Results of a Double-Blind, Randomized, Placebo-Controlled Study of Nabiximols Oromucosal Spray as Adjunctive Therapy in Advanced Cancer Patients With Chronic Uncontrolled Pain.

Journal of Pain and Symptom Management Home

“Prior phase 2/3 studies found that cannabinoids might provide adjunctive analgesia in advanced cancer patients with uncontrolled pain.

To assess adjunctive nabiximols (Sativex®), an extract of Cannabis sativa containing two potentially therapeutic cannabinoids (Δ9-tetrahydrocannabinol and cannabidiol, in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy.

Nabiximols was statistically superior to placebo on two of three quality-of-life instruments at week 3 and on all three at week 5.

The safety profile of nabiximols was consistent with earlier studies.

Although not superior to placebo on the primary efficacy endpoint, nabiximols had benefits on multiple secondary endpoints, particularly in US patients.

Nabiximols might have utility in patients with advanced cancer who receive a lower opioid dose, such as individuals with early intolerance to opioid therapy.”

https://www.ncbi.nlm.nih.gov/pubmed/28923526

http://www.jpsmjournal.com/article/S0885-3924(17)30465-7/fulltext

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Effects of Centrally Administered Endocannabinoids and Opioids on Orofacial Pain Perception in Rats.

British Journal of Pharmacology

“Endocannabinoids and opioids play a vital role in mediating pain-induced analgesia.

The specific effects of these compounds within orofacial region are largely unknown. In this study we tried to determine whether the increase of cannabinoid and opioid concentration in cerebrospinal fluid affects impulse transmission between the motor centers localized in the vicinity of the third and fourth cerebral ventricles.

We demonstrated that in the orofacial area analgesic activity is modulated by AEA and that EM-2-induced antinociception was mediated by MOR and CB1 receptors. The action of AEA and EM-2 is tightly regulated by FAAH and FAAH/MAGL, by preventing the breakdown of endogenous cannabinoids in regions where they are produced on demand.

Therefore, the current findings support the therapeutic potential of FAAH and FAAH/MAGL inhibitors as novel pharmacotherapeutic agents for orofacial pain.”

https://www.ncbi.nlm.nih.gov/pubmed/28771697

http://onlinelibrary.wiley.com/doi/10.1111/bph.13970/abstract

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Endocannabinoids in arthritis: current views and perspective.

International Journal of Rheumatic Diseases

“Preclinical and clinical studies using cannabis-based therapy have been shown to provide both analgesia and anti-inflammatory effects, with an overall alleviation of clinical symptoms in animal models of arthritis, highlighting its promising therapeutic application for humans. Despite this, the development of cannabis-based therapeutics remains in its infancy, with further investigation into its efficacy and safety profile in patients still required. This synopsis reviews the various components of the endocannabinoid system in health and disease and their potential as therapeutic targets.”

https://www.ncbi.nlm.nih.gov/pubmed/28736968

http://onlinelibrary.wiley.com/doi/10.1111/1756-185X.13146/abstract

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Nonopioid placebo analgesia is mediated by CB1 cannabinoid receptors.

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“Placebo analgesia is mediated by both opioid and nonopioid mechanisms, but so far nothing is known about the nonopioid component. Here we show that the specific CB1 cannabinoid receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (rimonabant or SR141716) blocks nonopioid placebo analgesic responses but has no effect on opioid placebo responses. These findings suggest that the endocannabinoid system has a pivotal role in placebo analgesia in some circumstances when the opioid system is not involved.”

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Continuous Intrathecal Infusion of Cannabinoid Receptor Agonists Attenuates Nerve Ligation-Induced Pain in Rats.

 

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“Cannabinoid receptors (CB1R/CB2R) are known to play important roles in pain transmission.

In this study, we investigated the effects of continuous intrathecal infusion of CB1/2R agonists in the L5/6 spinal nerve ligation pain model.

Continuous intrathecal infusion of CB1/2R agonists elicits antinociception in the pain model.

The mechanisms might involve their actions on neurons and glial cells. CB2R, but not CB1R, seems to play an important role in the regulation of nerve injury-induced neuroinflammation.”

https://www.ncbi.nlm.nih.gov/pubmed/28492437

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Cannabis for Pain and Headaches: Primer.

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“Marijuana has been used both medicinally and recreationally since ancient times and interest in its compounds for pain relief has increased in recent years. The identification of our own intrinsic, endocannabinoid system has laid the foundation for further research.

Synthetic cannabinoids are being developed and synthesized from the marijuana plant such as dronabinol and nabilone. The US Food and Drug Administration approved the use of dronabinol and nabilone for chemotherapy-associated nausea and vomiting and HIV (Human Immunodeficiency Virus) wasting. Nabiximols is a cannabis extract that is approved for the treatment of spasticity and intractable pain in Canada and the UK. Further clinical trials are studying the effect of marijuana extracts for seizure disorders.

Phytocannabinoids have been identified as key compounds involved in analgesia and anti-inflammatory effects.  Other compounds found in cannabis such as flavonoids and terpenes are also being investigated as to their individual or synergistic effects.

This article will review relevant literature regarding medical use of marijuana and cannabinoid pharmaceuticals with an emphasis on pain and headaches.”

https://www.ncbi.nlm.nih.gov/pubmed/28281107

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Cannabinoid receptor 2 agonist attenuates pain related behavior in rats with chronic alcohol/high fat diet induced pancreatitis

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“Chronic Pancreatitis (CP) is a complex and multifactorial syndrome. Many contributing factors result in development of dysfunctional pain in a significant number of patients. Drugs developed to treat a variety of pain states fall short of providing effective analgesia for patients with chronic pancreatitis, often providing minimal to partial pain relief over time with significant side effects.

Recently, availability of selective pharmacological tools has enabled great advances in our knowledge of the role of the cannabinoid receptors in pathophysiology. In particular, cannabinoid receptor 2 (CB2) has emerged as an attractive target for management of chronic pain, as demonstrated in several studies with inflammatory and neuropathic preclinical pain models. In this study, the analgesic efficacy of a novel, highly selective CB2 receptor agonist, LY3038404 HCl, is investigated in a chronic pancreatitis pain model, induced with an alcohol/high fat (AHF) diet.

LY3038404 HCl, a potent CB2 receptor agonist, possesses tissue protective and analgesic properties without effects on higher brain function. Thus, activation of CB2 receptors is suggested as a potential therapeutic target for visceral inflammation and pain management.

The major finding of the present study is that LY3038404 HCl, a potent CB2 receptor agonist, possesses tissue protective and analgesic properties. No effects on higher brain functions were observed including the diminished fear responses induced by the alcohol diet. Thus, activation of CB2 receptors is suggested as a potential therapeutic target for pancreas protection and pain management.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4242547/

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Effects on Spasticity and Neuropathic Pain of an Oral Formulation of Δ9-Tetrahydrocannabinol in Patients With Progressive Multiple Sclerosis

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“The aim of the present study was to evaluate the efficacy of an oral formulation of Δ9-tetrahydrocannabinol (ECP002A) in patients with progressive multiple sclerosis (MS).

Pain was significantly reduced when measured directly after administration of ECP002A in the clinic but not when measured in a daily diary. A similar pattern was observed in subjective muscle spasticity. Other clinical outcomes were not significantly different between active treatment and placebo. Cognitive testing indicated that there was no decline in cognition after 2 or 4 weeks of treatment attributable to ECP002A compared with placebo.

Implications This study specifically underlines the added value of thorough investigation of pharmacokinetic and pharmacodynamic associations in the target population. Despite the complex interplay of psychoactive effects and analgesia, the current oral formulation of Δ9-tetrahydrocannabinol may play a role in the treatment of spasticity and pain associated with MS because it was well tolerated and had a stable pharmacokinetic profile.”

https://www.ncbi.nlm.nih.gov/pubmed/28189366

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The central cannabinoid receptor type-2 (CB2) and chronic pain.

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“Cannabinoid receptor type-2 (CB2, CB2 Receptor, or CB2-R) mediates analgesia, via two mechanisms. CB2 receptors contained in peripheral immune tissue mediates analgesia by altering cytokine profiles, and thus has little adverse effects on central nervous systems. CB2 is also expressed in the neurons and glial cells of the Central Nervous System (CNS). This neuronal expression may also contribute to pain attenuation. The CB2 receptor has been proposed as a potential target in treating chronic pain of several etiologies.”

https://www.ncbi.nlm.nih.gov/pubmed/27842450

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NSAIDs, Opioids, Cannabinoids and the Control of Pain by the Central Nervous System.

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“Nonsteroidal anti-inflammatory drugs (NSAIDs) act upon peripheral tissues and upon the central nervous system to produce analgesia. A major central target of NSAIDs is the descending pain control system. The rostral structures of the descending pain control system send impulses towards the spinal cord and regulate the transmission of pain messages. Key structures of the descending pain control system are the periaqueductal gray matter (PAG) and the rostral ventromedial region of the medulla (RVM), both of which are critical targets for endogenous opioids and opiate pharmaceuticals. NSAIDs also act upon PAG and RVM to produce analgesia and, if repeatedly administered, induce tolerance to themselves and cross-tolerance to opioids. Experimental evidence shows that this is due to an interaction of NSAIDs with endogenous opioids along the descending pain control system. Analgesia by NSAIDs along the descending pain control system also requires an activation of the CB1 endocannabinoid receptor. Several experimental approaches suggest that opioids, NSAIDs and cannabinoids in PAG and RVM cooperate to decrease GABAergic inhibition and thus enhance the descending flow of impulses that inhibit pain.”

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