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A new study associates dispensation doses of tramadol with increased risk of mortality, cardiovascular events, and fractures compared to the use of codeine to treat pain.

Packet of Tramadol tablets

Although tramadol is increasingly used to manage non-cancer pain, few safety studies have compared it with other opioids in actual practice conditions. A new study, published in JAMA, provides evidence that tramadol is associated with an increased risk of mortality and adverse clinical outcomes, and highlights the need for future research on its safety.

The population-based cohort study on 368,960 participants reviewed a new dispensation of tramadol, compared with codeine. The international research team prespecified eight outcomes that had been previously correlated to the opioid use including: all-cause mortality, cardiovascular events, fractures, constipation, delirium, falls, opioid abuse/dependence, and sleep disorders within one-year after the first dispensation. Codeine was used as the comparator as both tramadol and codeine are weak opioids, prescribed for addressing similar pain and illness.

Junqing Xie, DPhil student and lead author said: "Compared with codeine, our study showed that tramadol was associated with an increased risk of mortality, cardiovascular events, and fractures, but we saw no increased risk for the other measures we explored. The results for mortality are quite surprising because tramadol is accepted as being a safer opioid. The findings should be interpreted cautiously given the potential for residual confounding."

The findings were also consistent when applied over a range of subgroups, which means these effects could be seen in different age groups, and across different pain indications in adults.

The use of opioids to treat severe cancer and non-cancer pain has led to a decades-long epidemic in the United States where death rates and adverse effects on public health from opioid use are significant. Recently, more and more data show that the opioids have been increasingly prescribed for a variety of painful conditions in other countries like Canada, Australia, Europe and the UK. "The increased use of tramadol is a concern because if it's considered a safe drug, it might be prescribed more casually. We think while more data is urgently needed for the tramadol safety profile, clinicians should err on the side of caution when considering this treatment," concluded Carlen Reyes, a doctor and the corresponding author for this study.