|Year : 2018 | Volume
| Issue : 4 | Page : 439-449
Strategies for prevention of lower limb post-amputation pain: A clinical narrative review
Vanita Ahuja1, Deepak Thapa1, Babita Ghai2
1 Department of Anaesthesia and Intensive Care, Government Medical College and Hospital, Chandigarh, India
2 Department of Anaesthesia and Intensive Care, Postgraduate Institute of Medical Education and Research, Chandigarh, India
|Date of Web Publication||3-Jan-2019|
Department of Anaesthesia and Intensive Care, Postgraduate Institute of Medical Education and Research, Chandigarh
Source of Support: None, Conflict of Interest: None
Postamputation limb pain or phantom limb pain (PLP) develops due to the complex interplay of peripheral and central sensitization. The pain mechanisms are different during the initial phase following amputation as compared with the chronic PLP. The literature describes extensively about the management of established PLP, which may not be applicable as a preventive strategy for PLP. The novelty of the current narrative review is that it focuses on the preventive strategies of PLP. The institution of preoperative epidural catheter prior to amputation and its continuation in the immediate postoperative period reduced perioperative opioid consumption (Level II). Optimized preoperative epidural or intravenous patient–controlled analgesia starting 48 hours and continuing for 48 hours postoperatively decreased PLP at 6 months (Level II). Preventive role of epidural LA with ketamine (Level II) reduced persistent pain at 1 year and LA with calcitonin decreased PLP at 12 months (Level II). Peripheral nerve catheters have opioid sparing effect in the immediate postoperative period in postamputation patients (Level I), but evidence is low for the prevention of PLP (Level III). Gabapentin did not reduce the incidence or intensity of postamputation pain (Level II). The review in related context mentions evidence regarding therapeutic role of gabapentanoids, peripheral nerve catheters, and psychological therapy in established PLP. In future, randomized controlled trials with long-term follow-up of patients receiving epidural analgesia, perioperative peripheral nerve catheters, oral gabapentanoids, IV ketamine, or mechanism-based modality for prevention of PLP as primary outcome are required.
Keywords: Analgesia, calcitonin, catheters, epidural, ketamine, phantom limb, prevention
|How to cite this article:|
Ahuja V, Thapa D, Ghai B. Strategies for prevention of lower limb post-amputation pain: A clinical narrative review. J Anaesthesiol Clin Pharmacol 2018;34:439-49
|How to cite this URL:|
Ahuja V, Thapa D, Ghai B. Strategies for prevention of lower limb post-amputation pain: A clinical narrative review. J Anaesthesiol Clin Pharmacol [serial online] 2018 [cited 2019 Mar 20];34:439-49. Available from: http://www.joacp.org/text.asp?2018/34/4/439/249289
| Introduction|| |
At present, approximately 1.6 million people in the United States require limb amputation, which might increase two folds by the year 2050. In 1983, the prevalence of amputees in India were about half a million and it was estimated that 23,500 were added every year. Amputees in India are predominantly male, from rural background, poor, and in working age group. A significant number of these patients have amputation as a result of injuries sustained in railway, road accidents, and due to agricultural equipment. In an epidemiological study done in 155 amputees in Kolkata, India, the most common cause of amputation was trauma (70.3%), followed by peripheral vascular disease. Lower limb amputation accounts for 94.8% of all amputations. The most common age group was 20s and 30s which is a productive population of the country.
Ambroise Paré, a French military surgeon, first described the postamputation phenomenon, which occurs after complete or partial amputation of a limb, during 16th century., The reported incidence of phantom limb pain (PLP) was 84% at 8 days after amputation and 67% after 6 months. The factors predisposing for PLP includes pain occurring before surgery,, upper limb amputations, and bilateral limbs amputation; and it occurs mostly in females. Anxiety and depression affect the development of PLP.,
The preventive strategies for the PLP pain is difficult to manage and if not addressed adequately may lead to chronic pain. The perioperative role of the anesthesiologist and the acute pain physician is important in the management of somatic and sometimes neuropathic postoperative pain. If the symptoms of hyperalgesia or neuropathic symptoms start developing, then it should be adequately diagnosed and managed. The association between preoperative symptoms and postoperative pain implies that symptoms and not the surgical insult should dictate early intervention when appropriate. Patients who require strong opioids in the preoperative period and are anxious should receive aggressive multimodal and patient-tailored pain management. Perioperative pain should be managed at all levels to prevent the transition of acute to chronic pain and also allow patients to return early to work which would reduce the global economic and social burden.
A search of the existing published literature was carried out from 1990 to 2017 for review articles, randomized controlled trials, observational studies, and case series for preventive strategies in postamputation chronic pain using “phantom limb; analgesia; epidural; catheters; ketamine; calcitonin; gabapentin” in Pub Med, EMBASE, and Google Scholar, and relevant articles were included. A systematic review was not possible due to heterogeneity of the studies. Hence, we conducted the narrative review, critically evaluating the existing published literature, and have included the level of evidence in related contexts.
The understanding of the phenomena and pathogenesis [Table 1] and [Figure 1] following amputations is essential for management. A patient having pain in the amputated part is labeled to have PLP if the pain persists after complete tissue healing and is characterized with symptoms of dysesthesia and pain. PLP is most commonly present in the limbs but may be seen in patients who have amputation of fingers, penis, tooth loss, after mastectomy, and gastrointestinal surgery. Majority of the patients report pain within a day following amputation, and some may not complain at all. After amputation, approximately 70% of the patients suffer from PLP and 50% continue to experience amputation pain 5 to 7 years after surgery.,
|Table 1: Understanding of phenomena and pathogenesis following lower limb amputations|
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|Figure 1: Pathophysiology and mechanism of initial and established phantom limb pain|
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Factors associated with phantom limb pain
- The pain following amputation and any ongoing pain due to infection or tissue ischemia
- Improper fit of the prosthesis can cause pain in the stump of the amputated part
- Due to improper fit of the prosthesis, there may be excessive pressure or stress on the normal joints and tissue, leading to a pain of new origin. This may sometimes lead to an abnormal gait or movement of the affected part
- An association has been observed between pain prior to amputation and the development of PLP. The evidence in this regard can be seen in less pain in diabetics and paraplegics, who have reduced peripheral nociceptive inputs and hence less PLP.
Pathophysiology of phantom limb pain
The PLP mechanisms can be broadly divided into four subprocesses such as all pain pathways into transduction, transmission, perception, and modulation. After limb amputation, the motor cortex remains intact and the brain perceives signals as if they are coming from the missing limb. As the limb is no longer present, there is a mismatch between motor commands to and proprioception or somatosensory inputs from the limb. Moreover, there is conflict between the signals coming from the missing limb and the efferent motor signal triggered by the incomplete somatosensory-motor feedback loop. There is an interplay of cortical functions and descending pain inhibitory pathways (thalamus, periaqueductal, nucleus gigantocellularis, and raphe nucleus) leading to reduction in the inhibitory pain pathways and enhanced N-methyl D-aspartate (NMDA) receptor activity at the spinal cord. An early intervention with multimodal acute pain management in these patients can prevent the development of chronic amputation pain or PLP.,
| Preventive Strategies|| |
The current published preventive strategies for the development of PLP has been described in the present clinical review into five main categories: surgical technique, regional analgesia, pharmacological agents, psychotherapy, and supportive management.
During an analysis of choice of technique for ligation of large diameter nerves, it is assumed that the ligation of large nerve fibers can cause PLP. Recently, preemptive coaptation and collagen nerve wrapping versus traction neurectomy alone in 17 patients undergoing transfemoral amputations resulted in reduced pain score and reported lower PLP (0% vs 63.6%; P = 0.01), neuroma formation (0% vs 54.5%; P = 0.03), and better ambulation rate (67% vs 9%; P = 0.01) during a follow-up of 6 months. Revised stump surgery was required only if there was a local pathology including bone spur, soft tissue, or bone infection. Recently, use of the targeted nerve implantation or traction neurectomy has been described to prevent or treat neuroma formation. Reliable attachment of muscle to bone allows weight bearing and joint movement in the rehabilitation period. At times, some patients may require revision or staged surgeries secondary to infection, trauma, and so on. These patients require comprehensive and patient-focused pain management. After achieving approximately 80% relief for 40 hours in a patient with ultrasound-guided femoral and sciatic nerve block, the patient received coblation of the femoral and sciatic nerve. This resulted in immediate relief from stump pain and phantom limb pain and 80% relief during 6 months of follow-up. Hence, improved understanding of transected nerves is essential as a preventive strategy for PLP.
Role of the anesthesiologist for preventive strategy in phantom limb pain
Role of the anesthesiologist for perioperative pain management requires a thorough understanding of the level of amputation and the choice of regional analgesia. Availability of round the clock acute pain service allows a preoperative formulation of analgesia plan and its execution. A patient-tailored approach is desired as the patient's pain perception is variable and causes are multifactorial., The role of objective pain scores is essential in these patients. Peri-operatively, visual analogue scale, verbal numeric rating scale, and McGill Pain Questionnaire have been used for pain assessment in postamputation patients. Quantitative sensory testing is a reliable objective measure of neuropathic pain, which can improve diagnosis and treatment. It has been used in patients of PLP. Level of evidence for perioperative preventive strategy for PLP is mentioned according to National Health and Medical Research Council (NHRMC) designation in the present review article.
In patients undergoing the lower limb amputation, role of epidural analgesia in immediate postoperative pain relief is well established in literature (Level I).,,,, Epidural analgesia as a preventive strategy of PLP, the published literature of epidural analgesia has shown variable results as shown in [Table 2]. Use of epidural analgesia as a preventive strategy for long-term PLP was reported by few studies, and for 6 months by Karanikolas et al. (Level II) Jahangiri et al. in a nonrandomized trial instituted preoperative epidural analgesia and continued it for at least 3 days postoperatively with an additional on-demand opioid therapy. This study showed reduction in PLP and phantom limb sensation with epidural analgesia over 1 year but there was no difference in stump pain. This suggested the role of preoperative local anaesthetic (LA) blockade in preventing the reorganization of the nervous system and formation of a “nociceptive engram” before amputation. Wilson et al. in a randomized double blind trial used epidural local anaesthetic (LA) and ketamine versus LA. The authors reported reduction in persistent pain at 1 year in both groups, with no significant difference between groups for stump and phantom pain (Level II). This study did not have a control group without LA and compared the reduction in PLP with the existing published literature. The authors, in their opinion, also attributed the role of combined spinal epidural anaesthesia during surgery versus general anesthesia to be a preventive strategy, as the former produced a dense sensory analgesia at the time of surgery. Karanikolas et al. compared five analgesic regimes in 65 patients. The authors found that the use of perioperative epidural analgesia and patient-controlled morphine analgesia produced similar reduction in PLP during 6 months of follow-up. The follow-up period was only for 6 months. Recently, the perioperative use of epidural LA-fentanyl-calcitonin for 48 hours in 60 diabetic vascular disease patients underwent either major (n = 21) or minor (n = 39) lower limb amputations under the combined spinal-epidural anesthesia. The authors reported improved grade of phantom pain and reduced the incidence of allodynia and hyperalgesia during 1 year of follow-up (Level II). The authors mentioned several limitations including mixed minor and major amputation patients in this study, follow-up of 1 year, and sample size calculation based on changes in acute pain (visual analogue scale).
|Table 2: Published studies of perioperative epidural analgesia in lower limb amputation patients|
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On the contrary, Nikolajsen et al. reported no difference in the development of PLP in patients receiving perioperative epidural bupivacaine with morphine infusion versus oral/intramuscular morphine group during a follow-up at 1 year. Lambert et al. compared preoperative epidural analgesia with intraoperative-placed perineural catheter. Both the infusions were continued in the postoperative period up to 3 days. The authors demonstrated superior pain relief in the immediate postoperative period with epidural analgesia but no differences in PLP at follow-up at 1 year with either preoperative epidural analgesia or intraoperative perineural catheters. Based on the effect of different anaesthetic techniques on reporting of PLP in patients undergoing postamputation lower limb surgery, the published studies found no difference as a preventive strategy for PLP., Sahin et al. reported superior analgesia in immediate postoperative period with epidural anaesthesia and peripheral nerve blocks as compared with general and spinal anaesthesia in a retrospective study of 65 patients. The results of anaesthetic technique with respect to the development of PLP did not differ during a follow-up of 14 to 17 months. Ong et al. in a cross-sectional study reported no difference in stump pain, phantom limb sensation, or phantom limb pain based on the different types of anaesthesia during lower limb amputation.
According to the existing literature, the majority of the studies have not shown the role of epidural analgesia as a long-term preventive strategy of PLP. However, in a few randomized trials, encouraging results of perioperative epidural LA, with/without adjuvants such as opioid, ketamine, and calcitonin, have been reported (Level II).
Due to the heterogeneity in the study designs of the above-mentioned studies and variable results of the literature (Level II), in future, multi-centric randomized controlled trials are required to establish the role of perioperative epidural analgesia with or without adjuvants as a preventive strategy for PLP during long-term follow-up.
Perineural catheters (PNCs) provide postoperative pain relief after amputation (Level I).,, Use of a prolonged postoperative perineural infusion of local anesthetic as a preventive strategy for PLP has shown beneficial results in few studies,,,, while no benefit in few studies,, as shown in [Table 3].
|Table 3: Published studies of perioperative perineural analgesia in lower limb amputation patients|
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In a systematic review, use of perioperative PNCs (3-30 days) reduced opioid consumption by 50% without effecting pain scores, in hospital mortality, PLP, or stump pain. The reported complications were minor when PNCs were kept for the prolonged duration and even when enoxaparin was used in the postoperative period. Literature confirms the role of PNCs in opioid sparing in the immediate postoperative period (Level I) in postamputation patients, but the evidence is low for prevention of PLP (Level III).,,,
Use of parenteral opioids for the management of short-term perioperative pain is well established in a systematic review of patients undergoing amputation surgeries (Level I)., Only one study reported that the role of IV opioid as a perioperative patient–controlled analgesia, started 48 hours preoperatively and continuing for 48 hours postoperatively, decreased PLP at 6 months (Level II). Use of opioid in epidural analgesia, prevented PLP at 1 year but the studies had limitations as one was a nonrandomized trial and the other included both minor and major amputations.
Use of IV tramadol in postoperative period is well established for acute pain, relief but not as a preventive strategy for PLP. Tramadol is a weak opioid agonist and acts by inhibiting the reuptake of serotonin and norepinephrine. On comparison, morphine provides superior analgesia as compared with tramadol. The side effects of all opioids are similar including constipation, drowsiness, nausea, and sedation.,
Further randomized controlled trials are required to evaluate the role of perioperative opioid as an evidence-based preventive strategy for PLP.
N-methyl D-aspartate (NMDA) receptor blockers
Ketamine is a noncompetitive blocker of NMDA rectors and its intravenous (IV) use in perioperative period is beneficial for short-term perioperative treatment of PLP. The literature produces conflicting results of use of ketamine for the prevention of PLP. In an observational study, use of IV ketamine (n = 14) for 72 hours compared with controls (n = 14) resulted in reduced PLP during a median follow-up of 557 days (Level III). Hayes et al., in a randomized controlled trial, showed that the PLP was lower in patients receiving IV ketamine but failed to reach statistical significance at 6 months (Level II). Recently, in a retrospective observational study, data collection is going on for patients who received IV ketamine within 30 days of limb amputation. So far, Jaremko et al. have reported a trend toward decreased neuropathic and phantom sensations with minimum side effect profile. The collected data were being taken from acute pain medicine service. The authors mentioned that the data could likely be biased due to the factors such as greater uncontrolled pain, potentially in conjunction with other comorbidities limiting medication management. The role of ketamine in epidural infusion has been described above (Level II).
To summarize, the current published literature is conflicting and insufficient regarding the role of perioperative IV ketamine and its long-term effect on PLP.
Nikolajsen et al. recruited a lower limb postamputation patient on the first day and continued till 30 days. Gabapentin was gradually increased to 2,400 mg/day as compared with placebo. Patients were evaluated at 7 days, 14 days, 30 days, 3 months, and 6 months during the treatment period. Gabapentin did not reduce the incidence or intensity of the postamputation pain (Level II). Although the present narrative review covers the preventive strategies for PLP, the published literature has evidence of gabapentin for established PLP. Bone et al. in a cross-over of placebo with gabapentin found gabapentin better in relieving established PLP but no difference in mood, sleep interference, or activities of daily life with mixed success. Here, we would like to mention that the beneficial role of oral gabapentin, and pregabalin, in established PLP in adult patients has been reported, but evidence-based studies are required for their role as a preventive strategy in PLP.
The exact mechanism of calcitonin remains unclear. The various mechanisms that are mentioned in the literature are opioid like action (μ receptors), stimulation of descending serotonergic inhibitory neurons, reduction in production of prostaglandins, pro-inflammatory cytokines, and modulation of voltage-gated Ca2+ channels on nociceptive neurons., Recently, epidural calcitonin has shown encouraging results as a preventive strategy (Level II) as described above. So far, there is no supportive evidence for use of the parenteral or oral calcitonin as preventive strategy in PLP. Furthermore, studies with larger sample size are required in this regard.
Paracetamol and NSAIDs
Role of paracetamol and non-steroidal anti-inflammatory drugs is useful in postoperative pain relief but not specific for prevention of PLP.,, The concerns and contraindications regarding the use of these drugs should be followed while using them.
Psychological treatment modalities
The aim of psychological therapies is to allow the patient to modify his or her perception and experience of pain. The main aim of multidisciplinary pain management is to allow the patient for early return of work. There is an ever-increasing need of psychological therapies with multidisciplinary approach for reducing pain and the development of chronic pain syndromes. The literature is lacking in preventive role of the psychological interventions for PLP. It is our opinion, early use of cognitive behavior therapy, mindfulness, hypnosis, acceptance and commitment therapy, brief interpersonal therapy, and biofeedback can play a role as a preventive strategy in PLP. The published literature is supportive regarding role of cognitive behavior therapy in helping patients to overcome dysfunctional thought patterns and behavior patterns.
It would be interesting to observe the results of these psychological interventions when used early in management of patients undergoing amputation surgery and the prevention of PLP.
Supportive management includes stump wrapping, elevation of surgical site, cold therapy, and massage therapy to relieve muscle spasms, group supports, advice regarding stump, and prosthesis care., Recently, the use of myoelectric prosthesis has been shown to decrease PLP. The possible mechanism is that behavioral stimulation of the affected amputated part of the body increases the degree of cortical representation and reorganization and use of myoelectric prosthesis reduces PLP and cortical reorganization in these patients.
A templet for multimodal perioperative pain plan as preventive strategy for PLP
- Identify patients for the prevention of PLP with detailed history taking, assessment of pain, special attention to neuropathic pain, pain questionnaire, anxiety and depression pain questionnaire, and neurological examination
- Consider a team approach including the surgeon, anesthesiologist, pain physician, physiotherapist, rehabilitation staff, and patient's caregivers
- Perioperative epidural analgesia with adjuvants (ketamine or calcitonin or opioids) (Level II) or IV opioid PCA (Level II) for optimized postoperative pain relief, starting 48 hours prior to surgery to minimum up to 72 hours postoperatively
- Include NSAIDs and paracetamol as part of multimodal analgesia
- Psychological support and rehabilitation
- Individualization approach regarding use of gabapentanoids as preventive strategy.
| Conclusion|| |
The current literature does not support any single technique or drug to be superior over another. However, optimized epidural analgesia and opioid PCA are acceptable as preventive strategies for the prevention of PLP. Use of adjuvants such as calcitonin or ketamine with LA in epidural analgesia shows encouraging results. In future, randomized controlled trials with long-term follow-up of patients receiving epidural analgesia, perioperative peripheral nerve catheters, oral gabapentanoids, IV ketamine, or mechanism-based modality for the prevention of PLP as primary outcome are required.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Sherman RA, Sherman CJ, Parker L. Chronic phantom and stump pain among American veterans: Results of a survey. Pain 1984;18:83-95.
Mohan D. A report on Amputees in India. Orthot Prosth 1986;40:16-32. [O&P Library]
Ghosh Das P, Lahiri S. Prevalence and aetiology of amputation in Kolkata, India: A retrospective analysis. Hong Kong Physiother J 2013;31:36-40.
Diefenbach WC. Ambroise Paré: Pioneer of modern surgery. Merck Rep 1952;61:26-9.
Nathanson M. Phantom limbs as reported by S. Weir Mitchell. Neurology 1988;38:504-5.
Jensen TS, Krebs B, Nielsen J, Rasmussen P. Phantom limb, phantom pain and stump pain in amputees during the first 6 months following limb amputation. Pain 1983;17:243-56.
Carlen PL, Wall PD, Nadvorna H, Steinbach T. Phantom limbs and related phenomena in recent traumatic amputations. Neurology 1978;28:211-7.
Nikolajsen L, Jensen TS. Phantom limb pain. Br J Anaesth 2001;87:107-16.
Katz J, Melzack R. Pain “memories” in phantom limbs: Review and clinical observations. Pain 1990;43:319-36.
Manchikanti L, Singh V. Managing phantom pain. Pain Phys 2004;7:365-75.
Bosmans JC, Geertzen JH, Post WJ, van der Schans CP, Dijkstra PU. Factors associated with phantom limb pain: A 3 1/2-year prospective study. Clin Rehabil 2010;24:444-53.
Hirsh AT, Dillworth TM, Ehde DM, Jensen MP. Sex differences in pain and psychological functioning in persons with limb loss. J Pain 2010;11:79-86.
Malik OS, Kaye AD, Urman RD. Perioperative hyperalgesia and associated clinical factors. Curr Pain Headache Rep 2017;21:4.
Richardson C, Crawford K, Milnes K, Bouch E, Kulkarni J. A clinical evaluation of postamputation phenomena including phantom limb pain after lower limb amputation in dysvascular patients. Pain Manag Nurs 2015;16:561-9.
Jackson T, Thomas S, Stabile V, Shotwell M, Han X, McQueen K. A systematic review and meta-analysis of the global burden of chronic pain without clear etiology in low- and middle-income countries: Trends in heterogeneous data and a proposal for new assessment methods. Anesth Analg 2016;123:739-48.
Bloomquist T. Amputation and phantom limb pain: A pain-prevention model. AANA 2001;69:211-7.
Tung ML, Murphy IC, Griffin SC, Alphonso AL, Hussey-Anderson L, Hughes KE, et al
. Observation of limb movements reduces phantom limb pain in bilateral amputees. Ann Clin Transl Neurol 2014;1:633-8.
Flor H. Phantom-limb pain: Characteristics, causes, and treatment. Lancet Neurol 2002;1:182-9.
Economides JM, DeFazio MV, Attinger CE, Barbour JR. Prevention of painful neuroma and phantom limb pain after transfemoral amputations through concomitant nerve coaptation and collagen nerve wrapping. Neurosurgery 2016;79:508-13.
Pet MA, Ko JH, Friedly JL, Mourad PD, Smith DG. Does targeted nerve implantation reduce neuroma pain in amputees? Clin Orthop Relat Res 2014;472:2991-3001.
Kent ML, Hsia HJ, Van de Ven TJ, Buchheit TE. Perioperative pain management strategies for amputation: A topical review. Pain Med 2017;18:504-19.
Zeng Y, Wang X, Guo Y, He L, Ni J. Coblation of femoral and sciatic nerve for stump pain and phantom limb pain: A case report. Pain Pract 2016;16:E35-41.
Chou R, Gordon DB, de Leon-Casasola OA, Rosenberg JM, Bickler S, Brennan T, et al
. Management of postoperative pain: A clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists' Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain 2016;17:131-57.
Buckenmaier C 3rd
, Mahoney PF, Anton T, Kwon N, Polomano RC. Impact of an acute pain service on pain outcomes with combat-injured soldiers at Camp Bastion, Afghanistan. Pain Med 2012;13:919-26.
Hsu E, Cohen SP. Postamputation pain: Epidemiology, mechanisms, and treatment. J Pain Res 2013;6:121-36.
Jahangiri M, Jayatunga AP, Bradley JWP, Dark CH. Prevention of phantom pain after major lower limb amputation by epidural infusion of diamorphine, clonidine, and bupivacaine. Ann R Coll Surg Engl 1994;76:324-6.
Lambert AW, Dashfield AK, Cosgrove C, Wilkins DC, Walker AJ, Ashley S. Randomized prospective study comparing preoperative epidural and intraoperative perineural analgesia for the prevention of postoperative stump and phantom limb pain following major amputation. Reg Anesth Pain Med 2001;26:316-21.
Ong BY, Arneja A, Ong EW. Effects of anesthesia on pain after lower-limb amputation. J Clin Anesth 2006;18:600-4.
Wilson JA, Nimmo AF, Fleetwood-Walker SM, Colvin LA. A randomised double blind trial of the effect of pre-emptive epidural ketamine on persistent pain after lower limb amputation. Pain 2008;135:108-18.
Sahin SH, Colak A, Arar C, Tutunculer E, Sut N, Yilmaz B, et al
. A retrospective trial comparing the effects of different anesthetic techniques on phantom pain after lower limb amputation. Curr Ther Res Clin Exp 2011;72:127-37.
Yousef AA, Aborahma AM. The preventive value of epidural calcitonin in patients with lower limb amputation. Pain Med 2017;18:1745-51.
Karanikolas M, Aretha D, Tsolakis I, Monantera G, Kiekkas P, Papadoulas S, et al
. Optimized perioperative analgesia reduces chronic phantom limb pain intensity, prevalence, and frequency: A prospective, randomized, clinical trial. Anesthesiology 2011;114:1144-54.
Nikolajsen L, Ilkjaer S, Christensen JH, Krøner K, Jensen TS. Randomized trial of epidural bupivacaine and morphine in prevention of stump and phantom pain in lower-limb amputation. Lancet 1997;350:1353-7.
Malawer MM, Buch R, Khurana JS, Garvey T, Rice L. Postoperative infusional continuous regional analgesia. A technique for relief of postoperative pain following major extremity surgery. Clin Orthop Relat Res 1991;226:227-37.
Grant AJ, Wood C. The effect of intra-neural local anaesthetic infusion on pain following major lower limb amputation. Scott Med J 2008;53:4-6.
Ayling OG, Montbriand J, Jiang J, Ladak S, Love L, Eisenberg N, et al
. Continuous regional anaesthesia provides effective pain management and reduces opioid requirement following major lower limb amputation. Eur J Vasc Endovasc Surg 2014;48:559-64.
Fisher A, Meller Y. Continuous postoperative regional analgesia by nerve sheath block for amputation surgery-a pilot study. Anesth Analg 1991;72:300-3.
Borghi B, D'Addabbo M, White P. The use of prolonged peripheral neural blockade after lower extremity amputation: The effect on symptoms associated with phantom limb syndrome. Anesth Analg 2010;111:1308-15.
Elizaga AM, Smith DG, Sharar SR, Edwards WT, Hansen ST Jr. Continuous regional analgesia by intraneural block: Effect on postoperative opioid requirements and phantom limb pain following amputation. J Rehabil Res Dev 1994;31:179-87.
Pinzur MS, Garla PG, Pluth T, Vrbos L. Continuous postoperative infusion of a regional anesthetic after an amputation of the lower extremity. A randomized clinical trial. J Bone Joint Surg Am 1996;78:1501-5.
Bosanquet DC, Glasbey JC, Stimpson A, Williams IM, Twine CP. Systematic review and meta-analysis of the efficacy of perineural local anaesthetic catheters after major lower limb amputation. Eur J Vasc Endovasc Surg 2015;50:241-9.
Stojadinovic A, Auton A, Peoples GE, McKnight GM, Shields C, Croll SM, et al
. Responding to challenges in modern combat casualty care: Innovative use of advanced regional anesthesia. Pain Med 2006;7:330-8.
Buckenmaier CC 3rd
, Shields CH, Auton AA, Evans SL, Croll SM, Bleckner LL, et al
. Continuous peripheral nerve block in combat casualties receiving low-molecular weight heparin. Br J Anaesth 2006;97:874-7.
Schug SA, Palmer GM, Scott DA, Halliwell R, Trinca J. APM: SE Working Group of the Australian and New Zealand College of Anaesthetists and Faculty of Pain Medicine 2015. Acute Pain Management: Scientific Evidence 4th
edition, ANZCA & FPM, Melbourne.
McCormick Z, Chang-Chien G, Marshall B, Huang M, Harden RN. Phantom limb pain: A systematic neuroanatomical-based review of pharmacologic treatment. Pain Med 2014;15:292-305.
Falzone E, Hoffmann C, Keita H. Postoperative analgesia in elderly patients. Drugs Aging 2013;30:81-90.
Byrne K, Nolan A, Barnard J, Tozer M, Harris D, Sleigh J. Managing postoperative analgesic failure: Tramadol versus morphine for refractory pain in the post-operative recovery unit. Pain Med 2017;18:348-55.
Irving GA. Contemporary assessment and management of neuropathic pain. Neurology 2005;64:S21-7.
Dworkin RH, O'Connor AB, Audette J, Baron R, Gourlay GK, Haanpää ML, et al
. Recommendations for the pharmacological management of neuropathic pain: An overview and literature update. Mayo Clin Proc 2010;85:S3-S14.
Dertwinkel R, Heinrichs C, Senne I, Maier C. Prevention of severe phantom limb pain by perioperative administration of ketamine—An observational study. Acute Pain 2002;4:9-13.
Hayes C, Armstrong-Brown A, Burstal R. Perioperative intravenous ketamine infusion for the prevention of persistent post-amputation pain: A randomized, controlled trial. Anaesth Intensive Care 2004;32:330-8.
Jaremko K, Viscusi E. A retrospective investigation into the impact of early post-operative intravenous ketamine infusion on recovery and phantom limb pain in new amputees. J Pain 2016;17: S75.
Nikolajsen L, Finnerup NB, Kramp S, Vimtrup AS, Keller J, Jensen TS. A randomized study of the effects of gabapentin on postamputation pain. Anesthesiology 2006;105:1008-15.
Bone M, Critchley P, Buggy DJ. Gabapentin in postamputation phantom limb pain: A randomized, double-blind, placebo-controlled, cross-over study. Reg Anesth Pain Med 2002;27:481-6.
Abbass K. Efficacy of gabapentin for treatment of adults with phantom limb pain. Ann Pharmacother 2012;46:1707-11.
Smith DG, Ehde DM, Hanley MA, Campbell KM, Jensen MP, Hoffman AJ, et al
. Efficacy of gabapentin in treating chronic phantom limb and residual limb pain. JRRD 2005;42:645-54.
Spiegel DR, Lappinen E, Gottlieb M. A presumed case of phantom limb pain treated successfully with duloxetine and pregabalin. Gen Hosp Psychiatry 2010;32:228.
Singh RK, Sinha VP, Pal US, Yadav SC, Singh MK. Pregabalin in post traumatic neuropathic pain: Case studies. Natl J Maxillofac Surg 2012;3:91-5.
Hagenacker T, Ledwig D, Busselberg D. Additive inhibitory effects of calcitonin and capsaicin on voltage activated calcium channel currents in nociceptive neurons of rat. Brain Res Bull 2011;85:75-80.
Wall GC, Hayneman CA. Calcitonin in phantom limb pain. Ann Pharmacother 1999;33:499-501.
Alviar MJ, Hale T, Dungca M. Pharmacologic interventions for treating phantom limb pain. Cochrane Database Syst Rev 2016;10:CD006380.
Macario A, Royal MA. A literature review of randomized clinical trials of intravenous acetaminophen (paracetamol) for acute postoperative pain. Pain Pract 2011;11:290-6.
Taylor S, Voytovich AE, Kozol RA. Has the pendulum swung too far in postoperative pain control? Am J Surg 2003;186:472-5.
Castelnuovo G, Giusti EM, Manzoni GM, Saviola D, Gatti A, Gabrielli S, et al
. Psychological treatments and psychotherapies in the neurorehabilitation of pain: Evidences and recommendations from the Italian Consensus Conference on pain in neurorehabilitation. Front Psychol 2016;7:115.
Dietrich C, Walter-Walsh K, Preißler S, Hofmann GO, Witte OW, Miltner WH, et al
. Sensory feedback prosthesis reduces phantom limb pain: proof of a principle. Neurosci Lett 2012;507:97-100.
[Table 1], [Table 2], [Table 3]