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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 -
BMJ (Clinical Research Ed.) Oct 2021To assess the effectiveness and safety of different preparations and doses of non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and paracetamol for knee and hip...
OBJECTIVE
To assess the effectiveness and safety of different preparations and doses of non-steroidal anti-inflammatory drugs (NSAIDs), opioids, and paracetamol for knee and hip osteoarthritis pain and physical function to enable effective and safe use of these drugs at their lowest possible dose.
DESIGN
Systematic review and network meta-analysis of randomised trials.
DATA SOURCES
Cochrane Central Register of Controlled Trials (CENTRAL), Medline, Embase, regulatory agency websites, and ClinicalTrials.gov from inception to 28 June 2021.
ELIGIBILITY CRITERIA FOR SELECTING STUDIES
Randomised trials published in English with ≥100 patients per group that evaluated NSAIDs, opioids, or paracetamol (acetaminophen) to treat osteoarthritis.
OUTCOMES AND MEASURES
The prespecified primary outcome was pain. Physical function and safety outcomes were also assessed.
REVIEW METHODS
Two reviewers independently extracted outcomes data and evaluated the risk of bias of included trials. Bayesian random effects models were used for network meta-analysis of all analyses. Effect estimates are comparisons between active treatments and oral placebo.
RESULTS
192 trials comprising 102 829 participants examined 90 different active preparations or doses (68 for NSAIDs, 19 for opioids, and three for paracetamol). Five oral preparations (diclofenac 150 mg/day, etoricoxib 60 and 90 mg/day, and rofecoxib 25 and 50 mg/day) had ≥99% probability of more pronounced treatment effects than the minimal clinically relevant reduction in pain. Topical diclofenac (70-81 and 140-160 mg/day) had ≥92.3% probability, and all opioids had ≤53% probability of more pronounced treatment effects than the minimal clinically relevant reduction in pain. 18.5%, 0%, and 83.3% of the oral NSAIDs, topical NSAIDs, and opioids, respectively, had an increased risk of dropouts due to adverse events. 29.8%, 0%, and 89.5% of oral NSAIDs, topical NSAIDs, and opioids, respectively, had an increased risk of any adverse event. Oxymorphone 80 mg/day had the highest risk of dropouts due to adverse events (51%) and any adverse event (88%).
CONCLUSIONS
Etoricoxib 60 mg/day and diclofenac 150 mg/day seem to be the most effective oral NSAIDs for pain and function in patients with osteoarthritis. However, these treatments are probably not appropriate for patients with comorbidities or for long term use because of the slight increase in the risk of adverse events. Additionally, an increased risk of dropping out due to adverse events was found for diclofenac 150 mg/day. Topical diclofenac 70-81 mg/day seems to be effective and generally safer because of reduced systemic exposure and lower dose, and should be considered as first line pharmacological treatment for knee osteoarthritis. The clinical benefit of opioid treatment, regardless of preparation or dose, does not outweigh the harm it might cause in patients with osteoarthritis.
SYSTEMATIC REVIEW REGISTRATION
PROSPERO number CRD42020213656.
Topics: Acetaminophen; Administration, Oral; Administration, Topical; Aged; Analgesics, Opioid; Anti-Inflammatory Agents, Non-Steroidal; Female; Humans; Male; Middle Aged; Minimal Clinically Important Difference; Network Meta-Analysis; Osteoarthritis, Hip; Osteoarthritis, Knee; Pain Management
PubMed: 34642179
DOI: 10.1136/bmj.n2321 -
The Cochrane Database of Systematic... Oct 2017Chronic pain is common and can be challenging to manage. Despite increased utilisation of opioids, the safety and efficacy of long-term use of these compounds for... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Chronic pain is common and can be challenging to manage. Despite increased utilisation of opioids, the safety and efficacy of long-term use of these compounds for chronic non-cancer pain (CNCP) remains controversial. This overview of Cochrane Reviews complements the overview entitled 'High-dose opioids for chronic non-cancer pain: an overview of Cochrane Reviews'.
OBJECTIVES
To provide an overview of the occurrence and nature of adverse events associated with any opioid agent (any dose, frequency, or route of administration) used on a medium- or long-term basis for the treatment of CNCP in adults.
METHODS
We searched the Cochrane Database of Systematic Reviews (the Cochrane Library) Issue 3, 2017 on 8 March 2017 to identify all Cochrane Reviews of studies of medium- or long-term opioid use (2 weeks or more) for CNCP in adults aged 18 and over. We assessed the quality of the reviews using the AMSTAR criteria (Assessing the Methodological Quality of Systematic Reviews) as adapted for Cochrane Overviews. We assessed the quality of the evidence for the outcomes using the GRADE framework.
MAIN RESULTS
We included a total of 16 reviews in our overview, of which 14 presented unique quantitative data. These 14 Cochrane Reviews investigated 14 different opioid agents that were administered for time periods of two weeks or longer. The longest study was 13 months in duration, with most in the 6- to 16-week range. The quality of the included reviews was high using AMSTAR criteria, with 11 reviews meeting all 10 criteria, and 5 of the reviews meeting 9 out of 10, not scoring a point for either duplicate study selection and data extraction, or searching for articles irrespective of language and publication type. The quality of the evidence for the generic adverse event outcomes according to GRADE ranged from very low to moderate, with risk of bias and imprecision being identified for the following generic adverse event outcomes: any adverse event, any serious adverse event, and withdrawals due to adverse events. A GRADE assessment of the quality of the evidence for specific adverse events led to a downgrading to very low- to moderate-quality evidence due to risk of bias, indirectness, and imprecision.We calculated the equivalent milligrams of morphine per 24 hours for each opioid studied (buprenorphine, codeine, dextropropoxyphene, dihydrocodeine, fentanyl, hydromorphone, levorphanol, methadone, morphine, oxycodone, oxymorphone, tapentadol, tilidine, and tramadol). In the 14 Cochrane Reviews providing unique quantitative data, there were 61 studies with a total of 18,679 randomised participants; 12 of these studies had a cross-over design with two to four arms and a total of 796 participants. Based on the 14 selected Cochrane Reviews, there was a significantly increased risk of experiencing any adverse event with opioids compared to placebo (risk ratio (RR) 1.42, 95% confidence interval (CI) 1.22 to 1.66) as well as with opioids compared to a non-opioid active pharmacological comparator, with a similar risk ratio (RR 1.21, 95% CI 1.10 to 1.33). There was also a significantly increased risk of experiencing a serious adverse event with opioids compared to placebo (RR 2.75, 95% CI 2.06 to 3.67). Furthermore, we found significantly increased risk ratios with opioids compared to placebo for a number of specific adverse events: constipation, dizziness, drowsiness, fatigue, hot flushes, increased sweating, nausea, pruritus, and vomiting.There was no data on any of the following prespecified adverse events of interest in any of the included reviews in this overview of Cochrane Reviews: addiction, cognitive dysfunction, depressive symptoms or mood disturbances, hypogonadism or other endocrine dysfunction, respiratory depression, sexual dysfunction, and sleep apnoea or sleep-disordered breathing. We found no data for adverse events analysed by sex or ethnicity.
AUTHORS' CONCLUSIONS
A number of adverse events, including serious adverse events, are associated with the medium- and long-term use of opioids for CNCP. The absolute event rate for any adverse event with opioids in trials using a placebo as comparison was 78%, with an absolute event rate of 7.5% for any serious adverse event. Based on the adverse events identified, clinically relevant benefit would need to be clearly demonstrated before long-term use could be considered in people with CNCP in clinical practice. A number of adverse events that we would have expected to occur with opioid use were not reported in the included Cochrane Reviews. Going forward, we recommend more rigorous identification and reporting of all adverse events in randomised controlled trials and systematic reviews on opioid therapy. The absence of data for many adverse events represents a serious limitation of the evidence on opioids. We also recommend extending study follow-up, as a latency of onset may exist for some adverse events.
Topics: Adult; Analgesics, Opioid; Chronic Pain; Humans; Patient Dropouts; Randomized Controlled Trials as Topic; Review Literature as Topic; Time Factors
PubMed: 29084357
DOI: 10.1002/14651858.CD012509.pub2 -
Neuron Dec 2023Traditional methods for site-specific drug delivery in the brain are slow, invasive, and difficult to interface with recordings of neural activity. Here, we demonstrate...
Traditional methods for site-specific drug delivery in the brain are slow, invasive, and difficult to interface with recordings of neural activity. Here, we demonstrate the feasibility and experimental advantages of in vivo photopharmacology using "caged" opioid drugs that are activated in the brain with light after systemic administration in an inactive form. To enable bidirectional manipulations of endogenous opioid receptors in vivo, we developed photoactivatable oxymorphone (PhOX) and photoactivatable naloxone (PhNX), photoactivatable variants of the mu opioid receptor agonist oxymorphone and the antagonist naloxone. Photoactivation of PhOX in multiple brain areas produced local changes in receptor occupancy, brain metabolic activity, neuronal calcium activity, neurochemical signaling, and multiple pain- and reward-related behaviors. Combining PhOX photoactivation with optical recording of extracellular dopamine revealed adaptations in the opioid sensitivity of mesolimbic dopamine circuitry in response to chronic morphine administration. This work establishes a general experimental framework for using in vivo photopharmacology to study the neural basis of drug action.
Topics: Analgesics, Opioid; Oxymorphone; Pharmaceutical Preparations; Dopamine; Naloxone; Receptors, Opioid, mu
PubMed: 37848025
DOI: 10.1016/j.neuron.2023.09.017 -
Frontiers in Pharmacology 2018One hundred fifteen Americans die every day from opioid overdose. These overdose fatalities have been augmented by the increased availability of potent synthetic... (Review)
Review
One hundred fifteen Americans die every day from opioid overdose. These overdose fatalities have been augmented by the increased availability of potent synthetic opioids, such as fentanyl and its derivatives. The death rate of synthetic opioids, other than methadone, increased by 72.2% from 2014 to 2015, and doubled from 2015 to 2016, situating the USA in the midst of an opioid overdose epidemic. The analytical identification of these opioids in postmortem samples and the correct toxicological data interpretation is critical to identify and implement preventive strategies. This article reviews the current knowledge of postmortem toxicology of synthetic opioids and the chemical and pharmacological factors that may affect drug concentrations in the different postmortem matrices and therefore, their interpretation. These factors include key chemical properties, essential pharmacokinetics parameters (metabolism), postmortem redistribution and stability data in postmortem samples. Range and ratios of concentrations reported in traditional and non-traditional postmortem specimens, blood, urine, vitreous humor, liver and brain, are summarized in tables. The review is focused on fentanyl and derivatives (e.g., acetyl fentanyl, butyryl fentanyl, carfentanil, furanyl fentanyl, 4-methoxybutyrylfentanyl, 4-fluorobutyrylfentanyl, ocfentanil) and non-traditional opioid agonists (e.g., AH-7921, MT-45, U-47700). All of these data are critically compared to postmortem data, and chemical and pharmacological properties of natural opioids (morphine), semi-synthetic (oxycodone, hydrocodone, hydromorphone, and oxymorphone), and synthetic opioids (methadone and buprenorphine). The interpretation of drug intoxication in death investigation is based on the available published literature. This review serves to facilitate the evaluation of cases where synthetic opioids may be implicated in a fatality through the critical review of peer reviewed published case reports and research articles.
PubMed: 30416445
DOI: 10.3389/fphar.2018.01210 -
The Cochrane Database of Systematic... May 2015Agitation is a common experience for people living with dementia, particularly as day-to-day function and cognition start to decline more. At the present time there are... (Review)
Review
BACKGROUND
Agitation is a common experience for people living with dementia, particularly as day-to-day function and cognition start to decline more. At the present time there are limited pharmacological options for relieving agitation and little is known about the safety and efficacy of opioid drugs in this setting.
OBJECTIVES
To determine the clinical efficacy and safety of opioids for agitation in people with dementia.
SEARCH METHODS
We searched ALOIS, the Cochrane Dementia and Cognitive Improvement Group Specialized Register, on 13 June 2014 using the terms: narcotic OR opioid OR opium OR morphine OR buprenorphine OR codeine OR dextromoramide OR diphenoxylate OR dipipanone OR dextropropoxyphene OR propoxyphene OR diamorphine OR dihydrocodeine OR alfentanil OR fentanyl OR remifentanil OR meptazinol OR methadone OR nalbuphine OR oxycodone OR papaveretum OR pentazocine OR meperidine OR pethidine OR phenazocine OR hydrocodone OR hydromorphone OR levorphanol OR oxymorphone OR butorphanol OR dezocine OR sufentanil OR ketobemidone.ALOIS contains records of clinical trials identified from monthly searches of a number of major healthcare databases such as MEDLINE, EMBASE and PscyINFO, as well as numerous trial registries and grey literature sources.
SELECTION CRITERIA
Randomised, controlled trials of opioids compared to placebo for agitation in people with dementia.
DATA COLLECTION AND ANALYSIS
Two authors independently assessed the studies identified by the search against the inclusion criteria.
MAIN RESULTS
There are currently no completed randomised, placebo controlled trials of opioids for agitation in dementia. There are two potentially relevant trials still in progress.
AUTHORS' CONCLUSIONS
We found insufficient evidence to establish the clinical efficacy and safety of opioids for agitation in people with dementia. There remains a lack of data to determine if or when opioids either relieve or exacerbate agitation. More evidence is needed to guide the effective, appropriate and safe use of opioids in dementia.
Topics: Analgesics, Opioid; Dementia; Humans; Psychomotor Agitation
PubMed: 25972091
DOI: 10.1002/14651858.CD009705.pub2 -
Drug Design, Development and Therapy 2011A formulation of crush-resistant extended-release opioids may deter abuse. The purpose of this study was to evaluate the bioequivalence of oxymorphone extended-release... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
A formulation of crush-resistant extended-release opioids may deter abuse. The purpose of this study was to evaluate the bioequivalence of oxymorphone extended-release (Oxy-ER) and a crush-resistant formulation of oxymorphone extended-release (Oxy-CRF).
METHODS
In three open-label, randomized studies, healthy adults at a clinical research center received two single oral doses of Oxy-ER and two single doses of Oxy-CRF, each separated by a ≥7-day washout. Doses were administered under fasted conditions (study 1, 5 mg doses; study 2, 40 mg doses) or after a high-fat breakfast (study 3, 40 mg doses). Subjects administered 40 mg doses also received naltrexone. The primary endpoint was systemic oxymorphone exposure; the bioequivalence criterion was met if the 90% confidence intervals of the geometric mean ratio (Oxy-CRF/Oxy-ER) for oxymorphone area under the curve from time 0 to the last measured concentration (AUC(0-t)), AUC from time 0 to infinity (AUC(0-inf)), and maximum plasma concentration (C(max)) were within 0.8-1.25. Safety was assessed by monitoring adverse events.
RESULTS
In studies 1, 2, and 3, the safety population comprised 30, 37, and 36 subjects and the pharmacokinetics population comprised 27, 30, and 29 subjects, respectively. Oxy-ER and Oxy-CRF produced similar mean ± standard deviation oxymorphone AUC(0-t) (study 1, 5.05 ± 1.55 versus 5.29 ± 1.52 ng · h/mL; study 2, 31.51 ± 10.95 versus 31.23 ± 10.33 ng · h/mL; study 3, 50.16 ± 14.91 versus 49.01 ± 14.03 ng · h/mL) and C(max) (0.38 ± 0.11 versus 0.37 ± 0.12 ng/mL; 2.37 ± 1.20 versus 2.41 ± 0.94 ng/mL; 5.87 ± 1.99 versus 5.63 ± 2.26 ng/mL) under all conditions. The 90% confidence intervals for plasma oxymorphone AUC(0-t), AUC(0-inf), and C(max) fulfilled the bioequivalence criterion. Adverse event rates were similar with Oxy-ER and Oxy-CRF (study 1, 25% versus 23%; study 2, 9% versus 16%; study 3, 20% each group).
CONCLUSION
Oxy-CRF and Oxy-ER (5 mg and 40 mg) are bioequivalent under fasted and fed conditions, suggesting that Oxy-CRF will have clinical efficacy and safety equivalent to Oxy-ER.
Topics: Adolescent; Adult; Analgesics, Opioid; Area Under Curve; Biotransformation; Chemistry, Pharmaceutical; Cross-Over Studies; Delayed-Action Preparations; Demography; Female; Hardness; Humans; Hydroxylation; Male; Middle Aged; Oxymorphone; Safety; Solubility; Therapeutic Equivalency; Young Adult
PubMed: 22162639
DOI: 10.2147/DDDT.S24372