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Objective: To assess the impact of extended-release (ER)/long-acting (LA) opioid prescriber training on prescribing behaviors.Design: Retrospective cohort study.Setting: Prescriber training was evaluated from June 1, 2013 through December 31, 2016. The full study period was 2 years longer, from June 1, 2012 through December 31, 2017, to include data for all prescribers’ 1-year pretraining and post-training periods.Participants: 24,428 prescribers who wrote ER/LA opioid prescriptions for eligible patients, with a record of training from the partner continuing education provider between June 1, 2013 and December 31, 2016.Intervention: ER/LA opioid prescriber training. Main outcome measures: Prescribing behaviors 1-year before (pretraining) and after (post-training) prescribers completed training, specifically the proportion of opioid-nontolerant patients receiving ER/LA opioids indicated for opioid-tolerant patients and for patients receiving ≥100 morphine equivalents dose daily, and the proportion of concomitant users of central nervous system depressant drugs.Results: The differences in the proportion of opioid-nontolerant patients receiving ER/LA opioids indicated for opioid-tolerant patients and for patients receiving ≥100 morphine equivalents dose daily were –0.69 percent (95 percent confidence interval [CI]: –1.78 percent, 0.40 percent) and –0.23 percent (95 percent CI: –1.18 percent, 0.68 percent), respectively. The differences in the proportion of concomitant users of central nervous system depressant drugs were –0.94 percent (95 percent CI: –1.39 percent; –0.48 percent) for benzodiazepines, 0.06 percent (95 percent CI: –0.13 percent; 0.25 percent) for antipsychotics, –0.41 percent (95 percent CI: –0.69 percent; –0.13 percent) for hypnotics/sedatives, and 0.08 percent (95 percent CI: –0.40 percent; 0.57 percent) for muscle relaxants.Conclusions: While prescribers showed some changes in prescribing behavior after completing training, training was not associated with clinically relevant changes in prescribing behaviors.

Objective: To assess the impact of extended-release (ER)/long-acting (LA) opioid prescriber training on prescribing behaviors.Design: Retrospective cohort study.Setting: Prescriber training was evaluated from June 1, 2013 through December 31, 2016. The full study period was 2 years longer, from June 1, 2012 through December 31, 2017, to include data for all prescribers’ 1-year pretraining and post-training periods.Participants: 24,428 prescribers who wrote ER/LA opioid prescriptions for eligible patients, with a record of training from the partner continuing education provider between June 1, 2013 and December 31, 2016.Intervention: ER/LA opioid prescriber training. Main outcome measures: Prescribing behaviors 1-year before (pretraining) and after (post-training) prescribers completed training, specifically the proportion of opioid-nontolerant patients receiving ER/LA opioids indicated for opioid-tolerant patients and for patients receiving ≥100 morphine equivalents dose daily, and the proportion of concomitant users of central nervous system depressant drugs.Results: The differences in the proportion of opioid-nontolerant patients receiving ER/LA opioids indicated for opioid-tolerant patients and for patients receiving ≥100 morphine equivalents dose daily were –0.69 percent (95 percent confidence interval [CI]: –1.78 percent, 0.40 percent) and –0.23 percent (95 percent CI: –1.18 percent, 0.68 percent), respectively. The differences in the proportion of concomitant users of central nervous system depressant drugs were –0.94 percent (95 percent CI: –1.39 percent; –0.48 percent) for benzodiazepines, 0.06 percent (95 percent CI: –0.13 percent; 0.25 percent) for antipsychotics, –0.41 percent (95 percent CI: –0.69 percent; –0.13 percent) for hypnotics/sedatives, and 0.08 percent (95 percent CI: –0.40 percent; 0.57 percent) for muscle relaxants.Conclusions: While prescribers showed some changes in prescribing behavior after completing training, training was not associated with clinically relevant changes in prescribing behaviors.

Daina B Esposito,1 Vibha CA Desai,1 Judith J Stephenson,1 M Soledad Cepeda,2 Jennifer G Lyons,1 Crystal N Holick,1 Gregory P Wedin,3 Stephan Lanes1 On behalf of members of the REMS Program Companies Metrics Subteam1HealthCore, Inc., Wilmington, DE, USA; 2Janssen Research and Development, Titusville, NJ, USA; 3Upsher-Smith Laboratories, LLC, Maple Grove, MN, USACorrespondence: Judith J StephensonHealthCore Inc, 123 Justison Street, Suite 200, Wilmington, DE, 19801, USATel +1 302-547-5770Email jstephenson@healthcore.comBackground/Rationale: The US Food and Drug Administration (FDA) approved a Risk Evaluation and Mitigation Strategy (REMS) for extended release/long-acting (ER/LA) opioids in 2012. The purpose of this study was to assess patient knowledge of the safe use of these products following implementation of the REMS and to determine possible effects of the REMS, including impact on medication access.Objective: To assess patient knowledge of safe use of ER/LA opioids and use of REMS patient education tools such as the Medication Guide (MG) and Patient Counseling Document (PCD).Methods: This was a cross-sectional survey of commercially insured (Commercial) and Medicare Advantage-insured (Medicare) adults with ≥ 1 pharmacy claim for an ER/LA opioid (10/01/2015 – 02/28/2017) in the HealthCore Integrated Research Database and Medicaid-insured (Medicaid) adult members of a research panel, about their knowledge of safe use of ER/LA opioids and receipt/comprehension of the MG and PCD.Results: Survey respondents consisted of 382 Commercial, 43 Medicare and 40 Medicaid adults. While ≥ 95% of respondents received and read the MG, fewer were aware of the PCD (Commercial: 47%, Medicare: 65%, Medicaid: 53%). Almost 75% of the knowledge questions were answered correctly by ≥ 80% of all respondents; fewer respondents recognized that use of opioids as directed can lead to death (Commercial: 73%, Medicare: 56%, Medicaid: 63%), the MG should be read at each dispensing (Commercial: 78%, Medicare: 53%, Medicaid: 75%), opioids should not be stored in the medicine cabinet (Commercial: 77%, Medicare: 79%, Medicaid: 58%), missed doses should not be taken as soon as possible (Commercial: 56%, Medicare: 51%, Medicaid: 50%), and pills should not be crushed (Commercial: 85%, Medicare: 67%, Medicaid: 52%).Conclusion: Although most respondents reported reading and understanding the MG and exhibited knowledge of safe use of ER/LA opioids, providers’ use of the PCD and increased understanding of safe use core messages need reinforcement.Keywords: Risk Evaluation and Mitigation Strategy, opioids, patient knowledge

Introduction Opioid overdose deaths in the United States have climbed sharply over the past two decades. Simultaneously, increased awareness of inadequately treated chronic pain has resulted in increased opioid analgesic prescribing. The correlation between these two phenomena has led policymakers to posit that they are causally linked, and to implement policy changes supporting safe opioid prescribing. Purpose To evaluate the impact of its Opioid Analgesic Risk Evaluation and Mitigation Strategy (REMS) program, the US Food and Drug Administration (FDA) requested the opioid manufacturers responsible for implementing that program provide information regarding opioid policy changes from 2016 to 2018. FDA also requested a survey of state requirements for pain and opioid prescribing continuing education (CE), the number of prescribers affected by those requirements, the extent to which a REMS-compliant CE program would meet each state's requirements, and the number of relevant CE programs available. Results Results indicate that 527 federal and state opioid-related policies (statutes, rules/regulations, and guidelines) were approved during the 2016-2018 study period. While the largest number of these policies focused on prescription drug monitoring programs, 170 specifically imposed limits on opioid prescribing and an additional 35 specifically referred to, or incorporated, the Centers for Disease Control and Prevention opioid prescribing guideline. We also found that 46 states and the District of Columbia mandated some amount of pain or opioid prescribing CE for prescribers renewing their licenses. These mandates potentially affected as many as 1.7 million prescribers. In 69% of cases, a REMS-compliant CE program would fully meet the state mandates for various types of prescribers. Conclusion The severity and complexity of the problems of pain management and opioid overdose have led to large-scale intervention by policymakers. Assessing the impact of these changes is difficult, at best, but will be necessary if interventions are to be refined to increase their effectiveness.

Daina B Esposito, 1 M Soledad Cepeda, 2 Crystal N Holick, 1 Caitlin Knox, 1 Vibha CA Desai, 1 Nianya Liu, 1 Shiva-Krishna Vojjala, 1 Jennifer G Lyons, 1 Gregory P Wedin, 3 Stephan Lanes 1 On Behalf of the REMS Program Companies Metrics Subteam 1HealthCore, Inc, Andover, MA, USA; 2Janssen Research and Development, Titusville, NJ, USA; 3Upsher-Smith Laboratories, LLC, Maple Grove, MN, USACorrespondence: Stephan LanesSafety and Epidemiology, HealthCore, Inc., 300 Brickstone Square, 8th Floor, Suite 801A, Andover, MA 01810, USATel +1 302-384-0673Fax +1 978-247-6650Email slanes@healthcore.comIntroduction: The United States (US) Food and Drug Administration (FDA) required a Risk Evaluation and Mitigation Strategy (REMS) for extended-release and long-acting (ER/LA) opioid analgesics on 09 July 2012.Methods: This study compared the incidence of opioid overdose before (July 2010-June 2012) and after (July 2013-September 2016) the initiation of the Risk Evaluation and Mitigation Strategy (REMS) for extended-release and long-acting (ER/LA) opioid analgesics. We identified patients with ≥ 1 ER/LA opioid dispensing in either time period in national data from the HealthCore Integrated Research DatabaseSM (HIRD) and in United States (US) Medicaid claims data from four states. We described each population, calculated the incidence rate (IR) of opioid overdose, and assessed crude and propensity score adjusted incidence rate ratios (IRR) comparing the overdose rate after vs before implementation of the REMS.Results: A total of 121,229 commercially insured and 11,488 Medicaid patients were included in the analysis. Rates of overdose were substantially higher in Medicaid patients than in the commercially insured patients (IR 192.0, 95% confidence interval [CI] 162.60– 225.18 versus 102.60, 95% CI 93.0– 112.93 in the active period). The IRRs for opioid overdose were 1.01 (95% CI 0.87– 1.17) in the commercially insured population and 0.70 (95% CI 0.52– 0.93) in Medicaid.Conclusion: This leveling off of overdose rates among commercially insured patients and decline among Medicaid patients is encouraging, but it is difficult to disentangle the specific impact of the REMS from many other ongoing initiatives with similar goals.Keywords: opioid, overdose, REMS, Medicaid, claims

Objective To assess changes in mortality rates in extended-release and long-acting (ER/LA) opioid analgesics after the implementation of the Risk Evaluation and Mitigation Strategy (REMS). Setting All drug poisoning deaths in three states: Florida, Oregon, and Washington. Data were obtained through state vital records offices and the Researched Abuse, Diversion and Addiction-Related Surveillance System Medical Examiner Program. Methods Using cause-of-death literal text from death certificates, individual opioid active pharmaceutical ingredients (APIs) involved in each death were identified using rules-based natural language processing. Population-adjusted and prescriptions dispensed–adjusted mortality rates were calculated for all ER/LA opioid analgesic and individual opioid APIs. Rates before and after implementation of the REMS were compared. Rate changes were compared with rates from two APIs with little or no inclusion in the REMS: benzodiazepines and hydrocodone. Results The mean ER/LA opioid analgesic population-adjusted mortality rate significantly decreased in all three states (FL: P = 0.003; OR: P = 0.003; WA: P Conclusions The population-adjusted mortality rate of ER/LA opioid analgesics has decreased in three states. Notably, the contributions to mortality rates by individual opioid analgesics were not uniform across the three states in this study. However, these changes were not generally distinct from changes in mortality rates where comparator substances were involved.

Objective Refilling an opioid prescription early is an important risk factor of prescription opioid abuse and misuse; we aimed to understand the scope of this behavior. This study was conducted to quantify the prevalence and distribution of early refills among patients prescribed opioids. Methods We conducted a retrospective cohort study utilizing dispensed prescription records. Patients filling one or more prescription opioids were identified and followed for one year. Early refills were defined as having a second prescription filled ≥15% early relative to the days’ supply of the previous prescription for the same opioid (according to the National Drug Code [NDC]). The distribution of the number of early refills and patient characteristics were assessed. Results A total of 60.6 million patients met the study criteria; 28.8% had two or more opioid prescriptions for the same opioid during follow-up. Less than 3% of all patients receiving an opioid had an early refill. Approximately 10% of those with two or more opioid prescriptions for the same drug had an early refill. For patients with multiple fills (N = 1.5 million with extended-release long-acting [ER/LA] opioids; N = 17.1 million with immediate-release short-acting [IR/SA] opioids), early refills were more common among patients with an ER/LA opioid (18.5%) compared with an IR/SA opioid (8.7%). Three-quarters of patients with an early refill had only one (70.9% and 78.4% for ER/LA and IR/SA, respectively). Conclusion Refilling an opioid prescription with the same opioid early is an infrequent behavior within all opioid users, but more common in ER/LA users. Patients who refilled early tended to do so just once.

Objective. Opioid abuse is a serious public health concern. In response, the Food and Drug Administration (FDA) determined that a risk evaluation and mitigation strategy (REMS) for extended-release and long-acting (ER/LA) opioids was necessary to ensure that the benefits of these analgesics continue to outweigh the risks. Key components of the REMS are training for prescribers through accredited continuing education (CE), and providing patient educational materials. Methods. The impact of this REMS has been assessed using diverse metrics including evaluation of prescriber and patient understanding of the risks associated with opioids; patient receipt and comprehension of the medication guide and patient counseling document; patient satisfaction with access to opioids; drug utilization and changes in prescribing patterns; and surveillance of ER/LA opioid misuse, abuse, overdose, addiction, and death. Results and Conclusions. The results of these assessments indicate that the increasing rates of opioid abuse, addiction, overdose, and death observed prior to implementation of the REMS have since leveled off or started to decline. However, these benefits cannot be attributed solely to the ER/LA opioid analgesics REMS since many other initiatives to prevent abuse occurred contemporaneously. These improvements occurred while preserving patient access to opioids as a large majority of patients surveyed expressed satisfaction with their access to opioids.

Purpose An unintended consequence of extended-release (ER) and long-acting (LA) prescription opioids is that these formulations can be more attractive to abusers than immediate-release (IR) formulations. The US Food and Drug Administration recognized these risks and approved the ER/LA Opioid Analgesic Risk Evaluation and Mitigation Strategy (ER/LA REMS), which has a goal of reducing opioid misuse and abuse and their associated consequences. The primary objective of this analysis is to determine whether ER/LA REMS implementation was associated with decreased reports of misuse and abuse. Methods Data from the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS(R)) System Poison Center Program were utilized. Poison center cases are assigned a reason for exposure, a medical outcome, and a level of health care received. Rates adjusted for population and drug utilization were analyzed over time. Results RADARS System Poison Center Program data indicate a notable decrease in ER/LA opioid rates of intentional abuse and misuse as well as major medical outcomes or hospitalizations following implementation of the ER/LA REMS. Conclusions While similar decreases were observed for the IR prescription opioid group, the decreasing rate for the ER/LA opioids exceeded the decreasing rates for the IR prescription opioids and was distinctly different than that for the prescription stimulants, indicating that the ER/LA REMS program may have had an additional effect on decreases in opioid abuse and intentional misuse beyond secular trends.

The discovery of gamma-hydroxybutyrate (GHB) over 40 years ago led to its immediate use as a general anesthetic agent. Subsequent research demonstrated that GHB is an endogenous compound in the mammalian brain and current research suggests that GHB is a probable neurotransmitter. In the United States, reports of anabolic effects lead to its misuse among body builders during the 1980's while the intoxicating properties of the drug lead to its popularization as a substance of abuse during the 1990's. GHB became associated with reports of drug-facilitated sexual assault and cases of physical dependence and withdrawal. Efforts to ban GHB caused increased use of GHB analogues and pro-drugs. Against this backdrop, GHB was being developed for the treatment of narcolepsy, leading to the approval of Xyrem (sodium oxybate) oral solution in 2002 for the treatment of cataplexy in patients with narcolepsy. A risk management program permits the safe handling and distribution of the approved product, minimizes the risk for diversion, provides professional and patient education about the risks and benefits of sodium oxybate, and includes physician and patient registries. Post-marketing surveillance indicates sodium oxybate has an acceptable safety profile and presents minimal risk for the development of physical dependence.

A great number of species in the animal kingdom possess means by which they subdue prey or defend against predators. Human encounters with these species may result in bites or stings that produce local injury or systemic toxicity ranging from local pain and varying degrees of tissue injury to systemic illness, organ failure and even death. Most of these animals deliver a dose of venom when they bite or sting, but some produce or accumulate toxin in their flesh that may produce illness if ingested. Venoms are generally complex mixtures of proteins and enzymes, but few are very well understood. Antivenoms have been produced to treat exposures to some species, but treatment generally consists of supportive measures and treatment of symptoms. This chapter presents an overview of some of more common animal species found throughout the world, the toxic syndromes they produce and current therapeutic strategies. Keywords: ants; antivenom; beaded lizard; stinging fish; gila monster; Hymenoptera; jellyfish; scorpion; shellfish; snake; spider; stingray; venom

The discovery of gamma-hydroxybutyrate (GHB) over 40 years ago led to its immediate use as a general anesthetic agent. Subsequent research demonstrated that GHB is an endogenous compound in the mammalian brain and current research suggests that GHB is a probable neurotransmitter. In the United States, reports of anabolic effects lead to its misuse among body builders during the 1980's while the intoxicating properties of the drug lead to its popularization as a substance of abuse during the 1990's. GHB became associated with reports of drug-facilitated sexual assault and cases of physical dependence and withdrawal. Efforts to ban GHB caused increased use of GHB analogues and pro-drugs. Against this backdrop, GHB was being developed for the treatment of narcolepsy, leading to the approval of Xyrem (sodium oxybate) oral solution in 2002 for the treatment of cataplexy in patients with narcolepsy. A risk management program permits the safe handling and distribution of the approved product, minimizes the risk for diversion, provides professional and patient education about the risks and benefits of sodium oxybate, and includes physician and patient registries. Post-marketing surveillance indicates sodium oxybate has an acceptable safety profile and presents minimal risk for the development of physical dependence.

Sir .—Clonidine hydrochloride is one of several medications that can produce serious toxicity in children with ingestion of only a small amount. We describe a 3-year-old child who ingested a single 0.2-mg clonidine hydrochloride tablet and developed coma, respiratory depression, and hypotension. This is the lowest dose reported to cause such profound toxicity in a young child. Patient Report .—A 3-year-old boy ingested one of his grandmother's 0.2-mg clonidine hydrochloride (Catapres) tablets. Actual ingestion was not observed, but a single tablet placed on a table was missing. The child indicated he had eaten it. He was transported by ambulance to the local emergency department. Approximately 1 hour after ingestion, the child was very lethargic and pale. His vital signs were as follows: heart rate, 76 beats per minute; respiratory rate, 8 to 10 per minute; and blood pressure, 100/80mm Hg. An intravenous line was placed and 5% dextrose in lactated

Although the highly toxic nature of castor bean (Ricinus communis) is well recognized, reports of human toxicity in the English medical literature are scarce. The potentially lethal doses reported for children and adults are three beans and four to eight beans respectively. Recent experience with two cases provides added insight into the expected course of toxicity. In both cases, repeated vomiting, diarrhea, and transiently elevated serum creatinine occurred. Dehydration was much more pronounced in the second case. Both patients recovered uneventfully. Other reported manifestations of castor bean toxicity, such as hepatic necrosis, renal failure, erythrocyte hemolysis, convulsions, and shock, did not occur.

Two cases of subcutaneously administered hydrocarbon based products are presented and the literature reviewed. The toxicity associated with subcutaneous administration is limited to the site of injection producing cellulitis and sterile abscess formation. Management is discussed with emphasis on the importance of incision and drainage of developing abscesses. Perceived toxicity and ready availability of these products suggests that similar exposures can be expected.Small volumes of hydrocarbons produce both local and systemic toxicity, depending upon the route of administration. Intravenous injection may produce a chemical pneumonitis similar to when these substances are aspirated. Subcutaneous injection of household insecticides or other hydrocarbon based products has produced marked cellulitis and sterile abscess formation. These effects, which may be delayed and progressive require incision and drainage. Close medical observation and follow-up are necessary when a history of injection of even s...

An elderly patient experienced an intracerebral bleed temporally related to the administration of syrup of ipecac. The experience of the certified regional poison centers of the American Association of Poison Control Centers shows that this is in uncommon event. The use and safety of ipecac in the elderly has not been adequately addressed in the past.

To compare the relative central nervous system and cardiac toxicity of amoxapine, maprotiline, and trazodone with the older tricyclic antidepressants, a three-year (1981 through 1983) retrospective review was performed on 1,313 cases involving cyclic antidepressant exposures reported to the Maryland Poison Center. Seizures were more common in the amoxapine (24.5%) and maprotiline (12.2%) groups, compared with either the tricyclic antidepressants (3.0%) or trazodone (0%) (P less than .01). A higher incidence of seizures also was observed in desipramine ingestors (17.9%) compared with other tricyclic antidepressants. No significant differences in the incidence of central nervous system depression or cardiotoxicity was found between the groups. These findings support reports of an increased incidence of seizures in overdoses of amoxapine and maprotiline, but do not substantiate claims of less cardiotoxicity.

Previous reports of lead foreign body (PbFB) ingestion by children include two cases of lead intoxication and two cases that resulted in death. It is generally accepted, however, that PbFB ingestion does not pose a risk of lead toxicity, provided that the PbFB is not retained in the gastrointestinal (GI) tract. Recent experience with two cases substantiates this belief. On separate occasions, two 9-year old girls ingested a PbFB. The first patient developed only mild, vague GI complaints. The highest reported blood lead level (BLL) was 15 mcg/dl. The second patient did not develop symptoms, and the highest reported BLL was 22 mcg/dl. Both patients passed the PbFB in the stool within two weeks. These cases suggest that PbFB ingestions can be treated in a manner similar to other uncomplicated foreign body ingestions.

To the Editor.— The toxic potential of organophosphate insecticides resides in the anticholinesterase activity of these compounds. The resulting accumulation of acetylcholine in the body causes muscarinic (increased secretions, bradycardia, miosis, and vomiting), nicotinic (muscular twitching and weakness), and CNS manifestations (anxiety, drowsiness, and depression of respiratory and circulatory centers). 1 We wish to report a case in which renal involvement occurred in addition to the typical clinical picture. Report of a Case.— On Aug 31, 1983, a 26-year-old man came to a local emergency department about one hour after ingesting an 8-oz mixture of an unknown concentration of the organophosphate insecticide dimpylate (Diazinon) in water in an apparent suicide attempt. Physical examination revealed a conscious, oriented man with vomiting, diaphoresis, bradycardia (55 beats per minute), and hypoactive bowel sounds. An initial 3-mg total dose of atropine resulted in marked improvement of symptoms. The patient was admitted to the coronary