Rosalie Sagraves, Pharm D Associate Professor of Pharmacy Practice College of Pharmacy Adjunct Associate Professor of Pediatrics College of Medicine University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma

Pediatric

Pain Management (Part II) .

n

Nancy Lau, Pharm D This article is the second in a two-part series on pediatric pain management. It primarily contains information about the use of narcotic analgesics for pediatric patients.

0

piates are phenanthrene alkaloids derived from opium. Some common names for the opiates include narcotics, from the Greek wordNarbot&os, which means benumbing, deadening, or opioids, referring to drugs with morphine-like effects, and strong analgesics(Payne et al., 1987; Yaster & Deshpande, 1988). Although synthetic opioids such as meperidine, methadone, and the phenylpiperidines (fentanyl and its analogues) are structurally different from naturally occurring opioids (for example, morphine and codeine), they have similar actions. Opioids can be classifiedas agonists, antagonists,and mixed agonist-antagonistson the basisof receptor-binding properties (Koren & Maurice, 1989). The four major receptor groups are designated as the mu, &&a, receptors, or subkappa, and sz&ru receptors. The speciesof the mu receptors, and delta receptors are responsible for analgesia, respiratory depression, euphoria, and physical dependence; receptors are associatedwith spinal analgesia,myosis, and sedation. The SE&U receptors are responsible for adverseeffects such as dysphoria and hallucinations that are more commonly observedwhen a mixed agonist-antagonist is administered (Jaffe & Martin, 1990; Payne et al., 1987; Yaster & Deshpande, 1988). Opioid analgesicseffectively relieve pain and are con-

mu

kappa

At the time of writing this paper, Nancy Lau was a clinical instructor and postdoctoral resident in Pediatric Pharmacy at the College of Pharmacy, the University of Oklahoma Health Sciences Center and Department of Pharmacy, Children’s Hospital of Oklahoma, Oklahoma City, Oklahoma.

214

sidered the mainstay for managing most types of severe acute and chronic pain. The exact mechanismfor opioid activity is unclear, but opioids are thought to produce analgesiaby binding to opioid receptors in the brain, brainstem, and spinal cord, thus mimicking endogenous opioid peptides, known as enkephalins. Pure agonists such asmorphine, fentanyl, meperidine, and methadone have essentiallyno ceiling effect and provide increasing levels of analgesiawith increasing doses. Other opioid effects include sedation, respiratory depression,nausea, pruritus, mental clouding, decreasedintestinal motility, miosis, urinary retention, biliary spasm,cough suppression, and vasodilation (J&e & Martin, 1990; Koren & Maurice, 1989; Shannon & Berde, 1989). n

MORPHINE

Morphine is the standard for analgesiaagainst which all other opioids are compared. Its activity at delta receptors is 50 to 100 times weaker than at mu receptors, which is opposite to those of endogenous opioids (Payne et al., 1987; Yaster & Deshpande, 1988). Pharmacokinetics

Morphine is readily absorbed from the gastrointestinal tract, but it has a bioavailability of only 15% to 50% because of a high first-pass effect (Table). Several researchershave evaluatedthe pharmacokineticsof morphine in neonates(Bhat et al., 1990; Dahlstrom, Bolme, Feychting, Noack, & Paalzow, 1979; Koren et al., 1985; Lynn & Slattery, 1987; Vandenberghe,Macleod, Chinyanga, Endrenyi, & Soldin, 1983). The pharmaJOURNAL

OF PEDIATRIC

HEALTH

CARE

Journal of Pediatric Health Care

cokinetics of morphine were determined for three groups of neonates (group 1 less than 30 weeks gestation; group 2, 31 to 37 weeks gestation; and group 3, 38 to 40 weeks gestation) who were less than 5 days old and who required mechanical ventilation. The mean elimination half-life for group 1 patients was 10 ? 3.7 hours as compared with 6.7 * 4.6 hours for group 3 patients. Similarly, total body clearance for morphine was lower in group 1 patients than group 3 patients (3.4 + 3.3 ml/kg/mm versus 15.5 + 10 ml/kg/mm). Therapeutic concentrations were maintained for up to 8 hours after initial dosing in 80% of group 1 infants. For more mature infants, such concentrations were noted at 4 hours after initial dosing. Therefore, the administration of morphine every 4 to 6 hours in more than 37 weeks gestation infants should provide adequate analgesia; less frequent administration may be sufficient for group 1 infants. When morphine was administered continuously at rates of 6.2 to 40 u.g/ kg/ hr to neonates (n = 12; mean age, 9.5 days) who were born at 35 to 41 weeks gestation, the mean elimination half-life was 13.9 * 6.4 hours (Koren et al., 1985). This finding was confirmed in a study of 10 infants (newborns and three infants between the ages of 1 and 2 months) who were 36 to 41 weeks gestation at birth. The newborn infants showed prolonged mean elimination half-lives of 6.8 hours versus half-lives of 3.9 hours observed in the older infants (Lynn & Slattery, 1987). Differences in clearance may be explained by a slower elimination rate in the newborns (6.3 versus 23.8 ml/min/kg) possibly caused by immature hepatic function. The authors also noted that neonates who received morphine at 20 pg/ kg/ hr had morphine plasma concentrations three times higher than those observed in older children who received the same dose (Lynn & Slattery, 1987). These studies indicate that a maturation process of morphine metabolism takes place during early infancy. After 6 months of age, infants appear to metabolize morphine similarly to that noted for adults (Bray, Beeton, Hinton, & Seviour, 1986). Adverse Effects Morphine more than any other opioid, has been studied extensively in pediatric patients; therefore its margin of safety, as well as its rates for adverse effects, is more accurately defined. Infants less than 2 months of age are exceedingly sensitive to the respiratory depressant effects of morphine. This may occur because of altered glucuronide conjugation secondarily to an immature liver, altered brain permeability, differences in pharmacokinetics, or differences in opiate receptors (Leslie, Tso, & Hurlbut, 1982; Lloyd-Thomas, 1990; Yaster & Deshpande, 1988; Yaster et al., 1989). Purcell-Jones et al. (1988) showed that 4 of 88 neonates failed to initially wean from controlled ventilation because of opioid-in-

Pediatric

Pharmacology

215

duced respiratory depression. Children older than 1 month of age have essentially adult-like morphine pharmacodynamics, and, if dosed appropriately on a milligram per kilogram basis, they should not experience increased toxicity (Eland & Anderson, 1977). Adverse effects such as peripheral vasodilation and venous pooling are primarily caused by morphine’s histamine-releasing effects. Significant hypotension may occur if sedatives such as diazepam are concurrently administered. Otherwise, morphine has virtually no cardiovascular effects when used alone. Constipation is common because morphine (and all other narcotics at equipotent doses) inhibits intestinal smooth muscle motility, which decreases peristalsis and increases sphincter tone. Morphine should be used with caution in patients with, or at risk for, cholelithiasis because it can potentiate biliary colic by inducing a spasm in the sphincter of Oddi (Yaster & Deshpande, 1988; Yaster et al., 1989). Dosing Guidelines Morphine (or any opioid) should be titrated until the desired level of analgesia is achieved. The parenteral: oral ratio for morphine is roughtly 1: 6, but with chronic dosing the parenteral: oral ratio may be closer to 1: 3. Because morphine has a relatively short halflife, it may be administered by continuous intravenous infusion, as sustained release tablets, or as patient-controlled analgesia (Yaster & Deshpande, 1988; Yaster et al., 1989). Because neonates have longer half-lives than older children, intermittent rather than continuous intravenous infusions may s&ice. For older children, intravenous morphine doses of 10 to 30 pg/kg/hr, with a loading dose of 0.1 to 0.2 mg/kg at the beginning of the infusion, has been recommended (Bhat et al., 1990; Bray, 1983; Bray et al., 1986; Lloyd-Thomas, 1990). The use of sustained-release morphine products (for example, MS Contin, Roxanol SR) for older children and adults may increase the effectiveness of oral morphine for the treatment of chronic pain. The use of such dosage forms allows for convenient two or three times daily dosing because sustained-release forms have an 8 to 12 hour duration of effect. “Rescue doses” of regular morphine can be administered before the scheduled 8 to 12-hour interval in patients with breakthrough pain. Morphine sulfate is also available as solutions for oral administration and rectal suppositories (Beyer & Levin, 1987; Koren & Maurice, 1989; Shannon & Berde, 1989). (See the Table for further dosing information.) n

FENTANYL

Fentanyl (Sublimaze) is a frequently used narcotic analgesic, but little information is available on its use for analgesia in children (Koren & Maurice, 1989). Fentanyl is approximately 100 times more potent than morphine. Although it is structurally related to meperidine,

Volume

216

w TABLE

Comparative

analgesic and pediatric doses of commonly

ROUTE

EQU&WAlGESlC ORAL DOSE

Morphine

IV, IM PO

10 mg

60 mg

I:6

Codeine

PO

120 mg

180 mg

1 :I.5

0.2-0.4 mg/kg q4h 0.3-0.6 m&kg ql2h (for a timed-release product that may be appropriate for older children) 0.5-l mg/kg q4-6h

Meperidine

IV, IM PO

75-100 mg

150-200 mg

1 :3-4

l-l.5

Fentanyl

IV

0.125 mg

Not relevant

-

Methadone

IV, IM, PO

10 mg

lo-20 mg

1 :I-2

Adapted

from

Farrington,

IV, Intravenously; *Narcotic vary

patients. adult

doses

widely

1990;

have

references.

of these

or from

Karen

agents

unpublished

been

Doses have

& Maurice,

1989;

DDSE

& Berde,

Shannon

1989;

t’AREWD%AL: ORAL RATIO

Greene

(Ed.),

IM

ORAL

mg/kg q3-4h

0.7 mg/kg/day vided q4-6h

The Harriet Lane Handbook,

0.1-O. 15 q3-4h

mg/ kg

0.5-l mg/kg q4-6h 0.8-l .3 mg/kg q3-4h 0.5-3 @g/kg q30-60 min

di-

1991.

PO, orally.

intramuscularly;

in this table

among

Some

studies

IM,

4

1992

used opioids*

EQlJIUWALGE?X PARENTERA DQSE

DRUG

6, Number

July-AuBust

Pediatric Pharmacology

collected are not

not been

from

intended approved

a variety

of references

for neonates, for pediatric

who

and

may

use, and

represent

require

some

doses

lower

doses

typically

doses.

reported

administered

Additionally,

in the literature

to pediatric

doses may

may

be based

need

patients, modification

on extrapolation

but doses for

may

indwidual

of doses

from

experiences

it lacks hypnotic or sedative activity. It is the narcotic of choice for trauma, heart, or intensive care patients becauseof its low hemodynamic effects (Wood, 1982). Fentanyl has also been shown to prevent biochemical and endocrine stress (catabolic) response to painful stimuli (Anand, Sippell, & Aynsley-Green, 1987). Pharmacokinetics

Fentanyl and its analogues (sufentanil, alfentanil) have shorter durations of effect than morphine. They are highly lipophilic drugs that rapidly penetrate all membranes, including the blood-brain barrier. Fentanyl is rapidly eliminated from plasmaas a result of its extensive uptake by body tissues. The pharmacokinetics of fentarry1was determined in 17 patients in five age groups (group 1, 0 to 1 month; group 2, 1 month to 1 year; group 3, 1 to 5 years; group 4; 10 to 14 years; and group 5; 20 to 35 years). The total body clearancewas greater (16.2 + 2.6, 18.1 + 1.4, 11.4 +- 4.2, 7.05 rt 1.2, and 10 t 1.7 m l/kg/m& respectively), and the elimination half-lives are longer in neonates and infants (294 + 113, 233 + 137, 244 + 79, 208 2 71, and 129 ? 42 m inutes, respectively) as compared with older children and adults. The volumes of distribution were 5.94 2 1.47, 4.45 2 1.64, 3.06 ? 1.02, 1.92 + 1.04 L/kg, respectively. Because the clearance and volume of distribution of fentanyl were greater in neonates than in infants or older chil-

dren, a larger initial dose may be needed to achieve a given plasma concentration in neonates (Johnson, Erickson, Holley, & Scott, 1984). The elimination halflife is prolonged (317 m inutes; Koehntop, Rodman, Brundage, Hegland, & Buckley, 1986) in neonatesand may be even longer in preterm infants ( 17.7 + 9.3 hours; Collins et al., 1985). Hence, repeated dosing of fentanyl may lead to drug accumulation. Sufentanil and alfentanil have lower clearancesand longer half-lives in neonatesas compared with older children (Davis et al., 1989; Greenley, deBruijn, & Davis, 1987). Adverse Effects

Fentanyl and its analoguesgenerate less histamine release than morphine, thereby producing less vasodilation and pruritus. Peak respiratory depression usually occurs 5 to 15 m inutes afier an intravenous bolus. Chest wall rigidity, a serious life-threatening adverse effect, can occur after a rapid fentanyl infusion of 0.005 mg/kg or greater and may make ventilation difficult or impossible. Chest wall rigidity can be treated with muscle relaxantssuch as succinylcholine or pancuronium or with naloxone (Shannon & Berde, 1989). Dosing Guidelines

In addition to intravenous administration, fentanyl has been administered mucosally (nose drops or lollipops) and transdermally. Becauseof its high lipophilicity, the

Journal of Pediatric Health Care

Pediatric

DOSE IV COt4TINUOlJS iNFUSlON

IV 0.08-0.1

Not 0.8-l

mglkg

q2h

recommended mg/kg

q2-4h

0.5-3 &g/kg qJO-60 min

0.015-0.06

mgJkg/hr

1-5 pgJkg/hr

transdermal therapeutic systems for fentanyl (Duragesic) has the potential to provide prolonged analgesia by producing sustained blood concentrations similar to those attained by intravenous infusion. Some pharmacokinetic data and clinical effects of this system are available for adult patients but are lacking for children (Gourlay, et al., 1989). (See the Table for further dosing information.) n

MEPERIDINE

Meperidine (Demerol) is commonly used in children for anesthesia, sedation, or postoperative pain. Meperidine is also a potent antitussive. Few quantitative or pharmacologic differences exist in the production of sedation, euphoria, dysphoria, rniosis, and respiratory depression between meperidine and morphine at equianalgesic doses (Shannon & Berde, 1989; Payne et al., 1987; Yaster & Deshpande, 1988; Yaster et al., 1989). However, in equianalgesic doses, meperidine produces a lower spasmogenic effect on the biliary tree and less constipation. In neonates, it produces less respiratory depression than morphine (Way, Costley, & Way, 1965). Pharmacokinetics Meperidine is well absorbed from the gastrointestinal tract with a bioavailability between 50% and 75%. Effective analgesia begins within 15 minutes after oral administration, and peak plasma concentrations occur within 1 to 2 hours and last from 2 to 4 hours. Intramuscular administration provides a more rapid onset of analgesia (approximately 10 minutes) than does oral administration and reaches a peak effect within 1 hour.

Pharmacology

217

Meperidine is almost completely metabolized hepatitally with an elimination half-life of approximately 3 hours (adult data). Normeperidine, an active metabolite of meperidine, is a central nervous system stimulant and can produce anxiety, tremors, myoclonus, generalized seizures, and convulsions if it accumulates with repetitive morphine dosing (Payne et al., 1987; Yaster & Deshpande, 1988; Yaster et al., 1989). Normeperidine is approximately half as active as meperidine as an analgesic, but it is twice as active as a convulsant. In patients with compromised renal function, accumulation of metabolites may occur because urinary excretion is responsible for drug elimination (Payne et al., 1987). In neonates, meperidine metabolism is decreased because of the immaturity of metabolic pathways (hydrolysis, demethylation, and conjugation). The elimination half-life of meperidine in newborn infants after in utero exposure ranged from 6 to 39 hours, and the half-life of normeperidine ranged from 15 to 36 hours, which are longer than those observed in adults (Morselli & Rovei, 1980). Adverse Effects Adverse effects associated with meperidine administration are similar to those for other opioid analgesics except at high doses (toxic serum concentrations) where meperidine may produce slow waves on the electroencephalogram. Though disputed by the authors of other studies, meperidine may exert less of an effect on the biliary tract, including the common bile duct, than does morphine (Economou & Ward-McQuaid, 1971; Radnay, Brodman, Mankikar, & Duncalf, 1980). Unlike other opioids, meperidine may produce tachycardia when administered intravenously (Koren & Maurice, 1989; Payne et al., 1987). Dosing Guidelines Meperidine is an effective analgesic whether administered orally or parenterally. Although not recommended for use in the following manner, meperidine is commonly administered intramuscularly for moderate to severe pain or as part of a lytic (sedative) “cocktail” (meperidine, promethazine hydrochloride, and chlorpromazine). The former is painful, and the latter is a dangerous sedative combination (Yaster & Deshpande, 1988; Yaster et al., 1989). n

METHADONE

Methadone is a synthetic opioid used for the relief of postoperative and intractable pain. Pharmacokinetics Methadone is well absorbed from the gastrointestinal tract, with analgesia observed within 10 to 30 minutes after the administration of an oral dose. Methadone has

218

Pediatric

Volume 6, Number 4 July-August 1992

Pharmacology

the longest elimination half-life (19.2 hours) of any commonly used opiate. It provides 12 to 36 hours of analgesia after intravenous administration in children (ages 1 to 18 years), which is similar to that for adults. The drug is primarily metabolized in the liver, and metabolites are excreted in the bile and urine (Berde, Sethna, Holzman, Rudy, & Gondek, 1987; Koren & Maurice, 1989; Yaster et al., 1989). In a randomized, double-blind prospective study of children between 3 and 7 years of age (n = 35), children in the methadone group required less supplemental opioid during a 36hour postoperative period than those children receiving morphine at the same dose of 0.2 mg/kg (Berde, Holzman, Sethna, Dieherson, & Brustowicz, 1988).

Dosing

Guidelines

Oral codeine is usually prescribed in combination with acetaminophen or aspirin, which can potentiate the analgesia produced by codeine. Such a combination allows for effective analgesia with the use of less narcotic (Yaster & Deshpande, 1988; Yaster et al., 1989). n

MIXED

AGONIST-ANTAGONIST

Methadone causes less sedation, euphoria, nausea, or vomiting than morphine, fentanyl, or meperidine; and it has a longer duration of action. Hence, tolerance develops at a slower rate when compared to that for shorter acting opioids (Koren & Maurice, 1989).

As the name implies, these agents (pentazocine, butorphanol, and nalbuphine) possess both agonist and antagonist properties. They not only produce analgesia, but they also reverse opioid analgesia and can precipitate withdrawal in patients taking opioid agonists. Their advantages include less respiratory depression, sedation, biliary sphincter spasm, and abuse. They are significantly less potent analgesics and exhibit ceiling effects to analgesia. Other disadvantages of the mixed agonist-antagonists include adverse effects such as dysphoria, confusion, and hallucinations, which are dose related. For these reasons, the routine use of pentazocine cannot be recommended (Payne et al., 1987; Anon, 1978).

Dosing

. CONCLUSION

Adverse

Effects

Guidelines

Methadone can be administered either orally or intravenously, but administration requires careful titration because of its long elimination half-life (Table; Yaster et al., 1989). n

CODEINE

Codeine is used for the treatment of mild or moderate pain, usually in the outpatient setting. Its main virtue is that little stigma is attached to prescribing it for moderate pain (Shannon & Berde, 1989). Its pharmacologic effects are similar to those of morphine, and at an equipotent dose, its efficacy approaches that of morphine as an analgesic and respiratory depressant. Codeine is also a potent antitussive. Pharmacokinetics

Codeine has a bioavailability of approximately 60% to 70% after oral ingestion. It undergoes nearly complete hepatic metabolism to norcodeine (mainly) and morphine (10%) and is excreted in the urine primarily as inactive metabolites. The elimination half-life for codeine is 3 to 4 hours. Its analgesic effect is about onetenth that of morphine, possibly derived from the 10% of codeine metabolized to morphine (Koren & Maurice, 1989; Yaster & Deshpande, 1988; Yaster et al., 1989). Adverse

Effects

Adverse effects from codeine use are (in decreasing order of frequency) sedation, rash, miosis, vomiting, itching, ataxia, and skin swelling. Respiratory failure may occur with doses greater than 5 mg/kg (Koren & Maurice, 1989).

Pain management is multidimensional and may involve a combination of pain relief techniques and pharmacologic intervention. The use of opioids for analgesia has been hampered by misunderstandings and fears shared by physicians, nurses, and, in some cases, patients. A clear understanding of concepts such as tolerance, dependence, withdrawal, and addiction is essential to the proper use of opioids as analgesics. If we accept the premise that neonates do feel pain, it is surely inhuman to deny them analgesia when needed. When dealing with children who are unable to adequately communicate their sensations, health professionals have a responsibility to give adequate doses of analgesics for pain relief. Nurses must make decisions about pain management on a daily basis because of their role in pediatric health care. Hopefully, this article will enable health care providers to make more educated decisions about analgesic use and, particularly, about the need for narcotics in pediatric patients. REFERENCES Anand K. J. S., Sippell, W. G., Aynsley-Green, A. (1987). Randomized trial of fentanyl anesthesia in preterm babies undergoing surgery: effects on the stress response. Luncet, I, 62-66. Anon. (1978). Postoperative pain. British Medical Jowrnd, 2, 517518. Berde, C. B., Holzman, R. S., Sethna, N. F., Dieherson, R. B., & Brustowicz, R. M. (1988). A comparison of methadone and morphine for post-operative analgesia in children and adolescents [Abstract] Anestbesdo~, 69, A768. Berde, C. B., Sethna, N. F., Holzman, R. S., Rudy, P., & Gondek, E. J. (1987). Pharmacokinetics of methadone in children and adolescents in perioperative period [Abstract]. Anedmiulu~, 67, A1.59.

Journal of Pediatric Health Care

Beyer, J. E., & Levin, C. R. (1987). Issues and advances in pain control in children. Nursing Clinti ofNorthAmerica, 22,661-675. Bhat, R., Chari, G., Gulati, A., Aldana, O., Velamati, R., & Bhargava, H. (1990). Pharmacokinetics of a single dose of morphine in preterm infants during the first week of life. Journal of Pediatrics, 117, 477-481. Bray, R. J. (1983). Postoperative analgesia provided by morphine infusion in children. Anesthesia, 38, 1075-1078. Bray, R. J., Beeton, C., Hinton, W., Seviour, J. A. (1986). Plasma morphine levels produced by continuous infusions in children. Am&he&, 41, 753-755. Collins, C., Koren, G., Crean, I’., Klein, J., Roy, W. L., &MacLeod, S. M. (1985). Fentanyl pharmacokinetics and hemodynamic effects in preterm infants during ligation of patent ductus arteriosus. Anesthesia and Analgesia, 64, 1078-1080. Dahlstrom, B., Bohne, P., Feychting, H., Noack, G., & Paalzow, L. (1979). Morphine kinetics in children. Clinical l%u~olo~y and Therapeutiq 26, 354-365. Davis, I’. J., Wian, A., Stiller, R. L., Cook, R., Guthrie, R. D., & Scierka, A. M. ( 1989). Pharmacokinetics of alfentanil in newborn premature infants and older children. Developmental Pharmacology and Therapeutics, 13, 21-27. Economou, G., & Ward-McQuaid, J. N. (1971). A cross-over comparison of the effect of morphine, pethidine, pentazocine and phenozocine on biliary pressure. Gut, 12, 218-221. Eland, J. M., & Anderson, J. E. (1977). The experience of pain in children. In A. Jacox (Ed.). Pain: a sourcebookfw noses and orhw bealthprofercimralr (pp. 453-476). Boston: Little, Brown. Farrington, E. (1990). Drugs used in the pediatric intensive care units. In D. L. Levin (Ed.). Essentials of pediutric intensive cure. A pocket companion. St. Louis: Quality Medical Publishing, Inc. Gourlay, G. K., Kowalski, S. R., Phunmer, J. L., Cherry, D. A., Gaukroger, I?., & Cousins, M. J. (1989). The transdermal administration of fentanyl in the treatment of postoperative pain: pharmacokinetics and pharmacodynamic effects. Pain, 37, 193202. Greene, M. G. (Ed.). (1991). Drug doses. The Hawiet Lane Handbook (pp. 141-244). St. Louis: Mosby-Year Book, Inc. Greenley, W. J., deBruijn, N. P., & Davis, D. P. (1987). Sufentanil pharmacokinetics in pediatric patients. Anesthesia and Analgesia, 66, 1067-1072. Jaffe, J. H., & Martin, W. R. (1990). Opioid analgesics and antagonists. In A. Goodman Gilrnan, T. W. Rail, A. S. Niers, & P. Taylor, (Eds.). The pharmucoloogital basis of therapeutics (pp. 485521). New York: Macmillan Publishing Company. Johnson, K. L., Erickson, J. P., Halley, F. O., & Scott, J. C. (1984). Fentanyl pharmacokinetics in the pediatric population [Abstract]. Anesthesiology, 61, A44

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Koehntop, D. E., Rodman, J. H., Brundage, D. M., Hegland, M. G., & Buckley, J. J. (1986). Pharmacokinetics of fentanyl in neonates. Anesthesiology and Ana&esia, 65, 227-232. Koren, G., Butt, W., Chinyanga, H., Soldin, S., Tan, Y. K., & Pape, K. (1985). Postoperative morphine in&ion in newborn infants: assessment of disposition characteristics and safety. Jourrtal of Pediatrics, 107, 963-967. Koren, G., & Maurice, L. (1989). Pediatric uses of opioids. Pediatric Clink of Nurtb America, 36, 1141-l 156. Leslie, F. M., Tso, S., & Hurlbut, D. E. (1982). Differential appearance of opiate receptor subtypes in neonatal brain. L:> Sciences, 31, 1393-1396. Lynn, A. M., & Slattery, J. T. (1987). Morphine pharmacokinetics in early infancy. Anesthesiolgy, 66, 136-139. Lloyd-Thomas, A. R. (1990). Pain management in paediatric patients. Britijh Journal OfAnaesthesia, 64, 85-104. Morse& P. L., & Rovei, V. (1980). Placental transfer of pethidine and norpethidine and their pharmacokinetics in the newborn. European Journal of Clinical Phannatology, 18, 25-30. Payne, R., Max, M., Inturrisi, C., Rogers, A., Miser, A., Perry, S., & Kanner, R. (1987). Principles of analgesic use in the treatment of acute pain or chronic cancer pain. Clinical Phwnaq, 6, 523532. Purcell-Jones, G., Dormon, F., & Summer, E. (1988). Paediatric anaesthetists’ perceptions of neonatal and infant pain. Pain, 33, 181-187. Radnay, P. A., Brodman, E., Mankikar, D., & Duncalf, D. (1980). The effect of equianalgesic doses of fentanyl, morphine, meperidine, and pentaz.ocine on common biie duet pressure. Anuesthet&, 29, 26-29. Shannon, M., & Berde, C. B. (1989). Pharmacologic management of pain in children and adolescents. Pediatric Clinti ofNortbAmerica, 36, 855-871. Vandenberghe, H., Macleod, S., Chinyanga, H., Endrenyi, L., & Soldin, S. (1983). Pharmacokinetics of intravenous morphine in balanced anesthesia: studies in children. Drug Metabolimt Reviews, 14, 887-903. Way, W. L., Costley, E. C., & Way, E. L. (1965). Respiratory sensitivity of the newborn infant to meperidine and morphine. Clinical Phamzacology and Therape&+ 6, 454461. Wood, M. (1982). Narcotic analgesics and antagonists. In M. Wood, & A. J. J. Wood, (Eds.). ms and anesthesia: pharwuuolq~yfi Itnesthesiu&g+s (pp. 163-197). Baltimore: Williams & W&ins. Yaster, M., & Deshpande, J. K. (1988). Management of pediatric pain with opioid analgesics. Journul of Pediatric, 113, 421-429. Yaster, M., Deshpande, J. K., & Maxwell, L. G. (1989). The pharmacologic management of pain in children. Compebemive Therapy, 15, 14-26.