Mark E. Epstein, DVM, Diplomate ABVP (Canine/Feline), CVPP
In this article, the second of the 3-part series, Dr. Epstein discusses additional modalities for treating osteoarthritis in dogs and cats, including therapeutic exercise, polysulfated glycosaminoglycans, omega-3 fatty acids, and suggested off-label dose s for pain-modifying analgesic drugs.
Part 1—The Two Most Important Tools in the Management of Osteoarthritis(November/December 2013, available at tvpjournal.com)—of this 3-part series addressed basic principles of chronic pain and also discussed treatment for its most common manifestation in companion animals: osteoarthritis (OA).
While Part 1 dealt with the 2 most important considerations in OA therapy: weight optimization and nonsteroidal anti-inflammatory drug (NSAID) therapy, this article discusses other modalities—both pharmacologic and nonpharmacologic—for treatment of canine and feline OA.
TOP 3 MODALITIES
Well-designed, systematic reviews evaluating treatment of OA and nonsurgical management of hip dysplasia in dogs are now available.1,2 Very good review articles are also available for cats diagnosed with OA.3
Based on these evidence-based perspectives—once weight optimization and NSAID therapy have been implemented—3 modalities rise to the top of the list.1.
1. Polysulfated Glycosaminoglycans
Veterinary polysulfated glycosaminoglycans (PSGAGs) administered by the parenteral route (ie, IV or IM injection) have met both regulatory scrutiny and quality control measures; independent studies appear to support their clinical utility.4,5 Examples include (Table 1):
- PSGAG (Adequan Canine, novartis.com)
- Sodium pentosan polysulfate (Cartrophen Vet for Dogs, biopharmaus.com.au).
In contrast, clinical evidence for oral nutraceuticals is limited in dogs and cats and, at best, conflicting in humans. However, it can be argued that initiating use of oral nutraceuticalsearly in life, particularly for at-risk breeds, is safe and may provide some long-term chondroprotective effect.
If nutraceuticals and oral supplements are used, caution is warranted due to the following concerns:
- Degree of quality control
- Potential drug interactions, especially with NSAIDs, because some over-the-counter products contain aspirin or other cyclooxygenase (COX)-inhibiting agents
- Ingredients derived from endangered species
- Need for clinical studies to demonstrate efficacy
|TABLE 1. On- and Off-Label Use of Polysulfated Glycosaminoglycans|
|On-Label Dose: Dogs||Off-Label Use||Comments|
|Adequan||4.4 mg/kg IM twice weekly for 4 weeks||
||Caution with patients at risk for bleeding dyscrasia|
|Cartrophen Vet||3 mg/kg SC Q 5—7 days, 4 times||
2. Omega-3 Fatty Acids
Several randomized placebo-controlled blinded studies6-10 and one systematic review11have demonstrated the efficacy of diets rich in:12,13
- Eicosapentaenoic acid (EPA) for dogs with OA
- Docosahexaenoic acid (DHA) for cats with OA.
The availability of multiple randomized placebo-controlled blinded studies and systematic reviews place these data high on the evidence-based pyramid. However, this type of supplementation should be reserved for pets at a healthy weight.
Gate Theory of Pain
The spinal cord has a functional, neurophysiologic “gate” that can either block or allow pain signaling to the brain;16 by sending other signals to the brain during exercise (eg, proprioception), pain signaling through the spinal cord “gate” is, to a degree, blocked.
3. Therapeutic Exercise
While a relatively new modality in veterinary medicine, controlled, prescribed exercise is well established in humans for amelioration of pain related to OA. There is every reason to believe that dogs and cats can benefit as well due to a variety of mechanisms, including:
- The Gate Theory of pain
- Activation of endogenous opioids
- Enhanced strength of periarticular soft tissue (eg, muscle, tendon, ligament) and resulting improved microstability of joints
- Weight loss (if needed).
Some studies already support use of this modality in painful dogs with OA.14,15
The evidence for other recommended treatments for OA pain is either limited, weak, conflicting, or based on in vitro cellular/molecular rather than clinical data. However, modalities that may play a role in management of OA in dogs and cats include:
- Pharmacologic (pain modifying analgesic drugs)
Diagnostic & Treatment Considerations for OA Patients
- Perform diagnostics.
- Conduct a thorough history, physical examination, imaging, and laboratory evaluation.
- Establish treatment goals with the owner, and then create the treatment plan.
- Explain that the reward for the pet can be great in terms of longevity and improved quality of life, but only with good cooperation, compliance, and communication.
- Educate owners on how to recognize potential drug adverse events. Explain what to do if adverse events occur.
- Follow-up. Schedule the next reassessment before the client leaves. Touch base periodically with one of the validated chronic pain/disability owner assessment tools.
Pharmacologic Therapy Options (Table 2)
No clinical studies evaluating gabapentin—as a single agent or an adjunct to NSAIDs—for the treatment of OA have been conducted in humans, dogs, or cats. However, a neuropharmacologic rationale exists for gabapentin’s ability to diminish central and peripheral sensitization, which is supported by a number of rodent studies.17,18
One canine study suggests that gabapentin may provide a chondroprotective effect in experimentally induced OA,19 and a pending study in cats appears to demonstrate the clinical efficacy of gabapentin for pain associated with naturally occurring feline hip OA.20
Macrostability: Gross subluxation
Microstability: Diminished laxity of joint that cannot be grossly appreciated
|TABLE 2. Recommended Doses for Pain Modifying Analgesic Drugs|
|SUGGESTED DOSE||PRIMARY ADVERSE EFFECTS & NOTES|
||10—15 mg/kg PO Q 12 H39
NMDA receptor antagonist
|3—5 mg/kg PO Q 12 H21
|Dogs, initial dose:
1—2 mg/kg PO Q 8—12 H39
Increase as needed to:
3—4 mg/kg PO Q 8—12 H29
|0.5—2 mg/kg PO Q 12 H39
|Initially 3—5 mg/kg PO Q 12 H, taper upwards to effect; doses as high as 20 mg/kg or more may be needed PO Q 8—12 H39
|0.22—0.5 mg/kg PO Q 8—12 H39
Morphine, 4 mcg/kg/min
Lidocaine, 50 mcg/kg/min
Ketamine, 10 mcg/kg/min
CRI for 24—48 H
1—4 mg/kg PO Q 12 H39Dogs:
2—10c mg/kg PO Q 8—12 H29
|3—4 mg/kg PO Q 8—12 H31||
|NMDA = N-methyl-D-aspartate; SSNRI = serotonin-norepinephrine reuptake inhibitor|
One study in dogs with refractory OA demonstrated the efficacy of amantadine and an NSAID versus NSAIDs alone.21
The pharmacokinetics of oral tramadol do not favor its use for OA pain in dogs.22-25In fact, the pharmacokinetics of oral tramadol are not favorable in the dog, in general, and especially not for chronic use (plasma levels, low to begin with, diminish rapidly to near negligible levels after sequential use over several days). Even with IV tramadol, dogs do not produce the mu receptor active metabolite that occurs in humans.26 It may be better suited pharmacologically for cats,27 but its extremely bitter taste may limit its use.
At this time, no studies have been published that demonstrate tramadol’s efficacy for treatment of OA in cats or dogs, either alone or as an adjunct to NSAIDs. The results of one canine study suggested that dogs with OA improved with tramadol according to owner assessments; however, the placebo group also improved, and there was no improvement in the tramadol group according to objective gait analysis.25 However, one study submitted for publication may reveal more encouraging results.28
The Role of Constant Rate Infusions
Intravenous constant rate infusions (CRI) of ketamine, lidocaine, opioids, or a combination can be used for a 24 to 48 hour pain holiday and to also reduce central sensitization. Used for severe neuropathic pain states in humans, this methodology has been anecdotally used but not yet investigated in canine and feline patients with OA.
Tricyclic Antidepressants & Selective Serotonin/Norepinephrine Reuptake Inhibitors
Although known for their ability to treat chronic and neuropathic pain conditions in humans, as of yet, no data support the use of these drugs for management of canine or feline OA.
- Duloxetine (Cymbalta, lilly.com), a selective serotonin/norepinephrine reuptake inhibitor, is labeled for musculoskeletal and low back pain in humans, but has very poor oral bioavailability in dogs.29
- Oral venlafaxine (Effexor, pfizer.com), labeled as an antidepressant in humans, has been demonstrated to diminish pain intensity and improve function in humans with OA.30 In dogs, it has approximately 50% bioavailability and a half-life of 3 hours.31
- There is no strong evidence for the pain modifying effect of fluoxetine, a selective serotonin reuptake inhibitor.
Intra-articular corticosteroid injection is a first-line therapy for OA in humans and horses. In dogs, studies in experimentally induced OA demonstrate that corticosteroid injections may have a disease modifying and, possibly, chondroprotective effect,32-35 but clinical studies are lacking.
Acetaminophen remains a first-line therapy for acute and chronic pain in elderly humans,36and unlike cats, a literature search for toxicity in dogs does not reveal any special sensitivity to adverse effects or toxicity in this species. Judicious use can be considered in dogs but not in cats.
Dogs have a robust first-pass effect with oral opioids, limiting their usefulness compared with human patients, but pharmacokinetic studies reveal the possible efficacy of codeine37and hydrocodone38 in this species.
Nonpharmacologic treatment of OA in dogs and cats includes a variety of therapies (Table 3). While unsupported at this time by strong clinical evidence, these modalities:
- Have plausible, if yet unproven, beneficial effects
- Are generally safe with proper use
- May be employed as an adjunct to other therapies, or when nonpharmacologic modalities are indicated or preferred.
As part of an integrated approach to treating pain, acupuncture, in particular, has been accepted by both the National Institutes of Health (nih.gov) and International Veterinary Academy of Pain Management (ivapm.org) in their respective position/consensus statements.
|Table 3. Common Nonpharmacologic Therapies for Canine & Feline OA|
The relative merits and roles of intra-articular stem cell therapy, platelet-rich plasma therapy, extracellular matrix bioscaffolds, hyaluronate, and even botulinum toxin remain areas of interest and research. How these modalities will fit into management of OA remains undetermined at this time.
One commercial autologous conditioned serum product (IRAP, arthrexvetsystems.com) is labeled for intra-articular injection in horses with OA; it suppresses the highly pro-inflammatory cytokine Interleukin-1. There is no similar commercial product for use in dogs, but there is indication that the modality may have a disease-modifying effect in this species.41
A commercial systemically administered anti-nerve growth factor monoclonal antibody product is currently in development for the treatment of canine OA. Investigations are also in progress for treatment of canine OA with Interleukin-10, a potent inhibitor of spinal cord glial activity.
The ideal pain management protocol for a particular OA patient will vary by stage of disease, doctor and client values, and of course, individual needs and responses.
COX = cyclooxygenase; CRI = constant rate infusion; DHA = docosahexaenoic acid; EPA = eicosapentaenoic acid; NSAID = nonsteroidal anti-inflammatory drug; OA = osteoarthritis; PSGAG = polysulfated glycosaminoglycan
Read Part 1 of this article, Managing Chronic Pain in Dogs and Cats (Osteoarthritis).
Read Part 3 of this article, Managing Chronic Pain (Nonosteoarthritic Pain Conditions).
- Marshall W, Bockstahler B, Hulse D, Carmichael S. A review of osteoarthritis and obesity: Current understanding of the relationship and benefit of obesity treatment and prevention in the dog. Vet Comp Orthop Traumatol 2009; 22(5):339-345.
- Kirby KA, Lewis DD. Canine hip dysplasia: Reviewing the evidence for nonsurgical management. Vet Surg 2011; [epub ahead of print].
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- Fujiki M, Shineha J, Yamanokuchi K, et al. Effects of treatment with polysulfated glycosaminoglycan on serum cartilage oligomeric matrix protein and C-reactive protein concentrations, serum matrix metalloproteinase-2 and -9 activities, and lameness in dogs with osteoarthritis. Am J Vet Res 2007; 68(8):827-833.
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- Roush JK, Dodd CE, Fritsch DA, et al. Multicenter veterinary practice assessment of the effects of omega-3 fatty acids on osteoarthritis in dogs. JAVMA 2010; 236(1):59-66.
- Roush JK, Cross AR, Renberg WC, et al. Evaluation of the effects of dietary supplementation with fish oil omega-3 fatty acids on weight bearing in dogs with osteoarthritis. JAVMA 2010; 236(1):67-73.
- Fritsch DA, Allen TA, Dodd CE, et al. A multicenter study of the effect of dietary supplementation with fish oil omega-3 fatty acids on carprofen dosage in dogs with osteoarthritis. JAVMA 2010; 236(5):535-539.
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- Bioleau C, Martel-Pelletier J, Brunet J, et al. PD-0200347, an alpha2delta ligand of the voltage gated calcium channel, inhibits in vivo activation of the Erk1/2 pathway in osteoarthritic chondrocytes: A PKCalpha dependent effect. Ann Rheum Dis 2006; 65(5):573-580.
- Troncy E. Personal communication, 2013; publication pending.
- Lascelles BD, Gaynor JS, Smith ES, et al. Amantadine in a multimodal analgesic regimen for alleviation of refractory OA pain in dogs. J Vet Intern Med 2008; 22(1):53-59.
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Mark Epstein, DVM, Diplomate ABVP (Canine/Feline), CVPP, is the senior partner and medical director of Carolinas Animal Pain Management & TotalBond Animal Hospitals, a group of AAHA-accredited practices in the Charlotte and Gastonia, North Carolina, areas. He is a member of the American Academy of Pain Management and International Veterinary Academy of Pain Management, and a past president of the IVAPM and ABVP, and an author and lecturer on the recognition, prevention, and treatment of pain. Dr. Epstein received his DVM from the University of Georgia.