Tylenol: 6 More Years of Failure

I wrote about the efficacy, mostly the lack thereof, of Tylenol (aka, acetaminophen, paracetamol) back in 2017 using reviews from the highly-regarded Cochrane Library. Briefly, the findings showed that acetaminophen:

• Is ineffective against pain from knee and hip arthritis.
• Is no more effective than a placebo for acute and chronic lower back pain.
• Is effective in reducing headache pain but only 10% more so than a placebo.
• Probably does not relieve cold symptoms.
• Augments the analgesic properties of ibuprofen in controlling pain following wisdom tooth extraction.
• Is effective in lowering fever in children.

Since Then

Tylenol is a 75-year-old drug. Could there be any significant, more recent reviews about the drug's efficacy in the past six years? Yes, there are. Following is a discussion of five high-quality publications, primarily reviews, that have appeared in the literature since then. 

1. IV Acetaminophen and Opioid-Sparing (2020) - "Evidence for the Efficacy of an Opioid-Sparing Effect of Intravenous Acetaminophen in the Surgery Patient: A Systematic Review." Pain Medicine,  Volume 21, Issue 12, 2020. 

Hillerman et al. examined whether intravenous acetaminophen could reduce the need for opioids (opioid-sparing) following a variety of surgeries. Criteria for inclusion in the review included:

• Randomized, double-blind controlled trials
• Publication in a peer-reviewed journal (written in English)
• Use of both IV acetaminophen and placebo in the trials

Findings

The group evaluated 44 treatment cohorts included in 37 studies and found that IV acetaminophen produced a statistically significant opioid-sparing effect in 14 of 44 cohorts (32%), but opioid-sparing was more common in placebo-controlled comparisons (46%). In other words, the IV acetaminophen did nothing to spare patients from the need for opioids.

Perhaps worse, "among the 16 active-control groups, opioid consumption was significantly greater with IV acetaminophen than the active comparator in seven cohorts and not significantly different than the active comparator in eight cohorts." We are obviously seeing a statistical abnormality here. For all its faults, acetaminophen doesn't increase pain; it just fails to treat it adequately. 

The Hillerman group concluded: [emphasis mine]

The results of this systematic analysis demonstrate that IV acetaminophen is not effective in reducing opioid consumption compared with other adjuvant analgesic agents in the postoperative patient. In patients where other adjuvant analgesic agents are contraindicated, IV acetaminophen may be an option.

But I wonder about the last sentence. If IV acetaminophen is not effective enough to permit lower doses of opioids or treat any significant pain, why give it at all? After all, it's not a benign drug. 

2. Pain relief (2021) "The efficacy and safety of paracetamol for pain relief: an overview of systematic reviews," Medical Journal of Australia

In this review, Shaheed et al. studied systematic reviews of the analgesic effects of acetaminophen in randomized, placebo-controlled trials, focusing on systematic reviews with a high quality of evidence as judged by Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria.

Findings

♦ Arthritis - Acetaminophen provides modest pain relief of pain from knee or hip osteoarthritis (0.3 points on a scale of 1-10) and pain following craniotomy (surgical opening of the skull, 0.8 points (high-quality evidence). (Note - these effects are essentially meaningless on a 1-10 pain scale. In the real world the difference between, let's say 7 and 7.8, is an artifact, especially when patient surveys are used. Both are torture.

♦ Back pain - Acetaminophen is ineffective in relieving acute low back pain (high-quality evidence).

♦ Headache - Although acetaminophen has some efficacy in treating the pain from tension headaches, the relative risk (RR) of 1.3 is probably too low to be significant (moderate quality evidence).

♦ Pain after childbirth - Women with perineal pain (the area between the vagina and anus) experienced a 50% reduction in pain (RR 2.4, moderate evidence). Note: These findings are disputed in a review from the Cochrane Library. 

♦ Neither acetaminophen nor placebo was associated with adverse side effects; however, when patients with spine pain received multiple doses, they had an elevation of liver enzyme levels (as you would expect since the drug is a known liver toxin).

The authors concluded:

For most conditions, evidence regarding the effectiveness of paracetamol is insufficient for drawing firm conclusions. Evidence for its efficacy in four conditions was moderate to strong, and there is strong evidence that paracetamol is not effective for reducing acute low back pain. Investigations that evaluate more typical dosing regimens are required.

3. Pain relief in children and adolescents (2017) "Paracetamol (acetaminophen) for chronic non‐cancer pain in children and adolescents" Cochrane Library.

In this Cochrane review, Cooper and colleagues examined the efficacy of acetaminophen in young people in treating chronic non‐cancer pain in children and adolescents in an age range between infancy and 17 years old. 

Findings

This one is trivial to analyze. The group found no studies of sufficient quality to draw any conclusions about the efficacy of acetaminophen in young people. This is rather alarming since it is the most commonly used drug in children; 11% of them (about 7 million) in the US use the drug weekly. (Keep in mind that acetaminophen is effective in reducing fever in children, so its use here is legitimate, but not for pain.)

Authors' conclusions

There is no evidence from randomised controlled trials to support or refute the use of paracetamol (acetaminophen) to treat chronic non‐cancer pain in children and adolescents. We are unable to comment about efficacy or harm from the use of paracetamol to treat chronic non‐cancer pain in children and adolescents.

4. Emergency department, various painful conditions (2023)

At first glance, a systematic review in BMJ Emergency Medicine Journal seems to contradict the myriad of other reviews claiming that acetaminophen provides little or no pain relief. 

Qureshi and colleagues at Qatar University in Doha published a systematic review that reported on randomized trials  (March 2021– May 2022) using pain relief at 30 minutes (T30) for all types of pain presented in the Emergency Department as the primary outcome.

Findings

♦ There was no significant difference in pain reduction at T30 between the intravenous paracetamol (IVP) (IV acetaminophen) group and opioids, nor was there a difference at 60 min.

♦ The need for rescue analgesia at T30 was significantly higher in the acetaminophen group compared with the NSAID group. (This means that acetaminophen required more rescue analgesia, which speaks to its efficacy – lower than opioids or NSAIDs

The authors concluded:

In patients presenting to the ED with a diverse range of pain conditions, IVP provides similar levels of pain relief compared with opiates/opioids or NSAIDs at T30 post administration. Patients treated with NSAIDs had lower risk of rescue analgesia, and opioids cause more [adverse events] suggesting NSAIDs as the first-choice analgesia and IVP as a suitable alternative

What's going on?

Perhaps this: [my emphasis]

The quality of the evidence using Grading of Recommendations, Assessments, Development and Evaluations [GRADE] methodology was low for [Mean Deviation] in pain scores.

I don't know why this review was published at all, let alone in BMJ. The authors present "important" conclusions about the relative analgesic properties of NSAIDs, opioids, and acetaminophen and then admit that it is all based on low-quality evidence. Take this for what it's worth, which isn't much.

5. Paracetamol: widely used and largely ineffective (2016)

My apologies for including a pre-2017 article. I must have missed it. And it's not even a review; it's a Cochrane UK blog. But not by a typical blogger. Dr. Andrew Moore, Director of Pain Research at Oxford, has written 200 systematic reviews (mostly on pain), 80 of them Cochrane reviews. Dr. Moore has much to say in his blog post titled "Paracetamol: widely used and largely ineffective." I've selected some representative quotes:

♦"For many years paracetamol has been the ‘go-to’ medicine for all sorts of acute and chronic pain conditions. NICE [National Institute for Health and Care Excellence] recommends it for back pain and osteoarthritis."

♦ "So how does paracetamol stack up against what people with acute back pain want? A Cochrane review is unequivocal – it doesn’t work. Not immediately, not later."

♦ "At no stage between one and 12 weeks is 4,000 mg daily any better than a placebo [for back pain]."

♦ "It is really difficult when an almost ubiquitous practice (using paracetamol) meets a distinctly inconvenient truth (it doesn’t work)."

♦"Our most recent best evidence [for osteoartiritis] indicates a barely significant and tiny benefit of around 3/100 mm over placebo, and a ranking barely above placebo in a network meta-analysis.

♦ For chronic neuropathic pain an ongoing Cochrane review reveals a complete lack of any evidence for paracetamol at all.

♦ Paracetamol is without effect in cancer pain, [or] acute postoperative pain and migraine.

(Dr. Moore also spends considerable time debunking the idea that acetaminophen is safe – the nearly unanimous public perception. I will not cover this here, but I urge you to read his post.)

Moore concludes:

There are no easy answers. We have very limited evidence on back pain. That makes it even more important that when solid evidence comes along – even if it is a solid negative as with paracetamol – we take it on the chin and move on. Too much in the past have we been like the ‘wise’ monkeys – unwilling to see, unwilling to hear, and unwilling to speak about obvious issues right under our noses. Time to look, listen, and open up a new conversation.

Bottom line

I searched for high-quality reviews published (mostly) within the past six years about the efficacy of acetaminophen. I did not cherry-pick papers that supported my thesis. Had there been high-quality studies supporting the use of the drug, I would have included them. It is also possible that I may have missed one or more, in which case I will issue a correction.

But the evidence is overwhelming that acetaminophen fails to provide adequate pain relief for any condition. Yet, hospitals will dispense the pills like candy and/or an expensive and useless IV form of the drug. As Dr. Moore opined, "Time to look, listen, and open up a new conversation."

I would argue that the time for this conversation for this has long passed.