Pros and cons to rectal administration of acetaminophen

December 2004

Acetaminophen is among the most commonly administered medications given to infants and children in the United States. Its availability over the counter and effectiveness as an antipyretic and analgesic afford acetaminophen its frequent use. Acetaminophen is available in a variety of dosage forms, including orally administered infant’s and children’s liquids and tablets. Acetaminophen, unlike ibuprofen, however, is also available in a rectal dosage form in several strengths. While the use of a rectal dosage form may offer advantages to some infants or children, such as those unable to tolerate oral medications due to emesis, rectally administered acetaminophen also requires precautions because of the potential adverse events.

The AAP published a discussion on the potential for acetaminophen toxicity in 2001. Factors affecting the unique potential for toxicity from use of acetaminophen suppositories include a wide variability in absorption and peak blood levels. The time to reach peak blood levels is longer after rectal administration as compared with orally administered acetaminophen, necessitating a longer dosing interval. Without awareness of this, caregivers have the potential of administering rectal doses too often. Additionally, even though acetaminophen suppositories are available in several pediatric strengths, caregivers may divide suppositories in an attempt to administer differing dosages. This practice may result in administration of inaccurate doses. Differing suppository bases may also affect bioavailability and additional risks for toxicity. These concerns caused the AAP to recommend that rectal dosage forms of acetaminophen generally be avoided, or used only with the acknowledgement of and assistance from health care providers.

Pharmacokinetics studies

A further analysis of the studies leading to the AAP statement is warranted. Birmingham evaluated the pharmacokinetics of acetaminophen given to 28 children aged 2 to 12 years undergoing orthopedic surgical procedures. Single doses of 10 mg/kg, 20 mg/kg and 30 mg/kg were randomly given at the start of the surgical procedure. Assuming a therapeutic range for antipyresis of 10 mg/L to 20 mg/L, a mean level within this range was obtained only with the 30 mg/kg dose, and the researchers recommended that a 40 mg/kg dose be further evaluated for efficacy. The time to a maximum blood level varied significantly, from 30 to 480 minutes, with a mean time of 210 minutes. Van Lingen studied the pharmacokinetics of rectal acetaminophen in 10 term neonates undergoing painful procedures. Four doses of 20 mg/kg were given every 6 hours. Similar to the previous study, Van Lingen found a wide variation in blood levels, with a mean value of 10.8 mg/L. Although the analgesia therapeutic range for acetaminophen is not well defined, some evidence indicates that a range of 10 mg/L to 20 mg/L can be applied. Not all infants in this study achieved blood levels within this range after administration of a 20-mg/kg dose. Wide variations were also found in the area under the curve for concentration time and for time to maximum blood level. Throughout the 24-hour dosing duration, drug accumulation was not found. A correlation between pain scoring and acetaminophen blood level was not determined. Although information from this study is useful, the small number of infants evaluated is limiting.

Cullen evaluated two differing acetaminophen suppository bases, lipophilic and hydrophilic, in 28 postoperative children (2 months to 8 years of age). This open, nonrandomized study evaluated a single 15 to 20 mg/kg dose of acetaminophen for antipyretic efficacy. Peak plasma levels were found to be significantly higher from suppositories with lipophilic bases as compared with suppositories with hydrophilic bases and correlated with greater decreases in temperature. Similar to the above studies, a wide variation in plasma levels among evaluated children was found. The published literature includes other studies evaluating the use of rectal acetaminophen, and a complete review of these studies is beyond the scope of this month’s column. The use of higher doses, up to 45 mg/kg, for perioperative analgesia has been evaluated in several studies, and results have been inconsistent. Higher rectal acetaminophen doses (15-30 mg/kg) have also been evaluated for fever and compared to an oral dose of 15 mg/kg, with no difference in outcome (Scolnik, 2001).

Educating caregivers

In summary, the pharmacokinetics of rectally administered acetaminophen are unique and deserve consideration for clinical applications. The extent of absorption from acetaminophen suppositories can vary widely among infants and children, with the potential for not achieving therapeutic blood levels. Absorption time has been shown to vary widely as well, with time to maximum absorption generally longer than anticipated from acetaminophen administered orally. These factors contribute to the longer dosing schedules and higher doses that can be found in common dosing handbooks or references. The potential exists for caregivers not to have an appreciation for these differences, possibly resulting in inappropriate dosing (doses given too often or administration of additional doses [“more is better”]).

Acetaminophen suppositories are available in several strengths: 80 mg, 120 mg, 125 mg, 300 mg, 325 mg and 650 mg. As with oral acetaminophen dosage forms, the potential for caregiver confusion over these available strengths and the administration of inappropriate doses exists. Case reports of such confusion, with resultant hepatotoxicity, have been published (eg, administration of 650-mg suppositories to an infant). Dividing acetaminophen suppositories may be inaccurate (eg, administration of one-half of a 120-mg suppository to yield a 60-mg dose).

If acetaminophen suppositories are to be administered by caregivers for fever, clinicians should additionally discuss with caregivers the therapeutic goal of antipyretic administration for most children – patient comfort, and not the attainment of a normal or specific body temperature. This may lessen the temptation by caregivers to give too many doses or inappropriately large doses.

While rectal administration of acetaminophen may offer important practical benefits to infants or children intolerant of orally administered medications, clinicians should educate caregivers on these issues and offer close follow-up.

For more information:

• Committee on Drugs, American Academy of Pediatrics. Acetaminophen toxicity in children. Pediatrics. 2001;108:1020-1024.
• Birmingham PK. Twenty-four-hour pharmacokinetics of rectal acetaminophen in children. Anesthesiology. 1997;87:244-252.
• Van Lingen RA. Multiple-dose pharmacokinetics of rectally administered acetaminophen in term infants. Clin Pharmacol Ther. 1999;66:509-515.
• Cullen S. Paracetamol suppositories; a comparative study. Arch Dis Childhood. 1989;64:1504-1505.
• Scolnik D. Comparison of oral versus normal and high-dose rectal acetaminophen in the treatment of febrile children. Pediatrics. 2002;110:553-556.

• Edward A. Bell, PharmD, BCPS, is an associate professor of pharmacy practice at Drake University College of Pharmacy, and a clinical specialist at Blank Children’s Hospital, Des Moines, Iowa.