Company Disclaimer
The following information is provided for veterinarians authorised to use such products in the United States where 2.5% PAAG is approved as a medical device for the treatment of osteoarthritis in dogs & cats (Synamid®), and in the United Kingdom where it is used under special import license.
2.5% PAAG is not registered in New Zealand/Australia for use in canines. No approval has been sought for its use in species other than for horses in New Zealand/Australia.
Any use of 2.5% PAAG in canines by veterinarians in New Zealand/Australia would be at the discretion of that veterinarian and would be considered ‘off-label’ use.
[If you wish to review further educational information or general advice concerning 2.5% PAAG in species other than its approved species, please contact IMS Vet LP to REQUEST FURTHER INFORMATION].
Osteoarthritis (OA) is one of the most common chronic musculoskeletal diseases in dog populations, causing lameness and a loss of quality of life. It is estimated that 20-37% of dogs> 1 year of age are affected1. Currently, veterinary treatments involve a multimodal approach to control intra-articular (joint) inflammation and pain and, restore mobility in an attempt to improve the overall quality of life2.
Treatments mostly include non-steroidal anti-inflammatory drugs (NSAIDs), chondro-protectants (e.g. Cartrophen®), an EPA (eicosapentaenoic acid) rich diet or other neutraceuticals, as well as adjunct management including weight management, exercise modification, and exercise rehabilitation. The use of intra-articular medications such as corticosteroids or biotechnological substances like stem cells, platelet rich plasma, or autologous conditioned serum (IRAP), are also employed by some veterinarians, but often late in the disease process or as a last attempt. NSAID’s are associated with safety and tolerability concerns pertaining to their GI, renal, and hepatotoxicity. Patient compliance, with the frequent administration of oral treatments, can also be problematic for some owners.
Whilst the adoption of multimodal management plans has improved the welfare of dogs with OA, many continue to suffer from chronic pain. Current research is therefore focussed on the need for new OA treatment options. The recent advent of an anti-nerve growth factor treatment bedinvetmab2 (Librela®- Zoetis) for osteoarthritis is highly encouraging, as well as new technologies like 2.5% PAAG (Arthramid Vet®- Contura Vet) that if administered early may serve to alter or even arrest the progression of the disease. The following discussion places more emphasis on 2.5% PAAG as this compound is presently available in New Zealand and the author has had some positive experiences with its use off-label in canine OA patients.
About Bedinvetmab (Librela®)
Bedinvetmab is the first-of-its-kind veterinary medicine that contains bedinvetmab, a monoclonal antibody that binds to Nerve Growth Factor (NGF), a key player in OA pain3 and in doing so reduces pain. It functions like naturally occurring antibodies, with minimal involvement of the liver or kidneys in its metabolism and elimination from the body; bedinvetmab also produces minimal gastrointestinal (GI) impact. After one injection of bedinvetmab, dogs with osteoarthritis exhibited increased mobility and decreased pain.
Bedinvetmab is administered as monthly injections and has demonstrated efficacy in lowering canine pain for up to nine months in clinical studies3.
About 2.5% PAAG (Arthramid® Vet)
2.5% Polyacrylamide hydrogel (PAAG) is a non-toxic, non-degradable synthetic product that has been trialed extensively in horses and humans for the treatment of osteoarthritis (OA).
To the authors knowledge no blinded or controlled studies of its efficacy and safety in dogs have been completed to date, although prospective clinical studies have been completed, and the outcomes from which are discussed below.
2.5% PAAG is administered via intra-articular injection by a veterinarian. It acts as a dynamic tissue scaffold (“bio-scaffold”), supporting cellular growth within the joint and giving rise to a novel and hypercellular sub-synovial cell layer that acts to restore joint function by a reduction in synovitis and increased joint capsule elastance. 2.5% PAAG appears to offer veterinarians a safe, versatile and minimally invasive way to modify the disease process associated with OA. 2.5% PAAG also appears to be long-lasting, with treatment benefits of up to 2 years and even longer reported in horses4 and humans.
Is there any evidence that 2.5% PAAG is effective in the treatment of osteoarthritis in dogs?
Three (3) separate canine veterinary centers in the United Kingdom were invited to perform a retrospective review and follow up of all dogs treated at their clinics with 2.5% PAAG using the Liverpool Osteoarthritis in Dogs (LOAD) questionnaire. The LOAD questionnaire is a 13-item clinical metrology instrument (CMI) used to assess canine articular disorders like OA. Individual question scores are summed to provide an overall “LOAD score” suggestive of the animal’s disease presence and severity.
A total of 166 dogs with joint disease were included in the study and a reduction in lameness post treatment was seen from 1 month and was maintained for at least six months in 71.7% of dogs, with up to 81.9% of owners being extremely likely or likely to recommend 2.5% PAAG injection to other dog owners. Furthermore, in 67.4% of dogs it was possible to reduce or stop the use of systemic anti-inflammatories.
These results tend to support that 2.5% PAAG is safe and efficacious at alleviating the clinical signs of OA as assessed by owners and veterinarians. Double-blinded randomised controlled studies however are required and the use of synovial biopsies or measures of synovial fluid quality may assist in determining if the treatment has the potential to delay or modify the progression of the disease. This should be the focus of future research.
Are veterinarians currently using 2.5% PAAG or Bedinvetmab for the treatment of osteoarthritis in dogs?
2.5% PAAG is a relatively novel OA intervention for dogs having been legitimately used as an ‘off-licence’ product, under the veterinary cascade system, in the UK since 2017 and in the USA (as Synamid®) since 2012.
In the USA, Synamid® is Food and Drug Administration (FDA) permitted for use under its classification as a ‘Medical Device’. In the UK Arthramid® can be obtained by a veterinary surgeon using the Special Import Certificate (SIC) Scheme of the Veterinary Medicines Directorate (VMD). Under this scheme, veterinary surgeons can use the cascade to source medicines authorised elsewhere in the world.
In other countries, licensed veterinary surgeons must either use the licensed product off-label (Australia and New Zealand) or seek permission from their own veterinary authorities to import 2.5% PAAG Arthramid® Vet for clinical use.
Bedinvetmap launched in the European Union, United Kingdom, and Switzerland in 2021 and is also now available in the US and Canada. The product is likely to be available to veterinarians in Australia and New Zealand by next year 2023.
What else do you need to know? FAQ's
How common is OA in dogs?
Osteoarthritis is common in dogs, being estimated to affect 2.5 to 6.6% of all dogs attending UK veterinary clinics, with much higher prevalence in older dogs and breeds such as the Labrador and Golden Retriever, German Shepherd Dog and Springer Spaniel. OA is often considered to be secondary to wear and tear on the joint and it is true that it is diagnosed more frequently in older dogs. It often occurs secondary to hereditary joint conditions, such as hip and elbow dysplasia and cruciate ligament disease, that are common in young dogs of certain breeds. OA in dogs has similarities to that in people, with the same joints being most commonly affected (stifles and hips).
What causes pain from OA in dogs?
In joints, two general types of pain stimulus occur: mechanical stimuli, from changes in the joint such as trauma, and chemical stimuli, from tissue inflammation. These stimuli are detected by mechanoreceptors and nociceptors in the joint, and forwarded
to peripheral nerves, spinal cord and ultimately to the brain to be processed and perceived.
Once damage has occurred, cellular metabolism is altered and a cascade of inflammatory mediators are released resulting in further damage to the joint tissues. The joint capsule loses elasticity, resulting in decreased ability to transfer load and increasing the forces through the joint. Microscopically, there is a loss of proteoglycan caused by enzymatic degradation. Damaged cartilage initially increases its water content and swells. Loss of chondrocytes results in fibrillation and resistance to shear forces is lessened, resulting in further damage. This can eventually lead to small fragments of cartilage and/or bone occupying the joint space, eliciting a further inflammatory response which perpetuates the cycle. Repeated loading of bone leads to subchondral bone sclerosis, and osteophytes (seen on radiographs) are also a common occurrence. These events all manifest clinically as a slow, progressively painful disease with pain, lameness and reduced joint function.
In dogs (and humans) there is also increasing recognition of the concept of hyperalgesia (also known as maladaptive pain or allodynia) where the animal has a heightened sensitivity to pain. This neuropathic pain is likely an under-recognized condition in veterinary patients with an assortment of neuromusculoskeletal diseases5 and is thought to be caused by the development of neuropathic pain elicited in the central nervous system as a result of chronic peripheral (nociceptive) nerve stimulation, such as that caused by OA.
This type of pain can have dramatic effects on patients as its more than just sensory; it involves an emotional component as well, potentially leading to fear, anxiety and stress and that can influence treatment outcomes. This concept should be a consideration in any animal that is non-responsive to treatments.
What species is 2.5% PAAG currently used in?
2.5% PAAG is formulated for intra-articular injection. Its excellent biocompatibility has been demonstrated in mice, rats, rabbits, goats, pigs, horses and humans. It is non-absorbable, non-degradable, non-pyrogenic and neuro-innocuous. These properties enable it to have a long-lasting augmentation effect. Its first use in veterinary patients was as a treatment for osteoarthritis in racing and sports horses. More recently, it has been used for osteoarthritis in human patients and in dogs.
Who manufactures 2.5% PAAG?
2.5% PAAG is produced by Contura BV in Denmark using a patented process called In-line Cross-Linking Technology (ILX Technology). This process forces water molecules between the cross-linked polymers of polyacrylamide (CAS No. 9003-05-8), and that provides the gel with exceptional molecular stability. It consists of polyacrylamide polymers that are cross linked in a stable three-dimensional network, which is hydrophilic and gives it viscoelastic properties. Large amounts of molecular water remain lightly bound within the structure and constantly interchange with surrounding tissues, supporting cell growth and tissue integration (adsorption), and in contrast to other PAAG hydrogel products.
Is 2.5% PAAG safe?
The polymers of acrylamide used to manufacture 2.5% PAAG are exceptionally stable and inert, making them non-toxic. 2.5% PAAG has been shown not to degrade or migrate for up to 8 years in human tissue. Localised mild to moderate inflammation is rarely reported, and over 500,000 doses have now been administered in human patients worldwide.
Where to from here?
In the past practitioners have had few approved treatment options for their OA patients, resulting in many painful pets left undertreated or untreated, and many pet owners frustrated. Owners also often fail to recognize the problem, even when their pets have reduced mobility, often chalking it up to the pet “slowing down with age.” However, there are consequences to this delayed OA pain management. Earlier recognition of the issue and better treatment interventions can help protect the nervous system and the joint, preventing damage and allowing the dog to maintain exercise, which in turn controls weight and maintains muscle mass, as well as the emotional benefits of this for animal and owner.
The challenge for veterinarians is increasing our knowledge of the OA disease process and understanding and implementing better treatment options. In turn this has the ability to open a new era of treatment options for OA in companion animal practice.
References
1. Anderson K.L, Zulch H. O’Neill D.G.et al. Risk factors for canine osteoarthritis and its predisposing arthropathies: a systematic review. Front Vet Sci. 2020; 7: 220
2. Corral, M., Moyaert, H., Fernandes, T., Kira S Tena, J., Walters, R.R., Stegemann, M.R. A prospective, randomized, blinded, placebo-controlled multisite clinical study of bedinvetmab, a canine monoclonal antibody targeting nerve growth factor, in dogs with osteoarthritis. Veterinary Anaesthesia and Analgesia. 2021; 48:6. p 943-955.
3. Schmelz, M., Mantyh, P., Malfait, A.M., Farrar, J., Yaksh, T., Tive, L. and Viktrup, L., 2019. Nerve growth factor antibody for the treatment of osteoarthritis pain and chronic low-back pain: mechanism of action in the context of efficacy and safety. Pain, 160(10), p.2210.
4. Tnibar A, Schougaard H, Camitz L, Rasmussen J, Koene M, Jahn W and Markussen B. An international multi-centre prospective study in the efficacy of an intraarticular polyacrylamide hydrogel in horses with osteoarthritis: a 24 months follow-up. Acta Veterinaria Scandinavia 2015; 57:20.
5. Moore, S.A. Managing neuropathic pain in dogs. Front Vet Sci 2016; 3. Available at https://doi.org/10.3389/fvets.2016.00012.
