By Allison Marin
Eleven years ago, Debbie had a routine bunion surgery that changed her life. Instead of finding relief, her pain grew worse and worse, until it was excruciating and constant. “I became disabled and had to stop working. My foot is permanently in an air cast and I walk with a cane. Most of the time the pain is a 10 out of 10,” says Debbie (whose last name is omitted for privacy reasons).
Debbie’s surgeon sent her to a pain specialist, who recommended a psychiatrist. “I knew the pain wasn’t in my head,” she says, but the medical community didn’t believe her. It wasn’t until she met Massachusetts General Hospital neurologist Anne Louise Oaklander that she finally received a diagnosis: Complex Regional Pain Syndrome, or CRPS. This condition was formerly known as Reflex Sympathetic Dystrophy, or RSD.
CRPS is a chronic pain condition that develops following trauma to a limb, such as surgery or a fracture. As Debbie learned, “this is a very controversial condition that not a lot of doctors understand,” says Oaklander. “Historically, the field of medicine has been very skeptical of patients with CRPS. On top of their illness, patients have had to navigate a medical system that is suspicious of them and hasn’t had effective treatment to offer. It adds insult to injury, literally.”
“This is a very real condition, but the lack of identifiable pathology leads to disbelief,” agrees Candy McCabe, a CRPS clinician and researcher at the University of the West of England, Bristol, UK. But those who treat CRPS are hopeful the tide is turning. Recent attempts to better understand CRPS have produced consensus guidelines for which patient outcomes should be included in future research, as well as internationally agreed-upon diagnostic criteria. Investigators are also learning more about the causes of CRPS from laboratory studies.
Life with CRPS
CRPS starts off with a surprising amount of pain that doesn’t match the initial trauma. In the first few months following a limb fracture or surgery, instead of the expected healing, patients describe an increase in pain levels. They often report that a cast on the affected limb feels excessively tight and the sensation that the limb might “explode,” says McCabe.
The limb often swells, changes color to red or purple, and is perceived by the patient as either very cold or very hot. Increases or decreases in hair and nail growth and sweating on the affected limb are also common. Research from Oaklander’s lab and others has identified persistent problems with certain neurons in patients’ injured limbs. These nerve cells carry pain messages, but also control the small blood vessels and sweat glands in the limbs, explaining why patients have a constellation of symptoms in addition to chronic nerve pain.
Many patients report that within a few days or weeks the limb feels completely alien, and of a very different size and shape than it really is. Many also describe very negative feelings toward the limb and a strong desire to have it amputated. “In CRPS, the brain’s perception of the limb changes pretty quickly,” McCabe says.
The good news is that, while in some cases CRPS becomes persistent, about 75% of people get better without intervention, by six months to a year. “Getting a CRPS diagnosis does not necessarily equate to a lifetime of disability,” she emphasizes.
While the features mentioned above describe the “average” CRPS patient, not everyone experiences the disease in the same way. Beyond differences in the length and severity of the syndrome, different patients report different symptoms as the most prominent and bothersome. For some, movement problems cause the most difficulty, while for others the pain takes center stage. “The presentation of CRPS is variable within a common picture, but unfortunately we don’t yet know why these different scenarios happen,” says McCabe.
Understanding the mechanisms
The heterogeneity among patients makes it challenging to study the biological mechanisms underlying CRPS, says Maral Tajerian, who uses animal models to study the disorder at Stanford University, US. “A lack of understanding of the underlying mechanisms is a big part of why we don’t have satisfactory treatments,” she says.
Tajerian and her lab use a CRPS model in rats and mice in which the tibia bone is fractured. After a few weeks of immobilization in a cast, the limb is swollen and painful, and the animal avoids using it, much like in the human disorder, she explains.
As reflected in the original name for CRPS, Reflex Sympathetic Dystrophy, one of the earliest ideas about the biological underpinnings of the condition is the presence of dysfunction of the sympathetic nervous system, the network of neurons that governs the body’s automatic “fight or flight” response. Currently, researchers believe that alterations in the sympathetic nervous system are important in the initial generation and acute phase of CRPS. For example, studies suggest that in the tibial fracture model, sympathetic neurons release an immune system protein called interleukin-6 that stimulates inflammation and pain.
The immune system also seems to play a role in chronic cases of CRPS, says Andreas Goebel, a clinician and pain researcher at the University of Liverpool, UK. Goebel and his lab have identified a number of autoantibodies, which are immune system proteins directed against a person’s own tissues or organs, in the blood of people with chronic CRPS.
In one study, transferring this collection of autoantibodies from humans with CRPS into rodents with an injured hind paw caused the animals to develop the pain condition, strongly suggesting that the autoantibodies contribute to CRPS, Goebel explains. “We still don’t whether the autoantibodies really cause CRPS, but where there is smoke there is probably fire,” he says.
Tajerian is pursuing CRPS-related autoantibodies in her mouse model as well. She is particularly interested in an autoantibody against the skin protein keratin 16, which appears to be elevated in mice as well as CRPS patients.
While the early phases of CRPS seem to be characterized mostly by changes in the peripheral nervous system, as the pain progresses, the central nervous system, which includes the brain and spinal cord, also becomes involved, says Tajerian. For example, work from Tajerian and colleagues has revealed differences in spinal cord gene expression—which genes are turned on or off—between acute and chronic phases in the tibial fracture model of CRPS. Another study from her lab found that chronic CRPS leads to a reorganization of neuronal structure in brain regions such as the amygdala and hippocampus, which are involved in anxiety and memory, respectively, changes in which are observed in CRPS patients.
Treatments: pharmacological and non-pharmacological
When it comes to treating CRPS, patients have many choices. “The good news is that there are a lot of treatment options. But, the bad news is that there are a lot of treatment options,” says Oaklander. “It’s good news because there are various ways for patients to help themselves and get better. It’s bad news because it means no single treatment works well enough to guarantee substantial improvement or a cure.”
The key is for patients to find a knowledgeable physician who knows those treatments that are supported by published research studies rather than word-of-mouth, she says.
The international consensus for treatment is to first minimize the pain using painkillers, but unfortunately there aren’t any such drugs to completely eliminate pain, says McCabe. “It’s really about reducing the level of pain to one that is tolerable.” There is a wide range of drugs used to treat the pain. One drug, called ketamine, is often prescribed in the U.S., however, whether or not it works is disputed, it has a number of side effects, and is not suitable for long-term treatment. “For some, it is not a pleasant drug to take,” McCabe says.
A recent analysis that compiled results from 16 different clinical trials of various CRPS drugs found that a class of drugs called bisphosphonates (see below) are most effective in the early stages of the disease, within the first year. Ketamine, as well as another drug called calcitonin, are better suited to treat the pain in the chronic phase of the illness, says Roberto Perez, of VU University Medical Center, in Amsterdam. “There are shifts in terms of when you should use a specific approach.”
A number of non-pharmacological strategies are also crucial to improving pain in CRPS. For instance, physical rehabilitation is key, to get people moving and using the limb, despite the pain, says McCabe. “That’s really difficult to do, but it really is the best way to resolve CRPS as quickly as possible.”
“We have a mantra here: touch it, love it, use it,” explains McCabe.
Psychological support is also critical, to help patients address the anxiety and depression that come from any type of chronic pain, and to motivate them to stay active. Finally, educating patients, to help them understand CRPS when often everyone around them has never heard of it, is also vital, says McCabe.
Toward a brighter future
Over the last 20 years, collaborative research on CRPS has increased, and scientists are making great strides not only in advancing knowledge of mechanisms and treatment, but also in standardizing the classification and diagnosis of the condition.
A number of key findings have come out of these efforts. For example, a large international study demonstrated that patients could be put into three main subgroups: 1) those who tend to have predominantly symptoms of inflammation such as redness and swelling, 2) those who tend to have mainly changes in limb color, temperature, and sweating (known as vasomotor symptoms), and 3) those with mainly sensory symptoms.
Perez helped form the Dutch Trauma-RElated Neuronal Dysfunction (TREND) Knowledge Consortium, which was focused on understanding the mechanisms underlying CRPS, and so far has resulted in about 200 research publications. The consortium issued its final report in 2011.
In addition, under the leadership of McCabe, the International Association for the Study of Pain’s CRPS Special Interest Group, of which Perez is the current chair, adopted an empirically-derived set of diagnostic criteria for CRPS, known as the Budapest Criteria, in 2010.
“The new diagnostic criteria are a major step forward when it comes to more uniformity in research studies and clinical trials,” says Perez. For example, a large international study used these criteria to provide evidence of “warm” and “cold” subgroups of patients. The warm group, which was made up mostly of patients who were diagnosed less than six months prior to the study, tended to have red, hot, and swollen limbs, while the cold group was made up of chronic CRPS patients who experienced cold, blue, and non-swollen limbs. Total pain intensity did not differ between groups, but the warm group experienced a much shorter pain duration (five months compared to 20).
Most recently, the International Research Consortium (IRC) for CRPS was formed with the goal of pooling resources in order to create high-quality studies on the mechanisms of and treatments for CRPS.
Seeking FDA approval
In 2014, the U.S. Food and Drug Administration (FDA) categorized CRPS as an official rare disease. This designation is important because it offers strong incentives for new drug development designed to spur new treatments for rare diseases, which overall have smaller markets, and thus are less lucrative for pharmaceutical manufacturers, says Oaklander. The FDA will accept clinical trials with fewer patients, making them more feasible, quicker, and cheaper.
The first CRPS trial spurred by this development is underway, to evaluate the efficacy and safety of neridronate, a new bisphosphonate, which is a class of drugs already widely used to prevent and treat osteoporosis. Several early and recent clinical trials had reported efficacy and safety of other bisphosphonates for CRPS. Then, a small Italian trial published in 2013 reported a significant reduction in pain with neridronate compared to placebo. This led to approval for use to market the drug for CRPS in Italy, China, Hong Kong, and Taiwan. “It’s not clear whether bisphosphonates improve CRPS symptoms by reducing painful bone resorption [the process by which bone tissue is broken down], or whether they work in other ways as well to reduce CRPS pain,” explains Oaklander.
A phase II/III placebo-controlled clinical trial of neridronate began in April 2015, and has completed enrollment of 230 patients at 59 sites in the US and Europe. The results are anticipated in late 2017. A previous large clinical trial of lenalidomide, a drug that works in a different way, failed to demonstrate efficacy for CRPS, so there is excitement around the new trial, says Oaklander.
Debbie is one of the trial participants, and has received several intravenous infusions. Neither she nor the trial organizers know yet if she received neridronate or placebo.
If this trial finds neridronate to be safe and effective in the US, as it is in Italy, and if it receives the FDA’s approval to be marketed for CRPS, it will be historic, says Oaklander. It’s only when there’s an approved drug that there’s advertising, which increases public awareness, and spurs doctors to learn more, she adds. “I felt it was important to participate in this trial because it makes a statement to the world that CRPS is a real medical disease that deserves high quality trials and the attention of the FDA. This could be a landmark trial.”
Allison Marin, PhD, is a neuroscientist-turned-science writer who resides in Pittsburgh, Pennsylvania, US.