Remembering the Classics: Morphine pharmacokinetics in early infancy
Anne M Lynn MD
As way of background: Dr. Anne Marie Lynn was one of the most influential women in pediatric anesthesiology of her generation. She embodies the spirit of discovery and advancement that have created the practice of pediatric anesthesiology as we know it today. A pioneer in pain medicine pharmacology, particularly morphine and ketorolac, her research transformed pediatric anesthesia, pediatric pain medicine, and pediatric intensive care medicine. Through her journal articles, book chapters, national and international lectures, mentoring of residents, fellows, and faculty, and leadership in the American Society of Anesthesiology and the Society for Pediatric Anesthesia, she inspired a generation of women and men physicians by demonstrating that gender should not be a barrier to undertaking roles once only held only by men. In 2017, for her many contributions, she was awarded the Society for Pediatric Anesthesia’s Myron Yaster lifetime achievement award. I’m lucky enough to count Anne (with an E!) Lynn (no E) as a friend and a swimming buddy at national meetings and I’ve asked her to review one of her early papers and give us the background of how it happened. Myron Yaster MD
Lynn AM, Slattery JT. Morphine Pharmacokinetics in Early Infancy. Anesthesiology 66: 136-139, 1987 PMID 3813075
Myron Yaster, Sean H Flack, Lynn D Martin, Philip G Morgan. An interview with Dr. Anne Marie Lynn, a pioneering woman in medicine. Paediatr Anaesth. 2021 Jul 22. doi: 0.1111/pan.14258. PMID: 34293231
In the late 1970s, as I finished my Pediatric residency and began my Anesthesiology training as preparation for pediatric intensive care, the standard of care in Seattle for mechanically ventilated infants and children was administration of intermittent iv doses of morphine or diazepam. Research was showing that neural pathways to transmit nociceptive (“pain”) signals were active by late second trimester in fetuses. This made not treating pain in infants due to concerns for respiratory or hemodynamic adverse effects less defensible. But information on how to accomplish pain relief safely was minimal.
The clinical dilemma: studies by Way et al.1,2 and Pediatric Anesthesia textbooks reported infants had increased respiratory depression compared to adults after morphine doses. This led to the practice of withholding all opiate and sedative medications once weaning from mechanical ventilation began in infants.
During my fellowship at Hospital for Sick Children in Toronto, I saw an alternative treatment. Low dose (10-30 mcg/kg/HOUR) continuous iv infusions of morphine were used for postoperative infants and children. Weaning from mechanical ventilation occurred without stopping the morphine infusion and arterial blood gases showed normocarbia and normal pH.
When I returned to a faculty position at the University of Washington/Children’s Orthopedic Hospital (now Seattle Children’s Hospital), I was eager to see if this protocol could be successfully replicated in Seattle.3 Initially, a study enrolled 44 children (14 months to 17 years) following cardiac surgery.4 Morphine infusions of 10-30 mcg/kg/HOUR showed that if serum morphine concentrations were less than 30 ng/mL at steady state there was not hypercarbia during weaning from mechanical ventilation or during spontaneous breathing (1 of 44 had PaCO2 elevation but many of the study patients had infusion rates adjusted if excess sedation or pain was seen, emphasizing the importance of close intensive care nursing monitoring).
The next step was to study handling of morphine in infants during the first 2 months of life when they were felt at highest risk of respiratory compromise.5 This was my first pharmacokinetic study and was possible with the help of Dr. John Slattery, then an associate professor of Pharmaceutics at the University of Washington. Funding came as one of the projects in an NIH Program Project Grant of pediatrics pharmacokinetics (PI Arnold Smith MD).
Ten term infants, mechanically ventilated and receiving intermittent iv doses of morphine had their average hourly use converted to continuous iv morphine infusion. Blood sampling for morphine concentration was done 12 hourly during infusions and then frequently for 48 hours when infusions were discontinued. Pharmacokinetic variables calculated included clearance, volume of distribution and terminal half-life.(article listed at top) The newborn group (1-7 days) showed clearances 3-4 fold lower than the older infants (17-65 days). Half-lives were 2 fold lower in the newborns than the older infants whose values were close to reported adult values. These PK differences would lead to newborns achieving higher serum morphine concentrations during infusions and longer elimination times given the same doses as older infants. This might help explain the clinical finding of prolonged respiratory depression duration after use of morphine in very young infants.
As research often does, these results generated more questions to explore. A number of further studies were done, many of which were recently summarized.3
One unforeseen result of introducing continuous iv morphine infusions to neonatal and pediatric intensive care was its enthusiastic acceptance by nurses doing the bedside care of these critically ill patients. Its use grew to include infants requiring mechanical ventilation for prolonged periods (weeks to months), requiring dose escalation as tolerance developed. Tapering doses became necessary to avoid signs of opiate withdrawal. The long-term developmental effects remain an active area of study as was recently reviewed on this forum.
Anne Lynn MD
1. Kupferberg HJ, Way EL: Pharmacologic basis for the increased sensitivity of the newborn rat to morphine. J.Pharmacol.Exp.Ther. 1963; 141: 105-109
2. Way WL, Costley EC, Way EL: Respiratory senstivity of the newborn infant to meperidine and morphine. Clin Pharmacol Ther 1965; 6: 454-461
3. Yaster M, Flack SH, Martin LD, Morgan PG: An interview with Dr. Anne Marie Lynn, a pioneering woman in medicine. Paediatr Anaesth 2021
4. Lynn AM, Opheim KE, Tyler DC: Morphine infusion after pediatric cardiac surgery. Crit.Care Med. 1984; 12: 863-866
5. Lynn AM, Slattery JT: Morphine pharmacokinetics in early infancy. Anesthesiology 1987; 66: 136-139