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Journal ArticleDOI: 10.1016/J.PNPBP.2020.110065

Opioid-sparing effects of cannabinoids: Myth or reality?

02 Mar 2021-Progress in Neuro-psychopharmacology & Biological Psychiatry (Elsevier)-Vol. 106, pp 110065
Abstract: A converging line of evidence is indicating that cannabinoids may have an opioid-sparing effect. This property, well validated in preclinical studies, allow when both drugs are co-administered to reduce the dose of opioids without loss of analgesic effects. A meta-analysis of pre-clinical studies indicated in 2017 that the median effective dose (ED50) of morphine administered in combination with delta-9-tetrahydrocannabinol (delta-9-THC) is 3.6 times lower than the ED50 of morphine alone ( Nielsen et al., 2017 ). However, very few studies have been conducted in humans to validate this effect. This narrative review provides an update on whether or not cannabinoid drugs can be used to produce an opioid sparing effect. For this, various lines of evidence ranging from preclinical, epidemiological and human studies will be summarized. Overall, this review indicates that the preclinical results are strongly and consistently supportive of the presence of an opioid sparing effect of cannabinoid drugs. However, to date the clinical studies have been mostly negative; and, the evidence collected in humans so far is so limited that it is premature to conclude. Therefore, prospective high quality controlled clinical trials are still required to validate this. Priorities for future research are also discussed.

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Topics: Opioid (52%)
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6 results found


Open accessJournal ArticleDOI: 10.3389/FPHAR.2021.633168
Abstract: BACKGROUND: Chronic non-cancer pain (CNCP) is estimated to affect 20% of the adult population. Current US and Canadian CNCP guidelines recommend careful reassessment of the risk-benefit ratio for doses greater than 90 mg morphine equivalent dose (MED), due to low evidence for improved pain efficacy at higher MED and a significant increase in morbidity and mortality. There are a number of human studies demonstrating cannabis opioid synergy. This preliminary evidence suggests a potential role of cannabis as an adjunctive therapy with or without opioids to optimize pain control. METHODS: In 2017, the Canadian Opioid Guidelines Clinical Tool was created to encourage judicious opioid prescribing for CNCP patients and to reevaluate those who have been chronically using high MED. Mirroring this approach, we draw on our clinical experiences and available evidence to create a clinical tool to serve as a foundational clinical guideline for the initiation of medical cannabis in the management of CNCP patients using chronic opioid therapy. FINDINGS: Following principles of harm reduction and risk minimization, we suggest cannabis be introduced in appropriately selected CNCP patients, using a stepwise approach, with the intent of pain management optimization. We use a structured approach to focus on low dose cannabis (namely, THC) initiation, slow titration, dose optimization and frequent monitoring. CONCLUSION: When low dose THC is introduced as an adjunctive therapy, we observe better pain control clinically with lower doses of opioids, improved pain related outcomes and reduced opioid related harm.

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Topics: Chronic pain (59%), Cannabis (51%), Opioid (51%) ... read more

3 Citations


Journal ArticleDOI: 10.1016/J.DRUGALCDEP.2021.108652
Abstract: Background Since the introduction of the National Medical Cannabis Programme in The Netherlands, many other countries in Europe have made medical cannabis (MC) and cannabis-based medicines (CBMs) available. However, each of them has implemented a unique legal framework and reimbursement strategy for these products. Therefore, it is vital to study healthcare professionals’ knowledge level (HCP) and HCPs in-training regarding both medical uses and indications and understand their safety concerns and potential barriers for MC use in clinical practice. Methods A comprehensive, systematic literature review was performed using PubMed/MEDLINE, EMBASE, and Google Scholar databases, as well as PsychINFO. Grey literature was also included. Due to the high diversity in the questionnaires used in the studies, a narrative synthesis was performed. Results From 6995 studies retrieved, ten studies, all of them being quantitative survey-based studies, were included in the review. In most studies, the majority of participants were in favor of MC and CBMs use for medical reasons. Other common findings were: the necessity to provide additional training regarding medical applications of cannabinoids, lack of awareness about the legal status of and regulations regarding MC among both certified physicians, as well as prospective doctors and students of other medicals sciences (e.g., nursing, pharmacy). Conclusions For most European countries, we could not identify any studies evaluating HCPs’ knowledge and attitudes towards medicinal cannabis. Therefore, similar investigations are highly encouraged. Available evidence demonstrates a need to provide medical training to the HCPs in Europe regarding medical applications of cannabinoids.

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Topics: Systematic review (55%), MEDLINE (50%)

1 Citations


Open accessJournal ArticleDOI: 10.1038/S41386-021-01007-4
Abstract: This Phase II study evaluated analgesia, abuse liability, and cognitive performance of hydromorphone and oral delta-9-tetrahydrocannabinol (THC; dronabinol) using a within-subject, double-blind, randomized, placebo-controlled, human laboratory trial. Healthy adults (N = 29) with no history of drug use disorder received combinations of placebo, hydromorphone (4 mg; oral), and dronabinol (2.5 mg, 5.0 mg, 10 mg; oral). Primary outcomes were quantitative sensory testing (QST) measures of acute (thermal, pressure pain; thermal, punctate probe temporal summation; cold pressor; conditioned pain modulation) and chronic pain (capsaicin 10% topical cream with thermal rekindling), measures of drug abuse liability, cognitive functioning, and adverse events. Subgroup analyses were conducted within opioid-responders (endorsed >20 on a Drug Effect visual analog scale during the hydromorphone-only condition) and nonresponders. A consistent dose-effect relationship of dronabinol on hydromorphone across all measures was not observed. Analgesia only improved in the hydromorphone + dronabinol 2.5 mg condition. Hydromorphone + dronabinol 2.5 mg showed the lowest and hydromorphone+dronabinol 5 mg showed the highest risk for abuse. Hydromorphone+dronabinol 10 mg produced a high rate of dysphoric effects, and hydromorphone+dronabinol 5 mg and hydromorphone + dronabinol 10 mg produced AEs. Subgroup analyses showed subjective effects and abuse risk was increased among opioid responders and largely absent among nonresponders. Overall, only hydromorphone+dronabinol 2.5 mg modestly enhanced hydromorphone-based analgesia and hydromorphone + dronabinol 5 mg and 10 mg increased risk for abuse and AEs. These data can help inform opioid-sparing efforts in clinical pain populations. Demonstration that potential opioid effects varied as a function of participant opioid sensitivity (e.g., responder status) is a novel finding that warrants additional research.

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Topics: Hydromorphone (63%), Dronabinol (61%), Chronic pain (52%) ... read more

1 Citations


Journal ArticleDOI: 10.1016/J.PNPBP.2021.110305
Erik B. Oleson1, Jibran Y. Khokhar2Institutions (2)
Abstract: Cannabinoids from the cannabis plant were one of the earliest psychoactive phytochemicals harnessed by humanity for their medicinal properties and remain one of the most frequently used and misused classes of chemicals in the world. Despite our long-standing history with cannabinoids, much more is said than is known regarding how these molecules influence the brain and behavior. We are in a rapidly evolving discovery phase regarding the neuroscience of cannabinoids. This period of insight began in the mid-1990s when it was discovered that phytocannabinoids (e.g., delta-9-tetrahydrocannabinol) act on G protein-coupled receptors (i.e., CB1/CB2) in the brain to produce their psychoactive effects. Shortly thereafter, it was discovered that endogenous ligands (i.e., endocannabinoids) exist for these receptor targets and, that they are synthetized on demand under a variety of physiological conditions. Thus, we can now study how phytochemicals, endogenous ligands, and synthetic/metabolic enzymes of the endocannabinoid system influence the brain and behavior by activating known receptor targets. Our increased ability to study cannabinoid interactions with the brain and behavior coincides with an increase in international interest in utilizing cannabinoids as a medicine. At the same time, the potency of, and administration routes by which cannabinoids are used is rapidly changing. And, these trends in cannabinoid misuse are producing lasting neural adaptations that have implications for mental health. In this special edition, we will summarize our recent period of discovery regarding how: 1) phytocannabinoids, synthetic cannabinoids and endocannabinoids act on the brain to produce behavioral effects; 2) cannabinoids can be harnessed to produce pharmacotherapeutic utility in the field of medicine; and 3) use of increasingly more cannabinoid variants through unique routes of administration alter the brain and behavior, especially when used in critical developmental periods like pregnancy and adolescence.

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Journal ArticleDOI: 10.1097/FBP.0000000000000657
Stevie C. Britch1, Rebecca M. Craft2Institutions (2)
Abstract: Studies have demonstrated antinociceptive synergy between morphine and delta-9-tetrahydrocannabinol (THC) in animals, but whether such synergy occurs against all types of pain and in humans is unclear. Because a majority of chronic pain patients are women, and sex differences in morphine and THC potencies have been observed in rodents, the present study examined sex-specific effects of morphine and THC given alone and in combination, in rats with persistent inflammatory pain. On day 1, baseline mechanical and thermal response thresholds, hindpaw weight-bearing, locomotor activity, and hindpaw thickness were determined. Inflammation was then induced via hindpaw injection of complete Freund's adjuvant (CFA). Three days later, morphine (s.c.), THC (i.p) or a morphine-THC combination (1:1, 3:1 and 1:3 dose ratios) was administered, and behavioral testing was conducted at 30-240 min postinjection. Morphine alone was antiallodynic and antihyperalgesic, with no sex differences, but at some doses increased weight-bearing on the CFA-treated paw more in males than females. THC alone reduced mechanical allodynia with similar potency in both sexes, but reduced thermal hyperalgesia and locomotor activity with greater potency in females than males. All morphine-THC combinations reduced allodynia and hyperalgesia, but isobolographic analysis of mechanical allodynia data showed no significant morphine-THC synergy in either sex. Additionally, whereas morphine alone was antinociceptive at doses that did not suppress locomotion, morphine-THC combinations suppressed locomotion and did not increase weight-bearing on the inflamed paw. These results suggest that THC is unlikely to be a beneficial adjuvant when given in combination with morphine for reducing established inflammatory pain.

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Topics: Allodynia (56%), Hyperalgesia (56%), Morphine (52%) ... read more

References
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91 results found


Journal ArticleDOI: 10.1124/PR.54.2.161
Abstract: Two types of cannabinoid receptor have been discovered so far, CB(1) (2.1: CBD:1:CB1:), cloned in 1990, and CB(2) (2.1:CBD:2:CB2:), cloned in 1993. Distinction between these receptors is based on differences in their predicted amino acid sequence, signaling mechanisms, tissue distribution, and sensitivity to certain potent agonists and antagonists that show marked selectivity for one or the other receptor type. Cannabinoid receptors CB(1) and CB(2) exhibit 48% amino acid sequence identity. Both receptor types are coupled through G proteins to adenylyl cyclase and mitogen-activated protein kinase. CB(1) receptors are also coupled through G proteins to several types of calcium and potassium channels. These receptors exist primarily on central and peripheral neurons, one of their functions being to inhibit neurotransmitter release. Indeed, endogenous CB(1) agonists probably serve as retrograde synaptic messengers. CB(2) receptors are present mainly on immune cells. Such cells also express CB(1) receptors, albeit to a lesser extent, with both receptor types exerting a broad spectrum of immune effects that includes modulation of cytokine release. Of several endogenous agonists for cannabinoid receptors identified thus far, the most notable are arachidonoylethanolamide, 2-arachidonoylglycerol, and 2-arachidonylglyceryl ether. It is unclear whether these eicosanoid molecules are the only, or primary, endogenous agonists. Hence, we consider it premature to rename cannabinoid receptors after an endogenous agonist as is recommended by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. Although pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging, other kinds of supporting evidence are still lacking.

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Topics: Cannabinoid Receptor Agonists (72%), Cannabinoid Receptor Modulators (66%), GPR18 (65%) ... read more

2,453 Citations


Open accessJournal ArticleDOI: 10.1523/JNEUROSCI.11-02-00563.1991
Miles Herkenham1, A B Lynn1, M R Johnson1, L S Melvin1  +2 moreInstitutions (1)
Abstract: A potent, synthetic cannabinoid was radiolabeled and used to characterize and precisely localize cannabinoid receptors in slide-mounted sections of rat brain and pituitary. Assay conditions for 3H-CP55,940 binding in Tris-HCl buffer with 5% BSA were optimized, association and dissociation rate constants determined, and the equilibrium dissociation constant (Kd) calculated (21 nM by liquid scintillation counting, 5.2 nM by quantitative autoradiography). The results of competition studies, using several synthetic cannabinoids, add to prior data showing enantioselectivity of binding and correlation of in vitro potencies with potencies in biological assays of cannabinoid actions. Inhibition of binding by guanine nucleotides was selective and profound: Nonhydrolyzable analogs of GTP and GDP inhibited binding by greater than 90%, and GMP and the nonhydrolyzable ATP analog showed no inhibition. Autoradiography showed great heterogeneity of binding in patterns of labeling that closely conform to cytoarchitectural and functional domains. Very dense 3H-CP55,940 binding is localized to the basal ganglia (lateral caudate-putamen, globus pallidus, entopeduncular nucleus, substantia nigra pars reticulata), cerebellar molecular layer, innermost layers of the olfactory bulb, and portions of the hippocampal formation (CA3 and dentate gyrus molecular layer). Moderately dense binding is found throughout the remaining forebrain. Sparse binding characterizes the brain stem and spinal cord. Densitometry confirmed the quantitative heterogeneity of cannabinoid receptors (10 nM 3H-CP55,940 binding ranged in density from 6.3 pmol/mg protein in the substantia nigra pars reticulata to 0.15 pmol/mg protein in the anterior lobe of the pituitary). The results suggest that the presently characterized cannabinoid receptor mediates physiological and behavioral effects of natural and synthetic cannabinoids, because it is strongly coupled to guanine nucleotide regulatory proteins and is discretely localized to cortical, basal ganglia, and cerebellar structures involved with cognition and movement.

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Topics: Cannabinoid receptor binding (68%), Cannabinoid (58%), Cannabinoid Receptor Agonists (58%) ... read more

1,967 Citations


Open accessJournal ArticleDOI: 10.1073/PNAS.1518393112
Anne Case1, Angus Deaton1Institutions (1)
Abstract: This paper documents a marked increase in the all-cause mortality of middle-aged white non-Hispanic men and women in the United States between 1999 and 2013. This change reversed decades of progress in mortality and was unique to the United States; no other rich country saw a similar turnaround. The midlife mortality reversal was confined to white non-Hispanics; black non-Hispanics and Hispanics at midlife, and those aged 65 and above in every racial and ethnic group, continued to see mortality rates fall. This increase for whites was largely accounted for by increasing death rates from drug and alcohol poisonings, suicide, and chronic liver diseases and cirrhosis. Although all education groups saw increases in mortality from suicide and poisonings, and an overall increase in external cause mortality, those with less education saw the most marked increases. Rising midlife mortality rates of white non-Hispanics were paralleled by increases in midlife morbidity. Self-reported declines in health, mental health, and ability to conduct activities of daily living, and increases in chronic pain and inability to work, as well as clinically measured deteriorations in liver function, all point to growing distress in this population. We comment on potential economic causes and consequences of this deterioration.

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Topics: Liver function (53%), Mortality rate (53%), Population (53%)

1,497 Citations


Open accessJournal ArticleDOI: 10.1152/PHYSREV.00004.2003
Abstract: Research of cannabinoid actions was boosted in the 1990s by remarkable discoveries including identification of endogenous compounds with cannabimimetic activity (endocannabinoids) and the cloning of their molecular targets, the CB1 and CB2 receptors. Although the existence of an endogenous cannabinoid signaling system has been established for a decade, its physiological roles have just begun to unfold. In addition, the behavioral effects of exogenous cannabinoids such as delta-9-tetrahydrocannabinol, the major active compound of hashish and marijuana, await explanation at the cellular and network levels. Recent physiological, pharmacological, and high-resolution anatomical studies provided evidence that the major physiological effect of cannabinoids is the regulation of neurotransmitter release via activation of presynaptic CB1 receptors located on distinct types of axon terminals throughout the brain. Subsequent discoveries shed light on the functional consequences of this localization by demonstrating the involvement of endocannabinoids in retrograde signaling at GABAergic and glutamatergic synapses. In this review, we aim to synthesize recent progress in our understanding of the physiological roles of endocannabinoids in the brain. First, the synthetic pathways of endocannabinoids are discussed, along with the putative mechanisms of their release, uptake, and degradation. The fine-grain anatomical distribution of the neuronal cannabinoid receptor CB1 is described in most brain areas, emphasizing its general presynaptic localization and role in controlling neurotransmitter release. Finally, the possible functions of endocannabinoids as retrograde synaptic signal molecules are discussed in relation to synaptic plasticity and network activity patterns.

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Topics: Retrograde signaling (61%), Synaptic signaling (60%), Cannabinoid (58%) ... read more

1,458 Citations


Open accessJournal ArticleDOI: 10.1056/NEJMRA1507771
Nora D. Volkow1, A. Thomas McLellanInstitutions (1)
Abstract: Chronic pain not caused by cancer is among the most prevalent and debilitating medical conditions but also among the most controversial and complex to manage. The urgency of patients’ needs, the demonstrated effectiveness of opioid analgesics for the management of acute pain, and the limited therapeutic alternatives for chronic pain have combined to produce an overreliance on opioid medications in the United States, with associated alarming increases in diversion, overdose, and addiction. Given the lack of clinical consensus and research-supported guidance, physicians understandably have questions about whether, when, and how to prescribe opioid analgesics for chronic pain without increasing public health risks. Here, we draw on recent research to address common misconceptions regarding the abuse-related risks of opioid analgesics and highlight strategies to minimize those risks.

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Topics: Chronic pain (62%)

779 Citations


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