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      The Basic Pharmacology of Opioids Informs the Opioid Discourse about Misuse and Abuse: A Review

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          Abstract

          Morphine and other opioids are widely used to manage moderate to severe acute pain syndromes, such as pain associated with trauma or postoperative pain, and they have been used to manage chronic pain, even chronic nonmalignant pain. However, recent years have seen a renewed recognition of the potential for overuse, misuse, and abuse of opioids. Therefore, prescribing opioids is challenging for healthcare providers in that clinical effectiveness must be balanced against negative outcomes—with the possibility that neither are achieved perfectly. The current discourse about the dual ‘epidemics’ of under-treatment of legitimate pain and the over-prescription of opioids is clouded by inadequate or inaccurate understanding of opioid drugs and the endogenous pain pathways with which they interact. An understanding of the basic pharmacology of opioids helps inform the clinician and other stakeholders about these simultaneously under- and over-used agents.

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          Most cited references130

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          OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines.

          To develop concise, patient-focussed, up to date, evidence-based, expert consensus recommendations for the management of hip and knee osteoarthritis (OA), which are adaptable and designed to assist physicians and allied health care professionals in general and specialist practise throughout the world. Sixteen experts from four medical disciplines (primary care, rheumatology, orthopaedics and evidence-based medicine), two continents and six countries (USA, UK, France, Netherlands, Sweden and Canada) formed the guidelines development team. A systematic review of existing guidelines for the management of hip and knee OA published between 1945 and January 2006 was undertaken using the validated appraisal of guidelines research and evaluation (AGREE) instrument. A core set of management modalities was generated based on the agreement between guidelines. Evidence before 2002 was based on a systematic review conducted by European League Against Rheumatism and evidence after 2002 was updated using MEDLINE, EMBASE, CINAHL, AMED, the Cochrane Library and HTA reports. The quality of evidence was evaluated, and where possible, effect size (ES), number needed to treat, relative risk or odds ratio and cost per quality-adjusted life years gained were estimated. Consensus recommendations were produced following a Delphi exercise and the strength of recommendation (SOR) for propositions relating to each modality was determined using a visual analogue scale. Twenty-three treatment guidelines for the management of hip and knee OA were identified from the literature search, including six opinion-based, five evidence-based and 12 based on both expert opinion and research evidence. Twenty out of 51 treatment modalities addressed by these guidelines were universally recommended. ES for pain relief varied from treatment to treatment. Overall there was no statistically significant difference between non-pharmacological therapies [0.25, 95% confidence interval (CI) 0.16, 0.34] and pharmacological therapies (ES=0.39, 95% CI 0.31, 0.47). Following feedback from Osteoarthritis Research International members on the draft guidelines and six Delphi rounds consensus was reached on 25 carefully worded recommendations. Optimal management of patients with OA hip or knee requires a combination of non-pharmacological and pharmacological modalities of therapy. Recommendations cover the use of 12 non-pharmacological modalities: education and self-management, regular telephone contact, referral to a physical therapist, aerobic, muscle strengthening and water-based exercises, weight reduction, walking aids, knee braces, footwear and insoles, thermal modalities, transcutaneous electrical nerve stimulation and acupuncture. Eight recommendations cover pharmacological modalities of treatment including acetaminophen, cyclooxygenase-2 (COX-2) non-selective and selective oral non-steroidal anti-inflammatory drugs (NSAIDs), topical NSAIDs and capsaicin, intra-articular injections of corticosteroids and hyaluronates, glucosamine and/or chondroitin sulphate for symptom relief; glucosamine sulphate, chondroitin sulphate and diacerein for possible structure-modifying effects and the use of opioid analgesics for the treatment of refractory pain. There are recommendations covering five surgical modalities: total joint replacements, unicompartmental knee replacement, osteotomy and joint preserving surgical procedures; joint lavage and arthroscopic debridement in knee OA, and joint fusion as a salvage procedure when joint replacement had failed. Strengths of recommendation and 95% CIs are provided. Twenty-five carefully worded recommendations have been generated based on a critical appraisal of existing guidelines, a systematic review of research evidence and the consensus opinions of an international, multidisciplinary group of experts. The recommendations may be adapted for use in different countries or regions according to the availability of treatment modalities and SOR for each modality of therapy. These recommendations will be revised regularly following systematic review of new research evidence as this becomes available.
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            Molecular mechanisms of opioid receptor-dependent signaling and behavior.

            Opioid receptors have been targeted for the treatment of pain and related disorders for thousands of years and remain the most widely used analgesics in the clinic. Mu (μ), kappa (κ), and delta (δ) opioid receptors represent the originally classified receptor subtypes, with opioid receptor like-1 (ORL1) being the least characterized. All four receptors are G-protein coupled and activate inhibitory G proteins. These receptors form homo- and heterodimeric complexes and signal to kinase cascades and scaffold a variety of proteins.The authors discuss classic mechanisms and developments in understanding opioid tolerance and opioid receptor signaling and highlight advances in opioid molecular pharmacology, behavioral pharmacology, and human genetics. The authors put into context how opioid receptor signaling leads to the modulation of behavior with the potential for therapeutic intervention. Finally, the authors conclude there is a continued need for more translational work on opioid receptors in vivo.
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              Signalling bias in new drug discovery: detection, quantification and therapeutic impact.

              Agonists of seven-transmembrane receptors, also known as G protein-coupled receptors (GPCRs), do not uniformly activate all cellular signalling pathways linked to a given seven-transmembrane receptor (a phenomenon termed ligand or agonist bias); this discovery has changed how high-throughput screens are designed and how lead compounds are optimized for therapeutic activity. The ability to experimentally detect ligand bias has necessitated the development of methods for quantifying agonist bias in a way that can be used to guide structure-activity studies and the selection of drug candidates. Here, we provide a viewpoint on which methods are appropriate for quantifying bias, based on knowledge of how cellular and intracellular signalling proteins control the conformation of seven-transmembrane receptors. We also discuss possible predictions of how biased molecules may perform in vivo, and what potential therapeutic advantages they may provide.
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                Author and article information

                Contributors
                joann@leqmedical.com
                Journal
                Pain Ther
                Pain Ther
                Pain and Therapy
                Springer Healthcare (Cheshire )
                2193-8237
                2193-651X
                24 March 2017
                24 March 2017
                June 2017
                : 6
                : 1
                : 1-16
                Affiliations
                [1 ]GRID grid.459798.e, , NEMA Research, Inc., ; Naples, FL USA
                [2 ]ISNI 0000 0001 2168 186X, GRID grid.134563.6, College of Pharmacy, , University of Arizona, ; Tucson, AZ USA
                [3 ]ISNI 0000 0001 2168 186X, GRID grid.134563.6, Department of Pharmacology and Toxicology, College of Pharmacy, , University of Arizona, ; Tucson, AZ USA
                Article
                68
                10.1007/s40122-017-0068-3
                5447545
                28341939
                1027fb5e-30d6-4d0c-b68d-6410b7184929
                © The Author(s) 2017
                History
                : 15 February 2017
                Categories
                Review
                Custom metadata
                © Springer Healthcare 2017

                opioid misuse,opioid pharmacology,opioids
                opioid misuse, opioid pharmacology, opioids

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