Opioid tramadol can cause potentially fatal blood sugar drop: study

TORONTO -- Researchers are reporting what appears to be another adverse effect of the drug tramadol, an opioid that's being increasingly prescribed by doctors for the treatment of pain.

Known possible effects of tramadol, sold in Canada under a number of brand and generic names, already include seizures and a risk of addiction and fatal overdose.

Now tramadol has been linked to another adverse side-effect: hypoglycemia, or a sudden and potentially fatal drop in blood sugar, requiring hospitalization.

"What we found was that the use of tramadol is associated with an over two-fold increased risk of hypoglycemia," said Laurent Azoulay, a pharmacoepidemiologist at McGill University and the Jewish General Hospital in Montreal.

The researchers analyzed a database of all patients newly treated with tramadol or codeine for non-cancer pain between 1998 and 2012, using hospital data from the United Kingdom. The study included 334,034 patients -- 28,110 new users of tramadol and 305,924 new users of codeine -- of whom 1,105 were hospitalized for hypoglycemia during an average followup of five years.

Compared with codeine, tramadol was linked to an increased risk of hospitalization for hypoglycemia, especially in the first 30 days after patients started taking the drug, the study published in Monday's edition of the journal JAMA Internal Medicine found.

Of those hospitalized for hypoglycemia, 112, or about 10 per cent, died.

The study looked at both patients with diabetes -- who have a risk of developing low blood sugar because of other medications to control the condition -- and those without diabetes.

"What we found was the risk was actually higher with patients who did not have diabetes," said Azoulay, but added that the finding must be interpreted with caution because many factors can affect blood glucose.

"Patients with diabetes are taking drugs like insulin known to cause hypoglycemia, so it's possible that those patients are able to recognize the early symptoms and signs of hypoglycemia and they're better able to adjust to that, whereas for the average 40- or 50-year-old who's taking (tramadol) for the first time ... maybe they're not able to recognize those effects," he said.

Signs of a plunge in blood sugar include feeling irritable, woozy and shaky. In many cases, drinking orange juice or eating a banana, for instance, can restore one's blood glucose balance.

Azoulay said tramadol differs from other opioids like codeine, morphine and oxycodone in that it binds "weakly" to opioid receptors in the body. But it also affects levels of serotonin, a neurotransmitter related to mood, sleep and memory.

"Serotonin seems to be related to regulation of glucose levels," he said from Montreal. "This drug seems to increase serotonin levels, leading to a sudden drop in blood glucose and a hypoglycemic event."

Dr. David Juurlink, head of clinical pharmacology and toxicology at Sunnybrook Health Sciences Centre in Toronto, said tramadol has been fingered for a number of side-effects and drug interactions, including serotonin syndrome -- an excess of the neurotransmitter in the body. But he hadn't appreciated its link to hypoglycemia before seeing the McGill study.

"It's one more problem."

When taken with antidepressants called selective serotonin re-uptake inhibitors, or SSRIs, tramadol can cause serotonin syndrome in some patients, said Juurlink, co-author of an accompanying commentary in the JAMA journal.

"And because pain and depression so often travel together, it's quite common for these drugs to be prescribed to the same patient."

Often physicians are unfamiliar with tramadol's side-effects and interactions, he said, yet many have the perception that the medication is "safer" than other opioids.

"One reason is that Health Canada has refused to list it as a scheduled (controlled-substance) drug. In Canada, this drug is treated the same way that a cholesterol-lowering drug or a blood pressure-lowering drug is treated. It's not got any special restrictions."

In August, the U.S. reclassified tramadol as a controlled substance like morphine and oxycodone, following the lead of Australia and the U.K.

Health Canada looked into the idea in 2007 of scheduling tramadol under the Controlled Drugs and Substances Act, but it wasn't reclassified and no explanation was given, said Juurlink.

"From a regulatory perspective, I think it's inexcusable that Health Canada hasn't placed tramadol on the schedule of controlled drugs," he said Monday. "This drug should not be treated any differently than codeine."

"It's completely illogical to treat codeine as a controlled substance and to treat tramadol as a garden-variety prescription drug."

A spokesman for Health Canada said the federal department regulates tramadol under the Food and Drug Regulations, but provided no reason as to why the medication has not been classified as a controlled substance.

"Health Canada will consider scheduling tramadol under the Controlled Drugs and Substances Act if there is evidence of abuse of tramadol in Canada," the spokesman said by email.

Juurlink said there are reports of people who use tramadol recreationally who prefer it to oxycodone, a potent opioid that has been redesigned by its manufacturer to make it more tamper-proof and less easy to abuse.

There have been increasing fatalities reported in association with tramadol use, including a tripling of deaths in England and Wales from 2009 to 2013. Health Canada lists nine deaths as possibly being caused by the drug.

That's why doctors need to be aware of the drug's potential for adverse reactions, including serious hypoglycemia, said Azoulay.

Patients need to be informed about a possible severe blood sugar drop and educated about the symptoms and how to counteract the condition, he said. "Because if they do recognize it early on, then there's an easy fix to it."