Robert H. Dworkin, PhD - US grants

Chronic pain is a poorly understood disorder that is accompanied by great personal suffering and substantial economic costs to society. The etiology of chronic pain is unknown, and the long-term objective of the proposed research is the identification of psychosocial antecedents and consequences of this disorder. Although chronic pain patients have been extensively studied, it has not been possible to determine whether the psychosocial characteristics of these patients are antecedents of their chronic pain or whether they have been caused by the experience of living with chronic pain. The primary aim of the proposed research is to identify psychosocial antecedents of a chronic pain syndrome using a prospective research design, and to distinguish such antecedents from concomitants and consequences of chronic pain. Herpes zoster, a viral disease in which a latent varicella virus is reactivated, provides a means by which this can be accomplished. Pain accompanies herpes zoster, and its duration varies widely among patients and is unremitting in a percentage of cases. Herpes zoster pain that persists beyond healing of the acute infection is a well-known chronic pain syndrome (postherpetic neuralgia) that is often accompanied by great disability and distress. In the proposed research, patients with acute herpes zoster will be assessed with respect to hypothesized psychosocial antecedents of chronic pain and will then be studied prospectively for one year. Periodic follow-up assessments of pain the selected psychosocial variables will allow antecedents of chronic pain to be identified and to be distinguished from its concomitants and consequences. The proposed research constitutes an important first step in understanding the processes involved in the development and maintenance of chronic pain. This knowledge is not only necessary in developing more effective treatments for chronic pain syndromes, but is also essential in formulating methods for the prevention of these disabling disorders.

Affective deficits have long been considered a prominent feature of schizophrenia. Affective flattening is the only negative symptom included in every major rating scale for the assessment of negative symptoms, and based on a review of research addressing the validity of the distinction between positive and negative symptoms, McGlashan and Fenton (1992) recently suggested that flat affect be included among the defining criteria for schizophrenia in DSM-IV. Given this recognition of the importance of affective deficits in schizophrenia, it is surprising that the characteristics of these symptoms have not been well described. It has recently been argued that current approaches to affective flattening are confounded by the social and neuromotor deficits that are also prevalent in schizophrenia (Dworkin, 1992). If the neurobiological and psychological processes underlying affective deficits are to be understood, approaches for examining affective flattening that are relatively unconfounded by social and neuromotor processes must be developed. The investigation of pain insensitivity in schizophrenia is one such approach to examining affective flattening. Insensitivity to pain has been reported frequently in individuals with schizophrenia, but this phenomenon has never been systematically investigated. The primary aims of the proposed research are to carefully characterize pain insensitivity in schizophrenia and its relationship to affective flattening and to examine the relationships between these two variables and social and neuromotor deficits. This will make it possible to test the hypothesis that pain insensitivity is a manifestation of affective flattening in schizophrenia, one which is relatively independent of social and neuromotor processes. In addition, the data will make it possible to evaluate the extent to which different measures of affective deficits are confounded with social and neuromotor deficits, which will not only lead to greater clarity in the conceptualization of affective flattening in schizophrenia but will also improve the construct validity of approaches to its assessment. The proposed research also has important implications for the welfare of individuals with schizophrenia; numerous clinical reports have suggested that pain insensitivity is very detrimental to health in schizophrenia and can have life-threatening consequences, and pain insensitivity may also account for various self- injurious behaviors that are found in individuals with schizophrenia, including some aspects of the behavior of homeless schizophrenics. A more complete characterization of pain insensitivity and affective flattening in schizophrenia will not only facilitate the investigation of their underlying neurobiological and psychological processes, but should also make it possible to develop more effective methods for ameliorating these important symptoms and their negative consequences for the health and well-being of individuals with schizophrenia.

DESCRIPTION (provided by applicant): Herpes zoster is a common and painful neurological disease that is caused by reactivation of the varicella-zoster virus. Herpes zoster pain that persists after healing of the acute infection is termed postherpetic neuralgia (PHN), a chronic pain syndrome that is often refractory to all treatment. The prevalence of PHN is expected to increase substantially in the coming decades because the incidence of herpes zoster and the risk of PHN will both increase as the population ages. Although research to improve treatment is continuing, as many as half of all patients do not currently obtain relief. For this reason, the development of interventions that prevent PHN would lead to major reductions in disability, distress, and use of health care resources. On the basis of the results of research on risk factors for PHN and its pathophysiologic mechanisms, it can be hypothesized that combined antiviral and analgesic treatment begun as soon as possible after the -onset of herpes zoster will reduce the risk of PHN. The specific aim of this planning grant is to develop the protocol and procedures for a clinical trial to test this hypothesis. The proposed trial will have the following major objectives: The primary aim will be to test the hypothesis that the risk of PHN is reduced by half in herpes zoster patients treated with an antiviral agent and an opioid analgesic compared with patients treated with the antiviral agent and matching placebo. Support for this hypothesis would have a major impact on the treatment of patients with herpes zoster and lead to a substantial reduction in the prevalence of PHN. A second major aim that will be accomplished by the proposed trial is determining whether the initiation of central mechanisms of chronic neuropathic pain can be prevented by attenuating acute pain. The answer to this question will provide important information about mechanisms of prolonged pain and have major implications for its prevention.

Project Summary/Abstract Millions of American experience acute and chronic pain. Despite considerable progress identifying pathophysiologic mechanisms of acute and chronic pain, available treatments remain inadequate. Consequently, there is a compelling public health need for the development of treatments with improved efficacy, safety, and tolerability. Unfortunately, numerous analgesic treatments examined in recent randomized clinical trials have failed to show efficacy. The explanations for these negative results are unknown, raising questions about the ability of clinical trials in chronic pain to distinguish efficacious treatments from placebo or less efficacious treatments (i.e., assay sensitivity). Patient characteristics, clinical trial research designs and methods, outcome measures, approaches to data analysis, and statistical power may all play a role in accounting for difficulties in demonstrating the benefits of efficacious analgesic treatments vs. placebo. The identification of specific clinical trial characteristics associated with assay sensitivity in existing data has the potential to establish an evidence-based approach to the design of analgesic clinical trials. The U.S. Food and Drug Administration recently launched Analgesic Clinical Trial Innovations, Opportunities, and Networks (ACTION), a public-private partnership intended to facilitate the discovery and development of analgesics with improved efficacy, safety, and tolerability for acute and chronic pain. ACTION will establish a collaborative initiative to prioritize research objectives, develop a standardized analgesic database platform, and conduct methodologically-focused studies to increase the assay sensitivity and efficiency of analgesic clinical trials. The results of these studies and other activities have the potential to inform and accelerate the development of improved pain management interventions of all types, not just pharmacologic treatments.

DESCRIPTION (provided by applicant): Fibromyalgia (FM) is a chronic widespread pain syndrome with a number of concurrent symptoms (e.g., sleep difficulties, fatigue, depression, anxiety), unknown pathogenesis, and no well-replicated biological markers that is estimated to affect 3-6 million people in the United States. The diversity of symptoms reported by FM patients is consistent with the view that FM is a multisystem disorder, involving a complex interaction of biological, psychological, and social mechanisms. Although evaluations of a number pharmacological have shown beneficial effects none are curative. These treatments reduce pain by approximately 35% but no more than half of patients experience clinically meaningful improvements. Similar outcomes have been reported by nonpharmacological treatments, particularly cognitive-behavior therapy (CBT), which has been shown to produce equivalent benefits to medication in reducing pain and improving function. The modest outcomes of these montherapies have led to calls for combination trials of drugs and nondrug treatments. No studies have evaluated the incremental benefits of combining CBT and medication as suggested in the American Pain Society. A primary objective of the proposed research is to evaluate the combination of a modified version of CBT, CBTfm that targets fatigue, sleep, pain, depression, and anxiety and tramadol, a medication that has analgesic, antiserotonergic properties, and inhibits the neuronal reuptake of norepinephrine for FM. Based on published literature and evidence-based clinical practice guideline, we hypothesize that the combination of CBTfm+Tramadol will lead to significantly greater improvement than Health Education + Tramadol, Health Education + Placebo, or CBTfm +Placebo. A second objective is to use actigraphy, an objective measure of sleep and activity, to evaluate the "perceptual dissociation" between patients'perceptions of their sleep quality and activity and objective indices of these two key variables. Based on evidence that FM patients avoid activity not only because of current exhaustion but also because of believe that fatigue and pain will worsen if they are active, we hypothesize that there will be a weak relationship between patients'perceptions and the objective indices of sleep and activity. The mechanisms by which treatments for FM are effective for FM are unknown. A 3rd objective is to evaluate psychological and neurophysiological variables as potential mediators of outcome. Finally, the 4th objective is to test a model of the mediational effects of fatigue on activity level, arising from pain, sleep and mood disturbance in FM. The results will have important implications for developing optimal treatment programs for FM, the mechanisms understanding treatment outcome, and the associations among sleep, fatigue, activity, pain, and mood in this prevalent pain condition. PUBLIC HEALTH RELEVANCE: The proposed research addresses treatment of fibromyalgia (FM), a prevalent syndrome that is estimated to affect 3 to 5 mission Americans. FM is characterized by widespread pain, fatigue, sleep disturbance, cognitive symptoms, depression, anxiety, among other symptoms. FM can lead to significant disability, complex management decision, and economic burden on society given this population's extensive use of health services. There is currently no cure for FM and available treatments only reduce symptoms by approximately 35% and in a minority of patients. This has led to calls for treatments that combine both pharmacological and nonpharmacological modalities. This project will evaluate the effects of a combination treatment based on promising individual treatments, namely, cognitive-behavior therapy and tramadol. Both of these treatments have been recommend as components of a comprehensive treatment approach to FM by evidence-based clinical practice guidelines. The combination has the potential to maximize the benefits of each individual treatment and to reduce suffering and improve the health-related quality of life for those with FM.

DESCRIPTION (provided by applicant): Fibromyalgia (FM) is a chronic widespread pain syndrome with a number of concurrent symptoms (e.g., sleep difficulties, fatigue, depression, anxiety), unknown pathogenesis, and no well-replicated biological markers that is estimated to affect 3-6 million people in the United States. The diversity of symptoms reported by FM patients is consistent with the view that FM is a multisystem disorder, involving a complex interaction of biological, psychological, and social mechanisms. Although evaluations of a number pharmacological have shown beneficial effects none are curative. These treatments reduce pain by approximately 35% but no more than half of patients experience clinically meaningful improvements. Similar outcomes have been reported by nonpharmacological treatments, particularly cognitive-behavior therapy (CBT), which has been shown to produce equivalent benefits to medication in reducing pain and improving function. The modest outcomes of these montherapies have led to calls for combination trials of drugs and nondrug treatments. No studies have evaluated the incremental benefits of combining CBT and medication as suggested in the American Pain Society. A primary objective of the proposed research is to evaluate the combination of a modified version of CBT, CBTfm that targets fatigue, sleep, pain, depression, and anxiety and tramadol, a medication that has analgesic, antiserotonergic properties, and inhibits the neuronal reuptake of norepinephrine for FM. Based on published literature and evidence-based clinical practice guideline, we hypothesize that the combination of CBTfm+Tramadol will lead to significantly greater improvement than Health Education + Tramadol, Health Education + Placebo, or CBTfm +Placebo. A second objective is to use actigraphy, an objective measure of sleep and activity, to evaluate the perceptual dissociation between patients' perceptions of their sleep quality and activity and objective indices of these two key variables. Based on evidence that FM patients avoid activity not only because of current exhaustion but also because of believe that fatigue and pain will worsen if they are active, we hypothesize that there will be a weak relationship between patients' perceptions and the objective indices of sleep and activity. The mechanisms by which treatments for FM are effective for FM are unknown. A 3rd objective is to evaluate psychological and neurophysiological variables as potential mediators of outcome. Finally, the 4th objective is to test a model of the mediational effects of fatigue on activity level, arising from pain, sleep and mood disturbance in FM. The results will have important implications for developing optimal treatment programs for FM, the mechanisms understanding treatment outcome, and the associations among sleep, fatigue, activity, pain, and mood in this prevalent pain condition.

Pain is the most common symptom leading patients to consult a physician in the United States. According to the 2012 National Health Interview Survey, over 100 million adults report experiencing pain within the past 3 months, and approximately 50% of these individuals reported that the impact of their pain was moderate or severe. Chronic pain is associated with both direct (e.g., health care) and indirect (e.g., disability) costs that have been estimated to range from $560-635 billion annually. Although considerable progress has been made in understanding the pathophysiologic mechanisms of pain, the most widely prescribed medications for acute and chronic pain?non-steroidal anti-inflammatory drugs and opioid analgesics?have major shortcomings, including modest efficacy and significant risks that can limit long-term use. Consequently, there is a compelling public health need for the development of treatments with improved efficacy and safety. Unfortunately, many analgesic treatments examined in recent randomized clinical trials have failed to show efficacy. The explanations for these results are unknown, raising questions about the ability of clinical trials to distinguish efficacious treatments from placebo or less efficacious treatments (i.e., assay sensitivity). Patient characteristics, clinical trial research methods, outcome measures, approaches to data analysis, and statistical power may all play a role in accounting for difficulties in demonstrating the benefits of efficacious treatments. The identification of specific clinical trial characteristics associated with greater assay sensitivity and the development of outcome measures with greater validity can provide the foundation for an evidence-based approach to the design of clinical trials, not only of pain treatment but also in other therapeutic areas. The primary objective of the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations, Opportunities, and Networks (ACTTION) public-private partnership is to facilitate the development of novel analgesic, anesthetic, addiction, and peripheral neuropathy interventions with improved efficacy and safety. ACTTION is a multidisciplinary collaboration that prioritizes research and other initiatives to achieve this objective. The major activities of the ACTTION partnership include conducting systematic reviews, consensus meetings, and methodologically-focused studies as well as developing and qualifying novel clinical outcome assessments with the aim of increasing the assay sensitivity and informativeness of clinical trials. The results of these efforts have the potential to inform and accelerate the development of improved treatments for pain, anesthesia and sedation, addiction, and peripheral neuropathy.

Abstract Pain is the most common symptom leading patients to consult a physician in the United States, and its negative effects on quality of life can be substantial. Chronic pain is associated with both direct (e.g., health care) and indirect costs (e.g., lost wages, disability days) that have been estimated to range from $560-635 billion annually. Although considerable progress has been made in understanding the pathophysiologic mechanisms of pain, the most widely prescribed medications for acute and chronic pain ? non-steroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics ? have major drawbacks, including modest efficacy and significant risks that can limit long-term use. Consequently, there is a compelling public health need for the development of pain treatments with improved efficacy and safety. Millions of Americans also suffer from addiction or receive anesthesia for surgical procedures, and although there are efficacious treatments available in each of these additional therapeutic areas, many existing interventions have only modest efficacy or have incompletely characterized safety risks. The primary objective of the Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership is to identify, prioritize, sponsor, coordinate, and promote innovative activities that will expedite the discovery and development of improved analgesic, anesthetic, and addiction treatments for the benefit of the public health. The major activities of the ACTTION partnership include conducting systematic reviews, consensus meetings, and methodologically-focused research studies as well as developing and qualifying novel clinical outcome assessments and biomarkers, with the aim of increasing the assay sensitivity and informativeness of clinical trials. The knowledge gained from these efforts will accelerate the development of novel medications and other treatments for pain, anesthesia, and addiction that are more effective and safer than existing treatments.