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SPA Pain Meeting syllabus 2014 Developmental Pharmacokinetics/Pharmacodynamics of Parenteral Opiates and NSAIDS in Infants: What are the Problems? The development of microassay techniques for drug concentrations in the late 1970s and 1980s allowed investigations of the metabolism of drugs in pediatric populations. The study of pharmacokinetics (drug distribution and handling in the body-PK) in children and infants and of pharmacodynamics (the effects of drugs on the body – PD) grew as small blood/serum samples could be analyzed for drug concentrations. Computer-assisted analysis of concentration vs. time graphs facilitated computation of pharmacokinetic parameters, such as clearance, volume of distribution and elimination half-life. This information showed differences between adult drug handling and that found in children and infants, helping to explain the different effects or durations of effect seen. Applying these analyses to opiate analgesics involved many investigators including this speaker. Pharmacodynamic effects may be more complex since this involves not only pharmacokinetic factors, but factors such as access to sites of action, different receptor avidity or number which may differ in different ages, races, ethnicities or with different genetic variants linked to opiate action. To begin, I want to define some PK terms reported in most PK studies- clearance, volume of distribution and half-life. Clearance is defined as the volume (usually of blood or serum) from which drug is removed in a unit of time (L/hr, mL/min), often corrected for weight to allow comparison across pediatric groups (L/hr/kg, mL/min/kg). Volume of distribution represents the volume necessary to account for the measured concentration after a drug dose, Vd= dose/concentration. This may or may not be equal to any real volume (such as blood volume or extracellular fluid volume) but shows how widely distributed a drug is in the body or how wel a blood concentration reflects how much drug is present in the body. Small Vd is seen in drugs that don't cross cell membranes easily due to large size, ionization or extensive binding to serum proteins. Half-life is a time term (min, hr) which represents the time needed to change drug concentration by 50%. Elimination half-life, t ½, occurs due to metabolism – renal, hepatic or other pathways and excretion of unchanged drug. This talk will focus on 2 opiates used widely in pediatric anesthesia and critical care, morphine and fentanyl. Many investigators have reported studies with these agents; I have been involved in the study of morphine in infants. In 1984, we reported a group of 44 children treated with morphine infusions following cardiac surgery (1). Children were able to wean from mechanical ventilation with normal PaCO2 (during morphine infusions of 10-30 mcg/kg/hr) with [Mo]ss < 30 ng/mL. A subset of older children reported good verbal pain scores if [Mo]ss was over 12 ng/mL. Pharmacokinetic evaluation of infants and children, most following cardiac surgery, showed a pattern seen with many drugs – initial low clearance which increased to reach adult values by 6 months, a slightly higher volume of distribution and an elimination half-life which is prolonged in infants reaching adult values at 6 months (2, 3). Subsequent studies in infants having non-cardiac surgery showed the same pattern but adult morphine clearance was reached more quickly, by 1-3 months of age (4). Several of our studies focused on the respiratory effects of morphine infusions, showing those infants with [Mo]ss > 20 ng/mL had a high incidence of hypercarbia and depressed CO2 response curves slopes (5). Comparing morphine infusion to bolus dosing in postoperative infants showed acceptable analgesia in both groups with fewer scores showing pain in the infusion group (6). Four of 57 (7%) infants showed respiratory depression/hypercarbia, all in the infusion group. In all of these studies variability between infants was notable, often 3-fold. Other groups completed PK studies in similar postoperative populations and in premature infants, with similar patterns and the large inter-patient variability (7, 8, 9). Pharmacokinetic studies of fentanyl, sufentanil, alfentanil, meperidine follow the same pattern, including the between patient variability (10, 11). Age and the closely-linked weight showed an important correlation with pharmacokinetic values, with a 2-3 fold inter-patient variability in drug concentrations. The choice of morphine or fentanyl for postoperative use seems a choice made by institutional tradition rather than by major differences in effects (12). Several research groups (Knibbe, Krekels, Tibboel, Encinas, Anderson – 13-15) have done sophisticated modeling of morphine and fentanyl to improve prediction of drug dosing. These are elegant studies but a level of uncertainty remains for the clinician treating an individual infant. Current investigators, including Jimenez, Galinkin, Cohen and others who are studying the ethnic, racial, and genetic factors affecting opiate handling will help to inform this arena. In the meantime, my clinical approach is to titrate opiate doses, particularly in infants breathing spontaneously: for morphine – 0.05 mg/kg load and infusions at 5-10 mcg/kg/hr in newborns and 10-20 mcg/kg/hr in infants(lower dose in cardiac surgical babies); for fentanyl – 0.5 mcg/kg load and infusions at 1 mcg/kg/hr. This assumes one may have an infant with low clearance but does not preclude adding more if clinical signs show an inadequate response. A recent report from Taylor suggests that morphine infusion dosing does not follow clearance maturation with infusion rates plateauing at 22 mcg/kg/hr by age 5y. (16) They also note increasing variability in dosing with increasing age, suggesting other factors are at play. Many clinical studies support the use of non-opiate analgesics to augment pain relief at lower opiate doses( 17, 18). In the US, ketorolac is the only parenteral NSAID available. Ketorolac is a racemic mixture of R- and S-isomers. The S-isomer is the more potent analgesic and anti-inflammatory compound. While several groups have reported ketorolac kinetic parameters, many report composite values for the racemate (19, 20). Hamunen and Kauffman showed that these 2 isomers have different kinetics in children and adults (21, 22). We studied the stereospecific pharmacokinetics of ketorolac in infants and toddlers (23). In 6-18 month old postoperative infants and children, the S-isomer showed rapid clearance. The same pattern was seen in infants 2-6 months given a single dose following surgery (24). No changes in renal or hepatic function occurred nor was there difference in surgical drain amounts. Modeling of the PK parameters show the S-isomer is cleared with repeat dosing q 6h while the R-isomer accumulates. Unknown is whether this bears any relation to the toxicity seen with longer-term use of ketorolac. Multiple dose studies are needed. In broadening the definition of multimodal therapies, non-pharmacologic therapies have a definite but incompletely-explored role to play. The use of swaddling, non-nutritive sucking, sucrose have shown positive effects in comfort in some studies. Another modality that needs systematic study is acupuncture. A retrospective review of our experience in infants (25) showed it to be of benefit in a small number of infants without limiting side effects but much more needs to be done to establish its place in care of postoperative infants or in those requiring critical care. 1. Lynn AM, Opheim KE, Tyler DC. Morphine infusions fol owing pediatric cardiac surgery. Crit Care Med 1984; 12:863-866 2. Lynn AM, Slattery JT. Morphine pharmacokinetics in early infancy. Anesthesiol 1987; 66:136-139 3. McRorie TI, Lynn AM, Nespeca MK, Opheim KE, Slattery JT. Maturation of morphine disposition. Am J Dis Child. 1992; 146:972-976 4. Lynn AM, Nespeca MK, Bratton SL, Strauss SG, Shen DD. Clearance of morphine in postoperative infants during intravenous infusions: Influence of age and surgery. Anesth Analg 1998; 86:958-963 5. Lynn AM, Nespeca MK, Opheim KE, Slattery JT. Respiratory effects of intravenous morphine infusions in neonates, infants and children following cardiac surgery. Anesth Analg 1993; 77:695-701 6. Lynn AM, Nespeca MK, Bratton SL, Shen DD. Intravenous morphine in postoperative infants: intermittent bolus dosing versus targeted continuous infusions. Pain 2000; 88:89-95 7. Bouwmeester NJ, Anderson BJ, Tibboel D, Holford NHG. Developmental pharmacokinetics of morphine and its metabolites in neonates, infants and young children. Br J Anaesth 2004; 92: 208-217 8. Pokela ML, Olkkola KT, Seppala T, Koivisto M. Age-related morphine kinetics in infants. Dev Pharmacol Ther 1993; 20:26-34 9. Anand KJS, Anderson BJ, Holford NHG et al. Morphine pharmacokinetics and pharmacodynamics in preterm and term infants: secondary results from the NEOPAIN trial. Br J Anaesth 2008; 101: 680-689 10. Koehntop DE, Rodman JH, Brundage DM et al. Pharmacokinetics of fentanyl in neonates. Anesth Analg 1986; 65:227-232 11. Collins C, Koren G, Crean P et al. Fentanyl pharmacokinetics and hemodynamics in preterm infants during ligation of patent ductus arteriosus Anesth Analg 1985; 64:1078-1080 12. Saarenmaa E, Huttunen P, Leppaluoto J et al. Advantages of fentanyl over morphine in analgesia for ventilated newborn infants after birth: a randomized trial. J Pediatr 1999; 134:144-150 13. Krekels EHJ, DeJongh J, van Lingen RA et al. Predictive performance od a recently developed population pharmacokinetic model for morphine and its metabolites in new datasets of (preterm) neonates, infants and children. Clin Pharmacokinet 2011; 50:51-63 14. Krekels EHJ, vanHasselt GC, Tibboel D, Danhof M, Knibbe CAJ. Systematic evaluation of the descriptive and predictive performance of pediatric morphine population models. Pharm Res 2011; 28:797-811 15. Encinas E, Calvo R, Lukas JC et al. A predictive pharmacokinetic/pharmacodynamic model of fentanyl for analgesia/sedation in neonates based on a semi-physiologic approach. Pediatr Drugs 2013; 15:247-257 16. Taylor J, Liley A, Anderson BJ. The relationship between age and morphine infusion rate in children. Ped Anesth 2013; 23:40-44 17. Splinter WM, Reid CW, Roberts DJ et al. Reducing pain after inguinal hernia repair in children: caudal anesthesia versus ketorolac tromethamine. Anesthesiol 1997; 87:542-546 18. Munro HM, Walton SR, Malviya S et al. Low-dose ketorolac improves analgesia and reduces morphine requirements following posterior spinal fusion in adolescents. Can J Anaesth2002; 49:461-466 19. Olkkola KT, Maunuksela EL. The pharmacokinetics of postoperative intravenous ketorolac tromethamine in children. Br J Clin Pharmacol 1991; 31:182-184 20. Dsida RM, Wheeler M, Birmingham PK et al. Age-stratified pharmacokinetics of ketorolac tromethamine in pediatric surgical patients. Anesth Analg 2002; 94:266-270 21. Hamunen K, Maunuksela EL, Sarvela J et al. Stereoselective pharmacokinetics of ketorolac in children, adolescents and adults. Acta Anesthesiol Scand 1999; 43:1041-1046 22. Kauffman RE, Lieh-Lai MW, Uy HG et al. Enantiomer-selective pharmacokinetics and metabolism of ketorolac in children. Clin Pharmacol Ther 1999; 65:382-388 23. Lynn AM, Bradford H, Kantor ED et al. Postoperative ketorolac tromethamine use in infants aaged 6-18 months: the effect on morphinr usage, safety assessments and stereo-specific pharmacokinetics. Anesth Analg 2007; 104:1040-1051 24. Lynn AM, Bradford H, Kantor E et al. Ketorolac tromethamine: stereo-specific pharmacokinetics and single dose use in postoperative infants aged 2-6 months. Ped Anesth 2011; 21:325-334 25. Gentry KR, McGinn KL, Kundu A, Lynn AM. Acupuncture therapy for infants:a preliminary report on reasons for consultation, feasibility and tolerability. Ped Anesth 2011; 22 690-695 DEVELOPMENTAL
KINETICS/DYNAMICS OF
PARENTERAL OPIOIDS AND NSAIDS
IN INFANTS
Anne M. Lynn MD Professor, Anesthesiology and Pediatrics University of Washington Seattle Children's Hospital CONFLICT OF INTEREST
None Most drugs do not have labeling for use in infants Review with focus on infants  pharmacokinetic terms  Clearance, volume of distribution, half-life  Kinetics of morphine and fentanyl  Kinetic modeling approaches  Kinetics of ketorolac  Suggested clinical approach

Children's Hospital and Children's
Regional Medical Hospital

Morphine Pharmacokinetics in Infants, 1987 10 term infants ≤ 10 weeks Age (days)
Clearance
Half-life
(mL/kg/min) distribution
Morphine Metabolism in Infants and Toddlers, 1992 49 children, 1 day-2.5 years, post-cardiac surgery Clearance
Volume of
Half-life
(mL/kg/min)
Respiratory Effects of Morphine Infusions After Cardiac Surgery, 1993 30 neonates, infants, and children PaCO >
CO Response
Slope <
No difference in respiratory depression by age at Morphine in Post-Operative Infants: Infusion vs. Bolus Dose, 2000 N=83, infn 57, bolus 26 • Analgesia better with infusion (pain in 13% vs. 32%) • Oximetry < 90% (RA) same (2.3% vs. 2.5% of POD1) • Ventilation effects in infusion group (4/57 = 7%)  Increased PvCO in 2, desat. in 1, both in 1 • PO intake 16hrs post-op in both groups Morphine Metabolism: Effect of Age and Surgery, 1998 29 infants, clearance during infusions Age (days)
Non-Cardiac
Cardiac Surgery
Interpatient variability 2-3 fold Morphine Clearance Morphine Study Noncardiac Surgery Rate for [Mo] ss = Morphine vs. Fentanyl Neonate/Infant Analgesia  Saarenmaa, J Pediatr 1999; 134:144-50  Randomized, double-blind trial ventilated newborns  N=163 Fentanyl – 10.5 mcg/k load, infuse 1.5 mcg/k/h Morphine – 140 mcg/k load, infuse 20 No difference in HR, BP, pressor use, length ventilation, opiate bolus doses, behavioral scores during suction [Epi] and [Norepi] decreases Difference in [beta-endorphin] – lower in fentanyl fewer with decreased GI motility in fentanyl Pharmacokinetic Modeling  Population PK models use factors influencing PK variables related to age, weight as regular covariates with other covariate factors, assessing improvement of model  Weight-based allometric models incorporate weight using exponential factors(0.75 for Clearance, 1 for Volume) augmented by age-based functions, eg bili or creat.  Both models have been used for morphine and fentanyl in neonates Fentanyl Kinetics in neonates Model vs. values in literature Parameter
Model Calculated Literature Value
Value
Encinas E. Predictive PK/PD model fentanyl in neonates Pediatric drugs
2013; 15:247-57
Fentanyl modeling Opiate Dosing in Infants  Two to three-fold variability in opiate clearance and models makes individual infant dosing hard  This supports ongoing studies of ethnic, racial and genetic factors important to help individualize care  My approach is to titrate to minimize the risk to the slow metabolizing infant  Morphine 0.05 mg/kg load, then infusion 5-10 mcg/kg/hr in neonate to 10-20 mcg/kg/hr in infants  Fentanyl 0.5 mcg/kg, then infusion at 1 mcg/kg/hr Nonsteroidal anti-inflammatory drug (NSAID)  Inhibits prostaglandin synthesis  Analgesia not opiate-receptor related  Drug effects on renal, gastric mucosa, platelet function  No drug effects on respiration,  Only parenteral NSAID released in U.S. Ketorolac: Pharmacokinetics  Cyclic propionic-acid derivative  Racemic mixture, S-isomer active analgesic,anti-  Tromethamine salt to increase solubility  Adult plasma level after 30 mg:  Therapeutic range: 0.3-5 mcg/ml Ketorolac in Infants Why?  Morphine infusions give good analgesia but respiratory depression in 7% of infants.  Can using ketorolac decrease this to 0%?  Does ketorolac have an acceptable safety profile in infants? Ketorolac in Postop. Infants  Intra- or postoperative use in children decreases opiate usage Splinter WM Anesthesiol. 87:542-6; 1997 Munro HM Can J Anesth. 49:461-6; 2002  Use of NSAIDs in infants: 11% in neonates (1-30 d) to 59% in infants (3-12 deLima J BMJ. 313:787; 1996  But how to dose to maximize effect/minimize Ketorolac in Postop. Infants  Randomized, blinded, placebo-control study of ketorolac pharmacokinetics, safety and efficacy  Infants 6-18 months admitted following surgery  IRB approval/ Informed parental consent  Exclusions: History of gi bleeding or coagulopathy (infant or family) Hepatic/renal impairment Ketorolac Kinetics in Infants  Why stereo-specific kinetics?  Kauffman and Hamunen reported differences in isomer kinetics in children  Animal studies suggest the S- isomer more potent analgesic  Isomer relation to toxicity – renal, GI, hematologic unknown Ketorolac in 6-18 mon infants Ketorolac in Postop. Infants 6-18 m Ketorolac Kinetics in Infants 2-6 mo R-isomer on left, S- on right side Ketorolac in Postop. Infants  S (-) ketorolac cleared rapidly like in children  Plasma concentration below "therapeutic" by  No respiratory , renal or hepatic problems  Surprising finding of no change in morphine Pharmacokinetic – S-isomer gone quickly Other reasons – nursing care change? Care Dilemma: Another Non-Pharmacologic Option • Acupuncture – a complimentary modality  Enhances circulation of life energy (Qi)  One mechanism involves endorphin system  No drug interaction issues • Anecdotal use in 6-10 infants over past year aided in weaning ventilation and excessive sedative/opiate medications  Needs systematic study  Multimodal therapy may be a good option to minimize undesired side effects  Opiate – use low doses and titrate  Ketorolac – single dose did not cause problems, but many unknowns still for repeated doses; would S-isomer be best since clearance is rapid even in infants?  Nonpharmacologic adjuncts  Sucrose if applicable  Non-nutritive sucking/swaddling  Acupuncture

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