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

To the Editor:

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.

Table

Summary of adverse events reported in placebo patients during the double‐blind phase of the trial
Verbatim term	COSTART term	Placebo group (N = 29)
Bruise chin; bruise forehead right side; abrasion	Accidental injury	1
Headache	Headache	2
Migraine headache	Migraine	1
Swollen lymph node in neck	Lymphadenopathy	1
Elevated AST	SGOT increased	1
Elevated ALT	SGPT increased	1
Anxiety; Increased anxiety	Anxiety	2
Dizziness	Dizziness	1
Insomnia	Insomnia	1
Increased awakening at night	Sleep disorder	1
Increased excessive daytime sleepiness	Somnolence	1
Upper respiratory infection	Pharyngitis	1
Slight erythema, right outer canthus	Rash	1

Each of the 15 physicians and scientists who conducted this trial are Diplomates of the American Board of Sleep Medicine and as such they are recognized as experts in the diagnosis and treatment of narcolepsy. It was the responsibility of these investigators to conduct the trial according to the approved protocol, ensure 24h access to medical personnel to each study participant in the event of an emergency, and to the best of their ability determine whether adverse events that occurred during the trial were directly related, possibly related, or unrelated to the study medication. As numerous other medications with addiction liability are commonly used in the treatment of narcolepsy, such as methylphenidate and amphetamines, these investigators are particularly observant for any evidence of abuse or dependence. In the opinion of these investigators, the adverse events reported were in many cases related to sodium oxybate (or its lack in placebo patients; i.e., due to narcolepsy); however, they were not symptoms of addiction, drug dependence, or a withdrawal syndrome.

Xyrem® (sodium oxybate) oral solution received marketing approval from the FDA in July 2002 for the treatment of cataplexy in patients with narcolepsy. Xyrem is available through a Risk Management Program that includes a postmarketing evaluation program. Each prescribing physician is requested to solicit the occurrence of adverse events with their patients at 3‐ and 6‐month clinic visits. In addition, physicians are encouraged to use these forms to record information about suspected patient abuse or misuse of Xyrem as well as any evidence of addiction or withdrawal. The information obtained in these patient interviews is faxed or mailed to an independent drug safety agency for data management and is reported quarterly to the FDA. As of August 31, 2003, 295 reports had been submitted representing 217 individuals taking Xyrem. Of note, 205 of the 295 reports describe no adverse events of any kind and none of these reports describe abuse, addiction, or withdrawal.

Regarding the suggestion that a daily dose of as little as 10 g and dosing every 4.8h may cause addiction, a careful read of the case indicates the patient “regular consumed 25 g (370 mg/kg) of GHB p.o. per day in five divided doses for 2 years” and “when she abruptly decreased her dose from 25 g to 10 g per day, she experienced anxiety that persisted for one week.” That is, 25 g daily for 2 yrs, not 10 g daily lead to dependence in this patient 14.

A careful re‐read of the abstract in which these data were first reported13 described “minimal signs of withdrawal such as insomnia, anxiety or tremor” (not and tremor) and was meant to contrast the findings of the present study with the severe symptoms which have been reported following the intentional abuse or misuse of GHB14-16.

Orphan Medical, Inc., remains dedicated to patients with uncommon diseases, and our company is proud to provide Xyrem® (sodium oxybate) oral solution to the many patients who suffer from narcolepsy in the United States. Additional information about this product may be obtained on the Internet by visiting www.xyreminfo.net.

William C. Houghton, M.D.

Chief Scientific and Medical Officer

Orphan Medical, Inc.

Minnetonka, Minnesota

[email protected]