EDITORIAL For reprint orders, please contact: [email protected]
Phantom limb pain: treatment strategies
Lone Nikolajsen*1,2
Kristian Friesgaard Christensen1
Phantom pain following limb amputation represents a challenge for medical science. Recent wars in Afghanistan and Iraq, combined with civil wars in Syria and other nations, have led to an increase in the number of traumatic limb amputations being carried out on otherwise healthy people. In addition to this, it has been estimated that the number of amputees in the USA will double by the year 2050 to 3.6 million [1]. In western countries few amputations are performed as a result of trauma, the majority occur in elderly patients with vascular disease and a comorbid diagnosis of diabetes mellitus. However, whether the cause is traumatic or medical, amputations are an increasingly prevalent part of the clinician’s reality, and it is for this reason that the problem of phantom limb pain should not be overlooked. Regardless of the reason for amputation, the prevalence of phantom limb pain is reported to be as high as 85%. In most amputees, the frequency and intensity of pain attacks decrease over the years; however, approximately 5–10% of amputees continue to have severe, intractable and
Simon Haroutiunian2
disabling phantom limb pain for many years after an amputation [2,3]. Unfortunately, the current treatment available for chronic phantom limb pain is far from satisfactory, and this represents a major challenge for the clinician. There is little evidence from randomized controlled trials to guide clinicians with treatment, and many studies are hindered by major methodological limitations [4]. The current editorial will include a brief discussion of preventive measures, but its primary focus will be on the treatment of phantom limb pain. The opinions expressed in the editorial are based on evidence where available and supported by the authors’ own research on phantom limb pain and their daily practice as pain clinicians. Although only partly supported by the literature, it seems that an effective analgesic treatment of early postoperative stump pain may delay the onset of phantom pain, or at least temporarily decrease its severity. At Aarhus University Hospital (Denmark), epidural or peripheral regional blocks are used, and these are most often
“...treatment for chronic phantom limb pain ... represents a major challenge for the clinician.”
Department of Anesthesiology, Aarhus University Hospital, Aarhus, Denmark Danish Pain Research Center, Aarhus University Hospital, Nørrebrogade 44, Building 1A, 8000 Aarhus C, Denmark *Author for correspondence: Tel.: +45 7846 4317; [email protected] 1 2
10.2217/PMT.13.51 © 2013 Future Medicine Ltd
Pain Manage. (2013) 3(6), 421–424
part of
ISSN 1758-1869
421
Editorial Nikolajsen, Christensen & Haroutiunian
“While perioperative analgesic interventions ... can reduce early postoperative stump and phantom limb pain, the results from studies on the long-term effects prove to be inconsistent.”
422
supplemented with paracetamol, nonsteroidal anti-inflammatory agents, opioids and, in some cases, gabapentin. Epidural blocks are likely to provide more effective analgesia than peripheral blocks, although the associated risk of hypotension and motor block governs their use, particularly in patients taking opioids prior to an amputation (this usually applies to chronic pain patients or patients on maintenance therapy with methadone or buphrenorphine for opioid dependency). The chronic opioid group can be described as an exception, since these patients may require a marked increase in opioids after surgery. While perioperative analgesic interventions with epidural and peripheral regional blocks can reduce early postoperative stump and phantom limb pain, the results from studies on the longterm effects prove to be inconsistent [5]. For example, a randomized double-blind placebocontrolled study, in which the epidural infusion was started 18 h prior to amputation and continued postoperatively, showed no effect on phantom limb pain [6]. However, a more recent study has suggested a reduction of phantom pain following a perineural infusion of ropivacaine for a median of 30 days following the amputation [7]. It is hoped that a planned multicenter trial on the prevention of phantom limb pain – including 400 patients randomized to either a placebo or local anesthetic infused via a sciatic nerve catheter and continued for 1 week after amputation – will shed new light on the potential preventive effect of regional blocks [8]. In addition to the use of epidural and peripheral blocks, adjuvant analgesic drugs such as ketamine, gabapentin and memantine have been used perioperatively in order to prevent phantom limb pain; however, almost always with negative results. It is unlikely that relatively short-lasting perioperative analgesic interventions will be sufficient to prevent the development of chronic phantom limb pain. Many vascular amputees suffer from pain for months or even years before the amputation, and the afferent nociceptive barrage from the amputated stump, which persists long after the perioperative intervention, is likely to maintain central sensitization and chronic pain. Treatment of established phantom limb pain relies on a multimodal approach that combines both pharmacological and nonpharmacological interventions. The pharmacological interventions are addressed first before continuing to
Pain Manage. (2013) 3(6)
examining the nonpharmacological options for pain relief. Since relatively few studies are available for phantom pain, the pharmacological treatment is based primarily on treatment guidelines for other neuropathic pain conditions. However, there is some evidence to suggest the efficacy of antidepressants, anticonvulsants, opioids, N-methyl-d-aspartate receptor antagonists and local anaesthetics in treating phantom limb pain. At least two studies have examined the effect of tricyclic antidepressants on phantom pain. One study, in which 39 patients were randomized to receive either amitriptyline (up to 125 mg/day) or an active placebo during a 6-week trial period, failed to show any effect of treatment [9]. In another study, 49 post-traumatic amputees were randomized to receive amitriptyline (mean dose: 55 mg/day), tramadol (mean dose: 448 mg/day) or placebo for 1 month. The administration of tramadol and placebo was blinded; amitriptyline was given nonblinded as open comparison. Nonresponders were switched to the alternative active treatment (from tramadol to amitriptyline treatment or vice versa) and placebo nonresponders were switched to tramadol or amitriptyline. Both tramadol and amitriptyline had almost entirely eliminated abolished stump and phantom pain by the end of the treatment period [10]. In some cases, gabapentin may relieve phantom pain. In a double-blind crossover study, which included 19 patients with phantom pain, gabapentin (at a maximum dose of 2400 mg/day) proved more effective than placebo in reducing phantom pain after a 6-week treatment period [11]. In another study, gabapentin (at a maximum dose of 3600 mg/day) or placebo was administered for 6 weeks to 24 amputees in a similar double-blind, crossover fashion. Gabapentin did not significantly decrease the intensity of pain, but more than half of the amputees reported a meaningful decrease in pain during treatment with gabapentin compared with a fifth who reported a meaningful decrease in pain during treatment with placebo [12]. Until now, the effect of pregabalin on phantom pain has not been examined in controlled trials, although it could be assumed that pregabalin is as effective as gabapentin. Opioids have been shown to be effective in the treatment of phantom limb pain. For example, 60 amputees were randomized to treatment with morphine, mexiletine or placebo in a doubleblind crossover study [13]. Each of the three
future science group
Phantom limb pain: treatment strategies treatment periods included a 4-week titration, a 2-week maintenance and a 2-week taper phase. Postamputation pain was only significantly reduced during the treatment with morphine (mean dose: 112 mg/day) [13]. However, caution must be taken when treating patients with nonmalignant pain conditions with opioids, since they risk developing dependency and addiction. Ketamine, a N-methyl-d-aspartate receptor antagonist, has been shown to reduce phantom pain when administered intravenously [14,15]. Ketamine may also be taken orally for chronic use, but such treatment should only be performed at pain clinics with specialist expertise. The use of lidocaine patches or capsaicin for phantom limb pain is not supported by the literature, although both may be used for chronic stump pain. Not all cases of phantom limb pain can be relieved by pharmacological treatment, and this highlights the importance of nonpharmacological interventions. Psychological intervention is very important, as depression and passive coping strategies have a negative impact on pain [16]. Physical therapy may prevent trophic changes and vascular congestion in the stump. And, in some cases, treatments such as transcutaneous electrical nerve stimulation, mirror treatment, acupuncture, sensory discrimination treatment of the stump, biofeedback and hypnosis may have a beneficial effect. The majority of these methods have no side effects, little risk of complications and can be repeated easily, which speaks in their favor. However, most studies on the efficacy of these methods take the form of uncontrolled observations. It is advisable to reserve surgery for cases with obvious stump pathology (e.g., infection References 1
Ziegler-Graham K, MacKenzie EJ, Ephraim PL et al. Estimating the prevalence of limb loss in the United States: 2005 to 2050. Arch. Phys. Med. Rehabil. 89(3), 422–429 (2008).
2
Hsu E, Cohen SP. Postamputation pain: epidemiology, mechanisms, and treatment. J. Pain Res. 6, 121–136 (2013).
3
4
Nikolajsen L. Phantom limb I. In: Textbook of pain (6th edition). Wall PD, Melzack R (Eds). Churchill Livingstone, Edinburgh, UK (2013). Alviar MJ, Hale T, Dungca M. Pharmacologic interventions for treating phantom limb pain. Cochrane Database Syst. Rev. (12), CD006380 (2011).
future science group
or nerve-end neuromas) as surgery implies further deafferentiation and thereby an increased risk of persistent pain. We examined the effect of surgical neuroma removal in patients with neuropathic pain, including stump and phantom pain, but surgery only relieved pain in two out of six patients [17]. Less invasive procedures, such as spinal cord stimulation, can relieve phantom limb pain, though it is probably more effective in the treatment of chronic stump pain. In conclusion, treatment of postamputation phantom limb pain should be individualized, preferably with a combination of pharmacological and nonpharmacological approaches. Perioperative approaches aimed at reducing the severity of acute postamputation pain and prevention of central sensitization may be attempted, especially in patients with preoperative risk factors for phantom pain, such as pain prior to the amputation [18], lowered thresholds to mechanical stimuli [19], passive coping strategies [16] and perhaps genetic factors [20]. In addition, it is hoped that further research into the underlying mechanisms of phantom pain will help us develop more effective treatment plans for the benefit of our patients.
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. Ypsilantis E, Tang TY. Pre-emptive analgesia for chronic limb pain after amputation for peripheral vascular disease: a systematic review. Ann. Vasc. Surg. 24(8), 1139–1146 (2010).
6
Nikolajsen L, Ilkjaer S, Christensen JH. Randomised trial of epidural bupivacaine and morphine in prevention of stump and phantom pain in lower-limb amputation. Lancet 350, 1353–1357 (1997).
8
“...treatment of postamputation phantom limb pain should be individualized, preferably with a combination of pharmacological and nonpharmacological approaches.”
Financial & competing interests disclosure
5
7
Editorial
Borghi B, D’Addabbo M, White PF et al. The Use of prolonged peripheral neural blockade after lower extremity amputation. Anesth. Analg. 111(5), 1308–1315 (2010). Lirk P, Stadlbauer KH, Hollmann MW. ESA Clinical Trials Network 2012: PLATA–
prevention of phantom limb pain after transtibial amputation: randomised, doubleblind, controlled, multicentre trial comparing optimised intravenous pain control versus optimised intravenous pain control plus regional anaesthesia. Eur. J. Anaesthesiol. 30(5), 202–204 (2013). 9
Robinson LR, Czerniecki JM, Ehde DM et al. Trial of amitriptyline for relief of pain in amputees: results of a randomized controlled study. Arch. Phys. Med. Rehabil. 85(1), 1–6 (2004).
10 Wilder-Smith CH, Hill LT, Laurent S.
Postamputation pain and sensory changes in treatment-naive patients. Anesthesiology 103(3), 619–628 (2005).
www.futuremedicine.com
423
Editorial Nikolajsen, Christensen & Haroutiunian 11 Bone M, Critchley P, Buggy DJ. Gabapentin
in postamputation phantom limb pain: a randomized, double-blind, placebocontrolled, cross-over study. Reg. Anesth. Pain Med. 27(5), 481–486 (2002). 12 Smith DG, Ehde DM, Hanley MA et al.
Efficacy of gabapentin in treating chronic phantom limb and residual limb pain. J. Rehabil. Res. Dev. 42(5), 645–654 (2005). 13 Wu CL, Agarwal S, Tella PK. Mexiletine for
treatment of postamputation pain. Anesthesiology 109(2), 289–296 (2008). 14 Nikolajsen L, Hansen CL, Nielsen J. The
effect of ketamine on phantom pain: a central
424
neuropathic disorder maintained by peripheral input. Pain 67(1), 69–77 (1996). 15 Eichenberger U, Neff F, Sveticic G et al.
Chronic phantom limb pain: the effects of calcitonin, ketamine, and their combination on pain and sensory thresholds. Anesth. Analg. 106(4), 1265–1273 (2008). 16 Vase L, Nikolajsen L, Christensen B et al.
Cognitive-emotional sensitization contributes to wind-up-like pain in phantom limb pain patients. Pain 152(1), 157–162 (2011). 17 Nikolajsen L, Black JA, Kroner K. Neuroma
removal for neuropathic pain: efficacy and
Pain Manage. (2013) 3(6)
predictive value of lidocaine infusion. Clin. J. Pain 26(9), 788–793 (2010). 18 Nikolajsen L, Ilkjær S, Kroner K. The
influence of preamputation pain on postamputation stump and phantom pain. Pain 72(3), 393–405 (1997). 19 Nikolajsen L, Ilkjær S, Jensen TS.
Relationship between mechanical sensitivity and postamputation pain: a prospective study. Eur. J. Pain 4(4), 327–334 (2000). 20 Costigan M, Belfer I, Griffin RS et al.
Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1. Brain 133(9), 2519–2527 (2010).
future science group
Phantom limb pain: treatment strategies
Lone Nikolajsen*1,2
Kristian Friesgaard Christensen1
Phantom pain following limb amputation represents a challenge for medical science. Recent wars in Afghanistan and Iraq, combined with civil wars in Syria and other nations, have led to an increase in the number of traumatic limb amputations being carried out on otherwise healthy people. In addition to this, it has been estimated that the number of amputees in the USA will double by the year 2050 to 3.6 million [1]. In western countries few amputations are performed as a result of trauma, the majority occur in elderly patients with vascular disease and a comorbid diagnosis of diabetes mellitus. However, whether the cause is traumatic or medical, amputations are an increasingly prevalent part of the clinician’s reality, and it is for this reason that the problem of phantom limb pain should not be overlooked. Regardless of the reason for amputation, the prevalence of phantom limb pain is reported to be as high as 85%. In most amputees, the frequency and intensity of pain attacks decrease over the years; however, approximately 5–10% of amputees continue to have severe, intractable and
Simon Haroutiunian2
disabling phantom limb pain for many years after an amputation [2,3]. Unfortunately, the current treatment available for chronic phantom limb pain is far from satisfactory, and this represents a major challenge for the clinician. There is little evidence from randomized controlled trials to guide clinicians with treatment, and many studies are hindered by major methodological limitations [4]. The current editorial will include a brief discussion of preventive measures, but its primary focus will be on the treatment of phantom limb pain. The opinions expressed in the editorial are based on evidence where available and supported by the authors’ own research on phantom limb pain and their daily practice as pain clinicians. Although only partly supported by the literature, it seems that an effective analgesic treatment of early postoperative stump pain may delay the onset of phantom pain, or at least temporarily decrease its severity. At Aarhus University Hospital (Denmark), epidural or peripheral regional blocks are used, and these are most often
“...treatment for chronic phantom limb pain ... represents a major challenge for the clinician.”
Department of Anesthesiology, Aarhus University Hospital, Aarhus, Denmark Danish Pain Research Center, Aarhus University Hospital, Nørrebrogade 44, Building 1A, 8000 Aarhus C, Denmark *Author for correspondence: Tel.: +45 7846 4317; [email protected] 1 2
10.2217/PMT.13.51 © 2013 Future Medicine Ltd
Pain Manage. (2013) 3(6), 421–424
part of
ISSN 1758-1869
421
Editorial Nikolajsen, Christensen & Haroutiunian
“While perioperative analgesic interventions ... can reduce early postoperative stump and phantom limb pain, the results from studies on the long-term effects prove to be inconsistent.”
422
supplemented with paracetamol, nonsteroidal anti-inflammatory agents, opioids and, in some cases, gabapentin. Epidural blocks are likely to provide more effective analgesia than peripheral blocks, although the associated risk of hypotension and motor block governs their use, particularly in patients taking opioids prior to an amputation (this usually applies to chronic pain patients or patients on maintenance therapy with methadone or buphrenorphine for opioid dependency). The chronic opioid group can be described as an exception, since these patients may require a marked increase in opioids after surgery. While perioperative analgesic interventions with epidural and peripheral regional blocks can reduce early postoperative stump and phantom limb pain, the results from studies on the longterm effects prove to be inconsistent [5]. For example, a randomized double-blind placebocontrolled study, in which the epidural infusion was started 18 h prior to amputation and continued postoperatively, showed no effect on phantom limb pain [6]. However, a more recent study has suggested a reduction of phantom pain following a perineural infusion of ropivacaine for a median of 30 days following the amputation [7]. It is hoped that a planned multicenter trial on the prevention of phantom limb pain – including 400 patients randomized to either a placebo or local anesthetic infused via a sciatic nerve catheter and continued for 1 week after amputation – will shed new light on the potential preventive effect of regional blocks [8]. In addition to the use of epidural and peripheral blocks, adjuvant analgesic drugs such as ketamine, gabapentin and memantine have been used perioperatively in order to prevent phantom limb pain; however, almost always with negative results. It is unlikely that relatively short-lasting perioperative analgesic interventions will be sufficient to prevent the development of chronic phantom limb pain. Many vascular amputees suffer from pain for months or even years before the amputation, and the afferent nociceptive barrage from the amputated stump, which persists long after the perioperative intervention, is likely to maintain central sensitization and chronic pain. Treatment of established phantom limb pain relies on a multimodal approach that combines both pharmacological and nonpharmacological interventions. The pharmacological interventions are addressed first before continuing to
Pain Manage. (2013) 3(6)
examining the nonpharmacological options for pain relief. Since relatively few studies are available for phantom pain, the pharmacological treatment is based primarily on treatment guidelines for other neuropathic pain conditions. However, there is some evidence to suggest the efficacy of antidepressants, anticonvulsants, opioids, N-methyl-d-aspartate receptor antagonists and local anaesthetics in treating phantom limb pain. At least two studies have examined the effect of tricyclic antidepressants on phantom pain. One study, in which 39 patients were randomized to receive either amitriptyline (up to 125 mg/day) or an active placebo during a 6-week trial period, failed to show any effect of treatment [9]. In another study, 49 post-traumatic amputees were randomized to receive amitriptyline (mean dose: 55 mg/day), tramadol (mean dose: 448 mg/day) or placebo for 1 month. The administration of tramadol and placebo was blinded; amitriptyline was given nonblinded as open comparison. Nonresponders were switched to the alternative active treatment (from tramadol to amitriptyline treatment or vice versa) and placebo nonresponders were switched to tramadol or amitriptyline. Both tramadol and amitriptyline had almost entirely eliminated abolished stump and phantom pain by the end of the treatment period [10]. In some cases, gabapentin may relieve phantom pain. In a double-blind crossover study, which included 19 patients with phantom pain, gabapentin (at a maximum dose of 2400 mg/day) proved more effective than placebo in reducing phantom pain after a 6-week treatment period [11]. In another study, gabapentin (at a maximum dose of 3600 mg/day) or placebo was administered for 6 weeks to 24 amputees in a similar double-blind, crossover fashion. Gabapentin did not significantly decrease the intensity of pain, but more than half of the amputees reported a meaningful decrease in pain during treatment with gabapentin compared with a fifth who reported a meaningful decrease in pain during treatment with placebo [12]. Until now, the effect of pregabalin on phantom pain has not been examined in controlled trials, although it could be assumed that pregabalin is as effective as gabapentin. Opioids have been shown to be effective in the treatment of phantom limb pain. For example, 60 amputees were randomized to treatment with morphine, mexiletine or placebo in a doubleblind crossover study [13]. Each of the three
future science group
Phantom limb pain: treatment strategies treatment periods included a 4-week titration, a 2-week maintenance and a 2-week taper phase. Postamputation pain was only significantly reduced during the treatment with morphine (mean dose: 112 mg/day) [13]. However, caution must be taken when treating patients with nonmalignant pain conditions with opioids, since they risk developing dependency and addiction. Ketamine, a N-methyl-d-aspartate receptor antagonist, has been shown to reduce phantom pain when administered intravenously [14,15]. Ketamine may also be taken orally for chronic use, but such treatment should only be performed at pain clinics with specialist expertise. The use of lidocaine patches or capsaicin for phantom limb pain is not supported by the literature, although both may be used for chronic stump pain. Not all cases of phantom limb pain can be relieved by pharmacological treatment, and this highlights the importance of nonpharmacological interventions. Psychological intervention is very important, as depression and passive coping strategies have a negative impact on pain [16]. Physical therapy may prevent trophic changes and vascular congestion in the stump. And, in some cases, treatments such as transcutaneous electrical nerve stimulation, mirror treatment, acupuncture, sensory discrimination treatment of the stump, biofeedback and hypnosis may have a beneficial effect. The majority of these methods have no side effects, little risk of complications and can be repeated easily, which speaks in their favor. However, most studies on the efficacy of these methods take the form of uncontrolled observations. It is advisable to reserve surgery for cases with obvious stump pathology (e.g., infection References 1
Ziegler-Graham K, MacKenzie EJ, Ephraim PL et al. Estimating the prevalence of limb loss in the United States: 2005 to 2050. Arch. Phys. Med. Rehabil. 89(3), 422–429 (2008).
2
Hsu E, Cohen SP. Postamputation pain: epidemiology, mechanisms, and treatment. J. Pain Res. 6, 121–136 (2013).
3
4
Nikolajsen L. Phantom limb I. In: Textbook of pain (6th edition). Wall PD, Melzack R (Eds). Churchill Livingstone, Edinburgh, UK (2013). Alviar MJ, Hale T, Dungca M. Pharmacologic interventions for treating phantom limb pain. Cochrane Database Syst. Rev. (12), CD006380 (2011).
future science group
or nerve-end neuromas) as surgery implies further deafferentiation and thereby an increased risk of persistent pain. We examined the effect of surgical neuroma removal in patients with neuropathic pain, including stump and phantom pain, but surgery only relieved pain in two out of six patients [17]. Less invasive procedures, such as spinal cord stimulation, can relieve phantom limb pain, though it is probably more effective in the treatment of chronic stump pain. In conclusion, treatment of postamputation phantom limb pain should be individualized, preferably with a combination of pharmacological and nonpharmacological approaches. Perioperative approaches aimed at reducing the severity of acute postamputation pain and prevention of central sensitization may be attempted, especially in patients with preoperative risk factors for phantom pain, such as pain prior to the amputation [18], lowered thresholds to mechanical stimuli [19], passive coping strategies [16] and perhaps genetic factors [20]. In addition, it is hoped that further research into the underlying mechanisms of phantom pain will help us develop more effective treatment plans for the benefit of our patients.
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties. No writing assistance was utilized in the production of this manuscript. Ypsilantis E, Tang TY. Pre-emptive analgesia for chronic limb pain after amputation for peripheral vascular disease: a systematic review. Ann. Vasc. Surg. 24(8), 1139–1146 (2010).
6
Nikolajsen L, Ilkjaer S, Christensen JH. Randomised trial of epidural bupivacaine and morphine in prevention of stump and phantom pain in lower-limb amputation. Lancet 350, 1353–1357 (1997).
8
“...treatment of postamputation phantom limb pain should be individualized, preferably with a combination of pharmacological and nonpharmacological approaches.”
Financial & competing interests disclosure
5
7
Editorial
Borghi B, D’Addabbo M, White PF et al. The Use of prolonged peripheral neural blockade after lower extremity amputation. Anesth. Analg. 111(5), 1308–1315 (2010). Lirk P, Stadlbauer KH, Hollmann MW. ESA Clinical Trials Network 2012: PLATA–
prevention of phantom limb pain after transtibial amputation: randomised, doubleblind, controlled, multicentre trial comparing optimised intravenous pain control versus optimised intravenous pain control plus regional anaesthesia. Eur. J. Anaesthesiol. 30(5), 202–204 (2013). 9
Robinson LR, Czerniecki JM, Ehde DM et al. Trial of amitriptyline for relief of pain in amputees: results of a randomized controlled study. Arch. Phys. Med. Rehabil. 85(1), 1–6 (2004).
10 Wilder-Smith CH, Hill LT, Laurent S.
Postamputation pain and sensory changes in treatment-naive patients. Anesthesiology 103(3), 619–628 (2005).
www.futuremedicine.com
423
Editorial Nikolajsen, Christensen & Haroutiunian 11 Bone M, Critchley P, Buggy DJ. Gabapentin
in postamputation phantom limb pain: a randomized, double-blind, placebocontrolled, cross-over study. Reg. Anesth. Pain Med. 27(5), 481–486 (2002). 12 Smith DG, Ehde DM, Hanley MA et al.
Efficacy of gabapentin in treating chronic phantom limb and residual limb pain. J. Rehabil. Res. Dev. 42(5), 645–654 (2005). 13 Wu CL, Agarwal S, Tella PK. Mexiletine for
treatment of postamputation pain. Anesthesiology 109(2), 289–296 (2008). 14 Nikolajsen L, Hansen CL, Nielsen J. The
effect of ketamine on phantom pain: a central
424
neuropathic disorder maintained by peripheral input. Pain 67(1), 69–77 (1996). 15 Eichenberger U, Neff F, Sveticic G et al.
Chronic phantom limb pain: the effects of calcitonin, ketamine, and their combination on pain and sensory thresholds. Anesth. Analg. 106(4), 1265–1273 (2008). 16 Vase L, Nikolajsen L, Christensen B et al.
Cognitive-emotional sensitization contributes to wind-up-like pain in phantom limb pain patients. Pain 152(1), 157–162 (2011). 17 Nikolajsen L, Black JA, Kroner K. Neuroma
removal for neuropathic pain: efficacy and
Pain Manage. (2013) 3(6)
predictive value of lidocaine infusion. Clin. J. Pain 26(9), 788–793 (2010). 18 Nikolajsen L, Ilkjær S, Kroner K. The
influence of preamputation pain on postamputation stump and phantom pain. Pain 72(3), 393–405 (1997). 19 Nikolajsen L, Ilkjær S, Jensen TS.
Relationship between mechanical sensitivity and postamputation pain: a prospective study. Eur. J. Pain 4(4), 327–334 (2000). 20 Costigan M, Belfer I, Griffin RS et al.
Multiple chronic pain states are associated with a common amino acid-changing allele in KCNS1. Brain 133(9), 2519–2527 (2010).
future science group
