Mechanistic Evaluation of Gabapentin and Opioid Polypharmacy - The purpose of this 5-year R01 grant application is to conduct a rigorous, double-blind, placebo-controlled human laboratory trial to examine the risks and therapeutic benefits associated with the co-use of opioids and gabapentin among individuals with a prototypic chronic pain condition. Over-prescription of short-acting opioids to treat chronic pain is considered a prominent contributor to the onset of the ongoing and persistent opioid epidemic resulting in overwhelming levels of morbidity and mortality. There is a major need to identify methods to mitigate the risks associated with prescribing opioids for pain management and identify novel effective methods to treat pain. Gabapentinoids are one such medication class that has been proposed as a safer option and potential complement to opioids. Clinically and functionally, the mechanisms of action of gabapentinoids are better suited for addressing chronic pain relative to opioids given their decreased risk for respiratory depression and non-medical use. However, following an increase in gabapentin prescribing, systematic reviews based on case studies, as well as longitudinal and epidemiological evidence suggest the risk for non-medical use may be greater than once suspected, especially among individuals with a history of opioid use. Human laboratory research is needed to complement the growing epidemiological, case study, and longitudinal literature on the combined use of opioids and gabapentin to identify specific mechanisms, risks, and benefits of the co-use of the two medications. We propose a within-subjects, placebo-controlled randomized study to evaluate the effects of gabapentin and the prototypic opioid agonist hydromorphone alone and in combination on risk for non-medical use, acute and chronic pain, stress, and physiological responses. We will enroll individuals with chronic lower back pain and any history of opioid use. Chronic lower back pain is the most common chronic pain disorder and represents a typical patient population enrolled into trials to assess analgesic interventions. Subjects will receive double-blind doses of (1) placebo, (2) 4mg hydromorphone, (3) 300 mg of gabapentin, (4) 900 mg of gabapentin, (5) 4 mg hydromorphone + 300 mg gabapentin, and (6) 4 mg hydromorphone + 900 mg of gabapentin across 6 outpatient sessions. Throughout the session, participants will complete standard subjective drug effect questionnaires, self-report and observer- rated sedation assessments, a psychomotor performance task, behavioral economic measures of drug demand, and Quantitative Sensory Testing to examine acute and chronic laboratory models of pain. Participants will provide blood samples throughout for pharmacokinetic testing of hydromorphone and gabapentin. Vital signs (e.g., blood pressure, heart rate, respiration rate, temperature) will be continuously monitored and recorded throughout the session. Together, these data will allow us to examine the impact of gabapentin alone and in combination with opioids on: Aim 1: risk for non-medical drug use, Aim 2: analgesia, and Aim 3: tolerability among individuals with a common chronic pain condition.
