Opioid abuse and misuse in the USA is a public health crisis. The use of prescription opioid analgesics increased substantially from 2002 through 2010, then plateaued and began to decrease in 2011. ...This study examined prescriptions of branded and generic immediate- and extended-release opioid analgesics from 1992 to 2016. This was juxtaposed against state and federal policies designed to decrease overutilization and abuse, as well as the launch of new opioid products, including opioids with abuse-deterrent properties (OADPs). The data indicate that these health policies, including the utilization and reimbursement of OADPs, have coincided with decreased opioid utilization. The hypothesis that OADPs will paradoxically increase opioid prescribing is not supported.
Although pain reduction is commonly the primary outcome in chronic pain clinical trials, physical functioning is also important. A challenge in designing chronic pain trials to determine efficacy and ...effectiveness of therapies is obtaining appropriate information about the impact of an intervention on physical function. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) and Outcome Measures in Rheumatology (OMERACT) convened a meeting to consider assessment of physical functioning and participation in research on chronic pain. The primary purpose of this article is to synthesize evidence on the scope of physical functioning to inform work on refining physical function outcome measurement. We address issues in assessing this broad construct and provide examples of frequently used measures of relevant concepts. Investigators can assess physical functioning using patient-reported outcome (PRO), performance-based, and objective measures of activity. This article aims to provide support for the use of these measures, covering broad aspects of functioning, including work participation, social participation, and caregiver burden, which researchers should consider when designing chronic pain clinical trials. Investigators should consider the inclusion of both PROs and performance-based measures as they provide different but also important complementary information. The development and use of reliable and valid PROs and performance-based measures of physical functioning may expedite development of treatments, and standardization of these measures has the potential to facilitate comparison across studies. We provide recommendations regarding important domains to stimulate research to develop tools that are more robust, address consistency and standardization, and engage patients early in tool development.
As the nontherapeutic use of prescription medications escalates, serious associated consequences have also increased. This makes it essential to estimate misuse, abuse, and related events (MAREs) in ...the development and postmarketing adverse event surveillance and monitoring of prescription drugs accurately. However, classifications and definitions to describe prescription drug MAREs differ depending on the purpose of the classification system, may apply to single events or ongoing patterns of inappropriate use, and are not standardized or systematically employed, thereby complicating the ability to assess MARE occurrence adequately. In a systematic review of existing prescription drug MARE terminology and definitions from consensus efforts, review articles, and major institutions and agencies, MARE terms were often defined inconsistently or idiosyncratically, or had definitions that overlapped with other MARE terms. The Analgesic, Anesthetic, and Addiction Clinical Trials, Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership convened an expert panel to develop mutually exclusive and exhaustive consensus classifications and definitions of MAREs occurring in clinical trials of analgesic medications to increase accuracy and consistency in characterizing their occurrence and prevalence in clinical trials. The proposed ACTTION classifications and definitions are designed as a first step in a system to adjudicate MAREs that occur in analgesic clinical trials and postmarketing adverse event surveillance and monitoring, which can be used in conjunction with other methods of assessing a treatment's abuse potential.
Previous studies implicated protein arginine methyltransferase 5 (PRMT5) as a synthetic lethal target for MTAP-deleted (MTAP del) cancers; however, the pharmacologic characterization of ...small-molecule inhibitors that recapitulate the synthetic lethal phenotype has not been described. MRTX1719 selectively inhibited PRMT5 in the presence of MTA, which is elevated in MTAP del cancers, and inhibited PRMT5-dependent activity and cell viability with >70-fold selecti-vity in HCT116 MTAP del compared with HCT116 MTAP wild-type (WT) cells. MRTX1719 demonstrated dose-dependent antitumor activity and inhibition of PRMT5-dependent SDMA modification in MTAP del tumors. In contrast, MRTX1719 demonstrated minimal effects on SDMA and viability in MTAP WT tumor xenografts or hematopoietic cells. MRTX1719 demonstrated marked antitumor activity across a panel of xenograft models at well-tolerated doses. Early signs of clinical activity were observed including objective responses in patients with MTAP del melanoma, gallbladder adenocarcinoma, mesothelioma, non-small cell lung cancer, and malignant peripheral nerve sheath tumors from the phase I/II study.
PRMT5 was identified as a synthetic lethal target for MTAP del cancers; however, previous PRMT5 inhibitors do not selectively target this genotype. The differentiated binding mode of MRTX1719 leverages the elevated MTA in MTAP del cancers and represents a promising therapy for the ∼10% of patients with cancer with this biomarker. See related commentary by Mulvaney, p. 2310. This article is featured in Selected Articles from This Issue, p. 2293.
Abstract A multi-state survey of 5663 opioid dependent persons enrolling in 72 methadone maintenance treatment programs (MMTPs) was conducted to determine the prevalence of prescription opioid (PO) ...abuse, factors associated with PO abuse and sources for POs. Regions where PO abuse was believed to be prevalent were oversampled; primary opioid was defined as the drug used the most before coming to the MMTP. Among primary heroin abusers, 69% reported abusing POs. Opioid abuse frequencies among primary PO abusers were oxycodone (79%), hydrocodone (67%), methadone (40%), morphine (29%), heroin (13%), hydromorphone (16%), fentanyl (9%) and buprenorphine (1%). Correlates ( p ≤ .01) of PO abuse, using general estimating equations, were: low urbanicity (MMTPs located in comparatively low population density counties), white ethnicity, no history of injecting primary drug, no previous methadone treatment, younger age, chronic pain, and pain as a reason for enrollment. The most frequent sources of POs were dealer, friend or relative, and doctor's prescription; least frequent were Internet and forged prescription. One-third of PO abusers reported a history of injecting their primary drug. PO abuse is highly prevalent among MMTP patients. Future studies should describe HIV/HCV needle injection practices, characteristics that predict treatment outcomes, and factors that contribute to higher prevalence of persistent pain among PO abusers.
A critical component in development of opioid analgesics is assessment of their abuse liability (AL). Standardization of approaches and measures used in assessing AL have the potential to facilitate ...comparisons across studies, research laboratories, and drugs. The goal of this report is to provide consensus recommendations regarding core outcome measures for assessing the abuse potential of opioid medications in humans in a controlled laboratory setting. Although many of the recommended measures are appropriate for assessing the AL of medications from other drug classes, the focus here is on opioid medications because they present unique risks from both physiological (e.g., respiratory depression, physical dependence) and public health (e.g., individuals in pain) perspectives. A brief historical perspective on AL testing is provided, and those measures that can be considered primary and secondary outcomes and possible additional outcomes in AL assessment are then discussed. These outcome measures include the following: subjective effects (some of which comprise the primary outcome measures, including drug liking; physiological responses; drug self-administration behavior; and cognitive and psychomotor performance. Before presenting recommendations for standardized approaches and measures to be used in AL assessments, the appropriateness of using these measures in clinical trials with patients in pain is discussed.
Assessing and mitigating the abuse liability (AL) of analgesics is an urgent clinical and societal problem. Analgesics have traditionally been assessed in randomized clinical trials (RCTs) designed ...to demonstrate analgesic efficacy relative to placebo or an active comparator. In these trials, rigorous, prospectively designed assessment for AL is generally not performed. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) convened a consensus meeting to review the available evidence and discuss methods for improving the assessment of the AL of analgesics in clinical trials in patients with pain. Recommendations for improved assessment include: (1) performing trials that include individuals with diverse risks of abuse; (2) improving the assessment of AL in clinical trials (eg, training study personnel in the principles of abuse and addiction behaviors, designing the trial to assess AL outcomes as primary or secondary outcome measures depending on the trial objectives); (3) performing standardized assessment of outcomes, including targeted observations by study personnel and using structured adverse events query forms that ask all subjects specifically for certain symptoms (such as euphoria and craving); and (4) collecting detailed information about events of potential concern (eg, unexpected urine drug testing results, loss of study medication, and dropping out of the trial). The authors also propose a research agenda for improving the assessment of AL in future trials.
Background: Although the link between drug abuse and suicide risk is established, few studies have examined the relationship between the nonmedical use of prescription drugs (NMUPD) and suicide risk, ...particularly among adolescents. Objectives: To explore the relationship between NMUPD and suicide risk among 4,148 adolescents in grades 9-12 enrolled in five public high schools. Methods: Logistic regression models were constructed for the nonmedical use of prescription pain relievers, depressants, stimulants, and a composite measure for any NMUPD. Models were estimated before and after controlling for key covariates. Results: About 21% of respondents reported lifetime NMUPD. After covariate adjustment, students who had reported any NMUPD were between 1.7 and 2.3 times more likely to report suicidal ideation, but not a suicide attempt (p < .0001). When stratified by sex and drug, nonmedical use of pain relievers, stimulants, and depressants were significantly associated with greater odds of suicidal ideation and behavior for both males and females (p < .05). However, NMUPD of pain relievers were not associated with greater odds of suicide attempts for males or females or among males who reported nonmedical use of stimulants. Nonmedical use of depressants was associated with greater odds of suicide attempts for both males and females (OR = 1.61 and 2.25, respectively) and among females who reported nonmedical use of stimulants (OR = 2.06, p < .01). Conclusions/Importance: Results suggest that some adolescents may be inappropriately self-medicating psychological distress with prescription medications or NMUPD may promote suicide risk, especially for males and females who use depressants and females who use stimulants.
Although extreme weight control behavior (EWCB) is associated with substance use, no research has examined the association between the nonmedical use of prescription drugs (NMUPD) and EWCB. ...Self-report data were collected from a sample of 4,148 students in Grades 9-12 enrolled in 5 high schools across the United States. Logistic regression models were constructed to examine the nonmedical use of prescription pain relievers, depressants, stimulants, and a composite measure for any NMUPD, and the EWCB of fasting, use of diet pills, powders, or liquids, and vomiting or laxative use. Models were estimated before and after controlling for key covariates for males and females. Approximately 16% of respondents reported any EWCB during the past 30 days, while 11% reported any NMUPD during the past 30 days. After covariate adjustment, any NMUPD was associated with any EWCB in both males and females (p < .05), and all EWCB remained significant in females who reported prescription pain reliever use (p < .01), with 2 out of 3 remaining significant for prescription stimulant and depressant use (p < .01). The only significant association detected for males was between prescription pain reliever use and using diet pills, powders, or liquids (OR = 2.2, p < .01). Results suggest significant associations between NMUPD and EWCB, with variations by sex. These findings provide directions for additional research and point to several potential identification and intervention efforts.
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