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Chronic pain clinical trials have historically assessed benefit and risk outcomes separately. However, a growing body of research suggests that a composite metric that accounts for benefit and risk in relation to each other can provide valuable insights into the effects of different treatments. Researchers and regulators have developed a variety of benefit-risk composite metrics, although the extent to which these methods apply to randomized clinical trials (RCTs) of chronic pain has not been evaluated in the published literature. This article was motivated by an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting and is based on the expert opinion of those who attended. In addition, a review of the benefit-risk assessment tools used in published chronic pain RCTs or highlighted by key professional organizations (ie, Cochrane, European Medicines Agency, Outcome Measures in Rheumatology, and U.S. Food and Drug Administration) was completed. Overall, the review found that benefit-risk metrics are not commonly used in RCTs of chronic pain despite the availability of published methods. A primary recommendation is that composite metrics of benefit-risk should be combined at the level of the individual patient, when possible, in addition to the benefit-risk assessment at the treatment group level. Both levels of analysis (individual and group) can provide valuable insights into the relationship between benefits and risks associated with specific treatments across different patient subpopulations. The systematic assessment of benefit-risk in clinical trials has the potential to enhance the clinical meaningfulness of RCT results.

The estimated probability of progressing from phase 3 analgesic clinical trials to regulatory approval is approximately 57%, suggesting that a considerable number of treatments with phase 2 trial results deemed sufficiently successful to progress to phase 3 do not yield positive phase 3 results. Deficiencies in the quality of clinical trial conduct could account for some of this failure. An Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting was convened to identify potential areas for improvement in trial conduct in order to improve assay sensitivity (ie, ability of trials to detect a true treatment effect). We present recommendations based on presentations and discussions at the meeting, literature reviews, and iterative revisions of this article. The recommendations relate to the following areas: 1) study design (ie, to promote feasibility), 2) site selection and staff training, 3) participant selection and training, 4) treatment adherence, 5) data collection, and 6) data and study monitoring. Implementation of these recommendations may improve the quality of clinical trial data and thus the validity and assay sensitivity of clinical trials. Future research regarding the effects of these strategies will help identify the most efficient use of resources for conducting high quality clinical trials. PERSPECTIVE: Every effort should be made to optimize the quality of clinical trial data. This manuscript discusses considerations to improve conduct of pain clinical trials based on research in multiple medical fields and the expert consensus of pain researchers and stakeholders from academia, regulatory agencies, and industry.

Diana S Meske,1 Ben J Vaughn,2 Ernest A Kopecky,3 Nathaniel Katz4,5 1Collegium Pharmaceutical, Inc, Stoughton, MA, USA; 2Rho, Chapel Hill, NC, USA; 3Teva Branded Pharmaceutical Products R&D, Inc, Frazer, PA, USA; 4WCG Analgesic Solutions, Wayland, MA, USA; 5Department of Anesthesia, Tufts University School of Medicine, Boston, MA, USACorrespondence: Diana S MeskeCollegium Pharmaceutical, Inc, Stoughton, MA, USATel +1 517 712 3087Email dsmeske@gmail.comBackground: Many aspects of study conduct impact the observed effect size of treatment. Data were utilized from a recently published meta-analysis of randomized, double-blind, placebo-controlled, clinical trials performed for the United States Food and Drug Administration (FDA) approval of full mu-agonist opioids for the treatment of chronic pain.Methods: The number of study sites in each clinical trial and standardized effect size (SES) were extracted and computed. Standardized effect size was plotted against number of sites, and a two-piece linear model was fit to the plot. Ten studies were included.Results: The SES decreased linearly by 0.13 units for every 10 sites (p=0.037), from 0.75 to 0.36, until an inflection point of 60 sites, after which SES did not decline further. The total number of subjects required for 90% power to discriminate drug from placebo increased from 78 to 336 subjects going from 30 to 60 sites.Conclusion: Results showed that the number of sites was a source of loss of assay sensitivity in clinical trials, which may contribute to the well-known problem of failure to successfully transition from Phase 2 to Phase 3 clinical development. Potential solutions include minimizing the number of sites, more rigorous and validated training, central statistical monitoring with rapid correction of performance issues, and more rigorous subject and site selection.Keywords: randomized controlled trials, opioids, chronic pain, clinical trials, effect size, study site number

Aims/objectives/background Children represent a patient demographic composed of multiple, unique subpopulations differentiated by rapidly changing age-related physiology, which includes the means of metabolizing opioids. Opioids are an important part of the pharmacological treatment of both acute and chronic pain. In both clinical medicine and clinical research, it is necessary to understand the differences in drug handling by age cohort in order to appropriately dose children to effect, and to avoid exacerbating deleterious adverse events with potentially grave sequelae. Methods Topical review using data from a targeted PubMed literature search. Results Protein binding, tissue solubility, weight, size (body mass, surface area), blood flow, drug metabolism, and renal function are key determinants of dosing across the different pediatric age cohorts. Each variable functions to elicit a change in drug exposure and therefore varying clinical effect. Conclusions Understanding how these variables change the pharmacokinetics and pharmacodynamics of each opioid is critical to the successful and safe management of pain in children.

There is tremendous interpatient variability in the response to analgesic therapy (even for efficacious treatments), which can be the source of great frustration in clinical practice. This has led to calls for “precision medicine” or personalized pain therapeutics (ie, empirically based algorithms that determine the optimal treatments, or treatment combinations, for individual patients) that would presumably improve both the clinical care of patients with pain and the success rates for putative analgesic drugs in phase 2 and 3 clinical trials. However, before implementing this approach, the characteristics of individual patients or subgroups of patients that increase or decrease the response to a specific treatment need to be identified. The challenge is to identify the measurable phenotypic characteristics of patients that are most predictive of individual variation in analgesic treatment outcomes, and the measurement tools that are best suited to evaluate these characteristics. In this article, we present evidence on the most promising of these phenotypic characteristics for use in future research, including psychosocial factors, symptom characteristics, sleep patterns, responses to noxious stimulation, endogenous pain-modulatory processes, and response to pharmacologic challenge. We provide evidence-based recommendations for core phenotyping domains and recommend measures of each domain.

Supplemental Digital Content is Available in the Text., Although certain risk factors can identify individuals who are most likely to develop chronic pain, few interventions to prevent chronic pain have been identified. To facilitate the identification of preventive interventions, an IMMPACT meeting was convened to discuss research design considerations for clinical trials investigating the prevention of chronic pain. We present general design considerations for prevention trials in populations that are at relatively high risk for developing chronic pain. Specific design considerations included subject identification, timing and duration of treatment, outcomes, timing of assessment, and adjusting for risk factors in the analyses. We provide a detailed examination of 4 models of chronic pain prevention (ie, chronic postsurgical pain, postherpetic neuralgia, chronic low back pain, and painful chemotherapy-induced peripheral neuropathy). The issues discussed can, in many instances, be extrapolated to other chronic pain conditions. These examples were selected because they are representative models of primary and secondary prevention, reflect persistent pain resulting from multiple insults (ie, surgery, viral infection, injury, and toxic or noxious element exposure), and are chronically painful conditions that are treated with a range of interventions. Improvements in the design of chronic pain prevention trials could improve assay sensitivity and thus accelerate the identification of efficacious interventions. Such interventions would have the potential to reduce the prevalence of chronic pain in the population. Additionally, standardization of outcomes in prevention clinical trials will facilitate meta-analyses and systematic reviews and improve detection of preventive strategies emerging from clinical trials.

Copyright © 2020 International Association for the Study of Pain., Interpreting randomized clinical trials (RCTs) is crucial to making decisions regarding the use of analgesic treatments in clinical practice. In this article, we report on an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) consensus meeting organized by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks, the purpose of which was to recommend approaches that facilitate interpretation of analgesic RCTs. We review issues to consider when drawing conclusions from RCTs, as well as common methods for reporting RCT results and the limitations of each method. These issues include the type of trial, study design, statistical analysis methods, magnitude of the estimated beneficial and harmful effects and associated precision, availability of alternative treatments and their benefit-risk profile, clinical importance of the change from baseline both within and between groups, presentation of the outcome data, and the limitations of the approaches used.

JohnMarkman,1 Diana S Meske,2 Ernest A Kopecky,2 Ben Vaughn,3 Melinda L O’Connor,2 Steven D Passik2 1Department of Neurosurgery, Translational Pain Research Program, University of Rochester, Rochester, NY, USA; 2Collegium Pharmaceutical Inc., Canton,MA, USA; 3Rho Inc., Chapel Hill, NC, USA 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

Clinical trials to test the safety and efficacy of analgesics across all pediatric age cohorts are needed to avoid inappropriate extrapolation of adult data to children. However, the selection of acute pain models and trial design attributes to maximize assay sensitivity, by pediatric age cohort, remains problematic. Acute pain models used for drug treatment trials in adults are not directly applicable to the pediatric age cohorts-neonates, infants, toddlers, children, and adolescents. Developmental maturation of metabolic enzymes in infants and children must be taken into consideration when designing trials to test analgesic treatments for acute pain. Assessment tools based on the levels of cognitive maturation and behavioral repertoire must be selected as outcome measures. Models and designs of clinical trials of analgesic medications used in the treatment of acute pain in neonates, infants, toddlers, children, and adolescents were reviewed and discussed at an Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) Pediatric Pain Research Consortium consensus meeting. Based on extensive reviews and continuing discussions, the authors recommend a number of acute pain clinical trial models and design attributes that have the potential to improve the study of analgesic medications in pediatric populations. Recommendations are also provided regarding additional research needed to support the use of other acute pain models across pediatric age cohorts.

Aim: To further characterize the pharmacokinetics of Xtampza® ER. Subjects & methods: This was an open-label, randomized, active-controlled, five-treatment, five-period, naltrexone-blocked, cross-over study. Healthy subjects received five equivalent oxycodone doses: Xtampza ER (intact or crushed), OxyContin® (intact or crushed) or immediate-release (IR) oxycodone (crushed). Blood samples were collected to assess oxycodone concentrations. Results: Crushed and intact Xtampza ER resulted in lower peak plasma concentrations compared with crushed oxycodone IR; crushed and intact Xtampza ER were bioequivalent. Crushed OxyContin exhibited a rapid increase in plasma oxycodone and was bioequivalent to crushed oxycodone IR. Conclusion: This second pharmacokinetic study demonstrated that Xtampza ER maintains its ER properties after crushing, unlike OxyContin, which failed to retain its ER properties after crushing. ANZCTR registration number: ACTRN12614000613606

Trial Design This was a phase III, randomized withdrawal, double-blind, placebo-controlled, enriched enrollment, parallel-group, multicenter study intended to demonstrate the safety, tolerability, and analgesic efficacy of oxycodone DETERx® (Xtampza™ ER) compared with matching placebo. Methods This post hoc analysis was performed using data from a subpopulation of enrolled patients who were ≥65 years of age. The study enrolled male and female patients with a clinical diagnosis of moderate-to-severe chronic low back pain for a minimum of 6 months prior to screening who required around-the-clock opioid therapy. To be eligible for enrollment, patients were required to have an average 24-h pain intensity score of ≥5 and ≤9 on an 11-point (0–10) Pain Intensity—Numerical Rating Scale at the screening visit. The study enrolled both opioid-experienced and opioid-naïve patients. The study consisted of an open-label titration phase followed by a 12-week double-blind maintenance phase. The dose range was 40–160 mg oxycodone hydrochloride equivalent per day. This post hoc analysis evaluated the safety, tolerability, and effectiveness of oxycodone DETERx among patients ≥65 years of age. The effectiveness of oxycodone DETERx was evaluated based on average pain intensity scores, Patient Global Impression of Change, responder analysis, and Kaplan–Meier survival analysis. The safety and tolerability of oxycodone DETERx were also evaluated. Patients were randomized to either oxycodone DETERx or placebo using a blocked randomization scheme in a 1:1 ratio. Randomization was stratified by previous opioid use (naïve or experienced). The study drug was coded in a manner that maintained the blinding. Study personnel and patients remained blinded to the assigned treatments throughout the study. Results For this post-hoc analysis, the intent-to-treat and randomized safety populations included 52 patients ≥65 years old, 26 each in the oxycodone DETERx and placebo groups, who participated in the study during the titration phase and were randomized to the double-blind maintenance phase. Clinically important pain reduction from screening was achieved with oxycodone DETERx, with the median pain intensity score decreasing from 7.50 at screening to 2.69 at Week 12. A clinically meaningful treatment difference of −0.9 in pain score between oxycodone DETERx and placebo was observed. All 18 elderly patients who completed the study reported improvement in pain, with 62% showing ≥30% improvement and 54% showing ≥50% improvement in pain intensity compared with patients on placebo (p = 0.0128 and p = 0.0501, respectively). Patients on oxycodone DETERx remained in the study longer than those on placebo. Of the 26 patients ≥65 years old randomized to continue oxycodone DETERx during the double-blind maintenance phase, 18 (69%) completed the study; only two patients (8%) in the oxycodone DETERx group discontinued due to adverse events. The safety and tolerability profiles showed no new or unexpected safety concerns. The adverse event profiles were similar between the titration and double-blind maintenance phases. Conclusions Oxycodone DETERx was efficacious and generally well tolerated in patients ≥65 years old. Trial Registration The study was registered with ClinicalTrials.gov (NCT01685684).

Oxycodone DETERx® (Collegium Pharmaceutical Inc, Canton, Massachusetts) is an extended-release, microsphere-in-capsule, abuse-deterrent formulation designed to retain its extended-release properties after tampering (eg, chewing/crushing). This randomized, double-blind, placebo-controlled, triple-dummy study evaluated the oral abuse potential of intact and chewed oxycodone DETERx capsules compared with crushed immediate-release oxycodone. Subjects with a history of recreational opioid use who were nondependent/nontolerant to opioids were enrolled. Treatments included intact oxycodone DETERx (high-fat, high-calorie meal and fasted), chewed oxycodone DETERx (high-fat, high-calorie meal and fasted), crushed immediate-release oxycodone (fasted), and placebo (high-fat, high-calorie meal). Plasma samples were collected to determine pharmacokinetic parameters. The primary endpoint was drug liking at the moment; other endpoints included drug effects questionnaire scores, Addiction Research Center Inventory/Morphine Benzedrine Group score, pupillometry measurements, and safety. Thirty-eight subjects completed the study. Chewed and intact oxycodone DETERx were bioequivalent, unlike crushed immediate-release oxycodone, which yielded higher peak oxycodone plasma concentrations compared with all methods of oxycodone DETERx administration. The mean maximum (peak) effect (Emax ) for drug liking was significantly lower for chewed and intact oxycodone DETERx than for crushed immediate-release oxycodone (P < .01). The time to Emax was significantly longer for chewed and intact oxycodone DETERx than for crushed immediate-release oxycodone (P < .0001). Scores for feeling high and Addiction Research Center Inventory/Morphine Benzedrine Group scores demonstrated lower abuse potential for chewed and intact oxycodone DETERx compared with crushed immediate-release oxycodone. Study treatments were well tolerated; no subjects experienced serious adverse events. These results demonstrate the lower oral abuse potential of chewed and intact oxycodone DETERx than crushed immediate-release oxycodone.

Patients with chronic pain may experience difficulty swallowing, in part due to worsening disease, comorbid conditions, iatrogenic etiology, or age. Patients or caregivers may manipulate extended-release (ER) opioid formulations to facilitate oral dosing due to a lack of therapeutic options that allow for sprinkle or enteral feeding tube administration. If crushed or broken, current oral ER opioids can be associated with adverse sequelae, including risk of potentially fatal overdose.To review the safety, in vitro dissolution data, and in vivo pharmacokinetic data that support alternative modes of administration of oxycodone DETERx (Xtampza ER) via sprinkling onto soft foods for oral ingestion or via enteral feeding tubes.A review of oxycodone DETERx data from in vitro and in vivo studies was conducted to demonstrate support for alternative routes and modes of administration.There was no difference in the dissolution profile when administered with various soft foods or when mixed with various liquid vehicles and administered via nasogastric (NG) or gastrostomy (G) tubes, based on in vitro studies. When sprinkled onto applesauce and administered orally, the microspheres were bioequivalent to the intact oxycodone capsules. When crushed or chewed, the formulation maintained its pharmacokinetic profile; no bolus dose of opioid was released. The sprinkle-dose study was limited by the single-dose study design, as well as the small sample size.Oxycodone DETERx is the first ER oxycodone formulation that can be administered either intact, sprinkled onto soft foods, or via NG/G tubes, thereby providing options for treating pain in patients who have difficulty swallowing.

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.

Opioid analgesics are commonly used for the treatment of chronic low back pain (CLBP); however, abuse potential is a major concern. This study used a randomized, double-blind, placebo-controlled, enriched-enrollment randomized-withdrawal study design to evaluate the safety, tolerability, and analgesic efficacy of an abuse-deterrent formulation of extended-release oxycodone, Xtampza ER, in opioid-naive and opioid-experienced adults with moderate-to-severe CLBP. Patients entered an open-label titration phase (N = 740); those who were successfully titrated on Xtampza ER (≥40 to ≤160 mg oxycodone hydrochloride equivalent per day) were randomized to active drug (N = 193) or placebo (N = 196) for 12 weeks. Primary efficacy results showed a statistically significant difference in average pain intensity from randomization baseline to treatment week 12 between the Xtampza ER and placebo groups (mean [±SE], -1.56 [0.267]; P < 0.0001). All sensitivity analyses results supported the primary result of the study. Secondary efficacy outcomes indicated that Xtampza ER vs placebo had more patients with improvement in patient global impression of change (26.4% vs 14.3%; P < 0.0001), longer time-to-exit from the study (58 vs 35 days; P = 0.0102), and a greater proportion of patients with ≥30% (49.2% vs 33.2%; P = 0.0013) and ≥50% (38.3% vs 24.5%; P = 0.0032) improvement in pain intensity. There was less rescue medication (acetaminophen) use in the Xtampza ER treatment group than in the placebo group. Xtampza ER had an adverse event profile consistent with other opioids and was well tolerated; no new safety concerns were identified. In conclusion, Xtampza ER resulted in clinically and statistically significant efficacy in patients with CLBP.

Objective Oxycodone DETERx® is an extended-release (ER), microsphere-in-capsule abuse-deterrent-formulation designed to retain its extended-release properties following tampering or misuse (e.g., chewing, crushing). This study assessed the safety and pharmacokinetics of orally administered intact and crushed Oxycodone DETERx® capsules compared with intact and crushed reformulated OxyContin® tablets and crushed immediate-release oxycodone tablets (IR oxycodone). Methods This was a randomized, open-label, active-controlled, cross-over study. Healthy subjects received five oxycodone treatments (40 mg) with a standardized high-fat, high-calorie meal: Oxycodone DETERx® (intact or crushed), OxyContin® (intact or crushed), and IR oxycodone (crushed). Blood samples were collected for assessment of oxycodone plasma concentrations. Results Thirty-eight subjects completed the study. Both crushed and intact Oxycodone DETERx® resulted in lower peak plasma concentrations when compared with IR oxycodone. Crushed Oxycodone DETERx® was bioequivalent to intact Oxycodone DETERx® and exhibited a numerically lower Cmax. Also, median Tmax was unchanged by crushing. In contrast, mean peak plasma oxycodone concentrations for crushed OxyContin® were significantly higher compared with intact OxyContin® and were bioequivalent to IR oxycodone. Median Tmax for crushed OxyContin® was the same as IR oxycodone and 3.25 hours shorter than intact OxyContin®. Conclusions These data demonstrate that when crushed and taken orally, Oxycodone DETERx® maintains its EXTENDED-release profile, while crushed OxyContin® shows a pharmacokinetic profile similar to an immediate-release product. These results suggest that Oxycodone DETERx® may be less attractive to illicit drug users compared with existing abuse-deterrent-formulations, while providing a safer option for patients who may unknowingly crush their medication such as those who have difficulty swallowing.

To further characterize the pharmacokinetics of XtampzaThis was an open-label, randomized, active-controlled, five-treatment, five-period, naltrexone-blocked, cross-over study. Healthy subjects received five equivalent oxycodone doses: Xtampza ER (intact or crushed), OxyContinCrushed and intact Xtampza ER resulted in lower peak plasma concentrations compared with crushed oxycodone IR; crushed and intact Xtampza ER were bioequivalent. Crushed OxyContin exhibited a rapid increase in plasma oxycodone and was bioequivalent to crushed oxycodone IR.This second pharmacokinetic study demonstrated that Xtampza ER maintains its ER properties after crushing, unlike OxyContin, which failed to retain its ER properties after crushing. ANZCTR registration number: ACTRN12614000613606.

Accurate assessment of inappropriate medication use events (ie, misuse, abuse, and related events) occurring in clinical trials is an important component in evaluating a medication's abuse potential. A meeting was convened to review all instruments measuring such events in clinical trials according to previously published standardized terminology and definitions. Only 2 approaches have been reported that are specifically designed to identify and classify misuse, abuse, and related events occurring in clinical trials, rather than to measure an individual's risk of using a medication inappropriately: the Self-Reported Misuse, Abuse, and Diversion (SR-MAD) instrument and the Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS). The conceptual basis, strengths, and limitations of these methods are discussed. To our knowledge, MADDERS is the only system available to comprehensively evaluate inappropriate medication use events prospectively to determine the underlying intent. MADDERS can also be applied retrospectively to completed trial data. SR-MAD can be used prospectively; additional development may be required to standardize its implementation and fully appraise the intent of inappropriate use events. Additional research is needed to further demonstrate the validity and utility of MADDERS as well as SR-MAD. Perspective Identifying a medication's abuse potential requires assessing inappropriate medication use events in clinical trials on the basis of a standardized event classification system. The strengths and limitations of the 2 published methods designed to evaluate inappropriate medication use events are reviewed, with recommended considerations for further development and current implementation.

Objective: In vitro: To assess the effect of common crushing techniques on particle size reduction (PSR) and in vitro drug-release kinetics of oxycodone DETERx® (herein DETERx) and of a commercially available oxycodone extended-release (ER) tablet. In vivo: To evaluate the impact of the most effective manipulation method identified in the in vitro study and the effect of chewing on the pharmacokinetics (PK) of DETERx relative to oxycodone solution. Design: In vitro: Mechanical manipulation of dosage forms using common household utensils. In vivo: Open-label, randomized, active-controlled, crossover PK study. Subjects: In vivo: Forty-four healthy male and female volunteers. Methods: In vitro: DETERx capsule contents and marketed comparator tablets were subjected to manipulation (crushing) using 10 different household utensils. Particle size and dissolution analysis were conducted. In vivo: Subjects were randomly assigned to receive DETERx 40-mg capsules intact, crushed, or chewed or oxycodone solution. Serial blood samples were drawn for PK assessment. Results: In vitro: The utensils used to manipulate DETERx capsule contents were either ineffective in reducing the particle size or produced only a small change in the median particle size and dissolution rate relative to the marketed comparator. In vivo: DETERx intact capsules provided significantly lower C max and longer T max values than oxycodone solution. Manipulation of DETERx by crushing (using the most effective method established in vitro) or chewing resulted in bioequivalent plasma concentration-time profiles to the intact dosage form . Conclusion: These mechanical manipulation and PK studies demonstrated that DETERx beads retained their ER properties after mechanical tampering and chewing by study subjects.

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.

Oxycodone DETERx® (Collegium Pharmaceutical Inc, Canton, Massachusetts) is an extended‐release, microsphere‐in‐capsule, abuse‐deterrent formulation designed to retain its extended‐release properties after tampering (eg, chewing/crushing). This randomized, double‐blind, placebo‐controlled, triple‐dummy study evaluated the oral abuse potential of intact and chewed oxycodone DETERx capsules compared with crushed immediate‐release oxycodone. Subjects with a history of recreational opioid use who were nondependent/nontolerant to opioids were enrolled. Treatments included intact oxycodone DETERx (high‐fat, high‐calorie meal and fasted), chewed oxycodone DETERx (high‐fat, high‐calorie meal and fasted), crushed immediate‐release oxycodone (fasted), and placebo (high‐fat, high‐calorie meal). Plasma samples were collected to determine pharmacokinetic parameters. The primary endpoint was drug liking at the moment; other endpoints included drug effects questionnaire scores, Addiction Research Center Inventory/Morphine Benzedrine Group score, pupillometry measurements, and safety. Thirty‐eight subjects completed the study. Chewed and intact oxycodone DETERx were bioequivalent, unlike crushed immediate‐release oxycodone, which yielded higher peak oxycodone plasma concentrations compared with all methods of oxycodone DETERx administration. The mean maximum (peak) effect (Emax) for drug liking was significantly lower for chewed and intact oxycodone DETERx than for crushed immediate‐release oxycodone (P < .01). The time to Emax was significantly longer for chewed and intact oxycodone DETERx than for crushed immediate‐release oxycodone (P < .0001). Scores for feeling high and Addiction Research Center Inventory/Morphine Benzedrine Group scores demonstrated lower abuse potential for chewed and intact oxycodone DETERx compared with crushed immediate‐release oxycodone. Study treatments were well tolerated; no subjects experienced serious adverse events. These results demonstrate the lower oral abuse potential of chewed and intact oxycodone DETERx than crushed immediate‐release oxycodone.

Barriers to clinical trial recruitment can delay study completion, potentially resulting in increased costs and an unrepresentative sample. In the current study of 150 participants with chronic pain, we used a computerized adaptive choice-based conjoint survey that included 8 characteristics that may affect enrollment in pharmacologic pain treatment trials (ie, treatment allocation, frequency of pain ratings, treatment administration method, current medications, number of study visits, availability of evening and weekend visits, invasiveness of laboratory procedures, payment). These data were analyzed using Sawtooth Software ver. 8.4.8 (Sawtooth Software, Inc, Orem, UT), which identifies the characteristics that dominate participants' decisions across multiple sets of potential trials. Three characteristics had the largest relative importance in participants’ trial preferences: 1) invasiveness of required laboratory procedures (ie, 22%), with no procedures or blood tests preferred over ice-water sensory testing or skin biopsy; 2) ability to continue current pain medications (21%); and 3) payment for study participation (21%), with higher payment preferred. The fourth most important characteristic was number of study visits (13%), with participants preferring fewer in-person visits and more phone contacts. Understanding the preferences of potential participants is an important step toward enhancing enrollment in pain treatment trials. Perspective This article presents the preferences of individuals with chronic pain conditions regarding modifiable pain treatment trial characteristics (eg, number of study visits, payment, treatment allocation). These findings may help to improve enrollment into analgesic clinical trials and in turn accelerate the development of new pain treatments.

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.

Clinical trial participants often require additional instruction to prevent idiosyncratic interpretations regarding completion of patient-reported outcomes. The Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership developed a training system with specific, standardized guidance regarding daily average pain intensity ratings. A 3-week exploratory study among participants with low-back pain, osteoarthritis of the knee or hip, and painful diabetic peripheral neuropathy was conducted, randomly assigning participants to 1 of 3 groups: training with human pain assessment (T+); training with automated pain assessment (T); or no training with automated pain assessment (C). Although most measures of validity and reliability did not reveal significant differences between groups, some benefit was observed in discriminant validity, amount of missing data, and ranking order of least, worst, and average pain intensity ratings for participants in Group T+ compared with the other groups. Prediction of greater reliability in average pain intensity ratings in Group T+ compared with the other groups was not supported, which might indicate that training produces ratings that reflect the reality of temporal pain fluctuations. Results of this novel study suggest the need to test the training system in a prospective analgesic treatment trial.

Abuse deterrent formulations (ADF) are designed to prevent the misuse of opioids by tampering (e.g. physical and chemical manipulation) in order to ingest the opioid in a manner other than intended. Extended-release (ER) formulations are formulated with a larger drug load than immediate-release (IR) formulations, which makes ER opioids more desirable to drug abusers than I.R. formulations. ADFs, therefore, are particularly useful with ER opioid agents, which are designed to produce consistent analgesia over prolonged dosing intervals. However, the drug release properties of these formulations vary and sometimes may not provide adequate pain relief throughout the intended dosing interval, requiring patients to take additional medication for pain relief. Oxycodone DETERx* (Xtampza ER * ) is a novel, microsphere-in-capsule opioid formulation, which allows for twice daily dosing (i.e. every 12 hours) and mitigates the ability to tamper with the formulation.To evaluate the durability of pain relief of a novel formulation of oxycodone throughout the 12 hour dosing interval.This study is a post-hoc analysis of 193 subjects in a Phase 3 randomized withdrawal, double-blind, placebo-controlled, enriched-enrollment, parallel-group, multicenter, 12-week clinical study.The analysis evaluated the frequency and distribution of use of oxycodone ER and rescue medication during the Double-blind Maintenance Phase of the study.Usage patterns captured by an electronic diary indicated limited overall and limited per-day use of rescue medication with no increase in rescue medication consumption 8 to 12 hours post-dose, suggesting that subjects did not experience end-of-dose failure during this time period.This study is limited in that it is a post-hoc analysis based on data gathered electronically from a large, prospective, double-blind, randomized, placebo-controlled, Phase 3 clinical study.The evaluation of dosing patterns indicates that this ER oxycodone capsule formulation has durability of effect over the entire 12-hour dosing interval. These data support the use of abuse-deterrent oxycodone ER as a 12-hour dosing formulation.

The heated lidocaine/tetracaine patch (Synera; ZARS Pharma, Inc, Salt Lake City, UT) is among the local topical anesthetic formulations used to prevent procedural pain. This study was conducted to determine the depth and duration of anesthesia provided by the patch and to evaluate safety and tolerability.This randomized, double-blind, placebo-controlled, 2-period crossover study was conducted in healthy subjects. Subjects were randomized to receive either the heated lidocaine/tetracaine patch (active patch) in period 1 and placebo patch in period 2 or vice versa. Patches were applied for 30 mins to the volar aspect of the forearm. Pain and sensory depths were measured at baseline and at 30, 60, 90, and 150 mins after patch application. Duration of anesthesia was measured at 40, 70, 110, and 130 mins after patch application by evaluating thermal and mechanical sensation.A total of 25 subjects were enrolled in the study. Twenty-four subjects completed the study. Pain and sensory depths with the active patch were greater than with placebo (P0.001) at all postdose time points. Maximum mean pain depth achieved with the active patch was 8.22 mm; anesthesia lasted at least 100 mins after patch removal. Cool and warm sensations and hot pain thresholds were increased compared with placebo (P0.001). Light touch and pinprick were detectable by most subjects.The heated lidocaine/tetracaine patch is well tolerated, and it provides favorable depth and duration of anesthesia without significant sensory loss for superficial venous access and minor dermatological procedures after a 30-min application.

For properly selected patients experiencing chronic pain, extended-release opioid formulations may represent an appropriate pain management choice. For the many adults, elderly, and children who have medical conditions that make swallowing solid, oral-dose formulations difficult (dysphagia) or painful (odynophagia), this option may be limited. The combination of chronic pain with dysphagia (CPD) presents a challenge to physicians and patients alike when oral opioid analgesia is needed to control pain, but patients are unable to swallow solid, oral dosage forms.A Medline search was performed (1990 to 2013) using the search terms swallowing difficulties, dysphagia, odynophagia, adults, pediatrics, elderly, chronic pain, pain, and opioids. The following websites were searched: American Dysphagia Network, Dysphagia Research Society, World Health Organization, American Pain Society, International Association for the Study of Pain, American Academy of Pain Medicine, and American Society of Interventional Pain Physicians. Chronic pain guidelines from the following professional organizations were searched: American Pain Society, National Comprehensive Cancer Network, American Society of Interventional Pain Physicians, British Geriatric Society, European Society of Medical Oncology, World Health Organization, and the European Association for Palliative Care.There is an unmet medical need for greater recognition of dysphagia, awareness of potential problems with medication administration in these patients, recognition of alternative drug formulations that are available for use in CPD, and an appreciation that there are new, solid, oral-dose, opioid formulations in development that can mitigate these issues associated with swallowing difficulty while still providing practical, effective analgesia. Current pharmacologic treatments have limitations; new, prospective opioid formulations in clinical development may offer physicians and patients with CPD effective treatment options while mitigating accidental exposure and abuse liability.The number of patients with CPD may be larger than is currently anticipated by healthcare providers. Physicians should proactively include a discussion of dysphagia as part of the patient examination. CPD is an unmet medical need. There are novel opioid formulations in clinical development that address the limitations of current opioid treatments. This manuscript reviews the problems associated with dysphagia on medication administration and adherence, currently available treatment options, and opioid analgesic formulations currently in clinical development.

Background Patients who have chronic pain with dysphagia (difficulty swallowing) (CPD) often have difficulty taking oral medication and, as such, alter their medications by crushing or chewing in an attempt to make it easier to swallow. Such manipulation of currently marketed, extended-release (ER) opioid analgesics can significantly alter the pharmacokinetic (PK) properties of the formulations, resulting in poor treatment outcome or serious adverse events. There is an unmet medical need for oral ER opioid formulations suitable for patients with CPD. Objective The primary objectives of this study were to conduct in vitro studies to evaluate alternate means of administration of a new, extended-release (ER), abuse-deterrent, microsphere-in-capsule formulation of oxycodone for patients with CPD. Specifically, these studies investigated the in vitro equivalence of drug release rates from Oxycodone DETERx® ER intact capsules (control condition) and administration via alternate modes—opening the capsule and sprinkling the microspheres onto soft foods or administration through enteral tubes. Secondary objectives were to compare alternate modes of administration of Oxycodone DETERx® to a commercially available ER-morphine product. Methods Soft food study: Oxycodone DETERx® microspheres were sprinkled onto and mixed with several soft foods (ie, applesauce, vanilla pudding, strawberry jam, yogurt, and vanilla ice cream); the effect of drug contact time (0, 30, and 60 minutes) on drug release was studied. Enteral tube study: Oxycodone DETERx® microspheres were administered through varying sizes of nasogastric (10 and 12 Fr.) tubes and a 16 Fr. gastrostomy tube using 5 different delivery vehicles (ie, water, liquid nutritional feeds [Jevity®, Ensure®], and milk [whole milk and 2% milk]). Drug release rate was characterized using a standard in vitro dissolution methodology; dissolution of intact Oxycodone DETERx® capsules served as the control for both the soft food and enteral tube studies. Oxycodone concentration was measured using a standardized high-performance liquid chromatography (HPLC) assay. Similarity factor (f2) analysis was used to compare similarity of the dissolution profiles of test and control conditions. Results The mean dissolution profile of Oxycodone DETERx® microspheres sprinkled onto and mixed with each of the soft foods were similar (f2 > 50) to that of the control. Study drug–food contact time did not impact dissolution profiles. The dissolution data obtained from Oxycodone DETERx® microspheres passed through enteral feeding tubes of varying sizes were similar (f2 > 50) to that of the control. Unlike a marketed morphine sulfate ER pellet formulation, Oxycodone DETERx® did not clog any of the studied enteral tubes. Conclusion A new ER, abuse-deterrent, microsphere-in-capsule formulation of oxycodone can be administered by sprinkling onto soft food without affecting the drug release profile of the formulation. The formulation can also be administered directly via enteral tubes without affecting drug release and without clogging enteral tubes. Oxycodone DETERx® may offer physicians and patients with CPD an alternate treatment option, especially in those patients who have dysphagia or an aversion to swallowing monolithic tablet/capsule formulations and for whom analgesic patches or other opioid formulations are not a viable therapeutic option.

Objective: We sought to determine the effects of maternally administered morphine on fetal response. Study Design: Singleton pregnancies requiring fetal blood sampling were enrolled. Only study patients were given morphine intramuscularly. Maternal vital signs, fetal heart rate, biophysical profile score, and umbilical artery Doppler indices (systolic/diastolic ratio, resistance index, and pulsatility index) were completed before and after fetal blood sampling. Maternal and cord blood morphine concentrations were measured. Results: Ten study and 6 control patients were enrolled. A significantly lower biophysical profile score was observed in study patients ( P =.001) as a result of absent fetal breathing movements and nonreactive nonstress tests. Gross and fine fetal movements were unaffected. A significant correlation was measured between the biophase morphine concentration and each of the Doppler indices. Conclusion: Morphine administered to the mother causes a significant decrease in the biophysical profile score. Correlation between the biophase morphine concentration and the Doppler indices was calculated. These results suggest that morphine acts as a vasoconstrictor of the placental vasculature but do not support the use of intramuscular morphine to suppress fetal movement. (Am J Obstet Gynecol 2000;183:424-30.)

Background Evidence of fetal damage or demise from occupational organic solvent levels that are not toxic to the pregnant woman is inconsistent in the medical literature. The risk for major malformations and spontaneous abortion from maternal inhalation of organic solvent exposure during pregnancy was summarized using meta-analysis. Methods Medline, Toxline, and Dissertation Abstracts databases were searched to locate all research papers published in any language from 1966 to 1994. Included were studies that were case-control or cohort in design and indicated first trimester (or up to 20 weeks gestation for spontaneous abortion) maternal solvent exposure. A summary odds ratio (ORs) with 95% confidence intervals (CI) was calculated from research results combined by the Mantel-Haenszel method. Results In total, 559 studies were obtained from the literature search. Five studies for each outcome of interest qualified for inclusion in the analysis. The ORs for major malformations from five studies (n = 7,036 patients) was 1.64 (CI 1.16–2.30) and for spontaneous abortion from five studies (n = 2,899 patients) was 1.25 (CI 0.99–1.58). Conclusions Maternal occupational exposure to organic solvents is associated with a tendency toward an increased risk for spontaneous abortion and additional studies may affect the trend. There is a statistically significant association with major malformations which warrants further investigation. Am. J. Ind. Med. 34:288–292, 1998. © 1998 Wiley-Liss, Inc.

This retrospective chart review presents the patient characteristics and utilization of the home-based palliative care program at The Hospital for Sick Children in Toronto. A total of 126 children dying from a broad spectrum of diseases was admitted during the period 1986–1994, referred from neurosurgery, genetic/metabolic, neurology, neonatology, nephrology, cardiology, general pediatrics, general surgery, and pulmonology. At the time of review, 15 patients remained alive and 18 had been discharged from the program. Mean age at the time of referral was 4.8 ± 0.51 years and mean age at death was 5.3 ± 0.55 years. The mean number of days in hospital was 26.5 ± 14.6 while days spent at home averaged 98.4 ± 15.2; thus 80% of the children's remaining time was spent at home. The average number of parent-team contacts was 3.5 ± 0.9 by pager and 24.0 ± 2.9 by telephone. Of the 93 patients who died in the program, 53% died at home, 18% died in community hospitals, and 29% died in a tertiary care facility. Analgesic medications were administered to 54% of the patients; 56% of these then required opioid analgesia for pain and symptom management. Home-based palliative care appeared to be an effective program for many children with a variety of terminal illnesses after adequate supports for the child and family had been established.

This study sought to determine whether saliva concentrations of morphine correlate with plasma levels of morphine in pediatric patients receiving morphine analgesia for severe pain, and to evaluate whether the measurement of saliva morphine concentrations would be a useful, noninvasive, clinical tool to diagnose systemic exposure to morphine. Fifteen pediatric patients were enrolled; for the control group, 18 adult volunteers were recruited. Patients received continuous morphine drips to ameliorate pain caused by a sickle cell vasoocclusive crisis (range, 10-40 micrograms/kg.h). Control subjects were randomized into those receiving acetaminophen with either 8 mg (n = 13) or 30 mg (n = 5) of codeine. All participants fasted at least 2 hours before sample collection. Blood and saliva samples were collected simultaneously. All samples were analyzed by radioimmunoassay for morphine. There was no correlation between saliva and plasma morphine concentrations in either the patients receiving intravenous morphine (r = 0.04, P = 0.89) or in the controls receiving codeine (r = 0.43, P = 0.08). There was no observed difference in the mean counts per minute (CPM) for saliva samples in the pH range 3.96 to 8.06. Saliva concentrations of morphine cannot be used to predict the plasma concentration of morphine in children or adults. However, the concentration of morphine in saliva may be used as a qualitative indicator of systemic exposure to morphine in a subject.

Dysphagia--difficulty eating and swallowing--can significantly impair a patient's ability to maintain adequate nutritional and medication intake. There are a large number of patients with chronic pain, including pediatric, geriatric, and palliative care patients, who suffer from dysphagia and, therefore, have difficulty achieving optimal pain management with solid, oral formulations. The objective of this study was to survey physicians and patients in the US to understand their knowledge, attitudes, and clinical management/analgesic usage patterns in the treatment of patients with chronic pain with dysphagia (CPD).Two separate surveys were administered to physicians and patients. The physician survey design was qualitative; physicians participated in a semi-structured phone interview. The patient survey design was quantitative; patients participated in a structured online survey. Purposive sampling was used to recruit participants into both studies. Physician participants were identified based on their specialty, prescribing practices, and geographic location. Patient participants were recruited through a consumer panel of pre-identified individuals who, for 3 months or longer, had chronic pain and were taking opioids.Thirty-four physicians and 1021 patients were surveyed. Physicians indicated that 5-20% of their patients had difficulty swallowing. Treatment for CPD consisted of the fentanyl patch, immediate-release opioids, methadone liquid, or extended-release morphine products. Physicians were not satisfied with currently available treatment options. Twenty-nine per cent of patients surveyed had trouble swallowing or disliked swallowing pills. Eighty per cent of patients were not asked about their ability to swallow solid, oral dosage forms by their physician. To circumvent swallowing difficulties, some patients (16%) cut/crush/grind their medication to facilitate swallowing. Most of these patients (65%) did not know that altering tablets could potentially change the drug release (pharmacokinetic) characteristics of the tablet and lead to serious adverse events.Qualitative survey research can be influenced by responder bias as well as selection bias. The number of survey participants for both the physician and patient surveys was small, thus responses may not reflect those in the general population.A proportion of patients with chronic pain have dysphagia and cannot swallow solid, oral dosage forms, which creates a serious treatment challenge for pain specialists and other healthcare providers. Currently available treatment options have limitations; new treatment options would be welcomed by both physicians and patients. Physician and patient education should be enhanced in order to promote awareness of the deleterious consequences associated with altering currently available analgesic formulations. Facilitating patient-physician communication on this topic may help to improve treatment outcomes.

Oxycodone DETERx® is an extended-release (ER), microsphere-in-capsule abuse-deterrent-formulation designed to retain its extended-release properties following tampering or misuse (e.g., chewing, crushing). This study assessed the safety and pharmacokinetics of orally administered intact and crushed Oxycodone DETERx® capsules compared with intact and crushed reformulated OxyContin® tablets and crushed immediate-release oxycodone tablets (IR oxycodone).This was a randomized, open-label, active-controlled, cross-over study. Healthy subjects received five oxycodone treatments (40 mg) with a standardized high-fat, high-calorie meal: Oxycodone DETERx® (intact or crushed), OxyContin® (intact or crushed), and IR oxycodone (crushed). Blood samples were collected for assessment of oxycodone plasma concentrations.Thirty-eight subjects completed the study. Both crushed and intact Oxycodone DETERx® resulted in lower peak plasma concentrations when compared with IR oxycodone. Crushed Oxycodone DETERx® was bioequivalent to intact Oxycodone DETERx® and exhibited a numerically lower Cmax . Also, median Tmax was unchanged by crushing. In contrast, mean peak plasma oxycodone concentrations for crushed OxyContin® were significantly higher compared with intact OxyContin® and were bioequivalent to IR oxycodone. Median Tmax for crushed OxyContin® was the same as IR oxycodone and 3.25 hours shorter than intact OxyContin®.These data demonstrate that when crushed and taken orally, Oxycodone DETERx® maintains its EXTENDED-release profile, while crushed OxyContin® shows a pharmacokinetic profile similar to an immediate-release product. These results suggest that Oxycodone DETERx® may be less attractive to illicit drug users compared with existing abuse-deterrent-formulations, while providing a safer option for patients who may unknowingly crush their medication such as those who have difficulty swallowing.

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.

A number of pharmacologic treatments examined in recent randomized clinical trials (RCTs) have failed to show statistically significant superiority to placebo in conditions in which their efficacy had previously been demonstrated. Assuming the validity of previous evidence of efficacy and the comparability of the patients and outcome measures in these studies, such results may be a consequence of limitations in the ability of these RCTs to demonstrate the benefits of efficacious analgesic treatments vs placebo ("assay sensitivity"). Efforts to improve the assay sensitivity of analgesic trials could reduce the rate of falsely negative trials of efficacious medications and improve the efficiency of analgesic drug development. Therefore, an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials consensus meeting was convened in which the assay sensitivity of chronic pain trials was reviewed and discussed. On the basis of this meeting and subsequent discussions, the authors recommend consideration of a number of patient, study design, study site, and outcome measurement factors that have the potential to affect the assay sensitivity of RCTs of chronic pain treatments. Increased attention to and research on methodological aspects of clinical trials and their relationships with assay sensitivity have the potential to provide the foundation for an evidence-based approach to the design of analgesic clinical trials and expedite the identification of analgesic treatments with improved efficacy and safety.

Objective . Evaluate the human abuse potential (HAP) of an experimental, microsphere-in-capsule formulation of extended-release oxycodone (oxycodone DETERx®) (herein “DETERx”). Design . Randomized, double-blind, double-dummy, positive- and placebo-controlled, single-dose, four-phase, four-treatment, crossover study. Setting . Clinical research site. Subjects . There were 39 qualifying subjects (72% male, 85% white, mean age of 27 years) with 36 completing all four Double-blind Treatment Periods. Methods . The four phases encompassed: 1) Screening; 2) Drug Discrimination; 3) Double-blind Treatment; and 4) Follow-up. Drug Discrimination tests ensured that subjects could distinguish placebo from opioid. The four Double-blind Treatments compared DETERx—administered as either a crushed intranasal (IN) or an intact oral (PO) preparation—with immediate-release oxycodone IN (OXY-IR IN) and with an intact IN and PO placebo DETERx control. Results . For primary pharmacokinetic (PK) assessments, abuse quotient (Cmax/Tmax) was lower with DETERx IN than DETERx PO; both treatments were substantially lower than OXY-IR IN (6.24, 8.60, and 69.6 ng/mL/h, respectively). For drug liking, the primary subjective pharmacodynamic (PD) endpoint, both DETERx IN and DETERx PO produced significantly lower scores than OXY-IR IN ( P ≤ 0.0001 for each); DETERx IN was less liked than DETERx PO ( P ≤ 0.05), mirroring the PK relationships. Objectively assessed pupillometry corroborated the more rapid and significantly greater effect of OXY-IR IN than either DETERx IN or DETERx PO ( P ≤ 0.007 for each). Overall safety profiles of DETERx and OXY-IR were comparable and both were well tolerated. Conclusions . Pharmacokinetic and pharmacodynamic outcomes suggest that DETERx IN has relatively low HAP; continued research in larger populations is suggested.

Background The etiology of acute chest syndrome, the most severe complication of the sickle cell crisis, is unknown. Objective Our objective was to assess exposure to morphine as an etiologic factor for acute chest syndrome in sickle cell disease. Methods A post hoc analysis of a randomized controlled trial comparing oral with continuous infusion of morphine was performed. Children (aged 5–17 years) with sickle cell crisis were randomized to receive oral sustained-release morphine, 1.9 mg · kg−1 · 12 h−1, or a continuous intravenous infusion of morphine at 0.04 mg · kg−1 · h−1 by use of a double-blind, placebo-controlled design. In a subgroup of 15 patients, the pharmacokinetics of morphine and its active metabolite morphine-6-glucuronide were also studied. Results At baseline, demographic and physiologic characteristics were similar between groups. There were no differences in the number of previous rescue doses per day, painful sites per episode, physician contacts per year, and hospitalizations per year between treatment arms. There was a 2-fold higher morphine area under the concentration-time curve at steady state (AUCss) and a 3-fold higher morphine-6-glucuronide AUCss with oral morphine than with a continuous intravenous infusion of morphine (P < .001 and P < .006, respectively). New onset of acute chest syndrome was 3-fold more prevalent in the oral group (57%) versus the continuous intravenous infusion group (17%) (P < .001). Conclusions The risk of acute chest syndrome is significantly associated with high systemic exposure to morphine and its active metabolite morphine-6-glucuronide after oral administration of slow-release morphine. Morphine may facilitate respiratory deterioration by eliciting a decrease in oxygen saturation, by inducing histamine release, or through an as-yet-unidentified mechanism. The safe systemic exposure to morphine in terms of area under the concentration-time curve should be further studied in children with sickle cell disease. Clinical Pharmacology & Therapeutics (2004) 75, 140–146; doi: 10.1016/j.clpt.2003.10.007

Summary Background Oral controlled-release morphine can provide effective analgesia through a non-invasive route and may facilitate outpatient management of severe episodes of sickle-cell pain. We compared the clinical efficacy and safety of oral morphine with continuous intravenous morphine in children with severe episodes of sickle-cell pain, by a double-blind, randomised, parallel-group design. Methods 56 children aged 5–17 years received loading doses of intravenous morphine of up to 0.15 mg/kg, followed by randomly assigned oral morphine 1.9 mg/kg every 12 h plus intravenous placebo (saline), or intravenous morphine 0.04 mg kg −1 h −1 , plus placebo tablet. Breakthrough pain was treated with oral, immediate-release morphine 0.4 mg/kg every 2–3 h as required. Pain was assessed daily at 0900 h, 1300 h, 1700 h, and 2100 h with a picture face scale, a pictorial scale (Oucher), a behavioural-observational scale (CHEOPS), and by an investigator. Findings 50 children completed the study (28 boys, 22 girls; mean age 11.2 years [SD 3.5]; mean oral morphine dose 2.99 mg/kg daily [0.75]; mean intravenous morphine dose, 0.81 mg/kg daily [0.30]). Mean overall pain scores were similar for oral and intravenous morphine (CHEOPS, 6.3 [1.5] vs 6.4 [1.4], p=0.8; Oucher, 31.5 [25.4] vs 39.2 [21.7], p=0.3; Faces, 2.2 [1.4] vs 2.4 [1.3], p=0.6; clinical rating, 1.7 [0.7] vs 1.9 [0.5], p=0.3). Opioid analgesia was required for a mean of 4.2 days (1.7) and 5.4 days (2.6), respectively (p=0.0591). Pain scores from all scales correlated significantly ( r =0.5865–0.8980, p=0.0001). Frequency of rescue analgesia did not differ significantly between the oral and intravenous morphine groups (0.7 [0.8] vs 0.9 [0.7] doses daily, p=0.2). Frequency and severity of adverse events did not differ significantly. Interpretation Oral, controlled-release morphine is a reliable, non-invasive alternative to continuous intravenous morphine for the management of painful episodes of sickle-cell disease in children.

Antimetabolites such as 5-fluorouracil and mitomycin C are known to delay wound healing. Epidermal growth factor (EGF) has been shown to accelerate corneal epithelial wound healing. This study was designed to investigate the effects of EGF on corneal epithelial healing that has been modified by antimetabolite treatment. New Zealand White rabbits were pretreated with either saline (controls) or 5-fluorouracil (5FU) injected subconjunctivally, or mitomycin C (MMC) applied topically. Circular anterior stromal wounds were created, followed by a 6-hour perfusion of normal saline or 50 micrograms/ml of EGF. Subconjunctival saline or 5FU, or topical MMC treatments were continued after wounding for a total of 6 days. Corneas were photographed and quantitative morphometry of the wound site was performed. Compared with saline controls, MMC significantly delayed wound healing (P0.05) whereas 5FU did not (P0.05). Compared with 5FU, MMC significantly delayed wound healing with either normal saline or EGF perfusion (P0.05). In the presence of either 5FU or MMC, EGF perfusion had no significant effect on the corneal wound-healing rate (P0.05). Corneal wound healing is not affected by subconjunctivally injected 5FU while it is delayed by topically applied MMC. EGF treatment does not overcome the inhibitory effects of MMC. EGF therapy may not be useful in the treatment of complications related to antimetabolite therapy.