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Anesth Analg 2003;97:526-533
© 2003 International Anesthesia Research Society

PAIN MEDICINE

Postoperative Sensitization and Pain After Cesarean Delivery and the Effects of Single IM Doses of Tramadol and Diclofenac Alone and in Combination

Clive H. Wilder-Smith, MD*, Lauren Hill, BSc (Med) Hons*, Robert A. Dyer, FCA (SA){dagger}, Gregory Torr, FCA (SA){dagger}, and Ed Coetzee, FRCOG FCOG (SA){ddagger}

*Visceral Physiology Institute and Departments of {dagger}Anaesthetics and {ddagger}Obstetrics and Gynaecology, Groote Schuur Hospital, University of Cape Town, South Africa

Address correspondence to Clive H. Wilder-Smith, MD, Nociception Research Group, Bubenbergplatz 11, CH-3011 Berne, Switzerland. Address e-mail to cws{at}ggp.ch No reprints will be available.


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 References
 
Combining different analgesic mechanisms can reduce postoperative pain. We investigated postoperative pain and sensory sensitization in a double-blinded, placebo-controlled, randomized, single-dose comparison of the monoaminergic and µ-opioid agonist tramadol, 100 mg, and diclofenac 75 mg given IM in combination or alone in 120 patients who had elective cesarean delivery. The time to first postoperative demand for rescue analgesia, pain, tramadol pharmacokinetics, and electrical sensory thresholds at or distant from the incision were studied. The median time to first rescue (interquartile range) was 197 min (70–1000 min) with tramadol plus diclofenac, 48 min (25–90 min) with tramadol plus placebo, 113 min (35–270 min) with diclofenac plus placebo, and 55 min (30–100 min) with double placebo (tramadol plus diclofenac versus all other groups, P < 0.05). Pain intensity decreased markedly over time in all groups, and time and drug effects were significant (analysis of variance; P < 0.00001). Side effects were similarly minimal with all treatments. Pain thresholds at or distant from the incision increased significantly after surgery only with tramadol plus diclofenac. Preoperative sensory thresholds correlated with postoperative sensory changes (r > 0.53; P < 0.0001). The pharmacokinetics of tramadol and O-desmethyltramadol were unchanged by diclofenac. The combination of tramadol and diclofenac resulted in improved analgesia compared with monotherapy. Only the analgesic combination prevented both primary and secondary hyperalgesia. Preoperative sensory thresholds may allow prediction of postoperative sensitization.

IMPLICATIONS: The parenteral combination of tramadol and diclofenac resulted in more prolonged and pronounced postoperative analgesia and reduced sensory sensitization compared with the single drugs, with no increase in side effects.


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 References
 
Tramadol is an effective postoperative analgesic (1,2). Supraadditive analgesic effects are well known for combinations of opioids and nonsteroidal antiinflammatory drugs (NSAIDs), often with the additional benefit of reduced side effects. The combination of several analgesics with different modes of action, also termed "balanced analgesia," may be more effective in reducing nociceptive input and side effects and thereby optimizing pain control (3,4). µ-Opioidergic and monoaminergic (5-hydroxytryptamine and noradrenaline) pathways and prostaglandin-dependent mechanisms are individually important in the modulation of pain (5). Besides µ-opioid agonist effects, tramadol has monoaminergic action (6). Additive effects could be expected when the two main modes of action of tramadol and a NSAID are combined, as was recently demonstrated with a combination of tramadol and acetaminophen (paracetamol) (7).

Postoperative neural sensitization is evident as hyperalgesia and allodynia, which can be demonstrated with quantitative sensory testing (8–11). Analgesic monotherapy has reduced, but not blocked, this sensitization, which is implicated in protracted pain (10–14).

The aim of this placebo-controlled study was to assess the analgesic and antinociceptive effects of single doses of tramadol and diclofenac given alone and in combination in a homogeneous postoperative population. The influence of pharmacokinetic factors on analgesic effects was assessed by measuring tramadol and O-desmethyltramadol plasma levels and by phenotyping each patient for cytochrome P450 2D6 metabolizer status.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 References
 
One-hundred-twenty patients between 18 and 45 yr old and scheduled for elective low-risk cesarean delivery were prospectively entered in this randomized, double-dummy, double-blinded, parallel four-arm study. Exclusion criteria were known allergy to diclofenac or tramadol, ASA status >III, a history of peptic ulcer disease or gastrointestinal bleeding, opioid use in last month, inability or unwillingness to give written informed consent, preeclampsia or eclampsia, significant pulmonary disease, intraoperative complications, modified surgical procedure, or deviations from the standardized anesthetic regimen. The protocol was approved by the University of Cape Town Faculty of Medicine Ethics Committee.

Patients were randomized before surgery to one of the four following treatment groups by using a computerized randomization list: 1) tramadol 100 mg (Tramal®; Grünenthal GmbH, Aachen, Germany) and placebo (0.9% NaCl), 2) sodium diclofenac 75 mg (Fortfen®; Compu Pharmaceutical Products, South Africa) and placebo, 3) tramadol 100 mg and sodium diclofenac 75 mg, or 4) placebo and placebo. The University Hospital Pharmacy performed blinding in identical and coded ampules.

Perioperative and anesthetic procedures were standardized. Patients received no premedication except prophylactic ampicillin 2 g IV, cimetidine 400 mg orally at 12 and 2 h before surgery, and sodium citrate 30 mg immediately before surgery. Spinal anesthesia was induced at L3-4 by using 0.5% bupivacaine with dextrose, dosed according to usual clinical standards (1.8–2 mL). The standardized IV fluid protocol was 20 mL/kg of modified lactated Ringer’s solution before the induction of spinal anesthesia; this continued at 1 L every 8–12 h for 24 h after surgery. No concomitant opioids were given. After surgery, the time of IM injection of the study drugs according to randomization was standardized to the time of regression of the sensory block to T10, which was tested by ethyl chloride swab beginning 1 h after surgery and repeated every 30 min, and patients with pain scores more than 2 on a five-point verbal rating scale (VRS; none, 0; mild, 1; moderate, 2; strong, 3; unbearable, 4) were included. The two study drug injections were given separately in the left and right buttock. Tramadol and diclofenac were not mixed because of the risk of incompatibility. All patients received prochlorperazine (Stemetil®) 12.5 mg IV for antiemetic prophylaxis.

On the basis of the usual departmental guidelines, morphine 10 mg IV was administered on demand up to every 4 h as analgesic rescue. No other analgesics were allowed in the first postoperative 24 h. The same two study personnel observed all patients.

Quantitative electrical sensory testing for sensation and pain tolerance thresholds was performed before and 4 and 24 h after surgery 1 cm from the incision for investigation of primary hyperalgesia and at a distant site, midclavicularly, for secondary hyperalgesia. A nerve stimulator (Digistim 3 Plus®; Organon Teknika, Switzerland) programmed to tetanic stimulation at 100 Hz and 0.2-ms square wave pulses and current increments of 1 mA/s was used. Subsequently, the phasic pain threshold was twice applied as a tonic suprathreshold stimulus for C-fiber activation for 60 s, and pain intensity was rated by VRS.

The cytochrome P450 2D6 metabolizer phenotype was determined with dextromethorphan 25 mg. Poor metabolizers were defined as having a dextromethorphan/dextrorphan metabolic ratio of >0.3 (15). Three postoperative blood samples were taken for population pharmacokinetics according to a randomized time schedule. Tramadol and the main metabolite, O-desmethyltramadol, were quantified by high-performance liquid chromatography.

All data were documented in standardized forms. The time to first analgesic demand after study drug injection was predefined as the primary efficacy variable. If no analgesic rescue was demanded within the maximum observation time of 24 h, a value of 1440 min was used as the time to first analgesic demand for statistical analysis. Secondary variables were pain at rest and during leg-raising and nausea intensity ratings (VRS: none, 0; mild, 1; moderate, 2; strong, 3; unbearable, 4) at 0, 30, 60, and 90 min and 2, 3, 4, 6, 7, 12, and 24 h after study drug injection, rescue drug use, and side effects.

Normally distributed, continuous data were analyzed by analysis of variance (ANOVA) and Tukey’s honest significant difference tests. Nonparametric data were compared by using the Kruskal-Wallis ANOVA, followed by Mann-Whitney U-testing. A significance threshold of P < 0.05 was assumed. Power analysis based on preliminary pilot data revealed that a sample size of 27 patients per group was required to demonstrate a 20% difference in time to first analgesic rescue demand between the tramadol-alone and tramadol and diclofenac treatments.

The computer program NONMEM, Version 5 (NONMEM Project Group, University of California, San Francisco), was used for population pharmacokinetic analysis of tramadol and O-desmethyltramadol concentrations. Individual data from each group were pooled and plotted to generate a naïve population pharmacokinetic profile, on the basis of which it was decided to use a one-compartment approach to the analysis. A combined additive and exponential model was used to model intraindividual error. The predicted values for the resultant models for Groups 1 and 2 were then subjected to analysis with the Pharsight WinNonlin 1.5 Standard program to calculate the relevant pharmacokinetic variables.


   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 References
 
One-hundred-seventy-seven consecutive patients were screened for inclusion of 120 patients in this study. Exclusion reasons were postponement of operation (n = 14), inadvertent intraoperative use of opioids (n = 10) or other analgesics (n = 2), conversion to general anesthetic (n = 9), vaginal delivery (n = 2), and other miscellaneous pre- or intraoperative reasons (n = 20). No patient withdrew consent during the study. Thirty patients in each of the four treatment groups were therefore evaluable. Patient and operative details are shown in Table 1


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  		Table 1. Patient Characteristics
 
The median time to first rescue (1st–3rd quartile) was 197 min (70–1000 min) with tramadol and diclofenac, 48 min (25–90 min) with tramadol and placebo, 113 min (35–270 min) with diclofenac and placebo, and 55 min (30–100 min) with double placebo. The overall drug effect was highly significant by ANOVA (P < 0.00001). The comparisons of tramadol and diclofenac with tramadol and placebo (P < 0.001), diclofenac and placebo (P < 0.05), and double placebo (P < 0.001) were statistically significant. Individual data are shown in Figure 1. The median pain score for all patients at the time of rescue request was 3 (1st–3rd quartile, 2–3), i.e., strong pain. The mean (95% confidence interval) total doses of rescue morphine given in the first 24 postoperative hours in the tramadol and diclofenac, tramadol and placebo, diclofenac and placebo, and placebo and placebo groups were 28 mg (24–33 mg), 35 mg (32–38 mg), 31 mg (26–36 mg), and 38 mg (35–41 mg), respectively. The overall drug effect was significant by ANOVA (P < 0.005). The rescue doses in the tramadol and diclofenac group were smaller than in the double-placebo group (P < 0.005). Trends to smaller doses were seen when tramadol and diclofenac were compared with tramadol and placebo (P = 0.08) and when diclofenac and placebo were compared with double placebo (P = 0.08). The number of patients not requiring any rescue analgesia in the first 24 postoperative hours was 7: 6 in the tramadol and diclofenac group and 1 in the diclofenac and placebo group.



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  		Figure 1. Median time to first postoperative request for additional analgesic in 120 patients (30 per treatment) after injection of tramadol 100 mg and diclofenac 75 mg (T&D), tramadol 100 mg and placebo (T&P), diclofenac 75 mg and placebo (D&P), or double placebo (P&P). Individual values (•) and group medians ({image}) are shown. 1P < 0.001, T&D versus T&P; 2P < 0.001, T&D versus P&P; 3P < 0.05, T&D versus D&P.

 
Pain intensity ratings at rest decreased highly significantly from initial median values of 3 to between 0 and 1 within 2 h in all treatment groups (Fig. 2A). Both drug and time effects were significant (P < 0.000001). Within every treatment group, before the study drug, pain intensity was significantly higher than all subsequent ratings (P < 0.001). Post hoc analysis demonstrated significantly lower pain intensity ratings at rest when comparing tramadol and diclofenac with tramadol and placebo (at 30 min, 6 h, and 7 h postinjection; P < 0.04) and with double placebo (at 30 and 60 min and 6 and 7 h; P < 0.05), but not compared with diclofenac and placebo. No significant differences were found at any time when comparing tramadol and placebo with either diclofenac and placebo or double placebo. Diclofenac and placebo pain ratings at rest were lower than double-placebo ratings 7 h after injection (P = 0.005).



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  		Figure 2. Median postoperative pain intensity ratings (A) at rest and (B) during movement in 120 patients (30 per treatment). A verbal rating scale (VRS) was used (0, no pain; 4, unbearable pain). T&D = tramadol and diclofenac group; T&P = tramadol and placebo group; D&P = diclofenac and placebo group; P&P = double-placebo group. See Results for significances.

 
Pain intensity during movement decreased significantly over time and was different between drugs (ANOVA; P < 0.001 and P < 0.000001, respectively) (Fig. 2B). With tramadol and diclofenac and diclofenac and placebo, postinjection pain ratings were significantly lower compared with preinjection ratings from 30 min onward (P < 0.0004). With tramadol and placebo and double placebo, all postinjection pain ratings were lower than preinjection ratings after 90 min (P < 0.04). Post hoc analysis showed lower pain ratings during movement with tramadol and diclofenac than with double placebo at 60 min and 6 h postinjection (P = 0.04 and P = 0.0008, respectively) but no differences compared with other active treatment groups at any time. There were no differences in pain ratings between tramadol and placebo versus diclofenac and placebo or double placebo, but ratings were lower after diclofenac and placebo versus double placebo at 6 and 7 h (P = 0.03 and 0.0001, respectively).

Median nausea ratings were 0 in all treatment groups at every time point throughout the 24-h period. Nausea was reported in four patients with tramadol and diclofenac (all slight intensity), in eight with tramadol and placebo (slight intensity, n = 5; moderate, n = 2; strong, n = 1), in six with diclofenac and placebo (slight, n = 5; unbearable, n = 1), and in five with double placebo (slight, n = 4; strong, n = 1). Vomiting occurred in six patients with tramadol and diclofenac, in three patients with tramadol and placebo, and in two patients each with diclofenac and placebo and double placebo. There were no significant group differences in the incidences of nausea and vomiting.

Sedation did not increase significantly from baseline during the 24-h study period, and median scores remained 0 in all groups throughout. Sleepiness or drowsiness in the first 24 postoperative hours was reported in 21 patients with tramadol and diclofenac, in 26 with tramadol and placebo, in 25 with diclofenac and placebo, and in 28 with double placebo. Respective incidences of dizziness and headache were n = 3 and 1, n = 11 and 3, n = 5 and 0, and n = 9 and 4. Incidences of shivering, cold, and hot were n = 0, 1, and 2 with tramadol and diclofenac; n = 1, 2, and 3 with tramadol and placebo; n = 1, 1, and 1 with diclofenac and placebo; and n = 2, 0, and 1 with double placebo, respectively. Miscellaneous other side effects were reported in five, two, six, and five patients, respectively. There were no serious side effects throughout the study. Overall, any side effects were reported in 16 patients with tramadol and diclofenac, in 21 patients with tramadol and placebo, in 20 patients with diclofenac and placebo, and in 18 patients with double placebo.

At incision, changes from baseline in sensation and pain tolerance thresholds were significantly greater with tramadol and diclofenac after 4 h, but not after 24 h, compared with tramadol and placebo and with double placebo (P < 0.05) (Fig. 3, A and B). Absolute sensation thresholds were higher after 4 h (P = 0.01) and pain tolerance thresholds were increased after 4 and 24 h compared with before surgery with tramadol and diclofenac (P < 0.01). With tramadol, diclofenac, or placebo alone, pain thresholds were significantly lower after 4 h than at baseline (P < 0.0002). Preoperative sensation thresholds and pain scores 2 h after surgery correlated inversely (r = -0.21; P = 0.03). Sensation thresholds over the wound correlated inversely with pain intensity after 4 h (r = -0.29; P = 0.003).



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  		Figure 3. Changes from preoperative baseline in electrical sensation (A) and pain (B) thresholds at the abdominal incision (black boxes) and over the clavicle (open boxes) at 4 (squares) and 24 (triangles) hours after surgery. Positive values denote increased postoperative thresholds (postoperative minus preoperative value). Means, 95% confidence intervals, and absolute ranges of 30 patients per treatment group are shown. T&D = tramadol and diclofenac group; T&P = tramadol and placebo group; D&P = diclofenac and placebo group; P&P = double-placebo group. A, *P < 0.05, T&D versus T&P and P&P. B, *1P < 0.05, T&D versus T&P and P&P; *2P < 0.05, T&D versus all other groups; *3P = 0.05, T&D versus P&P.

 
At the distant site (clavicle), there were no significant differences between treatment groups in changes from baseline or absolute sensation thresholds over the clavicle at either 4 or 24 h after surgery. Changes in pain tolerance thresholds from before surgery over the clavicle were significantly greater with tramadol and diclofenac at 4 h than in all other groups (P < 0.05) and at 24 h compared with double placebo (P = 0.05) (Fig. 3B). Absolute pain tolerance thresholds at 4 h were significantly higher than before surgery with tramadol and diclofenac (P = 0.02).

Preoperative sensation and pain thresholds correlated weakly but significantly inversely with pain scores 2 h after surgery (r = -0.22, P = 0.02 and r = -0.26, P = 0.006, respectively). Preoperative sensory thresholds correlated significantly with threshold changes after surgery (Table 2). Sensory thresholds and the time to first injection or analgesic rescue doses did not correlate significantly.


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  		Table 2. Correlations (Pearson correlation; r) of Preoperative Sensory Thresholds and Suprathreshold Stimulation Pain Ratings with Postoperative Changes from Baseline at 4 and 24 Hours at the Site of Incision and a Distant Location (Clavicle) in All 120 Study Patientsa
 
Changes from baseline in pain intensity with stimulation at twice the pain tolerance threshold over the wound or the clavicle were not significantly different among groups at 4 or 24 h after surgery, and neither were the absolute pain intensities. However, time effects were significant by ANOVA over both the wound (P = 0.04) and the clavicle (P = 0.0007), which reflected the consistent, albeit insignificant, trends to decreased pain scores at 4 h after surgery in all treatment groups. For correlations between preoperative values and postoperative changes, see Table 2.

There were 114 extensive or rapid metabolizers and 6 poor metabolizers of cytochrome P450 2D6 (2 each with tramadol and diclofenac and with double placebo, and 1 each with tramadol or diclofenac alone). Because of the small numbers of poor metabolizers, no statistical comparison of variables with extensive metabolizers was performed. The median time to first rescue analgesic (interquartile range) was 528 min (299–757 min) in extensive metabolizers and 367 min in the 2 poor metabolizers in the tramadol with diclofenac group. In the tramadol with placebo group, the respective times to first rescue analgesia were 81 min (49–114 min) and 30 min (there was only one poor metabolizer). There appeared to be a trend to decreased duration of action of tramadol in poor metabolizers. Explorative analysis showed a tendency to increased pain intensities in poor metabolizers during leg-raising (ANOVA; P = 0.06) but no differences in side effects or quantitative sensory testing in the tramadol treatment groups.

The pharmacokinetics of tramadol and O-desmethyltramadol are shown in Table 3. There were no significant differences in any variables.


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  		Table 3. Pharmacokinetics of Tramadol for Groups 1 and 2
 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
References
 
In this randomized and double-blinded postoperative study, parenteral tramadol and diclofenac showed significantly superior analgesic effects compared with tramadol or diclofenac alone and compared with placebo. This was evident in all three dimensions used to assess the effectiveness of pain control. The time to the first request for supplemental analgesia after injection of the study drugs was approximately four times as long with the tramadol and diclofenac combination compared with tramadol alone or placebo and was twice as long as with diclofenac alone. The total dose of supplemental morphine given in the first 24 postoperative hours was smaller with the combination than in the other groups. Additionally, pain intensity scores in the combination group were significantly lower at several times points than with tramadol only and placebo.

Tramadol monotherapy was clearly less effective than in combination with diclofenac; in some variables, it was less effective than diclofenac alone and was similar to placebo. Previous studies have shown tramadol to be an effective postoperative analgesic (1,2,16,17). The single-dose design of this study is likely to have emphasized a delayed onset of action of the monoaminergic action of single-dose tramadol, which is suggested by the similar time to first rescue, but there was a very prolonged time to second rescue (well within the duration of action of tramadol) compared with placebo. A slower onset of action than morphine has been previously noted (18). In an orthopedic surgery study, the time to first rescue analgesia was 18.7 hours after parenteral tramadol 100 mg and 15.2 hours after parenteral ketorolac 30 mg, and analgesia was rated as excellent in a larger percentage of patients with tramadol (19). In a second similar study using the same comparator drugs and doses, analgesic effects were not significantly different between the drugs (20). Because all our patients were pregnant, changes in metabolism or analgesic pathways or sensitivities in pregnancy could also explain the less than expected analgesia with tramadol. Induction of the cytochrome P450 2D6 enzyme in pregnancy is an unlikely explanation, because more of the metabolite O-desmethyltramadol, to which most of the µ-opioid activity is attributed, will be formed, and metabolizer status ratios were within the nonpregnant normal range (6,21).

The additional analgesic effect achieved by the addition of diclofenac to tramadol is unlikely to be explained by pharmacokinetic interactions, because diclofenac is mainly metabolized by the cytochrome P450 2C9 pathway, which is not one of the main metabolic pathways for tramadol. Accordingly, population pharmacokinetics for tramadol and O-desmethyltramadol were similar whether tramadol was given alone or with diclofenac.

Five percent of the patients were poor metabolizers in the cytochrome P450 2D6 pathway. They showed a trend to decreased duration and intensity of analgesia with tramadol, which could be explained by the generally smaller concentrations of the main opioid metabolite (6). Cytochrome P450 2D6 poor metabolizers showed no differences in side effects compared with fast metabolizers. Endogenous nociceptive function appeared similar between extensive and poor metabolizers, because all sensory thresholds and ratings were similar before surgery.

Animal and human studies have shown the importance of 5-hydroxytryptamine and noradrenergic mechanisms in modulating central, spinal, afferent, and efferent analgesic pathways and have also shown a synergism with µ-opioid agonism (5). NSAIDs exert their analgesic action via several pathways, including prostaglandin modulation supraspinally and spinally. The additive analgesic effects of opioids and NSAIDs are well documented (22,23). This study provided evidence of the additive effects of a NSAID and a mixed monoaminergic and opioid drug. The combination of additive analgesic actions, therefore, is useful in reducing postoperative pain, as suggested in the concept of balanced analgesia proposed by Kehlet et al. (3) and Kehlet (4).

Tramadol with diclofenac was tolerated similarly well as diclofenac or tramadol alone, and no significant increases in side effects were seen compared with placebo dosing. Overall rates of gastrointestinal complaints were small. It should be noted that this study was powered to investigate analgesic and nociceptive effects, but not differences in side effects.

Surgery causes allodynia and hyperalgesia both at the incision and at distant sites (primary and secondary hyperalgesia) (8–12). In this study, quantitative electrical sensory testing was used to assess primary hyperalgesia, mainly attributed to peripheral sensitization, and secondary hyperalgesia, due to central sensitization (9). Primary, but not secondary, hyperalgesia or allodynia developed in the early postoperative hours when tramadol or diclofenac was given alone. When both drugs were given in combination, sensation and pain thresholds were significantly increased after surgery at the incision and distant sites.

Opioids can reduce postoperative sensitization, especially secondary hyperalgesia and allodynia, and can also increase pain thresholds in nonoperative settings (8,12–14,24–27). In a rodent postoperative incisional model, A-{delta} fibers sensitized more extensively than C-fibers (28). Because A-{delta} fibers are preferentially activated by phasic, lower-intensity stimulation and C-fibers by tonic, higher-intensity stimulation, we used both phasic threshold testing and chronic suprathreshold stimulation to investigate this issue in humans. As predicted, phasic, lower-intensity stimulation demonstrated more marked sensitization effects than tonic, higher-intensity stimulation.

Preoperative sensation and pain thresholds correlated closely and inversely with postoperative sensitization. This was valid both for the wound and the distant sites and for the phasic and suprathreshold protracted stimulation. This robust correlation in a large number of patients implies that individuals with higher preoperative sensory thresholds or lower pain ratings during suprathreshold stimulation sensitize more extensively after surgery. The determinants of individual baseline sensory thresholds and the response to analgesics and to various types of noxious stimulus are multifactorial, including genetic and environmental factors, and these determinants differentially govern multiple interactive components of the peripheral, spinal, and central sensory pathways (29,30). This has been demonstrated in rodents and also appears likely in humans (29,30). Differential responses of each of the physiologic variables are therefore not surprising and may explain the absence of a close relationship between psychophysical and clinical pain measures. The good correlation between preoperative electrical sensory thresholds and postoperative threshold changes implies usefulness in the prediction of which patients are prone to postoperative sensitization, but it requires further examination in different pain models.

In conclusion, the combination of tramadol and diclofenac is more effective for postoperative analgesia and prevention of sensitization than the two drugs given individually. Preoperative sensory testing may be useful in predicting postoperative sensitization.


   Acknowledgments
 
Supported in part by a research grant from Grünenthal GmbH, Aachen, Germany.

We gratefully acknowledge the expert pharmacokinetic analysis and advice of Justin J. Wilkins, MSc, Grant M. Langdon, MSc, and Peter Smith, PhD, of the Division of Pharmacology, Department of Medicine, University of Cape Town, South Africa.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Accepted for publication March 10, 2003.




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Lippincott, Williams & Wilkins Anesthesia & Analgesia® is published for the International Anesthesia Research Society® by Lippincott Williams & Wilkins with the assistance of Stanford University Libraries' HighWire Press®. Copyright 2006 by the International Anesthesia Research Society. Online ISSN: 1526-7598   Print ISSN: 0003-2999 HighWire Press