Pauline Anderson

March 20, 2017

ORLANDO — Patients prescribed fentanyl, morphine, or codeine in the 100 days before being hospitalized have an increased risk for pneumonia while in the hospital, results of a new study suggest.

The relationship is probably due of immune suppression and not respiratory depression, the researchers speculate.

"This is just a signal finding, but it makes me think that in vulnerable patients, such as those who are already immune suppressed, including HIV patients and those on biologics, we might want to weigh immunosuppressive effects of opioids when we make decisions about how we prescribe," said lead researcher, Andrea Rubinstein, MD, Permanente Medical Group, Santa Rosa, California.

Dr Andrea Rubinstein

Dr Rubinstein discussed her research here at the American Academy of Pain Medicine (AAPM) 2017 Annual Meeting.

There's clear evidence in the scientific literature that some, but not all, opiates are strongly immunosuppressive. However, it's difficult to examine infections in adults taking these medications because the conditions are rare and "you need a giant data set to do it," said Dr Rubinstein.

The new study examined 40,403 admissions of patients aged 18 to 70 years to the Kaiser Permanente health system over a period of about 4 years. The Kaiser system includes 19 hospitals in northern California and, at the time of the study, had 3.9 million patients.

Researchers looked at opioids (at least a 60-day supply) prescribed in the 100 days before the hospital admission. They grouped patients into "no opioid"; "fentanyl, codeine, morphine"; and "other opioid," which could include hydrocodone, oxycodone, or hydromorphone.

They also looked at whether an opioid was prescribed during the first 2 days of the hospital stay.

Reportable Condition

The outcome was hospital-acquired pneumonia (HAP), a condition reportable to the Centers for Disease Control and Prevention. Here, researchers assessed HAP that developed on days 3 to 10 of the hospital stay.

"If you got it earlier, it's probably a community-acquired pneumonia that just hadn't shown up yet," Dr Rubinstein told Medscape Medical News.

HAP is expensive. Dr Rubinstein estimated that each case adds about $70,000 to the cost of the hospitalization.

The infection also has a high mortality rate, particularly in vulnerable people, such as those already immunosuppressed or those who are otherwise frail, said Dr Rubinstein.

For these reasons, hospitals are keen to reduce the rate of HAP. Already, staff have "come a long way" and are aware that early ambulation reduces the HAP risk, but it's possible that more can be done to drive the rates even lower, she said.

Of the over 40,000 patients, there were only 242 cases of HAP (0.60%), a rate Dr Rubinstein described as "slightly below the national average."

"We are on the low side, but in the ballpark," she said. Because the study ended in 2014, this rate has fallen further, she added. "We make strides year over year."

But notably, the rates differed according to the type of opioid prescribed. Among the 20,399 patients who had received any inpatient fentanyl, codeine, or morphine, the rate was 0.79%, but for the 20,004 who had no inpatient fentanyl, codeine, or morphine, the rate was 0.39%.

Dr Rubinstein noted that patients who had no opioid exposure as outpatients but who were given fentanyl or morphine on hospital day 1 or 2 were included in the fentanyl exposure group. "They are probably part of the increased risk, even with such a short exposure of just the first 2 days."  

The next question she and her colleagues wanted to address is whether patients got pneumonia because they had respiratory depression. Using the same algorithm, they looked at patients who developed pneumonia after being intubated.

"Those people can't be respiratorily depressed because they're on a ventilator," said Dr Rubinstein.

She and her colleagues saw "the exact same thing" in that patients exposed to fentanyl, codeine, or morphine had an increased risk for pneumonia.

"I don't think this is a respiratory depression effect; I think it's immunologic because we still see the signal in mechanically ventilated people who don't have respiratory depression," said Dr Rubinstein.

To further prove that this is a problem with immune suppression, the researchers looked at a totally different infection — Clostridium difficile (C difficile) infection.

Among the same hospital admission population, 2936 patients had used antibiotics for 10 or more days before admission. In this cohort, there were 16 cases of C difficile, for a rate of 0.54%.

The researchers found that the rate was almost four-fold higher (1.04%) among patients who had used any opioids in the 100 days before admission than among those with no long-term opioid exposure during this time (0.27%).

"We can't deduce mechanisms from this, but what we can say is that there is a signal here that we really need to investigate," Dr Rubinstein said.

Interesting Results

Asked by Medscape Medical News to comment on this research, Virtaj Singh, MD, a physiatrist and pain medicine expert at Seattle Spine & Sports Medicine, Washington, called the results "interesting."  

Dr Singh added that he wasn't familiar with the association between certain opioids and hospital-acquired infections.

"But this has opened my eyes," he said. "This is good to know, and good to keep in mind."

During a poster research highlight session, chair James C. Watson, MD, associate professor of neurology, Mayo Clinic College of Medicine, Rochester, Minnesota, asked Dr Rubinstein why hydromorphone would act differently than other opioids.

It's possible, said Dr Rubinstein, that synthetic and natural opioids act differently or that for different opioids, "their binding affinity or way of activating the receptor is different based on some intrinsic property of the molecule."

The study results suggest that there are more differences among opioids than previously thought, said Dr Rubinstein.

The study was funded by a Kaiser Permanente community benefit grant.

American Academy of Pain Medicine (AAPM) 2017 Annual Meeting. Abstract 163. Presented March 17, 2017.

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