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.