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Editorials: Editorial

“Randomization at the Expense of Relevance.” L. J. Cronbach and Intravenous Acetaminophen as an Opioid-Sparing Adjuvant

Nelson, Ariana M. MD*; Wu, Christopher L. MD

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doi: 10.1213/ANE.0000000000003577
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The impact our field has on the opioid epidemic extends beyond the anesthesiologist writing prescriptions in an outpatient pain clinic. Many patients initiate opioid therapy after surgery, and higher postoperative opioid doses are associated with increased incidence of chronic opioid use.1 This renders anesthesiologists staffing operating rooms (ORs) and acute pain services an initial line of defense against long-term opioid use. Anesthesia providers achieve this goal while maintaining patient comfort by using multimodal analgesia with opioid-sparing analgesics. These adjuvants are used in the OR and in enhanced recovery after surgery protocols, which are currently in development at many institutions. In this editorial, we focus on intravenous acetaminophen (ivAPAP) as there is genuine scientific uncertainty regarding its opioid-sparing efficacy.

To evaluate use of ivAPAP in inpatients, Morwald et al2 used the Premier Perspective database to retrospectively elucidate the impact of ivAPAP on postoperative opioid use and side effects in over 117,000 spine surgeries. Their study did not show meaningful reduction in opioid use with the addition of ivAPAP, a finding echoed in other retrospective investigations,3–5 and 3 placebo-based randomized controlled trials (RCTs).6–8 Additionally, 1 study showed ivAPAP’s opioid-sparing effect was inferior to an anti-inflammatory9 and another RCT was inconclusive.10 In contrast, 4 RCTs11–15 showed ivAPAP does have an opioid-sparing effect. Therefore, the existing literature on the topic balances out to near-perfect ambivalence.

Further complicating the question of ivAPAP’s potential utility, many investigations attest that acetaminophen is as effective orally as it is through the IV route.16–18 However, this may not hold true when acetaminophen is used as an opioid-sparing adjuvant. Administering oral but not IV acetaminophen alongside morphine may decrease analgesia, due to oral acetaminophen’s pharmacokinetic variability in morphine-exposed subjects.19 This challenges the conventional wisdom that a patient-tolerating oral intake should ingest all analgesics orally, but additional research is needed.

Finally, outside of physiologic barriers to use, many hospitals have established administrative barriers, typically as a cost-saving measure. For example, in one author’s current and former institutions, although the OR anesthesiologist may administer ivAPAP ad lib, a dedicated consult and subsequent approval from the acute pain service is required before administering it on the hospital floor. Other hospitals may include ivAPAP on their enhanced recovery after surgery protocols but only in limited quantity, as is the case in another author’s institution, where ivAPAP is restricted to 2 doses. Although possibly more expensive in the short term, ivAPAP may be a worthwhile investment if it reduces opioid consumption that results in tangible benefits such as decreased length of stay, increased patient satisfaction, and decreased postdischarge opioid use.20–23 However, we do not yet know for certain if ivAPAP improves any of these outcomes.

Fiscal considerations aside, it is challenging to interpret the conflicting results regarding ivAPAP’s opioid-sparing effect. Although RCTs have long been considered the gold standard for evidence-based medicine, they often lack external validity, that is, they do not reflect real-world health care. For example, RCTs evaluating ivAPAP generated conflicting results, likely due to the variable degree of postoperative pain for a given patient population. Patients with high-postoperative opioid requirements (eg, chronic pain patients, patients after extensive abdominal surgery, etc) may show clinically evident benefit from ivAPAP, but an opioid-naïve patient after a craniotomy will show no difference in opioid consumption.8 The Memtsoudis group’s retrospective trial2 in this edition of Anesthesia& Analgesia suggests that IV acetaminophen is ineffective when evaluated within the milieu of perioperative variables. Yet like all retrospective trials, it is likely influenced by bias. It is probable that patients predicted to have higher pain scores and thus higher postoperative opioid-requirement were more likely to receive ivAPAP. Therefore, the question remains: does ivAPAP reduce opioid requirements?

Strategies to minimize opioid use while maintaining adequate analgesia are desperately needed but ivAPAP should only be used if it is actually effective. Retrospective studies similar to the Morwald et al2 publication have found no opioid-sparing effect with the use of perioperative ivAPAP.3–5 In contrast, available RCTs on average demonstrate a modicum of opioid reduction with use of ivAPAP, but meta-analyses have acknowledged that these findings are not robust.14,24 In the short term, reducing immediate postoperative opioid use is one of the few moments in which physicians can potentially impact patients’ risk for future chronic opioid therapy. The long-term implications are even more substantial as the opioid-sparing medications we choose to endorse or reject in recovery after surgery protocols may shape the course of the opioid epidemic. Physicians cannot make this decision with confidence in the case of ivAPAP because they do not have access to reliable study results, and it is vitally important that they do. Although we valorize the RCT, this study design cannot control for the myriad variables of the complex perioperative environment. Well-conducted prospective studies are required to overcome this barrier and conclusively determine the true opioid-sparing potential of ivAPAP in a clinically relevant setting. However, as we await the results of investigations that we expect will be more illustrative of the true benefit of ivAPAP, clinical anesthesiologists require a recommendation. We feel the preponderance of evidence from RCTs favors an opioid-sparing effect and therefore ivAPAP should be administered to patients that are at an elevated risk for chronic opioid use after surgery. Even if the opioid-sparing effect is modest, every little adjuvant helps.


Name: Ariana M. Nelson, MD.

Contribution: This author helped interpret the available data, conceive the editorial design, and write the manuscript.

Name: Christopher L. Wu, MD.

Contribution: This author helped interpret the available data, conceive the editorial design, and write the manuscript.

This manuscript was handled by: Honorio T. Benzon, MD.


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