SUMMARY: This final rule is issued by the Deputy Administrator of the Drug Enforcement Administration (DEA) to place the substance pregabalin [(S)-3-(aminomethyl)-5-methylhexanoic acid], including its salts, and all products containing pregabalin into Schedule V of the Controlled Substances Act (CSA). As a result of this rule, the regulatory controls and criminal sanctions of Schedule V will be applicable to the manufacture, distribution, dispensing, importation and exportation of pregabalin and products containing pregabalin.
SUPPLEMENTARY INFORMATION:
Background
On December 31, 2004, the Food and Drug Administration (FDA) approved pregabalin [(S)-3-(aminomethyl)-5-methylhexanoic acid] for marketing under the trade name LyricaTM. LyricaTM will be marketed in the United States as a prescription drug product for the management of neuropathic pain associated with diabetic peripheral neuropathy (DPN) and postherpetic neuralgia (PHN). Pregabalin has recently been placed on the market in some European countries for the treatment of epilepsy and neuropathic pain.
On April 4, 2005, the Acting Assistant Secretary for Health of the Department of Health and Human Services (DHHS), sent the Administrator of the DEA a letter recommending that pregabalin, and its salts, be placed into Schedule V of the CSA. Enclosed with the April 4, 2005, letter was a document prepared by the FDA entitled, ``Basis for the Recommendation for Control of Pregabalin in Schedule V of the Controlled Substances Act (CSA).’’ The document contained a review of the factors which the CSA requires the Secretary to consider
Based on the recommendation of the Acting Assistant Secretary for Health and an independent review of the available data by the DEA, the Deputy Administrator of the DEA, in a May 13, 2005, Federal Register Notice of Proposed Rulemaking , proposed placement of pregabalin into Schedule V of the CSA. The proposed rule provided an opportunity for all interested persons to submit their comments, objections or requests for hearing to be received by the DEA on or before June 13, 2005.
Comments Received
The DEA received two comments in response to the Notice of Proposed Rulemaking. One commenter stated that the DEA should not minimize the similarity in effects produced by pregabalin and diazepam and should place pregabalin in Schedule IV of the CSA.
The DEA does not agree. Careful consideration of all the available data suggests that pregabalin has less abuse potential than Schedule IV substances. Pregabalin does not substitute for benzodiazepines in benzodiazepine-dependent animals. Data from clinical trials suggest that some of pregabalin’s positive psychic effects are limited and do not continue with time or continued drug use. The data are consistent with a substance that could be abused intermittently for reward, but not for reinforcement. In addition, withdrawal effects of pregabalin are less severe than with other substances currently controlled in Schedule IV.
Another commenter stated that, in their experience with pregabalin in clinical trials, pregabalin does not demonstrate any risk that would merit being considered a scheduled drug.
The DEA does not agree. Preclinical studies indicated that pregabalin is transiently and sporadically self-administered at rates greater than vehicle but substantially lower than active comparators pentobarbital (CII) and methohexital (CIV). In clinical trials, pregabalin produces some pharmacological effects characteristic of diazepam and alprazolam and is likely to be abused for its positive psychic effects. The percentage of individuals that experienced acute euphoric effects was unusually high for pregabalin in clinical trials. Pregabalin also produced dizziness, somnolence, dry mouth, edema, blurred vision, weight gain and attentional problems more frequently than placebo. These data suggest that pregabalin does have sufficient abuse potential to warrant control under the CSA. The DHHS recommended control in Schedule V of the CSA and the DEA concurs.
Scheduling of Pregabalin
Relying on the scientific and medical evaluation and the recommendation of the Acting Assistant Secretary for Health, received in accordance with section 201(b) of the Act , and the independent review of the available data by the DEA, and after a review of the comments received in response to the Notice of Proposed Rulemaking, the Deputy Administrator of the DEA, pursuant to sections 201(a) and 201(b) of the Act, finds that:
(1) Pregabalin has a low potential for abuse relative to the drugs or other substances in Schedule IV;
(2) Pregabalin has a currently accepted medical use in treatment in the United States; and
(3) Abuse of pregabalin may lead to limited physical dependence or psychological dependence relative to the drugs or other substances in Schedule IV.
Based on these findings, the Deputy Administrator of the DEA concludes that pregabalin, including its salts, and all products containing pregabalin, warrant control in Schedule V of the CSA."
Some other titbits (will try to find the full studies
LYRICA is not known to be active at receptor sites associated with drugs of abuse. As with any CNS active drug, physicians should carefully evaluate patients for history of drug abuse and observe them for signs of LYRICA misuse or abuse (e.g., development of tolerance, dose escalation, drug-seeking behavior).
Abuse
In a study of recreational users (N=15) of sedative/hypnotic drugs, including alcohol, LYRICA (450mg, single dose) received subjective ratings of “good drug effect,” “high” and “liking” to a degree that was similar to diazepam (30mg, single dose). In controlled clinical studies in over 5500 patients, 4 % of LYRICA-treated patients and 1 % of placebo-treated patients overall reported euphoria as an adverse reaction, though in some patient populations studied, this reporting rate was higher and ranged from 1 to 12%.
Dependence
In clinical studies, following abrupt or rapid discontinuation of LYRICA, some patients reported symptoms including insomnia, nausea, headache or diarrhea (see Warnings and Precautions), suggestive of physical dependence.
Apparently, the overall reporting of “euphoria” as an adverse effect was reported by 4% (range 3-12%) in post marketing trials, compared to <1% of those on placebo