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PeerJ 2019The US is experiencing an epidemic of opioid overdoses which may be at least partially due to an over-reliance on opioid analgesics in the treatment of chronic...
BACKGROUND
The US is experiencing an epidemic of opioid overdoses which may be at least partially due to an over-reliance on opioid analgesics in the treatment of chronic non-cancer pain and subsequent escalation to heroin or illicit fentanyl. As Texas was reported to be among the lowest in the US for opioid use and misuse, further examination of this state is warranted.
MATERIALS AND METHODS
This study was conducted to quantify prescription opioid use in Texas. Data was obtained from the publicly available US Drug Enforcement Administration's Automation of Reports and Consolidated Orders System (ARCOS) which monitors controlled substances transactions from manufacture to commercial distribution. Data for 2006-2017 from Texas for ten prescription opioids including eight primarily used to relieve pain (codeine, fentanyl, hydrocodone, hydromorphone, meperidine, morphine, oxycodone, oxymorphone) and two (buprenorphine and methadone) for the treatment of an Opioid Use Disorder (OUD) were examined.
RESULTS
The change in morphine mg equivalent (MME) of all opioids (+23.3%) was only slightly greater than the state's population gains (21.1%). Opioids used to treat an OUD showed pronounced gains (+90.8%) which were four-fold faster than population growth. Analysis of individual agents revealed pronounced elevations in codeine (+387.5%), hydromorphone (+106.7%), and oxycodone (+43.6%) and a reduction in meperidine (-80.3%) in 2017 relative to 2006. Methadone in 2017 accounted for a greater portion (39.5%) of the total MME than hydrocodone, oxycodone, morphine, hydromorphone, oxymorphone, and meperidine, combined. There were differences between urban and rural areas in the changes in hydrocodone and buprenorphine.
CONCLUSIONS
Collectively, these findings indicate that continued vigilance is needed in Texas to appropriately treat pain and an OUD while minimizing the potential for prescription opioid diversion and misuse. Texas may lead the US in a return to pre-opioid epidemic prescription levels.
PubMed: 31824762
DOI: 10.7717/peerj.8108 -
Drug, Healthcare and Patient Safety 2019The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), contains information on adverse drug events and medication error reports submitted to the...
BACKGROUND
The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), contains information on adverse drug events and medication error reports submitted to the FDA through the MedWatch program. A significant number of adverse events reported in the FAERS database have been for opioid use. The objective of this study was to determine the frequency counts and associated deaths of opioid drug names in the FAERS database.
METHODS
Drug data were obtained from the DRUG and OUTCOME files in the database. Drugs identified included: morphine, fentanyl, oxycodone, hydrocodone, tramadol, hydromorphone, methadone, codeine, oxymorphone, meperidine, propoxyphene, diphenoxylate, and heroin. Frequency counts and concomitant deaths of opioid drug names were determined via the MySQL database management system.
RESULTS
Fifteen different opioid drugs identified in the FAERS database were associated with ADEs, including death, and 3 drugs (oxycodone, hydrocodone, fentanyl) accounted for more than half of the reports. The highest frequency count value was 158,181 for oxycodone, which represents approximately 20.2% of the frequency counts for the opioids. The lowest frequency count value was 2,161 for dextromethorphan, which represents approximately 0.3% of the total. The opioid with the highest proportion of deaths to drug count was heroin (71.8%), followed by dextromethorphan (55.6%), methadone (37.2%), morphine (26.8%), and propoxyphene (23.7%).
CONCLUSION
The FAERS database represents an important source for detection and reporting of adverse drug events (ADEs), in particular the opioids and related drugs. It remains a challenge to estimate the true incidence of ADEs for this class of drugs in the general population.
PubMed: 31695510
DOI: 10.2147/DHPS.S214771 -
Frontiers in Veterinary Science 2019To assess the impact of the human opioid epidemic and associated shortages in drug supply on US general practice veterinarians. Cross-sectional study. Members of the...
To assess the impact of the human opioid epidemic and associated shortages in drug supply on US general practice veterinarians. Cross-sectional study. Members of the Veterinary Information Network (VIN). An electronic survey was used to examine veterinarians' views regarding opioid use in veterinary medicine and the impact of the opioid shortage on the provision of care. The survey was distributed via the VIN data collection portal from October 12-November 6, 2018. 697 veterinarians completed the survey. Most (99.7%) reported using, dispensing or prescribing opioids in veterinary practice. The most commonly used opioids were buprenorphine, tramadol and butorphanol. While most veterinarians (83.3%) reported difficulty in ordering opioids over the last 6 months, this decreased to 59.0% in the last month. The most difficult drugs to obtain were hydromorphone, morphine, injectable fentanyl, and oxymorphone. The reported rate of difficulty in obtaining all these drugs lessened over time. However, the opioid shortage caused significant difficulty in providing appropriate pain management for 41.1% of participants, and affected the ability of 44.8% of respondents to provide optimal anesthesia. Veterinarians' ability to provide opioids for their patients has been impacted by the opioid shortage, with a greater impact on full mu opioid agonists as compared to drugs like butorphanol, buprenorphine, and tramadol. The results confirm the important role of opioid analgesics in the delivery of modern veterinary medicine and highlight the importance of medical health professionals being able to access these critical medications.
PubMed: 31334257
DOI: 10.3389/fvets.2019.00222 -
Basic & Clinical Pharmacology &... Nov 2019The main sites of the analgesic action of oxycodone are the brain and spinal cord. The present study describes the concentrations of oxycodone and its metabolites in the...
The main sites of the analgesic action of oxycodone are the brain and spinal cord. The present study describes the concentrations of oxycodone and its metabolites in the brain and spinal cord after epidural administration to the ewe. Twenty pregnant ewes undergoing laparotomy were randomized into two groups to receive epidural oxycodone: infusion group (n = 10, 0.1 mg·kg bolus followed by continuous infusion of 0.05 mg·kg ·h for five days) or repeated boluses group (n = 10, 0.2 + 2x0.1 mg·kg bolus followed by a 0.2 mg·kg bolus every 12 hours for five days). After five days of oxycodone administration, arterial blood samples were collected, the sheep were killed, and a CSF sample and tissue samples from the cortex, thalamus, cerebellum and spinal cord were obtained for the quantification of oxycodone and its main metabolites. The median plasma and CSF concentrations of oxycodone were 9.0 and 14.2 ng·mL after infusion and 0.4 and 1.1 ng·mL after repeated boluses. In the infusion group, the cortex, thalamus and cerebellum oxycodone concentrations were 4-8 times higher and in the spinal cord 1310 times higher than in plasma. In the repeated boluses group, brain tissue concentrations were similar in the three areas, and in the spinal cord were 720 times higher than in plasma. Oxymorphone was the main metabolite detected, which accumulated in the brain and spinal cord tissue. In conclusion, first, accumulation of oxycodone and oxymorphone in the CNS was observed, and second, high spinal cord concentrations suggest that epidural oxycodone may provide segmental analgesia.
Topics: Analgesia; Analgesics, Opioid; Animals; Brain Chemistry; Cerebellum; Cerebral Cortex; Female; Injections, Epidural; Models, Animal; Oxycodone; Oxymorphone; Pregnancy; Sheep; Spinal Cord; Thalamus; Tissue Distribution
PubMed: 31222944
DOI: 10.1111/bcpt.13276 -
PloS One 2019Most clinically used opioids are thought to induce analgesia through activation of the mu opioid receptor (MOR). However, disparities have been observed between the...
Most clinically used opioids are thought to induce analgesia through activation of the mu opioid receptor (MOR). However, disparities have been observed between the efficacy of opioids in activating the MOR in vitro and in inducing analgesia in vivo. In addition, some clinically used opioids do not produce cross-tolerance with each other, and desensitization produced in vitro does not match tolerance produced in vivo. These disparities suggest that some opioids could be acting through other targets in vivo, but this has not been comprehensively tested. We thus screened 9 clinically relevant opioids (buprenorphine, hydrocodone, hydromorphone, morphine, O-desmethyl-tramadol, oxycodone, oxymorphone, tapentadol, tramadol) against 9 pain-related receptor targets (MOR, delta opioid receptor [DOR], kappa opioid receptor [KOR], nociceptin receptor [NOP], cannabinoid receptor type 1 [CB1], sigma-1 receptor [σ1R], and the monoamine transporters [NET/SERT/DAT]) expressed in cells using radioligand binding and functional activity assays. We found several novel interactions, including monoamine transporter activation by buprenorphine and σ1R binding by hydrocodone and tapentadol. Tail flick anti-nociception experiments with CD-1 mice demonstrated that the monoamine transporter inhibitor duloxetine selectively promoted buprenorphine anti-nociception while producing no effects by itself or in combination with the most MOR-selective drug oxymorphone, providing evidence that these novel interactions could be relevant in vivo. Our findings provide a comprehensive picture of the receptor interaction profiles of clinically relevant opioids, which has not previously been performed. Our findings also suggest novel receptor interactions for future investigation that could explain some of the disparities observed between opioid performance in vitro and in vivo.
Topics: Analgesics, Opioid; Animals; CHO Cells; Cricetulus; HEK293 Cells; Humans; Mice; Receptors, Opioid
PubMed: 31170174
DOI: 10.1371/journal.pone.0217371 -
PeerJ 2019The US mainland is experiencing an epidemic of opioid overdoses. Unfortunately, the US Territories (Guam, Puerto Rico, and the Virgin Islands) have often been overlooked...
BACKGROUND
The US mainland is experiencing an epidemic of opioid overdoses. Unfortunately, the US Territories (Guam, Puerto Rico, and the Virgin Islands) have often been overlooked in opioid pharmacoepidemiology research. This study examined common prescription opioids over the last decade.
METHODS
The United States Drug Enforcement Administration's Automation of Reports and Consolidated Orders System (ARCOS) was used to report on ten medical opioids: buprenorphine, codeine, fentanyl, hydrocodone, hydromorphone, meperidine, methadone, morphine, oxycodone, and oxymorphone, by weight from 2006 to 2017. Florida and Hawaii were selected as comparison areas.
RESULTS
Puerto Rico had the greatest Territorial oral morphine mg equivalent (MME) per capita (421.5) which was significantly higher ( < .005) than the Virgin Islands (139.2) and Guam (118.9) but significantly lower than that of Hawaii (794.6) or Florida (1,509.8). Methadone was the largest opioid by MMEs in 2017 in most municipalities, accounting for 41.1% of the total in the Virgin Islands, 37.9% in Florida, 36.6% in Hawaii but 80.8% in Puerto Rico. Puerto Rico and Florida showed pronounced differences in the distribution patterns by pharmacies, hospitals, and narcotic treatment programs for opioids.
CONCLUSIONS
Continued monitoring of the US Territories is needed to provide a balance between appropriate access to these important agents for cancer related and acute pain while also minimizing diversion and avoiding the opioid epidemic which has adversely impacted the US mainland.
PubMed: 30671308
DOI: 10.7717/peerj.6272 -
Journal of Medicinal Chemistry Jan 2019Herein, the synthesis and pharmacological characterization of an extended library of differently substituted N-methyl-14- O-methylmorphinans with natural and unnatural...
Synthesis, Biological, and Structural Explorations of New Zwitterionic Derivatives of 14- O-Methyloxymorphone, as Potent μ/δ Opioid Agonists and Peripherally Selective Antinociceptives.
Herein, the synthesis and pharmacological characterization of an extended library of differently substituted N-methyl-14- O-methylmorphinans with natural and unnatural amino acids and three dipeptides at position 6 that emerged as potent μ/δ opioid receptor (MOR/DOR) agonists with peripheral antinociceptive efficacy is reported. The current study adds significant value to our initial structure-activity relationships on a series of zwitterionic analogues of 1 (14- O-methyloxymorphone) by targeting additional amino acid residues. The new derivatives showed high binding and potent agonism at MOR and DOR in vitro. In vivo, the new 6-amino acid- and 6-dipeptide-substituted derivatives of 1 were highly effective in inducing antinociception in the writhing test in mice after subcutaneous administration, which was antagonized by naloxone methiodide demonstrating activation of peripheral opioid receptors. Such peripheral opioid analgesics may represent alternatives to presently available drugs for a safer pain therapy.
Topics: Analgesics, Opioid; Animals; Cell Membrane; Dipeptides; Humans; Male; Mice; Morphine; Oxymorphone; Pain; Protein Binding; Receptors, Opioid, delta; Receptors, Opioid, mu; Structure-Activity Relationship
PubMed: 30571123
DOI: 10.1021/acs.jmedchem.8b01327 -
EBioMedicine Nov 2018A high prevalence (92.3%) of hepatitis C virus (HCV) co-infection among HIV patients identified during a large HIV outbreak associated with injection of oxymorphone in...
BACKGROUND
A high prevalence (92.3%) of hepatitis C virus (HCV) co-infection among HIV patients identified during a large HIV outbreak associated with injection of oxymorphone in Indiana prompted genetic analysis of HCV strains.
METHODS
Molecular epidemiological analysis of HCV-positive samples included genotyping, sampling intra-host HVR1 variants by next-generation sequencing (NGS) and constructing transmission networks using Global Hepatitis Outbreak and Surveillance Technology (GHOST).
FINDINGS
Results from the 492 samples indicate predominance of HCV genotypes 1a (72.2%) and 3a (20.4%), and existence of 2 major endemic NS5B clusters involving 49.8% of the sequenced strains. Among 76 HIV co-infected patients, 60.5% segregated into 2 endemic clusters. NGS analyses of 281 cases identified 826,917 unique HVR1 sequences and 51 cases of mixed subtype/genotype infections. GHOST mapped 23 transmission clusters. One large cluster (n = 130) included 50 cases infected with ≥2 subtypes/genotypes and 43 cases co-infected with HIV. Rapid strain replacement and superinfection with different strains were found among 7 of 12 cases who were followed up.
INTERPRETATION
GHOST enabled mapping of HCV transmission networks among persons who inject drugs (PWID). Findings of numerous transmission clusters, mixed-genotype infections and rapid succession of infections with different HCV strains indicate a high rate of HCV spread. Co-localization of HIV co-infected patients in the major HCV clusters suggests that HIV dissemination was enabled by existing HCV transmission networks that likely perpetuated HCV in the community for years. Identification of transmission networks is an important step to guiding efficient public health interventions for preventing and interrupting HCV and HIV transmission among PWID. FUND: US Centers for Disease Control and Prevention, and US state and local public health departments.
Topics: Adult; Coinfection; Disease Outbreaks; Female; HIV Infections; Hepatitis C; Humans; Indiana; Male; Middle Aged; Oxymorphone; Rural Population; Substance Abuse, Intravenous
PubMed: 30448155
DOI: 10.1016/j.ebiom.2018.10.007 -
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 -
Clinical Infectious Diseases : An... May 2019Although evidence from animal and human studies indicates opioid analgesics increase susceptibility to infections, it is unclear whether the risk varies by specific...
BACKGROUND
Although evidence from animal and human studies indicates opioid analgesics increase susceptibility to infections, it is unclear whether the risk varies by specific opioid. We compared the risk of serious infection among patients initiating long-acting opioid analgesics with and without previously reported immunosuppressive properties.
METHODS
We conducted a retrospective cohort study of Tennessee Medicaid enrollees age ≥18 years initiating long-acting opioids (1995-2015). Hospitalizations for serious infection were identified using validated coding algorithms. We used multivariable Poisson regression models to calculate adjusted incidence rate ratios (aIRR) and 95% confidence intervals (CI) to compare the infection risk among patients using long-acting opioids with known immunosuppressive properties (morphine, fentanyl, methadone) to the infection risk among patients using long-acting opioids without known immunosuppressive properties (oxycodone, oxymorphone, tramadol) accounting for demographics, opioid dose, comorbidities and pain conditions, medication use, frailty indicators, and healthcare encounter history using exposure propensity scores. We further compared users of individual long-acting opioids to long-acting morphine users (considered the prototypical immunosuppressive opioid).
RESULTS
Among the 61 240 patients initiating opioids with immunosuppressive properties and 22 811 patients initiating opioids without immunosuppressive properties, we identified 1906 serious infections. Nonimmunosuppressive opioid users had a lower rate of infections than immunosuppressive opioid users (aIRR:0.78 [CI: 0.66-0.91]). Among individual opioids, oxycodone users had a lower rate of infection than morphine users (aIRR:0.73 [CI: 0.60-0.89]). There were no significant differences in the infection risk between other opioids and morphine.
CONCLUSION
The risk of serious infections among long-acting opioid users varies by opioid type. Providers should carefully consider the risk of serious infections when making pain management decisions.
Topics: Adult; Aged; Analgesics, Opioid; Chronic Pain; Female; Fentanyl; Hospitalization; Humans; Immunosuppressive Agents; Infections; Male; Medicaid; Methadone; Middle Aged; Morphine; Opioid-Related Disorders; Retrospective Studies; Risk Factors; Tennessee; United States
PubMed: 30239630
DOI: 10.1093/cid/ciy809