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A recent review published in the Lancet Neurology, written by Professor Gilron of Queen’s University, Kingston, Ontario, discusses clinical studies looking at combination therapies for chronic pain. Professor Gilron puts forth two proposals which he thinks should be included in designing and conducting future clinical trials using combination therapies for chronic pain.

Chronic pain is any pain that exists for longer than six months. Approximately 10% of the population is affected by some form of chronic pain. Some of the common causes of chronic pain include osteoarthritis, rheumatoid arthritis, fibromyalgia, and cancer. Current treatments for chronic pain are not always effective in decreasing pain, and they often have dose-limiting side effects, which prevent patients from taking higher doses that may actually be helpful at eliminating pain.

Professor Gilron supports the use of combination therapies, suggesting that combining lower doses of two mechanistically different drugs will potentially have a synergistic effect on pain reduction, while concurrently reducing the side effects associated with higher doses of either drug administered alone. This is supported by the fact that, in other clinical areas, such as asthma, oncology, and hypertension, rational use of combination therapies have been successful for some time.

At present, due to the limitations of current therapies, more than half of patients suffering with chronic pain are prescribed two or more drugs simultaneously. However, Professor Gilron states that there is not enough clinical data to provide a rationale for such practice, and that it is mostly done in an add-on fashion when one drug is no longer enough to reduce pain. He suggests that this common practice of multiple drug prescription emphasizes the need for specific research into combination therapies. Future studies should aim to elucidate the most effective combinations for the treatment of chronic pain. Moreover, he states that currently there are few studies available that distinguish which, if any, combinations are useful.

Professor Gilron suggests two ways in which future clinical trials should be designed in order to gain the most meaningful information: the first is to select two drugs for use in combination with a mechanistic basis. That is, selection of drugs acting on separate, complimentary pathways, in an effort to exert a synergistic effect on pain reduction, while reducing the side effect profile as much as possible. The second idea he proposes is that clinical trials should directly compare the combination treatment group with each drug alone. In this way, a direct comparison can be made between study groups, and an assessment of any supra-additive or synergistic effects in pain reduction when using the combination. By designing clinical trials in this way, a more systematic approach, and ultimately better outcome for patients’ pain management, can be reached.

There are several trials currently underway looking at combination therapies for treating chronic pain associated with osteoarthritis, rheumatoid arthritis, fibromyalgia, and lower back pain. These trials, however, are not designed to assess whether the combinations have any additive or synergistic effects on pain management because they do not compare the combination treatment with each treatment administered alone. While these studies may find new drug combinations that are safe for patients, Dr Gilron suggests that the greatest effects will likely be seen in rational combination of two drugs that act in a mechanistically different way.

There is great potential for helping patients who are suffering with chronic pain by using combination therapies, and future studies directed at assessing such combinations should follow the guidelines outlined in the reviewed article to provide the most potential benefit to patients.


Gilron, I., Jensen, TS., Dickenson AH., “Combination pharmacotherapy for management of chronic pain: from bench to bedside.” The Lancet Neurology, 12(11): 1084-1095, November 2013.


Written by Deborah Tallarigo, PhD


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