One severe complication of hemophilia is that of repeated joint bleeding, ultimately resulting in impairment of the joint and permanent damage. It is referred to a hemophilic arthropathy.

While there is no way to reverse the process of hemophilic arthropathy once it has started, according to Stacy Croteau, MD, associate director of the Boston Hemophilia Center at Boston Children's Hospital, slowing its progress is the best way to manage it. "Which means that improved prophylactic factor replacement is an important strategy for slowing down hemophilic arthropathy," she said.

Fortunately, "we are in an era where virtually all of my pediatric patients started on prophylaxis at a very early age and most of them have pretty pristine joints as function is concerned, so we've slowed down the process," she told MedPage Today. "And it is much more of an issue in either patients who have inhibitors as children and have had challenges keeping their bleeding under control, or in our adult population."

And in those patients, pain can become a chronic and debilitating consequence of damaged joints.

In a study published in Haemophilia, Michelle Witkop, DNP, who at the time was with the Munson Medical Center in Traverse City, Michigan, and colleagues surveyed 381 adult males (median age 34 years) to assess how they managed pain.

They found that during the 6 months prior to completing the survey, 85% of patients experienced pain -- including 20% reporting acute pain only, 34% with non-acute chronic pain, and 32% experiencing both acute and chronic pain.

In addition, despite a prevalence of severe hemophilia in the survey population, 30% of patients never received prophylaxis, and 32% had received prophylaxis for less than half their lives.

So, when it comes to managing pain in hemophilia, "we are trying to encourage and work with our patient population to make sure that they get on prophylaxis and prevent bleeds, because that's the best way to prevent pain," Witkop, now head of research for the National Hemophilia Foundation, told MedPage Today.

As for treating pain associated with arthropathy, that is complicated by the nature of the disease.

For example, a drug like acetaminophen is an obvious choice for many hemophilia patients, Witkop said, but may be resisted by older patients who have had exposure to hepatitis C and are concerned about acetaminophen's association with liver disease if taken in large doses.

And non-steroidal anti-inflammatory drugs such as aspirin or ibuprofen are problematic because they present patients with an increased risk of bleeding. "It's not that patients can't use them," Witkop said. "But, they have to be used with extreme caution."

As for opioids, Witkop pointed out that while many patients do well on those drugs, the hemophilia community is still trying to figure out what to do when they are not enough.

With the opioid crisis, Croteau said, hemophilia care providers are trying to be sensitive to the need for adequate pain control, but are also trying to maximize non-opiate therapies. "So, working closely with our pain specialist colleagues is very important," she said. "It's definitely an area of unmet medical need, partly because while many people with rheumatoid arthritis or osteoarthritis or other inflammatory conditions can just reach for ibuprofen or aspirin to help reduce inflammation and get their pain under control, that is a branch of medicine that is not routinely used in hemophilia patients."

What in the way of research efforts are underway to better meet this medical need?

"Clinical research is needed to help define and identify joint disease as early as possible to help us, as providers, do a better job educating patients as to the importance of prophylaxis," said Croteau, adding that if caregivers are able to see signs of early joint disease, they can urge their patients to be more aggressive about prophylaxis, or more aggressive about physical activity and bone health.

Croteau noted that one such research area is that of point-of-care ultrasound (POC-US).

In another recent study in Haemophilia, Dutch researchers compared the diagnostic accuracy of POC-US with MRI in evaluating early blood-induced joint changes. Knees and ankles of 24 hemophilia patients (ages 18-34 years) with no or minimal arthropathy on X-ray were scanned using POC-US and 3-T MRI. The researchers found that POC-US accurately assessed synovial hypertrophy, bone surface irregularities and cartilage abnormalities in hemophilia patients with limited joint disease.

"As POC‐US is an accurate and available alternative for MRI, it can be used for routine evaluation of early joint changes," they concluded.

Croteau noted that while therapy such as corticosteroid injections or joint aspiration have been standard parts of orthopedic joint management, it is rarely used in the bleeding disorder community because of concerns about worsening bleeding or joint damage. "But with point-of-care ultrasound we're able to reexamine the potential benefit of some of these therapies," she said.

According to Croteau, much of the research in this area in the U.S. is being led by Annette Von Drygalski, MD, PharmD, director of the Hemophilia and Thrombosis Treatment Center at the University of California San Diego.

Yet another study in Haemophilia, in which Von Drygalski was the senior author, found that 91% of POC-US-guided intra-articular corticosteroid joint injections in patients with hemophilic arthropathy resulted in significant pain relief (greater than a 30% reduction in pain), usually within 24 hours, and with no procedure-related complications. They concluded that, considering these results, this approach should be used to improve pain management in hemophilic arthropathy.

Other research efforts to address the issue of pain involve a renewed interest in COX-2 inhibitors. In the early 2000s, several COX-2 inhibitors such as rofecoxib and valdecoxib were taken off the market because of cardiovascular thrombotic risk concerns.

In 2017, the FDA gave rofecoxib -- Vioxx in that past life, but now under development by Tremeau Pharmaceuticals for different indications -- an orphan drug designation and agreed on a phase III trial plan to test the drug as a non-opioid alternative for treating hemophilic arthropathy pain.