Abuse-Deterrent Opioid Formulations: Pharmacokinetic and Pharmacodynamic Considerations

Oxycodone hydrochloride controlled-release, also known as extended-release oxycodone (ER oxycodone), was reformulated with physicochemical barriers to crushing and dissolving intended to reduce abuse through nonoral routes of administration (ROAs) that require tampering (eg, injecting and snorting). Manufacturer shipments of original ER oxycodone (OC) stopped on August 5, 2010, and reformulated ER oxycodone (ORF) shipments started August 9, 2010. A sentinel surveillance sample of 140,496 individuals assessed for substance abuse treatment at 357 U.S. centers between June 1, 2009, and March 31, 2012, was examined for prevalence and prescription-adjusted prevalence rates of past-30-day abuse via any route, as well as abuse through oral, nonoral, and specific ROAs for ER oxycodone and comparators (ER morphine and ER oxymorphone) before and after ORF introduction. Significant reductions occurred for 8 outcome measures of ORF versus OC historically. Abuse of ORF was 41% lower (95% CI: -44 to -37) than historical abuse for OC, with oral abuse 17% lower (95% CI: -23 to -10) and nonoral abuse 66% lower (95% CI: -69 to -63). Significant reductions were not observed for comparators. Observations were consistent with the goals of a tamper resistant formulation for an opioid. Further research is needed to determine the persistence and generalizability of these findings. This article presents preliminary findings indicating that 8 outcome measures of abuse of a reformulated ER oxycodone were lower than that for original ER oxycodone historically, particularly through nonoral ROAs that require tampering (ie, injection, snorting, smoking), in a sentinel sample of individuals assessed for substance use problems for treatment planning. Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.

Morphine is a widely used opioid for treatment of moderate to severe pain, but large interindividual variability in patient response and no clear guidance on how to optimise morphine dosage regimen complicates treatment strategy for clinicians. Population pharmacokinetic-pharmacodynamic models can be used to quantify dose-response relationships for the population as well as interindividual and interoccasion variability. Additionally, relevant covariates for population subgroups that deviate from the typical population can be identified and help clinicians in dose optimisation. This review provides a detailed overview of the published human population pharmacokinetic-pharmacodynamic studies for morphine analgesia in addition to basic drug disposition and pharmacological properties of morphine and its analgesic active metabolite, morphine-6-glucuronide, that may help identify future covariates. Furthermore, based on simulations from key pharmacokinetic-pharmacodynamic models, the contribution of morphine-6-glucuronide to the analgesic response in patients with renal insufficiency was investigated. Simulations were also used to examine the impact of effect-site equilibration half-life on time course of response. Lastly, the impact of study design on the likelihood of determining accurate pharmacodynamic parameters for morphine response was evaluated.

To assess the use of opioids by primary care physicians for the treatment of chronic pain. A written survey was completed by 248 primary care physicians. Outcomes of interest included type of opioids prescribed, common pain diagnoses treated, opioid prescribing concerns, treatment of patients with a history of substance use disorders and clinic-based protocols for pain management. The mean age of the physicians who completed the questionnaire was 41 years. The majority were between the ages of 30 and 49 years (68%) with an equal number of men and women. Seventy percent were family physicians, 28.7% internists and less than 2% were community physicians and geriatricians. Physician concerns regarding opioid therapy included prescription drug abuse (84.2%), addiction (74.9%), adverse effects (68%), tolerance (60.7%), and medication interaction (32%). The survey found that the majority of the physicians were comfortable in prescribing narcotics to patients with terminal cancer. However, they were less comfortable prescribing narcotics to patients with low back pain and persons with a current or past history of drug or alcohol abuse. Physician management practices suggested that urine toxicology tests were under-utilized with only 6.9% reporting obtaining this test before prescribing opioids and only 15.0% performing urine toxicology tests on patients already prescribed opioids. Logistic regression analysis revealed that whether or not physicians routinely conducted urine toxicology screens was significantly (p = 0.015) predicted by whether they had a system to track patients on opioids when prescribing narcotics. The primary limitation of the study is the reliance on physician self-report rather than objective measures of physician behavior. The survey suggests physicians are concerned about drug abuse, addiction, adverse effects, tolerance, and medication interaction. Their comfort level in prescribing opioids varies with the patient characteristics. Urine toxicology testing is underutilized in the primary care setting.