Using opioid painkillers for more than one month may increase the risk of depression, a new study suggests. People who take opioids and feel depressed should be aware that the drugs, and not just the pain, may be a potential cause, the researchers say.

While pain itself can be a cause of depression, the researchers found a link between opioids and depression even when they took patients’ pain into account, Fox News reports.

“We really did rigorous control for pain, and we feel strongly that these results are independent of the known contribution of pain to depression,” said study author Jeffrey Scherrer of Saint Louis University in Missouri.

The study included data from three groups of people who started taking opioids around the time the study began. One group had almost 71,000 people, while the second group had almost 14,000 people and the third had almost 23,000 people. None of the study participants were depressed when the study began. They were followed for seven to 10 years.

In the first group, 12 percent developed depression, compared with 9 percent in the second group and 11 percent in the third group. The longer people took opioids, the greater their risk of depression. Among the first group, 11.6 percent of those who took opioids from one to 30 days developed depression, compared with 13.6 percent of those who used opioids for one to three months, and 14.4 percent of those who used opioids for more than three months.

Scherrer said while it is not known why long-term opioid use is linked with an increased risk of depression, lowered levels of testosterone may play a role. In addition, he added, “Some patients may start to lose control and develop early symptoms of [opioid] misuse, which is known to be related to depression.”

The study appears in the Annals of Family Medicine.