title: Naloxone methiodide reverses opioid-induced respiratory depression and analgesia without withdrawal.
abstract: Illicit opioid overdoses are a significant problem throughout the world, with most deaths being attributed to opioid-induced respiratory depression which may involve peripheral mechanisms. The current treatment for overdoses is naloxone hydrochloride, which is effective but induces significant withdrawal. We propose that selectively peripherally acting opioid receptor antagonists, such as naloxone methiodide, could reverse respiratory depression without inducing predominantly centrally mediated withdrawal. Acute administration of morphine (300 mg/kg, i.p.) was found to significantly depress respiratory rate and induce analgesia (P<0.0001). Both naloxone hydrochloride and naloxone methiodide were able to reverse these effects but naloxone methiodide precipitated no significant withdrawal. Naloxone methiodide was also able to reverse opioid-induced respiratory depression (P<0.001) and antinociception (P<0.01) after chronic morphine administration (300 mg/kg/day for 5 days) without inducing significant withdrawal. Therefore, peripherally selective opioid receptor antagonists should be investigated as possible treatments for opioid-induced respiratory depression which do not induce adverse effects, such as withdrawal.
authors.affiliation: Department of Clinical and Experimental Pharmacology, University of Adelaide, 5th Floor Medical School North, Adelaide, South Australia 5005, Australia. tanya.lewanowitsch@adelaide.edu.au
authors.forename: Tanya
authors.initials: T
authors.lastname: Lewanowitsch
authors.forename: Rodney J
authors.initials: RJ
authors.lastname: Irvine
mesh_terms: D000698:Analgesia / Q000379:methods; D000701:Analgesics, Opioid / Q000009:adverse effects*; D000818:Animals; D008297:Male; D051379:Mice; D009020:Morphine / Q000009:adverse effects; D009270:Naloxone / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D009292:Narcotic Antagonists; D010147:Pain Measurement / Q000187:drug effects / Q000379:methods; D000644:Quaternary Ammonium Compounds; D011957:Receptors, Opioid / Q000502:physiology; D012131:Respiratory Insufficiency / Q000139:chemically induced* / Q000188:drug therapy* / Q000503:physiopathology; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology / Q000517:prevention & control*
chemical_list: D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D000644:Quaternary Ammonium Compounds; D011957:Receptors, Opioid; D009270:Naloxone; C041269:N-methylnaloxone; D009020:Morphine