Effects of intra-articular botulinum toxin type A (Botox) in dogs with chronic osteoarthritis
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254 © Schattauer 2010 Clinical Communication
Effects of intra-articular botulinum
toxin type A (Botox®) in dogs with
chronic osteoarthritis
A pilot study
H. S. Hadley1, 2; J. L. Wheeler1; S. W. Petersen1
1Wheat Ridge Veterinary Specialists, Wheat Ridge Animal Hospital, Wheat Ridge, Colorado, USA; 2College of Veterinary
Medicine, Department of Small Animal Clinical Sciences, Michigan State University, East Lansing, Michigan, USA
However, research has demonstrated that
Keywords Results: In experimental limbs, ground reac-
the administration of therapeutic doses of
Botox®, botulinum toxin type A, intra- tion forces (peak vertical force and vertical im-
BoNT/A may be helpful in treating various
articular injection, osteoarthritis, gait analysis pulse) consistently improved for a variable
medical conditions, including refractory
period of time following intra-articular
joint pain, in humans.
Summary BoNT/A therapy. These changes were not,
The analgesic properties of BoNT/A
Objectives: To evaluate the effects of however, observed in the contralateral limbs,
have been well documented and were in-
intra-articular botulinum neurotoxin type A in which values remained relatively un-
itially attributed to a reduction in muscle
(BoNT/A) in dogs with chronic osteo- changed or decreased. Four out of five owners
activity as the neurotoxin inhibits the re-
arthritis. reported at least some improvement in their
lease of acetylcholine at the neuromuscular
Methods: Client-owned dogs with lameness dog’s condition following treatment.
junction and causes localised muscular
and discomfort attributed to unilateral elbow Clinical significance: A multimodal ap-
paralysis. Research in rodent models, how-
or hip osteoarthritis were eligible for inclusion proach with the intra-articular administration
ever, has demonstrated that botulinum
(n = 5). All dogs had BoNT/A (25 units) admin- of BoNT/A may be an option for osteoarthritis
toxin inhibits the release of a variety of
istered to the affected joint (2 elbows, 3 hips). patients that are unresponsive to medical
neurotransmitters that would be secreted
Dogs were evaluated by pressure platform management and unable to undergo surgery.
upon nociceptive stimulation and periph-
gait analysis before and at two, four, eight, However, the findings of this study are pre-
eral nerve injury. Therefore, the toxin
and 12 weeks post-injection, and by client liminary and must be verified by further inves-
blocks peripheral sensitisation directly and
perception of outcome. tigation.
central sensitisation indirectly. This mech-
anism has lead to the suggestion that
Correspondence to: Vet Comp Orthop Traumatol 2010; 23: 254–258 BoNT/A may be helpful in treating inflam-
Heather S. Hadley, DVM doi:10.3415/VCOT-09-07-0076 mation and chronic pain (2).
College of Veterinary Medicine Received: July 14, 2009 Recently, BoNT/A has been evaluated
Department of Small Animal Clinical Sciences Accepted: April 1, 2010
Michigan State University Pre-published online: June 21, 2010 for the treatment of chronic joint pain in
D208 Veterinary Medical Center humans. Intra-articular botulinum toxin
East Lansing, MI 48824-1314 type A (IA-BoNT/A) was tested in 11 pa-
USA
tients (3 knees, 3 ankles, and 9 shoulders)
Phone: +1 517 353 5420
Fax: +1 517 355 5164 with chronic arthritis, all of which had
E-Mail: hadleyh@cvm.msu.edu failed to respond to treatment with oral and
intra-articular medications and were not
surgical candidates. A clinically and statis-
tically significant improvement was noted
Introduction Purified neurotoxin complex (onabo- after IA-BoNT/A injections, and no im-
tulinumtoxinA)a is a purified form of bo- mediate or delayed adverse effects related
Osteoarthritis continues to be a significant tulinum toxin type A (BoNT/A) that is pro- to BoNT/A were noted. Duration of pain
problem in the adult canine population. duced from the fermentation of Hall strain relief and improved function were variable
Although many osteoarthritis treatments Clostridium botulinum type A (1). Botuli- and ranged from three to 12 months (3).
have proven effective, there is a continued num neurotoxin is the most potent biologi- Although this study was small and uncon-
need for therapies that adequately reduce cal toxin known to man and is responsible trolled, the results suggest that IA-BoNT/A
chronic joint pain and improve function, for the severe food-borne illness, botulism. may be a safe and effective treatment for
yet avoid the adverse effects of systemic chronic joint pain in humans. These find-
therapy and the morbidity and mortality ings have also prompted further investi-
risks of surgery. a
Botox®: Allergan Inc.,Irvine, CA, USA gation of IA-BoNT/A.
Vet Comp Orthop Traumatol 4/2010H. S. Hadley et al.: Intra-articular botulinum toxin type A in dogs with osteoarthritis 255
Table 1 Patient characteristics of five dogs treated with intra-articular botulinum toxin type A for chronic osteoarthritis.
Dog 1 Dog 2 Dog 3 Dog 4 Dog 5
Age (years) 9 15 11 8 5
Sex Male, neutered Male, neutered Female, spayed Female, spayed Female, spayed
Breed Labrador Retriever Terrier mix German Shepherd mix Bouvier des Flanders Mixed breed
Weight (kg) 43.0 14.7 20.5 37.6 27.1
Joint affected Left elbow Right elbow Right hip Right hip Left hip
(severity) (severe) (severe) (severe) (moderate) (severe)
Concurrent ● Carprofen ● Firocoxib ● Carprofen ● Carprofen ● Carprofan
therapies ● Tramadol ● Glucosamine / ● Phenopropanolamine ● Glucosamine /
● Glucosamine / Chondroitin Chondroitin
Chondroitin ● Vitamin E
● Omega 3 fish oil ● Levothyroxine
Adjunctive therapy None None Acupuncture None None
Owner derived Mild Significant Significant Moderate No change
outcome improvement improvement improvement improvement
The purpose of this pilot study was to cations associated with an intra-articular in- quire peak vertical force (PVF) and vertical
describe the effects of IA-BoNT/A in five jection. The owners also agreed to continue impulse (VI) at a walk. The platform was
dogs with lameness and discomfort at- their dog’s existing osteoarthritis treatment linked to a dedicated computer with specific
tributed to chronic osteoarthritis. regime during the 12-week study period. softwarec designed for collection of gait
Therefore, all therapies that the dog had analysis data, and the walkway sensors were
been receiving previously would remain un- calibrated in accordance with manufacturer
changed. Haematology and serum bio- specificationsd prior to data acquisition.
Materials and methods chemistry profile were performed prior to Video recordings were made of all trials and
Inclusion criteria the start of the study and were required to be were used to confirm gait and foot contacts.
within normal limits in order to allow study
Dogs with lameness and pain attributed to entry.
unilateral elbow or hip osteoarthritis were Pressure platform gait analysis
eligible for inclusion in the study. Radio-
graphic evaluation was required to confirm Study design At each testing time point, each dog was
the presence of osteoarthritis as evidenced weighed on the same electronic scale and
by subchondral bone sclerosis, bone remod- Twenty-five units of BoNT/A were admin- allowed to become familiar with the press-
elling, or osteophytes or enthesophytes in istered as an intra-articular injection to a ure walkway and the testing area. For accli-
the affected joint. Thorough orthopaedic single affected elbow or hip joint in five mation, dogs were walked across the press-
and physical examinations were performed dogs (n = 5). The dogs were studied for 12 ure walkway in a manner consistent with
to ensure that osteoarthritis was indeed the weeks and were evaluated by pressure plat- the data acquisition process until they ap-
cause of the observed clinical signs and that form gait analysis at time zero and at two, peared comfortable. This typically required
general health was otherwise normal. In four, eight, and 12 weeks post-injection and three to five passages.
order to be considered for inclusion, the by owner perception of outcome. Data A comfortable walking velocity was de-
dog’s condition had to be considered were obtained for both the experimental termined for each individual dog during
chronic in nature and stable on the current (treated) limb and the contralateral limb. the acclimation period on day zero. Trials
medications (e.g. non-steroidal anti-inflam- within ± 0.2 m/s of this velocity were
matory drugs, analgesics), nutraceuticals deemed acceptable for analysis. Acceler-
(e.g. glucosamine or chondroitin, vitamin E, Equipment ation was restricted to ± 0.1 m/s². A suitable
omega 3 fish oil), or adjunctive therapies
(e.g. acupuncture) (씰Table 1). Informed A 1.7 m by 0.4 m pressure platformb, with
and written consent were obtained from all 9152 pressure-sensing cells, was used to ac-
c
owners following a discussion of BoNT/A, F-scan Research, Version 5.83: Tekscan Inc, Boston,
MA, USA
current clinical and experimental research b
4-Handle Walkway System with Matscan 3150 sen- d
Tekscan MatScan® User Manual, Version 5.83:
related to this drug, and potential compli- sors: Tekscan Inc. , Boston, MA, USA Tekscan Inc., Boston, MA, USA
© Schattauer 2010 Vet Comp Orthop Traumatol 4/2010256 H. S. Hadley et al.: Intra-articular botulinum toxin type A in dogs with osteoarthritis
trial occurred when the dog met the above Procedure ticular presence was confirmed by the ap-
velocity and acceleration criteria and pearance of joint fluid or arthography (with
moved in a straight line across the pressure On day zero, following initial gait analysis, iohexol), if needed. The needle was left in
walkway without pulling to one side or dogs were pre-medicated with diphenhydra- place for the intra-articular injection. The
turning its head. A single trained observer mine (2 mg/kg intramuscularly) and sedated BoNT/A was reconstituted with sterile saline,
(HSH) evaluated each foot strike and sub- with medetomidine hydrochloride (0.02 mg/ according to manufacturer’s recommen-
sequent force profile and determined kg intravenously). Oxygen was administered dations, and 0.5 ml (25 units) were injected
whether or not the trial was valid. Peak ver- by face mask and electrocardiographic into the affected joint. Following completion
tical force and VI were measured for the monitoring was maintained throughout the of the injection, sedation was reversed with
first two footfalls of the experimental limb procedure. Dogs were positioned in lateral administration of atipamezole hydrochlor-
and contralateral limb in each trial. The recumbency with the affected elbow down or ide (0.1 mg/kg intramuscularly). Dogs were
mean values from the first three valid trials the affected hip up. The hair over the medial monitored for several hours for the develop-
(6 footfalls for each limb) were recorded aspect of the elbow or over the lateral aspect ment of adverse clinical signs and then dis-
and all forces were normalised and express- of the hip was clipped and the skin aseptically charged. Owners were instructed to continue
ed as a percentage of the dog’s body weight. prepared. Using strict aseptic technique, rou- with osteoarthritis treatment as usual on the
tine arthrocentesis was performed. Intra-ar- day of the procedure. However, no additional
anti-inflammatory or analgesic therapy was
provided.
Table 2 Ground reaction forces for all dogs at all time points.
Time 0 Week 2 Week 4 Week 8 Week 12 Owner assessment
Dog 1 - Elbow
PVF - Experimental limb 29.2 31.8 36.0 29.2 29.7 General follow-up phone calls were per-
formed at 24 hours and one week post-in-
PVF - Contralateral limb 44.7 41.7 44.0 47.8 46.0
jection. At the conclusion of the study,
VI - Experimental limb 11.4 12.8 13.2 10.2 11.3 owners were asked to subjectively grade
VI - Contralateral limb 16.9 15.8 17.0 16.6 17.2 their dog’s condition (limb function, lame-
ness, discomfort) during the study period
Dog 2 - Elbow
as compared to that noted prior to the
PVF - Experimental limb 32.3 42.3 40.9 42.1 38.6 intra-articular injection of BoNT/A (op-
PVF - Contralateral limb 56.5 53.8 52.6 49.0 53.9 tions included no change, mildly im-
proved, moderately improved, significantly
VI - Experimental limb 5.5 9.6 8.3 9.7 8.4
improved, mildly worsened, moderately
VI - Contralateral limb 10.4 13.1 11.6 12.0 13.2 worsened, significantly worsened).
Dog 3 - Hip
PVF - Experimental limb 32.4 36.2 36.0 39.9 34.7
Results
PVF - Contralateral limb 41.0 40.9 40.6 41.8 38.4
VI - Experimental limb 4.9 9.2 7.3 7.9 7.7 Five dogs (씰Table 1) were followed
throughout the 12-week study period. The
VI - Contralateral limb 6.0 10.3 7.8 8.2 8.4
dogs’ ages ranged from five to 15 years
Dog 4 - Hip (mean = 9.6) and weights ranged from 14.7
PVF - Experimental limb 14.5 15.8 18.5 20.5 19.6 to 43 kg (mean = 28.6 kg). Of these dogs,
PVF - Contralateral limb 21.5 22.4 23.6 23.0 22.4
three were spayed females and two were
neutered males. All dogs were receiving
VI - Experimental limb 4.4 4.4 5.9 6.3 5.8 anti-inflammatory ± analgesic medi-
VI - Contralateral limb 6.8 6.4 6.9 7.0 6.7 cations prior to initiation of the study. One
Dog 5 - Hip
dog (Dog 3) was receiving adjunctive ther-
apy, in the form of acupuncture, two times
PVF - Experimental limb 27.0 25.4 26.5 28.6 26.5 a month. All dogs were suffering from
PVF - Contralateral limb 37.2 36.0 36.4 36.8 37.0 moderate to severe osteoarthritis, in the af-
VI - Experimental limb 6.4 6.9 6.6 6.5 6.0 fected joint, as determined subjectively by
the orthopaedic and radiographic examin-
VI - Contralateral limb 10.6 10.2 10.3 9.5 9.6 ation. Two elbow joints and three coxofe-
Key: PVF = Peak vertical force (% body weight); VI = Vertical impulse (% body weight x time). moral joints were injected with BoNT/A.
Vet Comp Orthop Traumatol 4/2010 © Schattauer 2010H. S. Hadley et al.: Intra-articular botulinum toxin type A in dogs with osteoarthritis 257
One dog (Dog 3) required arthrography to All five dogs appeared to tolerate the IA- fects of BoNT/A did not appear to be as
confirm intra-articular needle placement. BoNT/A injection well and without im- dramatic or to have the same duration of
All five dogs appeared to tolerate the injec- mediate adverse effect, however, two dogs action as that reported in the human litera-
tion well and without immediate adverse developed mild redness and swelling at the ture. Although further study is necessary to
effects. injection site and increased lameness dur- validate the effect of IA-BoNT/A in hu-
ing the first 24–48 hours post-injection. mans, there may be several reasons for the
While these complications are similar to differences observed between human and
Pressure platform gait analysis those reported with routine arthrocentesis, canine patients. First, Clostridium botuli-
serious or immediate hypersensitivity reac- num types A, B, E, and F cause human botu-
Peak vertical force and VI were measured at tions to BoNT/A have been rarely reported lism, whereas canine botulism has only
a walk at all time points (씰Table 2). In ex- in humans receiving treatment for neur- been reported to be caused by type C.
perimental limbs, ground reaction forces omuscular disorders. These reactions in- Therefore, it is possible that the canine
(GRF) consistently improved for a variable clude anaphylaxis, dyspnoea, urticaria, soft species is less susceptible to the effects of
period of time following IA-BoNT/A ther- tissue oedema and erythema, and pruritis neurotoxin type A and consequently, the ef-
apy. Conversely, GRF obtained from the (1). Although all dogs were pre-treated fects of IA-BoNT/A. Additionally, the dose
contralateral limbs generally remained un- with diphenhydramine, a localised reaction of BoNT/A administered in this study (25
changed or decreased over time. to IA-BoNT/A cannot be ruled out without units) was extrapolated from currently
future placebo-controlled testing. No ad- available human research (3). As a result,
verse systemic or lasting local effects of the dose may not have been high enough to
Owner assessment BoNT/A were observed during the study provide maximal anti-nociceptive effects in
period suggesting its safety as an intra-ar- the canine patient. In fact, recent research
At the follow-up phone call 24 hours post- ticular injection in canine patients at a dose has revealed that the effects of BoNT/A may
injection, the owners of Dogs 3 and 4 re- of 25 units. indeed be dose dependent in dogs and that
ported mild redness and swelling at the in- Pain is a dominant sign of osteoarthritis, effective doses may be much higher than
jection site and a mild increase in lameness. yet to date, no single objective measure- that utilised in this study (4). Ground reac-
These clinical signs resolved within two ment can reliably indicate the severity of tion forces in the experimental limbs in-
days in both dogs. At one week, the owners pain in the dog. Although limb function creased until four or eight weeks and then
of Dogs 1, 2, and 3 reported a mild subjec- may not be directly correlated to changes in began to decrease toward baseline. Al-
tive improvement in their dog’s character joint pain, one would expect limb function though these findings may indicate long
and comfort level as compared to that or load to increase with a reduction in joint term effects of IA-BoNT/A, the duration of
noted prior to the injection. At the con- pain. Pressure platform gait analysis has action cannot be fully elucidated as these
clusion of the study, the owners reported been used previously to evaluate normal dogs were only studied for three months.
the following in regard to the overall effect ground reaction forces and alterations in However, one owner (of Dog 3) requested
of IA-BoNT/A on their dog’s limb func- these forces due to disease or medical or re-injection at five months as she felt as
tion, lameness, and discomfort: Dog 1 – surgical interventions. Peak vertical force though her dog’s lameness had returned to
mild improvement, Dog 2 – significant im- (maximal force applied during the stance pre-injection status. Therefore, additional
provement, Dog 3 – significant improve- phase) and VI (vertical force applied x studies are needed to standardise dosing
ment, Dog 4 – moderate improvement, and time) are the most commonly measured and to determine the duration of effect of
Dog 5 – no change (씰Table 1). variables. The presence of improved GRF IA-BoNT/A in dogs.
in experimental limbs, and relatively un- In addition to those already mentioned,
changed GRF in contralateral limbs, over there are significant limitations to this
Discussion time, suggest that the observed increases in study that merit comment. First, this was a
the experimental limbs may have been due small case series (n = 5) without a control
This is the first report of the effects of IA- to the administration of IA-BoNT/A. The group. Although outcome measures were
BoNT/A in dogs with chronic osteoarthri- increases in PVF and VI may also indicate a both objective and subjective in nature, gait
tis. Results indicate that treatment with 25 decrease in joint pain with the adminis- analysis data was limited and owner obser-
units IA-BoNT/A may lead to improve- tration of IA-BoNT/A. Owner observa- vations were subject to bias as well as the
ments in ground reaction forces and owner tions further support these findings as four placebo effect. Secondly, this study assessed
perception of condition in dogs with re- out of five owners reported at least some the effects of IA-BoNT/A in dogs with vari-
fractory osteoarthritis joint pain. There- degree of improvement in their dog’s con- ation in age, sex, breed, weight, joint af-
fore, a multimodal approach with the addi- dition following administration of IA- fected, severity of disease, concurrent ther-
tion of IA-BoNT/A may be an option for BoNT/A. apies, and procedure (simple arthrocente-
osteoarthritis patients that are unrespon- Overall, these findings suggest that IA- sis vs. arthrography) (씰Table 1). Although
sive to medical management and unable to BoNT/A provides clinical improvement in these results are encouraging and indicate
undergo surgery. dogs with osteoarthritis. However, the ef- that the administration of IA-BoNT/A may
© Schattauer 2010 Vet Comp Orthop Traumatol 4/2010258 H. S. Hadley et al.: Intra-articular botulinum toxin type A in dogs with osteoarthritis
indeed provide a new therapeutic option Acknowledgments 2. Aoki KR. Evidence for antinociceptive activity of
botulinum toxin type A in pain management.
for patients suffering from refractory os- The authors would like to acknowledge Headache 2003; 43 Suppl 1: S9-S15.
teoarthritis joint pain, this study provides that the Botox® utilised in this study was 3. Mahowald ML, Singh JA, Dykstra D. Long term ef-
level 4 evidence, and therefore, must be generously provided by Allergan, Inc. The fects of intra-articular botulinum toxin A for re-
considered preliminary. In order to validate authors would also like to thank Dr. Maren fractory joint pain. Neurotox Res 2006; 9: 179–188.
4. Lin AT, Yang AH, Chen KK. Effects of botulinum
the results observed in this case series, IA- L. Mahowald for her assistance in protocol toxin A on the contractile function of dog prostate.
BoNT/A should be tested in prospective, development and Dr. Joe G. Hauptman for Eur Urol 2007; 52: 582–589.
randomised, placebo-controlled, blinded his support during data analysis. 5. Mahowald ML, Krug HE, Singh JA, et al. Intra-ar-
clinical trials. ticular botulinum toxin type A: a new approach to
treat arthritis joint pain. Toxicon 2009; 54: 658–667.
Since completion of this study, sub- 6. Boon AJ, Smith J, Dahm DL, et al. Efficacy of intra-
sequent investigations have demonstrated References articular botulinum toxin type-A in painful knee
that BoNT/A has an anti-nociceptive effect osteoarthritis: A pilot study. PM R 2010; 2:268-276.
upon intra-articular administration and 1. Allergan, Inc. Botox® (onabotulinumtoxinA)
[Product information page on internet]. Allergen
may, therefore, have a potential role in the Inc., Product Information; 2010 [cited 2008 Sep-
treatment of symptomatic osteoarthritis in tember 6]. Available from: http://www.allergan.
humans (5, 6). com/products/neurosciences/botox.htm.
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