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Tramadol associated with significantly greater risk of hypoglycaemia

TramadolThe opioid tramadol produced a 10-fold greater risk of developing hypoglycaemia than virtually every other opioid, found a US study.

Since its approval in 1995, the opioid tramadol (marketed as ConZip and Ultram) has become a widely prescribed remedy for osteoarthritis and other painful indications, in part because it presents a lesser risk for some side effects and has a lower abuse potential when compared to other opioids. It is currently ranked among the top five prescribed opioids and top 60 prescribed medications in the country.

But as tramadol has grown in popularity so too have documented cases of adverse effects among its users. Researchers at Skaggs School of Pharmacy and Pharmaceutical Sciences at University of California – San Diego show in a study that patients who take tramadol are at greater risk for developing hypoglycaemia, or abnormally low blood sugar.

The research team, led by senior author Dr Ruben Abagyan, professor of pharmacy, analysed more than 12m reports from the US Food and Drug Administration (FDA) Adverse Effect Reporting System (FAERS) and Adverse Event Reporting System (AERS) databases, which chronicle voluntary reports of adverse effects while taking a medication. The period studied ranged from January 2004 to March 2019.

"The impetus was the recent dramatic surge in tramadol popularity and prescriptions," said first author Dr Tigran Makunts, a researcher in Abagyan's lab. "We wanted to have an objective data-driven look at its adverse effects and bumped into a dangerous, unlisted and unexpected hypoglycaemia."

Recognised adverse drug reactions associated with tramadol include dizziness, nausea, headaches and constipation – all common side effects of opioids. More serious but rarer adverse drug reactions include serotonin syndrome and increased seizure risk. The link to hypoglycaemia is relatively new, though it had been previously suggested by case studies and animal model testing.

Hypoglycaemia is often related to the treatment of diabetes, but can also occur in persons without diabetes. Untreated, hypoglycaemia can lead to serious complications of its own, such as neurocognitive dysfunction, vision loss, greater risk of falls and loss of quality of life.

The researchers also looked at other widely prescribed opioids and similar acting, non-opioid medications, such serotonin and norepinephrine reuptake inhibitors (Cymbalta, Effexor XR) and NMDA receptors (ketamine and memantine). Only tramadol produced a significant risk of developing hypoglycaemia in patients. In fact, there was a 10-fold greater risk of hypoglycaemia using tramadol than virtually every other opioid. The only other drug identified with comparable effect was methadone, an opioid most commonly used to help persons reduce or quit addictions to heroin or other opiates.

While this study underscores an association between tramadol and hypoglycaemia, a large, randomised, controlled clinical trial would be needed to definitively establish causality.

"The takeaway message is to warn physicians about the likelihood of low blood sugar (and/or high insulin content), in particular if the patient is predisposed to diabetes," said Abagyan, "and to motivate research about the unique molecular mechanism leading to that side effect. It is particularly important for tramadol or methadone that are used widely and, often, chronically."

Tramadol is one of the most commonly used analgesics worldwide, classified as having a low abuse potential by U.S. Drug Enforcement Agency, and often recommended in pain management guidelines. Its pain-relieving mechanism of action is attributed to mild μ-opioid receptor agonism, serotonin and norepinephrine mediated nociception modulation, and N-methyl-D-aspartate receptor, NMDAR, antagonism. However, recent case reports and case-control studies have shown an association between tramadol use and hypoglycemia. The growing concern over increasing tramadol use and unexpected side effects warranted a further comparative and quantitative analysis of tramadol adverse reactions. In this study we analyzed over twelve million reports from United States Food and Drug Administration Adverse Event Reporting System and provided evidence of increased propensity for hypoglycemia in patients taking tramadol when compared to patients taking other opioids, serotonin-norepinephrine reuptake inhibitors, and drugs affecting NMDAR activity. Additionally, we identified that only methadone from the opioid cohort behaves similarly to tramadol and has an association with hypoglycemia.

Tigran Makunts, Andrew U, Rabia S Atayee, Ruben Abagyan

[link url=""]University of California – San Diego material[/link]
[link url=""]Scientific Reports abstract[/link]

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