A Closer Look At Evolving Treatments For Phantom Limb Pain

Given the prevalence of phantom limb pain following amputation, this author explores the pathophysiology of such pain as well as pharmacologic and alternative treatments.

Congenital limb deficiency, cancer, vascular problems and trauma are among the common causes of limb loss. In the United States, an estimated 1.7 million patients have experienced limb amputation and 60 to 80 percent of these patients develop phantom limb pain.1,2

   It is likely that post-amputation pain or phantom limb pain has plagued humans for countless millennia. However, our understanding of post-amputation pain has significantly evolved over the centuries with the full impact beginning to unravel only recently. The risk factors for this condition are unknown but an accurate diagnosis of phantom limb pain is important for appropriate management.3

   Phantom limb pain is a sensation of pain in an absent limb, which patients often describe as burning, throbbing or lancinating. Also, phantom limb sensations are non-painful feelings occurring in absent limbs. In residual limb pain, also known as stump pain, the pain is limited to the remaining stump.3 Since the onset of combat activity in Iraq and Afghanistan, there have been over 1,100 major limb amputations among United States servicemen.4,5 With a sustained military presence in the Middle East, continued severe lower extremity trauma is inevitable.5

   Further, there is a commonly held belief that patients with diabetic amputations experience less phantom limb pain than amputees without diabetes because of the effects of diabetic peripheral neuropathy.6 Clark and colleagues suggest there is no large difference in the prevalence, characteristics or intensity of phantom limb pain when comparing amputation patients with and without diabetes.6 Finally, the prevalence of limb loss is estimated to increase from 1.6 million in 2005 to 3.6 million by 2050.1,7

   For these reason, the podiatric physician would benefit with an understanding of both the pathophysiology of phantom limb pain as well as the treatments to facilitate functional outcomes for these patients.

A Closer Look At The Pathophysiology And Mechanisms Of Phantom Limb Pain

Physicians once thought phantom limb pain to primarily be a psychiatric illness.8 The accumulation of clinical evidence has revealed the etiology of phantom limb pain is actually multifactorial and includes central, peripheral and psychological components.8,9

   We can broadly categorize the pathophysiology underlying phantom phenomena in terms of supraspinal, spinal and peripheral mechanisms.9 However, according to Subedi and Grossberg, none of these proposed theories appear to be able to explain the phenomenon of phantom limb pain independently.8 Further, these investigators assert that many experts believe that multiple mechanisms are likely responsible for phantom limb pain.8 Central neural mechanisms and peripheral mechanisms are among the hypotheses that have gained consensus as proposed mechanisms over recent years.8

   Supraspinal mechanisms related to phantom limb phenomena primarily involve reorganization of the somatosensory cortex surrounding the area representing the differentiated limb. Ramachandran and coworkers demonstrated that brushing the face of upper limb amputees could elicit phantom sensations.10 Additional, they hypothesized that somatosensory cortical reorganization could explain why afferent nociceptive stimulation of a body part whose cortical representation is adjacent to that of the phantom limb can produce sensations in the phantom limb.8,10 Finally, specifically, tactile, proprioceptive and nociceptive input from the face and tissues near the residual limb take over regions of the brain that no longer receive afferent input.8,10

   Hsu and Cohen report that the spinal mechanisms for post-amputation pain are theoretically centered on functional changes in the dorsal horn of the spinal cord after deafferentation from peripheral nerve injury.9 Iacono and colleagues report that the loss of afferent input to the dorsal horn leads to decreased impulses from brainstem reticular areas, which normally exert inhibitory effects on sensory transmission.11 Reports from both Davis and Jensen and their respective coworkers note that the absence of inhibitory effects for sensory input arising from the missing peripheral body part cause an increased autonomous activity of dorsal horn neurons, in effect becoming “sensory epileptic discharges.”9,12,13 The role of spinal mechanisms is validated by the fact that both anticonvulsants, as well as lesions placed in the substantia gelatinosa, are effective in treating phantom pain.9,14

   Cortical reorganization is the most cited reason for the cause of phantom limb pain in recent years.8 These cortical areas representing the amputated extremity are taken over by the neighboring representational zones in both the primary somatosensory cortex and the motor cortex.8,15 Research has found the extent of cortical reorganization to be directly related to the degree of pain and the size of the deafferentiated region.8

   An amputation severs peripheral nerves, resulting in massive tissue and neuronal injury, and causing disruption of the normal pattern of afferent nerve input to the spinal cord.8 The process of differentiation follows this and the proximal portion of the severed nerve sprouts to form neuromas.16 During this process, there is an increased accumulation of molecules enhancing the expression of sodium channels in these neuromas that result in hyperexcitability.17

   Flor and colleagues report that this abnormal peripheral activity is theoretically a potential source of stump pain, including phantom limb pain.16 To validate the contributory influence of this mechanism to phantom limb pain, clinical studies have reported a reduction of phantom pain with drugs blocking these identified sodium channels.18,19 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 phantom limb pain.20

   Despite Berger and Bacon’s report that stress, anxiety, exhaustion and depression theoretically exacerbate phantom limb pain, the recent literature has not supported the psychogenic origin mechanism of phantom limb pain.21 Visual-proprioceptive dissociation involves a disconnect between proprioceptive memory, which refers to the awareness of limb position, and visual perception.22 This particular theory describes phantom limb pain as occurring because proprioceptive memory causes the neurons to remain in an active state after amputation.

   A notable limitation to the psychogenic mechanism is that most research on the relationship between psychological symptoms and phantom limb pain is based on either retrospective and/or cross-sectional designed studies rather than longitudinal designed studies.8 Therefore, this limits the inference that we can derive from these types of studies.8

A Guide To Pharmacologic Treatments For Phantom Limb Pain

Treatment of post-amputation pain is very challenging because the underlying mechanisms are multifactorial in nature (see “A Guide To Mechanism-Based Treatment Modalities For Postamputation Pain” below at right). Given that mechanistic-based pain treatment is generally acknowledged to be superior to etiologic-based treatment, the difficulty in identifying a discrete mechanism(s), which one can address directly, results in corresponding barriers to treatments. Given that multiple cellular, neurochemical and molecular changes underlie both the peripheral and central reorganization phenomena that occur in the post-amputation period, pharmacological interventions are a natural choice for the treating clinician.

   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.

   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

   Memantine, which is commonly used to treat Alzheimer’s disease, produces an analgesic effect that may be beneficial in the treatment of phantom limb pain. Several case reports involving patients with severe phantom limb pain 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.43 However, other studies using doses of 20 to 30 mg per day were unsuccessful in proving the effectiveness of memantine versus placebo.44,45 Although memantine demonstrated promising results in several case studies, there is insufficient substantiating evidence to support its wide use in clinical practice.

   Other pharmacologic therapies. In one study surveying patient self-reported treatments, acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) combined with opioids reportedly lessened pain intensity.46 The analgesic mechanism of acetaminophen is not clear but serotonergic and multiple other central nervous system pathways are likely to be involved.8 Other agents, such as propranolol (Inderal, Pfizer) and nifedipine (Procardia, Pfizer) have been effective in treating burning and cramping associated with phantom limb pain.8,47 Calcitonin may reduce the intensity and frequency of pain. However, a more recent randomized, placebo controlled trial showed that calcitonin alone was ineffective against phantom limb pain.8,9,48

Should You Consider Alternative Therapies?

Various non-pharmacologic options exist for managing phantom limb pain. These include transcutaneous electrical nerve stimulation, mirror therapy and surgical intervention.8,9,49 Of these treatments, mirror therapy is the most effective. One would place a mirror parasagittally between the patient’s lower limbs so there is a reflection of the intact limb. The reflection serves as a virtual representation of the missing limb.

   In one study, patients performed movements with their amputated limb while observing the movement of the intact limb in the mirror.49 This occurred for 15 minutes per day for four weeks. The mirror group reported a reduction in pain intensity and fewer episodes of breakthrough pain. The theory is that mirror therapy may help resolve the visual-proprioceptive dissociation associated with phantom limb pain.50

In Conclusion

Phantom limb pain is a relatively common and disabling entity. It is estimated that by 2050, there will be 3.6 million amputees in the U.S.1 Therefore, it has become increasingly important to understand and manage phantom limb pain properly. The management and treatment of neuropathic pain and phantom limb pain is complex since efficacy is mostly subjective. No single treatment is universally effective for phantom limb pain. One should tailor pharmacologic treatment to the patient and consider all concomitant disease states and medications.

   Dr. Smith is in private practice at Shoe String Podiatry in Ormond Beach, Fla. He is currently deployed.

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