Pharmacologic management of neonatal abstinence syndrome.

Substance abuse among pregnant women has become a national health issue. As a result of the increase in maternal consumption of illicit drugs during pregnancy, many more infants are experiencing signs and symptoms of withdrawal during the immediate newborn period. In many instances, pharmacologic management is required to alleviate the signs and symptoms of withdrawal experienced by these infants. The article provides a review of the common drugs of abuse consumed by women during pregnancy, identifies the common signs and symptoms of infant withdrawal, describes the onset and duration of these symptoms, and discusses potential pharmacologic agents that can be used to treat infant withdrawal or neonatal abstinence syndrome.

The maturation of morphine clearance and metabolism.

OBJECTIVE: To determine how early in childhood the clearance of morphine sulfate reaches that in adults. DESIGN: Patient series. SETTING: Children's Hospital and Medical Center, Seattle, Wash. PARTICIPANTS: Forty-nine children aged 1 day to 2.5 years with normal renal and hepatic function. All children were receiving a constant rate intravenous infusion of morphine for postoperative analgesia for greater than 24 hours. INTERVENTIONS: Blood and urine samples were collected during infusion and immediately after discontinuation of the morphine infusion. MEASUREMENTS: Morphine concentrations were determined and clearance was calculated using the infusion data. Half-life and volume of distribution were calculated using the postinfusion data. The formation of metabolites was evaluated using the urine data. Morphine clearance increased with age, median clearances ranging from 5 mL/kg per minute in neonates aged 1 to 7 days to 21 mL/kg per minute in infants aged 6 months and older. This change in clearance correlated with age. The formation clearance of morphine glucuronide was correlated with age, whereas the formation clearance of morphine sulfate and the renal clearance of morphine were independent of age. CONCLUSIONS: Morphine clearance reaches adult values by age 6 months to 2.5 years. In contrast to previous reports on the maturation of sulfate conjugation, it does not appear that morphine sulfate clearance is enhanced relative to glucuronidation in early infancy.

Pharmacokinetics and pharmacodynamics of morphine in infant monkeys.

We report the pharmacokinetics of morphine administered as intravenous boluses in newborn (less than 7 days) and 3- to 4-month-old macaque monkeys. Morphine was administered in a series of bolus doses until PaCO2 was elevated greater than 50 mm Hg. In newborns less than 7 days of age, a mean dose of 1.4 mg/kg was required (range 0.75-2.8 mg/kg), and in the 3-month-olds, a mean dose of 1.88 mg/kg was required (range 1.5-2.5 mg/kg). The respiratory effects measured by PaCO2 and respiratory rate did not correlate with declining serum or cerebrospinal fluid morphine levels. Both newborn and 3- to 4-month-old macaque monkeys show only mild respiratory depression after intravenous morphine, at serum concentrations as high as 300-400 ng/ml. Infant and young macaque monkeys appear to be less sensitive to the respiratory depressant effect of morphine than humans.

Age-dependent morphine partitioning between plasma and cerebrospinal fluid in monkeys.

Steady-state partitioning of morphine between blood and cerebrospinal fluid (CSF) was evaluated in pigtailed monkeys at three ages: 2-3 days, 1 month and 1 year. Protein binding of morphine to serum proteins was assessed by ultrafiltration. Newborns showed a higher CSF to plasma ratio than the 1-month- or 1-year-old monkeys (0.506 vs. 0.369 or 0.374, respectively). Protein binding of morphine was 11% in newborns, and 17% at 1 year of age, not explaining the increased morphine penetration into CSF in newborns. Increased CSF morphine is a transient finding in infant macaques, which appears to reach young adult values by 1 month of age.

Lack of effect of cimetidine on acetaminophen disposition in humans.

The effect of cimetidine administration on the disposition of acetaminophen was evaluated in seven men and six women. One gram of acetaminophen was administered to each volunteer after an overnight fast on two occasions in a balanced crossover design with and without cimetidine, 300 mg every 6 hours beginning 50 hours before acetaminophen administration and continuing for 22 hours after. N-Acetylcysteine was administered on both occasions when acetaminophen was ingested to protect against glutathione depletion. Blood samples were collected serially for 12 hours after acetaminophen administration, and total urine volume was collected for 24 hours. Fractional clearances of acetaminophen through renal and metabolic routes (sulfation, glucuronidation, 3-hydroxylation, and glutathione conjugate formation) were not altered by cimetidine administration. Studies in microsomes prepared from two human organ donors indicated that cimetidine inhibited acetaminophen reactive metabolite formation noncompetitively, with Ki values of 0.35 mmol/L and 0.32 mmol/L for the respective livers, which is 5 to 10 times the putative cimetidine concentration required for therapeutic effect.

Aminoglycoside ototoxicity in cystic fibrosis. Evaluation by high-frequency audiometry.

In this study, we sought to determine the clinical usefulness of high-frequency audiometry (8000 to 20,000 Hz) in detecting aminoglycoside-induced increases in pure-tone hearing thresholds before they are noticed in conventionally tested frequencies. We measured hearing thresholds from 250 to 20,000 Hz in 22 patients with cystic fibrosis who were treated with aminoglycosides. The audiograms were age-matched and were compared with those from 13 patients with cystic fibrosis and 38 subjects without cystic fibrosis, all of whom had never received aminoglycoside therapy. In patients with cystic fibrosis who were treated with aminoglycosides (younger than 20 years), there were statistically significant elevations only in frequencies higher than 16,000 Hz. Patients with cystic fibrosis who were treated with aminoglycosides who were 20 years and older had elevated thresholds in all frequencies tested. Patients with cystic fibrosis who were not treated with aminoglycosides did not differ statistically from controls. High-frequency audiometry may serve as a useful measure of elevation in pure-tone hearing thresholds that precede noticeable loss of auditory acuity in patients with cystic fibrosis who are receiving long-term aminoglycoside therapy.