The Challenges of Transitioning Pain Medication from Clinical Trials to Practice

Trial design and other factors can conspire to produce false positive or false negative results, which complicates not only the search for more effective pain treatments but also the safe and effective use of pain medications in practice.

Many clinical trials of new treatments for pain have either shown significant benefits or lack of efficacy in the same populations and it has become difficult to determine whether these drugs are truly efficacious or lack benefit in these populations. Robert Dworkin, PhD, of the University of Rochester School of Medicine and Dentistry in New York, provided insight into the sensitivity inherent in clinical trials and the use of evidence-based research in improving the treatment of chronic pain during a plenary session at the 2013 American Academy of Pain Medicine annual meeting, being held April 12-14 in Fort Lauderdale, FL.

In his presentation, Dworkin specifically focused on falsely positive and falsely negative results of clinical trials and the impact of evidence-based recommendations on clinical practice. Currently, treatment of chronic pain has a number of limitations, as approximately one-half of patients do not tolerate or respond to currently available treatment options, and many patients who do respond to treatment experience disturbances of mood, sleep, and activities of daily living.

Most clinical trials of pain medications involve standard parallel group trial design that involves a double-blind period and compares the amount of pain reduction with an active treatment to placebo or another comparator. However, in many cases, it is difficult to determine if the active treatment is truly safe and efficacious as compared to the placebo or comparator, as many cases of falsely positive results as well as falsely negative results have occurred.

In the case of falsely positive results, Dworkin said there is some evidence that investigators have manipulated data, potentially inadvertently, and manipulated the design, analysis, and/or results of clinical trials. Currently, in pain management, investigators follow the CONSORT (Consolidated Standards of Reporting Trials) guidelines during clinical trials for the evaluation of efficacy and safety. However, an analysis by Dworkin and colleagues found that many researchers are inadequately adhering to these guidelines in reporting safety and efficacy results.

Furthermore, key criteria used for clinical trial quality scoring that include determining whether a clinical trial is randomized, double blinded, and has a description of withdrawals and dropouts, leave out assessing whether selective outcome reporting was used properly, which leaves room for falsely positive results.

Investigators need to have pre-specified assessments established and make a decision on how they are going to handle the efficacy and safety endpoints, analysis of patients, missing data, multiple endpoints, and subgroup analyses prior to the start of a study. Addressing these factors after the beginning of a study leaves room for falsely positive results. Dworkin said that while one would think that falsely positive results would be more likely to come from large pharmaceutical companies (who have incentive to produce positive results), many of the falsely positive results come from researchers due to pressures associated with academia.

Falsely positive results are not the only manipulation of data that clinicians need to be wary of -- falsely negative results can have a similar but more devastating impact on the use of pain medications in clinical practice. In many pain medication trials, the challenging question is whether a negative result is truly negative or a falsely negative result.

One reason that a pain medication trial may result in a negative outcome is that the drug is truly not efficacious. However, more often than not, results turn out to be falsely negative for a number of reasons, including clinical trial design, patient population evaluated, and placebo patients. In an effort to improve on some of these factors to avoid falsely negative results, Dworkin and colleagues have lead an initiative to develop a pain training and education program to train patients on how they should think about their pain level when reporting pain scores.

In addition to falsely positive and falsely negative results, evidence-based guidelines may also impact results. An example of this is with academy guideline recommendations for pain medication. The classification system used may alter results just by categorization and clinicians should be aware of the guidelines and how they may impact the results and interpretation of clinical trial data.

Dworkin concluded that most clinical trials in pain medicine are not false but there are probably a significant number out there. Physicians should be wary of the possibly of this occurring in the literature and take heed when making decisions to use pain medications in clinical practice. It is very difficult to determine which drugs truly lack efficacy and which results are negatively false. Lastly, clinicians should pay heed to FDA approvals for pain medications and assess clinical trial results with caution.