J. David Haddox

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 patients 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 pains 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 patients level of pain.

Epidural opiates and local anesthetics for the management of cancer pain

&NA; 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 Pharmacotherapy for Chronic Non-Cancer Pain in the United States: A Research Guideline for Developing an Evidence-Base

UNLABELLED This document reports the consensus of an interdisciplinary panel of research and clinical experts charged with reviewing the use of opioids for chronic noncancer pain (CNCP) and formulating guidelines for future research. Prescribing opioids for chronic noncancer pain has recently escalated in the United States. Contrasting with increasing opioid use are: 1) The lack of evidence supporting long-term effectiveness; 2) Escalating misuse of prescription opioids including abuse and diversion; and 3) Uncertainty about the incidence and clinical salience of multiple, poorly characterized adverse drug events (ADEs) including endocrine dysfunction, immunosuppression and infectious disease, opioid-induced hyperalgesia and xerostomia, overdose, falls and fractures, and psychosocial complications. Chief among the limitations of current evidence are: 1) Sparse evidence on long-term opioid effectiveness in chronic pain patients due to the short-term time frame of clinical trials; 2) Insufficiently comprehensive outcome assessment; and 3) Incomplete identification and quantification of ADEs. The panel called for a strategic interdisciplinary approach to the problem domain in which basic scientists and clinicians cooperate to resolve urgent issues and generate a comprehensive evidence base. It offered 4 recommendations in 3 areas: 1) A research strategy for studying the effectiveness of long-term opioid pharmacotherapy; 2) Improvements in evidence-generation methodology; and 3) Potential research topics for generating new evidence. PERSPECTIVE Prescribing opioids for CNCP has outpaced the growth of scientific evidence bearing on the benefits and harms of these interventions. The need for a strong evidence base is urgent. This guideline offers a strategic approach to creating a comprehensive evidence base to guide safe and effective management of CNCP.

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

Abstract Terminology related to prescription drug misuse and abuse is inconsistently defined. An expert panel developed consensus classifications and definitions for use in clinical trials. Abstract 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.

Psychoactive substance use among American anesthesiologists: a 30-year retrospective study

The purpose of this study was to assess the cumulative incidence of substance use among anesthesiologists during training and practice, the effect of stress on drug use, and deterrent efficacy of institutional prevention programmes. The 260 anesthesiologists who had trained at the Medical College of Wisconsin between 1958–1988 were surveyed by mail regarding psychoactive substance use. Analysis of 183 responses focused on demographic and psychosocial factors. Substances used most frequently included: alcohol (91.6%), marijuana (30.8%) and cocaine (9.4%). Twenty-nine (15.8%) anesthesiologists were identified as being substance-dependent: 19 were alcohol-impaired; six were drug-impaired, and four were dependent on both alcohol and drugs. Impairment was more prevalent in anesthesiologists who had completed their training after 1975. Fifty-eight (32%) anesthesiologists had used illicit drugs to “get high”; 11 acknowledged daily use for two weeks or more, with eight admitting dependency. Substance abuse was more common in parents of impaired anesthesiologists (35.7%) than in unimpaired colleagues (8.1%; P < 0.001). The divorce rate for impaired anesthesiologists (24.1%) was greater than for unimpaired anesthesiologists (5.2%; P < 0.001). Increased stress during training was not reflected by increased substance use. Few recalled any drug counseling whatsoever. Seventy percent assessed hospital drug control policies as fair or poor. Younger respondents (bom after 1951) were more critical of drug control programmes than their older cohort. Incidents of substance abuse were reported for both residents and faculty. Psychoactive substance abuse remains a serious problem among anesthesiologists.RésuméCette étude avait pour objectif la recherche de la vérité sur la toxicomanie des anesthésistes pendant leur formation et l’exercice de leur profession lors de périodes de stress et l’efficacité des programmes de prévention. Les 260 anesthésistes formés au collège de médecine du Wisconsin entre 1958 et 1988 ont reçu par la poste un questionnaire sur l’utilisation des drogues psychoactives. Les 183 réponses reçues ont été analysées en tenant compte de facteurs démographiques et psychosociaux. Les produits les plus utilisés ont été dans l’ordre: l’alcool (91,6%), la marijuana (30.8%) et la cocaïne (9,4%). Vingt-neuf anesthésistes s’identifiaient comme toxicomanes: 19 par l’alcool, six par les drogues, et quatre par les deux substances associées. Les plus grands usagers sont ceux qui ont terminé après 1975. Cinquante-huit (32%) ont recherché l’effet euphorisant; onze ont reconnu leur utilisation pendant deux semaines ou plus. Huit se disent dépendants. L’abus des toxiques était plus fréquent chez les parents des anesthésistes toxicomanes (35%) que chez les non-utilisateurs (8,1%, P < 0.001). Le taux de divorces chez les anesthésistes utilisateurs (24,1%) était plus élevé que chez les non-utilisateurs (5,2%, P < 0.001). L’augmentation du stress pendant la formation ne coïncidait pas avec l’utilisation de narcotiques. Peu se sont rappelé d’avoir eu des conseils sur le sujet. Soixante-dix pourcent ont jugé la politique de contrôle hospitalier des narcotiques de moyenne à pauvre. Les plus jeunes parmi les répondants (nés après 1951) étaient plus critiques des programmes de contrôles des narcotiques que leurs confrères plus âgées. Des épisodes d’usage abusif ont été signalées tant chez les résidents que chez les professeurs. L’abus des substance psychoactives demeure un problème d’importance chez les anesthésistes.

Horner's syndrome and trigeminal nerve palsy following epidural anaesthesia for obstetrics

While Horner’s syndrome is a rare but occasionally reported side-effect of epidural block administered for labour, trigeminal nerve palsy has been described only once. The cases described in this report confirmed the benign nature of these neurological complications of epidurally administered anaesthetics which were not detrimental to fetal viability. The complications may be attributed to extensive cephalad spread of local anaesthetic, sometimes via unexplained routes and with surprisingly selective targeting effect (unilateral trigeminal nerve palsy). The atypical and unusually high cephalad spread of local anaesthetic in pregnant women at term is believed to be due to pregnancy-related altered anatomy and physiology of the epidural space.RésuméAlors que le syndrome de Horner est rare mais occasionnellement rapporté comme un effet secondaire du bloc épidural administré lors de l’accouchement, la paralysie du nerf trijumeau fut décrite une seule fois uniquement. Les cas rapportés dans cette revue confirme la nature bénigne de ces complications neurologiques après administration épidurale d’anesthésiques sans effet néfaste sur la viabilité foetale. Les complications peuvent être attribuées à l’extension de l’anesthésique local quelquefois à trovers des routes inexpliquées et avec une sensibilité sélective surprenante (paralysie du nerf trijumeau unilatéral). L’extension céphalique atypique et habituelle de l’anesthésique local chez les femmes enceintes à terme est attribuée à l’altération de l’anatomie et la physiologie de l’espace épidural lors de la grossesse.

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

Summary Assessing and mitigating the abuse liability (AL) of analgesics is an urgent clinical and societal problem. 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 the trial). Abstract 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.

Epidural blood patch as treatment for a surgical durocutaneous fistula

We describe the first case report of an epidural autologous blood patch used for the treatment of a durocutaneous fistula caused by a surgical dural tear. The epidural blood patch cured the patients headache and was followed by a sequelae of back pain that responded to conservative therapy.

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.

Case histories in pharmaceutical risk management

The development and implementation of programs in the U.S. to minimize risks and assess unintended consequences of new medications has been increasingly required by the Food and Drug Administration (FDA) since the mid 1990s. This paper provides four case histories of risk management and post-marketing surveillance programs utilized recently to address problems associated with possible abuse, dependence and diversion. The pharmaceutical sponsors of each of these drugs were invited to present their programs and followed a similar template for their summaries that are included in this article. The drugs and presenting companies were OxyContin, an analgesic marketed by Purdue Pharma L.P., Daytrana and Vyvanse, ADHD medications marketed by Shire Pharmaceuticals, Xyrem for narcolepsy marketed by Jazz Pharmaceuticals, and Subutex and Suboxone for opioid dependence marketed by Reckitt Benckiser Pharmaceuticals Inc. These case histories and subsequent discussions provide invaluable real-world examples and illustrate both the promise of risk management programs in providing a path to market and/or for keeping on the market drugs with serious potential risks. They also illustrate the limitations of such programs in actually controlling unintended consequences, as well as the challenge of finding the right balance of reducing risks without posing undue barriers to patient access. These experiences are highly relevant as the FDA increasingly requires pharmaceutical sponsors to develop and implement the more formalized and enforceable versions of the risk management term Risk Evaluation and Mitigation Strategies (REMS).