Association between Opioid-Benzodiazepine Trajectories and Injurious Fall Risk among US Medicare Beneficiaries.

Background/Objectives: Concurrent opioid (OPI) and benzodiazepine (BZD) use may exacerbate injurious fall risk (e.g., falls and fractures) compared to no use or use alone. Yet, patients may need concurrent OPI-BZD use for co-occurring conditions (e.g., pain and anxiety). Therefore, we examined the association between longitudinal OPI-BZD dosing patterns and subsequent injurious fall risk. Methods: We conducted a retrospective cohort study including non-cancer fee-for-service Medicare beneficiaries initiating OPI and/or BZD in 2016-2018. We identified OPI-BZD use patterns during the 3 months following OPI and/or BZD initiation (i.e., trajectory period) using group-based multi-trajectory models. We estimated the time to first injurious falls within the 3-month post-trajectory period using inverse-probability-of-treatment-weighted Cox proportional hazards models. Results: Among 622,588 beneficiaries (age ≥ 65 = 84.6%, female = 58.1%, White = 82.7%; having injurious falls = 0.45%), we identified 13 distinct OPI-BZD trajectories: Group (A): Very-low OPI-only (early discontinuation) (44.9% of the cohort); (B): Low OPI-only (rapid decline) (15.1%); (C): Very-low OPI-only (late discontinuation) (7.7%); (D): Low OPI-only (gradual decline) (4.0%); (E): Moderate OPI-only (rapid decline) (2.3%); (F): Very-low BZD-only (late discontinuation) (11.5%); (G): Low BZD-only (rapid decline) (4.5%); (H): Low BZD-only (stable) (3.1%); (I): Moderate BZD-only (gradual decline) (2.1%); (J): Very-low OPI (rapid decline)/Very-low BZD (late discontinuation) (2.9%); (K): Very-low OPI (rapid decline)/Very-low BZD (increasing) (0.9%); (L): Very-low OPI (stable)/Low BZD (stable) (0.6%); and (M): Low OPI (gradual decline)/Low BZD (gradual decline) (0.6%). Compared with Group (A), six trajectories had an increased 3-month injurious falls risk: (C): HR = 1.78, 95% CI = 1.58-2.01; (D): HR = 2.24, 95% CI = 1.93-2.59; (E): HR = 2.60, 95% CI = 2.18-3.09; (H): HR = 2.02, 95% CI = 1.70-2.40; (L): HR = 2.73, 95% CI = 1.98-3.76; and (M): HR = 1.96, 95% CI = 1.32-2.91. Conclusions: Our findings suggest that 3-month injurious fall risk varied across OPI-BZD trajectories, highlighting the importance of considering both dose and duration when assessing injurious fall risk of OPI-BZD use among older adults.

Dosing profiles of concurrent opioid and benzodiazepine use associated with overdose risk among US Medicare beneficiaries: group-based multi-trajectory models.

BACKGROUND AND AIMS: One-third of opioid (OPI) overdose deaths involve concurrent benzodiazepine (BZD) use. Little is known about concurrent opioid and benzodiazepine use (OPI-BZD) most associated with overdose risk. We aimed to examine associations between OPI-BZD dose and duration trajectories, and subsequent OPI or BZD overdose in US Medicare. DESIGN: Retrospective cohort study. SETTING: US Medicare. PARTICIPANTS: Using a 5% national Medicare data sample (2013-16) of fee-for-service beneficiaries without cancer initiating OPI prescriptions, we identified 37 879 beneficiaries (age ≥ 65 = 59.3%, female = 71.9%, white = 87.6%, having OPI overdose = 0.3%). MEASUREMENTS: During the 6 months following OPI initiation (i.e. trajectory period), we identified OPI-BZD dose and duration patterns using group-based multi-trajectory models, based on average daily morphine milligram equivalents (MME) for OPIs and diazepam milligram equivalents (DME) for BZDs. To label dose levels in each trajectory, we defined OPI use as very low (< 25 MME), low (25-50 MME), moderate (51-90 MME), high (91-150 MME) and very high (>150 MME) dose. Similarly, we defined BZD use as very low (< 10 DME), low (10-20 DME), moderate (21-40 DME), high (41-60 DME) and very high (> 60 DME) dose. Our primary analysis was to estimate the risk of time to first hospital or emergency department visit for OPI overdose within 6 months following the trajectory period using inverse probability of treatment-weighted Cox proportional hazards models. FINDINGS: We identified nine distinct OPI-BZD trajectories: group A: very low OPI (early discontinuation)-very low declining BZD (n = 10 598; 28.0% of the cohort); B: very low OPI (early discontinuation)-very low stable BZD (n = 4923; 13.0%); C: very low OPI (early discontinuation)-medium BZD (n = 4997; 13.2%); D: low OPI-low BZD (n = 5083; 13.4%); E: low OPI-high BZD (n = 3906; 10.3%); F: medium OPI-low BZD (n = 3948; 10.4%); G: very high OPI-high BZD (n = 1371; 3.6%); H: very high OPI-very high BZD (n = 957; 2.5%); and I: very high OPI-low BZD (n = 2096; 5.5%). Compared with group A, five trajectories (32.3% of the study cohort) were associated with increased 6-month OPI overdose risks: E: low OPI-high BZD [hazard ratio (HR) = 3.27, 95% confidence interval (CI) = 1.61-6.63]; F: medium OPI-low BZD (HR = 4.04, 95% CI = 2.06-7.95); G: very high OPI-high BZD (HR = 6.98, 95% CI = 3.11-15.64); H: very high OPI-very high BZD (HR = 4.41, 95% CI = 1.51-12.85); and I: very high OPI-low BZD (HR = 6.50, 95% CI = 3.15-13.42). CONCLUSIONS: Patterns of concurrent opioid and benzodiazepine use most associated with overdose risk among fee-for-service US Medicare beneficiaries initiating opioid prescriptions include very high-dose opioid use (MME > 150), high-dose benzodiazepine use (DME > 40) or medium-dose opioid with low-dose benzodiazepine use.

Association Between Dual Trajectories of Opioid and Gabapentinoid Use and Healthcare Expenditures Among US Medicare Beneficiaries.

OBJECTIVES: Little is known about relationships between opioid- and gabapentinoid-use patterns and healthcare expenditures that may be affected by pain management and risk of adverse outcomes. This study examined the association between patients' opioid and gabapentinoid prescription filling/refilling trajectories and direct medical expenditures in US Medicare. METHODS: This cross-sectional study included a 5% national sample (2011-2016) of fee-for-service beneficiaries with fibromyalgia, low back pain, neuropathy, or osteoarthritis newly initiating opioids or gabapentinoids. Using group-based multitrajectory modeling, this study identified patients' distinct opioid and gabapentinoid (OPI-GABA) dose and duration patterns, based on standardized daily doses, within a year of initiating opioids and/or gabapentinoids. Concurrent direct medical expenditures within the same year were estimated using inverse probability of treatment weighted multivariable generalized linear regression, adjusting for sociodemographic and health status factors. RESULTS: Among 67 827 eligible beneficiaries (mean age ± SD = 63.6 ± 14.8 years, female = 65.8%, white = 77.1%), 11 distinct trajectories were identified (3 opioid-only, 4 gabapentinoid-only, and 4 concurrent OPI-GABA trajectories). Compared with opioid-only early discontinuers ($13 830, 95% confidence interval = $13 643-14 019), gabapentinoid-only early discontinuers and consistent low-dose and moderate-dose gabapentinoid-only users were associated with 11% to 23% lower health expenditures (adjusted mean expenditure = $10 607-$11 713). Consistent low-dose opioid-only users, consistent high-dose opioid-only users, consistent low-dose OPI-GABA users, consistent low-dose opioid and high-dose gabapentinoid users, and consistent high-dose opioid and moderate-dose gabapentinoid users were associated with 14% to 106% higher healthcare expenditures (adjusted mean expenditure = $15 721-$28 464). CONCLUSIONS: Dose and duration patterns of concurrent OPI-GABA varied substantially among fee-for-service Medicare beneficiaries. Consistent opioid-only users and all concurrent OPI-GABA users were associated with higher healthcare expenditures compared to opioid-only discontinuers.

Dual-trajectories of opioid and gabapentinoid use and risk of subsequent drug overdose among Medicare beneficiaries in the United States: a retrospective cohort study.

BACKGROUND AND AIMS: Little is known about opioid and gabapentinoid (OPI-GABA) use duration and dose patterns' associations with adverse outcome risks. We examined associations between OPI-GABA dose and duration trajectories and subsequent drug overdose. DESIGN: Retrospective cohort study. SETTING: US Medicare. PARTICIPANTS: Using a 5% sample (2011-16), we identified 71 005 fee-for-service Medicare beneficiaries with fibromyalgia, low back pain, neuropathy and/or osteoarthritis initiating OPIs and/or GABAs [mean age ± standard deviation (SD) = 65.5 ± 14.5 years, female = 68.1%, white = 76.8%]. MEASUREMENTS: Group-based multi-trajectory models identified distinct OPI-GABA use patterns during the year of OPI and/or GABA initiation, based on weekly average standardized daily dose (i.e. OPIs = morphine milligram equivalent, GABAs = minimum effective daily dose). We estimated models with three to 12 trajectories and selected the best model based on Bayesian information criterion (BIC) and Nagin's criteria. We estimated risk of time to first drug overdose diagnosis within 12 months following the index year, adjusting for socio-demographic and health factors using inverse probability of treatment weighted multivariable Cox proportional hazards models. FINDINGS: We identified 10 distinct trajectories (BIC = -1 176 954; OPI-only = 3, GABA-only = 3, OPI-GABA = 4). Compared with OPI-only early discontinuers (40.6% of the cohort), 1-year drug overdose risk varied by trajectory group: consistent low-dose OPI-only users [16.6%; hazard ratio (HR) = 1.47, 95% confidence interval (CI) = 1.19-1.82], consistent high-dose OPI-only users (1.8%; HR = 4.57, 95% CI = 2.99-6.98), GABA-only early discontinuers (12.5%; HR = 1.39, 95% CI = 1.09-1.77), consistent low-dose GABA-only users (11.0%; HR = 1.44, 95% CI = 1.12-1.85), consistent high-dose GABA-only users (3.1%; HR = 1.43, 95% CI = 0.94-2.17), early discontinuation of OPIs and consistent low-dose GABA users (6.9%; HR = 1.24, 95% CI = 0.90-1.69), consistent low-dose OPI-GABA users (3.4%; HR = 2.49, 95% CI = 1.76-3.52), consistent low-dose OPI and high-dose GABA users (3.2%; HR = 2.46, 95% CI = 1.71-3.53) and consistent high-dose OPI and moderate-dose GABA users (0.9%; HR = 7.22, 95% CI = 4.46-11.69). CONCLUSIONS: Risk of drug overdose varied substantially among US Medicare beneficiaries on different use trajectories of opioids and gabapentinoids. High-dose opioid-only users and all consistent opioid and gabapentinoid users (regardless of doses) had more than double the risk of subsequent drug overdose compared with opioid-only early discontinuers.

Persistent Urinary Ethyl Sulfate in the Absence of Urinary Ethyl Glucuronide in a Patient with Alcohol Use Disorder Who Claimed Abstinence.

A 48-year-old nurse with an alcohol use disorder history was being monitored in a professional health program. She consistently produced low-to-moderate urinary ethyl sulfate (EtS) concentrations in the absence of detectable urinary ethyl glucuronide (EtG), blood phosphatidylethanol and breath alcohol. She denied intentional ethanol consumption. After prolonged monitoring in a drug treatment program, including a period in a controlled environment, we concluded that this individual's urinary EtS likely resulted from anatomical and microbial factors related to Roux-en-Y gastric bypass surgery, with possible contributions from hidden dietary sources of ethanol. We have no definitive explanation for the lack of urinary EtG.

Predictive Value of Positive Drug Screening Results in an Urban Outpatient Population.

Urine drug testing (UDT) has become an essential component in the management of patients prescribed opioid analgesics for the treatment of chronic non-malignant pain. Several laboratory methods are available to monitor adherence with the pharmacological regimen and abstinence from illicit or unauthorized medications. Immunochemical screening methods are rapid and economical, but they have limitations, including lack of specificity, and confirmatory methods are often necessary to verify presumptive positive results. We analyzed the results of confirmatory assays in an outpatient setting to determine the predictive value of presumptive positive urine drug screen results using an automated immunoassay for eight common drugs or drug classes. Positive predictive values (PPVs), in descending order, were as follows: cannabinoids (100%), cocaine (100%), opiates (86.8%), benzodiazepines (74.6%), oxycodone (67.6%), methadone (44.1%) and amphetamines (9.3%). The number of positive barbiturate results was too small to be included in the statistical analysis.

Acute Pain Medicine in the United States: A Status Report.

BACKGROUND: Consensus indicates that a comprehensive,multimodal, holistic approach is foundational to the practice of acute pain medicine (APM),but lack of uniform, evidence-based clinical pathways leads to undesirable variability throughout U. S. healthcare systems. Acute pain studies are inconsistently synthesized to guide educational programs. Advanced practice techniques involving regional anesthesia assume the presence of a physician-led, multidisciplinary acute pain service,which is often unavailable or inconsistently applied.This heterogeneity of educational and organizational standards may result in unnecessary patient pain and escalation of healthcare costs. METHODS: A multidisciplinary panel was nominated through the APM Shared Interest Group of the American Academy of Pain Medicine. The panel met in Chicago, IL, in July 2014, to identify gaps and set priorities in APM research and education. RESULTS: The panel identified three areas of critical need: 1) an open-source acute pain data registry and clinical support tool to inform clinical decision making and resource allocation and to enhance research efforts; 2) a strong professional APM identity as an accredited subspecialty; and 3) educational goals targeted toward third-party payers,hospital administrators, and other key stake holders to convey the importance of APM. CONCLUSION: This report is the first step in a 3-year initiative aimed at creating conditions and incentives for the optimal provision of APM services to facilitate and enhance the quality of patient recovery after surgery, illness, or trauma. The ultimate goal is to reduce the conversion of acute pain to the debilitating disease of chronic pain.

Sensitivity of an opiate immunoassay for detecting hydrocodone and hydromorphone in urine from a clinical population: analysis of subthreshold results.

Urine drug testing (UDT) is an emerging standard of care in the evaluation and treatment of chronic non-cancer pain patients with opioid analgesics. UDT may be used both to verify adherence with the opioid analgesic regimen and to monitor abstinence from non-prescribed or illicit controlled substances. In the former scenario, it is vital to determine whether the drug is present in the urine, even at low concentrations, because failure to detect the drug may lead to accusations of opioid abuse or diversion. Opiate immunoassays typically are developed to detect morphine and are most sensitive to morphine and codeine. Although many opiate immunoassays also detect hydrocodone (HC) and/or hydromorphone (HM), sensitivities for these analytes are often much lower, increasing the possibility of negative screening results when the drug is present in the urine. We selected 112 urine specimens from patients who had been prescribed HC or hydromorphone but were presumptive negative by the Roche Online DAT Opiate II™ urine drug screening assay, which is calibrated to 300 ng/mL morphine. Using a GC/MS confirmatory method with a detection limit of 50 ng/mL both for HC and for HM, one or both of these opiates were detected in 81 (72.3%) of the urine specimens. Examination of the raw data from these presumptive negative opiate screens revealed that, in many cases, the turbidity signal was greater than the signal obtained for the negative control, but less than the signal for the 300 ng/mL (morphine) threshold calibrator. A receiver operating characteristic curve generated for the reciprocal of the ratio of turbidity measurements in the patient specimens and negative (drug-free) controls, against the presence or absence of HC and/or HM by confirmatory analyses, produced an area under the curve of 0.910. We conclude that this opiate immunoassay has sufficient sensitivity to detect HC and/or HM in some urine specimens that screen presumptive negative for these commonly prescribed opiates at the established threshold.

Psychoactive "bath salts" intoxication with methylenedioxypyrovalerone.

Abuse of the psychoactive "designer drug" methylenedioxypyrovalerone (MDPV) has become a serious international public health concern because of the severity of its physical and behavioral toxicities. MDPV is the primary ingredient in so-called "bath salts," labeled as such to avoid criminal prosecution and has only been classified recently as a controlled substance in the United States and some other countries. However, it remains a danger because of illegal sources, including the Internet. MDPV is a synthetic, cathinone-derivative, central nervous system stimulant and is taken to produce a cocaine- or methamphetamine-like high. Administered via oral ingestion, nasal insufflation, smoking, intravenous or intramuscular methods, or the rectum, the intoxication lasts 6 to 8 hours and has high addictive potential. Overdoses are characterized by profound toxicities, causing increased attention by emergency department and law enforcement personnel. Physical manifestations range from tachycardia, hypertension, arrhythmias, hyperthermia, sweating, rhabdomyolysis, and seizures to those as severe as stroke, cerebral edema, cardiorespiratory collapse, myocardial infarction, and death. Behavioral effects include panic attacks, anxiety, agitation, severe paranoia, hallucinations, psychosis, suicidal ideation, self-mutilation, and behavior that is aggressive, violent, and self-destructive. Treatment is principally supportive and focuses on counteracting the sympathetic overstimulation, including sedation with intravenous benzodiazepines, seizure-prevention measures, intravenous fluids, close (eg, intensive care unit) monitoring, and restraints to prevent harm to self or others. Clinical presentation is often complicated by coingestion of other psychoactive substances that may alter the treatment approach. Clinicians need to be especially vigilant in that MDPV is not detected by routine drug screens and overdoses can be life-threatening.

Medical cannabis and chronic opioid therapy.

Fourteen states and the District of Columbia have legalized the use of cannabis for medical purposes. A small, high-quality literature supports the efficacy of medical cannabis for the treatment of neuropathic pain. The smoked botanical product, however, is associated with a number of adverse medical and psychiatric consequences. Furthermore, experimental data indicate that acute use of cannabis results in impairment of every important metric related to the safe operation of a motor vehicle. Epidemiological data show associations between recent cannabis use and both psychomotor impairment and motor vehicle crashes, associations that are strengthened by the concomitant use of alcohol and other central nervous system depressants. Finally, data from pain clinics reveals an unusually high prevalence of cannabis use in nearly all age groups and an association between cannabis use and opioid and other substance misuse. Based on available data and expert opinion, concomitant use of cannabis and opioids is an absolute contraindication to the operation of a motor vehicle. In patients who use cannabis and are prescribed opioids, heightened vigilance for opioid- and other substance-related problems is warranted. It is appropriate to refrain from prescribing opioids to individuals using medical cannabis if there is reasonable suspicion that the combination will pose a risk to the patient or others.

Urine drug test interpretation: what do physicians know?

OBJECTIVE: To determine the level of urine drug test (UDT) interpretive knowledge of physicians who use these instruments to monitor adherence in their patients on chronic opioid therapy. METHODS: A seven-question instrument consisting of six five-option, single-best-answer multiple choice questions and one yes/no question was completed by 114 physicians (77 who employ UDT and 37 who do not) attending one of three regional opioid education conferences. We calculated frequencies and performed chi2 analyses to examine bivariate associations between UDT utilization and interpretive knowledge. RESULTS: The instrument was completed by 80 percent of eligible respondents. None of the physicians who employ UDT answered all seven questions correctly, and only 30 percent answered more than half correctly. Physicians who employ UDT performed no better on any of the questions than physicians who do not employ UDT. CONCLUSIONS: Physicians who employ UDT to monitor patients receiving chronic opioid therapy are not proficient in test interpretation. This study highlights the need for improved physician education; it is imperative for physicians to work closely with certified laboratory professionals when ordering and interpreting these tests.

Rational use of sublingual opioids in palliative medicine.

The sublingual administration of opioid analgesics has been a mainstay in the pain management of homebound dying hospice patients who are no longer able to swallow. It is also a potentially useful route of administration in other situations in which the oral route is not available and other routes are impractical or inappropriate. Potential advantages of the sublingual route include rapid analgesic onset and avoidance of hepatic first-pass metabolism. Pharmacokinetic and pharmacodynamic studies have yielded widely disparate data on sublingual morphine. Other opioids have been less studied. Available data suggests limited sublingual availability of hydrophilic opioids (e.g., morphine, oxycodone, and hydromorphone) and superior absorption of the lipophilic opioids (e.g., methadone and the fentanils). Buprenorphine, a potent, lipophilic, partial mu-opioid receptor agonist, appears promising but awaits further study.