Comparison of rates of opioid withdrawal symptoms and reversal of opioid toxicity in patients treated with two naloxone dosing regimens: a retrospective cohort study.

INTRODUCTION: When managing opioid overdose (OD) patients, the optimal naloxone regimen should rapidly reverse respiratory depression while avoiding opioid withdrawal. Published naloxone administration guidelines have not been empirically validated and most were developed before fentanyl OD was common. In this study, rates of opioid withdrawal symptoms (OW) and reversal of opioid toxicity in patients treated with two naloxone dosing regimens were evaluated. METHODS: In this retrospective matched cohort study, health records of patients who experienced an opioid OD treated in two urban emergency departments (ED) during an ongoing fentanyl OD epidemic were reviewed. Definitions for OW and opioid reversal were developed a priori. Low dose naloxone (LDN; ≤0.15 mg) and high dose naloxone (HDN; >0.15 mg) patients were matched in a 1:4 ratio based upon initial respiratory rate (RR). The proportion of patients who developed OW and who met reversal criteria were compared between those treated initially with LDN or HDN. Odds ratios (OR) for OW and opioid reversal were obtained via logistic regression stratified by matched sets and adjusted for age, sex, pre-naloxone GCS, and presence of non-opioid drugs or alcohol. RESULTS: Eighty LDN patients were matched with 299 HDN patients. After adjustment, HDN patients were more likely than LDN patients to have OW after initial dose (OR = 8.43; 95%CI: 1.96, 36.3; p = 0.004) and after any dose (OR = 2.56; 95%CI: 1.17, 5.60; p = 0.019). HDN patients were more likely to meet reversal criteria after initial dose (OR = 2.73; 95%CI: 1.19, 6.26; p = 0.018) and after any dose (OR = 6.07; 95%CI: 1.81, 20.3; p = 0.003). CONCLUSIONS: HDN patients were more likely to have OW but also more likely to meet reversal criteria versus LDN patients.

Naloxone dosing in the era of ultra-potent opioid overdoses: a systematic review.

OBJECTIVES: Evaluate the relationship between naloxone dose (initial and cumulative) and opioid toxicity reversal and adverse events in undifferentiated and presumed fentanyl/ultra-potent opioid overdoses. METHODS: We searched Embase, MEDLINE, Cochrane Central Register of Controlled Trials, DARE, CINAHL, Science Citation Index, reference lists, toxicology websites, and conference proceedings (1972 to 2018). We included interventional, observational, and case studies/series reporting on naloxone dose and opioid toxicity reversal or adverse events in people >12 years old. RESULTS: A total of 174 studies (110 case reports/series, 57 observational, 7 interventional) with 26,660 subjects (median age 35 years; 74% male). Heterogeneity precluded meta-analysis. Where reported, we abstracted naloxone dose and proportion of patients with toxicity reversal. Among patients with presumed exposure to fentanyl/ultra-potent opioids, 56.9% (617/1,085) responded to an initial naloxone dose ≤0.4 mg compared with 80.2% (170/212) of heroin users, and 30.4% (7/23) responded to an initial naloxone dose >0.4 mg compared with 59.1% (1,434/2,428) of heroin users. Among patients who responded, median cumulative naloxone doses were higher for presumed fentanyl/ultra-potent opioids than heroin overdoses in North America, both before 2015 (fentanyl/ultra-potent opioids: 1.8 mg [interquartile interval {IQI}, 1.0, 4.0]; heroin: 0.8 mg [IQI, 0.4, 0.8]) and after 2015 (fentanyl/ultra-potent opioids: 3.4 mg [IQI, 3.0, 4.1]); heroin: 2 mg [IQI, 1.4, 2.0]). Where adverse events were reported, 11% (490/4,414) of subjects experienced withdrawal. Variable reporting, heterogeneity and poor-quality studies limit conclusions. CONCLUSIONS: Practitioners have used higher initial doses, and in some cases higher cumulative naloxone doses to reverse toxicity due to presumed fentanyl/ultra-potent opioid exposure compared with other opioids. High-quality comparative naloxone dosing studies assessing effectiveness and safety are needed.

Clinical characteristics and outcomes associated with bupropion overdose: a Canadian perspective.

Background: Therapeutic use, overdose and recreational abuse of bupropion are increasing. The purpose of this study was to describe the incidence and outcomes of bupropion exposures reported to the Ontario Poison Centre in Canada, and to identify predictors of seizures.Methods: This was a retrospective, chart review of bupropion exposures reported to the Ontario Poison Centre between 2013 and 2015. Extracted variables included demographics, formulation and dose of bupropion ingested, co-ingestants, timing of exposure, provided treatments, clinical characteristics on presentation (i.e. tachycardia, ECG changes), onset of seizures following exposure, and clinical outcomes (i.e. admission to hospital, ICU admission, intubation, death). Data were compared between patients who had a benzodiazepine co-ingestion and those that had a seizure using descriptive statistics. A multivariable logistic regression was then conducted to determine predictors of seizure.Results: In this study, there were 1,065 reported bupropion overdoses. Among patients with reported outcomes, 51.9% of patients had episodes of tachycardia, (23.9% of patients had ECG changes, and 17.3% of patients experienced a seizure. The dose of bupropion ingested was significantly associated with the odds of seizure, with a 13% increased odds of seizure for every 20 mg/kg increase in bupropion dose (Odds Ratio [OR] = 1.13, 95% CI = 1.05-1.21). Co-ingestion of benzodiazepines reduced the odds of seizure by over 60% (OR = 0.32, 95% CI = 0.15-0.69).Conclusion: Our findings contribute to the existing clinical toxicology literature by describing specific characteristics and outcomes of patients with acute bupropion overdoses. Patients were less likely to experience a seizure if they had co-ingested benzodiazepines.

Naloxone interventions in opioid overdoses: a systematic review protocol.

BACKGROUND: North America is in the midst of an unabated opioid overdose epidemic due to the increasing non-medical use of fentanyl and ultra-potent opioids. Naloxone is an effective antidote to opioid toxicity, yet its optimal dosing in the context of fentanyl and ultra-potent opioid overdoses remains unknown. This review aims to determine the relationship between the first empiric dose of naloxone and reversal of toxicity, adverse events, and the total cumulative dose required among patients with undifferentiated opioid overdoses and those with suspected toxicity from ultra-potent opioids. Secondary objectives include evaluating the relationship between the cumulative naloxone dose and toxicity reversal and adverse events, among patients with undifferentiated opioid overdoses and those with suspected toxicity from ultra-potent opioids. METHODS: To identify studies, we will search MEDLINE, Embase, CENTRAL, DARE, CDAG, CINAHL, Science Citation Index, multiple trial registries, and the gray literature. Included studies will evaluate patients with suspected or confirmed opioid toxicity from undifferentiated opioids and ultra-potent opioids, who received an empiric and possibly additional doses of naloxone. The main outcomes of interest are the relationship between naloxone dose and toxicity reversal and adverse events. We will include controlled and non-controlled interventional studies, observational studies, case reports/series, and reports from poison control centers. We will extract data and assess study quality in duplicate with discrepancies resolved by consensus or a third party. We will use the Downs and Black and Cochrane risk of bias tools for observational and randomized controlled studies. If we find sufficient variation in dose, we will fit a random effects one-stage model to estimate a dose-response relationship. We will conduct multiple subgroup analyses, including by type of opioid used and by suspected high and low prevalence of ultra-potent opioid use based on geographic location and time of the original studies. DISCUSSION: Our review will include the most up-to-date available data including ultra-potent opioids to inform the current response to the opioid epidemic, addressing the limitations of recent reviews. We anticipate limitations relating to study heterogeneity. We will disseminate study results widely to update overdose treatment guidelines and naloxone dosing in Take Home Naloxone programs.

Intermittent hypoxia reduces cerebrovascular sensitivity to isocapnic hypoxia in humans.

The purpose of this study was to determine the changes in human cerebrovascular function associated with intermittent poikilocapnic hypoxia (IH). Healthy men (n=8; 24+/-1 years) were exposed to IH for 10 days (12% O(2) for 5min followed by 5min of normoxia for 1h). During the hypoxic exposures, oxyhemoglobin saturation (SaO(2)) was 85% and the end-tidal partial pressure of CO(2) was permitted to fall as a result of hypoxic hyperventilation. Pre- and post-IH intervention subjects underwent a progressive isocapnic hypoxic test where ventilation, blood pressure, heart rate, and cerebral blood flow velocity (middle cerebral artery, transcranial Doppler) were measured to determine the ventilatory, cardiovascular and cerebrovascular sensitivities to isocapnic hypoxia. When compared to the pre-IH trial, cerebrovascular sensitivity to hypoxia significantly decreased (pre-IH=0.28+/-0.15; post-IH=0.16+/-0.14cms(-1)%SaO(2)(-1); P<0.05). No changes in ventilatory, blood pressure or heart rate sensitivity were observed (P>0.05). We have previously shown that the ability to oxygenate cerebral tissue measured using spatially resolved near infrared spectroscopy is significantly reduced following IH in healthy humans. Our collective findings indicate that intermittent hypoxia can blunt cerebrovascular regulation. Thus, it appears that intermittent hypoxia has direct cerebrovascular effects that can occur in the absence of changes to the ventilatory and neurovascular control systems.