US Pharm. 2013;38(3):HS14-HS16.
ABSTRACT: Phantom limb pain (PLP) is a sensation of pain in an absent
limb, often experienced as burning, throbbing, or lancinating pain or
the feeling of pins and needles. Approximately 60% to 80% of amputees
develop this debilitating condition, which is often misdiagnosed.
Although the exact cause of PLP is poorly understood, theories suggest a
multifactorial origin. While no clear-cut guidelines have been
developed for the management and treatment of PLP, researchers have
studied the use of anticonvulsants, antidepressants, anesthetics, N-methyl-D-aspartate
receptor antagonists, and opioids. A number of nonpharmacologic and
novel therapies have shown promise as well. As the number of amputees in
the United States increases, it is important to become familiar with
the various therapy options for PLP.
In the United States, an estimated 1.7 million patients have
undergone limb amputation, and 60% to 80% of these patients develop
phantom limb pain (PLP).1,2 The risk factors for this condition are unknown, but some studies suggest that preamputation pain has an association.3
Although PLP is prevalent among amputees, it is often mistaken for
other pain disorders, such as phantom limb sensation and residual limb
pain. PLP is a sensation of pain in an absent limb, often manifesting as
burning, throbbing, or lancinating pain or the feeling of pins and
needles. Phantom limb sensations are nonpainful feelings experienced in
absent limbs. In residual limb pain, also known as stump pain, the pain is limited to the remaining stump.3 An accurate diagnosis is important for appropriate management.
The etiology of PLP is multifactorial and includes central,
peripheral, and psychological components. Proposed mechanisms include
cortical reorganization, peripheral-nerve hyperexcitability (PNH),
central sensitization, and visual-proprioceptive dissociation. Cortical
reorganization is a phenomenon that involves the primary motor cortex
and somatosensory regions of the brain. It is believed that when a limb
is amputated, the neighboring zones remap these areas in the brain. When
the nociceptive neurons within the stump are stimulated, pain is
perceived in the phantom limb.4 There is an association between the degree of cortical reorganization and the intensity of perceived PLP.
PNH involves the development of neuromas resulting from the severing
of peripheral nerves during amputation. Upregulation of sodium channels
in these neuromas triggers the hyperexcitability.5,6 Central
sensitization occurs when neurons in the spinal cord that are not
associated with nociception sprout in areas that are responsible for the
transmission of pain. Another proposed mechanism is that the increase
in N-methyl-D-aspartate (NMDA) receptor activity results in a
change in neuronal firing of the nociceptive neurons, exacerbating PLP.7
Visual-proprioceptive dissociation involves a disconnect between proprioceptive memory, which refers to the awareness of limb position, and visual perception.8 In this theory, PLP occurs because proprioceptive memory causes the neurons to remain in an active state after amputation.
There are currently no guidelines for the management of PLP, which is
often treated with agents used for neuropathic pain. Although there are
overlaps in therapeutic options, it is important to select treatments
that target proposed PLP mechanisms. Since the pathophysiology of PLP is
multifactorial, effective treatment often involves a combination of
medications—such as anticonvulsants, antidepressants, opioids,
anesthetics, and NMDA receptor antagonists—that target multiple
Anticonvulsants: Gabapentin is an anticonvulsant
that is structurally similar to gamma-aminobutyric acid (GABA). Its
mechanism involves high-affinity binding to the alpha2/delta-1 subunit of voltage-gated calcium channels.9 One study concluded that gabapentin effectively improved PLP at doses ranging from 300 to 2,400 mg per day.10
However, a recent study by the Department of Veterans Affairs found no
significant difference in pain intensity for gabapentin versus placebo.11
Although studies have yielded mixed results, gabapentin is often used
as first-line treatment in clinical practice. Gabapentin is generally
well tolerated; however, it is important to monitor renal function and
make dosage adjustments.12 Carbamazepine, which also has been
used to manage PLP, inhibits sodium-channel activity. Carbamazepine
doses of 400 to 600 mg per day have been effective for treating
lancinating pain associated with PLP.13 In preliminary studies, the anticonvulsant pregabalin has also shown promise at doses of 300 to 600 mg per day.14-16
Antidepressants: Tricyclic antidepressants
(TCAs) are commonly prescribed to treat neuropathies. TCAs produce their
effect by blocking several receptors, including the norepinephrine and
serotonin reuptake pumps, sodium channels, and the muscarinic
acetylcholine, alpha1, histamine1, and GABAA receptors.17
Amitriptyline 55 mg has been shown to reduce pain intensity. Studies
indicate that TCAs, while effective for neuropathic pain related to
diabetic neuropathy or postherpetic neuralgia, are not as effective for
PLP.18 Although TCAs have been shown to provide some benefit
in the treatment of PLP, their use is limited by their negative
adverse-effect profile. Adverse drug reactions include cardiotoxicity,
orthostasis, tachycardia, arrhythmias, insomnia, dizziness, weight gain,
and anticholinergic effects.19 Since TCAs used for pain
control are prescribed at much lower doses than those used for
depression, the incidence of adverse drug reactions is diminished.
Serotonin-norepinephrine reuptake inhibitors (SNRIs), another
antidepressant class, have shown promise as a treatment option for
neuropathic pain and PLP. The role of norepinephrine in pain modulation
involves its action on alpha2a adrenoceptors in the spinal dorsal horn, which reduces nociceptive signals to the brain.20
In a review of clinical trials comparing SNRIs with placebo in the
treatment of neuropathic pain, the National Institute for Health and
Clinical Excellence concluded that duloxetine and venlafaxine lessen the
intensity of neuropathic pain. Due to the need for ECG monitoring and
the risk of hypertensive crisis with venlafaxine, duloxetine is
Mirtazapine, a tetracyclic antidepressant, has been effective for
treating neuropathic pain and PLP. It works by antagonizing alpha2-adrenergic receptors, resulting in an increased release of norepinephrine and serotonin.22 In a case series, doses of 7.5 to 30 mg effectively reduced PLP.23 Mirtazapine may provide additional benefit for PLP patients who are experiencing insomnia or diminished appetite.
Opioids: Opioids are commonly used for
moderate-to-severe pain, including chronic neuropathic disorders. It is
proposed that opioids act against cortical reorganization, directly
targeting a proposed mechanism of PLP. Extended-release oral morphine in
doses of 70 to 300 mg per day were shown to reduce pain intensity in
PLP.24 In case reports, methadone has demonstrated efficacy, but further studies are warranted.25 Other opioids, such as levorphanol and oxycodone, have been used in PLP, with moderate success.26
Tramadol, a centrally acting synthetic opioid, also was effective for
decreasing PLP. Patients who were nonresponsive to amitriptyline therapy
reported pain relief from tramadol.27 While opioids have
demonstrated analgesia in PLP patients, the high risk of physical and
psychological dependence limits long-term use. Also, the chronic use of
opioids increases the risk of tolerance, leading to dose escalation.
This places patients at higher risk for developing adverse effects,
possibly affecting quality of life.
Anesthetics: Clinical use of anesthetics for
neuropathic pain and PLP is limited, despite reports of moderate
effectiveness. IV lidocaine for difficult-to-manage neuropathic pain has
been shown to decrease deafferentation pain.28 Because of the risk of cardiovascular and neurologic toxicity, lidocaine is not a preferred treatment.29
Oral anesthetic analogues, such as mexiletine, are available, but the
risk of arrhythmias and mortality limits their use in clinical practice.30
A novel treatment option for PLP is the use of contralateral
injections of bupivacaine. In one study, patients were asked to identify
painful areas of their phantom limb. One-mL injections of bupivacaine
2.5 mg were administered to the contralateral areas of the intact limb.
There was a 70% reduction of pain in patients treated with bupivacaine
injections compared with placebo.31 Further studies are necessary to validate the use of bupivacaine in clinical practice.
NMDA Receptor Antagonists: When activated, NMDA
receptors play a role in sensitization at the spinal cord level, leading
to increased pain perception (central sensitization).32 Ketamine, an NMDA receptor antagonist, has shown promise in reducing PLP when administered as four IV infusions at 0.4 mg/kg.27
NMDA receptor antagonists such as memantine, which is commonly used to
treat Alzheimer’s disease, produce an analgesic effect that may be
beneficial in the treatment of PLP. Several case reports involving
patients with severe PLP that was refractory to anticonvulsants,
opioids, and antidepressants demonstrated improved pain management with
the use of memantine. One study using 20 to 45 mg per day in divided
doses showed significant improvement in pain, resulting in a reduced
dependence on opioids.33 However, other studies using doses
of 20 to 30 mg per day were unsuccessful in proving the effectiveness of
memantine versus placebo.34,35 Although memantine
demonstrated promising results in several case studies, there is
insufficient substantiating evidence to support its wide use in clinical
Other Pharmacologic Therapies: In one study
surveying patient self-reported treatments, acetaminophen or
nonsteroidal anti-inflammatory agents combined with opioids were
reported to lessen pain intensity; however, no dosages were given.36
Other agents, such as propranolol and nifedipine (no dosages reported),
have been effective in treating burning and cramping associated with
PLP.37 Calcitonin may reduce the intensity and frequency of
pain; however, a more recent randomized, controlled trial showed that
calcitonin alone was ineffective against PLP.27,38 While there is no conclusive evidence supporting the use of clonidine, an alpha2-adrenergic
agonist, in the treatment of neuropathic pain and PLP, the drug has
been used in clinical practice. It is hypothesized that peripheral alpha2 adrenoceptors are involved in pain inhibition.20
There are case reports of etanercept, a tumor necrosis factor-alpha
inhibitor, providing relief from PLP. Most patients had
moderate-to-severe PLP, and dramatic improvements in pain intensity were
seen after a series of three injections of etanercept 5 mg.39 Further research is necessary to evaluate the efficacy of these drugs.
Various nonpharmacologic options exist for managing PLP. These
include transcutaneous electrical nerve stimulation, mirror therapy, and
surgical intervention. Of these treatments, mirror therapy is the most
effective. A mirror is placed parasagittally between the patient’s lower
limbs so that there is a reflection of the intact limb. The reflection
serves as a virtual representation of the missing limb. In one study,
patients were instructed to perform movements with their amputated limb
while observing the movement of the intact limb in the mirror. This was
done for 15 minutes per day for 4 weeks. The mirror group reported a
reduction in pain intensity and fewer episodes of breakthrough pain.40 It is theorized that mirror therapy may help resolve the visual-proprioceptive dissociation associated with PLP.41
It is estimated that, by 2050, there will be 3.6 million amputees in the U.S.2
Therefore, it has become increasingly important to understand and
properly manage PLP. The management and treatment of neuropathic pain
and PLP is complex, since efficacy is subjective. No single treatment is
universally effective for PLP. Health care professionals must establish
an effective medication regimen that may involve a combination of
therapies to target the multiple disease elements. Although there are no
established treatment guidelines, pharmacists can play a crucial role
in optimizing medication therapy for PLP management. Pharmacologic
treatment should be tailored to the patient and consider all concomitant
disease states and medications. The pharmacist can recommend agents
that will result in the best health outcome for the patient while
minimizing adverse drug reactions and potential mishaps associated with
polypharmacy. Although the management and treatment of PLP remain a
challenge, further research will continue to bring forth more viable
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