Morphine Milligram Equivalents (MME) in children < 1 year of age
Alan Jay Schwartz, MD, MSEd, Lynne G Maxwell, MD, and Myron Yaster MD
Happy St Patrick’s Day!
Original article
Ing MC, Keane OA, Lakshmanan A, Kim E, Lee HC, Kelley-Quon LI. Opioid equipotency conversions for hospitalized infants: a systematic review. J Perinatol. 2024 Dec;44(12):1709-1718. doi: 10.1038/s41372-024-02121-z. Epub 2024 Sep 20. PMID: 39304731; PMCID: PMC11606914.
As pediatric anesthesiologists and intensivists, the management of acute and chronic pain is an essential element of the care we provide. As a young trainee (AJS) at the Children’s Hospital of Philadelphia (CHOP) in 1973, the “rule” at the time was that “morphine was the only opioid permitted to treat patients”. The rationale: everyone prescribing and administering an opioid would have one and only one choice. As a result, everyone became knowledgeable about and comfortable administering morphine. Dosing mistakes resulting from use of multiple opioids with differing potencies was completely avoided. Conversion of dose equivalents based on a standard, ie, morphine, was unnecessary. Obviously, this is no longer the case and other pure mu-opioid agonists such as fentanyl, hydromorphone, methadone, oxycodone, and hydrocodone are commonly used, indeed, oftentimes, more commonly than morphine. The decision as to which one to use is often based on the pharmacodynamics and kinetics of the drugs and when administered enterally on their oral bioavailability. In today’s PAAD, Ing et al. “performed a systematic review to identify opioid dosing conversions commonly used in hospitalized infants <1 year of age,”1
As many of you know, how opioids are prescribed and administered, particularly in ICU patients (NICU and PICU) is often chaotic with patients receiving multiple opioids in order to treat pain, reduce stress, and to produce immobility. It is not uncommon to find patients on continuous IV infusions or fentanyl, with supplemental demand/bolus doses of IV hydromorphone or morphine or more fentanyl. How to establish sanity to this chaos requires a knowledge of dosing based on morphine equivalents (MME).2,3 There are multiple published conversion tables and apps, almost all of which are based on adult and older children data, such as Opioids Dosage Conversion, Opioid Calculator (from ANZCA) (https://www.anzca.edu.au/safety-and-advocacy/opioid-calculator ), and MDcalc (https://www.mdcalc.com/calc/10170/morphine-milligram-equivalents-mme-calculator ). There are also conversion calculators built into many electronic medical records as well. All of these are available to assist you in your decision making. Unfortunately, much less is known on opioid equivalence in children < 1 year of age. Why would they be different?
Ah, “neonates are not small adults!” “Neonates and infants have distinct physiologies that contribute to their responses to analgesic medications. Infants have immature hepatic enzymatic functioning leading to decreased clearance of many drugs metabolized by the liver. Additionally, decreased glomerular filtration in the first 8 to 12 months of life leads to impaired clearance of renally excreted drugs. Neonates have larger body water composition relative to muscle and fat compartments, thus increasing the volume of distribution for water-soluble drugs. Neonates also have fewer plasma binding proteins, such that drugs with high protein binding will have an increased fraction of free drug circulating in neonates. These effects may be even more pronounced in preterm neonates. As it relates to opioids, studies have shown that both morphine and fentanyl have increased elimination half-lives in neonates.”1
“Hospitalized infants commonly receive opioids to reduce pain and minimize distress during invasive procedures. However, infant neurodevelopment is significantly impacted by cumulative and prolonged opioid exposures. While opioid conversion has been studied extensively in adults, no standardized equipotency opioid conversions exist for hospitalized infants and opioid stewardship efforts are inconsistent.”3 The review by Ing et al. was stimulated by the observation that conversion of opioids in multiple pediatric populations was based on recommendations developed for adult populations, not on empirical pharmacokinetic or pharmacodynamic studies in children, let alone neonates and infants. Their concern was that the use of these adult recommendations could result in either over or under medication (oversedation, respiratory depression or inadequate pain control) with over medication or inadequate pain control both known to be associated with subsequent adverse neurodevelopmental outcomes.4
As pointed out by Ing et al, one of the most common uses of opioid conversion tools is in the setting of opioid weaning for patients with iatrogenic exposure to opioids in the setting of prolonged treatment of pain or as a component of sedation in critically ill patients. It is also essential for changing opioids for pain management in patients with adverse reactions to the currently used opioid (e.g. irritability in infants receiving morphine, excess sedation, hyperalgesia) or desire to change from intravenous to enteral opioid. Another goal stated by Ing et al. is to provide consistency of MME reporting in studies of infant pain management or opioid weaning.
Ing and colleagues reviewed the literature to identify opioid conversion guidelines for infants< 1 year of age. They identified 14 articles which cited or calculated cumulative opioid exposure. Of note, 9 of the 14 publications employed MMEs used in adult clinical care. Surprisingly, or perhaps not surprisingly, they found that most of the conversion tables in the literature were based on adult data and not independently in neonatal/young infants studies. Thus, their conclusion stated,
“Efforts to expand safe opioid stewardship to hospitalized infants will require evidence-based consensus for opioid equipotency dose conversions which acknowledge the unique physiology of infants.”31
From the current literature and our personal experience, IV fentanyl is often said to be 80-100 times more potent than morphine. Thus, 0.1 mg/kg morphine is roughly equivalent to 0.001 mg/kg IV fentanyl (1 MICROgram/kg). In neonates the conversion may be (is?) different: It may be only 40-50 times more potent or 200 times more potent. Thus in the first few months of life, 0.1 mg/kg morphine is roughly equivalent to either 0.0005 or 0.002 mg/kg fentanyl (0.5-2 MICROgrams/kg).4 IV hydromorphone (Dilaudid) is 5 times more potent than morphine. Thus, 0.1 mg/kg morphine is equivalent to 0.02 mg/kg hydromorphone. Finally, IV methadone conversions are the most difficult to compute. If given acutely, morphine and methadone are thought to be roughly equivalent, so 0.1 mg/kg morphine = 0.1 mg/kg methadone. However, this conversion is way off in patients who have been on continuous infusions of fentanyl or morphine. A most conservative conversion in this instance is 0.1 mg/kg morphine is roughly equivalent to 0.025 mg/kg methadone.
For many reasons, fentanyl has become the go to mu-agonist opioid in anesthesia and in the ICUs. Based on what we’ve just discussed and regardless of what dose of fentanyl you choose, errors can be easily made. In the OR we recommend that when using fentanyl MICROgrams/kg be used instead of MILLIgrams/kg. Further, because fentanyl is dispensed as 50 MICROgrams/mL when used in infants < 5-10 kg, we think it should be diluted down to 10 MICROgrams/mL (2 mL fentanyl + 8 mL saline) and dosed with a 1 mL syringe.
Finally, while the focus of Ing et al. was publications about neonates and infants <1 year of age and available pharmacokinetic evidence suggests that metabolism and renal elimination of opioids reaches adult values at around 6 months of age. Thus, it is possible that using MME conversion in older infants and children may not be of concern and using adult calculators will be OK. That being said, it is probably impractical to conduct large scale studies of opioid conversion in an infant population to establish infant specific MME. It is important to remember that it is prudent to observe each patient carefully and individually when changing opioids and titrating to effect, in order to achieve safe and effective pain management or to start opioid weaning.
What MME guidelines do you use for care of pediatric patients? Does your practice environment limit the number of opioids available for treatment? Send your comments to Myron Yaster who will share them in a future reader response.
References
1. Ing MC, Keane OA, Lakshmanan A, Kim E, Lee HC, Kelley-Quon LI. Opioid equipotency conversions for hospitalized infants: a systematic review. Journal of perinatology : official journal of the California Perinatal Association 2024;44(12):1709-1718. (In eng). DOI: 10.1038/s41372-024-02121-z.
2. Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. Prescribing Opioids for Pain - The New CDC Clinical Practice Guideline. The New England journal of medicine 2022;387(22):2011-2013. (In eng). DOI: 10.1056/NEJMp2211040.
3. Dowell D, Ragan KR, Jones CM, Baldwin GT, Chou R. CDC Clinical Practice Guideline for Prescribing Opioids for Pain - United States, 2022. MMWR Recommendations and reports : Morbidity and mortality weekly report Recommendations and reports 2022;71(3):1-95. (In eng). DOI: 10.15585/mmwr.rr7103a1.
4. Saarenmaa E, Huttunen P, Leppäluoto J, Meretoja O, Fellman V. Advantages of fentanyl over morphine in analgesia for ventilated newborn infants after birth: A randomized trial. The Journal of pediatrics 1999;134(2):144-50. (In eng). DOI: 10.1016/s0022-3476(99)70407-5.