Pain management in patients with chronic kidney disease and end-stage kidney disease

Abstract

Purpose of Review

This review evaluates current recommendations for pain management in CKD and ESKD with a specific focus on evidence for opioid analgesia, including the partial agonist, buprenorphine.

Recent Findings

Recent evidence supports the use of physical activity and other nonpharmacologic therapies, either alone or with pharmacological therapies, for pain management. Nonopioid analgesics, including acetaminophen, topical analgesics, gabapentinoids, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants may be considered based on pain etiology and type, with careful dose considerations in kidney disease. NSAIDs may be used in CKD and ESKD for short durations with careful monitoring. Opioid use should be minimized and reserved for patients who have failed other therapies. Opioids have been associated with increased adverse events in this population, and thus should be used cautiously after risk/benefit discussion with the patient. Opioids that are safer to use in kidney disease include oxycodone, hydromorphone, fentanyl, methadone and buprenorphine. Buprenorphine appears to be a promising and safer option due to its partial agonism at the mu opioid receptor.

Summary

Pain is poorly managed in patients with kidney disease. Non-pharmacological and non-opioid analgesics should be first-line approaches for pain management. Opioid use should be minimized with careful monitoring and dose adjustment.

Introduction

Chronic pain is a common symptom experienced by patients with chronic kidney disease (CKD) and end-stage kidney disease (ESKD) [1,2]. Untreated pain in this population negatively impacts health related quality of life (HRQOL), dialysis adherence, healthcare utilization and mortality [3-5]; and may contribute to other physical and psychosocial symptoms such as depression, anxiety and fatigue [6].

There is a disproportionately high use of opioids in this population due to limited availability of non-pharmacological treatment options or safe non-opioid pharmacological options. In a study of over 400,000 ESKD patients, over half had received an opioid prescription, 3.2 times the rate in the US population [7] and 20% were on long term opioid therapy (LTOT) [8]. Chronic opioid use in patients with kidney disease has been associated with increased risk of altered mental status, falls, fractures, hospitalizations and mortality, in a dose-dependent manner [9-12]. However, closely-monitored LTOT may be warranted in some patients who fail to respond to other pain treatments. This requires careful consideration of risks and benefits.

Pain management in kidney disease is a top research priority, and is being fostered in the nephrology community by enterprises such as the Kidney Health Initiative, a public-private partnership between the American Society of Nephrology and US Food and Drug Administration [13,14]. Additionally, the recently established Hemodialysis Opioid Prescription Effort (HOPE) Consortium, funded by the National Institutes of Health’s Helping to End Addiction Long term mission and the National Institute of Diabetes and Digestive and Kidney diseases (NIDDK), will address pain management and opioid safety in this population [15].

The goal of the current review is to provide practical guidance for treating pain, summarize evidence on non-pharmacological and pharmacological options for pain, and focus on safety and efficacy of medications including opioids.

Approach to Pain Management

Multiple patient, provider, and healthcare-system factors make pain management challenging in this population (Figure 1) [16]. The multifactorial etiologioes of pain and common comorbid conditions in patients with kidney disease result in varying types of pain (neuropathic, nociceptive, or both). [17-21]. Provider- and system-related factors relate to lack of training for nephrologists in treating pain, fragmentation of care and most importantly lack of scientific evidence and guidelines around pain management in CKD and ESKD [22,23].

Fig 1.

Challenges in pain management in patients with kidney disease

Pain assessment

This should start with assessment of a) pain severity using various standardized tools, most common of which is the numerical rating scale [24]; b) pathophysiologic evaluation into mechanism of injury and type of pain; c) psychosocial evaluation of co-occurring factors that contribute to pain or make treatment of pain more challenging, such as depression, anxiety, and a history of substance use disorder [25]; and d) overall impact of pain using tools such as the PEG, a validated, three-item tool assessing Pain intensity, interferences with Enjoyment in life, and General activity [26].

Prior to initiating treatment, discussions should include realistic expectations for improvements in pain and function, which can strengthen the therapeutic alliance between patient and provider [27]. When patients’ anticipated pain relief does not align with their experience it requires calibration of expectations [28].

Non-pharmacologic approaches

Non-pharmacologic options range from psychosocial or behavioral based interventions (e.g.: cognitive behavioral therapy [CBT], acceptance and commitment therapy, relaxation, music therapy, mindfulness) to physically-oriented interventions (e.g.: exercise, physical therapy, yoga, acupuncture, electrical stimulation). Psychosocial interventions are supported by robust evidence from the general population as effective approaches for reducing pain severity, interference, pain-related disability and psychological distress, and have limited but promising evidence for reduction in opioid use, and even opioid misuse behaviors [29-35]. Currently, such evidence in kidney disease is very limited and of poor quality [36-39]. Two NIDDK-funded trials (Technology Assisted Collaborative Care and the HOPE Consortium trial [15]) are currently testing telemedicine-delivered CBT-based interventions for pain in patients receiving hemodialysis [40]. Physical therapy or exercise-based interventions have been successful in improving pain in the general population [41]. Few studies of exercise, physical therapy, yoga, or acupuncture in patients with kidney disease have included pain as an outcome but show promising results [42-45]. Given that non-pharmacological interventions are generally safe, further research should test the effectiveness, feasibility and acceptability of them for patients with kidney disease.

Pharmacological approaches

Review the available evidence on pharmacokinetic, efficacy, and safety profiles of analgesics in patients with kidney disease is provided in Supplementary Tables 1 and 2. Summary of dose recommendations are provided in Tables 1 and 2.

Table 1.

Recommended non-opioid medications in patients with kidney disease

Medication	Metabolism and PK comments	Dosing in CKD	Dosing in ESKD	Comments
Medications for nociceptive pain
Acetaminophen	Hepatic, excreted in the urine primarily as non-toxic metabolites High oral bioavailability 85-98% Median onset 11 minutes and median duration of action ~ 4 hours after 1000 mg oral dose [83]	ClCr 10-50 mL/min: 650 mg q 6h prn Max daily dose 4000 mg	ClCr < 10 mL/min or dialysis: 650 mg q 8h prn Max daily dose 4000 mg [84]	Use scheduled doses instead of as needed for continuous pain control Use with caution and Lower max daily dose (2000 mg) if liver disease or daily alcohol
NSAIDs, preferably COX-2 selective agents such as celecoxib		Reduce dose and increase dosing interval, use for short term (</= 5 days only) Contraindicated in CKD stage 5	No dose adjustment, use for short term only	Monitor for volume retention, cardiotoxicity, renal and gastrointestinal toxicity
Topical analgesics (NSAIDs, lidocaine, capsaicin)	Systemic exposure with topical NSAIDs is 2-3% than with oral, but increases with higher dose applied to larger surface area [85]			Avoid high dose topical NSAID use over large surface area
Medications for neuropathic pain
Pregabalin	Negligible, 90% excreted renally as unchanged drug High oral bioavailability ≥ 90% Onset of pain relief ~ 1 week	Max daily dose: ClCr 30-60 mL/min: 300 mg daily (2-3 divided doses) ClCr 15 to 30 mL/min: 150 mg daily (1-2 divided doses) ClCr < 15 mL/min: 75 mg daily (single dose)	Start at 25 mg once daily, Maximum dose 75 mg once daily Well dialyzed, Dose post-HD	Start at low dose and uptitrate every 1-2 weeks, monitor for altered mental status and falls
Gabapentin	Not metabolized, excreted renally as unchanged drug Bioavailability is dose dependent: is upto 80% with 300mg/d but decreases as dose increases to <50% above 1200 mg/d	Max daily dose: ClCr 50-79 mL/min: 1800 mg daily (3 divided doses) ClCr 30-49 mL/min: 900 mg/day (2-3 divided doses) ClCr 15-29 mL/min: 600 mg/day (1-2 divided doses) ClCr < 15 mL/min: 300 mg/day (single dose)	Maximum dose 300 mg once daily Well dialyzed, Dose post-HD	Start at low dose and uptitrate every 1-2 weeks, monitor for altered mental status and falls
Duloxetine	Extensively metabolized in the liver via CYP1A2 and 2D6 to inactive metabolites, Oral bioavailability 30-80%, >90% protein bound Excretion: renal 70%, fecal 20%	Start with 20 mg daily Max daily dose: 60 mg ClCr 30-80 mL/min: no dose adjustment necessary ClCr < 30 mL/min: avoid use	Avoid use (limited data)	Monitor for hyponatremia, can rarely cause serotonin syndrome
Venlafaxine	Hepatically metabolized via CYP2D6 to active metabolite, O-desmethylvenlafaxine. Bioavailability is ~ 13% for immediate release and 45% for extended release, primarily excreted renally	Extended release: Start at 37.5 mg once daily Max daily dose: ClCr 30-89 mL/min: 150 mg daily ClCr <30 mL/minute: 112.5 mg daily	Extended release: Start at 37.5 mg once daily Max daily dose: 112.5 mg daily Poorly dialyzed	Monitor for hyponatremia, can rarely cause serotonin syndrome
Desvenlafaxine (active metabolite of venlafaxine)	Hepatically metabolized Oral bioavailability approximately 80%. Excreted renally approximately 45% as unchanged drug and 24% as metabolites	Max daily dose: ClCr 30-50 mL/min: 50 mg once daily ClCr <30 mL/min: 25 mg once daily or 50 mg every other day	Max daily dose: 25 mg once daily or 50 mg every other day. Poorly dialyzed	Monitor for hyponatremia, can rarely cause serotonin syndrome
Amitriptyline	Hepatically metabolized to nortriptyline (active metabolite) Oral doses are completely and rapidly absorbed, > 90% protein bound. Excreted renally as metabolites, 18% as unchanged drug.	Start at 10 mg once daily at bedtime, No dose adjustment recommended Maximum dose 150 mg daily.	Start at 10 mg once daily at bedtime, No dose adjustment recommended Maximum dose 150 mg daily. Poorly dialyzed	Limited evidence in CKD The Beers Criteria recommends avoidance in older adults (strong anticholinergic properties, sedation, orthostatic hypotension, urinary retention)

Table 2.

Recommended opioid medications in patients with kidney disease

Medication	Metabolism and PK comments	Dosing in CKD	Dosing in ESRD	Comments
Oxycodone (short-acting)	Hepatically metabolized via mainly CYP3A4 to noroxycodone (weakly active) and some by CYP2D6 to oxymorphone (strongly active), High oral bioavailability of 50-87% , t1/2 prolonged to ~ 7 hours in ESKD [86]	Start at 2.5-5 mg every 12 hours, Recommend prolonged dosing interval in severe renal impairment	Start at 2.5-5 mg every 12 hours, Recommend prolonged dosing interval in ESKD Poorly dialyzed	Caution should be used with long acting formulations and when used concurrently with medications that affect CYP3A4 or CYP2D6 metabolism. [87]
Hydromorphone	Hepatically metabolized, Oral bioavailability is Low to moderate	Start at 2.5-5 mg every 6-8 hours	Start at 2.5-5 mg every 6-8 hours, well dialyzed but no supplemental dose required post HD	Use caution with high doses
Fentanyl (transdermal)	Hepatically metabolized, 10-20% excreted renally, low oral bioavailability	Dose equivalent dose of patient’s oral narcotics, wean oral opioids after 1-2 days	Dose equivalent dose of patient’s oral narcotics, wean oral opioids after 1-2 days Poorly dialyzed	Do not start in opioid naïve patient
Methadone	Hepatically metabolized to inactive metabolites, >80% oral bioavailability	Start 1-2 mg once or twice a day	Start 1-2 mg once or twice a day Poorly dialyzed	Do not start in opioid naïve patient. Obtain a baseline EKG and a follow-up EKF 2-4 weeks after starting to monitor for prolonged QT interval. Monitor and correct electrolyte abnormalities
Buprenorphine	Hepatically metabolized to B3G (inactive) and norbuprenorphine (active but does not cross blood brain barrier), low oral bioavailability but effective as sublingual or transdermal formulation, excreted mostly fecally (bile)	See Table 3	See Table 3 Poorly dialyzed	Do not start in opioid naïve patient. Lesser risk of overdose and respiratory and CNS depression as compared to other opioids

Non-opioid therapy for nociceptive pain

Acetaminophen

Acetaminophen, a common over-the-counter analgesic, and can be tried as scheduled doses for mild to moderate pain, although a Cochrane review found that efficacy in the general population may be limited [88]. It requires no dose adjustment and is generally safe in kidney disease, although may rarely cause analgesic nephropathy with long term use [89].

NSAIDs

Potential risks of NSAIDs include gastrointestinal, cardiovascular, and renal adverse events [90]. NSAIDs inhibit prostaglandin synthesis by interfering with the cyclo-oxygenase pathway, which may increase risk of acute kidney injury, sodium retention, hypertension, hyperkalemia, and heart failure. They may also increase cardiovascular events via vasoconstriction and platelet aggregation [91]. Gastrointestinal and bleeding risks are lower with COX-2 selective agents such as celecoxib [92,93]. Recent epidemiological evidence suggests association of chronic NSAID use with increased risk of CKD progression and hospitalization in patients with CKD, albeit less than that with opioid use [12]. Similarly, in ESKD, NSAID use has been associated with increased mortality, but these findings are confounded by limitations of observational data [63].

Most of these adverse effects are rare, related to cumulative dose and likely modified by an individual’s underlying risk factors, such as comorbidities and concomitant medications. Thus, short-term, cautious use of NSAIDs with consideration of individual risk factors, careful side effect monitoring, and risk/benefit discussion may be appropriate [95]. We agree with recommendations outlined by in a recent review that suggests short-acting NSAIDs could be used short-term (</= 5 days) in patients with CKD Stages 1-3; judiciously in patients with CKD Stage 4; and avoided in CKD 5 [96]. A similar case can be made for cautious use of NSAIDs in ESKD patients, in whom gastrointestinal toxicity and loss of residual renal function are the most concerning side effects. In anuric ESKD patients, there is no effect on glomerular blood flow or tubular function, thus NSAID-mediated electrolyte disturbances, volume retention, and hypertension are of less concern [60].

Topical agents

Topical agents (e.g.: topical NSAIDs, lidocaine patch, high dose capsaicin patch) may provide localized pain relief [97-100]. Topical NSAIDs are efficacious in both acute and chronic pain, have minimal systemic exposure (2-3% of oral dose), and are safe in patients with kidney disease when used over limited surface area [101].

Skeletal muscle relaxants

Skeletal muscle relaxants such as baclofen, methocarbamol, and tizanidine, do not have a role in chronic pain conditions and are only recommended for short-term use in some acute pain conditions such as spasticity and spasms [102]. All skeletal muscle relaxants may cause significant sedation, muscle weakness and dizziness and should be avoided in advanced CKD and ESKD. For example baclofen, which is renally cleared, can cause severe neurotoxicity and muscle paralysis in advanced CKD and ESKD, and should be avoided.

Cannabis

While cannabis may improve some painful conditions, it has not been tested in persons with kidney disease, and its role and safety in this population is unclear [103-105].

Non-opioid therapy for neuropathic pain

In the general population, evidence supports the use of gabapentinoids (pregabalin and gabapentin), tricyclic antidepressants (TCA), and serotonin-norepinephrine reuptake inhibitors (SNRI) as first-line treatments for neuropathic pain.[99] The clearance of both gabapentin and pregabalin decreases and half-life (t_½) increases proportionately with worsening renal function, requiring renal dose adjustment (Tables 1 and Supplementary Table 1) [106-108]. Both medications should be dosed post-HD. These agents have been associated with increased risk of altered mental status, falls, and fractures in ESKD patients [109], and concomitant use with opioids is associated with increased hospitalization and mortality [110]. They have been associated with potential misuse and addiction and should be used with caution and close monitoring [111].

Little evidence exists regarding use of TCAs and SNRIs for patients with kidney disease (Tables 1 and 3). TCAs are associated with dose-related anticholinergic and antihistaminic side effects; SNRIs are generally better tolerated. Both of these classes may cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion. The use of the SNRI duloxetine in patients with Cl_Cr < 30 mL/minute or on dialysis is not recommended by current FDA guidance; however, guidelines from the European Union and Canada suggest its use in severe CKD and ESKD with lower starting doses and cautious monitoring [112].

Table 3.

Comparison of Commonly Prescribed Buprenorphine Products

Trade Name	Generic Name	Route	FDA Indication	X-Waiver Required?	Starting Dose
Butransa	Buprenorphine	Transdermal patch	Chronic pain	No	5ug/hr week
Belbucab	Buprenorphine	Buccal tablet	Chronic pain	No	75ug once daily
Suboxonec	Buprenorphine-naloxone#	Sublingual film or tablet	Opioid use disorder	Yes*	2mg-0.5mg
Subutexc	Buprenorphine	Sublingual tablet	Opioid use disorder in patients who cannot tolerate naloxone	Yes	2mg

^aPurdue Pharma L.P., Stamford, CT, USA

^bBioDelivery Sciences International, Inc, Raleigh, NC, USA

^cReckitt Benckiser Pharmaceuticals Incorporation, Richmond, VA, USA

^#When taken sublingually, the effect of buprenorphine predominates; if injected however, the effect of naloxone predominates.

^*No X-waiver needed if used off-label for treatment of pain [125]

Opioid therapy for pain

Although the main indication for opioids is for nociceptive pain, they have also been shown to be effective in improving neuropathic pain, especially diabetic neuropathy, either alone or as adjuvants to gabapentinoids [113,114]. The decision to initiate LTOT should be made through a careful risk-benefit evaluation and shared decision-making. Opioids should be avoided if other options are effective, and should be used sparingly at the minimum effective doses. We recommend a similar approach to the CDC guidelines, including maximizing nonpharmacologic therapy and nonopioid analgesia, establishing clear therapeutic goals, initiating treatment with immediate-release opioids rather than long-acting, starting with low doses, and uptitrating gradually with close monitoring of side effects [8].

The benefits of treatment may include improved quality of life and better functioning. This should be balanced with the increased risks of opioids in kidney disease such as altered mental status, falls, fractures, hospitalizations, and mortality, which occurs in a dose-dependent manner and can be seen even at lower doses [9-12]. These risks may be more pronounced in the older adults, and those with concomitant sedating medications such as gabapentinoids and benzodiazepines [110,115]. LTOT can also have additional adverse effects such as hyperalgesia, sedation, overdose, and progression to opioid use disorder (OUD). An evidence-based tool to help evaluate risk of opioid misuse before initiating treatment is the Revised Opioid Risk Tool, which creates a risk category based on personal and family history of substance misuse, age, and psychological disease [116]. If OUD is suspected, we recommend referral to an addiction treatment provider.

Monitoring of long-term opioid therapy

A cornerstone of LTOT is ensuring proper monitoring. CDC guidelines recommend checking state-wide prescription drug monitoring programs to identify controlled medications prescribed by other providers [8]. Additionally, periodic drug screens are important to ensure prescribed medication use and evaluate for illicit substance use. Urine drug testing is the preferred method of screening due to high sensitivity and specificity [117]. However, this may be challenging in patients with ESKD who produce little or no urine. Oral buccal swabs or saliva testing offer a reasonable alternative but may have logistic issues with specimen collection as these patients frequently have xerostomia.

Specific opioid medications

The pharmacokinetic evidence of commonly used opioid medications in patients with kidney disease is summarized in Supplementary Table 2. Opioids that are safer to use in kidney disease include oxycodone, hydromorphone, fentanyl, methadone and buprenorphine. Oxycodone is one of the most commonly prescribed opioids for kidney disease patients in the US [9]. It has predominantly hepatic elimination and is poorly dialyzed (Table 2). Caution should be used with long-acting formulations and when prescribed concurrently with medications that affect CYP3A4 or CYP2D6 metabolism [118]. Similarly, hydromorphone has a reasonable safety profile in kidney disease at lower doses and is dialyzed by HD, but supplemental doses are usually not needed post-HD. Fentanyl appears to be safe in kidney disease, although evidence is limited. On the other hand, morphine and hydrocodone have high risk of accumulation and systemic exposure, thus are contraindicated in patients with CKD or ESKD.

Tramadol is an atypical, centrally-acting opioid with dual action as a weak mu-opioid receptor agonist and SNRI. Tramadol and its active M1 metabolite are renally excreted. Its metabolism can vary unpredictably depending on an individual’s cytochrome P450 genetic profile [119]. Tramadol also has multiple drug interactions that may result in serotonin syndrome or seizures. Thus, we recommend it be used with extreme caution and at reduced doses, but preferably avoided.

Special Consideration: Buprenorphine and Methadone

Less commonly used opioid medications for pain are methadone (full agonist at mu-opioid receptor) and buprenorphine (partial agonist). They are more commonly used for the treatment of OUD where they reduce cravings, abate withdrawal symptoms, and prevent overdose. However, there are formulations for methadone and buprenorphine that can be used to treat chronic pain, as discussed below.

Methadone

Methadone functions as an NMDA-receptor antagonist, giving it additional efficacy for neuropathic pain. The analgesic half-life is 6-8 hours, requiring multiple daily doses. Methadone and its metabolites do not accumulate in CKD or ESKD, thus no dose adjustment is needed and it is not dialyzed out by HD (Table 2 and Supplementary Table 2). Because it can prolong the QTc interval, the electrolyte abnormalities such as hypo/hyperkalemia or hypo/hypermagnesemia that are frequently present in kidney disease may exacerbate its arrhythmia potential.

For patients without OUD, methadone as an analgesic can be prescribed by any provider with an active Drug Enforcement Administration (DEA) license, does not require patients to attend a clinic with an Opioid Treatment Program license, and can be legally filled at commercial pharmacies. In contrast, for patients with OUD, methadone is highly regulated, must be dispensed from a federally licensed Opioid Treatment Program, is dosed once a day, and initially requires patients to travel daily to receive observed dosing.

Buprenorphine

Buprenorphine is an efficacious treatment of pain in the general population [120]. Due to its partial agonism, it has a “ceiling effect” which reduces the risks of respiratory sedation and overdose. It is metabolized in the bile duct, requires no dose adjustment in CKD, and is not dialyzed (Table 2). Given its better safety profile compared to full opioids and steady state in CKD/ESKD, it may provide a therapeutic advantage and a safer alternative for pain management in patients with kidney disease who have a physiologic dependence to opioids [121-123].

Buprenorphine prescribing for chronic pain remains low due to barriers depicted in Figure 2; potential solutions are offered. Barriers include provider confusion about available buprenorphine formulations, their indications, and federal regulations for X-waiver (Table 3) [124]. Notably, although sublingual buprenorphine-naloxone can be prescribed off-label as an analgesic, several logistical hurdles make that difficult, including requiring documentation of indication [125]. Insurance authorization may also be required for transdermal or buccal formulations of buprenorphine [126,127]. Lastly, given its traditional use as a treatment for OUD, buprenorphine may be stigmatized by patients and providers, similar to methadone [128]. The ongoing HOPE Consortium trial will provide valuable insight into the acceptability, tolerability and efficacy of buprenorphine in patients on dialysis.

Fig 2.

Barriers and potential solutions for increasing use of buprenorphine for chronic pain in patients with kidney disease

Conclusion

Pain is highly prevalent and challenging to treat among patients with kidney disease. Pain management requires careful assessment, continuous monitoring, and shared decision-making of risks and benefits of different pharmacological and non-pharmacological therapeutic options with patients. Long-term therapy with full agonist opioid treatment is associated with significantly higher adverse effects in this population, thus more research into safer alternatives such as buprenorphine is warranted.

Key Points.

• Pain management in patients with kidney disease is challenging due to multiple patient, provider, and structural factors.

• Nonpharmacologic management of pain includes behavioral-based and physically-oriented interventions.

• Preferred nonopioid analgesia in CKD and ESKD include acetaminophen, topical analgesics, gabapentinoids, serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants.

• Before starting opioids, providers should have risk/benefit discussions regarding opioid analgesia, including complete psychosocial assessment and regular monitoring for benefits and adverse effects with evidence-based tools and urine or oral drug screening.

• Preferred opioid analgesics include oxycodone, hydromorphone, fentanyl, methadone, and buprenorphine.