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Higher Overdose Risk in Kidney Patients Prescribed Opioids, Benzodiazepines

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About 75% of patients on dialysis received a prescription for an opioid medication and nearly one-third of them also received prescriptions for benzodiazepines—prescribing patterns that were associated with a substantially increased risk of hospitalization for overdose, according to a study presented at Kidney Week.

More than half of patients on dialysis experience pain, according to a previous study (1), and more than 60% receive a prescription for an opioid medication each year—20% of those received a more than 90-day supply. A growing nationwide opioid overdose epidemic has drawn attention to the potential risks associated with this common class of drugs and led the US Centers for Disease Control and Prevention to establish guidelines for more judicious prescribing (2). But the safety of this class of drugs hasn’t been well studied in patients on dialysis, said Rupam Ruchi, MD, assistant professor of medicine at the University of Florida.

“We know that pain affects so many of our patients, and it is associated with poor quality of life, increased morbidity, and mortality,” Ruchi said.


Now, Ruchi and her colleagues show that patients on dialysis are not immune to the potential overdose risks associated with opioids, particularly when they are given a concomitant prescription for benzodiazepines.

They looked at data from the US Renal Data System on hemodialysis patients enrolled in Medicare or Medicare’s Part D drug program between 2006 and 2012. Patients with cancer were excluded. They also used data from the ESRD Medicare Prescription Drug Events dataset for narcotics and benzodiazepines, and they used ICD-9 codes to identify patients hospitalized for opioid overdose. Of the 643,859 patients included in the analysis 74.6% (480,460 patients) received an opioid prescription and 30% of them received benzodiazepines—a combination associated with an elevated overdose risk in the general population, according to the National Institute on Drug Abuse. Patients who received at least one opioid prescription were more likely than those who didn’t receive opioids to have a history of smoking or substance use dependence.

Opioid prescriptions for patients in this population plateaued around 2011, when the CDC’s opioid prescribing recommendations were published. But hospitalizations due to opioid overdose among these dialysis patients continued to rise, noted Ruchi.

Of those patients in the study with an opioid prescription, 2225 (0.46%) were hospitalized for an opioid overdose, and four of them died. The average length of stay was 4 days and the average length of ICU stay was 2. Patients on dialysis who received opioids were also more likely than those without an opioid prescription to overdose on other drugs, suggesting substance abuse may be more common in this group, noted Ruchi. Patients who were hospitalized for an opioid overdose were also more likely to have been prescribed a benzodiazepine than patients who were not hospitalized for an overdose, she said.

When they broke down opioid overdose risk by drug, they found that risk of hospitalization within 30 days was lowest with hydrocodone (OR 1.6), that fentanyl (OR 3.0) and hydromorphone (OR 2.4) had moderate risks, and that methydone had a very high risk (OR 5.9), according to the abstract. Oxycodone had a moderate risk (OR 3.1) while oxymorphone had a high risk (OR 4.5).

“All opioids increase the odds of hospitalization from opioid overdose in 30, 60, or 90 days of prescription,” Ruchi said. “No opioid is safe to use in this population.”

She noted that some of the opioids associated with higher odds of overdose among dialysis patients are considered “safer” drugs. This suggests a new classification system is needed.

“We propose using a risk-based classification instead of one based on pharmacokinetics,” Ruchi said.

Magdalene Assimon, PharmD, PhD, postdoctoral fellow at the University of North Carolina Kidney Center in Chapel Hill, said the findings were cause for concern. She noted observational studies looking at other patient populations also have shown concurrent opioid and benzodiazepine use is associated with a higher risk of hospitalizations for opioid overdose than opioid prescriptions alone.

“Both opioids and benzodiazepines have sedating effects and increase the risk of respiratory depression,” Assimon said. “Each of these side effects has the potential to impact morbidity and mortality and warrants additional investigation in the dialysis population.”

Safer pain care

In a separate talk as part of a session on primary care for patients with kidney disease, Kim Zuber, a physician assistant who specializes in pain care at Metropolitan Nephrology Associates, which serves patients in Virginia and Maryland, recommended a more holistic approach to treating pain. She noted that pain is often multifactorial in patients with kidney disease, so it is important to consider the source of the pain when determining how to treat it.

“Up to half of our patients present with pain, and yet the problem is depression,” Zuber said. “A third of them also have some type of anxiety.”

She noted that CKD or end stage renal disease is a scary diagnosis. Patients may not recognize that they have these conditions, but clinicians may be able to tease out the symptoms if they ask in a diplomatic way.

“If we tone it into a particular way and we say you know, most of my dialysis patients, most of my CKD patients are depressed because of the situation, you’ll find you’ll get a higher number of patients who will admit it,” she said.

The same is true with patients who may not be getting adequate sleep. Zuber said she often tells patients that she remembers how difficult things felt when she had an infant and was sleep deprived.

It’s also important to set reasonable expectations for pain treatment.

“The pain centers will say to you the best we’re ever going to do is maybe get down some of your pain by about 30% which means 70% of the pain we are not going to get rid of,” Zuber said. “We do not expect to get rid of pain, we expect to make you functional.”

Zuber recommended that nephrologists get to know their local pain center, which may be able to offer treatments like epidural steroid blocks or help with more complicated cases.

“I know the pain centers from one end of the US to the other and scarily they have never met the rest of you,” she said. “They can help you and would love to meet you.”

She noted that there are many pain treatment options to try besides opioids. For example, physical therapy can be a good option for patients with musculoskeletal pain. If patients can’t get to a therapy center, Medicare may pay for home therapy. Cognitive behavioral therapy (CBT) is very effective, but there are a limited number of therapists available, Zuber noted. But social workers in the dialysis unit can get trained and certified in CBT. Lidocaine or lidocaine patches may ease conditions like post-therapeutic neuralgia. Capsaicin creams can also be used to dull nerve pain.

“Acetominophen works extremely well,” she said.

In some states where it is legal, medical marijuana may be an option, Zuber noted. However, she noted there isn’t much data on chronic pain treatment with the currently available medical marijuana products. While studies on alternative pain therapies like marijuana have been recently published, Assimon said more research is needed to fully understand the risks and benefits of such therapies in patients with kidney disease.

“If all else fails, fine opioids,” said Zuber. “But they should not be your first go to. There’s a whole list of things you can do prior to that.”

Before a patient is given a prescription for opioids, they should be screened for current or past substance abuse, Zuber urged. She noted that there are validated brief screening tools available and that screening is reimbursable by Medicare.

She noted that urine tests for substance use might not be effective for patients with kidney disease. Many states now require physicians to check prescription drug databases to see if patients are already being prescribed opioids, however, she noted they might not provide information about prescriptions in neighboring states or the Veterans Health Administration. It is important to be mindful of patients who may be misusing prescriptions, Zuber said. She said she once received a call from law enforcement when a patient was caught selling his prescription for oxycodone and acetaminophen.

Zuber also urged that nephrologists choose opioids with better safety profiles, and avoid benzodiazepines.

“Don’t give barbiturates and opioids together,” she said. “Don’t give barbiturates at all.”

Assimon also recommended an individualized approach to pain care in patients with kidney disease that considers comorbid conditions, concurrent medications, and the type of pain a patient is experiencing.

“When selecting therapy for pain in patients with kidney disease, clinicians need to consider both the potential benefits and risks of medications under consideration,” Assimon said. “Often this decision needs to be made on a patient-by-patient basis, taking into account each patient’s type of pain, level of pain severity, and current risk factors for potential medication-related adverse effects.”


“Opioid and Benzodiazepine Use in Patients on Hemodialysis,” Oral Abstract 095