A Closer Look At Evolving Treatments For Phantom Limb Pain

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


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

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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