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ORLANDO -- Some opiates were associated with a greater likelihood of hospital-acquired infection in a large-scale chart review, researchers reported here.

In an analysis of more than 40,000 hospital admissions from Kaiser Permanente Northern California, a significantly larger proportion of patients who were exposed to fentanyl, morphine, or codeine either right before or during their hospital stay developed hospital-acquired pneumonia than those with no opioid exposure (0.79% versus 0.39%, P<0.0001), , of that health system, reported at the .

"We have choices when we prescribe on the inpatient or outpatient side," Rubinstein said during an oral presentation. "Even though this is just a signal finding, it really makes me think that, particularly in vulnerable patients -- the immunosuppressed, HIV patients, patients on biologics -- we want to think about weighing the immunosuppressive effects of opioids when making decisions how we prescribe, because these are easily modifiable risks."

Although much attention has been paid to other risks of opioids, including addiction and overdose, Rubinstein noted that these drugs have also been associated with immunologic risks.

"What if we're using these drugs appropriately? Is there a way that we're still harming these patients?" she asked.

She said there's much animal data to support an immune-altering effect of opioids. To further investigate the relationship in humans, she and colleagues turned to data from their own hospital system, which captured 40,403 hospital admissions among patients ages 18 to 70 from Dec. 1, 2010 to Dec. 31, 2014.

The researchers assessed opioid exposure, with outpatient exposure being defined as filling an opioid script for 60 days or more in the past 100 days before admission, as well as inpatient exposure, and looked at the relationship with hospital-acquired infections. They also divided opioid exposure as either fentanyl, morphine, or codeine exposure, or as exposure to any other opiate such as hydrocodone or oxycodone.

Rubinstein noted that this was because animal studies have shown that fentanyl and morphine are the two opioids most associated with immunosuppression. They added codeine to the mix because it is a prodrug of morphine, she said.

Half of the patients had some exposure to fentanyl, codeine, or morphine (either as an inpatient or outpatient).

Overall, there were 242 cases of hospital acquired pneumonia, for a rate of 0.60%.

In addition to finding that a significantly larger proportion of those with opioid exposure had hospital-acquired pneumonia than those without exposure, the researchers also saw a similar relationship with ventilator-associated pneumonia. Risk of the condition was highest in those who had taken fentanyl, codeine, or morphine as an outpatient and also received those drugs in the hospital (HR 3.47, 95% CI 1.29-7.86).

The team also looked at Clostridium difficile infections to tease apart the respiratory depressant effects of opioids and their potential influence on susceptibility to pneumonia.

There were a total of 16 hospital-acquired C. difficile infections during the study period (0.54%), and significantly more of those with exposure to fentanyl, codeine, or morphine developed the infection, they found (11 versus 5 cases; 1.04% versus 0.27%, P=0.006).

Rubinstein acknowledged that her study couldn't offer any conclusions on the potential mechanism that may be at work here, but she said there's a "signal that we really need to investigate."

Since fentanyl and morphine have little in common -- the latter is a natural opioid, the former is synthetic, one is lipophilic, one is not -- it's not clear why these two opioids might affect the immune system in a way that others do not.

"There are mu opioid receptors throughout the immune system, and these drugs clearly bind to them and alter them in particular ways," she said. "It's possibly a binding affinity or differences in the way the receptor is activated based on some intrinsic property of the molecule."

She noted that methadone, for instance, can prolong QT interval, while that's not seen with other opioids.

"We think of these opioids as functionally equivalent, but they not be as similar as we previously thought," she added.

Rubinstein concluded that physicians should be cautious about the immunologic risks of fentanyl, morphine, and codeine: "If there's something we can do that's as simple as writing an order for hydromorphone instead of morphine, that seems like something we might want to consider."

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