Equality Study of Ofirmev vs Oral Acetaminophen
Equality Study of Ofirmev vs Oral Acetaminophen
Acetaminophen (Tylenol) is a drug that is used commonly for relief of mild to moderate pain.
 It is found in many pain medicines that people take after having surgery. Narcotics are other
 drugs also used for pain (examples of narcotics are morphine and related pain medications).
 Medical science knows for a fact that acetaminophen works well when taken with narcotics for
 moderate to severe pain. Recently, acetaminophen has become available in an intravenous (IV)
 form called Ofirmev®. The IV form means that acetaminophen can be given into a vein. The
 benefits of getting medicine from an IV include:

 -  making the medicine work quickly

 -  less medicine having to pass through the liver to be changed into a form that your body
 can process The investigators know that acetaminophen is helpful for pain relief at the
 time of surgery and after surgery. Acetaminophen is a very popular drug in outpatient
 surgery for pain control when patients go home. The patient's surgeon uses it to control
 pain after surgery at home in the form of Lortab or Percocet (Lortab and Percocet also
 have a narcotic medicine that mixes with acetaminophen). Also, currently at Surgicare,
 some anesthesiologists give intravenous acetaminophen while the patient is waiting to go
 to surgery. The investigators currently do not give any patient acetaminophen by mouth
 BEFORE surgery. However, since the addition of the IV form to the drug market, there has
 been interest to see if the oral form is just as good or better in reducing pain after
 surgery. This is why we are asking patients to join our study. The goal of this study is
 to find out if the oral form (by mouth) or the IV form (given into a vein) of
 acetaminophen controls pain after surgery better.
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)