The Future of Acute and Chronic Pain Management: Anti-NGF Monoclonal Antibodies Are Coming

In human clinical studies, several anti–nerve growth factor monoclonal antibodies have been evaluated and been shown to reduce pain and improve function in patients with osteoarthritis.

Advertisement

by Mike Petty, DVM, CCRT, CVPP, DAAPM

Get ready for what could be the biggest advancement in the treatment of chronic pain since veterinary practitioners were able to add nonsteroidal anti-inflammatory drugs (NSAIDs) to their pain treatment toolbox. Anti–nerve growth factor (NGF) monoclonal antibodies (mAbs) are on the horizon for the treatment of chronic pain in both dogs and cats.

Besides some pharmaceutical options, we currently have many tools that can be used for the treatment of chronic pain; however, many of them require advanced training or specialized equipment to employ them in our practice (see Table 1).

Every therapy has its limitations, often set by three factors: the degree of pathology in the patient, comorbidities that might limit its use in some patients, and the response of the patient to each of the therapies. Every new therapy that comes along will have to face these three basic issues. But these issues can often be mitigated as we have more therapeutic options.

How do anti-NGF mAbs control pain? Haven’t we been told that NSAIDs are the gold standard for treating pain? These are common questions that occur to many veterinarians as we look at an entirely new pathway to treat pain. See Table 2. You will notice that there are 10 different cytokines or mediators listed, all having an effect on a different receptor within the nociceptor, the pain “nerve ending.”

The cytokines and mediators are all responsible for causing pain when they are coupled with their receptors. However, not all receptors respond by causing similar degrees of pain signals to travel up the pain pathway to the brain. Two important mediators in blocking pain are prostaglandin E2 (PGE2) and NGF. NSAIDs block the action of PGE2 on the EPA 1 through 4 receptors. We know that this is an effective method of pain control, but they do not stop all of the pain, as some of the other mediators may be part of the entire chemical “soup” that is stimulating the nociceptor.

As just mentioned, NGF is also an important player in nociceptor stimulation after a pain-inducing event. NGF has an important and positive role in the development of nerves early in life. However, for some reason, once nerve growth is complete, it takes on a negative role by facilitating the transmission of pain. To date, there have been no pharmaceuticals that have effectively blocked the NGF molecule from attaching to the TrkA (tropomyosin kinase A, commonly pronounced “trek a”) receptor on the nociceptor. Once the NGF has attached itself to the TrkA receptor, this NGF-TrkA “complex” is then internalized and transported from peripheral nociceptor terminals to sensory cell bodies in the dorsal root ganglion. It also leads to upregulation of other receptors that add to the hypersensitivity reaction.

We currently have many tools that can be used for the treatment of chronic pain; however, many of them require advanced training or specialized equipment to employ them in our practice.

Although there are no pharmaceuticals that can effectively block NGF, there has recently been some development of long-acting anti-NGF mAbs that can stop the available NGF to reduce the binding to TrkA receptors. This is exciting news on several fronts. Not only is NGF a key regulator in chronic pain, it is also a key regulator in both acute and neuropathic pain. Additionally, by stopping the action of NGF, it can help stop the further development of hyperalgesia; continual bombardment of nerve endings by NGF can sensitize the nerve endings to other mediators, making nociceptors respond more easily to other painful stimuli. In human clinical studies, several anti-NGF mAbs have been evaluated and been shown to reduce pain and improve function in patients with osteoarthritis (OA).

Development of Anti-NGF Therapy for Canine OA

For canine patients, there are currently three companies holding patents for anti-NGF mAbs: Nexvet Biopharma, Abbott Laboratories, and Zoetis. (Note: Nexvet and Abbott have both been acquired by Zoetis.) In one Nexvet proof-of-concept study, a single injection of its test product, ranevetmab, was shown to have clinically significant improvement in pain scores for four weeks, with some reduction in pain seen at the six-week mark as well. The reduction in pain scores was similar to that seen with both Rimadyl and Galliprant. Even more importantly, not a single adverse event (AE) was reported.

Development of Anti-NGF Therapy for Feline OA

Currently, Abbott Laboratories and Nexvet Biopharma hold patents for anti-NGF mAbs in cats. However, the only published data in cats are for the Nexvet feline anti-NGF mAb frunevetmab. In the frunevetmab proof-of-concept study, subjective owner assessments showed a significant effect of treatment over the first three weeks after administration, the first time in the published literature that owners have been able to correctly distinguish between treatment and placebo in cats with OA-associated pain under a parallel-design, placebo-controlled study. This is particularly noteworthy given the very high caregiver placebo effect seen in feline chronic pain studies. As in the dog study, positive effects were seen for up to six weeks, with no AEs reported.

What We Don’t Know About Anti-NGF Therapy in Dogs and Cats

Although the mAbs appear to have an excellent safety profile, there are several unknowns. The first is the long-term effect of this therapy. In clinical studies, they were only given for several months. The second question, one that may be on everyone’s mind, is: Are they safe to give concurrently with NSAIDs? The answer to that question will have to wait for a future study. And finally, anti-NGF mAbs are probably not safe to give to pregnant or lactating animals; remember that NGF is extremely important in the developing animal.

What About Other Sources of Pain?

Increased levels of NGF are seen in a wide range of painful disorders besides osteoarthritis, including degenerative intervertebral disc disease, prostatitis, and cancer. Administration of anti-NGF mAbs has been shown to provide effective analgesia in a number of animal models of human disease, including inflammatory arthritis, fracture pain, joint surgery, cancer pain, and pancreatic pain.

Anti-NGF mAbs may also be useful for the treatment of acute pain. Orthopedic surgery studies in mice have shown positive benefits when given pre-emptively. There have also been human trials showing reduced pain in people with interstitial cystitis.

If you want to learn more about anti-NGF mAbs, I recommend that you read the paper where some of the information in this article was obtained: “Anti-Nerve Growth Factor Monoclonal Antibodies for the Control of Pain in Dogs and Cats,” an open-access article from the Veterinary Record, available on PubMed.

Mike Petty, DVM, CCRT, CVPP, DAAPM, is in private practice in Canton, Michigan. He is a frequent national and international lecturer on topics related to pain management. He was also a member of the task force for the 2015 AAHA/AAFP Pain Management Guidelines for Dogs and Cats.

Photo credits: ©iStock.com/mirror-images, ©iStock.com/Capuski