Functional rehabilitation and analgesia with botulinum toxin A in upper limb complex regional pain syndrome type I: case reports

Abstracts

JUSTIFICATIVA E OBJETIVOS: Freqüentemente, soma-se ao quadro de alodínia e hiperalgesia em pacientes portadores de Síndrome Dolorosa Regional Complexa (SDRC) tipo I a incapacidade funcional do segmento acometido. Relatam-se dois casos de SDRC em que a aplicação de toxina botulínica-A como fármaco coadjuvante contribuiu na recuperação funcional motora do membro acometido. RELATO DOS CASOS: Duas pacientes portadoras de SDRC tipo I foram inicialmente avaliadas para controle da dor no membro superior direito. Ambas apresentavam incapacidade para abrir a mão e dor pela escala analógica numérica (EAN) de 10 em repouso ou quando a mão ou os dedos eram passivamente manipulados. Iniciou-se seqüência de 5 bloqueios, do gânglio estrelado ipsilateral a intervalos semanais, com clonidina e lidocaína. Simultaneamente, durante a realização do terceiro bloqueio do gânglio estrelado, foram administrados 75 UI de toxina botulínica-A nos músculos flexores das falanges e da articulação do punho. Uma semana após a aplicação da toxina botulínica-A, as pacientes apresentavam relaxamento das falanges e punho, relatavam facilidade para execução da fisioterapia passiva e a dor classificada foi como 2 (EAN) à manipulação passiva. Ao término da realização da seqüência de bloqueios do gânglio estrelado, as pacientes foram submetidas a 3 sessões semanais de administração por via venosa regional de clonidina, lidocaína e parecoxib. Após 8 meses de avaliação, as pacientes apresentaram 70% e 80% de recuperação motora e funcional do membro acometido. CONCLUSÕES: A aplicação por via muscular de toxina botulínica A resultou em melhora da movimentação do membro acometido, analgesia auxiliando na sua recuperação funcional.

DOR, Crônica; DROGAS

Functional rehabilitation and analgesia...

CLINICAL REPORT

Functional rehabilitation and analgesia with botulinum toxin A in upper limb complex regional pain syndrome type I. Case reports^*

Rehabilitación funcional y analgesia con uso de toxina botulínica A en el síndrome doloroso regional compleja tipo I del miembro superior. Relato de casos

Gabriela Rocha Lauretti, M.D.^I; Fabrício dos Santos Veloso, M.D.^II; Anita Leocádia de Mattos, TSA, M.D.^III

^IProfessora Associada do Departamento de Biomecânica, Medicina e Reabilitação do Aparelho Locomotor, FMRP USP

^IIPós-Graduando da Disciplina Anestesia, Sub-Especialidade Dor, FMRP USP

^IIIProfessora Doutora do Departamento de Biomecânica, Medicina e Reabilitação do Aparelho Locomotor, FMRP USP

^{Correspondence}

SUMMARY

BACKGROUND AND OBJECTIVES: Functional inability of the affected limb is often added to alodynia and hyperalgesia in Complex Regional Pain Syndrome (CRPS) type I. Two CRPS cases are reported in which botulinum toxin A as coadjuvant drug has contributed to motor and functional recovery of the affected limb.

CASE REPORTS: Two CRPS type I patients were initially evaluated for upper limb pain control. Both were unable to open the hand and referred pain intensity by numeric analog scale (NAS) of 10 at rest or when hand and fingers were passively manipulated. A sequence of 5 weekly ipsilateral stellate ganglion blockade with clonidine and lidocaine was started. Simultaneously, during the third stellate ganglion blockade, 75 Ul botulinum toxin A was administered to flexor muscles of phalanges and wrist joint. One week after botulin toxin A administration patients presented phalanges and wrist relaxation, reported easy passive physical therapy and pain was classified as 2 (NAS) at passive manipulation. At stellate ganglion blockade sequence completion patients were submitted to 3 weekly regional intravenous clonidine, lidocaine and parecoxib. At 8 months evaluation patients presented 70% and 80% motor and functional recovery of the affected limb.

CONCLUSIONS: Muscular botulin toxin A has resulted in movement improvement of the affected limb and analgesia, favoring functional recovery.

Key words: DRUGS: botulinum toxin A; PAIN, Chronic: complex regional pain syndrome type I

RESUMEN

JUSTIFICATIVA Y OBJETIVOS: Frecuentemente, se suman al cuadro de alodínia e hiperalgesia en pacientes portadores de Síndrome Doloroso Regional Complejo (SDRC) tipo I la incapacidad funcional del segmento acometido. Se relatan dos casos de SDRC donde la aplicación de toxina botulínica-A como fármaco coadyuvante contribuyó en la recuperación funcional motora del miembro acometido.

RELATO DE LOS CASOS: Dos pacientes portadoras de SDRC tipo I fueron inicialmente evaluadas para control del dolor en miembro superior derecho. Ambas presentaban incapacidad para abrir la mano y dolor por la escala analógica numérica (EAN) de 10 en reposo o cuando la mano o los dedos eran pasivamente manejados. Se inició secuencia de 5 bloqueos, del ganglio estrellado ipsilateral a intervalos semanales, con clonidina y lidocaína. Simultáneamente, durante la realización del tercer bloqueo del ganglio estrellado, fue administrado 75 UI de toxina botulínica A en los músculos flexores de las falanges y de la articulación del puño. Una semana después de aplicación de la toxina botulínica A, las pacientes presentaban relajamiento de las falanges y del puño, relataban facilidad para la ejecución de la fisioterapia pasiva y el dolor clasificado fue como 2 (EAN) a la manipulación pasiva. Al término de la realización de la secuencia de bloqueos del ganglio estrellado, las pacientes fueron sometidas a 3 sesiones semanales de administración por vía venosa regional de clonidina, lidocaína y parecoxib. Después de 8 meses de evaluación las pacientes presentaron 70% y 80% de recuperación motora y funcional del miembro acometido.

CONCLUSIONES: La aplicación por vía muscular de toxina botulínica A resultó en mejora del movimiento del miembro acometido, analgesia auxiliando en su recuperación funcional.

INTRODUCTION

Complex Regional Pain Syndrome (CRPS) patients develop refractory pain associated to edema, vasomotor instability, joint stiffness, skin injuries and acute bone atrophy ^1,2. In general, changes in blood flow and regional sudoresis, dyscrasic phenomena, changes in active movement pattern of affected segments, including marked physiological shivering, trophic tegument, muscle and subcutaneous changes and functional incapacity of the affected limb are added to allodynia and hyperalgesia ^3. It is admitted that part of these changes is directly or indirectly related to functional or anatomic abnormalities of peripheral and central nervous system, sympathetic nervous system and hypoactivity of pain suppressing system ^3-5. In some patients, these symptoms may be partially ^6,7 relieved after intravenous regional block with clonidine, lidocaine and parecoxib ⁸; or with intravenous regional keterolac and lidocaine ⁹.

We report below the efficacy of botulinum toxin A as coadjuvant in the functional recovery of CRPS type I patients with motor functional incapacity (subtype 3) ³.

CASE REPORTS

Two female patients (38 and 42 years old); mulatto and black, respectively, with CRPS type I, who were initially evaluated in the Pain Treatment Clinic - Hospital das Clínicas - Faculdade de Medicina, Ribeirão Preto - Universidade de São Paulo, for pain control in right upper limb after orthopedic surgery (carpal tunnel). Both presented with allodynia and hyperalgesia, changes in regional sudoresis and temperature, marked physiological shivering, trophic changes in tegument, muscles and subcutaneous tissue, in addition to functional incapacity of the affected segment.

Patients presented increased tone of phalanges and wrist flexor muscles, resulting in inability to open the hand. Pain according to numeric analog scale (NAS) was classified as 10 (scale from 0 to 10), that is, the worst possible pain, at rest or when hand or fingers were passively manipulated. Patients were under postoperative physical therapy for 3.5 years, three times a week, without recovery of the affected limb. In addition, there was pain described as "burning", irradiated to the ipsilateral shoulder. Patients were being treated with daily oral 75 mg amitriptyline, at 10 p.m.

A sequence of ipsilateral stellate ganglion blocks was started with 30 µg clonidine associated to 70 mg lidocaine (final volume = 7 mL). Five weekly stellate ganglion blocks were performed in each patient. Immediately after each block, there has been increased affected limb temperature and pain relief (NAS 2 and 3, respectively). At the end of the second week patients classified pain at rest as 5 and 6 (NAS), however as 10 when phalanges or wrist were passively moved. Simultaneously, during the third stellate ganglion block, a total of 75 Ul muscular botulinum toxin, prepared according to manufacturer's guidance, was equitably administered to affected phalanges flexor muscles and wrist joint of each patient.

One week after botulinum toxin A administration, patients presented phalanges and wrist relaxation, reported easy passive physical therapy and pain was classified as 2 (NAS) at passive manipulation. After the sequence of stellate ganglion blocks, both patients were submitted to 3 weekly regional intravenous block of the affected limb.

The technique consisted of intravenous puncture of the affected limb followed by blood pressure cuff inflated to 7 to 8 mmHg above previously evaluated mean blood pressure. Immediately after cuff inflation, bolus 30 µg clonidine + 5 mg parecoxib + 70 mg lidocaine (final volume = 10 mL) was injected. Cuff was maintained inflated for 5 minutes at the pressure established for each patient, being then gradually deflated in 2 to 3 minutes.

Another venous puncture was achieved in contralateral limb with 20G catheter, which was maintained throughout the procedure. Venous punctures were removed when patients referred feeling well and were hemodynamically stable considering blood pressure and pulse, the respiratory rate was also evaluated. One patient received 60 Ul muscular botulinum toxin distributed through phalanges and wrist muscles in the fifth evaluation week. At 8 months evaluation, patients presented 70% and 80% motor and functional recovery of the affected limb. Patients remained under passive and then active physical therapy and were able to reintegrate to their routine tasks.

DISCUSSION

CRPS pathophysiology is still not totally understood. A relevant fact is the change in clinical expression, observed in many patients throughout the evolution of the disease, suggesting cerebral cortex reorganization contralateral to the affected limb ⁵. Scintigraphy of the affected limb has revealed vascular overflow of macromolecules during acute CRPS type I phase, favoring the hypothesis of inflammatory phenomenon ^6,7. A clinical study with MRI and 31P spectroscopy has shown decrease in high-energy phosphate metabolism of affected muscles, resulting in possible hypoxia by O₂ extraction impairment, being this phenomenon classically observed in inflamed tissues ^10,11. However, blood gases analysis was not useful for tissue oxygen saturation and lactate concentration analysis ¹².

Another important aspect of CRPS pathophysiology seems to be the expression of inflammation-induced cycloxygenase-2 and NSAIDs analgesic effects ¹³. Different local factors could be present, such as P substance release, which would promote protein leakage contributing to local edema ¹⁴, and exaggerated response to a₁-adrenergic peripheral receptors ¹⁵.

The association of sympathetic blocks ^6,7, regional venous blocks ^8,9 and physical therapy ¹⁶ helps CRPS type I patients by favoring pain relief (according to analgesic effect evaluation criteria through numerical NAS decrease of at least 3 cm or 50% of pain intensity) ¹⁰. However, pain relief should ideally be followed by motor function improvement since many patients start specialized treatment in the presence of major and limiting motor dysfunction of the affected limb.

In the past, CRPS type I, subtype 3 patients (with apparent motor involvement) ³ were unable to open the hand and this would even lead to hand amputation due to the difficulty in cutting nails and to palmar infection. For those patients, therapy associated to botulin toxin-A was effective, resulting in muscle relaxation, hand opening, improved physical therapy effects and partial functional recovery of the limb, with decreased incidence of palmar infection.

The reason for functional rehabilitation of one out of four patients using botulin toxin ¹⁷ as compared to both patients using it and described in this article is probably adjuvant therapies, such as regional venous blocks and stellate ganglion blocks in our cases. Literature reports on botulin toxin as coadjuvant for functional rehabilitation are preliminary, however encouraging ^17,18.

Classically, botulin toxin acts on the synaptic terminal blocking acetylcholine release through the binding to specific receptor on neuronal membrane, being then transported to inside the cell and stored in an endosomal compartment through pH-dependent translocation ¹⁹. Once inside the cytoplasm, type-A serum cleaves SNAP-25 protein, which is necessary for endosomal vesicle function.

SNAP-25 proteolysis is exacerbated by membrane depolarization secondary to K⁺ in the presence of Ca^{++ 19}. Locally, there would be decreased excitability of gamma moto-neuronal terminals and possible migration for neighbor or remote muscles ²⁰. However, in addition to local action, there are evidences suggesting botulin toxin action on the CNS. After peripheral application, it would reach spinal cord anterior horn through retrograde axonal transportation ²⁰ where it would act on central synapses inhibiting Renshaw's cell and exacerbating peripheral muscle relaxation effect of gamma moto-neuron ²⁰.

In terms of analgesic effect, botulin toxin seems to locally decrease the production of nociceptor sensitizers such as P substance ^21,22, in addition to blocking local autonomic pathways, resulting in analgesic effect through peripheral action ²², or by acting on muscle tone ²³. The inhibition of central neurotransmitter glutamate release and the prevention of Fos production, an immediate c-Fos gene product, would result in decreased central sensitization ²⁴.

In conclusion, botulin toxin associated to stellate ganglion and regional venous blocks in CRPS type I patients with major motor and functional involvement of the limb (subtype 3) ³, has resulted in improved movement, analgesia and functional recovery of the affected limb, helping physical therapy and could help patients reintegrate to their routine tasks.

REFERENCES

Submitted for publication July 12, 2004

Accepted for publication December 21, 2004

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Correspondence to

Dra. Gabriela Rocha Lauretti

Address: Rua Campos Sales, 330/44

ZIP: 14015-110 City: Ribeirão Preto, Brazil

^*

Received from Centro de Tratamento da Dor, Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo (HC FMRP USP), Ribeirão Preto, SP

Publication Dates

• Publication in this collection
  01 June 2005
• Date of issue
  Apr 2005

History

• Received
  12 July 2004
• Accepted
  21 Dec 2004