Anesth Analg 2002;94:1558-1559
© 2002 International Anesthesia Research Society
TECHNOLOGY, COMPUTING, AND SIMULATION
Oral Ketamine: A Promising Treatment for Restless Legs Syndrome
Neeraj Kapur, MD*, and
Robert Friedman, MD FACP
*Department of Anesthesiology, Department of Anesthesiology and Pain Management, Temple University Hospital, Philadelphia, Pennsylvania
Address correspondence and reprint requests to Robert Friedman, MD, FACP, Division of Pain Medicine, Cooper Hospital University Medical Center, One Cooper Plaza, Camden, NJ 08103. Address e-mail to DrRFriedman{at}aol.com
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Abstract
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IMPLICATIONS: Oral Ketamine, an NMDA receptor antagonist, can be used to treat restless legs syndrome. A mechanism for the efficacy of this treatment is discussed.
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Introduction
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Restless Legs Syndrome (RLS) affects up to 10%–15% of older patients who report unpleasant limb sensations at rest that are relieved by limb movement. No specific treatment of RLS has been uniformly successful. We report two patients with RLS who failed multiple treatments and whose symptoms were significantly improved with oral ketamine.
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Case Report 1
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A 70-yr-old woman presented with a history of back pain, neurogenic claudication, and RLS. Treatment with the dopaminergic agonist, pergolide, and oxycodone had been ineffective. In addition to RLS, her history included prior spinal surgery, insulin-dependent diabetes mellitus, sleep apnea, and congestive heart failure. Her family history was positive for RLS.
We prescribed amitriptyline 25 mg at bedtime and gabapentin 300 mg 3 times daily in addition to her other medications. A month later she returned with no improvement in her symptoms and reported a verbal analog pain score (VAS) of 6/10. We obtained an informed consent to evaluate single-dose efficacy of oral ketamine.
The patient received 30 mg of ketamine mixed in 50 mL water. After 20 min of observation, the patient noted that her VAS score had improved to 2/10. The patient felt relaxed and noted no dizziness or other distressing symptoms. She has continued to take oral ketamine 30 mg twice a day for the past 6 mo, noting improvement in sleep and RLS.
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Case Report 2
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A 61-yr-old man with a history of chronic lower back pain, spinal stenosis, scoliosis, and RLS complained of worsening neurogenic claudication. His VAS was 7/10. He had been treated with tramadol, rofecoxib, gabapentin, and quinine without success. Lumbar epidural steroid injections had also failed to relieve his RLS symptoms. We treated him with 50 mg of oral ketamine. Within 15 min, his VAS improved from 7/10 to 2/10 and he noted subjective improvement in walking. A month after the ketamine trial, the patient continues to take oral ketamine 40 mg twice a day, noting significant improvement in his sleep and RLS symptoms.
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Discussion
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A variety of etiologies have been proposed for RLS including pregnancy, polyneuropathy, spinal stenosis, Parkinson’s disease, peripheral microembolism, and drug withdrawal from sedatives and vasodilators (1). Two types of RLS have been characterized. The most common form is associated with peripheral and central nerve damage in the legs and the spinal cord. A hereditary form is much less common. While a number of mechanisms have been proposed for RLS, inflammation in the central nervous system (CNS) associated with impaired blood flow to spinal nerve roots may contribute to the nerve damage seen in Type 1 RLS (2). RLS might result from the accumulation of irritants in the legs that are removed by leg movement. Changes in nerve conduction tests have also been reported in patients with RLS, suggesting abnormalities in spinal cord function.
Neuroinflammation, which can contribute to chronic pain, may explain some of the mechanisms suggested for RLS. Neuroinflammation involves activation of endothelial cells, microglia, and astrocytes, with subsequent production of cytokines, chemokines and the expression of surface antigens that enhance the immune, inflammatory and excitotoxic cascades (3). Activated glial cells synthesize proinflammatory mediators that act through N-methyl-D-aspatate (NMDA) receptors to enhance pain. At the spinal cord level, glial activation leads to the release of cytokines, chemokines and adhesion molecules. Alterations in blood flow and glial function in the CNS have been identified in preclinical acute and chronic pain studies (4).
Ketamine, a noncompetitive NMDA receptor antagonist in clinical use for almost 35 years, has only recently been used in pain treatment (5). Ketamine is metabolized by hepatic cytochrome P450 system. The primary metabolite of oral ketamine is norketamine, which though one-third to one-fifth as potent as ketamine, contributes significantly to analgesia (6). Ketamine interacts with NMDA and a variety of other receptors, which affect analgesia (7). It inhibits activation of the NMDA receptor by glutamate, an excitatory neurotransmitter in the CNS. Ketamine also reduces the presynaptic release of glutamate and potentiates the effects of the inhibitory neurotransmitter, 
-aminobutyric acid.
Inflammatory mediators produced locally by compression of nerve roots can activate neutrophils that then adhere to blood vessels and impair blood flow. Ketamine suppresses neutrophil production of inflammatory mediators and improves blood flow (8). Ketamine reduces the migration of leukocytes through endothelial cells because of its influence on molecular mediators of cellular adhesion (9). Direct inhibition of cytokines in the human whole blood by ketamine may also account for its analgesic effects (10).
In these patients, who had type 1 RLS, ketamine improved abnormal limb sensations and insomnia. Both patients noted pain relief within 20 minutes of taking the medication. The dramatic response raises the possibility that ketamine inhibits neuroinflammation in the spinal cord or at higher centers. Within the spinal cord, RLS might result from NMDA receptor activation and production of inflammatory mediators that impairs blood flow in the spinal cord. Whether oral ketamine acts to improve local blood flow around damaged nerve roots or inhibits NMDA receptor dependent transmission of painful nerve signals will require more study. Oral ketamine may offer another avenue of study and help to control the symptoms of this disabling and common condition.
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Accepted for publication January 9, 2002.
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Abstract
Introduction
