Controlling postoperative pain reduces anxiety, somatic and autonomic reflexes and on the other hand, improves the function of the organs (Kehlet et al., 2003; Heid and Jage, 2002). Many patients suffer from mild to moderate pain after renal transplantation; however, usage of morphine and meperidine in these patients is limited due to renal impairment: clearance of active metabolite of morphine (M6G) is kidney-related and as a result, the accumulation of these metabolites is common in patients with renal failure (Stein et al., 2000; Katzung et al., 2005). Therefore, these patients usually receive a little analgesia in post operative periods.
Several drugs have been administered to control pain in these patients (Mycek, 2000; Miller, 2000; Lahtinen et al., 2002; Power, 2005). Propacetamol is a water-soluble analgesic used IV in order to relieve mild to moderate pain; using recommended doses every 4-6 h, it has a similar pharmacokinetics as morphine (Dahl et al., 2000). The purpose of this study was to gauge the analgesic efficacy of propacetamol against morphine in order to assess their analgesic profile and complications after single and repeated administration.
MATERIALS AND METHODS
This randomized, double blinded, single centered study was conducted at Sina hospital, in Iran between May 2005 and April 2006. The study was performed in accordance with the ethical principles of Helsinki declaration, after being approved in the ethics committee of the hospital.
Thirty End Stage Renal Diseased (ESRD) candidates for renal transplantation from live donors were studied. The patients were given a written informed consent and a detailed definition of the procedures and the used pain scales, before being enrolled.
Patients with a recent history of liver dysfunction, respiratory and cardiac insufficiency and any condition affecting the metabolism of the medications in this study were excluded. Patients with a history of alcohol or drug abuse, with known hypersensitivity to morphine or propacetamol were also excluded. It should be noted that the drugs confounding the quantification of analgesia (sedative, anxiolytics, antihistamine) were withheld the night prior to the surgery.
During the operation, 0.04 mg kg-1 midazolam and 2 μg kg-1 fentanyl were used as pre medication; general anesthesia was induced with 3-4 mg kg-1 thiopental. Muscular relaxation for intubation and during surgery was achieved by atracurium. Anesthesia was maintained by oxygen (50%), nitrous oxide (50%), Isoflurane and supplementary fentanyl.
The mean duration of surgery was 2.5-3 h. At the end of the surgery and before
the performance of the skin sutures, 2 g propacetamol (Bristol- Myers Squibb-Egypt)
was infused (in 10 min) to 15 patients while others received 5 mg morphine IV
(Daroo Pakhsh-Iran). The patients were evaluated for pain score, blood pressure,
heart rate, SPO2 and lab tests including: BUN, Cr, Uric acid, ALT, AST, Alb,
PT, PTT, Ca, P and blood sugar during the 24 h following the operation by an
anesthesiologist blind to the type of the anesthetic drug administered.
The patients were interviewed by the observer to obtain a self-assessment of the intensity of their pain based on a four point Verbal Rating Scale (VRS), 0.5, 1, 1.5, 3, 4.5, 6, 12, 18 and 24 h following the operation.
0 = no pain
1 = slight pain
2 = moderate pain
3 = severe pain
The rate of pain relief was assessed via a five point VRS, 24 h after the operation.
0 = complete pain relief
1 = good pain relief
2 = satisfactory pain relief
3 = unsatisfactory pain relief
4 = no pain relief
Re-injection was performed every 6 h (2.5 mg morphine IV (4 doses) or 1 g propacetamol IV infused in 10 min (4 doses)) on those with no acceptable response to the previous dose. Any adverse effects or complications were recorded, in both groups.
The gathered data were entered in SPSS version 11.5 and analyzed using chi-square and student t-test.
Thirty patients were studied in 2 groups and demographic and selected background characteristics were matched. The patients' age ranged from 18-60 years with the mean age of 40.3±11.2 years. Table 1 presents the demographic information of the two groups.
According to the 4 point VRS, intensity of pain was less in the morphine group compared with the other group at recovery (10 min after extubation) and 24 h after surgery (p<0.05 and p<0.04, respectively) (Fig. 1). There was no significant statistical difference reported between the intensity of pain during the times 0 and 24, in the two groups.
Morphine showed better pain relief in 5 point VRS, 24 h following the operation (0.87±0.52 VS, 1.8±0.95, p = 0.002). In other words, 73.3% of the patients who received morphine had complete or good pain relief in 24 h while only 53.3% of patients in the propacetamol group stated a complete or good response (p = 0.25) (Table 2).
Adverse events were reported in 17 and 10 patients of morphine and propacetamol
group, respectively. (p<0.05) The most frequently reported adverse events
are outlined in Table 3.
||Pain relief in each group according to the VRS system
||Demographic data and the intensity of pain at recovery of
the enrolled patients in each group
|Value in parenthesis show percentage
|| The intensity of pain during the times 0 and 24 in each group
|| Side effects in each group
|Value without parenthesis show numbers
Pain at the injection site was most common in the propacetamol group whilst
nausea and constipation were frequently seen in those receiving morphine.
Acetaminophen is a central acting drug with analgesic effects, used to relieve mild to moderate pain such as headache (Varrassi et al., 1999; Sinatra et al., 2005). Propacetamol, a powder requiring reconstitution, is the intravenous form of acetaminophen. It is water-soluble, so it can be administered parenterally (2 g of propacetamol equivalent to 1 g of acetaminophen). Propacetamol is a rapid onset, so it can be used in order to reduce the intensity of pain during the first hours after operation (Beaussier et al., 2005; Boccara et al., 2005; Romsing et al., 2002).
This study demonstrated no significant differences in the mean intensity of pain between the two groups in various intervals, while the mean intensity was reported to be lower in time zero (in recovery) and in 24 patients receiving IV morphine compared with the other group. These results correlate with those obtained in other studies comparing propacetamol and morphine. Veuilleumier et al. (1998) stated higher pain score in patients receiving 0.2 mg kg-1 morphine compared with 30 mg kg-1 propacetamol, following a general anesthesia. They concluded propacetamol to be a good substitute for morphine in preventing mild to moderate post-operation pain (Vuilleumier et al., 1998). In another study, a decreased need to morphine and also a lower intensity of pain was showed in patients receiving propacetamol after spinal surgery (Hernandez-Palazon et al., 2001).
On the contrary, some studies did not support these results. It has been shown that a significant pain relief was observed in patients receiving morphine or propacetamol compared with placebo; however, the study did not reveal a significant difference between morphine and propacetamol (Aken et al., 2004). Some studies has also demonstrated that combine of NSAID and paracetamol has superior analgesia and pain relief compared with single drugs (Romundstad et al., 2006).
Fewer adverse events were reported in the propacetamol group. The most common problem in patients receiving propacetamol was pain or local reaction in the administration site (26.7%), while as for the morphine group, nausea and constipation were more common (40%). Vomiting, pruritus and bradycardia were also more frequent in this group. Other adverse events of propacetamol as reported in other studies are: nausea and vomiting in 8.8-62%, injection site pain in 28-38% and injection site complications in 52% of the cases (Varrassi et al., 1999; Boccara et al., 2005; Aken et al., 2004; Moller et al., 2005). Gasterointestinal, cardiac and dermatic complications were reported less in our study compared with other studies, despite the fact that injection site pain was reported as like others (Aken et al., 2004; Bannwarth et al., 1992). Injection site pain after propacetamol infusion is thought to be due to low pH and high osmolarity of the solution (pH: 3.5, osmolarity: 410 mOsmol L-1) which is different from the plasma (Miller, 2000; Lahtinen et al., 2002).
We are indebted to the Research and Development Center of Sina Hospital for their support. The authors gratefully acknowledge Dr. Patrcia Khashayar in reviewing this manuscript and her helpful comments.