«Although rare, tramadol-induced hypoglycemia is a potentially fatal, adverse event,» the researchers state.
The study, published online in JAMA Internal Medicine December 8, was conducted by a group led by Jean-Pascal Fournier, MD, from the Jewish General Hospital, Montreal, Quebec, Canada.
Writers of an accompanying editorial note: «Because hypoglycemia can be life threatening, clinicians should remain vigilant for this potential complication of tramadol use, in patients taking the drug as directed, as well as those who abuse it.»
The editorialists say that hypoglycemia adds to mounting concerns about tramadol — a weak opioid — that counter the widely held perception that it is a safer alternative to full opioids.
Dr Fournier and colleagues explain that there have been several spontaneous reports of hypoglycemia associated with tramadol use. This, together with the fact that use of the drug is increasing, prompted them to conduct the current study, which linked prescription data and hospital records in the United Kingdom (UK).
From the UK Clinical Practice Research Datalink, the researchers identified 28,110 new users of tramadol and 305,924 patients newly prescribed codeine for noncancer pain between 1998 and 2012. They then used the Hospital Episode Statistics database, which logs all hospitalizations in England, to identify hospitalizations for hypoglycemia in the same time period. The 334,034 patients prescribed tramadol or codeine were matched to 11,019 controls.
The data were analyzed in three different ways: a case-control analysis, a cohort analysis, and a case-crossover analysis (in which cases serve as their own controls).
The use of tramadol increased more than eight-fold during the study period, they found.
Compared with codeine, tramadol use was associated with an increased risk for hospitalization for hypoglycemia, which was particularly elevated in the first 30 days of use. This 30-day increased risk was confirmed in the cohort and case-crossover analyses.
Table. Risk for Hospitalization With Tramadol vs Codeine
|Odds Ratio (95% Confidence Interval)
1.52 (1.09 – 2.10)
|Case-control analysis (first 30 days of use)
2.61 (1.61 – 4.23)
|Cohort analysis (first 30 days of use)
3.60 (1.56 – 8.34)
|Case-crossover analysis (first 30 days of use)
3.80 (2.64 – 5.47)
The researchers report that these analyses «associated tramadol use with a more than 3-fold increased risk of hospitalization for hypoglycemia.»
They say the increased risk seemed to be limited to the first 30 days of use and remained statistically significant in patients with no history of treated diabetes.
They add that the risk is small, approximately 7 per 10,000 per year, which may explain why it was not observed in randomized clinical trials.
Toxic Effects «Merit Respect»
But in their editorial, Lewis S. Nelson, MD, York University School of Medicine, and David N. Juurlink, MD, Sunnybrook Health Sciences Centre, both in Toronto, Ontario, Canada, point out that although hospitalization for hypoglycemia was uncommon in this study, the true rate of hypoglycemia will be higher because it may not be reported or recognized.
They note that animal studies support a physiologic mechanism of such an adverse effect, reporting that tramadol directly reduces hepatic gluconeogenesis and enhances peripheral glucose utilization in diabetic rats.
«The increased prescribing of tramadol most likely reflects aggressive marketing coupled with the perception that it is a safe analgesic not prone to abuse. Whereas the drug’s analgesic effects are at best moderate, its toxic effects are dangerous and merit respect, particularly when doses are escalated,» they write.
Dr Nelson and Dr Juurlink list the following adverse effects linked to the drug: seizures, serotonin syndrome, and drug-interactions, as well as the well-known opioid-related adverse effects. And hypoglycemia can now be added as «yet another potentially dangerous adverse effect.»
Noting that conventional full opioid agonists have risks that are more predictable than those of tramadol, they conclude: «If we replace conventional opioids with tramadol, as some guidelines have suggested, we may be left with more unintended consequences of the opioid epidemic to worry about.»
This study was funded in part by research grants from the Canadian Institutes of Health Research and Canada Foundation for Innovation. Senior author Samy Suissa, MD, is the recipient of the James McGill Chair. The study authors, Dr Nelson, and Dr Juurlink have disclosed no relevant financial relationships.
JAMA Intern Med. Published online December 8, 2014.