To the Editor:—
The recent meta-analysis by Møiniche et al.1
makes it clear that preemptive analgesia as currently envisioned by a large number of anesthesiologists is of limited clinical efficacy. In the accompanying editorial, Hogan 2
suggests reasons why this may be the case and proposes that current practice be modified accordingly. We are concerned that this may provide the impetus for less aggressive perioperative pain management, and that such a trend may have negative implications for perioperative pain relief, recovery of function, morbidity, and mortality.
As first conceived, 3
preemptive analgesia was based on the idea that systemic or regional analgesic regimens initiated before the onset of surgery could have effects that outlast the pharmacokinetic presence of the intervention. This view recognized that sensitization of the pain pathways was ongoing throughout the entire perioperative period. However, most trials of preemptive analgesia and all of those included in the meta-analysis involve interventions that differ only for the intraoperative portion of the perioperative period, generally permitting patients to enter the postoperative period with at least moderately effective analgesic interventions already active. Such studies parallel laboratory investigations of relatively discrete, low-intensity, noxious stimuli in which an animal receives the analgesic intervention either before or after the stimulus. As repeatedly emphasized by Kissin, 4,5
this approach to the clinical evaluation of preemptive analgesia is fraught with problems because of the limited ability of many analgesic interventions to prevent sensitization, the intensity and duration of the stimulus relative to the intervention, and the benefits of the analgesic regimen received by the control group.
In the editorial, Hogan 2
states that regardless of any intraoperative intervention, it should be possible to manage postoperative pain effectively. However, for reasons that are not always clear, and as illustrated by many of the trials included in the meta-analysis, this appears to be very difficult to do, even in the context of the increased sensitivity to the patient's analgesic needs that accompanies a clinical study of perioperative analgesia. Furthermore, even if sufficient analgesics can be administered in a highly structured environment to equalize pain between groups, very little is known about more typical clinical conditions, and even less is known about what happens once the patients leave this environment. For example, of the 80 studies included by the meta-analysis, only 9 report data for more than 72 h after surgery. However, long-term, painful sequelae following surgical procedures are more common than generally appreciated, 6–10
and even low-level pain can be associated with decreased function. 10,11
Thus, we still know little about limiting the very morbidity that we would most prefer perioperative analgesic regimens to prevent.
Unfortunately, pain scores alone might not be sufficient to evaluate the efficacy of perioperative analgesic regimens. As demonstrated in one longer-term positive evaluation of preemptive epidural analgesia that did not meet the inclusion criteria of the meta-analysis, even when pain scores are similar, functional differences may still be present. 12
Meaningful functional measures might be able to associate a benefit from the longer-term decreases in wound hyperalgesia seen after relatively simple interventions, 13,14
even when pain scores alone could not.
Given the lack of evidence of significant clinical efficacy of preemptive analgesia in the meta-analysis, the editorial advocated avoiding intraoperative opioid use and initiating epidural blockade only upon emergence “when analgesic needs can be directly assessed.”2
This may result in many more patients emerging with pain that must then be treated, and this pain may further sensitize the nociceptive pathways. The editorial also overlooks many of the other beneficial effects of intraoperative epidural blockade, which may include modulation of the stress response, decreased blood loss, ability to tolerate hemorrhagic shock, improved immune function, and decreased thromboembolic events. 15–18
Some of these effects may account for differences in morbidity and mortality when anesthetics involving regional anesthesia are compared with general anesthesia alone. 19–21
In summary, the authors of the meta-analysis have made a valuable contribution by demonstrating that relatively modest interventions made for relatively brief periods of time are, at best, of limited efficacy. This should not obscure the fact that surgical procedures are frequently associated with residual long-term pain and other morbidities, which might benefit from aggressive analgesic interventions throughout the entire perioperative period. Rather than limiting preemptive analgesia, the results of the meta-analysis should focus clinicians and clinical investigators on the broader definition of preemptive analgesia and the longer-term impact of such interventions on pain, functionality, and morbidity.
Allan Gottschalk, M.D., Ph.D.*
E. Andrew Ochroch, M.D.
1. Moiniche S, Kehlet H, Dahl JB: A qualitative and quantitative systematic review of preemptive analgesia for postoperative pain relief: The role of timing of analgesia. A nesthesiology 2002; 96: 725–41
2. Hogan QH: No preemptive analgesia: Is that so bad? A nesthesiology 2002; 96: 526–7
3. Wall PD: The prevention of postoperative pain. Pain 1988; 33: 289–90
4. Kissin I: Preemptive analgesia. Why its effect is not always obvious. A nesthesiology 1996; 84: 1015–9
5. Kissin I: Preemptive analgesia. A nesthesiology 2000; 93: 1138–43
6. Sherman RA, Devor M, Jones D, Katz J, Marbach JJ: Phantom Pain. New York, Plenum, 1997
7. Taddio A, Goldbach M, Ipp M, Stevens B, Koren G: Effect of neonatal circumcision on pain responses during vaccination in boys. Lancet 1995; 345: 291–2
8. Dajczman E, Gordon A, Kreisman H, Wolkove N: Long-term postthoracotomy pain. Chest 1991; 99: 270–4
9. de Vries J, Timmer P, Erftemeier E, van der Weele L: Breast pain after breast conserving therapy. Breast 1994; 3: 151–4
10. Haythornthwaite JA, Raja SN, Fisher B, Frank SM, Brendler CB, Shir Y: Pain and quality of life following radical retropubic prostatectomy. J Urol 1998; 160: 1761–4
11. Bay-Nielsen M, Perkins FM, Kehlet H: Pain and functional impairment 1 year after inguinal herniorrhaphy: A nationwide questionnaire study. Ann Surg 2001; 233: 1–7
12. Gottschalk A, Smith DS, Jobes DR, Kennedy SK, Lally SE, Noble VE, Grugan KF, Seifert HA, Cheung A, Malkowicz SB, Gutsche BB, Wein AJ: Preemptive epidural analgesia and recovery from radical prostatectomy: A randomized controlled trial. JAMA 1998; 279: 1076–82
13. Tverskoy M, Cozacov C, Ayache M, Bradley EL Jr, Kissin I: Postoperative pain after inguinal herniorrhaphy with different types of anesthesia. Anesth Analg 1990; 70: 29–35
14. Tverskoy M, Oz Y, Isakson A, Finger J, Bradley EL Jr, Kissin I: Preemptive effect of fentanyl and ketamine on postoperative pain and wound hyperalgesia. Anesth Analg 1994; 78: 205–9
15. Engquist A, Brandt MR, Fernandes A, Kehlet H: The blocking effect of epidural analgesia on the adrenocortical and hyperglycemic responses to surgery. Acta Anaesthesiol Scand 1977; 21: 330–5
16. Shibata K, Yamamoto Y, Murakami S: Effects of epidural anesthesia on cardiovascular response and survival in experimental hemorrhagic shock in dogs. A nesthesiology 1989; 71: 953–9
17. Cousins MJ, Veering B: Epidural neural blockade, Neural Blockade in Clinical Anesthesia and Management of Pain, 3rd edition. Edited by Cousins MJ, Bridenbaugh PO. New York, Lippincott-Raven, 1998, pp 243–322
18. Kehlet H: Modification of responses to surgery by neural blockade: Clinical implications, Clinical Anesthesia and Management of Pain, 3rd edition. Edited by Cousins MJ, Bridenbaugh PO. New York, Lippincott-Raven, 1998, pp 129–75
19. Yeager MP, Glass DD, Neff RK, Brinck-Johnsen T: Epidural anesthesia and analgesia in high-risk surgical patients. A nesthesiology 1987; 66: 729–36
20. Rodgers A, Walker N, Schug S, McKee A, Kehlet H, van Zundert A, Sage D, Futter M, Saville G, Clark T, MacMahon S: Reduction of postoperative mortality and morbidity with epidural or spinal anaesthesia: Results from overview of randomised trials. BMJ 2000; 321: 1493
21. Williams-Russo P, Sharrock NE, Haas SB, Insall J, Windsor RE, Laskin RS, Ranawat CS, Go G, Ganz SB: Randomized trial of epidural versus general anesthesia: Outcomes after primary total knee replacement. Clin Orthop 1996; 199–208
© 2003 American Society of Anesthesiologists, Inc.