Therapie mit Botulinumtoxin: Was ist außerhalb der Zulassung gesichert?

Zusammenfassung

Botulinumtoxin (Btx) hat sich in den zugelassenen Behandlungen wie den Dystonien und der spastischen Parese in der Neurologie längst etabliert. Dennoch gibt es bei beiden Erkrankungen auch eine Vielzahl von Off-Label-Indikationen, wie der Schreibkrampf oder Musikerdystonien und die Spastik der unteren Extremität, die mit Btx gut zu behandeln sind. Anders ist die Lage bei den Kopfschmerzen. Hier konnte für die Behandlung des Spannungskopfschmerzes und der Migräne in doppelblind-randomisierten Studien kein positiver Effekt im Vergleich zu Plazebo nachgewiesen werden. Beim täglichen chronischen Kopfschmerz bleibt die Entwicklung abzuwarten. Für den Einsatz von Btx bei Störungen des vegetativen Nervensystems haben sich viele Indikationen ergeben, die im Vergleich zu anderen Therapieverfahren häufig eine nicht invasive und nebenwirkungsarme Therapieoption darstellen. So können die Achalasie, Analfissuren und die Hypersalivation effektiv und schonend mit Btx behandelt werden. Weiterhin hat Btx die Behandlung von neurogenen Blasenstörungen erheblich erweitert. Zusammengefasst lässt sich festhalten, dass Btx auch in den meisten Indikationen des Off-Label-Gebrauchs in der Hand des Experten eine sichere und effektive Therapie darstellt, für die weitere Zulassungen notwendig sind. Dazu sind weitere hoch qualitative Plazebo- und Vergleichsstudien erforderlich.

Abstract

Botulinum toxin (Btx) has become the therapy of first-line in focal dystonia and focal spasticity. However, besides the approved therapeutic options, many indications in off-label use exist. It has been shown that for e. g. writer's cramp, musician's dystonia and spasticity of the lower extremities Btx is effective and safe. In contrast, Btx failed to show a reduction of headache attacks in tension-type headache and migraine. For chronic daily headache, a new entity of the headache classification, there is a possible effect. A lot of indications are arising for disorders of the autonomic nervous system, like achalasia, chronic anal fissure, hypersalivation and disorders of the lower unrinary tract. In these disorders Btx seems to be an alternative option with less-side effects compared to surgical procedures. In conclusion, it can be stated that in the hand of the expert, Btx is also safe and effective in many off-label indications. However, there is a need for further approvals and placebo-controlled trials in many neurological and non-neurological disorders.

Literatur

• 1 Brans J W, Lindeboom R, Snoek J W. et al . Botulinum toxin versus trihexyphenidyl in cervical dystonia: a prospective, randomized, double-blind controlled trial.  Neurology. 1996;  46 1066-1072
• 2 Bressman S B, Greene P E. Dystonia.  Curr Treat Options Neurol. 2000;  2 275-285
• 3 Ceballos-Baumann A O. Evidence-based medicine in botulinum toxin therapy for cervical dystonia.  J Neurol. 2001;  248, Suppl 1 14-20
• 4 Jost W H, Kohl A. Botulinum toxin: evidence-based medicine criteria in blepharospasm and hemifacial spasm.  J Neurol. 2001;  248, Suppl 1 21-24
• 5 Paiva A de, Meunier F A, Molgo J. et al . Functional repair of motor endplates after botulinum neurotoxin type A poisoning: biphasic switch of synaptic activity between nerve sprouts and their parent terminals.  Proc Natl Acad Sci U S A. 1999;  96 3200-3205
• 6 Naumann M, Moore A P. Long-term safety of botulinum toxin type A.  Mov Disord. 2003;  18 1080-1081
• 7 Olney R K, Aminoff M J, Gelb D J. et al . Neuromuscular effects distant from the site of botulinum neurotoxin injection.  Neurology. 1988;  38 1780-1783
• 8 Lange D J, Rubin M, Greene P E. et al . Distant effects of locally injected botulinum toxin: a double-blind study of single fiber EMG changes.  Muscle Nerve. 1991;  14 672-675
• 9 Garner C G, Straube A, Witt T N. et al . Time course of distant effects of local injections of botulinum toxin.  Mov Disord. 1993;  8 33-37
• 10 Jankovic J, Brin M F. Therapeutic uses of botulinum toxin.  N Engl J Med. 1991;  324 1186-1194
• 11 LeWitt P A, Trosch R M. Idiosyncratic adverse reactions to intramuscular botulinum toxin type A injection.  Mov Disord. 1997;  12 1064-1067
• 12 Li M, Goldberger B A, Hopkins C. Fatal case of BOTOX-related anaphylaxis?.  J Forensic Sci. 2005;  50 169-172
• 13 Kessler K R, Skutta M, Benecke R. Long-term treatment of cervical dystonia with botulinum toxin A: efficacy, safety, and antibody frequency. German Dystonia Study Group.  J Neurol. 1999;  246 265-274
• 14 Borodic G E, Duane D, Pearce C. et al . Antibodies to botulinum toxin.  Neurology. 1995;  45 204
• 15 Comella C L, Jankovic J, Daggett S. et al .Interim results of an observational study of neutralizing antibody formation with the current preparation of botulinum toxin type A treatment for cervical dystonia. 56^th Annual Meeting. American Academy of Neurology 2004
• 16 Dressler D, Bigalke H. Botulinum toxin type B de novo therapy of cervical dystonia Frequency of antibody induced therapy failure.  J Neurol. 2005;  252 904-907
• 17 Perfetto E M, Morris L S. Agency for Health Care Policy and Research clinical practice guidelines.  Ann Pharmacother. 1996;  30 1117-1121
• 18 Comella C L, Shannon K M, Jaglin J. Extensor truncal dystonia: successful treatment with botulinum toxin injections.  Mov Disord. 1998;  13 552-555
• 19 Burlina A P, Zara G, Hoffmann G F. et al . Management of movement disorders in glutaryl-CoA dehydrogenase deficiency: anticholinergic drugs and botulinum toxin as additional therapeutic options.  J Inherit Metab Dis. 2004;  27 911-915
• 20 Balash Y, Giladi N. Efficacy of pharmacological treatment of dystonia: evidence-based review including meta-analysis of the effect of botulinum toxin and other cure options.  Eur J Neurol. 2004;  11 361-370
• 21 Azher S N, Jankovic J. Camptocormia: pathogenesis, classification, and response to therapy.  Neurology. 2005;  65 355-359
• 22 Tsui J K, Bhatt M, Calne S. et al . Botulinum toxin in the treatment of writer's cramp: a double-blind study.  Neurology. 1993;  43 183-185
• 23 Yoshimura D M, Aminoff M J, Olney R K. Botulinum toxin therapy for limb dystonias.  Neurology. 1992;  42 627-630
• 24 Cole R, Hallett M, Cohen L G. Double-blind trial of botulinum toxin for treatment of focal hand dystonia.  Mov Disord. 1995;  10 466-471
• 25 Marion M, Afors K, Sheehy M. Problems of treating writer's cramp with botulinum toxin injections: result from 10 years experience.  Rev Neurol (Paris). 2003;  159 923-927
• 26 Schuele S, Jabusch H C, Ledermann R J. et al . Botulinum toxin injections in the treatment of musician's dystonia.  Neurology. 2005;  64 341-343
• 27 Blitzer A, Brin M F, Fahn S. et al . Botulinum toxin (BOTOX) for the treatment of „spastic dysphonia” as part of a trial of toxin injections for the treatment of other cranial dystonias.  Laryngoscope. 1986;  96 1300-1301
• 28 Sulica L, Verheyden J, Blitzer A. The larynx and pharynx. In: Moore AP, Naumann M (eds) Handbook of Botulinum Toxin Treatment. Malden, USA; Blackwell Science 2004: 142-157
• 29 Troung D D, Rontal M, Rolnick M. et al . Double-blind controlled study of botulinum toxin in adductor spasmodic dysphonia.  Laryngoscope. 1991;  101 630-634
• 30 Blitzer A, Brin M F, Stewart C F. Botulinum toxin management of spasmodic dysphonia (laryngeal dystonia): a 12-year experience in more than 900 patients.  Laryngoscope. 1998;  108 1435-1441
• 31 Adler C H, Bansberg S F, Hentz J G. et al . Botulinum toxin type A for treating voice tremor.  Arch Neurol. 2004;  61 1416-1420
• 32 Nash M C, Ferell R B, Lombardo M A. et al . Treatment of bruxism in Huntington's disease with botulinum toxin.  J Neuropsychiatry Clin Neurosci. 2004;  16 381-382
• 33 Tan E K, Chan L L, Chang H M. Severe bruxism following basal ganglia infarcts: insights into pathophysiology.  J Neurol Sci. 2004;  217 229-232
• 34 Tan E K, Jankovic J. Treating severe bruxism with botulinum toxin.  J Am Dent Assoc. 2000;  131 211-216
• 35 Brin M F, Lyons K E, Doucette J. et al . A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor.  Neurology. 2001;  56 1523-1528
• 36 Dauer W T, Burke R E, Greene P. et al . Current concepts on the clinical features, aetiology and management of idiopathic cervical dystonia.  Brain. 1998;  121 547-560
• 37 Bain P, Gregory R, Hyman N. Treatment of parkinsonian tremor with botulinum toxin: result of a pilot study. London; Presented to dystonia Forum 1994
• 38 Wieler M, Camicioli R, Jones C A. et al . Botulinum toxin injections do not improve freezing of gait in Parkinson disease.  Neurology. 2005;  65 626-628
• 39 Noth J, Dietz V, Ochs G. Spastik. In: Diener H, Putzki N, Berlit P (Hrsg) Leitlinien für Diagnostik und Therapie in der Neurologie. Stuttgart, New York; Thieme 2005: 596-604
• 40 Ward A B, Wissel J, Molteni F. et al . European consensus statement on the use of botulinum toxin type A in the management of adult spasticity.  Acta Neurol Belg. 2003;  103 39
• 41 Snow B J, Tsui J K, Bhatt M H. et al . Treatment of spasticity with botulinum toxin: a double-blind study.  Ann Neurol. 1990;  28 512-515
• 42 Hyman N, Barnes M, Bhakta B. et al . Botulinum toxin (Dysport) treatment of hip adductor spasticity in multiple sclerosis: a prospective, randomised, double blind, placebo controlled, dose ranging study.  J Neurol Neurosurg Psychiatry. 2000;  68 707-712
• 43 Burbaud P, Wiard L, Dubos J L. et al . A randomised, double blind, placebo controlled trial of botulinum toxin in the treatment of spastic foot in hemiparetic patients.  J Neurol Neurosurg Psychiatry. 1996;  61 265-269
• 44 Pittock S J, Moore A P, Hardiman O. et al . A double-blind randomised placebo-controlled evaluation of three doses of botulinum toxin type A (Dysport) in the treatment of spastic equinovarus deformity after stroke.  Cerebrovasc Dis. 2003;  15 289-300
• 45 Mancini F, Sandrini G, Moglia A. et al . A randomised, double-blind, dose-ranging study to evaluate efficacy and safety of three doses of botulinum toxin type A (Botox) for the treatment of spastic foot.  Neurol Sci. 2005;  26 26-31
• 46 Evers S. Botulinum toxin and the management of chronic headaches.  Curr Opin Otolaryngol Head Neck Surg. 2004;  12 197-203
• 47 Göbel H, Lindner V, Krack P. et al . Treatment of chronic tension-type headache with botulinum toxin.  Cephalalgia. 1999;  19 455
• 48 Smuts J A, Baker M K, Smuts H M. et al . Prophylactic treatment of chronic tension-type headache using botulinum toxin A.  Eur J Neurol. 1999;  6, Suppl 4 99-102
• 49 Rollnik J D, Tannenberger O, Schubert M. et al . Treatment of tension-type headache with botulinum toxin type A: a double-blind, placebo-controlled study.  Headache. 2000;  40 300-305
• 50 Burch C, Kokoska M S, Glaser D A. et al . Treatment of frontal tension headaches with botulinum toxin A.  Cephalalgia. 2001;  21 489
• 51 Schmitt W J, Slowey E, Fravi N. et al . Effect of botulinum toxin A injections in the treatment of chronic tension-type headache: a double-blind, placebo-controlled trial.  Headache. 2001;  41 658-664
• 52 Schulte-Mattler W J, Krack P. Treatment of chronic tension-type headache with botulinum toxin A: a randomized, double-blind, placebo-controlled multicenter study.  Pain. 2004;  109 110-114
• 53 Padberg M, Bruijn S F de, Haan R J de. et al . Treatment of chronic tension-type headache with botulinum toxin: a double-blind, placebo-controlled clinical trial.  Cephalalgia. 2004;  24 675-680
• 54 Relja M, Klepac N. Botulinum toxin A as prophylactic treatment in chronic tension-type headache: long-term follow-up study.  Neuology. 2001;  56, Suppl 3 A349-A350
• 55 Silberstein S, Mathew N, Saper J. et al . Botulinum toxin type A as a migraine preventive treatment. For the BOTOX Migraine Clinical Research Group.  Headache. 2000;  40 445-450
• 56 Brin M, Swope D M, O'Brian C. et al . Botox for migraine: double-blind, placebo-controlled, regio-specific evaluation.  Cephalalgia. 2000;  20 421-422
• 57 Schwaag S, Vollmer-Haase J, Rahmann A. et al . Botulinum toxin A in the prophylactic treatment of migraine - a randomised, double-blind, placebo-controlled study.  Cephalalgia. 2003;  23 703
• 58 Behmand R A, Tucker T, Guyuron B. Single-site botulinum toxin type a injection for elimination of migraine trigger points.  Headache. 2003;  43 1085-1089
• 59 Gobel H. Classification of headaches.  Cephalalgia. 2001;  21 770-773
• 60 Bigal M E, Rapoport A M, Tepper S J. et al . The classification of chronic daily headache in adolescents - a comparison between the second edition of the international classification of headache disorders and alternative diagnostic criteria.  Headache. 2005;  45 582-589
• 61 Dodick D W, Mauskop A, Elkind A H. et al . Botulinum toxin type a for the prophylaxis of chronic daily headache: subgroup analysis of patients not receiving other prophylactic medications: a randomized double-blind, placebo-controlled study.  Headache. 2005;  45 315-324
• 62 Foster L, Clapp L, Erickson M. et al . Botulinum toxin A and chronic low back pain: a randomized, double-blind study.  Neurology. 2001;  56 1290-1293
• 63 Difazio M, Jabbari B. A focused review of the use of botulinum toxins for low back pain.  Clin J Pain. 2002;  18, Suppl 6 S155-162
• 64 Schlereth T, Mouka I, Eisenbarth G. et al . Botulinum toxin A (Botox) and sweating-dose efficacy and comparison to other BoNT preparations.  Auton Neurosci. 2005;  117 120-126
• 65 Annese V, Basciani M, Perri F. et al . Controlled trial of botulinum toxin injection versus placebo and pneumatic dilatation in achalasia.  Gastroenterology. 1996;  111 1418-1424
• 66 Vaezi M F, Richter J E, Wilcox C M. et al . Botulinum toxin versus pneumatic dilatation in the treatment of achalasia: a randomised trial.  Gut. 1999;  44 231-239
• 67 Annese V, Bassotti G, Coccia G. et al . A multicentre randomised study of intrasphincteric botulinum toxin in patients with oesophageal achalasia. GISMAD Achalasia Study Group.  Gut. 2000;  46 597-600
• 68 Zaninotto G, Annese V, Constantini M. et al . Randomized controlled trial of botulinum toxin versus laparoscopic heller myotomy for esophageal achalasia.  Ann Surg. 2004;  239 364-370
• 69 Brisinda G, Bentivoglio A R, Maria G. et al . Treatment with botulinum neurotoxin of gastrointestinal smooth muscles and sphincters spasms.  Mov Disord. 2004;  19, Suppl 8 S146-156
• 70 Zaninotto G, Vergadoro V, Annese V. et al . Botulinum toxin injection versus laparoscopic myotomy for the treatment of esophageal achalasia: economic analysis of a randomized trial.  Surg Endosc. 2004;  18 691-695
• 71 Nyam D, Pemberton J H. Long-term results of lateral internal sphincterotomy for chronic anal fissure with particular reference to incidence of fecal incontinence.  Dis Colon Rectum. 1999;  42 1306-1310
• 72 Jost W H, Schimrigk K. Use of botulinum toxin in anal fissure.  Dis Colon Rectum. 1993;  36 974
• 73 Jost W H. One hundred cases of anal fissure treated with botulin toxin: early and long-term results.  Dis Colon Rectum. 1997;  40 1029-1032
• 74 Maria G, Cassetta E, Gui D. et al . A comparison of botulinum toxin and saline for the treatment of chronic anal fissure.  N Engl J Med. 1998;  338 217-220
• 75 Brisinda G, Maria G, Bentivoglio A R. et al . A comparison of injections of botulinum toxin and topical nitroglycerin ointment for the treatment of chronic anal fissure.  N Engl J Med. 1999;  341 65-69
• 76 Minguez M, Melo F, Espi A. et al . Therapeutic effects of different doses of botulinum toxin in chronic anal fissure.  Dis Colon Rectum. 1999;  42 1016-1021
• 77 Fruehauf H, Wegmueller B, Baturfeind P. et al . Therapy of chronic anal fissure: Efficacy and safety of botulinum toxin A injection compared to topical nitroglycerin ointment.  Gastroenterology. 2005;  128, Suppl 2 A50-51
• 78 Arroyo A, Perez F, Serrano P. et al . Surgical versus chemical (botulinum toxin) sphincterotomy for chronic anal fissure: long-term results of a prospective randomized clinical and manometric study.  Am J Surg. 2005;  189 429-434
• 79 Iswariah H, Stephens J, Rieger N. et al . Randomized prospective controlled trial of lateral internal sphincterotomy versus injection of botulinum toxin for the treatment of idiopathic fissure in ano.  ANZ J Surg. 2005;  75 553-555
• 80 Arroyo A, Perez-Vicente F, Miranda E. et al . Manometric factors associated with recurrence in botulinum toxin treatment for chronic anal fissure.  Gastroenterol Hepatol. 2005;  28 311-314
• 81 Lipp A, Trottenberg T, Schink T. et al . A randomized trial of botulinum toxin A for treatment of drooling.  Neurology. 2003;  61 1279-1281
• 82 Mancini F, Zangaglia R, Cristina S. et al . Double-blind, placebo-controlled study to evaluate the efficacy and safety of botulinum toxin type A in the treatment of drooling in parkinsonism.  Mov Disord. 2003;  18 685-688
• 83 Ondo W G, Hunter C, Moore W. A double-blind placebo-controlled trial of botulinum toxin B for sialorrhea in Parkinson's disease.  Neurology. 2004;  62 37-40
• 84 Dykstra D D, Sidi A A, Scott A B. et al . Effects of botulinum A toxin on detrusor-sphincter dyssynergia in spinal cord injury patients.  J Urol. 1988;  139 919-922
• 85 Jost W H, Naumann M. Botulinum toxin in neuro-urological disorders.  Mov Disord. 2004;  19, Suppl 8 S142-145
• 86 Seze M de, Petit H, Gallien P. et al . Botulinum a toxin and detrusor sphincter dyssynergia: a double-blind lidocaine-controlled study in 13 patients with spinal cord disease.  Eur Urol. 2002;  42 56-62
• 87 Schurch B, Seze M de, Denys P. et al . Botulinum toxin type a is a safe and effective treatment for neurogenic urinary incontinence: results of a single treatment, randomized, placebo controlled 6-month study.  J Urol. 2005;  174 196-200