Preemptive analgesia

Seminars in TIIE$1A Vol 1 6 , N o 4

December

1997

Preemptive Analgesia Stephen E. Abram

E GENERALLY CONSIDER postoperative pain to result from activation of nociceptors in the vicinity of tissues injured as a result of surgery. Certainly, one component of postoperative pain is the sensitization of nociceptors in peripheral tissues by substances released in response to surgical trauma. Peripheral sensitization involves both the lowering of response threshold and enhancement of the response to suprathreshold stimulation. It is initiated by activation of second messenger systems within the nociceptor, activation of the immune system, and interactions between sympathetic and afferent neurons. If there is sufficient peripheral nociceptor sensitization, the individual experiences each of the following: (1) pain at rest, the result of spontaneous activation of peripheral nociceptors; (2) primary hyperalgesia, or exaggerated pain in response to a noxious stimulus; and (3) allodynia, or pain evoked by a nonnoxious stimulus such as light pressure or muscle movement. Another component of the postoperative pain experience, mediated centrally, involves sensitization of dorsal horn neurons that are ordinarily activated by noxious stimuli. Following repetitive nociceptor discharge such neurons can be shown to fire more rapidly and for longer periods of time in response to subsequent noxious stimulation. In addition, they begin to respond briskly to stimulation of nociceptors that were previously outside their peripheral receptive fields and to stimulation of nonnociceptive afferents such as mechanoreceptors. These central changes are also associated with allodynia, hyperalgesia, and enhancement of spontaneous pain. The idea that changes occurring in the central nervous system are associated with heightened

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responses to noxious stimulation is not new. The notion that intense noxious stimulation, even in the presence of general anesthesia, can produce adverse effects on the central nervous system was expressed by George Crile over 80 years ago. At that time, he advocated the combined use of regional and general anesthesia to provide optimal physiological conditions. 1 His insight into the inability of general anesthesia to modify the detrimental effects of noxious stimulation is surprising. A statement published in 1913 is profoundly prophetic of concepts that are only now becoming accepted: "Although no pain is felt in operations under inhalation anesthesia, the nerve impulses set up by a surgical operation reach the brain. ''1 Although he did not document differences in postoperative pain intensity, he stated that a combined regional/general anesthesia technique resulted in lower heart rates, less postoperative fever, and lower mortality. The physiological evidence that noxious stimulation can sensitize neurons in the central nervous system is not new either. Mendell2 showed that repetitive peripheral nerve stimulation at electrical currents intense enough to activate C fibers resulted in a progressive increase in dorsal horn cell activity, a phenomenon he called "windup." Subsequent animal behavioral mod-

From the Department of Anesthesiology, University of New Mexico School of Medicine, Albuquerque, NM. Address reprint requests to Stephen E. Abram, AID, Department of Anesthesiology, Universityof New Mexico School of Medicine, Surge Bldg, 2701 Frontier, NE, Albuquerque, NM 87131-5216. Copyright 9 1997 by W.B. Saunders Company 02 77-0326/97/1604-0001$5.00/0

Seminars in Anesthesia, Vo116, No 4 (December),1997: pp 263-270

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264 els, such as intradermal capsaicin injection and the formalin test, provide further evidence that noxious stimulation can lead to a state of heightened sensitivity of spinal cord neurons, and there is now substantial evidence that certain analgesic interventions, if initiated before the onset of surgical stimulation, can reduce the severity of postoperative pain. The sequence of intracellular reactions that lead to sensitization of spinal dorsal horn neurons is triggered by the action of excitatory amino acids (EAAs) and neuropeptides on the Nmethyl-D-aspartate (NMDA) and other EAA (eg, metabotropic) receptors. The activation of intracellular phospholipase C (PLC) stimulates the formation of inositol triphosphate (IP3), which initiates release of intracellular Ca ++ stores, and diacylglycerol (DAG), which stimulates increased production of protein kinase C (PKC). PKC in turn enhances NMDA receptor response to EAAs and increases the expression of protooncogenes such as c-fos and c-jun, which act as third messengers to control transcription of genes that encode a variety of neuropeptides capable of modulating responses to noxious stimuli. 3'4 PKC has also been shown to interfere with the intracellular effects of opiate receptor activation. Agents that inhibit production of PLC (eg, neomycin) or PKC (eg, H-7) can block the delayed hyperalgesic response to subcutaneous formalin injection in rats. 5 Influx of Ca ++, in response to NMDA receptor activation, also leads to increased production of nitric oxide (NO), which is rapidly diffusible both within and outside the cell. NO activates guanylate cyclase to increase production of cyclic guanosine monophosphate (cGMP), which leads to increased PKC production. Following extracellular diffusion of NO to the primary afferent terminal, there is enhanced release of EAAs and peptides, substance P (sP) and calcitonin gene-related peptide (CGRP), in response to afferent nerve activity. It has been proposed that NO may also reduce function of inhibitory interneurons in the vicinity of the affected neurons. Ca ++ influx also results in the activation of phospholipase A2 (PLA2) and increased production of intracellular arachidonic acid and the products of the prostaglandin cascade. The resultant intracellular accumulation of prostaglandins

STEPHEN E. ABRAM augments the hyperalgesic state as evidenced by the facts that intrathecal (IT) prostaglandin administration induces hyperalgesia6 and that hyperalgesia induced by IT NMDA is inhibited by IT administration of nonsteroidal anti-inflammatory drugs (NSAIDs). 7 It would seem logical that spinal administration of corticosteroids or other agents that block prostaglandin production through inhibition of PLA2 would be capable of blocking spinal sensitization in a manner similar to that of NSAIDs. Such effects might help explain the beneficial effects of epidural steroid injections in patients with radiculopathy. However, spinally administered steroids and other PLA2 inhibitors have been shown to produce little if any suppression of the sensitization-dependent response (phase 2) on the formalin test in rats. 8'9 A composite of the intracellular events initiated by release of EAAs and sP from nociceptive primary afferent terminals is shown in Fig 1. Although inhalation anesthetics abolish the motor and autonomic responses to surgical stimulation, there is considerable evidence that they are not capable of blocking spinal hyperalgesia. Single-unit recording studies have shown that sensitization of dorsal horn neurons occurs in halothaneanesthetized animals, and both sP and glutamate are released from primary afferents in animals anesthetised with volatile anesthetics. A recent study assessed the ability of general anesthetics to suppress spinal sensitization following formalin injection in rats. 1~ Volatile anesthetics and propofol produced only partial suppression of centrally mediated hyperalgesia, and thiopental and combinations of nitrous oxide with volatile agents produce no suppression at all. It is likely, therefore, that during general anesthesia surgical stimulation can contribute to the central sensitization that contributes to postoperative pain. REGIONAL ANESTHESIA There is considerable evidence that local anesthetic blockade, instituted before incision, is associated with reduced postoperative pain and/or decreased postoperative analgesic requirements. One of the earliest studies to examine the influence of regional anesthesia in preventing postoperative hyperalgesia came from the dental profession. In 1947 Hutchins and Reynolds 11observed that some patients who underwent dental restorations or ex-

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PREEMPTIVE ANALGESIA

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Fig 1. Sequences of events leading to sensitization of dorsal born neurons following injury and inMnse nociceptive stimulotion. Intense activation of primary afferent neuron stimulates release of glutamate (Glu) and substance P (SP). The NMDA receptor, at physiological Mg §247 levels, is initially unresponsive to Glu, but following depolarization of the ,~-amino-3-hydroxy5-methyl-4-isaxazoproprionic acid (AMPA) receptor by Glu or the NeuroKinin-1 (NK-1) receptor by SP, it responds to Glu, allowing Ca** influx. The action of Glu on Ibo metabatmpic receptor stimulates G protein-mediated activation of PLC, which catalyzes hydrolysis of phosphatidylinositol 4,5-blspbosphate (PIPa) to produce IP3 and DAG. OAG stimulates production of PKC, which is activated in the presence of high levels of intmcellular Ca§247 (Ca~*). IP3 stimulates release of inlmcellulor Ca** from inlracellulor stores within the endoplasmic retlculum (Ca.+,*). Increased PKC induces a sustained increased membrane ~oDrmeability and, in conjunction with increased intracellulor Ca §247leads to increased expression of protooncngenes such as cs and c-jun. The proteins produced by these pmtooncogenes encode a number of neurapeptides such as enkephalins, dynorphin, and tachykinins. Increased Ca§247 also leads to activation of cakium/calmodulin-dependent protein kinase (CaMPK), which produces a brief increase in membrane permeability, and to activation of PLA2and nitric oxide synthase (NOS) through a calcium/calmodulin mechanism. PLA2catalyzes the conversion of pbosphatidyl choline (PC)to arachidonic acid (AA), which is acted on by cyclooxygenase (CO) to produce pmstoglandins (PGI and thromboxanes fiX) and by lipoxygenasa (LO) to produce leucoh'ienes (LT). NOS catalyzes the production of NO from L-arginine. NO activates soluble guam/late cyclose (GC), which increases the intracellular content of cyclic GMP and leads to increased production of protein kinases and alterations in gene expression. NO diffuses out of the cell to the primary afferent terminal, where, through a GC/cGMP mechanism, it increases the release of glutamate. It is speculated that NO may interfere with release of inhibitory neuratransmitters from inhibitory neurons. Reprinted with permission from Abram SE: Pharmacology of pain control, in Brown DL (ed): Regional Anesthesia and Analgesia. Philadelphia, WB Saunders, 1996, p 675.

tractions under nitrous oxide anesthesia, without block anesthesia, experienced a hyperalgesic state lasting several weeks, characterized by pain referred to the previously stimulated teeth evoked by mechanical stimulation of the nasal epithelium. Patients who had these procedures performed under block anesthesia failed to exhibit this phenomenon. The authors suggested in a subsequent publication that this was "evidence of a prolonged central excitatory state.'"1

Several other studies have shown greater postoperative patient comfort when regional blockade was initiated preoperatively. McQuay et al t2 showed significantly delayed times to initial analgesic request for orthopedic surgical patients who had regional as opposed to general anesthesia. Ringrose et a113 assessed the effect of femoral nerve block on postoperative analgesic use after knee surgery performed with general anesthesia. Patients who received femoral blocks preopera-

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tively required significantly lower opioid doses in the first 24 hours than patients who had general anesthesia alone. This study also showed that patients given femoral blocks preoperatively had significantly lower postoperative analgesic use than patients blocked at the end of surgery. Parnass et a114 compared the postoperative course of patients who received epidural anesthesia for ambulatory arthroscopic knee surgery with those given general anesthesia. They found that discharge times were shorter, and the incidence of pain and nausea and vomiting was lower in the epidural group. Gottfreosdottir et a115 conducted a double-blind prospective clinical investigation examining the effects of retrobulbar bupivicaine block in patients undergoing retinal detachment surgery performed under general anesthesia. Postoperative pain scores and nausea were significantly lower in the retrobulbar block group during the first postoperative hours than in the control group, and significantly fewer patients in the block group required analgesics during the first 48 hours postoperatively. In patients undergoing lower abdominal surgery, Katz et a116compared patients who received preoperative lumbar epidural bupivicaine with those given lumbar epidural bupivacaine 30 minutes after incision. The preincision block group had 20% to 30% lower morphine consumption levels at 24, 48, and 72 hours postoperatively. Not all studies comparing preoperative versus postoperative regional analgesia have shown significant preemptive effects. In a randomized, double-blind study by Pryle et a117patients given general anesthetic for abdominal hysterectomy or myomectomy received either 15 mL of bupivicaine 0.5% with adrenaline by lumbar epidural injection 15 minutes before surgery or the same dose at the end of surgery. There was no difference in postoperative pain scores between the two groups. Dahl TM studied 32 patients undergoing total knee arthroplasty randomized to receive epidural blocks initiated either 30 minutes before surgical incision or at the time of wound closure. No significant differences were observed in requests for additional opioids or in pain scores at rest or during mobilization of the operated limb. Abdulatif et a119compared the analgesic effect of interpleural bupivacaine instituted either before cholecystectomy or immediately postoperatively.

STEPHEN E. ABRAM

They showed significant reductions in intraoperative anesthetic requirements and lower intraoperative blood pressures, but did not show differences in postoperative analgesia or supplemental opiate requirements. An explanation for the lack of demonstrable preemptive effect of regional anesthetic techniques in some studies is the possibility that, when comparing preincisional to postoperative initiation of the regional block, the postoperative initiated block is sufficient to produce profound analgesia even in the centrally sensitized state. This may have been the case in the three studies cited above. LOCAL INFILTRATION

Several randomized studies have assessed the efficacy of preincisional local infiltration in reducing postoperative pain. Jebeles et al 2~ compared preincisional bupivicaine with saline infiltration of the tonsillar bed in patients undergoing tonsillectomy under general inhalation anesthesia. The study showed significantly lower spontaneous pain for 5 days and significantly less pain with swallowing for as long as 10 days postoperatively in the local infiltration group. However, when preincisional wound infiltrations are compared with postoperative infiltrations, the results are not always different. Ejlersen et a121 found that patients treated before incision requested postoperative analgesia significantly later, despite the fact that they recovered from the local anesthetic sooner. In addition, the preincisiontreated patients required fewer postoperative analgesic doses, and a significantly greater percentage of pretreated patients required no postoperative analgesics. In contrast, in a study by Dierking et a122 there was no significant difference between pretreated and posttreated groups in time to first analgesic request or in pain scores at rest, during activity, or with coughing. Similarly, Victory et a123 found no difference in pain scores or analgesic requirements between abdominal hysterectomy patients randomized to receive wound infiltration either before or after surgery. In fact neither group was significantly different from controls. For the local infiltration studies that showed benefit from treatment, it is not clear whether the reduction in postoperative analgesic requirements is the result of local effects of the anesthe-

PREEMPTIVE ANALGESIA sic on injured tissues or the result of blocking afferent impulses from reaching the spinal cord. Tverskoy et a124 addressed this issue in a study of inguinal herniorrhaphy patients who were randomized to receive general anesthesia, general anesthesia plus preincisional local anesthesia, or spinal anesthesia. Patients given spinal anesthesia had a significantly longer interval to first analgesic request, significantly lower pain scores, and significantly less pain with mechanical pressure to the wound than patients who had general anesthesia alone. These findings suggest that deafferentation of noxious input indeed plays a role in the attenuation of postoperative pain by preincisional technique. A peripheral tissue effect of the local anesthetic is not ruled out however, because the patients who received local infiltration had significantly less pain with movement or wound pressure and longer latencies to first analgesic requests than the spinal anesthesia patients. OPIOIDS A few studies have addressed the question of whether preincisional opioid administration attenuates spinal sensitization. We showed that high doses of systemic morphine or alfentanil did not suppress spinal sensitization as assessed by the formalin test. z~ Most clinical studies assessing the influence of preoperative systemic opioids on severity of postoperative pain have not shown a definitive effect, and some that have shown preemptive effects have significant design flaws. McQuay et al ~2 found that patients who received preoperative opioids had a significantly longer mean interval to first analgesic request (5 v 2 hours for the control group). However, this study is less than ideal, because neither the opioid drug nor the dose was specified, and selection was not randomized. A study by Kiss and Killian 26 also concludes that opioid premedication reduces postoperative analgesic needs. The study showed that patients who received 50 mg meperidine intramuscularly preoperatively were less likely to request postoperative analgesics following laminectomy under general anesthesia. Unfortunately, this study also has some major flaws, including the use of different preoperative tranquilizers in the two groups and the administration of fentanyl preincisionally in all patients. Tverskoy et a127 investigated whether the induction

267 and maintenance of anesthesia with the use of fentanyl reduced postoperative pain and wound hyperalgesia beyond the period when these effects can be explained by the direct analgesic action of these drugs. They found that the intensity of pain to mechanical stimulation of the wound was less in the fentanyl group than in controls. However there was no statistically significant changes in spontaneous incisional or movement-associated pain compared with the control group. Collis et a128 found no significant difference in postoperative morphine requirements or cutaneous sensitivity between a group receiving a large opioid premedication and one receiving a small premedication. Intrathecal opioids, combined with inhalation anesthesia, supresses spinal hyperalgesia as assessed by the formalin test. 29 Evidence that neuraxial opioids have preemptive analgesic effects is less convincing. Katz et al 3~evaluated the ability of preincisional epidural fentanyl to modify postthoracotomy pain. They administered epidural fentanyl either just before or just after incision and rib retraction. The group that received epidural fentanyl before incision exhibited significantly lower pain scores only at 6 hours postoperatively and had lower postoperative morphine consumption between 12 and 24 hours postoperatively. Values for pain ratings and morphine use were not significantly different at any other times. The relatively minor benefits observed with preoperative use of fentanyl may be related to the fact that fentnyl was administered in the lumbar, as opposed to the thoracic, epidural space. Also, administration of the epidural fentanyl after only 15 minutes of surgical trauma in the postincisional group may have reduced the apparent magnitude of the preemptive analgesic effect. The study that definitively answers the question of whether preoperative neuraxial opioids produce preemptive analgesic effects has not yet been performed. NSAIDs There is experimental evidence that spinally cyclooxygenase inhibitors can influence the development of spinal sensitization. Malmberg and Yaksh 6 showed that the intrathecal administration of NSAIDs in rats inhibited the hyperalgesic response to subcutaneous formalin injection of

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STEPHEN E. ABRAM

the hindpaw. Although intrathecal or epidural administration of NSAIDs has not been used in humans, it is conceivable that systemic NSAID administration might produce spinal cord effects that could reduce centrally mediated postoperative hyperalgesia. However, clinical evidence for a preemptive analgesic effect from NSAIDs is not particularly convincing. Murphy and Medley 31 compared preoperative with postoperative indomethacin administration for patients undergoing elective thoracic surgery. They found no significant difference between the two groups in terms of pain ratings, opioid requirement, or in the incidence of adverse effects. Fletcher et a132 compared preincisional with postincisional intravenous ketorolac using a randomized, doubleblind, placebo-controlled design in patients undergoing total hip replacement. They showed some advantage of the preoperative ketorolac, but only in the immediate postoperative period, ie, during the first 6 hours. Nelson et a133 were unable to show differences in postarthroscopy pain between two groups of patients, one of which received both preoperative and postoperative diclofenac, whereas the other was given both preoperative and postoperative drug.

there is some data on the influence of regional anesthesia on the incidence of postamputation pain. If pain is experienced preoperatively at the time of amputation, there is a high probability that the patient will experience phantom limb pain postoperatively. Reports of pain memories in phantom limbs appear to be less common when there has been a pain-free interval between the experience of limb pain and the amputation. 34 This phenomenon is consistent with the observations of Bach et al.35 They showed that patients who had relief from preamputation pain from continuous epidural block for 3 days before amputation had a lower incidence of phantom limb pain than patients undergoing epidural anesthesia induced just before surgery. The difference in incidence of phantom limb pain was still evident 6 months later. A similar study compared the incidence of phantom pain in patients who received epidural analgesia begun 24 to 48 hours preoperatively with the incidence among patients given general anesthesia only. 36 The epidural group experienced a lower incidence of phantom pain at 7 days, 6 months, and 1 year postoperatively.

CHRONIC POSTOPERATIVE PAIN A small minority of patients who undergo surgery develop severe postoperative pain that persists for long periods of time and, in some cases, becomes chronic. Pain following nerve injury, such as intercostal nerve transsection, can persist for many months or even years. Reflex sympathetic dystrophy occurs postoperatively in some patients, particularly following surgery to the palmar surface of the hand or plantar surface of the foot. Phantom limb pain and other postamputation pain syndromes often become chronic, particularly among patients who had experienced severe pain before amputation. Central mechanisms, initiated by the effects of primary afferent neurotransmitters on dorsal horn cells, may lead to long-term changes in central processing and probably play a major role in the pathophysiology of chronic postsurgical pain disorders. Unfortunately, there is little information available regarding the influence of anesthetic technique on the development of chronic neuropathic or sympathetically mediated pain. However,

An important component of postoperative pain is related to the change in function of spinal dorsal horn neurons following tissue injury and activation of nociceptors. Most general anesthetic techniques do not substantially suppress the development of sensitization of the central nervous system in response to intraoperative surgical trauma. In certain individuals, surgical intervention can contribute to the development of chronic pain as well. There is substantial evidence from both animal and clinical studies that local anesthetic blockade of afferent impulses initiated before the onset of surgical intervention can reduce the degree of central sensitization and can modify the severity of postoperative pain and reduce postoperative analgesic requirements. There is evidence from animal experiments that spinally administered opioids, particularly when given in conjunction with general anesthesia, can reduce the degree of nociceptor-mediated spinal hyperalgesia. Definitive proof that this occurs clinically is so far lacking. There is little clinical or laboratory evidence that systemic opioids or

CONCLUSIONS

PREEMPTIVE ANALGESIA N S A I D s are c a p a b l e o f m o d i f y i n g this h y p e r a l gesic response. H o w should this information m o d i f y our anesthetic m a n a g e m e n t techniques? F o r routine cases, the benefits we can achieve b y the application o f the principles o f p r e e m p t i v e analgesia are p r o b a b l y modest. H o w e v e r , for patients w h o are at risk for the d e v e l o p m e n t o f severe or chronic p o s t o p e r a t i v e pain the gains m a y be substantial. A t - r i s k patients include those w h o are taking long-term o p i o i d s for preexisting pain, patients with a history o f sympathetically m a i n t a i n e d pain or chronic neuropathic pain, and patients with preexisting l i m b pain w h o are to u n d e r g o a m p u tation or neurectomy.

THE FUTURE There are available in the laboratory a variety o f drugs that have little or no analgesic effect but that are c a p a b l e o f b l o c k i n g the d e v e l o p m e n t o f w i n d u p or central sensitization. There has been a great deal o f laboratory investigation but little clinical study o f such drugs. The N M D A antagonists have been shown to consistently b l o c k w i n d u p and to b l o c k the d e v e l o p m e n t o f phase 2, or sensitization-dependent pain behavior, in the formalin test. There are several drugs in this category that are a p p r o v e d for h u m a n use, such as k e t a m i n e and dextromethorphan, but there is little data available to determine w h e t h e r preincisional administration will substantially m o d i f y postoperative pain and analgesic requirement. Such studies can b e d o n e fairly easily. Other classes o f drugs, such as neurokinin-1 receptor antagonists, which b l o c k the effects o f sP released from the p r i m a r y afferent neuron, are c a p a b l e o f b l o c k i n g spinal sensitization as well. Drugs that m o d i f y the responses to intracellular second messengers, such as phospholipases, protein kinases, and NO, m a y also prove to be o f clinical benefit in the future.

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269 after formalin-induced tissue injury. J Neuroscience 12:36653670, 1992b 4. Coderre TJ, Katz J, Vaccarino AL, Melzack R: Contribution of central neural plasticity to pathological pain: Review of clinical and experimental evidence. Pain 52:259-285, 1993 5. Coderre TJ: Contribution of protein kinase C to persistent nociception following tissue injury in rats. Neurosci Lett 140:181-184, 1992a 6. Malmberg AB, Yaksh TL: Antinociceptive actions of spinal nonsteroidal anti-inflammatory agents on the formalin test in the rat. J Pharmacol Exp Ther 263:136-146, 1992a 7. Malmberg AB, Yaksh TL: Hyperalgesia mediated by spinal glutamate or SP receptor blocked by spinal cyclooxygenase inhibition. Science 257:1276-1279, 1992b 8. Abram SE, Marsala M, Yaksh TL: Analgesic and neurotoxic effects of intrathecal steroids in rats. Anesthesiology 81:1198-1205, 1994 9. Coderre TJ, Vaccarino AL, Melzack R: Central nervous system plasticity in the tonic pain response to subcutaneous formalin injection. Brain Research 535:155-158, 1990 10. O'Connor TC, Abram S: Inhibition of nociceptioninduced spinal sensitization by anesthetic agents. Anesthesiology 82:259-266, 1995 11. Hutchins HC, Reynolds OE: Experimental investigation of the referred pain of aerodontalgia. J Dent Res 26:38, 1947 12. McQuay HJ, Carroll D, Moore RA: Postoperative orthopedic pain--The effect of opiate premedication and local anesthetic blocks. Pain 33:291-295, 1988 13. Ringrose NH, Cross MJ: Femoral nerve block in knee joint surgery. Am J Sports Med 12:398-402, 1984 14. Parnass SM, McCarthy RJ, Bach BR, et al: Beneficial impact of epidural anesthesia on recovery after outpatient arthroscopy. Arthroscopy 9:91-95, 1993 15. Gottfreosdottir MS, Gislason I, Stefansson E, et al: Effects of retrobulbar bupivecaine on postoperative pain and nausea in retinal detachment surgery. Acta Ophthalmol Stand 71:544-547, 1993 16. Katz J, Clairoux M, Kavanagh BP: Pre-emptive lumbar epidural anaesthesia reduces postoperative pain and patient-controlled morphine consumbtion after lower abdominal surgery. Pain 59:395-403, 1995 17. Pryle BJ, Vanner RG, Enriquez N, et al: Can preemptive lumbar epidural blockade reduce postoperative pain following lower abdominal surgery? Anaesthesia 48:120-123, 1993 18. Dalai JB, Daugaard JJ, Rasmussen B: Immediate and prolonged effects of pre- versus postoperative epidural analgesia with bupivacalne and morphine on pain at rest and during mobilisation after total knee arthroplasty. Acta Anaesth Scand 38:557-561, 1994 19. Abdulatif M, AI-Ghamdi A, Gyamfi YA, EI-Sanabary M, A1-Metwally R: Can pre-emptive interpleural block reduce perioperative anesthetic and analgesic requirements? Reg Anesth 20:296-302, 1995 20. Jebeles JA, Reilly JS, Gutierrez JF, et al: The effect of pre-incisional infiltration of tonsils with bupivacaine on the pain following tonsillectomy under general anesthesia. Pain 47:305-308, 1991

270 21. Ejlersen E, Andersen HB, Eliasen K, et al: A comparison between preincisional and postincisional lidocaine infiltration and postoperative pain. Anesth Analg 74:495-498, 1992 22. Dierking GW, Dahl JB, Kanstrup K, et al: Effect of pre- vs postoperative inguinal field block on postoperative pain after hemiorrhaphy. Br J Anaesth 68:344-348, 1992 23. Victory RA, Gajraj NM, Van Elstraete A, Pace NA, Johnson ER, White PF: Effect of preincision versus postincision infiltration with bupivacaine on postoperative pain. J Clin Anesth 7:192-196, 1995 24. Tverskoy M, Cozacov C, Ayache M: Postoperative pain after inguinal hemiorrhaphy with different types of anesthesia. Anesth Analg 70:29-35, 1990 25. Abram SE, Olson EE: Systemic opioids do not suppress spinal sensitization after subcutaneous formalin in rats. Anesthesiology 80:1114-1119, 1994 26. Kiss IA, Kilian M: Does opiate premedication influence postoperative analgesia? A prospective study. Pain 48:157-158, 1992 27. 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 78:205-209, 1994 28. Collis R, Brandner B, Bromley LM, Woolf CJ: Is there any clinical advantage of increasing the pre-emptive dose of morphine or combining pre-incisional with postoperative morphine administration? Br J Anaesth 74:396-399, 1995

STEPHEN E. ABRAM 29. Abram SE, Yaksh TL: Morphine but not inhalation anesthesia blocks post-injury facilitation: The role of preemptive suppression of afferent transmission. Anesthesiology 78:713-721, 1993 30. Katz J, Kavanagh BP, Sandier AN, et al: Preemptive analgesia. Clinical evidence of neuroplasticity contributing to postoperative pain. Anesthesiology 77:439-446, 1992 31. Murphy DF, Medley C: Preoperative indomethacin for pain relief after thoracotomy: Comparison with postoperative indomethacin. Br J Anaesth 70:298-300, 1993 32. Fletcher D, Zetlaoui P, Monin M, Bombart M, Samii K: Influence of timing on the analgesic effect of intravenous ketorolac after orthopedic surgery. Pain 61:291-297, 1995 33. Nelson WE, Henderson RC, Almekinders LC, DeMasi RA, Taft TN: An evaluation of pre- and postoperative nonsteroid antiinflammatory drugs in patients undergoing knee arthroscopy. Am J Sports Med 21:510-516, 1993 34. Katz J, Melzack R: Pain "memories" in phantom limbs: Review and clinical observations. Pain 43:319-336, 1990 35. Bach S, Noreng MF, Tjellden NU: Phantom limb pain in amputees during the first 12 months following limb amputation, after preoperative epidural blockade. Pain 33:297-301, 1988 36. Jahangiri M, Bradley JWP, Jayatunga AP, et al: Prevention of phantom limb pain after major lower limb amputation by epidural infusion of diamorphine, clonidine and bupivacaine. Ann R Coll Surg Engl 76:324-326, 1994