Anesthetic neurotoxicity--clinical implications of animal models.

Some anesthetics and sedatives have been shown to cause neurotoxic effects in laboratory animals. The FDA collaboration SmartTots recommends undertaking large-scale clinical studies and avoiding nonurgent surgical procedures requiring anesthesia in children younger than 3 years of age.

Content validity of symptom-based measures for diabetic, chemotherapy, and HIV peripheral neuropathy.

INTRODUCTION: No treatments for axonal peripheral neuropathy are approved by the United States Food and Drug Administration (FDA). Although patient- and clinician-reported outcomes are central to evaluating neuropathy symptoms, they can be difficult to assess accurately. The inability to identify efficacious treatments for peripheral neuropathies could be due to invalid or inadequate outcome measures. METHODS: This systematic review examined the content validity of symptom-based measures of diabetic peripheral neuropathy, HIV neuropathy, and chemotherapy-induced peripheral neuropathy. RESULTS: Use of all FDA-recommended methods to establish content validity was only reported for 2 of 18 measures. Multiple sensory and motor symptoms were included in measures for all 3 conditions; these included numbness, tingling, pain, allodynia, difficulty walking, and cramping. Autonomic symptoms were less frequently included. CONCLUSIONS: Given significant overlap in symptoms between neuropathy etiologies, a measure with content validity for multiple neuropathies with supplemental disease-specific modules could be of great value in the development of disease-modifying treatments for peripheral neuropathies. Muscle Nerve 55: 366-372, 2017.

Evaluating Patient-Centered Outcomes in Clinical Trials of Procedural Sedation, Part 1 Efficacy: Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations.

The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research, established by the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks public-private partnership with the US Food and Drug Administration, convened a meeting of sedation experts from a variety of clinical specialties and research backgrounds with the objective of developing recommendations for procedural sedation research. Four core outcome domains were recommended for consideration in sedation clinical trials: (1) safety, (2) efficacy, (3) patient-centered and/or family-centered outcomes, and (4) efficiency. This meeting identified core outcome measures within the efficacy and patient-centered and/or family-centered domains. Safety will be addressed in a subsequent meeting, and efficiency will not be addressed at this time. These measures encompass depth and levels of sedation, proceduralist and patient satisfaction, patient recall, and degree of pain experienced. Consistent use of the recommended outcome measures will facilitate the comprehensive reporting across sedation trials, along with meaningful comparisons among studies and interventions in systematic reviews and meta-analyses.

Research design considerations for chronic pain prevention clinical trials: IMMPACT recommendations.

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.

Interpreting the clinical importance of treatment outcomes in chronic pain clinical trials: IMMPACT recommendations.

UNLABELLED: A consensus meeting was convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) to provide recommendations for interpreting clinical importance of treatment outcomes in clinical trials of the efficacy and effectiveness of chronic pain treatments. A group of 40 participants from universities, governmental agencies, a patient self-help organization, and the pharmaceutical industry considered methodologic issues and research results relevant to determining the clinical importance of changes in the specific outcome measures previously recommended by IMMPACT for 4 core chronic pain outcome domains: (1) Pain intensity, assessed by a 0 to 10 numerical rating scale; (2) physical functioning, assessed by the Multidimensional Pain Inventory and Brief Pain Inventory interference scales; (3) emotional functioning, assessed by the Beck Depression Inventory and Profile of Mood States; and (4) participant ratings of overall improvement, assessed by the Patient Global Impression of Change scale. It is recommended that 2 or more different methods be used to evaluate the clinical importance of improvement or worsening for chronic pain clinical trial outcome measures. Provisional benchmarks for identifying clinically important changes in specific outcome measures that can be used for outcome studies of treatments for chronic pain are proposed. PERSPECTIVE: Systematically collecting and reporting the recommended information needed to evaluate the clinical importance of treatment outcomes of chronic pain clinical trials will allow additional validation of proposed benchmarks and provide more meaningful comparisons of chronic pain treatments.

Use of anesthetic agents in neonates and young children.

BACKGROUND: Some drugs used for sedation and anesthesia produce histopathologic central nervous system changes in juvenile animal models. These observations have raised concerns regarding the use of these drugs in pediatric patients. We summarized the findings in developing animals and describe the steps that the Food and Drug Administration (FDA) and others are taking to assess potential risks in pediatric patients. The FDA views this communication as opening a dialog with the anesthesia community to address this issue. METHODS: We reviewed the available animal studies literature examining the potential neurotoxic effects of commonly used anesthetic drugs on the developing brain. The search strategy involved crossing the keywords neurotoxic and neuroapoptosis with the following general and specific terms: anesthetic, N-methyl-d-aspartate (NMDA), ketamine, midazolam, lorazepam, fentanyl, methadone, morphine, meperidine, isoflurane, nitrous oxide, sevoflurane, halothane, enflurane, desflurane, propofol, etomidate, barbiturate, methoxyflurane, and chloral hydrate. We summarized several studies sponsored by the FDA in rats and monkeys, initially examining the potential for ketamine, as a prototypical agent, to induce neurodegeneration in the developing brain. RESULTS: Numerous animal studies in rodents indicate that NMDA receptor antagonists, including ketamine, induce neurodegeneration in the developing brain. The effects of ketamine are dose dependent. The data suggest that limiting exposure limits the potential for neurodegeneration. There is also evidence that other general anesthetics, such as isoflurane, can induce neurodegeneration in rodent models, which may be exacerbated by concurrent administration of midazolam or nitrous oxide. There are very few studies that have examined the potential functional consequences of the neurodegeneration noted in the animal models. However, the studies that have been reported suggest subtle, but prolonged, behavioral changes in rodents. Although the doses and durations of ketamine exposure that resulted in neurodegeneration were slightly larger than those used in the clinical setting, those associated with isoflurane were not. There are insufficient human data to either support or refute the clinical applicability of these findings. CONCLUSIONS: Animal studies suggest that neurodegeneration, with possible cognitive sequelae, is a potential long-term risk of anesthetics in neonatal and young pediatric patients. The existing nonclinical data implicate not only NMDA-receptor antagonists, but also drugs that potentiate gamma-aminobutyric acid signal transduction, as potentially neurotoxic to the developing brain. The potential for the combination of drugs that have activity at both receptor systems or that can induce more or less neurotoxicity is not clear; however, recent nonclinical data suggest that some combinations may be more neurotoxic than the individual components. The lack of information to date precludes the ability to designate any one anesthetic agent or regimen as safer than any other. Ongoing studies in juvenile animals should provide additional information regarding the risks. The FDA anticipates working with the anesthesia community and pharmaceutical industry to develop strategies for further assessing the safety of anesthetics in neonates and young children, and for providing data to guide clinicians in making the most informed decisions possible when choosing anesthetic regimens for their pediatric patients.

The Potential Role of Sensory Testing, Skin Biopsy, and Functional Brain Imaging as Biomarkers in Chronic Pain Clinical Trials: IMMPACT Considerations.

Valid and reliable biomarkers can play an important role in clinical trials as indicators of biological or pathogenic processes or as a signal of treatment response. Currently, there are no biomarkers for pain qualified by the U.S. Food and Drug Administration or the European Medicines Agency for use in clinical trials. This article summarizes an Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials meeting in which 3 potential biomarkers were discussed for use in the development of analgesic treatments: 1) sensory testing, 2) skin punch biopsy, and 3) brain imaging. The empirical evidence supporting the use of these tests is described within the context of the 4 categories of biomarkers: 1) diagnostic, 2) prognostic, 3) predictive, and 4) pharmacodynamic. Although sensory testing, skin punch biopsy, and brain imaging are promising tools for pain in clinical trials, additional evidence is needed to further support and standardize these tests for use as biomarkers in pain clinical trials. PERSPECTIVE: The applicability of sensory testing, skin biopsy, and brain imaging as diagnostic, prognostic, predictive, and pharmacodynamic biomarkers for use in analgesic treatment trials is considered. Evidence in support of their use and outlining problems is presented, as well as a call for further standardization and demonstrations of validity and reliability.

Deficiencies in reporting of statistical methodology in recent randomized trials of nonpharmacologic pain treatments: ACTTION systematic review.

OBJECTIVE: The goal of this study was to assess the quality of reporting of statistical methods in randomized clinical trials (RCTs), including identification of primary analyses, missing data accommodation, and multiplicity adjustment, in studies of nonpharmacologic, noninterventional pain treatments (e.g., physical therapy, cognitive behavioral therapy, acupuncture, and massage). STUDY DESIGN: Systematic review of 101 articles reporting RCTs of pain treatments that were published between January 2006 and June 2013 in the European Journal of Pain, the Journal of Pain, and Pain. SETTING: Systematic review. RESULTS: Sixty-two percent of studies identified a primary outcome variable, 46% identified a primary analysis, and of those with multiple primary analyses, only 21% adjusted for multiplicity. Slightly over half (55%) of studies reported using at least one method to accommodate missing data. Only four studies reported prespecifying at least one of these four study methods. CONCLUSION: This review identified deficiencies in the reporting of primary analyses and methods to adjust for multiplicity and accommodate missing data in articles disseminating results of nonpharmacologic, noninterventional trials. Investigators should be encouraged to indicate whether their analyses were prespecified and to clearly and completely report statistical methods in clinical trial publications to maximize the interpretability of trial results.

Adverse Event Reporting in Clinical Trials of Intravenous and Invasive Pain Treatments: An ACTTION Systematic Review.

Thorough assessment and reporting of adverse events (AEs) facilitates a detailed understanding of a treatment's risk-benefit profile. Although the Consolidated Standards of Reporting Trials (CONSORT) 2004 statement provides recommendations regarding AE reporting, adherence to these standards is often inadequate. We investigated AE reporting in clinical trials of intravenous and invasive pain treatments published in 6 major anesthesiology and pain journals between 2000 to 2003 and 2006 to 2012. We examined whether AE reporting improved after publication of the 2004 CONSORT recommendations and also comprehensively reviewed AE assessment using the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) AE reporting recommendations. No improvement was found overall in CONSORT harms reporting scores from pre- to postpublication of the CONSORT recommendations, with only 5 of 10 fulfilled on average. AE reporting assessed using the ACTTION coding manual was generally inadequate, and 8% of articles failed to report any AE information at all. Anesthesiology and pain journals were similar in AE reporting quality, although industry-sponsored trials reported more AE information than nonindustry sponsored trials. Improvement is needed in AE reporting in analgesic clinical trials. The CONSORT checklist and ACTTION AE recommendations can assist investigators and editors in improving clinical trial transparency and quality. PERSPECTIVE: This systematic review of AE reporting in intravenous and invasive pain treatment trials shows that little improvement has been made since the 2004 CONSORT harms reporting guidelines. Better assessment and reporting of treatment AEs is necessary to understand the full clinical effect of intravenous and invasive treatments.

Pain intensity rating training: results from an exploratory study of the ACTTION PROTECCT system.

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.

Assessment of physical function and participation in chronic pain clinical trials: IMMPACT/OMERACT recommendations.

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.

Patient phenotyping in clinical trials of chronic pain treatments: IMMPACT recommendations.

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.

Research design considerations for single-dose analgesic clinical trials in acute pain: IMMPACT recommendations.

This article summarizes the results of a meeting convened by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) on key considerations and best practices governing the design of acute pain clinical trials. We discuss the role of early phase clinical trials, including pharmacokinetic-pharmacodynamic (PK-PD) trials, and the value of including both placebo and active standards of comparison in acute pain trials. This article focuses on single-dose and short-duration trials with emphasis on the perioperative and study design factors that influence assay sensitivity. Recommendations are presented on assessment measures, study designs, and operational factors. Although most of the methodological advances have come from studies of postoperative pain after dental impaction, bunionectomy, and other surgeries, the design considerations discussed are applicable to many other acute pain studies conducted in different settings.

Data interpretation in analgesic clinical trials with statistically nonsignificant primary analyses: an ACTTION systematic review.

UNLABELLED: Peer-reviewed publications of randomized clinical trials (RCTs) are the primary means of disseminating research findings. "Spin" in RCT publications is misrepresentation of statistically nonsignificant research findings to suggest treatment benefit. Spin can influence the way readers interpret clinical trials and use the information to make decisions about treatments and medical policies. The objective of this study was to determine the frequency with which 4 types of spin were used in publications of analgesic RCTs with nonsignificant primary analyses in 6 major pain journals. In the 76 articles included in our sample, 28% of the abstracts and 29% of the main texts emphasized secondary analyses with P values <.05; 22% of abstracts and 29% of texts emphasized treatment benefit based on nonsignificant primary results; 14% of abstracts and 18% of texts emphasized within-group improvements over time, rather than primary between-group comparisons; and 13% of abstracts and 10% of texts interpreted a nonsignificant difference between groups in a superiority study as comparable effectiveness. When considering the article conclusion sections, 21% did not mention the nonsignificant primary result, 22% were presented with no uncertainty or qualification, 30% did not acknowledge that future research was required, and 8% recommended the intervention for clinical use. PERSPECTIVE: This article identifies relatively frequent "spin" in analgesic RCTs. These findings highlight a need for authors, reviewers, and editors to be more cognizant of how analgesic RCT results are presented and attempt to minimize spin in future clinical trial publications.

Reporting of sample size calculations in analgesic clinical trials: ACTTION systematic review.

UNLABELLED: Sample size calculations determine the number of participants required to have sufficiently high power to detect a given treatment effect. In this review, we examined the reporting quality of sample size calculations in 172 publications of double-blind randomized controlled trials of noninvasive pharmacologic or interventional (ie, invasive) pain treatments published in European Journal of Pain, Journal of Pain, and Pain from January 2006 through June 2013. Sixty-five percent of publications reported a sample size calculation but only 38% provided all elements required to replicate the calculated sample size. In publications reporting at least 1 element, 54% provided a justification for the treatment effect used to calculate sample size, and 24% of studies with continuous outcome variables justified the variability estimate. Publications of clinical pain condition trials reported a sample size calculation more frequently than experimental pain model trials (77% vs 33%, P < .001) but did not differ in the frequency of reporting all required elements. No significant differences in reporting of any or all elements were detected between publications of trials with industry and nonindustry sponsorship. Twenty-eight percent included a discrepancy between the reported number of planned and randomized participants. This study suggests that sample size calculation reporting in analgesic trial publications is usually incomplete. Investigators should provide detailed accounts of sample size calculations in publications of clinical trials of pain treatments, which is necessary for reporting transparency and communication of pre-trial design decisions. PERSPECTIVE: In this systematic review of analgesic clinical trials, sample size calculations and the required elements (eg, treatment effect to be detected; power level) were incompletely reported. A lack of transparency regarding sample size calculations may raise questions about the appropriateness of the calculated sample size.

Reporting of adverse events and statistical details of efficacy estimates in randomized clinical trials of pain in temporomandibular disorders: Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks systematic review.

BACKGROUND: Statistical methods and adverse events (that is, harms) data affect the accuracy of conclusions about the risk-to-benefit ratio of treatments for temporomandibular disorders (TMDs). The authors reviewed the quality of reporting in TMD clinical trials to highlight practices that are in need of improvement. TYPES OF STUDIES REVIEWED: The authors included articles published between 1969 and May 31, 2013, in which the investigators reported randomized clinical trials of TMD treatments with pain as a principal outcome variable. Investigators in trials of nonpharmacologic and noninvasive treatments were required to at least mask the participants and assessors; all others were required to be double masked. RESULTS: Ninety articles qualified for this review: 39 published between 1971 and 2005 (older articles) and 51 published between 2006 and 2013 (newer articles). Specification of primary outcome analyses, methods to accommodate missing data, and adverse event collection methods and rates were generally poor. In some cases, there was apparent improvement from the older to the newer cohort; however, reporting of these methodological details remained inadequate even in the newer articles. PRACTICAL IMPLICATIONS: This review is designed to alert authors, reviewers, editors, and readers of TMD clinical trials to these issues and improve reporting quality in the future.