David N. Juurlink

Facing up to the prescription opioid crisis

Deaths resulting from prescription opioids tripled in the United States between 1999 and 2007 and are also increasing in many other countries, including the United Kingdom. Irfan A Dhalla, Navindra Persaud, and David N Juurlink describe how this situation developed and propose several ways to reduce morbidity and mortality from opioids

Treatment for calcium channel blocker poisoning: A systematic review

Abstract Context. Calcium channel blocker poisoning is a common and sometimes life-threatening ingestion. Objective. To evaluate the reported effects of treatments for calcium channel blocker poisoning. The primary outcomes of interest were mortality and hemodynamic parameters. The secondary outcomes included length of stay in hospital, length of stay in intensive care unit, duration of vasopressor use, functional outcomes, and serum calcium channel blocker concentrations. Methods. Medline/Ovid, PubMed, EMBASE, Cochrane Library, TOXLINE, International pharmaceutical abstracts, Google Scholar, and the gray literature up to December 31, 2013 were searched without time restriction to identify all types of studies that examined effects of various treatments for calcium channel blocker poisoning for the outcomes of interest. The search strategy included the following Keywords: [calcium channel blockers OR calcium channel antagonist OR calcium channel blocking agent OR (amlodipine or bencyclane or bepridil or cinnarizine or felodipine or fendiline or flunarizine or gallopamil or isradipine or lidoflazine or mibefradil or nicardipine or nifedipine or nimodipine or nisoldipine or nitrendipine or prenylamine or verapamil or diltiazem)] AND [overdose OR medication errors OR poisoning OR intoxication OR toxicity OR adverse effect]. Two reviewers independently selected studies and a group of reviewers abstracted all relevant data using a pilot-tested form. A second group analyzed the risk of bias and overall quality using the STROBE (STrengthening the Reporting of OBservational studies in Epidemiology) checklist and the Thomas tool for observational studies, the Institute of Health Economics tool for Quality of Case Series, the ARRIVE (Animal Research: Reporting In Vivo Experiments) guidelines, and the modified NRCNA (National Research Council for the National Academies) list for animal studies. Qualitative synthesis was used to summarize the evidence. Of 15,577 citations identified in the initial search, 216 were selected for analysis, including 117 case reports. The kappa on the quality analysis tools was greater than 0.80 for all study types. Results. The only observational study in humans examined high-dose insulin and extracorporeal life support. The risk of bias across studies was high for all interventions and moderate to high for extracorporeal life support. High-dose insulin. High-dose insulin (bolus of 1 unit/kg followed by an infusion of 0.5–2.0 units/kg/h) was associated with improved hemodynamic parameters and lower mortality, at the risks of hypoglycemia and hypokalemia (low quality of evidence). Extracorporeal life support. Extracorporeal life support was associated with improved survival in patients with severe shock or cardiac arrest at the cost of limb ischemia, thrombosis, and bleeding (low quality of evidence). Calcium, dopamine, and norepinephrine. These agents improved hemodynamic parameters and survival without documented severe side effects (very low quality of evidence). 4-Aminopyridine. Use of 4-aminopyridine was associated with improved hemodynamic parameters and survival in animal studies, at the risk of seizures. Lipid emulsion therapy. Lipid emulsion was associated with improved hemodynamic parameters and survival in animal models of intravenous verapamil poisoning, but not in models of oral verapamil poisoning. Other studies. Studies on decontamination, atropine, glucagon, pacemakers, levosimendan, and plasma exchange reported variable results, and the methodologies used limit their interpretation. No trial was documented in humans poisoned with calcium channel blockers for Bay K8644, CGP 28932, digoxin, cyclodextrin, liposomes, bicarbonate, carnitine, fructose 1,6-diphosphate, PK 11195, or triiodothyronine. Case reports were only found for charcoal hemoperfusion, dialysis, intra-aortic balloon pump, Impella device and methylene blue. Conclusions. The treatment for calcium channel blocker poisoning is supported by low-quality evidence drawn from a heterogeneous and heavily biased literature. High-dose insulin and extracorporeal life support were the interventions supported by the strongest evidence, although the evidence is of low quality.

Extracorporeal treatment for acetaminophen poisoning: Recommendations from the EXTRIP workgroup

Abstract Background. The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup was created to provide evidence-based recommendations on the use of extracorporeal treatments (ECTR) in poisoning and the results are presented here for acetaminophen (APAP). Methods. After a systematic review of the literature, a subgroup selected and reviewed the articles and summarized clinical and toxicokinetic data in order to propose structured voting statements following a pre-determined format. A two-round modified Delphi method was chosen to reach a consensus on voting statements, and the RAND/UCLA Appropriateness Method was used to quantify disagreement. Following discussion, a second vote determined the final recommendations. Results. Twenty-four articles (1 randomized controlled trial, 1 observational study, 2 pharmacokinetic studies, and 20 case reports or case series) were identified, yielding an overall very low quality of evidence for all recommendations. Clinical data on 135 patients and toxicokinetic data on 54 patients were analyzed. Twenty-three fatalities were reviewed. The workgroup agreed that N-acetylcysteine (NAC) is the mainstay of treatment, and that ECTR is not warranted in most cases of APAP poisoning. However, given that APAP is dialyzable, the workgroup agreed that ECTR is suggested in patients with excessively large overdoses who display features of mitochondrial dysfunction. This is reflected by early development of altered mental status and severe metabolic acidosis prior to the onset of hepatic failure. Specific recommendations for ECTR include an APAP concentration over 1000 mg/L if NAC is not administered (1D), signs of mitochondrial dysfunction and an APAP concentration over 700 mg/L (4630 mmol/L) if NAC is not administered (1D) and signs of mitochondrial dysfunction and an APAP concentration over 900 mg/L (5960 mmol/L) if NAC is administered (1D). Intermittent hemodialysis (HD) is the preferred ECTR modality in APAP poisoning (1D). Conclusion. APAP is amenable to extracorporeal removal. Due to the efficacy of NAC, ECTR is reserved for rare situations when the efficacy of NAC has not been definitively demonstrated.

Comparative gastrointestinal safety of bisphosphonates in primary osteoporosis: a network meta-analysis

SummaryWe completed a network meta-analysis of published papers to compare bisphosphonate gastrointestinal safety. We found that zoledronic acid had the highest chance of causing gastrointestinal adverse events. Etidronate had the highest chance of discontinuation due to an adverse event. No difference was found for serious adverse events.IntroductionBisphosphonates are first-line treatment for osteoporosis. Gastrointestinal (GI) adverse events (AE) are the primary reason for non-adherence. Little is known about the comparative GI safety of bisphosphonates.PurposeLeverage published clinical trial data to examine the comparative GI safety of bisphosphonates.MethodsWe completed a systematic review of all English-language clinical trials that assessed bisphosphonate safety and/or efficacy in primary osteoporosis through to 2012. Randomized, blinded, and controlled studies were eligible. The primary outcome was any GI-related AE. Subanalyses were completed for upper GI symptoms, serious GI, nausea, esophageal-related events, and discontinuation due to AE. A Bayesian-based network meta-analysis was completed to allow for indirect comparisons. Results were reported as the probability that a specific drug had the highest number of events.ResultsWe identified 50 studies: 32 alendronate, 12 risedronate, 5 etidronate, and 7 zoledronic acid. Zoledronic acid had the highest probability of having the highest number of any GI AE (91xa0%) and nausea (70xa0%). Etidronate (70xa0%) and zoledronic acid (28xa0%) had the highest probability of having the greatest attrition due to AE. Etidronate had the highest probability (56xa0%) of having the greatest number of upper GI symptoms among oral bisphosphonates.ConclusionZoledronic acid had the highest probability of causing the greatest number of GI AE, possibly related to nausea. These results question the assumption that annual zoledronic acid will translate into better adherence. Little difference was found between alendronate and risedronate for serious AE. More research into real-world implications of the comparative safety of bisphosphonates is needed.

Recurrence and Mortality Following Severe Cutaneous Adverse Reactions

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening conditions. Both primarily develop as idiosyncratic responses to drugs,1 resulting in extensive epidermal detachment. Recurrence has been reported in isolated cases, and the overall risk of recurrence is unknown. Given the rarity of SJS and TEN, valid inferences about recurrence rates require the study of large populations over an extended period. We examined the long-term risk of recurrence following a first SJS or TEN episode.

Postpartum maternal codeine therapy and the risk of adverse neonatal outcomes: A retrospective cohort study

Abstract Objectives. To examine whether postpartum maternal prescription of codeine was associated with an increased risk of harm to newborns. Design. Population-based retrospective cohort study. Setting. Ontario, Canada, from April 1, 1998 to March 1, 2008. Participants. A total of 7804 mothers with publically-funded prescription drug coverage. Women who received a prescription for a codeine-containing product within 7 days following hospital discharge and their neonates were matched to 7804 mothers who did not receive codeine following delivery. Main outcome measures. The primary outcome was readmission of the neonate to hospital for any reason within 30 days. Secondary outcomes included arrival to hospital by ambulance, hospitalization for dehydration, for injury, any hospitalization involving resuscitation or assisted ventilation, and all-cause mortality. Results. We studied 7804 infants whose mothers filled a prescription for codeine shortly after delivery and 7804 whose mothers did not. In the primary analysis, infants whose mothers received codeine were no more likely to be readmitted to hospital in the subsequent 30 days than children whose mothers did not (hazard ratio 0.95, 95% confidence interval (CI) 0.81–1.11). Moreover, we found no association between maternal codeine use and the other adverse neonatal outcomes studied. A stratified analysis revealed no differential risk among infants born by Caesarian section (hazard ratio 0.86; 95% CI 0.69–1.08). Conclusions. In this large population-based study, maternal prescription of codeine following delivery was not associated with death or hospitalization in the early neonatal period.

The enigma of metformin-associated lactic acidosis.

If there was a Hall of Fame for diabetes therapies, metformin would be the second most popular attraction. In patients with Type 2 diabetes, metformin therapy is associated with not only reduced hemoglobin A1c values (the criterion upon which most oral diabetes therapies receive market authorization), but also with a reduced risk of stroke, diabetes-related death, and all-cause mortality. 1 Moreover, the drug is inexpensive, generally does not cause hypoglycemia, and is well tolerated by most patients. Like most drugs, however, metformin has a dark side: metformin-associated lactic acidosis (MALA), an uncommon and heterogenous complication of therapy that in some series is associated with high mortality. By its nature, MALA tends to invite the involvement of a toxicologist, often in the form of unexplained acidemia, even before the diagnosis is appreciated. Here, we briefl y review aspects of the disorder relevant to toxicologists.

The Burden of Opioid-Related Mortality in the United States

Key Points Question What has been the burden of opioid-related deaths in the United States over a recent 15-year period? Findings In this serial cross-sectional study, we found that the percentage of all deaths attributable to opioids increased 292% (from 0.4% to 1.5%) between 2001 and 2016, resulting in approximately 1.68 million person-years of life lost in 2016 alone (5.2 per 1000 population). The burden was particularly high among adults aged 24 to 35 years; in 2016, 20% of deaths in this age group involved opioids. Meaning Premature death from opioids imposes an enormous and growing public health burden across the United States.

Medicinal cannabis: Time to lighten up?

See related commentary on page [895][1] and at [www.cmaj.ca/lookup/doi/10.1503/cmaj.131821][2]nn“Have you ever talked to your family physician about medical marijuana?” I recently asked this question of a patient for the first time in 20 years as a physician. The novelty of it sticks with me, as

Comparison of orally administered bisphosphonate drugs in reducing the risk of hip fracture in older adults: a population-based cohort study

BACKGROUNDnOrally administered bisphosphonate drugs (i.e., alendronate, etidronate, risedronate) can reduce the risk of vertebral fracture. However, only alendronate and risedronate have proven efficacy in reducing the risk of hip fracture. We sought to examine the comparative effectiveness of orally administered bisphosphonate drugs in reducing hip fractures among older adults.nnnMETHODSnWe identified new users of orally administered bisphosphonate drugs in British Columbia and Ontario between 2001 and 2008. We used province- and sex-specific propensity score-matching strategies to maximize comparability between exposure groups. We used Cox proportional hazards models to compare time-to-hip fracture within 1 year of treatment between exposures by sex in each province. Our secondary analyses considered hip fracture rates within 2 and 3 years follow-up. We used alendronate as the reference for all comparisons and pooled provincial estimates using random effects variance-weighted meta-analysis.nnnRESULTSnWe identified 321xa0755 patients who were eligible for inclusion in the study. We found little difference in fracture rates between men (pooled hazard ratio [HR] 0.94, 95% confidence interval [CI] 0.74-1.14) or women (pooled HR 1.15, 95% CI 0.73-1.56) taking risedronate and those taking alendronate. We similarly identified little difference in fracture rates between women taking etidronate and those taking alendronate (pooled HR 1.00, 95% CI 0.82-1.18). However, we identified lower rates of hip fracture among men taking etidronate relative to alendronate (pooled HR 0.77, 95% CI 0.60-0.94). Results extended to 2 and 3 years follow-up were similar. However, with 3 years follow-up, rates of hip fracture were lower among women in British Columbia who had taken alendronate.nnnINTERPRETATIONnWe identified little overall difference between alendronate and risedronate in reducing the risk of hip fracture in men or women. Our finding that etidronate is associated with lower fracture risk among men is likely due to selection bias. The long-term comparative effects of orally administered bisphosphonate drugs warrant further study.