Ther Clin Risk Manag. Feb;4(1) Cannabinoids in the management of difficult to treat pain. Russo EB(1). Author information: (1)GW. This article reviews recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms, as well as randomized clinical. PDF | This article reviews recent research on cannabinoid analgesia via the endocannabinoid system and non-receptor mechanisms, as well as randomized .
to the treat Cannabinoids difficult management pain of in
Serum levels peak in 1—4 hours Lemberger et al 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 Notcutt et al and other pain disorders Berlach et al 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 Beaulieu Table 1.
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 Maida However, 17 subjects dropped out, and the study was neither randomized nor controlled, and therefore is not included in Table 1.
Part of its analgesic activity may relate to binding to intracellular peroxisome proliferator-activator receptor gamma Liu et al Peak plasma concentrations have generally been attained in 1—2 hours, but with delays up to 4—5 hours is some subjects Karst et al Debate surrounds the degree of psychoactivity associated with the drug Dyson et al Current research is confined to the indication of interstitial cystitis. CBD ratios reviewed in Russo and Guy , generally approximately 2: Two pharmacokinetic studies on possibly related material have been reported Nadulski et al a ; Nadulski et al b.
Both Marinol and Cannador produced reductions in pain scores in long-term follow-up Zajicek et al Cannador was assayed in postherpetic neuralgia in 65 subjects with no observed benefit Ernst et al Table 1 , and in 30 post-operative pain subjects CANPOP without opiates, with slight benefits, but prominent psychoactive sequelae Holdcroft et al Table 1.
It was approved by Health Canada in June for prescription for central neuropathic pain in multiple sclerosis, and in August , it was additionally approved for treatment of cancer pain unresponsive to optimized opioid therapy.
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 patient years of exposure in over 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 a Phase II double-blind crossover study of intractable chronic pain Notcutt et al in 24 subjects, visual analogue scales VAS were 5. During that time, there was no escalation of dose indicating an absence of tolerance to the preparation. Similarly, no withdrawal effects were noted in a subset of patients who voluntarily stopped the medicine abruptly.
Upon resumption, benefits resumed at the prior established dosages. In a Phase II double-blind, randomized, placebo-controlled, 5-week study of 56 rheumatoid arthritis patients with Sativex Blake et al , employed nocturnal treatment only to a maximum of 6 sprays per evening In a study of spinal injury pain, NRS of pain were not statistically different from placebo, probably due to the short duration of the trial, but secondary endpoints were clearly positive Table 1.
Finally, in an RCT of intractable lower urinary tract symptoms in MS, accompanying pain in affected patients was prominently alleviated Table 1. Common adverse events AE of Sativex acutely in RCTs have included complaints of bad taste, oral stinging, dry mouth, dizziness, nausea or fatigue, but do not generally necessitate discontinuation, and prove less common over time.
While there have been no head-to-head comparative RCTs of Sativex with other cannabinoid agents, certain contrasts can be drawn. Sativex Rog et al and Marinol Svendsen et al have both been examined in treatment of central neuropathic pain in MS, with comparable results Table 1. However, adverse events were comparable or greater with Marinol than with Sativex employing THC dosages some 2.
Similarly, while Sativex and smoked cannabis have not been employed in the same clinical trial, comparisons of side effect profiles can be made on the basis of SAFEX studies of Sativex for over a year and up to several years in MS and other types of neuropathic pain Russo b ; Wade et al , and government-approved research programs employing standardized herbal cannabis from Canada for chronic pain Lynch et al and the Netherlands for general conditions Janse et al ; Gorter et al over a period of several months or more.
As is evident in Figure 2 Figure 2 , all adverse events are more frequently reported with herbal cannabis, except for nausea and dizziness, both early and usually transiently reported with Sativex see Russo b for additional discussion. Comparison of adverse events AE encountered with long term therapeutic use of herbal cannabis in the Netherlands Janse et al ; Gorter et al and Canada Lynch et al , vs that observed in safety-extension SAFEX studies of Sativex oromucosal spray Russo ; Wade et al Phytocannabinoids are lipid soluble with slow and erratic oral absorption.
While cannabis users claim that the smoking of cannabis allows easy dose titration as a function of rapid onset, high serum levels in a short interval inevitably result. This quick onset is desirable for recreational purposes, wherein intoxication is the ultimate goal, but aside from paroxysmal disorders eg, episodic trigeminal neuralgia or cluster headache attack , such rapid onset of activity is not usually necessary for therapeutic purposes in chronic pain states. The vast majority of subjects in Sativex clinical trials do not experience psychotropic effects outside of initial dose titration intervals Figure 2 and most often report subjective intoxication levels on visual analogue scales that are indistinguishable from placebo, in the single digits out of Wade et al Thus, it is now longer tenable to claim that psychoactive effects are a necessary prerequisite to symptom relief in the therapeutic setting with a standardized intermediate onset cannabis-based preparation.
Intoxication has remained a persistent issue in Marinol usage Calhoun et al , in contrast. Recent controversies have arisen in relation to non-steroidal anti-inflammatory drugs NSAID , with concerns that COX-1 agents may provoke gastrointestinal ulceration and bleeding, and COX-2 drugs may increase incidents of myocardial infarction and cerebrovascular accidents Fitzgerald ; Topol Frequent questions have been raised as to whether psychoactive drugs may be adequately blinded masked in randomized clinical trials.
Internal review and outside analysis have confirmed that blinding in Sativex spasticity studies has been effective Clark and Altman ; Wright Sativex and its placebo are prepared to appear identical in taste and color. Great public concern attends recreational cannabis usage and risks of dependency. The addictive potential of a drug is assessed on the basis of five elements: Drug abuse liability DAL is also assessed by examining a drug's rates of abuse and diversion.
US Congress placed cannabis in Schedule I of the Controlled Substances Act in , with drugs categorized as addictive, dangerous, possessing severe abuse potential and no recognized medical value. Marinol was placed in Schedule II, the category for drugs with high abuse potential and liability to produce dependency, but certain recognized medical uses, after its FDA approval in Marinol was reassigned to Schedule III in , a category denoting a lesser potential for abuse or lower dependency risk after documentation that little abuse or diversion Calhoun et al had occurred.
Nabilone was placed and has remained in Schedule II since The degree to which a drug is reinforcing is determined partly by the by the rate of its delivery to the brain Samaha and Robinson Sativex has effect onset in 15—40 minutes, peaking in a few hours, quite a bit slower than drugs of high abuse potential. It has been claimed that inclusion of CBD diminishes psychoactive effects of THC, and may lower potential drug abuse liability of the preparation see Russo b for discussion.
Prior studies from Sativex clinical trials do not support the presence reinforcement or euphoria as problems in administration Wade et al Certain facets of acute cannabinoid exposure, including tachycardia, hypothermia, orthostatic hypotension, dry mouth, ocular injection, intraocular pressure decreases, etc.
No dose tolerance to the therapeutic effects of Sativex has been observed in clinical trials in over patient-years of administration.
Additionally, therapeutic efficacy has been sustained for several years in a wide variety of symptoms; SAFEX studies in MS and peripheral neuropathic pain, confirm that Sativex doses remain stable or even decreased after prolonged usage Wade et al , with maintenance of therapeutic benefit and even continued improvement.
Debate continues as to the existence of a clinically significant cannabis withdrawal syndrome with proponents Budney et al , and questioners Smith While symptoms recurred after 7—10 days of abstinence from Sativex, prior levels of symptom control were readily re-established upon re-titration of the agent Wade et al Overall, Sativex appears to pose less risk of dependency than smoked cannabis based on its slower onset, lower dosage utilized in therapy, almost total absence of intoxication in regular usage, and minimal withdrawal symptomatology even after chronic administration.
No known abuse or diversion incidents have been reported with Sativex to date as of November Cognitive effects of cannabis have been reviewed Russo et al ; Fride and Russo , but less study has occurred in therapeutic contexts. Effects of chronic heavy recreational cannabis usage on memory abate without sequelae after a few weeks of abstinence Pope et al Studies of components of the Halstead-Reitan battery with Sativex in neuropathic pain with allodynia have revealed no changes vs placebo Nurmikko et al , and in central neuropathic pain in MS Rog et al , 4 of 5 tests showed no significant differences.
While the Selective Reminding Test did not change significantly on Sativex, placebo patients displayed unexpected improvement. Slight improvements were observed in Hospital Anxiety and Depression Scales depression and anxiety scores were noted with Sativex in MS patients with central neuropathic pain Rog et al , although not quite statistically significant. No long-term mood disorders have been associated with Sativex administration. Debate continues with regard to the relationship between cannabis usage and schizophrenia reviewed Fride and Russo An etiological relationship is not supported by epidemiological data Degenhardt et al , but if present, should bear relation to dose and length of high exposure.
It is likely that lower serum levels of Sativex in therapeutic usage, in conjunction with anti-psychotic properties of CBD Zuardi and Guimaraes , would minimize risks.
Children and adolescents have been excluded from Sativex RCTs to date. SAFEX studies of Sativex have yielded few incidents of thought disorder, paranoia or related complaints. Adverse effects of cannabinoids on immune function have been observed in experimental animals at doses 50— times the psychoactive level Cabral In four patients using herbal cannabis therapeutically for over 20 years, no abnormalities were observed in leukocyte, CD4 or CD8 cell counts Russo et al Investigation of MS patients on Cannador revealed no major immune changes Katona et al , and similarly, none occurred with smoked cannabis in a short-term study of HIV patients Abrams et al Hematological measures have been normal in all Sativex RCTs without clinical signs of immune dysfunction.
Concerns are frequently noted with new drug-drug interactions, but few have resulted in Sativex RCTs despite its adjunctive use with opiates, many other psychoactive analgesic, antidepressant and anticonvulsant drugs Russo a , possibly due to CBD ability to counteract sedative effects of THC Nicholson et al Thus, Sativex should be safe to use in conjunction with other drugs metabolized via this pathway.
The Sativex product monograph in Canada http: Given that THC is the most active component affecting such abilities, and the low serum levels produced in Sativex therapy vide supra , it would be logical that that patients may be able to safely engage in such activities after early dose titration and according to individual circumstances, much as suggested for oral dronabinol. This is particularly the case in view of a report by an expert panel Grotenhermen et al that comprehensively analyzed cannabinoids and driving.
Prior studies document that 4 rapid oromucosal sprays of Sativex greater than the average single dose employed in therapy produced serum levels well below this threshold Russo b. Sativex is now well established as a cannabinoid agent with minimal psychotropic effect. These include anti-emetic effects, well established with THC, but additionally demonstrated for CBD Pertwee , the ability of THC and CBD to produce apoptosis in malignant cells and inhibit cancer-induced angiogenesis Kogan ; Ligresti et al , as well as the neuroprotective antioxidant properties of the two substances Hampson et al , and improvements in symptomatic insomnia Russo et al The degree to which cannabinoid analgesics will be adopted into adjunctive pain management practices currently remains to be determined.
Given their multi-modality effects upon various nociceptive pathways, their adjunctive side benefits, the efficacy and safety profiles to date of specific preparations in advanced clinical trials, and the complementary mechanisms and advantages of their combination with opioid therapy, the future for cannabinoid therapeutics appears very bright, indeed. National Center for Biotechnology Information , U. Ther Clin Risk Manag. Author information Copyright and License information Disclaimer.
This article has been cited by other articles in PMC. Abstract 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.
Introduction Chronic pain represents an emerging public health issue of massive proportions, particularly in view of aging populations in industrialized nations.
Cannabinoids and analgesic mechanisms Cannabinoids are divided into three groups. Open in a separate window. Molecular structures of four cannabinoids employed in pain treatment. Available cannabinoid analgesic agents and those in development Very few randomized controlled trials RCTs have been conducted using smoked cannabis Campbell et al despite many anecdotal claims Grinspoon and Bakalar Table 1 Results RCTs of cannabinoids in treatment of pain syndromes.
Practical issues with cannabinoid medicines Phytocannabinoids are lipid soluble with slow and erratic oral absorption. Broad experience with pain sparks search for relief [online] Short-term effects of cannabinoids in patients with HIV-1 infection. A randomized, placbo-controlled clinical trial. Cannabis in painful HIV-associated sensory neuropathy: Cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors in nociceptors.
Cannabinoid CB1 receptor activation inhibits trigeminovascular neurons. J Pharmacol Exp Ther. Anandamide is able to inhibit trigeminal neurons using an in vivo model of trigeminovascular-mediated nociception.
Anandamide acts as a vasodilator of dural blood vessels in vivo by activating TRPV1 receptors. Are oral cannabinoids safe and effective in refractory neuropathic pain? Cannflavin A and B, prenylated flavones from Cannabis sativa L. Anti-inflammatory activity of oleoresin from Brazilian Copaifera.
Effects of nabilone, a synthetic cannabinoid, on postoperative pain: Experience with the synthetic cannabinoid nabilone in chronic noncancer pain. Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: Molecular targets for cannabidiol and its synthetic analogues: Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine Sativex in the treatment of pain caused by rheumatoid arthritis.
Rheumatology Oxford ; Therapeutic uses of cannabis. Harwood Academic Publishers; Analgesic and reinforcing proerties of delta9-THC-hemisuccinate in adjuvant-arthritic rats. Journal of Cannabis Therapeutics.
Review of the validity and significance of cannabis withdrawal syndrome. Lack of analgesic efficacy of oral deltatetrahydrocannabinol in postoperative pain. Inhibition of biosynthesis by the naturally occurring cannabinoids.
Russo EB, Grotenhermen F, editors. Pharmacology, toxicology and therapeutic potential. Abuse potential of dronabinol Marinol J Psychoactive Drugs.
Are cannabinoids an effective and safe option in the management of pain? A qualitative systematic review. Inhibition of an equilibrative nucleoside transporter by cannabidiol: In vitro experiment optimization for measuring tetrahydrocannabinol skin permeation.
Enhancement of mu opioid antinociception by oral delta9-tetrahydrocannabinol: Dose-response analysis and receptor identification. Antinociceptive synergy between delta 9 -tetrahydrocannabinol and opioids after oral administration. Modulation of oral morphine antinociceptive tolerance and naloxone-precipitated withdrawal signs by oral Delta 9-tetrahydrocannabinol.
Neurobehavioral actions of cannabichromene and interactions with delta 9-tetrahydrocannabinol. The breeding of cannabis cultivars for pharmaceutical end uses. Medicinal uses of cannabis and cannabinoids. Testing hypotheses about the relationship between cannabis use and psychosis. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Antihyperalgesic properties of the cannabinoid CT-3 in chronic neuropathic and inflammatory pain states in the rat.
Potency trends of delta9-THC and other cannabinoids in confiscated marijuana from — Standardized cannabis extract in the treatment of postherpetic neuralgia: The separation of central from peripheral effects on a structural basis.
Opiate, cannabinoid, and eicosanoid signaling converges on common intracellular pathways nitric oxide coupling. Prostaglandins Other Lipid Mediat. DEA, Congress, and the courts, oh my! Coxibs and cardiovascular disease. N Engl J Med. The role of central and peripheral Cannabinoid1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain. Schizophrenia, depression, and anxiety.
Taylor and Francis; Affective, behavior and cognitive disorders in the elderly with chronic musculoskelatal pain: Isolation, structure and partial synthesis of an active constituent of hashish.
J Am Chem Soc. International Cannabinoid Research Society; Cannabigerol behaves as a partial agonist at both CB1 and CB2 receptors; p. Flavonoids inhibit cytokine-induced endothelial cell adhesion protein gene expression.
Screening of plant extracts for new CB2-selective agonists revewals new players in Cannabis sativa ; p. IASP global year against pain in older persons: Cannabis vaporizer combines efficient delivery of THC with effective suppression of pyrolytic compounds.
Comparative study of different essential oils of Bupleurum gibraltaricum Lamarck. Study of the topical anti-inflammatory activity of Achillea ageratum on chronic and acute inflammation models. Z Naturforsch [C] ; Medical use of cannabis in the Netherlands. Marihuana, the forbidden medicine. Yale University Press; Pharmacokinetics and pharmacodynamics of cannabinoids. Cannabinoids for therapeutic use: American Journal of Drug Delivery. Findings and recommendations by an expert panel.
Developing science-based per se limits for driving under the influence of cannabis DUIC p. Guy GW, Robson P. A Phase I, double blind, three-way crossover study to assess the pharmacokinetic profile of cannabis based medicine extract CBME administered sublingually in variant cannabinoid ratios in normal healthy male volunteers GWPK Journal of Cannabis Therapeutics.
Cannabidiol and - Delta9-tetrahydrocannabinol are neuroprotective antioxidants. Evaluation of a vaporizing device Volcano for the pulmonary administration of tetrahydrocannabinol.
Cannabinoid receptor localization in brain. Pre- and postsynaptic distribution of cannabinoid and mu opioid receptors in rat spinal cord. Inhibition of noxious stimulus-evoked activity of spinal cord dorsal horn neurons by the cannabinoid WIN 55, An endocannabinoid mechanism for stress-induced analgesia. A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract Cannador for postoperative pain management.
In many countries cannabis use for medical reasons is legal and some countries have also decriminalized or legalized the recreational use of cannabis. The term medical cannabis is used to refer to the physician-recommended use of cannabis and its constituents, cannabinoids, to treat disease or improve symptoms Rahn and Hohmann, The use of cannabis and cannabinoids may be limited by its psychotropic side effects e.
As interest in the use of cannabinoids as adjunctive therapy for pain management has increased in the last decades Hill et al. Therefore, research on cannabis and cannabinoids has increased dramatically in recent years. However, there are several obstacles that need to be overcome, such as the regulations and policies that restrict access to the cannabis products, funding limitations, and numerous methodological challenges drug delivery, the placebo issue, etc.
This research is expected to explain and update the mechanisms of analgesic action of cannabis and its constituents, and to provide answers to questions about the safety of medicinal cannabis and its potential indications in the treatment of pain. Healthcare providers in all parts of the world must keep up to date with recent findings in order to provide valid information regarding the benefits, risks, and responsible medical use to patients in pain Wilsey et al.
The abstracts of the citations extracted were screened for relevance by two reviewers SV and DS. Discrepancies were resolved by discussion. Both preclinical in vitro and in vivo data and clinical studies were included. Data on cannabis use among children, adolescents and pregnant women were excluded. We also examined the reference lists of reviewed articles. For many years it was assumed that the chemical components of the cannabis plant, cannabinoids, produce analgesia by activating specific receptors throughout the body, in particular CB1, which are found predominantly in the CNS, and CB2, found predominantly in cells involved with immune function Rahn and Hohmann, However, recently this picture has become much more complicated, as it has been recognized that cannabinoids, both plant-derived and endogenous, act simultaneously on multiple pain targets Ross, ; Horvath et al.
It has been shown that all these receptors represent potentially attractive targets for the therapeutic use of cannabinoids in the treatment of pain. All of these provide an opportunity for the development of new multiple target ligands and polypharmacological drugs with improved efficacy and devoid of side effects for the treatment of pain Reddy and Zhang, Several lines of evidence indicate that cannabinoids may contribute to pain relief through an anti-inflammatory action Jesse Lo et al.
In addition, non-cannabinoid constituents of the cannabis plant that belong to miscellaneous groups of natural products terpenoids and flavonoids may contribute to the analgesic, as well as the anti-inflammatory effects of cannabis Andre et al.
Based on their origin, cannabinoids are classified into three categories: There are about different cannabinoids isolated from the cannabis plant Andre et al. THC is an analog to the endogenous cannabinoid, anandamide ananda is the Sanskrit word for bliss; arachidonoylethanolamide, AEA. It is responsible for most of the pharmacological actions of cannabis, including the psychoactive, analgesic, anti-inflammatory, anti-oxidant, antipruritic, bronchodilatory, anti-spasmodic, and muscle-relaxant activities Rahn and Hohmann, ; Russo, A very high binding affinity of THC with the CB1 receptor appears to mediate its psychoactive properties changes in mood or consciousness , memory processing, motor control, etc.
It has been reported that a number of side effects of THC, including anxiety, impaired memory and immunosuppression, can be reversed by other constituents of the cannabis plant cannabinoids, terpenoids, and flavonoids Russo and Guy, ; Russo, ; Andre et al. It is thought to have significant analgesic, anti-inflammatory, anti-convulsant and anxiolytic activities without the psychoactive effect of THC Costa et al. CBD also regulates the perception of pain by affecting the activity of a significant number of other targets, including non-cannabinoid GPCRs e.
It has been demonstrated that cannabidiol can act synergistically with THC and contribute to the analgesic effect of medicinal-based cannabis extract Russo, At the same time, CBD displays an entourage effect the mechanism by which non-psychoactive compounds present in cannabis modulate the overall effects of the plant , and is capable of improving tolerability and perhaps also the safety of THC by reducing the likelihood of psychoactive effects and antagonizing several other adverse effects of THC sedation, tachycardia, and anxiety Russo and Guy, ; Abrams and Guzman, The differences in concentration of THC and CBD in the plant reflect the differences in the effects of different cannabis strains.
Although CBD as a monotherapy in the treatment of pain has not been evaluated clinically, its anti-inflammatory Ko et al. Other phytocannabinoids that can contribute to the overall analgesic effects of medical cannabis are cannabichromene CBC , cannabigerol CBG , tetrahydrocannabivarin THCV , and many others Morales et al. Similarly to CBD, these compounds do not display significant affinities for cannabinoid receptors, but they have other modes of action. This is a new area of research that needs to be addressed Piomelli et al.
This system seems to regulate many functions in the body, including learning and memory, mood and anxiety, drug addiction, feeding behavior, perception, modulation of pain and cardiovascular functions. The endocannabinoid system consists of cannabinoid receptors, endogenous cannabinoids endocannabinoids , transport proteins and enzymes that synthesize or degrade the endocannabinoids.
They play an important role in peripheral, spinal, and supraspinal nociception, including ascendant and descendent pain pathways Hill et al. New evidence is emerging that different ligands can differentially activate these pathways, suggesting biased signaling through the cannabinoid receptors CB1 and CB2 Ibsen et al. The CB1 receptor is distributed throughout the nervous system.
It mediates psychoactivity, pain regulation, memory processing and motor control. CB1 is a presynaptic heteroreceptor that modulates neurotransmitter and neuropeptide release and inhibits synaptic transmission. Activation of CB1 results in the activation of inwardly rectifying potassium channels, which decrease presynaptic neuron firing, and in the inhibition of voltage-sensitive calcium channels that decrease neurotransmitter release Morales et al.
The CB1 receptor is strategically located in regions of the peripheral and CNS where pain signaling is intricately controlled, including the peripheral and central terminals of primary afferent neurons, the dorsal root ganglion DRG , the dorsal horn of the spinal cord, the periaqueductal gray matter, the ventral posterolateral thalamus and cortical regions associated with central pain processing, including the anterior cingulate cortex, amygdala and prefrontal cortex Hill et al.
CB1 receptors are observed more often on the gamma-aminobutyric acid GABA inhibitory interneurons in the dorsal horn of the spinal cord, and weakly expressed in most excitatory neurons Hill et al. CB1 receptors are also present in multiple immune cells such as macrophages, mast cells and epidermal keratinocytes. The CB2 receptor is found predominantly at the periphery in tissues and cells of the immune system, hematopoietic cells, bone, liver, peripheral nerve terminals, keratinocytes , but also in brain microglia Abrams and Guzman, Both CB2 and CB1 receptors on mast cells participate in the anti-inflammatory mechanism of action of cannabinoids Facci et al.
Under basal conditions, CB2 receptors are present at low levels in the brain, the spinal cord and DRG, but may be upregulated in microglia where they modulate neuroimmune interaction in inflammation and after peripheral nerve damage Hsieh et al. CB2 receptor activation inhibits adenylyl cyclase activity and stimulates MAPK activity, but the effect on calcium or potassium conductance is controversial Rahn and Hohmann, ; Atwood et al.
Stimulation of CB2 receptors does not produce cannabis-like effects on the psyche and circulation. Endocannabinoids are arachidonic acid derivatives. Endocannabinoids, similarly to THC, appear to activate cannabinoid receptors. They work as a part of a negative feedback loop that regulates neurotransmitter and neuropeptide release and thereby modulate various CNS functions, including pain processing Vaughan and Christie, Endocannabinoids, which are produced in neural and non-neural cells in the physiological response to tissue injury or excessive nociceptive signaling, suppress inflammation, sensitization and pain Piomelli and Sasso, ; Maccarrone et al.
There is a constant active exchange of substrates and metabolites between endocannabinoid and eicosanoid pathways. At present, there are two synthetic cannabinoids on the market, dronabinol and nabilone, which may be of benefit in the treatment of pain Abrams and Guzman, In general, their use in pain treatment is off-label.
It is approved for the treatment of chemotherapy-associated nausea and vomiting, and anorexia associated with human immunodeficiency virus infection. Their medical use is mostly limited by their psychoactive side effects, as well as their limited bioavailability Huestis, Cannabis delivered by way of inhalation smoked or inhaled through vaporization , orally or oromucosally, produces a host of biological effects Andre et al.
Unfortunately, clinical trials conducted on cannabis are limited, and no drug agency has approved the use of cannabis as a treatment for any medical condition. Although there is no formal approval, cannabis is widely used for the treatment of pain.
It is authorized by physicians where medical marijuana is legal Health Canada, Nabiximols, a generic name for the whole-plant extract with a 1: An approval under the Notice of Compliance with Conditions means that a product shows potential benefit, possesses high quality and an acceptable safety profile based on a benefit-risk evaluation Portenoy et al.
Nabiximols is also approved in the United Kingdom and some European countries e. Cannabis is mostly inhaled by smoking and to a lesser extent by vaporization. The pharmacokinetics of inhaled and oral cannabis differ significantly Agurell et al.
By inhalation, cannabis THC avoids the first passage metabolism in the liver, and the effect of inhaled cannabis is proportionate to the plasma levels of THC. The pharmacokinetic profile of the inhaled cannabis is similar to THC given by the intravenous route Agurell et al. When inhaled, cannabinoids are rapidly absorbed into the bloodstream. The advantages of inhaled over oral cannabis are the fast onset of action requiring minutes instead of hours , and rapid attainment of peak effect in 1 h vs.
The analgesic effect is experienced shortly after the first breath and can be maximized by self-titration patients adjust cannabis dosage themselves. However, self-titration of oral cannabis is not recommended due to the unpredictable appearance of side effects. The main disadvantage of smoking cannabis is inhalation of combustion byproducts with possible adverse effects in the respiratory tract Volkow et al.
Therefore, vaporization is considered a better alternative for the inhalation of cannabis. The bioavailability of inhaled THC varies considerably, probably due to differences in inhalation techniques and source of the cannabis product Agurell et al. Dronabinol, nabilone, and nabiximols are currently available oral pharmaceutical preparations of cannabinoids with standardized concentrations or doses.
The main limitation associated with the administration of oral cannabinoids is their poor pharmacokinetic profile characterized by slow, unpredictable and highly variable absorption, late onset of action, extended duration due to psychoactive metabolites and unpredictable psychotropic effects Ohlsson et al. Further efforts are aimed at improving the bioavailability of oral cannabinoids Smith, However, the distribution changes over time, with the steady state volume of distribution being about 3.
This is due to the high lipophilicity of THC, with high binding to fat tissue. THC crosses the placental barrier and small amounts also cross into breast milk Grotenhermen, Conversely, drugs that induce hepatic enzymes responsible for THC metabolism e.
In chronic-pain patients on opioid therapy, vaporized cannabis increases the analgesic effects of opioids without affecting significantly the plasma opioid levels Abrams et al.
Behavioral studies have shown that synthetic or plant-derived cannabinoid receptor agonists or endogenous cannabinoid ligands are effective in different animal models of acute pain Dhopeshwarkar and Mackie, However, data obtained in humans, including volunteers with experimental pain and clinical trial patients, suggest that cannabinoids may be more effective for chronic rather than acute pain conditions Kraft et al.
Also, a number of targets identified in animal studies have not been confirmed in clinical trials. These include the absence of apparent clinical activity in clinical trials with CB2 agonists Roche and Finn, ; Ostenfeld et al. In addition, FAAH inhibitors, although providing promising data in animal studies, did not demonstrate a significant efficacy against chronic pain in humans Huggins et al. These discrepancies may be explained by species differences, differences in methodology and outcomes measured in the studies, as well as lack of selectivity of the ligands used Dhopeshwarkar and Mackie, On the other hand, the outcome of a clinical trial of pain depends on the type of pain, trial design, target patient population, and several other factors Gewandter et al.
The effect of THC and other cannabinoids acting at CB1 receptors on motor activity in animals may easily be misinterpreted as pain-suppressing behavior Meng et al. In humans, multiple emotional and cognitive factors influence the perception and experience of pain and this result in high inter-individual variability. However, pain in animals is mainly measured as a behavioral response to noxious stimuli, so that results obtained from animal studies are often more consistent.
Also, volunteers with experimental pain respond more uniformly than patients with pathological pain, and pain pathways in healthy volunteers differ from those in patients Olesen et al. Due to CB1 receptor activation, the cannabinoid antinociception in animals may be accompanied by CNS side effects e. A growing body of evidence indicates that in the treatment of chronic pain conditions, stimulation of the endocannabinoid system presents a promising approach that may prevent the occurrence of CNS side effects Lomazzo et al.
Several new strategies on how to preserve analgesic activity and avoid psychoactivity of cannabinoids have been proposed and tested in animals. However, it is important to verify whether the efficacy of this multi-target strategy observed in rodent models of chronic pain and inflammation translates to humans and is not species-specific. Cannabinoids have been studied in various types of neuropathic pain in animals, including chronic nerve constriction traumatic nerve injury, trigeminal neuralgia, chemotherapy- and streptozotocin-induced neuropathy, etc.
Both CB1 and CB2 receptors have been found to be upregulated in nervous structures involved in pain processing in response to peripheral nerve damage Lim et al. It has been shown that increased CB2 expression is accompanied by the appearance of activated microglia Zhang et al. Both microglial activation and neuropathic pain symptoms can be suppressed by CB2 agonists Wilkerson et al.
Consistent with this, CB2 knockout mice and transgenic mice overexpressing CB2 are characterized by enhanced and suppressed reactivity of microglia and neuropathic pain symptoms, respectively Racz et al. TRPV1 expression is also increased in glutamatergic neurons of the medial prefrontal cortex in a model of spared nerve injury SNI in rats Giordano et al.
The CB2 selective agonists given intrathecally or systemically are also effective in several animal models of neuropathic pain Yamamoto et al. When given early in the course of diabetes, CBD attenuates microgliosis in the ventral lumbar spinal cord of diabetic mice, as well as tactile allodynia and thermal hyperalgesia. However, if given later in the course of the disease, CBD has a little effect on pain-related behavior Toth et al. A controlled cannabis extract containing numerous cannabinoids and other non-cannabinoid fractions such as terpenes and flavonoids demonstrated greater antinociceptive efficacy than the single cannabinoid given alone, indicating synergistic antinociceptive interaction between cannabinoids and non-cannabinoids in a rat model of neuropathic pain Comelli et al.
The anti-hyperalgesic effect did not involve the cannabinoid receptors but was mediated by TRPV1 and thus it most probably belongs to CBD. In animals with neuropathic pain, increased levels of endocannabinoids AEA and 2-AG have been detected in different regions of the spinal cord and brain stem Mitrirattanakul et al. However, they appeared to be differentially regulated in different models of neuropathic pain, depending on the characteristic of the pain and the affected tissues Starowicz and Przewlocka, The reduction in the side effects that accompany CB1 agonism, such as motor incoordination, catalepsy, sedation and hypothermia, suggests that mainly TRPV1, but not a cannabinoid receptor-dependent mechanism, mediate the analgesic properties of exogenously and endogenously elevated levels of AEA in neuropathic pain.
Monoacylglycerol lipase inhibitors demonstrated CB1-dependent behavioral effects, including analgesia, hypothermia and hypomotility Long et al. Co-administration of sub-threshold doses of FAAH inhibitor, PF and the non-selective COX inhibitor, diclofenac sodium, produced enhanced antinociceptive effects in rodent models of both neuropathic CCI and inflammatory pain intra-plantar carrageenan Grim et al.
They attenuated both inflammatory and neuropathic pain behavior without producing the CB1-mediated side effects of orthosteric CB1 agonists but did not produce tolerance after repeated administration Khurana et al. Different classes of cannabinoids i. Since inflammatory pain is a characteristic of several chronic diseases, including cancer, arthritis, inflammatory bowel disease, sickle-cell disease, etc.
It is well known that CB2 receptor expression increases in microglia in response to inflammation and serves to regulate neuroimmune interactions and inflammatory hyperalgesia Dhopeshwarkar and Mackie, However, the extent of CB2 expression in neurons is a subject of controversy Atwood and Mackie, ; Atwood et al. It has been suggested that peripheral inflammation, unlike peripheral nerve injury, does not induce CB2 receptor expression in the spinal cord Zhang et al.
In contrast, Hsieh et al. Systemic or local peripheral injection of the CB2-selective agonist was reported to reduce nociceptive behavior and swelling in different animal models of inflammation Quartilho et al. In addition, the CB2-selective agonist did not produce hypothermia or motor deficit that are CB1-mediated side effects Kinsey et al.
Therefore, a CB2 receptor selective agonist is expected to have less psychomimetic side effects and lower abuse potential as compared to the available non-selective or CB1-selective cannabinoid agonists. In animal models of inflammatory disease, CB2 agonists slow the progression of diseases Turcotte et al.
In a murine model of rheumatoid arthritis, collagen-induced arthritis CIA , CB2-selective agonists did not prevent the onset of arthritis, but did ameliorate established arthritis Sumariwalla et al. JWH, a selective CB2 agonist, inhibited in vitro production of cytokines in synoviocytes and in vivo reduced the arthritis score, inflammatory cell infiltration and bone destruction in CIA Fukuda et al. Another CB2-selective agonist, HU, was shown to reduce swelling, synovial inflammation and joint destruction, in addition to lowering circulating antibodies against collagen I in CIA Gui et al.
Although approved in a range of preclinical models of pain, LY, CB2 agonist, failed in a trial of patients with osteoarthritic knee pain Pereira et al. It was shown that formalin administration to the hind paw of rats induced AEA release into the periaqueductal gray matter Walker et al.
FAAH knockout mice and mice that express FAAH exclusively in nervous tissue, displayed anti-inflammatory and anti-hyperalgesic effects in both the carrageenan and CIA models, and the effects were prevented by administration of a CB2 but not a CB1 antagonist Lichtman et al.
Oral administration of PF, a highly efficacious and selective FAAH inhibitor, produced potent antinociceptive effects in the CFA model of arthritis in rats, and it was shown that both CB1 and CB2 receptors were implicated in this effect Ahn et al.
In contrast to animal data, PF failed to demonstrate efficacy in a randomized placebo and active-controlled clinical trial on pain in osteoarthritis of the knee Ahn et al.
The possible explanations are development of tolerance to chronically elevated endocannabinoids or sensitization of TRPV1 receptors. It has been suggested that specificity and non-selectivity of this molecule and several errors in the design of the study were responsible for its toxicity, and not targeting of FAAH per se Huggins et al.
More research is necessary to characterize both the efficacy and safety profiles of endocannabinoid-directed therapeutic strategies. However, local administration of URB into osteoarthritic knee joints reduced pain via CB1 receptors [monosodium iodoacetate MIA -induced osteoarthritis in rats and the model of spontaneous osteoarthritis in Dunkin-Hartley guinea pigs] Schuelert et al.
It was shown that inhibition of fatty acid binding proteins FABPs reduced inflammatory pain in mice. Recent animal findings suggest that cannabinoids may have beneficial effect on affective-emotional and cognitive aspect of chronic pain La Porta et al.
In mice with MIA-induced arthritis, selective agonists of both CB1 and CB2 receptors ameliorated the nociceptive and affective manifestations of osteoarthritis, while a CB1-selective agonist improved the memory impairment associated with arthritis La Porta et al. This is in agreement with human studies of cannabinoids that indicate a significant improvement in secondary outcome measures, such as sleep and mood Lynch and Ware, Experiments with animal models of cancer pain support the use of cannabinoids in the treatment of cancer pain in humans.
Systemic administration of non-selective, CB1 selective or CB2 selective agonist significantly attenuated mechanical allodynia in a mouse model which was produced by inoculating human oral cancer cell lines HSC3 into the hind-paw of mice Guerrero et al. A mechanical hyperalgesia associated with decreased anandamide levels were found in plantar paw skin ipsilateral to tumor induced by injection of fibrosarcoma cells into the calcaneum of mice.
The paw withdrawal frequency was reduced after local injection of anandamide Khasabova et al. Also, one study reported that the efficacy of synthetic CB1- and CB2-receptor agonists was comparable with the efficacy of morphine in a murine model of tumor pain Khasabova et al. An important finding is that cannabinoids are effective against neuropathic pain induced by exposure of animals to anticancer chemotherapeutics vincristine, cisplatin, paclitaxel Rahn et al.
Pain relief is the most commonly cited reason for the medical use of cannabis. However, cannabis is not the first drug of choice that a patient takes to relieve pain. As with many other analgesics, cannabinoids do not seem to be equally effective in the treatment of all pain conditions in humans. This is most probably due to the different mechanisms of pain e. Clinical studies have shown that cannabinoids are not effective against acute pain Buggy et al. Clinical data also indicate that cannabinoids may only modestly reduce chronic pain, like all presently available drugs for the treatment of chronic pain in humans Romero-Sandoval et al.
Until recently, there was no consensus about the role of cannabinoids for the treatment of chronic pain. More recently, the Canadian Pain Society supported their use as the third-line option for the treatment of neuropathic pain, after anti-convulsives, anti-depressants, and opioids Moulin et al. In addition, Health Canada provided preliminary guidelines for prescribing smoked cannabis in the treatment of chronic non-cancer pain Kahan et al.
There is a growing body of evidence to support the use of medicinal cannabis in the treatment of chronic pain. At present, there is a scientific consensus on the medicinal effects of cannabis for the treatment of chronic pain that is based on scientific evidence.
All 29 trials included about participants and their duration was up to several weeks. Twenty-two of 29 trials demonstrated a significant analgesic effect and several also reported improvements in secondary outcomes sleep, spasticity. The Canadian Agency for Drugs and Technologies in Health recently analyzed five systematic reviews including two with meta-analyses of nabiximols THC: CBD buccal spray for the treatment of chronic non-cancer or neuropathic pain Lynch and Campbell, ; Lynch and Ware, ; Jawahar et al.
The length of the follow-up across the studies was from 1 to 15 weeks. In this review, there are inconsistencies with regard to both the effectiveness and safety of nabiximols. The authors concluded that treatment with nabiximols in the short term may be associated with pain relief and good tolerability when compared with placebo therapy, but there is still insufficient evidence to support its use in the management of chronic neuropathic and non-cancer pain.
In these trials, the THC content ranged from 3. A dose-related effect of cannabis was found, with higher THC contents producing more pronounced pain relief. In one study, pain relief was not dose-dependent and was achieved with a low concentration of cannabis THC [1. The follow-up periods ranged from days to weeks. In a more recent randomized, placebo-controlled, double-blind crossover study 38—41 participants per group , Wilsey et al.
No recommendations regarding cannabinoid treatment of non-spastic and non-trigeminal neuralgic pain in adult patients with MS were reported in the systemic review of Jawahar et al. Results of another systematic review that analyzed the effectiveness of cannabis extracts and cannabinoids in the treatment of chronic non-cancer neuropathic pain suggested that cannabis-based medicinal extracts may provide pain relief in conditions that are refractory to other treatments Boychuk et al. It was pointed out that further studies are required to estimate the influence of the duration of the treatment.
A recently published systematic review Meng et al. This study shows that oral cannabinoids are modestly effective in reducing chronic neuropathic pain and that for this effect a minimum of 2 weeks of treatment is required. The study also showed improvements in the quality of life, sleep and increased patient satisfaction. However, the quality of the evidence is moderate and the strength of recommendation for analgesic efficacy of selective cannabinoids in this clinical setting is weak.
Of the different cannabinoids used, nabiximols and dronabinol but not nabilone demonstrated an analgesic advantage. All CBMs were superior to placebo in reducing pain intensity, sleep problems and psychological distress very low- to moderate-quality evidence. Between these two groups, no differences were found in improvements to health-related quality of life and discontinuation of the medication because of its ineffectiveness.
There was no difference between CBM and placebo in the frequency of serious adverse events low-quality evidence. Adverse events were reported by Some of the adverse events e. Four randomized controlled trials with patients with fibromyalgia, osteoarthritis, chronic back pain and rheumatoid arthritis treated with cannabinoids nabilone, nabiximols, and FAAH inhibitor or placebo or an active control amitriptyline , were included in a systemic review Fitzcharles et al.
The results were not consistent and did not reveal whether the cannabinoids were superior to the controls placebo and amitriptyline. The authors concluded that there is insufficient evidence for the recommendation for cannabinoid use for pain management in patients with rheumatic diseases.
Smoked cannabis has not been tested for pain relief in patients suffering from rheumatoid pain Ko et al. In a randomized, double-blind, placebo-controlled parallel-design phase 2 study 65 participants , no difference between a THC tablet and a placebo tablet in reducing pain measures in patients with chronic abdominal pain due to surgery or chronic pancreatitis was found de Vries et al.
Cancer pain is a chronic pain, often complex, consisting of nociceptive, inflammatory and neuropathic components. Severe and persistent cancer pain is often refractory to treatment with opioid analgesics Abrams and Guzman, Nabiximols has been considerably studied in patients with cancer pain. It has been conditionally approved in Canada and some European countries for the treatment of cancer-related pain. Currently, it is in phase 3 trials for cancer pain.
A multicenter, double-blind, randomized, placebo-controlled study patients demonstrated that nabiximols 2. A randomized, placebo-controlled, graded-dose trial with advanced cancer patients 88—91 per group whose pain was not fully relieved by strong opioids, demonstrated significantly better pain relief and sleep with THC: In an open-label extension study of 43 patients with long-term use of the THC: CBD oromucosal spray there was no need for increasing the dose of the spray or the dose of other analgesics Johnson et al.
However, results of more recent studies differ from previous ones and are not promising for the use of nabiximols in the treatment of cancer pain. Namely, two studies multicenter, randomized, double-blind, placebo-controlled, and parallel-group conducted by GW Pharmaceuticals, the manufacturer of nabiximols, suggested that the effects of nabiximols in patients with cancer pain resistant to opioid analgesics were not different from placebo Fallon et al.
In fact, it was shown that nabiximols is superior to placebo in a patient sub-population studied in the United States, but not in sub-populations studied outside of United States, and this finding warrants further examination.
At present, there is insufficient evidence to support the approval of dronabinol and nabilone for the treatment of any type of pain, including cancer pain. In an observational study of patients with advanced cancer, nabilone improved management of pain, nausea, anxiety and distress when compared with untreated patients. Nabilone was also associated with a decreased use of opioids and other pain killers, as well as dexamethasone, metoclopramide, and ondansetron Maida et al.
Two studies examined the effects of dronabinol on cancer pain. In the first, randomized, double-blind, placebo-controlled, dose-ranging study involving ten patients, significant pain relief was obtained with and mg doses; however, a mg dose induced somnolence Noyes et al.
In a follow-up, single-dose study involving 36 patients, doses of 10 and 20 mg of dronabinol produced analgesic effects that were equivalent to doses of 60 and mg of codeine, respectively Noyes et al. However, higher doses of dronabinol were found to be more sedating than codeine. It can be concluded that the effectiveness of cannabinoids in the treatment of chronic cancer pain is questionable.
However, whether cannabinoids show some other improvements in cancer patients sleep, quality of life remains to be explored. More research is required to establish the role of cannabinoids in the treatment of cancer pain. There are some case studies, but no published controlled clinical trials, on the use of inhaled cannabis for the treatment of pain in patients with cancer. Also, inhaled cannabis could be effective against chemotherapy-induced neuropathic pain in patients with cancer Wilsey et al.
Their short-term use was associated with an increased risk of adverse events, but they were mostly mild and well tolerated Wang et al. The psychoactive effects of inhaled cannabis were dose-dependent, rare and mild in intensity Andreae et al. The treatment with oral cannabinoids was associated with limited tolerability. They produce more cannabinoid-related side effects than placebo, but the side effects are mild to moderate and short-lived Meng et al.
One systematic review of safety studies 23 RCTs and 8 observational studies of medical cannabis and cannabinoids found that short-term use appeared to increase the risk of non-serious adverse events and that they represent Psychiatric adverse effects are the most common reason for withdrawal of the treatment. The most commonly reported adverse effect was dizziness Tolerance to these adverse effects develops soon after the beginning of treatment.
They can also worsen depression, mania or other mental illnesses. Due to lack of cannabinoid receptors in the brainstem areas controlling respiration, lethal overdoses from cannabis do not occur. The brain develops a tolerance to cannabinoids, and long-term studies with cannabinoids need to answer the question whether pain can be constantly controlled with these drugs, or whether tolerance and a hyperalgesic response can occur. However, at present there are few well-designed clinical trials and observational studies for long-term medicinal cannabis use that have examined tolerability and safety mostly in MS patients and in use of oral cannabinoids.
One controlled open-label study has evaluated the safety and tolerability of cannabis a standardized botanical cannabis product that contains There was a higher rate of adverse events mostly mild to moderate with respect to the nervous system and psychiatric disorders among cannabis users when compared to controls, but not for serious adverse events at an average dose of 2.
The conclusion of the authors of this study is that cannabis is tolerated well and relatively safe when used long-term. The beneficial effect persists over time, indicating that cannabis use for over 1 year does not induce analgesic tolerance. The effectiveness and long-term safety of cannabinoid capsules 2. The number of patients who withdrew due to side effects was similar between groups. Also, serious side effects were similar in the placebo and active groups and were related to the medical condition.
Generally, there were no safety concerns reported in this study. The safety and tolerability of nabiximols long-term use in different conditions cancer pain, spasticity and neuropathic pain in MS patients has been studied in a series of trials of up to 2 years duration Wade et al. All were uncontrolled, open-label extension trials.
Adverse events and serious adverse events were cannabinoid-related with no safety concerns reported. Also, there was no evidence for a loss of effect in the relief of pain with long-term use. Taking into account all long-term safety studies, cannabis appears to be better tolerated than oral cannabinoids Romero-Sandoval et al.
This interpretation is based on a single study with cannabis Ware et al. Long-term adverse effects of medical cannabis are difficult to evaluate. They mainly come from studies with recreational cannabis use Mattick, However, there are many differences between medical cannabis and recreational cannabis users as regards the amounts used, the existence of comorbidities, the mode of drug delivery Wang et al. Thus, the adverse effects of recreational cannabis use cannot be directly extrapolated to medical cannabis use.
The safety of medical and recreational cannabis should be evaluated separately. There is evidence that long-term cannabis use is associated with an increased risk of addiction, cognitive impairment, altered brain development and an increased risk of mental disorders anxiety, depression, and psychotic illness with adolescent use, and adverse physical health effects such as cardiovascular disease, chronic obstructive pulmonary disease and lung cancer Volkow et al.
It is well established and documented that CBD may lower the risk for developing psychotic illness that is related to cannabis use Iseger and Bossong, CUD are associated with psychiatric comorbidities. About one half of patients treated for CUD develop withdrawal symptoms such as dysphoria anxiety, irritability, depression, and restlessness , insomnia, hot flashes and rarely gastrointestinal symptoms.
These symptoms are mild when compared with withdrawal symptoms associated with opioid use. Most of the symptoms appear during the 1st week of cannabis withdrawal and resolve after a few weeks Gordon et al.
A number of studies have yielded conflicting evidence regarding the risks of various cancers associated with cannabis smoking Health Canada, Recently, NASEM has stated, with a moderate level of evidence, that there is no statistical association between cannabis smoking and lung cancer incidence.
Before grant approval, drug agencies need to be sure that the benefits of medicine outweigh the risks. As the benefits and risks of medical cannabis have not been thoroughly examined, individual products containing cannabinoids have not been approved for the treatment of pain Ko et al.
Observational studies have found that state legalization of cannabis is associated with a decrease in opioid addiction and opioid-related over-dose deaths Hayes and Brown, ; Powell et al. Previous studies suggested that the analgesic effects of cannabis are comparable to those of traditional pain medications Wilsey et al. New high-quality, long-term exposure trials are required to determine the efficacy and safety of long-term use of medicinal cannabis in the treatment of pain Hill et al.
The design of trials should be improved to ensure that they are blinded, placebo-controlled with active comparator, with consistency of pain diagnosis, long-enough duration of treatment, evaluation of the dose-response, homogeneity of the patient population and inclusion of quality of life as an outcome measure Ko et al. Current research evidence supports the use of medical cannabis in the management of chronic pain in adults NASEM, As its use in the treatment of chronic pain increases, additional research to support or refute the current evidence base is crucial to provide answers to questions concerning the risk-benefit ratio for medical cannabis use in pain treatment.
The implementation of monitoring programs is mandatory and provides an opportunity to accumulate data on the safety and effectiveness of long-term use of medical cannabis in the real world Hill et al. This is important for evidence-based policy making and implementation Nosyk and Wood,
Marijuana and CBD Oil, Powerful New Tools for Pain Relief!
Cannabinoids in the management of difficult to treat pain. Abstract; Metrics; Get Permission. Accumulated views by Dove Pres PMC accu Apr Feb. Beside acting on cannabinoid CB1/CB2 receptors, they may reduce pain through attractive targets for the therapeutic use of cannabinoids in the treatment of pain. Long-term adverse effects of medical cannabis are difficult to evaluate. Pain Management Centre, Queen's Medical Centre, Nottingham NG7 2UH . EDITOR—The systematic review on cannabinoids in the treatment of pain1 . For more difficult problems, such as painful spasms and neuropathic.