01.04.2021

Pain Management Considerations in ESRD

In this month’s Palliative Pearls Case Study, we discuss pain management in patients with renal failure. This is a particularly important topic considering the prevalence of pain in patients with renal failure and the complications that may result from selecting therapy not suited for this patient population. We encourage you to download this month’s case study to share with your colleagues or continue reading below.

PATIENT CASE

PY is a 76-year-old male patient with primary diagnosis of end-stage renal disease (ESRD) and history of diabetes, peripheral neuropathy, hyperlipidemia and hypertension. PY had been undergoing hemodialysis three times weekly until a recent stroke resulted in a significant change in mental status and general physical decline. After careful consideration and collaboration with the medical team, PY’s family made the decision to stop hemodialysis and admit him to hospice care.

Current Pain Medications:

  • Gabapentin (Neurontin®) 100mg; 1 capsule by mouth 2 times daily
  • Hydrocodone-acetaminophen (Norco®) 10-325mg; 2 tablets by mouth 4 times a day as needed for pain

During the initial admission assessment, PY’s fists were tightly clenched and he was grimacing. He has been receiving his gabapentin doses consistently and had six Norco® tablets in the past 24 hours. PY is still swallowing his medications but is beginning to have trouble with the Norco® tablets due to their size. The admitting nurse has used low dose morphine in ESRD patients in the past with positive outcomes, however the covering medical director is not comfortable using morphine in ESRD. Which medication, dose and frequency could be recommended at this time to manage PY’s unrelieved pain?

SYMPTOM BURDEN IN END STAGE RENAL DISEASE (ESRD)

A healthy, normally functioning kidney filters waste and electrolytes from the blood stream and excretes them in urine. In chronic kidney disease, kidneys are not able to excrete adequate amounts of waste and electrolytes, leading to accumulation in the blood stream. In ESRD an individual requires hemodialysis or a kidney transplant to survive.1

Individuals with ESRD can experience nausea, loss of appetite and fatigue. Accumulation of waste and metabolites can lead to itching and loss of mental acuity. Irregularities in the balance of electrolytes can lead to edema and swelling in lower extremities as well as involuntary movements and muscle twitching. Symptoms of ESRD are often like what would be observed in a patient with terminal cancer, the most significant being pain.1

Up to 50 percent of patients with ESRD experience some type of pain. Over 80 percent describe pain as chronic and severe. Despite management, just over 40 percent report experiencing significant pain on their last day of life as this symptom may be overlooked in the overall management of ESRD. Many will endure pain until it becomes severe and even when treatment is initiated, it is often under-dosed. It is estimated that as many as 75% of patients stating they have pain are not prescribed the appropriate analgesic, leaving pain uncontrolled. Recognizing the prevalence of pain in this population, being armed with pain assessment skills and awareness of appropriate therapies are important skills for hospice workers.2

The approach to pain management in ESRD patients must consider the etiology of pain, renal function, dialysis status and potential for toxicity.3

ETIOLOGY OF ESRD PAIN

While pain is common in ESRD, it can be difficult to determine the source of the pain. In some cases, pain may be the direct result of complications of renal disease. In other cases, it can be vascular or neuropathic, stemming from complications of diabetes or another comorbidity. It can also be the result of a completely unrelated condition. While the source of pain may not always be clear, it is important for practitioners to assess the perceived source and intensity of the pain and manage it accordingly.3

RENAL FUNCTION AND OPIOIDS

The kidneys play an important role in removing metabolites from a patient’s blood stream. Opioids have a wide dose range, driven by a patient’s level of pain, compared to other classes of medications. Opioid metabolites will accumulate in ESRD patients, leading to unwanted side effects and potential toxicity. Selecting an appropriate medication, starting at the lowest effective dose and slowly titrating to effect while monitoring for toxicity are integral to pain management in ESRD. Some medications, like fentanyl, have fewer metabolites and are generally considered superior to morphine in this patient population.3,4

DIALYSIS STATUS

Discontinuing hemodialysis is a prerequisite when electing the hospice benefit. However, in palliative care patients not yet eligible for hospice, hemodialysis would be a significant consideration when selecting an opioid for pain management. The larger the drug molecule, or higher molecular weight, the more likely it is to be removed during hemodialysis. Morphine should generally be avoided in any patient undergoing dialysis. Fentanyl, hydromorphone and methadone are preferred in these patients.3

POTENTIAL FOR TOXICITY

Specific pharmacokinetic differences among the opioid agonists exist:5

  • Morphine is metabolized by the liver primarily into the metabolites morphine 3-glucuronide (active, no analgesic effect, neurotoxic) and morphine 6-glucuronide (active, more potent than morphine in analgesia, potentially toxic) and eliminated primarily by the kidneys as these metabolites
  • Oxycodone is metabolized by the liver primarily into the metabolites noroxycodone (inactive, questionable toxicity) and oxymorphone (active), and eliminated primarily by the kidneys as oxycodone and these metabolites
  • Hydrocodone is metabolized by the liver into metabolites norhydrocone (active) and hydromorphone (active) and eliminated primarily by the kidneys
  • Hydromorphone is metabolized by the liver into metabolites hydromorphone-3-glucuronide (neuroexcitatory) and 6-hydroxy (active) and eliminated primarily by the kidneys
  • Methadone and fentanyl have no active metabolites

Selection of an appropriate medication, and slow, steady titration are important considerations to minimize unwanted side effects and toxicity resulting from pain management. These effects include nausea, vomiting, fatigue, respiratory depression, myoclonus and seizures. Concerns of toxicity due to the accumulation of toxic metabolites may lead practitioners to inadvertently provide subtherapeutic dosages.6

Generally considered safe3,7

  • Acetaminophen
  • Fentanyl
  • Methadone

Use with caution, start at a low dose, and proceed with caution3,7

  • Buprenorphine
  • Gabapentin
  • Hydromorphone
  • Oxycodone
  • Pregabalin

Not recommended for use3,7

  • Codeine
  • Hydrocodone
  • Meperidine
  • Morphine
  • Nonsteroidal anti-inflammatory drugs (NSAIDs)

There is no consensus in the literature regarding the use of morphine for patients with renal failure. Some suggest cautious use with lower dosages and extended dosing intervals while other clinicians suggest avoiding morphine altogether because of the potential for accumulation of metabolites.5 Morphine remains a common and familiar opioid in the hospice and palliative care population. Recognizing its utility at the end of life, the decision to use this medication in the environment of renal failure is only recommended with careful consideration and dependence on the experience of the clinician with active monitoring and slow titration.

PATIENT CASE DISCUSSION

PY fist clenching and grimacing improves within 30 minutes of Norco® dosing according to his family. Afterwards, PY appears calm and comfortable for a few hours. Hydrocodone, the opioid component in Norco, has 2 active metabolites, making it a “use with caution” medication in ESRD, and could be converted to a different opioid with less toxicity risk. Transdermal fentanyl is generally considered safe in ESRD, would provide a long-acting alternative and eliminate the pill burden imposed by Norco®. Methadone is also a viable option for PY. Gabapentin is a “use with caution” medication, however it is already dose-adjusted for PY’s renal function.

Recommendations:

  1. Discontinue Norco®
  2. Initiate transdermal fentanyl (Duragesic®) 25mcg; apply 1 patch topically every 72 hours
  3. Initiate hydromorphone (Dilaudid®) 5mg/5ml liquid; 2ml (2mg) by mouth every 4 hours as needed for breakthrough pain (encourage use especially during the first 24 hours after first Duragesic® patch applied)
  4. Continue gabapentin but switch to liquid formulation, 250mg/5ml

REFERENCES:

  1. Mayo Clinic. End-stage renal disease: Symptoms and causes. 2019. https://www.mayoclinic.org/diseases-conditions/end-stage-renal-disease/symptoms-causes/syc-20354532
  2. Harisingani R, Saad M, Cassagnol M. How to Manage Pain in Patients with Renal Insufficiency or End-Stage Renal Disease on Dialysis? The Hospitalist. 2013 August;2013(8). Article link
  3. Vanston VJ, Huffman GB, O’Connor N, Ganta N. UNIPAC 8: COPD, Heart Failure, and Renal Disease In: Essential Practices in Hospice and Palliative Medicine, 5th edition. Shega JW, Paniagua MA, eds. Chicago, IL: American Academy of Hospice and Palliative Medicine, Inc; 2017.
  4. Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage. 2004 Nov;28(5):497-504. Article link
  5. Enclara Pharmacia. Improving Formulary Adherence for Hospice Patients: A Focus on Managing Moderate to Severe Pain for Prescribers. August 8, 2016.
  6. Gelot S. Nakhla E. Opioid Dosing in Renal and Hepatic Impairment. US Pharm. 2014;39(8):34-38. Article link
  7. O’Connor NR, Corcoran AM. End-Stage Renal Disease: Symptom Management and Advance Care Planning. Am Fam Physician. 2012 Apr 1;85(7):705-710. Article link
  8. Arnold R, Verrico P, Kamell A, Davison SN. PCNOW Fast Facts #161: Opioid Use in Renal Failure. March 2020. Article link
  9. Davison SN. Chronic pain in end-stage renal disease. Advances in CKD. 2005 Jul;12(3):326-334. Article link

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