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.

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.

Pediatric analgesic clinical trial designs, measures, and extrapolation: report of an FDA scientific workshop.

Analgesic trials pose unique scientific, ethical, and practical challenges in pediatrics. Participants in a scientific workshop sponsored by the US Food and Drug Administration developed consensus on aspects of pediatric analgesic clinical trial design. The standard parallel-placebo analgesic trial design commonly used for adults has ethical and practical difficulties in pediatrics, due to the likelihood of subjects experiencing pain for extended periods of time. Immediate-rescue designs using opioid-sparing, rather than pain scores, as a primary outcome measure have been successfully used in pediatric analgesic efficacy trials. These designs maintain some of the scientific benefits of blinding, with some ethical and practical advantages over traditional designs. Preferred outcome measures were recommended for each age group. Acute pain trials are feasible for children undergoing surgery. Pharmacodynamic responses to opioids, local anesthetics, acetaminophen, and nonsteroidal antiinflammatory drugs appear substantially mature by age 2 years. There is currently no clear evidence for analgesic efficacy of acetaminophen or nonsteroidal antiinflammatory drugs in neonates or infants younger than 3 months of age. Small sample designs, including cross-over trials and N of 1 trials, for particular pediatric chronic pain conditions and for studies of pain and irritability in pediatric palliative care should be considered. Pediatric analgesic trials can be improved by using innovative study designs and outcome measures specific for children. Multicenter consortia will help to facilitate adequately powered pediatric analgesic trials.

Summary proceedings from the neonatal pain-control group.

Recent advances in neurobiology and clinical medicine have established that the fetus and newborn may experience acute, established, and chronic pain. They respond to such noxious stimuli by a series of complex biochemical, physiologic, and behavioral alterations. Studies have concluded that controlling pain experience is beneficial with respect to short-term and perhaps long-term outcomes. Yet, pain-control measures are adopted infrequently because of unresolved scientific issues and lack of appreciation for the need for control of pain and its long-term sequelae during the critical phases of neurologic maturation in the preterm and term newborn. The neonatal pain-control group, as part of the Newborn Drug Development Initiative (NDDI) Workshop I, addressed these concerns. The specific issues addressed were (1) management of pain associated with invasive procedures, (2) provision of sedation and analgesia during mechanical ventilation, and (3) mitigation of pain and stress responses during and after surgery in the newborn infant. The cross-cutting themes addressed within each category included (1) clinical-trial designs, (2) drug prioritization, (3) ethical constraints, (4) gaps in our knowledge, and (5) future research needs. This article provides a summary of the discussions and deliberations. Full-length articles on procedural pain, sedation and analgesia for ventilated infants, perioperative pain, and study designs for neonatal pain research were published in Clinical Therapeutics (June 2005).

Procedural distress in children with cancer: self-report, behavioral observations, and physiological parameters.

OBJECTIVES: To examine the relationship among different indicators of pain and distress, including self-report, behavioral observations, and physiological parameters, in children with cancer undergoing invasive procedures. METHODS: Forty-eight children between the ages of 3.1 and 17.7 years were evaluated while undergoing lumbar punctures. Self-report measures assessed anxiety, pain, self-efficacy, expectations of coping strategies, and coping self-efficacy. Parents reported on their own and their child's levels of anxiety, and physicians estimated their own level of stress and technical difficulty in completing the procedure. Behavioral observations were made prior to, during, and after the procedure. Physiological parameters included heart rate, cardiac vagal tone, and salivary cortisol. At the discretion of attending physicians, 32 children received deep sedation, 9 received light sedation, and 7 received cognitive-behavioral strategies with topical anesthetic as interventions to manage procedural distress. RESULTS: There was a high degree of consistency within self-report, behavioral, and physiological parameters, but correlations between measures in different modalities were low. There were floor effects for most behavioral and self-report measures of distress. Cortisol showed marked changes preprocedure to postprocedure, demonstrating high levels of physiological response despite lack of apparent or perceived discomfort. Heart rate was significantly lower in the group using cognitive-behavioral techniques, especially at the point of needle insertion. DISCUSSION: Self-report measures, behavioral indicators, and physiological changes are not interchangeable outcomes. Treatment strategies were effective for minimizing subjective and behavioral distress, but not necessarily for physiological reactions. Future research should focus on individual differences in these responses, and treatment outcome studies aimed at reducing distress must be clear about the specific goals of intervention.

Brief report: empathy and psychological adjustment in siblings of children with cancer.

OBJECTIVE: To examine relationships between empathy, illness concepts, sibling relationship variables, and psychological adjustment among siblings of children with cancer. METHODS: Participants were 29 siblings and 14 children diagnosed with acute lymphoblastic leukemia, acute myelocytic leukemia, or non-Hodgkin's lymphoma. Data included self- and parent-report questionnaires completed during active treatment. RESULTS: Siblings did not exhibit increased rates of behavior problems, but did display more social and academic difficulties. Empathy was a significant predictor of externalizing and total problems. Cancer knowledge was not related to adjustment, but was associated with empathy. Birth order of the child with cancer and closeness within the sibling relationship were associated with less positive adjustment. CONCLUSIONS: Empathy may play an important role in sibling adjustment following the diagnosis of cancer. Specific sibling relationship and family variables may be helpful in identifying siblings who are at greater need for psychosocial intervention.

Clinical trials in pediatric cancer: parental perspectives on informed consent.

To better understand parental perceptions of the informed consent process in pediatric oncology clinical trials, 20 parents of newly diagnosed children at two pediatric cancer centers described their perceptions in a semi-structured interview. They recalled well the diagnosis, the general treatment plan, and the statistics of survival and/or cure, but the research nature of the clinical trials, particularly randomization, was not well understood. However, despite the need to assimilate a great deal of information, time pressure to make decisions, and reportedly high levels of distress during the discussions, parents expressed general satisfaction with the informed consent discussions with their pediatric oncology providers. However, half to two thirds of parents felt there had been inadequate discussion of alternatives to the proposed treatment and of the research nature of the protocol. While further study of the informed consent process should be conducted in larger, representative samples, the findings from this pilot study suggest that a goal of future informed consent interventions should be to improve parents' understanding of the research aspects of treatment. It is critical to parents' ability to provide informed consent that they feel satisfied that they know alternatives to proposed treatment and that they understand the randomization of treatments, which is the gold standard of clinical trials in pediatric oncology.

Temperament and stress response in children with juvenile primary fibromyalgia syndrome.

OBJECTIVE: To examine temperament, stress response, child psychological adjustment, family environment, pain sensitivity, and stress response differences between children and adolescents with juvenile primary fibromyalgia syndrome (JPFMS), children with arthritis, and healthy controls. Parental psychological adjustment was also measured. METHODS: Subjects included 16 children with JPFMS, 16 children with arthritis, and 16 healthy controls. Participants completed the Dimensions of Temperament Survey-Revised (DOTS-R), State-Trait Anxiety Inventory, Children's Depression Inventory, Family Environment Scale (FES), Sensitivity Temperament Inventory for Pain (STIP), and Youth Self-Report. Responsiveness to an acute stressor was assessed by measuring salivary cortisol levels before and after venipuncture. Parents were asked to complete the parent versions of the DOTS-R, FES, STIP, Child Behavior Checklist, and Symptom Checklist-90-Revised. RESULTS: Children and adolescents with JPFMS demonstrated more temperamental instability, increased levels of depression and anxiety, less family cohesion, and higher pain sensitivity compared with the other 2 groups. Parents of children with JPFMS, in rating themselves, also reported higher levels of anxiety and depression, and lower overall psychological adjustment compared with parents of children in the other groups. CONCLUSION: These results suggest that a psychobiologic perspective may contribute to an increased understanding of JPFMS in children and adolescents, facilitating an approach to investigating the interaction of factors that appear to place a child at risk for development of a pain syndrome. Because temperamental instability, sensitivity to pain, vulnerability to stress, psychological adjustment, family context, and parental psychopathology are individual risk factors, the interaction of these factors may explain the breadth of symptoms associated with this pain syndrome, as well as its severity.