Abuse liability measures for use in analgesic clinical trials in patients with pain: IMMPACT recommendations.

Assessing and mitigating the abuse liability (AL) of analgesics is an urgent clinical and societal problem. Analgesics have traditionally been assessed in randomized clinical trials (RCTs) designed to demonstrate analgesic efficacy relative to placebo or an active comparator. In these trials, rigorous, prospectively designed assessment for AL is generally not performed. The Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) convened a consensus meeting to review the available evidence and discuss methods for improving the assessment of the AL of analgesics in clinical trials in patients with pain. Recommendations for improved assessment include: (1) performing trials that include individuals with diverse risks of abuse; (2) improving the assessment of AL in clinical trials (eg, training study personnel in the principles of abuse and addiction behaviors, designing the trial to assess AL outcomes as primary or secondary outcome measures depending on the trial objectives); (3) performing standardized assessment of outcomes, including targeted observations by study personnel and using structured adverse events query forms that ask all subjects specifically for certain symptoms (such as euphoria and craving); and (4) collecting detailed information about events of potential concern (eg, unexpected urine drug testing results, loss of study medication, and dropping out of the trial). The authors also propose a research agenda for improving the assessment of AL in future trials.

Classification and definition of misuse, abuse, and related events in clinical trials: ACTTION systematic review and recommendations.

As the nontherapeutic use of prescription medications escalates, serious associated consequences have also increased. This makes it essential to estimate misuse, abuse, and related events (MAREs) in the development and postmarketing adverse event surveillance and monitoring of prescription drugs accurately. However, classifications and definitions to describe prescription drug MAREs differ depending on the purpose of the classification system, may apply to single events or ongoing patterns of inappropriate use, and are not standardized or systematically employed, thereby complicating the ability to assess MARE occurrence adequately. In a systematic review of existing prescription drug MARE terminology and definitions from consensus efforts, review articles, and major institutions and agencies, MARE terms were often defined inconsistently or idiosyncratically, or had definitions that overlapped with other MARE terms. The Analgesic, Anesthetic, and Addiction Clinical Trials, Translations, Innovations, Opportunities, and Networks (ACTTION) public-private partnership convened an expert panel to develop mutually exclusive and exhaustive consensus classifications and definitions of MAREs occurring in clinical trials of analgesic medications to increase accuracy and consistency in characterizing their occurrence and prevalence in clinical trials. The proposed ACTTION classifications and definitions are designed as a first step in a system to adjudicate MAREs that occur in analgesic clinical trials and postmarketing adverse event surveillance and monitoring, which can be used in conjunction with other methods of assessing a treatment's abuse potential.

Core outcome measures for opioid abuse liability laboratory assessment studies in humans: IMMPACT recommendations.

A critical component in development of opioid analgesics is assessment of their abuse liability (AL). Standardization of approaches and measures used in assessing AL have the potential to facilitate comparisons across studies, research laboratories, and drugs. The goal of this report is to provide consensus recommendations regarding core outcome measures for assessing the abuse potential of opioid medications in humans in a controlled laboratory setting. Although many of the recommended measures are appropriate for assessing the AL of medications from other drug classes, the focus here is on opioid medications because they present unique risks from both physiological (e.g., respiratory depression, physical dependence) and public health (e.g., individuals in pain) perspectives. A brief historical perspective on AL testing is provided, and those measures that can be considered primary and secondary outcomes and possible additional outcomes in AL assessment are then discussed. These outcome measures include the following: subjective effects (some of which comprise the primary outcome measures, including drug liking; physiological responses; drug self-administration behavior; and cognitive and psychomotor performance. Before presenting recommendations for standardized approaches and measures to be used in AL assessments, the appropriateness of using these measures in clinical trials with patients in pain is discussed.

Epidural opiates and local anesthetics for the management of cancer pain.

The role of epidural morphine in chronic cancer pain treatment is unresolved. In a population of 1205 cancer patients, the aggressive use of systemic opiates limited the trial of epidural analgesia to 16 cases. Successful analgesia was achieved with epidural morphine alone in 6 of these 16 cases following systemic opiate failure. The addition of bupivacaine produced analgesia in all of the 10 remaining cases and was successful chronically in 6 cases. Complications occurred in 11 of the 16 cases of epidural analgesia and included dislodged or broken catheters, pain on injection, hyperesthesia from epidural morphine and bleeding or infection related to the epidural catheter. Epidural morphine is indicated only in selected cancer pain patients and, although bupivacaine extends the efficacy of epidural analgesia, these methods are accompanied by problems and limitations.

Opioid pseudoaddiction--an iatrogenic syndrome.

A case is presented of a 17-year-old with leukemia, pneumonia and chest-wall pain. Inadequate treatment of the patient's pain led to behavioral changes similar to those seen with idiopathic opioid psychologic dependence (addiction). The term pseudoaddiction is introduced to describe the iatrogenic syndrome of abnormal behavior developing as a direct consequence of inadequate pain management. The natural history of pseudoaddiction includes progression through 3 characteristic phases including: (1) inadequate prescription of analgesics to meet the primary pain stimulus, (2) escalation of analgesic demands by the patient associated with behavioral changes to convince others of the pain's severity, and (3) a crisis of mistrust between the patient and the health care team. Treatment strategies include establishing trust between the patient and the health care team and providing appropriate and timely analgesics to control the patient's level of pain.