Annals of Vascular Surgery
Volume 24, Issue 8 , Pages 1139-1146, November 2010

Pre-emptive Analgesia for Chronic Limb Pain After Amputation for Peripheral Vascular Disease: A Systematic Review

  • Efthymios Ypsilantis

      Affiliations

    • Department of Surgery, Conquest Hospital, The Ridge, St Leonards-on-Sea, East Sussex, United Kingdom
    • Corresponding Author InformationCorrespondence to: Efthymios Ypsilantis, MPhil, MRCS, Conquest Hospital, The Ridge, St Leonards-on-Sea, East Sussex, TN377RD, UK
    • ,
  • Tjun Y. Tang

      Affiliations

    • Cambridge Vascular Unit, Addenbrooke's Hospital, Cambridge University Hills Road, Cambridge, United Kingdom

published online 31 August 2010.

Article Outline

Background

Chronic stump and phantom limb pain after amputation for critical ischemia significantly affect patients' quality of life and pose challenging clinical problems. Pre-emptive analgesia attempts to prevent chronic postoperative pain by minimizing painful stimuli before and during surgery.

Methods

This systematic literature review aimed to evaluate the evidence supporting the use of pre-emptive analgesia in minimizing the risk of chronic stump and phantom pain after lower limb amputation for critical ischemia of peripheral vascular disease.

Results

A total of 11 studies have been retrieved. Five different types of analgesic drugs were evaluated (local anesthetics, opiates, N-methyl-d-aspartate receptor antagonists, a2-agonist, and gamma-aminobutyric acid analogues), administered separately or in combinations, through the oral, intravenous, epidural, or regional (perineural) route. The beneficial effect of combined bupivacaine, diamorphine, and clonidine in reducing the risk of phantom limb pain was supported by only one study (level 3 evidence). Epidural and perineural infusions containing local anesthetic ± opiates are effective in treating acute perioperative pain, although not without potentially serious complications. Most studies were characterized by high drop-out rates because of disease-associated mortality.

Conclusions

There is no robust evidence supporting the use of pre-emptive analgesia to minimize the risk of chronic pain after amputation for critical ischemia of peripheral vascular disease. The methods used are, however, effective in treating acute postoperative pain.

 

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Introduction 

Chronic post-amputation pain affects a maximum of 80% of patients during the first year, in the form of stump pain or phantom limb pain (PLP, neuropathic pain perceived in the area of the amputated limb).1 It incurs significant impairment of patients' quality of life, work, sleep, and social and daily activities, which highlights the need for effective preventive and therapeutic strategies.2 Inadequate treatment of acute postoperative pain, excessive intra-operative painful stimuli, and high levels of established preoperative pain have been proposed as potential risk factors.3 Pre-emptive analgesia refers to the attempt to prevent chronic pain by early intervention before it occurs, that is, before and during surgery.4

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Aims 

The present review aims to evaluate the evidence underpinning the potential effect of pre-emptive analgesia in prevention of chronic pain after amputation for lower limb critical ischemia. Critique of the available evidence is attempted along with recommendations for clinical practice.

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Search Strategy 

The MEDLINE, CINHAL, OVID, and EMBASE databases and the Cochrane Collaboration Library were searched using keywords “pre-emptive,” “preventive,” “prevention,” “prophylaxis,” “chronic,” “stump,” “phantom,” “pain,” “amputation,” “lower limb,” and “critical ischemia” in various combinations to retrieve all relevant articles published in English language till year 2009. Cross-referencing from the bibliography of retrieved articles was also used to increase the yield of relevant publications. A total of 11 articles were identified evaluating the pre-emptive use of analgesics for prevention of postamputation pain of peripheral vascular disease etiology: seven randomized controlled trials, two case-control studies, and two prospective observational cohort studies with historical controls (Table I). Another two case reports were retrieved but were excluded from the present analysis as sources of low-level evidence.5, 6

Table I. Overview of studies on the pre-emptive use of anesthetics for chronic post amputation phantom limb pain (PLP)
StudyYearTypeStudy group anestheticModeControl group anesthetic analgesic agentPatient numberPLP rate 6 months (%)Stat difPLP rate 1 year (%)Stat dif
Study groupControl groupStudy groupControl grouppStudy GroupControl Groupp% LTFU
Bach1988PCCBCN or M or BCN+MEDVarious analgesics1114038<0.05027<0.2024.0
Jahangiri1994PCCBCN + DM + CEDOpioids on demand1311873<0.002873<0.0020.0
Nikolajsen1997RCTBCN+MEDOpioids on demand29308155ns7569ns52.5
Wilson2008RCTKetamine + BCNEDBCN24294019ns5040ns33.3
Pinzur1996RCTBCNPNOpioids on demand1110uuns 6.5
Fisher1991POCHSBCNPNOpioids on demand11200 0 28.8
Reuben2006RCTBCN + CPN (single)Various analgesics4040 8682ns46.7
Lambert2001RCTBCN+DM vs. BCNED vs. PNOpioids on demand14166388ns3850ns10.7
Dertwinkel2002POCHSKetamineIVVarious analgesics1414 9a71a<0.01a31.1
Hayes2004RCTKetamineIVOpioids on demand22234771ns 0.0
Nikolajsen2006RCTGabapentin + BCN (ED)POBCN (ED)23235850ns 28.3

Studies: PCC, prospective case-controlled study; RCT, randomized controlled trial; POCHS, prospective observational cohort study with historical control; Anesthetic agents: BCN, Bupivacaine; M, Morphine; DM, Diamorphine; C, Clonidine; Mode of delivery of anesthetic: ED, epidural, PN, perineural block; IV, intravenous; PO, Orally; PLP, phantom limb pain; Stat dif, statistical difference; ns, non significant; u, unknown (data not given in the paper); % LTFU, percentage of initial patient population lost to end follow-up.

aIn the study of Dertwinkel et al. (2002) statistically significant difference was found for severe only PLP, not for overall prevalence of PLP between the groups.

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Mechanisms of Analgesic Action 

Analgesic drugs from five different categories, used separately or in combinations, have been evaluated in the retrieved studies; local anesthetics (Bupivacaine, Ropivacaine), opiates (Morphine, Diamorphine), the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine, the a2-agonist clonidine, and the gamma-aminobutyric acid analogue gabapentin. These drugs target mechanisms that have been proposed to contribute to chronic postamputation pain and include a constellation of central and peripheral neurologic factors.4 Pre-amputation pain, causing increased peripheral nociceptor activity, has been proposed to lead to permanent changes in the synaptic structure of the dorsal horn in the spinal cord (central sensitization); these are mediated by the NMDA receptor and its transmitter glutamate,7 thus providing a potential target for NMDA receptor antagonists.8 General disinhibition of the spinal cord9 with a reduction in gamma-aminobutyric acid activity and a downregulation of opioid receptors also seem to play a role,10 justifying the use of gabapentin and opiates (Morphine, Diamorphine). Supra-spinal changes, involving the brainstem and thalamus,11 and reorganization of the somatosensory cortex have also been demonstrated in association with phantom-limb pain.12 These cortical reorganization changes are influenced by opiates13 and can be reversed by eliminating afferent nociceptive stimuli from the amputation stump by means of regional anesthesia.14 Peripheral factors such as perioperative nociceptive input from the residual limb have been viewed as important determinants of phantom-limb pain and have led to trials of regional (perineural) blockade with local anesthetic agents (Bupivacaine, Ropivacaine) and opiates, along with general and spinal anesthesia.

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Results 

The retrieved studies and their results are presented in the following paragraphs, classified according to mode of delivery of the analgesic agent.

Lumbar Epidural Block 

Bach et al.15 evaluated the potential effect of eliminating preoperative limb pain by lumbar epidural analgesia on postamputation PLP. In a prospective case-control study, 11 pre-amputation patients with critical ischemia pain received epidural infusion of morphine or bupivicaine 0.25% or both for 3 days preoperatively. These were compared to a group of 14 similar patients managed with a variety of oral or parenteral analgesics preoperatively. Patients were assessed for phantom limb sensation, phantom pain, and chronic stump pain at 1 week, 6 months, and 1 year postoperatively. The prevalence of PLP was significantly lower in the epidural group at all time-points postoperatively; 27% vs. 64%, respectively, at 1 week (p < 0.10), 0% vs. 38% at 6 months (p < 0.05), and 0% vs. 27% at 1 year (p < 0.2). The prevalence of phantom limb sensation and chronic stump pain was too low to allow comparison between the two groups. This was the first study to demonstrate a potentially beneficial effect of epidural analgesia on phantom and chronic postamputation pain. The strength of recommendations would, however, be limited by the small size, poorly matched groups, lack of randomization, and nonconsistent use of analgesic agents.

Jahangiri et al.16 investigated the putative combined effect of bupivacaine, diamorphine, and clonidine on PLP in a prospective case-control study of 24 patients undergoing lower limb amputation for critical limb ischemia. In the study group (n = 13), an epidural infusion of bupivacaine 1.25 mg/mL, clonidine 2.5 μg/mL, and diamorphine 0.08 mg/mL was administered at 1–4 mL/hr from 24 to 48 hours preoperatively and maintained for at least 3 days postoperatively. The control group (n = 11) received on-demand opiate analgesia. At 7 days follow-up, the PLP rate was significantly lower in the study group (3 vs. 9 patients, p < 0.01). Similarly, at 6 months and 1 year, PLP was recorded in one patient in the study group and eight in the control (p < 0.002). There was no significant difference between groups regarding stump pain.

Nikolajsen et al.1 conducted a randomized controlled double-blind trial comparing preoperative epidural block (starting 18 hours before procedure) using a combination of bupivacaine (0.25%, 4-7 mL/hr) and morphine (0.16-0.28 mg/hr) administered to 29 patients, with epidural infusion of normal saline and morphine on-demand used as analgesia for a well-matched control group of 30 patients. Parameters assessed during the study included the intensity of preamputation pain, rate, and intensity of stump and PLP (expressed by a visual analogue scale [VAS]) at 1 week, 3, 6, and 12 months postoperatively and opiate analgesia requirements (expressed in morphine dose equivalents). The patients in the epidural group became completely pain-free after the initiation of epidural analgesia before the procedure (p < 0.0001), confirming the effectiveness of the blockade in eliminating the preoperative pain. The rate of phantom pain was found to be similar in the epidural and the control group after 1 week (52% vs. 56% respectively, p = 0.9), at 3 months (82% vs. 50%, p = 0.09), at 6 months (81% vs. 55%, p = 0.2), and at 12 months (75% vs. 69%, p = 1.0). Similarly, there was no significant difference in the intensity of stump and phantom pain at any of the postoperative interviews or in the opioid requirements between the two groups. Evaluation of complications revealed six cases of suspected epidural catheter sepsis in the epidural group, of which one resulted in meningitis and a second to a subcutaneous abscess. Although the on-demand administration of oral or intramuscular morphine to patients of the control group inevitably undermined the blinding process, the authors report that at 6 months, 29 of 33 (88%) patients were unable to tell whether they had received epidural blockade or saline preoperatively. A significant percentage of patients (52% of the initial study population) were lost to follow-up after 1 year (2 patients withdrew postrandomization, 20 died, four were not contactable) and five patients had undergone reamputation, events that occurred postrandomization and eroded the power of the study. In conclusion, this trial demonstrated that preoperative administration of epidural analgesia reduced the preoperative ischemic pain, but had no effect on the prevention of stump or phantom pain postamputation and was not without complications.

Recently, Wilson et al.17 investigated the potential prophylactic role of epidural ketamine on PLP. Fifty-three patients scheduled to undergo lower limb amputation under combined epidural or spinal anesthesia, were randomized to two groups of epidural infusion administered from induction to 48-72 hours postoperatively: the ketamine group (KG, n = 24; bupivacaine 0.125% with ketamine 3.3 mg/kg/L, rate 10-20 mL/hr) and the control group (epidural infusion of bupivacaine 0.125% with an equivalent volume of NaCl 0.9% at similar rate). Primary outcomes were the incidence and severity of PLP and stump pain. There was no difference between the two groups up to 1 year of follow-up; the rate of PLP was no more than 50% and of stump pain was no more than 33% in either group. Again, the study suffered from significant drop-out rate (33% for the KG and 42% for the control group at 1 year).

Perineural Block 

Fisher and Meller18 were the first to study the potential benefit of perineural anesthesia on chronic postamputation pain in a prospective observational cohort study with a historical control. Eleven consecutive patients received continuous postoperative regional analgesia by nerve sheath block (initial bolus of 20 mL of 0.25% bupivacaine followed by 10 mL/hr infusion for 72 hours postoperatively). Outcomes measured included acute postoperative pain expressed as opioid requirements (intramuscular doses of meperidine on demand), PLP, and any other complications assessed by telephone interviews monthly for a maximum of 6 months and quarterly up to a year. The study group was compared with respect to acute pain to a historical control group of 20 patients who had received only parenteral opiates on demand. No data were available for the control group regarding PLP. Two patients of the study group were lost (died) to 1-year follow-up but none of the remaining 9 patients (0%) complained of PLP.

Pinzur et al.19 randomized 21 patients to receive either continuous perineural infusion of bupivicaine 0.5% (bolus 10 mL and thereafter 1 mL/hr for 72 hours postoperatively, study group n = 11), or perineural infusion of normal saline (control group n = 10). It is not clear whether the two groups were matched regarding patient demographics or mode of anesthesia (general vs. spinal). Morphine requirements using patient controlled analgesia were used to quantify the level of acute postoperative pain. PLP was assessed at 3- and 6-months follow-up (McGill Pain Questionnaire). Patients who received perineural block used significantly less morphine during the first two postoperative days compared with control (p < 0.001). Surprisingly, no difference was detected during the third postoperative day, which could possibly be explained by technical failure (i.e., catheter patency or displacement problems) rather than physiologically. A significant proportion of patients (33%, n = 7, 2 patients died, 5 refused to complete the questionnaire) were lost to follow-up. However, there was no significant difference between the bupivacaine group and the control, regarding residual or phantom-limb pain at 3 and 6 months postamputation (p = 0.34).

The addition of clonidine in perineural block preparations was studied by Reuben et al.20 in a randomized control trial. A total of 80 consecutive patients scheduled to undergo elective lower extremity amputation for ischemic necrosis secondary to peripheral vascular disease were randomized to receive a single perineural injection of either 10 mL bupivacaine 0.25% and clonidine 100 μg (n = 40) or 10 mL of normal saline (n = 40) 5 minutes before nerve transection. Primary outcomes were pain scores and opioid use at 72 hour postoperatively and incidence of PLP and stump pain at 1 year. Patients receiving perineural bupivacaine and clonidine reported lower pain scores and consumed less opiates during the first postoperative day, but there were no differences in pain scores or opiate use on days 2 or 3. There were no differences between the study and control groups in the prevalence of PLP (86% vs. 82%, respectively) or stump pain (34% vs. 29%, respectively). A total of 23 patients were lost to 1-year follow up, 11 patients in the study group (nine died, two not contactable) and 12 patients in the control (10 died, two not contactable).

Epidural Versus Nerve Block 

Lambert et al.21 randomized 30 patients scheduled for lower limb amputation to two groups, the epidural (ED) and the perineural (PN) group. The ED group (n = 14 patients) received epidural bupivacaine 0.166% (rate, 2-8 mL/hr) and diamorphine (rate, 0.2-0.8 mg/hr) from 24 hours before up to 3 days postoperatively. The PN group (n = 16) received bupivacaine solution 0.25% into the perineurium of the nerve stump (rate 10 mL/hr) for the same period. Morphine on demand was additionally offered preoperatively and postamputation if pain recurred (for a VAS Score >4). Rate and intensity of stump and phantom pain as well as morphine consumption were recorded before amputation, during the initial 3 postoperative days, and at 6 and 12 months postoperatively. The results confirmed the therapeutic effect of epidural bupivacaine and diamorphine on limb pain preoperatively, as all patients had complete resolution of pain (p < 0.001). The epidural infusion was also found to be more effective than perineural block in relieving stump pain during the first 3 postoperative days (median VAS score 4 for the PN group, 1 for the ED group, p = 0.005). However, there was no significant difference between the ED and the PN group regarding prevalence of phantom pain (63% and 88%, respectively; p = 0.61) or stump pain (50% and 38%, respectively; p = 0.16) at 6-month follow-up. Similar results were recorded at 12 months. Similar to the studies mentioned earlier, 16 patients (53.3%) were lost to follow-up (12 patients died in 6 months, three had a re-amputation, and one was not contactable).

Intravenous Infusion 

In a prospective observational study by Dertwinkel et al.,22 a cohort of 14 consecutive patients scheduled for lower limb amputation received intravenous ketamine infusion commencing immediately after induction of anesthesia and for a total of 48 hours (0.5 mg/kg body weight bolus followed by 0.002 mg/kg body weight during the first 24 hours and 0.001 mg/kg body weight for the next 24 hours). The study group patients received analgesia and anesthesia intra-operatively using variable methods (general, epidural, regional analgesia in different combinations) and postoperatively analgesia was initiated at variable time-points. This group was compared with a historical control group, matched for amputation type and patient demographics, but not for mode or timing of delivery of analgesia and anesthesia. Patients were assessed for PLP daily until discharge and thereafter for prevalence (% patients) and intensity (Numeric Rating Scale [NRS], 0-10) of PLP and stump pain through telephone interviews (median follow-up, 560 days; range, 200-722 days). There was no significant difference between the two groups regarding immediate postoperative or chronic PLP and prevalence or intensity of stump pain. Patients on ketamine had significantly lower incidence of severe PLP compared with control (1 vs. 10 patients, respectively; p = 0.01) and significantly lower mean PLP intensity (p = 0.04). This study had a small sample size and suffered from high heterogeneity in the mode and timing of delivery of intra-operative and postoperative analgesic agents.

The potential pre-emptive effect of ketamine on persistent PLP and stump pain was also evaluated in a randomized, double-blind, placebo-controlled trial by Hayes et al.23 A total of 45 patients presenting for lower limb amputation were randomized to either intravenous (IV) infusion of ketamine Ketamine Group, KG, pre-induction IV bolus of ketamine 0.5 mg/kg body weight, followed immediately by IV infusion at 0.15 mg/kg body weight/hr) or normal saline (Placebo group, PG) from induction to anesthesia until 3 days postoperatively. Opioid consumption in the form of patient-controlled analgesia using morphine (1 mg bolus, 5 minute lockout period) was recorded on postoperative days 1 and 3 to quantify acute postamputation pain. Patients were assessed on postoperative days 3 and 6 (structured questionnaire) and at 6 months (telephone interview) for PLP and stump pain (intensity of pain graded by NRS 0-10). A total of 14 patients (31%) were lost to follow-up (mortality) at 6 months postoperatively. No difference was noted between the two groups regarding consumption of opioids on postoperative days 1 (p = 0.61) and 3 (p = 0.34) or in the consumption of complementary treatment for PLP. There was no difference between KG and control group in the incidence of PLP on days 3 (65% and 45%, respectively; p = 0.34) and 6 (55% and 50%, respectively; p = 1.0) or at 6 months (47% and 71%, respectively; p = 0.28). No difference was detected in the intensity of pain and the incidence of stump pain between groups throughout the study.

Oral Preparations 

Nikolajsen et al.24 have recently investigated the putative prophylactic effect of gabapentin which has been shown to reduce the incidence and intensity of established PLP.25 Patients were randomly assigned to receive oral gabapentin (n = 23, starting dose 300 mg/d escalating to at least 900 mg/d and up to 2,400 mg/d if renal function was normal and no side-effects were observed) or placebo (n = 23) from the first postoperative day for 30 days after the amputation. All patients underwent lower limb amputation for critical ischemia secondary to peripheral vascular disease, under epidural anesthesia (5-15 mL bolus doses of 0.5% bupivacaine, followed by bupivacaine 0.25%, at 3-8 mL/hr for 2-3 days after the amputation) or combined with spinal or general anesthesia. Paracetamol and opioids were used to supplement the epidural pain treatment and for treating the pain after removal of the epidural catheter. PLP and stump pain prevalence (%) and intensity (NRS) was assessed for at 7, 14, and 30 days and at 3 and 6 months postamputation. Five patients did not complete the first week of treatment, therefore results from 41 patients were included in the data analysis. A total of seven patients were withdrawn from the study before the end of the 30-day treatment period and 1 patient died after 3 months (total lost to follow-up, n = 8). There was no difference in prevalence of PLP between the two groups (gabapentin vs. placebo) at 1 month (55.0% vs. 52.6%, respectively; p = 0.88) or at 6 months (58.8% vs. 50.0%, respectively; p = 0.59). Similarly, there was no difference regarding intensity of stump or PLP at 1 and 6 months postoperatively.

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Discussion 

Patients with chronic stump pain and PLP after amputation for ischemic necrosis of peripheral vascular disease pose therapeutic challenges that dictate the need for further research on potential prophylactic regimes. The results of our systematic review reveal the paucity of well-designed randomized controlled trials that would be based on large patient numbers and would provide high levels of evidence. Most studies suffer from small sample sizes and postrandomization protocol violations. Most important, because of high mortality associated with amputation for critical limb ischemia and peripheral vascular disease,26 a plethora of patients are lost to follow-up in the majority of studies (up to 52%, Table I), further undermining the power of results that are not expressed on an intention-to-treat basis. However, only a very small percentage of patients are lost during the immediate postoperative period, suggesting that the study conclusions on the effect of trialed agents on acute stump pain bear higher level of evidence. Finally, the multiplicity of pain-control methods used during the perioperative period can hinder evaluation of the net effect of the trialed analgesic. As an example, opiates in their own right have been reported to show efficacy in the treatment of PLP, potentially by influencing cortical reorganization13; yet they have almost invariably been used as alternative analgesia for the control groups in the described studies, thus acting as possible confounding variables.

Despite the aforementioned weaknesses of the currently available trials, extraction of clinically useful conclusions can still be attempted, leading to recommendations for clinical practice (Table II). The perioperative use of epidural anesthesia based on local anesthetic alone, opiates alone, or their combination has been shown to be effective in relieving acute postoperative stump pain,1, 15, 16 unlike epidurally administered ketamine.17 Similarly, continuous postoperative perineural block with local anesthetic alone, combined with opiates or clonidine, relieves acute pain during the first day postamputation18, 19, 20 depending on the duration of infusion. Between the two modes of anesthesia delivery, the epidural combination of bupivacaine/diamorphine has been found to be more effective in treating acute postoperative stump pain than perineural block with bupivacaine alone.21 IV infusion of ketamine perioperatively has no effect in treating acute stump pain.22, 23

Table II. Summary of recommendations of studies on pre-emptive analgesia for chronic post amputation phantom limb pain (PLP)
ConclusionsLevel of evidencea
Epidural anesthesia
Combination of bupivacaine and morphine does not prevent chronic PLP but reduces acute postoperative stump pain2b
Combination of bupivacaine and ketamine is not superior to bupivacaine alone regarding acute stump pain or chronic PLP pain2b
Combination of bupivacaine, diamorphine, and clonidine may be effective as pre-emptive analgesia both for acute stump pain and chronic PLP3b
Peri-neural anesthesia
Peri-neural bupivacaine does not prevent chronic PLP1b
Single perineural infiltration with combination of bupivacaine and clonidine has no prophylactic effect2b
There is no difference in PLP between peri-operative epidural combination of bupivacaine and diamorphine and perineural bupivacaine alone1b
Intravenous anesthetics
Intravenous infusion of ketamine peri-operatively does not prevent PLP or acute post-op stump pain1b
Oral agents
Oral Gabapentin has no prophylactic effect on chronic PLP1b
RecommendationsGrade of recommendationsa
Acute post-operative stump pain
Epidural combination of Bupivacaine/Morphine is effective in treating acute peri-operative pain, where indicated, but is not without potentially serious complicationsA
Continuous post-operative perineural infusion of bupivacaine effectively reduces acute stump pain during first 48 hoursA
Epidural combination of Bupivacaine/Diamorphine is more effective than perineural infusion of bupivacaine alone in treating acute peri-operative pain (72 hours)A
Single intra-operative perineural infiltration with bupivacaine and clonidine provides analgesia during the first 24 hours post-operativelyA
Chronic post-amputation pain (stump pain and phantom linb pain)
In patients with critical limb ischemia secondary to peripheral vascular disease, peri-operative epidural infusion of combination of bupivacaine/diamorphine/clonidine may be effective as pre-emptive analgesiaB

aOxford Centre for Evidence-based Medicine Levels of Evidence (May 2001).

Regarding chronic postamputation pain (stump pain and PLP), the majority of anesthetic and analgesic agents trialed so far have failed to demonstrate pre-emptive analgesic properties. In patients scheduled to undergo amputation for critical ischemic necrosis secondary to peripheral vascular disease, only the perioperative epidural infusion of bupivacaine, diamorphine and clonidine has shown a potential prophylactic effect.16 A summary of study conclusions and recommendations, along with classification according to level of evidence is presented in Table II.

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Conclusions 

Overall, it becomes evident that more well-designed randomized controlled trials including large patient populations are necessary to further evaluate the potential for pre-emptive analgesia for chronic postamputation pain. In the meantime, the use of those anesthetic regimes is justified that have proven effective in relieving acute postoperative stump pain.

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 This review was submitted as a modular assignment for the first author's MSc Degree in Perioperative Care and Advanced Surgical Practice (Department of Anaesthetics, Cardiff University).

PII: S0890-5096(10)00192-5

doi:10.1016/j.avsg.2010.03.026

Annals of Vascular Surgery
Volume 24, Issue 8 , Pages 1139-1146, November 2010

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