title: The Pharmacology and Toxicology of the 'Holy Trinity'.
abstract: Combining opioids with benzodiazepines and skeletal muscle relaxants ('The Holy Trinity') has been reported to potentiate the 'high'. Through unique interactions with colocalized μ-opioid and GABAAreceptors, the combined use of these agents induces a synergistic increase in dopamine in the nucleus accumbens (NAc) and depression of respiration. The inhibition of GABA release mediated by μ1-opioid receptor activation results in a subsequent increase in dopamine in the NAc. Benzodiazepines activate the GABAAR to suppress respiration in the medullary respiratory centres. The skeletal muscle relaxant, carisoprodol, appears to bind to a unique binding domain within the GABAAR to further enhance the respiratory depressant effects of the benzodiazepines. Therefore, the opioids, the benzodiazepines and carisoprodol alone or in combination are capable of inducing respiratory depression. Current guidelines for opioid prescribing recommend against the concomitant use of benzodiazepines but do not recognize the potential risk associated with the addition of skeletal muscle relaxants.
authors.affiliation: Crystal Clinic Orthopaedic Center, Akron, OH, USA.
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Horsfall
authors.affiliation: The Ohio Attorney General's Center for the Future of Forensic Science, Bowling Green State University, Bowling Green, OH, USA.
authors.forename: Jon E
authors.initials: JE
authors.lastname: Sprague
mesh_terms: D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000009:adverse effects*; D000818:Animals; D001569:Benzodiazepines / Q000008:administration & dosage / Q000009:adverse effects*; D002328:Carisoprodol / Q000008:administration & dosage / Q000009:adverse effects*; D000075202:Contraindications; D004298:Dopamine / Q000378:metabolism; D054796:Drug Dosage Calculations; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005059:Euphoria / Q000187:drug effects*; D018757:GABA Modulators / Q000008:administration & dosage / Q000009:adverse effects*; D006801:Humans; D009465:Neuromuscular Agents / Q000008:administration & dosage / Q000009:adverse effects*; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D009293:Opioid-Related Disorders / Q000378:metabolism / Q000503:physiopathology / Q000523:psychology; D017410:Practice Guidelines as Topic; D012119:Respiration / Q000187:drug effects; D012131:Respiratory Insufficiency / Q000139:chemically induced* / Q000378:metabolism / Q000503:physiopathology; D018570:Risk Assessment; D015398:Signal Transduction / Q000187:drug effects; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D018757:GABA Modulators; D009465:Neuromuscular Agents; D001569:Benzodiazepines; D002328:Carisoprodol; D005680:gamma-Aminobutyric Acid; D004298:Dopamine