Original article 475

Comparison of analgesic effect of tramadol alone and a combination of tramadol and paracetamol in day-care laparoscopic surgery
Mohammad Ali and Fauzia A. Khan
Background and objective To compare the analgesic efcacy of tramadol alone (1.5 mg kgS1) with a tramadol (1 mg kgS1) and paracetamol combination in day-care laparoscopic patients. Methods The analgesic efcacy of intravenous tramadol alone (1.5 mg kgS1) (group T) was compared with a combination of intravenous tramadol (1 mg kgS1) and oral paracetamol 1 g (group TP) in 60 day-care laparoscopic patients in a prospective randomized double-blind clinical trial in a tertiary care hospital. Intraoperative haemodynamic responses and postoperative visual analogue scores were used to assess the analgesic efcacy. Results Only one patient (in group T) received a single dose of rescue analgesia intraoperatively. The highest pain scores were recorded at 30 min postoperatively in both groups, and rescue analgesia was needed in eight patients in group T and in 13 patients in group TP (P U 0.08). The incidence of moderate-to-severe nausea was high in group T (P U 0.001). Conclusion We conclude that reducing the dose of tramadol to 1 mg kgS1 and combining it with paracetamol 1 g orally decreased the incidence of side effects of tramadol without reducing analgesic efcacy. Eur J Anaesthesiol 26:475479 Q 2009 European Society of Anaesthesiology.

European Journal of Anaesthesiology 2009, 26:475479 Keywords: day care, laparoscopy, paracetamol, tramadol Department of Anaesthesia, Aga Khan University, Karachi, Pakistan Correspondence to Dr Mohammad Ali, Assistant Professor, Department of Anaesthesia, Aga Khan University, Stadium Road, P.O. Box 3500, Karachi 74800, Pakistan Tel: +92 21 486 4631; e-mail: ali.mohammad@aku.edu Presented at the 11th World Congress on Pain, 2126 August 2005, Sydney, Australia (Poster Presentation) and the 25th Annual Conference of Pakistan Society of Anaesthesiologists, 1517 April 2005, Karachi, Pakistan. (Paper Presentation). Received 24 June 2008 Revised 11 August 2008 Accepted 3 October 2008

Laparoscopy and dye test is a common day-care surgical procedure. It is associated with pain of moderate intensity. Narcotic analgesics when used for providing analgesia have multiple side effects (nausea, vomiting, constipation, respiratory depression and delayed recovery), which make these drugs less suitable for day-care patients [1]. Tramadol is a cyclohexanol derivative with weak mu agonist, opioid-like activity. It also inhibits the reuptake of norepinephrine and promotes the release of serotonin. The synergy of monoaminergic and opioid activity achieves analgesic effects. It is indicated for moderateto-severe pain. Its advantages over other narcotic drugs are that it causes less respiratory depression than morphine and codeine and does not share the propensity of nonsteroidal anti-inammatory drugs (NSAIDs) to provoke asthma, gastrointestinal mucosal damage and renal impairment [24]. Common side effects of tramadol are nausea, vomiting, dizziness, drowsiness and dry mouth. Paracetamol is a metabolite of phenacetin, which has also been used for mild-to-moderate pain. It is a cyclooxygenase inhibitor resulting in the inhibition of prostaglandin synthesis predominantly in the central nervous system rather than in peripheral tissues. In general, it is free
0265-0215 2009 Copyright European Society of Anaesthesiology

of side effects in dosages used for acute pain management, but a mild increase in hepatic enzymes is seen occasionally, which is reversible [5]. Tramadol alone or in combination with paracetamol may be considered as an alternative analgesic for day-care laparoscopic surgeries. Combining analgesics may provide greater analgesia than can be achieved by increasing doses of individual components. At the same time, the combination may improve tolerability by using lower doses of each medication. Combinations are most effective when individual agents act synergistically, and data from animal studies suggest that tramadol and paracetamol have synergistic activity [6]. If paracetamol is combined with lower doses of tramadol and the same or even better analgesia may be achieved as with tramadol alone because of synergism, this may also decrease the incidence of side effects of tramadol. The objective of this study was to compare the analgesic efcacy of tramadol alone (1.5 mg kg1) with a tramadol (1 mg kg1) and paracetamol (1 g) combination in day-care laparoscopic patients.

Methods
After approval from the ethics review committee and written informed consent, 60 ASA I or II women of childbearing age (1840 years), presenting for laparoscopy and
DOI:10.1097/EJA.0b013e328324b747

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476 European Journal of Anaesthesiology

2009, Vol 26 No 6

dye test, were recruited in the study. The methodology used for recruitment was convenience sampling. Patients with a history of allergy or hypersensitivity to tramadol or paracetamol or both, history of epilepsy, chronic usage of analgesic drugs or monoamine oxidase inhibitors were excluded. The sample size of 56 patients was based on detecting a difference of one unit on the visual analogue scale (VAS), keeping a error at 0.05 and b error at 0.2. Sixty patients were enrolled. They were divided into two groups, T and TP, of 30 patients each. Patients were randomized for treatment allocation. Sixty slips of paper were taken, and 30 were labelled as group T and the remainder as group TP. These slips were mixed and were placed in opaque envelopes and were picked randomly by an assistant anaesthetist who was not involved in taking observations during the study. All patients were premedicated with oral midazolam (7.5 mg) 1 h preoperatively and received a further oral tablet which was either placebo (group T) or paracetamol (1 g) (group TP) 30 min before induction. The calculated dose of tramadol for each group was prepared in a 5 ml syringe, and the total volume was made up to 5 ml by adding distilled water by a person unconnected to the study. Syringes were labelled as study drug. On arrival in the operating room, baseline blood pressure (BP) and heart rate (HR) were recorded. Patients were preoxygenated for 3 min with oxygen (O2) at a ow rate of 6 l min1 from a circle breathing system. Anaesthesia technique was standardized. Group T received 1.5 mg kg1 and group TP received 1.0 mg kg1 intravenous tramadol at induction. The anaesthetist administering the medication was blinded to the syringe content. Following study drug administration, anaesthesia was induced with propofol (2 mg kg1) slowly over 30 s followed by atracurium (0.6 mg kg1) intravenously. Maintenance was achieved with O2, nitrous oxide (N2O) in 1 : 2 ratio and isourane (0.61.2%). Ventilation used a volume control mode with a tidal volume of 810 ml kg1 and respiratory rate set to achieve normocapnia (end-tidal carbon dioxide, 35 40 mmHg). Electrocardiography, noninvasive BP, pulse oximetry capnography, inspiratory and expiratory concentrations of isourane and N2O (Datex Ohmeda, Helsinki, Finland) were continuously monitored. Intraoperative HR and noninvasive BP were used for assessment of pain. Pethidine (10 mg) intravenous bolus was administered as a rescue analgesic if patients HR or BP or both were increased to 30% above baseline and other causes of tachycardia and hypertension (e.g. hypercarbia, hypoxia and inadequate muscle paralysis) were excluded. Intraoperatively, HR and systolic and diastolic BPs were measured every 5 min and recorded as follows: baseline,

before incision, 1, 5, 20 and 40 min after incision. All measurements were taken by the person who was blinded to the study groups. At the end of the procedure, reversal of muscle relaxation was achieved with neostigmine (0.05 mg kg1) and atropine (0.02 mg kg1) intravenously. The number of intraoperative doses of rescue analgesia was noted. Postoperatively, patients were observed for pain, BP, HR, nausea and vomiting. A VAS of 110 was used to assess the pain in the recovery room; 13 was taken as mild pain, 46 as moderate pain and 710 as severe pain. The rst reading was taken 1 min after arrival in the recovery room and then at 10, 30 and 60 min intervals. The last reading was taken at 4 h from induction of anaesthesia (on the day-care unit). Pethidine (10 mg) was administered intravenously as rescue analgesia if the patient complained of moderate-to-severe pain (score of 4 or above on VAS of 110). Postoperative analgesia was administered by nursing staff blinded to treatment groups, and the number of doses received was noted. Nausea was assessed by verbal descriptive scale (no nausea, mild, moderate and severe nausea), and the episodes of both nausea and vomiting were noted. Metoclopramide (10 mg) was given intravenously if a patient complained of moderate or severe nausea or had vomiting. Other side effects such as dizziness, sweating, headache and dry mouth were also noted. All patients were observed for a total of 4 h starting from the time of induction.

Statistics
Data were entered on Statistical Package for Social Sciences (SPSS) version 11.5 (SPSS Inc., Chicago, Illinois, USA). VAS scores for pain and haemodynamic responses were analysed using repeated-measures analysis of variance. The independent samples t-test was used for comparing means of age and weight of patients and duration of anaesthesia. A P value of less than 0.05 was considered signicant. The chi-squared test was used to compare the number of patients in each group who received rescue analgesia and to compare the incidence of side effects.

Results
Patients characteristics and duration of anaesthesia are given in Table 1. A decrease in HR compared with the baseline was observed in both groups. The maximum
Table 1

Patients characteristics and duration of anaesthesia

Group T (n 30) Group TP (n 30) 28.7 3.3 68.3 10.8M 57.4 6.6

(n U 60)

Age (years) Weight (kg) Duration of anaesthesia (min) Values are means SD.
M

30.8 5.2 61.0 6.1 57.4 12.7

P 0.03.

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Analgesic effect of tramadol and paracetamol Ali and Khan 477

Fig. 1

Table 2

Number of patients who received rescue analgesia with pain scores more than 3 in the postoperative period
Group T (n 30) 0 1 6 1 0 Group TP (n 30) 0 0 12M 1 0

120 100

Time intervals On arrival in recovery room At 10 min At 30 min At 60 min At 4 h

M

HR (/min)

80 60 40 20 0 Baseline Before incision 1 min 5 min 20 min 40 min

P 0.04.

Time intervals
Comparison of mean heart rate between group T (n 30) and group TP (n 30) at comparable time intervals. Data are means SD. HR, heart , Heart rate in group T; , heart rate in group TP. rate.

in diastolic BP as compared with baseline were within 20% in both groups. Mean diastolic BP was comparable in groups T and TP in most readings except at 1 min and 20 min after incision (Fig. 2). Only one patient in group T received a single dose of rescue analgesia intraoperatively. None of the patients in group TP required rescue analgesia intraoperatively. Eight patients in group T and 13 patients in group TP had pain scores of more than 3, that is, VAS score 46 (P 0.08), and they all received rescue analgesia (Table 2). Postoperatively, none of the patients had severe pain (VAS score >6). The highest pain scores were recorded at 30 min postoperatively in the recovery room in both groups (Table 2). In group T, mean pain score was 2.43 (SD 1.77), and, in group TP, 3.13 (SD 1.25) at 30 min. Mean pain scores were comparable at different time intervals in both groups except at 4 h, group T, 0.33; group TP, 0.80 (P 0.03) (Table 3). Moderate-to-severe nausea in the recovery room was present in 30% (n 9) of patients in group T compared with no patients in group TP (P 0.001). Other side effects such as vomiting, dry mouth and dizziness were more frequent in group T, but the difference was not statistically signicant (Table 4).

decline in group T was 14% at 20 min after incision and 10% at 40 min after incision in group TP. HR was comparable in both groups at comparable time intervals with no statistically signicant difference (Fig. 1). Fluctuations in systolic BP were within 15% of baseline in both groups. Mean systolic BP was comparable in groups T and TP at comparable time intervals except before incision and 1 min after incision (Fig. 2). Changes
Fig. 2

160 140 120 100

Blood pressure mmHg

Discussion
80 60

* *

40 20 0
Baseline Before incision 1 min 5 min 20 min 40 min

Although laparoscopic surgery results in substantially less severe discomfort than the corresponding open procedure, pain associated with laparoscopy can be considerable. Prevention and treatment of pain relies on local anaesthesia, NSAIDs and opioid analgesics, often used in combination. Caudal block [7], inguinal block [8], local
Table 3 Comparison of postoperative pain scores among groups T and TP at different time intervals Time intervals Pain scores Group T (n 30) Group TP (n 30) 0.43 1.0 1.50 1.0 3.13 1.2 2.23 1.0 0.80 0.9M

Time intervals
Comparison of mean systolic and mean diastolic blood pressure between group T (n 30) and group TP (n 30) at comparable time , Systolic intervals. Data are means SD. P value < 0.05. , systolic blood pressure in group blood pressure in group T; , diastolic blood pressure in group T; , diastolic blood TP; pressure in group TP.
On arrival in recovery room At 10 min At 30 min At 60 min At 4 h Values are means SD.
M

0.30 0.7 1.60 1.0 2.43 1.7 1.87 1.2 0.33 0.6

P 0.03.

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478 European Journal of Anaesthesiology

2009, Vol 26 No 6

Table 4

Comparison of side effects between groups T and TP

Group T (n 30) 9 6 7 1 0 2
M

Side effects Moderate-to-severe nausea Vomiting Dry mouth Shivering Sweating Dizziness

Group TP (n 30) 0M 2 2 1 0 0 P 0.001.

BP and HR were only very slightly and transiently elevated following intravenous tramadol (100 mg) [16]. Postoperatively, patients mostly from the combination group complained of either mild or moderate pain, but the difference was not statistically signicant. None of the patients experienced severe pain in either group. By combining drugs with different mechanisms of action and pharmacokinetic proles, one can enhance efcacy even though lower doses of individual drugs are used [17]. Various studies have suggested enhanced analgesic efcacy using multimodal analgesic strategies compared with unimodal analgesic treatment so that one can limit side effects, reduce postoperative pain and analgesic requirements and facilitate an earlier return to normal activities. Many studies have conrmed the efcacy and tolerability of a combination of paracetamol and tramadol in both acute and chronic pain [1820]. Combinations of tramadol and paracetamol have demonstrated genuine synergy in animal studies [6]; therefore, in our present study, we reduced the dose of tramadol to 1 mg kg1 in combination with 1 g of paracetamol. Intraoperatively, none of the patients required rescue analgesia in the combination group (TP). Postoperatively, none of the patients had severe pain (VAS score >6). This again conrms its analgesic efcacy. The only side effect that had a signicantly higher incidence in group T was moderate-to-severe nausea. Safety data for tramadol have recently been summarized by Cossmann et al. [21]. The following side effects have been observed after the use of tramadol. The most frequent adverse events were nausea (6.1%), dizziness (4.6%), drowsiness (2.4%), tiredness or fatigue (2.3%), sweating (1.9%), vomiting (1.7%) and dry mouth (1.6%). Adverse events that occurred in less than 1% but more than 0.1% of patients were somnolence, hypotension, ushing, upset stomach, constipation, nausea and vomiting, sedation, sleep disorder, pruritus, abdominal pain, diarrhoea, tachycardia and local irritation. The frequency of nausea and vomiting was higher in our study than that reported with the use of tramadol. The higher frequency may be due to the fact that the patients in our study were young women undergoing laparoscopic surgery, who generally have a higher incidence of nausea and vomiting than other population groups [22]. Another contributory factor may be the use of pethidine as rescue analgesia (ve patients who had moderate or severe nausea or vomiting had received rescue analgesia). A statistically signicant difference between the two groups emerged regarding their body weight despite randomization (P 0.03), but we administered tramadol according to per kilogram body weight, therefore this difference is less likely to affect the efcacy of the drug.

Values are number of patients experiencing side effects.

inltration [9] and various other blocks have been used for providing analgesia for laparoscopy. Various NSAIDs are used in day-care patients, but they are associated with side effects [10]. Opioid analgesics are effective in treating pain after laparoscopic procedures; however, they are also associated with side effects. A variety of other therapeutic modalities have been used to try to reduce pain after laparoscopy, including anticholinergic drugs [11], tramadol and paracetamol [3,12]. Multiple studies have demonstrated the analgesic efcacy and tolerability of orally, intramuscularly or intravenously administered tramadol in acute pain. A metaanalysis of data from 3453 patients in 18 placebo-controlled trials established the safety and dose-dependent efcacy of tramadol in the treatment of moderate-tosevere dental or postsurgical pain [13]. Although tramadol has also been used in posttraumatic, obstetric and renal or biliary colic pain, most studies have investigated postoperative pain. Among these, only a few studies have investigated the analgesic efcacy of tramadol in patients undergoing day-care surgery. These studies proved that the analgesic efcacy of tramadol was better than fentanyl and ketorolac [12,14]. The benet of tramadol in day-care surgery was seen in a study of 228 patients undergoing surgery through a groin incision. Tramadol (100 mg) administered during and after operation was compared with the combination of intraoperative fentanyl (100 mg) and postoperative co-codamol. In these relatively painful procedures, tramadol provided superior analgesia [14]. Tramadol has been used in different doses (1.5 3 mg kg1) in various procedures, depending upon the expected severity of pain [12,15]. As pain associated with laparoscopy and dye test is expected to be moderate in intensity, tramadol was used in a dose of 1.5 mg kg1 in our study. Only one patient in our tramadol-alone group required rescue analgesia intraoperatively. This demonstrated the analgesic efcacy of tramadol intraoperatively for this procedure. The uctuations in HR and BP were within 15% of baseline, which shows the haemodynamic stability with the use of the drug. This has been found in previous studies in which tramadol had no clinically relevant haemodynamic effects. In healthy volunteers,

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Analgesic effect of tramadol and paracetamol Ali and Khan 479

There is no single well accepted and widely applicable method of measuring intraoperative pain. In our study, intraoperative pain was assessed by haemodynamic responses. Profound physiological changes often accompany pain, for example sympathetic response resulting in increase in HR and BP, but studies indicate that these physiological and endocrine events occurring concurrently with pain may be a general response to stress and not unique to pain [23]. Both our study groups were comparable in attenuating the haemodynamic responses. We assessed postoperative pain with a VAS, which is a valid tool for measurement of pain but has certain limitations [24]. A VAS measures pain as a unidimensional experience. It quanties only the intensity of pain and not the quality of pain. Patients may be very random in how they place their mark on the scale. The VAS is not easily administered to patients who have perceptual motor problems. Mean pain scores were comparable between the two groups at almost all time intervals. None of the patients had a score of more than 6. More patients in group TP (43%) than in group T (27%) had a pain score more than 3 (VAS score 46), but this difference is statistically insignicant (P 0.08). In conclusion, tramadol alone (1.5 mg kg1) and the tramadol (1 mg kg1) with paracetamol (1 g) combination provided adequate intraoperative and postoperative analgesia with haemodynamic stability in day-care gynaecological laparoscopic patients. Reducing the dose of tramadol to 1 mg kg1 and combining it with paracetamol (1 g) orally decreased the incidence of side effects of tramadol without reducing analgesic efcacy.

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Acknowledgement
The authors acknowledge Mr Salman Sabir and Mr Iqbal Azam (statisticians) for their help in statistical aspects of this study.

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