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 .
difficult of pain treat to the management Cannabinoids in
In general, the efficacy of medical cannabis in pain treatment is not completely clear due to several limitations. Clinical trials are scarce and most were of short duration, with relatively small sample sizes, heterogeneous patient populations, different types of cannabinoids, a range of dosages, variability in the assessment of domains of pain sensory, affective and modest effect sizes. Therefore, further larger studies examining specific cannabinoids and strains of cannabis, using improved and objective pain measurements, appropriate dosages and duration of treatment in homogeneous patient populations need to be carried out.
The current review of evidence from clinical trials of medicinal cannabis suggests that the adverse effects of its short-term use are modest, most of them are not serious and are self-limiting. Long-term safety assessment of medicinal cannabis is based on scant clinical trials, so the evidence is limited, and the safety interpretation should be taken cautiously. More research is needed to evaluate the adverse effects of long-term use of medical cannabis.
In view of the limited effect size and the low but not unimportant risk of serious, adverse events, a more precise determination of the risk-to-benefit ratio for medicinal cannabis in pain treatment is needed to help establishing evidence-based policy implementation.
Current evidence supports the use of medical cannabis in the treatment of chronic pain in adults. Monitoring and follow-up of patients is obligatory. SV conceived and wrote manuscript. DS participated in literature search. All authors revised the manuscript and approved the final manuscript for submission. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Cannabinoid-opioid interaction in chronic pain. Cannabis in cancer care. Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on man. PubMed Abstract Google Scholar. Mechanistic and pharmacological characterization of PF The nonpsychotropic cannabinoid cannabidiol modulates and directly activates alpha-1 and alphaBeta glycine receptor function. Targeting CB 2 receptors and the endocannabinoid system for the treatment of pain.
Inhaled cannabis for chronic neuropathic pain: EFNS guidelines on the pharmacological treatment of neuropathic pain: Functional selectivity in CB 2 cannabinoid receptor signaling and regulation: Coanalgesics for chronic pain therapy: Direct inhibition by cannabinoids of human 5-HT3A receptors: Effects of nabilone, a synthetic cannabinoid, on postoperative pain. Narrative review of the safety and efficacy of marijuana for the treatment of commonly state-approved medical and psychiatric disorders.
Medical cannabis use is associated with decreased opiate medication use in a retrospective cross-sectional survey of patients with chronic pain. The effectiveness of cannabinoids in the management of chronic nonmalignant neuropathic pain: Oral Facial Pain Headache 29, 7— Marijuana dependence and its treatment.
Lack of analgesic efficacy of oral deltatetrahydrocannabinol in postoperative pain. Antinociceptive effect of the cannabinoid agonist, WIN 55,, in the orofacial and temporomandibular formalin tests. Cannabidiol CBD and its analogs: Canadian Agency for Drugs and Technologies in Health Canadian Agency for Drugs and Technologies in Health.
The novel reversible fatty acid amide hydrolase inhibitor ST increases endocannabinoid brain levels and counteracts neuropathic pain in different animal models. A pro-nociceptive phenotype unmasked in mice lacking fatty-acid amide hydrolase. Monoacylglycerol lipase activity is a critical modulator of the tone and integrity of the endocannabinoid system.
Direct inhibition of T-type calcium channels by the endogenous cannabinoid anandamide. Anandamide suppresses pain initiation through a peripheral endocannabinoid mechanism. CB 1 and CB 2 cannabinoid receptors are implicated in inflammatory pain. Antihyperalgesic effect of a Cannabis sativa extract in a rat model of neuropathic pain: The non-psychoactive cannabis constituent cannabidiol is an orally effective therapeutic agent in rat chronic inflammatory and neuropathic pain.
Immunohistochemical localization of cannabinoid type 1 and vanilloid transient receptor potential vanilloid type 1 receptors in the mouse brain. Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Pain and nociception neuroscience research group. Chronic cannabinoid receptor 2 activation reverses paclitaxel neuropathy without tolerance or cannabinoid receptor 1-dependent withdrawal. CB 2 Cannabinoid receptors as a therapeutic target-what does the future hold?
Activation of CB 1 and CB 2 receptors attenuates the induction and maintenance of inflammatory pain in the rat. Phytochemistry of Cannabis sativa L. Mast cells express a peripheral cannabinoid receptor with differential sensitivity to anandamide and palmitoylethanolamide. Sativex oromucosal spray as adjunctive therapy in advanced cancer patients with chronic pain unalleviated by optimized opioid therapy: Selective inhibition of FAAH produces antidiarrheal and antinociceptive effect mediated by endocannabinoids and cannabinoid-like fatty acid amides.
Pharmacotherapy for neuropathic pain in adults: Efficacy, tolerability and safety of cannabinoids in chronic pain associated with rheumatic diseases fibromyalgia syndrome, back pain, osteoarthritis, rheumatoid arthritis: The role of central and peripheral cannabinoid 1 receptors in the antihyperalgesic activity of cannabinoids in a model of neuropathic pain. Cannabinoid receptor 2 as a potential therapeutic target in rheumatoid arthritis.
Interdisciplinary chronic pain management: Research designs for proof-of-concept chronic pain clinical trials: TRPV1-dependent and -independent alterations in the limbic cortex of neuropathic mice: Medical consequences of marijuana use: Pharmacokinetics and pharmacodynamics of cannabinoids. Peripheral cannabinoids attenuate carcinoma-induced nociception in mice. Activation of cannabinoid receptor 2 attenuates synovitis and joint distruction in collagen-induced arthritis.
US epidemiology of cannabis use and associated problems. DSM-5 criteria for substance use disorders: Legalization of medical marijuana and incidence of opioid mortality. Cannabis Marihuana, Marijuana and the Cannabinoids. Dried Plant for Administration by Ingestion or other Means. Information for Health Care Professionals: Delta9-tetrahydrocannabinol and endogenous cannabinoid anandamide directly potentiate the function of glycine receptors. A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract Cannador for postoperative pain management.
The role of TRPV1 receptors in the antinociceptive effect of anandamide at spinal level. Central and peripheral sites of action for CB2 receptor mediated analgesic activity in chronic inflammatory and neuropathic pain models in rats. Identification of a new class of molecules, the arachidonyl amino acids, and characterization of one member that inhibits pain.
An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee.
Enhancement of endocannabinoid signaling by fatty acid amide hydrolase inhibition: CB 2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Cannabinoid CB 1 and CB 2 receptor signaling and bias. In vivo characterization of the highly selective monoacylglycerol lipase inhibitor KML A systematic review of the antipsychotic properties of cannabidiol in humans.
The subjective psychoactive effects of oral dronabinol studied in a randomized, controlled crossover clinical trial for pain. A systematic review of pharmacological pain management in multiple sclerosis. The nuclear receptor peroxisome proliferator-activated receptor-alpha mediates the anti-inflammatory actions of palmitoylethanolamide. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC: Inhibition of fatty acid binding proteins elevates brain anandamide levels and produces analgesia.
Prescribing smoked cannabis for chronic noncancer pain: Control of synaptic function by endocannabinoid-mediated retrograde signaling. Global speculations and recommendations for future Phase I trials. CB 1 and CB 2 receptor agonists promote analgesia through synergy in a murine model of tumor pain. Cannabinoid type-1 receptor reduces pain and neurotoxicity produced by chemotherapy. A decrease in anandamide signaling contributes to the maintenance of cutaneous mechanical hyperalgesia in a model of bone cancer pain.
Modulation of CB 1 cannabinoid receptor by allosteric ligands: Fatty acid amide hydrolase and monoacylglycerol lipase inhibitors produce anti-allodynic effects in mice through distinct cannabinoid receptor mechanisms. The CB 2 cannabinoid receptor-selective agonist O reduces pain and inflammation without apparent cannabinoid behavioral effects. Rescue of impaired mGluR5-driven endocannabinoid signaling restores prefrontal cortical output to inhibit pain in arthritic rats.
Cannabinoid-based drugs as anti-inflammatory therapeutics. Medical cannabis - the Canadian perspective. Lack of analgesia by oral standardized cannabis extract on acute inflammatory pain and hyperalgesia in volunteers. Role of the endocannabinoid system in the emotional manifestations of osteoarthritis pain. Cannabidiol is a negative allosteric modulator of the cannabinoid CB 1 receptor. The synthetic cannabinoids attenuate allodynia and hyperalgesia in a rat model of trigeminal neuropathic pain.
Reversible inhibitors of fatty acid amide hydrolase that promote analgesia: Upregulation of spinal cannabinoidreceptors following nerve injury enhances the effects of Win 55, on neuropathic pain behaviors in rats.
Therapeutic potential of inhibitors of endocannabinoid degradation for the treatment of stress-related hyperalgesia in an animal model of chronic pain. Selective blockade of 2-arachidonoylglycerol hydrolysis produces cannabinoid behavioral effects.
Rationale for cannabis-based interventions in the opioid overdose crisis. Medical cannabis access, use, and substitution for prescription opioids and other substances: Drug Policy 42, 30— Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Cannabinoids for the treatment of chronic non-cancer pain: Endocannabinoid signaling at the periphery: Adjunctive nabilone in cancer pain and symptom management: Analgesic actions of N-arachidonoyl-serotonin, a fatty acid amide hydrolase inhibitor with antagonistic activity at vanilloid TRPV1 receptors.
Dual-acting compounds targeting endocannabinoid and endovanilloid systems-a novel treatment option for chronic pain management. Behavioral, biochemical, and molecular modeling evaluations of cannabinoid analogs. Selective cannabinoids for chronic neuropathic pain: An analgesia circuit activated by cannabinoids. Site-specific increases in peripheral cannabinoid receptors and their endogenous ligands in a model of neuropathic pain. Lessons from the fatal French study BIA Molecular targets of the phytocannabinoids-a complex picture.
Pharmacological management of chronic neuropathic pain: Cannabis-based medicines for chronic neuropathic pain in adults. An Evidence Review and Research Agenda. The Health Effects of Cannabis and Cannabinoids: Opioid-sparing effect of cannabinoids: Activation of dorsal horn cannabinoid CB 2 receptor suppresses the expression of P2Y 12 and P2Y 13 receptors in neuropathic pain rats. Drug Policy 23, — The analgesic properties of deltatetrahydrocannabinol and codeine.
Analgesic effect of deltatetrahydrocannabinol. Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Human experimental pain models for assessing the therapeutic efficacy of analgesic drugs. A randomized, controlled study to investigate the analgesic efficacy of single doses of the cannabinoid receptor-2 agonist GW, ibuprofen or placebo in patients with acute pain following third molar tooth extraction.
An update on PPAR activation by cannabinoids. Cellular approaches to the interaction between cannabinoid receptor ligands and nicotinic acetylcholine receptors. The endocannabinoid system as an emerging target of pharmacotherapy. A cannabinoid agonist, WIN 55,, reduces neuropathic nociception induced by paclitaxel in rats. Drugs R D 16, — Spinal endocannabinoids and CB 1 receptors mediate C-fiber-induced heterosynaptic pain sensitization.
The diverse CB 1 and CB 2 receptor pharmacology of three plant cannabinoids: International union of basic and clinical pharmacology. Cannabinoid receptors and their ligands: Changes in spinal and supraspinal endocannabinoid levels in neuropathic rats. More surprises lying ahead. The endocannabinoids keep us guessing. A guide to the national academy of science report on cannabis: Peripheral gating of pain signals by endogenous lipid mediators.
Substitution of medical cannabis for pharmaceutical agents for pain, anxiety, and sleep. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: Do medical marijuana laws reduce addictions and deaths related to pain killers? Allosteric modulation of the cannabinoid CB 1 receptor.
Inhibition of inflammatory hyperalgesia by activation of peripheral CB 2 cannabinoid receptors. Interferon-gamma is a critical modulator of CB 2 cannabinoid receptor signaling during neuropathic pain. Cannabinoids as pharmacotherapies for neuropathic pain: Activation of cannabinoid CB 1 and CB 2 receptors suppresses neuropathic nociception evoked by the chemotherapeutic agent vincristine in rats. Brain CB 2 receptors: A cyclooxygenase metabolite of anandamide causes inhibition of interleukin-2 secretion in murine splenocytes.
Involvement of the peroxisome proliferator-activated receptor PPAR alpha in vascular response of endocannabinoids in the bovine ophthalmic artery.
Cannabis and cannabinoids for chronic pain. Anandamide and vanilloid TRPV1 receptors. A tale of two cannabinoids: Agonistic properties of cannabidiol at 5-HT1a receptors. The orphan receptor GPR55 is a novel cannabinoid receptor.
Inhibition of fatty acid amide hydrolase produces PPAR-alpha-mediated analgesia in a rat model of inflammatory pain. Cannabinoid and opioid interactions: Inhibitors of endocannabinoid-metabolizing enzymes reduce precipitated withdrawal responses in THC-dependent mice. Local application of the endocannabinoid hydrolysis inhibitor URB reduces nociception in spontaneous and chemically induced models of osteoarthritis.
Inhibition of 5-HT 3 receptors-activated currents by cannabinoids in rat trigeminal ganglion neurons. Positive allosteric modulation of cannabinoid receptor type 1 suppresses pathological pain without producing tolerance or dependence. Patent and Trademark Office. Magnesium in pain research: Spinal anandamide produces analgesia in neuropathic rats: The putative cannabinoid receptor GPR55 plays a role in mechanical hyperalgesia associated with inflammatory and neuropathic pain. A novel synthetic, nonpsychoactive cannabinoid acid HU with antiinflammatory properties in murine collagen-induced arthritis.
In Canada, 21 subjects with chronic pain sequentially smoked single inhalations of 25 mg of cannabis 0, 2. 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 Food and Drug Administration ; Russo b , 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 Tashkin Although cannabis vaporizers reduce potentially carcinogenic polyaromatic hydrocarbons, they have not been totally eliminated by this technology Gieringer et al ; Hazekamp et al Two open label studies in France of oral dronabinol for chronic neuropathic pain in 7 subjects Clermont-Gnamien et al and 8 subjects Attal et al , respectively, failed to show significant benefit on pain or other parameters, and showed adverse event frequently requiring discontinuation with doses averaging 15— Dronabinol did demonstrate positive results in a clinical trial of multiple sclerosis pain in two measures Svendsen et al , but negative results in post-operative pain Buggy et al Table 1.
Another uncontrolled case report in three subjects noted relief of intractable pruritus associated with cholestatic jaundice employing oral dronabinol Neff et al Some authors have noted patient preference for whole cannabis preparations over oral THC Joy et al , and the contribution of other components beyond THC to therapeutic benefits McPartland and Russo THC absorption orally is slow and erratic with peak serum levels in 45— minutes or longer.
Systemic bioavailability is also quite low due to rapid hepatic metabolism on first pass to hydroxy-THC. A rectal suppository of THC-hemisuccinate is under investigation Broom et al , as are transdermal delivery techniques Challapalli and Stinchcomb The terminal half-life of THC is quite prolonged due to storage in body lipids Grotenhermen Nabilone Cesamet Figure 1 , is a synthetic dimethylheptyl analogue of THC British Medical Association that displays greater potency and prolonged half-life.
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? And, with hemp oil now being available, you don't have to get high, or take the risk of getting arrested, to use them!
Let's start with one clear and simple truth: Pain is more toxic than pain medications! Yet many are given a Sophie's Choice; Be in pain, or die from pain medication — a ridiculous choice to be offered. All too many doctors default to choice one, be in pain. There's a "door number three" available!
First, recognize that pain is not your enemy. Rather, it's the oil light on your body's dashboard telling you that something needs attention. You wouldn't put a Band-Aid on the light or surgically remove it right?
That's the sensible "third door" in dealing with pain. Give your body what is asking for, and the pain often goes away. In our study using the S. This success rate results because S. This makes fibromyalgia an excellent model for pain management, as it addresses most of the key biochemical components of pain listed below.
In fibromyalgia, these underlying sources of pain often exacerbate into creating combinations of multiple health issues, including:.
 Cannabinoids for Chronic Pain
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.