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Anesth Analg 2002;95:813-819
© 2002 International Anesthesia Research Society

CARDIOVASCULAR ANESTHESIA

Propacetamol as Adjunctive Treatment for Postoperative Pain After Cardiac Surgery

Pasi Lahtinen, MD*, Hannu Kokki, MD PhD*, Heikki Hendolin, MD PhD*, Tapio Hakala, MD{dagger}, and Markku Hynynen, MD PhD{ddagger}

*Department of Anesthesia and Intensive Care and {dagger}Department of Surgery, Kuopio University Hospital, Kuopio; and {ddagger}Department of Anesthesia and Intensive Care, Helsinki University Central Hospital, Jorvi Hospital, Espoo, Finland

Address correspondence and reprint requests to Pasi Lahtinen, MD, Department of Anesthesiology and Intensive Care, Kuopio University Hospital, FIN-70210 Kuopio, Finland. Address e-mail to pasi.lahtinen{at}kuh.fi


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Postoperative pain management after cardiac surgery has been mainly based on parenteral opioids. However, because opioids have numerous side effects, coadministration of non-opioid analgesics has been introduced as a method of reducing opioid dose. In this prospective, randomized, double-blinded study, we evaluated the efficacy of propacetamol, an IV administered prodrug of acetaminophen (paracetamol), as an adjunctive analgesic after cardiac surgery. Seventy-nine patients scheduled for elective coronary artery bypass grafting were randomized to receive either propacetamol 2 g (n = 40) or placebo (n = 39) IV in 6-h intervals for 72 h. From the time of extubation, patients had access to an opioid (oxycodone) via a patient-controlled analgesia device. Pain was evaluated on a visual analog scale four times daily, whereas respiratory function tests (forced vital capacity, forced expiratory volume in 1 s, peak expiratory flow, and arterial blood gas measurements) were performed once a day. The prespecified primary efficacy variable (cumulative oxycodone consumption at the end of the 72-h postoperative period) was 123.5 mg (51.3 mg) (mean [SD]) in the propacetamol group and 141.8 mg (57.5 mg) in the placebo group (difference in mean, 18.3 mg = 13%; 95% confidence interval, 6.1–42.7 mg; P = 0.15). Pain scores did not differ between the groups at rest (P = 0.65) or during a deep breath (P = 0.72). The groups were also similar in terms of pulmonary function tests, postoperative bleeding, and hepatic function tests, and no significant differences were noted in the incidences of adverse effects. After completion of the study, apost hoc analysis was also performed analyzing the first 24 h as split into 6-h intervals. This analysis showed a significantly (P = 0.036) smaller consumption of oxycodone in the propacetamol group at 24 h (47.1 mg [20.7 mg] versus 57.9 mg [23.9 mg]; difference in mean, 10.8 mg; 95% confidence interval, 0.7–20.9 mg). In conclusion, propacetamol did not enhance opioid-based analgesia in coronary artery bypass grafting patients, nor did it decrease cumulative opioid consumption or reduce adverse effects within 3 days after surgery. However, post hoc analysis showed that oxycodone requirement was reduced within the first 24 h in the propacetamol group.

IMPLICATIONS: This is the first placebo-controlled study to investigate the efficacy of propacetamol as a complementary analgesic to opioids after cardiac surgery. Propacetamol did not enhance analgesia, nor did it decrease cumulative opioid consumption or reduce adverse effects in a dose of 2 g given every sixth hour for 3 days after surgery.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
Pain therapy after cardiac surgery traditionally relies on parenterally administered opioids. However, although opioids are potent analgesics, their use may cause a variety of adverse effects, such as excessive sedation, respiratory depression, biliary spasm, depression of gastrointestinal motility, and postoperative nausea and vomiting (PONV). Opioid consumption can be significantly reduced by combining non-opioid analgesics in pain therapy. Nonsteroidal antiinflammatory drugs (NSAIDs) effectively reduce opioid consumption in noncardiac surgery patients (1). However, the fear of potentially serious side effects, such as predisposition to increased postoperative bleeding and deterioration of renal function, means that NSAIDs are not widely used as analgesics after cardiac surgery with cardiopulmonary bypass (CPB). Although not proven, acetaminophen (paracetamol), which is not an NSAID, might be a safer non-opioid analgesic in cardiac surgery because it does not depress platelet function (2) or renal function (3) as much as NSAIDs.

A study in cardiac surgery patients found the absorption of acetaminophen, administered via a nasogastric tube or rectally after surgery, insufficient to achieve an antipyretic plasma concentration (i.e., 10 mg/mL) (4). This was probably mainly because of delayed gastric emptying after anesthesia and surgery (5). Whether an effective plasma concentration of acetaminophen can be achieved via non-IV routes remains uncertain.

A desired plasma concentration of acetaminophen can be achieved by giving it IV as a prodrug, i.e., as propacetamol, which is quickly hydrolyzed to acetaminophen in the bloodstream (6). Two grams of propacetamol form 1 g of acetaminophen, which leads to a maximum mean plasma concentration of 13.0 mg/L in 30 min (6).

In a previous study, propacetamol reduced morphine consumption by more than 40% after orthopedic surgery (7). Propacetamol has also been evaluated in cardiac surgery patients in two trials, albeit not placebo-controlled studies (8,9). In this prospective, randomized, double-blinded, placebo-controlled study, we examined the efficacy of propacetamol as an adjunctive analgesic after coronary artery bypass grafting (CABG).


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
This study was approved by the Ethics Committee of Kuopio University Hospital and conducted in accordance with the latest (September 1999) revision of the Declaration of Helsinki. All patients were informed and gave written consent. Patients scheduled for elective CABG with CPB and younger than 70 yr of age were considered eligible for the study. We excluded patients with known renal or hepatic dysfunction or sleep apnea syndrome. Patients with low cardiac output syndrome (cardiac index [CI] <2.0 L · min-1 · m-2) after CPB or who could not be weaned from mechanical ventilation within 12 h of the end of operation were also excluded, as were those who underwent a combined cardiac operation, including valvular surgery and patients operated with a beating heart (off-pump technique).

Eighty-eight patients were randomized into the propacetamol group (n = 44) or placebo group (n = 44). Randomization was done using random numbers and a balanced design with a computer program. The propacetamol and placebo ampoules were supplied by UPSA pharmaceutical company (Agen, France) and were identical in package and appearance. The blinding procedure was performed in our hospital pharmacy according to the randomization. The code remained blinded until the end of the study. Patients in the propacetamol group received 2 g of propacetamol hydrochloride in 100 mL of normal saline, whereas the placebo group patients received a 100-mL infusion of normal saline. All patients received 12 doses of study drugs at 6-h intervals (i.e., for 72 postoperative h).

The first dose of the drug was given immediately after arrival in the postanesthesia care unit (PACU), and the protocol lasted until all the propacetamol/placebo ampoules (n = 12) were infused.

When the patients were awake and tracheally extubated, pain was assessed four times daily at rest and during a deep breath using a 10-cm visual analog scale (VAS) with 0 cm equalling no pain and 10 cm equalling worst pain imaginable. Overall satisfaction with pain therapy was estimated on a four-point scale: 1 = very satisfied, 2 = satisfied, 3 = unsatisfied, and 4 = very unsatisfied. Sedation (Ramsay score) (10), PONV, and all other adverse effects were concomitantly registered with pain assessments. All the assessments were accomplished by the attending PACU or surgical ward nurse blinded to group assignment. The data sampling of pain scores was incomplete in several patients during the last 6 h of study. Therefore, VAS scores were analyzed and are presented only for 66 postoperative h.

Pulmonary function tests: forced vital capacity, forced expiratory volume in 1 s, and peak expiratory flow rate were assessed with a portable pulmonary function monitor (Vitalograph Escort, Buckingham, England). The monitor was calibrated before each measurement according to the manufacturer’s recommendations. Each measurement was duplicated and the best value recorded. Samples for measuring arterial blood gas tensions were taken once a day between 10 and 12 h on the three postoperative mornings for the analysis of PCO2 and PO2. The samples were analyzed immediately (ABL-520, Radiometer, Copenhagen, Denmark).

From the time of extubation and after repetition of instructions, the patients had access to oxycodone with a patient-controlled analgesia device (PCA device; Graseby 3300P, Hoyer, Bremen, Germany) using a standardized protocol: bolus dose of 2 mg, dose duration of 2 min, lockout interval of 13 min (15 min effective lockout time), and with no background infusion and no upper dose limit. Before commencing the PCA, the nurses in the PACU were allowed to give oxycodone 5 mg IV before extubation for treatment of pain if required.

Opioid consumption was recorded (as oxycodone) from the PCA device at the end of the 72-h study period. Per protocol, the primary efficacy variable was cumulative oxycodone consumption (the combined amount administered via the PCA device and given as rescue doses) at the end of the 72-h postoperative period. If pain relief was insufficient (VAS score >3 at rest), nurses were allowed to give an extra bolus of oxycodone 5 mg IV as a rescue analgesic once an hour. Renal and liver function tests (serum creatinine, alanine aminotransferase [ALT], and {gamma}-glutamyl transferase) were measured the evening before surgery and 4 days after surgery. Bleeding after surgery was measured as chest tube drainage. The number of red cell units transfused was recorded.

A standardized anesthesia technique was used for all patients. The anesthetic drug doses were calculated according to body weight; diazepam at 0.25 mg/kg up to 20 mg was given as oral premedication. For the induction of anesthesia, the patients received propofol 1 mg/kg, fentanyl 15 µg/kg, midazolam 0.1 mg/kg, and pancuronium 0.1–0.15 mg/kg. Anesthesia was maintained with a continuous infusion of propofol 2–3 mg · kg-1 · h-1 and alfentanil 50 µg · kg-1 · h-1 until the end of surgery. Isoflurane supplementation was used at the discretion of the attending anesthesiologist. A 1–2.5 mg bolus of alfentanil was allowed if analgesia was considered unsatisfactory.

The operation consisted of a standard midline sternotomy, with harvesting of saphenous vein and internal thoracic artery as indicated. Antegrade intermittent cold crystalloid cardioplegia was used, and patients were cooled to 34°C and rewarmed to 37°C before decannulation. CPB was conducted using membrane oxygenation. Propofol sedation (2–4 mg · kg-1 · h-1) was continued in the PACU until the patients’ peripheral temperature exceeded 32°C, after which it was discontinued, and weaning from mechanical ventilation was started.

The sample size was estimated using a two-sided {alpha} level of 0.05 and a power of 0.80. When the opioid consumption was assumed to have decreased by 30% (11), the power analysis indicated 35 patients to be included in each group. To allow a 20% dropout, 44 patients per group were included.

Patient characteristics and anesthetic and operative variables were compared with the Mann-Whitney U-test and {chi}2 test (Pearson) when appropriate (categorical variables). Cumulative oxycodone consumption between the groups was compared with the Mann-Whitney U-test. Comparison of oxycodone consumption and VAS scores over time was performed using two-way analysis of variance for repeated measurements using a mixed design. A P value of less than 0.05 was considered statistically significant. Results are given as mean (SD) or number of patients. All statistical analyses were performed with SPSS version 10.0 software (SPSS Inc, Chicago, IL).


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Nine of the 88 randomized patients were excluded for the following reasons: withdrawal of consent (one patient), unstable preoperative angina (one patient), data sampling errors (one patient), scheduled CABG operation changed to combined valvular and CABG surgery (two patients), operation performed on beating heart (one patient), prolonged weaning from mechanical ventilation (one patient), bronchial obstruction requiring respirator therapy in the intensive care unit on the second postoperative day (one patient), and reoperation because of postoperative arterial bleeding from the pedicle of the left internal mammary artery graft (one patient). Hence, 79 patients, 39 in the placebo group and 40 in the propacetamol group, were included in the final analysis. Patient characteristics and operative and anesthetic variables, including opioid consumption during the procedure, did not differ significantly between the groups (Table 1).


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  		Table 1. Demographic, Operative, and Anesthetic Data
 
The variation of opioid (oxycodone) consumption was large in both groups (Table 2). Postoperative cumulative oxycodone consumption (the combined amount administered via the PCA device and given as rescue doses) was less in the propacetamol group than in the placebo group, but the difference was not significant (mean difference, 18.3 mg; 95% CI, 6.1–42.7 mg; P = 0.15). Opioid consumption decreased similarly in both groups with time (Fig. 1), and the amounts of oxycodone given as rescue doses were also similar (Table 2).


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  		Table 2. Consumption of Oxycodone, Laboratory Values, and Postoperative Bleeding
 


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  		Figure 1. Time course of cumulative opioid consumption over the 3 postoperative days. Values are expressed as mean + SD.

 
After completion of the study, a post hoc analysis of the cumulative oxycodone consumption within the first 24 h, split into 6-h intervals, was performed. This analysis showed that the opioid consumption was smaller (P = 0.036) in the propacetamol group during the first 24 h (47.1 ± 20.7 mg in the propacetamol and 57.9 ± 23.9 mg in the placebo group). The significant differences between the groups were localized to time points of 6 and 18 h. The opioid consumption was 7.2 ± 6.1 mg in the propacetamol and 10.0 ± 5.5 mg in the placebo group at 6 h and 12.5 ± 7.3 mg and 17.0 ± 8.4 mg at 18 h, respectively.

The overall VAS scores during the 66-h study period did not differ between the groups either at rest (P = 0.65) or during a deep breath (P = 0.72). The VAS scores were similar on successive postoperative days, both at rest (P = 0.38) and during a deep breath (P = 0.27), and they progressively decreased in both groups (Figs. 2 and 3). In both groups, the VAS scores at rest were around 3 or less at 24 h and thereafter, whereas during a deep breath, the VAS scores were at that level only at the end of the study, i.e., at 66 h. Overall satisfaction with analgesia was high and similar in both groups. Forty-five percent/58% of patients in the propacetamol group and 55%/42% in the placebo group were very satisfied/satisfied. Only one patient in the placebo group was very unsatisfied with the pain therapy.



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  		Figure 2. Time course of visual analog scale (VAS) pain scores at rest. Values are expressed as mean + SD.

 


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  		Figure 3. Time course of visual analog scale (VAS) pain scores during a deep breath. Values are expressed as mean + SD.

 
The groups were similar in terms of pulmonary function tests and blood gas analyses (Table 3) and postoperative bleeding (Table 2). There were no between-group differences in renal or liver function tests (Table 2).


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  		Table 3. Respiratory Variables Before Surgery and in 3 Postoperative Days
 
PONV was the most common adverse event (Table 4), with no differences between the groups. A breathing frequency of <10 breaths/min was observed in four patients (two in each group), but no patients had a breathing frequency less than 8 breaths/min. A few serious complications appeared among the patients during or after the study period (Table 4).


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  		Table 4. Adverse Events
 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
In this placebo-controlled study, propacetamol did not significantly decrease the cumulative oxycodone consumption within 72 hours after CABG surgery, which was the prespecified primary efficacy variable. Moreover, there were no differences in pain scores between the groups either at rest or during a deep breath. However, in the post hoc analysis, when the opioid consumption was examined only within the first 24 hours split into six-hour intervals, oxycodone requirement was smaller in the propacetamol group.

There are no previous placebo-controlled studies with propacetamol in cardiac surgical patients. However, in more minor surgery, propacetamol has been reported as an effective analgesic. In gynecologic surgery, propacetamol was found to have similar efficacy to ketorolac (a NSAID) and good tolerability when given in combination with morphine via PCA (12). However, in that study, the observation period was only 12 hours. The analgesic efficacy of propacetamol has also been demonstrated in orthopedic surgery by a decrease of 46% in morphine dose (7) within 24 hours after surgery. Moreover, analgesia was good or excellent in 87% of the patients receiving propacetamol compared with 65% of those receiving placebo. However, it is noteworthy that in the studies in gynecologic (12) and orthopedic (7) patients, the mean total doses of morphine were small, i.e., <20 mg, compared with more than 120 mg of oxycodone in the present study of cardiac surgical patients. Recently, Hernández-Palazón et al. (13) have also demonstrated a morphine-sparing effect of propacetamol with larger cumulative doses of morphine (mean dose of 112 mg in the placebo group and 60 mg in the propacetamol group) at 72 hours after spinal fusion surgery.

There are also reports of negative findings on the opioid-sparing effect of propacetamol. In a placebo-controlled study designed to evaluate the concept of balanced analgesia after vertebral disk surgery, Fletcher et al. (14) compared various analgesics given alone or in combination. Compared with placebo, pain scores and cumulative morphine consumption did not differ in the group receiving propacetamol only. In another placebo-controlled study, Zhou et al. (15) compared the analgesic efficacy of a single dose of propacetamol and ketorolac after total hip or knee replacement. Although both analgesics improved pain relief as assessed by pain intensity and pain relief scores, no morphine-sparing effect could be demonstrated during the six-hour postdosing evaluation period.

The cumulative opioid consumption in our patients, especially within the first 24 postoperative hours, was larger than that reported previously by others after cardiac surgery (16–18). Because we did not use, contrary to others (19,20), opioid titration before commencing the PCA dosing, the opioid consumption might have increased during the early postoperative phases. In addition, we used a larger bolus dose, i.e., oxycodone 2 mg (equivalent to morphine 2 mg) (21), and longer lockout time than some others (13). Furthermore, we did not set any upper dose limit per unit of time in the PCA delivering. All these factors might have predisposed to larger opioid consumption.

The reasons for the lack of analgesic effect of propacetamol during the 72-hour period in the present study are not clear. However, the large doses of oxycodone administered in the present study might have hindered the ability to show further analgesia, i.e., opioid-sparing effect, with propacetamol. Pain after sternotomy is excruciatingly intense (22,23). This was also observed in our patients during the first 24 postoperative hours when high pain scores were registered and large doses of oxycodone were consumed. Only during this early postoperative phase did propacetamol seem to decrease oxycodone consumption, as analyzed post hoc. Accordingly, in a study, Bjune et al. (24) noticed that paracetamol and an opioid (codeine) have additive analgesic effect in severe, but not in moderate, pain.

It remains uncertain, whether or not propacetamol dosing was too small with respect to pain intensity. Nonetheless, 2 g at six-hour intervals is the maximum dosing recommended in the literature and by the manufacturer. The antipyretic concentration of propacetamol, 10 mg/L, is achieved with 2 g IV within 30 minutes, but the concentration decreases less than this threshold after two hours (6). There does not seem to be definite data about the relationship of the antipyretic concentration of paracetamol to the analgesic concentration (25,26). Thus, the relationship of the dose of propacetamol used in the present study and the effective analgesic concentration remains unclear.

NSAIDs exert potent analgesic action after cardiac surgery (20,27). The effect is mediated by blocking the peripheral synthesis of cyclooxygenase 1 and 2. The mechanism behind the analgesic action of acetaminophen (paracetamol) is unclear. Acetaminophen has only a weak inhibitory influence on peripheral cyclooxygenases (28), and it has no substantial antiinflammatory activity. Acetaminophen-induced analgesia may be partially centrally mediated, and the peak cerebrospinal fluid concentrations may reflect the analgesic action (29). These different target sites and mechanisms of action with acetaminophen and NSAIDs may be reflected also as differences in their analgesic effects after cardiac surgery, especially when combined with large doses of potent centrally-acting analgesics such as oxycodone.

The pain scores per se in the present study were acceptably low (VAS <3) at rest from 24 hours onwards. However, they were high (VAS >5) during a deep breath until the end of the study, even though the patients had access to PCA oxycodone at all times. This may not be surprising because opioids seem to be more effective analgesics at rest than during function (e.g., cough or mobilization) (30). In addition, patients may have not been able to titrate the opioid dose in response to rapid changes in the nociceptive stimulus because of deep breathing with our PCA setting with a relatively long lockout time.

In our patients, PONV was a frequent adverse event. This may have been in part due to large opioid consumption. Nonetheless, our finding comports with the study of Woodward et al. (31) who reported a frequent incidence of PONV after cardiac surgery. By using propacetamol as an adjunctive analgesic, we could not demonstrate any decrease in this adverse event.

Our sample size was based on a power analysis with the assumption of a decrease in opioid consumption by 30% with propacetamol (11). The mean difference of 18 mg of opioid consumption between the groups was not statistically significant. Because the variation in opioid consumption was larger than assumed, we evaluated the possibility of too small a sample size, i.e., we calculated the 95% CI for the difference in the mean in opioid consumption between the groups. This analysis showed that the upper limit of the CI is 42.7 mg, i.e., just a 30% decrease in the mean oxycodone consumption with propacetamol as compared with placebo. This indicates that we cannot definitely exclude the possibility of the 30% decrease in opioid consumption with propacetamol. However, the observed small difference in the opioid consumption was not associated with any difference in clinically significant indices, such as the VAS scores, patient satisfaction, or ventilatory function.

In conclusion, only a minor (nonsignificant) difference was observed in opioid consumption and no difference in pain scores and respiratory function variables between the propacetamol and placebo groups. Therefore, no clinically significant effect of propacetamol could be demonstrated as an adjunct to PCA-oxycodone as assessed within 72 hours after cardiac surgery. Whether propacetamol has a definite opioid-sparing effect during the early postoperative phases of CABG remains to be evaluated in a prospective study with a modified methodology.


   Acknowledgments
 
The authors wish to thank P. Toroi, RN, T. Tuovinen, RN, and the nursing staff of the PACU and cardiac surgical ward of Kuopio University Hospital for invaluable collaboration for this study.


   Footnotes
 
Presented, in part, at the Annual Meeting of the Society of Cardiovascular Anesthesiologists, Vancouver, Canada, May 4–10, 2001.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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Accepted for publication May 7, 2002.




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Intravenous paracetamol as adjunctive treatment for postoperative pain after cardiac surgery: a double blind randomized controlled trial
Eur. J. Cardiothorac. Surg., September 1, 2007; 32(3): 527 - 531.
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P. F. White
The Changing Role of Non-Opioid Analgesic Techniques in the Management of Postoperative Pain
Anesth. Analg., November 1, 2005; 101(5S_Suppl): S5 - 22.
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I. Power
Recent advances in postoperative pain therapy
Br. J. Anaesth., July 1, 2005; 95(1): 43 - 51.
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C. Remy, E. Marret, and F. Bonnet
Effects of acetaminophen on morphine side-effects and consumption after major surgery: meta-analysis of randomized controlled trials
Br. J. Anaesth., April 1, 2005; 94(4): 505 - 513.
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P. Lahtinen, H. Kokki, T. Hakala, and M. Hynynen
S(+)-Ketamine as an Analgesic Adjunct Reduces Opioid Consumption After Cardiac Surgery
Anesth. Analg., November 1, 2004; 99(5): 1295 - 1301.
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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press