Pain Management in a Patient with Kidney Failure

Introduction

For most American Society of Nephrology (ASN) Kidney Week attendees, case-based clinical nephrology talks are one of the most exciting venues. The Nephrology Quiz and Questionnaire is the essence of clinical nephrology and represents what drew all of us into the field of nephrology. The expert discussants prepared vignettes of puzzling cases, which illustrated some topical, challenging, or controversial aspect of the diagnosis or management of key clinical areas of nephrology. These cases were presented and eloquently discussed by our four expert ASN faculty. Subsequently, each discussant prepared a manuscript summarizing his or her case discussions, which serves as the main text of this article (Mark A. Perazella and Michael Choi, comoderators).

Patient

A 70-year-old man with kidney failure secondary to diabetic nephropathy recently started hemodialysis. He reports improved appetite and energy but continues to describe “total body achiness” and a burning-like pain in his legs that is worse on dialysis and at bedtime. He has osteoarthritis and takes acetaminophen at bedtime.

Question 1

Which causes do you consider when establishing the etiology of this patient’s pain?

• A. Ischemic pain (secondary to peripheral vascular disease)

• B. Neuropathic pain (secondary to diabetes or uremic neuropathy)

• C. Bone pain (secondary to metabolic bone disease)

• D. Musculoskeletal pain (sitting in dialysis chair)

• E. Anxiety and depression associated with starting dialysis

• F. All of the above

Discussion of Question 1

The answer is F (all of the above).

Chronic pain affects >100 million adults and costs $600 billion in the United States. Pain is also common in patients with kidney failure, with 40%–60% of patients experiencing pain and approximately 50% reporting moderate or severe pain (1). Current pain medications have a modest effect on pain reduction (≅30%), often without improvement in function, and multiple adverse effects limit clinical use. Nephrologists are not adequately trained in evaluating pain, which requires a comprehensive patient assessment, including the effects of pain on the patient’s psychologic, social, and functional status (2).

Patients with kidney failure experience pain from their primary disease (e.g., polycystic kidney disease), metabolic bone disease, uremic neuropathy, and comorbid conditions. This patient’s pain is assessed using the following approach: provokes, palliates, quality, region, radiation, severity, and time. The chronic pain is determined to be both nociceptive pain from tissue damage from nonsurgical osteoarthritis of both knees and neuropathic pain from diabetic/uremic neuropathy, with overlapping mood disturbance and anxiety. Physiotherapist encourages activity and provides home exercises, and a topical nonsteroidal anti-inflammatory drug (NSAID) is used for knee pain. Social worker provides stress management skills, encourages use of a pain diary, and follows up on psychologic issues. The patient’s Beck depression score is 14, consistent with mild mood disturbance.

The patient’s treatment goals include sleeping through the night and mobilizing without excruciating pain. He asks for your advice to treat the nighttime burning pain.

Question 2

What neuropathic pain treatment options do you consider?

• A. Opioids

• B. Acetaminophen

• C. Gabapentin/pregabalin

• D. NSAIDs

Discussion of Question 2

The answer is C.

Anticonvulsants and cyclic antidepressants are the two classes of drugs for which there is the most evidence of efficacy in diabetic neuropathy. Gabapentin can be started at 50–100 mg nightly and slowly titrated to a maximum dose of 300 mg. If pain persists, carbamazepine can be started at 100 mg twice daily with addition of a low-dose tricyclic antidepressant such as amitriptyline, doxepin, or low-dose duloxetine (2). Notably, gabapentin and pregabalin are associated with higher risks of altered mental status, falls, and fractures, and this risk is present at dosing considered safe by guidelines (3). Gabapentin and pregabalin should be used with caution by patients on hemodialysis.

Option A

Neuropathic pain responds poorly to opioids or requires excessive doses, causing adverse effects with even higher risks of adverse effects in patients with kidney failure due to reduced elimination and higher accumulation (4). A recent study reported that, annually, two thirds of patients received at least one opioid prescription, that more than one fifth received chronic opioid prescriptions, and that more than one quarter received a dose exceeding 50 morphine mg equivalents per day (5). Opioid prescription is associated with a higher risk of death, dialysis discontinuation, and hospitalization among patients on dialysis. Opioids should only be considered after a full discussion about the risks and benefits and after a trial of adjuvant therapy plus acetaminophen.

Additionally, gabapentin use in combination with opioids is associated with a substantial increase in the risk of opioid-related death among patients not undergoing dialysis (6). When the combination is deemed necessary, the patient must be monitored for signs of confusion and fall risk.

Option B

Acetaminophen is an antipyretic with weak anti-inflammatory properties. Only 2%–5% is excreted unchanged in the urine. Lifetime cumulative dose is not related to CKD progression. The recommended maximum daily dose is 3000 mg daily to reduce the risk of liver injury.

Option D

NSAIDs are relatively ineffective in neuropathic pain. NSAID use can contribute to fluid and electrolyte disturbances, hypertension, worsening kidney function, cardiovascular events, and higher risks of bleeding. NSAIDs are best reserved for acute pain for short durations. Topical NSAIDs can provide effective pain relief without the systemic adverse effects.

This patient takes low-dose gabapentin, titrating up to 200 mg at bedtime, and experiences 70% neuropathic pain relief. He declines further dose titration and the use of antidepressants (amitriptyline and low-dose duloxetine) and anticonvulsants (carbamazepine) due to sedative effects. He continues to meet with the social worker and sleep improves, allowing him to cope during the day.

Two months later, he receives a cortisone and hyaluronic injection for worsening knee pain, with minimal relief. He is taking acetaminophen 3000 mg daily, is using a topical NSAID, and continues physiotherapy. He is a low risk for opioid misuse as assessed by the Opioid Risk Tool (7).

Question 3

Which opioid would you offer this patient?

• A. Morphine

• B. Tramadol

• C. Oxycodone/hydrocodone

• D. Hydromorphone

Discussion of Question 3

The answer is D.

The risk of opioid toxicity, poor analgesic response, and drug interactions are determined by the metabolism of the opioid and the patient’s medical conditions. Most opioids are metabolized in the liver and excreted by the kidney. Both the parent compound and metabolites can accumulate in patients with decreased kidney function, leading to a narrow therapeutic window between analgesia and toxicity. Hemodialysis can trigger opioid withdrawals, requiring supplemental dosing during or after hemodialysis.

Hydromorphone is metabolized to hydromorphone-6-glucuronide, which is cleared by the kidney but does not have biologic activity. A small study confirmed that hydromorphone does not accumulate in patients with anuria, and hydromorphone-6-glucuronide is readily cleared by hemodialysis (8). The World Health Organization (WHO) lists hydromorphone for severe pain in step 3 of its analgesic ladder that excludes medications unsafe in kidney failure (9).

Buprenophine is not removed during hemodialysis, and it is primarily metabolized by the liver with no reported accumulation in kidney failure. It can be started at 5 μg/h transdermally every 7 days for a more chronic pain.

Option A

Naturally occurring opioids (morphine and codeine) should be avoided in patients with kidney failure. Metabolites morphine-3-glucuronide and morphine-6-glucuronide are cleared by the kidney, but only morphine-6-glucuronide is biologically active, and it is responsible for morphine-related neurotoxicity. Morphine and codeine are minimally protein bound, moderately water soluble, and readily dialyzable.

Option B

Tramadol has two mechanisms of action: one at the opioid receptor and one as a serotonin-norepinephrine reuptake inhibitor, like duloxetine or venlafaxine. Tramadol is metabolized by the hepatic cytochrome P450 2D6 enzymes, which are variably expressed in different people. The CYP2D6 enzyme is functionally absent in large numbers of people who experience next to zero opioid analgesia but are at risk for toxicity if the dose is increased. CYP2D6 activity is also highly influenced by other medications (e.g., cinacalcet, paroxetine, fluoxetine, and bupropion). Tramadol is included in step 2 for moderate pain of the WHO analgesic ladder (9). For patients undergoing dialysis, the maximum dose recommended is 50 mg every 12 hours, given after dialysis. If the patient does not respond with analgesic relief, further dose titration is not recommended.

Option C

Oxycodone is a semisynthetic opioid with active metabolites, an unpredictable pharmacodynamic response, and drug interactions; <10% of oxycodone is excreted unchanged in the urine. However, both the parent drug and the active metabolite seem to accumulate in patients on dialysis, with reports of toxicity. It is not dialyzable, and patients experience no increase in postdialysis pain.

You elect to prescribe low-dose hydromorphone, and the patient takes three to four tablets weekly for severe pain. His home is assessed for falls, and safety equipment is installed.

The patient subsequently asks about the use of cannabis or cannabidiol (CBD) oil for management of his pain.

There is substantial evidence that cannabis is effective for the treatment of chronic pain in adults and moderate evidence that cannabinoids improve short-term sleep disturbances in people with chronic pain (10). Medical marijuana has been legalized in several countries, including Canada. Cannabis exerts its action via two major active ingredients: Δ9-tetrahydrocannabinol (THC) and CBD. THC activates cannabinoid receptors type 1 and 2. Using CBD may avoid the unwanted psychotropic effects of THC and potentiate the analgesic effects. Issues to consider include the route of delivery (inhaled versus ingested), clinical efficacy, side effects, and misuse. There is some rationale for cannabis use in patients with kidney failure and chronic pain, nausea, anorexia, or pruritus (11). Risks include orthostatic hypotension, effects of inhaled marijuana, cognitive dysfunction, sedation, and spatial visual distortion. Currently, research is being conducted on the clearance of THC and CBD on dialysis.

You describe the known risks and benefits of cannabis and CBD, but the patient declines until more information is available. The patient is meeting his goals of sleeping through most nights and managing most activities with minimal use of the opioid. You agree to revisit the situation in 3 months.

Disclosures

The author has received speaker honoraium from Otsuka, Janssen, and AstraZeneca and consultancy fees from Janssen, Otsuka, and Novo Nordisk.

Funding

None.