Funded Projects

This study will challenge current clinical approaches to managing the pregnant woman with opioid use disorder. Dosing of buprenorphine (BUP) in pregnant women is based on studies in non-pregnant subjects, which suggests that symptoms of withdrawal occur when plasma BUP concentrations are < 1ng/ml. No such data exist for pregnant women, but this is a prerequisite for defining an appropriate dosing regimen of BUP in pregnant women. We will define this threshold by monitoring women undergoing mild, medically directed withdrawal. The Clinical Opioid Withdrawal Scale score and the Finnegan score for NAS are key to defining when withdrawal occurs and thus dictate treatment in mother and baby. Neither scoring system is based on plasma BUP concentrations and thus, may not reflect true opioid withdrawal. This proposal aims to develop physiologic-based scoring systems that refine the accuracy of diagnosis and optimize treatment.

Opioid use disorders (OUDs) in pregnancy are a U.S. public health crisis; the current standard of care is treatment with an opioid agonist such as buprenorphine (BPH), which has an associated risk for neonatal abstinence syndrome (NAS) and possible long-term neurodevelopmental consequences. As a novel treatment option for OUD in pregnancy, naltrexone would not expose the developing fetus to opioids, greatly reducing the risk for NAS and potentially improving maternal and infant outcomes. This study will evaluate the safety, efficacy, pharmacokinetics, and pharmacogenomics of naltrexone for pregnant women with OUDs, evaluating comprehensive mother-infant outcomes throughout the pregnancy and first year after birth. It will enroll 50 pregnant women stabilized pre-pregnancy on extended-release naltrexone (XR-NTX) and 50 comparison women on BPH from Boston Medical Center and the University of North Carolina in this multi-center prospective comparative cohort study.

Low back pain (LBP) is a common and costly condition. Spinal manipulative therapy (SMT) is a common mind-body intervention for individuals with LBP. Studies that have supported SMT have generally found relatively small treatment effects. The prior work of this research team has identified two mechanisms explaining the therapeutic effects of SMT: a reduction in spinal stiffness and improved activation of the lumbar multifidus muscle. Our research team has also developed accurate, non-invasive methods to measure these effects and their response to SMT. Our overall goal is to optimize SMT treatment protocols for patients with LBP. In this project, we will use innovative methodology to efficiently evaluate the effects of various individual treatment components toward an overall effect. Results of this project will provide optimized SMT protocols that will be ready for application in future randomized controlled trials examining the efficacy and effectiveness of SMT.

This study leverages recent federal and state opioid use disorder treatment initiatives as a platform for testing a promising mind-body intervention, Mindful Awareness in Body-oriented Therapy (MABT) as an adjunct to MAT in two clinical settings funded through the Washington Opioid State Targeted Response (STR) program. MABT, a novel mindfulness-based intervention, uniquely addresses aspects of awareness, interoception, and regulation that may be associated with pain, mental health distress, and behavioral control that increase risk of relapse and poor treatment outcomes. Each setting employs a variation of the nationally recognized Massachusetts Nurse Care Manager model. Using a randomized, two-group, repeated measures design, we will compare those who receive MABT+MAT to MAT only. The overarching goal of this application is to test MABT to improve MAT health outcomes among patients receiving buprenorphine to treat OUD.

This study proposes to test the delivery of a comprehensive cognitive behavioral therapy, reSET, to determine whether it can improve treatment adherence and long-term outcome among patients with opioid use disorder initiating medication-assisted treatment within a community-based"Hub and Spoke” Model of buprenorphine maintenance in central Pennsylvania. reSET (Pear Therapeutics, Inc.) is a commercially available version of the web-based Therapeutic Education System (TES) delivered as a mobile app and recently approved by the FDA as the first digital therapeutic adjunct for the treatment of substance use disorders. Through a series of interactive therapy lessons, the program teaches patients cognitive-behavioral coping skills to resist drug use and to address factors such as craving, depression, and other mood problems and relationship issues that are associated with risk of relapse. The CM component provides concrete rewards contingent on performance of key target behaviors.

Migraine is the most common neurological disorder. Currently available treatments fail to effectively manage migraine in most patients. Development of new therapeutics has been slow due in large part to a poor understanding of the underlying pathology of migraine. Endogenous proteases, released in the meninges by resident mast cells, have been proposed as a potential driver of migraine pain via an action on protease activated receptor type 2 (PAR2). The central hypothesis is that PAR2 expression in nociceptors that project to the meninges plays a key role in the pathogenesis of migraine pain. The aims are to: 1) use the established PAR2 development pipeline to design new PAR2 antagonists with improved drug-like properties; 2) use pharmacological tools in a novel mouse migraine model to further understand the potential role of PAR2 in migraine; and 3) use mouse genetics to study the cell type–specific role of PAR2 in migraine pain.

We discovered a class of non-opioid modulators of the T-type Cav3.2 channel that could treat neuropathic pain. In vivo pharmacokinetic and pharmacodynamic studies and preliminary toxicological studies identified AFA-279 and other candidates, which did not produce observable side-effects and showed greater analgesic effects than other neuropathic pain medications in rodent models. The goal of this proposed project is to submit the IND application on our Cav3.2 modulator to the Food and Drug Administration (FDA). We will produce AFA-279 under Good Manufacturing Practice (GMP)–like conditions using chemical manufacturing controls for Good Laboratory Practice (GLP) nonclinical toxicity studies and GMP clinical batch future Phase 1 clinical trials, complete toxicological and safety studies to establish the safety profile of AFA-279, prepare and submit the IND application, and then initiate early clinical trials. Our ultimate goal is to deliver a safer, more effective, non-opioid Cav3.2 channel modulator to patients suffering from neuropathic pain.

Ethnic groups show substantial variability in the experience of acute and clinical pain, with African Americans (AAs) having more clinical pain conditions and higher levels of pain severity and pain-related disability compared to non-Hispanic whites (NHW). Ethnic differences in opioid neurotransmitters suggest that these systems function less efficiently among AAs and may account for differences in pain and analgesic responses. The overwhelming majority of clinically used opioids elicit their effects through activation of the mu-opioid receptor, making it a relevant target for investigation. We propose to examine ethnic differences in the supraspinal endogenous opioid system using positron emission tomography (PET) imaging of mu-opioid receptors employing the mu-selective agonist [11C]carfentanil. Healthy AAs and sex-, age-, SES-matched NHW participants will undergo one baseline (non-pain) and one capsaicin-induced pain PET session using [11C]carfentanil. The current proposal will measure µ-opioid binding potential and examine its role in ethnic group differences in pain sensitivity.

Data suggest that members of minority groups are more likely to develop chronic pain and to have greater pain burden. We will identify a set of promising intervention targets for reducing or eliminating racial/ethnic pain disparities. We will interview adult survivors of serious physical injury, comprised of roughly equal proportions of African-Americans (AA), Latinos, and non-Latino Whites (NLW), and examine their medical records for information on injury severity and medication use in-hospital. Our aims are to determine whether: 1) AA and Latino physical injury survivors experience more severe pain relative to NLW; 2) AA and Latino injury survivors experience greater pain burden relative to NLW counterparts; 3) differences in pain severity burden are linked to a set of target candidates for interventions; and (4) pain outcomes in at-risk minority groups can be linked to a set of target candidates for group-tailored interventions to reduce pain severity and pain burden.

Morbidity and mortality related to prescription opioids are accelerating in the United States. Identifying the factors that lead to new opioid dependence among opioid naïve patients is a critical opportunity to reduce prescription opioid dependence and unintended diversion. In the United States, the majority of individuals who become opioid dependent receive their first opioid prescription following surgical procedures, yet there are no clinical guidelines to inform appropriate postoperative opioid use. We will examine the patient factors that are associated with postoperative pain and opioid consumption among a cohort of patients undergoing common elective abdominal procedures. We will identify the provider characteristics in postoperative opioid prescribing practices, and design and implement a provider-directed intervention to optimize postoperative opioid prescribing. Findings will inform patients and providers regarding the risk of opioid dependence following surgery, and will establish a patient-centered data infrastructure that yields continuous feedback to providers regarding appropriate opioid prescribing practices.

Previous studies found that African American (AA) and low socioeconomic status (SES) patients are less likely to receive guideline-concordant pain care relative to White and high SES patients. According to research and theory, enhancing clinician perspective-taking is a promising strategy for improving the care of AA and low SES patients. We have developed an innovative methodology that utilizes computer-simulated patients and environments to assess, understand, and remediate pain treatment disparities. Our approach allows for the intervention to be individually tailored to each trainee, thereby enhancing its impact. It also allows for individual trainees to gain exposure to a greater range of racially and socioeconomically diverse patients than can normally be obtained in traditional training settings. We hypothesize that our perspective-taking intervention will increase trainees’ knowledge of their own biases, enhance trainees’ empathy toward patients, and reduce trainees’ anxiety/threat toward patients, and that these changes will reduce pain treatment disparities.

MAT is the most effective intervention for opioid use disorder (OUD), and methadone maintenance treatment (MMT) is the most commonly prescribed MAT; however, approximately half of people who begin MMT discontinue within a year, and half of people retained in MMT have an opioid relapse within six months. Chronic pain, affecting most people on MMT, could be contributing to relapse in this group. Novel behavioral interventions that address both chronic pain and opioid relapse among people on MAT are needed. Mindfulness Oriented Recovery Enhancement (MORE) was recently developed to treat both pain and opioid misuse. MORE is a group intervention that combines training in mindfulness, cognitive reappraisal, and positive emotion regulation skills to target the dysfunctional cognitive, affective, and behavioral pathways that lead to opioid use relapse. The objective of this proposal is to examine the impact of MORE on opioid relapse and chronic pain among individuals receiving MMT.