Slow release in every sense of the words

Ultram is marketed in some seventy countries around the world for the treatment of moderate to severe pain in multiple dose format. The simple rule is that the dose should be individualised so that each person takes the smallest dose required to produce the required relief from pain. Normally, this means that patients start with a very low daily dose and slowly increase the dosage every three days until a stable and effective concentration in the blood stream is achieved. After that, the level is maintained by taking one tablet every four to six hours. No-one should take more than 400mg per day. If there is a more urgent need for pain relief and that need outweighs the risk of dependence, people may take an initial high dosage. This well-established system may be about to change in the US.

Since 2006, Labopharm Inc. has been seeking approval from the Food and Drug Administration for the once-daily version of ultram already approved in twenty-two European countries. The format is based on Contramid technology which allows both rapid and sustained drug release to maintain stable blood levels within the therapeutic range over the twenty-four hour period. Now some two years into its campaign, the company is scheduled to meet with the director of the FDA's Center for Drug Evaluation and Research which will trigger a thirty day deadline for the FDA to give its decision. If that decision is positive, Labopharm Inc. has a further sixty days to comply with the labelling requirements. This could mean a formal approval for the slow-release version of ultram issued in August 2008.

This has been an unusually slow process. The company originally planned the product launch for September 2006, but the FDA has required more clinical trials to be undertaken as a precondition of taking the approval process forward. Although it is good that the FDA has become more cautious in giving approval to new products, this is a variation on a well-established product. Applying the same caution may seem somewhat unfair given the significant increase in the cost of the process. According to Labopharm Inc. the FDA gave notice in May 2007 that a different statistical method was to be used to analyse the clinical data. This required further testing to produce more data compatible with the new method. The disagreement about methodology affected the extent to which the company could rely only on data produced from those completing the trials. The FDA was concerned that the exclusion of data from those dropping out of the trials could skew the results on safety. But, for all the delay, the company is confident that the once-daily version of ultram is effective and safe.

Let us assume that it is approved in the US and go back to the initial statement about dosage. At present, it is easy for people to forget when a dose is due. Taking too little is less of a problem. Taking too much is always a problem. Because many of the people taking ultram are older, forgetfulness is more common. Further, if a patient is on a four-hour schedule, this means waking during the night to maintain the required blood concentration. Labopharm Inc. believes that a once-daily regime will improve compliance. The evidence from the European markets on this point is encouraging.