Effects of intra-articular botulinum toxin type A (Botox ) in dogs with chronic osteoarthritis A pilot study

Transcription

1 254 Schattauer 2010 Clinical Communication Effects of intra-articular botulinum toxin type A (Botox ) in dogs with chronic osteoarthritis A pilot study H. S. Hadley 1, 2 ; J. L. Wheeler 1 ; S. W. Petersen 1 1 Wheat Ridge Veterinary Specialists, Wheat Ridge Animal Hospital, Wheat Ridge, Colorado, USA; 2 College of Veterinary Medicine, Department of Small Animal Clinical Sciences, Michigan State University, East Lansing, Michigan, USA Keywords Botox, botulinum toxin type A, intraarticular injection, osteoarthritis, gait analysis Summary Objectives: To evaluate the effects of intra-articular botulinum neurotoxin type A (BoNT/A) in dogs with chronic osteoarthritis. Methods: Client-owned dogs with lameness and discomfort attributed to unilateral elbow or hip osteoarthritis were eligible for inclusion (n = 5). All dogs had BoNT/A (25 units) administered to the affected joint (2 elbows, 3 hips). Dogs were evaluated by pressure platform gait analysis before and at two, four, eight, and 12 weeks post-injection, and by client perception of outcome. Correspondence to: Heather S. Hadley, DVM College of Veterinary Medicine Department of Small Animal Clinical Sciences Michigan State University D208 Veterinary Medical Center East Lansing, MI USA Phone: Fax: hadleyh@cvm.msu.edu Introduction Osteoarthritis continues to be a significant problem in the adult canine population. Although many osteoarthritis treatments have proven effective, there is a continued need for therapies that adequately reduce chronic joint pain and improve function, yet avoid the adverse effects of systemic therapy and the morbidity and mortality risks of surgery. Vet Comp Orthop Traumatol 4/2010 Results: In experimental limbs, ground reaction forces (peak vertical force and vertical impulse) consistently improved for a variable period of time following intra-articular BoNT/A therapy. These changes were not, however, observed in the contralateral limbs, in which values remained relatively unchanged or decreased. Four out of five owners reported at least some in their dog s condition following treatment. Clinical significance: A multimodal approach with the intra-articular administration of BoNT/A may be an option for osteoarthritis patients that are unresponsive to medical management and unable to undergo surgery. However, the findings of this study are preliminary and must be verified by further investigation. Vet Comp Orthop Traumatol 2010; 23: doi: /vcot Received: July 14, 2009 Accepted: April 1, 2010 Pre-published online: June 21, 2010 Purified neurotoxin complex (onabotulinumtoxina) a is a purified form of botulinum toxin type A (BoNT/A) that is produced from the fermentation of Hall strain Clostridium botulinum type A (1). Botulinum neurotoxin is the most potent biological toxin known to man and is responsible for the severe food-borne illness, botulism. a Botox : Allergan Inc.,Irvine, CA, USA However, research has demonstrated that the administration of therapeutic doses of BoNT/A may be helpful in treating various medical conditions, including refractory joint pain, in humans. The analgesic properties of BoNT/A have been well documented and were initially attributed to a reduction in muscle activity as the neurotoxin inhibits the release of acetylcholine at the neuromuscular junction and causes localised muscular paralysis. Research in rodent models, however, has demonstrated that botulinum toxin inhibits the release of a variety of neurotransmitters that would be secreted upon nociceptive stimulation and peripheral nerve injury. Therefore, the toxin blocks peripheral sensitisation directly and central sensitisation indirectly. This mechanism has lead to the suggestion that BoNT/A may be helpful in treating inflammation and chronic pain (2). Recently, BoNT/A has been evaluated for the treatment of chronic joint pain in humans. Intra-articular botulinum toxin type A (IA-BoNT/A) was tested in 11 patients (3 knees, 3 ankles, and 9 shoulders) with chronic arthritis, all of which had failed to respond to treatment with oral and intra-articular medications and were not surgical candidates. A clinically and statistically significant was noted after IA-BoNT/A injections, and no immediate or delayed adverse effects related to BoNT/A were noted. Duration of pain relief and improved function were variable and ranged from three to 12 months (3). Although this study was small and uncontrolled, the results suggest that IA-BoNT/A may be a safe and effective treatment for chronic joint pain in humans. These findings have also prompted further investigation of IA-BoNT/A.

2 H. 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) 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) Joint affected (severity) Concurrent therapies Left elbow Right elbow Firocoxib Tramadol Omega 3 fish oil Right hip Vitamin E Levothyroxine Right hip (moderate) Phenopropanolamine Adjunctive therapy None None Acupuncture None None Owner derived outcome Mild Significant Significant Moderate Left hip Carprofan No change The purpose of this pilot study was to describe the effects of IA-BoNT/A in five dogs with lameness and discomfort attributed to chronic osteoarthritis. Materials and methods Inclusion criteria Dogs with lameness and pain attributed to unilateral elbow or hip osteoarthritis were eligible for inclusion in the study. Radiographic evaluation was required to confirm the presence of osteoarthritis as evidenced by subchondral bone sclerosis, bone remodelling, or osteophytes or enthesophytes in the affected joint. Thorough orthopaedic and physical examinations were performed to ensure that osteoarthritis was indeed the cause of the observed clinical signs and that general health was otherwise normal. In order to be considered for inclusion, the dog s condition had to be considered chronic in nature and stable on the current medications (e.g. non-steroidal anti-inflammatory drugs, analgesics), nutraceuticals (e.g. glucosamine or chondroitin, vitamin E, omega 3 fish oil), or adjunctive therapies (e.g. acupuncture) ( Table 1). Informed and written consent were obtained from all owners following a discussion of BoNT/A, current clinical and experimental research related to this drug, and potential complications associated with an intra-articular injection. The owners also agreed to continue their dog s existing osteoarthritis treatment regime during the 12-week study period. Therefore, all therapies that the dog had been receiving previously would remain unchanged. Haematology and serum biochemistry profile were performed prior to the start of the study and were required to be within normal limits in order to allow study entry. Study design Twenty-five units of BoNT/A were administered as an intra-articular injection to a single affected elbow or hip joint in five dogs (n = 5). The dogs were studied for 12 weeks and were evaluated by pressure platform gait analysis at time zero and at two, four, eight, and 12 weeks post-injection and by owner perception of outcome. Data were obtained for both the experimental (treated) limb and the contralateral limb. Equipment b 4-Handle Walkway System with Matscan 3150 sensors: Tekscan Inc., Boston, MA, USA A 1.7 m by 0.4 m pressure platform b, with 9152 pressure-sensing cells, was used to acquire peak vertical force (PVF) and vertical impulse (VI) at a walk. The platform was linked to a dedicated computer with specific software c designed for collection of gait analysis data, and the walkway sensors were calibrated in accordance with manufacturer specifications d prior to data acquisition. Video recordings were made of all trials and were used to confirm gait and foot contacts. Pressure platform gait analysis At each testing time point, each dog was weighed on the same electronic scale and allowed to become familiar with the pressure walkway and the testing area. For acclimation, dogs were walked across the pressure walkway in a manner consistent with the data acquisition process until they appeared comfortable. This typically required three to five passages. A comfortable walking velocity was determined for each individual dog during the acclimation period on day zero. Trials within ± 0.2 m/s of this velocity were deemed acceptable for analysis. Acceleration was restricted to ± 0.1 m/s². A suitable c F-scan Research, Version 5.83: Tekscan Inc, Boston, MA, USA d Tekscan MatScan User Manual, Version 5.83: Tekscan Inc., Boston, MA, USA Schattauer 2010 Vet Comp Orthop Traumatol 4/2010

3 256 H. S. Hadley et al.: Intra-articular botulinum toxin type A in dogs with osteoarthritis trial occurred when the dog met the above velocity and acceleration criteria and moved in a straight line across the pressure walkway without pulling to one side or turning its head. A single trained observer (HSH) evaluated each foot strike and subsequent force profile and determined whether or not the trial was valid. Peak vertical force and VI were measured for the first two footfalls of the experimental limb and contralateral limb in each trial. The mean values from the first three valid trials (6 footfalls for each limb) were recorded and all forces were normalised and expressed as a percentage of the dog s body weight. Procedure Table 2 Ground reaction forces for all dogs at all time points. Time 0 Week 2 Week 4 Week 8 Week 12 Dog 1 - Elbow PVF - Experimental limb PVF - Contralateral limb VI - Experimental limb VI - Contralateral limb Dog 2 - Elbow PVF - Experimental limb PVF - Contralateral limb VI - Experimental limb VI - Contralateral limb Dog 3 - Hip PVF - Experimental limb PVF - Contralateral limb VI - Experimental limb VI - Contralateral limb Dog 4 - Hip PVF - Experimental limb PVF - Contralateral limb VI - Experimental limb VI - Contralateral limb Dog 5 - Hip PVF - Experimental limb PVF - Contralateral limb VI - Experimental limb VI - Contralateral limb Key: PVF = Peak vertical force (% body weight); VI = Vertical impulse (% body weight x time). On day zero, following initial gait analysis, dogs were pre-medicated with diphenhydramine (2 mg/kg intramuscularly) and sedated with medetomidine hydrochloride (0.02 mg/ kg intravenously). Oxygen was administered by face mask and electrocardiographic monitoring was maintained throughout the procedure. Dogs were positioned in lateral recumbency with the affected elbow down or the affected hip up. The hair over the medial aspect of the elbow or over the lateral aspect of the hip was clipped and the skin aseptically prepared. Using strict aseptic technique, routine arthrocentesis was performed. Intra-articular presence was confirmed by the appearance of joint fluid or arthography (with iohexol), if needed. The needle was left in place for the intra-articular injection. The BoNT/A was reconstituted with sterile saline, according to manufacturer s recommendations, and 0.5 ml (25 units) were injected into the affected joint. Following completion of the injection, sedation was reversed with administration of atipamezole hydrochloride (0.1 mg/kg intramuscularly). Dogs were monitored for several hours for the development of adverse clinical signs and then discharged. Owners were instructed to continue with osteoarthritis treatment as usual on the day of the procedure. However, no additional anti-inflammatory or analgesic therapy was provided. Owner assessment General follow-up phone calls were performed at 24 hours and one week post-injection. At the conclusion of the study, owners were asked to subjectively grade their dog s condition (limb function, lameness, discomfort) during the study period as compared to that noted prior to the intra-articular injection of BoNT/A (options included no change, mildly improved, moderately improved, significantly improved, mildly worsened, moderately worsened, significantly worsened). Results Five dogs ( Table 1) were followed throughout the 12-week study period. The dogs ages ranged from five to 15 years (mean = 9.6) and weights ranged from 14.7 to 43 kg (mean = 28.6 kg). Of these dogs, three were spayed females and two were neutered males. All dogs were receiving anti-inflammatory ± analgesic medications prior to initiation of the study. One dog (Dog 3) was receiving adjunctive therapy, in the form of acupuncture, two times a month. All dogs were suffering from moderate to severe osteoarthritis, in the affected joint, as determined subjectively by the orthopaedic and radiographic examination. Two elbow joints and three coxofemoral joints were injected with BoNT/A. Vet Comp Orthop Traumatol 4/2010 Schattauer 2010

4 H. S. Hadley et al.: Intra-articular botulinum toxin type A in dogs with osteoarthritis 257 One dog (Dog 3) required arthrography to confirm intra-articular needle placement. All five dogs appeared to tolerate the injection well and without immediate adverse effects. Pressure platform gait analysis Peak vertical force and VI were measured at a walk at all time points ( Table 2). In experimental limbs, ground reaction forces (GRF) consistently improved for a variable period of time following IA-BoNT/A therapy. Conversely, GRF obtained from the contralateral limbs generally remained unchanged or decreased over time. Owner assessment At the follow-up phone call 24 hours postinjection, the owners of Dogs 3 and 4 reported mild redness and swelling at the injection site and a mild increase in lameness. These clinical signs resolved within two days in both dogs. At one week, the owners of Dogs 1, 2, and 3 reported a mild subjective in their dog s character and comfort level as compared to that noted prior to the injection. At the conclusion of the study, the owners reported the following in regard to the overall effect of IA-BoNT/A on their dog s limb function, lameness, and discomfort: Dog 1 mild, Dog 2 significant, Dog 3 significant, Dog 4 moderate, and Dog 5 no change ( Table 1). Discussion This is the first report of the effects of IA- BoNT/A in dogs with chronic osteoarthritis. Results indicate that treatment with 25 units IA-BoNT/A may lead to s in ground reaction forces and owner perception of condition in dogs with refractory osteoarthritis joint pain. Therefore, a multimodal approach with the addition of IA-BoNT/A may be an option for osteoarthritis patients that are unresponsive to medical management and unable to undergo surgery. All five dogs appeared to tolerate the IA- BoNT/A injection well and without immediate adverse effect, however, two dogs developed mild redness and swelling at the injection site and increased lameness during the first hours post-injection. While these complications are similar to those reported with routine arthrocentesis, serious or immediate hypersensitivity reactions to BoNT/A have been rarely reported in humans receiving treatment for neuromuscular disorders. These reactions include anaphylaxis, dyspnoea, urticaria, soft tissue oedema and erythema, and pruritis (1). Although all dogs were pre-treated with diphenhydramine, a localised reaction to IA-BoNT/A cannot be ruled out without future placebo-controlled testing. No adverse systemic or lasting local effects of BoNT/A were observed during the study period suggesting its safety as an intra-articular injection in canine patients at a dose of 25 units. Pain is a dominant sign of osteoarthritis, yet to date, no single objective measurement can reliably indicate the severity of pain in the dog. Although limb function may not be directly correlated to changes in joint pain, one would expect limb function or load to increase with a reduction in joint pain. Pressure platform gait analysis has been used previously to evaluate normal ground reaction forces and alterations in these forces due to disease or medical or surgical interventions. Peak vertical force (maximal force applied during the stance phase) and VI (vertical force applied x time) are the most commonly measured variables. The presence of improved GRF in experimental limbs, and relatively unchanged GRF in contralateral limbs, over time, suggest that the observed increases in the experimental limbs may have been due to the administration of IA-BoNT/A. The increases in PVF and VI may also indicate a decrease in joint pain with the administration of IA-BoNT/A. Owner observations further support these findings as four out of five owners reported at least some degree of in their dog s condition following administration of IA- BoNT/A. Overall, these findings suggest that IA- BoNT/A provides clinical in dogs with osteoarthritis. However, the effects of BoNT/A did not appear to be as dramatic or to have the same duration of action as that reported in the human literature. Although further study is necessary to validate the effect of IA-BoNT/A in humans, there may be several reasons for the differences observed between human and canine patients. First, Clostridium botulinum types A, B, E, and F cause human botulism, whereas canine botulism has only been reported to be caused by type C. Therefore, it is possible that the canine species is less susceptible to the effects of neurotoxin type A and consequently, the effects of IA-BoNT/A. Additionally, the dose of BoNT/A administered in this study (25 units) was extrapolated from currently available human research (3). As a result, the dose may not have been high enough to provide maximal anti-nociceptive effects in the canine patient. In fact, recent research has revealed that the effects of BoNT/A may indeed be dose dependent in dogs and that effective doses may be much higher than that utilised in this study (4). Ground reaction forces in the experimental limbs increased until four or eight weeks and then began to decrease toward baseline. Although these findings may indicate long term effects of IA-BoNT/A, the duration of action cannot be fully elucidated as these dogs were only studied for three months. However, one owner (of Dog 3) requested re-injection at five months as she felt as though her dog s lameness had returned to pre-injection status. Therefore, additional studies are needed to standardise dosing and to determine the duration of effect of IA-BoNT/A in dogs. In addition to those already mentioned, there are significant limitations to this study that merit comment. First, this was a small case series (n = 5) without a control group. Although outcome measures were both objective and subjective in nature, gait analysis data was limited and owner observations were subject to bias as well as the placebo effect. Secondly, this study assessed the effects of IA-BoNT/A in dogs with variation in age, sex, breed, weight, joint affected, severity of disease, concurrent therapies, and procedure (simple arthrocentesis vs. arthrography) ( Table 1). Although these results are encouraging and indicate that the administration of IA-BoNT/A may Schattauer 2010 Vet Comp Orthop Traumatol 4/2010

5 258 H. S. Hadley et al.: Intra-articular botulinum toxin type A in dogs with osteoarthritis indeed provide a new therapeutic option for patients suffering from refractory osteoarthritis joint pain, this study provides level 4 evidence, and therefore, must be considered preliminary. In order to validate the results observed in this case series, IA- BoNT/A should be tested in prospective, randomised, placebo-controlled, blinded clinical trials. Since completion of this study, subsequent investigations have demonstrated that BoNT/A has an anti-nociceptive effect upon intra-articular administration and may, therefore, have a potential role in the treatment of symptomatic osteoarthritis in humans (5, 6). Acknowledgments The authors would like to acknowledge that the Botox utilised in this study was generously provided by Allergan, Inc. The authors would also like to thank Dr. Maren L. Mahowald for her assistance in protocol development and Dr. Joe G. Hauptman for his support during data analysis. References 1. Allergan, Inc. Botox (onabotulinumtoxina) [Product information page on internet]. Allergen Inc., Product Information; 2010 [cited 2008 September 6]. Available from: com/products/neurosciences/botox.htm. 2. Aoki KR. Evidence for antinociceptive activity of botulinum toxin type A in pain management. Headache 2003; 43 Suppl 1: S9-S Mahowald ML, Singh JA, Dykstra D. Long term effects of intra-articular botulinum toxin A for refractory joint pain. Neurotox Res 2006; 9: Lin AT, Yang AH, Chen KK. Effects of botulinum toxin A on the contractile function of dog prostate. Eur Urol 2007; 52: Mahowald ML, Krug HE, Singh JA, et al. Intra-articular botulinum toxin type A: a new approach to treat arthritis joint pain. Toxicon 2009; 54: Boon AJ, Smith J, Dahm DL, et al. Efficacy of intraarticular botulinum toxin type-a in painful knee osteoarthritis: A pilot study. PM R 2010; 2: Vet Comp Orthop Traumatol 4/2010 Schattauer 2010