Funded Projects

This study will evaluate novel strategies to reduce opioid use and pain in patients with end-stage renal disease receiving chronic hemodialysis (HD). Specifically, the study will examine the effect of nonpharmacologic (Acceptance and Commitment Therapy [ACT] and acupuncture) and pharmacologic (buprenorphine) interventions in HD patients who are receiving chronic opioid medications due to chronic pain and/or high pain interference. The study will enroll 720 HD patients across U.S. Hemodialysis Opioid Prescription Effort Consortium Clinical Centers to (1) determine the effectiveness of ACT and acupuncture compared with the control condition in reducing opioid dose and improving pain among HD patients; (2) identify the best adaptive intervention sequence for improved outcomes; (3) explore age, sex, and comorbidities as potential moderators of the response to the intervention; and (4) describe facilitators and barriers to the implementation of the intervention using in-depth, semi-structured individual interviews with intervention participants and providers.

EicOsis is developing a first-in-class analgesic with efficacy against neuropathic pain that will reduce or replace the need for opioids and thus potentially prevent opioid use disorder (OUD). The target of the small molecule inhibitor EC5026 is the soluble epoxide hydrolase, a master regulatory enzyme that modulates the activity of endogenous bioactive lipids. The study will reach the next steps in clinical human clinical trials with EC5026 through additional preclinical studies to expand the efficacy into models of chronic pain conditions. Additionally, detailed pharmacokinetic, metabolism, and distribution studies are proposed that will provide the required information to optimize drug formulation and for advanced clinical trials examining efficacy in humans. EicOsis is meeting current development goals, and EC5026 is well positioned to meet the urgent need of reducing opioid use.

The Pain Reduction and Opioid Medication Safety in ESRD (PROMISE) study aims to improve the safety of opioid use and pain management in end-stage renal disease (ESRD) patients on hemodialysis (HD) using a Type I effectiveness-implementation hybrid design. A multisite randomized controlled trial of HD patients from the Hemodialysis Opioid Prescription Effort (HOPE) Consortium will examine the effectiveness of two separate nine-month evidence-based interventions: 1) Opioid Tapering Management (OTM) and 2) Behavioral Pain Management (BPM). We will examine the effectiveness of OTM (versus no OTM, Aim 1) and BPM (versus no BPM) over nine months for reducing opioid use (primary outcome) and improving pain severity (secondary outcome) in HD patients on chronic opioids. The implementation goal will take advantage of the diverse patient, provider, and organizational settings in the HOPE Consortium to evaluate process outcomes.

 Quell Therapeutics uses the Optopatch platform for making all-optical electrophysiology measurements in neurons at a throughput sufficient for phenotypic screening. Using engineered optogenetic proteins, blue and red light can be used to stimulate and record neuronal activity, respectively. Custom microscopes enable electrophysiology recordings from 100’s of individual neurons in parallel with high sensitivity and temporal resolution, a capability currently not available with any other platform screening technology. Here, researchers combine the Optopatch platform with an in vitro model of chronic pain, where dorsal root ganglion (DRG) sensory neurons are bathed in a mixture of inflammatory mediators found in the joints of osteoarthritis patients. The neurons treated with the inflammatory mixture become hyperexcitable, mimicking the anticipated cellular pain response. Investigators calculate the functional phenotype of arthritis pain, which captures the difference in action potential shape and firing rate in response to diverse stimuli. The team will screen for small molecule compounds that reverse the pain phenotype while minimizing perturbation of neuronal behavior orthogonal to the pain phenotype, the in vitro “side effects.” The highest ranking compounds will be chemically optimized and their pharmacokinetic, drug metabolism, and in vivo efficacy will be characterized. The goal is to advance therapeutic discovery for pain, which may ultimately help relieve the US opioid crisis.

The research team will develop an implantable neural stimulation system to provide natural and intuitive sensation for prosthesis users. The nerve cuff technology meets the requirements for a sensory feedback system capable of providing consistent and controlled electrical stimulation. Coupled with a multichannel implantable stimulator, this electrode array will offer substantial improvement over existing options to treat phantom limb pain (PLP). In Phase I, researchers will finalize array architectures for evaluation in cadaver studies, complete integration of electrodes with our stimulator, conduct benchtop verification of electrical and mechanical performance, send implants for third-party evaluation of system biocompatibility, and complete a Good Laboratory Practice animal study to validate safety and efficacy. In Phase II, researchers will conduct a 5-subject clinical study to test the implantable stimulation system. Each unilateral prosthesis user will be implanted for one year as researchers evaluate the safety and efficacy of this implantable device to treat PLP.

Chronic pancreatitis (CP) and the debilitating pain associated with it remains a common and challenging clinical syndrome that is difficult to treat effectively. Using rodent models of CP, preliminary studies have found that nerve growth factor (NGF) and transforming growth factor beta (TGFb) appear to be acting by the common effector, calcitonin-gene related peptide (CGRP), to induce pain in CP. CGRP is known to mediate pain as a neurotransmitter in the central nervous system, specifically as a potent vasodilator involved in migraine. This project will test the hypothesis that peripheral CGRP is a major mediator of peripheral nociceptive sensitization in CP, and that peripherally restricted anti-CGRP treatment could provide an efficient and sufficient approach for the treatment of pain in pancreatitis

Although there are effective prevention and treatment programs and services to address opioid misuse, opioid use disorder (OUD), and overdose, gaps remain between those needing and those receiving prevention and treatment, in part because of a need to better understand how to make these programs and services most effective at a local level. The National Institutes of Health (NIH) and the Substance Abuse and Mental Health Services Administration (SAMHSA) launched the HEALing Communities Study to generate evidence about how tools for preventing and treating opioid misuse and OUD are most effective at the local level. This multisite implementation research study will test the impact of an integrated set of evidence-based practices across health care, behavioral health, justice, and other community-based settings. The goal of the study is to reduce opioid-related overdose deaths by 40 percent over three years. Boston Medical Center is partnering with academic institutions in three other states to study the impact of these efforts in 67 highly affected communities. The study will also look at the effectiveness of coordinated systems of care designed to increase the number of individuals receiving medication to treat OUD, increase the distribution of naloxone, and reduce high-risk opioid prescribing.

According to SAMHSA’s 2017 National Survey on Drug Use and Health (NSDUH), 11.4 million persons in the U.S. report past-year opioid misuse; out of them, only 2.1 million individuals met criteria for an OUD. Very little is known about efficacious interventions for those who do not meet criteria for moderate/severe OUD (i.e., subthreshold OUD). The prevalence of subthreshold OUD in primary care settings is 5 percent to 10 percent, with higher rates (21 percent to 29 percent) among those receiving prescribed opioids. Although they are at high risk of developing moderate/severe OUD and/or dying from an overdose, little or no empirical evidence exists for pragmatic prevention interventions that can be adopted at integrated general medical settings. To study the efficacy of prevention interventions to arrest the progression from risky opioid use, researchers will test the efficacy of a STOP intervention in primary care settings. STOP adopts an early intervention approach, based on a collaborative care model to prevent progression to moderate/severe OUD, and consists of a practice-embedded nurse care manager who provides patient education and supports the primary care provider (PCP) in engaging, monitoring and guiding patients who have risky opioid use; brief advice delivered to patients by their PCP; and phone counseling of patients by behavioral health providers to motivate and support behavior change. Researchers will determine whether STOP reduces risky opioid use and examine the impact of STOP on progression to moderate/severe OUD, overdose risk behavior and overdose events in adults with risky use of illicit or prescription opioids.

Emergency department (ED)-initiated buprenorphine/naloxone (BUP) with referral for ongoing BUP is superior to referral alone in engaging patients with untreated opioid use disorder (OUD) in treatment at 30 days and is cost-effective. However, logistical barriers exist in translating research into practice. New BUP formulations such as the extended-release injectable BUP (CAM2038, XR-BUP) hold promise in addressing many of the barriers more effectively than sublingual buprenorphine (SL-BUP) by treating the patients’ symptoms for up to seven days. This study will recruit, train and provide resources to 30 ED sites throughout the U.S. using implementation facilitation strategies to address stigma and provide ED-initiated BUP for patients presenting with OUD who are not receiving medications for OUD. Once implementation is adequately achieved, the sites will conduct a randomized controlled trial (RCT) to compare the effectiveness of SL-BUP versus XR-BUP on ED patients’ engagement in formal addiction treatment seven days after their ED visit. In addition, in an ancillary component of the study, the use of XR-BUP will be assessed in ED patients with Clinical Opioid Withdrawal Scale (COWS) scores of

Inhibitors of the epigenetic enzymes histone deacetylases (HDACs) produce analgesic responses and are therefore therapeutic targets for pain. The research team recently resolved a PET imaging agent, [11C]Martinostat, that selectively binds to a subset of HDAC enzymes. A series of initial proof-of-concept clinical validation studies will be conducted to evaluate whether [11C]Martinostat PET is a sensitive biomarker to detect the typical (axial) chronic low back pain (cLBP). The research team will validate [11C]Martinostat PET’s ability to differentiate subtypes of pain by comparing axial cLBP and other cLBP patients with radiculopathy and longitudinally study subacute LBP patients (sLBP) to investigate whether there is a unique imaging signature that differentiates patients who develop cLBP and those who recover from low back pain. Using [11C]Martinostat to understand HDAC expression changes in chronic pain patients will validate an epigenetic drug target, refine patient selection based on HDAC expression, and facilitate proof of mechanism in developing novel analgesics.

Chronic pain affects over 100 million Americans, costing society about $600 billion annually. Despite numerous pharmacological and non-pharmacological therapies, over 50% of chronic pain sufferers feel little control over their pain. CognifiSense has developed a patent-pending Virtual Reality Psychological Therapy (VRPT), which is designed to create lasting reduction of chronic pain by addressing the maladaptive learning processes driving pain chronification. VRPT is an experiential learning system, which provides the brain a new set of signals that teaches it that the pain is not as bad as it perceived and that it has greater control over the pain than it perceived. VRPT combines the immersive power and the ability to individualize the therapy of Virtual Reality with well-researched principles of self-distancing, self-efficacy, and extinction to retrain the brain. The goal of this study is to determine the clinical feasibility of VRPT in achieving a lasting reduction of chronic pain, establish brain mechanisms associated with treatment response, and collect comprehensive user feedback to enable further refinement of the current product prototype. CognifiSense's VRPT has the potential to be a significant clinical and business opportunity in the treatment of chronic pain.

The opioid epidemic has increased the demand for a research workforce with the necessary expertise and skills to conceptualize and carry out studies to expand and improve treatment options for opioid use disorders (OUDs). In particular, as the NIDA-funded Clinical Trials Network (CTN) expands the number of nodes and takes on additional studies as part of the HEAL Initiative, the need for an increasing number of staff who are familiar with the CTN research environment is amplified, and opportunities to provide a platform for training new investigators interested in the OUD area are increased. The CTN Research workforce development and dissemination program will provide multi-modal training, including didactic, experiential, and mentoring, to prepare research staff (regulatory personnel, study coordinators, project managers), post-doctoral fellows and faculty from a variety of disciplines (MD, PhD, PharmD, Nurse Practitioners, etc.) to participate in HEAL Initiative studies being conducted within the CTN.

To address the need for novel therapeutics for opioid use disorder (OUD), this research group identified ghrelin as an endogenous regulator of the mesocorticostriatal circuit, which contributes to the enhanced motivational attributes of addictive drugs and drug-associated cues. Ghrelin binds to the growth hormone secretagogue receptor 1? (GHS1?R) to transduce several physiological and behavioral processes, including the reward-related effects of opioid agonists. Systemic administration of a GHS1?R antagonist/inverse agonist dose-dependently attenuated self-administration of the addictive opioid analgesic oxycodone as well as oxycodone-seeking. This project proposes to employ a suite of validated rodent OUD models to define the preclinical profile for PF5190457, a selective GHS1?R antagonist/inverse agonist. PF5190457’s abuse liability, ability to suppress withdrawal and relapse-like behaviors, drug metabolism and pharmacokinetics, and brain penetrability in rats will be assessed. Phase 1 clinical studies in non–treatment seeking OUD participants will follow to assess the safety and tolerability of PF5190457.