Toxine botulique

Report
Dr Emilie Guettard
Centre de Rééducation Fonctionnelle de Ste Clotilde
Plan
 Historique et mode d’action de la toxine botulique
 L’AMM et les indications en 2011
 Toxine et douleur : revue de la littérature
 Comment la toxine botulique peut-elle diminuer la
perception douloureuse?
Toxine botulique
historique
 1820 Justinus Kerner décrit la maladie
Rapporte la maladie à un poison: la toxine de la saucisse
 1895 Van Ermengem découvre la bactérie qui produit la

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

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toxine après une intoxication dans le village de Ellezelles
1920 H.Sommer purification toxine type A
1946 Lamamanna cristallise la toxine
1973 AB Scott utilise la toxine chez le singe
1977 chez l'homme pour le traitement du strabisme
1984 la FDA donne « l'AMM » à la toxine pour le strabisme
Toxine botulique
 Protéine de 1300 acides
aminés
 Produite par Clostridium
Botulinum
 Bactérie Gram +, anaérobie
 7 sérotypes individualisés de
AàG
 Protéine de 150 Kdaltons
 Deux chaines reliées par un
pont disulfure
Toxine botulique
1. Liaison
Mode d’action
Exocytose
Fibre musculaire
toujours contractile
Toxine botulique
Mode d’action
2. Internalisation
Clivage de la toxine
3
4
5
2
1
Fibre musculaire
toujours contractile
Toxine botulique
Mode d’action
3. Inhibition
S
S
Toxine botulique Mode d’action
4. Repousse axonale
Effet définitif au niveau de la jonction musculaire
cible mais les autres jonctions prennent le relais
Effet clinique réversible
Toxine botulique : à retenir
 La plus puissante des neurotoxines, arme biologique
 Inhibe l’action de l’acétyl-choline
 Injection au plus près de la jonction neuromusculaire
 Action durable mais/et réversible le plus svt en 1 à 6
mois
Et la toxine en pratique quotidienne…
Toxines botuliques
AMM
 Chez adulte et enfant de plus de 12 ans:
 Troubles de l’oculomotricité : strabisme, paralysies oculomotrices
récentes, myopathie thyroidienne récente
 Blépharospasme
 Spasme hémifacial
 Torticolis spasmodique
 Hyperhydrose axillaire
 Récemment indication urologique (détrusor, sphincter)
 Chez adulte et enfant de 2 ans et plus :
 Traitement symptomatique local de la spasticité (tonus
musculaire excessif ) des membres supérieurs et/ ou inférieurs
Qui peut l’utiliser?
« Ce produit est réservé à l’usage hospitalier en
raison de ses caractéristiques : vous ne pouvez en
détenir. Le préparation du produit doit être réalisée
par un personnel expérimenté dans un local approprié.
L’injection doit être réalisée par un médecin ayant une
bonne expérience de l’utilisation de la toxine
botulinique dans les indications prévues par l’AMM. »
Quelles précautions ?
« Des effets indésirables liés à la diffusion de la toxine à
distance du site d’injection ont été rapportés avec des
conséquences pouvant être graves voir fatales dans de
très rares cas. Le risque de survenue de tels effets est
d’autant plus grand que les patients présentent des
troubles de la déglutition…… »
Consentement éclairé
 Possibilité de formation d’anticorps
Respecter un délai entre 2 injections
 4 mois hyperhydrose
 3 mois spasticité
 2 mois autres indications.
Comment injecter ?
 Selon des points moteurs clés (atlas anatomie)
 Avec électrostimulation
 Avec détection EMG
 Sous échographie
 MEOPA : si besoin
 hypnose : pourquoi pas?
Quelle dose injecter ?
 Il existe des abaques avec nbre U/ muscle et nbre
points/muscle
 Pas d’homogénéité U Spywood et UBotox, facteur de
conversion peu clair
 Discussion sur la dilution : proposition de 100 U Botox
dans 2 mL ou 1 mL et 500 U Spywood dans 2,5 mL de
sérum physiologique
Délai et durée d’action ?
 Le plus souvent actif en 10j,
 max d’action à 1 à 2 mois (cs d’évaluation)
 épuisement à +/- 3 mois
Combien ça coûte?
 Botox 100 216.1 euros
Botox 50: 118 euros
 Dysport 500: 259.16 euros
Dysport 300: 186.6 euros
A la Réunion…
 Conservation au frigo avant de reconstituer le produit
 Importance de la chaîne du froid lors du transport
 Partenariat avec laboratoire pharmaceutique
Toxines botuliques
L’expérience en MPR
 Utilisation en routine par les médecins MPR formés
depuis plus de 10 ans
 Utilisation dans le cadre de l’AMM pour toute hypertonie
gênante chez l’enfant et l’adulte
 Nécessité de déterminer des objectifs pour chaque
muscle injecté.
“The patient’s main goals for intervention need to be etablished”
Oliver J and Al, Neurology 2010
 Souvent dans le cadre d’une discussion multidisciplinaire
 Apport de l’échelle GAS (Goal Attainment Scale)
Ex 1 :
Patient de 32 ans, hémiplégie G
post rupture de MAV à 18 mois
d’évolution.
Aucune commande motrice
volontaire sur le poignet et les
doigts
Spasticité des fléchisseurs sup et
pfds des doigts et du pouce.
Pas de limitation orthopédique ou
musculotendineuse
Le patient se plaint d’ avoir
« toujours la main fermée », des
difficultés pour la nettoyer et
couper les ongles, des douleurs
dans la paume et l’avant bras liées
aux contractures.
Obj :
Faciliter ouverture passive de la main pour hygiène
Antalgie
Aspect esthétique?
 Injection des fléchisseurs
superficiels et profonds des
doigts associés au fléchisseur
propre du pouce
Ex 2 :
Patient de 51 ans hémiplégie sévère
post infarctus sylvien à 5 ans
dévolution.
Marche en intérieur avec canne
tripode et orthèse releveur
Spasticité sur le triceps sural (genou
fléchi et tendu) sans limitation de la
dorsiflexion de cheville, pas de
commande sur le tibial antérieur ni
aucun muscle distal
Le patient se plaint d’avoir le « pied
tord », d’une instabilité lorsqu’il
pose le pied au sol avec tendance à
l’entorse en varus, d’une douleur de
la griffe d’orteils et d’un conflit
cutané avec le releveur
Obj :
Faciliter stabilité du pied au sol à la marche
Antalgie sur la griffe d’orteils
Sevrage orthèse ?
 Injection du tibial postérieur,
du triceps sural et des fléchisseurs
courts et longs des orteils
Ex 3 :
Patient de 68 ans, hémiparésie
droite post canal cervical étroit
opéré.
Troubles proprioceptifs du
membre supérieur droit avec
commande volontaire sur tous
les groupes musculaires et bonne
dextérité.
Depuis 1 mois, le patient dit ne
plus utiliser son membre sup
droit pour la vaisselle, la cuisine
car il présente une douleur de
l’épaule.
A l’examen, aucune limitation
des amplitudes, pas de
pathologie de coiffe, note
neurogène à cette douleur DN4 à
3, contracture palpable du petit
rond et du grand rond
Obj :
Antalgie pour secondairement permettre réintégration
du membre supérieur dans les AVQ
 Injection de ces 2 muscles
 Amélioration nette dès J2 avec perte d’effet à 2 mois.
Ajout de Lyrica. Réinjection à 3 mois avec effet encore
meilleur en combinaison
Cas particulier du syndrome épaule main ou
algoneurodystrophie chez l’hémiplégique
 Physiopathologie peu claire
 Etude randomisée contrôlée en double aveugle contre
placébo , 20 patients : injection de 500 u Speywood de
toxine botulique sous stimulation EMG dans le sous
scapulaire
 amélioration de 4 points sur EVA versus 1 gpe contrôle
Yelnik et al JNNP 2007
 Nous l’utilisons le plus souvent pour une hypertonie
fonctionnellement gênante avec objectif secondaire de
diminuer la douleur
 Nous l’utilisons parfois avec pour objectif principal de
diminuer la douleur et pour objectif secondaire
d’améliorer la fonction
1- Céphalées
Ou l’intérêt de lire PUBMED de manière
chronologique….
Headache. 2003 Sep;43(8):853-60.
Botulinum toxin type A as an effective prophylactic treatment in primary
headache disorders.
Blumenfeld A.
OBJECTIVE:
To measure the effect of botulinum toxin type A (Botox, Allergan, Inc, Irvine, CA) treatment in 271 patients diagnosed
with headache in accordance with International Headache Society (IHS) criteria.
BACKGROUND:
Botulinum toxin type A has shown promise for the treatment of headache in several clinical trials, but uncertainty
remains as to how botulinum toxin type A optimally should be used for treating headache and which patients are best
suited for this treatment.
METHODS:
This was a retrospective chart review of all patients who received botulinum toxin type A for the treatment of headache
from January 1999 to February 2002. Patients were injected with an average dose of 63.2 U (SD, 14.5) of botulinum toxin
type A on 2 or more visits, with treatments involving a "fixed-site" or a "follow-the-pain" (or a combination of both)
approach. In the fixed-site approach, botulinum toxin type A was injected into the procerus, corrugator, frontalis, and
temporalis muscles. In the follow-the-pain approach, botulinum toxin type A was injected into a combination of the
procerus, corrugator, frontalis, temporalis, occipitalis, trapezius, and/or semispinalis capitis muscles. The primary
outcomes for the trial were the reduction in headache days per month or headache intensity (0 to 3 scale) (or both)
from baseline. Patients were diagnosed according to IHS criteria and subsequently classified into the following
categories: chronic daily headache (more than 15 headache days per month), episodic tension-type headache, episodic
migraine, and "mixed" HA (less than 15 headache days per month, combination of migraine and tension-type
headache).
RESULTS:
Treatment period was an average of 8.6 months (SD, 6.4); patients received an average of 3.4 doses (SD, 1.6) 3 months
apart. Of the 271 patients, 29 (10.7%) had episodic migraine, 17 (6.3%) had episodic tension-type headache, 71 (26.2%)
had mixed headache, and 154 (56.8%) had chronic daily headache. Two-hundred fifty-six patients had data for the
number of headache days per month, 117 had data for headache intensity, and all 271 had data for headache days or
headache intensity. Botulinum toxin type A treatment significantly reduced the number of headache days per month
from 18.9 (SD, 10.3) to 8.3 (SD, 8.9) (n=256, P<.001)--a 56% reduction. Headache intensity decreased from 2.4 points
(SD, 0.6) to 1.8 points (SD, 0.8) (n=117, P<.001)--a 25% reduction. Of 263 patients surveyed, 225 (85.6%) reported
improvement in headache frequency and intensity. There was no correlation of effect/lack of effect with reason for
treatment, duration/number of treatments, injection technique, mean/total dose, age, gender, or comorbidity.
Approximately 95% of patients did not experience medication side effects.
CONCLUSION:
These results suggest that botulinum toxin type A may be an effective and safe prophylactic treatment for a variety of
moderate to severe chronic headache types.
J.Neurol. 2004 Feb;251 Suppl 1:I8-11.
Botulinum toxin in migraine prophylaxis.
Göbel H.
Migraine is a chronic headache disorder manifesting in attacks lasting 4-72 hours. Characteristics of headache are
unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine physical activity, and
association with nausea, photophobia and phonophobia. The migraine aura is a complex of neurological symptoms,
which occurs just before or at the onset of migraine headache. Botulinum toxin A represents a completely new option
for patients with chronic pain conditions. Numerous retrospective open-label chart reviews and 4 double-blind,
placebo-controlled studies have demonstrated that botulinum toxin type A is significantly effective in migraine
prophylaxis and reduces the frequency, severity, and disability associated with migraine headaches.
Studies have generally reported a good and consistent efficacy. The differential therapeutic use of botulinum toxin
appears to be worth attempting in migraine patients with the following characteristic features:
1) Muscular stress as migraine trigger, e. g., in craniocervical dystonia, pericranial painful muscular trigger points or
tender points, oromandibular dysfunction,
(2) concurrent chronic tension-type headache with the aggravating factors of muscular stress or oromandibular
dysfunction,
(3) chronic migraine with frequent migraine attacks on more than 15 days per month for longer than 3 months and if
other therapeutic options have been either ineffective or have not been tolerated.
The use of the agent does not cause CNS side effects. Migraine patients in particular, often suffer greatly, as a result of
the adverse effects of the drugs used, from fatigue, dizziness, reduced concentration, loss of appetite, weight gain, hair
loss and changes in libido. These side effects are not known in association with botulinum toxin A. To date, neither
organic damage nor allergic complications have been reported. Thus, both the tolerability and the safety of this
therapeutic measure are high. The mode of action by which botulinum toxin is effective in migraine prophylaxis is not
fully understood and is under investigation. Currently, a number of other randomized, placebo-controlled, clinical
trials are being conducted to evaluate the efficacy, optimal dosing, and side-effect profile of botulinum toxin type A in
the prophylaxis of migraine and other headache entities.
Headache. 2005 Apr;45(4):315-24.
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.
Dodick DW, Mauskop A, Elkind AH, DeGryse R, Brin MF, Silberstein SD; BOTOX
CDH Study Group.
OBJECTIVE:
To assess the efficacy and safety of botulinum toxin type A (BoNT-A; BOTOX, Allergan, Inc., Irvine, CA) for the prophylaxis
of headaches in patients with chronic daily headache (CDH) without the confounding factor of concurrent prophylactic
medications.
BACKGROUND:
Several open-label studies and an 11-month, randomized, double-blind, placebo-controlled study suggest that BoNT-A may be
an effective therapy for the prophylaxis of headaches in patients with CDH.
DESIGN AND METHODS: site d’injection? Dose?
This was a subgroup analysis of an 11-month, randomized double-blind, placebo-controlled study of BoNT-A for the
treatment of adult patients with 16 or more headache days per 30-day periods conducted at 13 North American study centers.
All patients had a history of migraine or probable migraine. This analysis involved data for patients who were not receiving
concomitant prophylactic headache medication and who constituted 64% of the full study population. Following a 30-day
screening period and a 30-day single-blind, placebo injection, eligible patients were injected with BoNT-A or placebo and
assessed every 30 days for 9 months The following efficacy measures were analyzed per 30-day periods: change from baseline
in number of headache-free days; change from baseline in headache frequency; proportion of patients with at least 30% or at
least 50% decrease from baseline in headache frequency; and change from baseline in mean headache severity. Acute
medication use was assessed, and adverse events were recorded at each study visit.
RESULTS:
Of the 355 patients randomized in the study, 228 (64%) were not taking prophylactic medication and were included in this
analysis (117 received BoNT-A, 111 received placebo injections). Mean age was 42.4+/-10.90 years; the mean frequency of
headaches per 30 days at baseline was 14.1 for the BoNT-A group and 12.9 for the placebo group (P=.205). After two injection
sessions, the maximum change in the mean frequency of headaches per 30 days was -7.8 in the BoNT-A group compared with
only -4.5 in the placebo group (P=.032), a statistically significant between-group difference of 3.3 headaches. The betweengroup difference favoring BoNT-A treatment continued to improve to 4.2 headaches after a third injection session (P=.023). In
addition, BoNT-A treatment at least halved the frequency of baseline headaches in over 50% of patients after three injection
sessions compared to baseline. Statistically significant differences between BoNT-A and placebo were evident for the change
from baseline in headache frequency and headache severity for most time points from day 180 through day 270. Only 5
patients (4 patients receiving BoNT-A treatment; 1 patient receiving placebo) discontinued the study due to adverse events
and most treatment-related events were transient and mild to moderate in severity.
CONCLUSIONS:
BoNT-A is an effective and well-tolerated prophylactic treatment in migraine patients with CDH who are not using other
prophylactic medications.
Headache. 2007 Apr;47(4):486-99.
Botulinum toxin type a prophylactic treatment of episodic migraine: a
randomized, double-blind, placebo-controlled exploratory study.
Aurora SK, Gawel M, Brandes JL, Pokta S, Vandenburgh AM; BOTOX North
American Episodic Migraine Study Group.
OBJECTIVE:
This exploratory trial evaluated the safety and efficacy of multiple treatments of botulinum toxin type A (BoNTA;
BOTOX, Allergan, Inc., Irvine, CA, USA) as prophylactic treatment of episodic migraine headaches.
DESIGN AND METHODS:
This was an 11-month randomized, double-blind, placebo-controlled, exploratory study. Patients were screened during
a 30-day baseline period, and eligible patients with 4 or more migraine episodes and < or =15 headache days entered a
single-blind 30-day placebo run-in period. Patients were classified as placebo nonresponders (PNR) if they had at least
4 moderate-to-severe migraine episodes and did not experience at least a 50% decrease from baseline in the frequency
of migraine episodes following their placebo treatment. All other subjects were classified as placebo responders (PR).
Patients were randomized within each stratum (PNR, PR) to 3 treatments with BoNTA (110 to 260 U of BoNTA per
treatment cycle) or placebo at 90-day intervals using a modified follow-the-pain treatment paradigm. The primary
efficacy outcome measure was the mean change from baseline in the frequency of migraine episodes for the 30 days
prior to day 180 in the PNR group. Secondary efficacy measures included the proportion of patients with a decrease
from baseline of 50% or more migraine episodes per 30-day period. Patients were allowed to take concomitant acute
and prophylactic headache medications. Adverse events were reported.
RESULTS:
A total of 809 patients were screened and 369 patients (89.2% female; mean age, 45 years; range, 20 to 65 years)
entered the placebo run-in period and were subsequently randomized to BoNTA or placebo. The mean total dose of
BoNTA was 190.5 units (U) (range, 110 U to 260 U). The predetermined primary efficacy endpoint was not met.
Substantial mean improvements of 2.4 and 2.2 fewer migraine episodes per month at day 180 in the PNR stratum
treated with BoNTA and placebo, respectively, were observed (P > .999). From day 180 through the end of the study
(day 270) at least 50% of all patients in each treatment group had a decrease from baseline of 50% or more migraine
episodes per 30-day period. However, in the group of patients with > or =12 headache days at baseline (and < or =15
headache days), BoNTA patients experienced a mean change from baseline of -4.0 headache episodes at day 180
compared with -1.9 headache episodes in the placebo group (P= .048). The majority of treatment-related adverse
events were transient and mild to moderate in severity. Only 7 patients (1.9%) discontinued the study due to adverse
events (6 BoNTA, 1 placebo).
CONCLUSION:
There were no statistically significant between-group differences in the mean change from baseline in the frequency of
migraine episodes per 30-day period. There were substantial, sustained improvements during the course of the study in
all groups. Multiple treatments with BoNTA were shown to be safe and well tolerated over an active treatment period
lasting 9 months.
Headache. 2011 Jun;51(6):980-4. doi: 10.1111/j.1526-4610.2011.01915.x.
Botulinum toxin for the treatment of chronic migraine: the placebo effect.
Solomon S.
Botulinum toxin A used to treat headache evokes prominent placebo effects and it is likely that these effects are solely
responsible for its apparent effectiveness.
….la suite???
Ce que j’en ai retenu :
 Indications à préciser, démembrement des céphalées
 Doses et points d’injection mal définis
 Importance de l’effet placébo
Pain Med. 2011 Sep 29. doi: 10.1111/j.1526-4637.2011.01245.x. [Epub ahead of print]
Treatment of Refractory Pain with Botulinum Toxins-An Evidence-Based Review.
Jabbari B, Machado D.
Objectives. To provide updated information on the role of botulinum toxins in the treatment of refractory pain based on
prospective, randomized, double-blind, placebo-controlled studies. Design of the Review. Class I and class II articles
were searched online through PubMed (1966 to the end of January 2011) and OvidSP including ahead-of-print
manuscripts. Results.
Level A evidence (two or more class I studies-established efficacy): pain of cervical dystonia, chronic migraine, and chronic
lateral epicondylitis.
Level B evidence (one class I or two class II studies-probably effective and recommended): post-herpetic neuralgia, posttraumatic neuralgia, pain of plantar fasciitis, piriformis syndrome, and pain in total knee arthroplasty.
Level C evidence (one class II study-possibly effective, may be used at discretion of clinician): allodynia of diabetic
neuropathy, chronic low back pain, painful knee osteoarthritis, anterior knee pain with vastus lateralis imbalance,
pelvic pain, post-operative pain in children with cerebral palsy after adductor hip release surgery, post-operative pain
after mastectomy, and sphincter spasms and pain after hemorrhoidectomy.
Level U evidence (efficacy not proven due to diverse class I and II results): myofascial pain syndrome and chronic daily
headaches. Studies in episodic migraine and tension headaches have shown treatment failure (level A-negative).
Conclusion. Evidence-based data indicate that administration of botulinum toxin in several human conditions can
alleviate refractory pain. The problems with some study designs and toxin dosage are critically reviewed.
2- Lombalgie et syndrome myofascial
.
Clin J Pain. 2006 May;22(4):363-9.
Treatment of chronic low back pain with successive injections of botulinum toxin a over 6
months: a prospective trial of 60 patients.
Ney JP, Difazio M, Sichani A, Monacci W, Foster L, Jabbari B.
OBJECTIVES:
The aim of this study was to evaluate the effects of two successive neurotoxin treatments for chronic
low back pain using multiple pain rating scales in an open-label, prospective study.
METHODS:
Adult patients with chronic low back pain received multiple paraspinal muscle injections with a
maximum dosing of 500 units of botulinum A toxin per session. Those with a beneficial clinical
response received a second treatment at 4 months. Pain was assessed by visual analog scale (VAS),
modified low back pain questionnaire (OLBPQ), and a clinical low back pain questionnaire (CLBPQ)
at baseline, 3 weeks, 2 months, 4 months, and 6 months after the first treatment.
RESULTS:
Eighteen women and 42 men, ages 21 to 79 years (mean 46.6 years), with low back pain of a mean
duration of 9.1 years were included. Significant improvement in back and radicular pain occurred at 3
weeks in 60% and at 2 months in 58% of the cohort. Beneficial clinical response to the first injection
predicted response to reinjection in 94%. A significant minority of patients had a sustained beneficial
effect from the first injection at 4 (16.6%) and 6 months (8.3%). Two patients had a transient flu-like
reaction after the initial treatment.
CONCLUSIONS:
Botulinum toxin A improves refractory chronic low back pain with a low incidence of side effects. The
beneficial clinical response is sustained with a second treatment.
Neurology. 2001 May 22;56(10):1290-3.
Botulinum toxin A and chronic low back pain: a randomized, double-blind study.
Foster L, Clapp L, Erickson M, Jabbari B.
OBJECTIVES:
To investigate the efficacy of botulinum toxin A in chronic low back pain and associated disabilities.
METHODS:
Thirty-one consecutive patients with chronic low back pain who met the inclusion criteria were
studied: 15 received 200 units of botulinum toxin type A, 40 units/site at five lumbar paravertebral
levels on the side of maximum discomfort, and 16 received normal saline. Each patient's baseline level
of pain and degree of disability was documented using the visual analogue scale (VAS) and the
Oswestry Low Back Pain Questionnaire (OLBPQ). The authors reevaluated the patients at 3 and 8
weeks (visual analogue scale) and at 8 weeks (OLBPQ).
RESULTS:
At 3 weeks, 11 of 15 patients who received botulinum toxin (73.3%) had >50% pain relief vs four of 16
(25%) in the saline group (p = 0.012). At 8 weeks, nine of 15 (60%) in the botulinum toxin group and
two of 16 (12.5%) in the saline group had relief (p = 0.009). Repeat OLBPQ at 8 weeks showed
improvement in 10 of 15 (66.7%) in the botulinum toxin group vs three of 16 (18.8%) in the saline
group (p = 0.011). No patient experienced side effects.
CONCLUSION:
Paravertebral administration of botulinum toxin A in patients with chronic low back pain relieved
pain and improved function at 3 and 8 weeks after treatment.
Pain Med. 2011 Sep 29. doi: 10.1111/j.1526-4637.2011.01245.x. [Epub ahead of print]
Treatment of Refractory Pain with Botulinum Toxins-An Evidence-Based
Review.
Jabbari B, Machado D.
Objectives. To provide updated information on the role of botulinum toxins in the treatment of refractory pain based on prospective,
randomized, double-blind, placebo-controlled studies. Design of the Review. Class I and class II articles were searched online through
PubMed (1966 to the end of January 2011) and OvidSP including ahead-of-print manuscripts. Results.
Level A evidence (two or more class I studies-established efficacy): pain of cervical dystonia, chronic migraine, and chronic lateral epicondylitis.
Level B evidence (one class I or two class II studies-probably effective and recommended): post-herpetic neuralgia, post-traumatic neuralgia, pain
of plantar fasciitis, piriformis syndrome, and pain in total knee arthroplasty.
Level C evidence (one class II study-possibly effective, may be used at discretion of clinician): allodynia of diabetic neuropathy, chronic low back
pain, painful knee osteoarthritis, anterior knee pain with vastus lateralis imbalance, pelvic pain, post-operative pain in children with cerebral
palsy after adductor hip release surgery, post-operative pain after mastectomy, and sphincter spasms and pain after hemorrhoidectomy.
Level U evidence (efficacy not proven due to diverse class I and II results): myofascial pain syndrome and chronic daily headaches. Studies in
episodic migraine and tension headaches have shown treatment failure (level A-negative).
Conclusion. Evidence-based data indicate that administration of botulinum toxin in several human conditions can alleviate refractory pain. The
problems with some study designs and toxin dosage are critically reviewed.
Reg Anesth Pain Med. 2010 May-Jun;35(3):255-60.
A double-blind, controlled, randomized trial to evaluate the efficacy of botulinum toxin for the
treatment of lumbar myofascial pain in humans.
De Andrés J, Adsuara VM, Palmisani S, Villanueva V, López-Alarcón MD.
BACKGROUND:
Among all the causes of chronic low back pain, myofascial pain syndrome of the spinal stabilizer muscles is one of the
most frequent, yet underconsidered sources of pain. The purpose of this prospective, randomized, double-blind,
controlled trial was to evaluate the efficacy of type-A botulinum toxin (BTX-A) in relieving myofascial pain in patients
experiencing mechanical low back pain due to bilateral myofascial pain syndrome involving the iliopsoas and/or the
quadratus lumborum muscles.
METHODS:
Each of the 27 enrolled patients received a bilateral, fluoroscopically guided injection in the affected muscle(s) to
randomly deliver BTX-A in one side of the low back and a control drug (randomly constituted by NaCl 0.9% or
bupivacaine 0.25%) in the opposite side. To evaluate the effects of treatment on daily life activities and psychologic
status, 5 different questionnaires were administered (Hospital Anxiety and Depression scale [HAD-A and HAD-D],
Lattinen, Oswestry, and Spielberger State-Trait Anxiety Index).
RESULTS:
BTX-A injection did not significantly reduce visual analog scale scores more than treatment with NaCl or bupivacaine
in the contralateral side; furthermore, the treatments administered did not result in a significant improvement of
patients' daily life activities or psychologic status. Although a trend toward a decrease in postintervention visual analog
scale scores could be recognized in all low back sides, this trend was significant only in the sides treated with BTX-A.
CONCLUSIONS:
BTX-A seems to provide significant postintervention pain relief. However, considering its high cost and the small
differences compared with control treatments, its use should be reserved only for patients with pain refractory to other
invasive treatments.
Clin J Pain. 2006 Jan;22(1):90-6.
The effect of small doses of botulinum toxin a on neck-shoulder myofascial pain syndrome: a
double-blind, randomized, and controlled crossover trial.
Ojala T, Arokoski JP, Partanen J.
OBJECTIVES:
Myofascial pain syndrome is a common cause of muscular pain in the shoulder-neck region. Injections of large
amounts of botulinum toxin A have been found to be beneficial for the alleviation of myofascial pain, but large doses
of this toxin may cause paresis of the muscle and other adverse events. The aim of this work was to determine the effect
of small doses (5 U) of botulinum toxin A (BTA) injected directly into the painful trigger points of the muscles, using a
double-blind crossover technique.
METHODS:
On the basis of the empirical criteria proposed for diagnosis of myofascial pain syndrome, 31 patients suffering from
myofascial pain in the neck-shoulder region were studied. The patients received either botulinum toxin A or
physiological saline injections on 2 occasions 4 weeks apart. The total dose varied from 15 to 35 U of botulinum toxin A
[28+/- 6 U (mean+/- SD)]. The follow-up measurements were carried out at 4 weeks after each treatment. Neck pain
and result of treatment were assessed with questionnaires. The pressure pain threshold was determined using a
dolorimeter.
RESULTS:
Neck pain values decreased from 4.3+/- 2.4 to 3.3+/- 2.0 after saline injections and from 4.1+/- 2.1 to 3.3+/- 2.2 after
botulinum toxin A. The pressure pain threshold values increased from 5.2+/-1.6 to 5.9+/-1.5 and from 5.7+/-1.6 to 5.9+/1.6 after injections with saline and botulinum toxin A, respectively. No statistically significant changes in the neck pain
and pressure pain threshold values occurred between the botulinum toxin A and saline groups. After the first
injections, the subjective result of treatment was significantly (P=0.008) in favor of botulinum toxin A, and after the
second injections, the subjective result was better for saline, but the difference was not statistically significant
(P=0.098). There was no significant difference in the prevalence of side effects between saline and botulinum toxin A.
CONCLUSIONS:
Our study shows that there was no difference between the effect of small doses of botulinum toxin A and those of
physiological saline in the treatment of myofascial pain syndrome.
Anesthesiology. 2005 Aug;103(2):377-83.
Evidence against trigger point injection technique for the treatment of cervicothoracic
myofascial pain with botulinum toxin type A.
Ferrante FM, Bearn L, Rothrock R, King L.
BACKGROUND:
Traditional strategies for myofascial pain relief provide transient, incomplete, variable, or
unpredictable outcomes. Botulinum toxin is itself an analgesic but can also cause sustained muscular
relaxation, thereby possibly affording even greater relief than traditional therapies.
METHODS:
The study goal was to determine whether direct injection of botulinum toxin type A (BoNT-A) into
trigger points was efficacious for cervicothoracic myofascial pain, and if so, to determine the presence
or absence of a dose-response relation. One hundred thirty-two patients with cervical or shoulder
myofascial pain or both and active trigger points were enrolled in a 12-week, randomized, doubleblind, placebo-controlled trial. After a 2-week washout period for all medications, patients were
injected with either saline or 10, 25, or 50 U BoNT-A into up to five active trigger points. The
maximum doses in each experimental group were 0, 50, 125, and 250 U per patient, respectively.
Patients subsequently received myofascial release physical therapy and amitriptyline, ibuprofen, and
propoxyphene-acetaminophen napsylate. Follow-up visits occurred at 1, 2, 4, 6, 8, and 12 weeks.
Outcome measures included visual analog pain scores, pain threshold as measured by pressure
algometry, and rescue dose use of propoxyphene-acetaminophen napsylate.
RESULTS:
No significant differences occurred between placebo and BoNT-A groups with respect to visual analog
pain scores, pressure algometry, and rescue medication.
CONCLUSIONS:
Injection of BoNT-A directly into trigger points did not improve cervicothoracic myofascial pain. The
role of direct injection of trigger points with BoNT-A is discussed in comparison to other injection
methodologies in the potential genesis of pain relief.
Spine (Phila Pa 1976). 1998 Aug 1;23(15):1662-6; discussion 1667.
A randomized, double-blind, prospective pilot study of botulinum toxin injection for refractory,
unilateral, cervicothoracic, paraspinal, myofascial pain syndrome.
Wheeler AH, Goolkasian P, Gretz SS.
STUDY DESIGN:
In a randomized, double-blind study, two dosage strengths of botulinum toxin type A were compared with normal
saline injected into symptomatic trigger points in the cervicothoracic paraspinal muscles.
OBJECTIVES:
To compare the effect of botulinum toxin type A injections with that of normal saline to determine the former's
usefulness in the management of neck pain and disability.
SUMMARY OF BACKGROUND DATA:
The results of several studies have suggested that botulinum toxin type A may reduce pain associated with myofascial
pain syndromes.
METHODS:
Thirty-three participants were divided randomly to receive either 50 or 100 units of botulinum toxin type A, or normal
saline. Patients were re-evaluated over a 4-month period by assessment of their pain and disability and pressure
algometer readings, and then offered a second injection of 100 units of botulinum toxin type A.
RESULTS:
All three groups showed significant treatment effects as measured by a decline in the scores on the Neck Pain and
Disability Visual Analogue Scale and an increase in the pressure algometer scores. Group differences were apparent
only when the authors considered the number of patients who were asymptomatic as a result of the injections.
CONCLUSIONS:
Although no statistically significant benefit of botulinum toxin type A over placebo was demonstrated in this study, the
high incidence of patients who were asymptomatic after a second injection suggests that further research is needed to
determine whether higher dosages and sequential injections in a larger cohort might show a botulinum toxin type A
effect.
Pain Med. 2011 Sep 29. doi: 10.1111/j.1526-4637.2011.01245.x. [Epub ahead of print]
Treatment of Refractory Pain with Botulinum Toxins-An Evidence-Based
Review.
Jabbari B, Machado D.
Objectives. To provide updated information on the role of botulinum toxins in the treatment of refractory pain based on prospective,
randomized, double-blind, placebo-controlled studies. Design of the Review. Class I and class II articles were searched online through
PubMed (1966 to the end of January 2011) and OvidSP including ahead-of-print manuscripts. Results.
Level A evidence (two or more class I studies-established efficacy): pain of cervical dystonia, chronic migraine, and chronic lateral epicondylitis.
Level B evidence (one class I or two class II studies-probably effective and recommended): post-herpetic neuralgia, post-traumatic neuralgia, pain
of plantar fasciitis, piriformis syndrome, and pain in total knee arthroplasty.
Level C evidence (one class II study-possibly effective, may be used at discretion of clinician): allodynia of diabetic neuropathy, chronic low back
pain, painful knee osteoarthritis, anterior knee pain with vastus lateralis imbalance, pelvic pain, post-operative pain in children with cerebral
palsy after adductor hip release surgery, post-operative pain after mastectomy, and sphincter spasms and pain after hemorrhoidectomy.
Level U evidence (efficacy not proven due to diverse class I and II results): myofascial pain syndrome and chronic daily headaches. Studies in
episodic migraine and tension headaches have shown treatment failure (level A-negative).
Conclusion. Evidence-based data indicate that administration of botulinum toxin in several human conditions can alleviate refractory pain. The
problems with some study designs and toxin dosage are critically reviewed.
3- Douleurs neuropathiques
Neurology. 2009 Apr 28;72(17):1473-8. Epub 2009 Feb 25.
Botulinum toxin for diabetic neuropathic pain: a randomized double-blind
crossover trial.
Yuan RY, Sheu JJ, Yu JM, Chen WT, Tseng IJ, Chang HH, Hu CJ.
BACKGROUND:
Diabetic neuropathy is a common complication in diabetes, with patients typically experiencing diverse sensory
symptoms including dysesthesias in the feet and usually accompanied by sleep disturbance. There is still no
comprehensive understanding of the underlying biologic processes responsible for diabetic neuropathic pain. Thus,
the current symptomatic therapy remains unsatisfactory. Recent experimental evidence suggests that botulinum toxin
type A (BoNT/A) may not only inhibit the release of acetylcholine at the neuromuscular junctions, but also modulate
afferent sensory fiber firing, thereby relieving neuropathic pain.
METHODS:
A double-blind crossover trial of intradermal BoNT/A for diabetic neuropathic pain in 18 patients was conducted to
evaluate the effectiveness.
RESULTS:
We find significant reduction in visual analog scale (VAS) of pain by 0.83 +/- 1.11 at 1 week, 2.22 +/- 2.24 at 4 weeks, 2.33
+/- 2.56 at 8 weeks, and 2.53 +/- 2.48 at 12 weeks after injection in the BoNT/A group, as compared to the respective
findings for a placebo group of 0.39 +/- 1.18, -0.11 +/- 2.04, 0.42 +/- 1.62, and 0.53 +/- 1.57 at the same timepoints (p <
0.05). Within the BoNT/A group, 44.4% of the participants experienced a reduction of VAS >/=3 within 3 months after
injection, whereas there was no similar response in the placebo group. At the 4-week postinjection stage, improvement
in sleep quality was measured using the Chinese version of the Pittsburgh Sleep Quality Index.
CONCLUSIONS:
This pilot study found that botulinum toxin type A significantly reduced diabetic neuropathic pain and transiently
improved sleep quality. Further large-scaled study is warranted.
Neuroscience. 2010 Nov 24;171(1):316-28. Epub 2010 Sep 6.
Botulinum neurotoxin type A counteracts neuropathic pain and facilitates
functional recovery after peripheral nerve injury in animal models.
Marinelli S, Luvisetto S, Cobianchi S, Makuch W, Obara I, Mezzaroma E, Caruso M, Straface
E, Przewlocka B, Pavone F.
A growing interest was recently focused on the use of Botulinum neurotoxin serotype A (BoNT/A) for
fighting pain. The aim of this study was to investigate the effects of BoNT/A on neuropathic pain. It
was observed that BoNT/A is able to counteract neuropathic pain induced by chronic constriction
injury (CCI) to the sciatic nerve both in mice and in rats. This effect is already present after a single
intraplantar (i.pl.) or intrathecal (i.t.) neurotoxin administration that significantly reduces the sciatic
nerve ligation-induced mechanical allodynia in mice and rats and thermal hyperalgesia in rats. This
effect was evident starting 24 h after the administration of BoNT/A and it was long-lasting, being
present 81 or 25 days after i.pl. injection of the higher dose in mice (15 pg/paw) and rats (75 pg/paw),
respectively, and 35 days after i.t. injection in rats (75 pg/rat). Moreover, BoNT/A-injected mice
showed a quicker recovery of the walking pattern and weight bearing compared to control groups.
The behavioral improvement was accompanied by structural modifications, as revealed by the
expression of cell division cycle 2 (Cdc2) and growth associated protein 43 (GAP-43) regeneration
associated proteins, investigated by immunofluorescence and Western blotting in the sciatic nerve,
and by the immunofluorescence expression of S100β and glial fibrillary acidic protein (GFAP)
Schwann cells proteins. In conclusion, the present research demonstrate long-lasting anti-allodynic
and anti-hyperalgesic effects of BoNT/A in animal models of neuropathic pain together with an
acceleration of regenerative processes in the injured nerve, as evidenced by both behavioral and
immunohistochemistry/blotting analysis. These results may have important implications in the
therapy of neuropathic pain.
Pain Med. 2010 Dec;11(12):1827-33. doi: 10.1111/j.1526-4637.2010.01003.x.
Subcutaneous injection of botulinum toxin a is beneficial in postherpetic neuralgia.
Xiao L, Mackey S, Hui H, Xong D, Zhang Q, Zhang D.
OBJECTIVE:
To assess the benefits of subcutaneous injection of botulinum toxin A (BTX-A) for the treatment of
postherpetic neuralgia (PHN).
DESIGN:
We investigated the therapeutic benefits of BTX-A in subjects with PHN in a randomized, doubleblind, placebo-controlled study. Sixty subjects with PHN were randomly and evenly distributed into
BTX-A, lidocaine, and placebo groups.
MEASURES:
After randomization, one of the following solutions was injected subcutaneously in the affected
dermatome: 5u/mL BTX-A, 0.5% lidocaine, or 0.9% saline (placebo). Visual analog scale (VAS) pain
and sleeping time (hours) were evaluated at the time of pretreatment, day 1, day 7, and 3 months
posttreatment. Opioid usage was calculated at day 7 and 3 months posttreatment.
RESULTS:
Compared with pretreatment, VAS pain scores decreased at day 7 and 3 months posttreatment in all
three groups (P<0.01). However, the VAS pain scores of the BTX-A group decreased more significantly
compared with lidocaine and placebo groups at day 7 and 3 months posttreatment (P<0.01). Sleep
time (hours) had improved at day 7 and at 3 months compared with pretreatment in all three groups,
but the BTX-A group improved more significantly compared with lidocaine and placebo groups
(P<0.01). The percent of subjects using opioids posttreatment in the BTX-A group was the lowest
(21.1%) compared with the lidocaine (52.6%) and placebo (66.7%) groups (P<0.01).
CONCLUSIONS:
Subcutaneous administration of BTX-A significantly decreased pain in PHN and reduced opioid use
compared with lidocaine and placebo at day 7 and 3 months post-treatment. It also increased
subjects' sleep times.
Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2011 Jan;111(1):47-50. Epub 2010 Jul 31.
Use of botulinum toxin A for drug-refractory trigeminal neuralgia: preliminary report.
Bohluli B, Motamedi MH, Bagheri SC, Bayat M, Lassemi E, Navi F, Moharamnejad N.
OBJECTIVE:
Botulinum toxin type A (BTX-A) has been used to treat migraine and occipital neuralgia. We report preliminary results
of an ongoing study that assesses the efficacy of BTX-A on trigeminal neuralgia (TN) patients refractory to medical
treatment.
STUDY DESIGN:
We treated 15 patients (8 men and 7 women) between 28 and 67 years of age who were suffering from drug-refractory
TN from February 2008 to January 2010. Symptoms, including pain duration, provoking factors, affected nerve branch,
frequency of TN attacks, and severity of pain just before injections, were evaluated 1 week, 1 month, and 6 months after
injection. We injected 50 U reconstituted BTX-A solution at the trigger zones. The overall response to treatment was
assessed via a 9-point patient global assessment scale and compared with values at baseline. Statistical analysis was
performed by the analysis of variance (ANOVA) test for frequency of TN attacks, the Friedman test for severity of pain,
and the Wilcoxon signed-rank test for PGA, and all with the use of SPSS software.
RESULTS:
Eight men and 7 women aged 28-67 years (mean 48.9 y) suffering from TN from 6 months to 24 years all improved
regarding frequency and severity of pain attacks; in 7 patients, pain was completely eradicated and there was no need
for further medication. In 5 patients, nonsteroidal antiinflammatory drugs were enough to alleviate pain attacks, and 3
patients again responded to anticonvulsive drugs after injection. All patients developed higher pain thresholds after
injections. The ANOVA test showed a significant difference in frequency of attacks before injection and at 1 week, 1
month, and 6 months after injection (P < .001). Friedman test and pair comparison of pain severity scores with
Bonferroni correction adjustment showed a significant difference (P < .001) between severity of pain before and after
injection. Wilcoxon signed-rank test showed significant improvement in all patients up to 6 months after injection (P
< .001). Complications included transient paresis of the buccal branch of the facial nerve in 3 patients.
CONCLUSION:
This study supports other similar studies and shows that BTX-A is a minimally invasive method that can play a role in
treating TN before other more invasive therapies, i.e., radiofrequency and surgery.
Pain Med. 2011 Sep 29. doi: 10.1111/j.1526-4637.2011.01245.x. [Epub ahead of print]
Treatment of Refractory Pain with Botulinum Toxins-An Evidence-Based
Review.
Jabbari B, Machado D.
Objectives. To provide updated information on the role of botulinum toxins in the treatment of refractory pain based on prospective,
randomized, double-blind, placebo-controlled studies. Design of the Review. Class I and class II articles were searched online through
PubMed (1966 to the end of January 2011) and OvidSP including ahead-of-print manuscripts. Results.
Level A evidence (two or more class I studies-established efficacy): pain of cervical dystonia, chronic migraine, and chronic lateral epicondylitis.
Level B evidence (one class I or two class II studies-probably effective and recommended): post-herpetic neuralgia, post-traumatic neuralgia, pain
of plantar fasciitis, piriformis syndrome, and pain in total knee arthroplasty.
Level C evidence (one class II study-possibly effective, may be used at discretion of clinician): allodynia of diabetic neuropathy, chronic low back
pain, painful knee osteoarthritis, anterior knee pain with vastus lateralis imbalance, pelvic pain, post-operative pain in children with cerebral
palsy after adductor hip release surgery, post-operative pain after mastectomy, and sphincter spasms and pain after hemorrhoidectomy.
Level U evidence (efficacy not proven due to diverse class I and II results): myofascial pain syndrome and chronic daily headaches. Studies in
episodic migraine and tension headaches have shown treatment failure (level A-negative).
Conclusion. Evidence-based data indicate that administration of botulinum toxin in several human conditions can alleviate refractory pain. The
problems with some study designs and toxin dosage are critically reviewed.
Contraction musculaire continue
Lésion des membranes
cellulaires musculaires
Ischémie musculaire
relargage de bradykikines
et autres
neurotransmetteurs
Acidification des tissus
sensitization ou excitation des
nocicepteurs périphériques
Relargage ATP
Liaison aux récepteurs
purinergiques
transmetteurs de signal
nociceptif
Nociception
Pickett Biodrugs 2010
 Probable effet indépendant de la relaxation musculaire
par liaison aux terminaisons nerveuses libres
nociceptives, en bloquant le relargage de substance P
et de Calcitonin gene related peptide (CGRP) contenu
dans les vésicules
 Désensitization au niveau périphérique et médullaire
 Études précliniques chez l’animal
 Expliquerait l’effet clinique antalgique observé
précocément après injection
 Probablement inefficace sur les fibres C et Aδ car pas
d’actions sur les douleurs thermiques
une sensibilisation périphérique conduit à
une sensibilisation centrale
Sécrétion de
Glutamate et Peptides
dans CNS
Stimulation
périphéque
CNS
Voies Funiculaires latérales
Sécrétion de Glutamate et Peptides
Sensibilisation périphérique
expression TRPV1
augmentation des signaux afférents
Activation Additionelle
Sensibilisation
centrale
BoNT-A inhibe la sensibilisation périphérique (direct)
+ la sensibilisation centrale (indirect)
La relevance clinique de ces résultats reste à déterminer complètement
Sécrétion de
Glutamate et
peptides
Stimulation
périphéque
BoNTA
CNS
Voies Funiculaires Latérales
Inhibe:
X
• sécrétion de Glutamate,
Activation Additionelle
cGRP, SubsP
• sensibilisation périphérique
• douleur induite par Formaline1
• expression TRPV1
1. Cui et al., Pain 2004;107:125-33;
Inhibe indirectement:
• Sensibilisation Centrale
• Inhibe c-Fos1
• Expansion des Recepteurs
• Allodynie
BioDrugs. 2010 Jun;24(3):173-82. doi: 10.2165/11534510-000000000-00000.
Re-engineering clostridial neurotoxins for the treatment of chronic
pain: current status and future prospects.
Pickett A.
Source
Biologicals Science and Technology, Ipsen Biopharm Limited, Wrexham, UK. [email protected]
Abstract
Clostridial neurotoxins from the botulinum neurotoxin (BoNT) family are protein complexes, derived
from the bacterium Clostridium botulinum, which potently inhibit acetylcholine release and result in
a reversible blockade of the neuromuscular junction. This feature led to the clinical development of
BoNT-A for a number of neuromuscular disorders. BoNT-A toxins are commercially available as three
different preparations: Dysport/Azzalure, Botox/Vistabel, and Xeomin/Bocouture. Although BoNT-A
preparations have not yet been approved for the treatment of pain, a substantial body of preclinical
and clinical evidence shows that BoNT-A is effective in treating a number of different types of pain. It
is thought to exert an analgesic effect both via muscle-relaxant properties and also directly, via
inhibition of nociceptive neuropeptides. This review explores the mechanistic basis of this analgesic
effect, summarizing current knowledge of the structure-function relationship of BoNT and discussing
effects on both motor and pain neurons. For a complete picture of the analgesic properties of BoNTA, clinical evidence of efficacy in myofascial pain and neuropathic pain is considered in tandem with
a mechanistic rationale for activity. Patients experiencing chronic pain are clear candidates for
treatment with a modified clostridial endopeptidase that would provide enduring inhibition of
neurotransmitter release. A strong preclinical evidence base underpins the concept that reengineering of BoNT could be used to enhance the analgesic potential of this neurotoxin, and it is
hoped that the first clinical studies examining re-engineered BoNT-A will confirm this potential.
Je vous remercie pour votre
attention

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