Physician anesthesiologist at Stanford at Associated Anesthesiologists Medical Group
Richard Novak, MD is a Stanford physician board certified in anesthesiology and internal medicine.Dr. Novak is an Adjunct Clinical Professor in the Department of Anesthesiology, Perioperative and Pain Medicine at Stanford University, the Medical Director at Waverley Surgery Center in Palo Alto, California, and a member of the Associated Anesthesiologists Medical Group in Palo Alto, California.

Intravenous acetaminophen was introduced in Europe in 2002. The United States Food and Drug Administration approved IV acetaminophen (Ofirmev, Cadence Pharmaceuticals) in 2010 for management of mild to moderate pain, moderate to severe pain with adjunctive opioid analgesics, and reduction of fever.


IV acetaminophen (Ofirmev)



Acetaminophen (Tylenol) has been available in oral and rectal forms for decades. 


Oral acetaminophen


Healthcare costs continue to skyrocket in the United States. In 2016 Americans spent $435 billion on prescription drugs.1 This month the Trump administration released a 44-page blueprint for executive action on drug pricing entitled “American Patients First.” Their goal is to drive prescription drug costs down by increasing competition. At this time it’s too early to tell how effective these efforts will be.

Anesthesiologists are the only physicians who prescribe and then directly administer medications themselves. CRNAs are the only nursing professionals who prescribe and then directly administer medications themselves. Because anesthesiologists and CRNAs typically don’t pay for the medications, there can be a disconnect regarding costs and value.

If you were in charge of pharmaceutical purchasing at a hospital or an ambulatory surgery center, and you had an identical acetaminophen molecule available for either 5 cents per dose or $42 per dose, which would you choose? The answer is obvious, but as an administrator you are not prescribing the drug.

A 2014 study showed that patients who received IV acetaminophen reported superior satisfaction with pain control compared to patients who received placebo.2 In inpatient and postoperative settings, intravenous acetaminophen became a route of choice for rapid analgesia, and appeared to reduce the need for other analgesics such as opioids. Disadvantages of IV acetaminophen included the time and equipment needed for IV drug administration, as well as increased costs.

In a publication from the Canadian Journal of Hospital Pharmacy, Jibril wrote, “The study drug (acetaminophen, either oral or IV) was given when patients first awakened after surgery, and additional doses were given every 6 h until 0900 the next morning. . . . The use of opioids was significantly lower in the group receiving acetaminophen by the IV route than in the group receiving acetaminophen by the oral route (p < 0.05). However, this difference did not translate into a significant difference in rates of postoperative nausea and vomiting or any significant difference in pain scores on a 100-mm visual analogue scale (VAS) at any time. . . . A major finding of this review was the absence of strong evidence suggesting superiority of IV acetaminophen administration over oral routes. . . . IV acetaminophen may be useful for opioid-sparing in postoperative pain. To date, no strong evidence exists that IV acetaminophen should replace any form of standard care. At most, the evidence indicates that this formulation could function as an adjunctive agent in patients unable to take oral forms. . . . . In the United States, there has been great debate regarding use of this formulation, which has led many hospitals to adopt policies and procedures that restrict use for a limited period or for patients not able to take medications by mouth. These restrictions are required because of the cost of the product, in addition to other administration-related inconveniences. Canadian hospitals and formulary committees should be aware of the available efficacy and safety data if the formulation is marketed in Canada and its use becomes widespread. Given the high cost and the lack of superiority over oral forms, Canadian hospitals may need to restrict use of the IV formulation, as their US counterparts have already done.”3

In a study of IV acetaminophen use in neurosurgical ICU patients at Virginia Commonwealth University, Gretchen Brophy, PharmD, of the departments of pharmacy and neurosurgery wrote, “We and every institution I’ve spoken to have restricted its use, because we don’t have data saying it’s more effective. At $33 a dose” – recently up from $10 – “it’s harder to justify. At least in the 0-3 hour window, it didn’t have any additional benefit over oral. It might still be better at 1 hour; kinetically, that would make sense, but there’s nothing yet to say from what we did that it’s better.”4 VCU restricted intravenous acetaminophen use to one dose per patient.

Mallinckrodt purchased Cadence Pharmaceuticals in 2014, and increased the price of Ofirmev from $17.70 to $42.48 per vial. (A full case of Ofirmev includes 24 vials.) Sales increased to $71 million during their fiscal first quarter, double the amount for the same period the previous year. Hospitals noted the rise in expenses and sought alternatives such as oral acetaminophen, and the volume of sales dropped. Robert Press, chief of hospital operations at NYU Langone, which anticipated $1 million in additional costs because of Ofirmev, was quoted to say, “We found out a lot of the use was really not necessary and we found we could give alternative products.”5

Some hospitals removed Ofirmev from their formularies after the price went up. Others simply switched to alternatives such as oral acetaminophen. Others increased their budgets to cover the cost of the drug, but the net effect of Mallinckrodt’s price hike was to reduce the doses of Ofirmev prescribed. Mallinckrodt’s U.S. headquarters are located in Missouri. Senator Claire McCaskill (D-Missouri) wrote a letter to Mallinckrodt CEO Mark Trudeau demanding information about pricing and revenue numbers. In the letter she also suggested that Ofirmev, expensive as it was, might actually be saving hospitals money because of opioid-sparing. Senator McCaskill wrote, “Any obstacle to prescribing non-opioid alternatives, even those used solely in a hospital setting, is cause for concern.” It should be noted that McCaskill received $2,500 in campaign financing from Mallinckrodt during the 2016 election cycle.6

Mallinckrodt released a statement that read, “One recent analysis of health economic data on the use of Ofirmev coupled with a one-level reduction in opioid use was linked to decreasing hospital stays, potential opioid-related complications and related costs for the treatment of acute surgical pain. . . . The study showed a potential of $4.7 million in annual savings for a typical, medium-sized hospital.”6

The clinical benefit of reduced opioid consumption with Ofirmev has not been evaluated nor demonstrated in prospective, randomized controlled trials. In a review in the journal Pharmacotherapeutics, Yeh wrote, “Although use of intravenous acetaminophen has reduced other postoperative resource utilization (e.g., hospital length of stay) in some studies outside the United States in patients undergoing abdominal surgery, a full economic evaluation in the United States has yet to be undertaken.”7

The research study anesthesiologists would like to read is a prospective, randomized, double-blind trial of 1000 mg of preoperative oral acetaminophen, versus 1000 mg of IV acetaminophen administered just prior to the end of surgery. Will this research ever be performed? I hope so, but you can bet Mallinckrodt is never going to fund that study.

I repeat Jibril’s conclusion to sum up the answer to our initial question above:“An absence of strong evidence suggesting superiority of IV acetaminophen administration over oral routes. . . . To date, no strong evidence exists that IV acetaminophen should replace any form of standard care. At most, the evidence indicates that this formulation could function as an adjunctive agent in patients unable to take oral forms. . . . Therefore, on the basis of current evidence, if a patient has a functioning gastrointestinal tract and is able to take oral formulations, IV formulations are not indicated.”3

And what is the solution regarding anesthesia providers who frequently choose to prescribe IV acetaminophen despite these recommendations? The hospital I work at, Stanford University Hospital, restricts Ofirmev usage to patients who are NPO (nothing by mouth), and each Ofirmev order has a hard stop after 24 hours, eliminating further usage. The owners of the surgery center I medically direct have an even more decisive solution: Ofirmev is not on the facility formulary at all.



  1.  Cortez J. Prescription Drug Spending Hits Record $425 Billion in U.S. Bloomberg, April 13, 2016.                                      
  2. Apfel CC et al. Patient satisfaction with intravenous acetaminophen: a pooled analysis of five randomized, placebo-controlled studies in the acute postoperative setting. J Healthc Qual. 2014 Jan 16.
  3. Jibril F, et al. Intravenous versus Oral Acetaminophen for Pain: Systematic Review of Current Evidence to Support Clinical Decision-Making, Can J Hosp Pharm. 2015 May-Jun; 68(3): 238–247.
  4. Otto MA et al. No pain benefit found for IV acetaminophen vs. oral in the neuro ICU. Clinical Neurology News. January 30, 2015.
  5. Staton T. Price hikes aren’t always sustainable: Just ask Mallinckrodt about Ofirmev. Fierce Pharma. Oct 12, 2015.
  6. Staton T. Mallinckrodt’s pain med Ofirmev gets scrutiny in Senate—but this pricing probe has a twist. Fierce Pharma. May 30, 2017.
  7. Yeh Y et al. Reviews of Therapeutics: Clinical and Economic Evidence for Intravenous Acetaminophen. Pharmacotherapeutics. 08 May 2012.


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