Health-related quality of life in patients given ciltacabtagene autoleucel for relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b-2, open-label study.

BACKGROUND: CARTITUDE-1 is a phase 1b-2 study evaluating ciltacabtagene autoleucel (cilta-cel), a chimeric antigen receptor T cell therapy with two B-cell maturation antigen-targeting single-domain antibodies, in patients with relapsed or refractory multiple myeloma. Primary efficacy outcomes have previously been reported. Here, we report health-related quality of life (HRQOL) secondary outcomes evaluated using patient-reported outcomes. METHODS: This single-arm, open-label, phwase 1b-2 study was done at 16 centres in the USA. Patients were aged 18 years or older with diagnosis of multiple myeloma and Eastern Cooperative Oncology Group performance status of 1 or less with three or more previous lines of therapy, or were double refractory to a proteasome inhibitor and immunomodulatory drug, and had received a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. A single cilta-cel infusion (target dose 0·75 × 106 CAR+ T cells per kg) was administered 5-7 days after lymphodepletion. Patient-reported outcomes were assessed using the European Organisation for Research and Treatment of Cancer (EORTC) quality of life questionnaire core 30-item, pre-specified items from the EORTC myeloma module, and EuroQol five-dimensional descriptive system questionnaire. Clinically meaningful changes in patient-reported outcomes were defined by anchor-based minimally important differences. This trial is registered with ClinicalTrials.gov, NCT03548207. This trial is completed but feeding into a long-term follow-up study. FINDINGS: Between July 16, 2018, and Oct 7, 2019, 78 patients were enrolled and underwent apheresis in phase 2 of the study. 68 patients were treated (43 [63%] male, 49 [72%] White), and their patient-reported outcomes assessed (median follow-up 16·9 months, IQR 15·7-17·5). After infusion, a transient decline was observed, followed by improvements in global health status (mean change from baseline to day 464 +8·0 points, SD 20·9), physical (+4·6 points, 21·1), and emotional functional scales (+1·9 points, 23·7) over time, and declines for symptom-based scores (-14·1 pain, SD 31·5 and -15·4 fatigue; SD 29·5), indicating improved patient HRQOL following treatment with cilta-cel. INTERPRETATION: These durable HRQOL improvements are consistent with clinical findings, in which a single cilta-cel infusion led to substantial and durable responses in heavily pre-treated patients with relapsed or refractory multiple myeloma. These results support the use of cilta-cel in patients with relapsed or refractory multiple myeloma. FUNDING: Janssen Research & Development and Legend Biotech USA.

Health-related Quality of Life at the SPARTAN Final Analysis of Apalutamide for Nonmetastatic Castration-resistant Prostate Cancer Patients Receiving Androgen Deprivation Therapy.

BACKGROUND: In SPARTAN, apalutamide improved metastasis-free and overall survival for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) with a prostate-specific antigen doubling time of ≤10 mo. OBJECTIVE: We evaluated health-related quality of life (HRQoL) at the final analysis of the SPARTAN study. INTERVENTION: Patients received apalutamide (240 mg/d) or placebo in 28-d cycles. All patients continued androgen deprivation therapy (ADT). DESIGN, SETTING, AND PARTICIPANTS: A total of 1207 patients with nmCRPC were randomized 2:1 to apalutamide or placebo. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: HRQoL was assessed using Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D-3L questionnaires at day 1 of cycle 1 (predose/baseline), cycles 2-6, every two cycles during cycles 7-13, every four cycles thereafter, at the end of treatment, and every 4 mo after progression to 1 yr. Results are presented using descriptive statistics. A mixed model for repeated measures was fitted to estimate the mean scores at each scheduled visit during treatment. RESULTS: At final analysis, with 52 mo follow-up for survival, the median treatment duration was 32.9 mo for apalutamide and 11.5 mo for placebo. Patients had good baseline HRQoL. At each scheduled collection during treatment, >90% per group completed the questionnaires. The change in FACT-P total score from baseline to cycles 21 and 25 significantly favored apalutamide over placebo (p = 0.0138 and 0.0009, respectively). The apalutamide group generally maintained favorable FACT-P (total and subscales) and EQ-5D-3L scores, while placebo scores tended to decline over time (starting in cycles 11-13 and pronounced by cycles 21-25). Notably, patient-reported fatigue did not worsen with apalutamide. Most patients reported being "not at all bothered" by side effects, and bother did not increase over time with apalutamide or placebo. Patients receiving apalutamide had minimal change in side-effect bother following symptomatic adverse events. CONCLUSIONS: Final analysis of SPARTAN confirms that HRQoL is preserved in patients with nmCRPC receiving apalutamide plus ADT, but declines in patients receiving placebo plus ADT after approximately 1 yr. PATIENT SUMMARY: Responses from patients with prostate cancer who were included in the SPARTAN study indicated that treatment with apalutamide, even after the most extensive follow-up time possible, did not reduce their quality of life. These results, along with improved survival and longer time to the development of metastases (reported separately), confirm the benefits of apalutamide for patients with nonmetastatic castration-resistant prostate cancer.

Patient-reported symptom burden of chronic graft versus host disease: a systematic literature review.

INTRODUCTION: Chronic graft-versus-host disease (GVHD) is a life-threating complication of allogeneic hematopoietic stem cell transplantation (HSCT) leading to high morbidity and quality of life issues. We conducted a systematic literature review on the patient reported symptom burden of chronic GVHD. AREAS COVERED: English-language articles published between 2005 and November 2018 were searched using CENTRAL, EMBASE and MEDLINE. Studies that used the 2005 or 2015 National Institute of Health consensus criteria for the diagnosis and staging of chronic GVHD were included. EXPERT OPINION: Patient reported symptom burden was widely assessed in the literature (n = 38). The Lee Chronic GVHD Symptom Scale was the most frequently used instrument (n = 28), followed by the NIH Patient-reported Symptom scores (n = 11). Association of symptom burden with clinical outcome assessment endpoints (e.g. mortality) and with quality of life measures was investigated by fairly low number of studies with limited generalizability. By systematically investigating the influencing factors of symptom burden this review helps to better understand patients' perceptions and may help improving the management and care of chronic GVHD. However, data on influencing factors was quite diverse, which indicates that specific questions identified as research gaps need to be incorporated in randomized clinical trials in a more systematic way.

Content validity of patient-reported outcomes for use in lower-risk myelodysplastic syndromes.

BACKGROUND: The lower-risk (low and intermediate-1 risk based on IPSS) myelodysplastic syndrome (MDS) has a negative impact on patients' health-related quality of life (HRQoL). Patient Reported Outcomes (PROs) instruments, which are used to collect patients' HRQoL data, should have established content validity in the target population to ensure that the instrument is comprehensive and comprehensible. The present study was conducted to evaluate the content validity of the Quality of Life in Myelodysplasia Scale (QUALMS) and the Functional Assessment of Cancer Therapy-Anemia (FACT-An) PRO instruments in patients with lower-risk MDS. METHODS: In this cross-sectional, qualitative study, 16 patients aged ≥18 years with lower-risk MDS, who were RBC transfusion dependent, literate and fluent in US-English were interviewed. Interviews were semi-structured comprising of two parts: concept elicitation (CE) explored symptoms and impacts important to patients, and cognitive debriefing (CD) assessed understanding and relevance of the QUALMS and FACT-An. A conceptual model was developed, which was used to map the concepts that emerged during CE onto the QUALMS and FACT-An to assess concept coverage and suitability of the instruments. RESULTS: The median age of participants was 67.5 years (range: 51-91), with half being female (n = 8). Nine (56.2%) participants had intermediate-1-risk MDS and 10 (62.5%) were relapsed or refractory to erythropoiesis-stimulating agent treatment. Fatigue/tiredness (100.0%), shortness of breath (87.5%), weakness (81.2%), and low energy (75.0%) were reported most commonly and were the most bothersome symptoms as well. Of seven high-level HRQoL domains identified, activities of daily living (n = 16, 100.0%), physical functioning (n = 15, 93.8%), emotional wellbeing (n = 13, 81.3%), social functioning (n = 12, 75.0%), sleep disturbance (n = 9, 56.3%), and impact on work (n = 9, 56.3%) were the most commonly reported. For CD, the QUALMS and FACT-An were found to be mostly relevant and very well understood; response options were easy to use, and recall period was appropriate. CONCLUSION: Both QUALMS and FACT-An demonstrated a strong face and content validity in patients with lower-risk MDS, suggesting that these instruments are appropriate for assessing HRQoL in this population.

Quantifying the importance of inhaler attributes corresponding to items in the patient satisfaction and preference questionnaire in patients using Combivent Respimat.

BACKGROUND: Physicians consider ease of use, satisfaction, and preferences when prescribing an inhaler device. These factors may impact appropriate usage and compliance. METHODS: The objectives were to quantify the relative importance of inhaler attributes in patients currently using Combivent Respimat by eliciting preferences for performance and convenience attributes assessed by items in the Patient Satisfaction and Preference Questionnaire (PASAPQ). Using a pharmacy database, 19,964 adults in the United States who filled ≥2 Combivent Respimat prescriptions were identified. Of those, 8150 patients were randomly selected to receive invitation letters. The online cross-sectional survey included the PASAPQ and best-worst scaling (BWS) questions. The PASAPQ measures satisfaction with medication attributes across two domains: performance and convenience. BWS questions asked participants to select the most and least important device attributes. A descriptive statistics analysis of the PASAPQ and a random-parameters logit model of BWS responses were conducted. RESULTS: The survey was completed by 503 participants. Most were female (57.3%), white (88.5%), and 51-70 years old (67.6%). Approximately 47% reported a chronic obstructive pulmonary disease diagnosis, 21.9% asthma, 8.2% other lung disease, and 23.1% more than one lung disease. PASAPQ scores indicated that the majority were satisfied or very satisfied; up to 20% reported being dissatisfied with Combivent Respimat. The three most important inhaler attributes were Feeling that your medicine gets into your lungs, Inhaler works reliably, and Inhaler makes inhaling your medicine easy. The most important attributes corresponded to six of seven items in the PASAPQ performance domain. CONCLUSIONS: Most participants reported satisfaction with Combivent Respimat. Performance attributes were more important than convenience attributes.

A randomized study to evaluate the analgesic efficacy of a single dose of the TRPV1 antagonist mavatrep in patients with osteoarthritis.

BACKGROUND/AIMS: Transient receptor potential vanilloid type 1 (TRPV1) receptor antagonists have been evaluated in clinical studies for their analgesic effects. Mavatrep, a potent, selective, competitive TRPV1 receptor antagonist has demonstrated pharmacodynamic effects consistent with target engagement at the TRPV1 receptor in a previous single-dose clinical study. The current study was conducted to evaluate the analgesic effects of a single dose of mavatrep. METHODS: In this randomized, placebo- and active-controlled, 3-way crossover, phase 1b study, patients with painful knee osteoarthritis were treated with a single-dose of 50mg mavatrep, 500mg naproxen twice-daily, and placebo. Patients were randomized to 1 of 6 treatment sequences. Each treatment sequence included three treatment periods of 7 days duration with a 7 day washout between each treatment period. The primary efficacy evaluation was pain reduction measured by the 4-h postdose sum of pain intensity difference (SPID) based on the 11-point (0-10) Numerical Rating Scale (NRS) for pain after stair-climbing (PASC). The secondary efficacy evaluations included 11-point (0-10) NRS pain scores entered into the Actiwatch between clinic visits, the Western Ontario and McMaster Universities Arthritis Index subscales (WOMAC) questionnaire, and use of rescue medication. Safety and tolerability of single oral dose mavatrep were also assessed. RESULTS: Of 33 patients randomized, 32 completed the study. A statistically significantly (p<0.1) greater reduction in PASC was observed for mavatrep versus placebo (4-h SPID least square mean [LSM] [SE] difference: 1.5 [0.53]; p=0.005 and 2-h LSM [SE] difference of PID: 0.7 [0.30]; p=0.029). The mean average daily current pain NRS scores were lower in the mavatrep and naproxen treatment arm than in the placebo arm (mavatrep: 7 day mean [SD], 3.72 [1.851]; naproxen: 7 day mean [SD], 3.49 [1.544]; placebo: 7 day mean [SD], 4.9 [1.413]). Mavatrep showed statistically significant improvements as compared with placebo on the WOMAC subscales (pain on days 2 [p=0.049] and 7 [p=0.041], stiffness on day 7 [p=0.075]), and function on day 7 [p=0.077]). The same pattern of improvement was evident for naproxen versus placebo. The mean (SD) number of rescue medication tablets taken during the 7-day treatment period was 4.2 (6.49) for mavatrep treatment, 2.8 (5.42) for naproxen, and 6.3 (8.25) for placebo treatment. All patients that received mavatrep reported at least 1 treatment emergent adverse event (TEAE). Feeling cold (79%), thermohypoesthesia (61%), dysgeusia (58%), paraesthesia (36%), and feeling hot (15%) were the most common TEAEs in the mavatrep group. Total 9% patients receiving mavatrep experienced minor thermal burns. No deaths or serious AEs or discontinuations due to AEs occurred. CONCLUSION: Overall, mavatrep was associated with a significant reduction in pain, stiffness, and physical function when compared with placebo in patients with knee osteoarthritis. Mavatrep's safety profile was consistent with its mechanism of action as a TRPV1 antagonist. IMPLICATIONS: Further studies are required to evaluate whether lower multiple doses of mavatrep can produce analgesic efficacy while minimizing adverse events, as well as the potential for improved patient counselling techniques to reduce the minor thermal burns related to decreased heat perception. TRIAL REGISTRATION: 2009-010961-21 (EudraCT Number).

Initial development of a patient-reported outcome measure of experience with cognitive impairment associated with schizophrenia.

Cognitive impairment is a serious, often distressing aspect of schizophrenia that affects patients' day-to-day lives. Although several interview-based instruments exist to assess cognitive functioning, a reliable measure developed based on the experiences of patients facing cognitive difficulties is needed to complement the objective performance-based assessments. The present article describes the initial development of a patient-reported outcome (PRO) measure to assess the subjective experience of cognitive impairment among patients with schizophrenia, the Patient-Reported Experience of Cognitive Impairment in Schizophrenia (PRECIS). The phases of development included the construction of a conceptual model based on the existing knowledge and two sets of qualitative interviews with patients: 1) concept elicitation interviews to ensure face and content validity from the perspective of people with schizophrenia and 2) cognitive debriefing of the initial item pool. Input from experts was elicited throughout the process. The initial conceptual model included seven domains. The results from concept elicitation interviews (n=80) supported these domains but yielded substantive changes to concepts within domains and to terminology. Based on these results, an initial pool of 53 items was developed to reflect the most common descriptions and languages used by the study participants. Cognitive debriefing interviews (n=22) resulted in the removal of 18 items and modification of 22 other items. The remaining 35 items represented 23 concepts within six domains plus two items assessing bother. The draft PRO measure is currently undergoing psychometric testing as a precursor to broad-based clinical and research use.

Measures That Identify Prescription Medication Misuse, Abuse, and Related Events in Clinical Trials: ACTTION Critique and Recommended Considerations.

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.

Development and preliminary validation of the focused analgesia selection test to identify accurate pain reporters.

Clinical trials of analgesics have been plagued with poor assay sensitivity due, in part, to variability in subjects' pain reporting. Herein, we develop and evaluate the focused analgesia selection test (FAST), a method to measure patients' pain reporting skills. Subjects with osteoarthritis of the hip, knee, and/or ankle with pain intensity of ≥3/10 on a 0-10 numerical rating scale were enrolled. Subjects underwent the FAST procedure, which consists of recording subjects' pain reports in response to repeated administration of thermal noxious stimuli of various intensities applied on the arm with the Medoc® Thermal Sensory Analyzer II. Subjects also rated non-noxious stimuli consisting of visual contrast rating. After performing an exercise task, subjects also rated clinical pain and were asked to report whether their pain had increased, decreased, or stayed the same. Overall, 88 subjects were enrolled, and 83 were included in the analyses. FAST's outcomes including the R2, intraclass correlation coefficient (ICC), and coefficient of variation (CoV) indicated that subjects' pain reporting skills were widely distributed. Higher FAST ICC significantly predicted greater changes in clinical pain following exercise (p=0.017), whereas the visual contrast test did not predict postexercise pain. FAST is the first method that measures subjects' pain reporting skills. Using FAST to enrich clinical trials with "good" pain reporters (with high FAST ICC) could increase assay sensitivity. Further evaluation of FAST is ongoing.

Response scale selection in adult pain measures: results from a literature review.

BACKGROUND: The purpose of this literature review was to examine the existing patient-reported outcome measurement literature to understand the empirical evidence supporting response scale selection in pain measurement for the adult population. METHODS: The search strategy involved a comprehensive, structured, literature review with multiple search objectives and search terms. RESULTS: The searched yielded 6918 abstracts which were reviewed against study criteria for eligibility across the adult pain objective. The review included 42 review articles, consensus guidelines, expert opinion pieces, and primary research articles providing insights into optimal response scale selection for pain assessment in the adult population. Based on the extensive and varied literature on pain assessments, the adult pain studies typically use simple response scales with single-item measures of pain-a numeric rating scale, visual analog scale, or verbal rating scale. Across 42 review articles, consensus guidelines, expert opinion pieces, and primary research articles, the NRS response scale was most often recommended in these guidance documents. When reviewing the empirical basis for these recommendations, we found that the NRS had slightly superior measurement properties (e.g., reliability, validity, responsiveness) across a wide variety of contexts of use as compared to other response scales. CONCLUSIONS: Both empirical studies and review articles provide evidence that the 11-point NRS is likely the optimal response scale to evaluate pain among adult patients without cognitive impairment.

Development and feasibility of the misuse, abuse, and diversion drug event reporting system (MADDERS®).

BACKGROUND AND OBJECTIVES: Inappropriate use of analgesic drugs has become increasingly pervasive over the past decade. Currently, drug abuse potential is primarily assessed post-marketing; no validated tools are available to assess this potential in phase II and III clinical trials. This paper describes the development and feasibility testing of a Misuse, Abuse, and Diversion Drug Event Reporting System (MADDERS), which aims to identify potentially abuse-related events and classify them according to a recently developed classification scheme, allowing the quantification of these events in clinical trials. METHODS: The system was initially conceived and designed with input from experts and patients, followed by field-testing to assess its feasibility and content validity in both completed and ongoing clinical trials. RESULTS: The results suggest that MADDERS is a feasible system with initial validity. It showed higher rates of the triggering events in subjects taking medications with known abuse potential than in patients taking medications without abuse potential. Additionally, experts agreed on the classification of most abuse-related events in MADDERS. DISCUSSION AND CONCLUSIONS: MADDERS is a new systematic approach to collect information on potentially abuse-related events in clinical trials and classify them. The system has demonstrated feasibility for implementation. Additional research is ongoing to further evaluate its validity. SCIENTIFIC SIGNIFICANCE: Currently, there are no validated tools to assess drug abuse potential during clinical trials. Because of its ease of implementation, its systematic approach, and its preliminary validation results, MADDERS could provide such a tool for clinical trials. (Am J Addict 2016;25:641-651).

Social Influence on Adolescent Polysubstance Use: The Escalation to Opioid Use.

BACKGROUND: Fewer than 9% of 12-17 year olds in need (∼146,000 of 1.7 million) receive inpatient or outpatient substance abuse recovery services or other mental health services (SAMHSA, 2012). The literature on adolescent addiction is sparse, however, as most published addiction recovery efforts involve adult populations-often college students. OBJECTIVES: The present study examined social influences on escalating substance use (from tobacco, alcohol, and marijuana use to polysubstance use involving opioids) for students enrolled in recovery high schools. METHODS: A sample of 31 adolescents enrolled in substance use recovery high schools were surveyed on their patterns of substance use leading to their abuse of opioids. RESULTS: Youth who begin their substance use as young as age 8 are often pressured by peer culture to do so and come from substance-using families. Their escalation in polysubstance use to a pattern including opioids was also most often attributed to peer influence over several years. Conclusions/Importance: This paper is one of scant few that address patterns of use in high school students. Perhaps most salient from this study are the tertiary prevention implications: similar to their adult counterparts, students enrolled in recovery high school programs are likely from substance-using families and have combined complex constellations of substances including opioids by dint of their relationships with substance-using peers.

Validation of the Hospital Anxiety and Depression Scale in Patients With Acute Low Back Pain.

UNLABELLED: The Hospital Anxiety and Depression Scale (HADS) is a self-report instrument used to evaluate depression and anxiety in clinical research. The HADS has advantages over other assessments of anxiety and depression; it is efficient in assessing both anxiety and depression with a total of 14 items, and it was originally developed on a general medical rather than psychiatric sample. However, the HADS has not been evaluated specifically for use in clinical trials of acute pain. Validation analyses were conducted on data from a randomized, double-blind, parallel-group study of tapentadol immediate release vs oxycodone immediate release for acute low back pain (N = 666). Analyses of psychometric properties, internal consistency, convergent validity, assessments of bias, and confirmatory factor analysis were conducted on pretreatment data. Additional analyses were performed to test the responsiveness and predictive validity of the HADS. Both the Anxiety and Depression subscales (1) showed good psychometric properties, (2) had high internal consistency, (3) displayed good convergent validity, (4) had no unexpected biases, (5) fit the a priori factor structure, and (6) were highly sensitive to changes as a result of analgesic treatment. We conclude that the HADS is a valid instrument for efficient, low-burden assessment of anxiety and depression in clinical trials with an acute low back pain population. PERSPECTIVE: Considered together with the results of other recent studies, the data suggest that the HADS can provide a valid, responsive, and efficient assessment of anxiety and depression in acute low back pain for clinical trials and other clinical research examining acute pain populations.

Predicting Response to Subacromial Injections and Lidocaine/Tetracaine Patch from Pretreatment Pain Quality in Patients with Shoulder Impingement Syndrome.

OBJECTIVES: No existing pain treatment is effective for all pain problems, and response to pain treatment is highly variable. Knowledge regarding the patient factors that predict response to different treatments could benefit patients by providing an empirical foundation for patient-treatment matching. This study sought to test the hypothesis that improvements following two treatments thought to operate via similar mechanisms would be predicted by similar baseline pain qualities. DESIGN: Prospective prediction analysis using data from a previously published open label trial comparing a heated lidocaine/tetracaine patch versus subacromial corticosteroid injection for the treatment of pain in individuals with shoulder impingement syndrome. RESULTS: Consistent with the study hypothesis, the response to the two treatments were predicted by similar baseline pain qualities; specifically, higher baseline levels of unpleasant, electric, and sensitive pain predicted subsequent improvements in sleep interference, work/activity interference, and patient global ratings of improvement, respectively. CONCLUSIONS: The findings are consistent with the combined ideas that (1) those who have the most to gain (i.e., those reporting the highest levels of various pain qualities) can expect the best response to effective treatments and (2) different pain qualities may be associated with different types of outcomes. The findings support further research to examine how pain quality measures may be used to improve patient-treatment matching, and therefore, ultimately improve the efficiency, efficacy, and overall benefit-risk of pain treatment.

Root cause analysis of prescription opioid overdoses.

Overdoses (ODs) of prescription opioids (RxOs) have become a major public health issue in the United States. OBJECTIVE: To determine the root causes of accidental prescription opioid overdoses (RxO-OD). DESIGN/SETTING/PARTICIPANTS/INTERVENTION: The authors conducted a root cause analysis using the Antecedent Target-Measurement method, interviewing three types of key informants: survivors of RxO-ODs, family members, and clinical experts. RESULTS: Ten survivors, five family members, and three experts were interviewed. Proximal causes of RxO-ODs described by survivors and family members were recent RxO dose escalation (n = 9), polysubstance use (n = 5), and polypharmacy use (n = 3). Proximal causes were elicited by the following six antecedent causes: wanting to feel good/high (n = 9), perceived tolerance to RxO (n = 6), didn't know/believe it was dangerous (n = 5), wanting to reduce psychosocial pain (n = 5), wanting to reduce physical pain (n = 4), and wanting to avoid discomfort due to withdrawal symptoms (n = 4). RxOs involved in the OD were either prescribed by a doctor (n = 7), purchased from a dealer (n = 6), given/purchased from family/friends (n = 3), or stolen from family (n = 1). Psychosocial stressors (n = 9), chronic recurrent depression (n = 3), and chronic substance abuse/addiction (n = 4) were also distal and proximal causes of OD. Experts cited similar causes but added prescriberrelated causes (eg, inadequate training) and healthcare system and culture. CONCLUSIONS: Patients at risk for OD can be identified and ODs potentially prevented. Opportunities for intervention include routine screening of patients using RxOs for psychosocial distress and coping, flagging of high-risk patients, care pathways for high-risk patients, clinician and patient training on OD prevention, and developing abuse-deterrent formulations of RxOs.

Validation of the Short-form McGill Pain Questionnaire-2 (SF-MPQ-2) in acute low back pain.

UNLABELLED: The Short-form McGill Pain Questionnaire (SF-MPQ-2) assesses the major symptoms of both neuropathic and nonneuropathic pain and can be used in studies of epidemiology, natural history, pathophysiologic mechanisms, and treatment response. Previous research has demonstrated its reliability, validity, and responsiveness in diverse samples of patients with chronic pain. However, the SF-MPQ-2 has not been evaluated for use in patients with acute pain. Data were examined from a double-blind, randomized clinical trial of immediate-release tapentadol versus immediate-release oxycodone in patients with acute low back and associated radicular leg pain (N = 666). Analyses of internal consistency, convergent validity, and confirmatory factor structure were conducted using baseline data, and analyses of responsiveness were conducted using baseline and endpoint data. The SF-MPQ-2 total score and its 4 subscale scores (continuous pain, intermittent pain, predominantly neuropathic pain, and affective descriptors) generally showed good psychometric properties and 1) were internally consistent, 2) displayed good convergent validity, 3) fit the a priori factor structure, and 4) were highly responsive to analgesic treatment. These data extend previous evidence of the reliability, validity, and responsiveness of the SF-MPQ-2 in patients with chronic pain to those with acute low back and associated radicular leg pain. PERSPECTIVE: Considered together with the results of other recent studies, the data suggest that the SF-MPQ-2 can provide a valid, responsive, and efficient assessment of both neuropathic and nonneuropathic pain qualities for clinical trials and other clinical research examining patients with various acute and chronic pain conditions.

Development of a bedside pain assessment kit for the classification of patients with osteoarthritis.

There are no standardized bedside assessments for subtyping patients with osteoarthritis (OA) based on pain mechanisms. Thus, we developed a bedside sensory testing kit (BSTK) to classify OA patients based on sensory profiles potentially indicative of pain mechanism. After usability and informal reliability testing (n = 22), the kit was tested in a formal reliability study (n = 20). Patients completed questionnaires and sensory testing: pressure algometry to detect hyperalgesia; repeat algometry after heterotopic noxious conditioning stimulation to measure diffuse noxious inhibitory control (DNIC); light touch using Von Frey filaments; and cold allodynia using a brass rod. The procedure was brief and well tolerated. Algometry and filament testing were highly reliable [intra-class correlation coefficients (ICCs) 0.71-0.91]; DNIC was acceptably reliable (ICCs 0.53-0.91); brass rod reliability was inconclusive. Patients were classified empirically into four groups: "All abnormal findings" (primary and secondary hyperalgesia and dysfunctional DNIC); "all normal findings"; and two intermediate groups. The "all abnormal findings" group had more neuropathic pain symptoms, and lower WOMAC total, stiffness, and activity scores than the "all normal findings" group. Simple BSTK procedures, consolidated in a kit, reliably classified OA patients into subgroups based on sensory profile, suggesting that OA patients differ in underlying pain mechanisms. Further research is needed to confirm these subgroups and determine their validity in predicting response to treatment.

The pain quality response profile of a corticosteroid injections and heated lidocaine/tetracaine patch in the treatment of shoulder impingement syndrome.

OBJECTIVES: To describe the effects of 2 pain treatments for shoulder impingement syndrome (SIS), and illustrate how investigators can use pain quality information to understand treatment response differences. MATERIALS AND METHODS: This study presents pain quality data from a randomized open-label study comparing the effects of an injection of triamcinolone and up to twice daily application of a heated lidocaine/tetracaine (Trilexis) patch in individuals with SIS. Study participants completed a measure of pain quality at baseline and again on study days 14, 28, and 42 following initiation of 2 treatments for SIS. Baseline and posttreatment pain quality scores were graphed to provide a visual representation of treatment-associated changes. Analyses of variance were used to examine the differences between treatment conditions in changes in pain quality with treatment. RESULTS: Both treatments resulted in substantial (and similar) pretreatment to posttreatment improvements in many pain qualities. However, differences in the time course of treatment effects were observed for itchy and heavy qualities. DISCUSSION: Although 2 different pain treatments appear to have the same effects when only pretreatment to posttreatment changes are examined, treatment differences emerged when the time course of treatment is examined. The findings support the importance of assessing both pain qualities and time course of treatment as outcome domains. The results illustrate how investigators can use data from clinical trials to provide a more fine-tuned description of treatment effects, providing knowledge that could be helpful in selecting treatment options at the individual patient level. SUMMARY: Examination of the effects of pain treatments on pain qualities over time will help researchers and clinicians understand if certain pain quality domains respond faster to one treatment versus another, and may identify differences between treatments that would not be observed by measures of global pain intensity alone.

A brief survey to characterize oxycodone abuse patterns in adolescents enrolled in two substance abuse recovery high schools.

BACKGROUND: Although oxycodone is one of the most widely available and abused opioids, little published information exists on the abuse of immediate-release oxycodone. OBJECTIVE: To obtain information on abuse of oxycodone and the effectiveness of abuse-deterrent strategies, especially for immediate-release oxycodone, we surveyed oxycodone abuse patterns in a population of experienced opioid abusers. METHODS: Students or recent graduates of two substance abuse recovery high schools in Massachusetts were surveyed on abuse behaviors with short-acting single-entity oxycodone (e.g., Roxicodone), short-acting combination oxycodone (e.g., Percocet), and extended-release oxycodone. RESULTS: Twenty-four students completed surveys. Mean age was 17.7 years (range 16-19), and mean age at first abuse of oxycodone was 15 (range 13-18). Overall, 56% of students reported oxycodone as their favorite prescription opioid to abuse. The primary preferred method of abuse of all oxycodone formulations was intranasal administration: 83% of single-entity oxycodone abusers preferred intranasal administration compared with 67% of combination oxycodone abusers and 69% of extended-release oxycodone abusers. Approximately half of our respondents preferred to ingest oxycodone orally, 25-38% of respondents swallowed the pill intact, and another 13-17% chewed the pill before swallowing. Maximum dose ever abused at one time ranged from 15 to 400 mg. Most respondents had abused ≥60 mg of oxycodone at a time. CONCLUSIONS: In this small study, adolescent oxycodone abusers use high quantities of oxycodone at a time, alter routes of administration for not only extended-release but also immediate-release products, and commonly abuse single-entity oxycodone products. Abuse-deterrent formulations may be one strategy for addressing such behaviors.

Determining the clinically important difference in visual analog scale scores in abuse liability studies evaluating novel opioid formulations.

PURPOSE: This study determined how the magnitude of change in positive subjective responses predicts clinical outcome in a treatment setting. Specifically, we attempted to define what constitutes a clinically important difference (CID) in subjective responses. METHODS: A 100-mm visual analog scale (VAS) measured subjective ratings of drug "high," calculated via an anchor-based method with published data from participants receiving sustained-release naltrexone (NTX) and heroin in a laboratory setting. The data were then compared to clinical outcomes in a treatment trial with sustained-release naltrexone. A distribution-based method subsequently analyzed data from participants who received ALO-01 (extended-release morphine with sequestered NTX) to predict its abuse liability. RESULTS: Differences in ratings of drug high of approximately 10 mm on a 100-mm line were clinically significant. By extrapolation, CIDs were also found between crushed or intact ALO-01 and immediate-release morphine sulfate (IRMS). No CIDs were found between intact and crushed ALO-01. CONCLUSIONS: From laboratory and treatment trial data involving naltrexone, calculation of CIDs in subjective ratings of high is possible. Consequently, crushing/swallowing or injecting ALO-01 produces clinically significantly less drug high than oral or intravenous morphine alone, suggesting that ALO-01 has lower abuse liability by those routes than morphine formulations.