Clinical Medicine , Orthopedics , Pain Management , Pharmacology

Managing Chronic Pain in Dogs & Cats Part 2
The Best of the Rest in the Management of Osteoarthritis

Managing Chronic Pain in Dogs & Cats Part 2</br>The Best of the Rest in the Management of Osteoarthritis

pdf_button


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 1The 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
  • Dogs and cats
  • Administer SC
  • Continue on long-term basis, (eg, Q 1 month and adjust frequency according to patient needs)
Caution with patients at risk for bleeding dyscrasia
Cartrophen Vet 3 mg/kg SC Q 5—7 days, 4 times
  • Continue on long-term basis, (eg, repeat protocol Q 4—6 months)


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

ADDITIONAL OPTIONS

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)
  • Nonpharmacologic
  • Biologic.

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)

Gabapentin
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
Acetaminophen
10—15 mg/kg PO Q 12 H39
  • Contraindicated in cats
  • No special proclivity toward hepatotoxicity in dogs; judicious use recommended
Amantadine
NMDA receptor antagonist 
3—5 mg/kg PO Q 12 H21
  • Primary adverse effects include agitation and diarrhea
  • Anticholinergic
Amitriptylinea
Tricyclic antidepressant
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
  • Primary adverse effects include, in humans, dry mouth, sedation, behavioral changes, and seizure potentiation
Codeineb
Opioid
0.5—2 mg/kg PO Q 12 H39
  • Some suggest dogs only
  • Pharmacokinetics, but no clinical data, available
Gabapentin
Anticonvulsant
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
  • Primary adverse effects include somnolesense, which can be minimized by starting with lower doses and gradually increasing to effect
  • For smaller animals, may be compounded into 50 mg/mL nonxylitol containing suspension
Hydrocodoneb
Opioid
0.22—0.5 mg/kg PO Q 8—12 H39
  • Some suggest dogs only
  • Pharmacokinetics, but no clinical data, available
  • Primary adverse effects include sedation
Morphine/lidocaine/ketamine CRI
Dogs:
Morphine, 4 mcg/kg/min
Lidocaine, 50 mcg/kg/min
Ketamine, 10 mcg/kg/min
CRI for 24—48 H
  • Clinical utility for chronic pain holiday anecdotal only
  • Administer combined or individually
  • Primary adverse effects include, in humans, GI effects, behavioral changes, seizure potentiation, hypertension, bleeding dyscrasia, sedation
  • Unfavorable pharmacokinetics in dogs; better in cats
Tramadola
Cats:
1—4 mg/kg PO Q 12 H39
Dogs:
2—10c mg/kg PO Q 8—12 H29
  • No safety or toxicity data in dogs or cats; limited to no data to support efficacy in dogs
  • Higher doses may increase risk for adverse effects
Venflaxinea
SSNRI
3—4 mg/kg PO Q 8—12 H31
  • Not in clinical use for chronic pain in dogs or cats
  • No safety or toxicity data
  1. Caution should be exercised when using these and other serotoninergic, monoaminergic drugs in combination.
  2. If used in combination with acetaminophen, base dosage administered on calculated acetaminophen dose.
  3. Higher doses are more likely to lead to adverse effects, and it is prudent to initiate dosing at 2—4 mg/kg.
NMDA = N-methyl-D-aspartate; SSNRI = serotonin-norepinephrine reuptake inhibitor

Amantadine

One study in dogs with refractory OA demonstrated the efficacy of amantadine and an NSAID versus NSAIDs alone.21

Tramadol

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.

Corticosteroids

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

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.

Oral Opioids

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

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
  • Acupuncture
  • Myofascial trigger point therapy
  • Therapeutic laser (photobiomodulation)
  • Pulsed acoustic wave therapy
  • Pulsed electromagnetic field therapy

Biologic

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.

IN SUMMARY

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

References

  1. 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.
  2. Kirby KA, Lewis DD. Canine hip dysplasia: Reviewing the evidence for nonsurgical management. Vet Surg 2011; [epub ahead of print].
  3. Bennett D, Zainal Ariffin SM, Johnston P. Osteoarthritis in the cat: 1. How common is it and how easy to recognise? and 2. How should it be managed and treated? J Fel Med Surg 2012; 14:65-84.
  4. 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.
  5. Smith JG, Hannon RL, Brunnberg L, et al. (2001) A randomised double blind comparator clinical study of the efficacy of sodium pentosan polysulfate injection and carprofen capsules in arthritic dogs. J OARSI 2001; 9(b):S21-S22.
  6. Moreau M, Troncy E, Del Castillo JR, et al. Effects of feeding a high omega-3 fatty acids diet in dogs with naturally occurring osteoarthritis. J Anim Physiol Anim Nutr (Berl) 2012; [epub ahead of print].
  7. 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.
  8. 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.
  9. 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.
  10. Fritsch D, Allen TA, Dodd CE, et al. Dose-titration effects of fish oil in osteoarthritic dogs. J Vet Intern Med 2010; 24(5):1020-1026.
  11. Vandeweerd JM, Coisnon C, Clegg P, et al. Systematic review of efficacy of nutraceuticals to alleviate clinical signs of osteoarthritis. J Vet Intern Med 2012; 26(3):448-456.
  12. Hahn K. Nutritional management of cats with arthritic discomfort: Results from a controlled clinical trial. Hill’s Global Mobility Symposium Proceedings, 2008, p 27 (hillsvet.com/conferenceproceedings).
  13. Corbee RJ, Barnier MM, van de Lest CH, Hazewinkel HA. The effect of dietary long-chain omega-3 fatty acid supplementation on owner’s perception of behaviour and locomotion in cats with naturally occurring osteoarthritis. J Anim Physiol Anim Nutr (Berl) 2012; [epub ahead of print].
  14. Krontveit RI, Trangerud C, S+�vik BK, et al. Risk factors for hip-related clinical signs in a prospective cohort study of four large dog breeds in Norway. Prev Vet Med 2012; 103(2-3):219-227.
  15. Conzemius M. Personal communication 2012.
  16. Melzack R, Wall PD. Pain mechanisms: A new theory. Science 1965; 150(3699):971-979.
  17. Ivanavicius SP, Ball AD, Heapy CG, et al. Structural pathology in a rodent model of osteoarthritis is associated with neuropathic pain: Increased expression of ATF-3 and pharmacological characterisation. Pain 2007; 128(3):272-282.
  18. Hanesch U, Pawlak M, McDougall JJ. Gabapentin reduces the mechanosensitivity of fine afferent nerve fibres in normal and inflamed rat knee joints. Pain 2003; 104(1-2):363-366.
  19. 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.
  20. Troncy E. Personal communication, 2013; publication pending.
  21. 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.
  22. Giorgi M, Saccomanni G, Lebkowska-Wieruszewska B, Kowalski C. Pharmacokinetic evaluation of tramadol and its major metabolites after single oral sustained tablet administration in the dog: A pilot study. Vet J 2009; 180(2):253-255.
  23. Kukanich B, Papich MG. Pharmacokinetics and antinociceptive effects of oral tramadol hydrochloride administration in greyhounds. Am J Vet Res 2011; 72(2):256-262.
  24. Matthiesen T, W+�hrmann T, Coogan TP, Uragg H. The experimental toxicology of tramadol: An overview. Toxicol Lett 1998; 95(1):63-71.
  25. Malek S, Sample SJ, Schwartz Z, et al. Effect of analgesic therapy on clinical outcome measures in a randomized controlled trial using client-owned dogs with hip osteoarthritis. BMC Vet Res 2012; 8:185.
  26. McMIllan CJ, Livingston A, Clark CR, et al. Pharmacokinetics of intravenous tramadol in dogs. Can J Vet Res 2008; 72(4):325-331.
  27. Pypendop BH, Ilkiw JE. Pharmacokinetics of tramadol, and its metabolite O-desmethyl-tramadol, in cats. J Vet Pharmacol Ther 2008; 31(1):52-59.
  28. Troncy E. Personal communication, 2013; abstract presented: Lembert 2003 WCVA p 157.
  29. KuKanich B. Outpatient oral analgesics in dogs and cats beyond nonsteroidal antiinflammatory drugs: An evidence-based approach. Vet Clin N Am Small Anim Pract 2013; 43(5):1109-1125.
  30. Sullivan M, Bentley S, Fan MY, Gardner G. A single-blind placebo run-in study of venlafaxine XR for activity-limiting osteoarthritis pain. Pain Med 2009; 10(5):806-812.
  31. Howell SR, Hicks DR, Scatina JA, Sisenwine SF. Pharmacokinetics of venlafaxine and O-desmethylvenlafaxine in laboratory animals. Xenobiotica 1994; 24(4):315-327.
  32. Pelletier JP, Mineau F, Raynauld JP, et al. Intraarticular injections with methylprednisolone acetate reduce osteoarthritic lesions in parallel with chondrocyte stromelysin synthesis in experimental osteoarthritis. Arthritis Rheum 1994; 37(3):414-423.
  33. Pelletier JP, Martel-Pelletier J. In vivo protective effects of prophylactic treatment with tiaprofenic acid or intraarticular corticosteroids on osteoarthritic lesions in the experimental dog model. J Rheumatol Suppl 1991; 27:127-130.
  34. Pelletier JP, Martel-Pelletier J. Protective effects of corticosteroids on cartilage lesions and osteophyte formation in the Pond-Nuki dog model of osteoarthritis. Arthritis Rheum 1989; 32(2):181-193.
  35. Pelletier JP, DiBattista JA, Raynauld JP, et al. The in vivo effects of intraarticular corticosteroid injections on cartilage lesions, stromelysin, interleukin-1, and oncogene protein synthesis in experimental osteoarthritis. Lab Invest 1995; 72(5):578-586.
  36. Abdulla A, Adams N, Bone M, et al. British Geriatrics Society. Guidance on the management of pain in older people. Age Ageing 2013; 42(suppl 1):i1-i57.
  37. KuKanich B. Pharmacokinetics of acetaminophen, codeine, and the codeine metabolites morphine and codeine-6-glucuronide in healthy greyhound dogs. J Vet Pharmacol Ther 2010; 33(1):15-21.
  38. KuKanich B, Paul J. Pharmacokinetics of hydrocodone and its metabolite hydromorphone after oral hydrocodone administration to dogs. ACVIM Proc 2010.
  39. Plumb DC. Plumb’s Veterinary Drug Handbook, 7th ed. Ames, IA: Wiley-Blackwell, 2011.
  40. Muir WW 3rd, Wiese AJ, March PA. Effects of morphine, lidocaine, ketamine, and morphine-lidocaine-ketamine drug combination on minimum alveolar concentration in dogs anesthetized with isoflurane. Am J Vet Res 2003; 64(9):1155-1160.
  41. Caron JP, Fernandes JC, Martel-Pelletier J, et al. Chondroprotective effect of intraarticular injections of interleukin-1 receptor antagonist in experimental osteoarthritis. Suppression of collagenase-1 expression. Arthritis Rheum 1996; 39(9):1535-1544.

F04_BMark 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.

DMCA.com Protection Status
MENU