Jeanmarie Perrone

Acetaminophen-Induced Nephrotoxicity: Pathophysiology, Clinical Manifestations, and Management

Acetaminophen-induced liver necrosis has been studied extensively, but the extrahepatic manifestations of acetaminophen toxicity are currently not described well in the literature. Renal insufficiency occurs in approximately 1–2% of patients with acetaminophen overdose. The pathophysiology of renal toxicity in acetaminophen poisoning has been attributed to cytochrome P-450 mixed function oxidase isoenzymes present in the kidney, although other mechanisms have been elucidated, including the role of prostaglandin synthetase and N-deacetylase enzymes. Paradoxically, glutathione is considered an important element in the detoxification of acetaminophen and its metabolites; however, its conjugates have been implicated in the formation of nephrotoxic compounds. Acetaminophen-induced renal failure becomes evident after hepatotoxicity in most cases, but can be differentiated from the hepatorenal syndrome, which may complicate fulminant hepatic failure. The role of N-acetylcysteine therapy in the setting of acetaminophen-induced renal failure is unclear. This review will focus on the pathophysiology, clinical features, and management of renal insufficiency in the setting of acute acetaminophen toxicity.

Can Prescription Drug Monitoring Programs Help Limit Opioid Abuse

RIMARY CARE PHYSICIANS,EMERGENCY PHYSICIANS,ONcologists, orthopedic surgeons, and other physicians are at the frontline of providing pain therapy for patients with acute illness and rescue treatments for patients with exacerbations of chronic pain. Increasingly, this role is compromised by concerns about the prevalenceofopioidabuseanddiversionofprescribedmedi

Medication Reconciliation for Controlled Substances — An "Ideal" Prescription-Drug Monitoring Program

In the face of an epidemic of misuse of prescription opioids and related deaths, many states have created prescription-drug monitoring programs to track prescribing of controlled substances. As such programs are developed, expanded, or retooled, reanalysis is in order.

Curbing the Opioid Epidemic in the United States: The Risk Evaluation and Mitigation Strategy (REMS)

HRONIC PAIN IS A MULTIDIMENSIONAL PROBLEM,WITH significant influence on the culture and economy of the United States. Although chronic pain associated with cancer is distinct from that associated with musculoskeletal or functional pain syndromes, common treatment strategies for both include the administration of opioids. Although it appears logical to prescribe potent analgesics to patients with chronic noncancer pain, the data to support the effectiveness of opioids for this indication are limited. 1 Prescription opioid analgesics have been used for decades for the outpatient treatment of acute medical, traumatic, and postoperative pain, as well as for chronic pain associated with malignancy and terminal disease. In the 1980s, a combination of factors, both patient-centered and business-oriented,ledtothebroaderuseofopioidsfortreatment of patients with chronic noncancer pain. This expanded use resulted in the dispensing of large quantities of opioids, of which a consequential, increasing minority was diverted to nonmedical uses, including inappropriate selfmedication and recreational abuse. Even used as prescribed, opioids are associated with significant morbidity and mortality. Reformulation of opioids as extended-release preparations to allow longer dosing intervals for patients in discomfort had the unintended consequence of making available large quantities of high-dose opioids and priming the epidemic of opioid misuse, abuse, addiction, and mortality. Sales of opioid analgesics, includingbothregular-andextended-release,increased4-foldbetween 1999 and 2010. 2 In 2008, more than 14000 deaths were related to the misuse of prescription medications, the vast majority of which were opioid analgesics. 2 Health care professionals, who may have prescribed analgesics to meet Joint Commissionanalgesia standards (and possibly to protect their patient satisfaction scores), 3 have become the primary supplier of the drugs fueling this epidemic. The US Food and Drug Administration (FDA) is tasked with ensuring that medications are effective and safe. However, the FDA is prevented from interfering with the “practice of medicine.” At the crossroads of these requirements is postmarketing, off-label prescribing, over which the FDA

Addressing the Opioid Epidemic

Afteralcohol intoxication,opioidsare themostcommoncause ofpoisoninginpatientspresentingtoNorthAmericanemergency departments.1Mostopioidsmisusedbypatientsoriginate from prescriptionmedication.Most patientswhooverdoseonprescription opioids are taking their medications differently thanprescribedorareusingopioidsprescribedtosomeoneelse. These2main typesofnonmedical opioiduse representamajor causeofmorbidityandmortality.Someindividualswhomisuse opioidsareseekingeuphoriceffects,butothershavedeveloped dependence through chronic opioid use and are simply trying toavoidopioidwithdrawal.Opioid-relatedharmhasnowreached epidemic levels: emergency department visits for nonmedical useofprescriptionopioidsmorethandoubledfrom2004to2011, accountingforanestimated488 000visits in2011.1Deathshave more than tripled since 1999, with an estimated 16 235 deaths attributable to prescription opioids in 2013.2,3 In this issueof JAMA, the studybyHanet al4 examined the current scopeof theopioidepidemic in theUnitedStates.Using datafromnearlyhalfamillionrespondentstotheannualNational SurveyonDrugUseandHealth(NSDUH), theauthors foundthat overalltrendsinself-reportednonmedicaluseofprescriptionopioidsdecreasedfrom5.4%to4.9%overan11-yearperiod, includingadecline innewusersofopioids, from1%in2003to0.6%in 2013.Althoughthisoverall findingofa reduction innonmedical useofprescriptionopioidsisencouraging,thestudyalsoreported increases in theprevalenceofprescriptionopioidusedisorders (abuseandaddiction)and increases in theprevalenceofopioidassociatedmortality,usingdatafromtheNationalVitalStatistics System’sMultipleCauseofDeathFiles.Theauthorsalsoreported an increasedprevalenceof frequentopioiduse (>100days/year) and highly frequent use (>200 days/year), as well as a greater prevalenceofprescriptionopioidusedisorders inpatientswith majordepressiveepisodes(MDEs)thaninpatientswithoutthem. The findings ofHan et al suggest thatmore patients are experiencing an inexorable progression from initial opioid use to frequent use, highly frequent use, or an opioid use disorder. Another report in this issue of JAMA by Saloner and Karthikeyanaddressedarelatedquestion:Dopatientswithnonmedical use of opioids access treatment?5 Among individuals identifiedinNSDUHashavinganopioidusedisorder, theauthors examined utilization of substance abuse treatment during the sameperiodasHanetal (2004-2013).Adjustedratesof individualswith opioid use disorders receiving treatmentwere lowand essentiallyunchangedduringthereportingperiod(18.8%in20042008to19.7%in2009-2013).SalonerandKarthikeyanalsofound thatthenumberofsettingsvisitedfortreatment(ie, inpatientservices,outpatientclinics,physicians’offices) increased, from2.8 to3.3, includingreceiptoftreatmentinofficesettings(from25.1% to34.8%)whereuseofbuprenorphineismost likely.Theauthors cannot explain why so many patients apparently did not seek treatment, suchaswhether it isnot available,not affordable, or notof interest.Furthermore, theoutcomesof treatmentcannot bemeasuredwiththesedata,butotherstudieshavereportedthat the long-termeffectiveness ofmost such therapies ismodest.6 Saloner and Karthikeyan also found that over time, survey respondents were older and were less likely to have private health insurance. Despite the Mental Health Parity and Addiction Equity Act of 2008,7 which mandated that insurersoffermentalhealthandaddictionbenefits comparablewith their medical-surgical benefits, an increase in treatment opportunitieswasnot observed in the latter part of the studyperiod, after the act was implemented. This suggests that ability topaymost likelywasnot theprimary factor in thedecision to forgo treatment but does not clarify the roles of access to, or interest in, treatment for an opioid use disorder. Prescribingofopioidanalgesics,particularlyforchronicpain, appears to be amain factor in themajority of nonmedical use. Basedonotherdataavailable in theNSDUH,prescribersare,directlyor indirectly, the sourceofmostmisusedopioids.8Anestimated53%ofnonmedicalusersreportedobtainingprescription opioidsfromafriendorrelative,81%ofwhomreceivedtheirdrug fromaphysician. It isunclearwhether theseprescriptionswere issuedfortherapeuticpurposesororiginatedfromunscrupulous prescribers (ie, “pillmills”); regardless, the sourceofopioiduse andmisuse is often a seemingly legitimate prescription. There is little evidence for long-term benefit from opioid therapy formost typesof chronicpain.9 It remainsunclearwhy thispracticeofopioidprescribingcontinuesdespite recommendationstothecontrary.9,10Newopioidmedications,manyofthem withtamper-resistantformulations,continuetobemarketeddespite the lackofevidencethat thesepreparationsreducetherisk ofaddiction.11More than10%ofpatientswho initiate treatment withopioidswill likelyprogress tochronicuse,definedasongoingtreatmentformorethan3months.12Nearlyallpatientstreated withlong-termopioidtherapydeveloptoleranceanddependence tovaryingdegrees,about25%becomenonmedicalusers,and10% developfeaturessuggestiveofaddiction.13Thesearesoberingpercentagesinlightofthemillionsofpatientsprescribedthesedrugs everyyear.14Consequently,forthemanypatientswhoneedtreatment for addictionor complicationsof substancemisuse, there areoftensignificantbarriers toobtainingcare.6Dependence,addiction, anddose escalation resulting from tolerancemakediscontinuingopioidsdifficult.Manypatientsunderstandablyperceivetheyneedongoingopioidanalgesic therapybecause,when thedrugsarediscontinued,anunpleasantwithdrawalsyndrome withassociatedpainensues.Patientsquickly learnthat resumpRelated articles pages 1468 and 1515 Opinion

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.

Occult Metformin Toxicity in Three Patients with Profound Lactic Acidosis

There are 20.8 million Americans with diabetes, and metformin is the most commonly prescribed oral diabetes agent. A review of our metformin experience highlights common pitfalls that lead to life-threatening or fatal poisonings. We describe 3 patients with metformin toxicity; 2 of 3 patients were prescribed metformin despite end-stage renal disease (ESRD). Case 1: a 40-year-old woman presented after a polysubstance overdose. Within 8 h, vomiting and lethargy developed; a profound acidosis, pH 6.95, pCO(2) 26, pO(2) 195, and elevated serum lactate 21 mmol/L (ref 0.5-1.6 mmol/L) were noted. Further inquiry revealed that the patient had ingested metformin. She was intubated; bicarbonate therapy and hemodialysis were initiated; however, she became hypotensive and died. A metformin level was 150 μg/mL (therapeutic 1-2 μg/mL). Case 2: a 69-year-old woman with non-insulin-dependent diabetes mellitus (NIDDM) and ESRD presented to the Emergency Department (ED), having missed dialysis. She was sluggish and complained of abdominal pain; an acidosis, pH 7.37, pCO(2) 20, pO(2) 171; anion gap 38, and elevated serum lactate 18.9 mmol/L were noted. Hemodialysis was initiated when it was revealed that she took metformin daily. She improved rapidly and a metformin level was 27.4 μg/mL. Case 3: a 57-year-old woman with a history of NIDDM and ESRD presented with dyspnea. Laboratory studies showed pH 7.03, pCO(2) 21, pO(2) 99; anion gap 36, and lactate 16 mmol/L. Bicarbonate therapy and hemodialysis were initiated after discovering that she had recently been prescribed metformin. She had a fatal cardiac arrest after dialysis was completed. We describe 3 ED patients with occult metformin toxicity diagnosed after laboratory results showed an anion gap metabolic acidosis and elevated lactate levels. All patients had lethargy, vomiting, or abdominal pain, also suggesting sepsis or mesenteric infarction. Despite sodium bicarbonate therapy and hemodialysis, metformin-associated lactic acidosis was fatal in 2 of 3 patients. Emergency Physicians must be vigilant to recognize metformin toxicity in patients at high risk for metformin-associated lactic acidosis.

Aldicarb Poisoning by an Illicit Rodenticide Imported into the United States: Tres Pasitos

Objective: Although intentional and unintentional rodenticide poisoning is common, most readily available agents are of relatively low acute toxicity. A four-year long epidemic of severe toxicity from rodenticide exposure continues among patients predominantly of Dominican descent living in New York City. This study characterizes the ongoing epidemic of acute cholinesterase inhibitor poisoning due to an illicit rodenticide and identifies its etiology. Methods: A prospectively collected case series of poisoned patients referred to the New York City Poison Control Center. The main outcome measures include the clinical characteristics upon presentation, antidotal and other therapeutic requirements, and patient outcome. Product analysis was performed with paper chromatography, gas chromatography/mass spectrometry, and high-performance liquid chromatography. A murine model assessing both clinical effect and cholinesterase activity was also performed. Results: Thirty-five patients were referred following exposure to Tres Pasitos. Patients developed signs of cholinergic hyperactivity and many required high doses of atropine (>10 mg) to control these symptoms. The source was identified as a rodenticidal compound sold illicitly in local groceries primarily within the Dominican community. Murine cholinesterase activity fell significantly following exposure to the rodenticide. High-performance liquid chromatography identified aldicarb, an extremely potent carbamate-type cholinesterase inhibitor, not licensed for rodenticidal use in this country. Conclusion: Illicit sale of undocumented compounds poses a substantial public health threat. Despite several public health interventions, the epidemic continues.

Prescribing Practices, Knowledge, and Use of Prescription Drug Monitoring Programs (PDMP) by a National Sample of Medical Toxicologists, 2012

Prescription opioid analgesic misuse and addiction are a significant public health concern in the USA. Through their concurrent roles as prescribers and public health stewards, medical toxicologists (MTs) have a unique perspective on this issue. They represent a physician group with a particular interest in prescription drug monitoring programs (PDMPs) because of their subspecialty knowledge of the negative consequences of opioid overprescribing in terms of misuse, diversion, addiction, and overdose death. This study surveyed a national sample of MTs about their opioid prescribing patterns and their knowledge and use of PDMPs. A link to a Web-based survey was disseminated by email to the physician membership of the American College of Medical Toxicology. The survey assessed the circumstances and details of the respondents prescribing practices for opioids and their knowledge and use of PDMPs. This included focused questions regarding their perceived limitation of their current PDMP. Responses were received from 205/445 surveys (46 %), representing responses from 35 states. The majority (78 %) of MTs responding to the survey reported that they primarily practice emergency medicine. Although awareness of PDMPs, in general, was high, approximately 25 % reported no knowledge of or did not have access to their state’s PDMP. Barriers to use included time and complexity required to access relevant information. MTs prescribe opioids primarily to patients in the Emergency Department (ED) for acute pain or acute exacerbations of chronic pain. MTs are generally aware of PDMPs, although many were unaware of or not using their state-based PDMPs when prescribing opioids in clinical practice.

The epidemiology of intentional non-fatal self-harm poisoning in the United States: 2001-2004.

IntroductionSuicide attempts through intentional poisoning are an important public health concern. This investigation sought to determine the different US incident rates of poisonings (with intent to do self-harm) by race, sex, and gender.MethodsWe used data from the National Electronic Injury Surveillance System — All Injury Program (NEISS-AIP) to describe differences in incidence rates of non-fatal, self-harm poisonings evaluated in US emergency departments (ED) from 2001 to 2004. WISQARS defines self-harm as “either confirmed or suspected from injury or poisoning resulting from a deliberate act inflicted on oneself with the intent to take one’s own life or harm oneself.”ResultsFrom 2001 to 2004, there were 976,974 (95% Confidence Interval (CI) 772,884 – 1,181,065) non-fatal self-harm poisonings reported in US Emergency Departments. Young white females between 15 to 19 years of age were at highest risk with an incidence rate of 248 per 100,000 (95% CI 180 – 315). Females had higher rates of self-harm poisonings than males: the rate for females was 101 per 100,000 (95% CI 81 – 123); the rate for males was 66 per 100,000 (95% CI 51 – 81), p < 0.001. Whites had slightly higher rates than blacks, and significantly higher rates than Hispanics: whites rates were 71 per 100,000 (95% 51 – 91); black rates were 65 per 100,000 (95% CI 35 – 96), and Hispanic rates were 23 per 100,000 (95% 10 – 37). There was a significant increase in the incidence rate from 2002 to 2003 (p < 0.001). Incident rates decreased for females and males older than 19 years of age (p < 0.001 for males and females).ConclusionRecently, the incidence of self-harm poisoning has risen considerably. It rose from 75 (CI 53–98) per 100,000 in 2002 to 94 (CI 74–115) per 100,000 in 2003; incidence remained relatively steady in 2004. Whites have higher incidence rates than blacks and significantly higher incidence rates than Hispanics. Females are at higher risk than males, and adolescent white females are at highest risk. An understanding of the demographic factors associated with self-harm poisoning may provide useful information to improve prevention and treatment strategies.