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Painful Sequelae Following Limb Salvage: Etiology and Management

Goff, Brandon J. DO; Castillo, Renan PhD; Raja, Srinivasa N. MD

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American Academy of Orthopaedic Surgeon: February 2011 - Volume 19 - Issue - p S23-S27
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Approximately one half of combat injuries are associated with severe trauma to the lower extremity. 1 Improved wound therapy, aggressive surgical approaches, early wound closure, and antibiotic therapy have resulted in limb salvage rates >90%.2 Chronic pain and impaired function are common sequelae of limb salvage and are major reasons why these patients request conversion to amputation. The accumulating evidence from the current wars substantiates clinical observations that injured soldiers with poorly controlled pain go on to experience chronic pain and posttraumatic stress disorder.3,4 Results from the Lower Extremity Assessment Project study have shown that poorly controlled postoperative pain is linked to increased disability (eg, decreased participation in therapy, increased delay in return to work), psychological distress (eg, anxiety, depression, posttraumatic stress disorder), social dysfunction, and chronic pain.5–8

Chronic pain produces unnecessary suffering and has a negative effect on long-term function. Pain following limb salvage must be managed early, aggressively, and comprehensively.


Pain during limb salvage is similar to the pain experienced by patients who proceed to amputation. Pain associated with limb salvage may have multiple causes. It may be the result of direct injury to soft tissue and/or bone, fused or partially fused joints, or heterotopic ossification, or it may occur secondary to posttraumatic arthritis. Neuropathic pain has multiple etiologies, as well, including partial or complete nerve injury, neuroma development, nerve entrapment, sympathetically maintained pain, and complex regional pain syndrome (CRPS). Stump and phantom pain may occur following amputation.

The degree of pain control during the limb salvage stage is a critical factor in the development of pain following amputation. Stump pain is often analogous to the traumatic pain of limb salvage. Treatment of a correctable cause of stump pain leads to a reduction in phantom pain.9 The study of phantom limb sensation and pain is important in the management of limb salvage pain because of the role of central sensitization and brain plasticity.10 Phantom pain often mimics pain in the injured limb before amputation. Amputees with significant persistent pain often experience intense and long-lasting preamputation pain. Chronic preamputation pain creates a pain imprint in neural networks in the central nervous system; this imprinting may account for persistent phantom pain.11 Epidural blockade with a combination of regional and peripheral blockade before and during extremity surgery has been suggested to prevent central sensitization.12 A higher prevalence of low back pain has been noted in amputees with prolonged use of prostheses.13 CRPS is one of the most debilitating pain conditions that occurs during limb salvage. Patients describe continuous, severe, functionally limiting pain associated with allodynia, hyperalgesia, skin color changes, edema, joint stiffness, and bone demineralization.14


Pharmacologic Options

Early multimodal pharmacologic intervention is the prevailing treatment strategy.15,16 Opioids are the mainstay in the management of acute trauma pain, including intramuscular (at the combat medic level), intravenous, patient-controlled, transdermal, transmucosal, and oral analgesia. Acetaminophen has gained in popularity because of its analgesic and antipyretic effects as well as its synergy with opioid agonist medications. Evidence suggests that acetaminophen also works at the level of cannabinoid receptors.17 Nonsteroidal anti-inflammatory drugs, which range from aspirin to celecoxib in safety profile, play an important role in preemptive analgesia.18 A more direct delivery to the site of pain using a transdermal diclofenac patch or gel is one option to help mitigate the side effects of nonsteroidal antiinflammatory drugs.19

Capsaicin depletes substance P and is effective in neuropathic pain states. A high-concentration patch (ie, 8%) was recently approved for postherpetic neuralgia.20 The drawback to traditional self-application of lower concentration capsaicin is that the skin must be intact and the cream must be applied every 8 hours. Although the 8% capsaicin patch has a longer duration of action of up to 12 weeks after a one-time treatment, it must be applied under a physician's supervision. Moreover, its efficacy in other neuropathic pain states has not been clearly demonstrated.

Excellent results have been reported with the use of antineuropathic pain medications in the management of limb trauma.21–23 The limiting side effect is usually drowsiness at higher doses—for example, gabapentin 600 to 1,200 mg every 8 hours or pregabalin 75 to 150 mg every 12 hours. These medications are more effective in lower doses when used in combination with tricyclic antidepressants.24

Antidepressant medications, specifically the serotonin-norepinephrine reuptake inhibitors (eg, duloxetine hydrochloride), improve sleep, depression, and neuropathic pain.25 Duloxetine and milnacipran are often used in combination with antineuropathic medications. Centrally acting medications must be used with caution when they are combined with a tricyclic antidepressant because of the potential for long QT syndrome.26

Agents that promote wakefulness, such as modafinil and armodafinil, are often underutilized in rehabilitation following limb trauma. Whether because of the environmental disruption of living in a hospital or the psychological stress caused by reintegration into society after injury, sleep quality suffers, and patients are often drowsy during the day. Opioid medications distort the sleep cycle by causing drowsiness.27 Modafinil and armodafinil work synergistically with analgesic medications and help to improve patient focus and alertness during the day.28

Treatment options for CRPS emphasize early intervention using activity and mobilization with physical and occupational therapy, movement therapies, and modalities. An especially helpful modality is desensitization using fluidized therapy. Selfmassage of the affected area is also helpful. Other options include compression garments, transcutaneous electrical nerve stimulation and related technologies, acupuncture, mirror therapy, and other complementary medical treatments. Because of the disabling nature of CRPS, pain psychology plays an important role in treatment and rehabilitation. This may include counseling, biofeedback, and relaxation training.

Options for Intervention

Bedside options include the injection of scars, neuromas, stumps, hardware, and deep fragments using various combinations of steroids, local anesthetics, and botulinum toxins (types A and B). Intra-articular injections may use steroids, local anesthetics, hyaluronic acids, and compounded capsaicin. Peripheral nerve blocks can be performed for diagnosis (ie, local anesthetic) or ablation (eg, phenol, alcohol). Many interventional pain procedures exist.29,30

When targeting a specific painful area of a limb, it may be helpful to treat the applicable dorsal root ganglion with pulsed radiofrequency le sioning. For example, the dorsal root ganglion of L4 is targeted in the management of medial leg and ankle pain.

Sympathetically maintained limb pain is one of the more difficult types to manage. Mainstays of treatment include stellate ganglion blocks for the upper extremities and lumbar sympathetic blocks for the lower extremities. These blocks may be repeated as necessary, or management may progress to pulsed radiofrequency lesioning of the plexus.31–33

Spinal cord stimulation (SCS) and neuromodulation refer to a group of similar procedures involving placement of electrodes in the epidural space or alongside peripheral nerves. This is traditionally considered to be an effective alternative or adjunct treatment. Technically, such procedures are reversible, in that the systems can be explanted. Pain is alleviated by the electrical activation of pain-inhibiting neuronal circuits in the dorsal horn, which induces a paresthesia that masks the sensations of pain. Effectiveness studies show that neuromodulation provides significant pain relief; it has been associated with substantial long-term success as measured by global perceived effect in CRPS and other neuropathic pain states.34–40 Other studies have demonstrated that SCS leads to reduction in medication use and improvements in function and activities of daily living, and that it enables patients to return to work.34–40

Targeted retrograde neuromodulation is a specialized technique in which the lead is advanced in retrograde fashion into the vertebral neuroforamina to cover the exiting nerve root. A significant technical limitation of SCS systems is their general incompatibility with MRI. MRI-compatible leads (≤7 T) are expected to be available soon. The introduction of MRI-compatible leads will make neuromodulation a viable option for even more patients. Neuromodulation is usually a two-step procedure, involving a trial that, if successful, is followed by permanent implantation. During the trial, a percutaneous lead is placed under fluoroscopic guidance, and the patient is sent home the same day with an external pulse generator. After a successful trial lasting ≤1 week, the device is removed in the clinic. A >50% decrease in pain warrants permanent surgical implantation involving the creation of a tunnel and of a pocket for the implantable pulse generator.34–40

The bion (Advanced Bionics, Valencia, CA) is a micro neurostimulator that is allowed for investigational use only in the United States. The device, 28 mm in length and 3 mm in diameter, is entirely self-contained. The bion is inserted percutaneously next to the nerve. Because it is self-contained, it eliminates the need for tunneled wires and an invasive implantable pulse generator pocket in the buttock or abdomen, both of which are required for peripheral nerve stimulation systems. This technology is already being used outside the United States to manage chronic pain.41


Interdisciplinary Pain Care

Comprehensive interdisciplinary pain care is the goal for limb salvage patients. Pain medicine is a young specialty. In 2006 the Accreditation Council for Graduate Medical Education began limiting the subspecialty certification process for pain medicine to physicians with primary boards in anesthesiology, physical medicine and rehabilitation, neurology, and psychiatry.42 It may be some time before core knowledge and common practice patterns unify the practice of pain medicine.

Ideally, a pain clinic should employ interventional and noninterventional pain medicine physicians along with experts in pain nursing, pain psychology, psychiatry, acupuncture, manual medicine, complementary medicine, physical therapy, occupational therapy, kinesiology, and exercise physiology. Pain clinics should have strong partnerships with primary care physicians, as well. Although not all of these resources may be organic to any given clinic, close relationships and referral patterns should exist. Interdisciplinary patient conferences should be held regularly to discuss difficult cases from many perspectives.


Since the commencement of Operations Enduring Freedom and Iraqi Freedom, we have learned that aggressive early pain care with continuous peripheral nerve block catheters before and during surgery provides improved overall pain relief. Continuous peripheral nerve block catheter usage decreases pain during limb salvage.43 The creation and staffing of pain clinics with pain specialists at facilities in or near theater reduces the number of unnecessary medical evacuations for treatable pain conditions. This, in turn, leads to a reduction in the number of soldiers who return to the United States with chronic pain, only to become lost in the military and Veterans Affairs disability systems.44 Patients should be referred to pain specialists early to begin treatment before the onset of the behavioral characteristics endemic to the patient with chronic disability. Patients should also be given realistic expectations; often, complete relief is not possible.

The future holds much promise for pain management in persons who undergo traumatic limb salvage. Pain management research is ongoing. Early intervention may prevent the onset of chronic pain and potentially reduce the number of unnecessary conversions to amputation for the management of functionally limiting pain.


1. Owens BD, Kragh JF Jr, Wenke JC, Macaitis J, Wade CE, Holcomb JB: Combat wounds in operation Iraqi Freedom and operation Enduring Freedom. J Trauma 2008;64(2):295-299.
2. Geiger S, McCormick F, Chou R, Wandel AG: War wounds: Lessons learned from Operation Iraqi Freedom. Plast Reconstr Surg 2008;122(1):146-153.
3. Clark ME, Bair MJ, Buckenmaier CC III, Gironda RJ, Walker RL: Pain and combat injuries in soldiers returning from Operations Enduring Freedom and Iraqi Freedom: Implications for research and practice. J Rehabil Res Dev 2007; 44(2):179-194.
4. Holbrook TL, Galarneau MR, Dye JL, Quinn K, Dougherty AL: Morphine use after combat injury in Iraq and posttraumatic stress disorder. N Engl J Med 2010;362(2):110-117.
5. Bosse MJ, MacKenzie EJ, Kellam JF, et al: An analysis of outcomes of reconstruction or amputation after legthreatening injuries. N Engl J Med 2002; 347(24):1924-1931.
6. Castillo RC, MacKenzie EJ, Webb LX, Bosse MJ, Avery J; LEAP Study Group: Use and perceived need of physical therapy following severe lower-extremity trauma. Arch Phys Med Rehabil 2005; 86(9):1722-1728.
7. Castillo RC, MacKenzie EJ, Wegener ST, Bosse MJ; LEAP Study Group: Prevalence of chronic pain seven years following limb threatening lower extremity trauma. Pain 2006;124(3): 321-329.
8. O'Toole RV, Castillo RC, Pollak AN, MacKenzie EJ, Bosse MJ; LEAP Study Group: Determinants of patient satisfaction after severe lower-extremity injuries. J Bone Joint Surg Am 2008; 90(6):1206-1211.
9. Nikolajsen L, Jensen TS: Phantom limb pain. Br J Anaesth 2001;87(1):107-116.
10. Flor H, Nikolajsen L, Staehelin Jensen T: Phantom limb pain: A case of maladaptive CNS plasticity? Nat Rev Neurosci 2006;7(11):873-881.
11. Melzack R, Coderre TJ, Katz J, Vaccarino AL: Central neuroplasticity and pathological pain. Ann N Y Acad Sci 2001;933:157-174.
12. Baker BC, Buckenmaier C, Narine N, Compeggie ME, Brand GJ, Mongan PD: Battlefield anesthesia: Advances in patient care and pain management. Anesthesiol Clin 2007;25(1):131-145, x.
13. Stam HJ, Dommisse AM, Bussmann HJ: Prevalence of low back pain after transfemoral amputation related to physical activity and other prosthesisrelated parameters. Disabil Rehabil 2004;26(13):794-797.
14. Harden RN, Bruehl S, Stanton-Hicks M, Wilson PR: Proposed new diagnostic criteria for complex regional pain syndrome. Pain Med 2007;8(4):326-331.
15. Buvanendran A, Kroin JS: Multimodal analgesia for controlling acute postoperative pain. Curr Opin Anaesthesiol 2009;22(5):588-593.
16. Montané E, Vallano A, Aguilera C, Vidal X, Laporte JR: Analgesics for pain after traumatic or orthopaedic surgery: What is the evidence. A systematic review. Eur J Clin Pharmacol 2006;62(11):971-988.
17. Smith HS: Potential analgesic mechanisms of acetaminophen. Pain Physician 2009;12(1):269-280.
18. Ochroch EA, Mardini IA, Gottschalk A: What is the role of NSAIDs in preemptive analgesia? Drugs 2003;63(24): 2709-2723.
19. Wolfe MM, Lichtenstein DR, Singh G: Gastrointestinal toxicity of nonsteroidal antiinflammatory drugs. N Engl J Med 1999;340(24):1888-1899.
20. Backonja M, Wallace MS, Blonsky ER, et al; NGX-4010 C116 Study Group: NGX-4010, a high-concentration capsaicin patch, for the treatment of postherpetic neuralgia: A randomised, double-blind study. Lancet Neurol 2008; 7(12):1106-1112.
21. Dworkin RH, O'Connor AB, Backonja M, et al: Pharmacologic management of neuropathic pain: Evidence-based recommendations. Pain 2007;132(3): 237-251.
22. Gilron I: Gabapentin and pregabalin for chronic neuropathic and early postsurgical pain: Current evidence and future directions. Curr Opin Anaesthesiol 2007;20(5):456-472.
23. Moore RA, Straube S, Wiffen PJ, Derry S, McQuay HJ: Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev 2009;3:CD007076.
24. Gilron I, Bailey JM, Tu D, Holden RR, Jackson AC, Houlden RL: Nortriptyline and gabapentin, alone and in combination for neuropathic pain: A double-blind, randomised controlled crossover trial. Lancet 2009;374(9697): 1252-1261.
25. Saarto T, Wiffen PJ: Antidepressants for neuropathic pain. Cochrane Database Syst Rev 2007;4:CD005454.
26. Alvarez PA, Pahissa J: QT alterations in psychopharmacology: Proven candidates and suspects. Curr Drug Saf 2010;5(1): 97-104.
27. Watson CJ, Lydic R, Baghdoyan HA: Sleep and GABA levels in the oral part of rat pontine reticular formation are decreased by local and systemic administration of morphine. Neuroscience 2007;144(1):375-386.
28. Reissig JE, Rybarczyk AM: Pharmacologic treatment of opioidinduced sedation in chronic pain. Ann Pharmacother 2005;39(4):727-731.
29. Manchikanti L, Boswell MV, Singh V, et al; ASIPP: Comprehensive review of neurophysiologic basis and diagnostic interventions in managing chronic spinal pain. Pain Physician 2009;12(4):E71-E120.
30. Boswell MV, Trescot AM, Datta S, et al; American Society of Interventional Pain Physicians: Interventional techniques: Evidence-based practice guidelines in the management of chronic spinal pain. Pain Physician 2007;10(1):7-111.
31. Baron R, Levine JD, Fields HL: Causalgia and reflex sympathetic dystrophy: Does the sympathetic nervous system contribute to the generation of pain? Muscle Nerve 1999;22(6):678-695.
32. Simopoulos TT, Kraemer J, Nagda JV, Aner M, Bajwa ZH: Response to pulsed and continuous radiofrequency lesioning of the dorsal root ganglion and segmental nerves in patients with chronic lumbar radicular pain. Pain Physician 2008;11(2):137-144.
33. Forouzanfar T, van Kleef M, Weber WE: Radiofrequency lesions of the stellate ganglion in chronic pain syndromes: Retrospective analysis of clinical efficacy in 86 patients. Clin J Pain 2000;16(2): 164-168.
34. Kumar K, Hunter G, Demeria D: Spinal cord stimulation in treatment of chronic benign pain: Challenges in treatment planning and present status, a 22-year experience. Neurosurgery 2006;58(3): 481-496.
35. Harke H, Gretenkort P, Ladleif HU, Rahman S: Spinal cord stimulation in sympathetically maintained complex regional pain syndrome type I with severe disability: A prospective clinical study. Eur J Pain 2005;9(4):363-373.
36. Kemler MA, de Vet HC, Barendse GA, van den Wildenberg FA, van Kleef M: Effect of spinal cord stimulation for chronic complex regional pain syndrome type I: Five-year final follow-up of patients in a randomized controlled trial. J Neurosurg 2008;108(2):292-298.
37. Kemler MA, De Vet HC, Barendse GA, Van Den Wildenberg FA, Van Kleef M: The effect of spinal cord stimulation in patients with chronic reflex sympathetic dystrophy: Two years' follow-up of the randomized controlled trial. Ann Neurol 2004;55(1):13-18.
38. Bennett DS, Alo KM, Oakley J, Feler CA: Spinal cord stimulation for complex regional pain syndrome [RSD]: A retrospective multicenter experience from 1995 to 1998 of 101 patients. Neuromodulation 1999;2(3):201-210.
39. Kemler MA, Barendse GA, Van Kleef M, Van Den Wildenberg FA, Weber WE: Electrical spinal cord stimulation in reflex sympathetic dystrophy: Retrospective analysis of 23 patients. J Neurosurg 1999;90(1 suppl):79-83.
40. Kumar K, Malik S, Demeria D: Treatment of chronic pain with spinal cord stimulation versus alternative therapies: Cost-effectiveness analysis. Neurosurgery 2002;51(1):106-115.
41. Misawa A, Shimada Y, Matsunaga T, et al: The use of the RF BION® microstimulator to relieve pain due to shoulder subluxation in chronic hemiplegic stroke patient: A case report. Presented at the 9th Annual Conference of the International FES Society, Bournemouth, UK, September 2004.
42. Accreditation Council for Graduate Medical Education: ACGME program requirements for graduate medical education in pain medicine. Available at: Accessed September 30, 2010.
43. Buckenmaier CC III, Rupprecht C, McKnight G, et al: Pain following battlefield injury and evacuation: A survey of 110 casualties from the wars in Iraq and Afghanistan. Pain Med 2009; 10(8):1487-1496.
44. White RL, Cohen SP: Return-to-duty rates among coalition forces treated in a forward-deployed pain treatment center: A prospective observational study. Anesthesiology 2007;107(6):1003-1008.
© 2011 by American Academy of Orthopaedic Surgeons