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Reply to Louis P. Gangarosa
232
PA1 01300
Reply to Louis P. Gangarosa
Szeged, 22 June 1%X
Dear Editor, It is kind of historical justice that the discussion on the value of iontophoretic treatment in post-herpetic neuralgia (PHN) takes place in this renowned journal since, due to the slings and arrows of editorial policy, the original paper dealing with this problem had to be published elsewhere [ 11. According to Schopenhauer, a novelty is regarded absurd at the beginning; later it becomes obvious and, finally, trivial 121. The history of transganglionic regulation 131 might illustrate this point, and, in this respect, I am greatly indebted to my friendly Doppelglnger, Prof. Patrick Wall, who never failed to repeat our experiments. (Occasional misquotings. let alone omissions be forgotten.) Iontophoretic application of vinca alkaloids to treat chronic, autochthonous pain syndromes, like PHN via transganglionic effects was started in 1981 by a group of young clinicians. For a humble neuroanatomist, the spectacular improvement in the pain state of these patients. now in the 8th year of the follow-up without any side effects proves not only the validity but also the practicality of this novel neurobiological principle. The number of patients treated successfully by this technique in the midget Pain Control Unit of the Albert Szent-Gyiirgyi Medical University (Szeged, Hungary) is now close to 500. the case histories awaiting a comprehensive evaluation. The clinical trials published by Layman et al. 0304-3959/88/$03.50
87)1988 Elsevier Science
Publishers
[4] essentially prove that the effect of vinca iontophoresis in PHN is statistically significant. Unfortunately, the original parameters of the treatment were changed by these authors which might be the reason of lesser effectiveness. The idea proposed by Dr. Gangarosa, i.e., to increase efficiency of the iontophoresis by using water instead of saline, had been tacitly adopted by the technicians of our Pain Control Unit in the meantime. DMSO is intended to increase permeability of the dermal barrier. In many cases it has been substituted by hyaluronidase. Neither DMSO, nor hyaluronidase alone (i.e., without vinca alkaloid} had any effect in the iontophoretic treatment of chronic pain syndromes. In the meantime, an entirely different class of chemicals emerged in the clinical trials with virtually identical results. Basic peptides. in general. exert transganglionic effects, as follows from the decreased FRAP (fluoride-resistant acid phosphatase) and TMP (thiamine monophosphatase) activity of the upper dorsal horn. Two basic peptides: Polymyxin& (Pfizer) and Colimycin” (Bellon), if applied perineurally, induce transganglionic degenerative atrophy (TDA) comparable to that obtained by vinca alkaloids or other microtubule inhibitors, It has been shown that the TDA-inducing effect of these two cyclic basic peptides (i) is not due to blockade of axoplasmic transport, (ii) is not due to hista~ne liberation. and (iii) is not due to calcium inactivation. Both drugs can be used also in iontophoretic application. It is assumed that their effect might be due
B.V. (Biomedical
Division)
233
to competitive interaction with the nerve growth factor [5]. A double-blind, randomized clinical study of 15 PHN patients (6 male, 9 female; average age: 70 years; average duration of pain before commencement of iontophoretic treatment: 18 months; average number of iontophoretic sessions: 18; average alleviation of pain: 76.5%; follow-up: 2-4 years) proves the potential usefulness of these two basic peptides in the iontophoretic therapy of PHN. In a recent survey [6], 37 different methods (various drugs, lotions, unctions, physiotherapeutic and surgical approaches, psychiatric techniques, etc.) were quoted as more or less effective measures in PHN, including glycocorticosteroids that have been used subcutaneously since 1972 [7]. One has to congratulate Dr. Gangarosa and his colleagues for the idea to use an iontophoretically applicable glycocorticosteroid, methylprednisolone sodium succinate, as a powerful treatment of PHN [8]. Since glycocorticosteroids, if applied perineurally, do not induce TDA, the effect observed by Dr. Gangarosa may rely upon some other principle. All the same: Salus aegroti suprema lex.
References 1 Knyihar-Csillik. E., Sziics, A. and Csillik, B., Iontophoretitally applied microtubule inhibitors induce transganglionic degenerative atrophy of primary central nociceptive terminals and abolish chronic autochthonous pain, Acta Neurol. Scand., 66 (1982) 401-412. 2 Schopenhauer, A., Parerga und Paralipomena, Berlin, 1851. 3 Csillik, B. and Knyihar-Csillik, E., The Protean Gate. Structure and Plasticity of the Primary Nociceptive Analyzer, Akadtmiai Kiadb, Budapest, 1986, pp. l-294. 4 Layman, P.R., Argyras, E. and Glynn, Ch.J., Iontophoresis of vincristine versus saline in post-herpetic neuralgia. A controlled trial, Pain, 25 (1986) 165-170. 5 Csillik, B., Kovacs, K., Per&e, B., Tajti, J., Szilard, J., Sziics, A. and Knyihar-Csillik, E., Transganglionic effect of basic peptides on the primary nociceptive analyzer. In: ES. Vizi, S. Fiirst and G. Zsilla (Eds.), Proc. 4th Congr. Hung. Pharmacol. Sot., Budapest, Vol. 2, 1985, pp. 235-242. 6 Sziics, A., The Pathomechanism and Therapy of PostHerpetic Neuralgia, PhD. Thesis, Szeged-Budapest, 1984. 7 Sziics, A. and Polay, A., Treatment of postherpetic neuralgia with triamcinolone. In: 27. Congress of Neurology and 16. Congress of Electroencephalography, Akademiai Kiado, Budapest, 1972, pp. 196-197. 8 Gangarosa, L.P., Haynes, M., Qureshi, S., Selim, M.M., Ozawa, A., Hayakawa, K., Ohkido, M. and Mahan, P.E., Treatment of postherpetic neuralgia by iontophoresis. In: Proc. 3rd Int. Dental Congr. on Modem Pain Control, 1985, pp. 263-265.
PA1 01300
Reply to Louis P. Gangarosa
Szeged, 22 June 1%X
Dear Editor, It is kind of historical justice that the discussion on the value of iontophoretic treatment in post-herpetic neuralgia (PHN) takes place in this renowned journal since, due to the slings and arrows of editorial policy, the original paper dealing with this problem had to be published elsewhere [ 11. According to Schopenhauer, a novelty is regarded absurd at the beginning; later it becomes obvious and, finally, trivial 121. The history of transganglionic regulation 131 might illustrate this point, and, in this respect, I am greatly indebted to my friendly Doppelglnger, Prof. Patrick Wall, who never failed to repeat our experiments. (Occasional misquotings. let alone omissions be forgotten.) Iontophoretic application of vinca alkaloids to treat chronic, autochthonous pain syndromes, like PHN via transganglionic effects was started in 1981 by a group of young clinicians. For a humble neuroanatomist, the spectacular improvement in the pain state of these patients. now in the 8th year of the follow-up without any side effects proves not only the validity but also the practicality of this novel neurobiological principle. The number of patients treated successfully by this technique in the midget Pain Control Unit of the Albert Szent-Gyiirgyi Medical University (Szeged, Hungary) is now close to 500. the case histories awaiting a comprehensive evaluation. The clinical trials published by Layman et al. 0304-3959/88/$03.50
87)1988 Elsevier Science
Publishers
[4] essentially prove that the effect of vinca iontophoresis in PHN is statistically significant. Unfortunately, the original parameters of the treatment were changed by these authors which might be the reason of lesser effectiveness. The idea proposed by Dr. Gangarosa, i.e., to increase efficiency of the iontophoresis by using water instead of saline, had been tacitly adopted by the technicians of our Pain Control Unit in the meantime. DMSO is intended to increase permeability of the dermal barrier. In many cases it has been substituted by hyaluronidase. Neither DMSO, nor hyaluronidase alone (i.e., without vinca alkaloid} had any effect in the iontophoretic treatment of chronic pain syndromes. In the meantime, an entirely different class of chemicals emerged in the clinical trials with virtually identical results. Basic peptides. in general. exert transganglionic effects, as follows from the decreased FRAP (fluoride-resistant acid phosphatase) and TMP (thiamine monophosphatase) activity of the upper dorsal horn. Two basic peptides: Polymyxin& (Pfizer) and Colimycin” (Bellon), if applied perineurally, induce transganglionic degenerative atrophy (TDA) comparable to that obtained by vinca alkaloids or other microtubule inhibitors, It has been shown that the TDA-inducing effect of these two cyclic basic peptides (i) is not due to blockade of axoplasmic transport, (ii) is not due to hista~ne liberation. and (iii) is not due to calcium inactivation. Both drugs can be used also in iontophoretic application. It is assumed that their effect might be due
B.V. (Biomedical
Division)
233
to competitive interaction with the nerve growth factor [5]. A double-blind, randomized clinical study of 15 PHN patients (6 male, 9 female; average age: 70 years; average duration of pain before commencement of iontophoretic treatment: 18 months; average number of iontophoretic sessions: 18; average alleviation of pain: 76.5%; follow-up: 2-4 years) proves the potential usefulness of these two basic peptides in the iontophoretic therapy of PHN. In a recent survey [6], 37 different methods (various drugs, lotions, unctions, physiotherapeutic and surgical approaches, psychiatric techniques, etc.) were quoted as more or less effective measures in PHN, including glycocorticosteroids that have been used subcutaneously since 1972 [7]. One has to congratulate Dr. Gangarosa and his colleagues for the idea to use an iontophoretically applicable glycocorticosteroid, methylprednisolone sodium succinate, as a powerful treatment of PHN [8]. Since glycocorticosteroids, if applied perineurally, do not induce TDA, the effect observed by Dr. Gangarosa may rely upon some other principle. All the same: Salus aegroti suprema lex.
References 1 Knyihar-Csillik. E., Sziics, A. and Csillik, B., Iontophoretitally applied microtubule inhibitors induce transganglionic degenerative atrophy of primary central nociceptive terminals and abolish chronic autochthonous pain, Acta Neurol. Scand., 66 (1982) 401-412. 2 Schopenhauer, A., Parerga und Paralipomena, Berlin, 1851. 3 Csillik, B. and Knyihar-Csillik, E., The Protean Gate. Structure and Plasticity of the Primary Nociceptive Analyzer, Akadtmiai Kiadb, Budapest, 1986, pp. l-294. 4 Layman, P.R., Argyras, E. and Glynn, Ch.J., Iontophoresis of vincristine versus saline in post-herpetic neuralgia. A controlled trial, Pain, 25 (1986) 165-170. 5 Csillik, B., Kovacs, K., Per&e, B., Tajti, J., Szilard, J., Sziics, A. and Knyihar-Csillik, E., Transganglionic effect of basic peptides on the primary nociceptive analyzer. In: ES. Vizi, S. Fiirst and G. Zsilla (Eds.), Proc. 4th Congr. Hung. Pharmacol. Sot., Budapest, Vol. 2, 1985, pp. 235-242. 6 Sziics, A., The Pathomechanism and Therapy of PostHerpetic Neuralgia, PhD. Thesis, Szeged-Budapest, 1984. 7 Sziics, A. and Polay, A., Treatment of postherpetic neuralgia with triamcinolone. In: 27. Congress of Neurology and 16. Congress of Electroencephalography, Akademiai Kiado, Budapest, 1972, pp. 196-197. 8 Gangarosa, L.P., Haynes, M., Qureshi, S., Selim, M.M., Ozawa, A., Hayakawa, K., Ohkido, M. and Mahan, P.E., Treatment of postherpetic neuralgia by iontophoresis. In: Proc. 3rd Int. Dental Congr. on Modem Pain Control, 1985, pp. 263-265.