EERW Trials: The Advantage of Response Before Randomization

Because someone fails with one drug it doesn't mean they will fail with all. Switching is the key.

An enriched-enrollment randomized-withdrawal trial for comparing a new drug for pain control to a placebo is very different from a classic randomized control trial (RCT). RCTs may still be the gold standard, but when it comes to chronic pain, an EERW trial may be more clinically relevant.1

A 2015 review of enriched-enrollment randomized-withdrawal (EERW) trials for chronic pain, published in Pain, concluded that these trials are entirely appropriate and promise greater effect on clinical management than RCT trials. But when updated guidelines for pain management are issued, EERW trials are often ignored. The review suggests ways to help these trials get the respect they deserve.1

“These trials have been less influential mainly because they are relatively new, and because they are done for a different purpose. This has made it hard for the uninformed reader – which means most of us – to know what to make of them,” said Andrew Moore, professor and director of pain research at Oxford University in the United Kingdom, and lead author of the review. 

“EERW trials are still the minority of pain trials, and major guidelines have usually not included their results because they are not comparable to RCT trials. Since the two don’t mix, they tend to ignore the EERWs,” added Simon Haroutounian, PhD, assistant professor in the department of anesthesiology at Washington University School of Medicine in Saint Louis, who also contributed to the review. 

How Is an EERW Trial Done?

To compare a new drug to a placebo for treatment of chronic pain, a typical EERW trial will screen patients for inclusion based on their type and severity of pain. All patients are taken off any current pain medications and started on the study drug. Only patients who respond to the drug and tolerate side effects are included in the study. This is the enrichment phase.1

After a period of maintenance, patients are blindly randomized to continue taking the study drug or switch over to a placebo. This withdrawal phase may be done by titrating down the effective drug. Both the drug and the placebo are and titrated back up.1

Advantages of EERW

To understand why an EERW trial may be better in some instances, it is important to realize that most pain relievers work for only 30 to 50% of patients. This does not mean the drugs are not effective, but it does mean they are effective only for some people. So when comparing a new drug to a placebo, it’s very helpful to know whether it will be better than a placebo for the patients who might really use it.1,2

“EERW trials are better when a drug is not expected to work well for everyone, and the condition it treats has a high rate of placebo response. If you just include everyone, the placebo effect will overwhelm the true response to the drug you are studying, especially if you are dealing with a small group of patients. That is a limitation of RCTs for chronic pain,” said Haroutounian. 

A Framework for Improving EERW Trials

“What we have done is to try and put in place a framework for EERW trials, in terms of what makes one of these trials good and unbiased. Longer duration EERW trials are directly usable in clinical practice. They tell us that only some people will have a benefit, but that is a really good benefit if we choose the outcomes properly, like good levels of pain relief,” said Moore.

Recommendations for improving EERW trials include:

  • State the EERW methodology in the title and abstract of the study. Explain the pragmatic purpose for the methodology. 1
  • Ensure an adequate, single-blind titration and maintenance periods to introduce the new drug and to titrate back down before starting randomization.1  “Titrating the drug gradually up to the target dose over one to two weeks avoids side effects. Maintain the effective dose for at least two weeks to make sure it is effective and tolerated. If you titrate back down too quickly, patients may be aware of a sudden lack of tolerated side effects, and this can unblind the study,” said Haroutounian. 
  • Determine a sensible criteria for effective pain relief to be achieved during the maintenance phase. The review recommends aiming for 50% relief. “Although effective relief may be between 30 and 50%, half is statistically more significant. Patients should keep a daily pain diary during the maintenance phase and rate their pain on a pain scale,” said Haroutounian.
  • Determine a sensible criteria for loss of response in the placebo group. The review suggests pain reduction consistently less than 30% or worsening pain.1

Pain Relief Complicated

A success rate over 50% is rare for any pain-relieving drug, and classic clinical trials almost always underestimate efficacy. However, EERW trials have lower failure rates. And although no single drug is likely to treat most patients successfully, it makes a big difference when treatment works. This can mean better sleep, less fatigue, less depression, and a much better quality of life. A drug’s effectiveness is usually evident within the first two weeks and is worth striving for because it tends to be long lasting when it happens.2

“Only some people benefit with any treatment in chronic pain. It’s not the drug, or the patient, or [the doctor], it’s the way it is. Pain is really rather complicated. Because someone fails with one drug it doesn’t mean they will fail with all. Switching is the key – benefits are felt early or not at all,” said Moore.

Medically reviewed by: Pat F. Bass III, MD, MS, MPH


1. Moore RA, et al. Pain. 2015;  DOI: 10.1097/j.pain.0000000000000088      

2. Moore A, et alBMJ. 2013; doi: