Pain Management
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Can neural blocks prevent phantom limb pain? Battista Borghi*,1, Marco D’Addabbo1 & Raffaele Borghi1
Practice points ●●
Phantom limb syndrome is the main problem for patients undergoing amputation because it has a very negative impact on their quality of life. Its etiology is very complex and involves peripheral and central nervous mechanisms.
●●
At the present time, no pharmacological or psychological (mind–body) treatment is really effective in the treatment and prevention of severe phantom limb pain.
●●
Epidural and peripheral nerve blocks are effective in reducing acute postamputation
pain but they do not prevent the later development of phantom limb pain when they are limited only to the early postamputation period (first 3 days). ●●
Peripheral nerve blocks seem to control phantom limb pain and reduce the further
development of phantom syndrome when they are continued for a prolonged time after amputation (approximately 30 days) even in an outpatient setting. Nevertheless, further studies are needed to confirm these positive results.
SUMMARY Phantom limb syndrome (PLS) is a syndrome including stump pain, phantom limb pain and not-painful phantom sensations, which involves a large part of amputee patients and often has devastating effects on their quality of life. The efficacy of standard therapies is very poor. Nerve blocks have been investigated for the treatment and prevention of PLS. Epidural and peripheral blocks limited to the first three postamputation days can only reduce acute pain but cannot prevent the later development of PLS. Recent studies have shown that ambulatory prolonged peripheral nerve block (up to 30 days postamputation) may represent a new possible option to treat phantom pain and prevent the development of PLS and chronic pain.
KEYWORDS
• continuous nerve blocks • limp amputation • phantom limb pain • phantom limb sensations • phantom pain management • prolonged
nerve blocks
Phantom limb syndrome (PLS) is a very frequent and probably the most important complication after limb amputation. PLS includes pain in the stump, phantom limb pain and phantom not-painful sensations [1–4] involving 30–90% of amputees. The etiology of PLS is still not fully understood and involves peripheral and spinal mechanisms, cortical changes and disturbed body perception. Risk factors include preamputation pain, bilateral amputation, loss of dominant upper limb, lower limb amputation, proximal amputation and depression [5,6] . Persistent stump pain (increasing over time in 5–10% of amputated patients [2]) is not considerated by many authors [1–4] as a simple risk factor but a real component of PLS syndrome. Stump pain is associated with a significantly higher prevalence of phantom pain and sensations after amputation. Research Unit of Anesthesia & Intensive Care, Department of Biomedical & Neuromotor Sciences, Rizzoli Orthopedic Institute, University of Bologna, Bologna, Italy *Author for correspondence: [email protected] 1
10.2217/PMT.14.17 © 2014 Future Medicine Ltd
Pain Manage. (2014) 4(4), 261–266
part of
ISSN 1758-1869
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Special Report Borghi, D’Addabbo & Borghi Phantom symptoms may be sometimes related to obvious stump pathologies (infection, neuromas, bone spurs) or hyperalgesia and allodynia phenomena in stump. Also, phantom pain and sensations may be improperly located in some patients proximally in the stump (‘teleporting’ phenomenon) [2]. In more than 75% of cases the syndrome is already present in the early postoperative period, but onset may be delayed in some patients for month or years [1–4]. Intensity usually decreases over time but many patients still suffer phantom pain several years after the amputation (approximately 60% 1–2 years after amputation in different studies [1,2]). At the present time no pharmacological and conservative therapy has been found to be really effective in acute phantom pain treatment and preventing the onset of PLS. Peripheral and central nerve blocks are common treatments in postoperative pain because of their high efficacy. In recent years several studies have also tried to define their possible role in treatment and prevention of PLS. Pharmacological & other treatments Several pharmacological treatments (opioids, gabapentin, N-methyl-d-aspartate receptor antagonists, antidepressants, calcitonins) have been proposed for the therapy of PLS. A recent Cochrane review [7] showed that short and long-term effectiveness of pharmacological interventions still remains unclear. Only opioids, ketamine and gabapentin seem to be slightly effective in the short-term (acute pain) treatment of PLS. The benefit of this therapy (acute pain relief) is often very small and several and serious side effects have been described. There is no evidence about effectiveness of other proposed pharmacological therapies as antidepressants, calcitonins or dextromethorphan. According to the present data no standard pharmacological therapy has a real long-term effectiveness in preventing PLS. Only in a recent, randomized but small number trial [8] an optimized intravenous perioperative patient-controlled analgesia (PCA) protocol (preoperative and postoperative fentanyl PCA) showed positive results in preventing PLS compared with standard opioid analgesia. Because of the small number of patients in the different groups in this study and the presence of conflicting results (positive effects compared with control group were shown only when preemptive and postoperative intravenous PCA was
262
Pain Manage. (2014) 4(4)
associated to general anesthesia and not when it was associated to intraoperative peridural anesthesia) further studies are needed to evaluate the real effectiveness of a perioperative intravenous therapy in preventing PLS. According to PLS etiology and similarly to other neuropathic chronic pain syndromes, also mind–body therapies [9] (mirror therapy in particular) have been recently proposed and studied also for phantom pain treatment. Despite the few positive results described, currently there is no evidence that mind–body therapies are also effective in PLS. Central block & short lasting peripheral blocks Nerve blocks have been investigated as a possible solution to prevent and treat PLS. There is an increasing evidence that the abnormal sprouting of cut fibers in amputated nerves might have a great role in causing the changes in the spinal dorsal horn function (increased excitability of nociceptive neurons) and in the cortical structures (activation of abnormal impulses, reduction in the inhibitory ways) observed in patients suffering from PLS [2] . Pre-emptive and postamputation epidural analgesia has been proposed in several studies for the prevention of PLS. In these trials epidural analgesia was started before amputation (1–3 days) up to 3 days after the intervention. The studies revealed very conflicting results. Earlier studies with a low number of patients showed promising results. In an first study [10] phantom limb pain was not present 1 year after the amputation in 11 patients with preemptive epidural analgesia started 3 days before the amputation. Pre-emptive epidural analgesia (24–48 h before the operation) was compared in one trial with postoperative systemic opioid analgesia [11] with the epidural group showing a lower incidence of phantom pain and phantom sensations at 6 months after surgery. Another trial [12] compared preoperative epidural analgesia with bupivacaine and morphine for 3 days before amputation and continued for 3 days after surgery to postoperative epidural analgesia for 3 days after surgery with a significantly lower incidence of phantom pain in the pre-emptive peridural group at the 6-month follow-up evaluation. Conversely, in two later controlled, randomized and blinded trials [13,14] when perioperative epidural analgesia (started 24 h before amputation) was compared with standard opioid
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Can neural blocks prevent phantom limb pain? analgesic therapy in preventing PLS there were no significant differences at any of the followup evaluations (from 1 week to 12 months after amputations). Recently, pre‑emptive peridural analgesia (but started 48 h before amputation and prolonged to 48 h after) showed again very effective in a blinded, randomized but small number trial [8] compared with standard opioid therapy and pre-emptive intravenous analgesia in treating early postoperative pain but also in preventing PLS appearance in the months following the amputation. All these conflicting data suggest that epidural blocks may be effective in acute phantom pain treatment in the first days after amputation compared with standard pain opioid treatment but still there is little evidence that epidural analgesia can prevent the onset of the PLS after the pain treatment is stopped; further data are needed to evaluate whether different pre-emptive and postoperative analgesia period can be really effective. Similarly to epidural blocks, continuous peripheral nerve blocks were also evaluated for treating and preventing phantom pain. Trials [15–18] differed markedly in local anesthetic, concentration and infusion rate. Local anesthetic administration was prolonged in almost all of these studies for a maximum period of three postoperative days. These studies showed a better postoperative pain relief in amputated patients treated with peripheral nerve blocks compared with patients treated with opioids but no evidence that perineural blocks can resolve chronic phantom pain when limited to the early postoperative period. Prolonged high-concentration continuous peripheral nerve block for PLS in an outpatient setting: a new therapy? Only a few recent studies have reported peripheral continuous nerve block for PLS treatment for a longer period even after hospital discharge in an outpatient setting. These studies show very promising results in the prevention of PLS. A first case report [19] reported the use of a prolonged perineural high concentration (0.5% ropivacaine 5 ml/h) local anesthetic infusion in a patient amputated 10 cm below the knee, with standard and invasive (intrathecal morphine pump system) therapy ineffective, who showed a severe (visual analog pain score 100/100 mm) PLS almost immediately after surgery. In this patient a continuous infusion of 0.5% ropivacaine 5 ml/h was started (after an initial dose
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of 0.5 ropivacaine 10 ml) through a perineuralsciatic catheter 2 days after surgery; phantom limb pain and sensations disappeared already in the first day with no recurrence up to the hospital discharge (with the perineural catheter still in situ). The patient (correctly instructed) was able to manage the local anesthetic infusion at home. A high concentration of anesthetic was used to allow the patient to periodically discontinue the infusion, reducing the anesthetic consumption and the need to reload the elastomeric pump system. On the first day, when the patient tried to stop the infusion for few hours, he rapidly redeveloped a severe phantom pain; so, considering the absence of side effects, the infusion of 0.5% ropivacaine at 5 ml/h was constantly kept on and only stopped every 7 days to evaluate the persistence of phantom pain. Phantom pain intensity gradually decreased in the following weeks. At the fourth week of infusion the patient reported the total absence of phantom pain and sensations and the catheter was removed. The patient reported no recurrence of PLS at 6, 12, 24, 36 months follow-ups. So, in the following randomized, doubleblind study PCA morphine therapy was compared with a prolonged continuous perineural infusion of local anesthetic. However, all the first four patients randomized to the PCA morphine group dropped out because of persistent severe-to-intolerable pain. Therefore, the PCA morphine arm of the study was discontinued, and all the patients received the continuous perineural local anesthetic infusion. So in the modified study [20] 62 patients undergoing lower limb amputation received a 0.5% ropivacaine 5 ml/h infusion through a perineural catheter (only sciatic, combined femoral-sciatic or lumbar-sciatic catheters, according to the amputation level, maintained even after the discharge from the hospital) for a median duration of 30 days (range 4–83 days). Local anesthetic infusion was discontinued every 7 days for a 48-h period to evaluate the presence of stump and phantom pain or sensations (any unpleasant sensation in the absent limb except pain interfering with daily activities). The local anesthetic infusion was continued until the patients experienced no or mild pain and no relevant phantom sensations in the evaluation period. At the end of the infusion protocol more than 60% of patients reported no phantom pain or sensations (with only the 6% of patients reporting phantom pain
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Controlled trial
Controlled trial
Randomized controlled and blinded trial
Randomized controlled and blinded trial
Randomized controlled and blinded trial
Randomized controlled and trial
Randomized controlled and blinded trial Case study
Jahangiri et al. (1994)
Katsuly-Liapis et al. (1996) (only abstract)
Nikolajsen et al. (1997 and 1998)
Karanikolas et al. (2011)
Karanikolas et al. (2011)
Pinzur et al. (1996)
Lambert et al. (2001)
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Prolonged perinervous continuous local anesthetic infusion (1 week in patients with chronic PLS) vs placebo
Perinervous continuous local anesthetic infusion (up to postoperative 72 h) vs preemptive 24-h epidural analgesia Prolonged perinervous continuous infusion (up to postoperative 4 weeks)
Perinervous continuous local anesthetic infusion (up to postoperative 72 h) vs systemic opioid analgesia
Pre-emptive 48-h iv. Fentanyl PCA (up to three postoperative days) vs systemic opioid analgesia
Pre-emptive 48-h epidural analgesia (up to two postoperative days) vs systemic opioid analgesia
Pre-emptive 18-h epidural analgesia (up to three postoperative days) vs epidural saline and systemic opioid analgesia
Pre-emptive 72-h epidural analgesia (up to three postoperative days) vs systemic opioid analgesia Pre-emptive 24–48-h epidural analgesia (up to three postoperative days) vs systemic opioid analgesia Pre-emptive 24–48-h epidural analgesia (up to three postoperative days) vs only postoperative epidural analgesia vs systemic opioid analgesia
Study treatment
PCA: Patient-controlled analgesia; PLS: Phantom limb syndrome.
Ilfeld et al. (2013)
Cross-over study
Randomized controlled trial
Bach et al. (1988)
Borghi et al. (2010)
Type of study
Study (year)
Two patients
62 patients in the observational group
11 patients in epidural group vs 16 patients in perinervous group
11 patients in perinervous group vs 10 patients in opioid group
13 patients PCA/intraop epidural group vs 13 patients PCA/intraop general anesthesia vs 12 patients in opioid group
13 patients in epidural group vs 12 patients in opioid group
29 patients in epidural group vs 31 patients in opioid group
15 patients in pre-emptive group vs 15 patients in postoperative epidural group vs 15 patients in opioid group
13 patients in epidural group vs 11 patients in opioid group
11 patients in epidural group vs 13 patients in opioid group
Patients (n)
Extreme reduction of phantom painafter perinervous treatment compared with placebo. The reduction was stable over time
At 6 months and 1 year extreme low incidence of PLS (compared with literature data. No control group)
At 12 months no difference between groups in PLS incidence or intensity
Better early postoperative period pain relief in perinervous group. No difference between the groups in PLS incidence and pain intensity at 6 months
At 6 months slightly lower PLS incidence and pain intensity for PCA/intraop general anesthesia compared with opioid group. No difference between PCA/intraop epidural and opioid group
At 6 months significantly lower PLS incidence and pain intensity in pre-emptive epidural group
At 6 months significantly lower PLS incidence in pre-emptive epidural group compared with other two group. No difference between postoperative epidural group and opioid group At 6 and 9 months no difference between the groups in PLS incidence, pain intensity, phantom sensations
At 6 months and 1 year significantly lower PLS incidence in epidural group
At 6 months and 1 year significantly lower PLS incidence in epidural group
Main results
Table 1. Principal studies investigating effectiveness of perioperative therapies in phantom limb syndrome prevention.
[22]
[20]
[18]
[17]
[8]
[8]
[13,14]
[12]
[11]
[10]
Ref.
Special Report Borghi, D’Addabbo & Borghi
Can neural blocks prevent phantom limb pain? or sensations badly interfering with daily life). More interestingly, the patients who reported no significant pain at the end of the local anesthetics continuous infusion did not report pain even in the following follow-up evaluations (up to 1 year). These findings may suggest that the abnormal activity of peripheral cut fibers that causes the phantom pain and later leads to changes in spinal cord and cerebral cortical centers, may outlast the early postoperative period; the prolonged perineural local anesthetic infusion following the amputation might block this late abnormal peripheral activity and prevent the PLS. In a following case report [21] a prolonged interscalene block was used with the same protocol in a patient with a severe PLS after upper extremity amputation causing PLS to disappear with no recurrence in the follow-up period. The great limitation about these positive results is the lack of the group control and the possible presence of confounding factors in neither randomized nor blinded case studies. Incidence of PLS after amputation is very variable even without any treatment according to literature. Also, PLS naturally decreases in intensity and frequency over time although a large number of patients with PLS still report considerable phantom symptoms 1–2 years after the amputation [1,2] . So, despite the positive results it is still impossible to assess real effectiveness of prolonged perineural blocks for treating PLS and to accurately quantify the possible therapeutic effect. In a recent study Ilfeld et al. [22] also experienced a prolonged high-concentration ambulatory peripheral block (ropivacaine 0.5% over 6 days in a randomized cross-over study) for the treatment of severe (10/10 in the scale pain) chronic intractable lower and upper PLS. Unfortunately this study evaluated very few patients (only two patients completed the crossover protocol of the study, first saline solution infusion and after 6 months local anesthetic infusion). The two patients experienced no differences in PLS intensity after the saline solution treatment; conversely they experienced complete resolution of PLS during the local anesthetic infusion with no recurrence for one patient and recurrence of mild pain (2/10 pain intensity compared with 10/10 in the pretreatment period) in the following 12-month follow-up period.
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Prolonged ambulatory peripheral blocks seem a future promising option in the treatment of PLS. Randomized and controlled will be needed to assess the best duration of the infusion, the possible onset of local anesthetic toxicity symptoms after a long period of infusion (in the present studies no toxicity was reported), to evaluate the real effectiveness in amputated patients and to compare prolonged peripheral neural blockades with actual pain therapies in preventing PLS. Conclusion & future perspective Phantom limb pain still represents an unresolved problem. Current studies are not able to indicate a really effective therapy not only in preventing PLS, but also in merely decreasing phantom pain intensity in the long term (see Table 1). Besides, in the future we will need to evaluate the effectiveness of different therapies not only considering pure prevalence and phantom pain reduction in the follow-up periods but also considering how much we can improve the quality of life and the functional recovery (e.g., the use of prosthesis) of amputated patients. According to present studies, neural blockades, both central and peripheral, are not or hardly useful in treating PLS when used in a ‘traditional’ way and then limited only to few days after the amputation. Optimizing ‘old’ therapies (perioperative intravenous and epidural analgesia) for selected cases (not emergency amputations) might increase our therapeutic success in treating PLS. On the other hand peripheral neural blocks, prolonged after the early postoperative period even after hospital discharge in an outpatient setting showed positive results in observational studies and might represent a new, useful for emergency patients too, option for preventing PLS. So, we absolutely need new randomized, controlled and blinded trial to evaluate their real effectiveness and the therapeutic role in preventing PLS. Financial & competing interests disclosure 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.
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Special Report Borghi, D’Addabbo & Borghi analgesia (also intravenous) showed effective in preventing PLS.
References Papers of special note have been highlighted as: • of interest; •• of considerable interest 1
Manchikanti L, Singh V. Managing phantom pain. Pain Physician 7, 365–375 (2004).
2
Nikolajsen L, Jensen TS. Phantom limb pain. Br. J. Anaesth. 87, 107–116 (2001).
3
Richardson C, Glenn S, Nurmikko T, Horgan M. Incidence of phantom phenomena including phantom limb pain 6 months after major lower limb amputation in patients with peripheral vascular disease. Clin. J. Pain 22, 353–358 (2006).
4
Houghton AD, Nicholls G, Houghton AL, Saadah E, McColl L. Phantom limb, phantom pain and stump pain in amputees during the first 6 months following limb amputation. Pain 17, 243–256 (1983).
5
Dijkstra PU, Geertzen JH, Stewart R, van der Schans CP. Phantom pain and risk factors: a multivariate analysis. J. Pain Symptom Manage. 24, 578–585 (2002).
6
Nikolajsen L, Ilkjaer S, KrØner K, Christensen JH, Jensen TS. The influence of preamputation pain on postamputation stump and phantom pain. Pain 72, 393–405 (1997).
7
•
8
•
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Alviar MJ, Hale T, Dungca M. Pharmacologic interventions for treating phantom limb pain Cochrane Database Syst. Rev. 2011(12), CD006380 (2011). Meta-analysis showing a little effectiveness in acute phantom pain relief of only opioids, ketamine and gabapentin (no effectiveness for other treatments. No effectiveness of pharmacological therapies in preventing phantom limb syndrome [PLS]) Karanikolas M, Aretha D, Tsolakis I et al. Optimized perioperative analgesia reduces chronic phantom limb pain intensity, prevalence, and frequency: a prospective, randomized, clinical trial. Anesthesiology 114(5), 1144–1154. (2001). Most recent trial about pre-emptive peridural analgesia (also pre-emptive intravenous analgesia is studied). In disaccording to earlier studies, pre-emptive
9
Moura VL, Faurot KR, Gaylord SA et al. Mind-body interventions for treatment of phantom limb pain in persons with amputation. Am. J. Phys. Med. Rehabil. 91(8), 701–714. (2012).
10 Bach S, Noreng MF, Tjellden NU. Phantom
limb pain in amputees during the first 12 months following limb amputation, after preoperative lumbar epidural blockade. Pain 33, 297–301 (1988). 11 Jahangiri M, Jayatunga AP, Bradley JW, Dark
CH. Prevention of phantom pain after major lower limb amputation by epidural infusion of diamorphine, clonidine and bupivacaine. Ann. R. Coll. Surg. Engl. 76, 324–326 (1994). 12 Katsuly-Liapis I, Georgakis P, Tierry C.
Pre-emptive extradural analgesia reduces the incidence of phantom pain in lower limb amputees [abstract]. Br. J. Anaesth. 76, 125 (1996). 13 Nikolajsen L, Ilkjaer S, Christensen JH,
KrØner K, Jensen TS. Randomised trial of epidural bupivacaine and morphine in prevention of stump and phantom pain in lower-limb amputation. Lancet 350, 1353–1357 (1997). •• Largest trial about pre-emptive epidural analgesia. In this trial there is no difference between pre-emptive analgesia and standard opioid analgesia in preventing PLS in the long term. 14 Nikolajsen L, Ilkjaer S, Jensen TS. Effect of
preoperative extradural bupivacaine and morphine on stump sensation in lower limb amputees. Br. J. Anaesth.81, 348–354 (1998). 15 Kiefer RT, Wiech K, Töpfner S et al.
Continuous brachial plexus analgesia and NMDA-receptor blockade in early phantom limb pain: a report of two cases. Pain Med. 3, 156–160 (2002). 16 Madabhushi L, Reuben SS, Steinberg RB,
Adesioye J. The efficacy of postoperative perineural infusion of bupivacaine and clonidine after lower extremity amputation in preventing phantom limb and stump pain. J. Clin. Anesth. 19, 226–229 (2007).
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17 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. 78, 1501–1505 (1996). • Trial showing effectiveness of peripheral blocks in treating early postamputation pain but no effectivenss in preventing PLS onset in the long term. 18 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. 26(4), 316–321 (2001) 19 Borghi B, Bugamelli S, Stagni G, Missiroli
M, Genco R, Colizza MT. Perineural infusion of 0.5% ropivacaine for successful treatment of phantom limb syndrome: a case report. Minerva Anestesiol. 75(11), 661–664 (2009). 20 Borghi B, D’Addabbo M, White PF et al.
The use of prolonged peripheral neural blockade after lower extremity amputation: the effect on symptoms associated with phantom limb syndrome. Anesth. Analg. 111(5), 1308–1315 (2010). •• First observational study showing (with the limitation of the lack of a group control) the possible effectiveness and safety of very prolonged (up to 4 weeks) perinervous blocks for treating PLS. 21 Tognù A, Borghi B, Gullotta S, White PF.
Ultrasound-guided posterior approach to brachial plexus for the treatment of upper phantom limb syndrome. Minerva Anestesiol.78(1), 105–108 (2012). 22 Ilfeld BM, Moeller-Bertram T, Hanling SR
et al. Treating intractable phantom limb pain with ambulatory continuous peripheral nerve blocks: a pilot study. Pain Med. 14(6), 935–942 (2013).
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SPECIAL REPORT For reprint orders, please contact: [email protected]
Can neural blocks prevent phantom limb pain? Battista Borghi*,1, Marco D’Addabbo1 & Raffaele Borghi1
Practice points ●●
Phantom limb syndrome is the main problem for patients undergoing amputation because it has a very negative impact on their quality of life. Its etiology is very complex and involves peripheral and central nervous mechanisms.
●●
At the present time, no pharmacological or psychological (mind–body) treatment is really effective in the treatment and prevention of severe phantom limb pain.
●●
Epidural and peripheral nerve blocks are effective in reducing acute postamputation
pain but they do not prevent the later development of phantom limb pain when they are limited only to the early postamputation period (first 3 days). ●●
Peripheral nerve blocks seem to control phantom limb pain and reduce the further
development of phantom syndrome when they are continued for a prolonged time after amputation (approximately 30 days) even in an outpatient setting. Nevertheless, further studies are needed to confirm these positive results.
SUMMARY Phantom limb syndrome (PLS) is a syndrome including stump pain, phantom limb pain and not-painful phantom sensations, which involves a large part of amputee patients and often has devastating effects on their quality of life. The efficacy of standard therapies is very poor. Nerve blocks have been investigated for the treatment and prevention of PLS. Epidural and peripheral blocks limited to the first three postamputation days can only reduce acute pain but cannot prevent the later development of PLS. Recent studies have shown that ambulatory prolonged peripheral nerve block (up to 30 days postamputation) may represent a new possible option to treat phantom pain and prevent the development of PLS and chronic pain.
KEYWORDS
• continuous nerve blocks • limp amputation • phantom limb pain • phantom limb sensations • phantom pain management • prolonged
nerve blocks
Phantom limb syndrome (PLS) is a very frequent and probably the most important complication after limb amputation. PLS includes pain in the stump, phantom limb pain and phantom not-painful sensations [1–4] involving 30–90% of amputees. The etiology of PLS is still not fully understood and involves peripheral and spinal mechanisms, cortical changes and disturbed body perception. Risk factors include preamputation pain, bilateral amputation, loss of dominant upper limb, lower limb amputation, proximal amputation and depression [5,6] . Persistent stump pain (increasing over time in 5–10% of amputated patients [2]) is not considerated by many authors [1–4] as a simple risk factor but a real component of PLS syndrome. Stump pain is associated with a significantly higher prevalence of phantom pain and sensations after amputation. Research Unit of Anesthesia & Intensive Care, Department of Biomedical & Neuromotor Sciences, Rizzoli Orthopedic Institute, University of Bologna, Bologna, Italy *Author for correspondence: [email protected] 1
10.2217/PMT.14.17 © 2014 Future Medicine Ltd
Pain Manage. (2014) 4(4), 261–266
part of
ISSN 1758-1869
261
Special Report Borghi, D’Addabbo & Borghi Phantom symptoms may be sometimes related to obvious stump pathologies (infection, neuromas, bone spurs) or hyperalgesia and allodynia phenomena in stump. Also, phantom pain and sensations may be improperly located in some patients proximally in the stump (‘teleporting’ phenomenon) [2]. In more than 75% of cases the syndrome is already present in the early postoperative period, but onset may be delayed in some patients for month or years [1–4]. Intensity usually decreases over time but many patients still suffer phantom pain several years after the amputation (approximately 60% 1–2 years after amputation in different studies [1,2]). At the present time no pharmacological and conservative therapy has been found to be really effective in acute phantom pain treatment and preventing the onset of PLS. Peripheral and central nerve blocks are common treatments in postoperative pain because of their high efficacy. In recent years several studies have also tried to define their possible role in treatment and prevention of PLS. Pharmacological & other treatments Several pharmacological treatments (opioids, gabapentin, N-methyl-d-aspartate receptor antagonists, antidepressants, calcitonins) have been proposed for the therapy of PLS. A recent Cochrane review [7] showed that short and long-term effectiveness of pharmacological interventions still remains unclear. Only opioids, ketamine and gabapentin seem to be slightly effective in the short-term (acute pain) treatment of PLS. The benefit of this therapy (acute pain relief) is often very small and several and serious side effects have been described. There is no evidence about effectiveness of other proposed pharmacological therapies as antidepressants, calcitonins or dextromethorphan. According to the present data no standard pharmacological therapy has a real long-term effectiveness in preventing PLS. Only in a recent, randomized but small number trial [8] an optimized intravenous perioperative patient-controlled analgesia (PCA) protocol (preoperative and postoperative fentanyl PCA) showed positive results in preventing PLS compared with standard opioid analgesia. Because of the small number of patients in the different groups in this study and the presence of conflicting results (positive effects compared with control group were shown only when preemptive and postoperative intravenous PCA was
262
Pain Manage. (2014) 4(4)
associated to general anesthesia and not when it was associated to intraoperative peridural anesthesia) further studies are needed to evaluate the real effectiveness of a perioperative intravenous therapy in preventing PLS. According to PLS etiology and similarly to other neuropathic chronic pain syndromes, also mind–body therapies [9] (mirror therapy in particular) have been recently proposed and studied also for phantom pain treatment. Despite the few positive results described, currently there is no evidence that mind–body therapies are also effective in PLS. Central block & short lasting peripheral blocks Nerve blocks have been investigated as a possible solution to prevent and treat PLS. There is an increasing evidence that the abnormal sprouting of cut fibers in amputated nerves might have a great role in causing the changes in the spinal dorsal horn function (increased excitability of nociceptive neurons) and in the cortical structures (activation of abnormal impulses, reduction in the inhibitory ways) observed in patients suffering from PLS [2] . Pre-emptive and postamputation epidural analgesia has been proposed in several studies for the prevention of PLS. In these trials epidural analgesia was started before amputation (1–3 days) up to 3 days after the intervention. The studies revealed very conflicting results. Earlier studies with a low number of patients showed promising results. In an first study [10] phantom limb pain was not present 1 year after the amputation in 11 patients with preemptive epidural analgesia started 3 days before the amputation. Pre-emptive epidural analgesia (24–48 h before the operation) was compared in one trial with postoperative systemic opioid analgesia [11] with the epidural group showing a lower incidence of phantom pain and phantom sensations at 6 months after surgery. Another trial [12] compared preoperative epidural analgesia with bupivacaine and morphine for 3 days before amputation and continued for 3 days after surgery to postoperative epidural analgesia for 3 days after surgery with a significantly lower incidence of phantom pain in the pre-emptive peridural group at the 6-month follow-up evaluation. Conversely, in two later controlled, randomized and blinded trials [13,14] when perioperative epidural analgesia (started 24 h before amputation) was compared with standard opioid
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Can neural blocks prevent phantom limb pain? analgesic therapy in preventing PLS there were no significant differences at any of the followup evaluations (from 1 week to 12 months after amputations). Recently, pre‑emptive peridural analgesia (but started 48 h before amputation and prolonged to 48 h after) showed again very effective in a blinded, randomized but small number trial [8] compared with standard opioid therapy and pre-emptive intravenous analgesia in treating early postoperative pain but also in preventing PLS appearance in the months following the amputation. All these conflicting data suggest that epidural blocks may be effective in acute phantom pain treatment in the first days after amputation compared with standard pain opioid treatment but still there is little evidence that epidural analgesia can prevent the onset of the PLS after the pain treatment is stopped; further data are needed to evaluate whether different pre-emptive and postoperative analgesia period can be really effective. Similarly to epidural blocks, continuous peripheral nerve blocks were also evaluated for treating and preventing phantom pain. Trials [15–18] differed markedly in local anesthetic, concentration and infusion rate. Local anesthetic administration was prolonged in almost all of these studies for a maximum period of three postoperative days. These studies showed a better postoperative pain relief in amputated patients treated with peripheral nerve blocks compared with patients treated with opioids but no evidence that perineural blocks can resolve chronic phantom pain when limited to the early postoperative period. Prolonged high-concentration continuous peripheral nerve block for PLS in an outpatient setting: a new therapy? Only a few recent studies have reported peripheral continuous nerve block for PLS treatment for a longer period even after hospital discharge in an outpatient setting. These studies show very promising results in the prevention of PLS. A first case report [19] reported the use of a prolonged perineural high concentration (0.5% ropivacaine 5 ml/h) local anesthetic infusion in a patient amputated 10 cm below the knee, with standard and invasive (intrathecal morphine pump system) therapy ineffective, who showed a severe (visual analog pain score 100/100 mm) PLS almost immediately after surgery. In this patient a continuous infusion of 0.5% ropivacaine 5 ml/h was started (after an initial dose
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of 0.5 ropivacaine 10 ml) through a perineuralsciatic catheter 2 days after surgery; phantom limb pain and sensations disappeared already in the first day with no recurrence up to the hospital discharge (with the perineural catheter still in situ). The patient (correctly instructed) was able to manage the local anesthetic infusion at home. A high concentration of anesthetic was used to allow the patient to periodically discontinue the infusion, reducing the anesthetic consumption and the need to reload the elastomeric pump system. On the first day, when the patient tried to stop the infusion for few hours, he rapidly redeveloped a severe phantom pain; so, considering the absence of side effects, the infusion of 0.5% ropivacaine at 5 ml/h was constantly kept on and only stopped every 7 days to evaluate the persistence of phantom pain. Phantom pain intensity gradually decreased in the following weeks. At the fourth week of infusion the patient reported the total absence of phantom pain and sensations and the catheter was removed. The patient reported no recurrence of PLS at 6, 12, 24, 36 months follow-ups. So, in the following randomized, doubleblind study PCA morphine therapy was compared with a prolonged continuous perineural infusion of local anesthetic. However, all the first four patients randomized to the PCA morphine group dropped out because of persistent severe-to-intolerable pain. Therefore, the PCA morphine arm of the study was discontinued, and all the patients received the continuous perineural local anesthetic infusion. So in the modified study [20] 62 patients undergoing lower limb amputation received a 0.5% ropivacaine 5 ml/h infusion through a perineural catheter (only sciatic, combined femoral-sciatic or lumbar-sciatic catheters, according to the amputation level, maintained even after the discharge from the hospital) for a median duration of 30 days (range 4–83 days). Local anesthetic infusion was discontinued every 7 days for a 48-h period to evaluate the presence of stump and phantom pain or sensations (any unpleasant sensation in the absent limb except pain interfering with daily activities). The local anesthetic infusion was continued until the patients experienced no or mild pain and no relevant phantom sensations in the evaluation period. At the end of the infusion protocol more than 60% of patients reported no phantom pain or sensations (with only the 6% of patients reporting phantom pain
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Controlled trial
Controlled trial
Randomized controlled and blinded trial
Randomized controlled and blinded trial
Randomized controlled and blinded trial
Randomized controlled and trial
Randomized controlled and blinded trial Case study
Jahangiri et al. (1994)
Katsuly-Liapis et al. (1996) (only abstract)
Nikolajsen et al. (1997 and 1998)
Karanikolas et al. (2011)
Karanikolas et al. (2011)
Pinzur et al. (1996)
Lambert et al. (2001)
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Prolonged perinervous continuous local anesthetic infusion (1 week in patients with chronic PLS) vs placebo
Perinervous continuous local anesthetic infusion (up to postoperative 72 h) vs preemptive 24-h epidural analgesia Prolonged perinervous continuous infusion (up to postoperative 4 weeks)
Perinervous continuous local anesthetic infusion (up to postoperative 72 h) vs systemic opioid analgesia
Pre-emptive 48-h iv. Fentanyl PCA (up to three postoperative days) vs systemic opioid analgesia
Pre-emptive 48-h epidural analgesia (up to two postoperative days) vs systemic opioid analgesia
Pre-emptive 18-h epidural analgesia (up to three postoperative days) vs epidural saline and systemic opioid analgesia
Pre-emptive 72-h epidural analgesia (up to three postoperative days) vs systemic opioid analgesia Pre-emptive 24–48-h epidural analgesia (up to three postoperative days) vs systemic opioid analgesia Pre-emptive 24–48-h epidural analgesia (up to three postoperative days) vs only postoperative epidural analgesia vs systemic opioid analgesia
Study treatment
PCA: Patient-controlled analgesia; PLS: Phantom limb syndrome.
Ilfeld et al. (2013)
Cross-over study
Randomized controlled trial
Bach et al. (1988)
Borghi et al. (2010)
Type of study
Study (year)
Two patients
62 patients in the observational group
11 patients in epidural group vs 16 patients in perinervous group
11 patients in perinervous group vs 10 patients in opioid group
13 patients PCA/intraop epidural group vs 13 patients PCA/intraop general anesthesia vs 12 patients in opioid group
13 patients in epidural group vs 12 patients in opioid group
29 patients in epidural group vs 31 patients in opioid group
15 patients in pre-emptive group vs 15 patients in postoperative epidural group vs 15 patients in opioid group
13 patients in epidural group vs 11 patients in opioid group
11 patients in epidural group vs 13 patients in opioid group
Patients (n)
Extreme reduction of phantom painafter perinervous treatment compared with placebo. The reduction was stable over time
At 6 months and 1 year extreme low incidence of PLS (compared with literature data. No control group)
At 12 months no difference between groups in PLS incidence or intensity
Better early postoperative period pain relief in perinervous group. No difference between the groups in PLS incidence and pain intensity at 6 months
At 6 months slightly lower PLS incidence and pain intensity for PCA/intraop general anesthesia compared with opioid group. No difference between PCA/intraop epidural and opioid group
At 6 months significantly lower PLS incidence and pain intensity in pre-emptive epidural group
At 6 months significantly lower PLS incidence in pre-emptive epidural group compared with other two group. No difference between postoperative epidural group and opioid group At 6 and 9 months no difference between the groups in PLS incidence, pain intensity, phantom sensations
At 6 months and 1 year significantly lower PLS incidence in epidural group
At 6 months and 1 year significantly lower PLS incidence in epidural group
Main results
Table 1. Principal studies investigating effectiveness of perioperative therapies in phantom limb syndrome prevention.
[22]
[20]
[18]
[17]
[8]
[8]
[13,14]
[12]
[11]
[10]
Ref.
Special Report Borghi, D’Addabbo & Borghi
Can neural blocks prevent phantom limb pain? or sensations badly interfering with daily life). More interestingly, the patients who reported no significant pain at the end of the local anesthetics continuous infusion did not report pain even in the following follow-up evaluations (up to 1 year). These findings may suggest that the abnormal activity of peripheral cut fibers that causes the phantom pain and later leads to changes in spinal cord and cerebral cortical centers, may outlast the early postoperative period; the prolonged perineural local anesthetic infusion following the amputation might block this late abnormal peripheral activity and prevent the PLS. In a following case report [21] a prolonged interscalene block was used with the same protocol in a patient with a severe PLS after upper extremity amputation causing PLS to disappear with no recurrence in the follow-up period. The great limitation about these positive results is the lack of the group control and the possible presence of confounding factors in neither randomized nor blinded case studies. Incidence of PLS after amputation is very variable even without any treatment according to literature. Also, PLS naturally decreases in intensity and frequency over time although a large number of patients with PLS still report considerable phantom symptoms 1–2 years after the amputation [1,2] . So, despite the positive results it is still impossible to assess real effectiveness of prolonged perineural blocks for treating PLS and to accurately quantify the possible therapeutic effect. In a recent study Ilfeld et al. [22] also experienced a prolonged high-concentration ambulatory peripheral block (ropivacaine 0.5% over 6 days in a randomized cross-over study) for the treatment of severe (10/10 in the scale pain) chronic intractable lower and upper PLS. Unfortunately this study evaluated very few patients (only two patients completed the crossover protocol of the study, first saline solution infusion and after 6 months local anesthetic infusion). The two patients experienced no differences in PLS intensity after the saline solution treatment; conversely they experienced complete resolution of PLS during the local anesthetic infusion with no recurrence for one patient and recurrence of mild pain (2/10 pain intensity compared with 10/10 in the pretreatment period) in the following 12-month follow-up period.
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Prolonged ambulatory peripheral blocks seem a future promising option in the treatment of PLS. Randomized and controlled will be needed to assess the best duration of the infusion, the possible onset of local anesthetic toxicity symptoms after a long period of infusion (in the present studies no toxicity was reported), to evaluate the real effectiveness in amputated patients and to compare prolonged peripheral neural blockades with actual pain therapies in preventing PLS. Conclusion & future perspective Phantom limb pain still represents an unresolved problem. Current studies are not able to indicate a really effective therapy not only in preventing PLS, but also in merely decreasing phantom pain intensity in the long term (see Table 1). Besides, in the future we will need to evaluate the effectiveness of different therapies not only considering pure prevalence and phantom pain reduction in the follow-up periods but also considering how much we can improve the quality of life and the functional recovery (e.g., the use of prosthesis) of amputated patients. According to present studies, neural blockades, both central and peripheral, are not or hardly useful in treating PLS when used in a ‘traditional’ way and then limited only to few days after the amputation. Optimizing ‘old’ therapies (perioperative intravenous and epidural analgesia) for selected cases (not emergency amputations) might increase our therapeutic success in treating PLS. On the other hand peripheral neural blocks, prolonged after the early postoperative period even after hospital discharge in an outpatient setting showed positive results in observational studies and might represent a new, useful for emergency patients too, option for preventing PLS. So, we absolutely need new randomized, controlled and blinded trial to evaluate their real effectiveness and the therapeutic role in preventing PLS. Financial & competing interests disclosure 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.
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Special Report Borghi, D’Addabbo & Borghi analgesia (also intravenous) showed effective in preventing PLS.
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Alviar MJ, Hale T, Dungca M. Pharmacologic interventions for treating phantom limb pain Cochrane Database Syst. Rev. 2011(12), CD006380 (2011). Meta-analysis showing a little effectiveness in acute phantom pain relief of only opioids, ketamine and gabapentin (no effectiveness for other treatments. No effectiveness of pharmacological therapies in preventing phantom limb syndrome [PLS]) Karanikolas M, Aretha D, Tsolakis I et al. Optimized perioperative analgesia reduces chronic phantom limb pain intensity, prevalence, and frequency: a prospective, randomized, clinical trial. Anesthesiology 114(5), 1144–1154. (2001). Most recent trial about pre-emptive peridural analgesia (also pre-emptive intravenous analgesia is studied). In disaccording to earlier studies, pre-emptive
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