IV APAP Works, So Why Don’t More EPs Use It?

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When intravenous acetaminophen hit the market, I was skeptical. But four recent studies proved me wrong, and convinced me that more emergency physicians should be applying this option.

I worked for McNeil Labs shortly after the release of OTC Tylenol in 1961. Given that, at the time, there were few other oral OTC analgesics, and it was prior to the days of the NSAIDS, Tylenol sales took off like a rocket. Everybody took it for every headache, musculoskeletal ache or pain – you name it. And it swiftly knocked aspirin off the shelves when it came to treating fever and pain. By 1976 it was the #1 brand of OTC analgesic in the U.S.

There is no question that acetaminophen (APAP), the active ingredient in Tylenol, is a safe, effective mild-moderate analgesic. Its side effect profile is safer than all other OTC products and accidental overdose is rare. Unfortunately, APAP overdoses can be nasty and within a few days your liver can turn into Jell-O. However, there is a largely effective treatment if the overdose is recognized early.

Because of the potential for intentional OD with APAP, the United Kingdom decided to limit the number of pills available in bottles and blister-packs of acetaminophen  APAP tablets. As a result, they cut their number of overdoses to a fraction of baseline (now you are likely to bleed to death from cuts on your fingers before you can obtain enough tablets to create a significant overdose). Currently you can only purchase 32 500mg tablets at a time in pharmacies and half that in non-pharmacy outlets.

We Americans, however, have not taken such steps, and you can still buy acetaminophen by the bucket. You can literally purchase tubs containing 1,000 tablets most anywhere that sells pharmaceuticals. So now APAP in the United States has gotten a bad rap. Specifically, APAP toxicity has replaced viral hepatitis as the most common cause of acute hepatic failure and it is the second most common cause of liver failure requiring a transplant (with prescription products containing APAP being responsible for about half of these). Concern that patients may be taking multiple products containing APAP and this could lead to inadvertent toxicity has put the brakes on the use of APAP to some degree.

In January of 2014, the FDA made a number of recommendations regarding the use of OTC APAP including lowering its maximum daily adult dose to 3gm from 4gm. Many would say this move was rather aggressive considering what the options are regarding other analgesics and their side-effect profiles.

One thing is certain: APAP’s use has become ubiquitous. It is reported that worldwide it is in more than 600 different medicines. So it isn’t difficult to imagine patients accidentally, inadvertently overdosing by taking multiple APAP-containing meds.

Knowing that APAP has been made available in virtually every form (tablet, gelcap, liquid) and combination – and knowing this is a great way to sell APAP – I was very suspicious when APAP became available in an IV form. What next? What possible benefit could APAP be in this form when compared with the myriad oral forms.

Well the results of the following studies have kept me humble. The 2nd-4th studies all indicate comparable results when compared to reasonable doses of IV morphine – and there is the advantage of no opiate side effects – nausea, somnolence, respiratory depression. The first study indicates that blood levels 70% higher than when taken orally are largely the reason IV APAP works and that these levels are safely achieved because the drug bypasses the liver (orally ingested APAP is all going to pass thru the liver upon absorption).

INTRAVENOUS ACETAMINOPHEN IN THE EMERGENCY DEPARTMENT
Kwiatkowski, J.L., et al, J Emerg Nurs 39(1):92, January 2013
This report, from the University of Michigan, reviews the IV administration of acetaminophen. Although this route of administration was approved by the FDA in 2010, it has been marketed in more than 80 countries since 2001. IV administration avoids first-pass hepatic metabolism. It achieves peak concentrations more quickly than oral treatment (within 15 minutes vs. up to one hour), producing a maximum concentration up to 70% higher. In the absence of inflammation, IV acetaminophen offers advantages over nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with a contraindication to these latter agents. Its analgesic effects have been reported to be comparable to those of opioids in ED patients with renal colic, traumatic limb pain and extremity injury. It is suitable as an alternative to opioids in patients with mild to moderate pain, and as an opioid-sparing adjunct in patients with severe pain. Studies have reported that IVacetaminophen is safe and effective in children. Approval in the US is limited to patients aged two years or older, but European studies have included younger children. Although the safety of IV acetaminophen has not been evaluated in pregnancy, oral formulations of this agent are widely used in pregnant women without evidence of teratogenicity. It is contraindicated in patients with severe hepatic impairment or active liver disease, and should be used with caution in others with liver disease. The cost of a 1g dose of acetaminophen is much higher when it is given by the IV route (just over $10) when compared with the same dose of oral (less than $0.05) or rectal ($1) formulations. The authors suggest that the higher cost of IV acetaminophen might be offset by its ability to reduce opioid consumption and opioid-related adverse effects. 19 references (jennifer.kwiatkowski@spectrumhealth.org)
Copyright 2013 by Emergency Medical Abstracts – All Rights Reserved 7/13 – #26

INTRAVENOUS PARACETAMOL VERSUS DEXKETOPROFEN VERSUS MORPHINE IN ACUTE MECHANICAL LOW BACK PAIN IN THE EMERGENCY DEPARTMENT: A RANDOMISED DOUBLE-BLIND CONTROLLED TRIAL
Eken, C., et al, Emerg Med J 31(3):177, March 2014
BACKGROUND: Low back pain (LBP) is a common presenting complaint in the ED accounting for more than six million visits annually in the United States alone. Effective pain management remains controversial.
METHODS: In this double-blind study from Turkey, 137 patients aged 18-55 presenting with acute mechanical low back pain were randomized to a single dose of IV acetaminophen (1g), morphine (0.1mg/kg) or dexketoprofen (50mg) and followed for 30 minutes.
RESULTS: Mean baseline pain scores on a visual analogue scale (VAS) of 0-100 were 82.6 in the acetaminophen group, 81.4 in the morphine group and 83.5 in the dexketoprophen group. By 30 minutes, mean scores were 19, 15.5 and 27.6, respectively. Mean pain score reductions were 65 points in theacetaminophen group and 67 points in the morphine group, but 58 points in the dexketoprophen group. On a verbal rating scale ranging from 1 (no pain) to 4 (severe pain), mean scores were 4 in all three groups at baseline and decreased to 1 in all of the groups at 30 minutes. Rescue medication was required at 30 minutes by 8/46 patients in the acetaminophen group, 7/45 in the morphine group and 4/46 in the dexketoprofen group. Adverse effects were most frequent in the morphine group (7/45 vs. 4 patients in each of the other two groups).
CONCLUSIONS: The three drugs evaluated in this study appeared to be equally effective for the initial management of adults presenting with acute mechanical low back pain. 18 references (mserinken@hotmail.com – no reprints)
Copyright 2014 by Emergency Medical Abstracts – All Rights Reserved 9/14 – #23

RANDOMISED COMPARISON OF INTRAVENOUS PARACETAMOL AND INTRAVENOUS MORPHINE FOR ACUTE TRAUMATIC LIMB PAIN IN THE EMERGENCY DEPARTMENT
Craig, M., et al, Emerg Med J 29(1):37, January 2012
BACKGROUND: IV paracetamol (acetaminophen) was approved in the US in 2010 for the treatment of mild to moderate pain, or as an adjunct to opioids for moderate to severe pain.
METHODS: In this prospective, double-blind, controlled British study, 55 patients aged 16-65 with isolated limb trauma and a pain score of at least 7/10 were randomized to treatment with 1g of IV acetaminophen or 10mg of IV morphine, infused over 15 minutes, and followed for one hour after treatment.
RESULTS: There was no statistical difference between the groups in reduction in mean pain score (on a scale of 0-100) over one hour (from 70.1 at baseline to 44.0 in patients randomized to morphine, and from 76.4 at baseline to 52.9 in the acetaminophen group). Rescue analgesia was required by eight patients in each group. An adverse reaction was more frequent in patients randomized to IV morphine (8/28 vs. 2/27 with acetaminophen). Fourteen of the 28 patients in the morphine group, and 9/27 in the acetaminophen group, reported being satisfied or very satisfied with their care.
CONCLUSIONS: In this small study, analgesic response to IV acetaminophen appeared to be similar to that with 10mg of IV morphine in adults with isolated limb trauma In the USA in 2011, the cost of a 100mg vial of Ofirmev IV acetaminophen (Cadence Pharmaceuticals) was $12.90 (so 1g would cost $129), while the typical cost of a dose of IV morphine is less than $1. 10 references (richard.jeavons@uhbristol.nhs.uk – no reprints)
Copyright 2012 by Emergency Medical Abstracts – All Rights Reserved 9/12 – #23

INTRAVENOUS PARACETAMOL VERSUS MORPHINE FOR RENAL COLIC IN THE EMERGENCY DEPARTMENT: A RANDOMISED DOUBLE-BLIND CONTROLLED TRIAL
Serinken, M., et al, Emerg Med J 29(11):902, November 2012
BACKGROUND: intravenous opioids and NSAIDs are effective in the treatment of acute renal colic, but can produce adverse effects. Intravenousacetaminophen (APAP) has a rapid onset of action, and early studies suggest potent analgesic effects.
METHODS: The authors, from Turkey and UC Irvine, performed a prospective clinical trial comparing IV APAP and morphine in patients with renal colic. Of 133 ED patients aged 18-55 (mean, 30) with acute renal colic (confirmed by imaging), 53 were excluded for various reasons, and 80 were treated double-blind with a single IV dose of morphine (MS) 0.1mg/kg or APAP 1g. Pain response was measured at 15 minutes and at 30 minutes using both a verbal rating scale (VRS) and a visual analog scale (VAS).
RESULTS: Results were analyzed in 73 patients who, on average, had severe pain prior to treatment (VAS around 80mm). Both treatments produced rapid, potent and equivalent analgesia, with a decrease in VAS at 15 minutes of 39mm with MS and 34mm with APAP; at 30 minutes the VAS decreased by 57mm and 64mm, respectively. Response as measured by the VRS was identical in the two groups, and rescue analgesia with fentanyl was given to seven patients treated with MS and six patients treated with APAP. An adverse effect (not further characterized) occurred in five vs. two patients, respectively.
CONCLUSIONS: In this small study of patients with acute renal colic, IV acetaminophen, at a dose of 1gm, produced rapid and potent analgesia to a degree equivalent to that of IV morphine at a dose of 0.1 mg/kg. 17 references (cenkereken@akdeniz.edu.tr – no reprints)
Copyright 2013 by Emergency Medical Abstracts – All Rights Reserved 5/13 – #20

Some have suggested that, at a retail cost of about $13 for the typical 1gm dose, IV APAP is unduly expensive compared to the costs of IV opiates (pennies). However, the charging systems in most EDs are so bizarre and overpriced (an average visit is over $1,000) that $13 for an effective, opiate-sparing analgesic is a drop in the bucket.

When you ask emergency physicians if they have any experience with IV APAP, most will say no. This is strange given how quickly both the emergency medicine and anesthesiologist community embraced Toradol (ketorolac) – and its costs are about $5 a dose. In addition to an insignificant difference in price, ketorolac is unlikely to be more effective than IV APAP except for use in biliary or ureteral colic where its antiprostaglandin synthetase effects are largely responsible for its efficacy in these unique settings.

What we need now is a head-to-head comparison of the two drugs. I put my money on IV APAP . . . though I also put my money on such a trial never occurring. In the meantime, seems our patients may get some substantial analgesia without opiate or NSAID side effects if we all start getting some clinical experience with this dosage form of APAP.

ABOUT THE AUTHOR

EXECUTIVE EDITOR
Dr. Bukata is the Editor of Emergency Medical Abstracts.

10 Comments

  1. IV acetaminophen is $130 per 1gram vial. So the biggest issue is cost. Why not just give oral APAP.

    “In the USA in 2011, the cost of a 100mg vial of Ofirmev IV acetaminophen (Cadence Pharmaceuticals) was $12.90 (so 1g would cost $129), while the typical cost of a dose of IV morphine is less than $1. 10 ” from this article.

    • The reason is stated in the article. IV APAP does not undergo first pass hepatic metabolism, so the concentration in the blood is much higher.
      It has been used for years in Europe and is often the IV pain medicine of choice.
      I use it in patients primarily that I don’t want to give IV narcotics too. Someone that needs to drive home, pregnant women afraid of IV narcs, or even drug seekers. I tell my nurses to not call it IV Tylenol, but only Ofirimev. I let the patients know it is been used for years in Europe for kidney stones and other painful conditions. All this is completely true so I am not deceiving the patient, I get excellent results. Cost is an issue, so it’s not my first choice for every patient, but the cost of repeated doses of cheaper medicines when you factor in the nursing charges, and the time spent in the ED, it has excellent advantages.

      • Also, the cost listed is not completely accurate. The only form we stock is glass containers of either 650 mg ( for patients <50kg) and containers of 1000mg. It is more expensive than morphine or oral acetminophen, but the cost ranges between $40-$90 ( the cost varies somewhat from order to order, even though it's the same manufacturer)

  2. Question, if a patient is identified with a condition that subsequently requires, say surgery, and IV Acetaminophen had been given: What is the risk of bleeding from this product? Should providers consider an increased risk of bleeding and not use the IV Acetaminophen until they have determined that their patient will not require an intervention with blood loss potential?

    • Acetaminophen in any form does not significantly increase bleeding. It is used intraoperatively in some European countries and has been studied in the US primarily in the acute postoperative setting

  3. Good reviews, but I’m not convinced.

    The question we want to know is whether IV acetaminophen is superior to oral acetaminophen. None of these studies investigates this. From the VAS scores, the natural conclusion I draw is that all protocols were equally bad at treating pain.

    How about this for a study design: Randomize one group to oral acetaminophen and IV placebo, the other to IV acetaminophen and oral placebo. Coprimary outcomes could include pain at 10 minutes and at one hour.

    • There are multiple studies from Europe demonstrating the IV route over the oral route. Again, it all has to do with first pass hepatic metabolism.
      From personal experience, it is excellent for controlling even Moderate to severe pain (extremity fractures, kidney stones, etc.)

  4. William Hardman, M.D. on

    In our ED anyone who makes it through triage gets parenteral Dilaudid for almost any painful complaint. If this is not administered, they patient surveys are negative and the employment of the physician is in jeopardy. When they can figure out how to get a high from acetaminophen, it will catch on.

    • I think your comment about pain control is absolutely correct!!!! if patients do not get the “feel good” medicine, then they complain we are not “doing our job”. Provider bonus’ are wiped out by patient complaints, we are given “nasty grams” from administration for not meeting “patient satisfaction” goals.

  5. The answer to the title’s question is: availability. Which is undoubtedly related to cost. Our hospital has IV APAP, but they don’t stock it in the ED. So, if I order it, we have to wait for it to come from the main pharmacy.
    Also – whether IV APAP is better than PO is not the relevant question. The ideal use for this is as an alternative to opiates in a patient who needs to be NPO. And it is clearly non-inferior to opiates. The main problem is that (just like Toradol) we can’t just keep giving escalating doses if the initial dose is ineffective.

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