- Email: [email protected]
Pre-emptive analgesia in postamputation pain: an update
J. Sand!&iler, B. Bromm and GE Gebhart (Eds.) Progress in Brain Research, Vol. 129 0 2000 Elsevier Science B.V. All rights reserved
CHAPTER 36
Pre-emptive analgesia in postamputation pain: an update Troels StaehelinJensen1,3,*and Lone Nikolajsen 2,3 ’ Department
of Neurology,
2 Department
of Anesthesiology, and 3 Danish Pain Research DK-8000 Aarhus C. Denmark
Introduction A key issue in current pain research and treatment is the transition of acute pain into chronic pain states and the identification of risk factors for such transition. Based on a series of experimental studies on neuronal hyperexcitability and the induction of sensitisation, the question was raised in 1988 (Wall, 1988) whether neuronal hyperexcitability and pain could be prevented by an analgesic treatment before injury as opposed to after the injury. This issue, termed pre-emptive analgesia has been explored extensively both experimentally and clinically within the last decade (for review see: McQuay, 1992, 1994; Woolf and Chong, 1993; Dahl, 1994; Kalso, 1997). The nociceptive system is not a fixed static system, but a dynamic neuronal network, which continuously alters its response characteristics depending on the prior exposure to noxious activity (for review see: Coderre and Katz, 1997; Woolf and Salter, 2000; Berthele et al., 2000, this volume; Gerber et al., 2000, this volume; Moore et al., 2000, this volume; Sandktihler et al., 2000, this volume). In classical studies, Woolf and others observed that the functional plastic changes with sensitisation of second-order neurons could be prevented by a neural blockade or by an opioid administration before, but not after injury (for review see Woolf, 1992). The
* Corresponding author: T.S. Jensen, Department of Neurology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark. Tel.: +45-8949-3283; Fax: +45-8949-3300; E-mail: tsj @panter.soci.aau.clk
Cente,:
Aarhus
University
Hospital,
clinical counterpart of such pre-emptive analgesia was initiated by a study carried out by Bach and colleagues in 1988 (Bach et al., 1988) in a group of amputees, where epidural treatment before amputation apparently reduced the incidence of phantom pain. This important landmark has since been the focus for a series of further experimental and clinical studies on the effect of blockade of noxious input to the nervous system and its possible influence on neuronal hyperexcitability, sensitisation and chronic pain. Some of these studies but not all support the idea of a pre-emptive effect in amputees to avoid the subsequent development of phantom pain. Although amputation only represents a small minority among patients undergoing surgery it is extremely important to clarify if phantom pain indeed can be prevented because such an observation will have a significant bearing not only for amputees but for future strategies in anaesthesiology and pain treatment. Several studies have dealt with other types of postoperative pain (for review see: Dahl, 1994; McQuay, 1994). In the present chapter we will examine the experimental and clinical evidence for a pre-emptive analgesic effect on nerve injury pain with emphasis on phantom and stump pains as consequences of limb amputation. Clinical aspects of postamputation
pain
A detailed description of postamputation phenomena can be found elsewhere. For the present purposes a few clinical highlights, however, are necessary. It is useful to distinguish between the following three elements of the phantom complex (Jensen and Niko-
494
lajsen, 1999): phantom limbpain: pain referred to the missing limb; phantom limb sensation: non-painful sensations referred to the missing limb; stump pain: pain localised to the stump. Although these phenomena can be separated and patients usually are able to distinguish between each they often coexist in the same patient.
of pain is considerably reduced with time (Jensen et al., 1983; Houghton et al., 1994; Nikolajsen et al., 1997a). Character and location
Phantom pain develops in about 70% of patients following amputation irrespective of the cause of amputation (Jensen and Nikolajsen, 1999). Gradual remission of pain over time is the rule, but for a significant group of amputees (approximately 10%) the pain persists in a severe form requiring treatment. Treatment of phantom pain, however, is difficult and there is at present no single therapy offering universal benefit. Most recent studies agree that the incidence of phantom pain is in the range of 60-80% (Houghton et al., 1994; Nikolajsen et al., 1997a; Wartan et al., 1997). The incidence does not seem to be influenced by age, gender, side or level of amputation (Jensen et al., 1983) or cause of amputation (Sherman and Sherman, 1983; Houghton et al., 1994), but phantom pain is less frequent in young children, and in congenital amputees (Flor et al., 1998; Wilkins et al., 1998).
Phantom pain is highly variable from patient to patient with some patients having only a few short-lasting spells of pain sensation and others suffering from daily excruciating pains lasting for months or years. However, only few patients are in constant pain. The description of pains varies considerably from shooting, stabbing, pricking, boring, squeezing pains to throbbing and burning types of pains (Jensen et al., 1983; Sherman and Sherman, 1983; Nikolajsen and Jensen, 2000). Phantom pains are most distinct in distal parts of the body (hand, fingers, foot, toes, etc.). A characteristic feature is a gradual shrinkage of the phantom as time passes by after amputation, a phenomenon known as telescoping. As for phantom pain character, the location also varies from patient to patient. It is important to take this variability both in character, intensity and location into account in clinical studies and assessdifferent aspects (intensity, number of attacks, duration of attacks, etc.) and ensure constancy in cross-over trials and similarities between groups in parallel study trials.
Time course
Mechanisms
The onset of phantom pain is usually in the first week following amputation. In a prospective study, 48% developed their pain within the first 24 h, and 83% within 4 days. In less than 10% is phantom pain delayed for more than 1 week (Jensen et al., 1983). Another prospective study showed similar results (Nikolajsen et al., 1997a). However, case reports suggest that the onset of phantom pain may be delayed until several years after amputation. For example, Rajbhandari and colleagues (Rajbhandari et al., 1999) described the development of diabetic neuropathic pain in a leg amputated 44 years earlier. Although phantom pain may diminish with time and in some cases even disappear, prospective studies show that 2 years after amputation the incidence of postamputation pains are almost the same as at onset. However, both duration, frequency, and intensity
The mechanisms responsible for stump and phantom pain in amputation are still under discussion and apparently both peripheral and central mechanisms are involved and contribute to the phantom pain perception. An understanding of underlying mechanism for phantom pain and other types of nerve injury pain may lead to new types of rational founded treatments.
Frequency
Peripheral generator
Several lines of evidence indicate that the periphery is a generator and a site for maintaining stump and phantom pain. (1) Neuromas are universal phenomena after a nerve cut. An extensive experimental literature shows that these neuromas express spontaneous and
abnormal evoked activity with an increased sensitivity to a variety of stimuli including mechanical stimuli (Devor et al., 1993; Devor and Seltzer, 1999). The ectopic and increased activity from the periphery is assumed to be the result of a novel expression and distribution of ion channels (Novakovic et al., 1998). Also in the DRG there are major changes in the expression of sodium channels with a switch of one channel type into another (Waxman, 1999; Cummins et al., 2000, this volume). (2) It is a common clinical experience that percussion of the stump or stump neuromas induces stump and phantom pain. In a classical microneurographic study in two amputees, Nystrom and Hagbarth (198 1) showed that tapping of neuromas was associated with an increased activity in afferent C-fibres and an increased pain sensation. Consistent with this observation it has been shown that there is an inverse, albeit small correlation between phantom pain intensity and pressure pain threshold of the stump in amputees early after the amputation (Nikolajsen et al., 2000b). It should be noted that such correlation can only be found in the early period after amputation but not later in the course, indicating that other than peripheral factors are involved in generating phantom pain. (3) Perineuromal injection of gallamine, a drug that increases neuronal activity by facilitating sodium conductance, produces pain, while a sodium channel blocker, lidocaine, blocks phantom pain at the site of neuroma (Chabal et al., 1989). An extensive literature has shown that changes both in the periphery of the nerve and in dorsal root ganglion cells may be involved in generating phantom pain (for review see Devor and Seltzer, 1999). These findings suggest that long-lasting pain may induce secondary changes in the nervous system that may persist after a nerve injury and predict post-injury pain. This observation is in accordance with previous studies showing that long-lasting and intense preamputation pain may increase the risk for phantom pain following amputation (Nikolajsen et al., 1997a). Central sensitisation It is well appreciated that peripheral sensitisation occurs as a result of spontaneous activity from sprout-
ing, regenerating nerve endings. This peripheral sensitisation in turn gives rise to secondary changes in otherwise silenced small dorsal root ganglia (DRG) cells. The increased barrage from neuromas (organised sprouts) and from DRG cells following nerve injury eventually sweeps centrally and induces long-term changes in central projecting neurons. It is conceivable that in certain patients, where an early afferent barrage and hence sensitisation has been particularly intense, central mechanisms may subsequently maintain sensitisation without any additional nociceptor input. The central sensitisation in the spinal dorsal horn induced by an increased barrage form C-fibres may originate from two sources: (1) a sustained C-fibre input recruit N-methyl-D-aspartate (NMDA) receptors located on second-order spinal neurons (Woolf and Thompson, 1991; see also Moore et al., 2000, this volume; Sandktihler et al., 2000, this volume; Svendsen et al., 2000, this volume); (2) in other cases a central reorganisation occurs because of sprouting of Ap-fibres from laminae III and IV into lamina II, forming a functional contact with second-order nociceptive neurons (Woolf et al., 1992). In both cases the result is an evocation of pain by Afi-fibre input, e.g. touch. However, while the former type of touch-evoked pain may respond to agents that counteract the NMDA receptor system, the latter is unlikely to be affected by such agents and may perhaps be more resistant to modulation at all. It is at present unclear whether central sensitisation can be present without a peripheral generator. The above observation that sprouting from lamina III to lamina II does occur suggests that this may indeed be the case. The central aspects of the hyperexcitability include chemical changes of cells and cell membranes in the dorsal horn of the spinal cord. The glutamate release cascade with release of glutamate, activation of NMDA receptors, increase of intracellular Ca2+ (see Gerber et al., 2000, this volume) and activation of nitrogen oxide synthase (see, however, Hoheisel and Mense, 2000, this volume) is particular important in this hyperexcitability. The clinical translation of such hyperexcitability phenomena may include expansion of painful areas and sensory abnormalities, a lowering of threshold to evoke noxious activ-
496 ity, a build of pain following repetitive stimulation, e.g. wind-up-like phenomena, after-sensations and a switch in modality to evoke pain (Jensen and Gottrup, 2000). While intravenous administered NMDA antagonists can block phantom pain and signs of sensitization oral administered NMDA antagonists are ineffective (Nikolajsen et al., 1996, 2000a). Cortical reorganisation The peripheral plasticity in the nervous system which sweeps into the dorsal horn of the spinal cord may subsequently project to more central relays in the thalamus and cortex and induce further changes at these sites. Recent magnetoencephalographic studies in amputees have shown a strong correlation between phantom limb pain and the extent of cortical reorganisation (Flor et al., 1995, 1998; Bromm et al., 2000, this volume; Casey, 2000, this volume; Flor, 2000, this volume). Currently, a study is carried out using the f-MRI technique to examine whether similar expansion of cortical representation occurs in those patients with pain as opposed to those without pain (M. Lindvig et al., 2000, pers. commun.). It has therefore been suggested that phantom limb pain could be the result of plastic changes in the somatosensory cortex (Larbig et al., 1996). Birbaumer et al. (1997) studied the effect of regional anaesthesia on cortical reorganisation in upper-limb amputees and found that a brachial plexus blockade abolished pain and reorganisation in three out of six amputees. Another aspect of central elements in phantom pain involves the concept of a neuromatrix in the brain proposed by Melzack (1995) in which a neuronal network in the brain produces a characteristic nerve-impulse pattern, which underlies the various body perceptions including phantom pains. So taken together, a cascade of events at several synaptic levels in the nervous system take place following a peripheral nerve injury and they may all contribute more or less to the development of pain. Biologically, a sustained noxious input to secondorder neurons may be expressed in several ways: cells expand their response repertoire to include noxious responding activity following non-noxious Ab-input, they show an increase in receptive fields, a reduction of firing threshold, after-discharges and the recruitment of silenced cells, etc. The clinical
counterpart of central sensitisation in terms of phantom pain is of course not clear, but it may include phenomena such as: spontaneous pain, increased pain following stimulation, tender neuromas, allodynia or hyperalgesia of the stump and invasion of such abnormal sensation to a distant dermatome. The latter phenomenon is occasionally seen in patients following repetitive surgery on stumps (Jensen and Nikolaj sen, 1999). Pre-emptive analgesia In trials on pre-emptive analgesia the effect of treatments (usually drugs) administered before injury are compared with the same type of treatment administered after injury. Studies of peri-operative analgesia usually compare pre-injury treatment with no treatment. An important point concerns the duration and the efficacy of the analgesic intervention. A shortlasting and incomplete analgesia is probably less effective than a long-lasting and profound nerve blockade in preventing sensitisation of noxious responding neurons upstream in the nervous system. There is a long list of studies that have examined the effect of a pre-emptive pain treatment in pain (see: Dahl and Kehlet, 1993; Dahl, 1994; McQuay, 1994). Experimental evidence for pre-emptive effect in neuropathic pain There is a long list supporting a pre-emptive analgesic effect in experimental pain including neuropathic pain (for review see Coderre and Katz, 1997; see also Wilder-Smith, 2000, this volume). The background for a pre-emptive effect is obtained from a series of classical studies in the mideighties by Woolf and others, demonstrating plastic changes in the nervous system following long-lasting and intense noxious activity (for review, see Woolf, 1992). See also: More et al. (2000) this volume. Peripheral injury or noxious stimulation either by capsaicin, thermal injury or repetitive C-fibre stimulation have all been shown to induce a sensitisation of spinal dorsal horn neurons. This sensitisation is manifested by a wide spectrum of peripheral and central phenomena. Dickenson and Sullivan (1987) observed that intrathecal administration of morphine in phase I of the formalin test inhibited dorsal horn
497
neuronal activity more than if administered after phase I. Similar effects were observed with the NMDA antagonist MK801 administered intrathetally (Yaksh, 1993), but subsequent studies have not unequivocally supported these findings. Brennan et al. (1997) in an incision model of the plantar hindpaw failed to find an effect of intrathecal opioids or local anaesthetics. In certain animal models of neuropathic pain it has been shown that noxious stimulation of the paw or the sciatic nerve in the rat before neurectomy significantly shortens the onset of autotomy and enhances its severity. An early literature in rodents showed that autotomy or hyperalgesia can be prevented if the initial nerve injury is preceded by an intense antinociceptive treatment. Several drugs have been examined, including local anaesthetics, clZadrenergic agonists, opioids and NMDA antagonists (Puke and Wiesenfeld-Hallin, 1993; Kalso, 1997). These studies have shown that local anaesthetics applied locally on the nerve before transection or constriction reduces hyperalgesia or other behavioural signs of pain. Similarly, morphine and NMDA antagonists given intrathecally or systemically have also been shown to prevent pain (for review see Kalso, 1997). Clinical evidence for prevention of postamputation pain At least three lines of evidence point to a possible role of pre-emptive pain treatment in amputees (Jensen and Nikolajsen, 1999). (1) Phantom pain is in many cases a replicate of pain experienced before amputation and patients with severe and long-lasting preamputation pain in the involved limb are more likely to develop postamputation pain. (2) Phantom pain represent the most radical example of neuropathic pain, a condition where prolonged noxious input impinging on central structures are known to induce long-term secondary changes. These plastic changes in the nervous system are experimentally amenable to modulation by pre-emptive measures (see above). (3) An early study in patients undergoing amputation has suggested that an effective pain treatment before amputation reduces the subsequent incidence
of phantom pain (Bach et al., 1988). This observation has been confirmed in some subsequent trials. The idea of a pre-emptive analgesic effect in postamputation pain was initiated by clinical observations that phantom pain in some cases is similar to previous experienced pain (Nathan, 1962; Jensen and Nikolajsen, 1999). This observation has led to the idea that preamputation pains may create an imprint in memorising structures of the central nervous system and that such imprint could be responsible for persistent pains after amputation. Some studies have shown that prior neuropathic pains have an influence on subsequent pains. Dworkin and colleagues in postherpetic neuralgia have noticed that severe postherpetic neuralgia often were preceded by severe zoster pains (Dworkin et al., 1992). Similarly, in amputees it has been shown that patients with severe phantom pain often have suffered from long-lasting and more severe preamputation pain than patients with less intense phantom pain (Jensen et al., 1985; Nikolajsen et al., 1997a). Preamputation pain seems to increase the risk of phantom pain after amputation, but the relation is not simple (Nikolajsen et al., 1997a). We prospectively followed 58 amputees (Jensen et al., 1983, 1985). Phantom pain was significantly more frequent after 8 days and 6 months, but not after 2 years in patients who had pain in the limb before the amputation compared to those who were free of pain. In a retrospective study by Houghton and colleagues (Houghton et al., 1994) similar results were found: in vascular amputees preamputation pain was related to phantom pain after 8 days, 6 months and 2 years, but in traumatic amputees preamputation pain was only related to phantom pain immediately after the amputation. In a prospective study of 60 amputees Nikolajsen et al. (1997a) found that intense preamputation pain was related to phantom pain after 1 week and 3 months but no relation was found later in the course. Several amputees presented statements as “I can still feel my ingrown toe-nail” and “I feel the hole, where the ulcer was” (Katz and Melzack, 1990; Hill et al., 1996; Nikolajsen et al., 1997a). Only few studies have examined the incidence with which preamputation pain persists as phantom pain. Katz and Melzack (1990) interviewed 68 amputees up to several years after the amputation. Fifty-seven per-
498
cent of those who reported having had preamputation pain before the amputation claimed that their phantom pain resembled the pain they had at the time of amputation. The incidence was much lower in two prospective studies (Jensen et al., 1983; Nikolajsen et al., 1997a). In the latter study patients were asked to describe their pain both before and after amputation using: (1) their own words, (2) specific pain descriptors, and (3) McGill Pain Questionnaire. Location of pain was also recorded. Although 42% of the patients claimed that their phantom pain was similar to the pain they had at the time of the amputation, actual similarity on the basis of (1) pain descriptors, (2) the patients’ own selection of pain words, and (3) on the basis of the McGill Pain Questionnaire were only found to be similar in a small minority of patients when comparing preamputation and postamputation recordings of pain. So although preamputation pain and a conditioning sensitisation of the nervous system play a role in phantom pain they are not the only mechanisms involved. Pre-emptive analgesic studies in postamputation pain While the issue of pre-emptive analgesia has been dealt with extensively by others (McQuay, 1992, 1994; Dahl, 1994; Kalso, 1997; see Wilder-Smith, 2000, this volume), its possible role in nerve injury has been less discussed. Peripheral nerve blockade
The effect of postoperative perineural analgesia to prevent phantom pain has been studied in a few trials (Table 1). Fischer and Meller (1991) introduced a catheter into the transected nerve sheath at the time of amputation and infused bupivacaine 0.25% at a rate of 10 ml/h for 72 h after amputation. None of the 11 patients studied developed phantom pain during the first year after amputation. In a retrospective study, Elizaga et al. (1994) found no difference in the incidence of phantom pain between two groups of patients who had received either bupivacaine 0.5% 2-6 ml/h for 72 h after amputation (9 patients) or opioid analgesics alone (12 patients). Pinzur and colleagues (Pinzur et al., 1996) conducted a randomised,
blinded and placebo-controlled trial in which 21 patients received either perineural infusion with bupivaCaine 0.5% or saline for three consecutive days after amputation. The incidence of phantom pain was similar in both groups 3 and 6 months after amputation. Epidural blockade
Bach et al. (1988) carried out the first study in which 25 patients scheduled for amputation of the lower limb were randomised by means of their year of birth to receive either epidural morphine, epidural bupivacaine 0.25% or both in combination for 3 days before the amputation (11 patients) or conventional analgesics such as opioids, paracetamol, dextropropoxyphene and acetylsalicylic acid (14 patients). All patients received epidural or spinal analgesia for the amputation and postoperatively their pain was treated with meperidine, paracetamol or ASA. Patients were interviewed about phantom pain after 1 week, 6 and 12 months. Pain was categorised as either present or not present and apparently interviewers were not blinded to the treatment. Six patients died during the follow-up period. The incidence of phantom pain was found reduced 6 months after amputation but not after 1 week or after 12 months in the epidural blocked group as compared to the non-blocked control group. At the 6-months follow-up, all 10 patients in the blockade group were free of pain while 5 out of 13 patients in the control group had phantom pain. In another study, Jahangiri et al. (1994) prospectively followed 24 patients undergoing limb amputation. In a non-randomised design patients received either an epidural infusion of bupivacaine, diamorphine and clonidine from 24 to 58 h before surgery and for at least 3 days after surgery (13 patients) or on demand opioid as analgesia (11 patients). Amputation was carried out under general anaesthesia. The presence of phantom pain was graded on a scale of l-10 and pain was considered significant when the score was >3. During follow-up two patients died. After 1 week, 6 and 12 months, the incidence of phantom pain was found significantly lower in the blocked group versus the unblocked control group. Schug and colleagues in a letter to the editor (Schug et al., 1994) presented data from a non-randornised trial. Methods of blinding and pain assess-
499 TABLE Effect
1 of perineural
or epidural
pre-emptive
analgesia
in amputees
Randomisation
Blinding
Bach et al., 1988
+
-
25
Jahangiri
-
-
-
-
Authors
Schug
et al., 1994 et al., 1994
Katsuly-Liapis
Nikolajsen
et al., 1996
et al., 1997a,b
Fischer
and Meller,
Elizaga
et al., 1994
Pinzur
1991
et al.. 1996
a B = blockade
group;
No. of patients
on phantom
pain
Treatment a
preoperative
intraoperative
B: I1 c: 14
+ -
+ +
24
B: 13 c: 11
+ -
+ -
+ -
+ -c
23
Bt: 8 B2: 7 C: 8
+
+ + -
+ + -
+ +
-
postoperative
Effect of treatment
+ +
Bl vsC
+
-
45
BI: 15 B2: 12 C: 18
+ + -
+ + Bt vsB2andC
+
+
60
B: 29 c: 31
+ +
-
-
-
11
B: 11 c: 0
+
t
-
-
21
B: 9 c: 12
+ -
-
21
B: 11 c: 10
+ -
-
+
C = control
+
-
-
group.
ment were not described. Twenty-three patients were divided into three groups. One group received an epidural infusion of bupivacaine 0.125% and fentanyl 0.0002% for 24 h before amputation and continued for at least 48 h after surgery (8 patients). Another group (7 patients) were operated in epidural anaesthesia and had postoperative epidural infusion of fentanyl and bupivacaine as described above. Finally, a group (8 patients) were operated under general anaesthesia and had systemic analgesia. After 1 year the incidence of phantom pain was significantly lower among the patients receiving pre-, intraand postoperative epidural analgesia, relative to patients who received general anaesthesia and systemic analgesia. Katsuly-Liapis and colleagues (Katsuly-Liapis et al., 1996) reported in abstract form a study where 45 patients were randomised into three groups to receive: (1) epidural analgesia with bupivacaine 0.25% and morphine for 3 days before amputation and continued for 3 days after the operation (15 patients), (2) epidural analgesia postoperatively (12 patients), or
(3) systemic analgesia with opioids and NSAID (18 patients). After 6 months the incidence of phantom pain was significantly lower in the group of patients who had epidural analgesia before, during and after amputation compared to the other two groups. No details about randomisation, blinding or pain assessment were presented. These data have to our knowledge so far not been published in an extended paper. In a blind and placebo-controlled trial (Nikolajsen et al., 1997b), 60 patients were randomly assigned to receive epidural bupivacaine (0.25% 4-7 ml/h) and morphine (0.16-0.28 mg/h) for 18 h before the amputation (29 patients) or epidural saline and systemic opioids (31 patients). Both groups underwent general anaesthesia for the amputation and all received epidural bupivacaine and morphine for postoperative pain management. Phantom pain both in terms of frequency and intensity was assessed after 1 week, 3 months, 6 months, and 12 months. Pain intensity was measured by means of a visual analogue scale (VAS) O-100. Fifty-six patients were available for
500 follow-up after 1 week; this number was reduced to 28 after 1 year, mainly because of deaths among the amputees (generally old people with generalised vascular diseases). The blindness in this study was ensured by two independent investigators, who were responsible for either the randomisation and preoperative pain treatment or for the postoperative pain treatment and follow-up. Patient blindness was secured by asking the patients after 6 months which type of treatment they had and they were not able at this time to distinguish between control and blockade treatment. After 1 week 52% in the blockade group and 56% in the control group had phantom pain. There was no difference in pain frequency and pain intensity at any time points between the two groups. So according to this study it was not possible to document a pre-emptive effect during an 18-h intense pain treatment before the operation. In the same group of patients the intense pre-injury pain treatment also failed to have any effect on subsequent stump sensitivity to mechanical and thermal stimuli (Nikolajsen et al., 1998). Discrepancy between experimental pre-emptive analgesia studies
and clinical
It is important to emphasise that despite failure to demonstrate a pre-emptive analgesic effect in many clinical studies, functional plastic changes of the nociceptive system by injury is an indisputable phenomenon. While there is firm experimental evidence for this notion, the clinical evidence for pre-emptive analgesia is much less clear. It is therefore of interest to speculate on differences between experimental and clinical studies that might explain this observation. TABLE 2 Factors influencing effectiveness of pre-emptive analgesia Genetic factors Pre-injury events Intensity of noxious injury Duration of noxious stimulus before during and after Type of injury (degree of inflammation and nerve injury) Duration of analgesia Efficacy of neural block Type of pharmacological blockade
Table 2 presents a list of possibilities why preemptive treatments may not work or only show a marginal effect in clinical studies. Clinical pains are much more complex than those in the laboratory. They may involve a mixture of inflammatory and neuropathic pain components and it can be difficult to dissect the contribution of each part. Patients are heterogeneous in terms of injury and pain experience before, during and after such injury. Another point concerns the duration of the analgesia. In animal experiment where the post-injury discharges are short lasting, a short pre-emptive pain treatment may be sufficient to prevent such discharges. It is also possible that an extended period might have been able to reveal a pre-emptive effect. The duration of post-injury neuronal discharges are not known. If post-injury neuronal activity from the periphery persists beyond the duration of analgesia this may mask a possible pre-emptive effect. Finally, an insufficient afferent blockade may lead to central sensitisation and prevent seeing a possible effect of the pre-emptive treatment (Dahl, 1994). It is possible that an extension of the analgesia to the peri-operative period may document an effect in terms of reduced pain and prevention of long-term sequelae. Conclusions The importance of sensitisation for chronic pain syndromes and the possible role of pre-injury pain for late post-injury pain has raised the issue whether phantom pain can be prevented. Early studies have shown that such prevention is possible by a preemptive analgesic treatment. However, subsequent randomised and controlled trials have failed to find evidence for such a pre-emptive effect. In fact it is not surprising that a short-lasting pre-injury treatment should prevent various aspects central sensitisation induced by an intense and long-lasting noxious input before, during and after the amputation. A future challenge lies in determining whether a long-lasting and intense pre-, peri- and postoperative analgesic treatment can in fact reduce the subsequent development of nerve injury pain including phantom pain. Moreover, it will be important to identify those patients that are likely to benefit from such a procedure.
501
References Bach, S., Noreng, M.F. and Tjellden, N.U. (1988) Phantom limb pain in amputees during the first 12 months following limb amputation, after preoperative lumbar epidural blockade. Pain, 33: 297-301. Berthele, A., Schadrack, J., Castro-Lopes, J.M., Conrad, B., Zieglgansberger, W. and Tolle, T.R. (2000) Neuroplasticity in the spinal cord of monoarthritic rats: from metabolic changes to the detection of interleukin-6 using mRNA differential display. In: J. Sandktlhler, B. Bromm and GE Gebhart (Eds.), Nervous System Plasticity and Chronic Pain. Progress in Brain Research, Vol. 129. Elsevier, Amsterdam, pp. 191-203. Birbaumer, N., Lutzenberger, W. and Montoya, P (1997) Effects of regional anaesthesia on phantom limb pain are mirrored in changes in cortical reorganization. J. Neurosci., 17: 55035508. Brennan, T.J., Umali, E.F. and Zahn, P.K. (1997) Comparison of pre- versus post-incision administration of intrathecal bupivacaine and intrathecal morphine in rat model postoperative pain. Anesthesiology, 87: 1517-1528. Bromm, B., Scharein, E. and Vahle-Hinz, C. (2000) Cortex areas involved in the processing of normal and altered pain. In: J. Sandktihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain. Progress in Brain Research, Vol. 129. Elsevier, Amsterdam, pp. 289-302. Casey, K.L. (2000) Concepts of pain mechanisms: the contribution of functional imaging of the human brain. In: J. Sandktihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain. Progress in Brain Research, Vol. 129. Elsevier, Amsterdam, pp. 277-287. Chabal, C., Jacobson, L. and Russell, L.C. (1989) Pain responses to perineuromal injection of normal saline, gallamine and lidocaine in humans. Pain, 36: 321-325. Coderre, T.J. and Katz, J. (1997) Peripheral and central hyperexcitability: differential signs and symptoms in persistent pain. Behav. Brain Sci., 20: 404-419. Cummins, T.R., Dib-Hajj, SD., Black, J.A. and Waxman, S.G. (2000) Sodium channels and the molecular pathophysiology of pain. In: J. Sandktihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain. Progress in Brain Research, Vol. 129. Elsevier, Amsterdam, pp. 3-19. Dahl, J.B. (1994) Neuronal plasticity and pre-emptive analgesia: implications for the management of post-operative pain. Dan. Med. Bull., 41: 434-442. Dahl, J.B. and Kehlet, H. (1993) The value of pre-emptive analgesia in the treatment of post-operative pain. B,: J. Anaesth., 70: 434-439. Devor, M. and Seltzer, Z. (1999) Pathophysiology of damaged nerves in relation to chronic pain. In: P.D. Wall and R. Melzack (Eds.), Textbook of Pain. 4th ed. Churchill Livingstone, Edinburgh, pp. 129-164. Devor, M., Govrin-Lippman, R. and Angelides, K. (1993) Na+ channels immunolocalization in peripheral mammalian axons and changes following nerve injury and neuroma formation. J. Neurosci., 135: 1976-1992. Dickenson, A.H. and Sullivan, A.F. (1987) Subcutaneous for-
malin-induced activity of dorsal horn neurones in the rat: different responses to an intrathecal opiate administered preor post-formalin. Pain, 30: 339-348. Dworkin, R.H., Hartstein, G. and Rosner, H.L. (1992) A high risk method for studying psychosocial antecedents of chronic pain: the prospective investigation of herpes zoster. J. Abnorm. Psychol., 101: 200-205. Elizaga, A.M., Smith, D.G., Sharar, S.R., Edwards, T. and Hansen, S.T. (1994) Continuous regional analgesia by intraneural block: effect on postoperative opioid requirements and phantom limb pain following amputation. J. Rehab. Res. Dev., 31: 179-187. Fischer, A. and Meller, Y. (1991) Continuous postoperative regional analgesia by nerve sheath block for amputation surgery - a pilot study. Anesth. Analg., 72: 300-303. Flor, H. (2000) The functional organization of the brain in chronic pain. In: J. Sandkiihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain. Progress in Brain Research, Vol. 129. Elsevier, Amsterdam, pp. 313322. Flor, H., Elbert, T. and Knecht, S. (1995) Phantom limb pain as a perceptual correlate of massive cortical reorganization in upper limb amputees. Nature, 375: 482-484. Flor, H., Elbert, T. and Mtihlnickel, W. (1998) Cortical reorganization and phantom phenomena in congenital and traumatic upper-extremity amputees. Exp. Brain Res., 119: 205-212. Gerber, G., Youn, D.-H., Hsu, C.H., Isaev, D. and Randic, M. (2000) Spinal dorsal horn synaptic plasticity: involvement of group I metabotropic glutamate receptors. In: J. Sandktihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain. Progress in Brain Research, Vol. 129. Elsevier, Amsterdam, pp. 115-134. Hill, A., Niven, C.A. and Knussen, C. (1996) Pain memories in phantom limbs: a case study. Pain, 66: 381-384. Hoheisel, U. and Mense, S. (2000) The role of spinal nitric oxide in the control of spontaneous pain following nociceptive input. In: J. Sandkiihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain. Progress in Brain Research, Vol. 129. Elsevier, Amsterdam, pp. 163-172. Houghton, A.D., Nicholls, G., Houghton, A.L., Saadah, E. and McCall, I. (1994) Phantom pain: natural history and association with rehabilitation. Ann. R. Coil. Surg. Eng., 76: 2225. Jahangiri, M., Jayatunga, A.P., Bradley and Dark, C.H. (1994) Prevention of phantom pain after major lower limb amputation by epidural infusion of diamorphine, clonidine and bupivaCaine. Ann. R. Coil. Surg. Engl., 76: 324-326. Jensen, T.S. and Gottrup, H. (2000) Assessment of neuropathic pain. In: C. Warheld. A. Rice, D. Justins and C. Eccleston (Eds.), Textbook of Clinical Pain Management. Arnold, London (in press). Jensen, T.S. and Nikolajsen, L. (1999) Phantom pain and other phenomena after amputation. In: P.D. Wall and R. Melzack (Eds.), Textbook of Pain. 4th ed. Churchill Livingstone, Edinburgh, pp. 799-8 14. Jensen, T.S., Krebs, B., Nielsen, J. and Rasmussen, P. (1983) Phantom limb, phantom pain and stump pain in amputees
502
during the first 6 months following limb amputation. Pain, 17: 243-256. Jensen, T.S., Krebs, B., Nielsen, J. and Rasmussen, P. (1985) Immediate and long-term, phantom limb pain in amputees: incidence, clinical characteristics and relationship to pre-amputation pain. Pain, 21: 267-278. Kalso, E. (1997) Prevention of chronicity. In: T.S. Jensen, J.A. Turner and Z. Wiesenfeld-Hallin (Eds.), Proceedings of the 8th World Congress on Pain. Progress in Pain Research and Management, Vol. 8. IASP Press, Seattle, WA, pp. 215-230. Katsuly-Liapis, I., Georgakis, P. and Tierry, C. (1996) Pre-emptive extradural analgesia reduces the incidence of phantom pain in lower limb amputees. BI: J. Anaesth., 76: 125. Katz, J. and Melzack, R. (1990) Pain memories in phantom limbs: review and clinical observations. Puin, 43: 319-336. Larbig, W., Montaya, P. and Flor, H. (1996) Evidence for a change in neural processing in phantom limb pain patients. Pain, 67: 275-283. McQuay, H.J. (1992) Pre-emptive analgesia. Br J. Anaesth., 69: l-3. McQuay, H.J. (1994) Do preemptive treatments provide better pain control. In: G.F. Gebhart, D.L. Hammond and T.S. Jensen (Eds.), Proceedings of the 7th World Congress on Pain. Progress in Pain Research and Management, Vol. 2. IASP Press, Seattle, WA, pp. 709-723. Melzack, R. (1995) Phantom-limb pain and the brain. In: B. Brommm and I.E. Desmedt (Eds.), Advances in Pain Research and Therapy, Vol. 22. Raven Press, New York, pp. 73-82. Moore, K.A., Baba, H. and Woolf, C.J. (2000) Synaptic transmission and plasticity in the superficial dorsal horn. In: J. Sandkiihler, B. Bromm and G.F. Gebhart (Eds.), Nervous Systern Plasticity and Chronic Pain. Progress in Brain Research, Vol. 129. Elsevier, Amsterdam, pp. 63-80. Nathan, P.W. (1962) Pain traces left in the central nervous system. In: C.A. Keele and R. Smith (Eds.), The Assessment of Pain in Man and Animals. E&S Livingstone, Edinburgh, pp. 129-134. Nikolajsen, L. and Jensen, T.S. (2000) Phantom limb pain. Curr: Rev. Pain, 4: 166-170. Nikolajsen, L., Hansen, C.L., Nielsen, J., Keller, J., ArendtNielsen, L. and Jensen, T.S. (1996) The effect of ketamine on phantom pain: a central neuropathic disorder maintained by peripheral input. Pain, 67: 69-77. Nikolajsen, L., Ilkjaer, S., Kroner, K., Christensen, J.H. and Jensen, T.S. (1997a) The influence of preamputation pain on postamputation stump and phantom pain. Pain, 72: 393-405. Nikolajsen, L., Ilkjaer, S., Kroner, K., Christensen, J.H. and Jensen, T.S. (1997b) Randomised trial of epidural bupivacaine and morphine in prevention of stump and phantom pain in lower-limb amputation. L.ancet b, 350: 348-354. Nikolajsen, L., Ilkjmr, S. and Jensen, T.S. (1998) Effect of preoperative extradural bupivacaine and morphine on stump sensation in lower limb amputees. BI: J. Anaesth., 81: 348354. Nikolajsen, L., Got&up, H., Kristensen, A.G.D. and Jensen, T.S. (2000a) Memantine (a N-methyl-D-aspartate receptor antagonist) in the treatment of neuropathic pain following amputa-
tion or surgery: a randomised, double-blind, cross-over study. Anesth. Analg., in press. Nikolajsen, L., Ilkjaer, S. and Jensen, T.S. (2OOOb) Relationship between mechanical sensitivity and postamputation pain: A prospective study. Eur: J. Pain, in press. Novakovic, S.D., Tzoumaka, E., McGivem, J.G., Haraguchi, M., Sangameswaran, L., Gogas, K.R., Eglen, R.M. and Hunter, J.C. (1998) Distribution of the tetrodotoxin-resistant sodium channel PN3 in rat sensory neurons in normal and neuropathic pain conditions. J. Neurosci., 18: 2174-2187. Nystriim, B. and Hagbarth, K.E. (1981) Microelectrode recordings from transected nerves in amputees with phantom limb pain. Neurosci. L&t., 27: 21 l-216. Pinzur, M.S., Garla, P.G.N., Pluth, T. and Vrbos, I. (1996) Continuous postoperative infusion of a regional anaesthetic after an amputation of the lower extremity. J. Bone Joint Surg., 78: 1501-1505. Puke, M.J.C. and Wiesenfeld-Hallin, Z. (1993) The differential effects of morphine and the ct2-adrenoceptor agonists clonidine and dexmedotomidine on the prevention and treatment of experimental neuropathic pain. Anesth. A&g., 77: 104-109. Rajbhandari, S.M., Jarett, J.A., Griffiths, P.D. and Ward, J.D. (1999) Diabetic neuropathic pain in a leg amputated 44 years previously. Pain, 83: 627-629. Sandkiihler, J., Benrath, J., Brechtel, C., Ruscheweyh, R. and Heinke, B. (2000) Synaptic mechanisms of hyperalgesia. In: J. Sandktihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain. Progress in Brain Research, Vol. 129. Elsevier, Amsterdam, pp. 81-100. Sherman, R.A. and Sherman, C.J. (1983) Prevalence and characteristics of chronic phantom limb pain among American veterans. Am. J. Phys. Med., 62: 227-238. Schug, S.A., Burell, R., Payne, J. and Tester, P. (1995) Pre-emptive epidural anaesthesia may prevent phantom limb pain. Reg. Anesth., 20: 256. Svendsen, F., Hole, K. and Tjolsen, A. (2000) Long-term potentiation in single WDR neurons induced by noxious stimulation in intact and spinalized rats. In: J. Sandkiihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain. Progress in Brain Research, Vol. 129. Elsevier, Amsterdam, pp. 153-161. Wall, P.D. (1988) The prevention of postoperative pain. Pain, 33: 289-290. Wartan, S.W., Hamann, W., Wedley, J.R. and McCall, I. (1997) Phantom pain and sensation among British veteran amputees. BI: J. Anaesth., 78: 652-659. Waxman, S.G. (1999) The molecular pathophysiology of pain: abnormal expression of sodium channel genes and its contrbutions to hyperexcitability of primary sensory neurons. Pain Sappl., 6: 133-140. Wilder-Smith, O.H.G. (2000) Pre-emptive analgesia and surgical pain. In: J. Sandktihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain. Progress in Brain Research, Vol. 129. Elsevier, Amsterdam, pp. 505-524. Wilkins, K.L., McGrath, P.J., Finley, G.A. and Katz, J. (1998) Phantom limb sensations and phantom limb pain in child and adolescent amputees. P&n, 78: 7-12.
503 Woolf, C.J. (1992) Excitability changes in central neurons following peripheral damage. Role of central sensitization in the pathogenesis of pain. In: W. Willis (Ed.), Hyperulgesia and Allodynia. Raven Press, New York, pp. 221-243. Woolf, C.J. and Chong, M. (1993) Pre-emptive analgesia: treating postoperative pain by preventing the establishment of central sensitization. Anesth. Analg., 71: 362-379. Woolf, C.J. and Salter, M.W. (2000) Neuronal plasticity: Increasing the gain in pain. Science, 288: 1765-1768. Woolf, C.J. and Thompson, S.W.N. (1991) The induction
and maintenance of central sensitisation is dependent on &‘-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain, 44: 293-299.
Woolf, C.J., Shortland, P. and Coggeshall, R.E. (1992) Peripheral nerve injury triggers central sprouting of myelinated afferents. Nature,
355: 75-78.
Yaksh, T.L. (1993) The spinal pharmacology of facilitation of afferent processing evoked by high threshold afferent input of the postinjury pain state. Cur< Opin. Neural. Neurosurg., 6: 250-256.
CHAPTER 36
Pre-emptive analgesia in postamputation pain: an update Troels StaehelinJensen1,3,*and Lone Nikolajsen 2,3 ’ Department
of Neurology,
2 Department
of Anesthesiology, and 3 Danish Pain Research DK-8000 Aarhus C. Denmark
Introduction A key issue in current pain research and treatment is the transition of acute pain into chronic pain states and the identification of risk factors for such transition. Based on a series of experimental studies on neuronal hyperexcitability and the induction of sensitisation, the question was raised in 1988 (Wall, 1988) whether neuronal hyperexcitability and pain could be prevented by an analgesic treatment before injury as opposed to after the injury. This issue, termed pre-emptive analgesia has been explored extensively both experimentally and clinically within the last decade (for review see: McQuay, 1992, 1994; Woolf and Chong, 1993; Dahl, 1994; Kalso, 1997). The nociceptive system is not a fixed static system, but a dynamic neuronal network, which continuously alters its response characteristics depending on the prior exposure to noxious activity (for review see: Coderre and Katz, 1997; Woolf and Salter, 2000; Berthele et al., 2000, this volume; Gerber et al., 2000, this volume; Moore et al., 2000, this volume; Sandktihler et al., 2000, this volume). In classical studies, Woolf and others observed that the functional plastic changes with sensitisation of second-order neurons could be prevented by a neural blockade or by an opioid administration before, but not after injury (for review see Woolf, 1992). The
* Corresponding author: T.S. Jensen, Department of Neurology, Aarhus University Hospital, DK-8000 Aarhus C, Denmark. Tel.: +45-8949-3283; Fax: +45-8949-3300; E-mail: tsj @panter.soci.aau.clk
Cente,:
Aarhus
University
Hospital,
clinical counterpart of such pre-emptive analgesia was initiated by a study carried out by Bach and colleagues in 1988 (Bach et al., 1988) in a group of amputees, where epidural treatment before amputation apparently reduced the incidence of phantom pain. This important landmark has since been the focus for a series of further experimental and clinical studies on the effect of blockade of noxious input to the nervous system and its possible influence on neuronal hyperexcitability, sensitisation and chronic pain. Some of these studies but not all support the idea of a pre-emptive effect in amputees to avoid the subsequent development of phantom pain. Although amputation only represents a small minority among patients undergoing surgery it is extremely important to clarify if phantom pain indeed can be prevented because such an observation will have a significant bearing not only for amputees but for future strategies in anaesthesiology and pain treatment. Several studies have dealt with other types of postoperative pain (for review see: Dahl, 1994; McQuay, 1994). In the present chapter we will examine the experimental and clinical evidence for a pre-emptive analgesic effect on nerve injury pain with emphasis on phantom and stump pains as consequences of limb amputation. Clinical aspects of postamputation
pain
A detailed description of postamputation phenomena can be found elsewhere. For the present purposes a few clinical highlights, however, are necessary. It is useful to distinguish between the following three elements of the phantom complex (Jensen and Niko-
494
lajsen, 1999): phantom limbpain: pain referred to the missing limb; phantom limb sensation: non-painful sensations referred to the missing limb; stump pain: pain localised to the stump. Although these phenomena can be separated and patients usually are able to distinguish between each they often coexist in the same patient.
of pain is considerably reduced with time (Jensen et al., 1983; Houghton et al., 1994; Nikolajsen et al., 1997a). Character and location
Phantom pain develops in about 70% of patients following amputation irrespective of the cause of amputation (Jensen and Nikolajsen, 1999). Gradual remission of pain over time is the rule, but for a significant group of amputees (approximately 10%) the pain persists in a severe form requiring treatment. Treatment of phantom pain, however, is difficult and there is at present no single therapy offering universal benefit. Most recent studies agree that the incidence of phantom pain is in the range of 60-80% (Houghton et al., 1994; Nikolajsen et al., 1997a; Wartan et al., 1997). The incidence does not seem to be influenced by age, gender, side or level of amputation (Jensen et al., 1983) or cause of amputation (Sherman and Sherman, 1983; Houghton et al., 1994), but phantom pain is less frequent in young children, and in congenital amputees (Flor et al., 1998; Wilkins et al., 1998).
Phantom pain is highly variable from patient to patient with some patients having only a few short-lasting spells of pain sensation and others suffering from daily excruciating pains lasting for months or years. However, only few patients are in constant pain. The description of pains varies considerably from shooting, stabbing, pricking, boring, squeezing pains to throbbing and burning types of pains (Jensen et al., 1983; Sherman and Sherman, 1983; Nikolajsen and Jensen, 2000). Phantom pains are most distinct in distal parts of the body (hand, fingers, foot, toes, etc.). A characteristic feature is a gradual shrinkage of the phantom as time passes by after amputation, a phenomenon known as telescoping. As for phantom pain character, the location also varies from patient to patient. It is important to take this variability both in character, intensity and location into account in clinical studies and assessdifferent aspects (intensity, number of attacks, duration of attacks, etc.) and ensure constancy in cross-over trials and similarities between groups in parallel study trials.
Time course
Mechanisms
The onset of phantom pain is usually in the first week following amputation. In a prospective study, 48% developed their pain within the first 24 h, and 83% within 4 days. In less than 10% is phantom pain delayed for more than 1 week (Jensen et al., 1983). Another prospective study showed similar results (Nikolajsen et al., 1997a). However, case reports suggest that the onset of phantom pain may be delayed until several years after amputation. For example, Rajbhandari and colleagues (Rajbhandari et al., 1999) described the development of diabetic neuropathic pain in a leg amputated 44 years earlier. Although phantom pain may diminish with time and in some cases even disappear, prospective studies show that 2 years after amputation the incidence of postamputation pains are almost the same as at onset. However, both duration, frequency, and intensity
The mechanisms responsible for stump and phantom pain in amputation are still under discussion and apparently both peripheral and central mechanisms are involved and contribute to the phantom pain perception. An understanding of underlying mechanism for phantom pain and other types of nerve injury pain may lead to new types of rational founded treatments.
Frequency
Peripheral generator
Several lines of evidence indicate that the periphery is a generator and a site for maintaining stump and phantom pain. (1) Neuromas are universal phenomena after a nerve cut. An extensive experimental literature shows that these neuromas express spontaneous and
abnormal evoked activity with an increased sensitivity to a variety of stimuli including mechanical stimuli (Devor et al., 1993; Devor and Seltzer, 1999). The ectopic and increased activity from the periphery is assumed to be the result of a novel expression and distribution of ion channels (Novakovic et al., 1998). Also in the DRG there are major changes in the expression of sodium channels with a switch of one channel type into another (Waxman, 1999; Cummins et al., 2000, this volume). (2) It is a common clinical experience that percussion of the stump or stump neuromas induces stump and phantom pain. In a classical microneurographic study in two amputees, Nystrom and Hagbarth (198 1) showed that tapping of neuromas was associated with an increased activity in afferent C-fibres and an increased pain sensation. Consistent with this observation it has been shown that there is an inverse, albeit small correlation between phantom pain intensity and pressure pain threshold of the stump in amputees early after the amputation (Nikolajsen et al., 2000b). It should be noted that such correlation can only be found in the early period after amputation but not later in the course, indicating that other than peripheral factors are involved in generating phantom pain. (3) Perineuromal injection of gallamine, a drug that increases neuronal activity by facilitating sodium conductance, produces pain, while a sodium channel blocker, lidocaine, blocks phantom pain at the site of neuroma (Chabal et al., 1989). An extensive literature has shown that changes both in the periphery of the nerve and in dorsal root ganglion cells may be involved in generating phantom pain (for review see Devor and Seltzer, 1999). These findings suggest that long-lasting pain may induce secondary changes in the nervous system that may persist after a nerve injury and predict post-injury pain. This observation is in accordance with previous studies showing that long-lasting and intense preamputation pain may increase the risk for phantom pain following amputation (Nikolajsen et al., 1997a). Central sensitisation It is well appreciated that peripheral sensitisation occurs as a result of spontaneous activity from sprout-
ing, regenerating nerve endings. This peripheral sensitisation in turn gives rise to secondary changes in otherwise silenced small dorsal root ganglia (DRG) cells. The increased barrage from neuromas (organised sprouts) and from DRG cells following nerve injury eventually sweeps centrally and induces long-term changes in central projecting neurons. It is conceivable that in certain patients, where an early afferent barrage and hence sensitisation has been particularly intense, central mechanisms may subsequently maintain sensitisation without any additional nociceptor input. The central sensitisation in the spinal dorsal horn induced by an increased barrage form C-fibres may originate from two sources: (1) a sustained C-fibre input recruit N-methyl-D-aspartate (NMDA) receptors located on second-order spinal neurons (Woolf and Thompson, 1991; see also Moore et al., 2000, this volume; Sandktihler et al., 2000, this volume; Svendsen et al., 2000, this volume); (2) in other cases a central reorganisation occurs because of sprouting of Ap-fibres from laminae III and IV into lamina II, forming a functional contact with second-order nociceptive neurons (Woolf et al., 1992). In both cases the result is an evocation of pain by Afi-fibre input, e.g. touch. However, while the former type of touch-evoked pain may respond to agents that counteract the NMDA receptor system, the latter is unlikely to be affected by such agents and may perhaps be more resistant to modulation at all. It is at present unclear whether central sensitisation can be present without a peripheral generator. The above observation that sprouting from lamina III to lamina II does occur suggests that this may indeed be the case. The central aspects of the hyperexcitability include chemical changes of cells and cell membranes in the dorsal horn of the spinal cord. The glutamate release cascade with release of glutamate, activation of NMDA receptors, increase of intracellular Ca2+ (see Gerber et al., 2000, this volume) and activation of nitrogen oxide synthase (see, however, Hoheisel and Mense, 2000, this volume) is particular important in this hyperexcitability. The clinical translation of such hyperexcitability phenomena may include expansion of painful areas and sensory abnormalities, a lowering of threshold to evoke noxious activ-
496 ity, a build of pain following repetitive stimulation, e.g. wind-up-like phenomena, after-sensations and a switch in modality to evoke pain (Jensen and Gottrup, 2000). While intravenous administered NMDA antagonists can block phantom pain and signs of sensitization oral administered NMDA antagonists are ineffective (Nikolajsen et al., 1996, 2000a). Cortical reorganisation The peripheral plasticity in the nervous system which sweeps into the dorsal horn of the spinal cord may subsequently project to more central relays in the thalamus and cortex and induce further changes at these sites. Recent magnetoencephalographic studies in amputees have shown a strong correlation between phantom limb pain and the extent of cortical reorganisation (Flor et al., 1995, 1998; Bromm et al., 2000, this volume; Casey, 2000, this volume; Flor, 2000, this volume). Currently, a study is carried out using the f-MRI technique to examine whether similar expansion of cortical representation occurs in those patients with pain as opposed to those without pain (M. Lindvig et al., 2000, pers. commun.). It has therefore been suggested that phantom limb pain could be the result of plastic changes in the somatosensory cortex (Larbig et al., 1996). Birbaumer et al. (1997) studied the effect of regional anaesthesia on cortical reorganisation in upper-limb amputees and found that a brachial plexus blockade abolished pain and reorganisation in three out of six amputees. Another aspect of central elements in phantom pain involves the concept of a neuromatrix in the brain proposed by Melzack (1995) in which a neuronal network in the brain produces a characteristic nerve-impulse pattern, which underlies the various body perceptions including phantom pains. So taken together, a cascade of events at several synaptic levels in the nervous system take place following a peripheral nerve injury and they may all contribute more or less to the development of pain. Biologically, a sustained noxious input to secondorder neurons may be expressed in several ways: cells expand their response repertoire to include noxious responding activity following non-noxious Ab-input, they show an increase in receptive fields, a reduction of firing threshold, after-discharges and the recruitment of silenced cells, etc. The clinical
counterpart of central sensitisation in terms of phantom pain is of course not clear, but it may include phenomena such as: spontaneous pain, increased pain following stimulation, tender neuromas, allodynia or hyperalgesia of the stump and invasion of such abnormal sensation to a distant dermatome. The latter phenomenon is occasionally seen in patients following repetitive surgery on stumps (Jensen and Nikolaj sen, 1999). Pre-emptive analgesia In trials on pre-emptive analgesia the effect of treatments (usually drugs) administered before injury are compared with the same type of treatment administered after injury. Studies of peri-operative analgesia usually compare pre-injury treatment with no treatment. An important point concerns the duration and the efficacy of the analgesic intervention. A shortlasting and incomplete analgesia is probably less effective than a long-lasting and profound nerve blockade in preventing sensitisation of noxious responding neurons upstream in the nervous system. There is a long list of studies that have examined the effect of a pre-emptive pain treatment in pain (see: Dahl and Kehlet, 1993; Dahl, 1994; McQuay, 1994). Experimental evidence for pre-emptive effect in neuropathic pain There is a long list supporting a pre-emptive analgesic effect in experimental pain including neuropathic pain (for review see Coderre and Katz, 1997; see also Wilder-Smith, 2000, this volume). The background for a pre-emptive effect is obtained from a series of classical studies in the mideighties by Woolf and others, demonstrating plastic changes in the nervous system following long-lasting and intense noxious activity (for review, see Woolf, 1992). See also: More et al. (2000) this volume. Peripheral injury or noxious stimulation either by capsaicin, thermal injury or repetitive C-fibre stimulation have all been shown to induce a sensitisation of spinal dorsal horn neurons. This sensitisation is manifested by a wide spectrum of peripheral and central phenomena. Dickenson and Sullivan (1987) observed that intrathecal administration of morphine in phase I of the formalin test inhibited dorsal horn
497
neuronal activity more than if administered after phase I. Similar effects were observed with the NMDA antagonist MK801 administered intrathetally (Yaksh, 1993), but subsequent studies have not unequivocally supported these findings. Brennan et al. (1997) in an incision model of the plantar hindpaw failed to find an effect of intrathecal opioids or local anaesthetics. In certain animal models of neuropathic pain it has been shown that noxious stimulation of the paw or the sciatic nerve in the rat before neurectomy significantly shortens the onset of autotomy and enhances its severity. An early literature in rodents showed that autotomy or hyperalgesia can be prevented if the initial nerve injury is preceded by an intense antinociceptive treatment. Several drugs have been examined, including local anaesthetics, clZadrenergic agonists, opioids and NMDA antagonists (Puke and Wiesenfeld-Hallin, 1993; Kalso, 1997). These studies have shown that local anaesthetics applied locally on the nerve before transection or constriction reduces hyperalgesia or other behavioural signs of pain. Similarly, morphine and NMDA antagonists given intrathecally or systemically have also been shown to prevent pain (for review see Kalso, 1997). Clinical evidence for prevention of postamputation pain At least three lines of evidence point to a possible role of pre-emptive pain treatment in amputees (Jensen and Nikolajsen, 1999). (1) Phantom pain is in many cases a replicate of pain experienced before amputation and patients with severe and long-lasting preamputation pain in the involved limb are more likely to develop postamputation pain. (2) Phantom pain represent the most radical example of neuropathic pain, a condition where prolonged noxious input impinging on central structures are known to induce long-term secondary changes. These plastic changes in the nervous system are experimentally amenable to modulation by pre-emptive measures (see above). (3) An early study in patients undergoing amputation has suggested that an effective pain treatment before amputation reduces the subsequent incidence
of phantom pain (Bach et al., 1988). This observation has been confirmed in some subsequent trials. The idea of a pre-emptive analgesic effect in postamputation pain was initiated by clinical observations that phantom pain in some cases is similar to previous experienced pain (Nathan, 1962; Jensen and Nikolajsen, 1999). This observation has led to the idea that preamputation pains may create an imprint in memorising structures of the central nervous system and that such imprint could be responsible for persistent pains after amputation. Some studies have shown that prior neuropathic pains have an influence on subsequent pains. Dworkin and colleagues in postherpetic neuralgia have noticed that severe postherpetic neuralgia often were preceded by severe zoster pains (Dworkin et al., 1992). Similarly, in amputees it has been shown that patients with severe phantom pain often have suffered from long-lasting and more severe preamputation pain than patients with less intense phantom pain (Jensen et al., 1985; Nikolajsen et al., 1997a). Preamputation pain seems to increase the risk of phantom pain after amputation, but the relation is not simple (Nikolajsen et al., 1997a). We prospectively followed 58 amputees (Jensen et al., 1983, 1985). Phantom pain was significantly more frequent after 8 days and 6 months, but not after 2 years in patients who had pain in the limb before the amputation compared to those who were free of pain. In a retrospective study by Houghton and colleagues (Houghton et al., 1994) similar results were found: in vascular amputees preamputation pain was related to phantom pain after 8 days, 6 months and 2 years, but in traumatic amputees preamputation pain was only related to phantom pain immediately after the amputation. In a prospective study of 60 amputees Nikolajsen et al. (1997a) found that intense preamputation pain was related to phantom pain after 1 week and 3 months but no relation was found later in the course. Several amputees presented statements as “I can still feel my ingrown toe-nail” and “I feel the hole, where the ulcer was” (Katz and Melzack, 1990; Hill et al., 1996; Nikolajsen et al., 1997a). Only few studies have examined the incidence with which preamputation pain persists as phantom pain. Katz and Melzack (1990) interviewed 68 amputees up to several years after the amputation. Fifty-seven per-
498
cent of those who reported having had preamputation pain before the amputation claimed that their phantom pain resembled the pain they had at the time of amputation. The incidence was much lower in two prospective studies (Jensen et al., 1983; Nikolajsen et al., 1997a). In the latter study patients were asked to describe their pain both before and after amputation using: (1) their own words, (2) specific pain descriptors, and (3) McGill Pain Questionnaire. Location of pain was also recorded. Although 42% of the patients claimed that their phantom pain was similar to the pain they had at the time of the amputation, actual similarity on the basis of (1) pain descriptors, (2) the patients’ own selection of pain words, and (3) on the basis of the McGill Pain Questionnaire were only found to be similar in a small minority of patients when comparing preamputation and postamputation recordings of pain. So although preamputation pain and a conditioning sensitisation of the nervous system play a role in phantom pain they are not the only mechanisms involved. Pre-emptive analgesic studies in postamputation pain While the issue of pre-emptive analgesia has been dealt with extensively by others (McQuay, 1992, 1994; Dahl, 1994; Kalso, 1997; see Wilder-Smith, 2000, this volume), its possible role in nerve injury has been less discussed. Peripheral nerve blockade
The effect of postoperative perineural analgesia to prevent phantom pain has been studied in a few trials (Table 1). Fischer and Meller (1991) introduced a catheter into the transected nerve sheath at the time of amputation and infused bupivacaine 0.25% at a rate of 10 ml/h for 72 h after amputation. None of the 11 patients studied developed phantom pain during the first year after amputation. In a retrospective study, Elizaga et al. (1994) found no difference in the incidence of phantom pain between two groups of patients who had received either bupivacaine 0.5% 2-6 ml/h for 72 h after amputation (9 patients) or opioid analgesics alone (12 patients). Pinzur and colleagues (Pinzur et al., 1996) conducted a randomised,
blinded and placebo-controlled trial in which 21 patients received either perineural infusion with bupivaCaine 0.5% or saline for three consecutive days after amputation. The incidence of phantom pain was similar in both groups 3 and 6 months after amputation. Epidural blockade
Bach et al. (1988) carried out the first study in which 25 patients scheduled for amputation of the lower limb were randomised by means of their year of birth to receive either epidural morphine, epidural bupivacaine 0.25% or both in combination for 3 days before the amputation (11 patients) or conventional analgesics such as opioids, paracetamol, dextropropoxyphene and acetylsalicylic acid (14 patients). All patients received epidural or spinal analgesia for the amputation and postoperatively their pain was treated with meperidine, paracetamol or ASA. Patients were interviewed about phantom pain after 1 week, 6 and 12 months. Pain was categorised as either present or not present and apparently interviewers were not blinded to the treatment. Six patients died during the follow-up period. The incidence of phantom pain was found reduced 6 months after amputation but not after 1 week or after 12 months in the epidural blocked group as compared to the non-blocked control group. At the 6-months follow-up, all 10 patients in the blockade group were free of pain while 5 out of 13 patients in the control group had phantom pain. In another study, Jahangiri et al. (1994) prospectively followed 24 patients undergoing limb amputation. In a non-randomised design patients received either an epidural infusion of bupivacaine, diamorphine and clonidine from 24 to 58 h before surgery and for at least 3 days after surgery (13 patients) or on demand opioid as analgesia (11 patients). Amputation was carried out under general anaesthesia. The presence of phantom pain was graded on a scale of l-10 and pain was considered significant when the score was >3. During follow-up two patients died. After 1 week, 6 and 12 months, the incidence of phantom pain was found significantly lower in the blocked group versus the unblocked control group. Schug and colleagues in a letter to the editor (Schug et al., 1994) presented data from a non-randornised trial. Methods of blinding and pain assess-
499 TABLE Effect
1 of perineural
or epidural
pre-emptive
analgesia
in amputees
Randomisation
Blinding
Bach et al., 1988
+
-
25
Jahangiri
-
-
-
-
Authors
Schug
et al., 1994 et al., 1994
Katsuly-Liapis
Nikolajsen
et al., 1996
et al., 1997a,b
Fischer
and Meller,
Elizaga
et al., 1994
Pinzur
1991
et al.. 1996
a B = blockade
group;
No. of patients
on phantom
pain
Treatment a
preoperative
intraoperative
B: I1 c: 14
+ -
+ +
24
B: 13 c: 11
+ -
+ -
+ -
+ -c
23
Bt: 8 B2: 7 C: 8
+
+ + -
+ + -
+ +
-
postoperative
Effect of treatment
+ +
Bl vsC
+
-
45
BI: 15 B2: 12 C: 18
+ + -
+ + Bt vsB2andC
+
+
60
B: 29 c: 31
+ +
-
-
-
11
B: 11 c: 0
+
t
-
-
21
B: 9 c: 12
+ -
-
21
B: 11 c: 10
+ -
-
+
C = control
+
-
-
group.
ment were not described. Twenty-three patients were divided into three groups. One group received an epidural infusion of bupivacaine 0.125% and fentanyl 0.0002% for 24 h before amputation and continued for at least 48 h after surgery (8 patients). Another group (7 patients) were operated in epidural anaesthesia and had postoperative epidural infusion of fentanyl and bupivacaine as described above. Finally, a group (8 patients) were operated under general anaesthesia and had systemic analgesia. After 1 year the incidence of phantom pain was significantly lower among the patients receiving pre-, intraand postoperative epidural analgesia, relative to patients who received general anaesthesia and systemic analgesia. Katsuly-Liapis and colleagues (Katsuly-Liapis et al., 1996) reported in abstract form a study where 45 patients were randomised into three groups to receive: (1) epidural analgesia with bupivacaine 0.25% and morphine for 3 days before amputation and continued for 3 days after the operation (15 patients), (2) epidural analgesia postoperatively (12 patients), or
(3) systemic analgesia with opioids and NSAID (18 patients). After 6 months the incidence of phantom pain was significantly lower in the group of patients who had epidural analgesia before, during and after amputation compared to the other two groups. No details about randomisation, blinding or pain assessment were presented. These data have to our knowledge so far not been published in an extended paper. In a blind and placebo-controlled trial (Nikolajsen et al., 1997b), 60 patients were randomly assigned to receive epidural bupivacaine (0.25% 4-7 ml/h) and morphine (0.16-0.28 mg/h) for 18 h before the amputation (29 patients) or epidural saline and systemic opioids (31 patients). Both groups underwent general anaesthesia for the amputation and all received epidural bupivacaine and morphine for postoperative pain management. Phantom pain both in terms of frequency and intensity was assessed after 1 week, 3 months, 6 months, and 12 months. Pain intensity was measured by means of a visual analogue scale (VAS) O-100. Fifty-six patients were available for
500 follow-up after 1 week; this number was reduced to 28 after 1 year, mainly because of deaths among the amputees (generally old people with generalised vascular diseases). The blindness in this study was ensured by two independent investigators, who were responsible for either the randomisation and preoperative pain treatment or for the postoperative pain treatment and follow-up. Patient blindness was secured by asking the patients after 6 months which type of treatment they had and they were not able at this time to distinguish between control and blockade treatment. After 1 week 52% in the blockade group and 56% in the control group had phantom pain. There was no difference in pain frequency and pain intensity at any time points between the two groups. So according to this study it was not possible to document a pre-emptive effect during an 18-h intense pain treatment before the operation. In the same group of patients the intense pre-injury pain treatment also failed to have any effect on subsequent stump sensitivity to mechanical and thermal stimuli (Nikolajsen et al., 1998). Discrepancy between experimental pre-emptive analgesia studies
and clinical
It is important to emphasise that despite failure to demonstrate a pre-emptive analgesic effect in many clinical studies, functional plastic changes of the nociceptive system by injury is an indisputable phenomenon. While there is firm experimental evidence for this notion, the clinical evidence for pre-emptive analgesia is much less clear. It is therefore of interest to speculate on differences between experimental and clinical studies that might explain this observation. TABLE 2 Factors influencing effectiveness of pre-emptive analgesia Genetic factors Pre-injury events Intensity of noxious injury Duration of noxious stimulus before during and after Type of injury (degree of inflammation and nerve injury) Duration of analgesia Efficacy of neural block Type of pharmacological blockade
Table 2 presents a list of possibilities why preemptive treatments may not work or only show a marginal effect in clinical studies. Clinical pains are much more complex than those in the laboratory. They may involve a mixture of inflammatory and neuropathic pain components and it can be difficult to dissect the contribution of each part. Patients are heterogeneous in terms of injury and pain experience before, during and after such injury. Another point concerns the duration of the analgesia. In animal experiment where the post-injury discharges are short lasting, a short pre-emptive pain treatment may be sufficient to prevent such discharges. It is also possible that an extended period might have been able to reveal a pre-emptive effect. The duration of post-injury neuronal discharges are not known. If post-injury neuronal activity from the periphery persists beyond the duration of analgesia this may mask a possible pre-emptive effect. Finally, an insufficient afferent blockade may lead to central sensitisation and prevent seeing a possible effect of the pre-emptive treatment (Dahl, 1994). It is possible that an extension of the analgesia to the peri-operative period may document an effect in terms of reduced pain and prevention of long-term sequelae. Conclusions The importance of sensitisation for chronic pain syndromes and the possible role of pre-injury pain for late post-injury pain has raised the issue whether phantom pain can be prevented. Early studies have shown that such prevention is possible by a preemptive analgesic treatment. However, subsequent randomised and controlled trials have failed to find evidence for such a pre-emptive effect. In fact it is not surprising that a short-lasting pre-injury treatment should prevent various aspects central sensitisation induced by an intense and long-lasting noxious input before, during and after the amputation. A future challenge lies in determining whether a long-lasting and intense pre-, peri- and postoperative analgesic treatment can in fact reduce the subsequent development of nerve injury pain including phantom pain. Moreover, it will be important to identify those patients that are likely to benefit from such a procedure.
501
References Bach, S., Noreng, M.F. and Tjellden, N.U. (1988) Phantom limb pain in amputees during the first 12 months following limb amputation, after preoperative lumbar epidural blockade. Pain, 33: 297-301. Berthele, A., Schadrack, J., Castro-Lopes, J.M., Conrad, B., Zieglgansberger, W. and Tolle, T.R. (2000) Neuroplasticity in the spinal cord of monoarthritic rats: from metabolic changes to the detection of interleukin-6 using mRNA differential display. In: J. Sandktlhler, B. Bromm and GE Gebhart (Eds.), Nervous System Plasticity and Chronic Pain. Progress in Brain Research, Vol. 129. Elsevier, Amsterdam, pp. 191-203. Birbaumer, N., Lutzenberger, W. and Montoya, P (1997) Effects of regional anaesthesia on phantom limb pain are mirrored in changes in cortical reorganization. J. Neurosci., 17: 55035508. Brennan, T.J., Umali, E.F. and Zahn, P.K. (1997) Comparison of pre- versus post-incision administration of intrathecal bupivacaine and intrathecal morphine in rat model postoperative pain. Anesthesiology, 87: 1517-1528. Bromm, B., Scharein, E. and Vahle-Hinz, C. (2000) Cortex areas involved in the processing of normal and altered pain. In: J. Sandktihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain. Progress in Brain Research, Vol. 129. Elsevier, Amsterdam, pp. 289-302. Casey, K.L. (2000) Concepts of pain mechanisms: the contribution of functional imaging of the human brain. In: J. Sandktihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain. Progress in Brain Research, Vol. 129. Elsevier, Amsterdam, pp. 277-287. Chabal, C., Jacobson, L. and Russell, L.C. (1989) Pain responses to perineuromal injection of normal saline, gallamine and lidocaine in humans. Pain, 36: 321-325. Coderre, T.J. and Katz, J. (1997) Peripheral and central hyperexcitability: differential signs and symptoms in persistent pain. Behav. Brain Sci., 20: 404-419. Cummins, T.R., Dib-Hajj, SD., Black, J.A. and Waxman, S.G. (2000) Sodium channels and the molecular pathophysiology of pain. In: J. Sandktihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain. Progress in Brain Research, Vol. 129. Elsevier, Amsterdam, pp. 3-19. Dahl, J.B. (1994) Neuronal plasticity and pre-emptive analgesia: implications for the management of post-operative pain. Dan. Med. Bull., 41: 434-442. Dahl, J.B. and Kehlet, H. (1993) The value of pre-emptive analgesia in the treatment of post-operative pain. B,: J. Anaesth., 70: 434-439. Devor, M. and Seltzer, Z. (1999) Pathophysiology of damaged nerves in relation to chronic pain. In: P.D. Wall and R. Melzack (Eds.), Textbook of Pain. 4th ed. Churchill Livingstone, Edinburgh, pp. 129-164. Devor, M., Govrin-Lippman, R. and Angelides, K. (1993) Na+ channels immunolocalization in peripheral mammalian axons and changes following nerve injury and neuroma formation. J. Neurosci., 135: 1976-1992. Dickenson, A.H. and Sullivan, A.F. (1987) Subcutaneous for-
malin-induced activity of dorsal horn neurones in the rat: different responses to an intrathecal opiate administered preor post-formalin. Pain, 30: 339-348. Dworkin, R.H., Hartstein, G. and Rosner, H.L. (1992) A high risk method for studying psychosocial antecedents of chronic pain: the prospective investigation of herpes zoster. J. Abnorm. Psychol., 101: 200-205. Elizaga, A.M., Smith, D.G., Sharar, S.R., Edwards, T. and Hansen, S.T. (1994) Continuous regional analgesia by intraneural block: effect on postoperative opioid requirements and phantom limb pain following amputation. J. Rehab. Res. Dev., 31: 179-187. Fischer, A. and Meller, Y. (1991) Continuous postoperative regional analgesia by nerve sheath block for amputation surgery - a pilot study. Anesth. Analg., 72: 300-303. Flor, H. (2000) The functional organization of the brain in chronic pain. In: J. Sandkiihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain. Progress in Brain Research, Vol. 129. Elsevier, Amsterdam, pp. 313322. Flor, H., Elbert, T. and Knecht, S. (1995) Phantom limb pain as a perceptual correlate of massive cortical reorganization in upper limb amputees. Nature, 375: 482-484. Flor, H., Elbert, T. and Mtihlnickel, W. (1998) Cortical reorganization and phantom phenomena in congenital and traumatic upper-extremity amputees. Exp. Brain Res., 119: 205-212. Gerber, G., Youn, D.-H., Hsu, C.H., Isaev, D. and Randic, M. (2000) Spinal dorsal horn synaptic plasticity: involvement of group I metabotropic glutamate receptors. In: J. Sandktihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain. Progress in Brain Research, Vol. 129. Elsevier, Amsterdam, pp. 115-134. Hill, A., Niven, C.A. and Knussen, C. (1996) Pain memories in phantom limbs: a case study. Pain, 66: 381-384. Hoheisel, U. and Mense, S. (2000) The role of spinal nitric oxide in the control of spontaneous pain following nociceptive input. In: J. Sandkiihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain. Progress in Brain Research, Vol. 129. Elsevier, Amsterdam, pp. 163-172. Houghton, A.D., Nicholls, G., Houghton, A.L., Saadah, E. and McCall, I. (1994) Phantom pain: natural history and association with rehabilitation. Ann. R. Coil. Surg. Eng., 76: 2225. Jahangiri, M., Jayatunga, A.P., Bradley and Dark, C.H. (1994) Prevention of phantom pain after major lower limb amputation by epidural infusion of diamorphine, clonidine and bupivaCaine. Ann. R. Coil. Surg. Engl., 76: 324-326. Jensen, T.S. and Gottrup, H. (2000) Assessment of neuropathic pain. In: C. Warheld. A. Rice, D. Justins and C. Eccleston (Eds.), Textbook of Clinical Pain Management. Arnold, London (in press). Jensen, T.S. and Nikolajsen, L. (1999) Phantom pain and other phenomena after amputation. In: P.D. Wall and R. Melzack (Eds.), Textbook of Pain. 4th ed. Churchill Livingstone, Edinburgh, pp. 799-8 14. Jensen, T.S., Krebs, B., Nielsen, J. and Rasmussen, P. (1983) Phantom limb, phantom pain and stump pain in amputees
502
during the first 6 months following limb amputation. Pain, 17: 243-256. Jensen, T.S., Krebs, B., Nielsen, J. and Rasmussen, P. (1985) Immediate and long-term, phantom limb pain in amputees: incidence, clinical characteristics and relationship to pre-amputation pain. Pain, 21: 267-278. Kalso, E. (1997) Prevention of chronicity. In: T.S. Jensen, J.A. Turner and Z. Wiesenfeld-Hallin (Eds.), Proceedings of the 8th World Congress on Pain. Progress in Pain Research and Management, Vol. 8. IASP Press, Seattle, WA, pp. 215-230. Katsuly-Liapis, I., Georgakis, P. and Tierry, C. (1996) Pre-emptive extradural analgesia reduces the incidence of phantom pain in lower limb amputees. BI: J. Anaesth., 76: 125. Katz, J. and Melzack, R. (1990) Pain memories in phantom limbs: review and clinical observations. Puin, 43: 319-336. Larbig, W., Montaya, P. and Flor, H. (1996) Evidence for a change in neural processing in phantom limb pain patients. Pain, 67: 275-283. McQuay, H.J. (1992) Pre-emptive analgesia. Br J. Anaesth., 69: l-3. McQuay, H.J. (1994) Do preemptive treatments provide better pain control. In: G.F. Gebhart, D.L. Hammond and T.S. Jensen (Eds.), Proceedings of the 7th World Congress on Pain. Progress in Pain Research and Management, Vol. 2. IASP Press, Seattle, WA, pp. 709-723. Melzack, R. (1995) Phantom-limb pain and the brain. In: B. Brommm and I.E. Desmedt (Eds.), Advances in Pain Research and Therapy, Vol. 22. Raven Press, New York, pp. 73-82. Moore, K.A., Baba, H. and Woolf, C.J. (2000) Synaptic transmission and plasticity in the superficial dorsal horn. In: J. Sandkiihler, B. Bromm and G.F. Gebhart (Eds.), Nervous Systern Plasticity and Chronic Pain. Progress in Brain Research, Vol. 129. Elsevier, Amsterdam, pp. 63-80. Nathan, P.W. (1962) Pain traces left in the central nervous system. In: C.A. Keele and R. Smith (Eds.), The Assessment of Pain in Man and Animals. E&S Livingstone, Edinburgh, pp. 129-134. Nikolajsen, L. and Jensen, T.S. (2000) Phantom limb pain. Curr: Rev. Pain, 4: 166-170. Nikolajsen, L., Hansen, C.L., Nielsen, J., Keller, J., ArendtNielsen, L. and Jensen, T.S. (1996) The effect of ketamine on phantom pain: a central neuropathic disorder maintained by peripheral input. Pain, 67: 69-77. Nikolajsen, L., Ilkjaer, S., Kroner, K., Christensen, J.H. and Jensen, T.S. (1997a) The influence of preamputation pain on postamputation stump and phantom pain. Pain, 72: 393-405. Nikolajsen, L., Ilkjaer, S., Kroner, K., Christensen, J.H. and Jensen, T.S. (1997b) Randomised trial of epidural bupivacaine and morphine in prevention of stump and phantom pain in lower-limb amputation. L.ancet b, 350: 348-354. Nikolajsen, L., Ilkjmr, S. and Jensen, T.S. (1998) Effect of preoperative extradural bupivacaine and morphine on stump sensation in lower limb amputees. BI: J. Anaesth., 81: 348354. Nikolajsen, L., Got&up, H., Kristensen, A.G.D. and Jensen, T.S. (2000a) Memantine (a N-methyl-D-aspartate receptor antagonist) in the treatment of neuropathic pain following amputa-
tion or surgery: a randomised, double-blind, cross-over study. Anesth. Analg., in press. Nikolajsen, L., Ilkjaer, S. and Jensen, T.S. (2OOOb) Relationship between mechanical sensitivity and postamputation pain: A prospective study. Eur: J. Pain, in press. Novakovic, S.D., Tzoumaka, E., McGivem, J.G., Haraguchi, M., Sangameswaran, L., Gogas, K.R., Eglen, R.M. and Hunter, J.C. (1998) Distribution of the tetrodotoxin-resistant sodium channel PN3 in rat sensory neurons in normal and neuropathic pain conditions. J. Neurosci., 18: 2174-2187. Nystriim, B. and Hagbarth, K.E. (1981) Microelectrode recordings from transected nerves in amputees with phantom limb pain. Neurosci. L&t., 27: 21 l-216. Pinzur, M.S., Garla, P.G.N., Pluth, T. and Vrbos, I. (1996) Continuous postoperative infusion of a regional anaesthetic after an amputation of the lower extremity. J. Bone Joint Surg., 78: 1501-1505. Puke, M.J.C. and Wiesenfeld-Hallin, Z. (1993) The differential effects of morphine and the ct2-adrenoceptor agonists clonidine and dexmedotomidine on the prevention and treatment of experimental neuropathic pain. Anesth. A&g., 77: 104-109. Rajbhandari, S.M., Jarett, J.A., Griffiths, P.D. and Ward, J.D. (1999) Diabetic neuropathic pain in a leg amputated 44 years previously. Pain, 83: 627-629. Sandkiihler, J., Benrath, J., Brechtel, C., Ruscheweyh, R. and Heinke, B. (2000) Synaptic mechanisms of hyperalgesia. In: J. Sandktihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain. Progress in Brain Research, Vol. 129. Elsevier, Amsterdam, pp. 81-100. Sherman, R.A. and Sherman, C.J. (1983) Prevalence and characteristics of chronic phantom limb pain among American veterans. Am. J. Phys. Med., 62: 227-238. Schug, S.A., Burell, R., Payne, J. and Tester, P. (1995) Pre-emptive epidural anaesthesia may prevent phantom limb pain. Reg. Anesth., 20: 256. Svendsen, F., Hole, K. and Tjolsen, A. (2000) Long-term potentiation in single WDR neurons induced by noxious stimulation in intact and spinalized rats. In: J. Sandkiihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain. Progress in Brain Research, Vol. 129. Elsevier, Amsterdam, pp. 153-161. Wall, P.D. (1988) The prevention of postoperative pain. Pain, 33: 289-290. Wartan, S.W., Hamann, W., Wedley, J.R. and McCall, I. (1997) Phantom pain and sensation among British veteran amputees. BI: J. Anaesth., 78: 652-659. Waxman, S.G. (1999) The molecular pathophysiology of pain: abnormal expression of sodium channel genes and its contrbutions to hyperexcitability of primary sensory neurons. Pain Sappl., 6: 133-140. Wilder-Smith, O.H.G. (2000) Pre-emptive analgesia and surgical pain. In: J. Sandktihler, B. Bromm and G.F. Gebhart (Eds.), Nervous System Plasticity and Chronic Pain. Progress in Brain Research, Vol. 129. Elsevier, Amsterdam, pp. 505-524. Wilkins, K.L., McGrath, P.J., Finley, G.A. and Katz, J. (1998) Phantom limb sensations and phantom limb pain in child and adolescent amputees. P&n, 78: 7-12.
503 Woolf, C.J. (1992) Excitability changes in central neurons following peripheral damage. Role of central sensitization in the pathogenesis of pain. In: W. Willis (Ed.), Hyperulgesia and Allodynia. Raven Press, New York, pp. 221-243. Woolf, C.J. and Chong, M. (1993) Pre-emptive analgesia: treating postoperative pain by preventing the establishment of central sensitization. Anesth. Analg., 71: 362-379. Woolf, C.J. and Salter, M.W. (2000) Neuronal plasticity: Increasing the gain in pain. Science, 288: 1765-1768. Woolf, C.J. and Thompson, S.W.N. (1991) The induction
and maintenance of central sensitisation is dependent on &‘-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain, 44: 293-299.
Woolf, C.J., Shortland, P. and Coggeshall, R.E. (1992) Peripheral nerve injury triggers central sprouting of myelinated afferents. Nature,
355: 75-78.
Yaksh, T.L. (1993) The spinal pharmacology of facilitation of afferent processing evoked by high threshold afferent input of the postinjury pain state. Cur< Opin. Neural. Neurosurg., 6: 250-256.