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Management of Phantom Limb Pain and Sensation with Milnacipran

To the Editor: Phantom limb pain is classified as neuropathic pain that develops after nerve injury. It is an aftereffect of amputation occurring in up to 85% of patients who have undergone such surgery.¹ Tricyclic antidepressants have shown effectiveness in reducing phantom limb pain. Analgesic effects have been reported for venlafaxine, a novel serotonin (5-HT) and noradrenaline reuptake inhibitor (SNRI), against various types of neuropathic pain;² however, there are still no reports of a successful treatment for phantom limb pain. As far as we know, this is the first report of the successful management of phantom limb pain and sensation with milnacipran, which is another SNRI.

Case Report
A 77-year-old man with an above-knee amputation on his right leg for arteriosclerosis obliterans was transferred to the department of orthopedics for the purpose of right hip disarticulation due to osteomyelitis in the amputation stump. On the 11th day after the operation, he was referred to the department of psychiatry because he developed paroxysmal phantom limb pain "squeezed" in the absent right knee and ankle joint. Simultaneously, the patient experienced a phantom limb sensation as if the "amputated right lower extremity was actually present." He was not depressive, anxious, or hypochondriacal. He was administered 100 mg/day of fluvoxamine for 3 years after the first operation to treat depressive symptoms. Other therapy included 25 mg/day of quetiapine for delirium and 0.5 mg/day of etizolam for sleep disturbances after the last operation. Milnacipran, 30 mg/day, was added to the regimen. The abnormal pain and sensation were reduced after 1 week but did not vanish. The dosage of milnacipran was increased to 50 mg/day in order to reach remission. After 3 weeks of milnacipran therapy, the phantom limb pain and sensation completely disappeared without adverse events. He continued to take 50 mg/day of milnacipran and was discharged without relapse.

Discussion
In our case, milnacipran rather than fluvoxamine was likely successful in the management of phantom limb pain and sensation because these phenomena developed abruptly during the long-term administration of fluvoxamine and there was rapid dose-dependent improvement following administration of milnacipran. There is a significant amount of evidence to show that tricyclic antidepressants have analgesic efficacy against different kinds of pain due to their action on noradrenergic and serotonergic systems in descending inhibitory pain pathways.³ Although several reports suggest that selective serotonin reuptake inhibitors (SSRIs) are also capable of alleviating neuropathic pain, meta-analysis found that tricyclic antidepressants showed outstanding analgesic efficacy as compared with SSRIs.⁴ Therefore, reuptake inhibition of both 5-HT and noradrenaline arguably play an important role in analgesic efficacy. Milnacipran would reveal a prominent analgesic effect by selectively inhibiting the reuptake of both 5-HT and noradrenaline.⁵ In addition, our patient experienced no adverse events. Milnacipran is devoid of affinity for various neuroreceptors associated with numerous adverse events.⁵ From a clinical point of view, with respect to pharmacodynamic characteristics, milnacipran could be expected to have tolerability and a therapeutic effect for phantom limb pain and sensation.

REFERENCES

1. Iacono RP, Linford J, Sandyk R: Pain management after lower extremity amputation. Neurosurgery 1987; 20:496–500[Medline]
2. Mattia C, Paoletti F, Coluzzi F, et al: New antidepressants in the treatment of neuropathic pain: a review. Minerva Anestesiol 2002; 68:105–114[Medline]
3. Barkin RL, Fawcett J: The management challenges of chronic pain: the role of antidepressants. Am J Ther 2000; 7:31–47[Medline]
4. Sindrup SH, Jensen TS: Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 1999; 83:389–400[CrossRef][Medline]
5. Mochizuki D, Tsujita R, Yamada S, et al: Neurochemical and behavioural characterization of milnacipran, a serotonin and noradrenaline reuptake inhibitor in rats. Psychopharmacology (Berl) 2002; 162:323–332[CrossRef][Medline]

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