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Canadian Journal of Anesthesia 54:254-261 (2007)
© Canadian Anesthesiologists' Society, 2007
Reports of Original Investigations

Early oral analgesia after fast-track cardiac anesthesia

[L’analgésie orale précoce après la technique accélérée d’anesthésie cardiaque]

Alexander Kogan, MD*, Benjamen Medalion, MD*, Ehud Raanani, MD*, Erez Sharoni, MD*, Alon Stamler, MD*, Natalia Pak, MD{dagger}, Bernardo A. Vidne, MD* and Leonid A. Eidelman, MD{dagger}

* From the Departments of Cardiothoracic Surgery and
{dagger} Anesthesiology, Rabin Medical Center, Beilinson Campus, Petah Tiqwa, and Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.

Address correspondence to: Dr. A. Kogan, Department of Cardiothoracic Surgery, Rabin Medical Center, Beilinson Campus, Petah Tiqwa 49100, Israel. Phone: +972-3-9376701; Fax: +972-3-9240762; E-mail: alexanderkogan140{at}hotmail.com


   Abstract
TOP
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 References
 
Purpose: Oral analgesia after "fast-track" cardiac anesthesia has not been explored. The aim of this study was to compare two oral oxycodone analgesic regimens.

Methods: One hundred-twenty patients scheduled for coronary artery bypass grafting were randomly assigned postoperatively to receive immediate-release oxycodone 5 mg and acetaminophen 325 mg (Percocet-5) (group I) per os four times daily, or controlled-release oxycodone 10 mg (OxyContin) (group II) per os every 12 hr and placebo twice daily. Acetaminophen 500 mg per os was used as first-line rescue medication, and immediate-release oxycodone (syrup form) 5 mg per os as second-line rescue medication. Pain intensity was assessed with a visual analogue scale on the first postoperative day, the morning after extubation, and thereafter four times daily for four days. Use of rescue medication and adverse events were recorded.

Results: Baseline demographic and operation-related characteristics were similar in both groups. While pain control was good in both groups, the immediate-release group experienced less pain on all postoperative days (P = 0.003), required significantly less rescue medication, and had fewer adverse effects such as somnolence and nausea.

Conclusion: Peroral oxycodone is effective for early pain control after fast-track cardiac anesthesia. Immediate-release oxycodone/ acetaminophen appears to provide better analgesia and fewer side effects compared to controlled-release oxycodone.


   Introduction
TOP
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 References
 
PAIN after cardiac surgery may be caused by the sternotomy, leg vein harvesting, pericardiotomy, and chest tube insertion.1,2 Opioids - specifically iv morphine - have been the mainstay of postoperative analgesia since the introduction of cardiac surgery. A potential alternative to iv morphine is oxycodone, a strong oral opioid agonist, used alone or in combination with mild analgesics. Oxycodone has an analgesic potency comparable to morphine3 and is suitable for oral administration due to its high bioavailability (60%). Several studies in patients after noncardiac surgery reported good pain control and high patient satisfaction with rapid conversion of iv opioid analgesics to oral immediate-release or controlled-release oxycodone.4–6

A review of the recent literature7 suggests that immediate-release and controlled-release oxycodone have similar efficacy in the treatment of noncancer pain and similar side effects. Controlled-release oxycodone may offer the advantage of less frequent dosing, thereby decreasing nursing workload. There is no difference in the bioavailability of these two formulations.

Immediate-release oxycodone is absorbed in a mono-exponential manner (time to maximum serum concentration, one hour; mean half-life by single-dose pharmacokinetics, 3.5–5.65 hr; mean time from administration to analgesia, 0.52 ± 0.33 hr) and controlled-release oxycodone in a bi-exponential manner (rapid phase with mean half-life of 0.52 hr accounting for 38% of the dose, followed by a slow phase with a mean half-life of 6.2 hr).8

In 2001, our department introduced a fast-track protocol for coronary artery bypass grafting (CABG), and peroral postoperative analgesia became part of routine practice. The aims of the present study were twofold: first, to investigate the safety and efficacy of early conversion from an iv to an oral opioid regimen after fast-track cardiac surgery; and secondly, to compare postoperative analgesia between immediate-release oxycodone/acetaminophen and controlled-release oxycodone. Our null hypothesis is the assumption that postoperative analgesia after use of immediate-release oxycodone/acetaminophen is not different from analgesia provided by controlled-release oxycodone.


   Materials and methods
TOP
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 References
 
The study was conducted in a tertiary-care, university-affiliated centre using a double-blind, randomized, controlled design. The protocol was approved by our institutional review board, and all patients provided written informed consent on enrolment. The study group consisted of 120 patients scheduled for elective CABG between January and June 2003 and targeted for fast-track anesthesia with low-to-moderate-dose fentanyl, early extubation, early mobilization, and an intensive care unit (ICU) stay of less than 24 hr. Preoperatively, patients scheduled for an off-pump coronary artery bypass procedure were excluded from the study, as were patients with a history of chronic analgesia or tranquilizer use or dependence on alcohol. Patients with clinical malabsorption, renal insufficiency, or hepatic disorders (abnormal liver function) were also excluded. Postoperative exclusion criteria consisted of delayed transfer to the general ward (i.e., ICU stay > 24 hr) or readmission to the ICU. The following data were collected: preoperative - age, sex, body mass index, history of diabetes, and renal insufficiency; intraoperative - type of procedure, urgent or emergent operation, duration of anesthesia, and duration of cardiopulmonary bypass (CPB); ICU-related - duration of ventilation, ICU length of stay, score on the visual analogue scale (VAS), and need for inotropic support at the time of extubation.

All patients received a standard anesthesia protocol. Premedication consisted of midazolam syrup 0.1 mg·kg–1 po, and anesthesia was induced with fentanyl 10 to 15 µg·kg–1 iv and midazolam 0.02 to 0.04 mg·kg–1 iv. Pancuronium bromide was given to facilitate endotracheal intubation, and the lungs were then ventilated with an oxygen/air mixture to maintain normocapnia. Anesthesia was maintained with isoflurane, fentanyl, and midazolam. The total intraoperative dose of fentanyl was 30.1± 9.2 µg·kg–1 and of midazolam, 0.12 ± 0.09 mg·kg–1. All operations were carried out through a median sternotomy. The internal thoracic artery was used in all cases and was harvested in a skeletonized manner; the left radial artery and saphenous vein were used at the discretion of the surgeon and were harvested in an open technique. Anticoagulation was achieved with 3 to 4 mg·kg–1 of heparin to reach and maintain an activated clotting time > 480 sec. Standard CPB management included use of a membranous oxygenator, arterial line filters, nonpulsatile flow, and maintenance of mean arterial pressure above 60 mmHg. Myocardial protection was achieved by multiple administration of anterograde and/or retrograde blood cardioplegia. Topical cooling was not mandatory. Core temperature was decreased to approximately 30°C in almost all cases according to our department policy. All patients were rewarmed to 37°C before discontinuation of CPB. At the end of surgery, heparin was reversed with protamine. Patients were returned to the cardiothoracic ICU while still intubated.

Postoperative care consisted of mechanical ventilation in the assist-control mode, cardioactive drugs when indicated, and the use of warm air heaters to maintain normothermia. Analgesia was provided by intermittent iv morphine injections, and sedation, by intermittent iv midazolam injection to maintain a Ramsay sedation score of ≥ 3 during assisted ventilation. All medications were given by a nurse. Midazolam and morphine consumption were recorded. Criteria for weaning from the ventilator were hemodynamic stability (no use, or decreasing use of cardioactive drugs), absence of significant bleeding (≤ 100 mL·hr–1), absence of significant arrhythmias, adequate urine output (≥ 1 mL·kg–1·hr–1), and oxygen saturation > 95% with fractional concentration in inspired oxygen less than 0.50; patients also needed to be sufficiently awake to follow commands. Patients fulfilling these criteria were placed on pressure support ventilation of 8 cm H2O for 20 to 30 min, and in the absence of respiratory or cardiac distress, extubation was performed immediately thereafter. Inotropic drug administration was continued when needed. According to our institutional protocol, based on the study of Ovrum,9 the patient was seated in a chair 45–70 min after extubation followed by transfer to the ward three to five hours later, and was full mobilized ten to 12 hr later.

After extubation, patients were randomized in a double-blind manner into two groups of 60 each. Randomization was achieved by placing instructions for one of the two postoperative analgesia options in each of 120 envelopes. The envelopes were sealed, mixed and assigned a number from 1 to 120. Each patient was consecutively assigned one envelope, and medication was administered according to the instructions, in a ratio of 1:1. All medical and nursing staff, except one of the investigators (N.P.), was blinded to the results of randomization. Group I patients received immediate-release oxycodone 5 mg and acetaminophen 325 mg per os (Percocet-5, Taro Pharmaceuticals, Israel) four times daily, at 06:00 hr, 12:00 hr, 18:00 hr, and bedtime (± 1.5 hr each time, at least four hours following the previous dose). Group II patients received controlled-release oxycodone 10 mg per os (OxyContin, Rafa Laboratories, Israel) twice daily, at 06:00 hr and 18:00 hr, with matching placebo at 12:00 hr and bedtime. The first dose was given 30–60 min after tracheal extubation. Pain intensity was assessed at rest with the ten-point VAS scale.10 Use of the scale was explained to the patients preoperatively. A difference of 1 in the VAS score corresponds to a 30–35% change in pain intensity after surgery, which may be considered a meaningful change, in accordance with previous studies.11 Pain assessment was performed on the first postoperative day, the morning after extubation, 1.5 hr after the first analgesic medication, and thereafter four times daily (morning, afternoon, evening and overnight) for four days. Acetaminophen 500 mg per os served as the first-line rescue medication, and immediate-release oxycodone (OxyCode syrup) 5 mg per os as the second-line rescue medication.

Use of rescue medication and adverse events were recorded. Somnolence was defined as difficulty to arouse during the pain assessment interview. Vomiting was defined as one episode of vomiting during the study period. Nausea, pruritus, headache and dizziness were recorded. Renal dysfunction was defined as a rise in creatinine of > 0.5 mg·dL–1 after cardiac surgery. Stroke was defined as a new fixed neurological defect that persisted at least 24 hr after surgery. Postoperative atrial fibrillation was defined as the characteristic arrhythmia, lasting for at least 15 min and confirmed on 12-lead electrocardiogram, and occurring within the first four postoperative days.

Statistical analysis
After we conducted a pilot study to assess the VAS mean and standard deviation, a sample size calculation estimated that 60 patients in each group were required to achieve 84% power to detect a difference of 1 VAS score unit between groups, with estimated group standard deviations of 2.4 at a significance level (alpha) of 0.05.

Continuous data are expressed as mean (± SD) and categorical data as number (%). Differences between groups were analyzed with Student’s t test, Chi-square or Fisher exact test, as appropriate. Repeated postoperative VAS measurements were analyzed by the repeated measures general linear model. A P value < than 0.05 was considered significant. The statistical analysis was performed with SPSS 13.0 for Windows.


   Results
TOP
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 References
 
All of the 120 randomized patients completed the study protocol. No patients were excluded because of delayed transfer to general ward or ICU stay > 24 hr, or re-admission to ICU. There were no significant differences between the immediate-and controlled-release oxycodone groups with respect to preoperative, intraoperative, or postoperative variables (Tables IGo and IIGo). Mean VAS scores were significantly higher in group II compared to group I (P < 0.05 for all assessment points) (FigureGo). On multivariate linear analysis with repeated measures, after adjustment for age, sex, use of bilateral thoracic arteries, diabetes, chronic obstructive pulmonary disease, renal failure, congestive heart failure and low left ventricular function, only the type of analgesia remained a strong independent predictor of VAS score (P = 0.003).


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  		TABLE I Patient Characteristics and Preoperative Medications
 

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  		TABLE II Intraoperative data and postoperative outcomes
 

Figure 1
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  		FIGURE Visual analogue scale scores in patients receiving immediate-release (Percocet) or controlled-release oxycodone (Oxycontin) for four days after fast-track cardiac surgery. Data are presented as means ± 95% confidence limits. Mean scores were higher in the controlled-release group (P < 0.05) at all assessment points.

 
More patients in group II required rescue analgesic medication at all time points (Table IIIGo), and more had adverse events (12/60, or 20% vs 7/60, 11.7% in group I) (Table IVGo). The most frequent adverse event was somnolence, occurring in seven patients (11.7%) in group II and two patients (3.3%) in group I (P < 0.01), followed by nausea in six patients (10%) and five patients (8.3%), respectively. No cases of impaired liver function were observed in either group. There were no analgesia-related or other complications that warranted readmission to the ICU.


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  		TABLE III Use of rescue analgesia in patients receiving oral analgesia after fast-track cardiac surgery
 

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  		TABLE IV Adverse events in 120 patients receiving oral analgesia after fast-track cardiac surgery
 

   Discussion
TOP
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
References
 
The key findings from this study disprove our null hypothesis, and demonstrate that immediate-release oxycodone/acetaminophen provides superior analgesia compared to controlled-release oxycodone.

Studies have shown that fast-track management is becoming common practice in many cardiac surgical departments, increasing bed turnover12 and decreasing resource utilization13 at no extra risk to patients.14 The rapid postoperative rehabilitation procedure that is mandatory for the success of fast-track management (early ambulation after tracheal extubation, followed by transfer to the ward within several hours and full mobilization on the same day)9 requires optimal pain management. For fast-tracking, administration of opioids, the mainstay of postoperative analgesia, via the standard iv or patient-controlled route15,16 is unfeasible. Once patients are able to tolerate oral medications, the oral route is preferred, because it is more convenient, noninvasive, and less expensive.17 Combined oral and rectal administration on the first postoperative day is also reliable,18,19 although some patients find the latter route of drug administration distressing.

Balanced or multimodal analgesia involves the selective use of specific drugs in combination. The concept relies on using multiple analgesic drugs with different modes of action (for example non-opioids combined with an opioid) There is now good evidence that this approach improves analgesia due to additive or synergistic effects, permitting the doses of the individual drugs to be reduced, thereby reducing the incidence and severity of adverse effects.20 The administration of non-opioid oral agents for postoperative pain would avoid the respiratory depression and drowsiness associated with opioids, but the limited analgesia makes them useful only as adjuncts. Legeby et al.21 reported that after breast surgery the addition of non-steroidal anti-inflammatory drugs (NSAIDs) to paracetamol and opioid-PCA reduced opioid consumption and improved pain relief at rest, but not convincingly during mobilization. Postoperative blood loss was also higher with diclofenac. Bainbridge et al.22 suggested that in patients less than 70 yr of age undergoing cardiothoracic surgery, the adjunctive use of NSAIDs with narcotic analgesia reduces 24-hr VAS pain scores and narcotic requirements. Fayaz et al.23 suggested that diclofenac alone or with paracetamol has a significant opioid-sparing effect after CABG, allowing for earlier extubation and improved oxygenation. Accordingly, Hynninen et al.18 and Kulik et al.24 suggested that NSAIDs not be used as monotherapy. Nonopioid analgesics, which include acetaminophen, aspirin, NSAIDs, and cyclooxygenase-2-specific inhibitors (coxibs), are frequently used for analgesia. Although all of these agents are effective at controlling pain, inhibition of prostaglandins (PGs) by NSAIDs may result in untoward cardio-renal effects, including hypertension, fluid and electrolyte abnormalities, congestive heart failure, acute renal failure, and nephrotic syndrome. Because acetaminophen has a different mechanism of action from conventional NSAIDs, it does not inhibit peripheral PGs at recommended dosing, and therefore appears to have a more favourable cardiovascular and gastrointestinal safety profile.25 Cyclooxygenase-2 inhibitors, such as paracoxib and valdecoxib were associated with an increased incidence of cardiovascular events after CABG, arousing serious concern regarding their use in this setting.26,27 Berger et al.28 reported that oral acetaminophen (paracetamol) was well absorbed in the early period after cardiac surgery. In our study, patients who received Percocet (oxycodone/acetaminophen) had better analgesia compared to patients who received oxycodone only. However, Lahtinen et al.29 suggested that iv propacetamol did not enhance analgesia, nor did it decrease cumulative opioid consumption or reduce adverse effects for three days after surgery.

Although Frenette30 emphasized that potent opioid analgesia can be administered orally, there are limited data on the conversion dosing from iv to oral opioids after fast-track cardiac surgery. The present study showed that the early conversion was well tolerated. Regarding the type of oral regimen, Reuben et al.,31 in a comparison of immediate-and controlled-release oxycodone after outpatient orthopedic surgery, found that a controlled-release regimen provides better analgesia. However, many orthopedic procedures are associated with more intense postoperative pain than cardiac surgery. In contrast, Gammaitoni et al.32 compared controlled-release oxycodone with immediate-release oxycodone/acetaminophen (Percocet) in patients after oral surgery and found the immediate-release agent to be superior. Our study also demonstrates better results with immediate release of a combination of opioid and acetaminophen than with controlled release of opioid alone following fast-track cardiac surgery.

We observed that the commonly reported opioid side effects6,31–34 were present with both regimens, namely, somnolence, dizziness, pruritus, nausea and vomiting. Respiratory depression, one of the most concerning side effects of opioid medications, was not observed in either group, nor were there any acetaminophen-related side effects, including hepatotoxicity. Overall, the incidence of side effects was lower in our study than previously reported, and the frequency of side effects was less in the immediate-than the controlled-release group.

The present study has several limitations. First, the anesthetic technique was not tightly controlled, and included different doses of fentanyl intraoperatively and morphine postoperatively. Second, we compared immediate-release oxycodone/acetaminophen with controlled-release oxycodone without acetaminophen. Third, only a single dosage and a single duration of treatment were assessed. Fourth, our inclusion of only low-risk patients with a EuroSCORE of 4–5, limits interpretation of the findings for higher-risk cardiac surgery populations.

In conclusion, this randomized, double-blind trial demonstrates that oral oxycodone effectively controls postoperative pain after cardiac surgery. The combination of immediate-release oxycodone/acetaminophen (Percocet) was associated with significantly better analgesia compared to controlled-release oxycodone, with fewer adverse effects. We suggest that the analgesia provided by the combined regimen provides an additive effect, allowing improved analgesia with smaller doses of each drug, thereby limiting side effects associated with each class of analgesic medication. Further studies are warranted to corroborate and expand these findings.


   Footnotes
 
Accepted for publication October 30, 2006. Revision accepted December 21, 2006.


   References
TOP
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 Mueller XM, Tinguely F, Tevaearai HT, Revelly JP, Chiolero R, Von Segesser LK. Pain pattern and left internal mammary artery grafting. Ann Thorac Surg 2000; 70: 2045–9.[Abstract/Free Full Text]

2 Mueller XM, Tinguely F, Tevaearai HT, Revelly JP, Chiolero R, Von Segesser LK. Pain location distribution, and intensity after cardiac surgery. Chest 2000; 118: 391–6.[Medline]

3 Poyhia R, Vainio A, Kalso E. A review of oxycodone’s clinical pharmacokinetics and pharmacodynamics. J Pain Symptom Manage 1993; 8: 63–7.[Medline]

4 Ginsberg B, Sinatra RS, Adler LJ, et al. Conversion to oral controlled-release oxycodone from intravenous opioid analgesic in the postoperative setting. Pain Med 2003; 4: 31–8.[Medline]

5 Czarnecki ML, Jandrisevits MD, Theiler SC, Huth MM, Weisman SJ. Controlled-release oxycodone for the management of pediatric postoperative pain. J Pain Symptom Manage 2004; 27: 379–86.[Medline]

6 Gammaitoni AR, Galer BS, Bulloch S, et al. Randomized, double-blind, placebo-controlled comparison of the analgesic efficacy of oxycodone 10 mg/ acetaminophen 325 mg versus controlled-release oxycodone 20 mg in postsurgical pain. J Clin Pharmacol 2003; 43: 296–304.[Abstract/Free Full Text]

7 Rischitelli DG, Karbowicz SH. Safety and efficacy of controlled-release oxycodone: a systematic literature review. Pharmacotherapy 2002; 22: 898–904.[Medline]

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9 Ovrum E, Tangen G, Schiott C, Dragsund S. Rapid recovery protocol applied to 5,658 consecutive "on-pump" coronary bypass patients. Ann Thorac Surg 2000; 70: 2008–12.[Abstract/Free Full Text]

10 DeLoach LJ, Higgins MS, Caplan AB, Stiff JL. The visual analog scale in the immediate postoperative period: intrasubject variability and correlation with a numeric scale. Anesth Analg 1998; 86: 102–6.[Abstract]

11 Jensen MP, Chen C, Brugger AM. Interpretation of visual analog scale ratings and change scores: a reanalysis of two clinical trials of postoperative pain. J Pain 2003; 4: 407–14.[Medline]

12 Flynn M, Reddy S, Shepherd W, et al. Fast-tracking revisited: routine cardiac surgical patients need minimal intensive care. Eur J Cardiothorac Surg 2004; 25: 116–22.[Abstract/Free Full Text]

13 Cheng DC, Wall C, Djaiani G, et al. Randomized assessment of resource use in fast-track cardiac surgery 1-year after hospital discharge. Anesthesiology 2003; 98: 651–7.[Medline]

14 Reis J, Mota JC, Ponce P, Costa-Pereira A, Guerreiro M. Early extubation does not increase complication rates after coronary artery bypass graft surgery with cardiopulmonary bypass. Eur J Cardiothorac Surg 2002; 21: 1026–30.[Abstract/Free Full Text]

15 Bowler I, Djaiani G, Abel R, Pugh S, Dunne J, Hall J. A combination of intrathecal morphine and remifentanil anesthesia for fast-track cardiac anesthesia and surgery. J Cardiothoracic Vasc Anesth 2002; 16: 709–14.[Medline]

16 Pettersson PH, Lindskog EA, Owall A. Patient-controlled versus nurse-controlled pain treatment after coronary artery bypass surgery. Acta Anaesthesiol Scand 2000; 44: 43–7.[Medline]

17 Follin SL, Charland SL. Acute pain management: operative or medical procedures and trauma. Ann Pharmacother 1997; 31: 1068–76.[Abstract]

18 Hynninen MS, Cheng DC, Hossain I, et al. Non-steroidal anti-inflammatory drugs in treatment of postoperative pain after cardiac surgery. Can J Anesth 2000; 47: 1182–7.[Abstract]

19 Reimer-Kent J. From theory to practice: preventing pain after cardiac surgery. Am J Crit Care 2003; 12: 136–43.[Abstract/Free Full Text]

20 Elia N, Lysakowski C, Tramer MR. Does multimodal analgesia with acetaminophen, nonsteroidal antiinflammatory drugs, or selective cyclooxygenase-2 inhibitors and patient-controlled analgesia morphine offer advantages over morphine alone? Meta-analyses of randomized trials. Anesthesiology 2005; 103: 1296–304.[Medline]

21 Legeby M, Sandelin K, Wickman M, Olofsson C. Analgesic efficacy of diclofenac in combination with morphine and paracetamol after mastectomy and immediate breast reconstruction. Acta Anaesthesiol Scand 2005; 49: 1360–6.[Medline]

22 Bainbridge D, Cheng DC, Martin JE, Novick R; Evidence-Based Perioperative Clinical Outcomes Research (EPiCOR) Group. NSAID-analgesia, pain control and morbidity in cardiothoracic surgery. Can J Anesth 2006; 53: 46–59.[Abstract/Free Full Text]

23 Fayaz MK, Abel RJ, Pugh SC, Hall JE, Djaiani G, Mecklenburgh JS. Opioid-sparing effects of diclofenac and paracetamol lead to improved outcomes after cardiac surgery. J Cardiothorac Vasc Anesth 2004; 18: 742–7.[Medline]

24 Kulik A, Ruel M, Bourke ME, et al. Postoperative naproxen after coronary artery bypass surgery: a double-blind randomized controlled trial. Eur J Cardiothorac Surg 2004; 26: 694–700.[Abstract/Free Full Text]

25 Whelton A. Clinical implications of nonopioid analgesia for relief of mild-to-moderate pain in patients with or at risk for cardiovascular disease. Am J Cardiol 2006; 97: 3–9.[Medline]

26 Nussmeier NA, Whelton AA, Brown MT, et al. Kogan et al.: Complications of the COX-2 inhibitors parecoxib and valdecoxib after cardiac surgery. N Engl J Med 2005; 352: 1081–91.[Abstract/Free Full Text]

27 Chang DJ, Desjardins PJ, Bird SR, et al. Comparison of rofecoxib and a multidose oxycodone/acetaminophen for the treatment of acute pain following oral surgery: a randomized controlled trial. Curr Med Res Opin 2004; 20: 939–49.[Medline]

28 Berger MM, Berger-Gryllaki M, Wiesel PH, et al. Intestinal absorption in patients after cardiac surgery. Crit Care Med 2000; 28: 2217–23.[Medline]

29 Lahtinen P, Kokki H, Hendolin H, Hakala T, Hynynen M. Propacetamol as adjunctive treatment for postoperative pain after cardiac surgery. Anesth Analg 2002; 95: 813–9.[Abstract/Free Full Text]

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32 Gammaitoni AR, Davis MW. Comparison of the pharmacokinetics of oxycodone administered in three Percocet formulations. J Clin Pharmacol 2002; 42: 192–7.[Abstract]

33 Kaplan R, Parris WC, Citron ML, et al. Comparison of controlled-release and immediate-release oxycodone tablets in patients with cancer pain. J Clin Oncol 1998; 16: 3230–7.[Abstract]

34 Sunshine A, Olson NZ, Colon A, et al. Analgesic efficacy of controlled-release oxycodone in postoperative pain. Clin Pharmacol 1996; 36: 595–603.





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