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Canadian Journal of Anesthesia 50:445-449 (2003)
© Canadian Anesthesiologists' Society, 2003
Regional Anesthesia and Pain

Prior ibuprofen exposure does not augment opioid drug potency or modify opioid requirements for pain inhibition in total hip surgery

[L’exposition préalable à l’ibuprofène n’augmente pas l’effet des opiacés ou ne modifie pas les besoins d’opiacés pour l’analgésie de l’arthroplastie totale de la hanche]

Marian L.T. Bugter, MD*, Ris Dirksen, MD PhD*, Khem Jhamandas, PhD{dagger}, Robert Slappendel, MD PhD*, Eric W.G. Weber, MD* and Brian Milne, MD FRCP(C){ddagger}

* From the Department of Anaesthesiology, Sint Maartensklinick, Nijmegen, the Netherlands; and
{dagger} the Departments of Pharmacology Toxicology; and
{ddagger} Anaesthesiology, Queen’s University, Faculty of Health Sciences, Kingston, Ontario, Canada.

Address correspondence to: Dr. Marian L.T. Bugter, Department of Anaesthesiology, Sint Maartensklinick, P.O. Box 9011, 6500 GM Nijmegen, the Netherlands. Phone: 024 3659911; Fax: 024 3659487; E-mail: m.bugter{at}maartenskliniek.nl


   Abstract
TOP
 Abstract
Introduction
 Methods and materials
 Results
 Discussion
 Conclusions
 References
 
Purpose: In previous animal studies, a prior exposure to non-steroidal anti-inflammatory drugs (NSAID) augmented opioid drug potency. This study was designed to answer the question whether a similar effect can be attained in man. The objective was to use NSAID for preoperative pain reduction and at the same time use the NSAID exposure to reduce opioid requirements for pain inhibition in major orthopedic surgery.

Methods: In this double-blind, randomized study, 50 patients scheduled for total hip surgery were included. Patients of Group I received a placebo drug three times a day two weeks before surgery, and those allocated to Group II received ibuprofen (600 mg) three times a day. For surgical anesthesia, all patients received intrathecal bupivacaine 20 mg plus 0.1 mg morphine in a total volume of 4 mL.

Results: The preoperative or postoperative visual analogue scale pain scores or the amount of iv morphine showed no differences between the two groups in the first 24 hr after surgery. The median total blood loss in the ibuprofen group was 1161 mL vs 796 mL in the placebo group (P < 0.01).

Conclusion: Pretreatment with ibuprofen before major hip surgery does not improve the pain scores or reduce morphine requirement but significantly increases blood loss. Considering the presence of relevant adverse effects, pretreatment with a non-selective NSAID is not recommended.


   Introduction
TOP
 Abstract
 Introduction
Methods and materials
 Results
 Discussion
 Conclusions
 References
 
MORPHINE and other opioid analgesics produce potent analgesia by activating specific receptors on the spinal and supraspinal neurons involved in pain transmission. At the spinal level, opioids elicit analgesia partly by inhibiting the spinal release of substance P1 or L-glutamate. These transmitters are localized in primary afferents that elicit pain behaviours by acting on the neurokinin and N-methyl-D-aspartate (NMDA) receptors, respectively. Evidence from experimental studies suggests that spinal prostanoids play an intermediary role in the expression of pain behaviours elicited by activity of these sensory transmitters.2,3 It has been demonstrated that hyperalgesia produced by activation of spinal NMDA receptors is mediated by prostaglandins since intrathecal injections of cyclo-oxygenase inhibitors, agents that block prostanoid synthesis, inhibit this response.4

Like hyperalgesia, the development of opioid tolerance is recognized as an NMDA receptor-dependant phenomenon as NMDA antagonists attenuate this response.5–9 A recent animal study10 showed that co-administration of chronic morphine with cyclo-oxygenase inhibitors, ketorolac and ibuprofen, significantly attenuates the decline in opioid agonist potency occurring with repeated drug administration. This suggests that chronic opioid drug treatment likely mobilizes prostanoids11 which act on presynaptic receptor sites12 to stimulate release of nociceptive transmitters13 and thus physiologically antagonize the analgesic action of the drug. However, it has also been observed that chronic spinal administration of the cyclo-oxygenase inhibitors alone significantly enhances the analgesic potency of acute morphine evaluated at the end of the treatment period, reflecting sensitization to the opioid action.10 While the mechanisms underlying this sensitization are unclear, this observation has important clinical implications. It suggests that a prior exposure to cyclo-oxygenase inhibitors has the potential to augment opioid drug potency and thus reduce opioid requirements for pain inhibition.

Clinically the use of prior exposure to cyclo-oxygenase inhibitors carries some attractive potentials. First, the drug may result in a reduction of preoperative pain, and in a recent study we found that lower preoperative visual analogue scale (VAS) scores correlated with lower postoperative morphine requirements for postoperative analgesia.14 Secondly, augmented opioid drug potency may contribute to reduction in opioid dosage and this may enhance safety. Intrathecal opiates are often used for postoperative pain control in major orthopedic surgery of the lower limb.15,16 In our clinic, we showed that - for total hip surgery - 0.1 mg of intrathecal morphine and repeated iv morphine by patient-controlled analgesia (PCA) pump for 24 hr results in appropriate analgesia, defined by VAS scores < 3.17 So far - in approximately 6,000 patients - the intrathecal dose of 0.1 mg morphine proved safe in that late respiratory depression did not occur. However, there continues to be a high incidence of other side effects such as urinary retention and itching.18 Also, the total iv PCA morphine dose is highly variable and ranges from 10 to 100 mg•24 hr-1.

The present double-blinded randomized study was designed to test whether a prior exposure to the cyclo-oxygenase inhibitor ibuprofen would reduce preoperative and postoperative pain and whether it would augment morphine’s potency.


   Methods and materials
TOP
 Abstract
 Introduction
 Methods and materials
Results
 Discussion
 Conclusions
 References
 
The Ethical Committee of our hospital approved the study and written informed consent was obtained from all patients. Fifty consecutive patients with coxarthrosis scheduled for primary elective total hip replacement surgery under intrathecal anesthesia were included. Exclusion criteria were those that exclude spinal anesthesia or the use of non-steroidal anti-inflamatory drugs (NSAID) or opioids.

Patients were allocated and randomized to two groups in a double-blind manner. All patients were pretreated during a two-week period before surgery: Group I with placebo drug, and Group II with ibuprofen 600 mg. Placebo and ibuprofen were prepared as look-alike tablets by the pharmacist, who was the only person aware of the type of pretreatment, and were given orally three times a day. The day of surgery all patients started with 15 mg movicox orally one hour preoperatively. This was continued for three days postoperatively.

Prophylaxis against thromboembolism was started in all patients the evening before surgery with 3 mg acenocoumarol orally. On the day of surgery 2 mg acenocoumarol was given 24 hr after the initial dose. All patients were premedicated with 7.5 mg midazolam orally one hour before intrathecal anesthesia. Spinal anesthesia was induced by the administration of 20 mg bupivacaine plus 0.1 mg morphine dissolved in 4 mL (isobaric solution).

Adequate sedation was provided at the patient’s request during the procedure: the anesthesiologist administered 1 mg midazolam at the minimum interval of five minutes until the patient indicated that the desired sedation was reached. Non-invasive blood pressure, heart rate (ECG), SpO2, and respiratory rate were continuously monitored during anesthesia and in the intensive care unit during the first 24 hr after surgery.

Pain
Pain was evaluated using VAS scores. VAS scores were assessed: 1) before starting pretreatment; 2) preoperatively (i.e., after two weeks of pretreatment); and 3) postoperatively on rest (0–10; with 0 = no pain) every three hours. The patients could use a PCA device with iv morphine if pain was present. The settings of the PCA pump (Braun®, Melsungen, Germany): baseline 0.0 mg•hr-1, bolus dose 1.0 mg, bolus interval five minutes, maximum 30.0 mg per four hours.

Side effects
The presence or absence of itching, postoperative nausea and vomiting (PONV), urinary retention, sedation were noted at a three-hour interval during the 24-hr observation period. Also, medications to treat these side effects were recorded at the same interval during the 24-hr observation period.

Blood loss was measured by weighing the gauzes and inspection of collection reservoirs.

Statistical analysis
Pain scores were analyzed using a paired t test. The incidence of PONV and itching was compared between the groups with Fisher’s exact tests. The amount of blood loss and morphine consumed was analyzed using a Mann Whitney U test, since they were non-normally distributed. It was planned to enroll 25 patients in each group to be able to detect a difference of one standard deviation in postoperative VAS pain score ({alpha} = 0.05 two sided, ß = 0.10)


   Results
TOP
 Abstract
 Introduction
 Methods and materials
 Results
Discussion
 Conclusions
 References
 
Demographic data are represented in Table IGo. As shown, the two groups did not differ significantly in age, height, weight or gender. Likewise other variables, e.g., preoperative use of beta blockers, percentages of patients who required sedation during surgery, duration of surgery, use of bone cement and blood pressure decreases (> 25% decrease in mean arterial pressure after bone cement) were not different between groups. Surgery was postponed more than three days in 14 patients (and the medication not continued), so these patients had to be excluded from the analysis.


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  		TABLE I Patient characteristics
 
The VAS scores before treatment (6.7 ± 1.4 and 7.1 ± 1.6) did not differ between the two groups. After the two-week pretreatment period, VAS scores were not different for the two groups (6.4 ± 1.4 and 6.5 ± 2.6 for patients pretreated with placebo and ibuprofen, respectively). There was no difference in the postoperative VAS scores (Figure 1Go; P = 0.35). Likewise, the amount of morphine consumed by patients using the PCA pump (26.6 ± 18.6 mg and 22.1 ± 9.6 mg for placebo and ibuprofen pretreated patients respectively) was not different (P = 0.52).



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  		FIGURE 1 Visual analogue scale (VAS) pain scores in the first 24 postoperative hours for placebo and ibuprofen pretreated patients

 
The median perioperative blood losses and (interquartile range) are given in Table IIGo. The median total perioperative blood loss in patients pretreated with ibuprofen was 1161 vs 796 mL in the placebo group: i.e., 30% higher after ibuprofen than after placebo (P < 0.01).


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  		TABLE II Perioperative blood losses
 
The incidence of PONV (Table IIIGo; Figure 2Go) was not significantly different between the two groups. Similarly, the incidence of postoperative itching was similar in both groups (Figure 3Go).


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  		TABLE III Postperative nausea and vomiting
 


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  		FIGURE 2 Incidence of postoperative nausea.

 


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  		FIGURE 3 Incidence of postoperative itching.

 

   Discussion
TOP
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
Conclusions
 References
 
Previous animal studies showed that a period of chronic intrathecal administration of ketorolac or S(+) ibuprofen increased the antinociceptive potency of acute morphine.10 In man, VAS scores after orthopedic surgery were lower in patients treated with iv ketorolac before surgery than for patients treated with iv saline or postoperative ketolorac.19 This prompted us to examine, in a clinical situation, whether prior treatment with a systemic NSAID would afford pain relief and reduce the requirements for morphine. Our main finding is that preoperative pretreatment with oral ibuprofen does not reduce VAS scores pre- or postoperatively and does not enhance the potency of morphine. Several factors may explain the absence of effect of NSAID on opioid requirements. In the surgical and immediate postoperative period, the combined administration of bupivacaine and morphine provides effective analgesia after total hip arthroplasty17 and, thus, the prevailing low postoperative pain VAS scores may have prevented us from appreciating putative improvement from oral ibuprofen. For the subsequent period, pain was treated by the use of PCA morphine and systemic ibuprofen failed to reduce the amount and variability of analgesic consumption. Likewise, previous clinical trials that tested NSAID for their ability to effect "pre-emptive analgesia" showed no clinical improvement in postoperative pain control.20 Finally, it should be noted that in the experimental study,10 the NSAID was used intrathecally and it is likely that the oral dose of ibuprofen used clinically failed to reach the concentration that influenced morphine action at the spinal level. The use of higher doses of the drug in this respect is not advisable as the ibuprofen dose used already produces COX-1 related side effects. The inhibition of COX-1 may result in impaired platelet aggregation,21–23 explaining the statistically and clinically relevant higher perioperative blood loss in patients pretreated with ibuprofen.

A potential clinical benefit pursued using pretreatment with ibuprofen was the possible reduction of opioid related side effects. We found no differences in the incidence of morphine side effects (urinary retention, itching, PONV) between the two groups. Consequently, we feel that there is no benefit in pretreating patients undergoing elective hip surgery with the NSAID ibuprofen. The use of COX-2 inhibitors may be more effective or ibuprofen might influence morphine action in other surgical situations, such as knee surgery when pain control is less optimal.


   Conclusions
TOP
 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
 Conclusions
References
 
Preclinical research indicated that prior exposure to NSAID has the potential to augment opioid drug potency and thus reduce opioid requirements for pain control. This double-blind randomized human study showed no change in preoperative VAS pain scores, surgical spinal anesthesia, postoperative pain, or morphine consumption for pain relief after primary hip surgery and the use of ibuprofen lead to augmented blood loss.


   Acknowledgments
 
The authors are indebted to Prof. Dr. M. Prins, Academic Hospital Maastricht, for his assistance and revision of the statistics.

Revision received February 13, 2003. Accepted for publication April 11, 2002.


   References
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 Abstract
 Introduction
 Methods and materials
 Results
 Discussion
 Conclusions
 References
 
1 Yaksh TL, Jessell TM, Gamse R, Mudge AW, Leeman SE. Intrathecal morphine inhibits substance P release from mammalian spinal cord in vivo. Nature 1980; 286: 155–7.[Medline]

2 Malmberg AB, Yaksh TL. Spinal actions of non-steroidal anti-inflammatory drugs: evidence for a central role of prostanoids in nociceptive processing. Prog Pharmacol Clin Pharmacol 1993; 10: 91–110.

3 McCormack K. Non-steroidal anti-inflammatory drugs and spinal nociceptive processing. Pain 1994; 59: 9–43.[Medline]

4 Malmberg AB, Yaksh TL. Hyperalgesia mediated by spinal glutamate or substance P receptor blocked by spinal cyclooxygenase inhibition. Science 1992; 257: 1276–9.[Abstract/Free Full Text]

5 Trujillo KA, Akil H. Inhibition of morphine tolerance and dependence by the NMDA receptor antagonist MK-801. Science 1991; 251: 85–7.[Abstract/Free Full Text]

6 Mao J, Price DD, Mayer DJ. Thermal hyperalgesia in association with the development of morphine tolerance in rats: roles of excitatory amino acid receptors and protein kinase C. J Neurosci 1994; 14: 2301–12.[Abstract]

7 Tiseo PJ, Inturrisi CE. Attenuation and reversal of morphine tolerance by the competitive N-methyl-D-aspartate receptor antagonist, LY274614. J Pharmacol Exp Ther 1993; 264: 1090–6.[Abstract/Free Full Text]

8 Dunbar S, Yaksh TL. Concurrent spinal infusion of MK801 blocks spinal tolerance and dependence induced by chronic intrathecal morphine in the rat. Anesthesiology 1996; 84: 1177–88.[Medline]

9 Shimoyama N, Shimoyama M, Inturrisi CE, Elliott KJ. Ketamine attenuates and reverses morphine tolerance in rodents. Anesthesiology 1996; 85: 1357–66.[Medline]

10 Powell KJ, Hosokawa A, Bell A, et al. Comparative effects of cyclo-oxygenase and nitric oxide synthase inhibition on the development and reversal of spinal opioid tolerance. Br J Pharmacol 1999; 127: 631–44.[Medline]

11 Fukuda K, Kato S, Morikawa H, Shoda T, Mori K. Functional coupling of the {delta}-, µ-, and {kappa}-opioid receptors to mitogen-activated protein kinase and arachidonate release in Chinese hamster ovary cells. J Neurochem 1996; 67: 1309–16.[Medline]

12 Matsumura K, Watanabe Y, Imai-Matsumura K, et al. Mapping of prostaglandin E2 binding sites in rat brain using quantitative autoradiography. Brain Res 1992; 581: 292–8.[Medline]

13 Nicol GD, Klingberg DK, Vasko MR. Prostaglandin E2 increases calcium conductance and stimulates release of substance P in avian sensory neurons. J Neurosci 1992; 12: 1917–27.[Abstract]

14 Slappendel R, Weber EWG, Bugter MLT, Dirksen R. The intensity of preoperative pain is directly correlated with the amount of morphine needed for postoperative analgesia. Anesth Analg 1999; 88: 146–8.[Abstract/Free Full Text]

15 Fournier R, Van Gessel E, Macksay M, Gamulin Z. Onset and offset of intrathecal morphine versus nalbuphine for postoperative pain relief after total hip replacement. Acta Anaesthesiol Scand 2000; 44: 940–5.[Medline]

16 Fournier R, Van Gessel E, Weber A, Gamulin Z. A comparison of intrathecal analgesia with fentanyl or sufentanil after total hip replacement. Anesth Analg 2000; 90: 918–22.[Abstract/Free Full Text]

17 Slappendel R, Weber EWG, Dirksen R, Gielen MJM, van Limbeek J. Optimization of the dose of intrathecal morphine in total hip surgery: a dose-finding study. Anesth Analg 1999; 88: 822–6.[Abstract/Free Full Text]

18 Carpenter RL, Caplan RA, Brown DL, Stephenson C, Wu R. Incidence and risk factors for side effects of spinal anesthesia. Anesthesiology 1992; 76: 906–16.[Medline]

19 Fletcher D, Zetlaoui P, Monin S, Bombart M, Samii K. Influence of timing on the analgesic effect of intravenous ketorolac after orthopedic surgery. Pain 1995; 61: 291–7.[Medline]

20 Kissin I. Preemptive analgesia. Anesthesiology 2000; 93: 1138–43.[Medline]

21 Schafer AI. Effects of nonsteroidal antiinflammatory drugs on platelet function and systemic hemostasis. J Clin Pharmacol 1995; 35: 209–19.[Abstract]

22 Rorarius MGF, Baer GA, Metsa-Ketala T, Miralles J, Palomaki E, Vapaatalo H. Effects of peri-operatively administered diclofenac and indomethacin on blood loss, bleeding time and plasma prostanoids in man. Eur J Anaesth 1989; 6: 335–42.[Medline]

23 Vane JR, Botting RM. Pharmacodynamic profile of prostacyclin. Am J Cardiol 1995; 75: 3A–10A.[Medline]





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