Chronic pain affects more patients than cancer, cardiovascular disease and diabetes combined. Its treatment falls to a wide array of physicians and other healthcare providers to address. Consult QD talked to Cleveland Clinic pain management specialist Robert Bolash, MD, to learn more about the challenges of helping patients manage their pain and the potential he sees in Nerve Growth Factor (NGF) inhibitors as an emerging treatment option.
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Q: How do you approach the pain symptoms of your patients?
A: As a pain specialist, I always try to understand the underlying pain generator for each patient. I weigh the risks and benefits of addressing the problem causing the pain symptom against addressing the symptom alone. Few would advocate for a pain management-exclusive approach to appendicitis when a reasonably established surgical treatment has a very high potential to resolve the underlying cause; a symptom-exclusive focused approach is rarely going to prove durable for appendicitis. Other cases are less apparent; at times, treating the underlying cause poses a risk greater than the potential benefit of alternative treatments, or the underlying cause is more obscure. Low back pain is a prime example. Most cases are “nonspecific,” and the vast majority of patients suffering from low back pain have no identifiable cause, or we currently lack the skills and tools of specificity to find it.
Despite the prevalence of chronic pain, the landscape of analgesic treatments has remained stagnant over the past several decades. In a survey of 492 physicians, more than 50% identified the lack of therapeutic options as a significant challenge.1 There is hope this may change as we begin to understand additional mechanisms facilitating chronic pain and work toward demonstrating efficacy of novel drugs to target the abnormalities seen with chronic pain diagnoses. One such pathway may be pharmacotherapeutic targeting of Nerve Growth Factor.
Q: What is NGF?
A: NGF is one of many inflammatory mediators that facilitate pain sensitization. It is released from mast cells along with other pro-inflammatory cytokines such as histamine and interleukins. At the peripheral nociceptor, NGF binds to tropomyosin receptor kinase A (TrkA) to facilitate pain sensitization in the periphery. For example, if you burn your arm with scalding water, you can appreciate how the peripheral nociceptors are ramped up when you touch areas adjacent to that same area a few hours later. At times, even light touch, such as clothing rubbing across the area, will result in allodynia. NGF appears to be pain-specific; it seems to only be involved in alterations in pain and temperature sensitivity, while exerting little to no influence on mechanical receptor and proprioceptor sensations, such as vibration or pressure.
Q: Why isn’t NGF more familiar to clinicians?
A: NGF was discovered in 1956, though it has largely remained off the radar of contemporary clinicians due to the lack of a pharmacotherapeutic compound available for use. That may be changing soon as there are several agents in late stages of development that hold promise to modulate pain via inhibiting NGF pathways.
Q: Why is there a need for a new class of pain medication?
A: Current medications for chronic pain have modest analgesic benefit, and few patients report that medication alone gives them more than partial benefit. Additionally, many available analgesics can interact with medications patients take for other diagnoses or prohibit their use altogether (think NSAIDs and blood thinners). In the physician survey mentioned earlier, more than 90% of respondents said they are concerned about the addictive potential of available analgesics and find that the subjective nature of chronic pain challenges their ability to treat patients effectively.1Patients are similarly frustrated, with more than half reporting that they feel they have little or no control over their chronic pain (2006 Voices of Chronic Pain Survey. American Pain Society).
Q: What are you doing for these patients now?
A: Current treatments for diagnoses such as low back pain include combining nonpharmacological therapies, such as physical therapy and/or cognitive behavioral therapy, with adjunctive analgesic pharmacotherapy, including NSAIDs and selective norepinephrine reuptake inhibitors. Osteoarthritis is similarly treated with education, physical therapy, assistive devices such as canes or walkers, as well as drugs such as acetaminophen and/or NSAIDs. At times, patients failing to respond to conservative therapy will be given interventional pain procedures or advanced implantable devices.
Q: What is the mechanism of how NGF impacts pain?
A: There are at least five ways that NGF likely works on pain perception. I already noted the way it binds to peripheral nerve endings at the TrkA receptor resulting in downstream effects on neurotransmission in the periphery. Secondly, it appears that the bound NGF/TrkA complex is transported up the axon, in a retrograde fashion, toward the dorsal root ganglion (DRG). Here it increases the transcription of neuropeptides and ion channels involved with pain, essentially facilitating pain conduction at the DRG. Thirdly, these regulated neurotransmitters, ion channels and receptors, are transported toward the peripheral nociceptors and the central nervous system at the dorsal horn of the spinal cord. Fourthly, there at the spinal dorsal horn, pain mediators such as substance P further facilitate pain transmission to the central nervous system. Lastly, an excess in NGF stimulates the peripheral immune cells, especially mast cells, to synthesize a further release of even more inflammatory mediators. This is likely a partial contributor to the vicious cycle of chronic pain.
Q: What conditions have NGF inhibitors been studied in?
A: NGF inhibitors have been studied in osteoarthritis, chronic low back pain and even cancer-related pain. Therapeutic benefits have been consistently reported across a number of diagnoses. Some recent studies show that NGF inhibitors seem to work better than some of our currently employed pain treatments, such as NSAIDs or weak opioids. These investigations are particularly meaningful for me as a pain physician, as we often simply see efficacy demonstrated against placebo; rarely is efficacy shown against our current best treatments. This is the best way contemporary clinical research should be done: compare the new treatment against your best current treatment and see which one wins out.
Q: What can you share about the results of using NGF inhibitors for patients with chronic low back pain?
A: Cleveland Clinic was recently involved in a multicenter, multicontinent, double-blind randomized controlled trial of an NGF inhibitor for treatment of patients with chronic low back pain. The results have been presented at the American Society of Regional Anesthesia and Pain Medicine, and demonstrated that not only was the NGF inhibitor effective for treatment of chronic low back pain, but it performed even better than weak opioids for this challenging subgroup. Others have repeatedly shown similarly promising results in patients with osteoarthritis, a condition that affects more than 300 million people worldwide.2-6
Q: How are NGF inhibitors administered?
A: In recent clinical trials, compounds have been administered via a subcutaneous or intravenous route.
Q: Are there any addiction issues with these medications?
A: Fortunately, there has been no significant evidence to suggest NGF inhibitors are demonstrating challenges with addiction or dependence in clinical trials to date.
Q: Are there other side effects to consider?
A: In the multicenter study evaluating NGF inhibitor administration for patients with chronic low back pain, nasopharyngitis, paresthesia, arthralgia and upper respiratory tract infections were reported at a higher incidence than in patients treated with placebo or tramadol. In a small subset of patients, NGF inhibitors advance the development of osteoarthritis at a more rapid rate than is seen with placebo. While this number is small, it was the reason the FDA put a temporary clinical hold on the study of NGF inhibitor molecules several years ago. Concomitant use of NGF inhibitors along with NSAIDs seems to pose a unique hazard for this side effect, and recent trials have limited concomitant use of the compounds.
Q: What is on the horizon?
A: As of this writing, we do not have an FDA-approved NGF inhibitor on the market for widespread patient use, though the FDA has acknowledged receipt of regulatory submission of one NGF inhibitor. I anticipate review will be occurring in the near term.