By Karla L. Palmer –
On Monday, November 4, 2013, the Drug Enforcement Administration (“DEA”) published a notice of proposed rulemaking (“NPR” ), proposing to place the substance 2 –((diemthylamino)methyl)-1-(3-methyloxyphenyl) cyclohexanol), and its salts, isomers, salts of isomers, and all isometric configurations of possible forms, including tramadol, in Schedule IV of the Controlled Substances Act (“CSA”). Although not entirely unexpected given DEA’s published concerns about the abuse potential, it comes at time almost eighteen years after the drug was first marketed in the Untied States.
Trade names of the substance include Ultram® and Ultracet®. Schedule IV controlled substances are those substances that have a low potential for abuse relative to drugs in Schedule III, have a currently accepted medical use in the United States, and the abuse of the drug could lead to limited physical dependence relative to the drugs in Schedule III. Tramadol was approved for marketing in 1995 as a non-controlled analgesic. The drug was not scheduled based on information related to its low potential for abuse and very weak narcotic effect. DEA now reports that data demonstrates, because of inadequate product labeling (which has undergone several revisions) and lack of established abuse potential, it has become known to narcotics abusers. As a result, DEA received numerous reports of its abuse and dependence (see here). At least 10 states have already scheduled tramadol as a controlled substance, and at least four citizen petitions to reschedule tramadol have been pending at DEA since approximately 2005.
The CSA provides that scheduling of any drug may be initiated by the Attorney General: (1) by his own motion; (2) at the request of the Secretary of HHS; or (3) on the petition of an interested party. The NPR states that this particular rulemaking is based on the recommendation from HHS and an evaluation of all other relevant data provided by DEA. The scheduling of tramadol has been under review for over seven years. In 2007, DEA submitted to HHS its request for a scientific and medical evaluation (which findings are binding on DEA), and for HHS’s recommendation on scheduling of tramadol. In 2010, the HHS provided to DEA its scientific and medical evaluation, recommending, after completing the eight-factor analysis required in 21 U.S.C. s 811(b), placement of tramadol in Schedule IV. DEA completed its own eight-factor review pursuant to 21 U.S.C. s 811(c) in 2011. Those analyses are attached here and here, and are briefly summarized below:
(1) Drug’s Actual and Relative Potential for Abuse: HHS and DEA found that since initial marketing of tramadol in 1995, the drug has been, and currently is, abused for its opioid effects. DEA also found that individuals are taking tramadol in sufficient amounts to create a public health threat, and there is “significant” diversion of tramadol from legitimate channels. Individuals are also taking tramadol on their own initiative, and not on the advice of medical practitioners. Tramadol also shares several pharmacological effects similar to other scheduled opioids.
(2) Scientific Evidence of the Drug’s Pharmacological Effects, if Known: DEA and FDA recognized tramadol as an opioid analgesic that produced effects, including adverse, analgesic, and other effects, similar to opioids in Schedules III and IV.
(3) The State of Current Scientific Knowledge Regarding the Drug or Other Substance: The NPR sets forth a chemical description of the substance that DEA seeks to schedule.
(4) Its History and Current Pattern of Abuse: Data reviewed by both FDA and DEA reveals that tramadol has been abused since 1995 “by a wide spectrum of individuals of different ages, alone and in combination with other psychoactive substances.” From 2009-2011, more prescriptions were written for tramadol than for any other opioid other than hydrocodone and oxycodone. Collected data from several national databases demonstrate the misuse, abuse, and diversion of tramadol in the United States. Data concerning tramadol most closely resembles that of propoxyphene (Darvon®), another Schedule IV narcotic.
(5) Scope, Duration and Significance of Abuse: Similar to factor four, HHS considered 15 years of various sources of data detailing the medical and non-medical use and abuse of tramadol. Data shows that tramadol has less abuse potential than several narcotics currently controlled in Schedule II. As evaluated by both HHS and DEA, data shows, however, that tramadol most closely compares to propoxyphene (Schedule IV) and codeine (Schedules II, III, and V). Thus, tramadol's similarity to other controlled opioids and clear evidence of significant non-medical use and abuse, accompanied by serious adverse events, indicates that tramadol has sufficient abuse potential and incidence of drug dependence and addiction to warrant control as a Schedule IV controlled substance.
(6) What, if any, Risk There is to the Public Health: DEA’s analysis reveals that there are “numerous risks” the public health that may result from tramadol abuse, which adverse effects on the public health are consistent with other opioids. The incidence of adverse events is similar to that of codeine-containing products, and emergency room visits due to non-medical use of tramadol is similar to that of propoxyphene (Schedule IV), yet lower than that of Schedule II and III opioids. Reported exposure and death cases quadrupled from 2004 to 2011, ranking third behind oxycodone and hydrocodone combination products. The collected data from a number of sources indicates that tramadol “presents risks to the public health,” which supports scheduling, but the data also suggest a lower schedule than Schedule III.
(7) Its Psychic or Physiological Dependence Liability: HHS reviewed information from clinical and pre-clinical studies, and found that repeated dosing of tramadol resulted in dependence development, and withdrawal symptoms occurred upon discontinuation of treatment. HHS states that tramadol may produce a “modest level of physical dependence;” studies suggested a decree of dependence development consistent with other opioids in Schedule IV.
(8) Whether the Substance is an Immediate Precursor of a Substance Already Controlled Under the CSA: Both HHS and DEA conclude that it is not an immediate precursor of other controlled substances.
Requirements for Handling Tramadol as a Schedule IV Controlled Substance
The NPR sets forth the requirements under the CSA and its implementing regulations for handling of a Schedule IV controlled substance. If tramadol is placed in schedule IV, those entities that handle tramadol will be , by the effective date of the final rule, subject to registration, security, labeling and packaging, inventory, recordkeeping, reporting (including ARCOS reporting), prescription, and import and export requirements required for substances placed in Schedule IV. Any activity involving tramadol occurring after the effective date of the final rule that is in violation of the CSA or its regulations could result in civil, criminal or administrative sanctions.
Written Comments and Hearing Requests
Written comments on the NPR are due within 60 days, or by January 3, 2014. Interested persons (those “adversely affected or aggrieved by any rule or proposed rule “) may file a request for a hearing within 30 days of the date of publication of the proposed rule, or by December 4, 2013.
Effect on International Scheduling
As a result of HHS’s findings and DEA’s scheduling action, one consideration is whether international scheduling will follow suit. The United States is a party to both the 1961 and the 1971 Conventions on Psychotropic Substances. Tramadol has been reviewed four times between 1992 and 2006 by the World Health Organization’s (“WHO’s”) Expert Committee for Drug Dependence (“ECDD”) for possible scheduling. The WHO makes recommendations to the Commission on Narcotic Drugs (“CND”) for scheduling under the international treaties. On each occasion the ECDD did not recommend scheduling tramadol based on its low potential for abuse. This latest action in the United States could lead to a new review by the WHO and the CND. Tramadol has been approved for marketing internationally since 1977. Any member country can request a review for scheduling of any substance. Tramadol’s status in other countries currently ranges from availably as an over-the-counter product availability by prescription yet non-controlled, to its scheduling as a controlled substance.
Further commentary on the proposed scheduling will be forthcoming. Stay tuned.