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Current Pain and Headache Reports Aug 2019Deaths associated to tramadol, a synthetic opioid, are rising globally. Herein, we characterize prescription patterns of tramadol relative to other opioids in the USA... (Review)
Review
PURPOSE OF REVIEW
Deaths associated to tramadol, a synthetic opioid, are rising globally. Herein, we characterize prescription patterns of tramadol relative to other opioids in the USA from 2012 to 2015, by geographic region and physician specialty.
RECENT FINDINGS
Data on opioid was obtained using Truven Health Analytics MarketScan for the years 2012-2015. Inclusion criteria included subjects living in the USA with ages from 12 to 64 years. Patterns of prescription of tramadol were contrasted with other prescription opioids including hydrocodone, codeine, oxycodone, oxymorphone, methadone, and fentanyl. Between 2012 and 2015, prescriptions for tramadol increased by 22.8%. The absolute rate of prescription varies considerably per region, with tramadol representing nearly 20% of opioid prescriptions in the South, which, in turn, represents nearly 50% of all prescriptions in the USA. Significant differences were seen when comparing prescribers of tramadol with other opioids (p < 0.0001). Tramadol was more frequently prescribed by family practice (40% vs. 32%) and internal medicine physicians (19% vs. 16%). Family medicine, internal medicine, and non-physician prescribers responded by 67.2% of all tramadol prescriptions in 2015. The proportion of patients receiving tramadol from non-physician prescribers increased by 56% between 2012 and 2015 (p < 0.001) IOM. Tramadol prescriptions rates have continuously increased both nationally and throughout all US regions. Important differences exist among regions and physician specialties. These results may be helpful in the creation of regional policies to monitor reasons for this increase and to avoid excessive use of tramadol.
Topics: Analgesics, Opioid; Drug Prescriptions; Humans; Physician's Role; Practice Patterns, Physicians'; Prescription Drug Misuse; Tramadol; United States
PubMed: 31388761
DOI: 10.1007/s11916-019-0777-x -
Forensic Science International. Genetics Jul 2021Genetic disposition can cause variation in oxycodone pharmacokinetic characteristics and decrease or increase the expected clinical response. In forensic medicine,...
Genetic disposition can cause variation in oxycodone pharmacokinetic characteristics and decrease or increase the expected clinical response. In forensic medicine, determination of cause of death or assessing time between drug intake and death can be facilitated by knowledge of parent and metabolite concentrations. In this study, the aim was to investigate if CYP2D6 genotyping can facilitate interpretation by investigating the frequency of the four CYP2D6 phenotypes, poor metabolizer, intermediate metabolizer, extensive metabolizer, and ultra-rapid metabolizer in postmortem cases, and to study if the CYP2D6 activity was associated with a certain cause of death, concentration, or metabolic ratio. Cases positive for oxycodone in femoral blood (n = 174) were genotyped by pyrosequencing for CYP2D6*3, *4, and *6 and concentrations of oxycodone, noroxycodone, oxymorphone, and noroxymorphone were determined by LC-MS/MS (LLOQ 0.005 µg/g). Digital droplet PCR was used to determine the copy number variation for CYP2D6*5. Cases were categorized by cause of death. It was found that poor and intermediate CYP2D6 metabolizers had significantly higher oxycodone and noroxycodone concentrations compared to extensive and ultra-rapid metabolizers. CYP2D6 phenotype were equally distributed between cause of death groups, showing that no phenotype was overrepresented in any of the cause of death groups. We also found that the concentration ratio between oxymorphone and oxycodone depended on the CYP2D6 activity when death was unrelated to intoxication. In general, a low metabolite to parent ratio indicate an acute intake. By using receiver operating characteristic (ROC) analysis, we conclude that an oxymorphone/oxycodone ratio lower than 0.075 has a high sensitivity for separating intoxications with oxycodone from other intoxications and non-intoxications. However, the phenotype needs to be known to reach a high specificity. Therefore, the ratio should not be used as a biomarker on its own to distinguish between different causes of death but needs to be complemented by genotyping.
Topics: Adolescent; Adult; Aged; Analgesics, Opioid; Cytochrome P-450 CYP2D6; DNA Copy Number Variations; Female; Forensic Genetics; Genotype; High-Throughput Nucleotide Sequencing; Humans; Male; Middle Aged; Morphinans; Oxycodone; Pharmacogenomic Testing; Phenotype; Polymorphism, Single Nucleotide; Young Adult
PubMed: 33799050
DOI: 10.1016/j.fsigen.2021.102510 -
Cancers Jun 2021Oxycodone is frequently used for treating cancer-related pain, while not much is known about the factors that influence treatment outcomes in these patients. We aim to...
Oxycodone is frequently used for treating cancer-related pain, while not much is known about the factors that influence treatment outcomes in these patients. We aim to unravel these factors by developing a population-pharmacokinetic model to assess the pharmacokinetics of oxycodone and its metabolites in cancer patients, and to associate this with pain scores, and adverse events. Hospitalized patients with cancer-related pain, who were treated with oral oxycodone, could participate. Pharmacokinetic samples and patient-reported pain scores and occurrence and severity of nine adverse events were taken every 12 h. In 28 patients, 302 pharmacokinetic samples were collected. A one-compartment model for oxycodone and each metabolite best described oxycodone, nor-oxycodone, and nor-oxymorphone pharmacokinetics. Furthermore, oxycodone exposure was not associated with average and maximal pain scores, and oxycodone, nor-oxycodone, and nor-oxymorphone exposure were not associated with adverse events (all > 0.05). This is the first model to describe the pharmacokinetics of oxycodone including the metabolites nor-oxycodone and nor-oxymorphone in hospitalized patients with cancer pain. Additional research, including more patients and a more timely collection of pharmacodynamic data, is needed to further elucidate oxycodone (metabolite) pharmacokinetic/pharmacodynamic relationships. This model is an important starting point for further studies to optimize oxycodone dosing regiments in patients with cancer-related pain.
PubMed: 34199534
DOI: 10.3390/cancers13112768 -
Journal of Palliative Medicine Nov 2022Equianalgesic tools are commonly utilized to guide dose of analgesic therapy, but there is no national consensus on equianalgesic calculations in the United States. To...
Equianalgesic tools are commonly utilized to guide dose of analgesic therapy, but there is no national consensus on equianalgesic calculations in the United States. To propose a summary of current opioid equianalgesic data that include variations and trends among national institutions. Opioid equianalgesic tools were obtained between May and September 2021. For meperidine, tramadol, codeine, hydrocodone, morphine, oxycodone, oxymorphone, hydromorphone, levorphanol, fentanyl, and tapentadol, details of adjustment for incomplete tolerance, opioid equianalgesic ratios, and formulation types were collected and analyzed. Baseline opioid pharmaco kinetic data were obtained through manufacturer labels on FDA databases, including half-life (), volume of distribution (), clearance (Cl), area under the curve (AUC), max concentration (), and time to max concentration (). Thirty-two institutions' equianalgesic tools were included with each study opioid appearing on an average of 23 institutions' tools. Few tools contained guidance on levorphanol or tapentadol; or included minimum and maximum recommended doses. All tools included guidance on fentanyl, hydromorphone, oxycodone, morphine, and hydrocodone. A minority of tools included guidance on cross-tolerance considerations ( = 12, 37.5%). Oral-tramadol-to-oral-morphine and oral-hydromorphone-to-intravenous (IV)-hydromorphone had the largest variances across equianalgesic tools (6.7 ± 2.8 and 4.06 ± 1.2 mg, respectively). Opioid equianalgesia tools from across the United States demonstrated significant variation in their inclusion of guidance on adjustment for incomplete cross-tolerance, oral-to-IV, and oral-to-oral opioid equianalgesic ratios, and which opioids and formulations were listed. Tramadol and hydromorphone had the most variation in their equianalgesic guidance among the opioids.
Topics: Humans; Analgesics, Opioid; Hydromorphone; Oxycodone; Tapentadol; Tramadol; Levorphanol; Hydrocodone; Administration, Oral; Fentanyl; Morphine
PubMed: 35559657
DOI: 10.1089/jpm.2021.0678 -
Molecular Neurobiology Dec 2021Sex differences in opioid analgesia occur in rodents and humans, and could be due to differences in drug and metabolite levels. Thus, we investigated the sex and cycle...
Sex differences in opioid analgesia occur in rodents and humans, and could be due to differences in drug and metabolite levels. Thus, we investigated the sex and cycle differences in analgesia (nociception) from oxycodone in rats and related these to sex and cycle differences in brain and plasma oxycodone and metabolite levels. Since numerous opioids are CYP2D enzyme substrates and variation in CYP2D alters opioid drug levels and response, we also initiated studies to see if the sex and cycle differences observed might be due to differences in brain CYP2D activity. Across oxycodone doses, females in diestrus had higher analgesia (using tail flick latency) compared to males and females in estrus; we also demonstrated a direct effect of estrous cycle on analgesia within females. Consistent with the analgesia, females in diestrus had highest brain oxycodone levels (assessed using microdialysis) compared to males and females in estrus. Analgesia correlated with brain oxycodone, but not brain oxymorphone or noroxycodone levels, or plasma drug or metabolite levels. Propranolol (a CYP2D mechanism-based inhibitor), versus vehicle pre-treatments, increased brain oxycodone, and decreased brain oxymorphone/oxycodone drug level ratios (an in vivo CYP2D activity phenotype in the brain) in males and females in estrus, but not in females in diestrus. Brain oxymorphone/oxycodone inversely correlated with analgesia. Together, both sex and estrous cycle impact oxycodone analgesia and brain oxycodone levels, likely through regulation of brain CYP2D oxycodone metabolism. As CYP2D6 is expressed in human brain, perhaps similar sex and cycle influences also occur in humans.
Topics: Analgesia; Analgesics, Opioid; Animals; Brain; Estrous Cycle; Female; Male; Oxycodone; Pain Measurement; Rats; Rats, Wistar; Sex Characteristics
PubMed: 34581987
DOI: 10.1007/s12035-021-02560-1 -
The Journal of Pharmacology and... Aug 2022Understanding the pharmacogenomics of opioid metabolism and behavior is vital to therapeutic success, as mutations can dramatically alter therapeutic efficacy and...
Understanding the pharmacogenomics of opioid metabolism and behavior is vital to therapeutic success, as mutations can dramatically alter therapeutic efficacy and addiction liability. We found robust, sex-dependent BALB/c substrain differences in oxycodone behaviors and whole brain concentration of oxycodone metabolites. BALB/cJ females showed robust state-dependent oxycodone reward learning as measured via conditioned place preference when compared with the closely related BALB/cByJ substrain. Accordingly, BALB/cJ females also showed a robust increase in brain concentration of the inactive metabolite noroxycodone and the active metabolite oxymorphone compared with BALB/cByJ mice. Oxymorphone is a highly potent, full agonist at the mu opioid receptor that could enhance drug-induced interoception and state-dependent oxycodone reward learning. Quantitative trait locus (QTL) mapping in a BALB/c F2 reduced complexity cross revealed one major QTL on chromosome 15 underlying brain oxymorphone concentration that explained 32% of the female variance. BALB/cJ and BALB/cByJ differ by fewer than 10,000 variants, which can greatly facilitate candidate gene/variant identification. Hippocampal and striatal cis-expression QTL (eQTL) and exon-level eQTL analysis identified , a candidate gene coding for a transcriptional repressor with a private BALB/cJ retroviral insertion that reduces expression and sex-dependent dysregulation of cytochrome P450 enzymes. Whole brain proteomics corroborated the eQTL and identified upregulated CYP2D11 that could increase brain oxymorphone in BALB/cJ females. To summarize, is a highly promising candidate gene underlying brain oxycodone metabolite levels. Future studies will validate and its site of action using reciprocal gene editing and tissue-specific viral manipulations in BALB/c substrains. SIGNIFICANCE STATEMENT: Our findings show that genetic variation can result in sex-specific alterations in whole brain concentration of a bioactive opioid metabolite after oxycodone administration, reinforcing the need for sex as a biological factor in pharmacogenomic studies. The cooccurrence of female-specific increased oxymorphone and state-dependent reward learning suggests that this minor yet potent and efficacious metabolite of oxycodone could increase opioid interoception and drug-cue associative learning of opioid reward, which has implications for cue-induced relapse of drug-seeking behavior and for precision pharmacogenetics.
Topics: Analgesics, Opioid; Animals; Brain; Female; Homeodomain Proteins; Male; Mice; Mice, Inbred BALB C; Oxycodone; Oxymorphone; Reward
PubMed: 35688478
DOI: 10.1124/jpet.122.001217 -
Deutsches Arzteblatt International Mar 2018Rotating several different WHO level III opioid drugs is a therapeutic option for patients with chronic cancer-related pain who suffer from inadequate analgesia and/or...
BACKGROUND
Rotating several different WHO level III opioid drugs is a therapeutic option for patients with chronic cancer-related pain who suffer from inadequate analgesia and/or intolerable side effects. The evidence favoring opioid rotation is controversial, and the current guidelines in Germany and other countries contain only weak recommendations for it.
METHODS
This review is based on pertinent publications retrieved by a systematic review of the literature on opioid rotation for adult patients with chronic cancerrelated pain who are regularly taking WHO level III opioids by the oral or trans - dermal route.
RESULTS
9 individual studies involving a total of 725 patients were included in the analysis, and 3 previous systematic reviews of studies involving a total of 2296 patients were also analyzed. Morphine, oxycodone, fentanyl, hydromorphone, and buprenorphine were used as first-line opioid drugs, and hydromorphone, bupre - norphine, tapentadol, fentanyl, morphine, oxymorphone, and methadone were used as second-line opioid drugs. In all of the studies, pain control was achieved for 14 days after each rotation. In most of them, the dose of the new drug introduced in each rotation needed to be increased above the dose initially calculated from a rotation ratio, with the exception of rotations to methadone. The frequency of side effects was only rarely lessened, but patients largely considered the result of opioid rotation to be positive. No particular opioid drug was found to be best.
CONCLUSION
Opioid rotation can improve analgesia and patient satisfaction. The success of opioid rotation appears to depend on the magnitude of the initial dose, among other factors. Tables of equianalgesic doses should be considered no more than a rough guide for determining the dose of the new drug. Rotations to methadone should be carried out under clinical supervision in experienced hands.
Topics: Analgesics, Opioid; Buprenorphine; Cancer Pain; Chronic Pain; Fentanyl; Germany; Humans; Hydromorphone; Morphine; Neoplasms; Oxycodone; Pain Management
PubMed: 29563006
DOI: 10.3238/arztebl.2018.0135 -
Biopharmaceutics & Drug Disposition Feb 2020Oxycodone is an opioid analgesic with several pharmacologically active metabolites and relatively narrow therapeutic index. Cytochrome P450 (CYP) 3A4 and CYP2D6 play...
Oxycodone is an opioid analgesic with several pharmacologically active metabolites and relatively narrow therapeutic index. Cytochrome P450 (CYP) 3A4 and CYP2D6 play major roles in the metabolism of oxycodone and its metabolites. Thus, inhibition and induction of these enzymes may result in substantial changes in the exposure of both oxycodone and its metabolites. In this study, a physiologically based pharmacokinetic (PBPK) model was built using GastroPlus™ software for oxycodone, two primary metabolites (noroxycodone, oxymorphone) and one secondary metabolite (noroxymorphone). The model was built based on literature and in house in vitro and in silico data. The model was refined and verified against literature clinical data after oxycodone administration in the absence of drug-drug interactions (DDI). The model was further challenged with simulations of oxycodone DDI with CYP3A4 inhibitors ketoconazole and itraconazole, CYP3A4 inducer rifampicin and CYP2D6 inhibitor quinidine. The magnitude of DDI (AUC ratio) was predicted within 1.5-fold error for oxycodone, within 1.8-fold and 1.3-4.5-fold error for the primary metabolites noroxycodone and oxymorphone, respectively, and within 1.4-4.5-fold error for the secondary metabolite noroxymorphone, when compared to the mean observed AUC ratios. This work demonstrated the capability of PBPK model to simulate DDI of the administered compounds and the formed metabolites of both DDI victim and perpetrator. However, the predictions for the formed metabolites tend to be associated with higher uncertainty than the predictions for the administered compound. The oxycodone model provides a tool for forecasting oxycodone DDI with other CYP3A4 and CYP2D6 DDI perpetrators that may be co-administered with oxycodone.
Topics: Computer Simulation; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme System; Drug Interactions; Gene Expression Regulation, Enzymologic; Humans; Models, Biological; Oxycodone; Software
PubMed: 31925778
DOI: 10.1002/bdd.2215 -
Current Pain and Headache Reports Aug 2017Chronic abdominal pain is a complex medical condition. The causes of chronic abdominal pain are extremely diverse ranging from chronic pancreatitis, Crohn's disease, to... (Review)
Review
PURPOSE OF REVIEW
Chronic abdominal pain is a complex medical condition. The causes of chronic abdominal pain are extremely diverse ranging from chronic pancreatitis, Crohn's disease, to chronic pain with no clear etiology. Treatment of chronic abdominal pain remains a challenge in our clinical practice. While current interventions with celiac plexus blocks and pain medications provide some relief for these patients, but these treatments are typically less efficacious and limited by various adverse effects. Opioid medications are commonly used to manage chronic pain syndromes that are refectory to other pain management interventions. The potential problems related to opioids include misuse, abuse, constipation, nausea pruritus, et al. Moreover, according to the recent centers for disease (CDC) control report, opioid abuse has reached epidemic proportions in the USA (LJ P. Centers for Disease Control and Prevention. 2016) and accounted for 28,000 deaths in 2014. Rudd et al. (MMWR Morb Mortal Wkly Rep 64(50-51):1378-82, 2016) Given this current situation, it is apparent that a careful review of clinical evidences supporting the use of opioid medications is necessary to guide our treatment approaches in the management of complex chronic abdominal pain patients. This review is set out to analyze efficacy of opioid medications for chronic abdominal pain.
RECENT FINDINGS
The literature referenced was obtained via a computer search with Google Scholar, Pubmed, Medline, and EMbase. The search terms used included Opioid, Oxycodone, Buprenorphine, Morphine, Fentanyl, Oxymorphone, Hydromorphone, chronic abdominal pain, Crohn's disease, and pancreatitis. All studies were considered eligible for inclusion if they were clinical studies evaluating the efficacy of opioid medications for chronic abdominal pain. Two studies were found according to these criteria. Chronic abdominal pain is a challenging medical condition in our daily practice. This condition often requires opioid medications when other treatments fail. This review provided very limited clinical evidence to support long-term opioid use for chronic abdominal pain. Given recent CDC report of opioid epidemic, it is prudent to use the best medical practice with appropriate evaluation of psychological comorbidities, urine drug screening, prescription drug monitor, and opioid treatment agreements to minimize adverse side effects related to opioids. Furthermore, well-designed clinical trials are needed to evaluate the effectiveness of long-term use of opioid medications, and more clinical research on which opioid medication is more effective for chronic abdominal pain.
Topics: Abdominal Pain; Analgesics, Opioid; Chronic Pain; Humans
PubMed: 28791598
DOI: 10.1007/s11916-017-0640-x -
The Hastings Center Report Jan 2020I first became aware of bioethics in the spring of 1980. I had spent a thirty-six-hour shift shadowing a medical resident, and I was struck that many of the resident's...
I first became aware of bioethics in the spring of 1980. I had spent a thirty-six-hour shift shadowing a medical resident, and I was struck that many of the resident's decisions had ethical dimensions. The next day, I came across the Hastings Center Report, and I realized I wanted to explore ethical issues I found implicit in clinical care, even though I still wanted to become a pediatrician. In September 2019, when I attended my first meeting of the U.S. Food and Drug Administration's Pediatric Advisory Committee, as a pediatric pulmonologist, I had the same sense of awe and curiosity that I had forty years ago. What had appeared initially as somewhat technical decisions about the regulation of drug labeling was suffused with ethical questions. The committee was asked to discuss possible changes to the labeling of two previously approved drugs.
Topics: Acetates; Advisory Committees; Bioethics; Cyclopropanes; Drug Labeling; Humans; Oxymorphone; Pediatrics; Quinolines; Sulfides; United States; United States Food and Drug Administration
PubMed: 32068277
DOI: 10.1002/hast.1074