Magdalena R. Naylor - US grants

DESCRIPTION (provided by applicant): This is an R21 application by a new investigator to utilize Interactive Voice Response (IVR) to develop a new strategy for preventing prescription drug abuse in patients with persistent pain. IVR is a computer-based, automated telephone that enables callers to respond to a recorded voice via the telephone keypad. Using this technology, we developed Therapeutic IVR (TIVR) as an intervention in patients using prescription medication for chronic pain. The TIVR reinforces group Coping Skills Training (CST) given in our pain clinic. It includes an automated daily diary for self monitoring, guided behavioral rehearsals of key CST coping skills, and monthly personalized feedback, all of which can be accessed by patients on demand. In our pilot test, ten subjects with severe, chronic musculoskeletal pain participated in 10 weeks of group CST followed by four months of TIVR. Subsequently, we recruited a second sample of eight patients as a comparison group who were given group CST but not the TIVR. Within subjects analysis (ANOVA) of the TIVR group showed that, compared to baseline values, the maximum mean positive change for nearly all outcome measures occurred at the post TIVR point. Several measures were significantly improved post TIVR despite lack of significance after CST. These included SF-36 Mental Health Composite Score (p<.0004), MPQ pain (p<.01), CSQ Catastrophizing (p<.0006), TOPS Total Pain Experience (p<.03) and Perceived Family/Social Disability (p<.02). Between subjects analysis (ANCOVA) of TIVR treatment and comparison groups revealed significantly higher TIVR group scores for TOPS Total Pain Experience (p< .01), TOPS Perceived Social Disability (p< .002) and SF-36 Mental Composite (p< .05). Finally, Hierarchial Linear Regression of the TIVR daily diary confirmed significant reductions in the highest level of pain (p<.0001), highest stress level (p<.0001), and frequency of resorting to maladaptive coping skills such as catastrophizing (p< .0001). Analyses of these daily data also revealed a significant (.0002) decrease in the use of medication during the TIVR trial. However these latter results are tentative since we asked only two general questions about medication use, and neither question related to specific types of medication. This R21 would enable us to pretest a revised TIVR designed specifically to monitor and reduce reliance on medication and to prevent prescription drug abuse in patients with persistent pain.

DESCRIPTION (provided by applicant): We propose to explore a well-known telephone-based technology (IVR) as a tool to reduce the pain, physical disability, and psychological distress experienced by patients with chronic musciiloskeletal pain. IVR (Interactive Voice Response) is a computer-based, automated telephone system that enables callers to respond to a recorded voice via the telephone keypad. Using this technology, we developed Therapeutic IVR (TIVR) as a tool for maintenance enhancement fallowing group cognitive-behavioral coping skills training (CST), a widely used behavioral treatment for chronic pain. The TFVR has four components: 1) an automated daily questionnaire for self monitoring, 2) a didactic review of coping skills, 3) guided behavioral rehearsals of CST coping skills, and 4) monthly feedback messages recorded on to the TIVR by the therapist. All four components can be accessed remotely by patients via any touch-tone phone. We initially tested the feasibility of the TIVR in a convenience pilot sample of 18 subjects. Ten patients with severe, chronic musculoskeletal pain participated in 11 weeks of group CST followed by four months of TIVR. A comparison sample of eight subjects received the same group CST by the same therapist, but not the TIVR. Both groups showed improvement after CST. However, between subjects analysis across the two groups showed that relevant outcome scores in the comparison sample worsened in the four months after CST whereas the same outcomes in the TIVR group improved during this period. In a second (ongoing) pilot study funded by a NIDA R21 grant, we are attempting to determine if the TIVR can be used to improve coping, decrease pain and reduce pain medication use. Study design and outcome measures are similar to those of the initial pilot study except that subjects are randomized. We have now analyzed data from 34 subjects, 15 probands and 19 controls. Preliminary results on the efficacy of the TIVR confirm the results of the initial pilot study. Between subjects analysis (ANCOVA) revealed statistically significant inter-group differences in: TOPS Pain Symptoms, TOPS Total Pain Experience, SF-36 Physical Composite, and CSQ Ability to Control Pain at both 4 and 8 months follow-up. The present R01 application is for a randomized controlled trial (RCT) of the TIVR in 150 patients with chronic musculoskeletal pain. We propose a 3-arm study. As before, all subjects will be given our standard 11 weeks of CST for pain coping skills. Consenting subjects will then be randomly assigned to one of three study conditions: 1) a no TIVR control condition (standard treatment); 2) an attention control condition, four months of calls to the Daily Self-monitoring Questionnaire with minimum monthly feedback; or 3) the full TIVR condition, four months of calls to the Full TIVR (all four components). The study goals are: 1) to attempt to replicate the results of the two pilot studies of TIVR in a full-scale RCT; and 2) to determine the efficacy of the full TIVR in relation to an attention control condition.

Acute; Acute Pain; Affect; Affective; After Care; After-Treatment; Aftercare; Amygdala; Amygdaloid Body; Amygdaloid Nucleus; Amygdaloid structure; Area; Attention; Behavior Therapy, Cognitive; Behavioral Therapy; Brain; Brain imaging; Chronic; Clinical; Cognitive Therapy; Complex; Condition; Data; Decision Making; Depressed mood; Depression, Unipolar; Development; Educational process of instructing; Emotional; Emotional well being; Emotions; Encephalon; Encephalons; Event; Exclusion Criteria; Feels well; Functional Magnetic Resonance Imaging; Goals; Intervention; Intervention Strategies; Investigation; MR Imaging; MR Tomography; MRI; MRI, Functional; Magnetic Resonance Imaging; Magnetic Resonance Imaging Scan; Magnetic Resonance Imaging, Functional; Measures; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; Mental well-being; Modality; Musculoskeletal Pain; NMR Imaging; NMR Tomography; Nervous; Nervous System, Brain; Neurobiology; Normal mental condition; Normal mental state; Normal psyche; Nuclear Magnetic Resonance Imaging; Outcome; Pain; Pain Control; Pain Therapy; Pain Threshold; Pain Tolerance Level; Pain management; Painful; Participant; Patients; Perception; Personal Satisfaction; Phobias; Phobic Disorders; Phobic Neuroses; Phobic anxiety disorder; Pilot Projects; Process; Psychiatry; Psychological Well Being; Psychotherapy; Psychotherapy, Cognitive; Public Health; Publishing; Randomized; Recovery; Reporting; Research; Science of neurophysiology; Sense of well-being; Sensory; Short-Form McGill Pain Questionnaire; Somatosensory Cortex; Spiders; Stimulus; Symptoms; Teaching; Testing; Therapy, Cognition; Unipolar Depression; Week; Well in self; Zeugmatography; amygdaloid nuclear complex; brain visualization; chronic pain; chronic painful condition; cognitive behavior intervention; cognitive behavior modification; cognitive behavioral intervention; cognitive behavioral modification; cognitive behavioral therapy; depressed; emotional experience; emotional expression; emotional stimulus; experience; expression of emotion; fMRI; improved; interventional strategy; neural; neural circuit; neural circuitry; neurobiological; neuroimaging; neurophysiology; novel; pain tolerance; pilot study; psychological wellness; public health medicine (field); randomisation; randomization; randomly assigned; relating to nervous system; response; sadness; self wellness; showing emotion; somesthetic sensory cortex; theories; well-being

DESCRIPTION (provided by applicant): The primary goal of this R01 application is to investigate whether a psychotherapeutic approach, group Cognitive Behavioral Therapy (CBT) plus relapse prevention program Therapeutic Interactive Voice Response (TIVR), modifies the dysfunctional sensory, emotional, and cognitive neural circuitry associated with chronic pain as examined by functional magnetic resonance imaging (fMRI). We propose to apply previously tested and accepted paradigms for symptom provocation (acute pain, emotional stimuli and cognitive tasks) to investigate psychological effects on neural correlates of chronic pain. Because chronic pain is not just an isolated sensory event but rather a complex sensory, cognitive and emotional experience, it is reasonable to expect that an intervention which improves chronic pain such as coping skills training followed by the relapse prevention program will alter responses to provocative stimuli and thus the underlying neural circuitry. Our pilot study (R21NIDA) demonstrated that patients with chronic musculoskeletal pain not only benefit from group CBT but continue to improve with the use of our telephone based relapse prevention program (TIVR). In addition, our fMRI pilot study results reveal that after group CBT chronic pain patients show reduced insula (IC), amygdala and primary somatosensory cortex (S1) reactivity to arousing stimuli, and increased activation in the prefrontal cortex and anterior cingulate cortex (ACC). This suggests that CBT may increase cortical suppression of amygdala and S1 and thus may be related to the reduction and the experience of pain. In this application we take advantage of the unique opportunity to obtain longitudinal clinical and neuroimaging data. One hundred twenty subjects who meet inclusion and exclusion criteria for the fMRI study will be randomly assigned to two study conditions: Eighty to 11-week CBT Treatment Condition and forty to Attention Control Condition. Eighty subjects who undergo group CBT will be randomized to TIVR or Treatment-as-Usual. Participants will undergo three fMRI examinations (at baseline, after group and after TIVR interventions) to explore two study goals: 1) whether psychological treatment changes the function of brain neural circuitry in response to application of acute noxious stimuli, cognitive tasks and emotional stimuli; 2) whether there is a relationship between altered activation in brain areas associated with the attentional, affective, and sensory aspects of chronic pain and quantifiable improvement in clinical measures reported at the conclusion of group CBT and 4 months of TIVR. Our approach is novel as there are no published studies that explore the neurobiological effects of psychotherapeutic approaches in chronic pain. Through the joint examination of painful, emotional, and cognitive paradigms via brain imaging and implementing this approach in a longitudinal, clinical framework, we will open important and novel avenues of research on chronic pain.

Abstract/Project Summary Chronic pain affects over 100 million Americans. Of the 9.4 million Americans who take opioids for chronic pain, 2.1 million are estimated by the NIH to be dependent on them and are in danger of turning to the black market. 4 of 5 heroin addicts say they come to the drug from prescription pain killers. Management of chronic pain has increasingly relied upon high-dose chronic opioid therapy, with this change paralleled by increasing numbers of individuals affected by opioid abuse, and dramatic rises in opioid-related overdose and death. Thus, it is imperative that we test and validate cost-effective, non-pharmacological interventions, such as Cognitive Behavioral Therapy (CBT), for the treatment of pain to reduce reliance upon high-dose chronic opioids. CBT can effectively reduce pain without increasing costs or producing debilitating side effects associated with opioid medications. Unfortunately, its use in clinical practice is limited, as most of CBT benefits are believed to be related to the improvement of coping but not to pain modulation itself. We have repeatedly shown that 11 weeks of CBT for pain management can significantly reduce pain, suggesting that CBT could be employed as an adjunct therapy in clinical pain settings. Furthermore, we have recently determined that CBT-related pain relief engages multiple neural mechanisms and increases in cognitive control, emotion regulation, and executive processing. However, it remains unknown if CBT related pain relief activates endogenous opioid systems. Interestingly, we and others found that placebo, meditation and CBT attenuates pain responses by activating brain regions (e.g., anterior cingulate cortex, anterior insula, orbitofrontal cortex) containing high concentrations of opioid receptors. In addition, CBT is postulated to attenuate pain by cognitive control processes and reducing expectations of impending noxious stimuli, mechanisms that are partially mediated by endogenous opioid systems. Therefore, we postulate that CBT engages endogenous opioid systems to reduce pain. This project will incorporate a unique combination of expertise and methodologies to achieve this aim, including a randomized, controlled 11 week CBT intervention, assessment of pre- to post-intervention changes in daily chronic back pain intensity based on telephone-based diaries, and controlled laboratory assessment of pre- to post- intervention changes in endogenous opioid function, tested by effects of opioid blockade on evoked pain responses relative to placebo condition. The proposed experiment will provide novel insight into the mechanisms supporting CBT-related pain relief, thereby providing a foundation for greater use of CBT in clinical settings. Project results would potentially lead to changes in clinical practice with significant population benefits, given the frequency with which chronic opioids are currently used and their recognized negative consequences.