Note: This post has been featured on MedPage Today, with personal commentary provided within the piece.For those of you who may have missed it on Twitter yesterday, the Drug Enforcement Administration (DEA) has officially classified tramadol as a Schedule IV substance within the United States under the Controlled Substance Act, which will be effective as of August 18 of this year.
You may be wondering, “So, what’s the big fuss about tramadol that led to this decision by the DEA?”
First, let me start off with a little bit about tramadol itself. Tramadol is a synthetic, centrally acting analgesic. It is actually a racemic mixture, where the (+) enantiomer is involved with binding to the mu opioid receptor as well as inhibition of reuptake of serotonin, while the (-) enantiomer is responsible for preventing the reuptake of norepinephrine. Upon ingestion, it is metabolized via CYP2D6 to O-desmethyltramadol, which is an active metabolite that has higher receptor affinity to the mu opioid receptors relative to the parent drug. It was first approved in Europe in the mid-1970s, and it made its way into the United States in 1995 when it was approved by the Food and Drug Administration (FDA).
Prior to its approval, the Drug Abuse Advisory Committee of the FDA did not initially recommend tramadol to be scheduled as a controlled substance due to preliminary human and animal studies demonstrating a low potential for abuse as well as its given history of being utilized extensively in Europe in the couple of previous decades. However, due to concerns for abuse within the United States, an independent steering committee was founded by the manufacturer of tramadol (Ortho-McNeil) to monitor abuse and dependence patterns of tramadol once it hit the market in the United States. At the time, this was the first time such a committee was developed for monitoring the abuse potential of any such psychoactive medication that was approved by the FDA. With this, strict criteria related to how this monitoring was going to take place were developed as well as factors taken into account that would allow for unbiased recognition of abuse.
Within the first three years of approval of tramadol in the United States, members of the steering committee quickly began to realize that patients on tramadol indeed abused the drug, and the commonly cited statistic is the monthly incidence being 2 to 3 cases per 100,000 patients in the first two years following its approval (1). In addition, complications of abuse were also recognized, including both opioid-like and atypical withdrawal following downward titration of the dose as well as abrupt discontinuation of the medication, which accounted for 40% of adverse effects associated with tramadol (2).
Despite these observations, numerous follow up analyses, and petitions from individuals and organizations, nothing was done. Several analyses have been conducted since then, including one performed by the Department of Health and Human Services demonstrating increased prescribing of tramadol relative to opioid analgesics such as hydrocodone and oxycodone from 2003 to 2008 (in 2012 alone, nearly 40 million prescriptions for tramadol were written for patients in the United States). In addition, a staggering growth in the non-medical use and diversion of tramadol has been observed in recent years, and within the United States, over 16,000 visits to the emergency department related to this occurred in 2010. Not surprisingly, the steering committee dissipated in 2005.
However, critical reviews of this issue have been flatly denied by the WHO Expert Committee on Drug Dependence. For this was not a growing issue that was unique to the United States alone; the abuse potential of tramadol has been supported through observations worldwide throughout Europe, the Asian Pacific, and the Middle East (3-9). Peer review comments from this committee, which convened in Geneva just this past June are available, and recommendations regarding the scheduling of tramadol are fairly mixed (10-12). Some have downplayed the potential for abuse and dependence of tramadol, and arguments against scheduling tramadol included reasoning such as reduced accessibility of the drug for those patients in chronic pain. This is creation of a non-issue, as those who have a valid prescription for tramadol for a legitimate medical condition can access the medication. However, some countries placed tramadol under strict control, the most recent being the United Kingdom, where it is now a class C schedule 3 drug, which ironically went into effect this past June.
Several states were proactive and scheduled tramadol as a schedule IV substance, which is currently recognized under state law in ten states. A retrospective review of exposures to tramadol reported to poison control centers was conducted by investigators with comparisons made in two states where tramadol was scheduled as a controlled substance compared to two states where tramadol was not scheduled. The results of the study demonstrated a decrease in reported exposures to tramadol in those two states following its new scheduling status, and in those states where tramadol was not scheduled, the number of reported exposures to tramadol increased by 14% on an annual basis (13).
What changes will we see following this new status of tramadol? Will patterns of abuse and dependence decrease as a result? Will new methods of diversion be created as a result? Will toxic exposures decrease on a national level? Will other countries follow suit with stricter control for prescribing and dispensing of tramadol? The answers to these questions remain to be seen, but this new scheduling of tramadol by the DEA is a step in the right direction.
- Cicero TJ, Adams EH, Geller A, et al. A postmarketing surveillance program to monitor Ultram (tramadol hydrochloride) abuse in the United States. Drug Alcohol Depend 1999; 57(1):7-22.
- Senay EC, Adams EH, Geller A, et al. Physical dependence on Ultram (tramadol hydrochloride): both opioid-like and atypical withdrawal symptoms occur. Drug Alcohol Depend 2003; 69(3):233-41.
- Radbruch L, Glaeske G, Grond S, et al. Topical review on the abuse and misuse potential of tramadol and tilidine in Germany. Subst Abus 2013; 34(3):313-20.
- Hawkes N. Deaths from tramadol and legal highs reach new highs in England and Wales. BMJ 2013; 347:f5336.
- Tjäderborn M, Jönsson AK, Ahlner J, et al. Tramadol dependence: a survey of spontaneously reported cases in Sweden. Pharmacoepidemiol Drug Saf 2009;18(12):1192-8.
- Zhang H, Liu Z. The investigation of tramadol dependence with no history of substance abuse: a cross-sectional survey of spontaneously reported cases in Guangzhou City, China. Biomed Res Int 2013; 2013:283425.
- Sarkar S, Nebhinani N, Singh SM, et al. Tramadol dependence: a case series from India. Indian J Psychol Med. 2012; 34(3):283-5.
- Progler Y. Drug addiction in Gaza and the illicit trafficking of tramadol. J Res Med Sci 2010; 15(3):185-8.
- Fawzi MM. Medicolegal Aspects Concerning Tramadol Abuse. The New Middle East Youth Plague: An Egyptian Overview. J Forensic Res 2010; 2:130.
- Expert Peer Review 1: Tramadol. 36th Meeting of Expert Committee on Drug Dependence. Available at: http://www.who.int/medicines/areas/quality_safety/6_1_EPR_1.pdf [Accessed 3 July 2014]
- Expert Peer Review 2: Tramadol. 36th Meeting of Expert Committee on Drug Dependence. Available at: http://www.who.int/medicines/areas/quality_safety/6_1_EPR_2.pdf [Accessed 3 July 2014]
- Expert Peer Review 3: Tramadol. 36th Meeting of Expert Committee on Drug Dependence. Available at: http://www.who.int/medicines/areas/quality_safety/6_1_EPR_3.pdf [Accessed 3 July 2014]
- Spiller HA, Scaglione JM, Aleguas A, et al. Effect of scheduling tramadol as a controlled substance on poison center exposures to tramadol. Ann Pharmacother 2010; 44(6):1016-21.