Which Opioids Are Safest and Most Effective in Patients With Renal or Hepatic Failure?


Introduction and Scope of the Problem

Opioids are a mainstay of pain management for patients with serious or advanced illness. For the majority of patients, there is no clearly preferred opioid; however, medication selection for patients with renal or hepatic impairment requires special consideration. Specifically, practitioners must be knowledgeable about the pharmacokinetic and pharmacodynamic differences between opioids and how organ dysfunction influences these properties. Pain is commonly experienced by patients who also have renal and hepatic dysfunction. Therefore it is important that practitioners make evidence-based decisions about opioid prescribing in this population.

Opioids and Renal Impairment

Scope of the Problem

Pain is highly prevalent among patients with chronic kidney disease (CKD): between 40% and 60% of patients on renal replacement therapy, 60% and 70% with advanced CKD, and nearly all hospitalized patients with CKD experience pain. The most common pain experienced by patients is musculoskeletal (60% to 70%), followed by neuropathic pain (15%) and ischemic pain (10%). Two-thirds of CKD patients report pain scores of 5 or greater out of 10. Pain that is related to end-stage kidney disease includes needlesticks to access a fistula for hemodialysis, ischemia distal to a fistula, headaches, and cramps. In addition, calciphylaxis, a feared complication of end-stage renal disease, results in painful skin ulcerations. For a discussion of the palliative care needs of these patients, see Chapter 50 .

Opioids are frequently used to treat pain in CKD for patients on renal replacement therapy. It is estimated that 50% of patients receiving hemodialysis will receive an opioid at some point during the course of their renal replacement therapy, and they are 3.2-fold more likely to be on opioids compared to the general population. The most common opioids prescribed between 2007 and 2014 were oxycodone and hydrocodone.

What Are the Benefits and Detriments to Prescribing Opioids for Patients With Chronic Kidney Disease?

While opioid therapy in the setting of CKD has the potential to improve pain, function, and quality of life, there are unintended detrimental effects associated with their use. Short-term opioid therapy has been associated with increased hospitalizations, and long-term opioid therapy, defined as continuous opioid therapy for greater than 90 days, may be associated with higher mortality in dialysis patients. Hazard of death for people on hemodialysis was found to increase with increasing daily morphine milligram equivalents (MME) when controlling for comorbid conditions. In patients not on hemodialysis, MME and lower glomerular filtration rate (GFR) were associated with increased risk of death. Finally, for people who undergo renal transplantation, pretransplant opioid therapy has been associated with reduced graft survival, increased posttransplant mortality, posttransplant cardiac arrhythmias, cardiac arrest, changes in mental status, drug and alcohol misuse, and accidents.

Relevant Pathophysiology

The evidence base guiding opioid therapy in CKD consists largely of retrospective case series, case reports, and few prospective studies. There are no randomized trials, and there are no head-to-head trials comparing different opioid medications. Safety recommendations have been determined more by pharmacokinetic data given a lack of clinical trials.

Data on opioid dosing strategies in CKD are sparse. In one review, between 1983 and 2015, only 13 studies involved patients with CKD. All were retrospective and seven focused on morphine. While recommended dosing is generally based on GFR, the correlation between renal clearance of medications and GFR is poor. Based on pharmacokinetic studies, opioids with a less than 30% dependence on renal function for clearance and no active metabolites have fewer altered pharmacokinetics in CKD and are considered “safe.” Opioids with a greater than 30% dependence on creatinine clearance or that have active metabolites derived through the cytochrome enzymes CYP2D6 and/or CYP3A are considered “less safe” or “unfavorable.” A list of favorable and unfavorable opioids is provided in Table 4.1 .

Table 4.1
Favorable and Unfavorable Opioids in Managing Pain in Renal Failure
From Coluzzi F, Caputi FF, Billeci D, et al. Safe use of opioids in chronic kidney disease and hemodialysis patients: tips and tricks for non-pain specialists. Ther Clin Risk Manag . 2020;16:821–837; Raina R, Krishnappa V, Gupta M. Management of pain in end-stage renal disease patients: short review. Hemodial Int . 2018;22:290–296; Davis MP, Fernandez C, Regel S, McPherson ML. Does nalbuphine have a niche in managing pain? J Opioid Manag . 2018;14:143–151; Hawi A, Alcorn H, Jr, Berg J, Hines C, Hait H, Sciascia T. Pharmacokinetics of nalbuphine hydrochloride extended release tablets in hemodialysis patients with exploratory effect on pruritus. BMC Nephrol . 2015;16:47.
Favorable opioids
  • Buprenorphine

  • Fentanyl

  • Hydromorphone

  • Methadone

  • Nalbuphine

  • Tapentadol

Unfavorable opioids
  • Codeine

  • Dihydrocodeine

  • Hydrocodone

  • Morphine

  • Oxycodone

  • Tramadol

For patients receiving hemodialysis, methadone, buprenorphine, fentanyl, and nalbuphine serum levels are not significantly altered by hemodialysis. Patients receiving high-efficiency (hyperpermeable) continuous renal replacement utilizing high blood flow and dialysate flow rates will have more drug removed from circulation than standard hemodialysis. Morphine may not be cleared by peritoneal dialysis and should be avoided in this context.

Summary of Evidence Regarding Treatment Recommendations

In general, opioid-naïve CKD patients should receive lower starting doses than patients without CKD. Sustained-release opioids and around-the-clock dosing should be avoided, particularly with “unfavorable” opioids. Employing an “as-needed” strategy with immediate-release products may be safer.

Favorable Opioids in Renal Impairment

Buprenorphine has high first-pass hepatic clearance and is metabolized sequentially by CYP3A4 to norbuprenorphine, then glucuronidated, or conjugated to glucuronic acid. In the case of buprenorphine, the glucuronidated parent drug and glucuronidated metabolite are largely inactive. Norbuprenorphine, buprenorphine-3 glucuronide, and norbuprenorphine-3 glucuronide are renally excreted. Plasma concentrations of norbuprenorphine increase 4-fold, and buprenorphine-3 glucuronide 15-fold, in advanced CKD. Both buprenorphine and norbuprenorphine are 30% cleared by the kidneys in individuals with normal renal function, with the rest excreted through the stool. Buprenorphine has a ceiling effect on respiratory depression and is well tolerated by older adults. Levels are stable on hemodialysis. Starting doses are 5 mcg per hour by transdermal patch or 75 mcg per day by buccal film.

Fentanyl is metabolized to the metabolite norfentanyl (which is inactive) by CYP3A4, and less than 1% is excreted in the urine. However, fentanyl clearance is reported to be impaired in severe renal failure. Around-the-clock fentanyl leads to accumulation in muscle and fat, resulting in redistribution when fentanyl is stopped and clearance is prolonged over days. The transdermal patch and immediate-release fentanyl products for breakthrough pain are not licensed for use in the opioid naïve—only in the opioid tolerant. The safety of transdermal fentanyl as a first-line opioid in advanced CKD has not been established. Fentanyl has a narrow utility relative to buprenorphine (i.e., the serum level at which analgesia occurs versus respiratory depression over time). Fentanyl is not dialyzed. High doses of fentanyl may rarely cause wooden chest syndrome, which is characterized by rigid muscles, seizure-like activity, cyanosis, and decreased consciousness and can occur shortly after fentanyl injection. The syndrome is so named because muscles in the chest wall and the diaphragm become rigid; therefore simultaneous laryngospasm can make intubation extremely challenging. This condition is worsened by naloxone and is highly fatal. The starting dose of transdermal fentanyl in CKD is 12 mcg/h.

Hydromorphone is glucuronidated and becomes hydromorphone-3-glucuronide, which is nonanalgesic and neurotoxic. Plasma levels of the parent drug are higher in the setting of renal failure and increase with worsening renal function. However, one study suggests that hydromorphone does not necessarily accumulate when the patient is on hemodialysis; the authors felt this was due to the rapid conversion of hydromorphone to hydromorphone-3-glucuronide, which accumulates, rather than hydromorphone between sessions and is then effectively removed during hemodialysis. From 50% to 60% of circulating hydromorphone and hydromorphone-3-glucuronide is removed by hemodialysis. In a study of 12 patients on hemodialysis, hydromorphone accumulation was modest (2.7-fold). Patients in renal failure on morphine with poor pain control or side effects can be safely rotated from morphine to hydromorphone with an expectation of improved adverse effects. A conservative starting dose of oral hydromorphone in renal failure is 1 to 2 mg every 6 hours.

Methadone is metabolized predominantly by CYP2B6 to an inactive pyrrolidine metabolite, EDDP. Methadone has a long half-life—up to 36 hours or more—that can be highly variable. Methadone and EDDP are excreted more in the stool when a patient has kidney failure; in advanced renal failure, 3% of methadone is excreted in the urine whereas 20% to 50% is excreted in the urine with normal function. Dialysis reduces serum levels by 14%. In one study involving patients with chronic pain and CKD on methadone, EDDP exhibited a half-life of 71 hours (from intravenous methadone) and 57 hours (from oral methadone). About 18% of the methadone dose is excreted via the urine as the parent drug over 0 to 96 hours, whereas 30% of the dose is excreted as EDDP over the same period. Little is known about the clearance of EDDP in someone with end-stage kidney disease on hemodialysis.

Methadone impairs cardiac repolarization, prolongs the QTC interval, and as a result, may cause torsades de pointes. Hyperkalemia and hyponatremia commonly occur in renal failure and can prolong the QTc interval, thus increasing the risk for an arrhythmia on methadone. EDDP may contribute to the prolonged QTc and potentiate methadone-related arrhythmia. It is prudent therefore to monitor the QTc intervals more closely in those patients with advanced CKD and on dialysis. Methadone is also subject to many drug–drug interactions. Polypharmacy is common with patients who have advanced CKD.

Several dosing strategies have been published for methadone. In renal failure, dosing should start at 1 to 2 mg twice daily, and up to 5 to 10 mg daily in divided doses, with increases in 5- to 10-mg increments at 5- to 7-day intervals. (For additional information on methadone, see Chapter 5 .)

Nalbuphine is a mu-opioid receptor (MOR) antagonist and a kappa opioid receptor G-protein partial agonist which is metabolized by UGT2B7 to an inactive glucuronide metabolite. Glucuronidated nalbuphine is excreted in the feces. Blocking UGT2B7 increases nalbuphine maximum serum concentrations 2.5-fold and area-under-the-curve (AUC) 1.6-fold. The elimination half-life of nalbuphine is also route dependent. It is 2 to 3 hours, on average, in parenteral administration but 7 to 8 hours in oral administration, largely due to enterohepatic recirculation. Nalbuphine is available only in parenteral form but the parenteral solution can be taken by mouth. The bioavailability of parenteral nalbuphine increases with age secondary to age-related reductions in hepatic portal blood flow. Oral bioavailability is 46% in those over the age of 65 years. Nalbuphine is better tolerated than morphine and has a ceiling on respiratory depression. Nalbuphine also reduces uremic pruritus. Low doses (1 to 2 mg) reduce more potent MOR agonist side effects including fentanyl and hydromorphone. Rotating from a potent opioid to equivalent doses of nalbuphine will precipitate a withdrawal syndrome. Nalbuphine is best used in the opioid naïve before going to potent MOR agonists. Starting doses are 5 to 10 mg every 4 hours.

Tapentadol is glucuronidated to an inactive metabolite. Twenty percent is excreted in the urine unchanged. Tapentadol is also metabolized by cytosolic sulfotransferases to tapentadol-sulfate. In renal failure, tapentadol is a very safe opioid to use. No adjustment is needed for patients with mild to moderate renal failure. There are no data on its use in patients with advanced kidney disease or those who are on dialysis. Tapentadol is believed to be dialyzed to some extent. This is an important analgesic for patients with diabetes, CKD, and neuropathic pain. Starting dose is 25 mg twice daily.

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