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Anesth Analg 2001;93:1626-1627
© 2001 International Anesthesia Research Society

LETTERS TO THE EDITOR

Acetaminophen Analgesia in Infants

Brian Anderson, FANZCA

Department of Anesthesia, Academisch Ziekenhuis Maastricht, The Netherlands

To the Editor:

Bremerich et al. (1) have attempted to describe the analgesic effect of acetaminophen in infants and small children. The assumption was made that analgesic effect is directly related to serum concentration. This might be true in rats (2) but not in humans. A delay of 1 h between peak serum concentration and maximum analgesia has been described in adults (3,4), and similar time delays exist for fever reduction in children (5). A T1/2keo of 1.6 h has been described for acetaminophen analgesia in children (Fig. 1) (6). Consequently, only half of the children can be expected to have an effect compartment concentrations of 10 mg/L 2 h after rectal administration 40 mg/kg. This may explain, in part, Bremerich et al.’s failure to observe any effect attributable to acetaminophen on emergence from anesthesia.



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  		Figure 1. Simulated mean serum and effect compartment concentrations after rectal acetaminophen 40 mg/kg in a 1-yr-old child. Pharmacokinetic parameter estimates were taken from Anderson et al. (6).

 
Prescott (7), in a study of 43 adult convalescent patients, reported an 80-fold range in concentrations 1 h after three 500-mg tablets. Even larger variability has been described after rectal administration in children (8). Pharmacodynamic variability is also large. The coefficient of variability for the EC50 is reported as 94% (6). The response of any one individual to rectal acetaminophen is unpredictable. Supplementation with nonsteroidal antiinflammatory drugs to improve analgesia, rather than increasing acetaminophen dose, might prove a safer option. Titrated IV opioids provide superior analgesia.

References

  1. Bremerich DH, Neidhart G, Heimann K, et al. Prophylactically-administered rectal acetaminophen does not reduce postoperative opioid requirements in infants and small children undergoing elective cleft palate repair. Anesth Analg 2001; 92: 907–12.[Abstract/Free Full Text]
  2. Granados Soto V, Flores Murrieta FJ, Lopez Munoz FJ, et al. Relationship between paracetamol plasma levels and its analgesic effect in the rat. J Pharm Pharmacol 1992; 44: 741–4.[Medline]
  3. Arendt Nielsen L, Nielsen JC, Bjerring P. Double-blind, placebo controlled comparison of paracetamol and paracetamol plus codeine–a quantitative evaluation by laser induced pain. Eur J Clin Pharmacol 1991; 40: 241–7.[ISI][Medline]
  4. Nielsen JC, Bjerring P, Arendt Nielsen L, et al. Analgesic efficacy of immediate and sustained release paracetamol and plasma concentration of paracetamol: double blind, placebo-controlled evaluation using painful laser stimulation. Eur J Clin Pharmacol 1992; 42: 261–4.[ISI][Medline]
  5. Kelley MT, Walson PD, Edge JH, et al. Pharmacokinetics and pharmacodynamics of ibuprofen isomers and acetaminophen in febrile children. Clin Pharmacol Ther 1992; 52: 181–9.[ISI][Medline]
  6. Anderson BJ, Holford NH, Woollard GA, et al. Perioperative pharmacodynamics of acetaminophen analgesia in children. Anesthesiology 1999; 90: 411–21.[ISI][Medline]
  7. Prescott LF. Gastrointestinal absorption of drugs. Med Clin North Am 1974; 58: 907–16.[Medline]
  8. Anderson BJ, Monteleone J, Holford NH. Variability of concentrations after rectal paracetamol. Paediatr Anaesth 1998; 8: 274.
 

Dorothee H. Bremerich, MD, and Gerd Neidhart, MD

Clinics of Anesthesiology, Intensive Care Medicine, and Pain Therapy, Johann Wolfgang Goethe-Universität, Frankfurt, Germany

In Response:

We appreciate the interesting comments made by Dr. Anderson regarding our recent article (1). The principle objective of our study was to determine early postoperative pain scores and opioid requirements after three different doses of prophylactically administered rectal acetaminophen (10–40 mg/kg) compared with placebo. Our study involved infants and small children undergoing elective cleft palate repair. Because the analgesic effects of acetaminophen are thought to be directly related to its plasma concentration (2), and the relationship between plasma concentration and analgesia for rectal acetaminophen has been established by Anderson et al. (3), we also measured single acetaminophen plasma concentrations at the end of surgery, which is the most important time in terms of analgesic efficacy. This time point corresponded, on average, to 123.9 min after initial suppository insertion.

The mean time to the maximum acetaminophen serum concentration in children is approximately 3.5 h (4), and we agree with Dr. Anderson that there might be a further delay between peak serum concentration and maximum analgesia achieved. Because of this well-known pharmacokinetic phenomenon, acetaminophen suppositories are commonly administered on induction of anesthesia. However, given the lack of efficacy of rectal acetaminophen in doses up to 40 mg/kg compared with placebo and the potentially delayed and erratic rectal absorption, we question whether rectal acetaminophen plays any role in postoperative pain management in infants and small children. When should the acetaminophen suppositories, in doses already far exceeding the manufacturer’s guidelines, be given to ensure timely and effective postoperative analgesia?

We acknowledge Dr. Anderson’s confirmation of our conclusion that acetaminophen absorption after rectal administration is unpredictable and bioavailability is highly variable. As demonstrated in our study, carefully titrated IV opioid boluses produce rapid and reliable postoperative pain relief in infants and small children and represent the superior clinical alternative.

References

  1. Bremerich DH, Neidhart G, Heimann K, et al. Prophylactically-administered rectal acetaminophen does not reduce postoperative opioid requirements in infants and small children undergoing elective cleft palate repair. Anesth Analg 2001; 92: 907–12.
  2. Levy G. Pharmacokinetic analysis of the analgesic effect of a single dose of acetaminophen in humans. J Pharm Sci 1987; 76: 88–9.[ISI][Medline]
  3. Anderson BJ, Holford NHG, Woolard GA, et al. Perioperative pharmacodynamics of acetaminophen analgesia in children. Anesthesiology 1999; 90: 411–21.
  4. Birmingham PK, Tobin MJ, Henthorn TK, et al. Twenty-four-hour pharmacokinetics of rectal acetaminophen in children: an old drug with new recommendations. Anesthesiology 1997; 87: 244–52.[ISI][Medline]




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press