Acetaminophen, pain, and ICUs
For decades, acetaminophen has been regarded as the first rung of the analgesic ladder. It has a nearly unparalleled risk/benefit profile when dosed correctly (it’s not tremendously effective, but it is extraordinarily safe). Theoretically, acetaminophen should be used very broadly among critically ill patients with pain.
However, this isn’t the case. A survey of Canadian intensive care units found that 85% of patients received opioids, while only 25% received acetaminophen.1 This has been my experience as well: opioids are used broadly, whereas acetaminophen is prescribed erratically (and usually in a PRN fashion for fever, rather than a scheduled fashion for analgesia).
Why isn’t acetaminophen used more often for pain? A few possibilities may include:
- The perception that acetaminophen is ineffective, adding little to opioids.
- Concern that scheduled acetaminophen could mask fever and thereby obscure the diagnosis of infection.
- Lack of high-quality evidence that acetaminophen improves patient-centered outcomes among the critically ill.
- Concern regarding the use of acetaminophen in patients with cirrhosis or severe alcoholism.
In 2011, intravenous acetaminophen was approved by the FDA for use in the United States. It has been used in over 80 countries since 2002, but the United States was late to the party.2 The existence of an expensive form of acetaminophen was beneficial for research, because it spurred many pharma-sponsored trials of the drug.
RCTs and meta-analyses regarding intravenous acetaminophen demonstrated that it does work as an analgesic in a variety of contexts (e.g. it decreases opioid requirements).3–6 This comes as no surprise, because acetaminophen has been used as an analgesic for over half a century. Nonetheless, it is nice to see this validated in prospective, placebo-controlled RCTs.
While these studies did show that IV acetaminophen reduces opioid requirements, questions remain regarding the degree of improvement in patient-centered outcomes (e.g. nausea/vomiting). In short, is the efficacy of acetaminophen substantial enough to be clinically meaningful? (regarding question #1 above). It’s possible that acetaminophen causes a statistically significant reduction in opioid use, without yielding clinically meaningful benefit. To date, results have been somewhat conflicting.7–9 No study has carefully looked at delirium – which is a significant complication of opioid use.
This is a single-center prospective RCT evaluating different strategies for sedation and analgesia following cardiothoracic surgery.10 It has a 2×2 factorial design, where patients were randomized into one of four groups:
- Patients were randomized to receive either propofol or dexmedetomidine for up to six hours postoperatively.
- Patients were randomized to receive 1 gram acetaminophen IV q6hr for 48 hours or placebo.
Assignment of patients to the placebo vs. acetaminophen groups was blinded. However, assignment to dexmedetomidine vs. placebo couldn’t be blinded (because propofol’s white color is easily identified).
Groups were well matched at baseline, albeit equally lacking in diversity:
Results are shown below. There was no statistically significant impact of using propofol or dexmedetomidine. This may be explained by the very short duration of sedation that patients were exposed to (usually under six hours).
The primary endpoint was acetaminophen’s effect on delirium. Acetaminophen did cause a statistically and clinically significant reduction in the incidence of delirium (from 28% to 10%). A quick back-of-the-envelope calculation shows:
- p = 0.019 using Fisher’s Exact Test11
- Fragility index is 2.
- Number needed to treat (NNT) is six.
Reduction in delirium is probably explained by the reduction in opioid use among patients treated with acetaminophen (although additional mechanisms, such as reduced inflammation and antipyretic effects, are certainly possible). Among patients treated with acetaminophen, reduced delirium translated into a shorter ICU length-of-stay. Time-to-event analysis confirms these findings:
Conclusions on the DEXACET trial
This study shows that acetaminophen reduces the rate of delirium, possibly by reducing the use of opioid. Statistically this is not an extremely robust trial (with a fragility index of two).
From a Bayesian perspective, prior studies indicate that acetaminophen reduces opioid use. This makes it likely that acetaminophen would reduce delirium. Therefore, the study’s conclusions appear valid (even without definitive statistics). However, it should be recognized that this study alone constitutes only a moderate level of evidence and should ideally be replicated.12
Intravenous vs. oral acetaminophen?
Many studies (including DEXACET) are pharma-sponsored studies of IV acetaminophen. Unfortunately, IV acetaminophen is bizarrely expensive in the United States (due partially to a price hike by Mallinckrodt pharmaceuticals, its cost in the US is ~10 times higher than in Australia).13 Would oral acetaminophen work equally well?
It should, yes. Available RCTs comparing oral versus intravenous acetaminophen have detected no difference in efficacy.14–20 Perhaps in the immediate post-operative period before return of gut function, IV acetaminophen has a transient advantage. However, overall both forms seem to work equally well.
It would be great to see an RCT which shows that oral acetaminophen when used as an analgesic reduces opioid requirements and delirium in critical illness. However, it’s unclear whether anyone will ever fund such a study.
Needed research: acetaminophen-acetylcysteine combination therapy
N-acetylcysteine is available over the counter at minimal cost. It replenishes hepatic glutathione levels, therefore preventing or treating acetaminophen toxicity (more on this here). Theoretically, co-administration of acetaminophen and N-acetylcysteine could greatly reduce the risk of acetaminophen toxicity. This could allow for acetaminophen to be used in patients with cirrhosis or hepatic injury at standard doses (e.g. 4 grams daily).
The concept of co-administering acetaminophen and N-acetylcysteine is an old idea.21 In mice, pre-treatment with n-acetylcysteine prevents toxicity from even a very high acetaminophen dose.22 An RCT was designed to investigate this at Columbia University, but wasn’t completed due to logistic problems (NCT01137591).
This idea has languished due to its low cost and lack of corporate sponsorship. If successful, a study on acetylcysteine/acetaminophen (e.g. 1000 mg/1500 mg q6hr) could be more useful than yet another trial on IV acetaminophen. As we are increasingly moving away from opioids in all venues, a high-dose acetaminophen option could be welcome.23
- Acetaminophen has previously been shown to be an effective analgesic which can reduce opioid consumption.
- DEXACET shows that in a cohort of critically ill post-cardiothoracic surgery patients, IV acetaminophen reduced the incidence of delirium. This suggests that acetaminophen use may offer meaningful, patient-oriented benefit.
- Although DEXACET was performed with IV acetaminophen, other studies have found equivalent efficacy between either oral or intravenous forms.
- Acetaminophen is probably an under-utilized analgesic among critically ill patients. For maximal efficacy, oral acetaminophen should be given in substantial doses in a scheduled fashion (e.g. 1 gram q6-q8 hours scheduled, not 650 mg q8hr PRN).
- DEXACET isn’t incredibly robust statistically (fragility index of two). However, it validates longstanding principles of analgesia (specifically, the “analgesic ladder”). Until further evidence is available, it’s sensible to use these principles in clinical practice. This isn’t a revolution, but rather a reminder of first principles.
References & notes
- IBCC chapter:Guide to APRV for COVID-19 - April 8, 2020
- PulmCrit Theoretical Post – The COVID Severity Index (CSI 1.0) - April 2, 2020
- PulmCrit wee – Why the SCCM/AARC/ASA/APSF/AACN/CHEST joint statement on split ventilators is wrong. - March 29, 2020