by July 10, 2014
Nadia Awad, PharmD is an emergency medicine pharmacist at Robert Wood Johnson University Hospital Somerset in New Jersey and Clinical Assistant Professor, Emergency Medicine, Ernest Mario School of Pharmacy at Rutgers, The State University of New Jersey. A version of this article first appeared on EMPharmD blog.
For those of you who may have missed it, the Drug Enforcement Administration (DEA) has officially scheduled tramadol as a Schedule IV substance within the U.S. 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?”
The legislation has been in the works by the DEA for over a year now. I am not sure if clinicians were expecting the new scheduling to take into effect so soon.
In terms of practice, EM physicians may prescribe tramadol as an alternative to opioids in the treatment of pain, and there is a widely purported belief that it has a better safety profile and is not associated with dependence to the same extent as opioid analgesics. When word catches on as to the reasoning for the scheduling, as I provided to you in the document yesterday, I think physicians will be more cognizant of these effects, and may perhaps be less likely to prescribe it for pain control.
In addition, the withdrawal profile of tramadol is quite impressive, and there have been several case reports published about it. Patients may also present to the emergency department secondary to tramadol overdose, which is known to lower the seizure threshold and potentially be associated with serotonin syndrome if co-ingestants are involved, which can be quite severe in nature if not timely recognized and managed appropriately. Whether we will see a decrease in these events in patients who present to the emergency department due to its new scheduling remains to be seen.
For a bit of context, 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 U.S. 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 U.S., 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 U.S. 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 3 years of approval of tramadol in the U.S., 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 two to three cases per 100,000 patients in the first 2 years following its approval.
In addition, complications of abuse was also recognized, including both opioid-like and atypical withdrawal following downward titration of the dose as well as abrupt discontinuations of the medication, which accounted for 40% of adverse effects associated with tramadol.
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 U.S.).
In addition, a staggering growth in the nonmedical use and diversion of tramadol has been observed in recent years, and within the U.S., 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 U.S. 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 (1, 2, 3).
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 nonissue, 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 U.K., 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 with 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.
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.
Given all the information that has come about as a result, my advice would be to think twice prior to prescribing, especially taking into account underlying factors for abuse and overdose potential in patients and pain severity. I would also take into account previous therapies that the patient may have been on that have failed to determine if use of tramadol is warranted.
Awad reported no relevant financial disclosures.
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by July 10, 2014