 46.6%, Odds Ratio [95% Confidence Interval] 2.85 [1.22, 6.65], p=0.016), pain freedom (34.5% vs. 15.5%, 3.30 [1.24, 8.80], p=0.017) and MBS freedom (60.3% vs. 34.5%, 3.32 [1.45, 7.64], p=0.005) at 2 hours, as well as sustained pain freedom at 24 hours and sustained MBS freedom at 24 and 48 hours. THC-dominant was superior to placebo for pain relief (68.9% vs. 46.6%, 3.14 [1.35, 7.30], p=0.008) but not pain freedom or MBS freedom at 2 hours. CBD-dominant was not superior to placebo for pain relief, pain freedom or MBS freedom at 2 hours. There were no serious adverse events.

Conclusions Acute migraine treatment with 6% THC+11% CBD was superior to placebo at 2 hours post-treatment with sustained benefits at 24 and 48 hours.”

Cannabidiol for Postoperative Pain Control After Arthroscopic Rotator Cuff Repair Demonstrates No Deficits in Patient-Reported Outcomes Versus Placebo: 1-Year Follow-up of a Randomized Controlled Trial

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“Background: Cannabidiol (CBD) has been shown recently to positively affect patient pain and satisfaction immediately after arthroscopic rotator cuff repair (ARCR). However, it is unclear whether the addition of CBD to a perioperative regimen could affect postoperative outcomes.

Purpose: To evaluate patient-reported outcomes among patients who underwent ARCR and received buccally absorbed CBD or an identical placebo for early postoperative pain management at 1-year follow-up.

Study design: Randomized controlled trial; Level of evidence, 2.

Methods: Eligible patients had previously participated in a multicenter, placebo-controlled, randomized, double-blinded trial that evaluated the analgesic effects of CBD in the immediate postoperative period after ARCR. The experimental group received 25 mg of CBD 3 times/day if <80 kg and 50 mg of CBD 3 times/day if >80 kg for 14 days, with the control group receiving an identical placebo. The following outcomes were assessed at minimum 1-year follow-up: visual analog scale (VAS) for pain, American Shoulder and Elbow Surgeons (ASES) score, Single Assessment Numeric Evaluation (SANE), and patient satisfaction. The rates of achievement of the Patient Acceptable Symptom State (PASS) were compared based on ASES at latest follow-up. Continuous and categorical variables were compared with the Mann-Whitney U test and Fisher exact test, respectively.

Results: Follow-up was obtained from 83 of 99 patients (83.8%) who completed the original trial. There were no significant differences between the CBD and control groups with respect to age, sex, body mass index, rate of concomitant procedures, or number of anchors used intraoperatively. At 1-year follow-up, there were no significant differences between the CBD and control groups in VAS pain (0.8 vs 1.2, P = .38), ASES (93.0 vs 91.1, P = .71), SANE (87.6 vs 90.1, P = .24), or satisfaction (97.4 vs 95.4, P = .41). A majority of patients achieved the PASS (81.0% [CBD] vs 77.5% [control]; P = .79).

Conclusion: Perioperative use of CBD for pain control among patients undergoing ARCR did not result in any significant deficits in pain, satisfaction, or patient-reported outcomes at 1-year postoperatively compared with a placebo control group. These findings suggest that CBD can be considered in a postoperative multimodal pain management regimen without detrimental effects on outcome.”

“The Cannabis sativa plant is a promising alternative for augmented pain control”