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Pain Physician May 2016Opioid overdose continues to be a significant and growing cause of preventable mortality and morbidity. Studies suggest that unintentional, non-fatal overdose from... (Review)
Review
BACKGROUND
Opioid overdose continues to be a significant and growing cause of preventable mortality and morbidity. Studies suggest that unintentional, non-fatal overdose from prescription opioid analgesics constitutes a large portion of total overdose events. The societal burden associated with these events is a frequently overlooked public health concern.
OBJECTIVES
To evaluate unintentional, non-fatal prescription opioid overdoses, including the identification of risk factors, societal burden, and knowledge gaps where further study is warranted.
STUDY DESIGN
Systematic review of the literature for unintentional, non-fatal opioid overdose.
METHODS
Preferred reporting items for systematic reviews and meta-analyses guidelines were used in constructing this systematic review. To determine the scope of the existing literature, a systematic search was conducted using the MEDLINE, CINAHL, PsycINFO, and Web of Science databases.
RESULTS
This systematic review analyzes 24 articles (21 retrospective descriptive analyses, 2 prospective analyses, one phase III trial, and one meta-analysis). Articles were reviewed by authors and relevant data examined. Results show that opioid overdose morbidity is significantly more prevalent than mortality and sequelae of non-fatal events should be studied in more detail.
LIMITATIONS
The limitations of this systematic review include the range of study populations and opioids discussed and the broad and variable definitions of "opioid overdose" in the literature.
CONCLUSIONS
Opioid overdose morbidity and mortality is seen across the entire spectrum of inpatient and outpatient use with significant numbers of adverse events occurring in population segments not identified by high risk indicators. Increased physician awareness and a multi-modal approach could help mitigate the overdose epidemic while maintaining effective pain control for patients.
KEY WORDS
Prescription, opioid, accidental drug overdose, unintentional overdose, drug poisoning, fentanyl, oxycodone, hydrocodone, methadone, oxymorphone, hydromorphone.
Topics: Analgesics, Opioid; Drug Overdose; Humans; Prescription Drug Overuse
PubMed: 27228510
DOI: No ID Found -
PloS One 2014Morphine and structurally related derivatives are highly effective analgesics, and the mainstay in the medical management of moderate to severe pain. Pharmacological...
Morphine and structurally related derivatives are highly effective analgesics, and the mainstay in the medical management of moderate to severe pain. Pharmacological actions of opioid analgesics are primarily mediated through agonism at the µ opioid peptide (MOP) receptor, a G protein-coupled receptor. Position 17 in morphine has been one of the most manipulated sites on the scaffold and intensive research has focused on replacements of the 17-methyl group with other substituents. Structural variations at the N-17 of the morphinan skeleton led to a diversity of molecules appraised as valuable and potential therapeutics and important research probes. Discovery of therapeutically useful morphine-like drugs has also targeted the C-6 hydroxyl group, with oxymorphone as one of the clinically relevant opioid analgesics, where a carbonyl instead of a hydroxyl group is present at position 6. Herein, we describe the effect of N-substituent variation in morphine and oxymorphone on in vitro and in vivo biological properties and the emerging structure-activity relationships. We show that the presence of a N-phenethyl group in position 17 is highly favorable in terms of improved affinity and selectivity at the MOP receptor, potent agonism and antinociceptive efficacy. The N-phenethyl derivatives of morphine and oxymorphone were very potent in stimulating G protein coupling and intracellular calcium release through the MOP receptor. In vivo, they were highly effective against acute thermal nociception in mice with marked increased antinociceptive potency compared to the lead molecules. It was also demonstrated that a carbonyl group at position 6 is preferable to a hydroxyl function in these N-phenethyl derivatives, enhancing MOP receptor affinity and agonist potency in vitro and in vivo. These results expand the understanding of the impact of different moieties at the morphinan nitrogen on ligand-receptor interaction, molecular mode of action and signaling, and may be instrumental to the development of new opioid therapeutics.
Topics: Analgesics; Animals; Brain; Guinea Pigs; In Vitro Techniques; Mice; Morphine; Oxymorphone; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, Opioid; Signal Transduction
PubMed: 24919067
DOI: 10.1371/journal.pone.0099231 -
Clinical Pharmacokinetics Jul 2023Up to 90% of patients with castration-resistant prostate cancer (CRPC) will develop symptomatic bone metastases requiring pain medication, with opioids being the...
BACKGROUND AND OBJECTIVE
Up to 90% of patients with castration-resistant prostate cancer (CRPC) will develop symptomatic bone metastases requiring pain medication, with opioids being the mainstay of therapy in treating moderate and severe pain. Enzalutamide is an androgen receptor antagonist for the treatment of CRPC and a strong inducer of cytochrome P450 (CYP)3A4. Hereby, enzalutamide potentially reduces the exposure of oxycodone, an opioid metabolized by CYP3A4 and CYP2D6. Our objective was to evaluate the potential drug-drug interaction of enzalutamide and oxycodone.
METHODS
A prospective, nonrandomized, open-label, two-arm parallel study was performed. All patients received a single dose of 15 mg normal-release oxycodone. Patients in the enzalutamide arm (ENZ-arm) received enzalutamide 160 mg once daily. Plasma concentrations of oxycodone and its metabolites were quantified using a validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) method.
RESULTS
Twenty-six patients (13 ENZ-arm; 13 control arm) were enrolled in the study. Enzalutamide decreased the mean AUC and C of oxycodone with, respectively, 44.7% (p < 0.001) and 35.5% (p = 0.004) compared with the control arm. The AUC and C of the active metabolite oxymorphone were 74.2% (p < 0.001) and 56.0% (p = 0.001) lower in the ENZ-arm compared with the control arm. In contrast, AUC and C of the inactive metabolites noroxycodone and noroxymorphone were significantly increased by enzalutamide.
CONCLUSION
Co-administration of enzalutamide significantly reduced exposure to oxycodone and its active metabolite oxymorphone in men with prostate cancer. This should be taken into account when prescribing enzalutamide combined with oxycodone.
Topics: Male; Humans; Oxycodone; Oxymorphone; Chromatography, Liquid; Prospective Studies; Prostatic Neoplasms, Castration-Resistant; Tandem Mass Spectrometry; Analgesics, Opioid; Pain
PubMed: 37162620
DOI: 10.1007/s40262-023-01255-1 -
British Journal of Clinical Pharmacology Apr 2021Prescription drug misuse in the USA increased during the 1990s to 2010. The epidemic stimulated the need new analytical strategies and techniques to understand the...
AIMS
Prescription drug misuse in the USA increased during the 1990s to 2010. The epidemic stimulated the need new analytical strategies and techniques to understand the medications involved, user characteristics and other factors needed to address the epidemic.
METHODS
A strategy of mosaic surveillance has evolved. Using real world evidence, the goal is to paint a more complete profile of a drug's real world misuse using triangulation-integrating results from multiple sources, where each approach has unrelated sources of bias.
RESULTS
Research findings have been remarkably consistent across multiple data sources. The most commonly misused opioid medications: hydrocodone = oxycodone > methadone = buprenorphine = tramadol = fentanyl (prescription form) > morphine > hydromorphone = oxymorphone > tapentadol. This rank order is similar to the number of prescriptions dispensed for each product in the USA. In the USA, prescription opioid misuse started to decrease about 2011. Typically, multiple drugs are misused together, particularly in lethal cases. Immediate release formulations are more commonly misused than extended release formulations. The introduction of tamper resistant formulations to resist crushing were followed by a decrease in misuse of those products.
CONCLUSIONS
The rapid expansion of opioid prescribing was accompanied by increasing misuse and mortality. Interventions such as prescription drug monitoring programmes, increased law enforcement and abuse deterrent formulations have been followed by decreases in misuse of most opioid analgesics.
Topics: Analgesics, Opioid; Humans; Opioid-Related Disorders; Oxycodone; Practice Patterns, Physicians'; Prescription Drug Misuse
PubMed: 33606888
DOI: 10.1111/bcp.14791 -
Basic & Clinical Pharmacology &... Mar 2012Pain is characterized by its multi-dimensional nature, explaining in part why the pharmacokinetic/pharmacodynamic (PK/PD) relationships are not straightforward for... (Review)
Review
Pain is characterized by its multi-dimensional nature, explaining in part why the pharmacokinetic/pharmacodynamic (PK/PD) relationships are not straightforward for analgesics. The first part of this MiniReview gives an overview of PK, PD and PK/PD models, as well as of population approach used in analgesic studies. The second part updates the state-of-the-art in the PK/PD relationship of opioids, focusing on data obtained on experimental human pain models, a useful tool to characterize the PD of analgesics. For the so-called weak opioids such as codeine, experimental human studies showed that analgesia relies mainly upon biotransformation into morphine. However, the time-course of plasma concentrations of morphine did not always reflect the time-course of effects, the major site of action being the central nervous system. For tramadol, a correlation has been observed between the analgesic response and the PK of the (+)R-O-demethyl-tramadol metabolite. For 'stronger' opioids such as oxycodone, studies assessing the PK/PD of oxycodone suggested that active metabolite oxymorphone also strongly contributes to the analgesia and that analgesia may also be partially related through an action to peripherally located κ-opioid receptors. Different models have been proposed to describe the time-course of buprenorphine. An effect-compartment model was adopted to describe the PK/PD of morphine and its active metabolite, morphine-6-glucuronide (M6G). A longer blood-effect site equilibration half-life t(1/2) k(e0) was observed for M6G, suggesting a longer onset of action. The studies assessing the PK/PD of fentanyl and its derivatives showed a short t(1/2) k(e0) for analgesia, between 0.2 and 9 min., reflecting a short onset of effect. In conclusion, depending on the speed of transfer between the plasma and the effect site as well as the participation of active metabolites, the time-course of the analgesic effects can be close to the plasma concentrations (alfentanil and derivates) or observed with a prolonged delay (codeine, buprenorphine, morphine). These PK/PD data can be used to better characterize the differences between opioids, and partly explain the important observed variability among opioids in experimental conditions and should be systematically evaluated during drug development to better predict their selection in specific clinical conditions.
Topics: Analgesics, Opioid; Animals; Drug Design; Half-Life; Humans; Models, Biological; Pain; Pain Measurement; Time Factors
PubMed: 21995512
DOI: 10.1111/j.1742-7843.2011.00814.x -
Clinical Chemistry and Laboratory... Aug 2017Oxycodone is a narcotic drug widely used to alleviate moderate and severe acute and chronic pain. Variability in analgesic efficacy could be explained by inter-subject...
Determination of oxycodone and its major metabolites noroxycodone and oxymorphone by ultra-high-performance liquid chromatography tandem mass spectrometry in plasma and urine: application to real cases.
BACKGROUND
Oxycodone is a narcotic drug widely used to alleviate moderate and severe acute and chronic pain. Variability in analgesic efficacy could be explained by inter-subject variations in plasma concentrations of parent drug and its active metabolite, oxymorphone. To evaluate patient compliance and to set up therapeutic drug monitoring (TDM), an ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) assay was developed and validated for the parent drug and its major metabolites noroxycodone and oxymorphone.
METHODS
Extraction of analytes from plasma and urine samples was obtained by simple liquid-liquid extraction. The chromatographic separation was achieved with a reversed phase column using a linear gradient elution with two solvents: acetic acid 1% in water and methanol. The separated analytes were detected with a triple quadrupole mass spectrometer operated in multiple reaction monitoring (MRM) mode via positive electrospray ionization (ESI).
RESULTS
Separation of analytes was obtained in less than 5 min. Linear calibration curves for all the analytes under investigation in urine and plasma samples showed determination coefficients (r2) equal or higher than 0.990. Mean absolute analytical recoveries were always above 86%. Intra- and inter-assay precision (measured as coefficient of variation, CV%) and accuracy (measured as % error) values were always better than 13%. Limit of detection at 0.06 and 0.15 ng/mL and limit of quantification at 0.2 and 0.5 ng/mL for plasma and urine samples, respectively, were adequate for the purpose of the present study.
CONCLUSIONS
Rapid extraction, identification and quantification of oxycodone and its metabolites both in urine and plasma by UHPLC-MS/MS assay was tested for its feasibility in clinical samples and provided excellent results for rapid and effective drug testing in patients under oxycodone treatment.
Topics: Aged; Aged, 80 and over; Chromatography, High Pressure Liquid; Female; Humans; Male; Middle Aged; Morphinans; Oxycodone; Oxymorphone; Tandem Mass Spectrometry
PubMed: 28080998
DOI: 10.1515/cclm-2016-0990 -
Journal of Chromatography. B,... May 2021The objective of this study was to develop and validate a highly sensitive method for the detection of oxycodone, noroxycodone, 6β-oxycodol, 6α-oxycodol, oxymorphone,...
The objective of this study was to develop and validate a highly sensitive method for the detection of oxycodone, noroxycodone, 6β-oxycodol, 6α-oxycodol, oxymorphone, and noroxymorphone in blood by liquid chromatography tandem mass spectrometry. The analytes were extracted from blood (0.5 mL) using Bond Elut Certify Solid Phase Extraction columns, evaporated to dryness and reconstituted before analysis was performed on an Acquity UPLC® I-class coupled to a Waters Xevo TQD. Academy Standards Board Standard Practices for Method Development in Forensic Toxicology were used for the validation of this method. The limit of quantitation for all analytes was established at 0.5 ng/mL. Calibration range for noroxymorphone, oxymorphone, 6α-oxycodol and 6β-oxycodol was 0.5-25 ng/mL and 0.5-100 ng/mL for noroxycodone and oxycodone. Precision (2.90-17.3%) and bias studies resulted in a ±15% deviation. There were no interferences observed from internal standard, matrix, or common drugs of abuse. Stability of all analytes at two concentrations at 24, 48, and 72 h in the autosampler did not exceed ±20% difference from the initial T. Dilution integrity at a ten-fold dilution was acceptable as analyte concentrations ranged between (±18%) of the target concentration. Once validated, the method was used in a pilot dosing study of one male subject after taking a 10 mg immediate release tablet of oxycodone. Blood samples were collected at 0.25, 0.50, 0.75, 1.0, 1.5, 2, 3, 4, 5, 6, 8, 9, and 24 h after ingestion. Oxycodone and noroxycodone both reached T at 1.5 h and had C values of 25.9 and 12.8 ng/mL, respectively. Oxycodone, 6α-oxycodol, and 6β-oxycodol were detectable up to 9 h, while noroxymorphone and noroxycodone were still detected at 24 h.
Topics: Chromatography, High Pressure Liquid; Humans; Limit of Detection; Linear Models; Male; Morphinans; Reproducibility of Results; Tandem Mass Spectrometry
PubMed: 33744597
DOI: 10.1016/j.jchromb.2021.122625 -
Journal of Analytical Toxicology 2013The opioid analgesic oxycodone is widely abused and increasingly associated with overdose deaths. A sensitive analytical method was developed for oxycodone and its...
Determination of oxycodone, noroxycodone and oxymorphone by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry in human matrices: in vivo and in vitro applications.
The opioid analgesic oxycodone is widely abused and increasingly associated with overdose deaths. A sensitive analytical method was developed for oxycodone and its metabolites, noroxycodone and oxymorphone, in human plasma, urine (±enzymatic hydrolysis at 50°C for 16 h) and liver microsomes (HLMs). Liquid-liquid extraction was followed by high-performance liquid chromatography-electrospray ionization-tandem mass spectrometry. The calibration range was 0.2-250 ng/mL for plasma and HLM and 10-5000 ng/mL for urine. Intra- and interrun accuracies were within 13.3% of target; precisions were within 12.8% for all matrices. Recoveries from plasma were: oxycodone, 75.6%; noroxycodone, 37.4% and oxymorphone, 18.2%. Analytes exhibited room temperature stability in plasma and urine up to 24 h, and freeze-thaw stability in plasma up to three cycles. In 24-h hydrolyzed urine from subjects administered intranasal oxycodone (30 mg/70 kg, n = 5), mean concentrations (ng/mL) and % daily doses excreted were: oxycodone, 1150, 6.53%; noroxycodone, 1330, 7.81% and oxymorphone, 3000, 17.1%. Oxycodone incubated with HLM produced more noroxycodone than oxymorphone. With a panel of recombinant human cytochrome P450s (CYPs), CYP2C18 and CYP3A4 produced the most noroxycodone, whereas CYP2D6 produced the most oxymorphone. These results demonstrate a new method suitable for both in vivo and in vitro metabolism and pharmacokinetic studies of oxycodone.
Topics: Analgesics, Opioid; Aryl Hydrocarbon Hydroxylases; Chromatography, High Pressure Liquid; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP3A; Humans; Liquid-Liquid Extraction; Microsomes, Liver; Morphinans; Oxycodone; Oxymorphone; Quality Control; Reproducibility of Results; Sensitivity and Specificity; Specimen Handling; Spectrometry, Mass, Electrospray Ionization; Tandem Mass Spectrometry
PubMed: 23743505
DOI: 10.1093/jat/bkt042 -
Biological Psychiatry Dec 2023Mu opioid receptors (MORs) are key for reward processing, mostly studied in dopaminergic pathways. MORs are also expressed in the dorsal raphe nucleus (DRN), which is...
BACKGROUND
Mu opioid receptors (MORs) are key for reward processing, mostly studied in dopaminergic pathways. MORs are also expressed in the dorsal raphe nucleus (DRN), which is central for the modulation of reward and mood, but MOR function in the DRN remains underexplored. Here, we investigated whether MOR-expressing neurons of the DRN (DRN-MOR neurons) participate in reward and emotional responses.
METHODS
We characterized DRN-MOR neurons anatomically using immunohistochemistry and functionally using fiber photometry in responses to morphine and rewarding/aversive stimuli. We tested the effect of opioid uncaging on the DRN on place conditioning. We examined the effect of DRN-MOR neuron optostimulation on positive reinforcement and mood-related behaviors. We mapped their projections and selected DRN-MOR neurons projecting to the lateral hypothalamus for a similar optogenetic experimentation.
RESULTS
DRN-MOR neurons form a heterogeneous neuronal population essentially composed of GABAergic (gamma-aminobutyric acidergic) and glutamatergic neurons. Calcium activity of DRN-MOR neurons was inhibited by rewarding stimuli and morphine. Local photo-uncaging of oxymorphone in the DRN produced conditioned place preference. DRN-MOR neuron optostimulation triggered real-time place preference and was self-administered, promoted social preference, and reduced anxiety and passive coping. Finally, specific optostimulation of DRN-MOR neurons projecting to the lateral hypothalamus recapitulated the reinforcing effects of total DRN-MOR neuron stimulation.
CONCLUSIONS
Our data show that DRN-MOR neurons respond to rewarding stimuli and that their optoactivation has reinforcing effects and promotes positive emotional responses, an activity which is partially mediated by their projections to the lateral hypothalamus. Our study also suggests a complex regulation of DRN activity by MOR opioids, involving mixed inhibition/activation mechanisms that fine-tune DRN function.
Topics: Dorsal Raphe Nucleus; Receptors, Opioid, mu; Neurons; Morphine; Analgesics, Opioid; Reward
PubMed: 37285896
DOI: 10.1016/j.biopsych.2023.05.019 -
The Cochrane Database of Systematic... Sep 2014Osteoarthritis is the most common form of joint disease and the leading cause of pain and physical disability in older people. Opioids may be a viable treatment option... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Osteoarthritis is the most common form of joint disease and the leading cause of pain and physical disability in older people. Opioids may be a viable treatment option if people have severe pain or if other analgesics are contraindicated. However, the evidence about their effectiveness and safety is contradictory. This is an update of a Cochrane review first published in 2009.
OBJECTIVES
To determine the effects on pain, function, safety, and addiction of oral or transdermal opioids compared with placebo or no intervention in people with knee or hip osteoarthritis.
SEARCH METHODS
We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and CINAHL (up to 28 July 2008, with an update performed on 15 August 2012), checked conference proceedings, reference lists, and contacted authors.
SELECTION CRITERIA
We included randomised or quasi-randomised controlled trials that compared oral or transdermal opioids with placebo or no treatment in people with knee or hip osteoarthritis. We excluded studies of tramadol. We applied no language restrictions.
DATA COLLECTION AND ANALYSIS
We extracted data in duplicate. We calculated standardised mean differences (SMDs) and 95% confidence intervals (CI) for pain and function, and risk ratios for safety outcomes. We combined trials using an inverse-variance random-effects meta-analysis.
MAIN RESULTS
We identified 12 additional trials and included 22 trials with 8275 participants in this update. Oral oxycodone was studied in 10 trials, transdermal buprenorphine and oral tapentadol in four, oral codeine in three, oral morphine and oral oxymorphone in two, and transdermal fentanyl and oral hydromorphone in one trial each. All trials were described as double-blind, but the risk of bias for other domains was unclear in several trials due to incomplete reporting. Opioids were more beneficial in pain reduction than control interventions (SMD -0.28, 95% CI -0.35 to -0.20), which corresponds to a difference in pain scores of 0.7 cm on a 10-cm visual analogue scale (VAS) between opioids and placebo. This corresponds to a difference in improvement of 12% (95% CI 9% to 15%) between opioids (41% mean improvement from baseline) and placebo (29% mean improvement from baseline), which translates into a number needed to treat (NNTB) to cause one additional treatment response on pain of 10 (95% CI 8 to 14). Improvement of function was larger in opioid-treated participants compared with control groups (SMD -0.26, 95% CI -0.35 to -0.17), which corresponds to a difference in function scores of 0.6 units between opioids and placebo on a standardised Western Ontario and McMaster Universities Arthritis Index (WOMAC) disability scale ranging from 0 to 10. This corresponds to a difference in improvement of 11% (95% CI 7% to 14%) between opioids (32% mean improvement from baseline) and placebo (21% mean improvement from baseline), which translates into an NNTB to cause one additional treatment response on function of 11 (95% CI 7 to 14). We did not find substantial differences in effects according to type of opioid, analgesic potency, route of administration, daily dose, methodological quality of trials, and type of funding. Trials with treatment durations of four weeks or less showed larger pain relief than trials with longer treatment duration (P value for interaction = 0.001) and there was evidence for funnel plot asymmetry (P value = 0.054 for pain and P value = 0.011 for function). Adverse events were more frequent in participants receiving opioids compared with control. The pooled risk ratio was 1.49 (95% CI 1.35 to 1.63) for any adverse event (9 trials; 22% of participants in opioid and 15% of participants in control treatment experienced side effects), 3.76 (95% CI 2.93 to 4.82) for drop-outs due to adverse events (19 trials; 6.4% of participants in opioid and 1.7% of participants in control treatment dropped out due to adverse events), and 3.35 (95% CI 0.83 to 13.56) for serious adverse events (2 trials; 1.3% of participants in opioid and 0.4% of participants in control treatment experienced serious adverse events). Withdrawal symptoms occurred more often in opioid compared with control treatment (odds ratio (OR) 2.76, 95% CI 2.02 to 3.77; 3 trials; 2.4% of participants in opioid and 0.9% of participants control treatment experienced withdrawal symptoms).
AUTHORS' CONCLUSIONS
The small mean benefit of non-tramadol opioids are contrasted by significant increases in the risk of adverse events. For the pain outcome in particular, observed effects were of questionable clinical relevance since the 95% CI did not include the minimal clinically important difference of 0.37 SMDs, which corresponds to 0.9 cm on a 10-cm VAS.
Topics: Administration, Cutaneous; Administration, Oral; Analgesics, Opioid; Humans; Osteoarthritis, Hip; Osteoarthritis, Knee; Pain Measurement; Randomized Controlled Trials as Topic
PubMed: 25229835
DOI: 10.1002/14651858.CD003115.pub4