Methadone-induced respiratory depression in the neonatal guinea pig.
Respiratory depression, the most serious side-effect of opioid treatment, is well documented for morphine, the most commonly used opioid in neonatal care. Less is known about methadone, a clinically relevant opioid analgesic, especially during neonatal development. This study was undertaken to determine the neonatal respiratory effects of methadone. We hypothesize that methadone is equipotent to morphine, compared to our previous morphine results in the same animal model, but has a much longer duration of action, due to its longer elimination half-life. Neonatal guinea pigs (3-14 days old) randomly received a single subcutaneous dose of methadone or saline. Using a non-invasive plethysmographic method, we measured ventilatory and metabolic parameters before injection and at intervals for 32 hr after injection while pups breathed "room air" or 5% CO(2) gas mixtures. Methadone-induced depression of ventilation was most evident during 5% CO(2) challenge. The onset of drug effects was within 15 min for all ages and doses, but the duration of action decreased with age. While the depth of methadone-induced respiratory depression did not depend on pup age, the control of breathing was different in 3-day-old pups, where inspiratory time increased fourfold; twice that of older pups. We conclude that methadone induces a naloxone reversible respiratory depression in guinea pig neonates and, in the very young, causes an abnormal breathing pattern due to changes in respiratory timing. Methadone is more potent than morphine with respect to neonatal respiratory depression, but surprisingly, the duration of methadone action was not longer than morphine.
Nettleton
Rosemary T
RT
Department of Physiology and Pharmacology, L334, School of Medicine, Oregon Health & Science University, Portland, Oregon 97239-3098, USA.
Ransom
Ty A
TA
Abraham
Stephanie L
SL
Nelson
Cole S
CS
Olsen
George D
GD
D000818:Animals; D000831:Animals, Newborn; D001784:Blood Gas Analysis / Q000379:methods; D001944:Breath Tests / Q000379:methods; D002245:Carbon Dioxide / Q000032:analysis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D005540:Forced Expiratory Flow Rates / Q000187:drug effects; D006168:Guinea Pigs; D007279:Injections, Subcutaneous; D007321:Inspiratory Reserve Volume / Q000187:drug effects; D008691:Methadone / Q000008:administration & dosage / Q000633:toxicity*; D009270:Naloxone / Q000627:therapeutic use; D009292:Narcotic Antagonists / Q000627:therapeutic use; D009294:Narcotics / Q000008:administration & dosage / Q000633:toxicity*; D010101:Oxygen Consumption / Q000187:drug effects; D010991:Plethysmography; D011379:Prognosis; D012131:Respiratory Insufficiency / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology
D009292:Narcotic Antagonists; D009294:Narcotics; D002245:Carbon Dioxide; D009270:Naloxone; D008691:Methadone