IV v PO acetaminophen: A randomized controlled trial
Myron Yaster MD, Rita Agarwal MD, and Lynne G Maxwell MD
First a disclosure: when IV acetaminophen was an investigational new drug, I was a paid consultant serving on the Drug Safety Monitoring Board in the original pediatric trials.(1) In those studies, IV acetaminophen’s safety and efficacy profile were outstanding and rapidly led to FDA approval. As a pediatric anesthesiologist and pain specialist, there were a lot of things I really liked about IV acetaminophen (Ofirmev®) and the original drug sponsor/developer (Cadence Pharmaceuticals). Like many of my colleagues, I thought acetaminophen was an invaluable analgesic, safer than the alternatives, really as safe as “mother’s milk”, and should be a fundamental component of anesthesia and pain management. Perhaps more importantly, Cadence and Dr. Mike Royal, the company’s Chief Medical Officer, went to great lengths to do pediatric trials and to get FDA labeling approval for this new formulation in newborns, infants, and children. As many of you know, this is a very important and unusual practice among pharmaceutical companies (see May 27th PAAD, “Why are children always last”?). In 2014 Cadence was acquired by Mallinckrodt for 1.3 billion dollars. Myron Yaster MD
Original article
Cathy R Lammers, Amy J Schwinghammer, Brent Hall, Robert Scott Kriss, Debbie A Aizenberg, Jamie L Funamura, Craig W Senders, Vinay Nittur, Richard L Applegate 2nd. Comparison of Oral Loading Dose to Intravenous Acetaminophen in Children for Analgesia After Tonsillectomy and Adenoidectomy: A Randomized Clinical Trial. Anesth Analg. 2021 Dec 1;133(6):1568-1576. PMID: 34304234
Tonsillectomy (with and without adenoidectomy) is among the most commonly performed surgical procedures performed in the U.S. Increasingly, pain management is shifting to non-opioid analgesics(2,3) and in this strategy, acetaminophen is the fundamental analgesic building block. Standard doses of acetaminophen (10-15 mg/kg every 4-6 hours, adult maximum: 90 mg/kg/day or 4,000 mg/day, for infants over one month of age to 2 years, the maximum dose is 60 mg/kg/day, and for those under 1 month the max dose is 50 mg/kg/day) and applies to both the IV and oral routes. Rectal dosing is higher (30 mg/kg q 8 hours, keeping the total maximum daily dose the same as for oral and IV routes of administration).(4) “Current research indicates no clear differences between IV and oral administration of acetaminophen in reducing postoperative pain, although onset of action may be faster with IV administration. Alternative dosing regimens of oral acetaminophen, designed to achieve higher, more reproducible plasma concentrations more quickly, have been proposed to provide better opioid-sparing effects than standard doses but no direct comparisons of oral with IV administration have been reported in children. Studies have evaluated the antipyretic, analgesic, and pharmacokinetic effects of acetaminophen loading doses (30-40 mg/kg orally) followed by standard doses or serial doses of 20 mg/kg”(5)
In this double-dummy randomized controlled trial patients received either oral acetaminophen 30 mg/kg about 1 hour preoperatively or IV acetaminophen 15 mg/kg after the induction of anesthesia with an oral or IV dummy drug depending to which arm the patient was assigned. Postoperatively, analgesia was maintained with ibuprofen 10 mg/kg every 6 hours starting 3 hours after the IV study drug and acetaminophen 15 mg/kg every 6 hours starting 6 hours after the IV study drug. Thus, all subjects received one or the other oral analgesic every 3 hours. Age appropriate pain scores and need for rescue opioids were the outcome measures. They also measured acetaminophen levels at the end of surgery and 3 hours later.
The good news: No acetaminophen levels exceeded the predefined safety threshold (40 mg/L). No difference was found in the percentage of patients with severe pain: 50.0% oral group, 47.2% IV group; relative risk of severe pain in IV 0.94; 95% CI, 0.57-1.6; P = .82. Postoperative plasma acetaminophen levels were higher in oral (18; IQR,15-21 mg/L) than IV (11; IQR, 10-13 mg/L) group (median difference 7.0; 4.0-8.0 mg/L; P = .0001).
Why should we care? IV acetaminophen costs a lot of money. We mean a lot of money! Depending on the hospital contract it costs anywhere from $28-130 a bottle. You can buy a sh*** load of oral acetaminophen for one dose of the IV product. Indeed, it is so expensive that many hospital formularies don’t allow the use of the IV formulation except in patients who are NPO and cannot be given rectal doses.
The bottom line: An oral loading dose may provide more consistent serum acetaminophen levels and equipotent analgesia at lower cost compared to the equivalent IV dose.
PS: A final comment from Myron: Many hospital/OR pharmacies will simply not allow a 30 mg/kg PO dose of acetaminophen because of the fear of acetaminophen toxicity. Indeed, they often will balk at the 30 mg/kg rectal dose! We all think this is a simple elegant study, but wish they had a ”Standard” po (15 mg/kg) acetaminophen dose arm.
References
1. Zuppa AF, Hammer GB, Barrett JS, Kenney BF, Kassir N, Mouksassi S, Royal MA. Safety and population pharmacokinetic analysis of intravenous acetaminophen in neonates, infants, children, and adolescents with pain or Fever. J Pediatr Pharmacol Ther 2011;16:246-61.
2. Franz AM, Martin LD, Liston DE, Latham GJ, Richards MJ, Low DK. In Pursuit of an Opioid-Free Pediatric Ambulatory Surgery Center: A Quality Improvement Initiative. Anesth Analg 2021;132:788-97.
3. Franz AM, Dahl JP, Huang H, Verma ST, Martin LD, Martin LD, Low DK. The development of an opioid sparing anesthesia protocol for pediatric ambulatory tonsillectomy and adenotonsillectomy surgery-A quality improvement project. Paediatr Anaesth 2019;29:682-9.
4. Birmingham PK, Tobin MJ, Henthorn TK, Fisher DM, Berkelhamer MC, Smith FA, Fanta KB, Cote CJ. Twenty-four-hour pharmacokinetics of rectal acetaminophen in children: an old drug with new recommendations. Anesthesiology 1997;87:244-52.
5. Lammers CR, Schwinghammer AJ, Hall B, Kriss RS, Aizenberg DA, Funamura JL, Senders CW, Nittur V, Applegate RL, 2nd. Comparison of Oral Loading Dose to Intravenous Acetaminophen in Children for Analgesia After Tonsillectomy and Adenoidectomy: A Randomized Clinical Trial. Anesth Analg 2021;133:1568-76.