Pain Agreements and Time-to-Event Analysis of Substance Misuse in a Primary Care Chronic Pain Program.

BACKGROUND: Types and correlates of pain medication agreement (PMA) violations in the primary care setting have not been analyzed. METHODS: A retrospective analysis was completed to examine patient characteristics and correlates of PMA violations, a proxy for substance misuse, over a 15-year period in an outpatient General Medicine Pain Service within the Division of General Medicine and Clinical Epidemiology, Department of Medicine, School of Medicine, University of North Carolina at Chapel Hill. Patients who signed the PMA were managed for chronic pain from 2002 through 2017 (N = 1,210). The incidence of PMA violations was measured over a 15-year span. Substance misuse was defined a priori in the study as urine toxicology screen positive for illicit or nonprescribed controlled substances, patient engagement in prescription alteration, doctor-shopping, or diversion. RESULTS: Most patients received a prescription for a controlled substance (77.4%). During enrollment, 488 (40.3%) patients had one or more violations of their PMA. One-third (33.4%) of pain service patients had a violation within 365 days of signing the agreement. Active tobacco smokers had double the incidence of agreement violation within the first 30 days of enrollment. Almost one-half (49.8%) of violations were due to inconsistent use of controlled substances. Patients with any prior DWI/DUI or drug-related offense had a significantly increased rate of substance misuse (P < 0.0001). CONCLUSIONS: PMA violations were common among a population of patients managed for chronic nonmalignant pain. Universal opioid prescribing precautions, including PMAs, require further investigation to assess their roles in mitigating the potential patient and societal harms associated with opioid prescribing.

Impact of in vitro heavy metal exposure on pancreatic ß-cell function.

Susceptibility to type-2 diabetes mellitus (DM) is determined, in part, by a variety of environmental factors, including exposure to metals. Heavy metals including inorganic arsenic (iAs), zinc (Zn), manganese (Mn), and cadmium (Cd) have been reported to affect glucose homeostasis or DM risk in population-based and/or laboratory studies. Previous evidence from our lab has shown that iAs can increase DM risk by impairing mitochondrial metabolism, one of the key steps in the regulation of glucose-stimulated insulin secretion (GSIS) in pancreatic ß-cells. The goal of the current study was to compare the effects of iAs on GSIS and mitochondrial function in INS-1 832/13 ß-cells with those of Cd, Mn, and Zn, and to evaluate effects of binary mixtures of these metals. As expected, 24-hour exposure to iAs (arsenite, ≥1 µM) significantly inhibited GSIS as did Cd (5 µM) and Mn (12.5, 25, or 50 µM). Zn had no effects on GSIS at concentrations up to 50 µM. Mitochondrial function was assessed by measuring oxygen consumption rate (OCR) after glucose stimulation and during simulated mitochondrial stress. While both iAs and Mn impaired mitochondrial function (inhibiting OCR, maximal respiration, and/or spare respiratory capacity of mitochondria), no significant effects were found in cells exposed to Cd. Interestingly, no additive or synergistic effects on GSIS or OCR were observed in binary mixtures of iAs with either Mn or Cd. These data suggest that Mn, like iAs, may inhibit GSIS by impairing mitochondrial function, whereas Cd may target other mechanisms that regulate GSIS in ß-cells.