Wednesday, July 9, 2014

IV Acetaminophen for Pain Management in the ED

One of the most entertaining emergency physicians I work with has fallen head over heels in love with intravenous (IV) acetaminophen. He jokes that he orders the product at least once per shift just to get a “visit” from me. I trade jabs, asking how many golf trips he’s received from the manufacturers of IV acetaminophen (trade name Ofirmev).

I had the opportunity a few years ago to complete a formulary review of the IV acetaminophen product during my pharmacy practice residency. One of the anesthesiologists had requested it for peri-operative use. At the time we suspected that if we added the agent to the hospital formulary (even if it was just for peri-operative use), it would expand to other areas of the hospital and it could have a substantial impact on the budget. We wanted to make sure that if it indeed would have an impact, that it should be offset by its perceived benefit with regard to better pain control and decreasing opioid-related adverse effects.

IV acetaminophen was marketed on the premise that it could serve as a foundation for “multi-modal” pain control by achieving more rapid and higher plasma concentrations than the oral and rectal formulations. Theoretically, this would reduce opioid use and therefore reduce opioid related adverse events. However, this hasn't exactly panned out in clinical studies. A meta-analysis by McNicol and colleagues found a whopping reduction of 1.3 mg morphine equivalent at 6 hours among 154 post-operative patients in whom IV acetaminophen was added. Not surprisingly, they found no decrease in opioid-related adverse events.1 These findings were replicated in another meta-analysis by Remy and colleagues who found a 9 mg morphine equivalent reduction at 24 hours among post-operative patients. Again, there was no difference in opioid-related adverse events between groups.2

So why the disconnect? Pharmacokinetic studies have demonstrated a clear difference between the oral and IV routes of administration (see figure below). Product promotional materials suggest that the threshold for analgesic effects is 16 mcg/ml (or 16 mg/L), and the threshold for antipyretic effects is 5 mcg/mL. However, these thresholds are based on small studies and pharmacokinetic models.3,4 There are numerous trials evaluating escalating doses of acetaminophen achieving higher serum concentrations, but lacking additional analgesic benefit.5-7 These findings were validated in a large Cochrane review of nearly 6,000 surgical patients that failed to demonstrated a clear dose-response relationship.8 Additionally, even though it appears that peak acetaminophen concentrations are reached rapidly with the IV formulation, there is a “lag-time” of at least 60-90 minutes for analgesic effect.9

Some proponents of IV acetaminophen may argue that in patients who are NPO, there aren't really many options for non-opioid pain control, especially when the bleeding risks of parenteral NSAIDs might outweigh any benefit. The rectal formulation of acetaminophen may be dismissed as “simply undignified.” I would argue that it’s equally (if not more) offensive to use a drug that is approximately 50-fold more costly than its rectal form, 13-fold more costly than an opioid, and 1000-fold more costly than its oral form.




What’s worse, the manufacturer of Ofirmev (now Mallinckrodt Pharmaceuticals) recently instituted a price hike of approximately 140% on the product in May 2014. You may say, why the fuss over a $30 dose of a drug? There are a lot more costly interventions they may be subjected to during the course of their visit. Fair enough. However, when you multiply that dose by even a mere 24 hours of therapy for routine use in your ED population over a year’s time, you may be incurring millions of budget dollars for a medication that hasn't demonstrated any clinical advantage over its alternate formulations. I’m certainly not saying there is absolutely no role for this product; I've just been having a difficult time finding its niche in the ED.


Meghan E. Groth, Pharm.D., BCPS (@EMPharmGirl)
Emergency Medicine Clinician, Fletcher Allen Health Care

References:
1)      McNicol ED, Tzortzopoulou A, Cepeda MS, et al. Single-dose intravenous paracetamol or propacetamol for prevention or treatment of postoperative pain: a systematic review and meta-analysis. Br J Anaesth 2011;106:764
2)      Remy C, Marret E, Bonnet F. Effects of acetaminophen on morphine side-effects and consumption after major surgery: meta-analysis of randomized controlled trials. Br J Anaesth 2005;94:505
3)      Gibb A, Anderson BJ. Paracetamol (acetaminophen) pharmacodynamics: interpreting the plasma concentration. Arch Dis Child 2008;000:1-8
4)      Fong L, Chang Y, et al. Open-label 4-period, randomized crossover study to determine the comparative pharmacokinetics of oral and intravenous acetaminophen administration in healthy male volunteers [poster]. 2007 American Society of Regional Anesthesia and Pain medicine (ASRA) Annual Pain Medicine Meeting and Workshops. Boca Raton (FL), 2007
5)      Skoglund LA, Skjelbred P, Fyllingen G. Analgesic efficacy of acetaminophen 1000 mg, acetaminophen 2000 mg, and the combination of acetaminophen 1000 mg and codeine phosphate 60 mg versus placebo in acute postoperative pain. Pharmacotherapy 1991;11:364-369
6)      Beck DH, Schenk MR, Hagemann K, et al. The pharmacokinetics and analgesic efficacy of larger dose rectal acetaminophen (40 mg/kg) in adults: a double-blinded, randomized study. Anesth Analg 2000;90:431-436
7)      Hahn TW, Mogenson T, Lund C, et al. Analgesic effect of I.V. paracetamol: possible ceiling effect of paracetamol in postoperative pain. Acta Anesthesiol Scand 2003;47:138
8)      Toms L, McQuay HJ, Derry S, Moore RA. Single dose oral paracetamol (acetaminophen) for postoperative pain in adults. Cochrane Database of Systematic Reviews 2008, CD004602
9)      Seymour RA, Rawlins MD. Pharmacokinetics of parenteral paracetamol and its analgesic effects in post-operative dental pain. Eur J Clin Pharmacol 1981;20:215, Nielsen JC, Bjerring P, Arendt-Nielsen L. A comparison of the hypoalgesic effect of paracetamol in slow-release and plain tablets on laser-induced pain. Br J Clin Pharmac 1991;31:267


Editorial Note:
IV acetaminophen is the simultaneously the bane of the clinical pharmacists’ existence and one of the main drugs that keep them employed.  Using a drug that makes no meaningful improvement in patient oriented outcomes, yet is orders of magnitude more expensive allows for heated debate and opportunity for “interventions” (I hate that term)- switching IV APAP to PO or PR formulations- which sure does look great on cost saving spreadsheets.

But looking at the data Meghan highlighted echoes the in house data we've analyzed here: IV APAP saves the patient on average 1 dose of their opioid pain management. It’s Tylenol folks. You wouldn't necessarily expect to slide a suppository into the patient and expect to clinically significantly reduce their opioid consumption. So why would we expect any different from the IV formulation of the same drug?

As pain management goes, there are a plethora of issues (oligoanalgesia, abuse, patient satisfaction scores, etc.) none of which are likely solved by IV APAP. This drug is simply not suitable for the ED. Save your pennies for dexmedetomidine or fosphenytoin.


--Craig Cocchio, Pharm.D., BCPS (@EMPharmacyPGY2)