How to Manage Pain in Patients with Renal Insufficiency or End-Stage Renal Disease on Dialysis?

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Table 2. Pregabalin dosing in renal impairment28

Review of Data

Nonopioid options. Nonopioids, such as acetaminophen and NSAIDs, have no associated tolerance but have a ceiling effect for analgesia, and NSAIDs are associated with dose-dependent acute renal failure, gastrointestinal ulceration and bleeding, and cardiac events. The nonopioids that are considered safe options in patients with renal insufficiency include acetaminophen, ibuprofen, and fenoprofen (Nalfon). However, in the elderly, American Geriatric Society (AGS) guidelines currently recommend avoiding all NSAIDs due to their safety profile in the geriatric population.⁴ Although all NSAIDs can potentially be used for pain, selected NSAIDs with an FDA indication for acute or chronic pain were included for this review.

Acetaminophen (APAP) is a dialyzable compound that is metabolized in the liver to five inactive metabolites. The terminal elimination half-life of its sulfate and glucuronide metabolites are prolonged in patients with renal failure; therefore, the dosing interval of APAP should be increased to six to eight hours in renally impaired patients.^5,6,7 Overall, acetaminophen is considered one of the safest agents to use for the treatment of pain, in renal patients and otherwise, as long as dosing is below the minimal daily dose (see Table 1).

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Figure 1. The WHO three-step analgesic ladder30

Ibuprofen is metabolized in the liver to inactive compounds. It does not accumulate in renal insufficiency, and two of the inactive compounds are dialyzable.⁸ It is considered a safe option for the treatment of pain in patients with renal insufficiency or dialysis.⁹

Fenoprofen is metabolized in the liver to inactive compounds. Renal impairment is likely to cause the accumulation of the inactive metabolites but not the parent compound, so dose reduction is not necessary with the use of this agent in renal insufficiency or dialysis.⁶

Mefenamic acid (Ponstel) is metabolized in the liver. Mefenamic acid can further deteriorate renal function in patients with underlying renal disease.12 However, the nephrotoxic potential of this agent is of little consideration in ESRD patients on dialysis, and therefore no dosage adjustments are necessary in these patients.⁶

Ketoprofen is metabolized in the liver, where approximately 80% of the dose is excreted in the urine as a glucuronide metabolite. Dose reduction is recommended in renal insufficiency and dialysis, as it not dialyzable.⁸

Ketorolac accumulates in renal insufficiency; therefore, it is contraindicated in these patients and in patients at risk for renal failure, including those with volume depletion.¹⁰ Ketorolac is unlikely to be removed by dialysis and so should be avoided.^10,11

Naproxen is metabolized in the liver to inactive compounds. Use of naproxen is not recommended in patients with moderate to severe renal impairment. If therapy must be initiated, close monitoring of the patient’s renal function is recommended.¹³

Celecoxib is the only cyclooxygenase-2 (COX-2) inhibitor available in the U.S. It is metabolized extensively by the liver and is unlikely to be removed by dialysis. Therefore, use of COX-2 inhibitors should be avoided in severe renal impairment and in those on dialysis.^14,15

Opioid options. The use of opioids in the renally impaired population is challenging, as one must balance opioid-related adverse events with adequate pain control. As such, it is recommended to start with lower-than-recommended doses and slowly titrate up the dose while extending the dosing interval. This will help limit adverse effects, such as respiratory depression and hypotension.³

Hydrocodone is metabolized to hydromorphone (Dilaudid), which is then metabolized to its major metabolite hydromorphine-3-glucuronide (H3G) and minor metabolite hydromorphine-6-hydroxy, all of which are excreted renally along with the parent compound. H3G has no analgesic properties, but it can potentially cause neuroexcitation, agitation, confusion, and hallucination. Hydromorphone has been used safely in patients with renal insufficiency and dialysis, as it is expected to be dialyzable. ^16,17