Opioid-sparing effects of cannabinoids: Myth or reality?
02 Mar 2021-Progress in Neuro-psychopharmacology & Biological Psychiatry (Elsevier)-Vol. 106, pp 110065
TL;DR: 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, the clinical studies have been mostly negative.
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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TL;DR: A recent systematic review on the opioid-sparing effects of cannabinoids considered preclinical and clinical studies where the outcome was analgesia or opioid dose requirements as mentioned in this paper , found that the median effective dose (ED 50 ) administered with delta-9-tetrahydrocannabinol was 3.5 times lower (95% CI 2.04, 6.03) than the ED 50 of morphine alone.
18 citations
TL;DR: In this article, a clinical tool for the initiation of medical cannabis in the management of chronic non-cancer pain (CNCP) patients using chronic opioid therapy is presented. And the authors suggest that low dose THC is introduced as an adjunctive therapy with or without opioids to optimize pain control.
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.
15 citations
TL;DR: In this paper, a comprehensive systematic literature review was performed using PubMed/MEDLINE, EMBASE, and Google Scholar databases, as well as PsychINFO to study healthcare professionals' knowledge level (HCP) and HCPs in-training regarding both medical uses and indications.
13 citations
TL;DR: In this article, the authors present a report from the National Cancer Institute's "Cannabis, Cannabinoid and Cancer Research Symposium" on the topic of "Cancer Symptom/Treatment Side Effect Management".
Abstract: Cannabis and cannabinoids are increasingly being accessed and used by patients with advanced cancer for various symptoms and general quality of life. Specific symptoms of pain, nausea and vomiting, loss of appetite and cachexia, anxiety, sleep disturbance, and medical trauma are among those that have prompted patients with cancer to use cannabis. This conference report from the National Cancer Institute's "Cannabis, Cannabinoid and Cancer Research Symposium" on the topic of "Cancer Symptom/Treatment Side Effect Management" is an expert perspective of cannabis intervention for cancer and cancer treatment-related symptoms. The purpose of the symposium was to identify research gaps, describe the need for high-quality randomized prospective studies of medical cannabis for palliative care in patients with cancer, and evaluate the impact of medical cannabis on cancer survivors' quality of life. Further, education of clinicians and affiliated health-care providers in guiding cancer patients in using cannabis for cancer care would benefit patients. Together, these steps will further aid in refining the use of cannabis and cannabinoids for symptom palliation and improve safety and efficacy for patients.
12 citations
TL;DR: In this paper, the authors evaluated the effect of delta-9-tetrahydrocannabinol (THC; dronabinol) on hydromorphone-based analgesia, abuse liability, and cognitive performance.
11 citations
References
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TL;DR: It is considered 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, because pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging and other kinds of supporting evidence are still lacking.
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.
2,619 citations
TL;DR: 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.
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.
2,070 citations
TL;DR: 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 reversed decades of progress in mortality and was unique to the United United States; no other rich country saw a similar turnaround.
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.
1,858 citations
TL;DR: The synthetic pathways of endocannabinoids are discussed, along with the putative mechanisms of their release, uptake, and degradation, and 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.
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.
1,511 citations
TL;DR: Recent research is drawn on to address common misconceptions regarding the abuse-related risks of opioid analgesics and highlight strategies to minimize those risks.
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.
949 citations