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BRIEF COMMUNICATIONS: E. J. Piovesan, H. G. Teive, P. A. Kowacs, M. V. Della Coletta, L. C. Werneck, and S. D. Silberstein An open study of botulinum-A toxin treatment of trigeminal neuralgia Neurology 2005; 65: 1306-1308 [Abstract] [Full text] [PDF]

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Elcio Juliato Piovesan, H.G. Teive, P.A. Kowacs, M.V. Della Coletta, L.C. Werneck, S.D. Silbertein   (16 January 2006)

An open study of botulinum-A toxin treatment of trigeminal neuralgia

Joanna M. Zakrzewska, Jeffrey Cohen (New York, NY), Jeffrey Brown (Mineola, NY) , John Alksne (San Diego, CA), Henry Gemillion (Gainsville, FLA), Mark Linskey (Irvine CA), David Sirois (New York, NY) , Bruce Pollock (Rochester, MN)   (16 January 2006)

An open study of botulinum-A toxin treatment of trigeminal neuralgia

Bernhard Voller, Thomas Sycha, Burkhard Gustorff, Gottfried Kranz, and Eduard Auff   (16 January 2006)

An open study of botulinum-A toxin treatment of trigeminal neuralgia

Steven R Brenner   (16 January 2006)

Reply from the Authors 16 January 2006
Elcio Juliato Piovesan, Hospital de Clínicas da Universidade Federal do Parana Rua General Carneiro - Curitiba, Paraná, Brazil, H.G. Teive, P.A. Kowacs, M.V. Della Coletta, L.C. Werneck, S.D. Silbertein Send Correspondence to journal: Re: Reply from the Authors piovesan{at}avalon.sul.com.br Elcio Juliato Piovesan, et al.	We thank Dr. Brenner, Dr. Voller et al and Dr. Zakrezewska et al. for their attention to our paper. [1] As Dr. Zakrezewska et al noted, our population is not representative of the entire trigeminal neuralgia (TN) patient population, mainly because our group had been refractory to medical therapy. Botulinum toxin type A (BoNT/A) has an antinociceptive effect [2], with transitory action over the trigeminal territory. [10] It inhibits the release of neurotransmitters (substance P, calcitonin gene-related peptide, and glutamate). [2] It has no direct effect on either the excitability or transduction velocity of sensory neurons, but it does reduce peripheral and central sensitization. [11] BoNT/A can produce analgesic effect in patients with intractable TN, probably because these patients have persistent pain and associated peripheral and central sensitization. The reduction of the pain, within ten days in our study, occured before muscular tonus decrease, suggesting that the reduction of the pain was not related to the chemodenervation of the motor endplate. [12] We used the visual analog scale, a reliable tool for pain evaluation, [13] along with a new method that could better reflect the action of BoNT/A in discrete territories. While anticonvulsants drugs may produce CNS AEs, BoNT-A produced only local, minor AEs in a few patients. [1] When scientific results are published in the lay media, the findings are frequently seized upon by sufferers who have had little or no success with past treatments. Although the benefits of randomized controlled trials are well known, the initial and unsupported reports of efficacy of medical therapy for TN were open studies. [14,15] We would expect enthusiasm for new approaches for TN patients from the medical advisors of the US Trigeminal Neuralgia Association (TNA). Perhaps with support from the US TNA, our trial could be further improved and expanded. We agree with Dr. Brenner that further studies are necessary to confirm the initial results and determine the best dose, duration of treatment, the necessity of repeated doses, and perhaps reduce the need for a placebo-controlled clinical trial if the treatment is strongly effective. In future studies, perhaps tools could be utilized to assessment the muscle tonus, as suggested for Dr. Voller and the quality of life, as suggested for Dr. Zakrzewska. [8] We believe that BoNT/A is another option for TN treatment especially when peripheral and central sensitization is present as is often the case with intractable TN. References 10. Piovesan EJ, Radunz V, Utiumi M, Teive HG, Werneck LC. Antinociceptive effect of botulinum toxin type-A over the orofacial pain. Neurology;2005;64 Suppl 6:P06.019. 11. Ishikawa H, Mitsui Y, Yoshitomi T et al. Presynaptic effects of Botulinum toxin type A on the neuronally evoked response of albino and pigmented rabit iris sphincter and dilator muscles. Jpn J Ophthalmol 2000;44:106-109. 12. Aoki KR. Evidence for antinociceptive activity of botulinum toxin type A in pain management. Headache 2003;43:S9-S15. 13. Zakrzewska JM. Trigeminal neuralgia. Major problems in neurology. Pain: Its assessment and effect on the quality of life. Chapter 3. London. WB Saunders Company Ltda,1995:21-39. 14. Zakrzewska JM, Patsalos PN. Oxcarbazepine: a new drug in the management of intractable trigeminal neuralgia. J Neurol Neurosurg Psychiatry 1989;52:472-476. 15. Sist T, Filadora V, Miner M, Lema M. Gabapentin for idiopathic trigeminal neuralgia: report of two cases. Neurology 1997;48:1467. The authors report no conflicts of interest.
An open study of botulinum-A toxin treatment of trigeminal neuralgia 16 January 2006
Joanna M. Zakrzewska, Barts and the London Queen Mary's School of Medicine and Dentistry Turner Street, London E1 2AD, UNITED KINGDOM, Jeffrey Cohen (New York, NY), Jeffrey Brown (Mineola, NY) , John Alksne (San Diego, CA), Henry Gemillion (Gainsville, FLA), Mark Linskey (Irvine CA), David Sirois (New York, NY) , Bruce Pollock (Rochester, MN) Send Correspondence to journal: Re: An open study of botulinum-A toxin treatment of trigeminal neuralgia J.M.Zakrzewska{at}qmul.ac.uk Joanna M. Zakrzewska, et al.	The study on the use of botulinum–A toxin in the treatment of trigeminal neuralgia (TN) [1] attracted the attention of the New York Times which gave the impression that Botox was better than any surgical treatment and that it was highly effective. As members of the Medical Advisory Board for the US Trigeminal Neuralgia Association (TNA), a patients support group, we were asked to provide guidance as one of TNA’s missions is to keep its members aware of advances in the area of TN. We assessed the scientific quality of the article and noted that this was an open-label study reported as case series. Its prominence was increased by placing it in the brief communication section rather than in the clinical/scientific note section. We think it lacks scientific merit for a number of reasons. The full demographics including baseline evaluations and drug dosage of each of the patients is missing. The long duration of pain, the high incidence of pure first division trigeminal pain and the repeated treatments suggest that these patients may not be representative of the population of TN sufferers. No details are provided of who administered the injections or who performed the post-injection evaluations. The International Association for the Study of Pain has provided guidance on outcome measures to be used in pain trials [7] and Zakrzewska and Lopez [8] have suggested specific ones after treatments for TN. This trial only measured pain intensity on a visual analogue scale. Outcomes from treatments for TN normally provide patients with a 100% pain relief whereas in this group only four patients had sufficient pain relief to stop all medication and the effect took several days. The Conclusion stated that there were no side effects yet in the Methods sections four patients had side effects. This study may follow the fate of proparacaine eye drops in TN which were reported in two papers but when subject to a randomized controlled trial (RCT) [9] showed that they provided no benefits. In the days of evidence-based medicine it is time we stopped publishing open-label trials that fail to include the basic requirements of careful baseline evaluations, multiple outcome measures including quality of life and independent evaluations. Such studies do not provide enough data to design a RCT. These studies raise false hopes in patients with TN especially when reported in the lay press. References 7. Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 2005;113:9-19. 8. Zakrzewska JM, Lopez BC. Quality of reporting in evaluations of surgical treatment of trigeminal neuralgia: recommendations for future reports. Neurosurgery 2003;53:110-122. 9. Kondziolka D, Lemley T, Kestle JR, et al. The effect of single-application topical ophthalmic anesthesia in patients with trigeminal neuralgia. A randomized double- blind placebo-controlled trial. J Neurosurg 1994;80:993-997. The authors report no conflicts of interest.
An open study of botulinum-A toxin treatment of trigeminal neuralgia 16 January 2006
Bernhard Voller, Department of Neurology, Medical University of Vienna Währingergürtel 18-20, A-1090 Wien, AUSTRIA, Thomas Sycha, Burkhard Gustorff, Gottfried Kranz, and Eduard Auff Send Correspondence to journal: Re: An open study of botulinum-A toxin treatment of trigeminal neuralgia bernhard.voller{at}meduniwien.ac.at Bernhard Voller, et al.	We read the report of Piovesan et al with interest. [1] The authors describe reduced pain in all 13 patients with trigeminal neuralgia (TN) treated with botulinum toxin type A (BoNT/A). Effects were described for all trigeminal nerve branches measured by visual analogue scale score, surface area of pain, and therapeutic coefficient. In their results, the authors offer several possible mechanisms derived from animal studies of how BoNT/A could directly affect the pain mediating nerve fibers. In contrast, we want to emphasize that in all experimental human pain models including our own investigation [5], several groups were unable to prove any effect of BoNT/A on primary or secondary hyperalgesia. Clinically, it is generally known that TN presents as intermittent pain triggered by touch, cold, or movement, with no pain between the paroxysms. Can the authors exclude that chemodenervation of the motor endplate and the resulting movement reduction contributed to lessening the pain by BoNT/A? Piovesan et al reported side effects in 4 of the 13 patients which can be attributed to chemodenervation. Although the doses appear to be low, they are still higher than doses used, for instance, in wrinkle therapy. It would be interesting to know if patients with local muscle weakness experienced the strongest pain reduction. It may also be difficult to blind patients and investigators in any future controlled study using BoNT/A vs. placebo. It is interesting that muscle and joint receptors are absent in human and non-human primate orofacial muscles. Cutaneous mechanoreceptors, presumably of high density may be used for facial proprioception. [6] Therefore, the reduction of cutaneous afferent input by weakening the underlying muscles may be the main effect of BoNT/A in treating TN. Regarding the special anatomical and physiological situation of the face other mechanisms of action for BoNT/A therapy cannot generally be excluded. As a consequence, new studies using pain models applied to the human face are needed. There is neither evidence from any human pain model for a direct analgesic effect of BoNT/A nor randomized controlled evidence from clinical studies. Therefore, omitting the well-known effect of BoNT/A on the motor endplate and only providing mechanisms of action gleaned from animal studies may cast a favorable light on the authors' results but does not result in a compelling Discussion. References 5. Voller B et al. A randomized, double-blind, placebo controlled study on analgesic effects of botulinum toxin A. Neurology 2003:61: 940- 944. 6. Connor NP, Abbs JH. Orofacial proprioception: Analysis of cutaneous mechanoreceptor population properties using artificial neural networks. J Commun Disord 1998:31: 535-542. The authors report no conflicts of interest.
An open study of botulinum-A toxin treatment of trigeminal neuralgia 16 January 2006
Steven R Brenner, St.Louis VA Medical Center and St. Louis University Neurology Department Dept. Neurology, St. Louis VA Med. Center, 915 North Grand, St. Louis, MO 63106 Send Correspondence to journal: Re: An open study of botulinum-A toxin treatment of trigeminal neuralgia SBren20979{at}aol.com Steven R Brenner	I read the article by Piovesan et al [1] with interest. The improvement in all 13 patients with Botulinum A treatment including patients with failure of surgical and radiation (Gamma knife) treatment indicated a strong effect, even enabling some patients to discontinue medication. There appears to be an antinociceptive effect of botulinum toxin in sensory neurons, which is separate from its neuromuscular effect. [2] Botulinum toxin type A has been observed to have an effect on sensory neurons, with treatment of rat trigeminal ganglia cultures resulting in decreased calcitonin gene related peptide. [3] Botulinum toxin has been found to block the release of glutame and also Fos., a product of the immediate early gene c Fos, expressed with neuronal stimuli, was prevented with peripheral exposure to botulinum A.[2] Enzymatic blockade of neurotransmitter release is believed to occur in both motor and sensory nerves [2] and to be responsible for the antinociceptive effect.It has also been found to relieve pain in non-neurologic conditions such as refractory plantar fasciitis. [4] The beneficial effect in all patients, even those with intractable trigeminal neuralgia following surgical treatments, would indicate a strong effect and would reduce the need for a placebo-controlled clinical trial to confirm the findings. Such trials are usually necessary when there is doubt about the effectiveness of treatment. However, if the treatment is effective, there would not be as much need for a placebo-controlled trial. Further studies determining dose, duration of treatment and whether treatments need to be repeated would avoid the need for patients to go through placebo treatments in a placebo-controlled trial for a potentially serious and often painful condition. References 1. Piovesan E, Teive H, Kowacs, et al. An open study of botulinum-A toxin treatment of trigeminal neuralgia. Neurology: 2005; 65:1306-1308. 2. Aoki K, Evidence for antinociceptive activity of botulinum toxin type A in pain management. Headache. 2001; 43 Suppl 1:S9-15. 3. Durham P, Cady R, Cady R. Regulation of calcitonin gener-related peptide secrtion from trigeminal nerve cells by botulinum toxin type A: implications for migraine therapy. Headache. 2004; 44:35-42. 4. Babcock M, Foster L, Pasquina P et al, Treatmetn of pain attributed to plantar fasciitis with botulinum toxin a: a short-term, randomized, placebo-controlled, double blind study. Am J Phys Med Rehabil. 2005; 84: 649-654. The author reports no conflicts of interest.