Andrew A. Monte

Diversion of Buprenorphine/Naloxone Coformulated Tablets in a Region with High Prescribing Prevalence

ABSTRACT The purpose of this article was to characterize practices of buprenorphine/naloxone (B/N) diversion in a region with a high prescribing prevalence. A cross-sectional, open-ended survey was administered to individuals entering opioid addiction treatment programs in two New England states. The authors obtained formative information about the knowledge, attitudes, beliefs, practices, and street economy of B/N diversion. The authors interviewed 51 individuals, 49 of which were aware of B/N medication. Of that number, 100% had diverted B/N to modulate opiate withdrawal symptoms arising from attempted “self-detoxification,” insufficient funds to purchase preferred illicit opioids, or inability to find a preferred source of drugs. Thirty of 49 (61%) participants obtained the illicit drug from an individual holding a legitimate prescription for B/N. A high proportion of individuals in the study locations who sought treatment for opioid addiction self-reported the purchase and use of diverted B/N. The diversion of B/N may be minimized by modifying educational, treatment, monitoring, and dispensing practices.

An Outbreak of Exposure to a Novel Synthetic Cannabinoid

Young men in Colorado presented with altered mental status and seizures after ingestion of a synthetic cannabinoid known as “black mamba.” Medical toxicologists and public health and law enforcement officials identified 263 cases of exposure to this novel substance.

Cannabinoid Hyperemesis Syndrome: Diagnosis, Pathophysiology, and Treatment-a Systematic Review.

Cannabinoid hyperemesis syndrome (CHS) is a syndrome of cyclic vomiting associated with cannabis use. Our objective is to summarize the available evidence on CHS diagnosis, pathophysiology, and treatment. We performed a systematic review using MEDLINE, Ovid MEDLINE, Embase, Web of Science, and the Cochrane Library from January 2000 through September 24, 2015. Articles eligible for inclusion were evaluated using the Grading and Recommendations Assessment, Development, and Evaluation (GRADE) criteria. Data were abstracted from the articles and case reports and were combined in a cumulative synthesis. The frequency of identified diagnostic characteristics was calculated from the cumulative synthesis and evidence for pathophysiologic hypothesis as well as treatment options were evaluated using the GRADE criteria. The systematic search returned 2178 articles. After duplicates were removed, 1253 abstracts were reviewed and 183 were included. Fourteen diagnostic characteristics were identified, and the frequency of major characteristics was as follows: history of regular cannabis for any duration of time (100%), cyclic nausea and vomiting (100%), resolution of symptoms after stopping cannabis (96.8%), compulsive hot baths with symptom relief (92.3%), male predominance (72.9%), abdominal pain (85.1%), and at least weekly cannabis use (97.4%). The pathophysiology of CHS remains unclear with a dearth of research dedicated to investigating its underlying mechanism. Supportive care with intravenous fluids, dopamine antagonists, topical capsaicin cream, and avoidance of narcotic medications has shown some benefit in the acute setting. Cannabis cessation appears to be the best treatment. CHS is a cyclic vomiting syndrome, preceded by daily to weekly cannabis use, usually accompanied by symptom improvement with hot bathing, and resolution with cessation of cannabis. The pathophysiology underlying CHS is unclear. Cannabis cessation appears to be the best treatment

Marijuana Tourism and Emergency Department Visits in Colorado

At a large hospital in Colorado, the rate of ED visits related to cannabis use doubled for out-of-state patients, with little change for in-state patients, from 2013 through 2014, the first year of retail marijuana sales. Statewide data confirmed these differential trends.

Dextromethorphan, chlorphenamine and serotonin toxicity: case report and systematic literature review.

The aim of this review was to describe a patient with serotonin toxicity after an overdose of dextromethorphan and chlorphenamine and to perform a systematic literature review exploring whether dextromethorphan and chlorphenamine may be equally contributory in the development of serotonin toxicity in overdose. A Medline literature review was undertaken to identify cases of serotonin toxicity due to dextromethorphan and/or chlorphenamine. Case reports were included if they included information on the ingested dose or plasma concentrations of dextromethorphan and/or chlorphenamine, information about co-ingestions and detailed clinical information to evaluate for serotonin toxicity. Cases were reviewed by two toxicologists and serotonin toxicity, defined by the Hunter criteria, was diagnosed when appropriate. The literature was then reviewed to evaluate whether chlorphenamine may be a serotonergic agent. One hundred and fifty-five articles of dextromethorphan or chlorphenamine poisoning were identified. There were 23 case reports of dextromethorphan, of which 18 were excluded for lack of serotonin toxicity. No cases were identified in which serotonin toxicity could be solely attributed to chlorphenamine. This left six cases of dextrometorphane and/or chlorphenamine overdose, including our own, in which serotonin toxicity could be diagnosed based on the presented clinical information. In three of the six eligible cases dextromethorphan and chlorphenamine were the only overdosed drugs. There is substantial evidence from the literature that chlorphenamine is a similarly potent serotonin re-uptake inhibitor when compared with dextrometorphan. Chlorphenamine is a serotonergic medication and combinations of chlorphenamine and dextromethorphan may be dangerous in overdose due to an increased risk of serotonin toxicity.

Prediction of Drug Response and Safety in Clinical Practice

Many clinicians hoped that the completion of the Human Genome Project would result in “individualized drug therapy,” i.e., determining the right medication at the right dose 100% of the time based upon the individuals genetics. The pharmacogenomic prediction of drug efficacy and safety has not become a reality due to continuing realization of the complexity dictating the human–drug interaction. New methods of metabolomics, proteomics, and transcriptomics that account for this complexity hold promise for translational researchers hoping to increase drug efficacy and decrease drug toxicity.

The accuracy of self-reported drug ingestion histories in emergency department patients.

Inaccuracies in self‐reports may lead to duplication of therapy, failure to appreciate non‐compliance leading to exacerbation of chronic medical conditions, or inaccurate research conclusions. Our objective is to determine the accuracy of self‐reported drug ingestion histories in patients presenting to an urban academic emergency department (ED). We conducted a prospective cohort study in ED patients presenting for pain or nausea. We obtained a structured drug ingestion history including all prescription drugs, over‐the‐counter medication (OTC) drugs, and illicit drugs for the 48 hours prior to ED presentation. We obtained urine comprehensive drug screens (CDS) and determined self‐report/CDS concordance. Fifty‐five patients were enrolled. Self‐reported drug ingestion histories were poor in these patients; only 17 (30.9%) of histories were concordant with the CDS. For the individual drug classes, prescription drug‐CDS was concordant in 32 (58.2%), OTC‐CDS was concordant in 33 (60%), and illicit drug‐CDS was concordant in 45 (81.8%) of subjects. No demographic factors predicted an accurate self‐reported drug history. Sixteen patients had drugs detected by CDS that were unreported by history. Nine of these 16 included an unreported opioid. In conclusion, self‐reported drug ingestion histories are often inaccurate and resources are needed to confirm compliance and ensure unreported drugs are not overlooked.

The effect of CYP2D6 drug-drug interactions on hydrocodone effectiveness.

OBJECTIVES The hepatic cytochrome 2D6 (CYP2D6) is a saturable enzyme responsible for metabolism of approximately 25% of known pharmaceuticals. CYP interactions can alter the efficacy of prescribed medications. Hydrocodone is largely dependent on CYP2D6 metabolism for analgesia, ondansetron is inactivated by CYP2D6, and oxycodone analgesia is largely independent of CYP2D6. The objective was to determine if CYP2D6 medication coingestion decreases the effectiveness of hydrocodone. METHODS This was a prospective observational study conducted in an academic U.S. emergency department (ED). Subjects were included if they had self-reported pain or nausea and were excluded if they were unable to speak English, were less than 18 years of age, had liver or renal failure, or carried diagnoses of chronic pain or cyclic vomiting. Detailed drug ingestion histories for the preceding 48 hours prior to the ED visit were obtained. The patients pain and nausea were quantified using a 100-mm visual analog scale (VAS) at baseline prior to drug administration and following doses of hydrocodone, oxycodone, or ondansetron. We used a mixed model with random subject effect to determine the interaction between CYP2D6 drug ingestion and study drug effectiveness. Odds ratios (ORs) were calculated to compare clinically significant VAS changes between CYP2D6 users and nonusers. RESULTS A total of 250 (49.8%) of the 502 subjects enrolled had taken at least one CYP2D6 substrate, inhibitor, or inducing pharmaceutical, supplement, or illicit drug in the 48 hours prior to ED presentation. CYP2D6 drug users were one-third as likely to respond to hydrocodone (OR = 0.33, 95% confidence interval [CI] = 0.1 to 0.8) and more than three times as likely as nonusers to respond to ondansetron (OR = 3.4, 95% CI = 1.3 to 9.1). There was no significant difference in oxycodone effectiveness between CYP2D6 users and nonusers (OR = 0.53, 95% CI = 0.3 to 1.1). CONCLUSIONS CYP2D6 drug-drug interactions appear to change effectiveness of commonly prescribed drugs in the ED. Drug-drug interaction should be considered prior to prescribing CYP2D6 drugs.

Low-Molecular-Weight Heparin Overdose: Management by Observation:

Objective: To describe 3 episodes of low-molecular-weight heparin (LMWH) overdose in 2 patients and discuss the clinical presentations, outcomes, and therapeutic options. Case Summaries: The first patient, a 35-year-old female, presented after an intentional overdose of 72,000 units of dalteparin. The peak measured anti-Xa activity was 6.2 U/mL at 7.5 hours postinjection. No interventions were performed and there were no bleeding complications. The patient presented 20 days later following another overdose of 72,000 units. Anti-Xa activity was 4.5 U/mL 2 hours postinjection. No treatment was given and the patient was discharged with plans for follow-up the next day. There was no evidence of bleeding complications on follow-up. The second patient, a 29-year-old male, presented after an intentional overdose of 480 mg of enoxaparin. The anti-Xa activity was 1.9 U/mL measured 2 hours postinjection. The patient was observed without intervention. There were no bleeding complications. Discussion: To our knowledge, there is only one previous report of an LMWH overdose in the literature, an iatrogenic overdose in an infant treated with protamine. In our 3 presented episodes of LMWH overdose, no therapeutic interventions were performed and there were no bleeding complications. Review of the literature regarding the efficacy of protamine and recombinant factor VIIa for reversal of LMWH coagulopathy revealed that protamine is only partially effective and recombinant factor VIIa is effective in in vitro studies and case reports. Conclusions: In cases of LMWH overdose, observation seems to be appropriate in the absence of clinically significant bleeding. Prolonged monitoring may be necessary for patients with renal failure. Use of protamine or recombinant factor VIIa is not supported by this case series in patients without significant bleeding. There is a lack of data regarding how to treat patients with significant bleeding.

Colorado Cannabis Legalization and Its Effect on Emergency Care

Colorado legalized the use of medical marijuana in 2000, although it was not truly commercialized in the state until the US attorney general ceased the prosecution of marijuana users and suppliers in 2009. The result was striking: from January 2009 to January 2011, the number of registered medical marijuana licenses in Colorado increased from 5,051 to 118,895 (Figure 1). Figure 1 Number of active marijuana licenses in Colorado. In 2012, Colorado voted to legalize recreational marijuana beginning in 2014, making it the first state alongside Washington to permit recreational use. Several other states have recently legalized the use of medical or recreational marijuana, with other states considering similar measures (Figure 2).1 Given this trend, emergency physicians in training will likely be confronted with increasing volumes of marijuana-related emergency department (ED) visits and may learn from Colorado’s recent experience with increased availability of marijuana products. Figure 2 Marijuana legalization by state (as of May 2015). THE EPIDEMIOLOGIC EFFECT OF LEGALIZATION Although the significant increase in medical marijuana registrations does not prove its increased use, this inference is supported by various survey data. According to the National Survey on Drug Use and Health, the percentage of young Coloradan adults aged 18 to 25 years reporting marijuana use within the past year increased significantly after medical marijuana legalization (35% in 2007 to 2008 versus 43% in 2010 to 2011). Simultaneously, the percentage of adults aged 26 years or older perceiving “great risk” to marijuana use significantly decreased, from 45% to 31%.2 Interstate comparisons also show a higher prevalence of marijuana use in states in which it has been legalized versus those in which it has not. According to National Survey on Drug Use and Health responses from 2011 to 2013, the prevalence of Coloradan adults endorsing marijuana use within the last month was 19% compared with a national prevalence of 12%.3 According to data from the National Epidemiologic Survey on Alcohol and Related Conditions, residents of states with medical marijuana legalization were twice as likely to endorse marijuana use compared with residents of states without legalized medical marijuana.4