PAIN 155 (2014) 22362242

www.elsevier.com/locate/pain

Topical review

A mechanism-based classication of phantom limb pain

Sarah C. Grifn a, Jack W. Tsao b,
a
b

Department of Rehabilitation, Walter Reed National Military Medical Center, Bethesda, MD, USA
Department of Neurology, Uniformed Services University of the Health Sciences, Bethesda, MD, USA

Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article.

1. A mechanism-based classication of pain

Despite the abundance of literature on phantom limb pain,
there remains no clear consensus on the mechanisms of the disorder: phantom limb pain has been attributed to genetic make-up
[11,25], memories [3,21], neuromata [28], spinal plasticity [15],
and cortical re-mapping [17,18]. A standard treatment for the disorder remains equally elusive. Treatments range from acupuncture
to deep brain stimulation [16] and include mirror/virtual reality
therapies [13,26], mental imagery [24], transcutaneous nerve stimulation [22], deep brain, motor cortex, and spinal cord stimulation
[2,8,23], and the pharmaceutical agents morphine [39], gabapentin
[9], amitriptyline [31], calcitonin [19], ketamine [15], and memantine [27], among others.
The divergence in theories on phantom limb pain stems in part
from the heterogeneity of the disorder itself. Although phantom
limb pain occurs in up to 85% of patients after amputation [32],
the characteristics of this pain vary drastically. The onset of phantom limb pain ranges from hours to decades [12,29], and the frequency of episodes vary from every few days to several times
each day [30]. The length of episodes can range from less than
1 minute to continuous [30], and pain descriptors include shooting,
squeezing, tingling, throbbing, stabbing, burning, and cramping
[32].
The heterogeneity of phantom limb pain is widely acknowledged, and it is recognized that the disorder likely arises from
multiple mechanisms [18]. Some authors have argued for mechanism-based management of pain [16,33,36], although others have
attempted to classify amputation pain according to severity [20]
and etiology [14,34]. However, phantom limb pain remains a
blanket term for pain in absent tissue, regardless of the qualities
and theorized mechanisms of this pain.
We believe that a paradigm shift in the conceptualization of
phantom limb pain from a single disorder to a cluster of pain

Corresponding author. Address: Department of Neurology, Uniformed Services

University of the Health Sciences, 4301 Jones Bridge Road, Room A1036, Bethesda,
MD 20814-4799, USA. Tel.: +1 301 295 3643; fax: +1 301 295 0620.
E-mail address: Jack.Tsao@med.navy.mil (J.W. Tsao).

conditions holds enormous potential. A mechanism-based classication of phantom limb pain promises to resolve major failures in
clinical research thus far, leading to more directed research and
effective treatment of pain in a missing limb. Further support for
the development of a mechanism-based classication of pain
comes from parallel work in other lines of pain research.
2. Current phantom limb pain research
The literature abounds with case studies that present novel and
promising treatments for phantom limb pain. Less common, yet
still prevalent, are randomized, controlled trials (RCTs) that rigorously assess these treatments. These trials tend to present less
promising results: although a few RCTs in the last decade have
shown sustained relief for phantom limb pain, the majority of RCTs
for phantom limb pain fail to show a statistically signicant reduction of pain in the group receiving the treatment of interest [37].
Taking into account the publication bias toward successful RCTs,
the treatment prognosis for phantom limb pain seems particularly
bleak [35].
However, it is possible that this trendin which a promising
treatment for phantom limb pain fails to prove effective in a
RCTis due to the treatments specicity rather than its efcacy.
That is to say, it is possible that a given treatment effectively
reduces pain but only for a subset of patients. When this subset
is part of a larger group, the outcomes of the group may dilute
these positive outcomes, leading to the false conclusion that the
treatment is not an effective therapy. In fact, a review of the literature (Table 1) conrms that inclusion/exclusion criteria for studies tend to be limited to basic characteristics such as intensity of
pain (ie, pain must be above a certain threshold), time since injury,
and type of injury as well as characteristics that are relevant not to
the condition, but rather to the practicality of the study itself, such
as pregnancy, history of allergy to the drug in question, and plans
to undergo major surgery in the near future. This tendency is particularly troublesome in light of the fact that the majority of treatments for phantom limb pain are predicated on a theory as to the
mechanism of the pain, and it is widely recognized that there are
multiple mechanisms for phantom limb pain [18].

http://dx.doi.org/10.1016/j.pain.2014.05.016
0304-3959/Published by Elsevier B.V. on behalf of International Association for the Study of Pain.

S.C. Grifn, J.W. Tsao / PAIN 155 (2014) 22362242

3. Research utility of classication of phantom limb pain

A mechanism-based classication system for phantom limb
pain would allow researchers to target a specic patient
population according to the theorized mechanism of action of the
treatment in question. This approach could reveal, in a subset of
patients, therapeutic effects that may be obscured with a more
diverse patient population.
Furthermore, a mechanism-based classication would provide
valuable direction and structure to the study of phantom limb pain.
This approach would direct research toward the elucidation of the
mechanisms behind phantom limb pain and the mechanisms of
action of pharmaceuticals and other treatments to reduce pain.
More importantly, this approach would generate testable hypotheses. A mechanism-based classication of pain creates a clear trajectory for a theory or treatment of phantom limb pain. For each
theory of phantom limb pain, it will be necessary to do the following: dene the clinical symptom and the mechanism involved,
select the affected population with that particular presentation of
phantom limb pain, select or develop a treatment targeting this
mechanism, test this treatment in the selected population, and
re-evaluate the theory based upon these results. For each treatment of phantom limb pain, besides testing the treatment, it will
be necessary to characterize this population for factors that
contribute to treatment response, determine the factor(s) for
treatment response, use this information to determine the
subpopulation of patients sensitive to this treatment, and seek to
determine the mechanism of pain for this population based upon
the mechanism of action of the treatment.
4. Clinical utility of classication of phantom limb pain
Currently treatment of phantom limb pain is through trial and
error. This method is inadequate not only in terms of providing
pain relief to patients, but also in protecting patients from side
effects and adverse reactions to treatments that may not even
relieve pain. Many treatments for phantom limb pain and pain in
general are associated with a number of side effects, ranging from
mild to severe. For example, gabapentin, a commonly used rstline treatment for amputation pain, can be associated with side
effects such as involuntary eye movement, lack of coordination,
blurred vision, dizziness, decreased energy, drowsiness, and
extremity edema [1]. Distinguishing between different types of
phantom limb pain would enable clinicians to offer stratied or
personalized therapy by selecting the most effective treatment(s)
among the many available, allowing safer and more effective
reduction of pain. The consequences of this approach could be particularly powerful if accompanied by efforts to characterize the
patient population not only in terms of likelihood to respond to
treatment but also likelihood to experience noxious effects.

5. Development of a mechanism-based classication system of

pain
The effort to develop a mechanism-based classication would
not be isolated, but rather would parallel work in other lines of
pain research. Although still in the preliminary stages, this work
lends credence to the potential utility of reclassifying phantom
limb pain. Furthermore, this work could indicate potentially useful
distinctions across phantom limb pain patients.
In 1998, Woolf et al. argued that the development of a taxonomy of pain would allow the development of drugs that target specic mechanisms, the creation of new guidelines for experimental
design, and the eventual development of more reliable, validated
diagnostic tools for treatment [38]. However, despite the appeal

2237

of this approach, it is not yet attainable, as the pathophysiological

mechanisms for pain identied in animal research have not yet
been translated into clinical practice [5].
Research has therefore emerged seeking to characterize
patients according to observable pathophysiology. The most obvious detectable manifestation of pain is the symptomie, the
qualitative aspects [4,5,10]. Although it remains unclear whether
symptoms truly correspond to the pathophysiology of pain, current research using this approach is promising. A study examining
neuropathic pain across etiologies used factor analysis to show
that pain qualities could be categorized into 5 independent
dimensions [6]. The various symptoms that formed these dimensions were rarely associated with a specic etiology, questioning
the importance of etiology in the clinical expression of neuropathic pain [6]. A second apparent manifestation of pain is sensory characteristics as measured by quantitative sensory testing
(QST). A recent study by Baron et al., which examined patients
with diabetic neuropathy and postherpetic neuralgia, used hierarchical cluster analysis to identify 5 distinct subgroups of patients
with a characteristic sensory prole [7]. Although more research
is necessary to link the pain in each of these dimensions or subgroups of patients to a shared pathophysiological mechanism, it is
possible that these studies will generate clinically signicant distinctions across patients that can be applied to phantom limb
pain research.
6. Challenges for a mechanism-based classication of phantom
limb pain
Accepting the utility of a mechanism-based classication of
phantom limb pain begets the larger challenge of developing such
a classication system. The critical component of this system is
validity, dened as how closely the system corresponds to the
underlying biology of the disorder. Woolf et al. list 2 approaches
for establishing validity in their 1998 article. The rst approach
is to dene validity in terms of a gold standard; the second
approach is to use an iterative, fallible process of searching for
and identifying symptom clusters, biological markers, history and
treatment response [38]. Phantom limb pain lacks a gold standard, requiring the second approach.
The key to initiating this fallible search is exploratory work to
identify distinctions that can be used to prole patients. These proles can then be scrutinized to determine whether they are scientically (ie, link to basic mechanisms identied in animal research)
or clinically (ie, predict treatment response or disease progression)
meaningful. This approach is inherently inefcient, as it is likely
that many distinctions across patients will fail to correspond to
underlying pathophysiology or clinical outcomes. However, until
a gold standard is established, this imperfect process is necessary
to build the classication system that may ultimately streamline
phantom limb pain research.
A mechanism-based classication of phantom limb pain will
not solve many of the problems intrinsic to the study of a condition
that lies at the intersection of experience, psychology, and biology.
However, carefully picking apart the mechanisms of phantom limb
pain on a given platform can only help to elucidate the factors contributing to pain on another.
7. Conclusion
This article seeks to redene phantom limb pain as a spectrum
of disorders. Discarding the conception of phantom limb pain as a
single disorder would allow the identication of distinct conditions
of phantom limb pain with clear mechanisms and treatment.
Although this article calls for a classication system of these

2238

Table 1
Summary of randomized controlled trials for phantom limb pain (PLP) published in the last 10 years.
Reference

Treatment

Sample size

Mechanism of action

Inclusion criteria

Exclusion criteria

Results (phantom limb pain only)

Jadad
scorea

Hsiao AF, York R, Hsiao I, Hansen E,

Hays RD, Ives J, Coulter ID. A
randomized controlled study to
evaluate the efcacy of
noninvasive limb cover for
chronic phantom limb pain
among veteran amputees.
[Randomized controlled trial;
Research Support, NIH;
Extramural research support,
US Govt, non-PHS]. Arch Phys
Med Rehabil 2012;93:617622
Ahmed MA, Mohamed SA, Sayed D.
Long-term antalgic effects of
repetitive transcranial magnetic
stimulation of motor cortex and
serum beta-endorphin in
patients with phantom pain.
[Randomized controlled trial].
Neurol Res 2011;33:953958

Noninvasive limb cover

(Farabloc)
Sham: identical limb
cover
Duration: 12 weeks

Enrolled: 57
(30 treatment,
27 sham)
Completed: 47
(23 treatment,
24 sham)

Farabloc can shield high-frequency

electromagnetic elds that are
theorized to cause cellular damage
and trigger PLP

Upper or lower
extremity
amputation
Healed residual
limb
3 or more
episodes of PLP
during past 6
weeks

Residual limb complications

Previous use of Farabloc within
last 6 months
Pregnancy

PLP outcome measure(s): numeric

pain rating severity scale

Repetitive transcranial
magnetic stimulation
(rTMS) of motor cortex
and serum b-endorphin
Sham: identical
treatment parameters
except with coil elevated
and angled to reproduce
subjective sensation of
rTMS but avoid
induction of current in
the brain
Duration: daily for 5
days
Electromagnetic own
signal-treatment
(EMOST):
Uses ltered, various
low-frequency and
intensity
electromagnetic elds
(between 1 Hz and
1MHz) that is controlled
via preprogrammed
computer
Sham: same conditions
as treatment group but
EMOST device turned off
Duration: 6 sessions (45
minutes for 6 days)
(1) Botulinum toxin type
A (Botox)
(2) Lidocaine/
depomedrol
Duration: Single
injection
No placebo or sham

Enrolled: 27
(17 active, 10
sham)

rTMS can cause plastic changes in

the brain that may target
maladaptive plasticity after
amputation

Upper or lower
extremity
amputation
Presence of
chronic PLP
Past treatment
with
pharmaceuticals
unsuccessful
Otherwise not
specied

Presence of intracranial metallic

devices, pacemakers, or any
other device
Presence of extensive
myocardial ischemia, epilepsy,
neurological or psychiatric
diseases

PLP outcome measure(s): Visual

analogue scale, Leeds Assessment
of Neuropathic Symptoms and
Signs scale
Signicant (P = .001) reduction in
PLP in treatment group
Between-group difference not
reported

Completed: 15
(10 treatment,
5 sham)

Non ionizing low-frequency and

intensity electromagnetic elds
may inuence numerous cell
functions to initiate various
healing processes

Amputation (due
to vascular or
arterial disease,
diabetes, and
accidents)
Otherwise not
specied

Not specied

PLP outcome measure(s): verbal

numeric rating scale
Between-group difference
signicant (P < .05)

Enrolled: 14 (7
botox, 7
lidocaine/
depomedrol)
Completed 1month followup: 12 (6 botox,
6 lidocaine/
depomedrol)
Completed (6month) study:

(1) The mechanism of botulinum

toxin effect may be due to (a) a
reduction in myofascial pain
related to muscle spasm/tightness
and (b) a reduction in ectopic
discharges from neuroma + a
reduction in release of nociceptors
in peripheral pain pathways
(2) Depomedrol: may inhibit
inammatory process by limiting
capillary dilation and permeability
of vascular structures present in
mechanisms of residual limb pain

Age >18 years

Lower extremity
amputation
Clinical
diagnosis of
daily RLP and/or
PLP >5/10 on
visual analogue
scale
Pain interference
with prosthetic
use, activities of
daily living, and/

Previous history of botulinum

toxin injections
Presence of: bleeding disorder,
myasthenia gravis, EatonLambert syndrome, amyotrophic
lateral sclerosis, allergy or
sensitivity to Botox, and
ischemic distal residual limb
Signs and symptoms of infection
at the injection site or systemic
infection
Pregnancy

PLP outcome measure(s): visual

analogue scale
No improvement of PLP observed
for either group

Wu H, Sultana R, Taylor KB, Szabo

A. A prospective randomized
double-blinded pilot study to
examine the effect of botulinum
toxin type A injection versus
lidocaine/depomedrol injection
on residual and phantom limb
pain: initial report.
[Randomized controlled trial;
Research support, NIH;
Extramural research support,
non-US Govt]. Clin J Pain
2012;28:108112

S.C. Grifn, J.W. Tsao / PAIN 155 (2014) 22362242

Bokkon I, Till A, Grass F, Erdo

Szabo A. Phantom pain
reduction by low-frequency and
low-intensity electromagnetic
elds. [Randomized controlled
trial; Research support, non-US
Govt]. Electromagn Biol Med
2011;30:115127

Nonsignicant reduction in PLP in

both groups
Between-group difference not
signicant

(RLP)

PLP outcome measure(s): visual

analogue scale
Between-group difference
signicant (P = .003)

Pain intensity for

past 48 hours >3
on 010 numeric
rating scale (0:
no pain, 10:
worst pain
imaginable)
Presence of pain
over past 6
months

Episodic pain with pain-free

intervals of >4 h
RLP without PLP
Phantom sensations without PLP
Age <18 years or >85 years
Contraindication to use of
calcitonin or ketamine

Ramachandran et al. originally

postulated that mirror therapy
could reverse learned paralysis
that may occur after amputation.
Learned paralysis occurs because
motor signals continue to be sent
to the missing limb without
feedback of successful movement.
Mirror therapy provides visual
input of successful limb
movement, reversing learned
paralysis and associated
discomfort due to sensation of
immobilization (not specied in
article)
Gabapentin (a) increases GABA
responses at non-synaptic sites
and (b) reduces release of monoamine neurotransmitters (not
specied in article)

Lower extremity
amputation
Otherwise not
specied

Not specied

PLP outcome measure(s): visual

analogue scale
Calcitonin + ketamine resulted in
signicantly lower pain both
during and after infusion
compared with sham (during:
P < .001; after: P < .001) and
calcitonin (during: P = .001; after:
P < .001)
Ketamine alone and
calcitonin + ketamine
signicantly reduced VAS
compared with placebo and
calcitonin (no difference between
ketamine alone and
calcitonin + ketamine in 10
patients who completed all 4
treatments)
PLP outcome measure(s): visual
analogue scale
Mirror therapy group differed
signicantly from both sham
(P = .04) and mental-visualization
group (P = .002)

Age > 18 years

Lower extremity
amputation due
to peripheral
vascular disease

Unclear; possibilities include (a)

reduction of ectopic neuroma
activity; (b) shielding of
electromagnetic weather

Age >18 years

PLP on >20 days
per month a
minimum of 3 on

Ipsilateral reamputation
Amputation of foot or toes only
Dementia or inability to answer
questionnaire about pain
Psychiatric disease
Severe cardiac, pulmonary, or
liver disease
Severely impaired kidney
function
Current history of alcohol or
drug abuse
Known allergy to gabapentin
Treatment with anticonvulsant
or tricyclic antidepressant
Pathologic residual limb
symptoms
RLP without PLP
Inadequate command of

Phantom limb may be mirroring

contralateral painful muscle areas

(1) 200 Internationale

Enheder (IE;
International Units)
calcitonin
(2) 200 IE calcitonin +
ketamine 0.4 mg/kg

Enrolled: 20
patients
(crossover)
Completed: 19
Note: only 10/
20 subjects
received
racemic
ketamine
treatment leg

(1) Mechanism of action of

calcitonin is unclear

Chan BL, Witt R, Charrow AP,

Magee A, Howard R, Pasquina P.
F, Tsao JW. Mirror therapy for
phantom limb pain.
[Comparative study; Letter;
Randomized controlled trial]. N
Engl J Med 2007;357:2206
2207

(1) Mirror therapy

(2) Mental visualization
Sham: covered mirror
therapy
Duration: 4 weeks

Enrolled: 22
Completed: 18
(6 mirror
therapy, 6
mental
visualization, 6
sham)

Nikolajsen L, Finnerup NB, Kramp

S, Vimtrup AS, Keller J, Jensen
TS. A randomized study of the
effects of gabapentin on
postamputation pain.
[Randomized controlled trial
Research support, non-US
Govt]. Anesthesiology
2006;105:10081015

Gabapentin
Sham: identical pill
capsules
Duration: 30 days

Enrolled: 46
(23 gabapentin,
23 placebo)
Completed
treatment: 34
(16 gabapentin,
18 placebo)
Completed 6
month followup: 33 (15
gabapentin, 18
placebo)

Kern U, Altkemper B, Kohl M.

Management of phantom pain
with a textile,
electromagnetically-acting

Electromagnetically
acting stump liner
Sham: dummy liner

Enrolled: 30
(crossover)
Completed
study: 27

(2) Combination of mechanisms

for treatments (1) calcitonin and
(3) ketamine
(3) Ketamine affects central
sensitization processes that may
be involved in PLP

Sham: 0.9% saline

Duration:
4 IV infusions spaced at
least 48 hours apart

PLP outcome measure(s): numeric

rating scale
Between-group difference not
signicant

PLP outcome measure(s): numeric

rating scale
Between-group difference
signicant (P = .008)

(continued on next page)

2239

Enrolled/
completed: 8
(crossover)

Contralateral myofascial
injection with 0.25%
bupivacaine;
Sham: contralateral
myofascial injection with
0.9% saline
Note: not a long-term
treatment

S.C. Grifn, J.W. Tsao / PAIN 155 (2014) 22362242

Presence of: residual limb pain,

non-healed surgical wound or
ulcers of stump, known allergy
to local anesthetics, clinical or
electromyographical signs of
polyneuropathy as possible
source of sensory alterations

Casale R, Ceccherelli F, Labeeb AA,

Biella GE. Phantom limb pain
relief by contralateral
myofascial injection with local
anaesthetic in a placebocontrolled study: Preliminary
results. [Randomized controlled
trial]. J Rehabil Med
2009;41:418422
Eichenberger U, Neff F, Sveticic G,
Bjorgo S, Petersen-Felix S,
Arendt-Nielsen L, Curatolo M.
Chronic phantom limb pain:
The effects of calcitonin,
ketamine, and their
combination on pain and
sensory thresholds.
[Randomized controlled trial;
Research support, non-US
Govt]. Anesth Analg
2008;106:12651273, table of
contents

(3) Racemic ketamine 0.4

mg/kg (only 10 of 20
patients)

or sleep and
mood
Lower extremity
amputation
Presence of PLP
over past 6
months

2240

Table 1 (continued)
Reference

Inclusion criteria

Exclusion criteria

Completed
documentation
for study: 22

impulses; (c) change in

electromagnetic eld

a 010 pain scale

language
Projected invasive interventions

Virtual limb
Treatment (mirror
condition) viewed intact
limb and movements of a
virtual limb
Control: viewed
movements of only
intact limb
Duration: single visit

Enrolled/
completed: 80
(41 mirror, 39
control)

Lower extremity
amputation
Presence of
phantom
sensation
Otherwise not
specied

Smith DG, Ehde DM, Hanley MA,

Campbell KM, Jensen MP,
Hoffman AJ, Robinson, LR.
Efcacy of gabapentin in
treating chronic phantom limb
and residual limb pain.
[Randomized controlled trial;
Research support, NIH;
Extramural research support,
non-US Govt]. J Rehabil Res Dev
2005;42:645654

Gabapentin
Sham: Lactose
Duration: 6 weeks, 7th
week titrated off
treatment

Enrolled: 24
(crossover)
Completed
documentation
for study: 22

Ramachandran and colleagues

originally postulated that mirror
therapy could reverse learned
paralysis that may occur after
amputation. Learned paralysis
occurs because motor signals
continue to be sent to the missing
limb without feedback of
successful movement. Mirror
therapy provides visual input of
successful limb movement,
reversing learned paralysis and
associated discomfort due to
sensation of immobilization. (not
specied in article)
Gabapentin (a) increases GABA
responses at non-synaptic sites
and (b) reduces the release of
mono-amine neurotransmitters

Wilder-Smith CH, Hill LT, Laurent

S. Postamputation pain and
sensory changes in treatmentnaive patients: Characteristics
and responses to treatment
with tramadol, amitriptyline,
and placebo. [Clinical trial,
randomized controlled trial;
Research support, non-US
Govt]. Anesthesiology
2005;103:619628

Tramadol tablets
Sham: identical placebo
tablets
Duration: 3 days
Also: examined openlabel amitryptiline

Enrolled: 103
Completed: 94
(33 tramadol,
31 sham, 30
amitryptiline)

Tramadol causes a reduction in

postoperative sensitization that
may contribute to PLP

Age >18 years

Lower-extremity
amputation
Pain >3 on 010
pain scale
Presence of pain
over past 6
months
Agreement with
medication
schedules and
protocols
Ability to read
and speak
English
PLP intensity
over 7 day
period averaging
>30 on 100-mm
visual analogue
scale

Wiech K, Kiefer RT, Topfner S,

Preissl H, Braun C, Unertl K,
Birbaumer N. A placebocontrolled randomized
crossover trial of the N-methylD-aspartic acid receptor
antagonist, memantine, in

Memantine
Sham: identical placebo
tablets
Duration: 4 weeks

Enrolled/
completed: 8
(crossover)

Memantine blocks NMDA

receptors that may be contributing
to central sensitization after nerve
trauma

Upper extremity
amputation
traumatic
Otherwise not
specied

Results (phantom limb pain only)

Jadad
scorea

Not specied

PLP outcome measure(s): visual

analogue scale, McGill Pain
Questionnaire
Signicant decrease in PLP in both
groups
Between-group difference not
signicant

Consumption of (a) antiepileptic

medication or cimetidine (b) >2
drinks per day
Pregnancy
History of kidney disease
Presence of high serum
creatinine clearance level or low
estimated creatinine clearance

PLP outcome measure(s): numeric

rating scale (primary)
Between-group difference not
signicant

Several successive limb

amputations
Signicant other pain besides
PLP or RLP
Use of centrally active
medication within last 2 weeks
Inability to communicate
adequately for participation
Participation in another clinical
trial
Breast-feeding
Pregnancy
History of neurological,
psychiatric, or renal disease(s)

PLP outcome measure(s): visual

analogue scale
Signicant decrease in PLP in all
groups (P < .0001)
Between-group difference not
reported

PLP outcome measure(s): visual

analogue scale
No signicant reduction in
phantom limb pain in treatment
group
Between-group difference not
signicant.

Mechanism of action

S.C. Grifn, J.W. Tsao / PAIN 155 (2014) 22362242

Sample size

stump liner: A randomized,

double-blind, crossover study.
[Randomized controlled trial
Research support, non-US
Govt]. J Pain Symptom Manage
2006;32:352360
Brodie EE, Whyte A, Niven CA.
Analgesia through the lookingglass? A randomized controlled
trial investigating the effect of
viewing a virtual limb upon
phantom limb pain, sensation
and movement. [Randomized
controlled trial; Research
support, non-US Govt]. Eur J
Pain 2007;11:428436

Treatment

Signicance is reported in boldface type.

a
The Jadad Scale is an instrument to assess the methodological quality of a clinical trial on a score of 0 (high risk of bias) to a score of 5 (low risk of bias). Jadad, A. R., Moore, R. A., Carroll, D., Jenkinson, C., Reynolds, D. J. M.,
Gavaghan, D. J., & McQuay, H. J.. Assessing the quality of reports of randomized clinical trials: is blinding necessary?. Controlled clinical trials, 1996; 17(1): 112.

patients with chronic phantom

limb pain. [Clinical trial
randomized controlled trial;
Research support, non-US
Govt]. Anesth Analg
2004;98:408413, table of
contents

S.C. Grifn, J.W. Tsao / PAIN 155 (2014) 22362242

2241

conditions, the key point is not to label conditions but, rather, to

reconceptualize phantom limb pain to recognize its complexity
without becoming lost in its idiosyncrasies. Abstraction is fundamental to science as a tool that allows the organization and prediction of natural phenomena. However, abstraction should only be
implemented when it provides a useful perspective on a phenomenon. In the case of phantom limb pain, simplication has produced a plenitude of contradictions but no unied account of the
disorder, diminishing the many insights into phantom limb pain
that research has provided. Recognizing the complexity of the disorder while still seeking to create a system that allows for generalization across patients is critical to the progress of phantom limb
pain treatment and research.
Conict of interest
The authors certify that they have no afliations of involvement
in any organization or entity with nancial interest or nonnancial
interest in the subject matter discussed in this manuscript.
Acknowledgements
The authors thank Kathryn R. Fox and Aimee Alphonso for their
helpful feedback on this article.
The opinions or assertions contained herein are the private
views of the authors and are not to be construed as ofcial or
reecting the views of the Department of the Navy or the Department of Defense.
References
[1] Abbass K. Efcacy of gabapentin for treatment of adults with phantom limb
pain. Ann Pharmacother 2012;46:170711.
[2] Ahmed MA, Mohamed SA, Sayed D. Long-term antalgic effects of repetitive
transcranial magnetic stimulation of motor cortex and serum beta-endorphin
in patients with phantom pain. Neurol Res 2011;33:9538.
[3] Anderson-Barnes VC, McAuliffe C, Swanberg KM, Tsao JW. Phantom limb
paina phenomenon of proprioceptive memory? Med Hypotheses 2009;73:
5558.
[4] Arning K, Baron R. Evaluation of symptom heterogeneity in neuropathic pain
using assessments of sensory functions. Neurotherapeutics 2009;6:73848.
[5] Attal N, Bouhassira D, Baron R, Dostrovsky J, Dworkin RH, Finnerup N, Gourlay
G, Haanpaa M, Raja S, Rice AS, Simpson D, Treede RD. Assessing symptom
proles in neuropathic pain clinical trials: Can it improve outcome. Eur J Pain
2011;15:4413.
[6] Attal N, Fermanian C, Fermanian J, Lanteri-Minet M, Alchaar H, Bouhassira D.
Neuropathic pain: Are there distinct subtypes depending on the aetiology or
anatomical lesion? PAIN 2008;138:34353.
[7] Baron R, Forster M, Binder A. Subgrouping of patients with neuropathic pain
according to pain-related sensory abnormalities: A rst step to a stratied
treatment approach. Lancet Neurol 2012;11:9991005.
[8] Bittar RG, Otero S, Carter H, Aziz TZ. Deep brain stimulation for phantom limb
pain. J Clin Neurosci 2005;12:399404.
[9] Bone M, Critchley P, Buggy DJ. Gabapentin in postamputation phantom limb
pain: A randomized, double-blind, placebo-controlled, cross-over study. Reg
Anesth Pain Med 2002;27:4816.
[10] Bouhassira D, Attal N, Fermanian J, Alchaar H, Gautron M, Masquelier E,
Rostaing S, Lanteri-Minet M, Collin E, Grisart J, Boureau F. Development and
validation of the Neuropathic Pain Symptom Inventory. PAIN 2004;108:
24857.
[11] Brugger P, Kollias SS, Muri RM, Crelier G, Hepp-Reymond MC, Regard M.
Beyond re-membering: Phantom sensations of congenitally absent limbs. Proc
Natl Acad Sci U S A 2000;97:616772.
[12] Carlen PL, Wall PD, Nadvorna H, Steinbach T. Phantom limbs and related
phenomena in recent traumatic amputations. Neurology 1978;28:2117.
[13] Chan BL, Witt R, Charrow AP, Magee A, Howard R, Pasquina PF, Heilman KM,
Tsao JW. Mirror therapy for phantom limb pain. N Engl J Med 2007;357:
22067.
[14] Clark RL, Bowling FL, Jepson F, Rajbhandari S. Phantom limb pain after
amputation in diabetic patients does not differ from that after amputation in
nondiabetic patients. PAIN 2013;154:72932.
[15] Eichenberger U, Neff F, Sveticic G, Bjorgo S, Petersen-Felix S, Arendt-Nielsen L,
Curatolo M. Chronic phantom limb pain: The effects of calcitonin, ketamine,
and their combination on pain and sensory thresholds. Anesth Analg
2008;106:126573.
[16] Flor H. Phantom-limb pain: Characteristics, causes, and treatment. Lancet
Neurol 2002;1:1829.

2242

S.C. Grifn, J.W. Tsao / PAIN 155 (2014) 22362242

[17] Flor H, Elbert T, Knecht S, Wienbruch C, Pantev C, Birbaumer N, Larbig W, Taub

E. Phantom-limb pain as a perceptual correlate of cortical reorganization
following arm amputation. Nature 1995;375:4824.
[18] Flor H, Nikolajsen L, Staehelin Jensen T. Phantom limb pain: A case of
maladaptive CNS plasticity? Nat Rev Neurosci 2006;7:87381.
[19] Jaeger H, Maier C. Calcitonin in phantom limb pain: A double-blind study.
PAIN 1992;48:217.
[20] Jensen MP, Smith DG, Ehde DM, Robinsin LR. Pain site and the effects of
amputation pain: Further clarication of the meaning of mild, moderate, and
severe pain. PAIN 2001;91:31722.
[21] Katz J, Melzack R. Pain memories in phantom limbs: Review and clinical
observations. PAIN 1990;43:31936.
[22] Katz J, Melzack R. Auricular transcutaneous electrical nerve stimulation (TENS)
reduces phantom limb pain. J Pain Symptom Manage 1991;6:7383.
[23] Krainick JU, Thoden U, Riechert T. Pain reduction in amputees by long-term
spinal cord stimulation. Long-term follow-up study over 5 years. J Neurosurg
1980;52:34650.
[24] MacIver K, Lloyd DM, Kelly S, Roberts N, Nurmikko T. Phantom limb pain,
cortical reorganization and the therapeutic effect of mental imagery. Brain
2008;131:218191.
[25] Melzack R, Israel R, Lacroix R, Schultz G. Phantom limbs in people with
congenital limb deciency or amputation in early childhood. Brain 1997;120:
160320.
[26] Mercier C, Sirigu A. Training with virtual visual feedback to alleviate phantom
limb pain. Neurorehabil Neural Repair 2009;23:58794.
[27] Nikolajsen L, Gottrup H, Kristensen AG, Jensen TS. Memantine (a N-methyl-Daspartate receptor antagonist) in the treatment of neuropathic pain after
amputation or surgery: A randomized, double-blinded, cross-over study.
Anesth Analg 2000;91:9606.
[28] Nystrom B, Hagbarth KE. Microelectrode recordings from transected nerves in
amputees with phantom limb pain. Neurosci Lett 1981;27:2116.

[29] Rajbhandari SM, Jarratt JA, Grifths PD, Ward JD. Diabetic neuropathic pain in
a leg amputated 44 years previously. PAIN 1999;83:6279.
[30] Richardson C, Glenn S, Nurmikko T, Horgan M. Incidence of phantom
phenomena including phantom limb pain 6 months after major lower limb
amputation in patients with peripheral vascular disease. Clin J Pain
2006;22:3538.
[31] Robinson LR, Czerniecki JM, Ehde DM, Edwards WT, Judish DA, Goldberg ML,
Campbell KM, Smith DG, Jensen MP. Trial of amitriptyline for relief of pain in
amputees: Results of a randomized controlled study. Arch Phys Med Rehabil
2004;85:16.
[32] Sherman RA, Sherman CJ. Prevalence and characteristics of chronic phantom
limb pain among American veterans. Results of a trial survey. Am J Phys Med
1983;62:22738.
[33] Sherman RA. Phantom limb pain. Mechanism-based management. Clin Podiatr
Med Surg 1994;11:85106.
[34] Sherman RA, Sherman CJ. A comparison of phantom sensations among
amputees whose amputations were of civilian and military origins. PAIN
1985;21:917.
[35] Sherman RA, Sherman CJ, Gall NG. A survey of current phantom limb pain
treatment in the United States. PAIN 1980;8:8599.
[36] Subedi B, Grossberg GT. Phantom limb pain: Mechanisms and treatment
approaches. Pain Res Treat 2011;2011. Artilce ID: 864605.
[37] Weeks SR, Anderson-Barnes VC, Tsao JW. Phantom limb pain: Theories and
therapies. Neurologist 2010;16:27786.
[38] Woolf CJ, Bennett GJ, Doherty M, Dubner R, Kidd B, Koltzenburg M, Lipton R,
Loeser JD, Payne R, Torebjork E. Towards a mechanism-based classication of
pain? PAIN 1998;77:2279.
[39] Wu CL, Agarwal S, Tella PK, Klick B, Clark MR, Haythornthwaite JA, Max MB,
Raja SN. Morphine versus mexiletine for treatment of postamputation pain: A
randomized, placebo-controlled, crossover trial. Anesthesiology 2008;109:
28996.