Opioid Management in Older Adults with Chronic Kidney Disease: A Review

Abstract

Chronic pain, a common comorbidity of chronic kidney disease, is consistently under-recognized and difficult to treat in older adults with non-dialysis chronic kidney disease. Given the decreased kidney function associated with aging and chronic kidney disease, these patients are at increased risk for drug accumulation and adverse events. Emerging research has demonstrated the efficacy of opioids in chronic kidney disease patients, but research specifically focusing on older, non-dialysis chronic kidney disease patients is scarce. The primary objective of this review is to determine which oral and transdermal opioids are the safest for older, non-dialysis chronic kidney disease patients. We discuss the limited existing evidence on opioid prescription in older, non-dialysis chronic kidney disease patients and provide recommendations for the management of oral and transdermal opioids in this patient population. Specifically, transdermal buprenorphine, transdermal fentanyl, and oral hydromorphone are the most tolerable opioids in these patients; hydrocodone, oxycodone, and methadone are useful but require careful monitoring; and tramadol, codeine, morphine, and meperidine should be avoided due to risk of accumulation and adverse events. Since older adults with non-dialysis chronic kidney disease are at increased risk for adverse events, vigilant monitoring of opioid prescription is critical. Lastly, collaboration among an interprofessional clinical team can ensure safe prescription of opioids in older adults with non-dialysis chronic kidney disease.

1. Introduction

Currently, there are approximately 30 million adults in the United States who have chronic kidney disease.¹ Chronic kidney disease, defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines as an estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73m² for greater than three months,² is more common in women,¹ and approximately 72% of patients are over the age of 60 years.³ While chronic pain is recognized as highly prevalent among patients with end-stage renal disease,^4-6 less research has been conducted in patients with non-dialysis chronic kidney disease.^7-20 In one study, 60.7% of participants with non-dialysis chronic kidney disease reported chronic pain.²¹ chronic kidney disease is also known to have a significant negative impact on patients’ quality of life (QoL) scores, due to the symptom load (including chronic pain) and severity of comorbid pain.²²

Chronic pain has been under-recognized and under-treated in the chronic kidney disease patient population, and the scarce research in this area has been heterogeneous.^22-24 While aggressive pain management has been advocated for the end-stage renal disease population, there are no specific guidelines for the management of chronic pain in older adults with chronic kidney disease.²⁵ The 2018 United States Renal Data System (USRDS) reported that 43.8% of chronic kidney disease patients were prescribed at least one opioid in 2016.²⁶ Opioid prescription type and duration in those with chronic kidney disease and end-stage renal disease has followed national prescribing patterns for the general Medicare population, which may lead to improper opioid prescription in older adults with chronic kidney disease due to changes in pharmacokinetics and pharmacodynamics caused by chronic kidney disease and age.²⁵

Because of the increased risk for adverse events, such as nausea, confusion, constipation, sedation, respiratory depression, and myoclonus, safe prescription of opioids is critical in the older, non-dialysis chronic kidney disease patient population.^8,27,28 It is imperative to state that opioids should be used only when absolutely indicated and initiated at the lowest dose or shortest duration possible. The primary objectives of this review are to summarize which oral and transdermal opioids are the safest for older, non-dialysis chronic kidney disease patients and to provide guidance on how to properly prescribe them given the scarcity of clinical evidence.

We review the sparse primary evidence and lack of specific clinical prescribing guidelines for the use of opioids in older adults with non-dialysis chronic kidney disease and provide recommendations for the management of oral and transdermal opioids in older adults with non-dialysis chronic kidney disease. We present a modified approach to pain using the American Geriatrics Society (AGS) Beer’s Criteria and Pharmacological Management of Persistent Pain in Older Persons guidelines adapted for older adults with non-dialysis chronic kidney disease. Finally, we present strategies for switching from one oral opioid to another safer agent as well as strategies for collaboration in complex pain management. Further studies are urgently needed in this area to address the pain management needs of the growing population of older adults with chronic kidney disease.²⁵

2. Summary of Clinical Evidence for Opioid Use in Older Adults with Chronic Kidney Disease

Current primary evidence for the safety and efficacy of opioids in older, non-dialysis chronic kidney disease patients is limited. Table 1 summarizes the findings of thirteen studies, spanning the years 1983 to 2015, evaluating opioid use in non-dialysis, renally-impaired patients.^7-20 These studies varied in opioid type, administration route and duration, and study population, making it difficult to generalize findings to the entire older, non-dialysis chronic kidney disease patient population.^7-20

Table 1.

Summary of primary evidence for opioid use in non-dialysis chronic kidney disease [7-20]

Opioid Agenta,b	Evidence for use in non- dialysis kidney disease	Harm	Considerations from study
Buprenorphine	Prospective parallel group, active-controlled study [8] Transdermal buprenorphine vs. Transdermal fentanyl N = 42	No	Small, convenient sample Renal impairment based on SCr at one timepoint, not eGFR over time No significant differences in pain score between the groups
Fentanyl	Retrospective study [9] Fentanyl vs. Oxycodone vs. Morphine N = 1147	No	Severe fatigue was experienced with oxycodone and severe constipation and cognitive dysfunction with morphine
	Retrospective study [10] Fentanyl (no comparator) N = 53	No	Small sample No comparator group
Hydromorphone	Retrospective study [11] Hydromorphone vs. Morphine, Coproxamol, Fentanyl, or Diamorphine N = 55	No	Small sample Less AE with hydromorphone vs. comparators
	Retrospective study [12] Hydromorphone (no comparator) N = 54	Yes	Small sample No comparator group AE: tremor, myoclonus, agitation, cognitive dysfunction Increasing occurrence of these events with increasing dose and duration
Oxycodone	Retrospective study [9] Oxycodone vs. Morphine vs. Fentanyl N = 1147	Yes	AE: severe fatigue
	Uncontrolled prospective study [20] Oxycodone vs. Morphine N = 27	No	Small sample size Tolerability was significantly increased following switch from morphine to oxycodone
Meperidine	Uncontrolled prospective study [13] Meperidine (no comparator) N = 67	Yes	Small sample No comparator group Longer administration is associated with higher occurrence of central nervous system excitatory events
Morphine	Non-randomized cohort study [14] Morphine (no comparator) N = 36	Yes	Small sample No comparator group AE: nausea, vomiting, confusion
	Non-randomized cohort study [15] Morphine (no comparator) N = 109	Yes	No comparator group Greater accumulation of morphine and M6G with decreased renal function
	Non-randomized, retrospective study [18] Morphine (no comparator) N = 177	Yes	No comparator group Age over 78 years and poor renal function associated with higher risk of morphine adverse events
	Non-randomized cohort study [19] Morphine (no comparator) N = 18	Yes	Small sample No comparator group Higher serum creatinine and worse cognitive impairment correlated with increased frequency of nausea and vomiting AE.
	Retrospective study [9] Morphine vs. Oxycodone vs. Fentanyl N = 1147	Yes	AE: severe constipation and cognitive dysfunction
	Non-randomized cohort study [16] Morphine (no comparator) N = 11	No	Small sample No comparator group No relationship between serum concentrations of morphine/M3G/M6G and pain intensity or adverse events
	Uncontrolled prospective study [17] Morphine (no comparator) N = 300	No	No comparator group No relationship between serum concentrations of morphine/M3G/M6G and pain intensity or adverse events

Scr serum creatinine, eGFR estimated glomerular filtration rate, AE adverse events, M6G morphine-6-glucuronide, M3G morphine-3-glucuronide

^aThe following studies were conducted in patients with cancer pain [8-11, 13-20]

^bThe following studies were conducted in patients on hospice [12, 14, 19]

Seven studies focused on morphine prescription in renally-impaired older adults and reported conflicting results.^9,14-19 Five of these studies reported that morphine may cause harm in renally-impaired patients.^{9,14,15,18,19} Specifically, greater accumulation of morphine and its metabolite, morphine-6-glucuronide (M6G), was found with decreased renal function.¹⁵ Accumulation of morphine and its metabolites can cause adverse events such as nausea, vomiting, confusion, severe constipation, and cognitive dysfunction.^9,14,18 Alternatively, two studies found no relationship between serum concentrations of morphine, M6G, and morphine-3-glucuronide (M3G) and pain intensity or adverse events.^16,17 Overall, the majority of research highlights the risks of morphine prescription, including harmful accumulation and adverse events, indicating that morphine should be avoided in older chronic kidney disease patients.

The remaining studies investigated the use of buprenorphine, fentanyl, hydromorphone, meperidine, and oxycodone in cancer patients with renal impairment.^8-13,20 A prospective parallel study compared transdermal buprenorphine to transdermal fentanyl and found no significant differences in pain level among patients with renal impairment who used buprenorphine compared with patients with preserved renal function who used fentanyl.⁸ Two retrospective studies evaluating fentanyl concluded that there was no increased risk of harm.^9,10 Specifically, when compared to oxycodone and morphine, patients on fentanyl did not experience adverse events, whereas patients on oxycodone experienced a higher incidence of severe constipation and patients on morphine experienced a higher incidence of cognitive dysfunction.⁹ Hydromorphone was evaluated in two retrospective studies with conflicting conclusions.^11,12 One study found hydromorphone to be safer than alternative opioids like morphine, fentanyl, and diamorphine.¹¹ The other study reported more adverse events such as tremor, myoclonus, and agitation with increasing dose and duration of hydromorphone.¹² A study evaluating meperidine highlighted the risk of central nervous system excitatory events with longer duration of administration.¹³ Lastly, two studies evaluated oxycodone. When compared to morphine and fentanyl, oxycodone demonstrated potential harm (severe fatigue).⁹ However, when compared to morphine, oxycodone was reported to be the safer alternative.²⁰

These thirteen studies of opioid prescription in older, non-dialysis chronic kidney disease patients are mostly small in sample size and inconsistently designed with variable outcomes. All but one of the thirteen studies focused specifically on renally-impaired cancer patients, limiting the generalizability of the studies and underscoring the lack of current research in this patient population. Without additional clinical evidence, it is difficult for review papers to establish necessary opioid-prescribing guidelines for older, non-dialysis chronic kidney disease patients. Often review articles that provide strategies for safe opioid use in this population extrapolate guidance from pharmacokinetic studies or evidence in other patient populations.^28-30

3. Lack of Guideline Recommendations for Opioid Use in Older Adults with Chronic Kidney Disease

Clinical guidelines are vital to allow for safe prescribing of medications. However, there are currently no guidelines, based on clinical research, for prescribing opioids to manage chronic pain in older adults with non-dialysis chronic kidney disease. The Centers for Disease Control offers extensive guidelines for the safe prescription of opioids in the management of chronic pain, but these guidelines do not offer considerations specifically for older, non-dialysis chronic kidney disease patients.³¹

The American Geriatrics Society (AGS) has published the AGS Beers Criteria³² and the Pharmacological Management of Persistent Pain in Older Persons guidelines,³³ both of which define how to properly prescribe opioids in the general older adult population. These guidelines compile research-based evidence on the usefulness and risks of opioids specifically for older adults. The AGS Beers Criteria is particularly useful for conceptualizing how to prescribe opioids to older, non-dialysis chronic kidney disease patients. The AGS Beers Criteria considers the pharmacokinetic and pharmacodynamic changes that occur with aging which in turn influence response to opioids.

While absorption and distribution are relatively unchanged with age, a natural decline in hepatic and renal function impairs metabolism and clearance of opioids in older adults.^28,34 Decreased function of the cytochrome P450 system in the liver, specifically CYP3A4 and/or CYP2D6, can lead to decreased metabolism and increased accumulation of opioids metabolized in the liver.²⁸ Additionally, opioids which rely heavily on renal elimination can accumulate and cause adverse events. Codeine, hydromorphone, meperidine, morphine, oxycodone, and tramadol are all broken down into active metabolites.²⁸ Notably, meperidine and its active metabolite, normeperidine, increase the risk for neurotoxicity in older adults with reduced renal function.^28,32 Lastly, older adults also have enhanced pharmacodynamic sensitivity, and thus the same opioid dose administered to a younger adult may lead to a more pronounced response in an older adult.²⁸ Due to the aforementioned physiological changes, determining proper dose adjustments in this patient population can be challenging, and this necessitates vigilant monitoring.

4. Safe Prescribing Practices for Opioid Use in Older Adults with Chronic Kidney Disease

Prior to initiation of opioids for pain management, nonopioid analgesics should be utilized. Table 2 provides detailed information about recommended initial dosing of nonopioid analgesics, dose adjustments for renal impairment, and the rationale for these recommendations.^32,33 Specifically, medications such as acetaminophen, capsaicin topical cream, and lidocaine topical patch are recommended in the older, non-dialysis chronic kidney disease patient population.^32,33 Topical nonsteroidal anti-inflammatory drugs (NSAIDs) can be used when necessary, but oral NSAIDs should be avoided due to their risks of hypertension, edema, and additional adverse events.^32,33

Table 2.

Initial dosing recommendations and patient-specific considerations for oral and topical pain medications to treat chronic pain in older adults with kidney impairment (Adapted from the 2019 American Geriatrics Society Beers criteria and 2009 American Geriatrics Society Pharmacological Management of Persistent Pain in Older Persons) [27, 29, 30, 32, 33]

Medications	Recommended Initial Dosinga	Rationale and Pearlsb
Nonopioid Analgesics
Acetaminophenc	325–500 mg by mouth every 4 hours or 500–1,000 mg every 6 hours	Do not exceed 4 g per day.
Capsaicin topical cream (0.025% to 0.15%)	Apply thin film topically to the affected area 3-4 times/day	Good choices for localized nerve pain. Minimal systemic absorption.
Lidocaine 5% topical patch	Apply up to three patches for 12 hours/day Patches may be cut to appropriate size	Good choices for localized nerve pain. Minimal systemic absorption.
Topical NSAIDs (e.g., diclofenac 1-1.6% topical gel)	Apply 2-4 g of gel to affected area 4 times daily	Maximum dose 16 g per upper extremity joint per day, 8 g per lower extremity joint. Good choices for localized nerve pain. Minimal systemic absorption.
Oral NSAIDs (e.g., celecoxib, ibuprofen, naproxen)	Avoid use with reduced renal function If needed, minimize use as much as possible (e.g., as needed rather than scheduled daily doses)	Acetaminophen is preferred over NSAIDs due to risks of hypertension, edema, hyperkalemia, bleeding, or kidney damage related to NSAID use.
Opioidsc,d
Buprenorphine patch	5 mcg/hour patch applied once every 7 days	No clinically significant accumulation in chronic kidney disease. Patches may not be cut.
Fentanyl patch	12 mcg/hour patch applied once every 72 hours for opioid tolerant patients onlye	No clinically significant accumulation in chronic kidney disease. Patches may not be cut.
Hydromorphone Immediate Release	1–2 mg by mouth every 3–4 hours as needed	The preferred short-acting opioid in chronic kidney disease.
Hydrocodone Immediate Release	2.5-5 mg of hydrocodone by mouth every 4-6 hours as needed	A reasonable short-acting opioid in chronic kidney disease. Product often is in combination with acetaminophen. Do not exceed 4 g of acetaminophen per day.
Oxycodone Immediate Release	2.5-5 mg by mouth every 4-6 hours as needed	A reasonable short-acting opioid in chronic kidney disease.
Methadone	Consult a specialist for dosing	No accumulation in chronic kidney disease. Complex pharmacokinetic profile, consult a pain specialist or palliative care provider for dosing.
Tramadol Immediate Release	25-50 mg every 6 hours as needed CrCl < 30 mL/min: reduce dose, maximum 200 mg/day Age > 75 years: maximum 300 mg/day	Increased risk of central nervous system adverse effects. Increased risk for syndrome of inappropriate antidiuretic hormone secretion /hyponatremia in older adults.
Codeine Immediate Release	15-60 mg every 4 hours as needed	No dose adjustment per package insert; clearance is decreased in kidney disease. Reduced clearance in kidney disease, leading to increased risk of nausea, vomiting, hypotension, central nervous system adverse effects.
Morphine	Avoid use	Active metabolite accumulates in kidney disease, leading to increased risk of central nervous system adverse effects and respiratory depression.
Meperidine	Avoid use	Increased risk of neurotoxicity, including delirium, compared with other opioids; safer alternatives available.
Tramadol Extended Release	CrCl < 30 mL/min: avoid use	Increased risk of central nervous system adverse effects. Increased risk for syndrome of inappropriate antidiuretic hormone secretion /hyponatremia in older adults.
Adjuvant Therapy
Duloxetinec	30 mg by mouth once daily CrCl < 30 ml/min: Avoid use.	Maximum dose for pain 60 mg daily.
Venlafaxinec	37.5 mg by mouth once daily	Maximum dose for pain 225 mg daily (off-label).
Gabapentin	100 - 300 mg by mouth once daily CrCl < 60 mL/min: dose reduce	Increased risk of central nervous system effects.
Pregabalin	25 mg by mouth once or twice daily CrCl < 60 mL/min: dose reduce	Increased risk of central nervous system effects.
Tricyclic antidepressants (e.g.,desipramine,nortriptyline,amitriptyline)f	Avoid use	Significant risk of adverse central nervous system effects in older adults.
Muscle relaxants (e.g., baclofen, cyclobenzaprinec, tizanidinec)	Avoid use	Anticholinergic adverse effects, sedation and increased risk of fractures. Significant risk of adverse central nervous system effects in older adults.
Keyb	No change needed	Use with caution	Avoid

g gram, mg milligram, CrCl creatinine clearance, mL/mm milliliters per minute

^aPer FDA labeling and package insert for individual drugs. See package inserts for additional dosing instructions

^bPer 2019 AGS Beers criteria, which may differ from FDA labeling recommendations

^cFor acetaminophen, all opioids listed, duloxetine, venlafaxine, cyclobenzaprine, and tizanidine: dose adjustment may be required for moderate to severe liver dysfunction. See individual package inserts for specific recommendations

^dFor all opioids, it is recommended to initiate and maintain the opioid dose at the lowest effective dose possible to reduce the risk of central nervous system adverse effects

^eSee package insert for details. Opioid tolerant patients per topical fentanyl package insert are those patients who are taking 60mg of oral morphine or more (or an equivalent dosage of an alternative opioid) per day

^fTricyclic antidepressants should be avoided when drug-drug or drug-disease interactions are present

No specific guidelines currently exist to steer safe prescribing of opioids in older adults with chronic kidney disease when they are required. By combining pharmacokinetic and pharmacodynamic considerations, the AGS Beers Criteria and the Pharmacologic Management of Persistent Pain in Older Persons Guidelines, we have synthesized recommendations to support appropriate opioid selection in older adults with chronic kidney disease. Table 2 summarizes this evidence and provides recommendations for the use of the safest agents for pain management in older adults with chronic kidney disease, including opioids and adjuvant therapies. To ensure safe opioid prescribing in older, non-dialysis chronic kidney disease patients, it is important to consider how their decreased renal function may result in accumulation of opioids and associated active metabolites. Codeine, hydromorphone, meperidine, morphine, oxycodone, and tramadol all have active metabolites that are renally-cleared.²⁸ Accumulation of active metabolites can lead to opioid toxicity in renally-impaired patients.

Transdermal buprenorphine and fentanyl are both recommended opioids for use in older non-dialysis chronic kidney disease patients^3,29,30 and have been studied head-to-head in a cancer population with and without renal impairment.¹¹ Both opioids are metabolized by the liver and converted to clinically insignificant metabolites.^27,35 Absorption of transdermal buprenorphine and fentanyl appears unaltered in older adults.^36,37 Buprenorphine is believed to be safe in older non-dialysis chronic kidney disease patients,²⁹ although primary evidence for its use is limited.⁸ Relevant adverse events that may be monitored in older adults with chronic kidney disease are confusion, nausea/vomiting, and constipation.^8,32 In non-dialysis chronic kidney disease patients, both transdermal buprenorphine and fentanyl do not require renal dose adjustment and should be initiated and maintained at the lowest effective dose to minimize side effects.^28,29 The starting dose for transdermal buprenorphine is a 5 mcg/hr patch applied once every 7 days.²⁹ The starting dose for transdermal fentanyl is a 12 mcg/hr patch applied once every 72 hours, and it is important to note that fentanyl is not recommended for opioid naïve patients.²⁹

Oral hydromorphone is the preferred short-acting opioid for older adults with non-dialysis chronic kidney disease.^29,30 Hydromorphone has been shown to be a more tolerable alternative to morphine in older adults with chronic kidney disease ^11,29,38 and has been studied in palliative care and hospice patients with and without renal impairment.^8,11,12 Neuroexcitatory adverse events can occur with the accumulation of metabolites.¹² Other adverse events associated with oral hydromorphone are nausea and constipation.³⁹ Therefore, it is recommended that non-dialysis older chronic kidney disease patients who are prescribed oral hydromorphone are administered 1-2 mg orally every 3-4 hours and maintained at the lowest effective dose in order to minimize central nervous system effects.³⁰

Hydrocodone is a recommended short-acting opioid in older chronic kidney disease patients²⁹ and is often administered in combination with acetaminophen.⁴⁰ Hydrocodone is broken down into active metabolites, and the parent compound along with its metabolites tend to accumulate in renally-impaired patients.⁴¹ While hydrocodone may be safe and effective, careful monitoring is recommended. It is advised to initiate and maintain hydrocodone at the lowest possible dose (2.5-5 mg orally, every 4-6 hours) in older adults with chronic kidney disease to minimize central nervous system adverse effects.²⁹ Adverse events such as headaches, nausea, and dizziness have also been reported when using hydrocodone.⁴¹ No primary studies were found supporting the use of hydrocodone specifically in older adults with non-dialysis chronic kidney disease.

Oxycodone is an acceptable short-acting opioid in older, non-dialysis chronic kidney disease patients when vigilantly monitored.^28-30 Oxycodone and its active metabolites are cleared renally, and this clearance may be greatly reduced in older, renally-impaired patients.^28,35 However, with proper dose adjustment, oxycodone can be used as a second-line treatment for severe chronic pain.²⁹ The recommended starting dose for oxycodone in older, non-dialysis chronic kidney disease patients is 2.5-5 mg orally, every 4-6 hours.³⁰ Oxycodone should be maintained at the lowest effective dose in order to minimize central nervous system effects. No primary studies were found supporting the use of hydrocodone in this population.

Oral methadone may be a useful longer-acting opioid for treating older adults with chronic kidney disease. However, it is highly recommended that a pain specialist is consulted when prescribing methadone.^27,30 Methadone is metabolized in the liver, and its metabolites are primarily excreted through the feces, with minimal renal clearance.^27,29 The pharmacokinetic and pharmacodynamic profiles of methadone vary greatly between individuals. Methadone has a very lengthy and unpredictable half-life, which can lead to the delayed onset of adverse events or toxicity in renally-impaired patients.²⁹ Given its unique pharmacokinetic profile, close supervision is required when administering this drug, and collaboration with a palliative care or pain specialty team is encouraged.^27,30

Tramadol (immediate release) is not recommended for usage in older chronic kidney disease patients. Tramadol and its active metabolites are predominantly renally cleared.⁴² There is also concern for increased risk of seizures and central nervous system adverse effects in older adults with prolonged tramadol use.³² Thus, tramadol is not a safe medication choice in older adults with chronic kidney disease and should be avoided when possible; other, safer opioid agents are recommended instead.³²

Codeine, morphine, and meperidine should not be used in non-dialysis chronic kidney disease patients.^7,29,30 Codeine is metabolized and excreted renally, with greatly reduced clearance with renal impairment.⁴³ Codeine’s metabolites have analgesic properties, and accumulation of these metabolites can lead to toxicity.⁴³ Morphine and its metabolites are renally cleared, and in patients with significant renal impairment, these compounds are likely to accumulate.^11,44 Meperidine has a high risk for neurotoxicity in renally-impaired patients.²⁷

Adjuvant therapy, including medications such as duloxetine, venlafaxine, gabapentin, and pregabalin, should be used with caution when indicated.^32,33 Gabapentin and pregabalin can increase the risk for central nervous system effects and require dosage adjustments in patients with diminished renal function. Other adjuvant therapies, such as tricyclic antidepressants and muscle relaxants, should be avoided in older, non-dialysis chronic kidney disease patients due to their significantly increased risk of central nervous system effects.^32,33

5. Monitoring and Co-management of Older Adults with Chronic Kidney Disease with Persistent Pain

Older adults with non-dialysis chronic kidney disease are at increased risk for adverse events from pain medications and other medications to treat their chronic conditions, and therefore, require close monitoring.^45,46 Older chronic kidney disease patients with obesity, pulmonary or cardiac disease, opioid-naivety, or gait unsteadiness are at higher risk for adverse events.⁴⁷ Because of these risk factors, it may be necessary to switch opioids during the course of treatment. Table 3 provides conversions for switching from one opioid to another, potentially safer option specifically in older, non-dialysis chronic kidney disease patients.^48-51

Table 3.

Equivalent analgesic doses of opioid agents and examples of a switch from a less safe opioid to a safer alternative in older adults with chronic kidney disease [49-52]

Oral or transdermal opioid	Equivalent dose	Example of a switch from a less safe opioid to a safer alternative in older adults with chronic kidney diseasea
Buprenorphine patchb	5 mcg/hour	Calculate current total daily dose of opioid Morphine 10 mg by mouth every 4 hours scheduled Total daily dose morphine = 60 mg Convert total daily dose to desired transdermal opioid 30 mg oral morphine = 5 mcg/hour buprenorphine 60 mg morphine × 5mcg/hour buprenorphine ÷ 30 mg morphine = 10 mcg/hour buprenorphine Taper the patient’s current around-the-clock opioids for up to 7 days to no more than 30 mg morphine or equivalent per day before beginning buprenorphine Reduce to morphine 5 mg by mouth every 4 hours scheduledd Initiate buprenorphine patch at the next dosing interval, discontinue all around-the-clock opioids. Buprenorphine 10 mcg/hour patch applied once for 7 days May use morphine 5 mg by mouth every 4 hours as needed for pain until analgesic efficacy with buprenorphine is attained
Fentanyl patchc	12.5 mcg/hour
Hydromorphone	7.5 mg	Calculate current total daily dose of opioid Morphine 10 mg by mouth every 4 hours as needed for pain Total daily dose morphine = 60 mg Convert total daily dose to desired oral opioid Desired opioid: hydromorphone 30 mg oral morphine = 7.5 mg oral hydromorphone 60 mg morphine × 7.5 mg hydrocodone ÷ 30 mg morphine = 15 mg hydrocodone Reduce equivalent total daily dose by 50% to account for cross tolerance 15 mg hydrocodone × 50% = 7.5 mg hydrocodone Divide reduced total daily dose into desired dosing interval Hydromorphone 1 mg by mouth every 3-4 hours as needed for pain
Hydrocodone	30 mg
Oxycodone	20 mg
Tramadol	300 mg
Morphine	30 mg

mcg microgram, mg milligram

^aReduce by 25 – 50% when converting due to opioid cross tolerance.

^bThe maximum buprenorphine dose is 20 mcg/hour, higher doses yield an increased risk for QTc prolongation.

^cThe onset of action is approximately 6 hours, by applying the patch with the last dose of the oral opioid the patient is being converted from, the chances of increased pain during the opioid conversion may be avoided.

^dIndividualize taper to patient as tolerated.

Polypharmacy is common in older adults with reduced renal function and poses a greater risk for adverse events.^45,46,52 Older adults often have more comorbidities and a higher medication burden which compound their risk for adverse events (from non-serious events to fatality).^45,46,52,53 A meta-analysis reported that 72% of patients prescribed opioids such as morphine, hydromorphone, and oxycodone also had risk factors for drug-drug interactions.⁵⁴ Opioids are subject to pharmacokinetic drug interactions (e.g., via cytochrome P450 induction or inhibition) and also pharmacodynamic drug interactions (e.g., when used with other agents causing central nervous system depression).²⁸ Adverse effects of opioids and other adjuvant medications may also lead to prescribing cascades, such as bowel regimens to mitigate opioid-related constipation or other pro-cholinergic medications for dry mouth or dry eyes to counteract the anticholinergic side effects of opioids and/or adjuvant agents.^32,45,46,52 Because of these risks, it is important to emphasize that opioids should only be prescribed to older, non-dialysis chronic kidney disease patients when they are absolutely indicated. Additionally, a multidisciplinary and interprofessional approach through collaboration with other specialists may ensure more positive outcomes when opioids are prescribed for high-risk older adults with chronic kidney disease. ^27,29,30 Pharmacists may play a role in safely managing dosing, monitoring for the adverse effects of pain medications, and utilizing strategies to reduce polypharmacy.^45,46 Non-pharmacologic modalities are highly recommended to improve pain management in older adults,³³ thus various members of the interprofessional team, such as pain specialists, nurses, physiotherapists, and psychologists, may offer their skill and expertise in this area.

6. Conclusions

Treating chronic pain in older adults with non-dialysis chronic kidney disease can be challenging. Physiologic changes associated with both aging and chronic kidney disease, including reduced drug metabolism and elimination, result in a greater risk for adverse events and the need for vigilant monitoring in this population. Opting for and appropriately dosing safer opioids in older adults with reduced renal function can help mitigate adverse drug events. There is a lack of research on opioid prescription in older, non-dialysis chronic kidney disease patients. While it is encouraged to avoid opioids when possible, there may be situations in which they are appropriately indicated, and for this reason, we emphasize strategies to help select the most appropriate opioid in older, non-dialysis chronic kidney disease patients. The lack of evidence-based guidelines for this patient population serves as a call for additional randomized and non-randomized controlled trials to guide safe and efficacious opioid prescribing in older adults with non-dialysis chronic kidney disease.

Clinical Significance Highlights:

• Opioid use in older adults with chronic kidney disease requires close monitoring for adverse events.

• Opioids should be reserved only for when they are absolutely indicated.

• Buprenorphine, fentanyl, and hydromorphone are the safest opioids in older adults with kidney disease.

• Hydrocodone, oxycodone, and methadone may accumulate with reduced renal function.

• Interprofessional collaboration can be beneficial for treating older patients with kidney disease.