Nonopioid pain management in otolaryngology—head and neck surgery: the pharmacist’s perspective

Overview

Acetaminophen (APAP) is a nonopioid analgesic that is available without a prescription and found both individually and in a wide variety of combination products (fixed dose with other analgesics, headache remedies, sleep aids, cold and flu preparations). Its full mechanism of action is not well understood. It is believed to provide analgesic effects through inhibiting descending serotonergic pathways in the central nervous system (CNS) in addition to possible interaction with other nociceptive systems. ^, It is commonly used for mild-to-moderate pain such as headaches and myalgia. It also provides antipyretic effects through inhibition of the hypothalamic heart-regulating center. It only weakly inhibits COX-1 and COX-2 enzymes in peripheral tissues and therefore has little antiinflammatory effects.

APAP is readily orally absorbed with an onset of action and peak effects reached within 60 min depending on gastric emptying time. It is also available in intravenous (IV) form, which may provide peak effects in as little as 15 min. APAP is widely distributed throughout the body. It has a 2–3 h half-life with a 4–6 h duration of effect (antipyretic effects may last longer). It is primarily metabolized through hepatic conjugation with glucuronic acid (∼60%) and sulfuric acid (∼35%). See Table 8.1 for specific dosing recommendations.

Common adverse effects include the following: nausea, vomiting, dizziness, mild hepatic enzyme elevation, and difficulty sleeping. At higher doses, a minor toxic metabolite ( N -acetyl- p -benzoquinone or NAPQI) can accumulate when normal metabolic pathways become saturated. The accumulation of NAPQI can lead to severe hepatotoxicity and acute renal impairment. It is recommended to avoid total daily doses of APAP greater than 4000 mg or single doses greater than 1000 mg in patients with normal hepatic function to reduce the risk of toxicity. Lower dosing cutoffs should be considered in patients with mild to moderate hepatic impairment and use should be avoided in patients with severe hepatic impairment. APAP has few clinically significant drug–drug interactions.

Use in otolaryngology surgery

APAP has been utilized for surgeries as both a single analgesic and as part of a multimodal pain medication approach. There is a large controversy around whether IV APAP is superior to oral. Most of the studies involving APAP use, either preoperatively or postoperatively, include IV APAP. There are conflicting data as a whole, but the proposed benefits include lower pain scores (VAS), less narcotic use, and longer time to rescue medication, as well as less nausea and vomiting compared to other analgesics. There are many studies involving APAP use in adenoidectomies, tonsillectomies, and ESS.

Most of the evidence for APAP use in otolaryngology involves pediatric patients undergoing adenoidectomies and tonsillectomies. APAP was reviewed in three studies, two for adenotonsillectomy and one for tonsillectomy. A double-blind randomized controlled trial of a single dose of IV APAP did not reduce pain scores in pediatric patients (ages 2–8) undergoing adenotonsillectomy ( N = 239). Patients received oral midazolam, propofol, and morphine before tracheal intubation. Intraoperatively IV APAP at 15 mg/kg ( n = 118) or saline placebo ( n = 121) was administered. Faces, Legs, Activity, Cry, Consolability (FLACC) scores and rescue analgesics did not differ at any postoperative time point between groups. Results were similar in a prospective trial of pediatric patients (ages 3–17) undergoing tonsillectomy or adenotonsillectomy ( N = 260). Patients either received IV APAP intraoperatively at 15 mg/kg ( n = 131) or did not. There were no differences in FLACC scores between the two groups up to 24 h postoperatively, but more incidences of nausea and vomiting with IV APAP. Lastly, a retrospective cohort study of 166 pediatric patients (age 1–16 years) evaluated the use of IV APAP ( n = 74) compared to none as the control group ( n = 92). Patients in the APAP cohort received a single dose of 15 mg/kg before anesthesia induction. Patients who received APAP received statistically significantly less morphine compared to the control cohort. Of note, this is a retrospective design compared to the prospective design of the previous two studies and they were assessing different outcomes.

APAP has also been utilized for postoperative pain control in ESS. Two double-blind, randomized controlled trials evaluated 1000 mg of IV APAP compared to placebo in adults undergoing ESS surgery. ^, In one study, there was a trend toward lower visual analog scores (VASs) in the APAP group at 1 h postoperatively, but also a trend toward the placebo at 12 and 24 h ( N = 62). However in the next study, significantly fewer patients in the APAP group required rescue analgesia and had less incidence of severe pain ( N = 74). The APAP dosing strategies were slightly different, with patients receiving APAP before surgery and then a second dose 4 h after versus right after completion of the surgery in the first and second studies, respectively. Another randomized, double-blind study evaluated 1000 mg of IV APAP 15 min before induction (Group I, n = 20) compared to at the end of surgery (Group II, n = 19) in adult ESS patients. Postoperative VAS pain scores were statistically significantly higher in Group II up to 6 h postoperatively, and the time to first analgesic was significantly longer in Group I. With conflicting results, it is hard to determine the optimal timing of APAP. Of note, the first trial had inconclusive results within the trial, possibly making a case that APAP should be dosed before surgery and continued throughout. ^, Lastly, a prospective study evaluated oral APAP at 665 mg modified-release tablets as either a scheduled regimen of three times daily for 5 days ( n = 38) versus on an as-needed basis ( n = 40). Although there was no difference between the scheduled and as-needed group in regards to recovery (average 9–10 days), there were significantly lower pain scores in the scheduled group. If using oral medication, due to the delay in absorption and peak effect, it is beneficial to schedule the medication rather than use as needed.

APAP has also been studied in combination with other analgesics. In a randomized, double-blind study, the efficacy of APAP alone was tested against the combination of APAP with codeine in pediatric patients (ages 3–12 years) undergoing outpatient tonsillectomy and adenoidectomy ( N = 51). Patients were transitioned to either APAP 15 mg/kg ( n = 31) or APAP/codeine 1 mg/kg ( n = 20), based on codeine dose. There was no difference in postoperative pain reported by the patients. APAP has also been reported to help with goal recovery (lower rates of severe pain) when used with remifentanil in ESS patients. A meta-analysis including 23 studies of otologic surgeries (myringotomy/tympanostomy, tympanomastoid, microtia reconstruction, middle ear surgeries) concluded that combination analgesics, such as APAP and codeine provided superior analgesia, while NSAIDs and α-agonists may be monotherapy options. Caution must be taken when using codeine in pediatric patients after tonsillectomy or adenoidectomy as there is now a Black Box Warning on the combination product. Due to a subset of the population being ultrarapid metabolizers of codeine, from a Cytochrome P450 2D6 polymorphism, codeine is converted to morphine at higher levels. The Black Box Warning came after pediatric deaths occurred with the use of APAP/codeine after tonsillectomies and adenoidectomies.

Common misconceptions

As seen in the evidence presented in this section, there is conflict in the data about whether APAP should be given IV or orally when used perioperatively. In adult clinical practice, IV APAP has a specific place in therapy for a patient that cannot take APAP via an enteral route and there is significant rectal pathology or a history of sexual abuse or trauma where administering rectal APAP could cause a psychological disturbance for the patient. Patients that are neutropenic (absolute neutrophil count less than 500) and do not have enteral access would be another reason to use IV APAP. We have created this type of restriction criteria at our institution to help curb unnecessary use of IV APAP, especially in the historical setting of the significant increased cost compared to the oral and rectal suppository formulations.

As of April 2021, the cost of generic APAP IV (10 mg/mL, 100 mL bottle) is ∼$0.45 per mL. With the IV route typically dosed at 1000 mg per dose, that is almost $50 per dose, whereas an oral APAP tablet (500 mg dose per tablet) and a rectal APAP suppository (650 mg dose per suppository) are roughly the same cost as 1 mL (10 mg) of IV APAP ($0.45 per tablet or suppository). If a patient is on scheduled APAP 1000 mg every 6 h for multimodal pain management, the cost of administering this regimen via an IV route definitely adds up and can generate thousands of dollars of unnecessary yearly drug spend for a hospital.

Another question that often comes up when putting together postoperative multimodal pain regimens is how to best utilize APAP with NSAID medications in patients where both medication classes are deemed safe for use. You may have heard before that alternating timing of NSAIDs with APAP can improve the effectiveness of pain control more than taking the medications together at the same time or even alone but is there evidence to support this strategy?

A retrospective chart review described outcomes in pain relief in children who received alternating regimens of APAP and ibuprofen after tonsillectomy or adenoidectomy. Out of 583 patients that were 1–18 years of age, only 56 (9.6%) reported inadequate pain control with this regimen. Overall, the incidence of postoperative bleeding and bleeding requiring surgical intervention was low at 24 patients (4.1%) and 9 patients (1.5%), respectively. Although this review was conducted in children, it is reasonable to say an alternating regimen of APAP and ibuprofen at doses appropriate for adults would also allow for improved pain control with little risk of postoperative bleeding concerns.

In contrast, a randomized controlled trial described a combined regimen of APAP 500 mg and ibuprofen 150 mg per tablet (studying the British prescription product Maxigesic), two tablets by mouth preoperatively, and then two tablets every 6 h for up to 48 h postoperatively in patients undergoing dental molar removal. This was compared to monotherapy of either APAP 500 mg by mouth every 6 h or ibuprofen 150 mg by mouth every 6 h. Of general relevance was the secondary endpoint of global pain rating, a subjective patient report, with the favored group being the combined regimen (68.4% of patients reported “none” or “mild” pain scores compared to 37.5% of patients taking APAP alone and 54.3% of patients taking ibuprofen alone). To note, only the APAP group had a statistically significant difference compared to the combined regimen ( p = .008). Also, patients on the combined therapy required less use of rescue pain medication, though this was not statistically significant. This example shows the potential of combined APAP/ibuprofen providing greater pain control compared to monotherapy with either of these agents. Although there is little evidence looking at a combined regimen versus an alternating regimen of these two medications, from a patient adherence standpoint a combined regimen, either in a combined tablet (not available in the United States as of May 2021) or taking these medications at the same time with equal frequency, will allow for better patient medication adherence and less confusion in trying to stagger medications and higher risk of potentially exceeding recommended maximum daily doses.