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Pain Management Among Soldiers With Amputations

Chapter 11

PAIN MANAGEMENT AMONG 

SOLDIERS WITH AMPUTATIONS

RANDALL J. MALCHOW, MD*; KEVIN K. KING, DO†; BRENDA L. CHAN‡; SHARON R. WEEKS§; and JACK W. TSAO, 

MD, Dphil¥

INTRODUCTION 

HISTORY

NEUROPHYSIOLOGY AND MECHANISMS OF PAIN

Neurophysiology

Mechanism of Phantom Sensation and Phantom Limb Pain

Residual Limb Pain

MULTIMODAL PAIN MANAGEMENT IN AMPUTEE CARE

Rationale

Treatment Modalities

LOW BACK PAIN

FUTURE RESEARCH

SUMMARY

*Colonel, Medical Corps, US Army; Chief, Regional Anesthesia and Acute Pain Management, Department of Anesthesia and Operative Services, Brooke 

Army Medical Center, 3851 Roger Brooke Drive, Fort Sam Houston, Texas 78234; formerly, Chief of Anesthesia, Brooke Army Medical Center, 3851 

Roger Brooke Drive, Fort Sam Houston, Texas, and Program Director, Anesthesiology, Brooke Army Medical Center-Wilford Hall Medical Center, Fort 

Sam Houston, Texas

† Major, Medical Corps, US Army; Resident Anesthesiologist, Department of Anesthesiology, Brooke Army Medical Center, 3851 Roger Brooke Drive, 

Fort Sam Houston, Texas 78234

‡ Research Analyst, CompTIA, 1815 South Meyers Road, Suite 300, Villa Park, Illinois 60181; Formerly, Research Assistant, Department of Physical 

Medicine and Rehabilitation, Walter Reed Army Medical Center, 6900 Georgia Avenue, NW, Washington, DC 20307

§ Research Assistant, Physical Medicine and Rehabilitation, Walter Reed Army Medical Center, 6900 Georgia Avenue, NW, Washington, DC 20307

¥ Commander, Medical Corps, US Navy; Associate Professor, Department of Neurology, Uniformed Services University of the Health Sciences, 4301 

Jones Bridge Road, Room A1036, Bethesda, Maryland 20814; Traumatic Brain Injury Consultant, US Navy Bureau of Medicine and Surgery, 2300 E 

Street, NW, Washington, DC
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Care of the Combat Amputee

INTRODUCTION

Pain management is increasingly recognized as a 

critical aspect of the care of the polytrauma patient. 

Aggressive analgesia not only decreases pain but also 

produces myriad benefits such as improving sleep–

wake cycles; decreasing anxiety, stress, and depression; 

improving pulmonary mechanics; decreasing ileus; 

reducing hospital stay; decreasing cost; and improving 

overall outcome. Additionally, aggressive acute pain 

control leads to a reduction in chronic pain, which 

remains a persistent challenge: chronic pain rates 

are over 50% following many surgeries and trauma 

conditions.1–6

HISTORY

Various methods to reduce pain were tried before 

the development of specific analgesics. In the 17th 

century, the Italian surgeon Marco Aurelio Severino 

applied ice to injured areas to reduce pain, but the 

technique was limited by resultant frostbite, slow 

onset of relief, painful administration, and limited 

depth of analgesia. In the 18th century, various compression devices used to reduce pain in extremities 

were somewhat effective yet limited by their associated ischemic pain and the direct discomfort of the 

device. The mid-19th century brought several pivotal 

developments in acute pain management.7–11 First, 

Friedrich Serturner extracted morphine from the 

opium plant in 1803, naming it “morphia” after the 

Greek god of dreams. Local anesthesia for analgesia 

became possible through the inventions of the syringe 

by Charles Gabriel Pravaz of France, the hollow needle 

by Alexander Wood of Scotland, and the extraction 

of cocaine from the coca leaf by Albert Niemann of 

Germany. Carl Koller demonstrated the effectiveness 

of topical cocaine at the Congress of Ophthalmology 

in Germany. 

Regional anesthesia quickly followed when American William Stewart Halsted performed various peripheral nerve blocks (PNBs), usually via cut-down 

techniques, in the late 1880s. James Leonard Corning 

injected cocaine in the lower thoracic “dorsal vertebrae,” with numbness occurring 20 minutes later, 

probably due to epidural blockade. In 1897 George 

Washington Crile, surgeon and founder of the Cleveland Clinic, performed one of the first leg blocks for a 

traumatic amputation and introduced the term “block” 

to describe the effect of blocking afferent input from 

the periphery to the brain. The desire for safer local 

anesthetics led Heinrich Braun of Germany to develop 

procaine (Novocain; Hospira, Inc, Lake Forest, Ill) at 

the turn of the century as well as the addition of epinephrine to prolong the duration of blockade. Harvey 

Williams Cushing furthered the use of “cocainization 

of nerve trunks” prior to amputation as a means to 

block neural fibers, which were felt to cause shock and 

hemorrhage in the early 1900s. 

Brachial plexus blockade techniques expanded at the 

outbreak of the First World War when three German 

physicians, G Hirshel, D Kulenkampff, and M Kappis, 

demonstrated the first axillary block, supraclavicular 

block, and interscalene block, respectively. In 1939 

meperidine became the first synthetic opioid available, 

and fentanyl followed 20 years later. Building on the 

continuous spinal anesthesia techniques of William 

Lemmon and EB Touhys, F Paul Ansbro introduced 

continuous supraclavicular techniques in 1946, followed by Manuel Martinez Curbelo’s 1949 continuous 

epidural technique.12–14 Early nerve localization techniques relied on paresthesias; later anesthesiologists 

pursued nerve stimulation in the 1960s and 1970s and 

most recently began using portable high-resolution 

ultrasound machines.15–21 Finally, Susan Steele and 

Ottmar Kick introduced continuous peripheral nerve 

blocks (CPNBs) in 1998 and 1999.22,23

Phantom limb pain (PLP) has been recognized 

as a significant problem in the amputee patient for 

centuries; as 16th century French surgeon Ambroise 

Paré noted, “Truly, it is a thing wondrous, strange, 

and prodigious which will scarce be credited, unless 

by such as have seen with their own eyes and heard 

with their own ears, the patients who many months 

after cutting away the leg, grievously complained that 

they yet felt exceeding great pain of that leg so cut 

off.” Silar Weir Mitchell, a surgeon during the US Civil 

War, is credited with the term “phantom limb pain” to 

describe this phenomenon.24

NEUROPHYSIOLOGY AND MECHANISMS OF PAIN

Neurophysiology

Understanding the normal nociceptive pathway, 

including the four processes in the sensory pathway 

of pain perception (transduction, transmission, perception, and modulation), is critical to understanding the 

specific types of neuropathic pain that many amputees 

experience. In addition, knowledge of the nociceptive 

pathway lays the foundation for an understanding of 

how regional analgesia at various points in the path-
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Pain Management Among Soldiers With Amputations

way may be beneficial, and demonstrates that regional 

analgesia is pathophysiologically a crucial part of the 

multimodal regimen, which is most effective in the 

treatment of pain.25,26

Transduction

Peripheral nociceptors such as free nerve endings 

and mechanoceptors convert noxious stimuli into 

neural impulses that travel along A-δ (fast, myelinated) fibers and C (slow, unmyelinated) fibers, which 

transmit first (sharp, injurious) pain and second (dull, 

visceral) pain, respectively. Peripheral sensitization, or 

lowering of the pain transduction threshold, occurs in 

severe tissue injury and is maintained by a cycle of mediators, including prostaglandins, leukotrienes, kinins, 

histamines, substance P, and serotonin, causing more 

tissue damage. These products of the arachidonic acid 

pathway are major mediators of hyperalgesia, so inhibitors of this pathway are likely key to any analgesic 

regimen for pain secondary to severe limb injury.25

Transmission

Nociceptive impulses including first (sharp, injurious) pain and second (dull, visceral) pain are transmitted via A-δ (fast, myelinated) fibers and C (slow, 

unmyelinated) fibers, respectively, which synapse 

with second order neurons within laminas I, II, and IV 

of the dorsal horn of the spinal cord using substance 

P and excitatory aminoacids (aspartate, glutamate). 

The contralateral spinothalamic tract comprises the 

majority of second order neurons and ascends to the 

thalamus; third order neurons transmit pain from the 

thalamus to the sensory cerebral cortex, the cingulate 

cortex, the amygdala, and the insulate gyrus. 

Perception

The third order neurons, including lateral thalamic 

projections to the cerebral cortex and medial thalamic projections to the reticular formation (emotional 

aspect), contribute to the perception of pain. Many 

medications including opioids, anticonvulsants, antidepressants, and α2

-agonists affect the perception of 

pain in these areas. 

Modulation

The efferent descending inhibitory fibers from the 

corticospinal tract, hypothalamus, and periaqueductal 

gray areas modulate afferent input at laminas I and 

V (primarily) of the dorsal horn by decreasing neurotransmitter release. Serotonin, norepinephrine, and 

opioid-like encephalins (especially within lamina II at 

the substantia gelatinosa) are known neurotransmitters in the descending pathways. Modulation is augmented by intrathecal spinal opioids and intrathecal 

α-agonists. 

Mechanism of Phantom Sensations and Phantom 

Limb Pain

A phantom limb experience is defined as the continued perception of a missing limb, the simple tactile 

awareness of the missing limb, and the perceived 

ability to move the missing limb, most likely due to 

a persisting central nervous system representation 

of the limb.26 Between 90% and 98% of all patients 

who have undergone limb amputation experience a 

vivid phantom, with even higher incidences following 

traumatic limb loss or following a preexisting painful condition in the limb. Phantom limb sensations, 

including tingling, itching, burning, movement, temperature changes, pressure, and pain occur as soon as 

an anesthetic wears off in 75% of cases, but development of these sensations may be delayed up to several 

weeks.27–30 PLP and phantom sensations tend to be 

brief and last from days to weeks for most amputees, 

but can become chronic. Sherman et al31 found in a 

study of several thousand amputees that over 70% continue to experience PLP as long as 25 years following 

a limb amputation. A recent epidemiologic study by 

Richardson and Turo32 was performed to investigate all 

postamputation phenomena in a homogenous group 

of amputees (all with peripheral vascular disease). 

Sixty amputees were recruited, but only 52 survived 

until a 6-month postoperative interview. Phantom 

sensations (kinetic, kinesthetic, exteroceptive) were 

universal (100%). “Telescoping,” the sensation of the 

distal end of the phantom limb becoming progressively 

closer to the residual limb, was the most common kinesthetic aspect reported in 67.3% of cases, PLP occurred 

in 78.8% of cases, and residual limb pain occurred in 

51.2% of cases.32

The phantom limb tends to occupy a fixed or “habitual” posture. For example, following upper limb 

amputation, many patients report experiencing the 

limb as partially flexed at the elbow, with the forearm 

pronated. However, the phantom limb sometimes 

occupies a painful or awkward posture (ie, a tightly 

clenched fist).28 A soldier who was holding a grenade 

that exploded in his hand reportedly experienced a 

phantom hand clenched in a painful posture,33 and the 

authors have heard similar experiences from Operation Enduring Freedom and Operation Iraqi Freedom 

patients treated at Walter Reed Army Medical Center. 

Thus, the phantom limb may sometimes be experienced as a reactivation of preamputation memories 

of the limb. Telescoping occurs in two-thirds of limb 
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Care of the Combat Amputee

amputees.

Many theories have been proposed for the etiology of PLP.34 The development of neuromas was 

once thought to cause phantom sensations and pain. 

Neuromas are bundles of severed nerve fibers that can 

send ectopic pain impulses through the spinal cord 

and the thalamus to the somatosensory cortex. However, removal of neuromas does not relieve phantom 

limb sensation or phantom pain.35 Modifications of 

spinal neurons that were dependent on the neurons 

that subserved the formerly innervated limb may be 

another explanation for phantom limb sensations. 

Excessive spontaneous firing of spinal neurons that 

have lost their proper sensory input from the deafferented limb may be interpreted as PLP or phantom 

sensations when these abnormal impulses reach the 

brain.36–38 However, studies of individuals who were 

born without limbs but still exhibit phantom limb 

sensations show no excessive firing of spinal neurons 

because peripheral nerves connected to these neurons 

have never developed, suggesting that this theory is 

probably incorrect.27

Most likely, a central representation of the limb 

persists and is responsible for meaningful experiences 

of the limb, as proposed by Melzack’s “neuromatrix 

theory.”39 According to this theory, a central representation of the limb is formed and modified within 

a neuromatrix, a neural network that subserves body 

sensation; contains the somatic, visual, and limbic 

systems; and produces characteristic nerve-impulse 

patterns.39 This network of neurons is present throughout the brain and has synaptic links that are genetically 

determined but later sculpted by sensory inputs. The 

repeated cyclical processing and synthesis of nerve 

impulses creates a characteristic pattern called the 

neurosignature. The phantom limb experience is 

produced by the same neuromatrix that underlies 

the intact bodily experience. Phantom pain may thus 

result from the deprivation of modulating inputs from 

the limbs to the neuromatrix, which can then cause an 

abnormal neurosignature to be produced.39

Therefore, PLP is most likely the result of cortical 

reorganization within the somatosensory and motor 

cortices. The brain contains several complete somatotopic maps (homunculi) of the body surface.40 The 

primary motor area, lateral premotor area, supplementary motor area, parietal cortex, and basal ganglia 

all contain complete somatotopic representations of 

the body.41,42 It was once believed that these maps 

were fixed following critical periods during infancy.43

However, many studies suggest that sensory maps can 

undergo remodeling in the adult brain. 

Experimental evidence demonstrates that the 

amount of cortical reorganization is associated with 

the severity of PLP and likely plays a prominent role 

in its emergence.44 Studies using noninvasive imaging 

techniques, such as functional magnetic resonance 

imaging, have demonstrated changes within the 

somatosensory and motor cortices in amputees.45,46

Ramachandran and Hirstein28 found that sensory maps 

reorganize in such a way that specific points along the 

neighboring sensory area evoke modality-specific referred sensations such as warmth and pain. However, 

if there is a slight error in cortical reorganization such 

that some of the touch input is accidentally connected 

to pain areas, it is theorized that amputees may experience pain when these regions are touched.28 Finally, 

a sympathetic mechanism that increases sympathetic 

activity may maintain pain by noradrenergic stimulation of the neuromas or nerve endings in a residual 

limb.37

Residual Limb Pain

Residual limb pain, previously referred to as stump 

pain, can be a painful and frustrating postamputation 

phenomena. Residual limb pain is common in early 

postoperative and rehabilitation phases but regresses 

to a greater extent than any other of the postamputation phenomena. After 2 years postamputation, 

prevalence may be as low as 20%.37 Typically, residual 

limb pain should subside with healing, but if it persists 

more than a few months, poor prosthetic fit or overuse 

and overtraining is often the cause. Residual limb pain 

is more likely if chronic pain was a problem before 

surgery and will likely persist longer if postoperative 

analgesia is inadequate. A survey of veteran amputees 

in the early 1980s revealed that the severity and duration of residual limb pain correlated well with presence 

and persistence of phantom pain.31,47 Multiple other 

reasons may explain why residual limb pain can persist 

beyond the normal healing period. 

The treatment of residual limb pain is typically 

the domain of the physiatrist or physical therapist; 

however, anesthesiologists and surgeons can also be 

helpful in the early postoperative period by screening for anatomic residual limb pathology that may be 

causative. Anatomic causes include ulcers or inflammation secondary to improper prosthesis fit; bony 

abnormalities (ischemia, spurs, heterotopic ossification, and osteomyelitis); neuroma formation; and, 

rarely, malignancies or tumors, many of which may 

be amenable to surgical correction such as neuroma 

excision and repositioning of the nerve within bone or 

muscle.37 Nonsurgical treatments include botulinum 

toxin injection; nerve blocks; transcutaneous electrical nerve stimulation (TENS); acupuncture; Farabloc 

(Farabloc, Coquitlam, British Columbia, Canada) steel 

fiber sheet sheaths or socks; and oral medications, such 

as nonsteroidal antiinflammatory drugs (NSAIDs), 
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Pain Management Among Soldiers With Amputations

cyclooxygenase (COX)-2 inhibitors, and acetaminophen for somatic pain, and tricyclic antidepressants 

and anticonvulsants (eg, gabapentin, pregabalin) for 

neuropathic pain.48 Mexiletine and clonidine have also 

been used successfully for PLP, and are likely effective 

for residual limb pain as well.49 A recent case report by 

Nikolajsen et al50 proposes that low-dose ketamine is 

effective in treating residual limb pain when conventional tricyclic antidepressants and opioid therapy 

have failed. Ketamine decreases the hyperactivity of 

N-methyl-d-aspartate (NMDA) receptors and thus 

decreases neuronal excitability. Ketamine reduced 

allodynia and wind-up response, and increased the 

pressure-pain threshold. Amputee soldiers and veterans may benefit from ketamine therapy to allow 

reductions in residual limb pain caused by neuromas, 

which may allow more function with prostheses.50

Other medications such as mirtazapine, a serotoninnorepinephrine reuptake inhibitor antidepressant, 

may be more cost-effective than newer generation 

anticonvulsants and are probably more efficacious 

than older tricyclic antidepressants.35 Each component of this multimodal approach is described more 

extensively below.

MULTIMODAL PAIN MANAGEMENT IN AMPUTEE CARE

Rationale 

Capitalizing on synergy among various medications and modalities, multimodal therapy affects the 

nociceptive pathway at multiple points (Figure 11-1). 

Synergy among medications should allow the provider 

to use less of each medication, thereby reducing side 

effects and the potential risks of each medication. Treating pain at various points of the nociceptive pathway 

allows multimodal therapy to be more effective than 

simply increasing the treatment at one point in the 

pathway. “Practice Guidelines for Acute Management in the Perioperative Setting”51 recommends that 

all patients receive an around-the-clock regimen of 

NSAIDs, selective COX-2 inhibitory blockers, and/or 

acetaminophen unless contraindicated,51 because all 

of these medications reduce inflammatory mediators 

(which increase after tissue injury), thereby decreasing 

the transduction aspect of the pain pathway. Regional 

anesthesia, however, blocks the transmission process 

in the pain pathway. PNBs and epidurals use local 

anesthetics to decrease or halt transmission at large 

peripheral nerves and the dorsal root, respectively. Epidural local anesthetics also diffuse into the intrathecal 

space and spinal cord to a lesser degree and thus have 

an effect at the dorsal horn. Intuitively, if pain cannot 

be transmitted, it will not be perceived or modulated. 

Adjunctive medications, such as anticonvulsants, antidepressants, and α2-agonists affect primarily spinal 

and supraspinal sites. Finally, intrathecal opioids, 

ketamine, and α-agonists modulate the pain pathway 

at the dorsal horn.52 

The basis for multimodal therapy is achieving 

optimal acute and subacute pain management to optimize the polytrauma patient’s overall recovery and 

rehabilitation. Excellent postoperative analgesia aids 

postoperative healing by increasing oxygenation and 

mobility and also reduces anxiety, stress, and depression. Multimodal therapy reduces the potential for 

opioid-related physical dependence, addiction, and the 

recently recognized phenomenon of opioid-induced 

hyperalgesia (OIH)53,54 resulting from opioid-centered 

analgesia. Of course, postoperative respiratory depression is a continual threat with opioid-centered 

postoperative pain plans such as intermittent dosing 

and patient-controlled analgesia (PCA).55 The pracFigure 11-1. Multiple sites of action with multimodal 

therapy. 

NMDA: N-methyl-d-aspartate

Reproduced with permission from: Buckenmaier C, Bleckner 

L. Military Advanced Regional Anesthesia and Analgesia Handbook. Washington, DC: Borden Institute; 2009: Figure 27-1.
234

Care of the Combat Amputee

tice guidelines

51 state that acute perioperative pain 

management helps maintain the patient’s functional 

abilities and psychological well-being, enhances the 

quality of life, and prevents the results of undertreatment of perioperative pain. The adverse outcomes of 

undertreatment include thromboembolic and pulmonary complications, increased intensive care or hospital 

time, needless suffering, and possibly the development 

of chronic pain. The guidelines continue by stating that 

interdisciplinary perioperative analgesia programs 

with dedicated acute pain service and 24-hour anesthesiologist availability enhance patient comfort and 

prevent analgesic gaps. Multimodal techniques are 

specifically recommended.51

Treatment Modalities

Regional Anesthesia and Analgesia 

Although perioperative regional anesthesia and 

analgesia (PRAA) has strong support,51,56,57 the literature on its success in reducing chronic postamputation 

pain has been inconclusive.58 However, the weight of 

evidence suggests a long-term benefit. Studies have 

demonstrated an association between acute and chronic pain as well as between preamputation pain and 

chronic pain4,59; therefore, postamputation phantom 

pain may be reduced by inducing local anaesthesia in 

the limb prior to a planned surgical amputation.60

Benefits. Significant benefits to the use of PRAA, including epidural analgesia or PNBs, in the polytrauma 

patient have been established. Intraoperatively, PRAA 

provides a stable hemodynamic profile, minimal pulmonary concerns, avoidance of side effects from general anesthesia if used as a sole technique, improved 

operating room efficiency, and decreased blood loss. 

Postoperatively, recovery in the postanesthesia care 

unit improves, postoperative analgesia improves, 

overall hospital costs diminish, overall outcome 

improves, and both patient and surgeon satisfaction 

scores are high. 

Intraoperative Hemodynamic Stability. Following 

the Vietnam War, San Diego Naval Medical Center 

(California) treated a large number of patients, but 

the patient demand exceeded the supply of operating 

room time. Therefore, a system was designed whereby 

patients underwent surgical procedures in the orthopaedic clinic after a regional anesthetic was placed by 

the anesthesia department. Over 15,000 patients were 

safely given regional anesthesia over a 30-year period. 

In 1997 Waters et al61 reported findings in a 1-year 

prospective study of 677 patients. Upper and lower 

extremity blocks were placed without sedation, after 

which patients were transported to the clinic for their 

procedures accompanied only by a corpsman, with 

minimal monitors. The incidence of complications was 

low (0.3%) with no postoperative sequelae, attesting 

to the overall hemodynamic and respiratory safety of 

peripheral blocks.

In centroneuroaxis blockade, PRAA generally has 

fewer hemodynamic perturbations than single-shot 

spinal anesthesia. Auroy and colleagues62 reported provocative findings in a 1997 French prospective study 

of over 103,000 regional anesthetics, including over 

40,000 spinal blocks, over 30,000 epidural blocks, over 

20,000 PNBs, and over 11,000 intravenous (IV) regional 

anesthetics. The study surveyed 736 anesthesiologists, 

half in private practice and half in academic settings, 

with an average of 12 years of experience. The risk of 

cardiac arrest was 1 per 1,500 for spinal anesthesia, 1 

per 10,000 for epidural anesthesia, and 1 per 7,000 for 

PNB, suggesting a higher cardiac arrest rate for spinal 

anesthesia compared to other regional anesthetics. 

Although the authors acknowledged the possibility of 

selection bias because sicker patients received spinal 

anesthesia, other studies also report a relatively high 

rate of cardiac arrest during spinal anesthesia, ranging 

from 1 per 500 to 1 per 4,000.63– 66 Caplan et al67 reviewed 

14 cases of cardiac arrest in a closed claims analysis, all 

of which involved healthy patients for minor surgery 

who suffered cardiac arrest after decreasing blood 

pressure and pulse. All but one patient had a poor 

outcome. de Visme and colleagues68 reported in 2000 

“more prolonged hemodynamic effect” in isobaric 

spinal anesthesia compared to PNBs for hip fractures 

in 29 elderly patients. Finally, spinal anesthesia often 

results in significant hypotension and severe bradycardia (33% and 13% incidence, respectively).69

Likewise, PNBs may have a greater safety profile 

than centroneuroaxis blockade. In a 1996 French prospective study by Giaufre et al,70 over 24,000 regional 

anesthetics were studied in a pediatric population. The 

group included 89% receiving a combined anesthetic 

and general anesthesia, 61% with a centroneuroaxis 

block, 17% with a PNB, and 22% with local infiltration. 

Only the centroneuroaxis group reported complications, including dural puncture, cardiac arrhythmias, 

IV injections, and paresthesias.

Avoiding General Anesthesia Side Effects. If used 

as a sole anesthetic, regional anesthesia minimizes 

the risk of central nervous system complications such 

as postoperative delirium and excessive drowsiness. 

The likelihood of airway complications including sore 

throat, traumatized airway, aspiration, and potential 

for loss of airway in a difficult airway are minimized. 

Both elevated rate-pressure products during laryngoscopy and intubation as well as potentially low 

perfusion states during patient positioning and preparation are avoided. Finally, PRAA minimizes the risk 

of postoperative nausea and vomiting.71
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Pain Management Among Soldiers With Amputations

Improving Operating Room Efficiency. Surgeons 

are often concerned about the additional time required 

for the placement of regional anesthesia; however, use 

of central and peripheral blocks can actually decrease 

“anesthesia-controlled time” if managed by a separate 

“block team” prior to surgery. In 2000 Williams and 

colleagues72 studied 369 patients for anterior cruciate 

ligament repair in a retrospective review using the 

same surgeon for all the operations. Total time, including intraoperative anesthesia-controlled time plus 

turnover time, was 31 minutes for PNBs, 36 minutes 

for PNB combined with general anesthesia, and 41 

minutes for general anesthesia.72 Additionally, regional 

anesthesia can significantly reduce or eliminate phase 

I recovery and expedite phase II recovery.73,74

Decreasing Blood Loss. Central neuroaxis blockade 

can decrease perioperative blood loss by 37% to 46%, 

as demonstrated in many studies,75,76 but PNBs may 

also accomplish this benefit. Lumbar plexus blocks 

have been demonstrated to decrease total blood loss 

by 49% in total hip arthroplasty.77,78 Mechanisms by 

which regional anesthesia decreases blood loss include 

shunting of blood from the operative site, decreased 

venous pressure by blockade of sympathetic tone, and 

the lack of positive-pressure ventilation. 

Improving Early Recovery Period. Regional anesthesia potentially improves the recovery period. Ford 

and colleagues71 reported a retrospective review of 801 

patients comparing general anesthesia to PNBs and a 

combined general and regional anesthetic. Regional 

anesthesia patients had less nausea and vomiting (6% 

vs 20%), less supplemental oxygen requirement (12% 

vs 81%), and quicker discharge times (51 min vs 104 

min). Along with less nausea and vomiting, regional 

anesthesia patients have less postoperative ileus due 

to decreased opioid use and decreased sympathetic 

tone with epidural analgesia. 

Decreasing Deep Vein Thrombosis. Regional anesthesia, especially when extended into the postoperative 

period, has been shown to decrease the rate of deep 

vein thrombosis in many studies79–81; this finding is 

particularly evident when no further pharmacologic 

prophylaxis is prescribed. Modig et al79 examined 

60 patients undergoing total hip arthroplasty who 

received either epidural analgesia or systemic narcotics. Only 13% experienced a deep vein thrombosis, 

and 10% had a pulmonary embolism in the epidural 

group compared to 67% and 30%, respectively, in the 

systemic narcotic group.79 In 1991 Tuman and colleagues82 showed a decrease in the alpha angle and 

maximum amplitude value on postoperative thromboelastogram in 80 major vascular patients, as well as 

fewer arterial occlusions in the epidural group compared to the systemic narcotic group. Finally, in 1993 

Christopherson et al83 examined the effect of epidural 

analgesia with lower extremity vascular surgery and 

found a decreased need for revascularization in the 

epidural group.

Decreasing Hospital Costs. In addition, regional 

anesthesia can save hospitals significant costs. In 2004 

Williams and colleagues84 reviewed 948 anterior cruciate ligament repairs, comparing the overall hospital 

costs between patients with and without PNBs. Of 

those who received blocks, 82% were able to bypass 

phase I recovery and only 4% required unplanned admissions, compared with an admission rate of 17% for 

those who did not receive blocks. Based on an average 

of 3,000 outpatient orthopaedic cases annually, hospital 

savings could reach $1.8 million annually through the 

use of regional anesthesia. Other studies also support 

fewer costs associated with regional anesthesia.85–87

Improved Postoperative Analgesia. Many studies 

report improved postoperative analgesia utilizing regional analgesia with fewer side effects.76,87–89 Regional 

analgesia minimizes the risk of central nervous system 

side effects such as delirium and drowsiness compared 

to systemic opioids. Grass76 reported less sedation 

with sufentanil patient-controlled epidural analgesia 

compared to IV morphine PCA and intramuscular (IM) 

opioids, while Guinard et al87demonstrated greater sedation with IV fentanyl compared to epidural fentanyl. 

Salomaki and colleagues90 showed decreased nausea 

and vomiting with epidural fentanyl (20%) compared 

to IV fentanyl (65%).Regional analgesia patients have 

less nausea and vomiting, less supplemental oxygen 

requirement, and less postoperative ileus resulting 

from fewer opioids and the resultant sympathectomy 

with epidural analgesia.71 Horlocker et al91 eliminated 

the need for any opioids through the use of multimodal 

analgesia with a continuous lumbar plexus catheter in 

addition to acetaminophen and ketoroloc for a total 

knee replacement, and Mulroy et al92 demonstrated 

extended relief with up to 24 hours of analgesia using 

single shot femoral nerve blocks following anterior 

cruciate ligament reconstruction. PNBs may also decrease pruritis, urinary retention, hypotension, difficulty with ambulation, and respiratory depression.76

Because of improved analgesia with fewer side effects 

and fewer opioids used, nursing requirements are 

significantly diminished.

Improving Patient Outcome. Several studies have 

shown improved patient outcome with PRAA,93,94 

including decreased intensive care unit stay,82,86 

decreased hospital stay,86,89 decreased cardiac morbidity,82,86,95,96 decreased pulmonary dysfunction,82, 

87–89, 90 earlier return of bowel function,89,93 decreased 

neuroendocrine stress,86,97 fewer infections,86 decreased 

mortality,86,98 and improved rehabilitation. Yeager et 

al86 examined 53 patients after abdominal, thoracic, 

and vascular surgery in 1987, and Tuman et al82 ex-
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Care of the Combat Amputee

amined 80 major vascular patients in 1991. Both studies reported decreased intensive care unit stays with 

epidural analgesia versus systemic narcotics. In addition, Yeager’s epidural group had a 14% incidence of 

cardiac morbidity (myocardial infarction, congestive 

heart failure, angina, or arrhythmia) compared to 52% 

in the systemic narcotic group; Tuman also demonstrated a significant difference (10% vs 27%) in cardiac 

events. Blomberg and others95,96 in a series of studies 

demonstrated a favorable myocardial oxygen supply 

versus demand balance with a decrease in heart rate, 

contractility, preload, and afterload, yet an increased 

coronary blood flow to the endocardium during 

thoracic epidural blockade. Furthermore, coronary 

perfusion pressure was maintained, and stenotic but 

not nonstenotic coronary vessels became dilated.96,99–104

Studies88,89 demonstrated fewer pulmonary complications including atelectasis, infiltrates, and cough in an 

epidural group compared to a systemic narcotic group, 

and Boylan and colleagues88 demonstrated earlier 

tracheal extubation in the epidural group.

Liu et al105 examined various analgesic techniques 

on recovery of bowel function and found a local anesthetic plus opioid combination to provide the optimal 

result, especially compared to systemic opioids. Epidural opioids have been shown to decrease the stress 

response, specifically free cortisol levels, compared to 

systemic opioids.97 Yeager86 showed a 7% incidence of 

major infections (pneumonia, sepsis) in the epidural 

analgesia group, compared to 40% in the systemic 

narcotic group. In addition, Yeager’s epidural group 

had no deaths while the systemic narcotic group had a 

16% mortality rate.86 Wu and colleagues98 reported an 

analysis of the Medicare claims database in 2004 over 

a 4-year period and showed significantly lower odds 

of death at 7 and 30 days postoperatively for those 

patients who had postoperative epidural analgesia.

Finally, PRAA has been shown to decrease pain scores, 

increase range of motion, decrease hospital stay, and 

decrease rehabilitation time compared to IV PCA, 

although CPNBs had fewer side effects compared to 

epidural analgesia.106,107

Improving Patient Satisfaction. In 2001 Wu and 

colleagues108 reviewed 18 trials that examined patient 

satisfaction with PRAA and reported that over 70% of 

these studies demonstrated greater patient satisfaction 

with regional anesthesia and analgesia compared to 

general anesthesia with IV PCA. Specifically, Vloka 

et al109 demonstrated greater patient satisfaction with 

PNBs compared to spinal anesthesia for varicose vein 

surgery, and Borgeat et al110 demonstrated greater 

patient satisfaction with postoperative interscalene 

analgesia compared to IV PCA for shoulder anesthesia. Although patient satisfaction is a complex issue, 

critical determinants are judicious sedation during the 

regional procedure as well as optimal postoperative 

analgesia.108,111–113

Risks of Perioperative Regional Anesthesia and 

Analgesia. Although PRAA has many significant 

benefits, its use also introduces potential risks, which 

must be considered for each individual patient. This 

section will focus first on the “big three” risks, as 

termed by Finucane,114,115 namely, local anesthetic toxicity, pneumothorax, and nerve injury.Additionally, the 

provider should consider other miscellaneous risks 

before employing PRAA.

Local Anesthesia Toxicity. Local anesthetic toxicity 

resulting in seizures, cardiac arrest, or both can be a 

devastating complication that all anesthesia providers 

must consider. With PNBs, the incidence of seizures 

is roughly 1 per 1,000, whereas the incidence with 

epidural anesthesia is roughly 1 per 8,000.62,116 Brown 

et al116 completed a retrospective review of over 25,000 

patients with caudal, epidural, and brachial plexus 

blocks and found the highest rate of local anesthetic 

toxicity with caudal anesthesia, followed by PNBs, 

followed by epidural anesthesia. Most cases of seizures occurred after bolusing local anesthesia through 

needles or catheters, as opposed to perioperative infusions, and did not necessarily result in cardiac arrest 

even with bupivacaine in this series of patients. The 

incidence of cardiac arrest, resulting from several different mechanisms, appeared to be similar between 

epidural anesthesia and PNBs, approximately 1 per 

10,000 and 1 per 7,000, respectively.116 Both epidurals 

and PNBs may elicit the vasovagal reaction, which is 

usually self-limiting, as well as cardiac arrest due to 

local anesthetic toxicity.117 In addition, accidental intrathecal (spinal) injection and the Bezold-Jarisch reflex 

may cause cardiac arrest during epidural anesthesia. 

Because local anesthetic toxicity can be life-threatening, efforts to decrease this event have largely focused 

on prevention, including using the lowest effective 

dose, frequent aspiration with intermittent boluses, 

the use of a vascular marker such as epinephrine, 

and avoiding agents with a low therapeutic index 

(eg, bupivacaine) in highly vascular areas. However, 

determining meaningful maximum dosages for local 

anesthetics has been elusive, since the maximum dose 

depends primarily on where the local anesthetic is 

given; a standard maximum dose of a particular local 

anesthetic is not helpful unless location is specified. 

For example, a greater dose is allowed moving within 

a continuum from IV, to intercostals, to caudal, to epidural, to PNBs, and finally to subcutaneous administration.118–120 On the one hand, although 5 to 7 mg/kg 

of lidocaine is frequently quoted as a maximum dose, 

twice that dose could be used for PNBs and subcutaneous administration.114,121–130 On the other hand, even 5 

mg/kg lidocaine intravenously could have disastrous 
237

Pain Management Among Soldiers With Amputations

consequences. Therefore, rather than relying on set 

maximum dosages, the provider must be sure not to 

inject within a vessel, to use the lowest effective local 

anesthetic dose possible, and to have Intralipid (KabiVitrum Inc, Alameda, Calif) readily available. 

Unfortunately, detection of an intravascular injection can be difficult; merely aspirating for heme prior 

to injection does not preclude the possibility of an 

intravascular injection. Therefore, a test dose is critical, 

which most commonly is epinephrine 15 μg (6 mL of 

1:400,000 solution). If the heart rate increases more than 

10 points, the practitioner should withdraw the needle 

and either abandon the procedure or reattempt it if the 

patient is stable. Additionally, extreme vigilance is required during the bolus injection, especially when using an immobile needle with fractionated 5-mL doses; 

mobile or multiple injection techniques may decrease 

the rate of local anesthestic toxicity by spreading local 

anesthesia in multiple locations. 

Choice of the local anesthetic is a critical aspect of 

decreasing patient risk, because local anesthetics can 

have varying effects on different organ systems. Lidocaine, for example, can cause seizures and eventually 

cardiac shock at high concentrations.131 In addition, 

according to numerous studies, lidocaine is less cardiotoxic than ropivacaine, which is less cardiotoxic 

than bupivacaine.132–136 Providers must be aware of the 

potential for cardiac complications with the use of local 

anesthetics, and early treatment of cardiac complications is essential (decreasing mortality from 83% to 

33% for bupivacaine and 17% to 0% for ropivacaine in 

one study).137,138 The cardiotoxicity of these anesthetics 

results from both depressed left ventricular function 

as well as arrhythmogenicity. Animal studies have 

shown significantly less cardiovascular depression and 

arrhythmias, greater rate of successful resuscitations, 

and less mortality after cardiac arrest with ropivacaine 

compared to bupivacaine. For constant infusions, maximum epidural bupivacaine rates should not exceed 

0.5 mg/kg/hr (0.25 mg/kg/hr in infants),139–143 and 

this rate should be decreased in the elderly, pregnant 

women, and those with uremia or liver failure. 

Finally, treatment of local anesthesia toxicity should 

focus on airway management, possible administration 

of induction agents and/or benzodiazepines to control 

seizure activity, and control of arrhythmias with amiodarone, vasopressin, epinephrine, Intralipid therapy, 

and/or defibrillation. Perhaps the most remarkable 

recent discovery about local anesthesia toxicity is 

the ability for Intralipid to act as an antidote: the free 

plasma local anesthetic binds to Intralipid, thereby 

dramatically decreasing circulating local anesthesia 

levels.144–147 In 2003 Weinberg et al145 reported a study 

in which 12 dogs were given lethal doses of IV bupivacaine, and the group treated with Intralipid all survived while the control group all died. The currently 

recommended dosing is 1 mL/kg over 1 minute, followed by 3 mL/kg over 10 minutes, followed by an 

infusion of 0.25 mL/kg/min after establishment of 

normal sinus rhythm until hemodynamics have been 

stabilized. Maintaining an immediately available supply of Intralipid, which is inexpensive and stable at 

room temperature for long periods, while blocks are 

performed has become the standard of care. 

Pneumothorax. Pneumothorax, the second of the 

“big three” risks of PRAA, is primarily a risk with 

supraclavicular brachial plexus block and thoracic 

paravertebral block, but has been seen with other 

blocks as well.148 The risk of pneumothorax during 

supraclavicular blockade has been reported as high as 

5%,107 but other studies indicate this risk is much less 

in experienced hands; Franco and Vieira149 reported 

no pneumothorax in 1,001 supraclavicular blocks. Incidence of pneumothorax with thoracic paravertebral 

block is roughly 1 per 300, but it is highly dependent 

on patient factors such as the presence of scoliosis, as 

well as provider experience.150 During block placement, cough, chest pain, or aspiration of air are signs 

of possible pleural puncture. To reduce the risk of 

pneumothorax after block placement, nitrous oxide 

and positive pressure ventilation should be avoided, 

and a chest film should be considered, particularly 

if the patient is symptomatic. Outpatients undergoing supraclavicular or thoracic paravertebral blocks 

should be instructed to report immediately to the 

emergency room for dyspnea or chest pain. Treatment 

includes a chest tube if pneumothorax is greater than 

25% or symptomatology is severe. Again, prevention 

is critical and requires adequate training, education, 

and experience as well as the use of ultrasound imaging techniques. 

Nerve Injury. Nerve injury is the third major risk 

associated with PRAA. Due to an inconsistent definition (various etiologies, sensory versus motor deficits, 

duration of persistent block, severity, etc), the incidence 

of nerve injury varies widely among studies, ranging 

from 0.2% to 2%.151 Auroy et al62 reported an incidence 

of 1 in 5,000 for both epidural and PNBs, compared to 

1 in 1,670 for spinal anesthesia. Although the number 

of patients with persistent neural deficits was small, 

all patients in the epidural and PNB groups had either 

paresthesias during block placement or pain on injection.62 Nerve injury may be more common after general 

anesthesia than regional anesthesia: the American 

Society of Anesthesiologists closed-claims analysis 

found that 61% of the total number of nerve injuries 

occurred during general anesthesia, and 39% during 

regional anesthesia, although 90% of lower extremity 

claims involved regional anesthesia, especially spinal 

anesthesia.152 The incidence of nerve injury appears to 
238

Care of the Combat Amputee

decrease with time, as Borgeat et al148 demonstrated in 

a prospective study examining interscalene blockade 

and shoulder surgery, finding that 14% of the patients 

had persistent sensory deficits on the 10th postoperative day, but the number had decreased to 4% at 

3 months and 0.2% at 9 months. Bergman and colleagues153 showed that using continuous techniques in 

over 400 axillary catheter placements did not increase 

the risk of neural injury compared to using single injections. Still, many surgeons perceive that PNBs are 

associated with a relatively high rate of neural deficits; 

21% of hand surgeons reported having seen a “major 

nerve injury” following axillary blockade.154

Sources of nerve injury include trauma, toxicity, 

ischemia, or more frequently a combination of thesemechanisms.114 Neural trauma could result from the 

needle, intraneural injection, compression, or stretch. 

Whether the choice of technique (paresthesia or nerve 

stimulation) or the use of short bevel needles affects 

neural trauma is controversial.155,156 Toxicity from local 

anesthetic correlates with potency (2-chloroprocaine 

< lidocaine < etidocaine), although 4% lidocaine or 

greater causes the greatest injury. High concentrations 

of local anesthetics can be neurotoxic, but concentrations used at clinical concentrations are considered 

safe. Clearly, any substance injected within the epineurium can result in neural injury as a result of all three 

mechanisms. Intraneural or extraneural compression, 

edema, and vasoconstriction could result in neural 

ischemia. Partridge157 examined the use of epinephrine 

and found that lidocaine with 1:200,000 epinephrine 

decreased neural blood flow, but so did plain lidocaine, 

also probably as a result of the coupling of neural activity with oxygen requirements and blood flow. No 

evidence exists that 1:400,000 epinephrine significantly 

decreases neural blood flow, and this concentration 

appears to be an acceptable balance between maintaining a reliable intravascular marker and avoiding 

neural ischemia.157

Prevention of neural injury involves adequate 

informed consent and effective communication with 

the patient preoperatively, minimizing sedation to 

obtain feedback during a 1-mL test dose to help rule 

out pain on injection that could be associated with 

intraneural injection, avoiding high concentrations of 

local anesthesia, avoiding 1:200,000 epinephrine, and 

possibly implementing the use of ultrasound, which 

allows visualization of neural tissue, the needle, and 

local anesthesia spread. Treatment of a possible neural 

injury begins with a comprehensive yet focused history and physical examination of the complaint with 

consideration of a wide range of possible etiologies, 

including preexisting nerve injury, prolonged use or 

high pressure of the tourniquet, surgical trauma, local 

edema and swelling, patient position, tight splints or 

casts, and regional anesthesia. Workup may include 

imaging studies to evaluate for hematoma, which 

could be evacuated with return of function, and possibly electromyogram/nerve conduction velocity 

studies to record baseline function, because changes in 

these studies lag weeks behind neural injury.158 Treatment should focus on reversible causes (hematoma, 

casts), multimodal therapy to treat possible neuropathic pain, and reassurance that most neural injuries 

improve with time. 

Other Risks. Other risks associated with PRAA 

include epinephrine toxicity, phrenic blockade, 

bronchospasm, failure of the technique, inadvertent 

epidural or spinal spread, hematoma, and infection. 

Epinephrine toxicity may occur with a small, inadvertent IV dose in a susceptible patient or from slow 

systemic uptake if epinephrine is mixed in the local 

anesthesia solution, especially if total epinephrine dose 

exceeds 250 μg, including the surgeon’s possible use 

of epinephrine-containing solutions. Phrenic blockade 

occurs with virtually all interscalene blocks and deep 

cervical plexus blocks, although it is well tolerated 

in patients who don’t have significant pulmonary 

disease. Roughly 40% of supraclavicular blocks result 

in phrenic blockade. Bronchospasm has also been reported after interscalene block159 but is not typically 

seen after other regional anesthetics. Failure of the 

technique comprises 5% to 15% of regional anesthetics 

that required a backup plan for all patients; higher failure rates occur with poor patient selection, insufficient 

time allowed for local anesthesia onset, surgery outside 

the area of blockade, surgery outlasting the duration of 

the regional block, and minimal experience or training 

in regional techniques. 

Inadvertent epidural spread occurs frequently with 

paravertebral blockade,160 occasionally with lumbar 

plexus blockade (up to 10% of the time), and rarely 

with interscalene and deep cervical plexus block. Inadvertent spinal anesthesia possibly resulting in total 

spinal anesthesia can occur during lumbar plexus 

block, paravertebral block, interscalene block, and 

epidural anesthesia via inadvertent dural puncture. 

Hematoma formation is a well-known complication of 

epidural/spinal anesthesia, with an incidence between 

1 per 5,000 and 1 per 150,000, depending the presence 

of anticoagulation and needle size.161,162 The American 

Society of Regional Anesthesia has specific guidelines 

on its Web site (www.asra.com) that pertain to central 

neuroaxis blockade in the presence of anticoagulants. 

Particularly concerning is the recent relatively high 

rate of epidural hematoma formation especially with 

high-risk dosing of low-molecular-weight heparin. Hematoma has also been associated with PNBs, namely 

lumbar plexus block with Lovenox163 (Sanofi Aventis, 

Bridgewater, NJ) as well as axillary catheters.153
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Pain Management Among Soldiers With Amputations

Finally, infection can result particularly from catheter techniques, varying from 1 case in 10,000 with 

epidural catheters to up to 1% of cases with CPNB 

catheters.153 As many as 30% of catheters become 

colonized with skin flora, and a small percentage of 

patients develop either superficial or deep infections. 

Risk factors associated with catheter infections include 

diabetes, traumatic placement, longer duration of 

catheter, frequent unnecessary dressing changes, and 

lack of systemic antibiotics. Additionally, type and 

concentration of local anesthesia may affect the risk of 

infection. In a series of deep CPNB catheter infections 

treated at Brooke Army Medical Center, patients noted 

primarily pain deep to the catheter site in the absence 

of erythema, induration, or drainage.164

Evidence-Based Medicine for Regional Analgesia 

in the Prevention of Phantom Limb Pain. This section 

reviews both positive and negative epidural and PNB 

studies that focus on the potential benefits of preemptively administering regional anesthesia to decrease 

the incidence of PLP. PRAA plays a pivotal role as 

part of a multimodal plan. Therapies for chronic PLP 

should address the above hypothesized mechanisms of 

pain. Regional analgesia addresses two of the putative 

sites of PLP: the peripheral nerves and the dorsal horn 

of the spinal cord. Additionally, preemptive analgesia 

may affect all four components of the nociceptive 

pathway. As Birbaumer et al165 revealed, regional anesthesia may prevent cortical reorganization, which 

may decrease pain perception. Ong and colleagues58

reported that intraoperative spinal anesthesia alone 

benefited the amputee with less postoperative pain 

during the first week, compared to those who did not 

receive neuraxial anesthesia. Presumably, a mechanism 

related to spinal modulation and preemptive analgesia 

accounts for the analgesia lasting long after the sensory 

blockade has subsided. Preemptive analgesia is also 

supported by better postoperative analgesia in patients 

who received regional anesthesia interventions prior to 

surgical stimulus.25,34 Regional analgesia with continuous epidural infusion or CPNBs is beneficial because of 

the ability to provide preoperative, intraoperative, and 

postoperative analgesia during much of the inflammatory period.107 First, studies demonstrating a reduction 

of PLP with PRAA will be discussed, followed by studies that fail to demonstrate a specific benefit. 

Epidural studies demonstrating benefit:

1. In 1988 Bach et al166 published an often 

referenced article, “Phantom Limb Pain in 

Amputees During the First 12 Months Following Limb Amputation, After Preoperative 

Lumbar Epidural Blockade,” a prospective, 

randomized, controlled trial of 25 geriatric 

vascular patients. The epidural group of 11 

patients received analgesia for 3 days preoperatively to alleviate preoperative limb 

pain, and the control group of 14 patients 

received perioperative opioids. Both groups 

had either epidural or spinal anesthesia for 

their amputation surgery and postoperative 

meperidine and acetaminophen for analgesia. At 6 and 12 months postamputation, 

none of the epidural patients reported PLP, 

while the control group reported incidences 

of 38% and 27%, respectively. However, the 

study was small and six patients died before 

follow-up was complete (see Table 11-1). The 

relatively low incidence of PLP even in the 

control group could possibly be attributed to 

the intraoperative use of preemptive regional 

anesthesia.166 

2. Jahangiri and colleagues167 reported in 1994 

that perioperative epidural infusion of 

diamorphine, clonidine, and bupivicaine 

0.125% is safe and effective in reducing the 

incidence of phantom pain after amputation. Thirteen epidural study patients were 

compared to 11 control patients who received 

on-demand opioids. The epidural solution 

was infused at 1 to 4 mL/hr for 1 to 2 days 

preoperatively and at least 3 days postoperatively, and both groups received general 

anesthesia intraoperatively. The study group 

reported significantly less PLP at 7 days, 6 

months, and 1 year, with 8% incidence in 

the epidural group compared to 73% in the 

control group at 1 year.167

3. In 1996 Katsuly-Liapis168 reported that 

preemptive epidural analgesia reduces the 

incidence of phantom pain in lower limb 

amputees. This prospective study divided 45 

patients for lower-limb amputation into three 

TABLE 11-1 

INCIDENCE OF PHANTOM LIMB PAIN IN 

BACH’S STUDY

Time Since Operation

Study Group 7 day 6 mo 12 mo

Epidural 27% 0% 0%

Control 64% 38% 27%

Data source: 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. 1988;33:297–301.
240

Care of the Combat Amputee

groups. Group A received 3 days of preoperative and 3 days of postoperative epidural 

analgesia with 0.25% bupivacaine and morphine. Group B received opioids and NSAIDs 

for preoperative pain followed by epidural 

analgesia for postoperative pain. Group C 

received no epidural analgesia. At 6 months 

and 1 year, the patients in group A reported 

no phantom pain, while a significant portion 

of groups B and C did experience phantom 

pain. The authors concluded that preemptive 

epidural analgesia reduced the incidence of 

phantom pain in lower limb amputees during 

the first year following amputation.168

Epidural studies demonstrating no benefit:

1. Nikolajsen et al published a relatively large 

study in 1997 titled “Randomised Trial of Epidural Bupivicaine and Morphine in Prevention of Stump and Phantom Pain in LowerLimb Amputation.”169 The 29 patients in the 

epidural group received bupivacaine 0.25% 

at 4 to 7 mL/hr with epidural morphine at 

0.16 to 28 mg/hr preoperatively, bupivacaine 

0.5% intraoperatively (with general anesthesia), and 0.25% bupivacaine at 4 to 7 mL/hr 

with epidural morphine in 2- to 8-mg boluses 

as needed postoperatively for an average 

of 6.9 days. The control group’s 31 patients 

received epidural saline intraoperatively 

and postoperatively. All patients received 

postoperative parental opioids as needed as 

well. Although Nikolajsen found no reduction in PLP at 1 week, 3 months, 6 months, 

or 12 months postamputation (Table 11-2), 

the results are questionable because half the 

patients were lost to follow-up due to death, 

reamputation, or inability to contact them. 

In addition, the infusion rate was somewhat 

low for lumbar epidural, which may have 

resulted in inadequate spread.169

2. In 2001 Lambert170 reported on a study designed to compare the effect of two different 

regional techniques, perioperative epidural 

analgesia and postoperative sciatic catheter 

analgesia, on PLP. The 14 patients in the epidural analgesia group received bupivacaine 

0.166% with morphine at 0.2 to 0.8 mg/h for 

24 hours preoperatively, intraoperatively, 

and continued for 3 days postoperatively. In 

the sciatic analgesia group, 16 patients had 

a perineural sciatic catheter placed intraoperatively, which was infused postoperatively 

with bupivacaine 0.25% at 10 mL/hr for 3 

days. Epidural analgesia was shown to provide greater relief of residual limb pain during the first 3 days, yet there was no significant difference in the incidence and severity 

of PLP at 6 and 12 months. Like Nikolajsen’s 

study, this unblinded study lost 40% of patients to follow-up due to death, and had 

low epidural infusion rates. Additionally, it 

was hampered by the lack of a control group 

(without regional analgesia).170

Continuous peripheral nerve block studies demonstrating benefits:

1. In 1991 Fisher and Meller171 reported on a 

small, prospective study of 11 vascular patients in whom sciatic catheters were placed 

intraoperatively and infused postoperatively 

with bupivacaine 0.125% at 10 mL/h for 72 

hours, concluding that perineural catheters 

may have a role in diminishing PLP. These 

patients demonstrated a 50% decrease in 

morphine administration within the first 3 

days and, more importantly, no PLP at 12 

months after above-knee or below-knee amputation; however, the study used retrospective controls and studied a limited number of 

patients.171

2. In 1997 Birbaumer et al published a study 

titled “Effects of Regional Anesthesia on 

Phantom Limb Pain Are Mirrored in Changes 

in Cortical Reorganization”165 that supports a 

benefit of PRAA in treating established PLP 

and possibly in preventing PLP in amputees. 

As noted above, studies have revealed that 

substantial reorganization of the primary 

somatosensory cortex occurs subsequent to 

amputation and that such cortical reorganiTABLE 11-2

INCIDENCE OF PHANTOM LIMB PAIN IN 

NIKOLAJSEN’S STUDY

Study 

Group

Time Since Operation

1 wk 3 mo 6 mo 12 mo

Epidural 52% 82% 81% 75%

Control 56% 50% 55% 69%

Data source: Nikolajsen L, Ilkjaer S, Christensen JK, Kroner K, Jensen 

TS. Randomised trial of epidural bupivacaine and morphine in 

prevention of stump and phantom pain in lower-limb amputation. 

Lancet. 1997;350:1353-1357.
241

Pain Management Among Soldiers With Amputations

zation is positively correlated with PLP. The 

Birbaumer study hypothesized that pain 

reduction induced by regional anesthesia 

leads to less cortical reorganization and thus 

less phantom pain. Six males with traumainduced unilateral arm amputations with 

established PLP were investigated and controlled against four arm amputees without 

PLP. After the patients were given brachial 

plexus anesthesia to influence their PLP, researchers performed neuroelectric source 

imaging while stimulating the fingers and the 

mouth of each subject, as cortical reorganization was assessed as a dependent variable. 

The blockade abolished all aspects of cortical 

reorganization seen by neuroelectric source 

imaging and simultaneously eliminated 

the current experience of PLP. Birbaumer 

concluded that cortical reorganization likely 

contributes to PLP but probably does not 

maintain PLP by itself.165

3. In 1998 Lierz and colleagues172 published 

a case report that demonstrated successful 

elimination of PLP with regional analgesia 

after unsuccessful extensive pharmacologic 

therapy. A 39-year-old male with 39% totalbody surface area burns requiring bilateral 

upper extremity amputations developed severe phantom pain by postoperation day 18, 

which was treated with NSAIDs, calcitonin, 

amitriptyline, and carbamazepine, as well as 

TENS therapy. Due to unrelenting PLP, the 

patient had bilateral brachial plexus catheters 

placed on postoperation day 39 (left interscalene and right axillary perineural catheters), 

which were infused with ropivicaine 0.2% at 

4 to 6 mL/hr for 6 days. The regional analgesia resulted in complete pain relief through 

the 7 months of follow-up.172

Continuous peripheral nerve block studies demonstrating no benefit:

1. Elizaga et al173 reported a retrospective, 

unblinded study of 19 lower extremity amputees in which study patients received a 

sciatic catheter placed intraoperatively and 

maintained postoperatively for an average 

of 4 days. Patients in the treatment group 

received 10 mL of bupivacaine 0.5% bolused 

intraoperatively, then 2 to 6 mL/hr of bupivacaine 0.5% infused intraoperatively and 

postoperatively; patients in both the treatment and control group received an IV PCA. 

No differences were found in opioid use or 

PLP between the two groups, although 70% 

of patients were lost to follow-up and the 

intraoperative anesthetic technique was not 

controlled.173

2. Pinzur and colleagues174 published a prospective, randomized study for the prevention of 

PLP in 1996. Twenty-one vascular patients 

scheduled for lower extremity amputations 

for peripheral vascular disease were given 

spinal anesthesia intraoperatively as well 

as perineural sciatic nerve catheters, which 

were infused with either bupivacaine 0.5% at 

1 mL/hr or saline for 72 hours. Residual limb 

and PLP were assessed for the first 72 hours 

as well as at 3 and 6 months. While patients 

who received bupivacaine via the sciatic 

catheters reported lower pain scores and 

decreased opioid use for the first 48 hours, 

there was no difference in the incidence of 

PLP. Weaknesses of the study included lack 

of any attempt at preemptive analgesia, and 

very low infusion rate, resulting in probable 

inadequate blockade.174

Considering the quality of the studies that examined the benefit of epidural and CPNB analgesia 

in reducing chronic postamputation pain, a greater 

weight of evidence favors PRAA having some degree 

of prevention of the development and successful treatment of established PLP. Therefore, regional analgesia 

may be central to a successful multimodal approach 

to preventing and treating chronic postamputation 

pain.

Techniques of Regional Analgesia. This section 

reviews the placement of epidural and continuous 

peripheral nerve catheters, localization of nerves, and 

administration of solutions used during continuous 

infusions. Because many seriously injured patients 

present with multiple injuries, ongoing, adequate analgesia naturally remains a paramount patient concern 

as well as a significant provider challenge. Examining 

the timing and duration of regional analgesia, Kissin175

reviewed the need for continuous regional anesthesia 

techniques when attempting to provide preemptive 

analgesia by preventing central hypersensitivity. Ideally, regional anesthesia techniques should cover the 

entire “initiation phase”—the initial inflammatory 

response, which lasts days or sometimes weeks in the 

case of polytrauma—which may require sequential 

catheters to provide optimal long-lasting analgesia.25, 

34,175,176 In the current military conflict, these continuous 

regional analgesia techniques have been successfully 

placed in the combat theater or at the earliest opportunity in Europe with pumps that accompany the service 

member back to the United States.
242

Care of the Combat Amputee

Epidural Catheters. Epidural analgesia has been 

the mainstay of perioperative regional analgesia 

for several decades. Using a dilute solution of local 

anesthesia often combined with an opioid, the anesthesia provider can effectively block transmission of 

afferent nociception and achieve profound analgesia. 

Epidural catheters should be placed at the “epicenter” of the incision to optimize segmental analgesia, 

thereby targeting only those nerve roots requiring 

blockade. For example, a standard thoracotomy incision at T6 should have a T6 epidural catheter, whereas 

a standard exploratory laparotomy should have a 

low thoracic epidural placed for optimal analgesia. 

Standard technique incorporates a sterile preparation and drape, skin localization, advancement of an 

epidural needle either with a midline or paramedian 

approach, confirmation of epidural needle placement 

by a “loss of resistance” technique, and threading a 

20-gauge multiorifice catheter 3 to 5 cm within the 

epidural space. Typical local anesthetic and opioid 

concentrations, boluses, and rates are listed in Table 

11-3. In addition to the above risks and benefits, 

epidural analgesia can result in hypotension in up 

to 30% of cases, particularly with larger boluses of 

high-concentration local anesthesia in hypovolemic 

patients. However, establishment of blockade after 

volume resuscitation in a stable patient with dilute 

solutions can provide excellent analgesia while maintaining stable hemodynamics.

Peripheral Nerve Blocks. PNBs, which may reduce 

the risk of hypotension, respiratory depression, urinary retention, and difficulty with ambulation, offer 

an attractive alternative to epidural analgesia. PNBs 

include upper and lower extremity blocks, head and 

neck blocks, and paravertebral blocks. Upper extremity blocks include interscalene, supraclavicular, 

infraclavicular, and axillary approaches to the brachial 

plexus; lower extremity approaches include lumbar 

plexus, sciatic, femoral, popliteal, and ankle blocks. 

The approach to the brachial plexus (Figure 11-2) is 

based primarily on the location of the injury or surgery: the interscalene approach is used for shoulder 

analgesia and the axillary approach for forearm and 

hand surgery. Similarly, proximal lower extremity 

blocks can provide analgesia to a neural plexus; for 

example, the lumbar plexus block results in femoral, 

obturator, and lateral femoral cutaneous nerve blockade with a single injection. Paravertebral blockade 

can be performed in the thoracic or lumbar region, 

resulting in excellent unilateral blockade of nerve 

roots with minimal risk for hypotension, bradycardia, 

or respiratory depression. 

TABLE 11-3

ROUTINE VOLUMES AND RATES FOR REGIONAL ANESTHESIA TECHNIQUES IN ADULTS

Approach Single Injection 

(using 0.5% ropivacaine)*

Continuous Infusion 

(using 0.2% ropivacaine)*

Patient-Controlled Bolus (total rate should be < 20 mL/hr)

Interscalene 30–50 mL 6–10 mL/hr 2–5 mL bolus q 20–60 min

Supraclavicular 30–40 mL 6–10 mL/hr 2–5 mL bolus q 20–60 min

Infraclavicular 30–40 mL 6–10 mL/hr 2–5 mL bolus q 20–60 min

Axillary 30–50 mL 6–10 mL/hr 2–5 mL bolus q 20–60 min

Paravertebral 3–5 mL each level 6–10 mL/hr 2–4 mL bolus q 20–30 min

Lumbar plexus 30 mL 6–10 mL/hr 2–4 mL bolus q 20–30 min

Femoral 30 mL 6–10 mL/hr 2–5 mL bolus q 20–60 min

Sciatic 20–30 mL 6–10 mL/hr 2–5 mL bolus q 20–60 min

Popliteal 30–40 mL 6–10 mL/hr 2–5 mL bolus q 20–60 min

Epidural-thoracic 6–10 mL 6–10 mL/hr w/ opioid 2–3 mL bolus q 20–30 min

Epidural-lumbar 10–20 mL 10–20 mL/hr w/ opioid 3–4 mL bolus q 20–30 min

Epidural-morphine 3–5 mg 40 μg/mL at 0.4–0.8 mg/hr NA 

Epidural-fentanyl 50–100 μg 2–5 μg/mL at 0.3–1.0 μg/kg/hr NA

*Ropivacaine percentages not applicable to morphine or fentanyl epidural.

NA: not applicable
243

Pain Management Among Soldiers With Amputations

Localization techniques:

	 •	 Nerve stimulation, which originated in the 

1960s, is now used for most PNBs. This technique provides a quantifiable endpoint for 

needle placement without causing a potentially uncomfortable paresthesia.18,19,177 However, 

little evidence exists that the widespread use 

of nerve stimulation has increased the safety 

of neural blockade.178 Typically, the needle is 

advanced close to the nerve as the nerve stimulator is dialed to a final stimulation between 

0.2 and 0.5 mA.179 After negative aspiration, a 

1-mL test dose (“Raj test”) is injected to rule 

out a possible intraneural injection (marked 

by pain or high pressure on injection) and to 

confirm proper needle position, followed by 

an intravascular test dose using local anesthesia with 15 μg of epinephrine (6 mL with a 

1:400,000 solution); an increase of greater than 

10 beats/minute or greater than 15 points on 

the systolic blood pressure over the resting 

values indicates intravascular position of the 

needle, requiring its withdrawal. After negative test doses, the total local anesthesia dose 

(see Table 11-3) is given in 5-mL aliquots with 

frequent aspiration. 

	 •	 Ultrasound technology specifically for regional anesthesia has revolutionized regional 

anesthesia within the past 5 years. Nerve 

blocks using ultrasound may be performed 

with either ultrasound alone or in combination with nerve stimulation. The potential 

benefits of ultrasound-guided regional 

anesthesia are numerous. Higher success 

rates and decreased onset times have been 

demonstrated in several studies, because the 

anesthesiologist can optimize needle placement during injection to ensure appropriate 

spread.21,180,181 Because vascular and neural 

structures, as well as others such as pleura, 

can be well-visualized, fewer complications 

from needle penetration or vascular injection 

occur. In the case of trauma, the sole use of 

ultrasound technique should also decrease 

pain compared to nerve stimulation, which 

causes extremity movement. In the case of 

amputation, ultrasound allows for block 

placement when the loss of a limb precludes 

the ability to observe motor stimulation from 

a nerve stimulator. The risks of the application 

of ultrasound are minimal; however, indirect 

challenges do exist, including potential breaks 

in sterile technique with extra equipment 

or inability to see the actual needle tip on 

ultrasound, resulting in inadvertent needle 

advancement. 

Continuous Peripheral Nerve Blocks. CPNBs offer 

improved analgesia over single shot nerve blocks by 

virtue of longer duration with minimal motor block. 

Many combat-wounded service members present with 

multiple-extremity injury, and ongoing, adequate analgesia remains a paramount concern. Occasionally, dual 

catheters may be required in a single patient to achieve 

adequate analgesia in multiple areas. Ganesh and 

Cucchiaro182 reported on a study in which adolescents 

were discharged 24 hours following extremity surgery 

Figure 11-2. Peripheral nerve block of the brachial plexus. (a) Axillary approach. (b) Interscalene approach.

Reproduced with permission from: Buckenmaier C, Bleckner L. Military Advanced Regional Anesthesia and Analgesia Handbook. 

Washington, DC: Borden Institute; 2009: Figures 10-5 (a) and 7-5 (b).

a b
244

Care of the Combat Amputee

with dual CPNBs with good to excellent analgesia. This 

practice will likely become more common because it 

potentially reduces hospital stay, economic impact, 

opioid use, and opioid side effects. Ropivacaine may 

be preferred for its greater safety margin in cases when 

multiple infusions are employed, and until more data 

is available, total infusion rates should be less than 

0.5 mg/kg/hr.139

Catheters and Pumps. Peripheral catheters are either 

stimulating or nonstimulating devices, most commonly a “catheter through needle” technique. The stimulating system (eg, Arrow StimuCath, Teleflex Medical, 

Research Triangle Park, NC) employs an insulated 

needle as well as a stimulating, single-orifice catheter 

that is advanced 3 to 5 cm through the needle; once 

proper stimulation is achieved, incremental boluses are 

administered through the catheter. The nonstimulating catheter system utilizes an insulated needle with 

a side port for aspiration and injection; after proper 

needle placement, injection of local anesthesia is made 

through the needle, followed by advancement of the 

multiorifice catheter an additional 3 to 5 cm through 

the needle. 

Electronic pumps, such as Stryker (Stryker Instruments, Kalamazoo, Mich) and AmbIT (Sorenson 

Medical Inc, West Jordan, Utah; Figure 11-3), as well 

as elastomeric pumps, such as Accufuser (McKinley 

Medical, Wheat Ridge, Colo) and On-Q (I–Flow Corporation, Lake Forest, Calif; Figure 11-4), are commercially available. Electronic pumps are very reliable and 

programmable for various settings, including patientcontrol settings. Both the Stryker and the Sorenson 

pumps are approved for flight within the Department 

of Defense. Elastomeric pumps are simple devices that 

allow dependable infusion rates and do not require 

batteries. Both types are small, portable, and disposable, although the Sorenson pump may be reused by 

replacing a disposable cassette. 

Solutions. When utilizing epidural analgesia, the 

combination of local anesthesia and opioids appears to 

afford the greatest advantage, resulting in synergistic 

analgesia.105,183–186 Opioid choices include morphine, a 

hydrophyllic, and fentanyl and sufentanyl, which are 

lipophyllic. Morphine can be used in lesser amounts: 

its epidural/IV dose ratio is 0.25, compared to 1.0 for 

fentanyl and over 1.0 for sufentanyl; however, some 

studies suggest that fentanyl and sufentanyl have fewer side effects.187 Epidural hydromorphone has steadily 

gained in popularity over the past decade, with one 

study showing that it causes less pruritis.188 Typically, 

either 0.0625% to 0.125% bupivacaine or 0.1% to 0.2% 

ropivacaine is used in conjunction with an opioid at 

10 to 20 mL/hr (6–10 mL/hr for thoracic and 2–3 mL 

every 20–30 min for lumbar epidural analgesia).183,189,190

As noted above, maximum epidural bupivacaine rates 

should not exceed 0.5 mg/kg/hr (0.25 mg/kg/hr in 

infants),139–143 and the rate should be decreased for 

pregnant or elderly patients or those with uremia or 

liver failure. Morphine rates should be infused at 0.4 

to 0.8 mg/hr, and fentanyl typically ranges from 0.25 

to 1.0 μg/kg/hr. Higher opioid rates should prompt 

increased monitoring within the intensive care unit. Figure 11-3. AmbIT (Sorenson Medical Inc, West Jordan, 

Utah) portable electronic pump (used with permission).

Figure 11-4. On-Q pump (I –Flow Corporation, Lake Forest, 

Calif; used with permission).
245

Pain Management Among Soldiers With Amputations

Medications

The treatment of PLP has been a difficult process, 

with a variety of treatments attempted but few providing consistent long-term relief. Drug therapies are the 

most commonly used treatment modalities for PLP. 

Drug therapies used to treat PLP include opioids, 

anticonvulsants, lidocaine/mexiletene, clonidine, ketamine, amitriptyline, NSAIDs, and calcitonin. These 

drugs have been shown to reduce PLP severity and 

have an analgesic effect on pain in some cases, but few 

have demonstrated long-term PLP relief.191

Opioids

Traditionally, opioids form the cornerstone of acute 

pain management; however, they are often overused, 

and recent studies have revealed more problems with 

an opioid-based regimen. Still, as a component of 

multimodal therapy, opioids complement both oral 

analgesics and regional analgesia. Opioids notably 

bind with opioid receptors peripherally and centrally, 

providing analgesia without loss of touch, proprioception, or consciousness. Peripherally, they reduce 

neurotransmitter release and nociceptor sensitization, 

particularly in inflammatory tissue; centrally, they 

modulate afferent input in the substantia gelatinosa 

of the dorsal horn lamina where C fibers terminate, 

as well as in cortical areas to blunt perception of pain. 

Acute pain specialists currently are armed with a 

wide range of opiate choices including (in increasing potency) meperidine, morphine, methadone, 

hydromorphone, and fentanyl, with various route of 

administration such as IV (including PCA), intramuscular, oral, transmucosal, transdermal, subcutaneous, 

epidural, intrathecal, and intraarticular. Providers 

should remember that morphine-6-glucuronide can 

accumulate in the presence of renal insufficiency.191

Methadone is unique in acting through NMDA receptor antagonism and serotonin reuptake inhibition, yet 

can be challenging to manipulate because of its long 

half-life.192 Transdermal fentanyl (Duragesic, OrthoMcNeil-Janssen Pharmaceuticals, Inc, Raritan, NJ) is 

approved for chronic pain management but not for 

acute pain management, in which its use has resulted 

in several negative outcomes. 

PCAs offer a significant advantage over opioids 

administered by nurses, empowering the patient to 

self-administer analgesia as needed, thereby decreasing analgesia gaps and decreasing excess opioid dosing 

that could result in excess sedation and respiratory 

depression. Expanding the PCA arsenal to include 

various agents (eg, morphine, hydromorphone, 

fentanyl) at equianalgesic doses allows the opioid 

to be easily changed if it is ineffective or causes side 

effects. A novel, transdermal fentanyl PCA, IONSYS 

(Janssen-Cilag International, Beerse, Belgium) is currently available that could dramatically reduce some 

of the drawbacks of the PCA modality. IONSYS uses 

an iontopheretic transdermal system in which a small 

current is applied to a reservoir of fentanyl, allowing 

a 40-μg dose to move effectively across the dermis 

and be readily absorbed via cutaneous capillaries. 

The system significantly reduces both nursing and 

pharmacy workload. It has a built-in 10-minute lockout 

and requires replacement after 80 doses or 24 hours, 

whichever occurs first.193,194 Table 11-4 lists various 

PCA options. 

Oral opioid choices include short-acting agents 

such as Percocet (Endo Pharmaceuticals, Chadds 

Ford, Pa), a combination of oxycodone and acetaminophen; Vicodin (Abbott Laboratories, Abbott 

Park, Ill), made of hydrocodone and acetaminophen; 

and hydromorphone; as well as long-acting agents 

including methadone, sustained-release morphine, 

and sustained-release oxycodone (OxyContin, Purdue Frederick Co, Stamford, Conn). When changing 

either the opiate or the route of administration, the 

TABLE 11-4 

PATIENT-CONTROLLED ANALGESIA MODALITIES

Drug Equianalgesic 

Dose (mg/mL)

Basal (mg/hr) PCA Dose (mg) Lockout (min) Load (mg)

Morphine 1 0, 1 1, 2, 3 6–12 5–10

Meperidine 10 0, 10 10, 20, 30 6–10 50–100

Hydromorphone 0.2 0, 0.2 0.2, 0.4, 0.6 6–10 1–2

Fentanyl (μg) 25 0, 25 20, 25, 30 6–10 100–200

PCA: patient-controlled analgesia
246

Care of the Combat Amputee

provider must use great care in converting the dose 

(Table 11-5). Once a new 24-hour dose is calculated 

based on a different medication or route, half the 

calculated dose should be given in divided doses in 

an appropriate frequency to allow for varying pharmacodynamics and pharmacokinetics. In addition, 

multimodal therapy with adjunctive agents requires 

reduced dosing as well. 

In spite of their popularity, opioids cause both 

short- and long-term sequelae that are particularly 

problematic in the trauma patient.56 Besides the side 

effects of sedation and the potential for respiratory 

depression, as well as their ineffectiveness in dynamic 

and neuropathic pain, opioids frequently are associated with nausea, vomiting, constipation, ileus, urinary retention, and pruritis. Long-term consequences 

include possible immunosuppression of B and T cell 

function, opioid tolerance, OIH, and the potential for 

opioid addiction in susceptible patients. OIH can occur even after short-term administration and results 

in a paradoxical decrease in a patient’s pain threshold 

such that they are more sensitive to pain. The mechanism of OIH appears to include enhanced NMDA 

activity, increased levels of the pronociceptive spinal 

dynorphin, and increased excitatory pathways from 

the rostral ventromedial medulla to the dorsal horn. 

“Rekindling” of OIH may occur with a subsequent 

administration of a small dose of opioid after the apparent resolution of OIH.53,56,195

In the acute treatment of amputation pain in 31 

patients, Wu et al196 compared an IV bolus and infusion of morphine and lidocaine administration with a 

diphenhydramine control group in a cross-over study. 

They found that morphine relieved 45% of residual 

limb pain and 48% of PLP, while IV lidocaine relieved 

only 33% of residual limb pain and only 25% of PLP.196

In another cross-over study, Huse et al197 reported the 

efficacy of oral morphine for chronic PLP. They administered long-acting, oral morphine (70–300 mg daily) 

to 12 patients in a cross-over method, half receiving 

morphine for 12 weeks and the other half receiving 

placebo, followed by 6- and 12-month follow-ups. Although 42% of patients had greater than 50% reduction 

in pain, 50% of patients reported no pain relief. In three 

patients who responded to morphine, somatosensory 

evoke potential evaluations demonstrated decreased 

cortical reorganization.197 Loeser6 may offer the best 

advice on opioid use with amputees: as long as the 

patients’ activities of daily living increase, a cautious 

trial of opioids is reasonable; however, if their activities of daily living decrease while their opioid dose 

increases, then the provider should wean them off of 

opioids. 

Anticonvulsants

Anticonvulsants have long played a role in the 

treatment of neuropathic pain conditions, including 

peripheral diabetic neuropathy, postherpetic neuralgia, causalgia, and reflex sympathetic dystrophy (now 

called chronic regional pain syndrome). With the advent of newer and safer anticonvulsants, researchers 

have demonstrated a significant benefit with their use 

in acute pain management. Gabapentin and pregabalin, which are structural analogs of γ-aminobutyric 

acid, reduce calcium influx at the calcium channel and 

activate spinal noradrenergic activity, thereby reducing 

spinal cord excitatory amino acids, glutamate, and aspartate.198 Pregabalin is the newest agent and although 

more expensive, it has a more favorable pharmacokinetic profile, allowing more rapid titration as well as 

twice daily dosing. Most commonly, gabapentin is 

dosed at 300 mg three times daily, then increased by 

300 mg per dose every 3 days to a maximum daily dose 

of 3,600 mg. The most frequent side effects of these 

drugs are dizziness and drowsiness in roughly 10% 

of patients, yet both drugs seem to be well-tolerated 

in most patients. In several studies, including a look 

at the use of gabapentin in the treatment of PLP, their 

benefits include improved analgesia with an average 

use of 50% less opioids, decreased opioid-induced 

hyperalgesia and tolerance, decreased anxiety, possibly decreased chronic pain, and increased patient 

satisfaction.199–202

Carbamazepine reduces intense, brief, lancinating 

PLP, but has not been demonstrated to be effective 

for other types of phantom pain.24,203 Gabapentin 

had little immediate effect on PLP but was shown to 

reduce pain intensity and visual analog scale scores 

after a 5-week treatment period in one study,201 but 

this pain reduction was not replicated in subsequent 

studies,204,205 although gabapentin was shown to be 

opioid-sparing.

TABLE 11-5

NARCOTIC CONVERSION CHART

Narcotic IV Dose (mg) PO Dose (mg)

Morphine 10 30–60

Hydromorphone 2 10

Methadone 10 20

OxyContin (Purdue 

Frederick Co, Stamford, Conn)

15 30

IV: intravenous

PO: orally
247

Pain Management Among Soldiers With Amputations

Lidocaine/Mexiletene

The local anesthetic lidocaine and the oral analog 

mexiletene, class Ib antiarrhythmics, provide analgesia separate from their direct local anesthetic properties. Administered systemically, local anesthetics 

can decrease pain and opioid requirements, possibly 

through decreasing ectopic afferent neural activity at 

the NMDA receptor within the dorsal horn. IV lidocaine continuous infusion (1–2 mg/min) and topical 

lidocaine have been shown to decrease pain in the burn 

patient.206 Mexiletene (with an initial dose of 150 mg 

twice daily) can be administered empirically or following a positive IV lidocaine test, after documenting the 

absence of conduction abnormalities on a 12-lead electrocardiogram. Mexiletene can be increased by 150 mg 

every 3 days to a maximum of 900 mg daily, although 

nausea and vomiting may limit dose escalation. 

The combination of clonidine and mexiletene 

appears particularly beneficial in difficult, centralmediated pain syndromes such as PLP, as reported by 

Davis49 and in one author’s (RJM) personal experience 

in treating Brooke Army Medical Center patients from 

2003 to 2007. As indicated above, Wu et al196 demonstrated minimal benefit from the acute administration 

of IV lidocaine in PLP, and Davis49 reported good to 

excellent relief from oral mexiletene alone in 58% of 

patients and good relief with a combination of mexiletene and clonidine in an additional 35% of patients, 

for a total 83% response rate for mexiletene when used 

in conjunction with clonidine. 

Clonidine

Clonidine is an α2-agonist acting at the locus caeruleus and in the dorsal horn of the spinal cord at α2 antinociceptive receptors, causing analgesia, sedation, and 

anxiolysis from a supraspinal, spinal, and peripheral 

site of action. Whether given by an oral, IV, intrathecal, epidural, transdermal, or perineural route, it has 

been shown to decrease pain scores, decrease opioid 

requirements, decrease opioid-induced hyperalgesia, 

and prolong nerve blocks in a synergistic manner with 

other analgesics. In a hemodynamically stable patient, 

clonidine should be initiated at 0.1 mg by mouth twice 

daily, increasing to a maximum of 0.3 mg twice daily, 

observing for hypotension. While Davis49 reported 

success with transdermal clonidine for outpatients, 

especially combined with mexiletene, providers at 

Brooke Army Medical Center found oral clonidine 

effective and easier to titrate for inpatients.

Ketamine

Historically, ketamine has played a central role in 

anesthesia for the trauma patient due to the profound 

analgesia and hemodynamic stability it provides. 

However, ketamine has increasingly been used for 

postoperative analgesia and acute pain management 

in the trauma patient; in fact, its use throughout the 

inflammatory period of injury may result in decreased 

central hypersensitivity resulting from the continual C 

fiber wind-up phenomenon in the polytrauma patient. 

Ketamine binds noncompetitively to the phencyclidine 

site of the NMDA receptor as well as to the σ-opioid 

receptor, resulting in intense analgesia; other benefits 

include prevention of opioid-induced hyperalgesia, 

decreased opioid tolerance, decreased opioid requirements, increased sense of well-being and patient satisfaction, decreased nausea and vomiting, decreased 

risk of respiratory depression, and decreased chronic 

pain. Although anesthetic doses may be associated 

with secretions as well as agitation and hallucinations, 

subanesthetic doses, with the addition of a benzodiazepine if necessary, are tolerated extremely well. The 

combination of ketamine and morphine in low PCA 

doses (1 mg morphine and 1 mg ketamine) has been 

shown to be particularly beneficial, with few side effects when ketamine doses are below 150 μg/kg/hr 

(2.5 μg/kg/min).207–209

Studies on ketamine have shown that it does not 

reduce the occurrence of PLP, but may temporarily reduce the severity of pain. A prospective observational 

study of 14 limb amputees showed that following 

administration of ketamine, 72% of subjects continued 

to experience PLP. However, only 9% of subjects given 

ketamine reported severe PLP, compared to 71% of 

controls.210 Nikolajsen et al211 reported profound acute 

reduction of both residual limb pain and PLP after a 

0.1-mg/kg bolus followed by a 7-μg/kg/min infusion 

for 45 minutes. Nikolajsen50 also reported on the efficacy of oral ketamine on chronic residual limb pain 

over a 3-month period. Another NMDA antagonist, 

dextromethorphan, was given daily (120–180 mg/day) 

to three amputation patients with PLP for 3 months, 

resulting in a significant reduction in PLP without 

side effects.212 However, a further follow-up study 

randomizing 53 subjects to either epidural ketamine 

plus bupivacaine or epidural saline plus bupivacaine 

failed to demonstrate increased efficacy of epidural 

ketamine in treating PLP.213

Antidepressants

Tertiary amines, most notably amitriptyline, as 

well as secondary amines such as nortriptyline and 

desipramine, are effective in neuropathic and central 

hypersensitivity conditions primarily by blocking 

norepinephrine and serotonin reuptake in the dorsal 

horn. Their limitations result from a broad side-effect 
248

Care of the Combat Amputee

profile including antihistamine, anticholinergic, and 

antiadrenergic effects that together frequently cause 

sedation, dry mouth, constipation, and possible 

tachycardia and orthostasis. Although amitriptyline 

has been most studied, the secondary amines may be 

equally effective and have fewer side effects. After ruling out significant cardiac contraindications by history, 

physical, and electrocardiogram, amitriptyline can 

be started at 10 to 25 mg every evening, increasing to 

50 mg after 1 week of therapy, although its analgesic 

properties may take 3 to 4 weeks to take effect.

Amitriptyline has not been shown to be a consistently effective treatment for PLP. A randomized, 

placebo-controlled study of amitriptyline showed 

that it did not significantly reduce chronic PLP over 

a 6-week period.214 Panerai et al,215 however, demonstrated efficacy of both chlorimipramine and nortriptyline in central pain syndromes such as PLP in 

a randomized, controlled trial. Finally, mirtazapine, a 

newer antidepressant that modulates both serotonin 

and norepinephrine with fewer side effects than the 

tricyclic antidepressants, demonstrated efficacy in 

reducing PLP in one case series.35

Acetaminophen

Atlhough acetaminophen is a relatively weak analgesic, it is attractive as part of a multimodal pain 

regimen because it does not cause platelet dysfunction, gastritis, significant renal toxicity, bone-healing 

concerns, or associated nausea and vomiting. The 

mechanism of action is reported to function at a central COX-3 receptor, producing analgesia. Numerous 

studies have demonstrated synergy with other analgesics with at least 20% opioid sparing,216,217 as well as 

decreased nausea, vomiting, and sedation using up to 

4,000 mg daily in divided doses. 

Nonsteroidal Antiinflammatory Drugs 

NSAIDs also play a potentially critical role in multimodal therapy although with notable limitations. 

Traditional NSAIDs inhibit both COX-1 and COX-2 

receptors, thereby decreasing the production of prostaglandins and thromboxane, and also decreasing 

nociception, respectively. Traditional NSAIDs bind 

receptors only peripherally, whereas the newer COX-2 

agents work both peripherally and centrally, decreasing both peripheral and central sensitivity.3

 Their use 

is associated with many benefits including decreased 

opioid requirements, decreased pain scores, decreased 

nausea and vomiting, decreased constipation, decreased sedation, and finally decreased heterotopic 

ossification, a complication frequently associated with 

the polytrauma patient. Traditional NSAIDs are limited by potential adverse effects such as platelet dysfunction, gastritis, renal impairment, and impaired bone 

healing, most of which is dose-dependent. Oral COX-2 

agents, currently only celecoxib, may be an attractive 

alternative because they do not cause platelet dysfunction and have decreased gastritis risk, although their 

risk of renal impairment and bone-healing problems 

is similar to traditional NSAIDs. Unfortunately, the 

COX-2 inhibitors have been associated with increased 

thromboembolic events including myocardial infarction, as well as higher rates of congestive heart failure 

and hypertension. Recently, some of the traditional 

NSAIDs have also been associated with an increased 

thromboembolic risk.218,219 However, in some patients, 

traditional NSAIDs, including ketorolac (for up to 5 

days) and COX-2 inhibitors can be helpful in achieving 

greater analgesia, particularly for dynamic pain and 

as part of a multimodal regimen.220–222

Calcitonin

Salmon calcitonin has been noted to have analgesic 

properties in the treatment of Paget disease, possibly 

related to binding with serotonin receptors within the 

hypothalamus and limbic system. Calcitonin has been 

shown to provide analgesic effects for PLP.170,223 Jaeger 

and Maier223 reported a prospective, double-blinded, 

cross-over trial with calcitonin 200 units over 30 minutes. Each of the calcitonin groups showed a significant 

reduction in pain scores compared to placebo. 

Nontraditional Therapies

TENS, acupuncture, and virtual reality mirror 

treatments have also shown some success in reducing PLP or delaying the onset of chronic phantom 

pain.192,224,225

Transcutaneous Electrical Nerve Stimulation, Spinal 

Cord Stimulation, and Deep Brain Stimulation

 TENS has shown some success in relieving PLP, 

but again, study results have been varied. Spinal cord 

stimulation and deep brain stimulation of the ventral 

caudal thalamic nucleus are techniques that have led 

to short-term relief of PLP in several studies.226–230 A 

series of studies showed that the stimulation of the 

posterior columns of the spinal cord led to 65% of 

patients having a 25% reduction in pain levels immediately after surgery, but only 33% showing long-term 

reduction in pain levels.231,232 Other reports have shown 

little or no reduction in PLP following dorsal column 

stimulation.233,234
249

Pain Management Among Soldiers With Amputations

Sympathetic Blocks for Postamputation Pain

An infrequent intervention for amputation pain is 

sympathetic blocks, specifically lumbar sympathetic 

block and stellate ganglion block. A practitioner must 

first recognize the signs of sympathetically mediated 

pain, which include allodynia, decreased range of 

motion, edema, and possible skin changes such as a 

cold and clammy or sweaty extremity with possible 

hair changes. Pain may become worse during physical or emotional stress due to catecholamine release, 

which may activate nerve terminals and neuromas. 

Classically, local anesthetics are injected near the sympathetic ganglia, which relieves pain and sympathetic 

symptoms within minutes, making the extremity 

warm with improved blood flow and color. Pain physicians have documented the effective use of stellate 

ganglion blocks to prevent reactivation and worsening 

of pain in patients with a history of chronic regional 

pain syndrome who are undergoing upper extremity 

surgery. In addition, there are case reports of stellate 

ganglion block to treat acute postoperative pain in 

patients without chronic regional pain syndrome.235

A stellate ganglion block with fentanyl alone has also 

been reported to be effective.236 Temperature increase 

in the extremity without motor or sensory blockade 

is indicative of effective stellate ganglion or lumbar 

sympathetic block; stellate ganglion blocks may be 

accompanied by a possible Horner syndrome (ptosis, 

miosis, and anhydrosis). However, pain relief following sympathetic blocks may result from undetected 

somatic block from local anesthetic spread to the epidural space or lumbar nerve roots.237

Acupuncture

Some amputees have gained relief from PLP by 

rubbing their intact limb and stimulating normal afferent input at the peripheral, spinal, and cortical levels. 

Based on this concept, acupuncture in the intact limb 

has been used as a means to stimulate normal afferent 

input to the nervous system and elicit an analgesic 

effect that reduces the intensity of PLP and phantom 

sensations.238,239 Bradbrook239 found that acupuncture 

was an effective treatment in two patients who had had 

nontraumatic limb amputation (following congenital 

talipes and myeloma of the pelvis). These two patients 

reported immediate and significant reduction in severity of PLP as measured with a visual analog scale following several sessions of acupuncture in regions of the 

intact limb anatomy in relation to the subjects’ PLP and 

phantom sensations. 239 However, in another single case 

of a patient who had undergone traumatic limb amputation following a motor vehicle accident, acupuncture 

was not effective in reducing the severity of PLP and 

phantom sensations. It remains unclear through what 

specific mechanism acupuncture alleviates PLP, and as 

with many other therapies, accupuncture has not been 

shown to consistently relieve PLP in patients who have 

undergone traumatic limb amputations.

Figure 11-5. Right lower extremity amputee participating in mirror therapy as treatment for phantom limb pain.
250

Care of the Combat Amputee

Mirror Therapy

Another proposed treatment is based on the concept 

that the perception and experience of PLP may emerge 

due to conflicts within the brain between visual and 

proprioceptive feedback mechanisms.224 Based on this 

visual-proprioceptive dissociative feedback postulate, 

Ramachandran and colleagues224 proposed that using the reflected image of the intact limb in a mirror 

to create the visual illusion of the missing limb might 

reduce the conflict between visual and proprioceptive 

inputs and, consequently, reduce PLP. They used this 

technique in upper extremity amputees and found that 

approximately 60% of subjects in one case series of 15 

amputees reported an improvement in their PLP.224

This technique required the amputee to view the reflected image of the intact hand performing specific 

movements, while performing the same movements 

with the amputated, or “phantom,” hand. While performing these movements with the intact hand, many 

subjects reported feeling the phantom hand moving 

simultaneously, accompanied by pain relief. 

Two of the authors (BLC and JWT) were part of a recently concluded randomized, sham-controlled study 

of unilateral lower extremity amputees using mirror 

therapy (Figure 11-5) compared to cover mirror and 

mental visualization therapies, finding a strong benefit 

of mirror therapy (Figure 11-6).225 This study showed 

that all six amputees (100%) who were randomized to 

mirror therapy had pain relief and eight of nine subjects (89%) who crossed over to mirror therapy after 

being randomized initially to either covered mirror or 

mental visualization therapies had benefit from mirror 

therapy, so that a total of fourteen of fifteen subjects 

(93%) using mirror therapy had pain relief. 

Although the results of these studies appear to 

provide further support for the postulate that a 

mismatch between visual and proprioceptive inputs 

contributes to the generation of PLP, it is not clear why 

a mismatch would cause pain. Head first posited the 

existence of two major somatesthetic sensory systems, 

one he termed epicritic and the other protopathic.240

The epicritic system is rapid and is transmitted to the 

brain by lemniscal afferent pathways. In contrast the 

protopathic system is slow and is carried to the brain 

by a chain of neurons. Head suggested that the epicritic 

system gates the protopathic system and that loss of 

the epicritic system can induce pain because the protopathic system is uninhibited.240 Melzack and Wall27

subsequently put forth a similar gating hypothesis. 

Rossi et al241 postulated and provided evidence to 

demonstrate that imagery of movements or actual 

movements reduces the amplitude of the somatosensory evoked potentials (ie, a gating effect), suggesting 

that this gating may help reduce phantom pain. The 

mirror therapy paradigm has been more successful 

than imagery alone because it led to the activation of 

mirror neurons, neurons that fire both when a person 

performs an action and when observing the same 

action performed, in the cortex contralateral to the 

amputated limb. Since the activation of these mirror 

neurons modulates somatosensory inputs, their activation may have blocked protopathic pain perception 

in the phantom limb.241 Mirror therapy has now been 

adopted as part of the routine treatment for PLP offered 

by several military medical centers, including Walter 

Reed Army Medical Center.

(Baseline)

Visual Analogue Scale (0-100)

0 1 2 3 4 5 6 7 8 

70

60

50

40

30

20

10

0

Study Week

Mental Visualization Covered Mirror Mirror

----Randomized Trial---- ----Cross over to Mirror----

Figure 11-6. Results of controlled trial of mirror therapy. 

Change in phantom limb pain measured using the VAS. 

Group medians are depicted for each time point.

Reproduced with permission from: Chan BL, Witt R, Charrow AP, et al. Mirror therapy for phantom limb pain. N Engl 

J Med. 2007;357:2206–2207. Copyright 2007 Massachusetts 

Medical Society. All rights reserved.

LOW BACK PAIN

Low back pain (LBP) is reported as a significant impairment in approximately 71% of patients with lower 

limb amputations.242 Patients with transfemoral amputations tend to have a greater incidence and severity 

of LBP than those with transtibial amputations.243 Leg 

length discrepancy, excessive lumbar lordosis, and 

excessive trunk motion may be related to LBP in transfemoral patients. Friel et al244 found that patients with 

transfemoral amputations exhibited greater strength 

but less endurance in their back extensor muscle than 
251

Pain Management Among Soldiers With Amputations

those with transtibial amputation. Friberg245 found that 

amputees with LBP tended to have greater leg length 

discrepancies than those without pain. Back pain tends 

to decrease following leg length discrepancy correction. In some studies, lumbar lordosis has been correlated with increased LBP, particularly in circumstances 

with poor prosthetic fit.245 Leg length discrepancy, 

lumbar lordosis, and excessive motion of the lumbar 

spine may lead to abnormal spinal loads, which produce abnormal stress distributions in the tissues. No 

specific evidence is available to guide treatment of 

LBP in patients with lower extremity amputations. 

However, the high prevalence of LBP among patients 

with lower extremity amputations may have as strong 

an impact on disability, function, and rehabilitation as 

residual limb pain and phantom sensations.

FUTURE RESEARCH

Research into methods for preventing and treating postoperative residual limb pain and PLP have 

demonstrated several therapeutic options. It is likely 

that a combination of therapies may be needed to 

effectively treat pain through acute, subacute, and 

chronic pain conditions following limb amputation. 

Areas that require additional research are more effective analgesics to be deployed in the battlefield 

setting, pain immediately following amputation, 

and treatments for chronic pain (eg, headaches, osteoarthritis, PLP, and LBP). The appropriate timing 

and duration of regional anesthesia in the acute and 

subacute period to decrease both acute and chronic 

pain needs further evaluation. Understanding the 

mechanism for the development of pain sensation 

will lead to improved pharmacologic as well as nontraditional methods for controlling and regulating 

the pain response. Also, further understanding of 

the cognitive response to pain, especially phantom 

pain, will help in the development of more effective 

treatments for PLP and possibly a means for tracking 

the response to therapies.

SUMMARY

In summary, PLP and pain in the residual limb are 

significant medical problems after amputation. Many 

different therapies have been tried with few successes, although multimodal therapy appears to be most effective. 

Multimodal therapy including appropriate continuous 

regional analgesia, multiple medications aimed at various locations along the nociceptive pathway, and nontraditional therapies such as mirror therapy, is a promising 

method of treatment that may bring desperately needed 

pain relief to service members with limb loss. 

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