Category Archives: Pain

Cannabinoid Buccal Spray for Chronic Non-Cancer or Neuropathic Pain: A Review of Clinical Effectiveness, Safety, and Guidelines [Internet].

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“Chronic pain is a complex, severe and debilitating condition which can lead to a considerable reduction in function and quality of life. Patients may present with different forms of chronic pain resulting from a number of identifiable causes, including pain due to lesion or dysfunction of the nerves, spinal cord or brain (neuropathic pain), or persistent pain caused by other non-malignant conditions, such as low-back pain or pain due to inflammation of various arthritic conditions. The prevalence of chronic non-cancer pain or neuropathic pain among Canadian adults is not well known. However, prevalence estimates using large, population-based questionnaires have shown that 4% to 8% of the general population in the developed world experiences neuropathic pain, suggesting that approximately two million Canadians may be affected by this disabling condition. Chronic pain is of particular concern among Canadians aged 65 years and older; based on cross-sectional data from the 1996/1997 National Population Health Survey and the 2005 Canadian Community Health Survey, chronic pain was estimated to affect 27% and 38% of seniors living in households and health care institutions, respectively. A number of treatments are available for the management of neuropathic pain or chronic non-cancer pain. These include tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (duloxetine, venlafaxine), anticonvulsants (pregabalin, gabapentin, carbamazepine, phenytoin), topical lidocaine, and opioid analgesics. However, these medications are associated with limited pain relief and numerous adverse effects. The therapeutic use of several synthetic cannabinoid products for the symptomatic relief of chronic pain has also been studied. In particular, a combination of two products, delta-9-tetrahydrocannabinol and cannabidiol (THC:CBD) marketed under the name Sativex® is available for use as a buccal spray. This cannabis-based agent is approved for use in Canada as an add-on therapy for adult patients experiencing muscle spasticity caused by multiple sclerosis (MS), and it has received a Notice of Compliance with conditions for MS-related central neuropathic pain and the treatment of cancer pain unresponsive to opioids. The purpose of this review is to examine the available published literature relating to THC:CBD buccal spray for the treatment of chronic non-cancer or neuropathic pain in adults.”

https://www.ncbi.nlm.nih.gov/pubmed/27831665

Descending serotonergic and noradrenergic systems do not regulate the antipruritic effects of cannabinoids.

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“For centuries, cannabinoids have been known to be effective in pain states. Itch and pain are two sensations sharing a lot in common.

OBJECTIVE:

The goal of this research was to observe whether the cannabinoid agonist WIN 55,212-2 reduces serotonin-induced scratching behaviour and whether neurotoxic destruction of descending serotonergic and noradrenergic pathways mediate the antipruritic effect of WIN 55,212-2.

CONCLUSION:

Our findings indicate that cannabinoids dose-dependently reduce serotonin-induced scratching behaviour and neurotoxic destruction of descending inhibitory pathways does not mediate this antipruritic effect.”

https://www.ncbi.nlm.nih.gov/pubmed/27805543

 

Opioids Out, Cannabis In

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“Negotiating the Unknowns in Patient Care for Chronic Pain”

“With the current nationwide epidemic of opioid abuse, dependence, and fatalities, clinicians are being asked by federal agencies and professional societies to control their prescribing of narcotic medications for pain. Federal guidelines emphasize tapering, discontinuing, and limiting initiation of these drugs except in provision of end-of-life care. Reducing reliance on opioids, however, is a massive task. According to one estimate, more than 650 000 opioid prescriptions are dispensed each day in the United States. Unless the nation develops an increased tolerance to chronic pain, reduction in opioid prescribing leaves a vacuum that will be filled with other therapies.”

http://jamanetwork.com/journals/jama/article-abstract/2576617

Crystal Structure of the Human Cannabinoid Receptor CB1.

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“Cannabinoid receptor 1 (CB1) is the principal target of Δ9-tetrahydrocannabinol (THC), a psychoactive chemical from Cannabis sativa with a wide range of therapeutic applications and a long history of recreational use.

CB1 is activated by endocannabinoids and is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders.

Here, we present the 2.8 Å crystal structure of human CB1 in complex with AM6538, a stabilizing antagonist, synthesized and characterized for this structural study.

The structure of the CB1-AM6538 complex reveals key features of the receptor and critical interactions for antagonist binding.

In combination with functional studies and molecular modeling, the structure provides insight into the binding mode of naturally occurring CB1 ligands, such as THC, and synthetic cannabinoids.

This enhances our understanding of the molecular basis for the physiological functions of CB1 and provides new opportunities for the design of next-generation CB1-targeting pharmaceuticals.”

https://www.ncbi.nlm.nih.gov/pubmed/27768894

Effect of medical cannabis on thermal quantitative measurements of pain in patients with Parkinson’s disease.

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“Cannabis can alleviate pain of various etiologies.

This study assessed the effect of cannabis on motor symptoms and pain parameters in patients with Parkinson’s disease (PD).

CONCLUSIONS:

Cannabis improved motor scores and pain symptoms in PD patients, together with a dissociate effect on heat and cold pain thresholds. Peripheral and central pathways are probably modulated by cannabis.

SIGNIFICANCE:

Quantitative sensory test results are significantly altered following cannabis consumption in patients with PD. Cannabis probably acts on pain in PD via peripheral and central pathways.”

https://www.ncbi.nlm.nih.gov/pubmed/27723182

The Role of Cannabinoid Receptors in the Descending Modulation of Pain.

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“The endogenous antinociceptive descending pathway represents a circuitry of the supraspinal central nervous system whose task is to counteract pain. It includes the periaqueductal grey (PAG)-rostral ventromedial medulla (RVM)-dorsal horn (DH) axis, which is the best characterized pain modulation system through which pain is endogenously inhibited. Thus, an alternative rational strategy for silencing pain is the activation of this anatomical substrate.

Evidence of the involvement of cannabinoid receptors (CB) in the supraspinal modulation of pain can be found in several studies in which intra-cerebral microinjections of cannabinoid ligands or positive modulators have proved to be analgesic in different pain models, whereas cannabinoid receptor antagonists or antisense nucleotides towards CB1 receptors have facilitated pain.

Like opioids, cannabinoids produce centrally-mediated analgesia by activating a descending pathway which includes PAG and its projection to downstream RVM neurons, which in turn send inhibitory projections to the dorsal horn of the spinal cord.

Indeed, several studies underline a supraspinal regulation of cannabinoids on g-aminobutyric acid (GABA) and glutamate release which inhibit and enhance the antinociceptive descending pathway, respectively. Cannabinoid receptor activation expressed on presynaptic GABAergic terminals reduces the probability of neurotransmitter release thus dis-inhibiting the PAG-RVM-dorsal horn antinociceptive pathway.

Cannabinoids seem to increase glutamate release (maybe as consequence of GABA decrease) and to require glutamate receptor activation to induce antinociception. The consequent outcome is behavioral analgesia, which is reproduced in several pain conditions, from acute to chronic pain models such as inflammatory and neuropathic pain.

Taken together these findings would suggest that supraspinal cannabinoid receptors have broad applications, from pain control to closely related central nervous system diseases such as anxiety and depression.”

https://www.ncbi.nlm.nih.gov/pubmed/27713370

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.”

 https://www.ncbi.nlm.nih.gov/pubmed/27713305

β-caryophyllene and β-caryophyllene oxide-natural compounds of anticancer and analgesic properties.

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Cancer Biology & Medicine

“Natural bicyclic sesquiterpenes, β-caryophyllene (BCP) and β-caryophyllene oxide (BCPO), are present in a large number of plants worldwide.

Both BCP and BCPO (BCP(O)) possess significant anticancer activities, affecting growth and proliferation of numerous cancer cells.

In addition, both compounds potentiate the classical drug efficacy by augmenting their concentrations inside the cells.

BCP is a phytocannabinoid with strong affinity to cannabinoid receptor type 2 (CB2 ), but not cannabinoid receptor type 1 (CB1 ). In opposite, BCP oxidation derivative, BCPO, does not exhibit CB1/2 binding, thus the mechanism of its action is not related to endocannabinoid system (ECS) machinery.

It is known that BCPO alters several key pathways for cancer development, such as mitogen-activated protein kinase (MAPK), PI3K/AKT/mTOR/S6K1 and STAT3 pathways. In addition, treatment with this compound reduces the expression of procancer genes/proteins, while increases the levels of those with proapoptotic properties.

The selective activation of CB2 may be considered a novel strategy in pain treatment, devoid of psychoactive side effects associated with CB1 stimulation. Thus, BCP as selective CB2 activator may be taken into account as potential natural analgesic drug.

Moreover, due to the fact that chronic pain is often an element of cancer disease, the double activity of BCP, anticancer and analgesic, as well as its beneficial influence on the efficacy of classical chemotherapeutics, is particularly valuable in oncology.

This review is focused on anticancer and analgesic activities of BCP and BCPO, the mechanisms of their actions, and potential therapeutic utility.”

https://www.ncbi.nlm.nih.gov/pubmed/27696789

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.”  http://www.ncbi.nlm.nih.gov/pubmed/23138934

Gonadal hormone modulation of ∆9-tetrahydrocannabinol-induced antinociception and metabolism in female versus male rats.

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“The gonadal hormones testosterone (T) in adult males and estradiol (E2) in adult females have been reported to modulate behavioral effects of ∆9-tetrahydrocannabinol (THC). This study determined whether activational effects of T and E2 are sex-specific, and whether hormones modulate production of the active metabolite 11-hydroxy-THC (11-OH-THC) and the inactive metabolite 11-nor-9-carboxy-THC (THC-COOH). Adult male and female rats were gonadectomized (GDX) and treated with nothing (0), T (10-mm Silastic capsule/100g body weight), or E2 (1-mm Silastic capsule/rat). Three weeks later, saline or the cytochrome P450 inhibitor proadifen (25mg/kg; to block THC metabolism and boost THC’s effects) was injected i.p.; 1h later, vehicle or THC (3mg/kg females, 5mg/kg males) was injected i.p., and rats were tested for antinociceptive and motoric effects 15-240min post-injection. T did not consistently alter THC-induced antinociception in males, but decreased it in females (tail withdrawal test). Conversely, T decreased THC-induced catalepsy in males, but had no effect in females. E2 did not alter THC-induced antinociception in females, but enhanced it in males. The discrepant effects of T and E2 on males’ and females’ behavioral responses to THC suggests that sexual differentiation of THC sensitivity is not simply due to activational effects of hormones, but also occurs via organizational hormone or sex chromosome effects. Analysis of serum showed that proadifen increased THC levels, E2 increased 11-OH-THC in GDX males, and T decreased 11-OH-THC (and to a lesser extent, THC) in GDX females. Thus, hormone modulation of THC’s behavioral effects is caused in part by hormone modulation of THC oxidation to its active metabolite. However, the fact that hormone modulation of metabolism did not alter THC sensitivity similarly on all behavioral measures within each sex suggests that other mechanisms also play a role in gonadal hormone modulation of THC sensitivity in adult rats.”

https://www.ncbi.nlm.nih.gov/pubmed/27670094

Medical Marijuana: Just the Beginning of a Long, Strange Trip?

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Physical Therapy Journal

“Medical marijuana continues to gain acceptance and become legalized in many states. Various species of the marijuana plant have been cultivated, and this plant can contain up to 100 active compounds known as cannabinoids.

Two cannabinoids seem the most clinically relevant: Δ9-tetrahydrocannabinol (THC), which tends to produce the psychotropic effects commonly associated with marijuana, and cannabidiol (CBD), which may produce therapeutic effects without appreciable psychoactive properties.

Smoking marijuana, or ingesting extracts from the whole plant orally (in baked goods, teas, and so forth), introduces variable amounts of THC, CBD, and other minor cannabinoids into the systemic circulation where they ultimately reach the central and peripheral nervous systems.

Alternatively, products containing THC, CBD, or a combination of both compounds, can also be ingested as oral tablets, or via sprays applied to the oral mucosal membranes. These products may provide a more predictable method for delivering a known amount of specific cannabinoids into the body.

Although there is still a need for randomized controlled clinical trials, preliminary studies have suggested that medical marijuana and related cannabinoids may be beneficial in treating chronic pain, inflammation, spasticity, and other conditions seen commonly in physical therapist practice.

Physical therapists should therefore be aware of the options that are available for patients considering medical marijuana, and be ready to provide information for these patients.”

http://www.ncbi.nlm.nih.gov/pubmed/27660328