Stopping the pain of sickle cell disease at its source

The pain of sickle cell disease can be unbearable. But there's a new view emerging on how that pain comes about, one that has spurred a new clinical trial aimed at stopping the pain at its source. (stevendepolo/Flickr)

If there’s one thing most patients with sickle cell disease will agree on, it’s that sickle cell hurts. A lot.

The characteristic rigid, sticky, C-shaped red blood cells of this inherited disease tend to get stuck in the small blood vessels of the body. If so many get stuck in a vessel that they cut off blood flow, the body sends out a warning signal in the form of searing pain that doctors call a pain or vaso-occlusive crisis (at least, that’s the historic view; more on that in a minute). The pain can happen anywhere in the body, but most often occurs in the bones of the arms, legs, chest and spine.

Preventing flare-ups—and stopping them when they happen—is a major part of the care plan for any patient with sickle cell. Right now doctors try to avoid pain crises largely by diluting a patient’s blood with fluids or transfusions, thereby keeping the numbers of sickled cells relatively low.

What these treatments don’t do is tackle the pain directly. Doctors can use pain medications, but over time, patients can become tolerant to painkillers, requiring ever-larger doses. What’s needed is something that can stop the complex cascade of events that ignite a pain crisis.

“There is a new view emerging of how a pain crisis emerges, where a simple blockage of vessels may not actually be the trigger,” says Matthew Heeney, MD, director of the Sickle Cell Program at Dana-Farber/Children’s Hospital Cancer Center. “Rather, it could be that inflammation builds up as vessels get blocked, unplugged and blocked over and over again.” The new view looks beyond sickled red blood cells to the contributions of normal red blood cells, white blood cells (including specialized iNKT cells), platelets, clotting factors, chemical signals from the immune system and the endothelial cells that line blood vessels to emerging crises.

With David Nathan, MD, former physician-in-chief at Boston Children’s and president emeritus of the Dana-Farber Cancer Institute, Heeney is leading the DF/CHCC arm of a clinical trial that makes use of this new view to stop pain crises in their tracks.

The trial focuses on a drug called regadenoson (which also goes by the brand name Lexiscan®). It belongs to a family of drugs called vasodilators, which help blood vessels expand and blood flow faster. Cardiologists find regadenoson useful when carrying out cardiac stress tests on patients with heart disease, especially those who can’t exercise hard enough to get their heart rate up.

But when it comes to sickle cell, regadenoson appears to have other tricks up its sleeve.

Matthew Heeney, MD

“At low dose and slow infusion, the drug looks to be much more potent as an anti-inflammatory than as a vasodilator,” Heeney explains. “iNKT cells really drive the inflammation in a pain crisis, and they’re loaded with adenosine receptors, the proteins that regadenoson latches on to.

“We already know that the drug can shut these cells off and reduce inflammation in a mouse model of sickle cell,” he continues. “If it works clinically, it could possibly help us halt a crisis relatively quickly.”

The trial has already shown that regadenoson is safe and does indeed disarm iNKT cells in adult sickle cell patients who haven’t yet had an acute crisis. Heeney’s team is working on the next step: testing whether the drug can help children during a pain crisis.

“We’re giving it to children in crisis over a 24-hour period to see if it can help reduce the inflammation and the intensity of the crisis,” Heeney says. “We also want to firm up our data on what dose of regadenoson children with sickle cell can tolerate.”

Should regadenoson earn its chops, it could be a big step towards improving the management of sickle cell disease. “Because relatively few patients with sickle cell can be cured right now, we need to move beyond supportive treatments to ones that address the cause of these crises,” Heeney adds. “If this new model of pain crisis proves true, regadenoson could go a long way in helping us get there.”