A Closer Look At Evolving Treatments For Phantom Limb Pain

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A Primer On The Early Research Into Phantom Limb Pain

Ambroise Paré was a 16th-century French barber, a surgeon who served in the military. Paré documented the pain experienced by amputees who perceived sensation in the “phantom” amputated limb.51 Paré believed that phantom pains occur in the brain and not in the remnants of the limbs.

In 1872, American neurologist S. Weir Mitchell, MD, described a bizarre symptom complex resulting from wounds to peripheral nerves in his book, Injuries of Nerves and Their Consequences. Mitchell saw a large number of patients who had been wounded in the Civil War and suffered from a chronic affliction he called causalgia and coined the term “phantom limb pain,” recording an incidence as high as 90 percent.8,52 The common treatment for causalgia associated with peripheral nerve injury was amputation.

In 1937, Leriche wrote his classic work La Chirurgie de la Douleur, in which he detailed his work on causalgia and phantom limbs.53,54 He acknowledged Mitchell's contribution and looked for ways to solve the problem of pain. Leriche's opportunity to study phantom limb pain came during World War I when he saw many soldiers with peripheral nerve damage.54 He observed vasomotor changes, which suggested to him an abnormality of vascular stimulation. In 1916, he attempted to alleviate the pain through periarterial sympathectomy.54 Leriche also saw patients with painful stumps and phantom limb pain.

W.K. Livingston, MD, had learned at Harvard that pain was a specific response to an unpleasant stimulus, a warning of tissue damage. One of the problems that puzzled him early in his career was visceral pain. Patients might experience no apparent pain from tissue damage to certain internal organs but would report "referred pain" in another part of the body.54 He studied other pain phenomena, such as causalgia and phantom limb pain, which presented similar enigmas.54 During World War II, Livingston was assigned to the Oakland Naval Hospital, where he assumed responsibility for patients with peripheral nerve injury and other difficult pain problems, including causalgia cases.54 Livingston used periarterial sympathectomies, ganglionectomies and novocaine blocks to treat his patients, but he recorded several cases in which the relief was only temporary and the pain returned.54

Robert G. Smith, DPM, MSc, RPh, C.Ped

   There are currently no guidelines for the management of phantom limb pain. When choosing pharmacotherapy for patients with phantom limb pain, the clinician must consider chronicity, route of administration and side effects.9 Several categories of medications for which there is a clinical base evidence in the treatment of phantom limb pain are: anticonvulsants, antidepressants, opioids, injection therapies and NMDA receptor antagonists (see “A Guide To Pharmacotherapy Treatments For Phantom Limb Pain” below at left).

   Anticonvulsants. Anticonvulsants have long been a mainstay in the treatment of neuropathic pain. On the other hand, specific studies examining anticonvulsants and their beneficial outcomes when treating phantom limb pain are limited.
Gabapentin (Neurontin, Pfizer) is an anticonvulsant that is structurally similar to gamma-aminobutyric acid (GABA). Its mechanism involves high-affinity binding to the alpha-2/delta-1 subunit of voltage-gated calcium channels.23 One study concluded that gabapentin effectively improved phantom limb pain at doses ranging from 300 to 2,400 mg per day.24 However, a recent study by the Department of Veterans Affairs found no significant difference in pain intensity for gabapentin versus placebo.25

   Although studies have yielded mixed results, gabapentin is often a first-line treatment in clinical practice. Patients generally tolerate gabapentin well. However, it is important to monitor renal function and make dosage adjustments as well as significant side effects reported in clinical studies include: somnolence, dizziness, headache and nausea.24-26

   Carbamazepine (Tegretol, Novartis), which can also manage phantom limb pain, inhibits sodium-channel activity. Carbamazepine doses of 400 to 600 mg per day have been effective for treating stabbing and lancinating pain associated with phantom limb pain.8,27 In preliminary studies, the anticonvulsants pregabalin (Lyrica, Pfizer) and oxcarbazepine (Oxtellar, Supernus Pharmaceuticals) have demonstrated some promise for treatment of phantom limb pain.8,28-30

   Antidepressants. Tricyclic antidepressants are among the most commonly used medications for various types of neuropathic pains to include phantom limb pain. Tricyclic antidepressants produce their effect by blocking several receptors, including the norepinephrine and serotonin reuptake pumps, sodium channels, as well as the muscarinic acetylcholine, alpha 1, histamine 1 and GABA receptors.

   Although research has shown tricyclic antidepressants to provide some benefit in the treatment of phantom limb pain, their use is limited by their negative adverse effect profile to include dry mouth and dizziness.31 Other noted adverse drug reactions include cardiotoxicity, orthostasis, tachycardia, arrhythmias, insomnia, dizziness, weight gain and anticholinergic effects.

   Serotonin-norepinephrine reuptake inhibitors (SNRIs), another antidepressant class, have shown promise as a treatment option for neuropathic pain and phantom limb pain. The role of norepinephrine in pain modulation involves its action on alpha-2a adrenoceptors in the spinal dorsal horn, which reduces nociceptive signals to the brain.32

   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 (Cymbalta, Eli Lilly) and venlafaxine (Effexor, Pfizer) lessen the intensity of neuropathic pain.33 Empowered with this data, the treating podiatric clinician may want to use these agents for phantom limb pain.

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Bob Smithsays: October 5, 2013 at 10:59 pm

My deep gratitude to Podiatry Today and its staff for publishing this manuscript while I am away.

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DrDpmsays: October 30, 2013 at 1:13 pm

This is an excellent article on the topic of peripheral neuropathy! Phantom limb pain syndrome and residual limb pain syndrome are both variant examples of peripheral neuropathy in the distal lower extremities.

I disagree with this article that stated that people with peripheral neuropathy cannot feel the pain sensations from phantom or residual pain syndromes. Let me elaborate. There are two types of pain: nociceptive pain and neuropathic pain. A patient with diabetic neuropathy and residual pain syndrome (from an amputated toe) will not feel nociceptive pain but will feel neuropathic pain emanating from that amputated toe. Although the patient may feel "numbness," neuropathic pain is still present because the nerve is damaged from resection due to amputation.

I had a patient with diabetic neuropathy in the feet who experiences debilitating lancinating pain from an amputated toe. That agonizing pain flareup is the neuropathic pain, not nociceptive pain.

When it comes to the medical topic of peripheral neuropathy, all physicians, including podiatrists, must distinguish nociceptive pain mechanisms from neuropathic pain mechanisms. This can help improve diagnosis and treatment management.

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