Phantom Limb Pain: A Systematic
Neuroanatomical-Based Review of
Zachary McCormick, MD, George Chang-Chien,
DO, Benjamin Marshall, DO, Mark Huang, MD, and
R. Norman Harden, MD
Department of Physical Medicine and Rehabilitation,
The Rehabilitation Institute of Chicago/Northwestern
McGaw Medical Center, Chicago, Illinois, USA
Reprint requests to: Zachary McCormick, MD, 780 S.
Federal, Chicago, IL 60605, USA. Tel: 510-388-7084;
Fax: 312-238-1035; E-mail: firstname.lastname@example.org.
Disclosures: None of the authors have any conflicts of
interest to report.
This research effort was not directly or indirectly
Objective. Review the current evidence-based phar-
macotherapy for phantom limb pain (PLP) in the
context of the current understanding of the patho-
physiology of this condition.
Design. We conducted a systematic review of origi-
nal research papers specifically investigating the
pharmacologic treatment of PLP. Literature was
sourced from PubMed, Embase, Scopus, and the
Cochrane Central Register of Controlled Trials
(CENTRAL). Studies with animals, “neuropathic”
but not “phantom limb” pain, or without pain scores
and/or functional measures as primary outcomes
were excluded. A level of evidence 1–4 was ascribed
to individual treatments. These levels included
meta-analysis or systematic reviews (level 1), one or
more well-powered randomized, controlled trials
(level 2), retrospective studies, open-label trials,
pilot studies (level 3), and anecdotes, case reports,
or clinical experience (level 4).
Results. We found level 2 evidence for gabapentin,
both oral (PO) and intravenous (IV) morphine,
tramadol, intramuscular (IM) botulinum toxin, IV and
epidural Ketamine, level 3 evidence for amitriptyline,
dextromethorphan, topiramate, IV calcitonin, PO me-
mantine, continuous perineural catheter analgesia
with ropivacaine, and level 4 evidence for metha-
done, intrathecal (IT) buprenorphine, IT and epidu-
ral fentanyl, duloxetine, fluoxetine, mirtazapine,
clonazepam, milnacipran, capsaicin, and pregabalin.
Conclusions. Currently, the best evidence (level 2)
exists for the use of IV ketamine and IV morphine for
the short-term perioperative treatment of PLP and
PO morphine for an intermediate to long-term treat-
ment effect (8 weeks to 1 year). Level 2 evidence is
mixed for the efficacy of perioperative epidural
anesthesia with morphine and bupivacaine for short
to long-term pain relief (perioperatively up to 1 year)
as well as for the use of gabapentin for pain relief of
intermediate duration (6 weeks).
Key Words. Neuropathic Pain; Pain Management;
Postoperative Pain; Acute Pain; Chronic Pain
Historically, phantom sensations (PLS) and phantom limb
pain (PLP) were widely believed to be psychogenic
.With recent advances, we now know that pathologi-
cal changes occur in both the peripheral and central
nervous system after amputation [2–4]. PLS are charac-
terized by cortical sensory perception of an amputated
body part. These phenomena may or may not be painful
. When pain is experienced in the area of the missing
limb, this is known as phantom limb pain (PLP) [2–6].
PLP descriptions are diverse, but commonly include
burning, gnawing, stabbing, pressure, and aching. The
experience may feel like a sharp muscle spasm, such as
a painfully clenched fist in an absent upper extremity
[2,6]. PLP has been described after the loss of any limbs
or organs such as the tongue, eye, breast, tooth [7–10].
The presence of PLP has also been described in bra-
chial plexus avulsion  and in people with congenitally
absent limbs [12,13]. The nature of PLP can be
episodic or continuous and vary significantly in intensity
Pain Medicine 2013; *: **–**
Wiley Periodicals, Inc.
Currently, there are over 1.6 million people in the United
States that live with limb loss, and that number is
expected to double by the year 2050 . Causes for
amputation include peripheral vascular disease, trauma,
and malignancy . Risk factors associated with PLP
include pain immediately prior to the amputation—as in
dysvascular amputees [18,19], gender (PLP being more
common in women), upper extremity amputation, and
temporal proximity to the amputation. Psychological
factors such as stress, anxiety, and depression may also
potentiate PLP [4,5,20,21]. PLP has a variable time of
onset, and may decrease or resolve over time. Seventy-
five percent of individuals who will develop PLP do so
rapidly post-amputation .
Previous surveys indicate that approximately 80% of
amputees will experience phantom sensation or pain at
some point following their amputation . However, there
is a very large range of reported prevalence, from 2% to
97% [23,24], which is probably due to the various ways of
defining the categories of PLP, various populations, etiolo-
gies, differences in time since amputation, and the multi-
tude of methodologies for measuring pain itself. There are
two survey studies that appropriately describe the inci-
dence of PLP separately from PLS in general and residual
limb pain. One was performed in the general population of
Denmark  and the other in veterans with post-traumatic
amputations . Jensen and colleagues showed that the
incidence of PLP was 84% 8 days after amputation .
After six months, 67% of these individuals reported PLP.
Carlen and colleagues describe Israeli veterans who suf-
fered amputations and reveal that, in 1 to 6 months after
limb loss, 67% experienced PLP that was usually tran-
sient. Longitudinal studies suggest that the prevalence of
PLP decreases over time [26,27].
A multitude of treatments for PLP have been attempted
over the years. In the mid to late 1970s, Wall reported that
a total of 68 methods of treatment could be found in the
literature at that time and stated, “This wide spread scatter
of departments and methods warns that there is some-
thing seriously wrong with our understanding of [the
pathophysiology of this] disorder” [28,29]. Decades later,
our understanding of the pathophysiology of PLP, while
far from complete, has improved and consequently,
increased the variety of attempted therapies. A meta-
analysis of all trials including patients with PLP pain found
in MEDLINE between 1966–1999 concluded that, of the
available treatments, there is little evidence from random-
ized trials to guide clinicians with regards to treatment .
In 2011, the Cochrane group produced a meta-analysis of
13 of the 583 existing studies up to September 2011
investigating pharmacologic treatment of PLP and con-
cluded that morphine, gabapentin, and ketamine demon-
strate trends toward short-term analgesic efficacy .
We have conducted an updated systematic review of the
literature specifically investigating pharmacologic treat-
ment of PLP, which we structure around a review of the
current state of understanding of pathophysiological
mechanisms of PLP, as proper control of pain requires a
reasonable scientific understanding of the targets of
therapy [32–34]. There are three general neuro-axial com-
partments implicated in the mechanisms of PLP, which
likely interact: 1) peripheral/afferent pathways that include
neuromas at the site of the residual limb, 2) central
pathways that involve hyperexcitability in the spinal cord,
especially the dorsal horn, or the cerebrum that lead to
somatosensory cortical reorganization, and 3) efferent
pathways, in which the sympathetic nervous system may
maintain a stimulus for further development and provoca-
tion of PLP. We provide the level of evidence for current
treatments organized around these interacting mecha-
nisms in order to provide the clinician with a rational
A systematic review was completed of original research
papers investigating the pathophysiology and treatment
of phantom pain. Literature was sourced from PubMed,
Embase, Scopus, and the Cochrane Central Register of
Controlled Trials (CENTRAL) up to September of 2013.
Broad searches and searches for classes of medications
and therapies were conducted, which were followed by
search terms including specific medications and thera-
pies found in the broad searches. Search terms included
“pathophysiology phantom limb pain,” “treatment of
phantom limb pain,” “medication phantom limb pain,”
“therapy phantom limb pain,” “opiate phantom limb
pain,” “morphine phantom limb pain,” “fentanyl phantom
limb pain,” “hydromorphone phantom limb pain,” “metha-
done phantom limb pain,” “tramadol phantom limb pain,”
“topiramate phantom limb pain,” “calcitonin phantom
limb pain,” “capsiacin phantom limb pain,” “anti-epileptic
phantom limb pain,” “gabapentin phantom limb pain,”
phantom limb pain,” “antidepressants phantom limb
pain,” “SSRI phantom limb pain,” “SNRI phantom limb
pain,” “TCA phantom limb pain,” “duloxetine phantom
limb pain,” “amitryptiline phantom limb pain,” “nortripty-
line phantom limb pain,” “mirtazapine phantom limb
pain,” “nsaids phantom limb pain,” “acetaminophen
phantom limb pain,” “ketamine phantom limb pain,”
“memantine phantom limb pain,” and “detromethorphan
phantom limb pain.”
We included studies that met the following criteria:
1. Pathophysiology studies were performed in human or
2. Treatment studies were performed in human subjects.
3. Studies investigating treatment of PLP included pain
scores or “functional” outcome measures as primary
We excluded studies that met the following criteria:
1. Pathophysiology studies performed without human or
2. Treatment studies performed in non-human subjects.
McCormick et al.
3. Studies that were conducted in patients with “neuro-
pathic pain” but not specifically PLP.
Levels of evidence were ascribed to studies for each
described treatment based on a hierarchy of quality of
evidence from level 1 to 4 (Table 1), as previously
Peripheral Afferent Mechanisms as a Target
The peripheral afferent theory of PLP centers around the
neuroma as a generator of pain and potentially a driver of
secondary central changes. Neuromas form at the cut end
of the nerves in the residual limb. They generate ectopic
afferent impulses that may be perceived as pain by the
brain. Early studies of animal models, such as rat sciatic
nerve, demonstrated that the neuroma site is complicated
and dynamic [28,29,36]. Images of neuromas show mul-
tiple sprouts growing out from each cut axon and can
travel in many directions, including back along the axon.
Cajal describes these sprouts, “in complete disarray,
crisscrossing and entangling . . . doubled backwards and
forwards [to] form intricate coils” . These changes have
been observed within 24 hours of tissue section .
There is an initial period during which each axon will
produce a large number of sprouts, but many of these
degenerate, leaving only a few that form the “stable
neuroma” . Nerve section damages the nerve blood
barrier, and molecules that are not normally active on the
nerve membrane can begin to modulate nerve firing and
possibly ectopic activity . There are nearly immediate
changes in the transport of chemicals not only from the
periphery to the central nervous system but also from the
dorsal root ganglia distally . Ectopic activity has been
demonstrated within all nerve fiber types. However, there
is significant ectopic activity in A-delta and in A-beta fibers
and a lowered mechanical threshold which is most likely
mediated primarily by A-δ fibers [28,36].
The neuroma shows sensitivity to a variety of compounds,
especially norepinephrine [28,40], which is possibly due to
cytokine imbalance at the site of the neuroma and/or
pathological receptor formation on the neuroma tissue
[41,42]. Support for this mechanism of PLP is provided by
upregulation and as well as damage to ion pumps leading
to “leaky membranes” in these neuromas in the residual
limb, both of which lead to hyperexcitability and sponta-
neous afferent impulses . PLP improves with sodium
channel blockade in residual limb tissue. However, periph-
eral nerve blocks and lysis of neuromas do not reliably
relieve phantom pain [44–47]. Furthermore, patients with
congenital absence of limbs experience phantom pain,
but do not have classic neuromas from nerve resection
[47–50]. Therefore, this mechanism cannot account for
PLP in isolation and does not explain the entire patho-
physiology of all cases of PLP.
Level 2 to 4 evidence exists for the treatment of PLP with
medications that may affect peripheral afferent mecha-
nisms. Medications within this category that have been
studied include oral (PO) amitriptyline, epidural morphine
and bupivacaine, perineural ropivacaine, topical capsaicin,
and intramuscular (IM) botulinum toxin. Level 2 and 3
evidence is summarized in Table 2.
Level 3 evidence has shown little efficacy of PO amitrip-
tyline, a tricyclic antidepressant with significant Na+
channel blocking effect [51,52]. Level 4 evidence suggests
there may be some benefit in a subset of patients,
Some investigators have hypothesized that a pain-free
interval may prevent peripheral sensitization by injured
nerves, and that reduction in afferent nerve impulses
may prevent higher level cortical changes seen post-
amputation that are also implicated in PLP [54,55]. There
is mixed level 2 evidence that pre-amputation anesthesia
with epidural morphine and bupivacaine prevents PLP
[56–58]. One level 3 study showed improvement in pain
with epidural anesthesia compared with peripheral nerve
block that persisted until 14 months postsurgery .
Level 4 evidence showed benefit of IT morphine and
bupivacaine in a case of chronic PLP .
Level 3 evidence exists that suggests efficacy of short-
term to subacute continuous administration of peri-neural
anesthesia for the prevention of the development of PLP
[45,61]. Level 4 evidence has shown benefit with a com-
bination of perineural clonidine and perineural bupivacaine
 as well as perineural ropivacaine .
Mixed level 4 evidence exists for the topical use of cap-
saicin [64–66], a selective activator of TRPV1 presynaptic
calcium channels that leads to peripheral nociceptive C
fibers defunctionalization [67,68].
Botulism toxin injection is commonplace in the treatment
of pain syndromes related to tonic muscle spasm and has
recently been appreciated to have analgesic properties
independent of its effect on neuromuscular transmission
[69,70]. Though initial level 4 evidence demonstrated
some promise in the treatment of PLP with local botulism
toxin injection [71–73], a recent randomized, double-
blinded pilot study of 14 patients with chronic PLP found
Levels of evidence used in this review
Level 1: Meta-analysis or systematic reviews.
Level 2: One or more well-powered randomized,
Level 3: Retrospective studies, open label trials, pilot
Level 4: Anecdotes, case reports, clinical experience, etc.
Neuroanatomical-Based Review of Pharmacologic Treatment of Phantom Limb Pain
Phantom limb pain pharmacotherapy summary—level 2 and 3 evidence
Medication Level of EvidenceStudy Details
Peripherally acting agents
Level 3: No effect on
long-term relief of
RCT, N = 42. Amitriptyline vs placebo. Complete resolution of
symptoms after 1 month in both groups .
RCT, N = 39: Amitriptyline vs placebo. No significant difference
compared with placebo .
Uncontrolled prospective cohort, N = 71. Perineural ropivacaine.
Infusion continued after surgery until pain was absent. Median
duration of infusion was 30 days (range of 4–83 days).
Eighty-four percent of patients had no pain at 12 months after
RCT, N = 80: perineural bupivacaine and clonidine injection vs
saline intra-operatively. Improvement in pain in the acute
postoperative period, but no difference between groups at
1 year .
RCT, N = 24. Epidural Bupivavaine, morphine, and clonidine vs
morphine alone. Epidural began 24 hours prior to surgery.
Significant decrease in incidence of PLP at 1 year, with 75%
vs 25% in experimental and control groups, respectively .
RCT, N = 60. Morphine and bupivacaine vs saline vs IM
morphine. Epidural began 18 hours prior to surgery. No
difference in pain or opioid consumption between groups at
1 week to 1 year .
RCT, N = 30. Epidural bupivacaine and diamorphine vs
perineural catheter administration of bupivacaine.
Post-amputation incidence of PLP similar to published rates.
No statistical difference between epidural vs perineural
catheter arms at 6 and 12 months .
RCT, N = 14. IM botulinum toxin injection vs lidocaine and
depomedrol. Reduction in RLP but not PLP .
Bupivuicaine + clonidine
Level 3: Effective for
acute, but mixed for
morphine + clonidine
Bupivacaine + morphine
Level 2: Mixed
development of PLP
vs no effect.
Level 2: No reduction
in the severity of
Centrally acting agents
AntiepilepticsGabapentin Level 2: mixed for
reduction in PLP
RCT, N = 19. Gabapentin vs Placebo. Gabapentin reduced PLP
significantly more than placebo at six weeks, though no
reduction in anxiety, depression, or improvement in ADLs .
RCT, N = 24. Gabapentin vs Placebo. No difference in pain
reduction compared with placebo, though more than half of
subjected who received gabapentin reported a “meaningful
change in pain” at the end of treatment, in contrast to 20%
with placebo .
RCT, N = 41. Gabapentin vs Placebo. No difference in pain
reduction compared with placebo, though intergroup difference
may have been difficult to detect as both groups’ pain intensity
scores decreased from a median of 8 to a median below 2
after six months .
RCT, N = 4. Topiramate vs placebo. Three of 4 patients with
chronic PLP showed an average 68% reduction in PLP after
14 weeks of escalating doses of topiramate. Required
relatively high dosing (400 mg BID) to achieve maximal effect
in all cases .
RCT, N = 32. IV morphine vs IV liocaine vs IV diphenhydramine.
Significant short-term reduction in PLP with morphine .
RCT, N = 60. Slow release morphine sulfate vs placebo.
Significant reduction in pain with morphine at 2 months (53%
vs 19% in placebo group) .
RCT, N = 12. Slow release morphine sulfate vs placebo. Greater
than 50% pain relief in 5 of 12 subjects up to 1 year after a 6
week treatment period. Reduced cortical reorganization in
these 5 subjects compared with the other seven .
RCT, N = 50. Complete resolution of symptoms after 1 month of
treatment with tramadol, however placebo group also
demonstrated complete relief .
TopiramateLevel 3: Significant
reduction in PLP
Level 2: Effective for
acute treatment of
PLP in the short
Level 2: Effective
of PLP compared
Level 2: No effect
McCormick et al.
no improvement in pain intensity up to 6 months following
local injection .
Central Nervous System Mechanisms as a Target
The Central Nervous System Theory of PLP implicates
neuroplastic changes in dorsal horn and somatosensory
cortical neurons. The initial nociceptive stimulation of the
amputation and the ongoing ectopic afferent drive from
the active neuroma can cause an increase of synaptic
activity between first and second order neurons in noci-
ceptive pathways [50,75]. These changes in the dorsal
horn result in a decreased response to higher level inhibi-
tory signaling [29,38,76], leading to unregulated afferent
pain signals to the brain . Imbalances in norepineph-
rine, serotonin, and gamma-amino butyric acid (GABA)
have been implicated in this process [78,79]. Additionally,
while not yet well-characterized, changes in the distribu-
tion and sensitivity of AMPA and NMDA have been sug-
gested to contribute to dysfunctional neuroplasticity in the
dorsal horn . Notably, it is unlikely that dorsal horn
neural changes primarily account for PLP as the phenom-
enon is experienced in cases of complete spinal cord
transection , but as in the Peripheral Afferent Theory,
maladaptive neuroplasticity in the dorsal horn likely con-
tributes to PLP in many cases.
Support exists for the presence of somatosensory cor-
tical changes involved in PLP. This possibility was initially
proposed in 1915 after a patient’s phantom left leg pain
completely disappeared following a right cortical lesion
that included the territory of the somatosensory cortex
. Contralateral somatosensory cortical changes are
now well described, and may include neuro-plastic
changes such as augmentation, excitotoxicity, glial
MedicationLevel of Evidence Study Details
Level 2: mixed
evidence for efficacy
RCT, N = 21. Perioperative infusion of 200 IU calcitonin vs
placebo. Improvement in PLP severity with calcitonin observed
at 1 week to 1 year .
RCT, N = 20. IV ketamine and calcitonin vs IV ketamine vs IV
calcitonin. Relief for 2–48 hours after infusion of IV ketamine
and calcitonin and ketamine alone but not calcitonin alone
RCT, N = 20. See above .
RCT, N = 11. IV ketamine vs saline. Complete resolution of pain
for up to 30–120 minutes with ketamine compared with saline.
No long-term effects were measured .
RCT, N = 45. IV ketamine vs saline placebo perioperative. No
difference at 3 days, 3 months, or 6 months. Strong trend
toward a significant rate of pain reduction (P = 0.28) at 6
months, where 47% of the group receiving ketamine continued
to have PLP compared with 71% of the control group .
RCT, N = 31. High vs low dose IV ketamine vs IV magnesium.
Significantly reduced PLP with ketamine and dose-dependent
effect observed. The higher dose arm had a complete
absence of PLP and the low dose arm had a 50% absolute
reduction in the incidence of PLP at 3 months .
RCT, N = 53. Epidural ketamine and bupivacaine vs epidural
saline and bupivacaine immediately postoperatively.
Significant reduction in PLP immediately. However, no
significant differences were observed at 8 days to 1 year
RCT, N = 19. Memantine vs placebo perioperatively. Decrease in
PLP intensity at 6 days to 6 months but not at 1 year
compared with placebo .
RCT, N = 36. 47% Memantine vs placebo. Significant relief of
PLP at 4 weeks compared with placebo, but not at 16 months
RCT, N = 8. Memantine vs placebo. No alleviation of chronic
PLP after 1 month of treatment. No difference found in cortical
representation of the lower limbs between groups .
Uncontrolled prospective study, N = 10. Greater than 50%
additional relief despite other pharmacologic agents in patients
with amputations due to cancer .
Level 2: Effective
acute but not
long-term relief of
Level 2: Short-term to
persistence of relief
Level 2: No efficacy
for the treatment of
Level 3: Long-term
treatment of PLP
Definitions: Acute = post-amputation phantom limb pain; Long term: = greater than 6 months; PLP = phantom limb pain; RCT = randomized controlled
trial; Subacute = up to 6 months.
Neuroanatomical-Based Review of Pharmacologic Treatment of Phantom Limb Pain
potentiation, and axonal sprouting [82–95]. In addition to
the somatosensory cortex, there is also evidence for
reorganization in the motor cortex and likely multiple
other areas of the cerebrum, such as the prefrontal
cortex [84,86,96–99]. During reorganization, the cortical
areas representing the amputated limb are assumed by
adjacent areas of the somatosensory cortex [6,50,100].
Cortical reorganization leads to the development of
abnormal circuitry and firing patterns that encode pain
signals . Notably, cortical reorganization is associ-
ated with PLP but not necessarily non-painful phantom
limb sensations [82,88]. Interestingly, the cortex continu-
ously reorganizes in PLP [96,97] in contrast to acute
nociceptive pain in which this has not been not observed
Support for cortical reorganization as a mechanism of PLP
includes the fact that these neuroplastic changes are less
apparent in congenital amputees and amputees without
phantom sensations . Imaging studies have correlated
a greater extent of cortical reorganization with more
intense PLP [105,106]. More extensive cortical reorgani-
zation is seen in patients with chronic pain preceding their
amputation compared with those without pain, which is
consistent with the fact these patients typically experience
more severe PLP post-amputation compared with those
without chronic pain prior to amputation . Additionally,
the high frequency of psychological and affective changes
 such as depression [108,109] and anxiety [109,110]
may support the involvement of cortical (and limbic) path-
ways in PLP.
Level 2 and 3 evidence exists for the treatment of PLP that
may target central mechanisms. Medications that have
been studied in this category include PO gabapentin,
intravenous (IV) and PO morphine, PO tramadol, IV and
epidural ketamine, PO memantine, IV calcitonin, and PO
dextromethoraphan. Level 4 evidence for medications
in this category include PO methadone, intrathecal
(IT) buprenorphine, IT or epidural fentanyl, mirtazapine,
duloxetine. Level 2 and 3 evidence is summarized in
Level 2 and 3 evidence is mixed for the efficacy of
gabapentin [111–113], an agent that has shown to be
efficacious for other causes of neuropathic pain though
through a poorly defined mechanism. Level 4 evidence for
gabapentin includes a case series of seven children who
experienced complete resolution of symptoms at 1.75
years follow-up after treatment with this medication .
Level 2 evidence exists for the efficacy of PO and IV
morphine with regard to short-term  as well as to
subacute to chronic PLP [116,117]. Evidence for the use
of other opioids is limited to one level 2 study that did not
show efficacy of tramadol  and level 4 studies for PO
methadone, IT buprenorphine, and IT or epidural fentanyl
Level 2 evidence exists for the perioperative use of
ketamine (IV or epidural), which noncompetitively blocks
NMDA receptors, for acute pain reduction but little for a
prolonged duration of treatment effect [124–128]. These
beneficial effects of perioperative IV ketamine are echoed
in a prospective observational series and case studies
Level 3 evidence exists for the short-term to subacute but
not long-term reductions of PLP with the perioperative use
of PO memantine [132,133], an NMDA receptor antago-
nist. In addition, there is level 4 evidence for its use in both
the acute  and subacute context . However,
when used for chronic PLP, level 2 evidence indicates no
efficacy of memantine .
Level 3 evidence exists for the use of the NMDA-receptor
antagonist, dextromethorphan (PO) . A double-blind
placebo-controlled crossover study of three patients by
the same principle, author resulted in similar beneficial
effects on PLP severity after 1 month of treatment .
There is mixed level 2 evidence supporting postoperative
infusion of the polypeptide hormone calcitonin for the
treatment on PLP [125,139]. This perioperative benefit is
echoed in several case studies [140–142].The exact
mechanism of calcitonin’s efficacy on PLP is unknown at
this time, but authors have speculated that effects on
central serotoninergic pathways play a large role .
Level 3 and 4 evidence exists for the use of topiramate
[144,145], an anti-epileptic medication whose exact
mechanism of action is unknown but does decrease the
activity of voltage-sensitive sodium channels, enhance the
frequency of GABA receptor activation, and antagonize
non-NMDA glutamate receptors (no effect on NMDA
Minimal level 4 evidence exists for the treatment of PLP
with mirtazapine, pregabalin, midazolam, milnacipran,
fluoxetine, and duloxetine, which includes a small case
series and several case reports [146–153].
Efferent Sympathetic Mechanism as a Target
The Efferent Theory of PLP hypothesizes that sympathetic
dysregulation serves as a mechanism that stimulates and
maintains PLP [154,155]. A large subset of individuals
exhibit significant dysfunction and asymmetry of sympa-
thetic tone in the residual limb after amputation ,
suggesting that a distinct component of PLP may be
sympathetically maintained pain [157–161]. Electrical and
mechanical stimulation of the para-vertebral sympathetic
chain causes intense pain in the phantom limb . This
may be due in part to the impact of vasoconstriction in the
McCormick et al.
tissues (especially the neuroma) of the residual limb [162–
165]. Physiologically, it is well established that nocicep-
tive afferents are not influenced by sympathetic fibers
under normal conditions [166,167]. However, there may
norepinepherine receptors in the neuroma or the residual
limb tissues  or sympathetically triggered afferent
transmission . The neuroma shows sensitivity to a
variety of compounds including norepinephrine . Sec-
tioned nerves immediately proximal to the damage can
form physiologic ephapsis, which can connect afferent to
efferent sympathetic pathways [28,36].
Interestingly, post amputation residual limbs are consis-
tently cooler than the contralateral unaffected limb, which
has been linked to sympathetic dysfunction . Using
quantitative thermography, a “patchy asymmetric” tem-
perature distribution in the residual limb has been demon-
strated, specifically in patients suffering from residual limb
pain . Excessive sweating has been noted in some
residual limbs  and skin conductance (an indirect
correlate of sudomotor activation) significantly correlates
with the intensity of PLP but not with other qualities of
phantom sensation . Further evidence for involve-
ment of the sympathetic nervous system in PLP is sug-
gestedby pain reduction
blockade of the sympathetics  or surgical interruption
Few pharmacologic treatments for PLP that specifically
target the sympathetic nervous system have been inves-
tigated. Current evidence is limited to level 4 studies for
the use of beta-adrenergic blockade, which includes a
number of cases of individuals with PLP who improved
after starting a beta-blocker [169,170], as well as a case
report of diminished PLP after lumbar sympathetic block
While beyond the scope of our targeted systematic review
of pharmacologic treatments of PLP, a discussion on inter-
ventions and treatments for PLP would not be complete
without addressing the numerous non-pharmacological
therapies that have been studied to treat this challenging
condition. Mind–body therapies are well tolerated, and a
constantly evolving body of evidence supports these
modalities in the treatment of PLP. These modalities
include biofeedback, mirror therapy, mental imagery,
hypnosis, and meditation. Techniques such as mental
imagery and mirror therapy can be relatively easy to imple-
ment, while biofeedback may require specialized equip-
ment such as an electromyography device or virtual reality
These therapies have many distinct advantages over more
invasive interventions. They have little to no side effects,
and can be taught to patients for self-delivery . It is in
our opinion that mind–body therapies should be used
in conjunction with pharmacologic agents in treating
phantom limb pain. A 2012 review highlights these mind–
body interventions in treating PLP and reaffirms the need
for more high-quality research to determine which modali-
ties are the most efficacious .
The existing literature that describes pathophysiological
mechanisms of PLP suggests a possible model that
includes ectopic activity at the neuroma, which drives
central plasticity and sensitization, leading to increased
sympathetic tone that serves as a feedback loop to main-
tain PLP. A logical approach to pharmacotherapy for PLP
should include disruption of pathologic mechanisms at
these sites. Our systematic review of the literature
indicates that further research is needed, as no level
1 evidence that is specific to the treatment of PLP
Currently, the best evidence (level 2) exists for the use of IV
ketamine and IV morphine perioperatively for short-term
treatment of PLP and PO morphine for an intermediate to
long-term treatment effect (8 weeks to 1 year). Level 2
evidence is mixed for the efficacy of perioperative epidural
anesthesia with morphine and bupivacaine for short to
long-term pain relief (perioperatively up to 1 year) as well
as for the use of gabapentin for pain relief of intermediate
duration (6 weeks). Sympathetic targets have not been
well studied and warrant further investigation given the
growing evidence for involvement of the autonomic
nervous system in PLP.
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