Toxina Botulínica no Tratamento da Dor*

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<ul><li><p>366 Revista Brasileira de AnestesiologiaVol. 59, No 3, Maio-Junho, 2009</p><p>Rev Bras Anestesiol ARTIGO DE REVISO2009; 59: 3: 366-381 REVIEW ARTICLE</p><p>RESUMO:Colhado OCG, Boeing M, Ortega LB - Toxina Botulnica no Tratamentoda Dor.</p><p>JUSTIFICATIVA E OBJETIVOS: A toxina botulnica (TxB), uma dasmais potentes toxinas bacterianas conhecidas, tem reconhecida-mente ao teraputica eficaz no tratamento de algumas sndromesdolorosas. Entretanto, algumas de suas indicaes ainda esto emfase de comprovao com relao a sua eficcia. O objetivo des-te estudo foi revisar o histrico, propriedades farmacolgicas e apli-caes clinicas da TxB, quando empregada no tratamento de doresde diferentes origens.</p><p>CONTEDO: A TxB o produto da fermentao do ClostridiumBotulinum, uma bactria anaerbia Gram-positiva. Comercialmen-te, as TxB existem nas formas A e B, agentes biolgicos obtidoslaboratorialmente. A TxB, uma neurotoxina que possui alta afini-dade pelas sinapses colinrgicas, ocasiona bloqueio na liberaode acetilcolina pelo terminal nervoso, sem alterar a conduoneural de sinais eltricos ou sntese e armazenamento deacetilcolina. Comprovadamente, a TxB pode enfraquecer seletiva-mente a musculatura dolorosa, interrompendo o ciclo espasmo-dor.Com relao dor, varias publicaes tm demonstrado a efic-cia e segurana da TxB-A no tratamento da cefaleia tipo tenso,migrnea, dor lombar crnica e dor miofascial.</p><p>CONCLUSES: A TxB-A segura e bem tolerada em desordensdolorosas crnicas, onde regimes de farmacoterapia podemsabidamente provocar efeitos colaterais. Outra vantagem a re-duo do uso de analgsicos e o tempo de ao de 3 a 4 mesespor dose. Entretanto pesquisas futuras sero necessrias para seestabelecer a eficcia da TxB-A em desordens dolorosas crnicase seu exato mecanismo no alivio da dor, bem como seu potencialem tratamentos multifatoriais.</p><p>Unitermos: DOR, Crnica; DROGAS: toxina botulnica tipo A.</p><p>SUMMARYColhado OCG, Boeing M, Ortega LB Botulinum toxin in PainTreatment.</p><p>BACKGROOUND AND OBJECTIVES: Botulinum toxin (BTX) isone of the most potent bacterial toxins known and its effectivenessin the treatment of some pain syndromes is well known. However,the efficacy of some of its indications is still in the process of beingconfirmed. The objective of this study was to review the history,pharmacological properties, and clinical applications of BTX in thetreatment of pain of different origins.</p><p>CONTENTS: Botulinum toxin is produced by fermentation ofClostridium botulinum, a Gram-positive, anaerobic bacterium.Commercially, BTX comes in two presentations, types A and B.Botulinum toxin, a neurotoxin with high affinity for cholinergicsynapses, blocks the release of acetylcholine by nerve endingswithout interfering with neuronal conduction of electrical signals orsynthesis and storage of acetylcholine. It has been proven that BTXcan selectively weaken painful muscles, interrupting the spasm-pain cycle. Several studies have demonstrated the efficacy andsafety of BTX-A in the treatment of tension headaches, migraines,chronic lumbar pain, and myofascial pain.</p><p>CONCLUSIONS: Botulinum toxin type A is well tolerated in thetreatment of chronic pain disorders in which pharmacotherapyregimens can cause side effects. The reduction in the consumptionof analgesics and length of action of 3 to 4 months per doserepresent other advantages of its use. However, further studies arenecessary to establish the efficacy of BTX-A in chronic paindisorders and its exact mechanism of action, as well as its potentialin multifactorial treatments.</p><p>Keywords: DRUGS: Botulinum toxin type A; PAIN, chronic.</p><p>INTRODUO</p><p>A histria da toxina botulnica (TxB) tem origem quando em1817 foi publicada primeira descrio do botulismo (ou seja,envenenamento pela TxB). O autor, Justinus Kerner, asso-ciou mortes resultantes de intoxicao com um veneno en-contrado em salsichas defumadas (do latim botulus quesignifica salsicha). Ele concluiu que tal veneno interferia coma excitabilidade do sistema nervoso motor e autonmico.Isto permitiu a publicao de duas monografias descreven-do as caractersticas clnicas do botulismo 1. Kerner propsuma variedade de potenciais usos da TxB na Medicina, prin-cipalmente em desordens de origem no sistema nervosocentral que, atualmente, atravs de novas pesquisas vmsendo comprovadas 2,3.Somente em 1895 que o agente bacteriano, bem como omecanismo de ao responsvel pela toxicidade do botu-</p><p>Toxina Botulnica no Tratamento da Dor*Botulinum Toxin in Pain Treatment</p><p>Orlando Carlos Gomes Colhado1, Marcelo Boeing2, Luciano Bornia Ortega3</p><p>* Recebido da (Received from) Santa Casa de Maring, PR</p><p>1. Doutorando em Cincias Mdicas pela USP de Ribeiro Preto; ProfessorAuxiliar da Faculdade de Medicina da Universidade Estadual de Maring(UEM); Corresponsvel pela residncia mdica em anestesiologia do Hospi-tal Universitrio da UEM2. Anestesiologista da Santa Casa de Maring3. Mdico Residente da Santa Casa de Maring</p><p>Apresentado (Submitted) em 12 de maio de 2008Aceito (Accepted) para publicao em 9 de fevereiro de 2009</p><p>Endereo para correspondncia (Correspondence to):Dr. Orlando C. G. ColhadoRua Marechal Deodoro 682/6187030-020 Maring ParanE-mail: esperanssoli@uol.com.br</p></li><li><p>Revista Brasileira de Anestesiologia 373Vol. 59, No 3, Maio-Junho, 2009</p><p>BOTULINUM TOXIN IN PAIN TREATMENT</p><p>serotonina e prostaglandinas, que podem alterar ou sensi-bilizar a transmisso neuronal e criar estado temporrio dedor neuroptica. Diferentemente, a dor neuroptica crnicaresulta da leso do sistema nervoso perifrico ou central erepresenta anormalidade na transmisso nervosa que sedesenvolveu em decorrncia da leso.Pacientes com sndrome complexa de dor regional tipo I(SCDR I), frequentemente sofrem de dor miofascial emmsculos prximos do membro afetado mostrando que di-ferentes tipos de dor podem coexistir no mesmo paciente 31.Pacientes com sndrome dolorosa miofascial podem apre-sentar sensaes caractersticas da dor neuroptica, comohiperestesia, parestesia, queimao, fisgada e alodnea.Disfuno autonmica tambm tem sido observada nospontos gatilhos e distalmente a eles.Em pacientes com sndrome complexa de dor regional tipoI, que concomitantemente apresente sndrome dolorosamiofascial, est demonstrada a importncia do uso da TxB-A em msculos do mesmo lado da leso como em regiesparacervical, suboccipital e periescapular, com doses de300 UI de TxB-A, injetados nos msculos esternocleidomas-toideo, trapzio, esplnio da cabea (splenio captis), espl-nio do pescoo (splenio cervicis), supra e infraespinhal eromboide. A seleo dos msculos para receber a TxB-A baseada no relato do paciente de dor mxima e na identifi-cao de pontos gatilho no exame fsico. Um total de 25 a50 UI de TxB-A pode ser injetado em cada msculo depen-dendo do seu tamanho 32.Em trabalho apresentado em 2002, um estudo sobre aefetividade da TxB-A no tratamento de dor segmentar emqueimao originada da medula espinhal, dois pacientescom leso medular em regio cervical, que desenvolveramalodnea, hiperestesia e dor espontnea em queimao comdistribuio segmentar, foram tratados com injees subcu-tneas mltiplas (16 a 20) de 5 UI de TxB-A (com dose totalde 100 U), repetidas a cada dois a trs meses por 3 anos.</p><p>O autor concluiu que injees subcutneas de TxB-A podemreduzir os sintomas da dor neuroptica por alterar os me-canismos perifricos da transmisso da dor, tendo comoconsequncia a reduo da sensibilizao central 33. CONCLUSO</p><p>A terapia com TxB-A segura e bem tolerada em desordensdolorosas crnicas, onde regimes de farmacoterapia podemsabidamente provocar efeitos colaterais. O tratamento comTxB-A, inicialmente de alto custo, deveria ser consideradodevido a baixa incidncia de efeitos colaterais e, quandonecessria, internao hospitalar de curto perodo. Outravantagem a reduo de medicamentos adjuvantes e tem-po de ao, com durao de trs a quatro meses por dose,diferentemente do uso contnuo de outras medicaes.Pesquisas futuras sero necessrias para se estabelecera eficcia da TxB-A em desordens dolorosas crnicas e seuexato mecanismo de ao no alvio da dor, bem como seupotencial em tratamentos multifatoriais 34. </p><p>Botulinum Toxin in Pain Treatment</p><p>Orlando Carlos Gomes Colhado, M.D.; Marcelo Boeing, M.D.;Luciano Bornia Ortega, M.D.</p><p>INTRODUCTION</p><p>The history of botulinum toxin (BTX) begins in 1817 when thefirst description of botulism (i.e., BTX poisoning) was pu-blished. The author, Justinus Kerner, associated deathscaused by intoxication with a poison found in smoked sau-sages (from the Latin, botulus means sausage). He con-cluded that poison interfered with the excitability of the motorand autonomous nervous system. This led to the publica-tion of two studies describing the clinical characteristics ofbotulism 1. Kerner proposed several potential medical usesof BTX at the time, especially in disorders of the centralnervous system, which have been supported lately by newstudies 2,3.Only in 1895 the bacterial agent as well as the mechanismof action responsible for the toxicity of botulism were dis-covered; the discovery was attributed to Professor Emile VanErmengen, who published a paper in 1897 2.Botulinum toxin, one of the most potent bacterial toxinsknown, is a result of the fermentation of Clostridium botu-linum, a Gram-negative, spore-forming, anaerobic organismcommonly found in the soil and oceans throughout the world 3.Eight immunologically distinct serotypes have been identified.Of those, seven: A, B, C1, D, E, F, and G are neurotoxins(another BTX, C2, is also produced by C. botulinum, but it isnot a neurotoxin) 4.</p><p>Quadro II - Critrios de Incluso e Excluso na Seleo de</p></li><li><p>374 Revista Brasileira de AnestesiologiaVol. 59, No 3, Maio-Junho, 2009</p><p>COLHADO, BOEING AND ORTEGA</p><p>Although all serotypes inhibit the release of acetylcholine fromnerve endings, their intracellular proteins, mechanisms ofaction, and potencies vary considerably. Type A is the mostextensively studied serotype; however, the number of studieson the effects of the remaining serotypes has been increasing.In 1978, Alan Scott conducted the first tests with BTX-A inhumans for the treatment of strabismus2. Posteriorly, itsindication was extended to segmental dystonias, tremors,and other abnormal movements.Botulinum toxin was first used in the treatment of spasticityin 1989; the results of its use in muscles with severe spasmfor six months in adults with hemiplegia secondary to strokewere published. Neurologists realized the potential of usingBTX in neurologic disorders involving excessive musclecontraction or tonus 5.The International Unit (IU) is used to define the biologicalpotency of all preparations of BTX, in which one IU is theamount of BTX capable of killing (in the laboratory) half of amice population (DL50) 6.</p><p>MECHANISMS OF ACTION</p><p>The active principle of BTX is a protein complex derived fromClostridium botulinum. This protein complex consists of a150,000-Dalton neurotoxin linked non-covalently to non-toxicaccessory proteins that stabilize and protect the pharma-cologically active component, resulting in a final molecularweight that varies from 300,000 to 900,000 Daltons 1,3,4. Thecomposition and total molecular weight of the macromole-cular complex depend on the serotype and species of Clos-tridium botulinum that produced it, as well as on purificationand analysis methods. Commercially, BTX types A and B arebiological agents obtained in laboratory, being stable,crystalline, lyophilized substances associated with humanalbumin, and used after dilution in normal saline (NS) 7.In physiological conditions, it is expected that the complexwill dissociate and release pure neurotoxin since thosecomplexes are stable only in acid pH 4.Botulinum toxin is composed of a light and a heavy proteinchain linked by a disulfide bridge. The heavy chain is res-ponsible for the internalization of BTX into pre-synapticcholinergic terminals. On the other hand, the light chain is azinc endopeptidase responsible for its toxic effects.Ingenious and patient biochemical studies have shown thatthose toxins are highly specific proteases that cleave pre-synaptic SNARE proteins (Soluble NSF Attachment proteinReceptors) involved with the exocytosis process of synapticvesicles in nerve endings. Destruction of those pre-synapticproteins is the basis of the action of those toxins on therelease of neurotransmitters 8.</p><p>EFECTS ON THE RELEASE OF ACETYLCHOLINE</p><p>Botulinum toxin is a neurotoxin with high affinity for choli-nergic synapses, blocking the release of acetylcholine from</p><p>those nerve endings; however, it does not change neuralconduction of electrical signals and/or the syntheses andstorage of acetylcholine 7. The intramuscular injection of BTXin appropriated doses and locations causes partial chemicaldenervation and reduction of muscular contraction withoutcausing complete paralysis. In glandular tissue, it blocks thesecretion.After local intramuscular administration of a selected dilutionof BTX, it deposits rapidly in the interstitial tissue and spe-cifically in the motor neuron terminal of skeletal muscles(neuromuscular junction).Inhibition of the release of acetylcholine by BTX involvesseveral steps. First, BTX binds irreversibly to receptors in thepre-synaptic membrane of the motor nerve ending. Thisbinding specificity guarantees the high selectivity of BTX forcholinergic synapses. Those pre-synaptic receptors areresponsible for the endocytosis of the neurotoxin into themotor nerve ending 7.After internalization the molecule is separated in two poly-peptidic chains by proteases present in the motor nerveending. Cleavage of BTX is considered the decisive step forits activation since as a single 150,000-Dalton chain it haslittle pharmacological activity. Cleaving results in two poly-peptide fragments: a heavy chain with 100,000 Daltons anda light chain with 50,000 Daltons. The percentage of cleavingvaries according to the serotype. Type A shows the higherpercentage of cleaving, usually from 90 to 95%, while type Bshows a smaller percentage (approximately 70%) 3,4.The light chain is translocated through the membrane of theendocytic vesicle into the cytosol showing a high-specificityfor SNARE protein complex. The protein target also variesaccording to the serotype. Playing the role of enzymes, thelight chains of each serotype cleave a distinct peptidic bondin one or more sites of the SNARE proteins in such a waythat none of the serotypes attacks the same location, and,therefore, their actions and potencies vary considerably,although all subtypes present the same final effect: inhibitionof the release of acetylcholine from nerve endings 4.Serotypes A and E cleave SNAP-25 (Synaptosomal-Associa-ted Protein of 25 kDa), serotype C behaves as a protease onsyntaxin; both are SNARE proteins of the pre-synaptic mem-brane. Botulinum toxin types B, D, F, and G cleave specifi-cally VAMP (Vesicle-Associated Membrane Protein), betterknown as synaptobrevin II, a protein located in the synapticvesicle 1,9.Proteolytic cleavage of the SNARE complex by the light chainof BTX prevents the synaptic vesicle from anchoring on theinterna...</p></li></ul>

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