Are opioid receptor antagonists adequate for "Opioid" overdose in a changing reality?

WHAT IS KNOWN AND OBJECTIVE: Deaths due to opioid-induced respiratory depression (OIRD) continue to rise despite intense regulatory and professional actions. COVID-19 has only worsened this situation.1 An opioid receptor antagonist (ORA) such as naloxone is the most common intervention for OIRD. However, with increasing overdose from highly potent illicit opioids and polysubstance abuse, appraisal of the adequacy of ORA seems warranted and timely. COMMENT: OIRD results from the binding of an excess number of agonist molecules to opioid receptors. Mechanistically, it makes sense to reverse this by displacing agonist molecules by administering an ORA. But realistically, the trend to higher-potency agonists and polysubstance abuse diminishes the effectiveness of this approach. We are left facing a crisis without a solution. WHAT IS NEW AND CONCLUSION: For the increasingly common OIRD from highly potent illicit agonists and polysubstance overdose, ORAs are correspondingly less effective. Alternatives are needed-soon.

Safety and effectiveness concerns of lopinavir/ritonavir in COVID-19 affected patients: a retrospective series.

CONTEXT: Originally developed for treatment of human immunodeficiency virus (HIV), the antiviral combination lopinavir/ritonavir (LPV/r) is being repurposed for treating the novel coronavirus disease (COVID-19) despite minimal experience in this markedly different population and an in-vitro derived EC50 against SARS-CoV-2 several hundred-fold greater than for HIV. We present a case series including a case of severe hyponatremia and a 32-fold overdose raising safety and effectiveness concerns in COVID-19 patients. METHODS: We measured LPV trough concentrations in 12 patients and reviewed their clinical charts for side effects known to occur in HIV patients. FINDINGS: Compared to established LPV trough concentrations in HIV patients, concentrations in COVID-19 patients were 3-fold greater (19.37 ± 10.12 mcg/mL versus 6.25 mcg/mL). In addition, cholestasis and dyslipidemia toxicity thresholds were exceeded in 12/12 and 11/12 patients respectively. No patients achieved the presumed therapeutic concentration. Side effects included gastrointestinal symptoms (5/12), electrolyte imbalances (4/12), liver enzyme disturbances (5/12) and triglyceride elevations (2/12). CONCLUSION: No patients reached presumed therapeutic LPV concentrations despite experiencing side effects and exceeding cholestasis and dyslipidemia toxicity thresholds. This raises concerns for the safety and effectiveness of LPV/r. Clinicians should consider closely monitoring for side effects and not necessarily attribute them to COVID-19.

Relatively mild symptoms after chronic overdose with a double-dose encorafenib: a case report.

Encorafenib (Braftovi) is indicated for the treatment of adult patients with unresectable or metastatic melanoma with a BRAF V600 mutation, in combination with binimetinib (Mektovi). According to the product label of encorafenib, there are no specific treatment recommendations in case of an overdose. We report on a 63-year-old man who ingested a double dose (900 mg) of encorafenib for 16 days. He developed overall minor chronic overdose symptoms such as nausea and vomiting grade 1 and muscle pain. Based on the most occurring adverse events of encorafenib, liver values, kidney function parameters and QTc interval were measured. Kidney function parameters were normal, whereas liver values were slightly increased (grade 1) and QTc slightly prolonged. The plasma concentration 3 h after the last dose was 2110 ng/mL. We describe the course of a case with a chronic overdose during 16 days of the double dose of encorafenib as well as the followed approach, which could be taken into account when observing an encorafenib overdose. Providing information in times of Covid-19 is challenging, but remains necessary for good clinical care.

Countermeasures for Preventing and Treating Opioid Overdose.

The only medication available currently to prevent and treat opioid overdose (naloxone) was approved by the US Food and Drug Administration (FDA) nearly 50 years ago. Because of its pharmacokinetic and pharmacodynamic properties, naloxone has limited utility under some conditions and would not be effective to counteract mass casualties involving large-scale deployment of weaponized synthetic opioids. To address shortcomings of current medical countermeasures for opioid toxicity, a trans-agency scientific meeting was convened by the US National Institute of Allergy and Infectious Diseases/National Institutes of Health (NIAID/NIH) on August 6 and 7, 2019, to explore emerging alternative approaches for treating opioid overdose in the event of weaponization of synthetic opioids. The meeting was initiated by the Chemical Countermeasures Research Program (CCRP), was organized by NIAID, and was a collaboration with the National Institute on Drug Abuse/NIH (NIDA/NIH), the FDA, the Defense Threat Reduction Agency (DTRA), and the Biomedical Advanced Research and Development Authority (BARDA). This paper provides an overview of several presentations at that meeting that discussed emerging new approaches for treating opioid overdose, including the following: (1) intranasal nalmefene, a competitive, reversible opioid receptor antagonist with a longer duration of action than naloxone; (2) methocinnamox, a novel opioid receptor antagonist; (3) covalent naloxone nanoparticles; (4) serotonin (5-HT)1A receptor agonists; (5) fentanyl-binding cyclodextrin scaffolds; (6) detoxifying biomimetic "nanosponge" decoy receptors; and (7) antibody-based strategies. These approaches could also be applied to treat opioid use disorder.

Toxicity of chloroquine and hydroxychloroquine following therapeutic use or overdose.

INTRODUCTION: While chloroquine, a derivative of quinine, has been used as an antimalarial for 70 years, hydroxychloroquine is now used to treat conditions such as rheumatoid arthritis and systemic lupus erythematosus. In 2020, hydroxychloroquine (and to a lesser extent chloroquine) also received attention as a possible treatment for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). During investigation for treating coronavirus disease 2019 (COVID-19) caused by SARS-CoV-2, concerns for serious adverse events arose. OBJECTIVE: We review the toxicity associated with hydroxychloroquine and chloroquine use both short-term and long-term and in overdose. METHODS: Medline (via OVID) was searched from its inception through June 7 2020 using the following as either MeSH or keyword terms: ("Chloroquine/" or "Hydroxychloroquine/") AND ("Adverse Drug Event/" or "Toxicities, Drug/" or "Toxic.mp." or "Toxicity.mp." or "Overdose.mp."). We limited resultant articles to those published in English and reporting on Human subjects. This search yielded 330 articles, of which 57 were included. Articles were excluded due to lack of relevance, not reporting desired outcomes, or being duplicative in their content. Twenty-five additional articles were identified through screening references of included articles. To identify toxicities in individuals treated with hydroxychloroquine or chloroquine with COVID-19, we searched PubMed on June 10th, 2020: ("Chloroquine" or "Hydroxychloroquine") AND ("Coronavirus" or "COVID-19" or "SARS-CoV-2"). This search resulted in 638 articles. We reviewed articles for reporting of adverse events or toxicities. Most citations were excluded because they did not include original investigations or extrapolated data from subjects that did not have COVID-19; 34 citations were relevant. For the drug-interactions section, relevant classes and agents were identified through a screen of the https://www.covid19-druginteractions.org/ website. We then conducted targeted searches of PubMed up to June 7th 2020 combining "chloroquine" and "hydroxychloroquine" with terms for specific drug classes and drugs identified from the drug-interaction site as potentially relevant. We found 29 relevant articles. TOXICITY WITH SHORT-TERM USE: Gastrointestinal: Gastrointestinal toxicities are the most common to occur following initiation of chloroquine or hydroxychloroquine. Nausea, vomiting, and diarrhea account for most reported intolerances. Glucose abnormalities: Alterations in blood glucose concentrations may occur with hydroxychloroquine but are rare with standard therapeutic use. Cardiotoxicity: Short-term use can produce conduction abnormalities. Evidence from COVID-19 treatment suggests QT/QTc prolongation is of concern, particularly when used in combination with azithromycin, although disagreement exists across studies. Dermatologic: Drug eruptions or rashes, followed by cutaneous hyperpigmentation, pruritis, Stevens-Johnson syndrome, and toxic epidermal necrolysis, may occur within days to weeks of exposure but usually resolve with the discontinuation of therapy. Neuropsychiatric: Reported symptoms include confusion, disorientation, and hallucination within 24-48 h of drug initiation. Other toxicities: Hemolysis and anemia may occur in patients with glucose-6-phosphate dehydrogenase. Chloroquine treatment of COVID-19 was associated with elevation in creatine kinase and creatine kinase-MB activities with more events in the higher-dose group. TOXICITY WITH LONG-TERM USE: Retinopathy: Retinopathy is the major dose-limiting toxicity associated with long-term use; the risk is higher with increasing age, dose, and duration of usage. Cardiotoxicity: Long-term use has been associated with conduction abnormalities, cardiomyopathy, and valvular disorders. Neurotoxicity: Rarely myositis and muscle weakness, extremity weakness, and pseudoparkinsonism have been reported. TOXICITY IN OVERDOSE: Symptoms in overdose manifest rapidly (minutes to hours) and cardiotoxicity such as cardiovascular shock and collapse are most prominent. Neurotoxic effects such as psychosis and seizure may also occur. CONCLUSIONS: Hydroxychloroquine is a generally well-tolerated medication. Short-term (days to weeks) toxicity includes gastrointestinal effects and rarely glucose abnormalities, dermatologic reactions, and neuropsychiatric events. Cardiotoxicity became of increased concern with its use in COVID-19 patients. Long-term (years) toxicities include retinopathy, neuromyotoxicity, and cardiotoxicity (conduction abnormalities, cardiomyopathy). Deaths from overdoses most often result from cardiovascular collapse.