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Oct 21, 2015 - Cannabinoids. Cannabinoids are basically derived from three sources: (a) Phytocannabinoids are cannabinoid compounds produced by plants Cannabis sativa or Cannabis indica; (b) Endocannabinoids are neurotransmitters produced in the brain or in peripheral tissues, and act on cannabinoid receptors;. Cannabis Therapeutics 2001;1:29-42. 5) Machado Rocha FC, Stefano SC, De Cassia Haiek R, et al. Therapeutic use of Cannabis sativa on chemotherapy-induced nausea and vomiting among cancer patients: systematic review and meta-analysis. Eur J Cancer Care 2008;17:431-443. Cancer (cachexia and anorexia).
This article reviews recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms, as well as randomized clinical trials employing cannabinoids in pain treatment. Tetrahydrocannabinol (THC, Marinol ®) and nabilone (Cesamet ®) are currently approved in the United States and other countries, but not for pain indications. Other synthetic cannabinoids, such as ajulemic acid, are in development. Crude herbal cannabis remains illegal in most jurisdictions but is also under investigation. Sativex ®, a cannabis derived oromucosal spray containing equal proportions of THC (partial CB 1 receptor agonist ) and cannabidiol (CBD, a non-euphoriant, anti-inflammatory analgesic with CB 1 receptor antagonist and endocannabinoid modulating effects) was approved in Canada in 2005 for treatment of central neuropathic pain in multiple sclerosis, and in 2007 for intractable cancer pain.
Numerous randomized clinical trials have demonstrated safety and efficacy for Sativex in central and peripheral neuropathic pain, rheumatoid arthritis and cancer pain. An Investigational New Drug application to conduct advanced clinical trials for cancer pain was approved by the US FDA in January 2006. Cannabinoid analgesics have generally been well tolerated in clinical trials with acceptable adverse event profiles. Their adjunctive addition to the pharmacological armamentarium for treatment of pain shows great promise. Introduction Chronic pain represents an emerging public health issue of massive proportions, particularly in view of aging populations in industrialized nations. Associated facts and figures are daunting: In Europe, chronic musculoskeletal pain of a disabling nature affects over one in four elderly people , while figures from Australia note that older half of older people suffer persistent pain, and up to 80% in nursing home populations.
Responses to an ABC News poll in the USA indicated that 19% of adults (38 million) have chronic pain, and 6% (or 12 million) have utilized cannabis in attempts to treat it. Particular difficulties face the clinician managing intractable patients afflicted with cancer-associated pain, neuropathic pain, and central pain states (eg, pain associated with multiple sclerosis) that are often inadequately treated with available opiates, antidepressants and anticonvulsant drugs. Physicians are seeking new approaches to treatment of these conditions but many remain concerned about increasing governmental scrutiny of their prescribing practices , prescription drug abuse or diversion. The entry of cannabinoid medicines to the pharmacopoeia offers a novel approach to the issue of chronic pain management, offering new hope to many, but also stoking the flames of controversy among politicians and the public alike. This article will attempt to present information concerning cannabinoid mechanisms of analgesia, review randomized clinical trials (RCTs) of available and emerging cannabinoid agents, and address the many thorny issues that have arisen with clinical usage of herbal cannabis itself (“medical marijuana”).
An effort will be made to place the issues in context and suggest rational approaches that may mitigate concerns and indicate how standardized pharmaceutical cannabinoids may offer a welcome addition to the pharmacotherapeutic armamentarium in chronic pain treatment. Cannabinoids and analgesic mechanisms Cannabinoids are divided into three groups. The first are naturally occurring 21-carbon terpenophenolic compounds found to date solely in plants of the Cannabis genus, currently termed phytocannabinoids. The best known analgesic of these is Δ 9-tetrahydrocannabinol (henceforth, THC), first isolated and synthesized in 1964. In plant preparations and whole extracts, its activity is complemented by other “minor” phytocannabinoids such as cannabidiol (CBD) , cannabis terpenoids and flavonoids, as will be discussed subsequently.
Molecular structures of four cannabinoids employed in pain treatment. Long before mechanisms of cannabinoid analgesia were understood, structure activity relationships were investigated and a number of synthetic cannabinoids have been developed and utilized in clinical trials, notably nabilone (Cesamet ®, Valeant Pharmaceuticals), and ajulemic acid (CT3, IP-751, Indevus Pharmaceuticals). In 1988, the first cannabinoid receptor was identified (CB 1) and in 1993, a second was described (CB 2). Both are 7-domain G-protein coupled receptors affecting cyclic-AMP, but CB 1 is more pervasive throughout the body, with particular predilection to nociceptive areas of the central nervous system and spinal cord (; ), as well as the peripheral nervous system (; ) wherein synergy of activity between peripheral and central cannabinoid receptor function has been demonstrated. CB 2, while commonly reported as confined to lymphoid and immune tissues, is also proving to be an important mediator for suppressing both pain and inflammatory processes. Following the description of cannabinoid receptors, endogenous ligands for these were discovered: anandamide (arachidonylethanolamide, AEA) in 1992 in porcine brain , and 2-arachidonylglycerol (2-AG) in 1995 in canine gut tissue. These endocannabinoids both act as retrograde messengers on G-protein coupled receptors, are synthesized on demand, and are especially active on glutamatergic and GABA-ergic synapses.
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Together, the cannabinoid receptors, their endogenous ligands (“endocannabinoids”) and metabolizing enzymes comprise the endocannabinoid system (ECS) , whose functions have been prosaically termed to be “relax, eat, sleep, forget and protect” (p. The endocannabinoid system parallels and interacts at many points with the other major endogenous pain control systems: endorphin/enkephalin, vanilloid/transient receptor potential (TRPV), and inflammatory.
Interestingly, our first knowledge of each pain system has derived from investigation of natural origin analgesic plants, respectively: cannabis ( Cannabis sativa, C. Indica) (THC, CBD and others), opium poppy ( Papaver somniferun) (morphine, codeine), chile peppers (eg, Capsicum annuum, C.
Frutescens, C. Chinense) (capsaicin) and willow bark ( Salix spp.) (salicylic acid, leading to acetylsalicylic acid, or aspirin).
Interestingly, THC along with AEA and 2-AG, are all partial agonists at the CB 1 receptor. Notably, no endocannabinoid has ever been administered to humans, possibly due to issues of patentability and lack of commercial feasibility (Raphael Mechoulam, pers comm 2007).
For an excellent comprehensive review of the endocannabinoid system, see, while Walker and Huang have provided a key review of antinociceptive effects of cannabinoids in models of acute and persistent pain. A clinical endocannabinoid deficiency has been postulated to be operative in certain treatment-resistant conditions , and has received recent support in findings that anandamide levels are reduced over controls in migraineurs (Sarchielli et al 2006), that a subset of fibromyalgia patients reported significant decreased pain after THC treatment , and the active role of the ECS in intestinal pain and motility in irritable bowel syndrome wherein anecdotal efficacy of cannabinoid treatments have also been claimed. The endocannabinoid system is tonically active in control of pain, as demonstrated by the ability of SR141716A (rimonabant), a CB 1 antagonist, to produce hyperalgesia upon administration to mice. As mentioned above, the ECS is active throughout the neuraxis, including integrative functions in the periacqueductal gray (; ), and in the ventroposterolateral nucleus of the thalamus, in which cannabinoids proved to be 10-fold more potent than morphine in wide dynamic range neurons mediating pain. The ECS also mediates central stress-induced analgesia , and is active in nociceptive spinal areas (; ) including mechanisms of wind-up and N-methyl-D-aspartate (NMDA) receptors.
It was recently demonstrated that cannabinoid agonists suppress the maintenance of vincristine-induced allodynia through activation of CB 1 and CB 2 receptors in the spinal cord. The ECS is also active peripherally where CB 1 stimulation reduces pain, inflammation and hyperalgesia. These mechanisms were also proven to include mediation of contact dermatitis via CB 1 and CB 2 with benefits of THC noted systemically and locally on inflammation and itch. Recent experiments in mice have even suggested the paramount importance of peripheral over central CB 1 receptors in nociception of pain Cannabinoid agonists produce many effects beyond those mediated directly on receptors, including anti-inflammatory effects and interactions with various other neurotransmitter systems (previously reviewed. Briefly stated, THC effects in serotonergic systems are widespread, including its ability to decrease 5-hydroxytryptamine (5-HT) release from platelets , increase its cerebral production and decrease synaptosomal uptake. THC may affect many mechanisms of the trigeminovascular system in migraine (;;;; ).
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Eye test for driver`s license in ohio. Dopaminergic blocking actions of THC may also contribute to analgesic benefits. The glutamatergic system is integral to development and maintenance of neuropathic pain, and is responsible for generating secondary and tertiary hyperalgesia in migraine and fibromyalgia via NMDA mechanisms. Thus, it is important to note that cannabinoids presynaptically inhibit glutamate release , THC produces 30%–40% reduction in NMDA responses, and THC is a neuroprotective antioxidant. Additionally, cannabinoids reduce hyperalgesia via inhibition of calcitonin gene-related peptide.
As for Substance P mechanisms, cannabinoids block capsaicin-induced hyperalgesia , and THC will do so at sub-psychoactive doses in experimental animals. Among the noteworthy interactions with opiates and the endorphin/enkephalin system, THC has been shown to stimulate beta-endorphin production , may allow opiate sparing in clinical application , prevents development of tolerance to and withdrawal from opiates , and rekindles opiate analgesia after a prior dosage has worn off. These are all promising attributes for an adjunctive agent in treatment of clinical chronic pain states. The anti-inflammatory contributions of THC are also extensive, including inhibition of PGE-2 synthesis , decreased platelet aggregation , and stimulation of lipooxygenase. THC has twenty times the anti-inflammatory potency of aspirin and twice that of hydrocortisone , but in contrast to all nonsteroidal anti-inflammatory drugs (NSAIDs), demonstrates no cyclo-oxygenase (COX) inhibition at physiological concentrations. Cannabidiol, a non-euphoriant phytocannabinoid common in certain strains, shares neuroprotective effects with THC, inhibits glutamate neurotoxicity, and displays antioxidant activity greater than ascorbic acid (vitamin C) or tocopherol (vitamin E). While THC has no activity at vanilloid receptors, CBD, like AEA, is a TRPV 1 agonist that inhibits fatty acid amidohydrolase (FAAH), AEA’s hydrolytic enzyme, and also weakly inhibits AEA reuptake.
These activities reinforce the conception of CBD as an endocannabinoid modulator, the first clinically available. CBD additionally affects THC function by inhibiting first pass hepatic metabolism to the possibly more psychoactive 11-hydroxy-THC, prolonging its half-life, and reducing associated intoxication, panic, anxiety and tachycardia. Additionally, CBD is able to inhibit tumor necrosis factor-alpha (TNF-α) in its own right in a rodent model of rheumatoid arthritis.
At a time when great concern is accruing in relation to NSAIDs in relation to COX-1 inhibition (gastrointestinal ulcers and bleeding) and COX-2 inhibition (myocardial infarction and cerebrovascular accidents), CBD, like THC, inhibits neither enzyme at pharmacologically relevant doses. A new explanation of inflammatory and analgesic effects of CBD has recently come to light with the discovery that it is able to promote signaling of the adenosine receptor A2A by inhibiting the adenosine transporter.
Other “minor phytocannabinoids” in cannabis may also contribute relevant activity. Cannabichromene (CBC) is the third most prevalent cannabinoid in cannabis, and is also anti-inflammatory , and analgesic, if weaker than THC. Cannabigerol (CBG) displays sub-micromolar affinity for CB 1 and CB 2.
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It also exhibits GABA uptake inhibition to a greater extent than THC or CBD , suggesting possible utilization as a muscle relaxant in spasticity. Furthermore, CBG has more potent analgesic, anti-erythema and lipooxygenase blocking activity than THC , mechanisms that merit further investigation. It requires emphasis that drug stains of North American (; ), and European cannabis display relatively high concentrations of THC, but are virtually lacking in CBD or other phytocannabinoid content. Cannabis terpenoids also display numerous attributes that may be germane to pain treatment. Myrcene is analgesic, and such activity, in contrast to cannabinoids, is blocked by naloxone , suggesting an opioid-like mechanism. It also blocks inflammation via PGE-2. The cannabis sesquiterpenoid β-caryophyllene shows increasing promise in this regard.
It is anti-inflammatory comparable to phenylbutazone via PGE-1 , but simultaneously acts as a gastric cytoprotective. The analgesic attributes of β-caryophyllene are increasingly credible with the discovery that it is a selective CB 2 agonist , with possibly broad clinical applications. Α-Pinene also inhibits PGE-1 , while linalool displays local anesthetic effects. Cannabis flavonoids in whole cannabis extracts may also contribute useful activity. Apigenin inhibits TNF-α , a mechanism germane to multiple sclerosis and rheumatoid arthritis.
Cannflavin A, a flavone unique to cannabis, inhibits PGE-2 thirty times more potently than aspirin , but has not been subsequently investigated. Finally, β-sitosterol, a phytosterol found in cannabis, reduced topical inflammation 65% and chronic edema 41% in skin models. Available cannabinoid analgesic agents and those in development Very few randomized controlled trials (RCTs) have been conducted using smoked cannabis despite many anecdotal claims. One such study documented slight weight gain in HIV/AIDS subjects with no significant immunological sequelae.
A recent brief trial of smoked cannabis (3.56% THC cigarettes 3 times daily) in HIV-associated neuropathy showed positive results on daily pain, hyperalgesia and 30% pain reduction (vs 15% in placebo) in 50 subjects over a treatment course of only 5 days. This short clinical trial also demonstrated prominent adverse events associated with intoxication. In Canada, 21 subjects with chronic pain sequentially smoked single inhalations of 25 mg of cannabis (0, 2.5, 6.0, 9.5% THC) via a pipe three times a day for 5 days to assess effects on pain with results the authors termed “modest”: no changes were observed in acute neuropathic pain scores, and a very low number of subjects noted 30% pain relief at the end of the study.
Even after political and legal considerations, it remains extremely unlikely that crude cannabis could ever be approved by the FDA as a prescription medicine as outlined in the FDA Botanical Guidance document (; ), due to a lack of rigorous standardization of the drug, an absence of Phase III clinical trials, and pulmonary sequelae (bronchial irritation and cough) associated with smoking. Although cannabis vaporizers reduce potentially carcinogenic polyaromatic hydrocarbons, they have not been totally eliminated by this technology (; ). Results RCTs of cannabinoids in treatment of pain syndromes Oral dronabinol (THC) is marketed in synthetic form as Marinol ® (Solvay Pharmaceuticals) in various countries, and was approved in the USA for nausea associated with chemotherapy in 1985, and in 1992 for appetite stimulation in HIV/AIDS. Oral dronabinol’s expense, variability of action, and attendant intoxication and dysphoria have limited its adoption by clinicians.
Two open label studies in France of oral dronabinol for chronic neuropathic pain in 7 subjects and 8 subjects , respectively, failed to show significant benefit on pain or other parameters, and showed adverse event frequently requiring discontinuation with doses averaging 15–16.6 mg THC. Dronabinol did demonstrate positive results in a clinical trial of multiple sclerosis pain in two measures , but negative results in post-operative pain. Another uncontrolled case report in three subjects noted relief of intractable pruritus associated with cholestatic jaundice employing oral dronabinol. Some authors have noted patient preference for whole cannabis preparations over oral THC , and the contribution of other components beyond THC to therapeutic benefits. Inhaled THC leads to peak plasma concentration within 3–10 minutes, followed by a rapid fall while levels of intoxication are still rising, and with systemic bioavailability of 10%–35%. THC absorption orally is slow and erratic with peak serum levels in 45–120 minutes or longer.
Systemic bioavailability is also quite low due to rapid hepatic metabolism on first pass to 11-hydroxy-THC. A rectal suppository of THC-hemisuccinate is under investigation , as are transdermal delivery techniques. The terminal half-life of THC is quite prolonged due to storage in body lipids. Nabilone (Cesamet) , is a synthetic dimethylheptyl analogue of THC (British Medical Association 1997) that displays greater potency and prolonged half-life. Serum levels peak in 1–4 hours. It was also primarily developed as an anti-emetic in chemotherapy, and was recently re-approved for this indication in the USA. Prior case reports have noted analgesic effects in case reports in neuropathic pain and other pain disorders.
Sedation and dysphoria were prominent sequelae. An RCT of nabilone in 41 post-operative subjects actually documented exacerbation of pain scores after thrice daily dosing. An abstract of a study of 82 cancer patients on nabilone claimed improvement in pain levels after varying periods of follow-up compared to patients treated without this agent. However, 17 subjects dropped out, and the study was neither randomized nor controlled, and therefore is not included in. Ajulemic acid (CT3, IP-751) , another synthetic dimethylheptyl analogue, was employed in a Phase II RCT in 21 subjects with improvement in peripheral neuropathic pain.
Part of its analgesic activity may relate to binding to intracellular peroxisome proliferator-activator receptor gamma. Peak plasma concentrations have generally been attained in 1–2 hours, but with delays up to 4–5 hours is some subjects. Debate surrounds the degree of psychoactivity associated with the drug. Current research is confined to the indication of interstitial cystitis. Cannador ® (IKF-Berlin) is a cannabis extract administered in oral capsules, with differing figures as to THC:CBD ratios (reviewed in ), generally approximately 2:1.
Two pharmacokinetic studies on possibly related material have been reported (; ). In a Phase III RCT employing Cannador in spasticity in multiple sclerosis (MS) (CAMS) , no improvement was noted in the Ashworth Scale, but benefit was observed in spasm-associated pain on subjective measures. Both Marinol and Cannador produced reductions in pain scores in long-term follow-up. Cannador was assayed in postherpetic neuralgia in 65 subjects with no observed benefit , and in 30 post-operative pain subjects (CANPOP) without opiates, with slight benefits, but prominent psychoactive sequelae. Sativex ® (GW Pharmaceuticals) is an oromucosal whole cannabis-based spray combining a CB 1 partial agonist (THC) with a cannabinoid system modulator (CBD), minor cannabinoids and terpenoids plus ethanol and propylene glycol excipients and peppermint flavoring (; ). It was approved by Health Canada in June 2005 for prescription for central neuropathic pain in multiple sclerosis, and in August 2007, it was additionally approved for treatment of cancer pain unresponsive to optimized opioid therapy.
Sativex is a highly standardized pharmaceutical product derived from two Cannabis sativa chemovars following Good Agricultural Practice (GAP) , yielding Tetranabinex ® (predominantly-THC extract) and Nabidiolex ® (predominantly-CBD extract) in a 1:1 ratio. Each 100 μL pump-action oromucosal Sativex spray actuation provides 2.7 mg of THC and 2.5 mg of CBD. Pharmacokinetic data are available, and indicate plasma half lives of 85 minutes for THC, 130 minutes for 11-hydroxy-THC and 100 minutes for CBD.
Sativex effects commence in 15–40 minutes, an interval that permits symptomatic dose titration. A very favorable adverse event profile has been observed in over 2500 patient years of exposure in over 2000 experimental subjects. Patients most often ascertain an individual stable dosage within 7–10 days that provides therapeutic relief without unwanted psychotropic effects (often in the range of 8–10 sprays per day). In all RCTs, Sativex was adjunctively added to optimal drug regimens in subjects with intractable symptoms, those often termed “untreatable.” Sativex is also available by named patient prescription in the UK and the Catalonia region of Spain. An Investigational New Drug (IND) application to study Sativex in advanced clinical trials in the USA was approved by the FDA in January 2006 in patients with intractable cancer pain. The clinical trials performed with Sativex have recently been assessed in two independent review articles (; ).
In a Phase II clinical trial in 20 patients with neurogenic symptoms , Tetranabinex, Nabidiolex, and Sativex were tested in a double-blind RCT vs placebo. Significant improvement was seen with both Tetranabinex and Sativex on pain (especially neuropathic), but post-hoc analysis showed symptom control was best with Sativex (p.