In Wake of Opioid Epidemic, Nephrologists Aim to Balance Pain Control, Safety in Patients

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More than 60% of dialysis patients had one or more prescriptions for a short course of opioid medications each year between 2006 and 2010, according to a recent analysis by scientists from the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). About 20% of these patients had a prescription for a supply of 90 days or more of these medications.

The analysis, which used information from the U.S. Renal Data System on about 300,000 patients receiving dialysis with Medicare coverage, also found that both short-term and long-term use of opioids was associated with worse patient outcomes, including increased mortality, dialysis discontinuation, and hospitalization, according to lead author Paul Kimmel, MD, program director in NIDDK’s Division of Kidney, Urologic, and Hematologic Diseases, and his colleagues.

“The only question is, are these drugs causing [poor outcomes] or are they a marker for poor health,” Kimmel said in an interview. “Are patients who are sicker having more pain?”

The findings are the latest wrinkle in an ongoing debate about the use of opioids in medicine in the United States and how to balance the benefits of pain control with the risks associated with this class of drugs, including a growing epidemic of opioid abuse. For nephrologists, finding the right balance is a particularly delicate task. More than 50% of patients receiving dialysis report pain of varying degrees, which has been linked to greater depression and poorer quality of life, according to Kimmel and his colleagues. But safely and effectively treating pain in these patients, who are more vulnerable to adverse effects, is challenging.

“Patients with poor kidney function may be more prone to [opioid-related] drug toxicity compared to those with good kidney function,” explained Phuong-Chi Pham, MD, chair of the division of nephrology at the Olive View–University of California Medical Center. “The increased toxicity may be due to reduced renal clearance, increased free drug levels, and/or increased volume of distribution and possibly increased tissue sensitivity to the same drug compared to patients without chronic kidney disease.”

This leaves nephrologists with a difficult balancing act.

“We’re responsible for optimizing their heath-related quality of life, minimizing their symptom burden; and part of that is understanding and treating them if they have substantial pain,” said Sara Davison, MD, MSc, director of the Kidney Supportive Care Research Group at the University of Alberta in Canada. “We, as a community, need to commit to being able to do this in an effective manner, and that also means a safe manner.”

Too much or too little?

The use of opioids to treat pain, particularly chronic pain, has increased substantially in medicine in the United States since the late 1990s. But the practice has received growing scrutiny because of a parallel increase in opioid abuse and overdose deaths. These trends, along with regional variations in prescribing, “suggest inconsistent practice patterns and a lack of consensus about appropriate opioid use,” according to a report from the U.S. Centers for Disease Control and Prevention (CDC).

Kimmel and his colleagues also found a substantial regional variation in rates of chronic opioid prescriptions for patients receiving dialysis, varying from 9.5% in Hawaii to 40.6% in West Virginia. More than one quarter of patients in Kimmel’s study also received doses that were higher than those recommended by the CDC in a new guideline.

“Regional variations suggest that medical practice and social context is important in addition to patients’ symptoms and diagnoses,” Kimmel said.

Davison agreed that factors other than patient characteristics are likely driving the variation. “That suggests that there is some inappropriate prescribing, but there could be as much inappropriate overprescribing as underprescribing,” she noted.

The United States as a whole prescribes far more opioids than the rest of the world, with use in the United States accounting for 80% of the world’s supply although this country is home to only 5% of the world’s population, according to a report from Express Scripts. The United States also consumes 99% of the world’s hydrocodone. In fact, Kimmel’s study found that the drugs most commonly prescribed for 90 days or more were hydrocodone and oxycodone.

“You’re the only country that uses hydrocodone,” Davison said. There are no data on the safety and effectiveness of hydrocodone in ESRD, so studies in the United States are needed, she said.

Data on the long-term use of opioids to treat pain in any patients are limited, with most studies lasting 12 weeks or less. A recent study published in the Journal of the American Medical Association found that the use of opioids versus nonopioid pain medications did not offer better pain-related function in patients with chronic knee or back pain at 12 months. There are no data on the long-term use of opioids in kidney disease that look at their effect on pain, function, cognition, quality of life, and adverse effects, Davison said. There is also little information on dosing in patients with kidney disease, she noted.

Pham expressed concern about the potential for adverse events associated with high dose and high potency opioids in patients with end stage renal disease (ESRD).

“The level of opioids prescribed among patients with ESRD is quite high and could be concerning among those who require high frequency and high doses of potent opioids,” Pham said. “In particular, some patients with ESRD may have severe metabolic acidosis and rely on their intact respiratory drive to achieve optimal acid-base balance. High dose opioids may lead to reduced respiratory drive, concurrent respiratory acidosis, hence severe acidemia, which could lead to circulatory collapse and cardiac arrest.”

Holistic approach

Experts in the field recommend that nephrologists take a holistic, stepwise, and multidisciplinary approach to treating pain in patients with kidney disease, reserving the use of opioids only when other options fail to provide relief.

Physicians should start with a thorough assessment of the pain, its cause, and whether it is reversible, according to an update on treatment of pain in chronic kidney disease by Pham and colleagues. For example, Kimmel noted that cramping and discomfort related to dialysis shouldn’t be treated with opioids because they are unlikely to help. The same is true of neuropathic pain, which also doesn’t respond well to most analgesics and would require very high doses of opioids, which would likely cause adverse effects, Davison said. For patients with musculoskeletal pain, early physical therapy with or without thermotherapy should always be encouraged, said Pham.

Options for managing pain

Once the patient’s pain has been assessed, physicians should discuss with them and their families their options for managing pain, Pham and colleagues wrote. When pain medications are necessary, physicians should follow the World Health Organization’s three-step ladder approach, which starts with the use of nonopioid analgesics for mild pain; adds low-dose, lower-potency opioids to this regimen for moderate pain when needed; and reserves higher-dose or higher-potency opioids for patients who still require relief after the initial steps.

“In my opinion, opioids should only be given when the pain is obviously severe and cannot be treated by nonopioids or when patients have failed nonopioids such as acetaminophen, neuroleptics, or antidepressants whenever appropriate,” said Pham.

Kimmel urged clinicians not to discount the use of nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen in some patients with ESRD who are receiving dialysis. He and his colleagues found better outcomes in ESRD patients treated with NSAIDs than with opioids.

“We have to evaluate whether relatively safer drugs are underused in patients with end stage renal disease,” he said. Nephrologists, he said, need to balance a potential loss of renal function with quality of life and other considerations. Davison said she typically reserves NSAIDs for patients with no residual renal function and limits their use to short periods of time.

A role for nondrug therapies

Kimmel, Pham, and Davison also recommended that nondrug therapies always be used alongside pain medication. These may include interventions like physical therapy, cognitive behavioral therapy, yoga, massage, or acupuncture.

“If we rely on medications alone we tend not to be successful,” Davison said.

Kimmel and Davison recommended that nephrologists seek help from pain or palliative care specialists in managing chronic pain. “It has to be a medical community decision,” Kimmel said. This is particularly important when pain management for patients with a history of substance use disorders is considered, noted Davison. In these cases, a pain specialist can provide close monitoring, develop adherence plans, and perhaps even dispense medications 1 week at a time, she noted.

Often, nephrologists may be seeing patients who have been prescribed pain medications for arthritis, postsurgical pain, or other types of pain by other physicians, noted Tess Novick, MD, a nephrology clinical fellow at Johns Hopkins University in Baltimore. But there’s still a role for nephrologists in guiding pain care in these patients.

“We’d still be the ones helping the prescribers understand what their renal function is and if they should be adjusting the dose, like we do for all other medications,” Novick said.

When opioids are chosen, Pham said, “always start with low-potency opioids at lowest dose and titrate up as needed.” Patients should also be educated about adverse effects and the risk of opioid dependence, Pham said. Novick suggested also educating patients about the risk of overdose and the overdose antidote naloxone. The Substance Abuse and Mental Health Services Administration currently recommends that all patients prescribed chronic opioids have a prescription for naloxone as well, and provides information for physicians.

In the longer term, Kimmel would like to see clinical trials of drugs like buprenorphine, a partial opioid agonist also used in the treatment of opioid addiction, in patients with kidney disease to see whether it is a safer alternative. Kimmel also was optimistic about the future development of safer pain medications, including some nonaddictive treatments for chronic pain being studied at the National Institutes of Health.

Davison agreed on the need for more study.

“We need pragmatic clinical trials of multipronged approaches, of pain algorithms,” she said. “We need to understand the effect of our approaches on the overall function of our patients. There’s no point in treating pain effectively if we’re causing patients to fall, we’re causing them to have decreased cognition. We need to look at it holistically.”