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Pain Physician Mar 2008Mu agonists have been an important component of pain treatment for thousands of years. The usual pharmacokinetic parameters (half-life, clearance, volume of... (Review)
Review
BACKGROUND
Mu agonists have been an important component of pain treatment for thousands of years. The usual pharmacokinetic parameters (half-life, clearance, volume of distribution) of opioids have been known for some time. However, the metabolism has, until recently, been poorly understood, and there has been recent interest in the role of metabolites in modifying the pharmacodynamic response in patients, in both analgesia and adverse effects. A number of opioids are available for clinical use, including morphine, hydromorphone, levorphanol, oxycodone, and fentanyl. Advantages and disadvantages of various opioids in the management of chronic pain are discussed.
OBJECTIVE
This review looks at the structure, chemistry, and metabolism of opioids in an effort to better understand the side effects, drug interactions, and the individual responses of patients receiving opioids for the treatment of intractable pain.
CONCLUSION
Mu receptor agonists and agonist-antagonists have been used throughout recent medical history for the control of pain and for the treatment of opiate induced side effects and even opiate withdrawal syndromes.
Topics: Analgesics, Opioid; Drug Interactions; Humans; Models, Molecular; Narcotic Antagonists; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu
PubMed: 18443637
DOI: No ID Found -
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 -
Mayo Clinic Proceedings Jul 2009Clinicians understand that individual patients differ in their response to specific opioid analgesics and that patients may require trials of several opioids before... (Review)
Review
Clinicians understand that individual patients differ in their response to specific opioid analgesics and that patients may require trials of several opioids before finding an agent that provides effective analgesia with acceptable tolerability. Reasons for this variability include factors that are not clearly understood, such as allelic variants that dictate the complement of opioid receptors and subtle differences in the receptor-binding profiles of opioids. However, altered opioid metabolism may also influence response in terms of efficacy and tolerability, and several factors contributing to this metabolic variability have been identified. For example, the risk of drug interactions with an opioid is determined largely by which enzyme systems metabolize the opioid. The rate and pathways of opioid metabolism may also be influenced by genetic factors, race, and medical conditions (most notably liver or kidney disease). This review describes the basics of opioid metabolism as well as the factors influencing it and provides recommendations for addressing metabolic issues that may compromise effective pain management. Articles cited in this review were identified via a search of MEDLINE, EMBASE, and PubMed. Articles selected for inclusion discussed general physiologic aspects of opioid metabolism, metabolic characteristics of specific opioids, patient-specific factors influencing drug metabolism, drug interactions, and adverse events.
Topics: Analgesics, Opioid; Cytochrome P-450 Enzyme System; Humans; Opioid-Related Disorders; Pain; Prodrugs
PubMed: 19567715
DOI: 10.1016/S0025-6196(11)60750-7 -
Journal of Pain and Symptom Management May 2005Fentanyl, a potent lipid-soluble opioid which was first synthesized more than 40 years ago, is still the most popular opioid used in the perioperative period throughout...
Fentanyl, a potent lipid-soluble opioid which was first synthesized more than 40 years ago, is still the most popular opioid used in the perioperative period throughout the world. Fentanyl's introduction, versatility, and popularity have resulted in its use in many acute and chronic pain conditions and a multitude of novel delivery systems in the last two decades. In spite of the development of more potent, safer, faster onset, and both shorter and longer lasting alternative opioids, fentanyl remains the mainstay of anesthesiologists and Certified Registered Nurse Anesthetists in the perioperative period, and for many pain physicians throughout the world.
Topics: Analgesics, Opioid; Anesthetics, Intravenous; Animals; Drug Delivery Systems; Europe; Fentanyl; History, 20th Century; Humans; United States
PubMed: 15907648
DOI: 10.1016/j.jpainsymman.2005.01.009 -
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 -
The American Journal of Managed Care Sep 2011Pharmacokinetic drug-drug interactions (DDIs) involving opioid analgesics can be problematic. Opioids are widely used, have a narrow therapeutic index, and can be... (Review)
Review
Pharmacokinetic drug-drug interactions (DDIs) involving opioid analgesics can be problematic. Opioids are widely used, have a narrow therapeutic index, and can be associated with severe toxicity. The purpose of this review is to describe pharmacokinetic DDIs associated with opioids frequently encountered in managed care settings (morphine, codeine, oxycodone, oxymorphone, hydrocodone, hydromorphone, fentanyl, tramadol, and methadone). An introduction to the pharmacokinetic basis of DDIs is provided, and potential DDIs associated with opioids are reviewed. Opioids metabolized by the drug metabolizing enzymes of the cytochrome P450 (CYP450) system (codeine, oxycodone, hydrocodone, fentanyl, tramadol, and methadone) are associated with numerous DDIs that can result in either a reduction in opioid effect or excess opioid effects. Conversely, opioids that are not metabolized by that system (morphine, oxymorphone, and hydromorphone) tend to be involved in fewer CYP450-associated pharmacokinetic DDIs.
Topics: Analgesics, Opioid; Cytochrome P-450 Enzyme System; Drug Interactions; Humans; Managed Care Programs; Pharmacogenetics
PubMed: 21999760
DOI: No ID Found -
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 -
The American Journal of Managed Care May 2018Opioid analgesics are commonly used to treat acute and chronic pain; in 2016 alone, more than 60 million patients had at least 1 prescription for opioid analgesics... (Review)
Review
Opioid analgesics are commonly used to treat acute and chronic pain; in 2016 alone, more than 60 million patients had at least 1 prescription for opioid analgesics filled or refilled. Despite the ubiquitous use of these agents, the effectiveness of long-term use of opioids for chronic noncancer pain management is questionable, yet links among long-term use, addiction, and overdose deaths are well established. Because of overprescribing and misuse, an opioid epidemic has developed in the United States. The health and economic burdens of opioid abuse on individuals, their families, and society are substantial. Part 1 of this supplement will provide a background on the burden of pain and the impact of opioid abuse on individuals, their families, and society; the attempts to remedy this burden through prescription opioid use; and the eventual downward spiral into the current opioid epidemic, including an overview of opioid analgesics and opioid use disorder and the rise in opioid-related deaths.
Topics: Analgesics, Opioid; Chronic Pain; Cost of Illness; Epidemics; Health Care Costs; Humans; Opioid-Related Disorders; Quality of Life; United States
PubMed: 29851449
DOI: No ID Found -
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 -
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