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CNS Drugs Oct 2019Opioids are very potent and efficacious drugs, traditionally used for both acute and chronic pain conditions. However, the use of opioids is frequently associated with... (Review)
Review
Opioids are very potent and efficacious drugs, traditionally used for both acute and chronic pain conditions. However, the use of opioids is frequently associated with the occurrence of adverse effects or clinical problems. Other than adverse effects and dependence, the development of tolerance is a significant problem, as it requires increased opioid drug doses to achieve the same effect. Mechanisms of opioid tolerance include drug-induced adaptations or allostatic changes at the cellular, circuitry, and system levels. Dose escalation in long-term opioid therapy might cause opioid-induced hyperalgesia (OIH), which is a state of hypersensitivity to painful stimuli associated with opioid therapy, resulting in exacerbation of pain sensation rather than relief of pain. Various strategies may provide extra-opioid analgesia. There are drugs that may produce independent analgesic effects. A tailored treatment provided by skilled personnel, in accordance with the individual condition, is mandatory. Any treatment aimed at reducing opioid consumption may be indicated in these circumstances. Interventional techniques able to decrease the pain input may allow a decrease in the opioid dose, thus reverting the mechanisms producing tolerance of OIH. Intrathecal therapy with local anesthetics and a sympathetic block are the most common techniques utilized in these circumstances.
Topics: Analgesics, Opioid; Chronic Pain; Drug Tolerance; Humans; Hyperalgesia
PubMed: 31578704
DOI: 10.1007/s40263-019-00660-0 -
Annual Review of Neuroscience Jul 2018Opioids are the most commonly used and effective analgesic treatments for severe pain, but they have recently come under scrutiny owing to epidemic levels of abuse and... (Review)
Review
Opioids are the most commonly used and effective analgesic treatments for severe pain, but they have recently come under scrutiny owing to epidemic levels of abuse and overdose. These compounds act on the endogenous opioid system, which comprises four G protein-coupled receptors (mu, delta, kappa, and nociceptin) and four major peptide families (β-endorphin, enkephalins, dynorphins, and nociceptin/orphanin FQ). In this review, we first describe the functional organization and pharmacology of the endogenous opioid system. We then summarize current knowledge on the signaling mechanisms by which opioids regulate neuronal function and neurotransmission. Finally, we discuss the loci of opioid analgesic action along peripheral and central pain pathways, emphasizing the pain-relieving properties of opioids against the affective dimension of the pain experience.
Topics: Analgesics, Opioid; Animals; Humans; Pain; Pain Perception; Receptors, G-Protein-Coupled
PubMed: 29852083
DOI: 10.1146/annurev-neuro-080317-061522 -
Journal of Psychiatric Practice Jan 2020
Topics: Analgesics, Opioid; Humans; Opioid Epidemic; Pain; Prescription Drug Misuse
PubMed: 31913964
DOI: 10.1097/PRA.0000000000000444 -
Expert Opinion on Investigational Drugs Oct 2018Opioids are the oldest and most potent drugs for the treatment of severe pain, but they are burdened by detrimental side effects such as respiratory depression,... (Review)
Review
INTRODUCTION
Opioids are the oldest and most potent drugs for the treatment of severe pain, but they are burdened by detrimental side effects such as respiratory depression, addiction, sedation, nausea, and constipation. Their clinical application is undisputed in acute (e.g. perioperative) and cancer pain, but their long-term use in chronic pain has met increasing scrutiny and has contributed to the current 'opioid crisis.'
AREAS COVERED
This article reviews pharmacological principles and research strategies aiming at novel opioids with reduced side effects. Basic mechanisms underlying pain, opioid analgesia, and other opioid actions are outlined. To illustrate the clinical situation and medical needs, plasticity of opioid receptors, intracellular signaling pathways, endogenous and exogenous opioid receptor ligands, central and peripheral sites of analgesic, and side effects are discussed.
EXPERT OPINION
The epidemic of opioid misuse has taught us that there is a lack of fundamental knowledge about the characteristics and management of chronic pain, that conflicts of interest and validity of models must be considered in the context of drug development, and that novel analgesics with less abuse liability are badly needed. Currently, the most promising perspectives appear to be augmenting endogenous opioid actions and selectively targeting pathological conformations of peripheral opioid receptors.
Topics: Analgesics, Opioid; Animals; Chronic Pain; Drug Design; Humans; Opioid-Related Disorders; Receptors, Opioid; Signal Transduction
PubMed: 30148648
DOI: 10.1080/13543784.2018.1516204 -
Cell Nov 2023Opioids are used for pain management despite the side effects that contribute to the opioid crisis. The pursuit of non-addictive opioid analgesics remains unattained due... (Review)
Review
Opioids are used for pain management despite the side effects that contribute to the opioid crisis. The pursuit of non-addictive opioid analgesics remains unattained due to the unresolved intricacies of opioid actions, receptor signaling cascades, and neuronal plasticity. Advancements in structural, molecular, and computational tools illuminate the dynamic interplay between opioids and opioid receptors, as well as the molecular determinants of signaling pathways, which are potentially interlinked with pharmacological responses. Here, we review the molecular basis of opioid receptor signaling with a focus on the structures of opioid receptors bound to endogenous peptides or pharmacological agents. These insights unveil specific interactions that dictate ligand selectivity and likely their distinctive pharmacological profiles. Biochemical analysis further unveils molecular features governing opioid receptor signaling. Simultaneously, the synergy between computational biology and medicinal chemistry continues to expedite the discovery of novel chemotypes with the promise of yielding more efficacious and safer opioid compounds.
Topics: Humans; Analgesics, Opioid; Receptors, Opioid; Signal Transduction; Animals
PubMed: 37995655
DOI: 10.1016/j.cell.2023.10.029 -
Archives of Toxicology Aug 2021Opioid-induced respiratory depression is potentially life-threatening and often regarded as the main hazard of opioid use. Main cause of death is cardiorespiratory... (Review)
Review
Opioid-induced respiratory depression is potentially life-threatening and often regarded as the main hazard of opioid use. Main cause of death is cardiorespiratory arrest with hypoxia and hypercapnia. Respiratory depression is mediated by opioid μ receptors expressed on respiratory neurons in the CNS. Studies on the major sites in the brainstem mediating respiratory rate suppression, the pre-Bӧtzinger complex and parabrachial complex (including the Kӧlliker Fuse nucleus), have yielded conflicting findings and interpretations but recent investigations involving deletion of μ receptors from neurons have led to greater consensus. Some opioid analgesic drugs are histamine releasers. The range of clinical effects of released histamine include increased cardiac output due to an increase in heart rate, increased force of myocardial contraction, and a dilatatory effect on small blood vessels leading to flushing, decreased vascular resistance and hypotension. Resultant hemodynamic changes do not necessarily relate directly to the concentration of histamine in plasma due to a range of variables including functional differences between mast cells and histamine-induced anaphylactoid reactions may occur less often than commonly believed. Opioid-induced histamine release rarely if ever provokes bronchospasm and histamine released by opioids in normal doses does not lead to anaphylactoid reactions or result in IgE-mediated reactions in normal patients. Hypersensitivities to opioids, mainly some skin reactions and occasional type I hypersensitivities, chiefly anaphylaxis and urticaria, are uncommon. Hypersensitivities to morphine, codeine, heroin, methadone, meperidine, fentanyl, remifentanil, buprenorphine, tramadol, and dextromethorphan are summarized. In 2016, the FDA issued a Drug Safety Communication concerning the association of opioids with serotonin syndrome, a toxicity associated with raised intra-synaptic concentrations of serotonin in the CNS, inhibition of serotonin reuptake, and activation of 5-HT receptors. Opioids may provoke serotonin toxicity especially if administered in conjunction with other serotonergic medications. The increasing use of opioid analgesics and widespread prescribing of antidepressants and psychiatric medicines, indicates the likelihood of an increased incidence of serotonin toxicity in opioid-treated patients.
Topics: Analgesics, Opioid; Animals; Drug Hypersensitivity; Hemodynamics; Histamine Release; Humans; Respiratory Insufficiency; Serotonin Syndrome
PubMed: 33974096
DOI: 10.1007/s00204-021-03068-2 -
Neuropsychopharmacology : Official... Dec 2018Mu opioid receptor agonists are among the most powerful analgesic medications but also among the most addictive. The current opioid crisis has energized a quest to... (Review)
Review
Mu opioid receptor agonists are among the most powerful analgesic medications but also among the most addictive. The current opioid crisis has energized a quest to develop opioid analgesics that are devoid of untoward effects. Since their discovery in the 1970's, there have been major advances in our understanding of the endogenous opioid systems that these drugs target. Yet many questions remain and the development of non-addictive opioid analgesics has not been achieved. However, access to new molecular, genetic and computational tools have begun to elucidate the structural dynamics of opioid receptors, the scaffolding that links them to intracellular signaling cascades, their cellular trafficking and the distinct ways that various opioid drugs modify them. This mini-review highlights some of the chemical and pharmacological findings and new perspectives that have arisen from studies using these tools. They reveal multiple layers of complexity of opioid receptor function, including a spatiotemporal specificity in opioid receptor-induced cellular signaling, ligand-directed biased signaling, allosteric modulation of ligand interactions, heterodimerization of different opioid receptors, and the existence of slice variants with different ligand specificity. By untangling these layers, basic research into the chemistry and pharmacology of opioid receptors is guiding the way towards deciphering the mysteries of tolerance and physical dependence that have plagued the field and is providing a platform for the development of more effective and safer opioids.
Topics: Affect; Allosteric Regulation; Analgesics, Opioid; Animals; Brain; Humans; Pain; Receptors, Opioid; Signal Transduction
PubMed: 30250308
DOI: 10.1038/s41386-018-0225-3 -
Lancet (London, England) Apr 2019Opioids are a mainstay of acute pain management but can have many adverse effects, contributing to problematic long-term use. Opioid tolerance (increased dose needed for... (Review)
Review
Opioids are a mainstay of acute pain management but can have many adverse effects, contributing to problematic long-term use. Opioid tolerance (increased dose needed for analgesia) and opioid-induced hyperalgesia (paradoxical increase in pain with opioid administration) can contribute to both poorly controlled pain and dose escalation. Hyperalgesia is particularly problematic as further opioid prescribing is largely futile. The mechanisms of opioid tolerance and hyperalgesia are complex, involving μ opioid receptor signalling pathways that offer opportunities for novel analgesic alternatives. The intracellular scaffold protein β-arrestin-2 is implicated in tolerance, hyperalgesia, and other opioid side-effects. Development of agonists biased against recruitment of β-arrestin-2 could provide analgesic efficacy with fewer side-effects. Alternative approaches include inhibition of peripheral μ opioid receptors and blockade of downstream signalling mechanisms, such as the non-receptor tyrosine kinase Src or N-methyl-D-aspartate receptors. Furthermore, it is prudent to use multimodal analgesic regimens to reduce reliance on opioids during the perioperative period. In the third paper in this Series we focus on clinical and mechanism-based understanding of tolerance and opioid-induced hyperalgesia, and discuss current and future strategies for pain management.
Topics: Analgesics, Opioid; Drug Tolerance; Humans; Hyperalgesia; Pain, Postoperative; Perioperative Care
PubMed: 30983591
DOI: 10.1016/S0140-6736(19)30430-1 -
Journal of Clinical Pharmacology Sep 2018This is an article in the Core Entrustables in Clinical Pharmacology series that describes opioid therapy in acute and chronic pain. Opioid use during surgical...
This is an article in the Core Entrustables in Clinical Pharmacology series that describes opioid therapy in acute and chronic pain. Opioid use during surgical procedures or anesthesia is not discussed. Basic pharmacokinetic and pharmacodynamic properties of opioids are reviewed. The safe and effective use of opioids, including clinical assessment and treatment plan, equianalgesic dosing, opioid rotation, opioid risks and side effects, and clinical adherence monitoring are discussed. Individualized opioid use can be a safe and effective component of a patient-specific multimodal treatment plan for acute or chronic pain. Adverse effects and risks can be prevented or effectively managed when anticipated and recognized. The article is followed by 4 clinical vignettes with discussions.
Topics: Acute Pain; Analgesics, Opioid; Chronic Pain; Decision Making; Drug Tolerance; Humans; Medication Adherence; Opioid-Related Disorders; Substance Withdrawal Syndrome; Substance-Related Disorders
PubMed: 29985526
DOI: 10.1002/jcph.1276 -
American Society of Clinical Oncology... Jan 2019Use of opioids for the treatment of pain is necessary for the majority of patients with advanced cancer, however its use has become challenging in the face of the opioid... (Review)
Review
Use of opioids for the treatment of pain is necessary for the majority of patients with advanced cancer, however its use has become challenging in the face of the opioid epidemic and the emerging evidence that patients with cancer are also at risk for nonmedical opioid use. This article proposes an assessment and treatment plan that incorporates universal screening with monitoring for all patients with cancer who are considered for opioid treatment to assess their risk for opioid misuse and harm. Timely identification with appropriate management, including referral of at-risk patients, will allow oncology professionals to optimize the risk-to-benefit and support the safe use of opioids for patients with cancer.
Topics: Analgesics, Opioid; Cancer Pain; Cognition; Comorbidity; Disease Management; Drug Prescriptions; Drug Substitution; Humans; Neoplasm Staging; Neoplasms; Opioid-Related Disorders; Pain Management; Pain Measurement; Risk Factors; Syndrome
PubMed: 31099619
DOI: 10.1200/EDBK_100020