All That Glitters is Not Gold: Is Tramadol the Safer, Middle Road to Analgesia?

No one questions the fundamental premise that people with pain seek relief—but the choices in our therapeutic armamentarium are limited. And here lies what may be the therapeutic paradox of our time. 

There are basic, but not so effective standbys—eg, aspirin, acetaminophen, and nonsteroidals—that help in some degree, but have serious downsides. When pain is debilitating (eg, in cases of cancer or post-surgery recovery), doctors may turn to opioids, but a new set of problems, including addiction and abuse, must now be factored into the equation. There is also the worry of overprescribing potential gateway drugs to consider. 

On one hand, our profession is accused of minimizing the importance of pain control, but on the other, of overprescribing narcotics. I thought there might be a middle ground in this polarizing, analgesic environment, but concerns abound. 

Is there a safer “middle” alternative than narcotic analgesics—a treatment that delivers fewer side effects than aspirin, acetaminophen, and NSAIDs? Let’s discuss tramadol. 

An Alternative to Narcotics

This month’s Top Paper¹ questions whether hypoglycemia-related hospitalization was higher as a result of tramadol or codeine. 

In animals, tramadol increases peripheral glucose utilization.¹ For the study, researchers conducted a nested case-control analysis using research from 1998 to 2012. All prescriptions were written for patients with noncancerous pain. Of note, the study involved 334,034 participants; 1005 of which were hospitalized for hypoglycemia. When tramadol was compared to codeine, the overall risk was 1.52 times greater (95% CI, 1.09-210) and an even more striking 2.61 times higher (95% CI, 1.61-4.23) within the first 30 days,

Safety Concerns

Unfortunately, there is more to the tramadol story, including concerns regarding safety.² Tramadol has a low affinity for opioid receptors, but like selective serotonin reuptake and serotonin-norepinephrine uptake inhibitors, decreases reuptake of both serotonin and norepinephrine. This action has led, at least in part, to a certain empirical attractiveness for the analgesic’s increasing use in the setting of neuropathic pain. The Top Paper authors amplify their concerns observing increasing tramadol usage in clinical guidelines for pain.² 

Here are some caveats to use:

• Tramadol’s metabolism takes place via a cytochrome P450 isoform 2D6. Expression of this isoform is extremely variable in different groups of people. For example, 10% of persons of Italian ethnicity are ultrarapid (most efficient) metabolizers.² But the sheer variety of metabolism rates runs a gamut from ultrarapid through poor. ² The bottom line: Any given dose of tramadol is equivalent to an unknown dose—ie, a variation on Russian Roulette.² 

• Another problem is the so-called previous low “abuse liability of the drug.” That perception was and is patently incorrect, and why tramadol was moved to a schedule IV status.² 

• Recently, tramadol has also been associated with serotonin syndrome and, on occasion, this potentially fatal complication can occur at “very low doses.”² 

It is no accident that “discretion is the better part” of prescribing practices and should apply to tramadol. It has abuse potential, is unpredictable in its metabolism characteristics, and may cause hypoglycemia and serotonin syndrome. Not only are the consequences serious, they can be fatal. ■

Gregory W. Rutecki, MD, is a physician at the National Consult Service at the Cleveland Clinic. He is also a member of the editorial board of Consultant. Dr Rutecki reports that he has no relevant financial relationships to disclose.

References:

1.Fournier JP, Azoulay L, Hui Y, et al. Tramadol use and the risk of hospitalization for hypoglycemia in patients with noncancer pain. JAMA Intern Med. 2014 Dec 8 [epub ahead of print].

2.Nelson LS, Juurlink DN. Tramadol and hypoglycemia: one more thing to worry about. JAMA Intern Med. 2014 Dec 8 [epub ahead of print].