Novel Future Pharmacological Therapies for Chronic Pain
World Small Animal Veterinary Association World Congress Proceedings, 2015
S. Robertson, BVMS (Hons), PhD, DACVAA, DECVAA, DACAW, DECAWBM (WSEL), Specialist in Welfare Science, Ethics and Law, MRCVS
Department of Small Animal Clinical Sciences, College of Veterinary Medicine, Michigan State University, East Lansing, MI, USA

Chronic pain afflicts a large percentage of human and animal populations, and current treatments do not fully meet the needs of many of these patients; in fact, medicine and science are failing to help those whose lives are impacted by pain. Most drug therapies such as non-steroidal anti-inflammatory agents are not fully effective or are associated with adverse side effects. A goal of pain research is to better understand the underlying mechanisms of pain and to identify new therapeutic targets.

Targeting Novel Mediators of Pain

Nerve growth factor (NGF) has been identified as an important mediator of inflammatory and neuropathic pain and is therefore a potential therapeutic target.1

NGF levels are increased in many naturally occurring acute and chronic pain conditions and in animal models of pain. Inhibiting or sequestering NGF alleviates hyperalgesia in many of these models. Current areas of study for targeting NGF include monoclonal antibodies to NGF or its tyrosine kinase receptor and sequestration of NGF with a soluble receptor protein with high binding affinity.1 Tanezumab, a human monoclonal antibody directed against NGF and administered by the intravenous or subcutaneous route, has undergone human trials for a wide range of painful conditions including osteoarthritis, diabetic neuropathy, post-herpetic neuralgia and interstitial cystitis with good results, although the benefit to risk ratio and optimal dose are still being defined.

In dogs, a fully caninised anti-NGF monoclonal antibody (NV-01) has been developed; treatment must be species specific to avoid an immune response.2 In a preclinical trial using a kaolin model of inflammatory pain, NV-01 reduced the signs of lameness, had a serum half-life of 9 days and was well tolerated. The target population for this drug is dogs with osteoarthritis. In one clinical trial, Canine Brief Pain Inventory scores decreased in dogs for up to four weeks following intravenous administration of NV-01.3

NV-02, a feline specific NGF antibody, is currently undergoing clinical trials at North Carolina State University; this is given once (subcutaneously) and may have an effect of several weeks' duration (https://cvm.ncsu.edu/research/clinical-trials) (VIN editor: The original link was not accessible and was modified as of 3-6-16).

Grapiprant (AT-001) is being evaluated in dogs for its potential to provide targeted pain relief; this drug directly blocks the prostaglandin EP4 receptor, a key receptor involved in pain and inflammation. Preliminary data from a field study in dogs with osteoarthritis showed positive results (http://aratana.com/therapeutics/pipeline/pain) (VIN editor: This link was not accessible as of 3-6-16).

Neurokinin-1 (NK-1) antagonists; maropitant is a NK-1 receptor antagonist and inhibits binding of substance P to NK-1 receptors and is marketed as an antiemetic for dogs and cats. Maropitant is effective against a wide range of peripheral and central emetic stimuli. Because substance P is involved in pain pathways, maropitant may have some analgesic properties. Preliminary work evaluating its anesthetic sparing effects suggests it may provide visceral analgesia in dogs4 and cats.

NMDA antagonists. The NMDA receptor, located in the dorsal horn of the spinal cord, plays an important role in central sensitization.5 Ketamine is the most widely studied NMDA antagonist in veterinary medicine and shows anti-hyperalgesic properties. Ketamine is most effective when given intravenously, therefore is not practical for long-term use in chronic pain patients. Amantadine, which also works at the NMDA receptor, can be given orally and one study in dogs supports its use as an adjunct drug in the treatment of osteoarthritis.6

Selective Neurotoxins

Inhibition or destruction of specific nociceptive neurones without altering other sensory or motor functions is an attractive option for the control of severe pain. The vanilloid receptor which is present in the nociceptive neurons of the dorsal root and trigeminal ganglia has been targeted by resiniferatoxin (RTX) administered intrathecally in dogs with painful and debilitating bone cancers and osteoarthritis.7,8 In dogs with bone cancer, pain relief was excellent.

Substance P-saporin (SP-SAP) is a chemical conjugate of Substance P and a recombinant version of a ribosome inactivating protein (saporin). It acts as a targeted neurotoxin and selectively destroys cells in the dorsal horn of the spinal cord that bear NK-1 receptors. SP-SAP is given by intrathecal injection and has been studied in dogs.9

In a prospective blinded controlled study of dogs with naturally occurring bone cancer, results during the first two weeks after treatment were equivocal, but after two weeks the dogs that received SP-SAP had lower pain scores compared to dogs that received "standard of care" analgesic therapies (non-steroidal anti-inflammatory agents, tramadol and gabapentin), but some dogs in the SP-SAP group developed ataxia.9

Stem Cell Therapies

There is great interest in the use of stem cells as a therapeutic option for many companion animal diseases, in particular osteoarthritis. These therapies are commercially available in several countries but are expensive. In veterinary medicine, mesenchymal stem cells isolated from adipose tissue are most commonly used. A recent review indicates that we need to be cautious because the purported benefits and "hype" surrounding these therapies are not yet supported by rigorously controlled scientific studies.10

Palliative stereotactic radiosurgery is the precise delivery of a large, single dose of radiation to a tumor target. This technique has been applied to dogs with appendicular osteosarcoma with good outcomes compared to alternative treatments; pain was reduced and limb function was good to excellent after treatment.11 The major limitations of this treatment are cost and limited availability.

Developing targeted therapies to alleviate chronic pain is an active area of research; many spontaneous painful diseases in dogs and cats, such as bone cancers and degenerative joint disease, are being used as models for similar conditions in humans. Several new compounds show great promise and are being developed specifically for use in companion animals.

References

1.  Watson JJ, Allen SJ, Dawbarn D. Targeting nerve growth factor in pain: what is the therapeutic potential? BioDrugs. 2008;22(6):349–359.

2.  Gearing DP, Virtue ER, Gearing RP, Drew AC. A fully caninised anti-NGF monoclonal antibody for pain relief in dogs. BMC Vet Res. 2013;9:226.

3.  Webster RP, Anderson GI, Gearing DP. Canine brief pain inventory scores for dogs with osteoarthritis before and after administration of a monoclonal antibody against nerve growth factor. Am J Vet Res. 2014;75(6):532–535.

4.  Boscan P, Monnet E, Mama K, Twedt DC, Congdon J, Steffey EP. Effect of maropitant, a neurokinin 1 receptor antagonist, on anesthetic requirements during noxious visceral stimulation of the ovary in dogs. Am J Vet Res. 2011;72(12):1576–1579.

5.  Pozzi A, Muir WW, Traverso F. Prevention of central sensitization and pain by N-methyl-D-aspartate receptor antagonists. J Am Vet Med Assoc. 2006;228(1):53–60.

6.  Lascelles BD, Gaynor JS, Smith ES, Roe SC, Marcellin-Little DJ, Davidson G, et al. Amantadine in a multimodal analgesic regimen for alleviation of refractory osteoarthritis pain in dogs. J Vet Intern Med. 2008;22(1):53–59.

7.  Karai L, Brown DC, Mannes AJ, Connelly ST, Brown J, Gandal M, et al. Deletion of vanilloid receptor 1-expressing primary afferent neurons for pain control. J Clin Invest. 2004;113(9):1344–1352.

8.  Brown DC, Iadarola MJ, Perkowski SZ, Erin H, Shofer F, Laszlo KJ, et al. Physiologic and antinociceptive effects of intrathecal resiniferatoxin in a canine bone cancer model. Anesthesiology. 2005;103(5):1052–1059.

9.  Brown DC, Agnello K. Intrathecal substance P-saporin in the dog: efficacy in bone cancer pain. Anesthesiology. 2013;119(5):1178–1185.

10. Whitworth DJ, Banks TA. Stem cell therapies for treating osteoarthritis: prescient or premature? Vet J. 2014;202(3):416–424.

11. Farese JP, Milner R, Thompson MS, Lester N, Cooke K, Fox L, et al. Stereotactic radiosurgery for treatment of osteosarcomas involving the distal portions of the limbs in dogs. J Am Vet Med Assoc. 2004;225(10):1567–1572, 1548.

  

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Sheilah Robertson, BVMS (Hons), PhD, DACVAA, DECVAA, DACAW, DECAWBM (WSEL), MRCVS
Department of Small Animal Clinical Sciences
College of Veterinary Medicine
Michigan State University
East Lansing, MI, USA


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