Effect of perioperative administration of dexketoprofen on opioid requirements and inflammatory response following elective hip arthroplasty

G. Iohom*,1, M. Walsh1, G. Higgins2 and G. Shorten1

1Department of Anaesthesia and Intensive Care Medicine and 2Clinical Sciences Building, Cork University Hospital and National University of Ireland, Cork, Republic of Ireland*Corresponding author

Accepted for publication: November 22, 2001


    Abstract
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Background. In this double-blind, randomized, placebo-controlled trial, the safety and analgesic efficacy of perioperative dexketoprofen were evaluated.

Methods. Thirty ASA I or II patients undergoing elective hip arthroplasty were randomized to one of two groups. One group (D) received dexketoprofen 25 mg tds for 24 h before and 48 h after surgery; the second group (P) received placebo tablets at equivalent times. Hyperbaric 0.5% bupivacaine (17.5 mg if greater than 70 kg and 15 mg if less than 70 kg) and preservative-free morphine (0.6 mg) were administered intrathecally. Postoperatively, PCA was provided (bolus morphine sulphate 1 mg; lockout 5 min; no continuous infusion).

Results. The two groups were similar in terms of age, gender, weight, height, ASA class, duration of operation, and level of sensory block on arrival to the recovery room. Groups were also similar in terms of blood loss, transfusion requirements, ventilatory frequency, and haemodynamic variables. According to visual analogue pain scores patients in group D experienced less pain at 15 h (P=0.02) postoperatively. Cumulative morphine consumption was also less in group D compared with group P at 6 (0.06 (0.2) vs 0.85 (1.4) mg, P=0.04) and 48 h postoperatively (10.1 (8) vs 26.2 (20) mg, P<0.01). Plasma interleukin 6 concentrations increased postoperatively to a significantly lesser extent in group D than in group P (P=0.02). Nausea and vomiting were less (P<0.01) in group D compared with group P at 18 h postoperatively. Sedation scores were less (P=0.03) in group D.

Conclusions. Perioperative administration of dexketoprofen 25 mg 8 hourly markedly improves analgesia and decreases opioid requirements (and associated adverse effects) following hip arthroplasty. It appears that this regimen decreases the postoperative pro-inflammatory response.

Br J Anaesth 2002; 88: 520–6

Keywords: analgesia, postoperative; surgery, orthopaedic; analgesics non-opioid, dexketoprofen; polypeptides, interleukin 6


    Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Administration of non-steroidal anti-inflammatory drugs (NSAID) and opioids in combination for postoperative pain following major orthopaedic surgery is routinely practiced but incompletely effective.1 The potential to enhance analgesia and decrease opioid adverse effects justifies continued efforts to identify the optimal combination, mode of administration, and timing of administration of these drugs.

Dexketoprofen trometamol, the active enantiomer of racemic ketoprofen, is a relatively new oral NSAID with analgesic and anti-pyretic properties. The advantages of this product compared with ketoprofen are faster onset of action, increased potency, and possibly decreased potential for gastrointestinal side effects.2 3 Early studies indicate that dexketoprofen is effective and well tolerated in clinical practice.4 Dexketoprofen 25 mg tds has greater analgesic efficacy and fewer side effects than racemic ketoprofen in patients with osteoarthritis of the knee.5 Dexketoprofen trometamol possesses characteristics which may be of particular benefit to patients during the perioperative period. Its cyclo-oxygenase inhibitory effects decrease arachidonic acid metabolism to PGE1, PGE2, PGF1, PGF2{alpha}, and thromboxanes A2 and B2, which accounts in part for its analgesic effects. To date, its analgesic efficacy has been established for patients with postoperative dental pain.6 Its optical isomer, R(–)-ketoprofen, is not only pharmacologically inactive as a COX inhibitor, but endowed with toxic potential, especially in terms of prostaglandin-independent ulcerogenity (possibly related to neutrophil margination).7

Hip arthroplasty is routinely performed with a regional anaesthetic technique by administering a combination of hyperbaric bupivacaine and morphine intrathecally. This provides excellent conditions for surgery and appears to give satisfactory analgesia in the early postoperative period. However, clinical observation indicates that a period of inadequate analgesia often occurs between the offset of intrathecal opioid effect and the onset of effect of systemically administered opioids. Typically, this interval occurs 12–24 h postoperatively.

We hypothesized that the perioperative administration of dexketoprofen 25 mgs tds orally to patients undergoing elective hip arthroplasty under spinal anaesthesia would decrease the postoperative opioid requirements and attenuate the perioperative inflammatory response. To test this hypothesis, we carried out a prospective randomized, double-blinded, controlled clinical trial in patients undergoing hip arthroplasty under spinal anaesthesia with perioperative administration of dexketoprofen or placebo.


    Methods
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
With institutional ethical approval and written informed patient consent, 30 ASA I or II patients aged 45–70 yr undergoing elective hip arthroplasty under spinal anaesthesia were studied. Patients with chronic illnesses other than osteoarthritis or who had recent (2 months) surgery or infection, patients receiving concurrent medication with NSAID or with drugs known to interact with NSAID, patients with allergies or contraindications to NSAID or opioids were excluded.

Patients were randomly allocated to two groups: one group (D) received dexketoprofen 25 mg tds for 24 h before and 48 h after surgery; the second group (P) received a placebo tablet at equivalent times. As the interval from a single preoperative dose of dexketoprofen to the surgical incision may vary in practice between 1 and 2 h, the result would be markedly different dexketoprofen plasma concentration during surgery. In order to minimize this variability, the trial drug was administered for 24 h preoperatively.

All patients were instructed in the use of the Vygon patient-controlled pump and the use of the visual analogue scale for pain assessment. Patients received diazepam 10 or 15 mg 1 h preoperatively, if this was deemed appropriate by the anaesthetist.

On arrival to the operating room, standard monitoring was established (pulse oximetry, ECG, non-invasive arterial pressure monitoring with a Datex AS/3, Dale Corp., Madison, WI, USA Monitor). A 14G cannula was sited in a peripheral vein under local anaesthesia (2% lidocaine) in the non-dominant forearm and an infusion of compound sodium lactate 1000 ml commenced, of which 500 ml was administered rapidly. Patients were then placed in the lateral position with the operative site dependent. Using standard aseptic technique, the third and fourth lumbar interspace was located with palpation and infiltrated with 2% lidocaine (23G needle). Hyperbaric bupivacaine 0.5% (17.5 mg if greater than 70 kg and 15 mg if less than 70 kg) and preservative-free morphine (0.6 mg) were administered intrathecally through a 25G Whitacre B-D spinal needle (Becton Dickinson and Co., Franklin Lakes, NJ, USA). Sensory block was assessed during the subsequent 5–10 min using ethyl chloride spray. Postoperatively, all patients had access to disposable Vygon PCA pump (bolus 1 mg; lockout 5 min; no continuous infusion) (Laboratoires Pharmaceutique Vygon, Ecouen, France). Cyclizine 50 mg i.m. prn 8 hourly was prescribed for nausea and vomiting. The level of sensory block was again assessed on arrival to the postanaesthesia care unit. Intraoperative and total blood loss were estimated (by weighing swabs) and transfusion of blood products were also recorded.

Venous blood samples (10 ml) were withdrawn for estimation of plasma concentration of urea, creatinine, liver function tests, and the pro-inflammatory interleukin 6 (IL-6) on five occasions: 24 and 18 h preoperatively and 6, 24, and 48 h postoperatively. The samples for estimation of plasma IL-6 concentration were collected in sterile EDTA tubes, centrifuged at 1000 g, and the supernatant stored at –80°C. Plasma IL-6 concentration was measured using specific enzyme linked immunosorbent assays (ELISA) with specific polyclonal rabbit antibodies to recombinant IL-6 commercial kits (R&D System, Abingdon, Oxon, UK).

At 24 and 18 h preoperatively and at 2, 6, 12,15,18, 24, and 48 h postoperatively the following data were collected: heart rate, ventilatory frequency, temperature, and arterial pressure; pain (visual analogue scale); cumulative opioid consumption; adverse effects associated with opioid administration. (i) Nausea, vomiting (1, no nausea; 2, complaints of nausea but tolerable; 3, needs cyclizine 50 mg i.m.); (ii) respiratory depression (ventilatory frequency less than 8 min–1); (iii) pruritus (1, no itch; 2, itching but tolerable; 3, severe itch needs piriton 5 mg i.m.); (iv) sedation (1, awake; 2, drowsy; 3, asleep, easily rousable; 4, asleep, hard to rouse); (v) urinary retention (C, catheterized electively postoperatively; N, no catheter required; R, catheter sited because of urinary retention). In addition, adverse effects associated with dexketoprofen administration, that is dyspepsia, heartburn, abdominal pain, headache, and dizziness were noted.

Previous data on patients who had received a spinal anaesthetic with bupivacaine and morphine for joint replacement and morphine PCA for 24 h postoperatively showed a mean morphine consumption of 20 (SD 9.75) mg.8 It was calculated that 26 patients (13 pairs) would be required to have an 80% power of detecting a 50% reduction in the 24 h morphine consumption at a significance level of 0.05.

Statistical analyses were undertaken with StatView 4.5 for Windows (1992–1996). Data on patients’ weight and height, operating time, total blood loss, and transfusion requirements were analysed using Student’s t-test. P<0.05 was considered significant. Repeated measures ANOVA was used to compare morphine consumption, VAS for pain and sedation, IL-6 concentrations, pruritus, postoperative nausea and vomiting, biochemistry, and physiological parameters. Fisher’s exact test was used to compare non-parametric data (i.e. necessity of a urinary catheter). P<0.05 was considered significant.


    Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The two groups were similar with respect to age, gender, weight, height, ASA class, duration of surgery, and level of sensory block on arrival to recovery room (Table 1). One patient in the placebo group was excluded as he received diclofenac 100 mg pr intraoperatively. Groups were also similar in terms of intra- or postoperative blood loss and in the transfusion requirements (Table 2), ventilatory frequency (Table 3), or haemodynamic variables (Table 4).


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Table 1 Patient characteristics, duration of surgery, and the upper level of sensory block on arrival to recovery
 

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Table 2 Blood loss and transfusion requirements. Data are mean (SD)
 

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Table 3 Ventilatory frequency. Data are mean (SD). *P<0.05 compared with the preoperative baseline. No difference between groups was found
 

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Table 4 Haemodynamic measures. Data are mean (SD). *P<0.05 refers to comparison with the preoperative baseline. No difference between the groups
 
Cumulative morphine consumption was less in group D compared with group P at 6 (0.06 (0.2) vs 0.85 (1.4) mg, P=0.04) and 48 h postoperatively (10.1 (8) vs 26.2 (20) mg, P<0.01) (Fig. 1). The time to first analgesia postoperatively was significantly greater in group D (1277 (1031) min) than group P (642 (317) min) (P=0.03). Figure 2 displays the VAS scores for pain recorded at the time points mentioned. Although patients in group D tended to experience less pain throughout the postoperative period, this achieved statistical significance only at 15 h (P=0.02) postoperatively. Plasma IL-6 concentrations were less in group D than in group P at 6 h (94.4 (70) vs 162 (83) pg ml–1, P=0.02) but not at 24 and 48 h postoperatively (Fig. 3).



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Fig 1 Data are mean (SD). *P<0.05 refers to between groups comparisons. P, placebo group; D, dexketoprofen group.

 


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Fig 2 Data are mean (SD). *P<0.05 refers to between groups comparisons. P, placebo group; D, dexketoprofen group.

 


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Fig 3 Data are mean (SD). *P<0.05 refers to comparison with the baseline. {dagger}P<0.05 refers to between groups comparisons. P, placebo group; D, dexketoprofen group.

 
Nausea and vomiting were less (P<0.01) in group D compared with group P at 18 h postoperatively (Fig. 4). Patients in both groups experienced pruritus, which was greatest in intensity 2 and 6 h postoperatively (Fig. 5). Sedation scores were increased compared with the baseline in group D at 2 and 6 h (P<0.01) postoperatively and in group P at 12, 15, and 18 h (P<0.01) postoperatively. At 18 h postoperatively, sedation scores were less in group D than in group P (P=0.03) (Fig. 6). Seven patients in each group were electively catheterized postoperatively. However, three patients in group P were catheterized on a total of four occasions for urinary retention. Only one patient in group D required catheterization for this reason.



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Fig 4 Data are mean (SD). *P<0.05 refers to comparison with the baseline. {dagger}P<0.05 refers to between groups comparisons. P, placebo group; D, dexketoprofen group.

 


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Fig 5 Data are mean (SD). *P<0.05 refers to comparisons to the baseline. P, placebo group; D, dexketoprofen group.

 


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Fig 6 Data are mean (SD). *P<0.05 refers to comparisons to the baseline. {dagger}P<0.05 refers to comparison between the two groups. P, placebo group; D, dexketoprofen group.

 
The renal (urea, creatinine, potassium plasma concentration) and hepatic (ALT, total bilirubin, alkaline phosphatase) profiles were normal in all patients at each time point. No complication or side effect attributable to dexketoprofen (dyspepsia, heartburn, abdominal pain, headache, dizziness, diarrhoea, constipation, paraesthesia, skin rash) was reported.


    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Ketoprofen is well established as an effective analgesic and anti-inflammatory agent in the treatment of conditions such as rheumatoid arthritis, osteoarthritis, and mild to moderate pain from a variety of causes.9 However, this compound is a racemic mixture of two stereoisomers, of which only the dextro-rotatory enantiomer, dexketoprofen, has biologic activity. Therefore, dexketoprofen potentially offers several advantages over the racemic parent drug. In humans, the relative bioavailability of oral dexketoprofen trometamol (12.5 and 25 mg, respectively) is similar to that of oral racemic ketoprofen (25 and 50 mg, respectively), as measured in all cases by the area under the concentration-time curve values for S(+)-ketoprofen.2 Similarly, the activity of dexketoprofen was twice that of racemic ketoprofen in all models investigated. Thus, the pure enantiomer may be administered at half the dosages of the racemic compound analgesic (12.5 and 25 vs 25 and 50 mg, respectively), which reduces the hepatic metabolic load and the total amount of metabolites formed.2

Use of a single enantiomer simplifies the pharmacokinetic profile of the compound by eliminating enantiomer inversion; therefore, dexketoprofen has the potential to decrease pharmacokinetic variability compared with racemic ketoprofen.9 Trometamol was added to dexketoprofen to increase solubility more than 1000-fold compared with the free acid form. It has been shown that its absorption after oral administration is much faster (tmax 0.25–0.75 h) and consistent than after the administration of either dexketoprofen-free acid or racemic ketoprofen (tmax 0.5–3 h). Its half-life is 1–4 h, distribution volume 0.1–0.2 litre kg–1, with greater than 99% plasma protein binding. Excretion is predominantly by urinary route, with glucuronide conjugates accounting for 90% of the administered dose. There is neither metabolic inversion of the active S(+)-enantiomer (eutomer) to its essentially inactive optical opposite (distomer), nor incorporation into fat tissue.7

In the past, i.m. ‘prn’ opioids were routinely prescribed for postoperative analgesia and often provided suboptimal analgesia and considerable morbidity. Currently, regional anaesthetic techniques, epidural and intrathecal opioids, and combinations of these are routine components of anaesthetic practice. It is likely that the benefits of providing adequate analgesia postoperatively extends beyond patient satisfaction and also leads to improved patient outcome.10 The concept of combining an opioid with a non-sedating, non-opioid analgesic is a simple form of multimodal therapy. The aim of such a combination is to make use of the synergism between the analgesic effects of the individual drugs.1113 Advantages also include decreased opioid requirements and thus associated adverse effects.

Timing of NSAID administration is clinically important because the onset of effect of these drugs is 30–60 min following oral administration. Their opioid sparing effect is not apparent until 4 h after oral administration.14 In experimental studies, the evidence favouring pre-emptive analgesia is very convincing. However, clinical studies have produced conflicting results possibly because of differing study designs.15 In this study, the trend towards opioid sparing was apparent throughout the postoperative period, although it reached statistical significance only at 6 and 48 h. The time to first (opioid) analgesia was 1277 (1031) min in group D vs 642 (317) min in group P (P=0.03), which in group D is well beyond the offset of intrathecal opioid effect.

The current investigation addressed two questions. (i) Does perioperative dexketoprofen administration possess opioid sparing effects in the postoperative period? (ii) Does perioperative dexketoprofen administration influence the perioperative pro-inflammatory state as assessed by the plasma IL-6 concentration?

The most important finding of the study is the marked reduction in postoperative opioid requirements, followed by decrease in postoperative nausea and vomiting, sedation, urinary retention, and prolongation of time to first analgesia with no evident complications or adverse effects.

Secondly, the perioperative pro-inflammatory state was attenuated as shown by the decreased IL-6 levels 6 h postoperatively.

Although IL-6 is an integral mediator of the physiologic acute phase response to injury, excessive and prolonged post-injury elevations of circulating IL-6 concentrations are associated with mortality and morbidity. IL-6 has been the most consistently identified cytokine mediator of post-injury complications.16 A greater degree of pain in the placebo group may have resulted in an increased stress response and thus increased plasma IL-6 concentration. An increased use of morphine in this group may have had a direct effect in increasing IL-6, as morphine has been shown to promote the release of IL-6 from lipopolysaccharide stimulated monocytes.17

Our selection of sampling times was based on previous evidence that demonstrated that the postoperative increase in plasma IL-6 concentration begins at 2–4 h. Although IL-6 concentrations tended to increase to a lesser extent in group D at all postoperative time points, the difference was statistically significant at 6 h only. The limited extent of the IL-6 response (in both groups) at 24 and 48 h after the procedure may have decreased the likelihood of demonstrating an inhibitory effect of dexketoprofen.

In conclusion, dexketoprofen 25 mg tds, administered perioperatively as an adjuvant to opioids is a highly effective analgesic regimen in the treatment of pain after hip arthroplasty. In addition, this regimen appears to decrease the postoperative pro-inflammatory response.


    Acknowledgement
 
Part of this project was supported by A. Menarini Pharmaceuticals Ireland Ltd.


    References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
1 Kehlet H, Rung GW, Callesen T. Postoperative opioid analgesia: time for reconsideration? J Clin Anesth 1996; 8: 441–5[ISI][Medline]

2 Mauleon D, Artigas R, Garcia ML, Carganico G. Preclinical and clinical development of dexketoprofen. Drugs 1996; 52 (Suppl 5): 24–45[ISI][Medline]

3 Cabre F, Fernandez MF, Calvo L, et al. Analgesic, anti-inflammatory and antipyretic effects of S(+)-ketoprofen in vivo. J Clin Pharmacol 1998; 38 (Suppl 12): 3S–10S[Abstract/Free Full Text]

4 Ezcurdia M, Cortejoso FJ, Lanzon R, et al. Comparison of the efficacy and tolerability of dexketoprofen and ketoprofen in the treatment of primary dysmenorrhea. J Clin Pharmacol 1998; 38 (Suppl 12): 65S–73S[Abstract/Free Full Text]

5 Beltran J, Martin-Mole E, Figueroa M, et al. Comparison of dexketoprofen trometamol and ketoprofen in the treatment of osteoarthrits of the knee. J Clin Pharmacol 1998; 38 (Suppl 12): 74S–80S[Abstract/Free Full Text]

6 McGurk M, Robinson P, Rajayogeswaran V, et al. Clinical comparison of dexketoprofen trometamol, ketoprofen, and placebo in postoperative dental pain. J Clin Pharmacol 1998; 38 (Suppl 12): 46S–54S[Abstract/Free Full Text]

7 Jamali F, Brocks DR. Clinical pharmacokinetics of ketoprofen and its enantiomers. Clin Pharmacokinet 1990; 19: 197–217[ISI][Medline]

8 Cole PJ, Craske DA, Wheatley RG. Efficacy and respiratory effects of low-dose spinal morphine for postoperative analgesia following knee arthroplasty. Br J Anaesth 2000; 85: 233–7[Abstract/Free Full Text]

9 Barbanoj MJ, Gich I, Artigas R, et al. Pharmacokinetics of dexketoprofen trometamol in healthy volunteers after single and repeated oral doses. J Clin Pharmacol 1998; 38 (Suppl 12): 33S–40S[Abstract/Free Full Text]

10 Sharrock NE, Cazan MG, Hargett MJL, Willliams-Russo P, Wilson PD. Changes in mortality after total hip and knee arthroplasty over a ten year period. Anesth Analg 1995; 80: 242–8[Abstract]

11 Jaffe JH, Martin WR. Opioid analgesics and antagonists. In: Goodman Gilman A, Rall TW, Nies AS, Taylor P, eds. The Pharmacological Basis of Therapeutics. USA: McGraw-Hill, Inc., 1993; 485–522

12 Dahl JB, Kehlet H. Non-steroidal anti-inflammatory drugs: rationale for use in severe postoperative pain. Br J Anaesth 1991; 66: 703–12[ISI][Medline]

13 Casali R, Girardi G, Mediati RD, Livi P, Novelli GP. Evaluation of the synergism between ketorolac and morphine in the treatment of postoperative pain. Minerva-Anestesiol 1995; 61: 501–7

14 Camu F, Vanlersberghe C, Lauwers MH. Timing of perioperative non-steroidal anti-inflammatory drug treatment. Acta Anaesthesiol Belg 1996; 47: 125–8[Medline]

15 Kissin I. Pre-emptive analgesia: why its effect is not always obvious. Anesthesiology 1996; 84: 1015–9[ISI][Medline]

16 Biffl WL, Moore EE, Moore FA, Peterson VM. Interleukin-6 in the injured patient. Ann Surg 1996; 224: 647–64[ISI][Medline]

17 Chao CC, Hu S, Molitor TW, et al. Morphine potentiates transforming growth factor-beta release from human peripheral blood mononuclear cell cultures. J Pharmacol Exp Ther 1992; 262: 19–24[Abstract]





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