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How effective is tramadol



The Median Effective Dose of Tramadol and Morphine for Posto

8.22.2018 | Alexander Mercer
How effective is tramadol

Tramadol is a centrally-acting analgesic drug. In a search of an effective balanced analgesia technique with a morphine-sparing component, we studied the median effective analgesic doses (ED 50) of tramadol, morphine, and their combination to determine the nature of their interaction using an isobolographic analysis.

This study is the first to define the IV median effective analgesic dose of tramadol in postoperative patients. An isobolographic analysis demonstrated that tramadol and morphine were infra-additive when administrated in combination. The ED 50 of tramadol was 86 mg (57–115 mg), whereas morphine had an ED 50 of 5.7 mg (4.2–7.2 mg).

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Accepted for publication July 27, 2004.

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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. Webb et al. The morphine-sparing effect and the absence of difference in adverse effects are confirmed by our study. Tramadol is a weak norepinephrine and 5-HT reuptake inhibitor and a weak opioid agonist. 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. In the treatment of moderate pain, IV tramadol 50 to 150 mg was equivalent in analgesic efficacy to morphine 5 to 15 mg. 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. The combination of morphine and tramadol has been reported in two clinical studies but only one in the context of IV postoperative analgesia. ( 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. Several trials have compared tramadol and morphine in an attempt to determine their equianalgesic ratio. 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. In the context of acute postoperative pain, we did not find the synergy between opioids that has been described in animal studies ( 13 ).

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. 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. 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. In a recent retrospective study, tramadol caused dry mouth in 10.7%–33% of the patients ( 21 ). 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.

For morphine, an ED 50 of 5.7 mg (4.2–7.2 mg) was found, confirming our previous results ( 19 ). Administration of tramadol by patient-controlled analgesia (PCA) also proved to be effective in many trials ( 17,18 ). Clinically, this first dose, relieving only 50% of patients, may be insufficient in acute pain management. Recommendations for the use of tramadol for postoperative pain are not well defined and vary among countries. However, the rational basis for these recommendations for postoperative pain management is unclear and the ED 50 has not been reported. Tramadol has proved to be an effective and well tolerated analgesic in the management of moderate to severe acute postoperative pain in adults ( 10 ). We calculated an ED 50 of 86 mg (57–115 mg), which is close to the bolus recommended by the manufacturer. 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 ). 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.

The ED 50 (95% CI) of tramadol and morphine alone were, respectively, 86 mg (57–115 mg) and 5.7 mg (4.2–7.2 mg). The ED 50 (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 ED 50 was infra-additive ( Fig. The sequences of effective and ineffective analgesia are shown in Figure 2. 3 ).

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. The efficacy of study drugs was assessed using the NPS 20 min after T0 (T20). In addition to NPS measurements, heart rate, arterial blood pressure, and oxygen saturation were recorded. Two outcomes were considered: 1) NPS <3 at T20: effective analgesia. 2) NPS ≥3 at T20: ineffective analgesia. 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 next patient received an increased dose with the same increment as above.

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.

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.

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Blinding was ensured by using blinded syringes prepared by an anesthesiologist who was not involved in patient pain assessment. The increment was 6.67 mg for tramadol and 0.5 mg for morphine. In group T, the first patient received 100 mg of tramadol, and subsequent increments were 10 mg. 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 M, the first patient received 5 mg of morphine and the increment was 1 mg. 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. 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.

On a weight basis, the analgesic potency of tramadol is 1/10 that of IV morphine and 1/13 epidurally ( 11 ). 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. 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 ED 50 of tramadol by using an up-down sequential allocation technique and 2) to compare it with the ED 50 of morphine by isobolographic analysis to define the nature of their interaction ( 15 ). Its safety, however, suggests a place in combination with other drugs or with a regional anesthetic technique. Synergy between different opioids has been reported in animal studies ( 13 ). 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 ). 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 ). At the usually recommended dosage, the lack of full analgesic efficacy limits tramadol as a sole drug for treating severe pain after surgery. Unlike other opioids, tramadol has no clinically relevant effect on respiratory or cardiovascular variables at recommended doses. The ED 50, defined as the clinical dose for which 50% of the patients had their pain adequay relieved, has never been reported.

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 ). Moreover, optimal pain relief demonstrates clinically significant advantages for surgical outcome. Balanced analgesia combining morphine with other analgesics has been encouraged to “spare” doses of morphine and to limit its adverse effects. Morphine remains the standard reference drug for managing postoperative pain. 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 ). Administered IV, it has both supraspinal and spinal actions and at small doses, it activates the descending analgesic pathway, inhibiting nociceptive signal transduction. 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 is a validated concept in the postoperative period and is now recommended by national guidelines and publications ( 1,2 ). Pain relief accelerates postoperative surgical recovery and rehabilitation and contributes to reducing the duration of hospital stay ( 5 ).

All patients received a standard anesthetic technique consisting of IV induction with propofol or thiopental and remifentanil or sufentanil. The evening before surgery, patients were instructed how to use the NPS. Anesthesia was maintained with either an IV infusion of propofol or nitrous oxide and desflurane. Pain intensity was assessed using NPS, immediay on patient arrival in the postanesthesia care unit (PACU), and then every 5 min or when the patient complained of pain. Intraoperative analgesia was provided with remifentanil or sufentanil. As soon as the NPS score reached 3 (time defined as “T0”), patients were included and received analgesia as defined by the protocol. At the end of surgery, IV droperidol (1 mg) was administrated systematically as an antiemetic in prevention of nausea and vomiting.

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. 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. The pharmacodynamic and pharmacokinetic properties of tramadol and morphine are well documented ( 11 ). 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 adequay compare them. 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 ). For morphine, the recommended interval is 5 to 10 minutes.

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A classical isobolographic technique was used in a second stage to assess the possible interaction between the two drugs ( 15 ). 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 three groups were compared for demographic data and side effects using χ 2 or analysis of variance. NPS was compared among groups at T0 and at T20 using the Kruskal-Wallis test. ED 50, 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 ). The 95% confidence contours of the joint action were drawn by joining the 95% confidence intervals in each axis of the isobologram.

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We do not recommend the combination of morphine and tramadol for postoperative analgesia. Their potency ratio was 10:3 (morphine:tramadol) and the combination showed infra-additivity. IMPLICATIONS: The pharmacologic interaction between tramadol and morphine was studied in the postoperative period.

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. A study of the interaction of morphine and tramadol using isobolographic analysis found that the combination was infra-additive. The ED 50 of tramadol (86 mg) is close to the recommended dosing of 100 mg, but this recommendation appears insufficient to adequay relieve pain in more than 50% of patients. 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. We determined the ED 50 of tramadol and morphine and their combination in the postoperative period of mild to moderate painful surgery in ASA physical status I–II patients.

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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.

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Marcou, Thi Aurore MD ; Marque, Sophie MD ; Mazoit, Jean-Xavier MD, PhD ; Benhamou, Dan MD.

Initial doses and increments were, respectively, 100 mg and 10 mg in the tramadol group and 5 mg and 1 mg in the morphine group. Tramadol is a centrally-acting analgesic drug. Isobolographic analysis was subsequently applied. In a search of an effective balanced analgesia technique with a morphine-sparing component, we studied the median effective analgesic doses (ED 50 ) of tramadol, morphine, and their combination to determine the nature of their interaction using an isobolographic analysis. The threshold of effective analgesia was defined as 3 or less on a numerical pain score (0–10). The ED 50 values (95% confidence interval) of tramadol and morphine were, respectively, 86 mg (57–115 mg) and 5.7 mg (4.2–7.2 mg). In this double-blind, randomized, two-stage prospective study, 90 postoperative patients were enrolled in one of three groups. The combination of tramadol and morphine was infra-additive and thus not recommended for postoperative analgesia. The dose of tramadol and morphine received by a particular patient was determined using an up-down allocation technique. The ED 50 of the combination was 72 mg (62–82 mg) for tramadol and 5.4 mg (4–6.6.2 mg) for morphine. In the second part, a 40:3 tramadol:morphine dosing ratio was used.

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. The demographic data (age, sex ratio, weight, and type and duration of surgery) of the three groups were similar ( Table 1 ). 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).

Supported by grants from the French Ministry of Research and the Association MAPAR.

All patients were scheduled for surgery considered as slightly to moderay painful. After Ethics Committee approval and written informed consent were obtained, 90 ASA physical status I–II patients were enrolled and allocated to three groups. 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).

Dan Benhamou, Department of Anesthesiology, Hôpital de Bicêtre, F-94275 Le Kremlin Bicêtre Cedex, France. Address to. Address correspondence to Pr.