Letter to the editor: hypoglycemia and treatment with opioids

KEYWORDS:

• Hypoglycemia
• opioids
• diabetes
• tramadol
• hypoglycemic coma

We read with interest the review article by Chrétien et al, “Comparative study of hypoglycemia induced by opioids. Is it a class effect?” published online in this journal [1]. The authors performed a disproportionality analysis in the WHO global individual case safety report database and in the French PharmacoVigilance DataBase (FPVD) with nine opioids (codeine, fentanyl, hydromorphone, methadone, morphine, oxycodone, tramadol, buprenorphine, and nalbuphine) looking for any indications of hypoglycemia. The authors concluded that this work highlighted a significant association between all opioids and hypoglycemia, thereby indicating that opioid-induced hypoglycemia is probably a class effect. Women and diabetics seem to be more at risk for developing opioid-induced hypoglycemia.

The authors should be congratulated on their efforts to collect and analyze such a large amount of data leading to an interesting debate and highlighting this very important topic. Although we agree with many of the conclusions of this interesting and important study, we would like to make several comments.

All 133 cases found in FPVD were described separately according to the type of opioid. We have several remarks relating to cases involving tramadol which point to some possible study weaknesses. These weaknesses may also apply to the other opioids cases collected in the article. Of those 93 tramadol cases, 45 were related to diabetic patients (type 1: 19, type 2: 21, not reported: 5). Based on our clinical experience we speculate that all cases could have some connection to antihyperglycemic treatment (insulin in type 1, type of treatment in type 2 diabetes patients were not stated in the article), as a result for example, of one of the common side effect of opioids which is sleepiness. We also do not have any information about the frequency of hypoglycemia and the severity in the period before the treatments with opioids was introduced to make a comparison.

Therefore,we think a detailed analysis of hypoglycemic events related not only to tramadol in nondiabetic subjects would be a much more valuable support to the authors´ conclusions (we presume that the remaining 48 cases are related to non-diabetic patients). It would be interesting to know the hypoglycemia definition used in those cases, the value of hypoglycemia and concomitant diseases, especially those which could contribute to hypoglycemia like renal and liver diseases, if such data are available.

Finally, it should be noted that in both studies [2,3] cited in the article to support the connection between tramadol and hypoglycemia, the definition of hypoglycemia used is disputable. In the first one [2], the threshold for the hypoglycemic event was 70 mg/dl (3.9 mmol/l), which is correct for diabetic patients. This criterion was also used for non-diabetic subjects who were involved in the study. However, the normal lower value of glycemia in healthy adults is considered to be 63 mg/dl (3.5 mmol/l) [4]. Thus, some of the cases could falsely be interpreted as indicating hypoglycemia. In the second study [3], the criterion of hypoglycemia that was used was hospitalization for a hypoglycemic event, without any other specific hypoglycemia definition. As in the first example, some of the cases in this study could also be falsely interpreted as indicating hypoglycemia.

We respectfully suggest taking these points into account if the continuation of this important study is planned.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.