Pediatric pain trials beget novel approaches

Children can't experience more pain through a study treatment than they would in standard care

Researchers say there need to be more clinical trials examining the safety and effectiveness of pain medications used with children, which are too often administered based on information from adult trials.

Gary Walco, PhD, director of pain medicine at Seattle Children's Hospital, says extrapolating from adult clinical data doesn't provide assurance that pain medications are safe for children.

Children often metabolize drugs differently, and there is the possibility that medications, especially those used long-term, may affect development.

Despite the need for pediatric pain trials, Walco says there have been obstacles to conducting them, including a lack of consistent guidance. Now, as a result of a 2009 conference involving the FDA and pediatric pain experts, that obstacle may be overcome.

"A paper has been written that lays out all of these issues so that when (pharmaceutical companies) come to the FDA, they could say, 'Look at this paper, it's peer-reviewed, that's your road map," Walco says.

He says the paper is scheduled to be published later this year.

No greater pain

One ethical issue Walco says is important in conducting a pain trial for children is the idea that pediatric participants cannot be disadvantaged as a function of being in the trial.

"That means they can't endure any more clinical pain than they would in standard clinical care," he says. "For example, if you were (participating in) a placebo-controlled trial, even if it's for one-time acute pain, that's fine if you're an adult and you agree to it. But we would say that you cannot expose a child to more pain."

Walco says it is possible to design trials that meet this requirement. For example, in an opioid sparing trial, patients have ready access to an opioid such as morphine to treat pain. In addition, they would take a study drug or placebo. The effectiveness of the study drug would be measured not by how much pain the child reported, but by how much morphine had to be used to minimize pain vs. that used with placebo.

He says IRBs reviewing protocols may have to make fine-tuned judgments about the degree to which participation in a study may potentially cause more pain for a participant than standard care. For example, defining standard care may be tricky.

"If you're doing study of needle pain, I can argue that in the year 2011, no child should be stuck with a needle without a topical anesthetic," Walco says. "So I could say that's the standard of care. But you could go to Institution X and they'll say 'What are you talking about? We don't use topical anesthetic for needle sticks in our institution.' The IRB needs to make that determination, as to what is the local standard?"

Long term effects

Walco says other issues IRBs should consider when reviewing pediatric pain studies include:

— Children participating should get some direct benefit from the study.

— Physical and emotional pain should be prevented as much as possible and effectively treated when unavoidable. Physical pain and distress must be monitored appropriately.

— Painful procedures such as blood sampling should be minimized.

— Walco says that in general, pediatric analgesic trials should be conducted in pediatric facilities, because they're most attuned to the needs of children.

He says consent and assent procedures are generally the same as they are for other pediatric trials.

Walco says it's important for pain trials to look not just at the immediate effects of using pain medication, but at the long-term impact, including any effects on the development of children.

"Especially if you're talking about some of the medications that are going to be used for more recurrent and chronic pain, where you're using them over time," he says. "How likely are negative side effects to occur? What is the magnitude of their occurrence? How long might they last?"

Even with the new guidelines for pediatric pain trials, Walco says obstacles remain, including finding enough patients to study. He and other pain experts are starting an international research collaborative to create multi-site analgesic trials for children. So far, 55 centers around the world have expressed interest.

"We hope by setting up a research consortium to do these trials and getting centers on board, they will be more likely to get done," he says.