Non-steroidal anti-inflammatory drugs (NSAIDs) have analgesic and opioid-sparing effects . They have been shown to reduce the postoperative opioid consumption after major orthopaedic surgery . Acetaminophen (paracetamol) is widely used as a basic analgesic drug in the postoperative setting, but is thought to be less efficacious than the NSAIDs. However, in one report, equianalgesic potency was demonstrated when acetaminophen 1 g was compared with diclofenac 50 mg . As acetaminophen and NSAIDs probably have different sites of action , their combined use may have additive or synergistic effects. The use of acetaminophen in combination with NSAIDs has been shown to improve analgesia in dental and postoperative pain models [5,6]. However, some concern has been raised about a potential nephrotoxic effect of this combination .
The objective of this randomized, double-blinded trial was to compare the analgesic properties of ibuprofen and acetaminophen given separately or together. We also wanted to explore whether a combination affected renal function in young patients undergoing anterior cruciate ligament reconstruction under general anaesthesia.
Approval from the Regional Ethics Committee and written informed consent was obtained from our patients who were ASA I and scheduled for anterior cruciate ligament reconstruction. The patients were randomized according to a computer generated list of random numbers. The study was conducted in a double-blinded manner. One hour prior to the operation, all patients received the first dose of study drug orally. Group A (acetaminophen) received two tablets of acetaminophen 500 mg (Paracet®; Weider Pharmaceutical, Groenland, Oslo, Norway) and two placebo tablets. The same medication was repeated at 6 and 12 h after the initial medication. Group I (ibuprofen) received two tablets of ibuprofen 400 mg (Ibux®; Weider Pharmaceutical, Groenland, Oslo, Norway) and two placebo tablets 1 h before the operation, and repeated identical medication at 6 and 12 h. Group AI (combination) received two tablets of acetaminophen 500 mg and two tablets of ibuprofen 400 mg at the same time intervals. A senior consultant anaesthetist, who was not participating in the assessment of the patients, performed the randomization and preparation of the study drug. Except for thrombosis prophylaxis with low molecular weight heparin (dalteparine 5000 IE subcutaneously), no other premedication was administered. The preoperative data recorded were: patient characteristics data, haemoglobin and creatinine concentration, smoking habits, history of motion sickness and headache. Anaesthesia was induced with midazolam 0.03 mg kg−1, fentanyl 3 μg kg−1 and propofol 4 μg mL−1 using a target control system (Diprifusor®; AstraZeneca AS, Vinderen, Oslo, Norway). A laryngeal airway mask was used for maintaining a free airway and anaesthesia was maintained with propofol, at a serum target of 2-3 μg mL−1, and 70% nitrous oxide in oxygen. The perioperative monitoring included vital signs such as heart rate (HR), end-tidal CO2, non-invasive blood pressure (BP) and O2-saturation. An endoscopic reconstruction of the anterior cruciate ligament was performed using a patellar tendon-bone autograft from the ipsilateral knee. At the end of the operation, bupivacaine 0.5% 10 mL was inserted intra-articularly and a cold compression device (Aircast Cryo Cuff®, Hässelby, Sweden) was applied and used continuously until the patient was discharged on the following day. Vital signs were monitored regularly, i.e. BP, HR and alertness. Starting at the patient's arrival in the recovery unit and every hour until discharge, the following was recorded: degree of pain estimated by a visual analogue scale (VAS) 0-100 mm, a verbal subjective pain score (the verbal pain score, VPS, 0 = no pain, 1 = slight pain, 2 = medium pain, 3 = strong pain and 4 = unbearable pain); need of rescue analgesia (i.e. ketobemidone 1-2 mg intravenously (i.v.)), alertness (1 = fully awake, 2 = sleepy, 3 = asleep, but can be awoken and 4 = not arousable); respiratory rate (RR) and side-effects (nausea, vomiting, dizziness and pruritus). Rescue analgesia was given either at patients' request or when pain > 30 mm on the VAS. After 6 h, the patients were transferred to the surgical ward. At 24 h the patients were asked to estimate their average level of pain during the 6-24 h period by VAS and verbal scale. The amount of rescue analgesia (i.e. ketobemidone) from 6 to 24 h was recorded. Urine was collected for the whole 24 h period for measurement of creatinine clearance. Haemoglobin and creatinine concentrations were measured at 24 h. At 24 h the amount and quality of sleep was also assessed.
The VAS and verbal scores were analysed with repeated measures ANOVA, with Duncan new multiple range test to assess pairwise differences between the treatment groups. P < 0.05 was considered significant. The variances and residuals were inspected to assure homoscedasticity (i.e. similar variances in the groups) and normality. The verbal score was treated as a continuous variable. The Kruskal-Wallis test with P corrected for ties was used for comparison of other variables, as homoscedasticity and/or normality could not be assumed in some of these. As the Kruskal-Wallis test is non-parametric, median and interquartile range were given for variables tested with this method. The software used was SuperAnova® 1.11 and StatView® 4.0 (Abacus Concepts, Berkeley, CA, USA).
Sixty-one patients were included in the study; no patient was excluded after recruitment. There were no differences in the patient characteristics data, perioperative blood loss - estimated by the reduction of haemoglobin concentration - duration of surgery, or postoperative creatinine clearance (Table 1). The acetaminophen group (Group A) required significantly more rescue analgesia during the first 6 and 24 h postoperatively (Table 2). During the first 6 h, 13 patients did not require rescue analgesia, one in the acetaminophen group, five in the ibuprofen group and seven in the combination group - all were non-significant (n.s.). Seven patients received no rescue analgesia during the whole 24 h study period; five of these were in the combination group, and one in each of the two other groups (n.s., Table 2). Patients in the acetaminophen group reported significantly more pain during the first 6 h (VAS and verbal scale) after operation than the two other groups (Fig. 1, Table 3). The incidence of side-effects such as nausea or vomiting was low, with seven patients (11%) requiring a single dose of antiemetic (i.e. metoclopramide i.v.). Two of these patients were in the acetaminophen group and five in the combination group (n.s.).
This study showed that ibuprofen 800 mg thrice daily was superior to acetaminophen 1 g thrice daily in reducing pain after anterior cruciate ligament reconstruction. The combination of acetaminophen with ibuprofen may have an additional analgesic effect, but the possible benefit of the combination did not reach significance in our study. This may be due to a too low statistical power for this level of difference. Other investigators have found a superior analgesic effect of the combination. Montgomery and colleagues showed that diclofenac 100 mg and acetaminophen 1.5 g, rectally administered, was more opioid sparing than diclofenac alone in patients undergoing elective abdominal surgery . Seymor and colleagues showed that the combination of ketorolac, 12.5 or 25 mg, in combination with acetaminophen 1 g provided good analgesia after third molar surgery . There are also several negative studies; a review concludes that there is little evidence supporting the hypothesis that the combination is better than NSAIDs alone . Evidently, further studies are needed in order to answer this question.
The use of NSAIDs in the perioperative period is beneficial and opioid sparing, thus reducing unwanted side-effects from opioids such as nausea, vomiting, drowsiness and respiratory depression. Acetaminophen is an analgesic and anti-pyretic drug with poor anti-inflammatory properties. Since it is well known that the inflammation process after surgery is a major contributor to hyperalgesia, the anti-inflammatory effect of ibuprofen may explain its superior analgesic effect compared to acetaminophen. The dosage of acetaminophen used in our study equals the maximal dose advised by the manufacturers. Oral administration of acetaminophen ensures near 100% bioavailability and plasma concentration peaks after 1-2 h . As our study did not include a placebo group, we cannot be sure that acetaminophen alone is beneficial in this group of patients. However, a published metaanalysis on the analgesic efficacy of acetaminophen reveals that acetaminophen 1 g as a single oral dose is a better analgesic than 600 mg, or tramadol 100 mg, or a combination of aspirin 650 mg and codeine 60 mg . Still, there are studies suggesting that the doses recommended by the manufacturers are too low . In children, the recommended dosage of rectally administered acetaminophen is 20 mg kg−1, while studies have shown a dose/response analgesic efficacy in the postoperative period up to a single dose of 60 mg kg−1 without any side-effects . However, the therapeutic window of acetaminophen is small, and even moderate acetaminophen overdosage can result in liver damage . Recently, an i.v. precursor of acetaminophen, propacetamol, has been developed. One gram of the precursor readily converts into 0.5 g of acetaminophen. Propacetamol seems to have good analgesic potency, and in a study with patients undergoing gynaecological surgery, propacetamol 2 g equalled ketorolac 30 mg in analgesic efficacy . This may indicate that the i.v. administration of propacetamol with a higher initial peak plasma concentration may result in better analgesia than the oral acetaminophen in our study.
We found ibuprofen 800 mg thrice daily as a basic oral analgesic to be well tolerated and efficacious. The analgesic efficacy of ibuprofen in the postoperative period is well established [15,16]. Although there are reports of a prolonged bleeding time after the perioperative use of NSAIDs , especially if used in combination with low molecular weight heparin, it is still disputed whether this has a clinical relevance [2,18]. The amount of surgical bleeding in our study, estimated by the reduction in haemoglobin concentration after operation, was identical in all three groups. Thus, although this is a rough estimation of blood loss, the use of NSAID did not seem to affect the haemoglobin concentration.
Acetaminophen is metabolized by glucuronidation in the liver, but a small portion is metabolized through oxidation to the intermediate N-acetylbenzoequinoeimin (NABQI). NABQI is highly cytotoxic, and in the kidney, prostaglandin-hyperperoxidase is the major oxidizing enzyme contributing to the production of NABQI. By inhibition of the cyclo-oxygenase with NSAIDs, more prostaglandin hyperperoxidase is available to produce NABQI. The effect of NSAIDs on local prostaglandin production in the kidney may affect glomerular filtration rate (GFR) and renal blood flow, thereby affecting renal function. Therefore, the use of perioperative NSAIDs is not recommended in patients with marginal kidney function, although a recently published study failed to detect any reduction in renal function when NSAIDs were used in a group of elderly patients undergoing orthopaedic surgery . Theoretically, the combination of a NSAID and acetaminophen should impair renal function to a larger extent than the use of NSAIDs alone. Although no significant differences in creatinine clearance were found between the study groups, the number of patients included is far too small and the study period too short to make any conclusions about the renal function.
In conclusion, ibuprofen 800 mg thrice daily after anterior cruciate ligament reconstruction under general anaesthesia had a better analgesic effect than acetaminophen 1 g thrice daily. Both ibuprofen and the combination of ibuprofen and acetaminophen reduced pain and were opioid sparing.
This study has received financial support from Foinco Invest, Box 1671, Vika N-0120 Oslo, Norway (20 000 Norwegian Kroners).
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