Patients who take tramadol are at greater risk for developing hypoglycemia


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.

In a new paper, published August 28, 2019 by Scientific Reports, researchers at Skaggs School of Pharmacy and Pharmaceutical Sciences at University of California San Diego show that patients who take tramadol are at greater risk for developing hypoglycemia, or abnormally low blood sugar.

The research team, led by senior author Ruben Abagyan, Ph.D., professor of pharmacy, analyzed more than 12 million reports from the 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 Tigran Makunts, PharmD, 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 hypoglycemia.”

Recognized 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 hypoglycemia is relatively new, though it had been previously suggested by case studies and animal model testing.

Hypoglycemia is often related to the treatment of diabetes, but can also occur in persons without diabetes.

Untreated, hypoglycemia 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 hypoglycemia in patients.

In fact, there was a 10-fold greater risk of hypoglycemia 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 hypoglycemia, a large, randomized, 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.”


In outpatient populations, hypoglycemia has been associated with tramadol. We sought to determine the magnitude of risk for hypoglycemia associated with tramadol use in hospitalized patients.


During a 2-year period of observation, adult inpatients who received ≥1 dose of tramadol were identified and their medical records were reviewed. Patients were included if they had blood or plasma glucose (BG) concentrations measured on at least two occasions within five days after the initial administration of tramadol. A contemporary comparator group of hospitalized oxycodone recipients was similarly reviewed.


Tramadol was administered to 2927 patients who met inclusion criteria. Among these, hypoglycemia (BG ≤70 mg/dL) was documented in 22 (46.8%) of 47 patients with type 1 diabetes, 113 (16.8%) of 673 patients with type 2 diabetes, and 103 (4.7%) of 2207 patients who did not have a diabetes mellitus diagnosis. In those without a diabetes diagnosis, the causality association between hypoglycemia and tramadol use was probable in 77 patients (3.5%). By comparison, hypoglycemia was documented in 8 (1.1%) of 716 matched oxycodone recipients without diabetes (p = 0.002). As compared with tramadol recipients who did not develop low BG concentrations, those who experienced tramadol-related hypoglycemia were relatively young (mean age 52.0 versus 59.8 years; p = 0.027) and predominantly female (74.0% versus 59.8%; p = 0.012).


Tramadol use was causally associated with hypoglycemia in hospitalized patients. The proportion of patients without diabetes who developed hypoglycemia was higher among those who received tramadol than among those who received oxycodone.

Trial registration

Colorado Multiple Institutional Review Board Protocol № 15–2215. Registered/approved 8 December 2015.


Tramadol is a centrally-acting analgesic medication that has been in clinical use for several decades.

The antinociceptive effects of tramadol are imparted by drug and metabolite binding to μ-opioid receptors and inhibition of neuronal reuptake of serotonin and norepinephrine [1].

In pharmacological models, both of these actions have been shown to not only enhance insulin effects but also directly promote glucose utilization [23].

Clinically, this may result in decreased blood glucose concentrations. Individual case reports have highlighted severe hypoglycemia as a possible consequence of tramadol overdose [4] and recent epidemiological surveys documented increased risk for symptomatic hypoglycemia among diabetic and nondiabetic outpatients taking therapeutic doses of tramadol [56].

However, the overall magnitude of hypoglycemic risk associated with tramadol remains unclear and no recommendations for patient monitoring are currently available.

The aims of this investigation were to determine

(1) if hospitalized patients are affected by tramadol-related hypoglycemic effects;

(2) whether tramadol administration imparts increased risk for hypoglycemia as compared with use of other opioid analgesic medications; and

(3) which patient characteristics or comorbidities confer increased risk for tramadol-related hypoglycemia.


Our study design is diagrammed in Fig. ​Fig.1.1. Briefly, we performed a retrospective case-control observational study.

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Fig. 1
Study design


The primary outcome event was objective documentation of hypoglycemia occurring within 5 days after the initiation of tramadol or oxycodone therapy. Consistent with alerting values in current guidelines [910], hypoglycemia was defined as having at least one recorded BG concentration ≤ 70 mg/dL.

Percentage occurrence rates for hypoglycemia were compared between patients with T1DM and T2DM and patients without a diabetes mellitus diagnosis who received either tramadol or oxycodone.

Additional outcomes related to hypoglycemia were investigated.

To determine whether the occurrence rate for hypoglycemia after tramadol administration was different than the occurrence rate for hypoglycemia that occurs in the general hospital population, the post-tramadol percentage occurrence rates for hypoglycemia in patients with and without diabetes occurring during the 2-year period of observation were compared with the overall percentage occurrence rate for hypoglycemia documented in a convenience sample that contained hospital-wide results of all point-of-care BG concentrations measured from October 1 through November 30, 2015. BG measurements in the convenience sample were sourced from patients with and without a diabetes mellitus diagnosis.

More information:Scientific Reports (2019).

Journal information: Scientific Reports
Provided by University of California – San Diego


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