Chronic Widespread Pain in HIV: Novel Mechanisms and Therapeutics

Role of Endogenous Opioid Peptides in HIV-associated Chronic Widespread Pain

To determine if decreased production or release of endogenous opioid peptides by peripheral immune cells contributes to hypersensitivity in people with HIV

The prevalence of chronic widespread pain (CWP) in individuals infected with the human immunodeficiency virus (HIV-1) includes regional and widespread musculoskeletal pain of neuropathic and inflammatory nature. HIV-related CWP leads to 10x greater odds of functional impairment. However, the specific mechanisms that contribute to CWP in HIV are not understood. Thus, pharmacological and non-pharmacological approaches to mitigate CWP have had minimal benefits, contributing to an overreliance on opioids and alarming rise in addiction and overdose. The overall objective of this study is to address the gap in the knowledge of the pathogenesis of HIV-related CWP. Specifically, the role of impaired endogenous opioid synthesis/release from leukocytes in people with HIV (PWH) who self-report CWP will be explored. Leukocytes (neutrophils, monocytes/macrophages, and lymphocytes) are a rich source of opioid peptides (Met-enkephalin, dynorphin A, β-endorphin) that inhibit nociception by binding to peripheral opioid receptors. Therefore, to establish whether decreased peripheral opioid peptides correlate with experimental pain measures in PWH with self-reported CWP, quantitative sensory testing (QST) will be completed before and after administration of methylnaltrexone bromide (RELISTOR), a clinically available, peripherally acting opioid receptor antagonist.

Inclusion Criteria:

• Confirmed HIV diagnosis and currently a patient in the UAB 1917 HIV Clinic
• Age 19 - 65; the lower end of this age range was chosen to capture young adults with HIV infection, and participants over 65 years are increasingly likely to meet one or more exclusion criteria
• All people living with HIV must be currently receiving stable antiretroviral therapy (ART) for inclusion in this study
• Non-HIV participants must be confirmed as HIV negative. HIV-negative participants with chronic widespread pain must self-report bodily pain more than once per week for at least three consecutive months and HIV-negative participants without chronic pain must self-report no pain, or pain less frequently than once per week for at least three consecutive months

Exclusion Criteria:

• Anemia
• Current or past history of blood disorders which may increase hemolysis
• Active microbial infections which may alter the quantity or quality of blood inflammatory cells such as monocytes and neutrophils
• Use of certain medication other than antiretroviral therapy that might conflict with study observations. However, participants will not be excluded or asked to withdraw from medications used for pain management since temporary withdrawal from these medications could affect pain measures (exceptions will be therapies such as methadone or buprenorphine used to treat opioid addiction). Only those who are stable on these medications for at least 60 days will be included. All patient medications used for at least the 60 days prior to participation will be recorded and controlled in statistical analyses as needed
• Systemic rheumatic disease (e.g., rheumatoid arthritis, systemic lupus erythematosus). These rheumatologic conditions will be excluded due to their autoimmune characteristic. . Cachexia (wasting syndrome) and severe frailty. This exclusion is in place to protect against the stress of experimental pain testing
• A history of clinically significant surgery in the past year
• Uncontrolled hypertension (i.e. SBP/DBP of >150/95) or cardiovascular or peripheral arterial disease. These exclusions are in place primarily for safety reasons because the cold pressor task represents a cardiovascular challenge. However, uncontrolled hypertension can also affect pain perception, which is another reason for excluding these individuals
• Poorly controlled diabetes (HbA1c > 8%) for both safety reasons, and because diabetic neuropathy could alter pain perception
• Neurological disease (e.g. Parkinson's, multiple sclerosis, epilepsy)
• Serious psychiatric disorder requiring hospitalization within the past 12 months or characterized by active suicidal ideation
• Any participant deemed to be actively suicidal upon study screening will be escorted to the UAB emergency room and evaluated by the Psychiatry Service
• Diminished cognitive function that would interfere with understanding of study procedures. The Realm Health Literacy Test will be administered to ensure that participants are free of cognitive impairment that would compromise study participation
• Pregnancy. Inclusion/exclusion criteria will be verified using the screening tool in combination with review of participants' medical records