Polydrug use among patients on methadone medication treatment: Evidence from urine drug testing to inform patient safety.

AIMS: Patients in methadone medication treatment for opioid use disorder (M-MOUD) typically have a complex history of opioid use, often in combination with other drugs. It is unknown how frequently M-MOUD patients experience persistent substance or polysubstance use. We measured trends in illicit substance use in a large, multistate population of M-MOUD patients and persistence of substance use in the first year of treatment. DESIGN: Retrospective cohort study of United States (US) M-MOUD patients from 2017 to 2021, focused on urine drug specimens provided for testing to Millennium Health, a third-party laboratory. Specimens were analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Generalized estimating equations (GEE) were used to estimate the average trends in positivity during time in treatment. SETTING: Specimens were obtained from clinics in 10 US states that provided at least 300 unique patients during the study period (Alaska, Arizona, Florida, Illinois, Kentucky, Minnesota, New Mexico, Ohio, Virginia and Washington). PARTICIPANTS: Patients with opioid use disorder receiving M-MOUD (n = 16 386). MEASUREMENTS: Positivity rates for heroin, fentanyl, methamphetamine and cocaine. FINDINGS: From 2017 to 2021, yearly crude positivity rates for first collected specimens increased for fentanyl (13.1%-53.0%, P < 0.001), methamphetamine (10.6%-27.2%, P < 0.001) and cocaine (13.8%-19.5%, P < 0.001); for heroin positivity did not significantly change (6.9%-6.5%, P = 0.74). In regression models estimating patient trajectories from week 1 to week 52, marginal fentanyl positivity declined from 21.8% to 17.1% (incidence rate ratio [IRR] = 0.78, P < 0.001) and heroin positivity declined from 8.4% to 4.3% (IRR = 0.51, P < 0.001), but positivity for methamphetamine and cocaine did not significantly change, remaining at an average of 17.7% (IRR = 0.98, P = 0.53) and 9.2% (IRR = 0.96, P = 0.36), respectively. CONCLUSIONS: Between 2017 and 2021, United States patients presenting to opioid treatment programs increasingly tested positive for fentanyl, methamphetamine and cocaine. Methadone medication treatment for opioid use disorder appears to remain an effective intervention for reducing illicit opioid use.

Association of Patients' Direct Addition of Buprenorphine to Urine Drug Test Specimens With Clinical Factors in Opioid Use Disorder.

Importance: The direct addition of buprenorphine to urine drug test specimens to mimic results suggestive of adherence is a clinically significant result, yet little is known about the phenomenon. Objective: To characterize factors associated with the direct addition of buprenorphine to urine specimens among patients prescribed buprenorphine for opioid use disorder. Design, Setting, and Participants: This cross-sectional study of urine drug test specimens was conducted from January 1, 2017, to April 30, 2022, using a national database of urine drug test specimens ordered by clinicians from primary care, behavioral health, and substance use disorder treatment clinics. Urine specimens with quantitative norbuprenorphine and buprenorphine concentrations from patients with opioid use disorder currently prescribed buprenorphine were analyzed. Exposures: Nonprescribed opioid or stimulant co-positive, clinical setting, collection year, census division, patient age, patient sex, and payor. Main Outcomes and Measures: Norbuprenorphine to buprenorphine ratio less than 0.02 identified direct addition of buprenorphine. Unadjusted trends in co-positivity for stimulants and opioids were compared between specimens consistent with the direct addition of buprenorphine. Factors associated with the direct addition of buprenorphine were examined with generalized estimating equations. Results: This study included 507 735 urine specimens from 58 476 patients. Of all specimens, 261 210 (51.4%) were obtained from male individuals, and 137 254 (37.7%) were from patients aged 25 to 34 years. Overall, 9546 (1.9%) specimens from 4550 (7.6%) patients were suggestive of the direct addition of buprenorphine. The annual prevalence decreased from 2.4% in 2017 to 1.2% in 2020. Opioid-positive with (adjusted odds ratio [aOR], 2.01; 95% CI, 1.85-2.18) and without (aOR, 2.02; 95% CI, 1.81-2.26) stimulant-positive specimens were associated with the direct addition of buprenorphine to specimens, while opioid-negative/stimulant-positive specimens were negatively associated (aOR, 0.78; 95% CI, 0.71-0.85). Specimens from patients aged 35 to 44 years (aOR, 1.59; 95% CI, 1.34-1.90) and primary care (aOR, 1.60; 95% CI, 1.44-1.79) were associated with the direct addition of buprenorphine. Differences by treatment setting decreased over time. Specimens from the South Atlantic census region had the highest association (aOR, 1.4; 95% CI, 1.25-1.56) and New England had the lowest association (aOR, 0.54; 95% CI, 0.46-0.65) with the direct addition of buprenorphine. Conclusions and Relevance: In this cross-sectional study, the direct addition of buprenorphine to urine specimens was associated with other opioid positivity and being collected in primary care settings. The direct addition of buprenorphine to urine specimens is a clinically significant finding, and best practices specific for this phenomenon are needed.

Preliminary validation of the Diversion Risk Scale (DRS): Using environmental and individual factors to predict opioid-related diversion events.

The standard of care calls for the assessment of patients with chronic pain prior to the initiation of opioids, with one part of this assessment including assessment of the risk of misuse of medications. However, traditional opioid risk assessment tools focus almost entirely on individual factors and on the risk of misuse and addiction to opioids. Diversion of opioid medications has been found to be not uncommon, but to date, there have been no assessment tools specifically designed to assess the risk of diversion. In this study, we developed a measure designed specifically to assess the risk of an opioid medication ending up in the hands of someone other than the chronic pain patient to whom they were prescribed. A 15-item measure, the Diversion Risk Scale, was created and administered to 85 patients at a chronic pain practice. Results found that the measure had acceptable predictive validity. It was moderately correlated with traditional opioid risk assessment tools and showed improved ability to predict specific indicators of diversion. Diversion has been an understudied phenomenon, and the clinical value of an assessment tool that can help predict diversion in the chronic pain population is discussed.

Definitive urine drug test findings in patients prescribed opioids for pain from a large national database.

OBJECTIVE: Clinicians and policymakers have been wrestling with the appropriateness and safety of opioid therapy during the opioid crisis. Policy and clinical decisions have often been made without much current data on trends in drug use in patients with pain. Thus, we evaluated definitive urine drug test (UDT) results in patients being treated for pain to see if those taking their prescribed opioids were less likely to be positive for the primary illicit drugs currently driving overdose deaths: cocaine, heroin, fentanyl, and methamphetamine. DESIGN, SETTING, AND PATIENTS: A cross-sectional study of UDT results from January 1, 2015 to September 30, 2021, from 600,000 patient specimens submitted for testing by pain management specialists. INTERVENTIONS: UDT by liquid chromatography-tandem mass spectrometry as ordered by the treating clinician. MAIN OUTCOME MEASURES: Presence of other substances stratified by whether a patient's prescribed opioid was found. RESULTS: The presence of cocaine, heroin, fentanyl, and methamphetamine for the total population was low (<5 percent). Of the 347,092 patients prescribed opioids, 76 percent (n = 264,961) were positive on UDT for their prescribed opioid ("consistent"). Compared to patients without their prescribed opioid present ("inconsistent"), patients consistent with therapy were 54 percent (incidence rate ratio (IRR) 1.54, 95 percent confidence interval (CI) 1.47-1.59) less likely to be positive for cocaine, 47 percent [IRR 1.47, 95 percent CI 1.34-1.57] less likely to be positive for heroin, and 35 percent [IRR 1.35, 95 percent CI 1.24-1.45] less likely to be positive for methamphetamine, p < 0.001. Differences between the groups for fentanyl were not significant. CONCLUSIONS: Overall positivity rates for cocaine, heroin, fentanyl, and methamphetamine were low. Patients with prescribed opioid present were less likely to be positive for cocaine, heroin, or methamphetamine. Patterns of substance use within this pain management population should be used to inform ongoing policy decisions.

Analysis of Urine Drug Test Results From Substance Use Disorder Treatment Practices and Overdose Mortality Rates, 2013-2020.

Importance: Drug overdose deaths in the US are currently the highest ever recorded; data collected from public health surveillance sources can help to identify emerging drug use patterns associated with overdose mortality rates, but the time lag in results often limits utility. Urine drug testing (UDT) is one potentially underused source that could augment surveillance efforts through timely data collection. Objective: To evaluate the correlation between real-time UDT results from a proprietary national database and overdose mortality data from the National Vital Statistics System. Design, Setting, and Participants: This retrospective cross-sectional study included 500 000 urine specimens submitted for UDT by substance use disorder (SUD) treatment health care practices and collected between January 1, 2013, and December 31, 2020. Real-time UDT data were obtained from the Millennium Health proprietary national database, and overdose mortality data were obtained from the National Vital Statistics System of the Centers for Disease Control and Prevention (CDC WONDER). Specimens were analyzed for specific drugs in 5 categories (cocaine, heroin, methamphetamine, synthetic opioids, and other opioids) using liquid chromatography-tandem mass spectrometry. Participants were adults aged 18 years and older who provided urine specimens at SUD treatment practices. Exposures: Urine drug testing. Main Outcomes and Measures: The primary outcome was the correlation between UDT positivity rates and overdose mortality rates at national, state, and county levels. Univariate and multivariate regression models were also used to evaluate the association between state- and county-level overdose mortality and standardized UDT positivity rates. Results: Among 500 000 unique patient specimens collected from SUD treatment practices between 2013 and 2020, 288 534 specimens (57.7%) were from men, and the median age of the study population was 34 years (IQR, 17-51 years). On a national level, synthetic opioids and methamphetamine were highly correlated with overdose mortality (Spearman ρ = 0.96 for both). When synthetic opioids were coinvolved, methamphetamine (ρ = 0.98), heroin (ρ = 0.78), cocaine (ρ = 0.94), and other opioids (ρ = 0.83) were also highly correlated with overdose mortality. In the absence of synthetic opioids, all drug categories were highly correlated (ρ = 0.75 for other opioids, 0.81 for heroin, and 0.88 for methamphetamine), with the exception of cocaine (ρ = -0.37). Synthetic opioids (ρ = 0.77) and methamphetamine (ρ = 0.80) had the strongest state-level correlations over time, whereas other opioids had the lowest correlation for both total positivity (ρ = 0.31) and positivity in the absence of synthetic opioids (ρ = 0.23). In Ohio, county-level correlation was strongest for synthetic opioids (ρ = 0.71), followed by heroin (ρ = 0.69) and methamphetamine (ρ = 0.67). At the state level, the multivariate incidence rate ratio (IRR) for synthetic opioids was 1.16 (95% CI, 1.14-1.19; P < .001), and at the county level, the IRR was 1.13 (95% CI, 1.09-1.17; P < .001), suggesting that for every 1-SD increase in the UDT positivity rate, there were 16.2% and 12.8% increases, respectively, in monthly overdose deaths. Both methamphetamine (11.7% increase per 1-SD increase in UDT positivity rate; IRR, 1.12; 95% CI, 1.09-1.14; P < .001) and cocaine (5.1% increase per 1-SD increase in UDT positivity rate; IRR, 1.05; 95% CI, 1.03-1.07; P < .001) also had significant positive associations with mortality rates, but the effect sizes were smaller than that of synthetic opioids (IRR, 1.16). Conclusions and Relevance: In this study, UDT results were highly correlated with mortality rates at national, state, and county levels. These findings suggest that real-time UDT surveillance can help to quickly identify changes in drug use patterns that might inform targeted harm reduction strategies designed to prevent overdose deaths.

A US Retrospective Claims Analysis Comparing Healthcare Costs of Patients Transitioning from Immediate-Release Oxycodone to Two Different Formulations of Extended-Release Oxycodone: Xtampza ER or OxyContin.

Purpose: Opioid therapy for managing chronic pain remains a challenge, as providers must weigh the medical benefit to the patient with the risk of adverse events. Manipulation of many extended-release (ER) opioid formulations may lead to increased serious medical outcomes or death. The economic burden of opioid use disorders due to opioid misuse and abuse may vary depending on which abuse deterrent opioid formulation is prescribed. The study aimed to compare demographic and clinical characteristics and healthcare costs of chronic pain patients treated with two different abuse-deterrent opioid formulations, Xtampza ER and reformulated OxyContin. Methods: The source of data was IBM® MarketScan® Commercial Claims and Encounters Medicare Supplemental database, from January 2016 through February 2020. Patients with chronic pain were assigned to either the Xtampza ER or the OxyContin cohort based on the initial ER opioid prescription set as the index date. Continuous healthcare coverage was required during a minimum 3-month pre-index and 9-month post-index periods. Pre-index patients' characteristics were analyzed. Healthcare costs of Xtampza ER vs OxyContin were assessed in the post-index period. Results: After applying selection criteria, 464 patients were observed in the Xtampza ER cohort versus 1927 patients in the OxyContin cohort. In unmatched patients, ER opioid costs were lower for Xtampza ER than OxyContin ($2645 vs $3141; p<0.001), which ultimately led to lower total prescription costs for the Xtampza ER cohort compared to the OxyContin cohort ($7492 vs $8754; p=0.016). In matched patients, the total healthcare costs were significantly lower in the Xtampza ER cohort than in the OxyContin cohort, $22,630 vs $28,386 (p=0.005), respectively. Conclusion: This study suggests that Xtampza ER may result in lower healthcare costs than OxyContin for a population of chronic pain patients switching from immediate release oxycodone based on real-world data.

Tapentadol is the least common opioid found in admission urine drug-test results at an intensive outpatient opioid-use disorder treat-ment program in Ohio: A brief report.

BACKGROUND: Previous data suggest that tapentadol, an atypical opioid with a putative dual mechanism of action, has relatively low rates of abuse. A better understanding of the rates of abuse among different prescription opioids may help clinicians when considering their potential risks and benefits. The results of urine drug tests (UDTs) may provide a unique opportunity to help answer this question. METHOD: To investigate different rates of prescription-opioid abuse in this retrospective study, we examined urine drug test results from patients seeking treatment at four facilities of an opioid-use-disorder (OUD) treatment program in Ohio. Urine specimens were collected on admission, one from each patient, in the regular course of care. The opioids reviewed in the present study were tapentadol, hydrocodone, oxycodone, hydromorphone, oxymorphone, and tramadol. Drug dispensing data, including morphine-milligram equivalents (MME) dispensed, were examined to adjust for the relative prevalence of each opioid being examined. RESULTS: Data from 4,162 patients were examined. Tapentadol was the least common finding in UDT results in this cohort and remained so after adjusting for drug availability. The percentage of specimens positive for a given opioid ranged from 0.12 percent (tapentadol) to 7.04 percent (oxycodone). The availability and MME adjustments resulted in a change of rank order, with tapentadol remaining the lowest but tramadol replacing oxycodone as the prescription opioid with the highest rate of abuse. CONCLUSIONS: In this sample of UDT results from patients seeking treatment at an OUD program in Ohio, tapentadol was the least frequent finding among the opioids examined, and this remained true when adjusting for dispensing data. Factors potentially contributing to this difference may include pharmacological properties unique to tapentadol. Several important limitations notwithstanding, these findings are consistent with previous real-world evidence and warrant an ongoing line of inquiry.

Prospective evaluation of functional brain activity and oxidative damage in breast cancer: changes in task-induced deactivation during a working memory task.

Cancer-related cognitive dysfunction is an important issue for breast cancer survivors. Previous research has identified both cross-sectional and longitudinal alterations in brain function related to cancer status and treatment. In this study, we prospectively collected functional magnetic resonance imaging data in breast cancer cases treated with adjuvant chemotherapy and in controls with no cancer history during a working memory task. Data and blood specimens were collected immediately prior to the start of treatment (baseline) and following completion of treatment (follow-up), and at yoked intervals for controls. In secondary analysis we assessed the levels of oxidative DNA damage in peripheral blood lymphocytes of cases and controls using the Comet assay. A significant group*time interaction revealed reduced deactivation in the superior frontal gyrus in the controls at follow-up, in contrast to cases, who exhibited similar magnitude of deactivation at baseline and follow-up. Working memory performance indicated a significant improvement in the controls at follow-up, and no change in performance in cases. In secondary analyses, oxidative DNA damage levels were elevated in the cases at follow-up compared to controls, but no associations were found between the Comet assay variables and functional imaging at either time-point or group. In light of previous reports on task induced deactivations, our findings reflect continuing effortful processing at follow-up in the breast cancer group, with relatively less effortful processing in the control group given the reduced novelty and practice effects from the baseline to follow-up.

Concomitant use of benzodiazepines in chronic pain patients adherent to extended-release tapentadol or oxycodone treatment-A retrospective claims analysis.

OBJECTIVE: To compare concomitant benzodiazepine (BZDs) use among chronic pain patients adherent to extended-release tapentadol (TapER) or oxycodone (OxnER) and estimate the number of lives potentially saved by switching pa-tients to the less BZD coprescribed treatment. DESIGN: Retrospective database study. SETTING: Patients were identified using the IBM MarketScan® Commercial Database. The opioid overdose death esti-mates were obtained from the US national mortality register and were used to estimate the number of lives potentially saved by switching patients to the opioid treatment with lower rates of BZD coprescribing. PATIENTS, PARTICIPANTS: The authors identified 30,213 chronic pain patients between October 2012 and March 2016. Af-ter propensity score matching, N = 2,355 and N = 6,761 patients were adherent (proportion of days covered ≥80 percent) to TapER and OxnER, respectively. INTERVENTIONS: TapER versus OxnER, during the 180-day treatment. MAIN OUTCOME MEASURE(S): Proportions of BZD coprescribing, BZD dosing patterns in matched patients, and the esti-mated number of lives potentially saved by the opioid treatment switch. RESULTS: TapER patients were less coprescribed BZDs during the treatment period (38.9 percent versus 49.2 percent, OR = 0.659, p < 0.001), and had fewer days of BZD supply per patient (mean: 49.6 versus 70.2 days, p < 0.001) with similar BZD average daily dose. Due to less frequent coprescribing of BZDs with TapER, it is estimated that ~800 deaths may have been avoided in the U.S. as a result of switching patients from OxnER to TapER. CONCLUSIONS: Among treatment-adherent patients, TapER patients had fewer BZD coprescriptions than OxnER pa-tients had. Moreover, when BZDs were coprescribed, those BZD prescriptions were for shorter periods of time. Pro-spective studies are warranted to explore rates and consequences of BZD coprescribing among opioids.

Does the perceived accuracy of urine drug testing impact clinical decision-making?

Background: Urine drug testing techniques have different rates of false-positive and false-negative test results. However, clinicians may have highly varying perceptions of test accuracy and may compensate for perceived inaccuracy by incorporating other factors into their interpretation of observed test results. Thus, there is the potential for adverse consequences from decisions based on inaccurate test results or interpretation. Methods: We surveyed 466 members of the American Society of Addiction Medicine to examine clinicians' perceptions of the accuracy of 2 types of urine drug tests, immunoassay (IA) and liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the extent to which behavioral and demographic factors influence the interpretation of test results. Participants read 4 brief vignettes describing positive and negative test results in hypothetical patients who differed along several dimensions (gender, age, race/ethnicity, comorbid mental disorder, court-ordered versus voluntary status, treatment compliance). Outcome variables include likelihood of renewed drug use, likelihood of test error, whether to request additional testing, and whether to report the violation to a probation officer. Results: The strongest predictor of study outcomes was treatment compliance (consistent versus inconsistent attendance), as this was the only independent variable to generate effect sizes of medium strength. Significant effect sizes were also found for type of test used (IA versus LC-MS/MS), legal status (court-mandated versus voluntary), presence of a comorbid mental disorder, treatment history, and race, although effect sizes for these variables were small and less consistently observed. Conclusions: These results highlight the potential for error in clinician judgments about urine drug testing. Not only were participants likely to underestimate the accuracy of "confirmatory" LC-MS/MS testing, but vignettes suggested that a number of historical and demographic factors may influence interpretation of test results.

Using opioid therapy for pain in clinically challenging situations: questions for clinicians.

Healthcare professionals and organizations increasingly face the conundrum of treating patients with active substance use disorder, a history of personal or familial substance use disorder, or those at elevated risk for substance abuse. Such patients need compassionate care when facing painful conditions; in fact, denying them pain control makes it likely that they will seek out ways to self-medicate with illicit drugs. Yet it remains unclear how to safely and effectively treat patients in these challenging situations. The authors have formulated ten questions to address in order to provide adequate analgesia for such patients. These questions demand a highly individualized approach to analgesia. These ten questions involve understanding the painful condition (presumed trajectory, duration, type of pain), using validated metrics such as risk assessment tools, guidelines, protocols, and safeguards within the system, selection of the optimal analgesic product(s) or combination therapy, and never starting opioid therapy without clear treatment objectives and a definitive exit plan. It is tempting but inaccurate to label these individuals as "inappropriate patients," rather they are high-risk individuals in very challenging clinical situations. The challenge is that both options - being in pain or being treated with opioids to control pain - expose the patient to a risk of rekindling an addiction. The question is how do we, as clinicians, adequately respond to these very perplexing clinical challenges?

Episodic memory for visual scenes suggests compensatory brain activity in breast cancer patients: a prospective longitudinal fMRI study.

It has been hypothesized that breast cancer and its chemotherapy can impart functional neural changes via an overlap with biological mechanisms associated with aging. Here we used fMRI to assess whether changes in neural activity accompanying visual episodic memory encoding and retrieval suggest altered activations according to patterns seen in functional imaging of cognitive aging. In a prospective longitudinal design, breast cancer patients (n = 13) were scanned during memory encoding and retrieval before and after chemotherapy treatment, and compared to healthy-age matched controls (n = 13). Our results indicate that despite equivalent behavioral performance, encoding and retrieval resulted in increased activation of prefrontal regions for the breast cancer group compared to controls for both before and after chemotherapy treatment. This was accompanied by decreased activity in posterior brain regions after chemotherapy, particularly those involved in visual processing, for the breast cancer group compared to controls. These findings are discussed as evidence for a possible anterior shift in neural processing to compensate for deficiencies in posterior brain regions, consistent with an accelerated aging account. Cancer and chemotherapy can impact brain regions underlying episodic memory, leading to additional recruitment of control regions, which may be linked to mechanisms related to aging.

Impact of opioid dose reduction on individuals with chronic pain: results of an online survey.

BACKGROUND: In 2016, the Centers for Disease Control and Prevention (CDC) released a guideline on opioid prescribing for primary care physicians. Patients with chronic pain receiving long-term opioid therapy were surveyed to assess the incidence and impact of opioid dose reduction following this guideline's promulgation. METHODS: Members of an advocacy organization for people with chronic pain were invited to participate in a 16-item, anonymous, online survey conducted in September/October 2017. Eligibility requirements included current treatment of ≥7 months' duration for chronic pain with the same extended-release (ER)/long-acting (LA) opioid. The final sample consisted of respondents who reported being on the same ER/LA opioid for ≥1 year and excluded respondents whose 1) ER/LA opioid dose increased; 2) ER/LA opioid dose decreased and immediate-release (IR) opioid dose increased; and 3) ER/LA opioid dose was unchanged and IR opioid dose was changed. Survey results were analyzed using z-test to ascertain differences between proportion of responses for ER/LA opioid dose decreased vs dose unchanged groups. RESULTS: Of the 511 eligible respondents, 362 respondents were included in the final sample. In the final sample, the subgroup with decreased ER/LA opioid dose (n=149) was significantly more likely (P≤ 0.05) than those who reported no dose change (n=213) to rate their condition as "worse" for level of pain (73.2 vs 33.3%), level of function (67.8 vs 31.5%), mental health (64.4 vs 32.9%), ability to work (62.9% of 97 respondents vs 33.8% of 145 respondents), and interpersonal relationships (48.3 vs 25.8%) during the previous 6 months. CONCLUSION: In this Internet-based survey of people with chronic pain, reduction of ER/LA opioid dose was associated with reduced pain control and diminished function. These results indicate a need for further guidance on how to apply the CDC guideline to patients with chronic pain who are stable on long-term opioid therapy.

Evaluation of the oral human abuse potential of Oxycodone DETERx® formulation (Xtampza® ER).

OBJECTIVE: To further characterize the human abuse potential and pharmacokinetics (PK) of Oxycodone DETERx (Xtampza® ER) after intact and chewed oral administration. DESIGN: Randomized, double-blind, triple-dummy, active- and placebo-controlled, single-dose, six-period, crossover comparison study. SETTING: Clinical research unit. SUBJECTS: Adult, nondependent recreational opioid users who liked the effects of crushed immediate-release (IR) oxycodone in solution and were able to differentiate the effects from placebo solution. INTERVENTIONS: Oral administration of intact Oxycodone DETERx (fasted and fed), chewed Oxycodone DETERx (fasted and fed), crushed IR oxycodone (fasted), and placebo (fed). MAIN OUTCOME MEASURES: Subject ratings (100-point visual analog scales) of Drug Liking (primary measure) and Take Drug Again (key secondary measure). RESULTS: The pharmacodynamic (PD) analysis included 52 subjects who completed the study; the PK analysis included 71 subjects. Compared with crushed IR oxycodone fasted, the least-squares mean maximum effect (Emax) was statistically significant (p < 0.01) for Drug Liking and Take Drug Again, respectively, for chewed Oxycodone DETERx fasted (LS mean difference ± standard error of the mean: 13.1 ± 2.2 and 10.0 ± 3.2 points) and fed (10.9 ± 2.2 and 9.7 ± 3.3 points) and intact Oxycodone DETERx fasted (12.2 ± 2.2 and 9.3 ± 3.3 points) and fed (10.3 ± 2.2 and 9.2 ± 3.3 points). Results were consistent for other PD measures (Good Effects, Feeling High). Chewed Oxycodone DETERx fasted and fed treatments were bioequivalent to the respective intact treatments based on PK parameters. CONCLUSIONS: This study showed that when chewed or swallowed intact, under fasted or fed conditions, Oxycodone DETERx had statistically significantly lower abuse potential via the oral route compared with IR oxycodone.

Analgesic efficacy, safety, and tolerability of a long-acting abuse-deterrent formulation of oxycodone for moderate-to-severe chronic low back pain in subjects successfully switched from immediate-release oxycodone.

OBJECTIVES: This post hoc analysis of data from a randomized, double-blind, placebo-controlled, enriched-enrollment randomized-withdrawal Phase III study evaluated the safety, tolerability, and analgesic efficacy of Oxycodone DETERx extended-release (ER), abuse-deterrent capsules (Xtampza® ER) in subjects with chronic low back pain who were successfully transitioned from immediate-release (IR) oxycodone. METHODS: Continuous outcomes were analyzed using a mixed-model repeated-measures approach; binomial outcomes were analyzed using chi-squared; and time-to-event outcomes using Kaplan-Meier analyses. RESULTS: A total of 110 subjects previously prescribed IR oxycodone entered the Open-label Titration Phase. Forty-four subjects were randomized to Oxycodone DETERx (n=22) or placebo (n=22) in the 12-week Double-blind Maintenance Phase. Efficacy results in this subgroup showed a statistically significant difference between Oxycodone DETERx and placebo in average pain intensity scores from Randomization Baseline to Week 12 (least squares mean [± standard error], -1.88 [0.70]; P=0.0078). Additional efficacy results indicated that Oxycodone DETERx vs placebo was associated with a statistically significant benefit in durability of effect from Week 2 through Week 12 (P<0.01), numbers of subjects with a ≥30% (n [%] 10 [45.5%] vs 0 [0%]; P=0.0004) and ≥50% (10 [45.5%] vs 0 [0%]; P=0.0004) improvement in pain intensity, longer time-to-exit (P=0.0014), a greater number of subjects who completed the study (14 [63.6%] vs 4 [18.2%]), and less rescue medication use (acetaminophen; mean [SD], 163.5 [337.8] mg) vs 216.2 [377.3] mg). Adverse event profiles were consistent with opioid class effects and results from the original study; Oxycodone DETERx was well tolerated in subjects previously treated with short-acting oxycodone. CONCLUSIONS: Oxycodone DETERx resulted in clinically meaningful and statistically significant efficacy in subjects with chronic low back pain who were previously prescribed IR oxycodone and were successfully switched to ER Oxycodone DETERx.

Converting from Transdermal to Buccal Formulations of Buprenorphine: A Pharmacokinetic Meta-Model Simulation in Healthy Volunteers.

Objective: To develop a model to predict buprenorphine plasma concentrations during transition from transdermal to buccal administration. Design: Population pharmacokinetic model-based meta-analysis of published data. Methods: A model-based meta-analysis of available buprenorphine pharmacokinetic data in healthy adults, extracted as aggregate (mean) data from published literature, was performed to explore potential conversion from transdermal to buccal buprenorphine. The time course of mean buprenorphine plasma concentrations following application of transdermal patch or buccal film was digitized from available literature, and a meta-model was developed using specific pharmacokinetic parameters (e.g., absorption rate, apparent clearance, and volumes of distribution) derived from analysis of pharmacokinetic data for intravenously, transdermally, and buccally administered buprenorphine. Results: Data from six studies were included in this analysis. The final transdermal absorption model employed a zero-order input rate that was scaled to reflect a nominal patch delivery rate and time after patch application (with decline in rate over time). The transdermal absorption rate constant became zero following patch removal. Buccal absorption was a first-order process with a time lag and bioavailability term. Simulations of conversion from transdermal 20 mcg/h and 10 mcg/h to buccal administration suggest that transition can be made rapidly (beginning 12 hours after patch removal) using the recommended buccal formulation titration increments (75-150 mcg) and schedule (every four days) described in the product labeling. Conclusions: Computer modeling and simulations using a meta-model built from data extracted from publications suggest that rapid and straightforward conversion from transdermal to buccal buprenorphine is feasible.

Sleep problems in breast cancer survivors 1-10 years posttreatment.

ABSTRACTObjective:Sleep can affect quality of life (QoL) during cancer survivorship, and symptoms related to poor sleep can be exacerbated. We examined the prevalence, severity, and nature of subjective sleep complaints in women surviving stage I-III breast cancer who were 1-10 years posttreatment. We also examined the demographic, medical, physical, and psychosocial correlates of poor sleep in these women in order to identify the subgroups that may be most in need of intervention. METHOD: A total of 200 patients at a comprehensive cancer center who were 1-10 years posttreatment for primary stage I-III breast cancer with no evidence of disease at the time of enrollment completed a battery of questionnaires on demographics, sleep, physical symptoms, mood, cancer-specific fears, and QoL. RESULTS: The women had a mean age of 57 years (SD = 10.0), with a mean of 63.3 months (SD = 28.8) of post-cancer treatment. Some 38% of these patients were identified as having poor-quality sleep. Women with poor sleep took longer to fall asleep, had more awakenings, and acquired 2 hours less sleep per night than those with good sleep. They also had a lower QoL, greater severity of pain, more concerns about health and recurrence, and increased vasomotor symptoms (p < 0.05). Daytime sleepiness and depression were found to be not significantly correlated with sleep quality. SIGNIFICANCE OF RESULTS: Many breast cancer survivors had severe subjective insomnia, and several breast cancer survivor subgroups were identified as having members who might be most in need of sleep-improvement interventions. Addressing physical symptoms (e.g., vasomotor symptoms and pain) and providing education about the behavioral, social, environmental, and medical factors that affect sleep could result in substantial improvement in the life course of breast cancer survivors.

Nonmedical Prescription Opioid Use for the Self-treatment of Pain in Young Adults: A National Shame.

: Evans et al. (2017) have pointed out how frequently and pervasively nonmedical prescription opioid use is associated with severe pain in young adults, especially young white males. This is a subset of such nonmedical users at tremendous risk of overdose (indeed 1/3 of the study respondents had an overdose event), especially given their concomitant use of benzodiazepines. Avoiding further contributing to the catastrophic rise in overdoses requires access to comprehensive pain care for these young adults. If they were to require opioid therapy, it would have to be in the context of a highly complex and expert variety of such care. If we fail to make it available, we will fail to address the root cause of overdoses for a sizeable subset of nonmedical prescription opioid users.

Reality and responsibility revisited: Stakeholder accountability in the effort to develop safer opioids.

This supplement is dedicated to an exploration of the science, potential utility, and the current state of abuse-deterrent formulations (ADF) of opioid analgesics. There are many stakeholders in the search for safer pain treatments in general, and safer opioid therapy in particular. Healthcare providers, patients, third-party payors, law enforcement and government regulators, the pharmaceutical industry, and the media all have a stake in seeing pain treated and addiction and overdose avoided. As it applies to ADFs, obviously not everyone has a stake in seeing that ADFs succeed commercially; but all stakeholders certainly have a responsibility to see that any potential advance, including ADFs, in protecting the public health is fairly and thoroughly evaluated. Particularly at a time of crisis. In this article, we revisit the framework used by Passik, Heit, and Kirsh (2006) to evaluate stakeholders' responsibilities with regard to both the opioid abuse and chronic pain epidemics. After evaluating the present status of aspirations delineated over a decade ago, we discuss the updated roles and responsibilities of each stakeholder, with emphasis on the role of ADFs as this technology was unavailable when the original manuscript was written.

Definitive LC-MS/MS Drug Monitoring Impacts Substance-use Treatment Planning and Patient Outcomes: A Brief Report.

Clinical drug monitoring has an increasingly important role in the treatment of substance use disorders. Through semistructured interviews, we asked substance-use counselors about the clinical impact of drug tests on patients' treatment planning and outcomes. This study was conducted around the time of a facility-wide switch to a laboratory utilizing definitive liquid chromatography with tandem mass spectrometry from a laboratory that had utilized the less-sensitive, presumptive immunoassay-based drug-testing methodology. Twelve counselors volunteered to be interviewed, and each counselor chose 2 patients to discuss. Counselors reported that the facility-wide switch to definitive drug testing revealed some patients with newly identified relapses and substance use. They also reported that, as a result of the new information provided by definitive liquid chromatography with tandem mass spectrometry monitoring, 75% of the patients they discussed had a change made to their treatment plan, 79% were provided enhanced education, and 63% had an increase in their treatment intensity. Counselors also reported that 58% of these patients reduced their illicit drug and nonmedical prescription medication use as a result of treatment changes associated with the newly implemented definitive testing. Improvements in therapeutic relationships and honesty were also reported. These preliminary data are consistent with previous data and guidelines, suggesting that the results of definitive drug monitoring inform clinical decision-making and can help clinicians enhance treatment outcomes.