Amantadine for Painful Diabetic Neuropathy
Abstract & Commentary
Source: Amin P, Sturrock ND. A pilot study of the beneficial effects of amantadine in the treatment of painful diabetic peripheral neuropathy. Diabet Med. 2003;20:114-118.C
Almost all patients with diabetes eventually develop neuropathy. New therapeutic options for the control of painful diabetic neuropathy are constantly being investigated. Many agents are effective, including anticonvulsants, tricyclic antidepressants (TCA), serotonin reuptake inhibitors, and analgesics. None work in all patients, and all have unwanted side effects. Amantadine, a noncompetitive N-methyl-D-aspartate (NMDA) antagonist, is the latest agent to show promise.
Twenty diabetic neuropathy patients were randomized into a double-blind, placebo-controlled, crossover trial of 200-mg intravenous amantadine infused once weekly for 2 weeks following an initial 28-day analgesic wash-out period and a single placebo infusion. Type 1 or type 2 diabetics were eligible and had at least 6 months of painful diabetic neuropathy diagnosed clinically with or without abnormal electrodiagnostic studies. Exclusionary criteria included other causes of peripheral neuropathy, renal insufficiency, pregnancy, prostatism, or psychiatric history. Outcome measurements comprised a 100-mm visual analogue scale for pain intensity and pain relief, the Neuropathy Symptom Score, and Physician’s Global Evaluation. Statistical analysis was provided by Student’s t-test.
Seventeen patients completed the study; a foot ulcer, a transient ischemic attack, and the need for opiates excluded 1 patient each. Most were male (n = 9), type 2 diabetic (n = 15), and Caucasian (n = 16), with a mean duration of diabetes for 21 years and neuropathy for 29 months. Mean age was 58.4 years, and prior treatments included TCA (n = 6), carbamazepine, gabapentin, or paracetamol (3 each), capsaicin or nonsteroidals (2 each), and acupuncture (n = 1). Compared to placebo, amantadine infusion resulted in significant improvement in all measured ways. Intravenous amantadine provided relief from painful diabetic neuropathy, and the improvement was sustained for at least 1 week following infusion.
Commentary
Hyperglycemia, the clear and proximate antecedent of diabetic neuropathy, sets off a plethora of metabolic abnormalities leading to oxidative stress and mitochondrial malfunction, resulting in neuronal and Schwann cell apoptosis and consequent neuropathy.1 Metabolic abnormalities include enhanced aldose reductase activity with resultant sorbitol and fructose accumulation and myoinositol depletion in nerve. Protein kinase C is inappropriately activated, advanced glycation end products are produced, and oxygen free radicals are generated. Diabetic neuropathy is multifactorial.
Hedgehog (Hh) proteins, including sonic, desert, and indian Hh protein, are crucial for normal nervous system development—sonic Hh (SHh) protein in the central nervous system and desert Hh (DHh) protein in the peripheral nervous system. DHh is found only in Schwann cells, and in diabetic rats DHh mRNA is reduced.2 Complete normalization of motor and sensory nerve conduction velocities was achieved with infusion of SHh-IgG (ibid.), suggesting that therapeutic benefit may accrue from this management strategy.
Overt clinical hyperglycemia may not be a prerequisite for the development of neuropathy.3 Among 73 patients with peripheral neuropathy of unknown cause who completed an oral glucose tolerance test, 41 (56%) were abnormal. Diabetes (defined as fasting glucose > 126 mg/dL or 2-hour postglucose challenge > 200 mg/dL) was found in 15 and impaired glucose tolerance in 26 (IGT, fasting glucose 110-126 mg/dL or 2-hour postglucose challenge 140-200 mg/dL). IGT patients predominantly suffered from small fiber neuropathy, as documented by distal leg intraepidermal nerve fiber densities and had less severe large-fiber neuropathy compared to those with diabetes. Diabetes may cause significant painful neuropathy before it is evident, and all idiopathic painful polyneuropathy patients should undergo oral glucose tolerance testing. — Michael Rubin
Dr. Rubin is Professor of Clinical Neurology, New York Presbyterian Hospital-Cornell Campus.
References
1. Simmons Z, Feldman EL. Curr Opin Neurol. 2002; 15:595-603.
2. Calcutt NA, et al. J Clin Invest. 2003;111:507-514.
3. Sumner CJ, et al. Neurology. 2003;60:108-111.
Almost all patients with diabetes eventually develop neuropathy. New therapeutic options for the control of painful diabetic neuropathy are constantly being investigated.Subscribe Now for Access
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