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No Preemptive Analgesia: Is That So Bad?

Hogan, Quinn H. M.D.

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THE practice of operative anesthesia is an application of Hippocrates’ dictum “primum non nocere”—first of all, do no harm. A successful anesthetic is one that minimally interferes with the patient's homeostasis and does not add to the unavoidable quotient of surgical trauma. In this context, it is understandable that the notion of preemptive analgesia, by which early application of therapies may diminish later misery, is an enticing grail to pursue. The anesthesiologist's ministrations might then actually improve the patients state, rather than being at best a necessary evil. It is therefore a potential disappointment to conclude, as do Møiniche et al.1 in a detailed meta-analysis published in this issue of Anesthesiology, that there is little experimental support for a preemptive analgesic effect in clinical settings. They reviewed 80 randomized and blinded studies that compared various analgesic techniques applied before incision and later in the perioperative period. Only modest differences were noted, and these were present only with epidural injections.
The quest to identify a benefit from preinjury analgesic administration for surgical patients has been fueled by repeated and convincing demonstrations of this phenomenon in animals. The reason that a robust experimental finding cannot be confirmed in patients is not forthcoming, but several explanations can be considered. First, sensory blockade may not be adequate during surgery. The basis of preemptive analgesia is the prevention of increased responsiveness of central nociceptive pathways triggered by intense afferent neural activity. Even very brief sensory events can result in central sensitization, 2,3 so effective prevention may require continuous sensory ablation throughout the surgical event. The intensity of afferent blockade is also important. Addition of systemic morphine to volatile anesthesia has no preemptive effect, 4 whereas the more thorough action of intrathecal morphine does prevent central sensitization in rats. 5 Small doses of intrathecal opioid show no preemptive effect, whereas larger doses have an amplified action given before injury, 6 presumably through greater efficacy in blocking input from small nonmyelinated C fibers. 7 The persistence of neuronal traffic, even during successful neuraxial anesthesia, 8 may limit the preemptive effect of this modality, indicating the importance of thorough regional blockade. 9 Increased strength of sensory stimulation may overcome the preemptive action of analgesics, even spinal local anesthetic, particularly if inflammation is a component of the injury. 10
Demonstrations of preemptive effects in experimentation on animals have used various types of injuries, including formalin injection and nerve trauma. However, in models that more closely emulate typical clinical surgery, the results are mixed. Spinal hyperexcitability 11 and preemptive analgesia 12 are evident in some studies of abdominal surgical injury, but there is no influence of analgesic timing on pain behaviors after peripheral surgery 13 because of the minimal contribution of central facilitation. 14
The most obvious reason for diverging experimental and clinical findings is that animals may differ substantially from humans in pain pathophysiology and neuropharmacology. In rats, the species with which most studies of preemptive analgesia have been performed, sensitization is readily induced in spinal sensory pathways after conditioning stimuli. A large effect can then be seen when intense afferent activity is prevented from reaching the dorsal horn, which may not be the case in other species less prone to sensitization. Because genetic differences, even between various strains of rats, strongly affect the development of neuronal hyperexcitability 15 and hyperalgesia 16 after injury, comparison across species to human injury responses must be suspect.
It is not clear to me that the failure of preemptive analgesia is a great loss in the pragmatic clinical setting. Consider the outcomes used in studies of the topic. The analysis by Møiniche et al.1 tabulates pain scores, supplemental analgesic demand, and time to first postoperative analgesic. Pain scores, while important, should not differ if appropriate care is provided because postoperative pain in the absence of preemptive treatment is nonetheless responsive to adequate doses of analgesia, consistent with electrophysiologic observations in animals. 6 A difference in supplemental analgesic demand should also not be an important medical issue. The need for 12 mg morphine in the recovery room instead of 4 mg before induction of anesthesia is itself not necessarily problematic. Although increased side effects from larger doses can be expected, there are no data to confirm this suspicion. Finally, a decreased time to first analgesic request in the absence of preemptive analgesia should not be a treatment problem, provided timely medication is available when the need arises.
The challenge, of course, is not to use the least amount of drug, but to minimize complications and optimize postoperative recovery. So far, there is minimal support for the belief that preemptive techniques aid recovery. One promising report confirms a favorable effect of early medication on the incidence and severity of chronic postoperative pain. 17 In future studies of the timing of analgesic agents, it will be helpful to focus on aspects of recuperation, not only on initial postoperative pain levels or analgesic consumption.
Rather than being disappointed, I find the conclusions of Møiniche et al.1 to be encouraging. Trauma patients may be adequately treated with analgesics even though their injury has occurred without pretreatment because an early window of opportunity has not been missed. In scheduled surgery, the various side effects and complications that accompany intraoperative analgesic use may be avoided. For instance, intraoperative administration of opiates may lead to histamine release, dysfunction of the bowel, and disfunction of the biliary and urinary tracts, as well as acute opiate tolerance 18,19 and hyperalgesia, 20 which make postoperative pain treatment more difficult. Epidural local anesthetic block may complicate general anesthesia with hypotension and create diagnostic ambiguity afterward if paresis masks neurologic injury. For these reasons, initiating analgesic care at the time of emergence from general anesthesia may be more desirable; this is also a time when analgesic needs can be directly assessed. Because pain is “an unpleasant sensory and emotional experience,”21 it cannot exist during general anesthesia. If preoperative and intraoperative analgesic treatment has little effect on the long-term course of sensory processes, their use before emergence lacks a clear motive.
There can be little doubt that great benefit will emerge from the burgeoning knowledge of processes underlying pain. Although experimentation may lead to drugs and techniques that can preemptively prevent pain in the clinical setting, our clinical attention must remain on treating pain when it presents, with adequate doses of proven agents.
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References

1. Møiniche 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. Seltzer Z, Beilin BZ, Ginzburg R, Paran Y, Shimko T: The role of injury discharge in the induction of neuropathic pain behavior in rats. Pain 1991; 46: 327–36

3. Yamamoto T, Shimoyama N, Mizuguchi T: Role of the injury discharge in the development of thermal hyperesthesia after sciatic nerve constriction injury in the rat. A nesthesiology 1993; 79: 993–1002

4. Abram SE, Olson EE: Systemic opioids do not suppress spinal sensitization after subcutaneous formalin in rats. A nesthesiology 1994; 80: 1114–9

5. Abram SE, Yaksh TL: Morphine, but not inhalation anesthesia, blocks post-injury facilitation. A nesthesiology 1993; 78: 713–21

6. Chapman V, Haley JE, Dickenson AH: Electrophysiologic analysis of preemptive effects of spinal opioids on N-methyl-D-aspartate receptor-mediated events. A nesthesiology 1994; 81: 1429–35

7. Woolf CJ, Wall PD: Morphine-sensitive and morphine-insensitive actions of C-fiber input on the rat spinal cord. Neurosci Lett 1986; 64: 221–5

8. Lund C, Selmar P, Hansen OB, Hjortso NC, Kehlet H: Effect of epidural bupivacaine on somatosensory evoked potentials after dermatomal stimulation. Anesth Analg 1987; 66: 34–8

9. Shir Y, Raja SN, Frank SM: The effect of epidural versus general anesthesia on postoperative pain and analgesic requirements in patients undergoing radical prostatectomy. A nesthesiology 1994; 80: 49–56

10. Yashpal K, Katz J, Coderre TJ: Effects of preemptive or postinjury intrathecal local anesthesia on persistent nociceptive responses in rats: Confounding influences of peripheral inflammation and the general anesthetic regimen. A nesthesiology 1996; 84: 1119–28

11. Lascelles BDX, Waterman AE, Cripps PJ, Livingston A, Henderson G: Central sensitization as a result of surgical pain: Investigation of the pre-emptive value of pethidine for ovariohysterectomy. Pain 1995; 62: 201–12

12. Welsh EM, Nolan AM: The effect of abdominal surgery on thresholds to thermal and mechanical stimulation in sheep. Pain 1995; 60: 159–66

13. Zahn PK, Brennan TJ: Incision-induced changes in receptive field properties of rat dorsal horn neurons. A nesthesiology 1999; 91: 772–85

14. Brennan TJ, Umali EF, Zahn PK: Comparison of Pre-versus post-incision administration of intrathecal bupivacaine and intrathecal morphine in a rat model of postoperative pain. A nesthesiology 1997; 87: 1517–28

15. Hao J-X, Wiesenfeld-Hallin Z: Variability in the occurrence of ongoing discharges in primary afferents originating in the neuroma after peripheral nerve section in different strains of rats. Neurosci Lett 1994; 169: 119–21

16. Shir Y, Zeltser R, Vatine JJ, Carmi G, Belfer I, Zangen A, Overstreet D, Raber P, Zeltzer Z: Correlation of intact sensibility and neuropathic pain-related behaviors in eight inbred and outbred rat strains and selection lines. Pain 2001; 90: 75–82

17. Obata H, Saito S, Fujita N, Fuse Y, Ishizaki K, Goto F: Epidural block with mepivacaine before surgery reduces long-term post-thoracotomy pain. Can J Anaesth 1999; 46: 1127–32

18. Vinik HR, Kissin I: Rapid development of tolerance to analgesia during remifentanil infusion in humans. Anesth Analg 1998; 86: 1307–11

19. Chia YT, Liu K, Wang JJ, Kuo MC, Ho ST: Intraoperative high dose fentanyl induces postoperative fentanyl tolerance. Can J Anaesth 1999; 46: 872–7

20. Celerier E, Rivat C, Jun Y, Laulin J-P, Larcher A, Reynier P, Simonnet G: Long-lasting hyperalgesia induced by fentanyl in rats: Preventive effects of ketamine. A nesthesiology 2000; 92: 465–72

21. Mersky H: Classification of chronic pain: Descriptions of chronic pain syndromes and definitions. Pain 1986; 3 (suppl): S1–225

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