Marcou, Thi Aurore MD; Marque, Sophie MD; Mazoit, Jean-Xavier MD, PhD; Benhamou, Dan MD
Department of Anesthesiology, Hôpital Bicêtre, Assistance Publique-Hôpitaux de Paris, F-94275 Le Kremlin-Bicêtre and Anesthesia Laboratory UPRES EA 3540, Faculté de Médecine du Kremlin-Bicêtre, Université de Paris-Sud, F-94276 Le Kremlin-Bicêtre, France
Supported by grants from the French Ministry of Research and the Association MAPAR.
Presented in an abstract form at the European Society of Anaesthesiologists congress Glasgow, June, 2003, and the French Society of Anesthesia and Intensive Care Congress Paris, September, 2003.
Accepted for publication July 27, 2004.
Address correspondence to Pr. Dan Benhamou, Department of Anesthesiology, Hôpital de Bicêtre, F-94275 Le Kremlin Bicêtre Cedex, France. Address e-mail to email@example.com.
Balanced analgesia is a validated concept in the postoperative period and is now recommended by national guidelines and publications (1,2). The association of analgesic drugs is expected to improve pain relief and limit the incidence and the severity of the side effects of each drug (3,4). Moreover, optimal pain relief demonstrates clinically significant advantages for surgical outcome. Pain relief accelerates postoperative surgical recovery and rehabilitation and contributes to reducing the duration of hospital stay (5). Morphine remains the standard reference drug for managing postoperative pain. Administered IV, it has both supraspinal and spinal actions and at small doses, it activates the descending analgesic pathway, inhibiting nociceptive signal transduction. At large doses, it decreases directly the nociceptive transduction across the synapse in the spinal cord by inhibiting the release of substance P or by hyperpolarizing postsynaptic interneurons (6). Because morphine exerts a global inhibitory effect on the central nervous system, its analgesic activity cannot be dissociated from its numerous adverse effects, in particular, respiratory depression (respiratory rate, tidal volume, and carbon dioxide sensitivity), nausea and vomiting, urine retention, and constipation (7,8). Balanced analgesia combining morphine with other analgesics has been encouraged to “spare” doses of morphine and to limit its adverse effects.
Tramadol is a centrally-acting analgesic with two distinct mechanisms of action: One enantiomer exerts a predominantly weak μ opioid effect, whereas the other inhibits norepinephrine and serotonin reuptake, activating descending monoaminergic inhibitory pathways (9). These complementary actions are thought to enhance the analgesic efficacy of tramadol by improving its tolerability profile. Parenteral and oral tramadol has proven effective and well tolerated in the management of moderate to severe acute postoperative pain in adults (10). Unlike other opioids, tramadol has no clinically relevant effect on respiratory or cardiovascular variables at recommended doses. On a weight basis, the analgesic potency of tramadol is 1/10 that of IV morphine and 1/13 epidurally (11). At the usually recommended dosage, the lack of full analgesic efficacy limits tramadol as a sole drug for treating severe pain after surgery. Its safety, however, suggests a place in combination with other drugs or with a regional anesthetic technique. The ED50, defined as the clinical dose for which 50% of the patients had their pain adequately relieved, has never been reported. The association of morphine and tramadol reported in one study suggests an eventual benefit from the combination of the two substances (12), but the ratio of the combination was not based on pharmacological evidence. Synergy between different opioids has been reported in animal studies (13). This synergy, with different receptor affinities and different pharmacokinetic properties, is also proposed as a rationale for the concept of opioid rotation (14). Thus, the aim of this study was 1) to define the ED50 of tramadol by using an up-down sequential allocation technique and 2) to compare it with the ED50 of morphine by isobolographic analysis to define the nature of their interaction (15).
After Ethics Committee approval and written informed consent were obtained, 90 ASA physical status I–II patients were enrolled and allocated to three groups. All patients were scheduled for surgery considered as slightly to moderately painful. Exclusion criteria were age <18 yr, contraindications to the use of tramadol or morphine, pregnancy, intraoperative regional anesthesia, any anticipated need for profound postoperative analgesia, postoperative pain <3 on a numeric pain scale (NPS; 0 = no pain; 10 = the worst possible pain).
The evening before surgery, patients were instructed how to use the NPS. All patients received a standard anesthetic technique consisting of IV induction with propofol or thiopental and remifentanil or sufentanil. Anesthesia was maintained with either an IV infusion of propofol or nitrous oxide and desflurane. Intraoperative analgesia was provided with remifentanil or sufentanil. At the end of surgery, IV droperidol (1 mg) was administrated systematically as an antiemetic in prevention of nausea and vomiting. Pain intensity was assessed using NPS, immediately on patient arrival in the postanesthesia care unit (PACU), and then every 5 min or when the patient complained of pain. As soon as the NPS score reached 3 (time defined as “T0”), patients were included and received analgesia as defined by the protocol.
In the first part of the study, 60 patients were randomized to receive either IV morphine (group M) or tramadol (group T), in a double-blind, randomized design using computer generated assignment. The dose of morphine or tramadol received by a particular patient was determined by the response of the previous patient within the same group using an up-down sequential allocation technique (16). In group T, the first patient received 100 mg of tramadol, and subsequent increments were 10 mg. In group M, the first patient received 5 mg of morphine and the increment was 1 mg. In the second part of the study, 30 other patients received a mixture of tramadol and morphine in a 40:3 dose ratio, corresponding to the calculated equianalgesic ratio. The first patient received 3 mg of morphine and 40 mg of tramadol. The increment was 6.67 mg for tramadol and 0.5 mg for morphine. Blinding was ensured by using blinded syringes prepared by an anesthesiologist who was not involved in patient pain assessment.
The efficacy of study drugs was assessed using the NPS 20 min after T0 (T20). Two outcomes were considered: 1) NPS <3 at T20: effective analgesia. The next patient received a smaller dose, i.e., 10 mg in group T, 1 mg in group M, 6.67 mg of tramadol and 0.5 mg of morphine in group M+T. 2) NPS ≥3 at T20: ineffective analgesia. The next patient received an increased dose with the same increment as above. In addition to NPS measurements, heart rate, arterial blood pressure, and oxygen saturation were recorded. Adverse effects of both tramadol and morphine (nausea, vomiting, dizziness, sweating, dry mouth, sedation, and respiratory depression) were recorded at T20 and thereafter at 30-min intervals until discharge from the PACU.
The three groups were compared for demographic data and side effects using χ2 or analysis of variance. NPS was compared among groups at T0 and at T20 using the Kruskal-Wallis test. ED50, the median dose leading to the probability of 0.5 for a patient of having a NPS <3 was calculated using the up-and-down method (16). A classical isobolographic technique was used in a second stage to assess the possible interaction between the two drugs (15). The 95% confidence contours of the joint action were drawn by joining the 95% confidence intervals in each axis of the isobologram. The combination was considered additive if these contours overlap, and as supra-additive or infra-additive otherwise. Results are reported as the mean ± sd or as the median (interquartile range) for continuous variables and as the frequency and 95% confidence interval (CI) for dichotomous variables.
The demographic data (age, sex ratio, weight, and type and duration of surgery) of the three groups were similar (Table 1). The number of patients given remifentanil was similar (7 of 30, 5 of 30, and 11 of 30 in the T, M, and T+M groups, respectively). On arrival in the PACU at T0, patient intensity of pain assessed by NPS was similar in the three groups with a median value of 5 (Table 2 and Fig. 1).
No difference was observed in the occurrence of side effects among the three groups, except for the incidence of dry mouth, which occurred significantly more frequently in the T+M group than in the other two groups (Table 2). Respiratory depression occurred in three patients in group M.
The ED50 (95% CI) of tramadol and morphine alone were, respectively, 86 mg (57–115 mg) and 5.7 mg (4.2–7.2 mg). The sequences of effective and ineffective analgesia are shown in Figure 2. The ED50 (95% CI) of the drug combination was 72 mg (62–82 mg) of tramadol and 5.4 mg (4.6–6.2 mg) of morphine. This ED50 was infra-additive (Fig. 3).
This study is the first to define the IV median effective analgesic dose of tramadol in postoperative patients. The ED50 of tramadol was 86 mg (57–115 mg), whereas morphine had an ED50 of 5.7 mg (4.2–7.2 mg). An isobolographic analysis demonstrated that tramadol and morphine were infra-additive when administrated in combination.
Tramadol has proved to be an effective and well tolerated analgesic in the management of moderate to severe acute postoperative pain in adults (10). Recommendations for the use of tramadol for postoperative pain are not well defined and vary among countries. A slow IV bolus of 100 mg followed by titration (50 mg every 10 to 20 minutes, to a total dose of 250 mg) is usually recommended as the initial dosing scheme. Maintenance is usually achieved with additional doses of 50 to 100 mg every 4 to 6 hours, to a maximum dose of 600 mg per day (10). Administration of tramadol by patient-controlled analgesia (PCA) also proved to be effective in many trials (17,18). However, the rational basis for these recommendations for postoperative pain management is unclear and the ED50 has not been reported. We calculated an ED50 of 86 mg (57–115 mg), which is close to the bolus recommended by the manufacturer. Clinically, this first dose, relieving only 50% of patients, may be insufficient in acute pain management. For morphine, an ED50 of 5.7 mg (4.2–7.2 mg) was found, confirming our previous results (19).
The pharmacodynamic and pharmacokinetic properties of tramadol and morphine are well documented (11). The onset of the action of tramadol after parenteral administration is in the range of minutes; the maximum effect is reached after 15–30 minutes, and the duration of its effect is 3–6 hours. Because rapid onset of analgesia is required in the postoperative period, a short interval of 10 to 20 minutes is recommended to assess the efficacy of the bolus and to further the titration, although the maximum analgesic effect is not reached yet. For morphine, the recommended interval is 5 to 10 minutes. A preliminary study found that the onset time of IV tramadol 100 mg or of morphine 10 mg boluses were actually comparable and estimated as 13 and 10 minutes, respectively (20). Thus, the 20-minute interval chosen to assess the efficacy of both drugs in our study appears adequate both to measure the full effect of the drugs and to adequately compare them.
We did not observe any significant difference in the incidence of adverse effects, except for dry mouth, which occurred significantly more frequently with the combination. Mouth dryness was reported by 17% and 13% of the patients in group T or M, respectively, whereas 50% of the patients receiving the combination reported this side effect. In a recent retrospective study, tramadol caused dry mouth in 10.7%–33% of the patients (21). Although this side effect is commonly reported with μ-opioids (22), the large proportion of subjects reporting mouth dryness in the combination group may have been the result of a greater additivity of this side effect or simply because the combination group was studied after the two other groups. Respiratory depression occurred in three patients in group M, whereas no depression was observed in the two other groups. Although not statistically significant, this fact should be mentioned.
Several trials have compared tramadol and morphine in an attempt to determine their equianalgesic ratio. In the treatment of moderate pain, IV tramadol 50 to 150 mg was equivalent in analgesic efficacy to morphine 5 to 15 mg. For intraoperative analgesia, a mean cumulative dose of tramadol of 137 mg was equivalent to 12.2 mg of morphine (tramadol:morphine ratio, 11.2:1) (23). We found a ratio of 86:5.7 mg (15:1), comparable to the ratios previously reported. The isobolographic analysis revealed that the combination of tramadol with morphine was infra-additive. Tramadol is a weak norepinephrine and 5-HT reuptake inhibitor and a weak opioid agonist. It may interfere with the morphine pathway, in which case we speculate that both substances compete for the same effector, particularly for the μ receptor. The combination of morphine and tramadol has been reported in two clinical studies but only one in the context of IV postoperative analgesia. Webb et al. (12) compared the combination of tramadol and morphine (1 mg/kg then 0.2 mg · kg−1 · h−1) to morphine alone for PCA after abdominal surgery in 69 randomized patients. They found that the addition of tramadol was associated with improved analgesic efficacy and smaller morphine requirement with no increase of side effects. Although it is difficult to compare different results obtained in different contexts (minor surgery versus major abdominal surgery) it may be hypothesized that the addition of tramadol to morphine may lead to improved pain relief but with increasing dosing of the μ-agonist drugs. The morphine-sparing effect and the absence of difference in adverse effects are confirmed by our study. However, because the combination is infra-additive, this sparing effect is not as important as might be expected if the drugs had additive or synergistic properties. In the context of acute postoperative pain, we did not find the synergy between opioids that has been described in animal studies (13).
In conclusion, the isobolographic analysis of ED50s determined by up-down allocation technique is an easy and valuable tool to screen and validate drug associations. We determined the ED50 of tramadol and morphine and their combination in the postoperative period of mild to moderate painful surgery in ASA physical status I–II patients. The ED50 of tramadol (86 mg) is close to the recommended dosing of 100 mg, but this recommendation appears insufficient to adequately relieve pain in more than 50% of patients. A study of the interaction of morphine and tramadol using isobolographic analysis found that the combination was infra-additive. The morphine-sparing effect appears to be very small, and the use of two μ opioid agonists in combination may only increase the number of side effects rather than decrease their incidence.
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