This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Thévenin, A. Articles by Mazoit, J.-X. Search for Related Content PubMed PubMed Citation Articles by Thévenin, A. Articles by Mazoit, J.-X. Related Collections Pain Medicine Pain Pharmacology

---

ANALGESIA

The Limited Efficacy of Tramadol in Postoperative Patients: A Study of ED₈₀ Using the Continual Reassessment Method

From the AP-HP, Univ Paris-Sud, Hôpital Bicêtre, Département d'Anesthésie-Réanimation, France F-94275, Le Kremlin-Bicêtre, France.

Address correspondence and reprint requests to Jean-Xavier Mazoit, MD, PhD, Univ Paris-Sud, Hôpital Bicêtre, Département d'Anesthésie-Réanimation, France F-94275, Le Kremlin-Bicêtre, France. Address e-mail to jean-xavier.mazoit{at}kb.u-psud.fr.

Abstract

BACKGROUND: The aim of this study was to reevaluate the efficacy of tramadol for postoperative analgesia and to determine its ED₈₀ (the clinical dose for which 80% of the patients had their pain adequately relieved) using the Continual Reassessment Method. Because the preliminary results of the first 24 patients were contradictory to the literature, we performed a second trial to verify and validate our data.

METHODS: The study was double-blind and prospective. Participants were allocated to a dose of tramadol by 3-patient cohorts, in order of inclusion. The dose of tramadol received in each cohort was determined by the reaction of all previous patients. Five doses were chosen before beginning, with a probability of a positive reaction associated with each: 60 (0.4), 100 (0.55), 140 (0.7), 190 (0.8), and 260 mg (0.9). Tramadol was considered effective if the numeric pain scale was 3/10 at T30.

RESULTS: The effective dose in 80% of patients was 260 mg for both trials. The probability of success of the 260 mg dose was 0.699 (95% credibility interval, 0.471–0.874) and 0.657 (95% credibility interval, 0.437–0.853) for trial 1 and trial 2, respectively.

CONCLUSION: Tramadol used as a sole drug cannot be considered the drug of choice after moderately painful surgery. The doses needed to relieve pain in 80% of patients are much larger than the usual dose of 100 mg. The Continual Reassessment Method allowed us to determine the ED₈₀ of tramadol with a limited number of patients.

Tramadol is a unique analgesic offering moderate, dose-related pain relief through its action at multiple sites. It consists of two enantiomers, both of which contribute to analgesic activity via different mechanisms. (+) Tramadol and the metabolite (+)-O-desmethyl-tramadol are agonists of the µ opioid receptor. (+) Tramadol also stimulates presynaptic release of serotonin and inhibits serotonin reuptake whereas (–) tramadol inhibits norepinephrine reuptake.1 Thus, tramadol enhances inhibitory effects on pain transmission both by opioid and monoaminergic mechanisms. The complementary and synergistic actions of the two enantiomers improve the analgesic efficacy and tolerability profile of the racemate. In contrast to pure opioid agonists, it carries a low risk of respiratory depression, as well as limited tolerance and dependence.2,3 It is effective in different types of moderate-to-severe acute and chronic pain, including low back pain and osteoarthritis pain.4 It has also proved to be an effective and well tolerated analgesic in the management of moderate-to-severe acute postoperative pain in adults.5 Recommendations for the use and the dosage of tramadol for postoperative pain are, however, not well defined and vary among countries. No formal dose–response curve has been constructed in this setting, explaining why doubt regarding the optimal analgesic dose of tramadol after surgery. Using the Dixon's up-and-down technique, we previously reported an ED₅₀ (the clinical dose for which 50% of the patients had their pain adequately relieved) of 86 mg (57–115 mg),6 which is close to the bolus of 100 mg recommended by the manufacturer. Clinically, this first dose, relieving pain in only 50% of patients, may be insufficient in acute pain management. In daily clinical practice, it is however necessary to obtain satisfactory pain relief in at least 80%–90% of the patients. Because the up-and-down technique is not considered the best method to determine the ED₈₀ (the effective dose in 80% of the patients),7,8 we recently used the Continual Reassessment Method (CRM)9 to estimate the ED₈₀ of nefopam.10 This method uses all the information gained by incorporating data from consecutive patients. Therefore, the number of patients required to calculate the ED₈₀ (or the dose leading to any other probability of success) of a drug is markedly reduced. The aim of this study was to reevaluate the efficacy of tramadol for postoperative analgesia and to determine its ED₈₀ using the CRM. Because dosing depends on the shape of the dose-effect or dose-probability-of-success curve,10 we conducted this study using tramadol as a sole antinociceptive drug. The first results obtained were surprisingly in contradiction with the literature, including our prior study. We therefore submitted an amendment to the protocol and performed a second trial to verify and validate our data.

METHODS

Patient Selection
After obtaining Ethical Committee's approval (Cochin-Port-Royal hospital, Assistance Publique-Hôpitaux de Paris, Paris, France) and patient's written informed consent, 24 patients with ASA physical status I or II were enrolled (trial 1). All patients were scheduled for surgery considered as moderately painful (such as inguinal hernia repair surgery, minor ear, nose and throat surgery). Exclusion criteria were as follows: 1) contraindications to the use of tramadol, including pregnancy; 2) age younger than 18 years; 3) chronic opiate exposure or chronic pain; 4) postoperative pain <3 on a numeric pain scale (NPS) (0 = no pain to 10 = the worst possible pain) on arrival in the postanesthesia care unit (PACU). Because results of the first 24 patients significantly differed from previously published results, we made an amendment to the protocol and enrolled 24 additional patients to verify and consolidate our primary data (trial 2).

Anesthetic Protocol
The evening before surgery, patients were instructed on how to use the NPS. All patients received general anesthesia with propofol or thiopental and desflurane or sevoflurane. The opioids authorized were remifentanil or sufentanil. All patients received 1 mg droperidol IV at the end of surgery to prevent nausea and vomiting.

Analgesic Protocol
The study was double-blind and prospective. Participants were allocated to a dose of tramadol by 3-patient cohorts, in order of inclusion. Blinding was ensured by using syringes freshly prepared by an anesthesiologist not involved in any other part of the study, including patient pain assessment. Pain intensity was determined using a NPS immediately after arrival in the PACU, and thereafter every 5 min. As soon as the pain score was >3 (defined as "T0"), the patient was definitely included and received analgesia as defined by the protocol, i.e., tramadol IV in 1 min. The dose of tramadol received in each cohort was determined by the reaction of all previous patients. Five doses were chosen before beginning the study with a probability of positive reaction associated with each: 60 (0.4), 100 (0.55), 140 (0.7), 190 (0.8), and 260 mg (0.9). It is based on previous tramadol studies in postoperative pain management. The efficacy of the study drug was assessed using the NPS 30 min after drug administration. Two outcomes were considered: 1) effective—3/10 at T30; 2) ineffective—NPS >3 at T30. At T30, patients who complained of ineffective analgesia were given rescue analgesia, and morphine titration was started according to the usual rules of our PACU.

Adverse Effects
The known adverse effects of tramadol (seizure, nausea, or vomiting, respiratory depression, dizziness, dry mouth, sedation, pruritus, sweating) were collected every 15 min after the injection, until discharge from the PACU.

Statistical Analysis
Only patients with a pain intensity >3/10 on arrival in the PACU were selected for study. We determined the ED₈₀ of tramadol, i.e., the dose of tramadol leading to satisfactory analgesia in 80% of patients.

Tramadol P₈₀ (probability of 80% of efficiency) was first modeled using the CRM using the software BPCT.11 In a second stage, the whole probability–dose curve was fitted using the procedure glmmPQL (S-Plus 6.0, library MASS).12

As previously described in detail,10 the CRM is a Bayesian technique that uses the memory of all previous events. Briefly, the principle consists of giving a dose to the first patient (or cohort of patients) and increasing or decreasing the dose for the next patient (or cohort of patients) according to the posterior conditional probability of success (or failure), i.e., the probability calculated using the results of all previous information, using the Bayes formula. After each cohort, the probability of success of each dose is updated, and the dose given to the next cohort of patients is then chosen accordingly. A binomial probability distribution is considered. The doses, the associated prior-probabilities, the number of patients in the cohorts, and the dose escalation rules are chosen a priori according to the clinical experience of the experimenter(s). For both trials, we used the software BPCT with cohorts of three patients, the one-step escalation rule (the next cohort receiving the next higher dose, even if a much higher dose seems adequate according to the probabilities calculated by the software), and a low initial dose to have the maximum number of patients treated in a wide range of the dose–response curve. We used the following doses: 60, 100, 140, 190, and 260 mg with the following associated a priori probability 0.4, 0.55, 0.7, 0.8, 0.9. The first three patients received 60 mg of tramadol. We considered the minimum number of patients to be 24 and the maximum 36. Between these two numbers, we decided to use the following stopping rules13:

1. A posterior probability of the response less than the lower dose (inappropriate dosing scheme with dosing out of range).
   
2. A posterior probability of the response more than the higher dose (inappropriate dosing scheme with dosing out of range).
   
3. A width of the 95% credibility interval <0.30, i.e., twice the difference between two prior probabilities (success of the procedure).
   
4. The probability that the administered dose remains unchanged for the next six patients (next two cohorts) more than 0.90 (success of the procedure). This last condition is calculated by the software, by the mean of the Bayes formula.
   

A full two parameter logistic equation was also fitted a posteriori to the whole data set (trials 1 and 2) using the procedure glmmPQL. We made the choice of this procedure rather than the usual glm (generalized linear model) procedure because it allows the incorporation of a random effect that considers the variability between the two trials.

Demographic data and adverse effects are reported as the mean ± sd or counts and proportions. The results of the CRM and full logistic modeling are reported as the probability of success and 95% credibility^* interval (CRM) or as the fitted parameter(s) of the logit and their standard error, respectively. Figures are given with three significant digits.

RESULTS

The demographic data (age, sex ratio, body weight, type and duration of surgery, and ratio of number of patients receiving remifentanil/sufentanil) are shown in Table 1. No statistical difference was noted between the groups. One patient in trial 1 had a NPS lower than three on arrival in the PACU and was not included. The NPS at the time of inclusion and 30 min later are shown in Table 2. One patient and three patients (4%/12.5%) experienced nausea in trials 1 and 2, respectively (Table 3). No respiratory depression, hemodynamic change, or seizure was observed. The inclusion was stopped after the 24th patient in trials 1 and 2 (the probability that the administered dose remained unchanged for the next six patients was more than 0.99 for both trials).

The number of patients who received each dose is depicted in Figure 1. Eleven and 13 patients in trials 1 and 2 had insufficient analgesia and received rescue analgesia. Rescue analgesia consisted of 1 g propacetamol infused in 3–5 min in all patients and morphine by IV titration in three patients in each trial. The dose leading to satisfactory analgesia closer to the P₈₀, the dose effective in 80% of the patients, was 260 mg for both trials. The probability of success of the 260 mg dose was 0.699 (95% credibility interval, 0.471–0.874) and 0.657 (95% credibility interval, 0.437–0.853) for trials 1 and 2, respectively (Fig. 2). After the inclusion of the 21st patient in either trial, the probability and credibility interval remained constant (Fig. 3).

View larger version (11K): [in this window] [in a new window]   Figure 1. Fraction of responders with successful analgesia in each cohort. Histograms represent the fraction of patients with successful analgesia in each cohort (cohort 1 in white, cohort 2 in gray). The number of patients in each cohort is displayed on each bar.

View larger version (10K): [in this window] [in a new window]   Figure 2. Result of the Continual Reassessment Method and the corresponding a posteriori maximum likelihood fitting of the two-parameter equation (after the 24th patient). The filled square and circle are the probability of success of the 260 mg dose with their credibility interval calculated by the CRM in trials 1 and 2, respectively. The solid line is the dose–probability curve fitted by the maximum likelihood method with the procedure glmmPQL of S-Plus.

View larger version (10K): [in this window] [in a new window]   Figure 3. Probability of success of the 260 mg dose according to the number of patients included. The dashed lines are the limits of the 95% credibility interval.

When the logistic equation is used to model the whole data set, the parameters of the logit are (fitted value and standard error in brackets): intercept = –2.72 (1.02) and slope = 0.0144 (0.00546). The corresponding values of the probability of response for dose = 0 (placebo effect) and of the P₅₀ (probability of satisfactory analgesia in 50% of the patients) are 0.06 and 189 mg, respectively. In this case, the probability of success of the 260 mg dose was 0.735, which was close to the values calculated by the CRM (Fig. 2).

DISCUSSION

The main finding of this study is that tramadol, used as a sole drug after moderately painful surgery, is effective in 80% of patients when doses administered are larger than the one recommended by the manufacturer. The ED₈₀ of tramadol was slightly higher than 260 mg in both trials.

Tramadol has proved to be an effective and well tolerated analgesic for the management of pain in adults.5 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 10–20 min, to a total dose of 250 mg) is usually recommended as the initial dosing scheme. Maintenance is usually achieved with additional doses of 50–100 mg every 4–6 h, to a maximum dose of 600 mg/d.5 Administration of tramadol by patient-controlled analgesia (PCA) also proved to be effective in many trials.14,15 We previously showed that the median effective analgesic dose (ED₅₀) of tramadol was 86 mg (57–115 mg).6 The ED₅₀ is far from being relevant for clinical purposes. We therefore used the CRM to determine the ED₈₀. The CRM, which is a Bayesian method, has the advantage of focusing on a specific probability using all the information given by the entire cohort of patients. Therefore, the probability of interest may be calculated with a very small group of patients. Our choice of an intercept of –3 was dictated by the fact that this value is the most commonly used in the literature, likely because computations are stable in this case and because this value leads to a negligible intercept of the probability–effect curve (placebo effect). The only limitation to the use of the technique seems to be a weak dose-response curve.13,16,17 In clinical trials where the CRM failed, an a posteriori analysis of the data shows that no clear relationship was present between dose and effect. In the field of anesthesia, effects are usually clearly related to the dose (either with muscle relaxants or with analgesic drugs) and the CRM appears to be a method leading to a precise response with a minimal number of patients.

The CRM technique previously allowed us to determine the ED₈₀ of nefopam with a reasonable accuracy in a small number of patients.10 In the present study, the dose of 260 mg was associated with a probability of success (P = 0.699) that was the closest to 0.8. This dose obtained in the first trial was surprisingly large. We therefore conducted a second trial to verify our results. In trial 2, a dose of 260 mg was also associated with the closest probability of success to 0.8 (P = 0.657). Taken together, results of both trials showed that a large dose of tramadol is needed to treat 80% of patients after moderately painful surgery. The efficacy of tramadol used as a sole drug for relieving chronic pain, i.e., osteoarthritis, is well documented.18 The literature on the efficacy of tramadol in the management of moderate-to-severe acute postoperative pain in adults is more contentious. Webb et al.19 found that the addition of tramadol to morphine PCA was associated with improved analgesic efficacy and smaller morphine requirement with no increase of side effects after abdominal surgery. On the other hand, Stiller et al.20 reported no effect of the addition of tramadol to morphine PCA after total knee arthroplasty.

We previously showed that the combination of tramadol with morphine was infra-additive, i.e., the combination of the two drugs did not lead to the total addition of the individual effects6 confirming a morphine-sparing effect. 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. When the log likelihood method was fitted to the data, an ED₅₀ of 189 mg was found, much higher than the ED₅₀ we reported previously with the up-and-down technique. Dixon's up-down method is less powerful than the CRM.20 Among other hypothesis potentially explaining this discrepancy in the results is the fact that the dose-probability curve is very flat (Fig. 2). We previously hypothesized that the addition of tramadol to morphine may lead to improved pain relief but with increasing dosing of the µ-agonist drugs.6 Few studies have shown the efficacy of tramadol when used as a sole drug. Its efficacy to relieve early pain after abdominal hysterectomy was reported.21 However, the results were not satisfying, considering the large number of patients (26.8%) who required rescue IV morphine. The large dose administered in our study was not associated with an excessive number of patients with side effects. The occurrence of adverse effects was not increased in the present study when compared with our previous results.6 As no dose–response curve is available, it is difficult to ascertain the relation between dose and incidence or severity of side effects. However, because of the small number of patients studied, we are unable to draw any definite conclusion.

In conclusion, the CRM allowed us to determine the ED₈₀ of tramadol with a limited number of patients. According to our results, tramadol used as a sole drug cannot be considered a drug of choice after moderately painful surgery. The doses needed to relieve pain in 80% of patients are much larger than the usual dose of 100 mg. Using a Bayesian method allows us to reasonably predict the probability of success of a predetermined dose with a small number of patients. However, the extrapolation to other parts of the dose– probability curve is difficult with the small number of patients we studied. Also, this small number of patients does not allow us to draw conclusions on the relation between dose and incidence or severity of side effects.

Footnotes

*The Bayesian credibility (or credible) interval is the probability given the data that the true value is in this interval.

Accepted for publication October 3, 2007.

REFERENCES

1. Lee CR, McTavish D, Sorkin EM. Tramadol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs 1993;46:313–40[Web of Science][Medline]
2. Grond S, Meuser T, Zech D, Hennig U, Lehmann KA. Analgesic efficacy and safety of tramadol enantiomers in comparison with the racemate: a randomised, double-blind study with gynaecological patients using intravenous patient-controlled analgesia. Pain 1995;62:313–20[Web of Science][Medline]
3. Houmes RJ, Voets MA, Verkaaik A, Erdmann W, Lachmann B. Efficacy and safety of tramadol versus morphine for moderate and severe postoperative pain with special regard to respiratory depression. Anesth Analg 1992;74:510–4[Abstract/Free Full Text]
4. Babul N, Noveck R, Chipman H, Roth SH, Gana T, Albert K. Efficacy and safety of extended-release, once-daily tramadol in chronic pain: a randomized 12-week clinical trial in osteoarthritis of the knee. J Pain Symptom Manage 2004;28:59–71[Web of Science][Medline]
5. Scott LJ, Perry CM. Tramadol: a review of its use in perioperative pain. Drugs 2000;60:139–76[Web of Science][Medline]
6. Marcou TA, Marque S, Mazoit JX, Benhamou D. The median effective dose of tramadol and morphine for postoperative patients: a study of interactions. Anesth Analg 2005;100:469–74[Abstract/Free Full Text]
7. Paul M, Fisher DM. Are estimates of MAC reliable? Anesthesiology 2001;95:1362–70[Web of Science][Medline]
8. Lu W, Ramsay JG, Bailey JM. Reliability of pharmacodynamic analysis by logistic regression: mixed-effects modeling. Anesthesiology 2003;99:1255–62[Web of Science][Medline]
9. O'Quigley J, Pepe M, Fisher L. Continual reassessment method: a practical design for phase 1 clinical trials in cancer. Biometrics 1990;46:33–48[Web of Science][Medline]
10. Beloeil H, Eurin M, Thevenin A, Benhamou D, Mazoit JX. Effective dose of nefopam in 80% of patients (ED80): a study using the Continual Reassessment Method. Br J Pharmacol 2007;64:686–93
11. Zohar S, Latouche A, Taconnet M, Chevret S. Software to compute and conduct sequential Bayesian phase I or II dose-ranging clinical trials with stopping rules. Comput Methods Programs Biomed 2003;72:117–25[Web of Science][Medline]
12. Venables W, Ripley B. Modern applied statistics with S-Plus. Statistics and computing series. 3rd ed. New York: Springer-Verlag, 1999
13. Fabre E, Chevret S, Piechaud JF, Rey E, Vauzelle-Kervoedan F, D'Athis P, Olive G, Pons G. An approach for dose finding of drugs in infants: sedation by midazolam studied using the continual reassessment method. Br J Clin Pharmacol 1998;46: 395–401[Web of Science][Medline]
14. Lehmann KA, Kratzenberg U, Schroeder-Bark B, Horrichs-Haermeyer G. Postoperative patient-controlled analgesia with tramadol: analgesic efficacy and minimum effective concentrations. Clin J Pain 1990;6:212–20[Web of Science][Medline]
15. Silvasti M, Svartling N, Pitkanen M, Rosenberg PH. Comparison of intravenous patient-controlled analgesia with tramadol versus morphine after microvascular breast reconstruction. Eur J Anaesthesiol 2000;17:448–55[Web of Science][Medline]
16. Dougherty TB, Porche VH, Thall PF. Maximum tolerated dose of nalmefene in patients receiving epidural fentanyl and dilute bupivacaine for postoperative analgesia. Anesthesiology 2000;92: 1010–6[Web of Science][Medline]
17. Desfrere L, Zohar S, Morville P, Brunhes A, Chevret S, Pons G, Morietet G, Rey E, Treluyer JM. Dose-finding study of ibuprofen in patent ductus arteriosus using the continual reassessment method. J Clin Pharm Ther 2005;30:121–32[Web of Science][Medline]
18. Gana TJ, Pascual ML, Fleming RR, Schein JR, Janagap CC, Xiang J, Vorsanger GJ. Extended-release tramadol in the treatment of osteoarthritis: a multicenter, randomized, double-blind, placebo-controlled clinical trial. Curr Med Res Opin 2006; 22:1391–401[Web of Science][Medline]
19. Webb AR, Leong S, Myles PS, Burn SJ. The addition of a tramadol infusion to morphine patient-controlled analgesia after abdominal surgery: a double-blinded, placebo-controlled randomized trial. Anesth Analg 2002;95:1713–8[Abstract/Free Full Text]
20. Stiller CO, Lundblad H, Weidenhielm L, Tulberg T, Grantinger B, Lafolie P, Jansson KA. The addition of tramadol to morphine via patient-controlled analgesia does not lead to better post-operative pain relief after total knee arthroplasty. Acta Anaesthesiol Scand 2007;51:322–30[Web of Science][Medline]
21. Torres LM, Rodriguez MJ, Montero A, Herrera J, Calderon E, Cabrera J, Porres R, de la Torre MR, Martinez T, Gomez JL, Ruiz J, Garcia-Magaz I, Camara J, Ortiz P. Efficacy and safety of dipyrone versus tramadol in the management of pain after hysterectomy: a randomized, double-blind, multicenter study. Reg Anesth Pain Med 2001;26:118–24[Web of Science][Medline]
22. O'Quigley J, Chevret S. Methods for dose finding studies in cancer clinical trials: a review and results of a Monte Carlo study. Stat Med 1991;10:1647–64[Web of Science][Medline]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Web of Science (1) Citing Articles via Google Scholar Google Scholar Articles by Thévenin, A. Articles by Mazoit, J.-X. Search for Related Content PubMed PubMed Citation Articles by Thévenin, A. Articles by Mazoit, J.-X. Related Collections Pain Medicine Pain Pharmacology