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LETTER TO THE EDITOR

Combined Therapy with Clonidine and Amantadine May Act in Two Stages of Glutamate-Mediated Neuropathic Pain Caused by a Needle Puncture in an Upper Extremity

Shinichi Inomata, MD^*, Yoshihiro Kakiuchi, PhD, Masayuki Miyabe, MD^*, Yuki Ohara, MD^*, Iwao Sukegawa, MD^*, Yoshiko Osaka, MD^*, Yukinao Kohda, PhD, and Hidenori Toyooka, MD^*

*Department of Anesthesiology Department of Clinical Pharmacy; University of Tsukuba; Tsukuba, Ibaraki, Japan; inomatas{at}md.tsukuba.ac.jp

To the Editor:

We report on two patients with neuropathic pain and a fear of needles. They were successfully treated with a combination therapy of oral clonidine and amantadine. This combination may therefore be an alternative treatment for neuropathic pain in patients for whom invasive therapy is not chosen.

A 29-yr-old female patient had median nerve injury after blood sampling, and a 45-yr-old male patient had ulnar nerve injury after IV cannulation into the cubital vein. The two patients subsequently had neuropathic pain in the upper extremity for 11 months (pain score, 7–8 of 10) and 17 months (pain score, 10 of 10), respectively. Neither patient, however, would consent to receiving block therapy. A strategy for therapy without the use of needles was required. The female patient received oral administration of many drugs; however, they were not effective (pain score, 7–8 of 10). We persuaded her to undergo phentolamine and ketamine tests. Based on these tests, oral administration of ketamine 150 mg/day was started. It was gradually increased to 400 mg/day. The pain score was maintained at 3–4 of 10. We changed ketamine into amantadine (an N-methyl-d-aspartate antagonist) tablets (450 mg/day) as an out-of-hospital substitute. The dose of amantadine was increased to 1000 mg/day in 14 days (pain score, 3–4 of 10). After additional administration of an 2-adrenergic agonist, clonidine 150 µg/day, for 5 days the pain score was reduced to 0–1 of 10. The doses of amantadine and clonidine were gradually reduced over a period of 3 mo. After termination of these drugs, the pain did not recur for 1 yr after discharge.

Next, based on the result of the ketamine test and the treatment of the female patient (the first case), administration of amantadine tablets (400 mg/day) and clonidine (150 µg/day) were started in the male patient. The dose of clonidine was reduced to 75 µg/day because of sleepiness. Five days after administration of these drugs, the pain score was reduced to 1 of 10. The patient had no difficulties in daily life and was discharged. Administration of these drugs was discontinued 3 mo after discharge from the hospital, and pain did not recur as of 6 mo after the discontinuation.

It has been reported that the most common side effects of amantadine are gastrointestinal and central nervous system complaints, such as nervousness, difficulty concentrating, insomnia, and loss of appetite or nausea (1).

The treatment with clonidine and amantadine utilized in the present cases may have suppressed the N-methyl-d-aspartate-related pain in two stages: 1) a reduction of glutamate production by inhibiting voltage-gated N-type Ca²⁺ channel currents in dorsal root ganglion cells (2,3), and 2) blocking the channel by the action of amantadine on N-methyl-d-aspartate receptors (Fig. 1). Moreover, the effect of our combined therapy is consistent with a study showing that 2-adrenoceptors modulate N-methyl-d-aspartate-evoked responses of neurons in the dorsal horn of the medulla (4).

View larger version (23K): [in this window] [in a new window]   Figure 1. Schematic diagram of the 2-step effector mechanisms: (1) 2-agonist (clonidine) inhibits glutamate release via N-type Ca2+ channels, and (2) the NMDA receptor antagonist (amantadine) inhibits NMDA receptors.

References

1. Douglas RG Jr. Drug therapy. Prophylaxis and treatment of influenza. N Engl J Med 1990;322:443–50.[Web of Science][Medline]
2. Cox DH, Dunlap K. Pharmacological discrimination of N-type from L-type calcium current and its selective modulation by transmitters. J Neuroscience 1992;12:906–14.[Abstract]
3. Kamisaki Y, Hamada T, Maeda K, et al. Presynaptic 2 adrenoceptors inhibit glutamate release from rat spinal cord synaptosomes. J Neurochem 1993;60:522–6.[Web of Science][Medline]
4. Zhang K-M, Wang X-M, Peterson AM, et al. 2-adrenoceptors modulate NMDA-evoked responses of neurons in superficial and deeper dorsal horn of the medulla. J Neurophysiol 1988;80:2210–4.

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