Charles Cleeland | MD Anderson Cancer Center (original) (raw)

Papers by Charles Cleeland

Cancer, 2014

BACKGROUND: A prospective longitudinal study to profile patient-reported symptoms during radiothe... more BACKGROUND: A prospective longitudinal study to profile patient-reported symptoms during radiotherapy (RT) or concurrent chemoradiotherapy (CCRT) for head and neck cancer was performed. The goals were to understand the onset and trajectory of specific symptoms and their severity, identify clusters, and facilitate symptom interventions and clinical trial design. METHODS: Participants in this questionnaire-based study received RT or CCRT. They completed the University of Texas MD Anderson Cancer Center Symptom Inventory-Head and Neck Module before and weekly during treatment. Symptom scores were compared between treatment groups, and hierarchical cluster analysis was used to depict clustering of symptoms at treatment end. Variables believed to predict symptom severity were assessed using a multivariate mixed model. RESULTS: Among the 149 patients studied, the majority (47%) had oropharyngeal tumors, and nearly one-half received CCRT. Overall symptom severity (P <.001) and symptom interference (P <.0001) became progressively more severe and were more severe for those receiving CCRT. On multivariate analysis, baseline Eastern Cooperative Oncology Group performance status (P <.001) and receipt of CCRT (P <.04) correlated with higher symptom severity. Fatigue, drowsiness, lack of appetite, problem with mouth/throat mucus, and problem tasting food were more severe for those receiving CCRT. Both local and systemic symptom clusters were identified. CONCLUSIONS: The findings from this prospective longitudinal study identified a pattern of local and systemic symptoms, symptom clusters, and symptom interference that was temporally distinct and marked by increased magnitude and a shift in individual symptom rank order during the treatment course. These inform clinicians about symptom intervention needs, and are a benchmark for future symptom intervention clinical trials. Cancer 2014;120:1975-84.

European Journal of Cancer Care, 2009

The Journal of Thoracic and Cardiovascular Surgery, 2015

Measuring patient-reported outcomes (PROs) has become increasingly important for assessing qualit... more Measuring patient-reported outcomes (PROs) has become increasingly important for assessing quality of care and guiding patient management. However, PROs have yet to be integrated with traditional clinical outcomes (such as length of hospital stay), to evaluate perioperative care. This study aimed to use longitudinal PRO assessments to define the postoperative symptom recovery trajectory in patients undergoing thoracic surgery for lung cancer. Newly diagnosed patients (N = 60) with stage I or II non-small cell lung cancer who underwent either standard open thoracotomy or video-assisted thoracoscopic surgery lobectomy reported multiple symptoms from before surgery to 3 months after surgery, using the MD Anderson Symptom Inventory. We conducted Kaplan-Meier analyses to determine when symptoms returned to presurgical levels and to mild-severity levels during recovery. The most-severe postoperative symptoms were fatigue, pain, shortness of breath, disturbed sleep, and drowsiness. The median time to return to mild symptom severity for these 5 symptoms was shorter than the time to return to baseline severity, with fatigue taking longer. Recovery from pain occurred more quickly for patients who underwent lobectomy versus thoracotomy (8 vs 18 days, respectively; P = .022). Patients who had poor preoperative performance status or comorbidities reported higher postoperative pain (all P &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt; .05). Assessing symptoms from the patient&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s perspective throughout the postoperative recovery period is an effective strategy for evaluating perioperative care. This study demonstrates that the MD Anderson Symptom Inventory is a sensitive tool for detecting symptomatic recovery, with an expected relationship among surgery type, preoperative performance status, and comorbid conditions.

Oncology (Williston Park, N.Y.), Jan 30, 2011

Cancer care and palliative care each require a complex multi- and interdisciplinary approach to m... more Cancer care and palliative care each require a complex multi- and interdisciplinary approach to maximize the care of people with cancer. Recommendations for cancer treatment should both relieve the symptoms of cancer and prevent and treat side effects of anticancer therapy. Unrelieved symptoms not only contribute to worse quality of life but also can reduce a patient's ability to tolerate cancer therapy and may have a negative impact on survival. Consistent integration of palliative care practices into standard oncology care is needed across the trajectory of the cancer experience. This article will review the overlap between palliative care and oncology and discuss the available evidence that true integration of palliative and oncology care provides patients with optimal oncology care.

Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery, 2014

Radiation therapy (RT), with or without chemotherapy, can cause significant acute toxicity among ... more Radiation therapy (RT), with or without chemotherapy, can cause significant acute toxicity among patients treated for head and neck cancer (HNC), but predicting, before treatment, who will experience a particular toxicity or symptom is difficult. We created and evaluated 2 multivariate models and generated a nomogram to predict symptom severity during RT based on a patient-reported outcome (PRO) instrument, the MD Anderson Symptom Inventory-Head and Neck Module (MDASI-HN). This was a prospective, longitudinal, questionnaire-based study. Tertiary cancer care center. Subjects were 264 patients with HNC (mostly oropharyngeal) who had completed the MDASI-HN before and during therapy. Pretreatment variables were correlated with MDASI-HN symptom scores during therapy with multivariate modeling and then were correlated with the composite MDASI-HN score during week 5 of therapy. A multivariate model incorporating pretreatment PROs better predicted MDASI-HN symptom scores during treatment th...

Cancer, 2015

Minority patients with breast cancer are at risk for undertreatment of cancer-related pain. The a... more Minority patients with breast cancer are at risk for undertreatment of cancer-related pain. The authors evaluated the feasibility and efficacy of an automated pain intervention for improving pain and symptom management of underserved African American and Latina women with breast cancer. Sixty low-income African American and Latina women with breast cancer and cancer-related pain were enrolled in a pilot study of an automated, telephone-based, interactive voice response (IVR) intervention. Women in the intervention group were called twice weekly by the IVR system and asked to rate the intensity of their pain and other symptoms. The patients&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; oncologists received e-mail alerts if the reported symptoms were moderate to severe. The patients also reported barriers to pain management and received education regarding any reported obstacles. The proportion of women in both groups reporting moderate to severe pain decreased during the study, but the decrease was significantly greater for the intervention group. The IVR intervention also was associated with improvements in other cancer-related symptoms, including sleep disturbance and drowsiness. Although patient adherence to the IVR call schedule was good, the oncologists who were treating the patients rated the intervention as only somewhat useful for improving symptom management. The IVR intervention reduced pain and symptom severity for underserved minority women with breast cancer. Additional research on technological approaches to symptom management is needed. Cancer 2015. © 2015 American Cancer Society.

PloS one, 2014

Chemotherapy-induced peripheral neuropathy (CIPN) characterized by loss of sensory sensitivity an... more Chemotherapy-induced peripheral neuropathy (CIPN) characterized by loss of sensory sensitivity and pain in hands and feet is the major dose-limiting toxicity of many chemotherapeutics. At present, there are no FDA-approved treatments for CIPN. The anti-diabetic drug metformin is the most widely used prescription drug in the world and improves glycemic control in diabetes patients. There is some evidence that metformin enhances the efficacy of cancer treatment. The aim of this study was to test the hypothesis that metformin protects against chemotherapy-induced neuropathic pain and sensory deficits. Mice were treated with cisplatin together with metformin or saline. Cisplatin induced increased sensitivity to mechanical stimulation (mechanical allodynia) as measured using the von Frey test. Co-administration of metformin almost completely prevented the cisplatin-induced mechanical allodynia. Co-administration of metformin also prevented paclitaxel-induced mechanical allodynia. The cap...

The impact of new oncology therapies on OS is often assessed by comparing median OS times in rand... more The impact of new oncology therapies on OS is often assessed by comparing median OS times in randomised controlled trials. Although this data is usually available even when many patients remain alive at the end of the trial, the survival times of those surviving beyond the median point may not be adequately accounted for in this comparison. In this case study, we discuss the median and the mean OS using data from a recently published randomised trial. METHODS: Median OS in the ipilimumab-alone (IPI) and gp100 alone-arms of the trial of IPI in pre-treated metastatic melanoma (MM) patients (Hodi et al., 2010, NEJM) was compared with non-parametric estimates of mean survival (area under digitised Kaplan-Meier survivor function) over four years (maximum follow up 55 months). We reviewed the methods literature and approaches adopted in relevant assessments. RESULTS: In this case study, for MM population followed over four years median OS was reached in the control arm at 6.4 months, and at 10.1 months in the IPI alone arm, a difference in medians of 3.7 months. Mean OS (area under the curve) over 4 years was 11.5 months in the control arm and 17.6 months in the IPI alone arm, a difference for IPI of 6.1 months. Though larger than the difference in median OS, this represents a lower bound on the mean OS benefit over the remaining lifetime, since the survival benefit was truncated at the end of the trial. CONCLUSIONS: Mean and median OS both have a place in characterizing OS. In this case study, it would appear that mean OS may be more informative in describing the potential benefit of the treatment in patients with MM. Health care decision makers should consider all the available data when assessing the potential benefits offered by new therapies in oncology.

Journal of the National Cancer Institute, 2014

The standard approach for documenting symptomatic adverse events (AEs) in cancer clinical trials ... more The standard approach for documenting symptomatic adverse events (AEs) in cancer clinical trials involves investigator reporting using the National Cancer Institute's (NCI's) Common Terminology Criteria for Adverse Events (CTCAE). Because this approach underdetects symptomatic AEs, the NCI issued two contracts to create a patient-reported outcome (PRO) measurement system as a companion to the CTCAE, called the PRO-CTCAE. This Commentary describes development of the PRO-CTCAE by a group of multidisciplinary investigators and patient representatives and provides an overview of qualitative and quantitative studies of its measurement properties. A systematic evaluation of all 790 AEs listed in the CTCAE identified 78 appropriate for patient self-reporting. For each of these, a PRO-CTCAE plain language term in English and one to three items characterizing the frequency, severity, and/or activity interference of the AE were created, rendering a library of 124 PRO-CTCAE items. Thes...

Value in Health, 2010

Background: We aimed to determine the smallest changes in health-related quality of life (HRQoL) ... more Background: We aimed to determine the smallest changes in health-related quality of life (HRQoL) scores in the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire core 30 and the Brain Cancer Module (QLQ-BN20), which ...

Twin Research and Human Genetics, 2009

To our knowledge, no comprehensive, interdisciplinary initiatives have been taken to examine the ... more To our knowledge, no comprehensive, interdisciplinary initiatives have been taken to examine the role of genetic variants on patient-reported quality-of-life outcomes.

Value in Health, 2009

Abstracts A53 instrument has fi ve functional scales (physical, role, cognitive, emotional, and s... more Abstracts A53 instrument has fi ve functional scales (physical, role, cognitive, emotional, and social), three symptom scales (fatigue, pain, and emesis), and a global health/quality of life scale. The remaining single items assess dyspnoea, appetite loss, sleep disturbance, constipation, and diarrhoea. The analyses focused on intraclass correlation coeffi cients (ICCs), comparing the ICC 95% lower confi dence interval with a critical value of 0.70. RESULTS: Subjects who did not complete the second assessments within 72 hours or who had score differences on the scales or items exceeding two standard deviations were excluded from the per protocol analyses. The sample sizes used in the per protocol analyses ranged from 112 to 115 subjects. The ICCs for the 9 multi-item scales were all above 0.69, ranging from 0.698 to 0.926 (ICC 95% lower CI range: 0.608 to 0.901). All of the scales were signifi cantly different from our threshold reliability of 0.70, with the exception of the cognitive functioning scale. The ICCs for the 6 single items ranged from 0.782 to 0.908 (ICC 95% lower CI range: 0.714 to 0.876) and all were statistically different from 0.70. The evidence supports the stability of the scores obtained on the IVR version of the QLQ-C30 upon repeated measurement. CONCLUSIONS: The equivalence of the IVR and paper versions of the QLQ-C30 has been demonstrated elsewhere. This analysis provides additional evidence of the test-retest reliability of the IVR version of the QLQ-C30.

Supportive Care in Cancer, 2011

The objective of this retrospective analysis was to determine the smallest changes in health rela... more The objective of this retrospective analysis was to determine the smallest changes in health related quality of life (HRQOL) scores on the European Organisation for Research and Treatment of Cancer quality of life core questionnaire (EORTC QLQ-C30) which could be considered as representing minimal important differences (MID).

Quality of Life Research, 2006

Objectives: This study explored the relationship between the M. D. Anderson Symptom Inventory (MD... more Objectives: This study explored the relationship between the M. D. Anderson Symptom Inventory (MDASI), an instrument measuring the severity of symptoms common to patients with cancer, and utility derived from the SF-36. Methods: Cancer patients from Tianjin Cancer Hospital in China (n = 249) completed a demographic questionnaire and Chinese versions of the MDASI and SF-36. Using a published algorithm converting SF-36 scores to standard gamble (SG) utilities, we examined the association between utility and individual symptoms using Spearman's rank correlation, and explored the association between utility and aggregate symptom scores through multivariate regression analyses. Results: The mean SG utility was 0.81 (SD = 0.11); utilities were significantly but moderately correlated with the majority of symptoms, especially those of distress, sadness, fatigue, and pain. Regression models showed a significantly negative association between the total symptom score and the utility. After controlling for sociodemographics, cancer stage and performance status, a significantly negative association between the total symptom scores and utility was found in the multivariate analyses. We also found the total number of severe symptoms to be a stronger predictor of ''disutility.'' Conclusions: Symptom measures were significantly albeit moderately associated with utility derived from the SF-36 scores, suggesting that a full study with rigorously collected utilities is worth exploring.

$Research paper thumbnail of Epidural and Intrathecal Analgesia Is Effective in Treating Refractory Cancer Pain$

Pain Medicine, 2004

The use of neuraxial (intrathecal and epidural) analgesia has been suggested in treatment guideli... more The use of neuraxial (intrathecal and epidural) analgesia has been suggested in treatment guidelines put forth for the treatment of refractory cancer pain. We review the literature and present our algorithm for using neuraxial analgesia. We also present our outcomes using this algorithm over a 28-month period.

Pain Medicine, 2010

Industry on the use of patient-reported outcomes (PRO) Measures in Medical Product Development to... more Industry on the use of patient-reported outcomes (PRO) Measures in Medical Product Development to Support Labeling Claims. This draft guidance outlines psychometric aspects that should be considered when designing a PRO measure, including conceptual framework, content validity, construct validity, reliability, and the ability to detect clinically meaningful score changes. When finalized, it may provide a blueprint for evaluations of PRO measures that can be considered by sponsors and investigators involved in PRO research and drug registration trials.

Pain, 2002

This study examined the impact of pain on self-rated health status in the community-dwelling olde... more This study examined the impact of pain on self-rated health status in the community-dwelling older adults using the 1993 public release data of the Asset and Health Dynamics Among the Oldest Old (AHEAD). AHEAD is a population-based household survey designed to examine the dynamic interactions between health, family, and economic variables among US older adults. Results showed that 33% of the older adults reported frequent pain and 20% reported significant pain resulting in activity limitation. Controlling for clinical health status, socio-demographic characteristics, and access to medical care, logistic regression analyses showed that those who often have pain were more than twice as likely (odds ratio (OR)=2.63; confidence interval (CI)=2.35, 2.95; P=&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.0001) to perceive their health status to be &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;poor&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;. Other predictors (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.01) include functional impairment (OR=2.78), chronic diseases (OR=1.89), minority status (OR=1.88), education (OR=1.77), and physician visits (OR=1.64). This study documents the adverse impact of pain on self-rated health as well as the fact that the experience of pain and poor subjective health and well-being is greatest among the most socially disadvantaged older adults (minorities and those with the least education). The findings suggest that treating and controlling pain may significantly enhance the subjective health and well-being of community-dwelling older adults.

Pain, 2008

This two-phase study was conducted to identify relevant domains of patient-reported outcomes from... more This two-phase study was conducted to identify relevant domains of patient-reported outcomes from the perspective of people who experience chronic pain. In Phase 1, focus groups were conducted to generate a pool of patient outcome-related domains and their components. The results of the focus groups identified 19 aspects of their lives that were significantly impacted by the presence of their symptoms and for which improvements were important criteria they would use in evaluating the effectiveness of any treatment. Phase 2 was conducted to examine the importance and relevance of domains identified from a much larger and diverse sample of people with chronic pain. A survey was developed and posted on the American Chronic Pain Association website. Participants were asked to rate the importance of each item or domain identified by the focus groups on a scale of 0 to10 (i.e., 0 = ''not at all important'' and 10 = ''extremely important''). The survey was completed by 959 individuals. The results indicate that all 19 aspects of daily life derived from the focus groups were considered important with a majority of respondents indicating a score of 8 or greater. In addition to pain reduction, the most important aspects were enjoyment of life, emotional well-being, fatigue, weakness, and sleep-related problems. Chronic pain clearly impacts health-related quality of life. The results of the two phases of the study indicate that people with chronic pain consider functioning and well-being as important areas affected by the presence of symptoms and as appropriate targets of treatment. These multiple outcomes should be considered when evaluating the efficacy and effectiveness of chronic pain treatments. Ó

Pain, 2003

To provide recommendations for the core outcome domains that should be considered by investigator... more To provide recommendations for the core outcome domains that should be considered by investigators conducting clinical trials of the efficacy and effectiveness of treatments for chronic pain. Development of a core set of outcome domains would facilitate comparison and pooling of data, encourage more complete reporting of outcomes, simplify the preparation and review of research proposals and manuscripts, and allow clinicians to make informed decisions regarding the risks and benefits of treatment. Under the auspices of the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT), 27 specialists from academia, governmental agencies, and the pharmaceutical industry participated in a consensus meeting and identified core outcome domains that should be considered in clinical trials of treatments for chronic pain. There was a consensus that chronic pain clinical trials should assess outcomes representing six core domains: (1) pain, (2) physical functioning, (3) emotional functioning, (4) participant ratings of improvement and satisfaction with treatment, (5) symptoms and adverse events, (6) participant disposition (e.g. adherence to the treatment regimen and reasons for premature withdrawal from the trial). Although consideration should be given to the assessment of each of these domains, there may be exceptions to the general recommendation to include all of these domains in chronic pain trials. When this occurs, the rationale for not including domains should be provided. It is not the intention of these recommendations that assessment of the core domains should be considered a requirement for approval of product applications by regulatory agencies or that a treatment must demonstrate statistically significant effects for all of the relevant core domains to establish evidence of its efficacy.