-
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 -
Molecules (Basel, Switzerland) Sep 2020Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for... (Review)
Review
Achieving effective pain management is one of the major challenges associated with modern day medicine. Opioids, such as morphine, have been the reference treatment for moderate to severe acute pain not excluding chronic pain modalities. Opioids act through the opioid receptors, the family of G-protein coupled receptors (GPCRs) that mediate pain relief through both the central and peripheral nervous systems. Four types of opioid receptors have been described, including the μ-opioid receptor (MOR), κ-opioid receptor (KOR), δ-opioid receptor (DOR), and the nociceptin opioid peptide receptor (NOP receptor). Despite the proven success of opioids in treating pain, there are still some inherent limitations. All clinically approved MOR analgesics are associated with adverse effects, which include tolerance, dependence, addiction, constipation, and respiratory depression. On the other hand, KOR selective analgesics have found limited clinical utility because they cause sedation, anxiety, dysphoria, and hallucinations. DOR agonists have also been investigated but they have a tendency to cause convulsions. Ligands targeting NOP receptor have been reported in the preclinical literature to be useful as spinal analgesics and as entities against substance abuse disorders while mixed MOR/NOP receptor agonists are useful as analgesics. Ultimately, the goal of opioid-related drug development has always been to design and synthesize derivatives that are equally or more potent than morphine but most importantly are devoid of the dangerous residual side effects and abuse potential. One proposed strategy is to take advantage of biased agonism, in which distinct downstream pathways can be activated by different molecules working through the exact same receptor. It has been proposed that ligands not recruiting β-arrestin 2 or showing a preference for activating a specific G-protein mediated signal transduction pathway will function as safer analgesic across all opioid subtypes. This review will focus on the design and the pharmacological outcomes of biased ligands at the opioid receptors, aiming at achieving functional selectivity.
Topics: Analgesics, Opioid; Arrestin; Furans; Humans; Ligands; Pain; Pyrones; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Signal Transduction
PubMed: 32948048
DOI: 10.3390/molecules25184257 -
JAMA Apr 2016Primary care clinicians find managing chronic pain challenging. Evidence of long-term efficacy of opioids for chronic pain is limited. Opioid use is associated with... (Review)
Review
IMPORTANCE
Primary care clinicians find managing chronic pain challenging. Evidence of long-term efficacy of opioids for chronic pain is limited. Opioid use is associated with serious risks, including opioid use disorder and overdose.
OBJECTIVE
To provide recommendations about opioid prescribing for primary care clinicians treating adult patients with chronic pain outside of active cancer treatment, palliative care, and end-of-life care.
PROCESS
The Centers for Disease Control and Prevention (CDC) updated a 2014 systematic review on effectiveness and risks of opioids and conducted a supplemental review on benefits and harms, values and preferences, and costs. CDC used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework to assess evidence type and determine the recommendation category.
EVIDENCE SYNTHESIS
Evidence consisted of observational studies or randomized clinical trials with notable limitations, characterized as low quality using GRADE methodology. Meta-analysis was not attempted due to the limited number of studies, variability in study designs and clinical heterogeneity, and methodological shortcomings of studies. No study evaluated long-term (≥1 year) benefit of opioids for chronic pain. Opioids were associated with increased risks, including opioid use disorder, overdose, and death, with dose-dependent effects.
RECOMMENDATIONS
There are 12 recommendations. Of primary importance, nonopioid therapy is preferred for treatment of chronic pain. Opioids should be used only when benefits for pain and function are expected to outweigh risks. Before starting opioids, clinicians should establish treatment goals with patients and consider how opioids will be discontinued if benefits do not outweigh risks. When opioids are used, clinicians should prescribe the lowest effective dosage, carefully reassess benefits and risks when considering increasing dosage to 50 morphine milligram equivalents or more per day, and avoid concurrent opioids and benzodiazepines whenever possible. Clinicians should evaluate benefits and harms of continued opioid therapy with patients every 3 months or more frequently and review prescription drug monitoring program data, when available, for high-risk combinations or dosages. For patients with opioid use disorder, clinicians should offer or arrange evidence-based treatment, such as medication-assisted treatment with buprenorphine or methadone.
CONCLUSIONS AND RELEVANCE
The guideline is intended to improve communication about benefits and risks of opioids for chronic pain, improve safety and effectiveness of pain treatment, and reduce risks associated with long-term opioid therapy.
Topics: Acute Pain; Adult; Analgesics, Opioid; Benzodiazepines; Centers for Disease Control and Prevention, U.S.; Chronic Pain; Communication; Contraindications; Drug Prescriptions; Drug Therapy, Combination; Goals; Humans; Observational Studies as Topic; Prescription Drug Misuse; Primary Health Care; Randomized Controlled Trials as Topic; Treatment Outcome; United States; Withholding Treatment
PubMed: 26977696
DOI: 10.1001/jama.2016.1464 -
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 -
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 -
The New England Journal of Medicine Jan 2019
Review
Topics: Analgesics, Opioid; Critical Illness; Drug Tolerance; Humans; Hyperalgesia; Intensive Care Units; Neurons; Pain Management; Pain Measurement; Pain Threshold
PubMed: 30673555
DOI: 10.1056/NEJMra1800222 -
Molecules (Basel, Switzerland) Aug 2020Several over-the-counter (OTC) drugs are known to be misused. Among them are opioids such as codeine, dihydrocodeine, and loperamide. This work elucidates their... (Review)
Review
Several over-the-counter (OTC) drugs are known to be misused. Among them are opioids such as codeine, dihydrocodeine, and loperamide. This work elucidates their pharmacology, interactions, safety profiles, and how pharmacology is being manipulated to misuse these common medications, with the aim to expand on the subject outlined by the authors focusing on abuse prevention and prevalence rates. The reviewed literature was identified in several online databases through searches conducted with phrases created by combining the international non-proprietary names of the drugs with terms related to drug misuse. The results show that OTC opioids are misused as an alternative for illicit narcotics, or prescription-only opioids. The potency of codeine and loperamide is strongly dependent on the individual enzymatic activity of CYP2D6 and CYP3A4, as well as P-glycoprotein function. Codeine can also be utilized as a substrate for clandestine syntheses of more potent drugs of abuse, namely desomorphine ("Krokodil"), and morphine. The dangerous methods used to prepare these substances can result in poisoning from toxic chemicals and impurities originating from the synthesis procedure. OTC opioids are generally safe when consumed in accordance with medical guidelines. However, the intake of supratherapeutic amounts of these substances may reveal surprising traits of common medications.
Topics: Analgesics, Opioid; Codeine; Drug Misuse; Humans; Loperamide; Nonprescription Drugs
PubMed: 32867117
DOI: 10.3390/molecules25173905 -
Molecules (Basel, Switzerland) Mar 2018The comprehensive treatment of pain is multidimodal, with pharmacotherapy playing a key role. An effective therapy for pain depends on the intensity and type of pain,... (Review)
Review
The comprehensive treatment of pain is multidimodal, with pharmacotherapy playing a key role. An effective therapy for pain depends on the intensity and type of pain, the patients' age, comorbidities, and appropriate choice of analgesic, its dose and route of administration. This review is aimed at presenting current knowledge on analgesics administered by transdermal and topical routes for physicians, nurses, pharmacists, and other health care professionals dealing with patients suffering from pain. Analgesics administered transdermally or topically act through different mechanisms. Opioids administered transdermally are absorbed into vessels located in subcutaneous tissue and, subsequently, are conveyed in the blood to opioid receptors localized in the central and peripheral nervous system. Non-steroidal anti-inflammatory drugs (NSAIDs) applied topically render analgesia mainly through a high concentration in the structures of the joint and a provision of local anti-inflammatory effects. Topically administered drugs such as lidocaine and capsaicin in patches, capsaicin in cream, EMLA cream, and creams containing antidepressants (i.e., doxepin, amitriptyline) act mainly locally in tissues through receptors and/or ion channels. Transdermal and topical routes offer some advantages over systemic analgesic administration. Analgesics administered topically have a much better profile for adverse effects as they relieve local pain with minimal systemic effects. The transdermal route apart from the above-mentioned advantages and provision of long period of analgesia may be more convenient, especially for patients who are unable to take drugs orally. Topically and transdermally administered opioids are characterised by a lower risk of addiction compared to oral and parenteral routes.
Topics: Administration, Cutaneous; Administration, Topical; Analgesics; Analgesics, Opioid; Animals; Humans; Pain
PubMed: 29562618
DOI: 10.3390/molecules23030681 -
American Society of Clinical Oncology... 2015Pain remains a serious consequence of cancer and its treatment. Although significant advances have been made in providing effective cancer pain control, barriers... (Review)
Review
Pain remains a serious consequence of cancer and its treatment. Although significant advances have been made in providing effective cancer pain control, barriers persist. Lack of knowledge, limited time, financial restrictions, and diminished availability of necessary medications serve as significant obstacles. Safe and effective opioid use in a patient with cancer requires skill to overcome these challenges. Understanding the mechanism of action, along with the pharmacokinetics and pharmacodynamics, of opioids will lead to appropriate selection, dosing, and titration of these agents. Rotation from one opioid or route to another is an essential proficiency for oncologists. As opioid-related adverse effects often occur, the oncology team must be expert in preventing and managing constipation, nausea, sedation, and neurotoxicities. An emerging concern is overtreatment-the excessive and prolonged use of opioids in patients when these agents may produce more harm than benefit. This can occur when opioids are used inappropriately to treat comorbid psychologic issues such as anxiety and depression. Recognizing risk factors for overuse along with key components of universal precautions will promote safe use of these medications, supporting adherence and preventing diversion, thereby protecting the patient, the prescriber, and the community. Because substance use disorders are not rare in the oncology setting, attention must be given to the balance of providing analgesia while limiting harm. Caring for patients with substance misuse requires compassionate, multidisciplinary care, with input from supportive oncology/palliative care as well as addiction specialists.
Topics: Analgesics, Opioid; Drug Overdose; Humans; Neoplasms; Opioid-Related Disorders; Pain; Pain Management; Prescription Drug Misuse; Treatment Outcome
PubMed: 25993228
DOI: 10.14694/EdBook_AM.2015.35.e593 -
Nature Reviews. Nephrology Feb 2022Chronic pain is highly prevalent among adults treated with maintenance haemodialysis (HD) and has profound negative effects. Over four decades, research has demonstrated... (Review)
Review
Chronic pain is highly prevalent among adults treated with maintenance haemodialysis (HD) and has profound negative effects. Over four decades, research has demonstrated that 50-80% of adult patients treated with HD report having pain. Half of patients with HD-dependent kidney failure (HDKF) have chronic moderate-to-severe pain, which is similar to the burden of pain in patients with cancer. However, pain management in patients with HDKF is often ineffective as most patients report that their pain is inadequately treated. Opioid analgesics are prescribed more frequently for patients receiving HD than for individuals in the general population with chronic pain, and are associated with increased morbidity, mortality and health-care resource use. Furthermore, current opioid prescribing patterns are frequently inconsistent with guideline-recommended care. Evidence for the effectiveness of opioids in pain management in general, and in patients with HDKF specifically, is lacking. Nonetheless, long-term opioid therapy has a role in the treatment of some patients when used selectively, carefully and combined with an ongoing assessment of risks and benefits. Here, we provide a comprehensive overview of the use of opioid therapy in patients with HDKF and chronic pain, including a discussion of buprenorphine, which has potential as an analgesic option for patients receiving HD owing to its unique pharmacological properties.
Topics: Adult; Analgesics, Opioid; Chronic Pain; Humans; Pain Management; Practice Patterns, Physicians'; Renal Dialysis; Renal Insufficiency
PubMed: 34621058
DOI: 10.1038/s41581-021-00484-6