A Reply to “Comment on ‘The Abrupt Cessation of Therapeutically Administered Sodium Oxybate (GHB) May Cause Withdrawal Symptoms’”

Abstract

We appreciate the care with which Dr. Zvosec reviewed the recently published article by the Xyrem Multicenter Study Group (1). For many, GHB is an emotionally charged subject, and Orphan Medical is grateful for the opportunity to provide additional clarity to her concerns on behalf of the authors. More than 25 yrs of clinical research experience with sodium oxybate has not provided any reports of drug craving, tolerance, or withdrawal suggestive of physical dependence when used in the treatment of narcolepsy (2–9). Similar results have been previously obtained by the authors of the current report (10,11). Taken together, the above body of literature provides little reason to anticipate addiction and subsequent withdrawal symptoms in patients participating in the trial presently under discussion; nevertheless, we would like to respond to the comments of Dr. Zvosec. As stated in the introduction (1), the results reported in the present study were obtained during a randomized, placebo-controlled, long-term efficacy trial, in which patients were abruptly removed in blinded fashion from chronic open-label treatment with sodium oxybate for 7 to 44 months. This study was designed to demonstrate long-term efficacy of sodium oxybate, at the time an investigational new drug, for the treatment of cataplexy without imposing the hardship of receiving placebo treatment for many months. This protocol was approved by local and regional ethics committees as well as the U.S. Food and Drug Administration. The system used for reporting adverse events was the Coding Symbols for a Thesaurus of Adverse Reaction Terms dictionary, commonly referred to as COSTART (12). At the time this trial was being conducted, COSTART was the FDA-preferred means of standardized adverse event reporting. The verbatim description of an adverse event, as reported by the patient, was forwarded to a clinical research organization where verbatim terms were translated into COSTART terms. Of note, COSTART captures verbatim terms that translate to Addiction, Drug Dependence, and Withdrawal Syndrome as adverse events. The accompanying table lists verbatim and COSTART descriptions of the adverse events reported in placebo patients during the double-blind phase of the study.