All-cause mortality among males living with and without HIV initiating long-term opioid therapy, and its association with opioid dose, opioid interruption and other factors.
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ABSTRACT: Background
While the relationship between long-term opioid therapy (LTOT) dose and overdose is well-established, LTOT's association with all-cause mortality is less understood, especially among people living with HIV (PLWH). There is also limited information regarding the association of LTOT cessation or interruption with mortality.Methods
Among PLWH and matched uninfected male veterans in care, we identified those who initiated LTOT. Using time-updated cox regression, we examined the association between all-cause mortality, unnatural death, and overdose, and opioid use categorized as 1-20 (reference group), 21-50, 51-90, and ≥ 91 mg morphine equivalent daily dose (MEDD).Results
There were 22,996 patients on LTOT, 6,578 (29 %) PLWH and 16,418 (71 %) uninfected. Among 5,222 (23 %) deaths, 12 % were unnatural deaths and 6 % overdoses. MEDD was associated with risk of all 3 outcomes; compared to patients on 1-20 mg MEDD, adjusted risk for all-cause mortality monotonically increased (Hazard Ratios (HR) [95 % CI] for 21-50 mg MEDD = 1.36 [1.21, 1.52], 51-90 mg MEDD = 2.06 [1.82, 2.35], and ≥ 91 mg MEDD = 3.03 [2.71, 3.39]). Similar results were seen in models stratified by HIV. LTOT interruption was also associated with all-cause, unnatural, and overdose mortality (HR [95 % CI] 2.30 [2.09, 2.53], 1.47 [1.13, 1.91] and 1.52 [1.04, 2.23], respectively).Conclusions
Among PLWH and uninfected patients on LTOT we observed a strong dose-response relationship with all 3 mortality outcomes. Opioid risk mitigation approaches should be expanded to address the potential effects of higher dose on all-cause mortality in addition to unnatural and overdose fatalities.
SUBMITTER: Gordon KS
PROVIDER: S-EPMC7644145 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BackgroundIndividuals undergoing hemodialysis in the United States frequently report pain and receive three-fold more opioid prescriptions than the general population. While opioid use is appropriate for select patients, high-dose utilization may contribute to an increased risk of death due to possible accumulation of opioid metabolites.MethodsWe studied high-dose opioid utilization (≥120 morphine milligram equivalents [MME] per day) among adults initiating hemodialysis in the United States between 2007 and 2014 using national registry data. We calculated the cumulative incidence (%) of high-dose utilization and depicted trends in the average percentage of days individuals were exposed to opioids. We used adjusted Cox proportional hazards models to identify which opioid doses were associated with mortality.ResultsAmong 327,344 adults undergoing hemodialysis, the cumulative incidence of high-dose utilization was 14.9% at 2 years after initiating hemodialysis. Among patients with ≥1 opioid prescription during follow-up, the average percentage of days exposed to high-dose utilization increased from 13.9% in 2007 to 26.1% in 2014. Compared to 0MME per day, doses < 60MME were not associated with an increased risk of mortality, but high-dose utilization was associated with a 1.63-fold (95% CI, 1.57, 1.69) increased risk of mortality. The risk of mortality associated with opioid dose was highest in the first year after hemodialysis initiation.ConclusionsThe risk of mortality associated with opioid utilization among individuals on hemodialysis increases as doses exceed 60MME per day and is greatest during periods of high-dose utilization. Patients and clinicians should carefully weigh the risks and benefits of opioid doses exceeding 60MME per day.
| S-EPMC7901089 | biostudies-literature
Project description:(1) Background: The prevalence of opioid use in Taiwan increased by 41% between 2002 and 2014. However, little is known regarding the risk of mortality among long-term opioid analgesics users who do not have cancer. This study investigated this mortality risk with an emphasis on the calendar year and patients' age and sex. (2) Methods: This retrospective cohort study included 12,990 adult individuals without cancer who were long-term users of opioid analgesics and were randomly selected from the data set of Taiwan's National Health Insurance program from 2000 to 2012. They were then followed up through 2013. Information on the underlying causes of death was retrieved from the Taiwan Death Registry. Age, sex, and calendar year-standardized mortality ratios (SMRs) of all-cause and cause-specific mortality were calculated with reference to those of the general population. (3) Results: With up to 14 years of follow-up, 558 individuals had all-cause mortality in 48,020 person-years (cumulative mortality: 4.3%, mortality rate: 11.62 per 1000 person-years). Compared with the general population, the all-cause SMR of 4.30 (95% confidence interval (95% CI): 3.95-4.66) was significantly higher: it was higher in men than in women, declined with calendar year and age, and was significantly higher for both natural (4.15, 95% CI: 3.78-4.53) and unnatural (5.04, 95% CI: 3.88-6.45) causes. (4) Conclusions: Long-term opioid analgesics use among individuals without cancer in Taiwan was associated with a significantly increased risk of mortality. The notably increased mortality in younger adults warrants attention. Strategies to reduce long-term opioid analgesics use, especially their overuse or misuse, are in an urgent need.
| S-EPMC8625753 | biostudies-literature
Project description:PurposeFor patients receiving long-term opioid therapy (LtOT), the impact of guideline-concordant care on important clinical outcomes--notably mortality--is largely unknown, even among patients with a high comorbidity and mortality burden (e.g., HIV-infected patients). Our objective was to determine the association between receipt of guideline-concordant LtOT and 1-year all-cause mortality.MethodsAmong HIV-infected and uninfected patients initiating LtOT between 2000 and 2010 through the Department of Veterans Affairs, we used Cox regression with time-updated covariates and propensity-score matched analyses to examine the association between receipt of guideline-concordant care and 1-year all-cause mortality.ResultsOf 17,044 patients initiating LtOT between 2000 and 2010, 1048 patients (6%) died during 1 year of follow-up. Patients receiving psychotherapeutic co-interventions (hazard ratio [HR] 0.62; 95% confidence interval [CI] 0.51-0.75; P?<?0.001) or physical rehabilitative therapies (HR 0.81; 95% CI 0.67-0.98; P?=?0.03) had a decreased risk of all-cause mortality compared to patients not receiving these services, whereas patients prescribed benzodiazepines concurrent with opioids had a higher risk of mortality (HR 1.39; 95% CI 1.12-1.66; P?<?0.001). Among patients with a current substance use disorder (SUD), those receiving SUD treatment had a lower risk of mortality than untreated patients (HR 0.47; 95% CI 0.32-0.68; P?=?< 0.001). No association was found between all-cause mortality and primary care visits (HR 1.12; 95% CI 0.90-1.26; P?=?0.32) or urine drug testing (HR 0.96; 95% CI 0.78-1.17; P?=?0.67).ConclusionsProviders should use caution in initiating LtOT in conjunction with benzodiazepines and untreated SUDs. Patients receiving LtOT may benefit from multi-modal treatment that addresses chronic pain and its associated comorbidities across multiple disciplines.
| S-EPMC4835362 | biostudies-literature
Project description:BackgroundOpioid withdrawal symptoms prior to buprenorphine initiation may be intolerable and as a result, alternative strategies have emerged. We aim to systematically review the efficacy and safety of buprenorphine initiation that aims to omit prerequisite withdrawal.MethodsWe conducted a systematic literature search of MEDLINE and CENTRAL from 1996 through April 10, 2020, augmented with searches in Google Scholar and www.clinicaltrials.gov . A study was included if it was in patients with substance use disorder or chronic pain that were taking a full mu opioid agonist and transitioning to buprenorphine without preceding withdrawal, and reported withdrawal during initiation as an outcome. Two investigators independently screened citations and articles for inclusion, collected data using a standardized data collection tool, and assessed study risk of bias.ResultsWe included 15 case reports/series, reporting 24 unique cases, in our qualitative synthesis. No controlled studies were identified. Microdosing and bridging with a buprenorphine patch were the most common strategies reported. Transition to buprenorphine with complete cessation of opioid agonists was achieved in 87.5% (n = 21) of cases. Withdrawal during initiation occurred in 58.3% (n = 14) of cases, two of which were at least moderate in severity.ConclusionBuprenorphine initiation strategies that omit prerequisite withdrawal have emerged. Low quality evidence from case reports suggests withdrawal during initiation is common but most often mild in severity. There is an unmet need for controlled studies to inform their efficacy and safety compared with traditional strategies, including outcomes during initiation and in the long-term.
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Project description:ImportanceAlthough overall rates of opioid use have been plateauing, coprescriptions of benzodiazepines and opioids have increased greatly in recent years. It is unknown whether this combination is an independent risk factor for all-cause mortality as opposed to being more frequently used by persons with a baseline elevated risk of death.ObjectiveTo evaluate whether benzodiazepine use, with or without opioid use, is associated with increased all-cause mortality relative to the use of low-risk antidepressants.Design, setting, and participantsThis retrospective cohort study used a large, nationally representative US data set (the National Health and Nutrition Examination Surveys [NHANES]) from 1999 to 2015. Eight cycles of NHANES data were used, spanning 37 610 person-years of follow-up time among 5212 individuals. Statistical analysis was performed from August 24, 2019, through May 23, 2020.ExposuresThe primary exposure variable was benzodiazepine and opioid coprescriptions. Individuals taking selective serotonin reuptake inhibitors (SSRIs) served as an active comparator reference group.Main outcomes and measuresAll-cause mortality was obtained via linkage of NHANES to the National Death Index. Propensity scores were calculated from covariates associated with sociodemographic factors, comorbidities, and medication use for more than 1000 prescription types. Propensity score-weighted mortality hazards were calculated from Cox proportional hazards regression models.ResultsOf 5212 participants aged 20 years or older (1993 men [38.2%]; mean [SD] age, 54.8 [16.9] years) followed up for a median of 6.7 years (range, 0.2-16.8 years), 101 deaths (33.0 per 1000 person-years) occurred among those receiving cotreatment, 236 deaths (26.5 per 1000 person-years) occurred among those receiving only benzodiazepines, and 227 deaths (20.2 per 1000 person-years) occurred among SSRI recipients taking neither opioids nor benzodiazepines. After propensity score weighting, a significant increase in all-cause mortality was associated with benzodiazepine and opioid cotreatment (hazard ratio, 2.04 [95% CI, 1.65-2.52]) and benzodiazepines without opioids (hazard ratio, 1.60 [95% CI, 1.33-1.92]). Subgroup analyses revealed an increased risk of mortality for individuals receiving cotreatment who were 65 years or younger but not for those older than 65 years; similar findings were observed for those receiving benzodiazepines without opioids.Conclusions and relevanceThis study found a significant increase in all-cause mortality associated with benzodiazepine use with or without opioid use in comparison with SSRI use. Benzodiazepine and opioid cotreatment, in particular, was associated with a 2-fold increase in all-cause mortality even after taking into account medical comorbidities and polypharmacy burden.
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Project description:BackgroundHitherto only studies with selected populations have found an increased all-cause mortality of some selected opioids compared to selected non-opioids for chronic non-cancer pain (CNCP). We have examined the all-cause mortality for CNCP associated with all established opioids compared to non-opioid analgesic therapy (anticonvulsants, antidepressants, dipyrone, non-steroidal agents).MethodsThe study used the InGef (Institute for Applied Health Research Berlin) database which is an anonymized healthcare claims database including 4,711,668 insured persons who were covered by 61 German statutory health insurances between 2013 and 2017.The health insurance companies are the owners of the database. All-cause mortality was determined from death certificates. Adjusted hazard ratios (HRs) including age, gender, comorbidity index, and propensity score as covariates and risk differences (RD) in incidence of death between patients with long-term opioid therapy (LTOT) and control-drug therapy were calculated.ResultsThe mean age of participants was 66 years; 55% were women. There were 554 deaths during 10,435 person-years for the LTOT patients, whereas there were 340 deaths during 11,342 person-years in the control group. The HR for all-cause mortality was 1.59 (95% CI, 1.38-1.82) with a risk difference of 148 excess deaths (95% CI 99-198) per 10,000 person-years. The elevated risk of death for LTOT was confined to the out-of-hospital deaths: LTOT patients had 288 out-of-hospital deaths during 10,435 person-years (276 per 10,000 person-years) whereas there were 110 deaths during 11,342 person-years (97 per 10,000 person-years) in the control group. HR was 2.29 (95% CI 1.86, 2.83). Although our propensity score matching model indicated a good classification, residual confounding cannot be fully excluded. The opioid group had a higher prevalence of heart failure and a higher use of anti-thrombotic and antiplatelet agents and of psycholeptics.ConclusionsLTOT for CNCP compared to non-opioid analgesics was associated with an increased risk for all-cause mortality. When considering treatment options for patients with CNCP, the relevant risk of increased all-cause mortality with opioids should be discussed.Trial registrationClinicalTrials.gov, NCT03778450, Registered on 7 December 2018.
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Project description:ImportanceAttempts to discontinue opioid therapy to reduce the risk of overdose and adhere to prescribing guidelines may lead patients to be exposed to variability in opioid dosing. Such dose variability may increase the risk of opioid overdose even if therapy discontinuation is associated with a reduction in risk.ObjectiveTo examine the association between opioid dose variability and opioid overdose.Design, setting, and participantsA nested case-control study was conducted in a large Colorado integrated health plan and delivery system from January 1, 2006, through June 30, 2018. Cohort members were individuals prescribed long-term opioid therapy.ExposuresDose variability was defined as the SD of the milligrams of morphine equivalents across each patient's follow-up and categorized based on the quintile distribution of the SD in the cohort (0-5.3, 5.4-9.1, 9.2-14.6, 14.7-27.2, and >27.2 mg of morphine equivalents).Main outcomes and measuresOpioid overdose cases were identified using International Classification of Diseases, Ninth Revision and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes. Each case patient with overdose was matched to up to 20 control patients using risk set sampling. Conditional logistic regression models were used to generate matched odds ratios and 95% CIs, adjusted for age, sex, race/ethnicity, drug or alcohol use disorder, tobacco use, benzodiazepine dispensings, medical comorbidities, mental health disorder, opioid dose, and opioid formulation.ResultsIn a cohort of 14 898 patients (mean [SD] age, 56.3 [16.0] years; 8988 [60.3%] female) prescribed long-term opioid therapy, 228 case patients with incident opioid overdose were matched to 3547 control patients. The mean (SD) duration of opioid therapy was 36.7 (33.7) months in case patients and 33.0 (30.9) months in control patients. High-dose variability (SD >27.2 mg of morphine equivalents) was associated with a significantly increased risk of overdose compared with low-dose variability (matched odds ratio, 3.32; 95% CI, 1.63-6.77) independent of opioid dose.Conclusions and relevanceVariability in opioid dose may be a risk factor for opioid overdose, suggesting that practitioners should seek to minimize dose variability when managing long-term opioid therapy.
| S-EPMC6481879 | biostudies-literature
Project description:ImportanceRapid reduction or discontinuation of long-term opioid therapy may increase risk of opioid overdose or opioid use disorder (OUD). Current guidelines for chronic pain management caution against rapid dose reduction but are based on limited evidence.ObjectiveTo characterize the association between rapid reduction or abrupt discontinuation of opioid therapy (vs maintained or gradual reduction) and incidence of opioid overdose and OUD among patients prescribed high-dose, long-term opioid therapy (HDLTOT).Design, setting, and participantsThis retrospective cohort study was conducted among patients aged 18 to 64 years who were prescribed HDLTOT (≥90 daily morphine milligram equivalents for ≥90% of 90 days) from January 2006 to September 2018, with follow-up up to 4 years after cohort entry. Claims data were drawn from a large private health insurer in North Carolina and analyzed from March 1, 2006, to September 30, 2018.ExposuresTime-varying exposure of rapid dose reduction or discontinuation (>10% dose reduction/week) vs maintenance, increase, or gradual reduction or discontinuation.Main outcomes and measuresThe main outcome was incident opioid overdose (fatal or nonfatal) or diagnosed OUD. Inverse probability-weighted cumulative incidence of outcomes were estimated using the cumulative incidence function and hazard ratios (HRs) using marginal structural Fine-Gray models as a function of rapid dose tapering or discontinuation (vs gradual reduction or discontinuation or maintained or increased), accounting for competing risks.ResultsA total of 19 443 patients (median [IQR] age, 49 [41-55] years; 10 073 [51.8%] men) who received HDLTOT were identified. Rapid reduction or discontinuation was associated with higher risk of fatal and nonfatal overdoses compared with gradual reduction after the first year (year 1: HR, 1.43; 95% CI, 0.94-2.18; years 2-4: HR, 1.95; 95% CI, 1.31-2.90). There was no association between rapid reduction or discontinuation and diagnosed OUD through 2 years of follow-up; however, the hazard of incident OUD among patients exposed to rapid tapering or discontinuation was greater 25 to 48 months after the start of follow-up (HR, 1.28; 95% CI, 1.01-1.63).Conclusions and relevanceIn this cohort study, rapid dose reduction or discontinuation was associated with increased risk of opioid overdose and OUD during long-term follow-up. These findings reinforce prior concerns about safety of rapid dose reductions for patients receiving HDLTOT and highlight the need for caution when reducing opioid doses.
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Project description:Background:There is limited empirical evidence on the relationship between hyperglycemia, tuberculosis (TB) comorbidity, and mortality in the context of HIV. We assessed whether hyperglycemia at enrollment in HIV care was associated with increased risk of all-cause mortality and whether this relationship was different among patients with and without TB disease. Methods:We conducted a retrospective analysis of adult (?15 years) HIV-positive patients enrolled into HIV care between 2011 and 2016 who had random blood glucose (RBG) measurements at enrollment. We used hazards regression to estimate associations between RBG and rate of all-cause mortality. Results:Of 25 851 patients, 43% were female, and the median age was 36 years. At registration, the median CD4 count (interquartile range [IQR]) was 162 (68-310) cell/mm3, the median RBG level (IQR) was 88 (75-106) mg/dL, and 6.2% (95% confidence interval [CI], 6.0%-6.5%) had hyperglycemia (RBG ?140 mg/dL). Overall 29% of patients had TB disease, and 15% died during the study period. The adjusted hazard of death among patients with hyperglycemia was significantly higher (adjusted hazard ratio [aHR], 1.2; 95% CI, 1.1-1.4) than among those with normoglycemia without TB disease, but not among patients with TB disease (aHR, 1.0; 95% CI, 0.8-1.2). Using 4 categories of RBG and restricted cubic spline regression, aHRs for death were significantly increased in patients with RBG of 110-140 mg/dL (categorical model: aHR, 1.3; 95% CI, 1.2-1.4; restricted spline: aHR, 1.1; 95% CI, 1.0-1.1) compared with those with RBG <110 mg/dL. Conclusions:Our findings highlight an urgent need to evaluate hyperglycemia screening and diagnostic algorithms and to ultimately establish glycemic targets for PLHIV with and without TB disease.
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