Comparative out-of-hospital mortality of long-acting opioids prescribed for non-cancer pain: A retrospective cohort study.

PURPOSE: Despite significant growth of opioid prescriptions, only limited data are available regarding the comparative safety of long-acting opioids for chronic non-cancer pain. Recent data suggest that transdermal fentanyl and oxycodone CR may have greater toxicity than morphine SR in patients with non-cancer pain. Thus, we compared the risk of out-of-hospital deaths in patients with non-cancer pain filling prescriptions for transdermal fentanyl or oxycodone CR with that for morphine SR. METHODS: We conducted a retrospective cohort study in 50 658 patients enrolled in Tennessee Medicaid who filled prescriptions for transdermal fentanyl (n = 8717), oxycodone CR (n = 14 118), or morphine SR (n = 27 823) between 1999 and 2011. We excluded individuals with cancer or other life-threatening diagnoses and used propensity scores to adjust for multiple potential confounders. The primary outcome was out-of-hospital mortality. RESULTS: During 44 385 person-years of follow-up, 689 patients died. The out-of-hospital mortality rate among all study subjects was 155/10 000 patient-years. Contrary to earlier data suggesting greater risk, mortality was not significantly different in patients filling prescriptions for transdermal fentanyl compared with morphine SR (adjusted HR = 0.96, 95% C.I.: 0.77-1.21); moreover, patients filling prescriptions for oxycodone CR had lower mortality risk compared with those filling prescriptions for morphine SR (adjusted HR = 0.79, 95% C.I. 0.66-0.95). CONCLUSION: In the study population, long-acting opioids for non-cancer pain were associated with high out-of-hospital mortality rates. We found comparable out-of-hospital mortality risks associated with transdermal fentanyl and morphine SR. The risk of out-of-hospital death for oxycodone CR was lower than that for morphine SR.

Correlations between population-levels of prescription opioid dispensing and related deaths in Ontario (Canada), 2005-2016.

Canada is experiencing an ongoing opioid-related public health crisis, including persistently rising opioid (e.g., poisoning) mortality. Previous research has documented marked correlations between population-levels of opioid dispensing and deaths. We examined possible correlations between annual population-level dispensing of specific opioid formulations and related poisoning deaths in Ontario (Canada), for the period 2005-2016. Annual coroner statistics-based numbers of poisoning deaths associated with six main opioid formulations (codeine, fentanyl, hydromorphone, methadone, morphine, and oxycodone) for Ontario were converted into annual death rates (per 100,000 population). Annual dispensing data for the opioid formulations under study were based on commercial retail-sales data from a representative, stratified sample of community pharmacies (IMSQuintiles/IQVIA CompuScript), converted into Defined Daily Doses (DDD/1,000 population/day). Possible relationships between the annual death and dispensing rates were assessed by Pearson's correlation coefficient analyses. Death rates increased for almost all, while dispensing rates increased for half of the opioid categories. A significant positive correlation between death and dispensing rates was found for hydromorphone (r = 0.97, 95% CI: 0.88-0.99) and oxycodone (r = 0.90, 95% CI: 0.68-0.97) formulations; a significant negative correlation was found for codeine (r = -0.78, 95% CI: -0.93 to -0.37). No significant correlations were detected for fentanyl, methadone, and morphine related deaths. Strong correlations between levels of dispensing and deaths for select opioid formulations were found. For select others, extrinsic factors - e.g., increasing involvement of non-medical opioid products (e.g., fentanyl) in overdose deaths - likely confounded underlying correlation effects. Opioid dispensing levels continue to influence population-level mortality levels, and need to be addressed by prevention strategies.

Body pushing, prescription drugs and hospital admission.

A 39-year-old man died of multi-organ failure complicating mixed drug toxicity that included methadone, oxazepam, oxycodone and nitrazepam. His past medical history involved alcohol and poly-substance abuse with chronic self-harm and suicidal ideation. There had been multiple hospital admissions for drug overdoses. At autopsy the most unusual finding was of two packages of 10 tablets each, wrapped in thin plastic film within the rectum. The insertion of drugs into body orifices and cavities has been termed body pushing to distinguish it from body packing where illicit drugs are wrapped and swallowed for transport and smuggling, and body stuffing where small amounts of loosely wrapped or unwrapped drugs are swallowed to conceal evidence from police. This case demonstrates that body pushing may not always involve illicit drugs or attempted concealment from police or customs officials. It appears that the drugs had been hidden to ensure an additional supply during the time of residence in hospital. The extent to which body pushing is currently being used by patients to smuggle drugs into secure medical facilities is yet to be determined.

Interrupted (self -)medication with pancuronium(bromide) and fatal outcome.

Pancuronium(bromide) is used because of its relaxing effect on striated muscles and usually requires artificial respiration. A 52-year-old woman suffered from long-standing "generalized dystonia", which had become resistant to conventional therapy. Therefore, an anesthetist established a permanent medication scheme with pancuronium using a PCA pump. This pump had been controlled by the patient herself ensuring an acceptable quality of life with broad personal autonomy. Finally, the woman was found dead in her flat by a member of a home nursing service. The infusion hose showed a fixed knot and further blocking by a clamp. The autopsy findings were non-specific, except for the presence of opioid tablets in the colon. Toxicological analyses showed 72ng/ml pancuronium and 21 ng/ml oxycodone (therapeutic) in the femoral venous blood. The range of published pancuronium levels varies from approx. 80 to 2,000 ng/ml. Thus it had to be assumed that the pancuronium level was too low (72 ng/ml) so that symptoms of dystonia recurred. Based on extensive literature research, the described case can be qualified as unique. The therapy concept had been innovative, sufficient and effective for more than 10 years. It allowed the patient to enjoy a maximum of autonomy. Ultimately, death was due to the blocked pancuronium infusion. The relatively low pancuronium level had provoked the dystonia to return with generalized spasms also involving the respiratory muscles resulting in respiratory arrest. During the police investigations, two previous suicide attempts came to light.

Decline in drug overdose deaths after state policy changes - Florida, 2010-2012.

During 2003-2009, the number of deaths caused by drug overdose in Florida increased 61.0%, from 1,804 to 2,905, with especially large increases in deaths caused by the opioid pain reliever oxycodone and the benzodiazepine alprazolam. In response, Florida implemented various laws and enforcement actions as part of a comprehensive effort to reverse the trend. This report describes changes in overdose deaths for prescription and illicit drugs and changes in the prescribing of drugs frequently associated with these deaths in Florida after these policy changes. During 2010-2012, the number of drug overdose deaths decreased 16.7%, from 3,201 to 2,666, and the deaths per 100,000 persons decreased 17.7%, from 17.0 to 14.0. Death rates for prescription drugs overall decreased 23.2%, from 14.5 to 11.1 per 100,000 persons. The decline in the overdose deaths from oxycodone (52.1%) exceeded the decline for other opioid pain relievers, and the decline in deaths for alprazolam (35.6%) exceeded the decline for other benzodiazepines. Similar declines occurred in prescribing rates for these drugs during this period. The temporal association between the legislative and enforcement actions and the substantial declines in prescribing and overdose deaths, especially for drugs favored by pain clinics, suggests that the initiatives in Florida reduced prescription drug overdose fatalities.

State-level variation in distribution of oxycodone and opioid-related deaths from 2000 to 2021: an ecological study of ARCOS and CDC WONDER data in the USA.

OBJECTIVES: This study aims to characterise oxycodone's distribution and opioid-related overdoses in the USA by state from 2000 to 2021. DESIGN: This is an observational study. SETTING: More than 80 000 Americans died of an opioid overdose in 2021 as the USA continues to struggle with an opioid crisis. Prescription opioids play a substantial role, introducing patients to opioids and providing a supply of drugs that can be redirected to those seeking to misuse them. METHODS: The Drug Enforcement Administration annual summary reports from the Automation of Reports and Consolidated Orders System provided weights of oxycodone distributed per state by business type (pharmacies, hospitals and practitioners). Weights were converted to morphine milligram equivalents (MME) per capita and normalised for population. The Centers for Disease Control and Prevention Wide-ranging ONline Data for Epidemiologic Research provided mortality data for heroin, other opioids, methadone, other synthetic narcotics and other/unspecified narcotics. RESULTS: There was a sharp 280.13% increase in total MME/person of oxycodone from 2000 to 2010, followed by a slower 54.34% decrease from 2010 to 2021. Florida (2007-2011), Delaware (2003-2020) and Tennessee (2012-2021) displayed consistent and substantial elevations in combined MME/person compared with other states. In the peak year (2010), there was a 15-fold difference between the highest and lowest states. MME/person from only pharmacies, which constituted >94% of the total, showed similar results. Hospitals in Alaska (2000-2001, 2008, 2010-2021), Colorado (2008-2021) and DC (2000-2011) distributed substantially more MME/person over many years compared with other states. Florida stood out in practitioner-distributed oxycodone, with an elevation of almost 15-fold the average state from 2006 to 2010. Opioid-related deaths increased +806% from 2000 to 2021, largely driven by heroin, other opioids and other synthetic narcotics. CONCLUSIONS: Oxycodone distribution across the USA showed marked differences between states and business types over time. Investigation of opioid policies in states of interest may provide insight for future actions to mitigate opioid misuse.

Refractory Hypoglycemia Due to Sulfonylurea Contamination of Illicit Opioid Medications.

Illicit drug supply adulteration can heighten the risk for adverse health outcomes. Sulfonylurea medications are widely used in the treatment of diabetes mellitus (DM). Unintentional or intentional overdose of sulfonylureas can cause refractory hypoglycemia. This case report describes a 62-year-old male patient who presented to the emergency department (ED) after being found on the ground with signs of mild trauma. He was noted to be persistently hypoglycemic despite boluses of intravenous dextrose, a dextrose infusion, and oral nutrition. The patient did report purchase and oral ingestion of pills sold as oxycodone and that the pill shape and color were different from his usual supply. The patient was empirically treated with octreotide resulting in normalization of his serum glucose. Testing demonstrated a serum glipizide concentration six times the reporting range. This case represents unintentional sulfonylurea exposure in the setting of non-prescribed oxycodone use, resulting in hypoglycemia refractory to intravenous dextrose and oral nutrition. Octreotide is an additional potential treatment for this condition. As in this case, ingestion of street drugs may present a potential source of sulfonylurea exposure. Opioid contamination with sulfonylureas has not been widely reported in the literature and knowledge about this potential exposure is important for the prompt recognition and treatment of these patients by emergency physicians.

Maternal use of oxycodone resulting in opioid intoxication in her breastfed neonate.

A 4-day-old breastfed infant presented with opioid intoxication resulting from the maternal use of oxycodone after cesarean delivery. The infant was hypothermic, lethargic, and had pinpoint pupils. A dose of naloxone reversed the symptoms. This report highlights the importance of recognizing the potential effects of maternal oxycodone on the breastfed neonate in the emergency department setting.

A novel case of transient right ventricular failure in a patient with respiratory distress.

Right ventricular (RV) failure is characterized by an inability to pump blood into the pulmonary circulation and can often lead to hemodynamic instability. Common causes of RV failure include left ventricular (LV) failure, RV infarction, sepsis, cor pulmonale due to acute respiratory distress syndrome, pulmonary emboli, or pulmonary hypertension. We report the case of a 61-year-old woman with no significant pulmonary or cardiac disease who presented with hypoxic respiratory failure in the setting of opioid overdose. She remained obtunded despite naloxone treatment and required endotracheal intubation as well as norepinephrine therapy for persistent hypotension. A transthoracic echocardiogram demonstrated isolated severe RV dysfunction without any LV abnormalities. Cardiac catheterization showed no obstructive coronary artery disease, pulmonary hypertension, or elevated left atrial pressures, and chest imaging only revealed signs of aspiration. Over the next 6 days, the patient's cardiac and respiratory function improved, and a repeat echocardiogram demonstrated complete normalization of RV function. This case demonstrates a novel finding that marked, but transient, RV dysfunction can occur in the setting of acute respiratory failure.

Six-year follow-up of impact of co-proxamol withdrawal in England and Wales on prescribing and deaths: time-series study.

BACKGROUND: The analgesic co-proxamol (paracetamol/dextropropoxyphene combination) has been widely involved in fatal poisoning. Concerns about its safety/effectiveness profile and widespread use for suicidal poisoning prompted its withdrawal in the UK in 2005, with partial withdrawal between 2005 and 2007, and full withdrawal in 2008. Our objective in this study was to assess the association between co-proxamol withdrawal and prescribing and deaths in England and Wales in 2005-2010 compared with 1998-2004, including estimation of possible substitution effects by other analgesics. METHODS AND FINDINGS: We obtained prescribing data from the NHS Health and Social Care Information Centre (England) and Prescribing Services Partneriaeth Cydwasanaethau GIG Cymru (Wales), and mortality data from the Office for National Statistics. We carried out an interrupted time-series analysis of prescribing and deaths (suicide, open verdicts, accidental poisonings) involving single analgesics. The reduction in prescribing of co-proxamol following its withdrawal in 2005 was accompanied by increases in prescribing of several other analgesics (co-codamol, paracetamol, codeine, co-dydramol, tramadol, oxycodone, and morphine) during 2005-2010 compared with 1998-2004. These changes were associated with major reductions in deaths due to poisoning with co-proxamol receiving verdicts of suicide and undetermined cause of -21 deaths (95% CI -34 to -8) per quarter, equating to approximately 500 fewer suicide deaths (-61%) over the 6 years 2005-2010, and -25 deaths (95% CI -38 to -12) per quarter, equating to 600 fewer deaths (-62%) when accidental poisoning deaths were included. There was little observed change in deaths involving other analgesics, apart from an increase in oxycodone poisonings, but numbers were small. Limitations were that the study was based on deaths involving single drugs alone and changes in deaths involving prescribed morphine could not be assessed. CONCLUSIONS: During the 6 years following the withdrawal of co-proxamol in the UK, there was a major reduction in poisoning deaths involving this drug, without apparent significant increase in deaths involving other analgesics.

Window of opportunity: flexion myelopathy after drug overdose.

BACKGROUND: Cervical and thoracic flexion myelopathy are uncommon causes of spinal cord injury that can lead to irreversible paralysis, autonomic dysfunction, and death. To the authors' knowledge, this report is the first to describe the natural history of flexion myelopathy and the simultaneous occurrence of cervical and thoracic flexion myelopathy in the setting of drug overdose. OBJECTIVES: To report the association of cervical and thoracic flexion myelopathy and drug overdose; to describe the subacute natural history of flexion myelopathy in the setting of drug overdose; to emphasize the need for first responders to document positioning of unresponsive individuals; and to suggest careful neurological examination and early spinal cord imaging in appropriately identified patients at risk of flexion myelopathy. CASE REPORT: We describe the case of a 34-year-old woman who developed flexion myelopathy resulting in severe quadriparesis after overdose of quetiapine fumarate, oxycodone/acetaminophen, and chloral hydrate. CONCLUSION: Flexion myelopathy in the setting of drug overdose is a subacute injury. Early intervention may limit neurological disability. However, the clinical diagnosis of flexion myelopathy is inevitably delayed by the patient's altered level of consciousness or mental status at presentation, and concurrent multiple organ failure.

Drug overdose deaths--Florida, 2003-2009.

In the United States in 2007, unintentional poisonings were the second leading cause of injury death (after motor-vehicle crashes); approximately 93% of all unintentional poisoning deaths were caused by drug poisoning, also known as drug overdose. From 1990 to 2001 in Florida, the nonsuicidal poisoning death rate increased 325%. To characterize recent trends in drug overdose death rates in Florida, CDC analyzed data from the Florida Medical Examiners Commission. This report summarizes the results of that analysis, which found that, from 2003 to 2009, the number of annual deaths in which medical examiner testing showed lethal concentrations of one or more drugs increased 61.0%, from 1,804 to 2,905, and the death rate increased 47.5%, from 10.6 to 15.7 per 100,000 population. During 2003-2009, death rates increased for all substances except cocaine and heroin. The death rate for prescription drugs increased 84.2%, from 7.3 to 13.4 per 100,000 population. The greatest increase was observed in the death rate from oxycodone (264.6%), followed by alprazolam (233.8%) and methadone (79.2%). By 2009, the number of deaths involving prescription drugs was four times the number involving illicit drugs. These findings indicate the need to strengthen interventions aimed at reducing overdose deaths from prescription drugs in Florida. Medical examiner records are a timely, population-based source for data regarding overdose deaths from specific drugs. The data in this report and subsequent analyses can be used to design and measure the effectiveness of interventions.

Prescription of opioid analgesics and related harms in Australia.

OBJECTIVE: To document trends in: (i) prescribing of morphine and oxycodone; (ii) hospital separations for overdose; (iii) presentations for treatment of problems associated with these drugs; and (iv) oxycodone-related mortality data in Australia. DESIGN AND SETTING: Cross-sectional study analysing prescriptions for morphine and oxycodone based on figures adjusted using Australian Bureau of Statistics estimated resident population and prospectively collected data from: (i) the National Hospital Morbidity Database on hospital separations primarily attributed to poisoning with opioids other than heroin ("other opioids"); (ii) the Alcohol and Other Drug Treatment National Minimum Data Set for treatment episodes where morphine or oxycodone were the primary or other drugs of concern; (iii) the National Coronial Information System on deaths where oxycodone was the underlying cause of death or a contributory factor. MAIN OUTCOME MEASURES: Population-adjusted numbers of (i) prescriptions for morphine and oxycodone by 10-year age group, (ii) hospital separations for "other opioid" poisoning, and (iii) treatment episodes related to morphine or oxycodone; and (iv) number of oxycodone-related deaths. RESULTS: Prescriptions for morphine declined, while those for oxycodone increased. Prescriptions for both were highest among older Australians. Hospital separations for "other opioid" poisoning doubled between the financial years 2005-06 and 2006-07. Treatment episodes for morphine remained stable, while those for oxycodone increased. There were 465 oxycodone-related deaths recorded during 2001-2009. CONCLUSIONS: Oxycodone prescriptions in Australia have increased, particularly among older Australians. The increase may, in part, reflect appropriate prescribing for pain among an ageing population. However we are unable to differentiate non-medical use from appropriate prescribing from this data. In comparison to heroin, the morbidity and mortality associated with oxycodone is relatively low in Australia. There is a continued need for comprehensive training of general practitioners in assessing patients with chronic non-malignant pain and prescribing of opioids for these patients, to minimise the potential for harms associated with use of these medications.

Increasing deaths involving oxycodone, Victoria, Australia, 2000-09.

OBJECTIVE: In light of an emerging epidemic identified in the United States and Canada, to identify trends in fatal drug toxicity involving oxycodone and the demographic characteristics and indicators of socioeconomic disadvantage of the deceased. STUDY DESIGN: Population-based observational study in Victoria, Australia. POPULATION: Decedents whose death was reported to the Victorian Coroner between 2000 and 2009 and where oxycodone was detected. MAIN OUTCOME MEASURES: Association between supply of oxycodone and deaths. Demographic characteristics of decedents. Rate ratios of the rural or metropolitan location and socioeconomic indicators of disadvantage of the deceased. RESULTS: Supply to Victoria has increased nine-fold from 7.5 mg per capita in 2000 to 67.5 mg per capita in 2009. Detection of oxycodone in deaths reported to the Victorian Coroner has increased from 4 (0.08/100,000 population) in 2000 to 97 (1.78/100,000 population) in 2009-a 21-fold increase in deaths. Of the 320 cases described, 53.8% (172) were the result of drug toxicity. Of these, 52.3% were unintentional and 19.8% intentional self-harm; the remaining 27.9% are either still under investigation by the coroner or intent is unknown. Drug toxicity deaths were overrepresented in both rural areas and areas indexed with high levels of disadvantage. CONCLUSIONS: The substantial increase in the number of deaths involving oxycodone is strongly and significantly associated with the increase in supply. Most drug toxicity deaths involving oxycodone were unintentional. This newly identified trend in fatalities in Victoria supports concerns that a pattern of increasing deaths involving oxycodone is emerging globally.

Pharmacists' experiences with dispensing opioids: provincial survey.

OBJECTIVE: To explore pharmacists' beliefs, practices, and experiences regarding opioid dispensing. DESIGN: Mailed survey. SETTING: The province of Ontario. PARTICIPANTS: A total of 1011 pharmacists selected from the Ontario College of Pharmacists' registration list. MAIN OUTCOME MEASURES: Pharmacists' experiences with opioid-related adverse events (intoxication and aberrant drug-related behaviour) and their interactions with physicians. RESULTS: A total of 652 pharmacists returned the survey, for a response rate of 64%. Most (86%) reported that they were concerned about several or many of their patients who were taking opioids; 36% reported that at least 1 patient was intoxicated from opioids while visiting their pharmacies within the past year. Reasons for opioid intoxication included the patient taking more than prescribed (84%), the patient using alcohol or sedating drugs along with the opioid (69.9%), or the prescribed dose being too high (34%). Participants' most common concerns in the 3 months before the survey were patients coming in early for prescription refills, suspected double-doctoring, and requests for replacement doses for lost medication (reported frequently by 39%, 12%, and 16% of respondents, respectively). Pharmacists were concerned about physician practices, such as prescribing benzodiazepines along with opioids. Pharmacists reported difficulty in reaching physicians directly by telephone (43%), and indicated that physicians frequently did not return their calls promptly (28%). The strategies rated as most helpful for improving opioid dispensing were a provincial prescription database and opioid prescribing guidelines. CONCLUSION: Pharmacists commonly observe opioid intoxication and aberrant drug-related behaviour in their patients but have difficulty communicating their concerns to physicians. System-wide strategies are urgently needed to improve the safety of opioid prescribing and to enhance communication between physicians and pharmacists.

Opiate overdose in an adolescent after a dental procedure: a case report.

Oxycodone/acetaminophen is a combination of acetaminophen and the opiate oxycodone. It is an effective analgesic that is commonly prescribed postoperatively. The potential for misuse, diversion, abuse, and overdose with opiates in general is an area of increasing concern to all prescribing clinicians. This case report illustrates the possibility of a severe or potentially fatal outcome to a common prescribing practice. Caution is emphasized when prescribing opiates, and screening for substance misuse and suicide risk factors is recommended.

Trends in hydrocodone combination product exposures reported to California Poison Control System (CPCS) following DEA rescheduling.

CONTEXT: On October 6, 2014, the United States Drug Enforcement Administration (DEA) implemented a regulatory change for hydrocodone combination products (HCPs), moving them from Schedule III to II, in an effort to decrease drug overdoses. Existing research suggests this regulatory action reduced HCP prescribing and dispensing; however, there is limited research assessing its possible effects on overdoses and accidental exposures. OBJECTIVE: To analyze the changes in opioid exposures reported to the California Poison Control System (CPCS) before and after DEA rescheduling of HCPs. METHODS: We collected monthly exposure data reported to CPCS from 2012 to 2019 and conducted interrupted time series analyses to assess changes in exposures after rescheduling for HCPs, tramadol, oxycodone, morphine, codeine, fentanyl, and heroin. Additional analyses were done to assess any changes in exposures resulting in severe outcomes (moderate or major health effects). For HCPs, we also conducted logistic regressions to identify characteristics of exposures resulting in severe outcomes before and after rescheduling. RESULTS: Overall monthly opioid exposures reported to CPCS decreased after DEA rescheduling of HCPs. These decreases were significant for HCP, tramadol, and morphine (p < 0.001). Exposures significantly increased for heroin and fentanyl (p < 0.001). There were no significant changes in the share of severe outcomes attributed to HCP exposures after rescheduling. DISCUSSION: The DEA rescheduling of HCPs was associated with a significant decrease in HCP exposures and prescription opioid exposures overall, but was associated with increased fentanyl and heroin exposures. While other initiatives may have contributed to this decrease, our findings suggest that rescheduling may be a useful regulatory strategy to reduce drug exposures. CONCLUSION: DEA rescheduling of HCPs was associated with a significant reduction in prescription opioid exposures, suggesting that rescheduling high-risk drugs may be an effective strategy to improve public health.