Cannabinoids for the treatment of refractory neuropathic pruritus in amyotrophic lateral sclerosis: A case report

Journals | SAGE Publications Inc“Background: Neuropathic symptoms have a wide variety of manifestations, ranging from pain to pruritus. Neuropathic pruritus is a type of chronic pruritus related to damaged small fibers. Cannabinoids have evidence to manage neuropathic symptoms. We present a case of refractory neuropathic pruritus that was successfully managed with the use of oral cannabinoids.

Case presentation: A 60-year-old male with amyotrophic lateral sclerosis with ongoing pruritus despite the use of standard neuropathic therapies.

Formulation of a plan: A balanced oral cannabinoid from a licensed producer was preferred as it has evidence for neuropathic symptoms and is generally well tolerated.

Outcome: The patient showed improvement to his pruritus score from 7/10 to 3/10. There was initial increased sedation but tolerance developed quickly.

Lessons learned from case: Cannabinoids are possibly safe and effective in management of neuropathic pruritus.”

https://pubmed.ncbi.nlm.nih.gov/34510973/

“Neuropathic pruritus is a chronic form of pruritus that causes significant symptom burden and can be difficult to treat. Cannabinoids have evidence to manage chronic neuropathic pain. This case demonstrates the safe and effective use of cannabinoids to manage neuropathic pruritus.”

https://journals.sagepub.com/doi/10.1177/02692163211045314

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Targeting the endocannabinoid system for management of HIV-associated neuropathic pain: A systematic review

IBRO Neuroscience Reports“Human immunodeficiency virus (HIV) infection and antiretroviral therapy can independently induce HIV-associated neuropathic pain (HIV-NP).

Smoked cannabis has been reported to improve pain measures in patients with neuropathic pain.

Two clinical trials demonstrated greater efficacy of smoked cannabis over placebo in alleviating HIV-NP.

The available preclinical results suggest that targeting the ECS for prevention and treatment of HIV-NP is a plausible therapeutic option.

Clinical evidence shows that smoked cannabis alleviates HIV-NP.” 

https://pubmed.ncbi.nlm.nih.gov/34179865/

“Smoked cannabis has been shown to be effective for managing HIV-NP in two RCTs.”

https://www.sciencedirect.com/science/article/pii/S2667242121000051?via%3Dihub

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Antinociception mechanisms of action of cannabinoid-based medicine: an overview for anesthesiologists and pain physicians

 Pain Rounds“Cannabinoid-based medications possess unique multimodal analgesic mechanisms of action, modulating diverse pain targets.

Cannabinoids are classified based on their origin into three categories: endocannabinoids (present endogenously in human tissues), phytocannabinoids (plant derived) and synthetic cannabinoids (pharmaceutical). Cannabinoids exert an analgesic effect, peculiarly in hyperalgesia, neuropathic pain and inflammatory states.

Endocannabinoids are released on demand from postsynaptic terminals and travels retrograde to stimulate cannabinoids receptors on presynaptic terminals, inhibiting the release of excitatory neurotransmitters. Cannabinoids (endogenous and phytocannabinoids) produce analgesia by interacting with cannabinoids receptors type 1 and 2 (CB1 and CB2), as well as putative non-CB1/CB2 receptors; G protein-coupled receptor 55, and transient receptor potential vanilloid type-1. Moreover, they modulate multiple peripheral, spinal and supraspinal nociception pathways.

Cannabinoids-opioids cross-modulation and synergy contribute significantly to tolerance and antinociceptive effects of cannabinoids. This narrative review evaluates cannabinoids’ diverse mechanisms of action as it pertains to nociception modulation relevant to the practice of anesthesiologists and pain medicine physicians.”

https://pubmed.ncbi.nlm.nih.gov/33239391/

https://rapm.bmj.com/content/early/2020/11/24/rapm-2020-102114

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A Critical Review of the Role of the Cannabinoid Compounds Δ 9-Tetrahydrocannabinol (Δ 9-THC) and Cannabidiol (CBD) and their Combination in Multiple Sclerosis Treatment

molecules-logo“Many people with MS (pwMS) use unregulated cannabis or cannabis products to treat the symptoms associated with the disease. In line with this, Sativex, a synthetic combination of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (Δ9-THC) has been approved to treat symptoms of spasticity.

In animals, CBD is effective in reducing the amounts of T-cell infiltrates in the spinal cord, suggesting CBD has anti-inflammatory properties. By doing this, CBD has shown to delay symptom onset in animal models of multiple sclerosis and slow disease progression. Importantly, combinations of CBD and Δ9-THC appear more effective in treating animal models of multiple sclerosis.

While CBD reduces the amounts of cell infiltrates in the spinal cord, Δ9-THC reduces scores of spasticity. In human studies, the results are less encouraging and conflict with the findings in animals. Drugs which deliver a combination of Δ9-THC and CBD in a 1:1 ratio appear to be only moderately effective in reducing spasticity scores, but appear to be almost as effective as current front-line treatments and cause less severe side effects than other treatments, such as baclofen (a GABA-B receptor agonist) and tizanidine (an α2 adrenergic receptor agonist).

The findings of the studies reviewed suggest that cannabinoids may help treat neuropathic pain in pwMS as an add-on therapy to already established pain treatments.

Long term double-blind placebo studies are greatly needed to further our understanding of the role of cannabinoids in multiple sclerosis treatment.”

https://pubmed.ncbi.nlm.nih.gov/33113776/

https://www.mdpi.com/1420-3049/25/21/4930

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Insights on cannabidiol’s antiallodynic and anxiolytic mechanisms of action in a model of neuropathic pain

PAIN Impact Factor Increase to 6.029 - IASP“Recent studies have shown that cannabidiol (CBD) could have a great therapeutic potential for treating disorders such as chronic pain and anxiety. In the target article, the authors propose that CBD modulates serotonergic transmission and reverses allodynia and anxiety-like behaviour in a rat model of neuropathic pain. Furthermore, this study shows an antinociceptive effect mediated by TRPV1 and partially by 5-HT1A receptors, as well as an anxiolytic effect mediated by 5-HT1A receptors.”

https://pubmed.ncbi.nlm.nih.gov/32766463/

https://journals.lww.com/painrpts/Fulltext/2019/10000/Insights_on_cannabidiol_s_antiallodynic_and.10.aspx

“Cannabidiol modulates serotonergic transmission and reverses both allodynia and anxiety-like behavior in a model of neuropathic pain”  https://pubmed.ncbi.nlm.nih.gov/30157131/

 

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Spinal cannabinoid CB1 or CB2 receptors activation attenuates mechanical allodynia in streptozotocin-induced diabetic rats

 Behavioural Pharmacology“Diabetes is a chronic disease associated with a high number of complications such as peripheral neuropathy, which causes sensorial disturbances and may lead to the development of diabetic neuropathic pain (DNP). The current treatment for DNP is just palliative and the drugs may cause severe adverse effects, leading to discontinuation of treatment. Thus, new therapeutic targets need to be urgently investigated.

Studies have shown that cannabinoids have promising effects in the treatment of several pathological conditions, including chronic pain.

Thus, we aimed to investigate the acute effect of the intrathecal injection of CB1 or CB2 cannabinoid receptor agonists N-(2-chloroethyl)-5Z, 8Z, 11Z, 14Z-eicosatetraenamide (ACEA) or JWH 133, respectively (10, 30 or 100 μg/rat) on the mechanical allodynia associated with experimental diabetes induced by streptozotocin (60 mg/kg; intraperitoneal) in rats.

Cannabinoid receptor antagonists CB1 AM251 or CB2 AM630 (1 mg/kg) were given before treatment with respective agonists to confirm the involvement of cannabinoid CB1 or CB2 receptors. Rats with diabetes exhibited a significant reduction on the paw mechanical threshold 2 weeks after diabetes induction, having the maximum effect observed 4 weeks after the streptozotocin injection. This mechanical allodynia was significantly improved by intrathecal treatment with ACEA or JWH 133 (only at the higher dose of 100 μg). Pre-treatment with AM251 or AM630 significantly reverted the anti-allodynic effect of the ACEA or JWH 133, respectively.

Considering the clinical challenge that the treatment of DPN represents, this study showed for the first time, that the intrathecal cannabinoid receptors agonists may represent an alternative for the treatment of DNP.”

https://pubmed.ncbi.nlm.nih.gov/32804775/

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Protective role of neuronal and lymphoid cannabinoid CB 2 receptors in neuropathic pain

 eLife logo“Cannabinoid CB2 receptor (CB2) agonists are potential analgesics void of psychotropic effects.

Peripheral immune cells, neurons and glia express CB2, however the involvement of CB2 from these cells in neuropathic pain remains unresolved. We explored spontaneous neuropathic pain through on-demand self-administration of the selective CB2 agonist JWH133 in wild-type and knockout mice lacking CB2 in neurons, monocytes or constitutively. Operant self-administration reflected drug-taking to alleviate spontaneous pain, nociceptive and affective manifestations. While constitutive deletion of CB2 disrupted JWH133-taking behavior, this behavior was not modified in monocyte-specific CB2 knockouts and was increased in mice defective in neuronal CB2 knockouts suggestive of increased spontaneous pain. Interestingly, CB2-positive lymphocytes infiltrated the injured nerve and possible CB2transfer from immune cells to neurons was found. Lymphocyte CB2depletion also exacerbated JWH133 self-administration and inhibited antinociception.

This work identifies a simultaneous activity of neuronal and lymphoid CB2that protects against spontaneous and evoked neuropathic pain.”

https://pubmed.ncbi.nlm.nih.gov/32687056/

https://elifesciences.org/articles/55582

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The Therapeutic Effectiveness of Full Spectrum Hemp Oil Using a Chronic Neuropathic Pain Model

life-logo“Few models exist that can control for placebo and expectancy effects commonly observed in clinical trials measuring ‘Cannabis’ pharmacodynamics. We used the Foramen Rotundum Inflammatory Constriction Trigeminal Infraorbital Nerve injury (FRICT-ION) model to measure the effect of “full-spectrum” whole plant extracted hemp oil on chronic neuropathic pain sensitivity in mice.

Results: Mechanical allodynia was alleviated within 1 h (d = 2.50, p < 0.001) with a peak reversal effect at 4 h (d = 7.21, p < 0.001) and remained significant throughout the 6 h observation window. There was no threshold change on contralateral whisker pad after hemp oil administration, demonstrating the localization of anesthetic response to affected areas.

Conclusion: Future research should focus on how whole plant extracted hemp oil affects multi-sensory and cognitive-attentional systems that process pain.

The present study shows for the first time that common, commercially available, and easily reproducible full-spectrum hemp oil induces significant anti-allodynic effects with a bell-shaped pain sensitivity effect peeking between 2 and 4 h and lasting over 6 h. The study provides evidence that phytochemical extracts of the Cannabis plant, even with relatively low levels of THC, can significantly improve mechanical pressure pain in animals with established chronic neuropathic hypersensitivity.”

https://www.mdpi.com/2075-1729/10/5/69/htm

“Legal Cannabis hemp oil effectively treats chronic neuropathic pain: study”   https://medicalxpress.com/news/2020-05-legal-cannabis-hemp-oil-effectively.html

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Investigation of cannabidiol gastro retentive tablets based on regional absorption of cannabinoids in rats.

European Journal of Pharmaceutics and Biopharmaceutics“The cannabis plant has been widely researched for many therapeutic indications and found to be effective in many chronic conditions such as epilepsy, neuropathic or chronic pain and more. However, biased opinion against compounds of the plant, regulatory as well as compounding challenges have led to very few approved medicinal products. Those formulations which are approved are dosed several times a day, creating an unmet need for controlled release (CR) formulations of cannabinoids. Conventional CR formulations rely on prolonged absorption including the colon. The purpose of this work is to investigate regional absorption of major cannabinoids THC and CBD from the colon and develop a suitable CR formulation. As hypothesized by researchers, THC and CBD have poor absorption from the colon compared to small intestine, suggesting that these compounds have a narrow absorption window. The suggested formulation examined in-vitro was a floating gastro retentive tablet based on egg albumin matrix, gas generating agents and surfactants. In-vivo investigation of CBD containing formulation in the freely moving rat model proved a prolonged absorption phase with a substantial increase in bioavailability compared to CBD solution. The findings of this paper answer a crucial question regarding potential application of CR dosage forms for cannabinoids and shed light on the regional intestinal absorption of these compounds. Ultimately, these results cement the way for future development of cannabinoid gastro retentive dosage forms.”

https://www.ncbi.nlm.nih.gov/pubmed/32422168

https://www.sciencedirect.com/science/article/abs/pii/S0939641120301375?via%3Dihub

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Novel approaches and current challenges with targeting the endocannabinoid system.

 Publication Cover“The pathophysiological relevance of the endocannabinoid system has been widely demonstrated in a variety of diseases including cancer, neurological disorders, and metabolic issues. Therefore, targeting the receptors and the endogenous machinery involved in this system can provide a successful therapeutic outcome.

Ligands targeting the canonical cannabinoid receptors, CB1 and CB2, along with inhibitors of the endocannabinoid enzymes have been thoroughly studied in diverse disease models. In fact, phytocannabinoids such as cannabidiol or Δ9-tetrahydrocannabinol are currently on the market for the management of neuropathic pain due to spasticity in multiple sclerosis or seizures in children epilepsy amongst others.

Expert opinion: Even if orthosteric CB1 and CB2 ligands are on the forefront in cannabinoid clinical research, emerging strategies such as allosteric or biased modulation of these receptors along with controlled off-targets effects may increase the therapeutic potential of cannabinoids.”

https://www.ncbi.nlm.nih.gov/pubmed/32336154

“Multi-target approaches could be promising strategies for the treatment of endocannabinoid system-related disorders. The authors believe that phytocannabinoids are at the forefront of future clinical research.”

https://www.tandfonline.com/doi/abs/10.1080/17460441.2020.1752178?journalCode=iedc20

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