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

   A small case series demonstrated that mirtazapine (Remeron, Merck), a tetracyclic antidepressant, has been effective for treating neuropathic pain and phantom limb pain.34 It works by antagonizing alpha-2 adrenergic receptors, resulting in an increased release of norepinephrine and serotonin. This clinical report describes that doses of 7.5 to 30 mg effectively reduced phantom limb pain. Mirtazapine may provide additional benefit for phantom limb pain patients who are experiencing insomnia and diminished appetite.

   Opioids. Opioids bind to the peripheral and central opioid receptors and provide analgesia without the loss of touch, proprioception or consciousness.8 Researchers propose that the benefits of opioids occur at both the spinal level and the supraspinal level, acting against cortical reorganization and directly targeting one of the proposed mechanism of phantom limb pain.8,30 Randomized controlled trials have demonstrated the effectiveness of opioids (oxycodone, methadone, morphine and levorphanol) for the treatment of neuropathic pain, including phantom limb pain.

   Research has shown that extended-release oral morphine in doses between 70 to 300 mg per day reduces pain intensity in patients with phantom limb pain.35 Tramadol (Ultram, Janssen Pharmaceuticals), a weak opioid and mixed serotonin-noradrenaline reuptake inhibitor, can treat phantom limb pain. Patients who were unresponsive to amitriptyline (Elavil) therapy reported pain relief with tramadol.36

   While opioids have provided effective analgesia in patients with phantom limb pain, there is always a high risk of physical and psychological dependence limits long-term use. Also, the chronic use of opioids increases the risk of tolerance, leading to opioid dose escalation. Of course, this places patients at higher risk for developing adverse effects and possibly affects quality of life.

   Injection therapies. Based on the available evidence, local injection therapy appears to be more efficacious in the treatment of residual limb pain in comparison to phantom limb pain.9 The use of regional nerve blocks with lidocaine and/or corticosteroids often result in immediate relief of residual limb pain. However, the duration of pain relief is both highly variable and only temporary.37,38 Data on the clinical use of local anesthetics for neuropathic pain and phantom limb pain is limited despite reports of moderate effectiveness.

   Oral anesthetic analogues, such as mexiletine (Mexitil), are available but the risk of arrhythmias and mortality limits their use in phantom limb pain in clinical practice.39 A novel treatment option for phantom limb pain is the use of contralateral injections of bupivacaine. In one study, researchers asked patients to identify painful areas of their phantom limb.40 They received injections of 1 mm of bupivacaine to the contralateral areas of the intact limb. There was a 70 percent greater reduction of pain in patients treated with bupivacaine injections in comparison to those treated with placebo. Further studies are necessary to validate the use of bupivacaine in clinical practice.

   N-methyl-D-aspartate (NDMA) receptor antagonists. When activated, NMDA receptors play a role in sensitization at the spinal cord level, leading to increased pain perception.41 Researchers believe the NMDA receptor antagonists, including ketamine, dextromethorphan (Delsym, Reckitt Benckiser) and memantine (Namenda, Forest Pharmaceuticals), block a cascade of events leading to sensitization of dorsal horn wide dynamic range neurons.9 Ketamine has shown promise in reducing phantom limb pain when clinicians administer the medication as four intravenous infusions at 0.4 mg/kg.42

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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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