Equality Study of Ofirmev vs Oral Acetaminophen

The American Society of Anesthesiologists recommends acetaminophen, NSAIDS, or COX-2
inhibitors as part of a multimodal pain management strategy to limit opioid usage (1). As
the surgical patient population becomes more complex with comorbidities ranging from
obesity, obstructive sleep apnea , and asthma becoming more common, the medical community
continues to search for efficacious analgesics with a high safety profile. While
non-steroidal anti-inflammatory drugs play an important role in multi-modal analgesia, their
use is limited based on concerns for platelet inhibition, asthma exacerbation, and renal
artery perfusion in patients of advanced age or reduced creatinine clearance.

Acetaminophen has proven to be an important analgesic in the perioperative setting. It is
frequently combined with opiates to allow for synergism, or it can be used as a sole
analgesic to provide up to 4 hours of relief for moderate pain. While acetaminophen's main
role as a multimodal analgesic regimen has been in tablet form as an opioid/acetaminophen
combination in the post- anesthesia care unit (PACU), acetaminophen has emerged as an
important perioperative analgesic due to FDA approval of an intravenous (IV) formulation
(Ofirmev®) in the United States in 2010. While the new intravenous formulation was approved
based upon its postoperative effectiveness and safety, there is also an interest in its
preoperative use. [12, 13] The benefit IV acetaminophen claims over the oral modality is a
70% higher blood concentration than a single similar dose (1 gram) of oral acetaminophen and
a rapid onset with peak blood concentration within 15 minutes of infusion while similar oral
doses may take 90 minutes to reach peak plasma concentrations. Many studies have compared
the IV formulation of acetaminophen (Ofirmev®) with the oral formulation at the same dose of
1 gram. However, this does not take into account the difference in pharmacokinetics of oral
and intravenous formulations. A 15-minute constant infusion of 1 gram acetaminophen resulted
in an average plasma concentration of 25.02 μg/ml at the end of the infusion with subsequent
decline to approximately 11 μg/ml at 1 hour and 7 μg/ml at 3 hour after the start of
infusion. Pain scores were lowest at one hour but remained significantly low for at least
three hours. [FDA med review] Moreover, the pharmacokinetics of the immediate release oral
formulation of acetaminophen are well-known. The absorption half life for acetaminophen in
healthy subjects ranges from 0.06-0.7 hours (8). The relative bioavailability ranges from
85% to 98%. Moreover, it has a low first pass metabolism with a hepatic extraction ratio of
0.11 to 0.37 (9). After oral administration of 1 gram acetaminophen in the immediate release
formulation (IR), peak concentrations of acetaminophen in adults ranged from 7.7 to 17.6
μg/mL within 1 hour.

Although the therapeutic range for acetaminophen is not well established, plasma
concentrations of 10-20 mcg/ml are associated with antipyretic activity, and previous work
has assumed that antipyretic and analgesic doses will be similar. (3-4). However, another
study developed two compartmental pharmacokinetic/pharmacodynamic models to relate plasma
concentration to pain score relationship in children who received oral acetaminophen 30
minutes before outpatient tonsillectomy. The model demonstrated only a one point decrease in
pain score when the concentration increased from 10 μg/mL to 20 μg/mL and a steep loss of
pain protection when the concentration fell below 6 - 7 μg/mL. Therefore, this study
indicates a saturation of the analgesic effect of acetaminophen at a threshold plasma
concentration of as low as 7 μg/mL.

The basis for our proposal stems from a recent study by J Van Der Westhuizen, et al. They
set out to determine if the traditional one gram unit dose reached adequate serum
concentrations of greater than 10 mcg/ml. They compared 1 gram each of intravenous (IV) and
oral acetaminophen to see if one or both achieved therapeutic plasma concentrations
peri-operatively and for how long. This study questioned the use of oral acetaminophen at 1
gram because if it was not achieving therapeutic concentrations, the patients were not
getting optimal care (5). From this study, they were able to extrapolate oral doses of 20
mg/kg that would achieve a maximum concentration of 19 mcg/ml (which is the median maximum
concentration achieved by IV acetaminophen). The study concluded that for subjects over 75
kg, an effective IV equivalent oral acetaminophen dose would be 1.5 grams or even 2 grams if
the subject exceeded 100 kg (5). This study further recommended a follow up study to
evaluate these higher doses of oral acetaminophen as it relates to pain scores and rescue
medications postoperatively compared to the IV dose of 1 gram. The current unit dose of oral
acetaminophen is 1 gram every 6 hours. However, many studies have evaluated the effects of
higher doses of oral acetaminophen as well (10, 11). One study supported the use of 5-6
grams of acetaminophen in a 24- hour period in order to reduce requirements for
postoperative morphine. requirements (6). Another study measured serum and CSF
concentrations one hour after administration of 500 mg, 1 gm, 1.5 gm, or 2 gm of oral
acetaminophen (7).

In summary, the investigator's hypothesis is that while a similar dose is less effective, a
1.5 gram dose of oral acetaminophen (as determined by the extrapolation of maximum serum
concentrations from the Van Der Westhuizen, et al. study (5)) may be as effective as 1.0
gram of IV acetaminophen in reducing postoperative pain scores and total opioid consumption,
thus resulting in lower cost to the patient and provider.

II. Specific Aims:

The investigator's aim is to compare the effects of a 1.5 gram oral acetaminophen to 1 gram
IV acetaminophen when given preoperatively to patients undergoing arthroscopic rotator cuff
repair by a single surgeon at a single facility. The primary outcomes will evaluate total
opioid consumption in the post anesthesia care unit PACU and nominal pain scores. The
investigators theorize that 1.5 grams of oral acetaminophen will be as efficacious as 1 gram
IV acetaminophen resulting in lower costs to the patient and provider.

Inclusion Criteria:

- Age ≥18

- Weight 75kg -120 kg

- Undergoing arthroscopic rotator cuff repair by same surgeon at Surgicare of Wichita

- Patients who sign informed consent

- Patients who do not meet any of the exclusion criteria

Exclusion Criteria:

- Age < 18 yrs (will reduce risk of overdosing oral acetaminophen)

- History of opioid abuse or chronic opioid use greater than 3 months (may skew data
with regards to pain control due to the concept of tolerance)

- Acetaminophen allergy (avoids risk of allergic reaction)

- Liver disease as determined by anesthesiologist by history (acetaminophen involves
the liver for metabolism, therefore, if the liver is not functioning appropriately,
doses could accumulate and cause damage.)

- Daily alcohol consumption (same explanation as for liver disease)

- Renal failure (patient on dialysis or health history indicates renal dysfunction)
(acetaminophen has some renal excretion)

- Asthma (recent concerns for acetaminophen leading to asthma exacerbations)

- Any other contraindication to taking acetaminophen

- Surgeon requested pre-operative Interscalene block (this will cause the patient to
cease having pain, therefore the effects of acetaminophen reducing pain scores will
not be able to be evaluated)

- Current warfarin, carbamazepine, or phenytoin use (these medications can accumulate
in the presence of excessive acetaminophen use or may harm the liver and affect
acetaminophen use or may harm the liver and affect acetaminophen concentrations).

- Weight greater than 120 kg (1.5 gram doses of acetaminophen may be too low to
appropriately evaluate the effects in this patient population)

- Patients scheduled for "possible rotator cuff repair" (including these patients in
our studies could skew enrollment numbers should a rotator cuff repair not be done,
so these patients will be screened and excluded prior to enrollments)

- Any consumption of acetaminophen containing products in the 24 hour period prior to
surgery (excluded because acetaminophen can induce its own metabolism, therefore
reducing serum concentrations)

- Any significant medical disease(s), laboratory abnormalities or condition(s) that in
the Investigator's judgment could compromise the subject's welfare, ability to
communicate with the study staff, complete study activities, or would otherwise
contraindicate study participation.

- Non-English speaking patients

- Patients who are not able to consent for themselves.

- pregnant patients (All female patients of childbearing potential are given a
pregnancy test prior to any elective surgery at Surgicare. Though acetaminophen is
NOT harmful to these patients, they will be excluded given the fact that elective
surgery in itself is contraindicated in pregnancy)