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Original Article

Intravenous magnesium sulphate decreases postoperative tramadol requirement after radical prostatectomy*

Tauzin-Fin, P.; Sesay, M.; Delort-Laval, S.; Krol-Houdek, M. C.; Maurette, P.

Author Information
European Journal of Anaesthesiology: December 2006 - Volume 23 - Issue 12 - p 1055-1059
doi: 10.1017/S0265021506001062

Abstract

Introduction

Abdominal urologic surgery is associated with intense postoperative pain [{L-End} 1] and a large amount of opioid analgesic drugs is often needed during the post-operative period for adequate pain relief. However opioids are associated with side-effects such as respiratory depression, ileus, nausea and vomiting, pruritus and urinary retention [{L-End} 2]. Because of their analgesic properties and their lack of opioid-induced adverse effects, local anaesthetic drugs have become a relevant alternative in the treatment of surgical pain. After infiltration into the surgical wound, the local anaesthetic agent reduces peripheral pain by inhibiting the transmission of nociceptive inputs from the surgery site [{L-End} 3,{L-End} 4]. So a multimodal approach combining the effects of ropivacaine wound infiltration, intravenous (i.v.) tramadol and paracetamol can be proposed [{L-End} 5,{L-End} 6]. Magnesium is a physiological blocker of the N-methyl-d-aspartate (NMDA) receptors [{L-End} 7]. Post-synaptic depolarization following nociceptive inputs decreases this ability to block calcium inflow through the receptor. Thus, by blocking the NMDA receptor throughout the perioperative period, magnesium might play a key role in postoperative pain, sensitization processes and hyperalgesia. Magnesium could then lead to a decrease in postoperative pain and analgesic consumption [{L-End} 7]. Magnesium has been used as an effective adjuvant in postoperative pain management after orthopaedic and gynaecologic surgery [{L-End} 8–11]. The aim of this study was to assess whether the addition of i.v. magnesium at the induction of anaesthesia to balanced analgesia including wound infiltration, paracetamol and tramadol patient-controlled analgesia (PCA) resulted in improved analgesic efficiency after radical prostatectomy.

Methods

Following Ethics Committee approval and informed patients consent, 30 ASA I or II males scheduled for radical retropubic prostatectomy with general anaesthesia were recruited, into a prospective, randomized, double-blind and placebo-controlled study. Preoperatively, patients were taught how to use the PCA device and a standardized horizontal 100 mm linear visual analogue scale (VAS) was used for pain assessment at rest. Moreover, patients were informed of bladder drainage and the risk of bladder spasm pain that was treated systematically by oxybutinin 5 mg three times a day. Exclusion criteria were inability to use the PCA device, chronic pain history or long-term use of opioids and treatment with calcium channel blockers.

Patients were randomly assigned to one of the two groups: patients in the magnesium group (Gr Mg, n = 15) received 50 mg kg−1 (0.2 mmol kg−1) body weight of MgSO4 in 100 mL of isotonic saline solution over 20 min immediately after induction of anaesthesia and before skin incision, whereas patients in the control group (Gr C, n = 15) received the same volume of saline over the same period. Randomization was performed using a computer randomization list based on a study identification number, and the anaesthetist in charge of the patient received from the chief nurse an infusion bag containing either MgSO4 or isotonic saline solution. The anaesthetist was unaware of which solution was administered.

All patients were premedicated with oral hydroxyzine 100 mg, 1 h before surgery and a standardized general anaesthetic was performed. Anaesthesia was induced using i.v. propofol 2.5 mg kg−1 and sufentanil 0.8 μg kg−1. Tracheal intubation was facilitated with cisatracrium 0.15 mg kg−1. Anaesthesia was maintained with an end-tidal sevoflurane concentration of 2–2.5% and a target-controlled infusion of sufentanil (0.4 ng mL−1). Neuromuscular block was achieved by a continuous infusion of cisatracrium 4 mg h−1. The patients were mechanically ventilated with a mixture of air–oxygen 50% and ventilation was adjusted to keep end-tidal PCO2 between 4.7 and 6 kPa. Isotonic saline solution was infused at the rate of 10–15 mL kg−1 h−1. Heart rate, systolic, mean and diastolic blood pressure, oxygen saturation and oesophageal temperature were recorded at 5-min intervals throughout the surgical procedure. A colloid infusion (Elohes® 500 mL) was used when surgical blood losses were up to 500 mL. The variations in systolic arterial pressure during mechanical ventilation (Δ down) were used to detect hypovolaemia and improve fluid replacement. Normothermia was maintained with a forced warm air device throughout anaesthesia.

At the time of abdominal wall closure which was about 20 min before the end of surgery, wound infiltration was performed on both the sides with ropivacaine 190 mg (40 mL) and the continuous infusions of sufentanil and cisatracrium were stopped. Concomitantly, an i.v. infusion of paracetamol 2 g and a loading dose of tramadol 100 mg were infused over a 15-min period.

In the recovery room, a staff anaesthetist, blinded to the assignment of the patients, was in charge of the pain management. The time of tracheal extubation was the start of the study period and was noted as ‘time 0’. The level of pain at rest was assessed by a VAS from 0 to 100 mm (0 = no pain, 100 = unbearable pain), every 4 h, for the first postoperative 24 h. A PCA device containing tramadol 8 mg mL−1 and droperidol 0.05 mg mL−1 was provided to all patients using the following setting: 16 mg bolus dose, 10-min lockout interval, no background infusion. Tramadol consumption was noted every 4 h during the same period. In the two groups, 10 mg metoclopramide and 1 g paracetamol were administered i.v. as the antiemetic and rescue analgesic drugs (if VAS > 50), respectively when required. Sedation was assessed using a 5-point scale with 0 = alert and 4 = deep sleep. Duration of surgery, perioperative anaesthetic drug consumption and blood losses, total and bolus doses of tramadol and side-effects (such as sedation >2, nausea and vomiting) were also recorded. Blood samples for determination of serum magnesium concentration were obtained the day prior to surgery and in the recovery room. The normal range of our laboratory was between 0.65 and 1 mmol L−1.

Statistical analysis

Data were expressed as mean values ± SD (and ranges). Continuous variables such as patient characteristics data and total tramadol consumption were analysed using t-test. Ordinal data (VAS values, sedation score) were analysed using the U-test. Tramadol consumption was analysed by analysis of variance (ANOVA) test for repeated measures. The χ2-test was used to analyse dichotomous data. We decided that a 10% difference in tramadol consumption between the two groups would be important. Therefore n = 15 patients in each group would be necessary to detect a difference if α = 0.05 and β = 0.2 (power: 80%). A P value of <0.05 was considered statistically significant.

Results

The two groups were similar regarding patient characteristics data, surgery duration, intraoperative blood loss, intraoperative doses of sufentanil and cisatracrium and time to tracheal extubation (Table 1). Two patients in each group received blood tansfusions. Cumulative mean tramadol dose after 24 h was 226 ± 73 mg in the magnesium group and 444 > 60 mg in the control group (P < 0.001) (Table 2). Analysis of tramadol consumption during the 24-h postoperative period showed that patients in the magnesium group consumed significantly less tramadol at each 4-h time interval than those in the control group (P < 0.001). The consumption of tramadol was constant over time (Fig. 1). Pain values at rest were similar in the two groups throughout the study period (Fig. 2). No sedation was observed, all patients being fully awake (score 1). Postoperative nausea occurred in two patients in each group after the start of tramadol PCA, and this responded rapidly to i.v. metoclopramide. Two patients in the magnesium group required analgesic rescue as compared to eight patients in the control group; however, the difference was not statistically significant (P = 0.053). Pre- and post-serum magnesium concentrations were similar in both groups.

Table 1
Table 1:
Patient characteristics and intraoperative data.
Table 2
Table 2:
Postoperative events and total tramadol consumption.
Figure 1.
Figure 1.:
Tramadol consumption in the two groups. The cumulative tramadol consumption at each 4-h interval was lower in group mg (data are presented as mean ± SD); *P < 0.001.
Figure 2.
Figure 2.:
Pain VAS at rest (data are presented as median ± SD).

Discussion

The results of this study demonstrate that 50 mg kg−1 magnesium sulphate given as a bolus at induction of anaesthesia induces an analgesic-sparing effect as shown by the decrease in the tramadol consumption over the 24-h postoperative period. Patients were pain free at tracheal extubation in the two groups because the analgesic effects of paracetamol and tramadol are effective, at this period, confirming the efficiency of the multimodal analgesia [{L-End} 5,{L-End} 6]. The cumulative tramadol consumption was significantly lower in the Mg group for each period, leading to a 50% reduction over the 24-h period, as compared with the control group. The incidence of side-effects (nausea) was low in each group and no sedation was reported. This low incidence of side-effects in the control group could explain the lack of decrease in side-effects when tramadol consumption is reduced in the Mg group.

The rationale for multimodal analgesia for the treatment of postoperative pain is to achieve additive or synergistic analgesic properties while decreasing the incidence of side-effects [{L-End} 5,{L-End} 6]. Many data propose the use of local analgesic agents for postoperative pain relief [{L-End} 3,{L-End} 4]. Ropivacaine is a long-acting amide with onset, potently and duration similar to those of bupivacaine [{L-End} 12]. Its slight vasoconstrictor effect at lower concentrations increases its local duration of action, with less cardiac and central nervous system toxicity [{L-End} 13]. Wound infiltration with ropivacaine has been used successfully for postoperative analgesia in patients undergoing various surgical procedures [{L-End} 14–16]. Moreover, at the dose of 30 mL (7.5 mg mL−1) for wound infiltration, Horn and colleagues reported a unbound ropivacaine plasma concentration peak at 0.08 ± 0.09 μg mL−1 after 15 min with a maximum of 0.3 μg mL−1, compared with a toxic threshold of 0.6 μg mL−1 and no cardiac complications were identified [{L-End} 15]. Tramadol, a synthetic μ opioid agonist (of the amino cyclo hexanol group) is a centrally acting analgesic with weak opioid agonist properties, and effects in noradrenergic and seretonergic neurotransmission [{L-End} 17]. Tramadol is effective in i.v. PCA in various conditions [{L-End} 18–20], and does not give clinically significant respiratory depression [{L-End} 20,{L-End} 21]. Paracetamol is commonly used because of its morphine-sparing effect.

Pain assessments after urologic surgery show high pain scores ranging from 60 to 70 mm on VAS [{L-End} 1]. After radical prostatectomy, VAS pain intensity of 45 and 70 mm are reported in the treated group and in the placebo group respectively, hence confirming the need of an effective postoperative pain management [{L-End} 22]. Time to tracheal extubation and the first 4 postoperative hours were pain free in the two groups confirming the efficiency of our protocol. Thus, this approach avoids opioid titration and its side-effects such as sedation and respiratory depression [{L-End} 23,{L-End} 24]. VAS pain scores are low (<30–40 mm), do not differ significantly between groups over time and are consistent with the appropriate use of the PCA pump. Moreover, the PCA technique maintains an effective analgesic effect, already present at the start of the PCA [{L-End} 21].

In this study, i.v. administration of magnesium reduced tramadol consumption by about 50%. This analgesic-sparing effect has also been reported in studies using morphine in the management of postoperative pain [{L-End} 8–11]. Magnesium does not exert a non-specific effect by preventing hypomagnesaemia since preoperative magnesium concentrations were normal. Moreover, a magnesium bolus does not act pharmacologically throughout the 24-h study period and cannot enhance the analgesic effects of tramadol [{L-End} 25]. Analgesia from a bolus dose of magnesium might result from its action as a non-competitive NMDA receptor antagonist [{L-End} 7]. Opioids not only exert an antinociceptive effect, but also modulate central NMDA receptors, resulting in hyperalgesia and acute opioid tolerance as previously widely described [{L-End} 26,{L-End} 27]. NMDA receptor antagonists, such as ketamine or magnesium, have been demonstrated to increase the analgesic effects of opioids, probably by limiting these NMDA mediated facilitating processes [{L-End} 26,{L-End} 28,{L-End} 29]. Tramadol consumption remains significantly lower in the magnesium group as compared to the control group and is constant over time, as assessed every 4 h throughout the 24-h study. The propagation of intense nociceptive stimuli has been reported as being susceptible to lowering the nociceptive threshold and inducing the hyperalgesic process by sensitizing the NMDA receptors [{L-End} 30]. The incidence of PONV after tramadol PCA is about 20–30% [{L-End} 31]. In our study the incidence decreased to 13%, due to the addition of droperidol to tramadol in the PCA pump [{L-End} 32], and the perioperative loading dose of tramadol [{L-End} 33]. One important limitation of this study is that overall patient satisfaction was not assessed. Therefore, we cannot tell whether the patients would have chosen again the same analgesia after a similar operation.

In conclusion, the role of NMDA receptor antagonists in the management of postoperative pain remains controversial. However, existence of side-effects and lack of clear evidence of efficacy of conventional analgesic protocols plead in favour of the use of NMDA receptor antagonists. Intravenous magnesium sulphate, associated with a balanced analgesia, reduces tramadol consumption. This combination represents a suitable technique for postoperative pain management [{L-End} 34].

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Keywords:

MAGNESIUM; PAIN POSTOPERATIVE; COMBINED MODALITY THERAPY; ANALGESIC OPIOID, sufentanil, tramadol; SURGERY, urologic; ANAESTHETICS LOCAL, ropivacaine; ACETAMINOPHEN

© 2006 European Society of Anaesthesiology