For those with osteoarthritis, a slowly progressing joint disease, the most concerning symptom is pain. Indeed, pain is the reason most people later diagnosed with osteoarthritis seek out medical care in the first place.
Initially felt as a sharp ache or burning sensation accompanying movement, osteoarthritis pain can become constant over time. The problem is widespread, as joint pain related to osteoarthritis accounts for about twenty percent of all chronic pain experienced worldwide. To address this problem, the International Association for the Study of Pain (IASP), a nonprofit association that brings together clinicians, researchers, healthcare providers and policymakers to advance pain research and treatment, has made joint pain the focus of its Global Year Against Pain in 2016.
Yet, physicians lack effective ways to manage osteoarthritis joint pain. Limited options for treatment in part reflect an incomplete understanding of how osteoarthritis affects the nervous system to cause pain. To a large degree, this has resulted from a longstanding divide between those studying osteoarthritis and those studying joint pain.
“There was not much dialogue at all between osteoarthritis research and pain research,” says Hans-Georg Schaible, a joint pain researcher at Jena University, Germany. “They were of two different worlds.”
Fortunately, the two fields finally seem to be coming together, offering hope that a better grasp of osteoarthritis joint pain—and perhaps a path to new treatments too—are on the way.
Do changes in joint structure matter?
Researchers have tried to tease out the relationship between osteoarthritis pain and alterations in the structure of the affected joints. Perhaps the most well known of these changes is the gradual loss of cartilage, a flexible tissue covering the ends of bones in the joint. But, while this tissue is important, “fully expressed osteoarthritis is not only a disease of the cartilage, it is a disease of the whole joint” says Schaible. Tissues like the synovium, a thin membrane that lines the inner surface of the joint, as well as bone and fat surrounding the joint, are now thought to contribute to osteoarthritis, though researchers don’t know at what stage of the disease they become involved.
Surprisingly, many studies have failed to find evidence that changes in joint structure predict pain levels. “Some people can have terrible-looking x-rays with minimal pain, and other people can have fairly mild-looking x-rays and have a lot of pain,” says Tuhina Neogi, a rheumatologist and epidemiologist at Boston University School of Medicine, US.
But this does not necessarily show that joint structure is irrelevant. “Pain is a complex phenomenon,” says Neogi, shaped by factors that inevitably vary from person to person. Because of differences in genetic makeup, psychology, and sociocultural context, people experience pain differently, even with the same input to the nervous system. That makes it difficult to ascertain the role of joint structure per se as a contributor to osteoarthritis joint pain, since there are so many other factors that underlie a person’s pain sensitivity.
To overcome this problem, Neogi and colleagues have studied people with or at risk of knee osteoarthritis, and who reported pain in one knee, but not the other. In one study, they compared the structure of the two knee joints in each individual patient; by making the comparison in this way, the researchers ensured that all other factors that could contribute to a person’s experience of pain remained constant. They found that joints with greater structural changes were associated with more frequent, consistent, and severe pain, evidence that joint structure does in fact matter, though it is not the only contributor.
Using animals to study osteoarthritis joint pain
The type of study described above does not prove that alterations in joint structure cause pain, but rather only that these changes are correlated with pain. For insight into how specific changes in the joint could lead to pain, researchers have turned to animal models of osteoarthritis.
In one classic model in rodents, researchers inject into the knee a drug that rapidly kills chondrocytes, the cells that make up cartilage. This leads to behaviors reminiscent of those in people with joint pain—the animals place less weight on the injured limb and show painful responses to normally harmless touch.
However, “the model bears very little relationship to osteoarthritis,” says Anne-Marie Malfait, a researcher investigating both osteoarthritis and joint pain at Rush University, Chicago, US. “The drug kills chondrocytes, but chondrocytes are considered a major driver of the osteoarthritic process.”
For her research, Malfait uses a different model in which one small but crucial ligament in the knee joint is severed in mice. This spurs “very slowly progressing joint damage, which bears a lot of similarities to the human condition,” she says. Moreover, she thinks that the time course of this model, which spans several months, allows researchers to better understand the contribution of specific changes in the joint to pain.
Others, like Duncan Lascelles, North Carolina State University, Raleigh, US, are focusing their attention on animals that have naturally occurring osteoarthritis—in this case, dogs and cats. “Rodent models are really useful, and we’ve learned a lot about the neurobiology of pain from them, but the Achilles heel of rodent models is that they are induced models,” says Lascelles. He stresses that findings from animal models where pain is triggered experimentally may not accurately represent what happens in people.
Inflammation takes center stage
Early on in osteoarthritis, joint pain usually coincides with movement. “People will typically say, for instance, that their knee starts hurting when they go up stairs,” says Malfait. “People really avoid these certain behaviors.”
But researchers still are not sure how nerve fibers in the joint convert movement into a pain signal. A role for cartilage may seem like part of the answer, since it helps reduce friction between bones and other joint tissues during movement. However, cartilage does not have a nerve supply. “Cartilage is not innervated by nerve fibers at all, so it can’t explain pain” in osteoarthritis, says Schaible.
Nonetheless, research performed in rats has shown that nerve fibers have a protein on their surface, called Nav1.8, which can respond to harmful mechanical stimuli, such as movement that occurs during osteoarthritis. When Nav1.8 is activated in neurons, the cells fire and transmit pain signals. Blocking this protein in animals whose cartilage has been destroyed allows them to place more weight on the affected joint and be less sensitive to innocuous touch.
More and more, studies suggest that inflammation in the joint may represent a link between movement and pain, perhaps including pain generated by Nav1.8. “There’s a lot of interest now in studying inflammation,” says Malfait, which is surprising, as osteoarthritis was previously considered a non-inflammatory disease. Yet, it is currently not clear how inflammation starts in osteoarthritis, primarily because “no one knows exactly when osteoarthritis begins as a disease,” says Schaible.
The inflammatory process in osteoarthritis is now known to involve a handful of proteins used as signals sent from different types of cells in the joint to nerve fibers. For example, it has been shown in rodents that inflammatory signaling molecules, such as small proteins known as cytokines, can act on nerve fibers to heighten their responses to normal and harmful movement.
Many of these inflammatory molecules are present in the joints of those with osteoarthritis, suggesting that they may also contribute to pain signaling in patients. Consistent with this idea, joint inflammation correlates with patients’ reports of pain sensitivity.
Clinical trials are underway to determine whether inflammatory molecules are effective and safe drug targets for long-term relief of osteoarthritis joint pain. One approach has tried to neutralize an inflammatory protein in neurons, called nerve growth factor (NGF), using antibodies that bind to NGF and block its actions. While the therapy was promising in late-stage trials to relieve osteoarthritis knee pain, the studies came to a halt when additional joint damage was observed in some patients, especially when the antibodies were given at high doses or along with non-steroidal anti-inflammatory drugs (NSAIDs).
One reason why the antibodies produced damage in the joint may be that NGF is involved in more than just inflammation. “NGF is fundamental for the integrity and functionality of nerve fibers—it keeps them alive,” says Schaible. Therefore, blocking the protein could end up damaging neurons, though how damage to neurons could in turn damage the joint is unclear.
Nonetheless, since the NGF antibodies relieved joint pain in many patients, clinical trials have recently been rebooted for knee and hip osteoarthritis pain, with the addition of more restrictions on the trials in order to avoid the safety issues seen in the earlier studies. “If these antibodies work, it could be a new era for pain treatment,” adds Schaible.
Sensitivity of the nervous system
Upon receiving inflammatory signals from joint tissues, pain-transmitting nerve fibers in the joint start firing more easily. Normally harmless movement becomes painful, and painful movement becomes even more painful. “The pain system is not a static system,” says Lars Arendt-Nielsen, a clinical pain researcher at Aalborg University, Denmark, and co-chair of IASP’s 2016 Global Year Against Joint Pain. With osteoarthritis, “a little bit of input to the joint can cause a lot of pain,” he adds.
Inflammatory signals like cytokines and NGF can set off this process in the joint by activating proteins on neurons–for example, NGF activates a protein called TrkA–triggering a cascade of events inside the cells that have long-lasting effects on the cells’ sensitivity to mechanical stimulation. Additionally, the breakdown of key structural proteins in the joint can remove protective brakes on nerve cell activity, leading to exaggerated firing of neurons.
But changes in nerve cell activity do not just happen in the joint. Increased activity of neurons residing there also restructures the central nervous system (CNS), which includes the spinal cord and brain. Enhanced sensitivity of CNS neurons may explain why the absolute amount of input to joint nerve fibers cannot usually predict a person’s degree of pain, says Arendt-Nielsen—that is, pain signals that originate in the joint may be greatly amplified by already-sensitized CNS neurons.
Remarkably, surgically replacing the affected joint, along with the nerve fibers it harbors, can reverse these changes in the CNS, as well as relieve pain, hinting that uninterrupted pain signals coming from the the joint leads to osteoarthritis pain. “There is overwhelming evidence that the pain in osteoarthritis is really driven by continuous peripheral input from nerve fibers in the joint,” says Malfait.
Shortcomings of treatment
To counter osteoarthritis pain, patients are commonly prescribed drugs like acetaminophen and NSAIDs. But these have serious issues. “The drugs that are currently available are fundamentally not safe,” says Arendt-Nielsen, since their long-term use can result in potentially dangerous side effects. In addition, they often provide insufficient pain relief. The greatest shortcoming of current treatment approaches, however, is that while they target pain, which is a symptom of osteoarthritis, they do not affect the root causes of the condition. Unfortunately, “there is no disease-modifying therapy available,” explains Schaible.
As a result, many patients resort to surgery to replace the affected joint. While beneficial for most individuals, pain persists in about 1 in 5 patients. Researchers blame this lingering pain on the CNS changes described above. Even though, at this point, the problem is within the CNS, “many who still have pain will go on to have a second joint replacement,” says Arendt-Nielsen.
But this only makes matters worse. Most patients who undergo a second surgery will experience even more pain, likely because post-operative pain further heightens the activity of CNS neurons that have already been sensitized. To avoid this outcome, Arendt-Nielsen and colleagues are now working on tools to predict which patients would benefit from surgery, and which ones would not. “So far, this is not standard,” he says.
Looking to the future
By 2030, the number of knee joint replacements in the US, for osteoarthritis and other conditions, is expected to reach approximately 3.48 million procedures. Arendt-Nielsen hopes that instead of opting for surgery, osteoarthritis patients will soon benefit from drugs in development. “It will be a game-changer if we have drugs that not only inhibit osteoarthritis pain, but also slow down or even prevent the progression of the disease,” he says.
To identify additional drug targets, researchers agree that studying the joint and the nerves in isolation from each other will have a limited payoff. “The important thing is to study the interaction between the joint and the nerves,” says Malfait. For this to happen though, she says researchers studying osteoarthritis must work with those studying joint pain.
Encouragingly, Malfait along with Camilla Svensson, a pain researcher at the Karolinska Institute in Stockholm, Sweden, began to bridge this well-known gap by bringing researchers in each field together at a conference in Stockholm last year. “It was really the first time these people were talking to each other,” says Malfait.
International Association for the Study of Pain 2016 Global Year Against Pain in the Joints (http://www.iasp-pain.org/GlobalYear).
Matthew Soleiman is a neuroscientist-turned-science writer currently residing in Nashville, Tennessee. Follow him on Twitter @MatthewSoleiman.