Rachel S. Wightman

Likeability and Abuse Liability of Commonly Prescribed Opioids

IntroductionNonmedical use of prescription opioid analgesics is associated with epidemic levels of morbidity and mortality. There are several factors that affect the abuse liability of the various opioids, including likability or the pleasurable subjective effects. Due to rising public health concerns over escalating prescription opioid abuse, we sought to examine the literature about abuse liability with a specific focus on likability studies.MethodsA search of EMBASE and MEDLINE databases identified articles that described the comparative likeability and/or abuse potential of hydrocodone and oxycodone relative to each other and/or of either one to morphine. After an assessment of study quality using the Oxford/Jadad scale, relevant details such as demographics, study design, and outcome measures were compiled into an evidence table.ResultsWe identified nine studies that met inclusion criteria. All were double-blinded, randomized, placebo-controlled crossover studies and scored 5 out of 5 Jadad scale. There was no consistent clinically significant difference between abuse liability of morphine and hydrocodone. Oxycodone demonstrated high abuse liability on the basis of its high likability scores and a relative lack of negative subjective effects.ConclusionOral oxycodone has an elevated abuse liability profile compared to oral morphine and hydrocodone.

Electromagnetic navigational bronchoscopy: an effective and safe approach to diagnose peripheral lung lesions unreachable by conventional bronchoscopy in high-risk patients.

Purpose The purpose of this study was to investigate the diagnostic yield and safety of electromagnetic navigation bronchoscopy (ENB) on peripheral lung lesions deemed otherwise unreachable using conventional bronchoscopy in high-risk patients. Methods This was a retrospective chart review involving adults (age, 18 y and older) who underwent ENB for pulmonary lesions located at the fourth order of bronchi or beyond, including subpleural lesions, at the University of Chicago Medical Center. Forty-eight patients underwent ENB by 3 different trained operators from January 2006 to September 2008. There was a short period of inactivity when the device was withdrawn from the market. ENB was reserved for use only in lesions at the fourth order of bronchi or beyond, including subpleural lesions, in patients who are considered high risk for other invasive procedures. Pathologic, cytologic, and microbiologic studies were carried out on recovered samples. Postprocedural chest radiographs were obtained on all patients to detect the presence of procedure-associated complications. Results ENB led to the diagnosis of 37 of 48 (77%) lesions not amenable to conventional bronchoscopic biopsy in high-risk patients. Of the 37 successful procedures, malignancy was identified in 18 patients (49%). Nonsmall cell lung cancer (NSCLC) was diagnosed 16 times, whereas both small cell lung cancer and carcinoid tumor were diagnosed once. In addition, 4 lesions (11%) were found to be infectious, 1 lesion (3%) was found to be granulomatous (noncaseating), and 1 lesion (3%) was diagnosed as organizing pneumonia. Of the 37 successful diagnoses, 13 lesions (35%) were determined to be nonpathologic, benign lesions. Eleven procedures (22%) were unsuccessful in yielding the correct pathologic diagnosis. Nine of the 11 unsuccessful ENB cases (82%) were found to be malignant, 9 of which were identified as NSCLC. Other than NSCLC, 1 neuroendocrine tumor (9%) and 1 metastatic transitional cell carcinoma of the kidney (9%) were identified by alternative, invasive testing methods. The 2 other lesions unsuccessfully diagnosed by ENB were not malignant. One was determined to be infection (histoplasmosis) and the other was diagnosed as an organizing pneumonia. The most common complication noted by all modalities was pneumothorax. ENB carried a pneumothorax rate of 5 of 49 (10%), 2 of which required chest tube insertion for treatment. In the ENB success group, 4 cases (11%) were complicated by pneumothoraces. In the ENB failure group, 1 case (9%) was complicated by a pneumothorax. Conclusions ENB is an effective and low-risk modality for diagnosing pulmonary lesions that are difficult to reach in patients deemed to be at high risk for invasive procedures. Although no clear criteria for the use of ENB currently exist, our study shows that diagnostic sampling can be obtained in 77% of lesions at the fourth order of bronchi or beyond, including subpleural lesions. Clinical Implications ENB is an effective, minimally invasive method for the diagnosis of pulmonary nodules previously deemed unreachable by conventional bronchoscopy in high-risk patients and harbors a low complication rate.

Not your regular high: cardiac dysrhythmias caused by loperamide

Abstract Objective: Loperamide, a non-prescription anti-diarrheal agent, is a peripheral mu-opioid receptor agonist that is excluded from the blood-brain barrier by p-glycoprotein at therapeutic doses. Overdoses of loperamide penetrate the central nervous system (CNS), leading to abuse. We report cardiac conduction abnormalities and dysrhythmias after ingestion of a recreational supra-therapeutic dose of loperamide confirmed with an elevated blood loperamide concentration. Case details: A 48-year-old woman with a history of alcohol and benzodiazepine abuse presented to the emergency department (ED) with somnolence, weakness and slurred speech. She was taking 20 to 40 tablets of 2 mg loperamide 1–2 times/day for weeks along with clonazepam and whiskey. Vital signs were: blood pressure (BP), 124/90 mmHg; heart rate (HR), 88/min; respiratory rate(RR), 20/min; T, 36.9 °C; O2 saturation 100% on room air (RA). Glucose was 6.4 mmol/L. Electrocardiogram (ECG) had a ventricular rate of 58/min, QRS 164 ms, QT 582 ms with no discernable p-waves. Lactate was 3.5 mmol/L and potassium was 6.2 mEq/L. Labs were notable for an anion gap of 20 mEq/L, ethanol of 3.9 mmol/L, creatinine of 2.3 mg/dL and loperamide concentration of 210 ng/mL (average therapeutic plasma concentration 1.2 ng/mL). She became hypotensive, but responded to fluids. Following treatment for hyperkalemia with calcium, insulin, dextrose, and hypertonic sodium bicarbonate a repeat ECG had a ventricular rate of 66/min, QRS 156 ms, and QT 576 ms. Magnesium was given and pacer pads were placed. During the infusion of magnesium, her BP fell to 92/58 mmHg with a HR of 54/min, RR 14/min, O2 saturation of 97% on RA so the infusion was stopped. The ECG after the magnesium infusion had a ventricular rate of 51/min, QRS of 134 ms, and QT 614 ms. In the ICU she had multiple runs of non-sustained ventricular tachycardia that did not require therapy. Over the next 48 h she improved and was transferred to a floor bed. On day four of hospitalization the patient left against medical advice. At that time, her ECG showed sinus tachycardia with a heart rate 114/min, QRS 82 ms, QT 334 ms. Discussion: Loperamide produces both QRS and QT prolongation at supra-therapeutic dosing. A blood loperamide concentration of 210 ng/mL is among the highest concentrations reported. Supra-therapeutic dosing of loperamide is promoted on multiple drug-use websites and online forums as a treatment for opioid withdrawal, as well as for euphoric effects. With the current epidemic of prescription opioid abuse, toxicity related to loperamide, an opioid agonist that is readily available without a prescription is occurring more frequently. It is important for clinicians to be aware of the potentially life-threatening toxicity related to loperamide abuse in order to provide proper diagnosis, management and patient education.

Opioid Prescribing: How Well Do We Know Ourselves?

Get your facts first, then you can distort them as you please.—Mark Twain BI would rather over-prescribe and risk some medication diversion or non-medical use, than under-prescribe and not treat a patient’s pain.^ This statement, taken from a survey published in the current issue of JMT by Pomerleau et al. 2016 [1], was used to assess clinicians’ self-reported attitude about the challenge in meeting individual patient needs while balancing public health risk. The statement essentially pinpoints the current dilemma in the ED: alleviation of suffering in an individual may expose that patient or others (through misuse or diversion) to the risk of opioid analgesic (OA) abuse, addiction, overdose, and death. Pain-related complaints are the most common reason for Emergency Department (ED) visits [2, 3], and ED providers are among the top fivemedical specialist groupswriting prescriptions for OAs in patients under 40 years of age [4]. However, only 17 % of ED patients are given a prescription for an OA on discharge and the majority of prescriptions dispensed are for a small number of immediate release pills [5, 6]. Still, iatrogenic opioid abuse and addiction remain a concern, because half of ED patients with opioid-use disorders were first exposed to an opioid by a prescription from a medical provider [7]. Responsible opioid analgesic prescribing is paramount in our efforts to combat the epidemic of opioid abuse and promote safe opioid use, but little is currently known about which factors drive decision-making among emergency department (ED) prescribers of OAs. Pomerleau et al. highlights the complexity of the decision-making process and brings forth a number of interesting issues. Through a series of queries, the study explores the factors providers believe affect their OA prescribing practices, as well as their attitudes toward OA prescribing. Of course, individual provider opinions and attitudes cannot provide the complete picture. Patient age, race, type of insurance, provider training and experience, functionality of PDMPs, and geographic location are a few of the many factors highlighted in the literature to affect OA prescribing decisions. Whether to prescribe an OA for any given patient not only depends on the aforementioned patient and provider factors and the culture of the work environment, but also on the quality and type of patient doctor communication. One study showed that when faced with identical hypothetical case scenarios, ED physicians’ decisions whether to prescribe an OA varied greatly [14]. For the same clinical scenario, subtle differences in the patient-doctor interaction (for example, a patient requesting a specific drug or an additional dose of pain medication) could change the likelihood of prescribing substantially [18]. To support this unconscious bias, Pomerleau, et al. uncovered some interesting paradoxes. For example, survey respondents report that they would be less likely to write a prescription for a patient with an opioid use disorder, but they also state their skills to identify patients with opioid use disorders and determine who is doctor shopping are poor. The emergency physician respondents in Pomerleau et al. ranked patient’s overall satisfaction as a neutral factor in their decision to prescribe an opioid. Though this may be more true in the ED, patient satisfaction has a more prominent impact on the decision to prescribe an opioid in other clinical settings. For example, many hospitals collect data on the patient’s experience and tie such feedback with physician payments (althoughCME recently announced that this may end). Although * Rachel S. Wightman rachel.wightman@nyumc.org

Zonisamide Toxicity in a Patient with an Intentional Overdose

TO THE EDITOR: Zonisamide is an antiepileptic agent approved for use in managing partial seizures. Its foremost mechanism of action is believed to involve blockade of axonal sodium and calcium channels. It has a biphasic effect on dopamine function.1 We report the case of a patient who stated that she ingested only zonisamide in a suicide attempt. Case Report. A 20-year-old female with a history of bipolar disease, epilepsy, and 3 previous suicide attempts ingested up to 8.7 g of zonisamide, based on capsule count. The ingestion occurred at approximately 0900 hours. One episode of emesis occurred at 1200 hours and the patient saw “many” capsules in the vomitus. There was a second episode of emesis, but no capsules were seen. In the emergency department 5 hours after ingestion, the patient’s vital signs were temperature 36.7 ̊C, blood pressure 130/80 mm Hg, heart rate 75 beats per minute, respiratory rate 20 breaths per minute, and pulse oximetry 100% on room air. Results of an electrocardiogram were within normal limits. She complained of nausea, diffuse chest pain, blurred vision, dizziness, and mild headache. Results of basic metabolic panel, complete blood cell count, and arterial blood gas values were noncontributory, other than mild leukocytosis. Activated charcoal was recommended if feasible and there was no undue risk of aspiration. The patient had a 5-minute episode of seizure-like activity consisting of tremors and altered mental status responsive solely to sternal rub. She recovered spontaneously with no obvious postictal state. An electroencephalogram showed no epileptiform discharges. Plasma zonisamide concentrations measured 5.5 and 48 hours postingestion were 110 mg/L and 38 mg/L, respectively (therapeutic concentration 10-30). The calculated half-life was 30 hours. The patient became asymptomatic and was transferred to the inpatient psychiatric ward on hospital day 2. Discussion. To our knowledge, this is the first reported case of a zonisamide overdose as a single agent in which 2 plasma concentrations were obtained. Zonisamide is completely absorbed from the gastrointestinal tract and peak plasma concentrations are reached in 2-6 hours.1 This patient’s plasma concentrations likely represented a postabsorption phase based on the stated time of ingestion. Zonisamide’s calculated half-life of 30 hours in this patient deviates from the published half-life of 63 hours in the nonoverdose setting.1 Explanations for the shortened half-life in this patient include (1) time of ingestion by history was incorrect (a higher peak concentration would have resulted in a longer half-life), (2) the drug’s halflife varies widely among patients,1 and (3) enzyme-inducing agents would have shortened the half-life. Zonisamide undergoes hepatic metabolism via CYP3A4, CYP2C19, and CYP3A5 enzymes and is renally excreted. This patient’s constellation of symptoms is distinctly different from previous reported cases of zonisamide poisoning. Naito et al. reported on a 26-year-old female who exhibited hypotension, respiratory depression, and coma after ingesting zonisamide, clonazepam, and carbamazepine.2 Her zonisamide plasma concentration 31 hours after ingestion was 100.1 mg/L; the half-life was 56.5 hours. In another case, an 18-year-old female died of sustained cardiopulmonary arrest and anoxic brain injury after ingesting zonisamide.3 A perimortem blood concentration was 44 mg/L and the comprehensive drug screen indicated the presence of caffeine, diphenhydramine metabolites, and mirtazapine. The patient reported here, despite having toxic plasma zonisamide concentrations, did not exhibit the range or severity of symptoms associated with zonisamide poisoning. Clinicians should be aware that zonisimide’s half-life might be altered in the overdose patient.

Comparative Analysis of Opioid Queries on Erowid.org: An Opportunity to Advance Harm Reduction

ABSTRACT Background: Many individuals who use opioids turn to online resources to gather information on effects, availability, and safety. Objective: Describe opioid index page views on Erowid.org to assess trends in public interest in particular opioids. Methods: Retrospective analysis of Erowid.org site traffic was performed to identify unique average daily visits to opioid pages. All data was normalized to that of visits to the heroin index page. Average daily visits to the index pages of each of 6 commonly abused opioids were assessed during the period of 2009 to 2015. Similarly, visits to 15 distinct opioid index pages at 5 time points (July, October 2014 and Jan, April, and July 2015) were described. Results: From 2009 to 2015 a decrease in the number of page visits versus heroin (1.00) occurred for hydrocodone (0.87 to 0.59, −32%), oxycodone (1.38 to 0.99, −28%), and morphine (0.26 to 0.25, −6%). Increases in page visits compared to heroin occurred for fentanyl (0.18 to 0.47, +157%), tramadol (0.43 to 0.88, +106%), hydromorphone (0.19 to 0.24, +29%), and oxymorphone (0.11 to 0.13, +18%). Indexed to heroin (1.00) average opioid page visit frequencies from July 2014 to July 2015 were highest for oxycodone (1.02) and tramadol (0.81). Conclusion/Importance: Oxycodone and tramadol represent the greatest number of Erowid.org opioid page visits compared to heroin. The largest increase in visits over the study periods was for fentanyl and tramadol. The relationship of page visits on Erowid.org creates a unique opportunity for real-time evaluation of emerging drug trends and epidemiological study.

In Response to: “Single Versus Multiple Hyperbaric Sessions for Carbon Monoxide Poisoning in a Murine Model”

While hyperbaric oxygen (HBO) is the best-studied treatment for prevention of the delayed neurologic sequelae (DNS) in carbon monoxide (CO) poisoning, its effectiveness is unclear. Human and animal studies demonstrate contradictory results, and several reviews highlight significant methodological weaknesses in the existing literature [1, 2]. Thus, we read with interest the recent article by Carstairs et al. [3] regarding single versus multiple HBO sessions in a murine model of CO poisoning. The authors sought to answer a compelling and pertinent question with a promising study design. However, we are concerned that the model used for DNS was not sufficiently reliable to adequately address their question. No significant difference was found in the outcome measures between the group of mice that were CO-poisoned and received no treatment and the control group of mice that were not poisoned at all. Simply put, this study failed to induce DNS in CO-poisoned mice. Thus, since the chosen outcome measure does not accurately reflect the disease process, any results are consequently impossible to interpret. Although the authors attribute this shortcoming to wide variations between animals and suggest that the study suffers from a small sample size problem, they present a curious power analysis that should have taken this variability into consideration. Unfortunately, it is unclear whether passive avoidance testing is an appropriate model or that the mice were adequately trained [4, 5] or whether there were other flaws in the study design or implementation. Regardless of the cause, there are no conclusions that can be drawn from their data.