Introduction: Opioid analgesics are often used to manage moderate to severe pain. A significant proportion of patients taking opioids have compromised kidney function. This systematic review aimed to examine the available evidence on the safety and analgesic effect of opioid use in adults with kidney disease. Methods: We searched eight electronic databases from inception to January 26, 2023. Published original research articles in English reporting on opioid use and pharmacokinetic data among adults with reduced renal function were included. Article screening, data extraction, and quality assessment were conducted by at least two investigators independently. This review was registered prospectively on PROSPERO (ID: CRD42020159091). Results: There were 32 observational studies included, 14 of which reported on morphine use, three involved fentanyl use, two involved hydromorphone use, and 13 articles reported on other opioids including codeine, dihydrocodeine, and buprenorphine. Conclusion: There is limited and low-quality evidence to inform the safety and analgesic effect of opioid use in reduced renal function. Morphine remains the opioid for which there is the most evidence available on safety and analgesic effect in the context of renal disease. Greater caution and consideration of potential risks and benefits should be applied when using other opioids. Further high-quality studies examining clinical outcomes associated with the use of different opioids and opioid doses in renal disease are warranted.

Strong pain is often managed using a type of pain medication called opioids. Many people taking opioids for strong pain also have reduced kidney function. The kidneys are responsible for removing excess medication from the body, so opioids may build up if the kidneys are not working optimally. However, we do not know the overall effect of taking opioids when people have reduced kidney function. This study summarised all the available research on the safety and analgesic effects of opioid use in adults with reduced kidney function. We found there is overall limited evidence on this topic. Most of the research involves a type of opioid called morphine. Further research is needed to address this gap in the evidence.

Opioid analgesics are widely used for the management of moderate to severe pain, including acute [1] and chronic non-cancer pain [2] as well as cancer-related pain [3]. A significant proportion of patients taking opioid analgesics have compromised kidney function, such as chronic kidney disease. Chronic kidney disease is defined as “abnormalities of kidney structure or function, present for >3 months, with implications for health” [4]. A 2017 systematic review found that the prevalence of opioid use among patients with chronic pain and chronic kidney disease ranged between 18% and 36% [5]. Approximately 60% of patients with cancer have reduced renal function [6], and up to 85% of patients with cancer-related pain are prescribed opioid analgesics [7].

Reduced renal function can affect the elimination of opioid analgesics and/or active metabolites, resulting in accumulation and/or supratherapeutic serum concentrations of these compounds [8]. This can contribute to an increased risk of opioid-related harm including sedation, changes in cognition, syndromic delirium, or less commonly, respiratory depression [8], and even death [9]. A robust, evidence-based approach should thus be applied to ensure appropriate analgesia is balanced with patient safety. Current practice guidelines are largely informed by opioid pharmacokinetic data and expert consensus rather than synthesis of existing evidence [10].

Other literature reviews have synthesised the available evidence informing opioid use in renal disease in the context of cancer-related pain but not for non-cancer pain. A 2011 systematic review of 15 observational studies on opioid use in patients with cancer pain and renal disease identified low-quality evidence suggesting potential toxicity associated with morphine, diamorphine, and codeine use in renal impairment due to metabolite accumulation [11]. To our knowledge, no review has been performed to summarise the existing knowledge on the safety and analgesic effect of opioid use among patients with both non-cancer and cancer-related pain and reduced kidney function. Therefore, this study aimed to examine the available evidence on the safety and analgesic effect of opioid use in adults with kidney disease. We also examined differences in outcomes between patients with and without kidney disease.

This review was performed in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [12]. This review was prospectively registered on PROSPERO (ID: CRD42020159091).

Inclusion and Exclusion Criteria

In our study, original research articles (including observational studies and randomised trials) which reported on the safety and/or analgesic effect of opioid analgesics among adults (≥18 years) with reduced kidney function, as quantified by recognised criteria such as glomerular filtration rate (GFR), creatinine clearance (CrCl), or serum creatinine were included. Studies in which an identifiable subset of patients with reduced renal function were apparent within a wider patient sample were also included. Articles written in languages other than English or articles reporting opioid use in the context of procedural sedation, opioid substitution, illicit use, or contexts outside analgesia (such as for antitussive or antidiarrhoeal purposes) were excluded. Case reports, case series, editorials, expert opinion articles, and articles reporting exclusively on outcomes before and after haemodialysis were also excluded.

Search Strategy

A systematic search was conducted on eight electronic databases including the Cumulative Index of Nursing and Allied Health Literature (CINAHL), MEDLINE, PubMed, Scopus, Embase, Cochrane Central Register of Controlled Trials, International Pharmaceutical Abstracts, and PsycINFO. The search was conducted from database inception to January 26, 2023. The full search strategy is available in Supplementary Table 1 (for all online suppl. material, see https://doi.org/10.1159/000538258). References of relevant articles were screened to identify additional studies not captured by the search strategy.

Data Extraction and Analysis

Selection of Studies

After the removal of duplicates, articles were merged into Covidence, a web-based collaboration software platform (Veritas Health Innovation, Melbourne, Australia) [13]. Fifteen investigators (M.S., S.L., B.B., D.B., J.P., J.K., M.A., G.R., J.T., A.K., B.C., B.L., K.C., K.K., and M.F.) independently filtered articles by title and abstract for potentially eligible studies. Thirteen investigators (J.K., S.L., M.S., D.B., B.B., K.C., B.C., B.L., M.F., A.K., J.P., K.K., and S.F.) performed independent full-text screening to confirm eligibility. Each article was reviewed by at least two investigators during the title, abstract, and full-text screen. Any discrepancies were reviewed by a third author to reach consensus.

Data Extraction and Management

Four investigators (S.L., S.F., M.S., and J.K.) extracted data using a standard data extraction form (online suppl. Table 2) including details of the study, details of participants, opioid analgesics administered, and clinical outcomes reported. The primary outcome of this review was the incidence of opioid-related adverse events as defined by the study. Secondary outcomes included indicators or opioid analgesic effects, such as pain intensity, functional outcomes, and pharmacokinetic parameters. Outcomes between patients with and without kidney disease were compared.

Assessment of Risk of Bias in Included Studies

Quality assessment of all included studies was conducted by four investigators (M.S., S.L., S.F., and J.K.). The Risk of Bias in Non-Randomised Studies of Interventions (ROBINS-I) tool was used for observational studies [14] and involved seven domains (confounding, participant selection, classification of interventions, deviations from interventions, missing data, measurement of outcome, selective reporting) to categorise studies as having low, moderate, serious, or critical risk of bias.

Data Synthesis

Heterogeneity between studies was assessed by comparing study design, study population, opioids given, and outcomes reported. Due to heterogeneity in the study population, opioids given, and outcomes between studies, a meta-analysis could not be conducted and therefore a narrative synthesis was conducted. Included studies were grouped by (1) opioid type; (2) studies comparing groups with reduced versus normal renal function or studies involving patients with reduced renal function only; (3) whether the study reported on safety or efficacy outcomes; and (4) study design. The Kidney Disease: Improving Global Outcomes (KDIGO) Foundation recommends the classification of chronic disease based on GFR category [4]. However, due to heterogeneity in the measurement of kidney function (such as GFR, CrCl, or serum creatinine), standardised reporting of chronic kidney disease stage by GFR category was not feasible.

The search strategy generated a total of 8,752 articles, of which 313 full-text articles were assessed for eligibility. Refinement using the inclusion and exclusion criteria resulted in 21 studies being eligible for inclusion. Three additional articles were obtained by a manual search of the reference list of identified articles, resulting in a total of 32 articles included (Fig. 1) [15‒46].

Fig. 1.

Study flow diagram.

Fig. 1.

Study flow diagram.

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Study Characteristics

All 32 included studies were observational [15‒46], of which 25 studies reported on outcomes in patients with reduced compared to normal renal function [15‒20, 23‒28, 30‒32, 34, 35, 37‒39, 41‒45] and six studies reported on outcomes in patients with reduced renal function only [21, 22, 29, 33, 40, 46]. Twelve articles involved patients with cancer [15, 18, 30, 31, 34, 36‒38, 41‒43, 46], four studies involved patients receiving haemodialysis [17, 24, 28, 29], four studies involved patients in palliative care settings [22, 32, 33, 40], four studies involved surgical patients [23, 27, 39, 44], and the remaining studies involved patients in the intensive care unit [16, 35] or those with heart failure [21] or hepatic disease [26]. There were 14 articles reporting on morphine use (Table 1) [15, 16, 21, 23, 24, 30, 34‒36, 38, 39, 41, 43, 44], three articles involving fentanyl use (Table 2) [18, 33, 37], two studies involving hydromorphone use (Table 3) [32, 40], and 13 articles reporting on other opioids, including codeine [19], dihydrocodeine [17], hydrocodone [25, 26], buprenorphine [27], and a range of opioids (Table 4) [20, 22, 29, 31, 42, 46].

Table 1.

Summary of included studies reporting on morphine use among patients with reduced renal function

Author, year, countryStudy design, sample size (total); reduced versus normal renal functionPatient demographics, gender (reduced vs. normal renal function), age (reduced vs. normal renal function)Patients’ renal function, serum Cr concentrationaOpioid(s) administered: route, formulation, frequency, and doseSafety: opioid-related adverse events for reduced versus normal renal function cohortEfficacy: pain scores for reduced versus normal renal function cohortsOther: serum opioid concentration for reduced versus normal renal function cohorts
Observational studies (reduced vs. normal renal function) 
Studies reporting on safety and/or efficacy outcomes of opioid use 
 Choi et al. [23] (2019), South Korea Retrospective cohort study, N = 6,612; 79%, 5,230/6,612 versus 21%, 1,382/6,612 Patients who underwent major laparoscopic surgery, gender: 43.8% (2,897/6,612) female, age: 58.7±13.2 years eGFR = 96.9±25.8, serum Cr concentration = NR Morphine (total MME consumption from POD 0–3 = 516.6±303.3 mg (frequency and route NR) NR No statistically significant difference in postoperative NRS pain scores between those with normal and reduced function on PODs 0, 1, 2, or 3 (p > 0.05) NR 
Patients with preoperative eGFR <30 mL/min/1.73 m2 had 3.5% lower MME consumption on POD 0–3 than patients with preoperative eGFR ≥90 mL/min/1.73 m2 (coefficient −0.035, 95% CI: −0.064 to 0.005, p = 0.023) 
 Ashby et al. [15] (1997), Australia Retrospective cross-sectional study, N = 36; 19%, 7/36 versus 81%, 29/36 Hospice patients with advanced, incurable cancer, gender: 50% (18/36) female, age: 59±13 years CrCl = NR, serum Cr concentration >120 Morphine oral solution (47%), subcutaneous injection or continuous infusion (47%), or bolus injection (6%) Nausea, vomiting, and brain dysfunction: 100% versus 41% (p = 0.01) NR NR 
 Kurita et al. [30] (2012), Norway Retrospective cross-sectional analysis; subset of European Pharmacogenetic opioid study, N = 578; reduced versus normal renal function NR Cancer patients on scheduled opioid treatment, gender: 48% (277/578) female, age: 61.9±12.4 years Reduced renal function group CrCl <60, severe reduction in renal function CrCl <30, Normal renal function CrCl = NR, serum Cr concentration = NR Morphine (route, dose, and frequency NR) Greater incidence of loss of appetite in patients with mild (OR = 1.45, 95% CI: 0.93–2.27), moderate, or severe reduction in renal function (OR = 2.33, 95% CI, 1.31–4.16, p = 0.02) NR NR 
Greater incidence of constipation in patients with mild (OR = 2.16, 95% CI, 1.38–3.39), moderate, or severe reduction in renal function (OR = 1.69, 95% CI, 0.95–3.01, p = 0.003) 
Studies reporting on pharmacokinetic data related to morphine use only 
 Sear et al. [44] (1989), England Prospective observational study, N = 14;, 64%, 9/14 versus 36%, 5/14 Patients undergoing renal transplantation versus normal renal function subjects undergoing elective surgery, gender: 40% (6/15) female, age: range 16–55 years (median NR)  Morphine IV infusion 10 mg NR NR Higher peak concentrations of M-3-G (p = 0.001) and M-6-G (p = 0.01) in the renal transplant patients and decreased volume of distribution at steady state of morphine (241 L v. 141 L, p = 0.002) in patients with reduced renal function 
 D’Honneur et al. [24] (1994), France] Prospective observational study, N = 14; 43%, 6/14 versus 57%, 8/14 Patients with renal failure receiving haemodialysis or normal renal function, gender = NR, age: 70±2 versus 67±9 years CrCl = NR, reduced renal function group: serum Cr concentration: range 506–1,133, normal renal function group: serum Cr concentration: range 80–106 Morphine oral ER 30 mg single dose NR NR AUC of plasma morphine concentration from 0 h to 24 h: 110±11 versus 38±4 ng/mL/h (p < 0.01) 
 Oosten et al. [38] (2017), Netherlands Prospective observational study, N = 49; reduced versus normal renal function NR In patients with cancer, gender: 45% (22/49) female, age: 60 (range 38–80) years eGFR = 81 (range 33–90), serum Cr concentration = 72 (range 25–190) Morphine oral ER 40 mg twice daily with IR morphine 10 mg or morphine subcutaneous infusion 2 mg/h NR NR Renal function was significantly correlated with clearance of metabolites, which increased 0.602 L/h per every 10 mL/min/1.73 m2 increase of eGFR, reaching plateau for eGFR >90 mL/min/1.73 m2 
 Narabayashi et al. [36] (2018), Japan Prospective cohort study, N = 25; 36%, 9/25 versus 64%, 16/25 Hospital inpatients with cancer pain who switched from morphine to oxycodone,b, gender: 24% (6/25) female, age: 63±12 years CrCl = 37.2±14.2, serum Cr concentration = 114.9±61.9 Morphine oral ER, (frequency NR), daily MME = 44.4±33.8 mg NR NR Serum M-3-G concentration: 791±373 versus 384±332 ng/mL (p = 0.009), serum M-6-G concentration: 109±44 versus 60.0±51.2 ng/mL (p = 0.02) 
 Milne et al. [35] (1992), Australia Prospective observational study, N = 15; reduced versus normal renal function NR Intensive care unit patients, gender: 47% (7/15) female, age: 52 (range 17–78) years CrCl = range 2.5–170, serum Cr concentration = NR Morphine IV infusion, doses from 2 to 5 mg/h NR NR Linear relationships identified between renal clearances of morphine, M-3-G or M-6-G and CrCl (r ≥0.910, p < 0.001) 
 Sawe and Odar- Cederlof., [43] (1987), Sweden Observational study, N = 13; 54%, 7/13 versus 46%, 6/13 Patients with advanced renal failure or patients with normal renal function patients who had cancer, gender: 15% (2/13) female, age: 47 (range 30–69) versus range 57–77 years (median NR) CrCl = NR, serum Cr concentration for patients with reduced renal function = range 220–1,452 Morphine IV 4 mg bolus single dose NR NR Mean elimination half-life of morphine in patients with renal failure: 2.4 (range 1.5–4.0) hours 
No statistically significant differences for the pharmacokinetic data between uraemic patients and patients with normal renal function group (n = NR) 
 Ball et al. [16] (1985), England Cohort study, N = 20; 50%, 10/20 versus 50%, 10/20 Intensive care unit patients, gender: 30% (6/20) female, age: 62±14.6 years CrCl = NR, serum Cr concentration >140 Morphine IV infusion, median 4-hourly rate = 12 mg (range 0–35 mg/4 h) NR NR Dose-corrected plasma morphine concentration was linearly correlated to plasma creatinine (r = 0.79, p < 0.001) and CrCl (r = 0.45, p = 0.003) 
Morphine clearance was linearly related to CrCl (r = 0.82, p < 0.001) 
 Osborne et al. [39] (1993), England Retrospective cohort study, N = 36; 72%, 26/36 versus 28%, 10/36 Patients with kidney failure undergoing surgery, gender = NR, age: 39 (range 22–70) years Transplant group: CrCl between 0 and 5, serum Cr concentration = range 620–1,155, non-dialysis group: CrCl range 0–5, serum Cr concentration = range 540–838, normal volunteers: CrCl range 78–130, serum Cr concentration = NR Morphine IV 0.1 mg/kg bolus single dose NR NR Plasma morphine concentration at 5 min: 
  • Non-dialysis group: 531 nmol/L versus

  • Transplant group: 358 nmol/L (p < 0.001)

  • Mean plasma morphine AUC

  • Non-dialysis group: 398 nmol × h/L versus

  • Transplant group: 302 nmol × h/L (p < 0.001)

 
 Peterson et al. [41] (1990), Australia Retrospective observational study, N = 21; reduced versus normal renal function NR Terminally ill cancer patients receiving chronic morphine therapy, gender: 48% (10/21) female, age: 68.5±8.7 years CrCl = 60.9±29.4 (range 20.5–124.2), serum Cr concentration = NR Morphine oral (median daily dose 1.87 mg/kg) or subcutaneously (median daily dose 1.64 mg/kg) NR NR Ratio of glucuronide to morphine concentration significantly related to renal function for both M-3-G and M-6-G: 
  • Oral administration (r = 0.60 for M-3-G and M-6-G, p = 0.05)

  • Subcutaneous administration (r = 1.00 for M-3-G and r = 0.99 for M-6-G, p < 0.01)

 
 McQuay et al. [34] (1990), England Case series, N = 151; 37%, 56/151 versus 63%, 95/151 Cancer patients with chronic pain taking regular oral morphine, gender = NR, age: 64 (range 28–92) years CrCl = NR, serum Cr concentration = NR Morphine oral daily dose = 223 (range 10–2,540) mg NR NR Reduced renal function patients had on average double the serum concentrations of M-3-G and M-6-G compared with normal renal function patients (p < 0.01) 
Observational studies (patients with reduced renal function only) 
 Caspi et al. [21] (2019), Israel Retrospective cross-sectional study, N = 13,788 Patients hospitalised for new-onset or worsening of pre-existing heart failure, morphine group: gender: 58% (442/761) female, age: 78±11 years, no morphine group: gender: 50% (6,525/13,027) female, age: 75±12 years eGFR = 47±28, serum Cr concentration = NR Morphine, mean dose = 5±4 mg (route and frequency NR) Acute kidney injury more frequent in morphine-treated patients (aOR 1.81; 95% CI: 1.39–2.36, p < 0.0001) NR NR 
Author, year, countryStudy design, sample size (total); reduced versus normal renal functionPatient demographics, gender (reduced vs. normal renal function), age (reduced vs. normal renal function)Patients’ renal function, serum Cr concentrationaOpioid(s) administered: route, formulation, frequency, and doseSafety: opioid-related adverse events for reduced versus normal renal function cohortEfficacy: pain scores for reduced versus normal renal function cohortsOther: serum opioid concentration for reduced versus normal renal function cohorts
Observational studies (reduced vs. normal renal function) 
Studies reporting on safety and/or efficacy outcomes of opioid use 
 Choi et al. [23] (2019), South Korea Retrospective cohort study, N = 6,612; 79%, 5,230/6,612 versus 21%, 1,382/6,612 Patients who underwent major laparoscopic surgery, gender: 43.8% (2,897/6,612) female, age: 58.7±13.2 years eGFR = 96.9±25.8, serum Cr concentration = NR Morphine (total MME consumption from POD 0–3 = 516.6±303.3 mg (frequency and route NR) NR No statistically significant difference in postoperative NRS pain scores between those with normal and reduced function on PODs 0, 1, 2, or 3 (p > 0.05) NR 
Patients with preoperative eGFR <30 mL/min/1.73 m2 had 3.5% lower MME consumption on POD 0–3 than patients with preoperative eGFR ≥90 mL/min/1.73 m2 (coefficient −0.035, 95% CI: −0.064 to 0.005, p = 0.023) 
 Ashby et al. [15] (1997), Australia Retrospective cross-sectional study, N = 36; 19%, 7/36 versus 81%, 29/36 Hospice patients with advanced, incurable cancer, gender: 50% (18/36) female, age: 59±13 years CrCl = NR, serum Cr concentration >120 Morphine oral solution (47%), subcutaneous injection or continuous infusion (47%), or bolus injection (6%) Nausea, vomiting, and brain dysfunction: 100% versus 41% (p = 0.01) NR NR 
 Kurita et al. [30] (2012), Norway Retrospective cross-sectional analysis; subset of European Pharmacogenetic opioid study, N = 578; reduced versus normal renal function NR Cancer patients on scheduled opioid treatment, gender: 48% (277/578) female, age: 61.9±12.4 years Reduced renal function group CrCl <60, severe reduction in renal function CrCl <30, Normal renal function CrCl = NR, serum Cr concentration = NR Morphine (route, dose, and frequency NR) Greater incidence of loss of appetite in patients with mild (OR = 1.45, 95% CI: 0.93–2.27), moderate, or severe reduction in renal function (OR = 2.33, 95% CI, 1.31–4.16, p = 0.02) NR NR 
Greater incidence of constipation in patients with mild (OR = 2.16, 95% CI, 1.38–3.39), moderate, or severe reduction in renal function (OR = 1.69, 95% CI, 0.95–3.01, p = 0.003) 
Studies reporting on pharmacokinetic data related to morphine use only 
 Sear et al. [44] (1989), England Prospective observational study, N = 14;, 64%, 9/14 versus 36%, 5/14 Patients undergoing renal transplantation versus normal renal function subjects undergoing elective surgery, gender: 40% (6/15) female, age: range 16–55 years (median NR)  Morphine IV infusion 10 mg NR NR Higher peak concentrations of M-3-G (p = 0.001) and M-6-G (p = 0.01) in the renal transplant patients and decreased volume of distribution at steady state of morphine (241 L v. 141 L, p = 0.002) in patients with reduced renal function 
 D’Honneur et al. [24] (1994), France] Prospective observational study, N = 14; 43%, 6/14 versus 57%, 8/14 Patients with renal failure receiving haemodialysis or normal renal function, gender = NR, age: 70±2 versus 67±9 years CrCl = NR, reduced renal function group: serum Cr concentration: range 506–1,133, normal renal function group: serum Cr concentration: range 80–106 Morphine oral ER 30 mg single dose NR NR AUC of plasma morphine concentration from 0 h to 24 h: 110±11 versus 38±4 ng/mL/h (p < 0.01) 
 Oosten et al. [38] (2017), Netherlands Prospective observational study, N = 49; reduced versus normal renal function NR In patients with cancer, gender: 45% (22/49) female, age: 60 (range 38–80) years eGFR = 81 (range 33–90), serum Cr concentration = 72 (range 25–190) Morphine oral ER 40 mg twice daily with IR morphine 10 mg or morphine subcutaneous infusion 2 mg/h NR NR Renal function was significantly correlated with clearance of metabolites, which increased 0.602 L/h per every 10 mL/min/1.73 m2 increase of eGFR, reaching plateau for eGFR >90 mL/min/1.73 m2 
 Narabayashi et al. [36] (2018), Japan Prospective cohort study, N = 25; 36%, 9/25 versus 64%, 16/25 Hospital inpatients with cancer pain who switched from morphine to oxycodone,b, gender: 24% (6/25) female, age: 63±12 years CrCl = 37.2±14.2, serum Cr concentration = 114.9±61.9 Morphine oral ER, (frequency NR), daily MME = 44.4±33.8 mg NR NR Serum M-3-G concentration: 791±373 versus 384±332 ng/mL (p = 0.009), serum M-6-G concentration: 109±44 versus 60.0±51.2 ng/mL (p = 0.02) 
 Milne et al. [35] (1992), Australia Prospective observational study, N = 15; reduced versus normal renal function NR Intensive care unit patients, gender: 47% (7/15) female, age: 52 (range 17–78) years CrCl = range 2.5–170, serum Cr concentration = NR Morphine IV infusion, doses from 2 to 5 mg/h NR NR Linear relationships identified between renal clearances of morphine, M-3-G or M-6-G and CrCl (r ≥0.910, p < 0.001) 
 Sawe and Odar- Cederlof., [43] (1987), Sweden Observational study, N = 13; 54%, 7/13 versus 46%, 6/13 Patients with advanced renal failure or patients with normal renal function patients who had cancer, gender: 15% (2/13) female, age: 47 (range 30–69) versus range 57–77 years (median NR) CrCl = NR, serum Cr concentration for patients with reduced renal function = range 220–1,452 Morphine IV 4 mg bolus single dose NR NR Mean elimination half-life of morphine in patients with renal failure: 2.4 (range 1.5–4.0) hours 
No statistically significant differences for the pharmacokinetic data between uraemic patients and patients with normal renal function group (n = NR) 
 Ball et al. [16] (1985), England Cohort study, N = 20; 50%, 10/20 versus 50%, 10/20 Intensive care unit patients, gender: 30% (6/20) female, age: 62±14.6 years CrCl = NR, serum Cr concentration >140 Morphine IV infusion, median 4-hourly rate = 12 mg (range 0–35 mg/4 h) NR NR Dose-corrected plasma morphine concentration was linearly correlated to plasma creatinine (r = 0.79, p < 0.001) and CrCl (r = 0.45, p = 0.003) 
Morphine clearance was linearly related to CrCl (r = 0.82, p < 0.001) 
 Osborne et al. [39] (1993), England Retrospective cohort study, N = 36; 72%, 26/36 versus 28%, 10/36 Patients with kidney failure undergoing surgery, gender = NR, age: 39 (range 22–70) years Transplant group: CrCl between 0 and 5, serum Cr concentration = range 620–1,155, non-dialysis group: CrCl range 0–5, serum Cr concentration = range 540–838, normal volunteers: CrCl range 78–130, serum Cr concentration = NR Morphine IV 0.1 mg/kg bolus single dose NR NR Plasma morphine concentration at 5 min: 
  • Non-dialysis group: 531 nmol/L versus

  • Transplant group: 358 nmol/L (p < 0.001)

  • Mean plasma morphine AUC

  • Non-dialysis group: 398 nmol × h/L versus

  • Transplant group: 302 nmol × h/L (p < 0.001)

 
 Peterson et al. [41] (1990), Australia Retrospective observational study, N = 21; reduced versus normal renal function NR Terminally ill cancer patients receiving chronic morphine therapy, gender: 48% (10/21) female, age: 68.5±8.7 years CrCl = 60.9±29.4 (range 20.5–124.2), serum Cr concentration = NR Morphine oral (median daily dose 1.87 mg/kg) or subcutaneously (median daily dose 1.64 mg/kg) NR NR Ratio of glucuronide to morphine concentration significantly related to renal function for both M-3-G and M-6-G: 
  • Oral administration (r = 0.60 for M-3-G and M-6-G, p = 0.05)

  • Subcutaneous administration (r = 1.00 for M-3-G and r = 0.99 for M-6-G, p < 0.01)

 
 McQuay et al. [34] (1990), England Case series, N = 151; 37%, 56/151 versus 63%, 95/151 Cancer patients with chronic pain taking regular oral morphine, gender = NR, age: 64 (range 28–92) years CrCl = NR, serum Cr concentration = NR Morphine oral daily dose = 223 (range 10–2,540) mg NR NR Reduced renal function patients had on average double the serum concentrations of M-3-G and M-6-G compared with normal renal function patients (p < 0.01) 
Observational studies (patients with reduced renal function only) 
 Caspi et al. [21] (2019), Israel Retrospective cross-sectional study, N = 13,788 Patients hospitalised for new-onset or worsening of pre-existing heart failure, morphine group: gender: 58% (442/761) female, age: 78±11 years, no morphine group: gender: 50% (6,525/13,027) female, age: 75±12 years eGFR = 47±28, serum Cr concentration = NR Morphine, mean dose = 5±4 mg (route and frequency NR) Acute kidney injury more frequent in morphine-treated patients (aOR 1.81; 95% CI: 1.39–2.36, p < 0.0001) NR NR 

Values are expressed as number (%), mean ± standard deviation, or median (range).

N, sample size; NR, not reported; CrCl, creatinine clearance; Cr, creatinine; GFR, glomerular filtration rate; eGFR, estimated glomerular filtration rate; OR, odds ratio; aOR, adjusted odds ratio; 95% CI, 95% confidence interval; AUC, area under the curve; IR, immediate release; ER, extended release; M-3-G, morphine-3-glucuronide; M-6-G, morphine-6-glucuronide; MME, morphine milligramme equivalents; IV, intravenous; POD, Post-operative day; NRS, numeric rating scale.

aCrCl reported as mL/min, estimated glomerular filtration rate reported as mL/min/1.73 m2, and serum creatinine concentration reported as µmol/L.

bNo outcomes reported for patients on oxycodone with reduced versus normal renal function.

Table 2.

Summary of included studies reporting on included fentanyl use among patients with reduced renal function

Author, year, countryStudy design, sample size (total); reduced versus normal renal functionPatient demographics, gender (reduced vs. normal renal function), age (reduced vs. normal renal function)Patients’ renal function, serum Cr concentrationaOpioid(s) administered: route, formulation, frequency, and doseSafety: opioid-related adverse events for reduced versus normal renal function cohortEfficacy: pain scores for reduced versus normal renal function cohortsOther: serum opioid concentration for reduced versus normal renal function cohorts
Observational studies (reduced vs. normal renal function) 
 Barratt et al. [18] (2014), Australia Retrospective, cross-sectional, N = 676; reduced versus normal renal function NR Cancer pain patients, gender: 51% (342/676) female, age: 64±12.5 years CrCl = 86±46 (range 13–308), serum Cr concentration = NR Fentanyl transdermal, delivery rate = 50±55.1 μg/h NR NR Kidney disease associated with increased metabolic ratio of serum norfentanyl:fentanyl and serum norfentanyl concentrations (p = 0.006) 
 Oh et al. [37] (2018), Japan Retrospective cross-sectional study, N = 611; reduced versus normal renal function NR Cancer pain patients, gender: 34% (205/611) female, age: 63.6 (range 18–89) years eGFR <60 in 15% (80/523) of patients (eGFR available for 523 patients), serum Cr concentration = NR Fentanyl sublingual tablets, total mean dose = 23,330±42,111 μg NR NR Median duration of fentanyl use significantly shorter in patients with CKD: 42 (95% CI 8.2–6.3) versus 66 (95% CI, 40.0–92.0) days (p < 0.001), No significant correlation between total prescribed fentanyl dose and renal function (p = NR) 
Observational studies (patients with reduced renal function only) 
 Mazzocato et al. [33] (2006), Switzerland Retrospective cross-sectional study, N = 53 Palliative care patients with renal failure, gender = NR, age: 79 (range 46–100) years eGFR = 25 (range 4–59), serum Cr concentration = NR Fentanyl subcutaneously: 49% (26/53) presented with suspected opioid-related neurotoxicity Pain control: NR 
  • Median initial daily dose = 360 (range 60–3,600) mg

  • Median final daily dose = 720 (range 144–6,720) mg

  • Median treatment duration = 7 (range 1–68) days

 
  • Complete: 59% (31/53)

  • Partial: 26% (14/53)

  • Not achieved: 2% (1/53)

  • Not evaluated: 13% (7/53)

 
Author, year, countryStudy design, sample size (total); reduced versus normal renal functionPatient demographics, gender (reduced vs. normal renal function), age (reduced vs. normal renal function)Patients’ renal function, serum Cr concentrationaOpioid(s) administered: route, formulation, frequency, and doseSafety: opioid-related adverse events for reduced versus normal renal function cohortEfficacy: pain scores for reduced versus normal renal function cohortsOther: serum opioid concentration for reduced versus normal renal function cohorts
Observational studies (reduced vs. normal renal function) 
 Barratt et al. [18] (2014), Australia Retrospective, cross-sectional, N = 676; reduced versus normal renal function NR Cancer pain patients, gender: 51% (342/676) female, age: 64±12.5 years CrCl = 86±46 (range 13–308), serum Cr concentration = NR Fentanyl transdermal, delivery rate = 50±55.1 μg/h NR NR Kidney disease associated with increased metabolic ratio of serum norfentanyl:fentanyl and serum norfentanyl concentrations (p = 0.006) 
 Oh et al. [37] (2018), Japan Retrospective cross-sectional study, N = 611; reduced versus normal renal function NR Cancer pain patients, gender: 34% (205/611) female, age: 63.6 (range 18–89) years eGFR <60 in 15% (80/523) of patients (eGFR available for 523 patients), serum Cr concentration = NR Fentanyl sublingual tablets, total mean dose = 23,330±42,111 μg NR NR Median duration of fentanyl use significantly shorter in patients with CKD: 42 (95% CI 8.2–6.3) versus 66 (95% CI, 40.0–92.0) days (p < 0.001), No significant correlation between total prescribed fentanyl dose and renal function (p = NR) 
Observational studies (patients with reduced renal function only) 
 Mazzocato et al. [33] (2006), Switzerland Retrospective cross-sectional study, N = 53 Palliative care patients with renal failure, gender = NR, age: 79 (range 46–100) years eGFR = 25 (range 4–59), serum Cr concentration = NR Fentanyl subcutaneously: 49% (26/53) presented with suspected opioid-related neurotoxicity Pain control: NR 
  • Median initial daily dose = 360 (range 60–3,600) mg

  • Median final daily dose = 720 (range 144–6,720) mg

  • Median treatment duration = 7 (range 1–68) days

 
  • Complete: 59% (31/53)

  • Partial: 26% (14/53)

  • Not achieved: 2% (1/53)

  • Not evaluated: 13% (7/53)

 

Values are expressed as number (%), mean ± standard deviation, or median (range).

N, sample size; NR, not reported; CrCl, creatinine clearance; Cr, creatinine; GFR, glomerular filtration rate; eGFR, estimated glomerular filtration rate; CKD, chronic kidney disease; 95% CI, 95% confidence interval.

aCrCl reported as mL/min, estimated glomerular filtration rate reported as mL/min/1.73 m2, and serum creatinine concentration reported as µmol/L.

Table 3.

Summary of included studies reporting on included hydromorphone use among patients with reduced renal function

Author, year, countryStudy design, sample size (total); reduced versus normal renal functionPatient demographics, gender (reduced vs. normal renal function), age (reduced vs. normal renal function)Patients’ renal function, serum Cr concentrationaOpioid(s) administered: route, formulation, frequency, and doseSafety: opioid-related adverse events for reduced versus normal renal function cohortEfficacy: pain scores for reduced versus normal renal function cohortsOther: serum opioid concentration for reduced versus normal renal function cohorts
Observational studies (reduced vs. normal renal function) 
 Lee et al. [32] (2001), Scotland Retrospective cross-sectional study, N = 55; 53%, 29/55 versus 47%, 26/55 Palliative care patients, gender: 31% (9/29) versus 50% (13/26) female, age: 63.7 (range 37–89) years CrCl = NR reduced renal function: serum Cr concentration = 127.5 (range 90–756), normal renal function: serum Cr concentration = 81.5 (range 53–96) Hydromorphon oral, MME dose: Overall adverse event profile improved for 80% (44/55) of patients upon switch to hydromorphone from other opioids including morphine, coproxamol, fentanyl, and diamorphine (p = NR) Pain improvement upon switch to hydromorphone: 55.2% versus 73.1% (p = NR) NR 
  • Reduced renal function group: 60 (range 20–600) mg/24 h

  • Normal renal function group: 120 (range 20–600) mg/24 h

  • Transdermal fentanyl (n = 2; doses 75 and 150 μg/h) given equivalent MME = 270 and 540 mg/24 h, respectively. Other dosage conversions NR

 
Observational studies (patients with reduced renal function only) 
 Paramanandam et al. [40] (2011), USA Retrospective cross-sectional study, N = 54 Palliative care inpatients with renal dysfunction, gender: 52% (28/54) female, age: 68.5±72 years eGFR = 41.5±44, serum Cr concentration = 150.3±115.0 Hydromorphone continuous infusion, dose = 6.5±2 mg/h Tremor: 20% (11/54), myoclonus: 20% (11/54), agitation: 48% (26/54), cognitive dysfunction: 39% (21/54), with increasing hydromorphone dose or duration, strong and graded increase in agitation (p < 0.0001) and cognitive dysfunction (p < 0.002) NR NR 
Author, year, countryStudy design, sample size (total); reduced versus normal renal functionPatient demographics, gender (reduced vs. normal renal function), age (reduced vs. normal renal function)Patients’ renal function, serum Cr concentrationaOpioid(s) administered: route, formulation, frequency, and doseSafety: opioid-related adverse events for reduced versus normal renal function cohortEfficacy: pain scores for reduced versus normal renal function cohortsOther: serum opioid concentration for reduced versus normal renal function cohorts
Observational studies (reduced vs. normal renal function) 
 Lee et al. [32] (2001), Scotland Retrospective cross-sectional study, N = 55; 53%, 29/55 versus 47%, 26/55 Palliative care patients, gender: 31% (9/29) versus 50% (13/26) female, age: 63.7 (range 37–89) years CrCl = NR reduced renal function: serum Cr concentration = 127.5 (range 90–756), normal renal function: serum Cr concentration = 81.5 (range 53–96) Hydromorphon oral, MME dose: Overall adverse event profile improved for 80% (44/55) of patients upon switch to hydromorphone from other opioids including morphine, coproxamol, fentanyl, and diamorphine (p = NR) Pain improvement upon switch to hydromorphone: 55.2% versus 73.1% (p = NR) NR 
  • Reduced renal function group: 60 (range 20–600) mg/24 h

  • Normal renal function group: 120 (range 20–600) mg/24 h

  • Transdermal fentanyl (n = 2; doses 75 and 150 μg/h) given equivalent MME = 270 and 540 mg/24 h, respectively. Other dosage conversions NR

 
Observational studies (patients with reduced renal function only) 
 Paramanandam et al. [40] (2011), USA Retrospective cross-sectional study, N = 54 Palliative care inpatients with renal dysfunction, gender: 52% (28/54) female, age: 68.5±72 years eGFR = 41.5±44, serum Cr concentration = 150.3±115.0 Hydromorphone continuous infusion, dose = 6.5±2 mg/h Tremor: 20% (11/54), myoclonus: 20% (11/54), agitation: 48% (26/54), cognitive dysfunction: 39% (21/54), with increasing hydromorphone dose or duration, strong and graded increase in agitation (p < 0.0001) and cognitive dysfunction (p < 0.002) NR NR 

Values are expressed as number (%), mean ± standard deviation, or median (range).

N, sample size; NR, not reported; CrCl, creatinine clearance; Cr, creatinine; GFR, glomerular filtration rate; eGFR, estimated glomerular filtration rate; MME, morphine milligramme equivalents.

aCrCl reported as mL/min, estimated glomerular filtration rate reported as mL/min/1.73 m2, and serum creatinine concentration reported as µmol/L.

Table 4.

Summary of included studies reporting on included other opioid use among patients with reduced renal function

Author, year, countryStudy design, sample size (total); reduced versus normal renal functionPatient demographics, gender (reduced vs. normal renal function), age (reduced vs. normal renal function)Patients’ renal function, serum Cr concentrationaOpioid(s) administered: route, formulation, frequency, and doseSafety: opioid-related adverse events for reduced versus normal renal function cohortEfficacy: pain scores for reduced versus normal renal function cohortsOther: serum opioid concentration for reduced versus normal renal function cohorts
Observational studies (reduced vs. normal renal function) 
 Bochner et al. [19] (1990), Australia Observational study, N = 15; reduced versus normal renal function NR Elderly patients: gender = NR, age: 80±11 years, young, healthy patients: gender = NR, age: 27±5 years Elderly patients: CrCl = 10–120, serum Cr concentration = NR, young, healthy patients: CrCl = 90–132, serum Cr concentration = NR Codeine phosphate oral, 30 mg 8-hourly for ≥7 doses NR NR Positive correlation between renal clearance of codeine (r2 = 0.62, p < 0.01), C-6-G (r2 = 0.56, p < 0.01), and CrCl 
Negative correlation between plasma codeine concentration (r2 = 0.89, p < 0.01), C-6-G (r2 = 0.70, p < 0.01), and CrCl 
 Barnes et al. [17] (1985), England Cohort study, N = 18; 50%, 9/18 versus 50%, 9/18 Patients receiving maintenance haemodialysis or normal subjects, gender: 44% (4/9) versus 22% (2/9) female, age: 34.2±4.2 versus 40.8±5.2 years CrCl = NR, serum Cr concentration patients with renal failure = 1,114.7±101.2, serum Cr concentration normal subjects = 82.6±5.9 Dihydrocodeine tartrate oral 60 mg single dose NR NR Mean plasma dihydrocodeine concentrations were significantly higher at 4 and 6 h for patients with renal failure (p < 0.05) 
AUC mean plasma dihydrocodeine at 0–6 h was greater for patients with renal failure (p < 0.05) 
 Darwish et al. [25] (2016), USA Open label, single-dose, parallel group study, N = 55; 75%, 41/55 versus 25%, 14/55 Adults, gender: 53% (29/55) female, age range: 42–82 years (median NR) Normal renal function (CrCl >80), reduced renal function: mild (CrCl >50–80), moderate (CrCl = 30–50), severe (CrCl <30), ESRD (CrCl = NR), serum Cr concentration = NR. Hydrocodone oral ER 45 mg single dose General opioid-related adverse events in groups with reduced renal function: mild (38%), moderate (44%) and severe (33%), ESRD (56%) versus normal renal function (57%, p = NR) NR Hydrocodone Cmax
Reduced renal function: 
  • Mild: 33.4±9.8 ng/mL

  • Moderate: 42.4±11.6 ng/mL

  • Severe: 36.5±12.4 ng/mL

  • ESRD: 31.6±6.8 ng/mL versus Normal renal function: 28.6±5.7 ng/mL (p = NR)

 
 Gould et al. [26] (2016), USA Prospective open-label parallel-group design, N = 9–10/group (total sample size NR); reduced versus normal renal function NR Patients with mild, moderate, or severe hepatic disease, gender = NR, age = NR NR Hydrocodone oral ER 20 mg single dose NR NR Hydrocodone AUC: mild (391±122 ng × h/mL), moderate (547±184 ng × h/mL), severe (487±123 ng × h/mL) reduction in renal function versus normal renal function (343±105 ng × h/mL) 
Hydrocodone Cmax: mild (21.3±5.1 ng/mL), moderate (27.5±7.5 ng/mL), severe (25.8±6.0 ng/mL) reduction in renal function versus normal renal function (18.5±4.4 ng/mL) 
 Hand et al. [27] (1990), England Prospective observational study, single-dose study: N = 15; 60% 9/15 versus 40%, 6/15, multiple-dosing study: N = 20; 40%, 8/20 versus 60%, 12/20 Single dose study: patients undergoing lower abdominal or body surface surgery, gender: 44% (4/9) versus 83% (5/6) female, age: 34.7±13.8 versus 49±16.6 years, multiple dosing study: intensive care unit patients, gender: 25% (2/8) versus 17% (2/12) female, age: 60.3 (range 37–80) versus 60.7 (range 22–80) years Single dose study: renal disease patients, CrCl <5, serum Cr concentration = 420–1,031, normal renal function patients, CrCl = NR, serum Cr concentration = 85–103, multiple dosing study: renal disease patients, CrCl <9, serum Cr concentration >250, normal renal function patients, CrCl = 53–140, serum Cr concentration = 60–124 Single dose study: buprenorphine IV 0.3 mg single dose, multiple-dosing study: loading dose of buprenorphine 0.6 mg IV, then continuous infusion 30 μg/mL NR NR Single dose study: buprenorphine elimination half-life range: 101–560 versus 148–694 min (p = NR) 
Buprenorphine mean residence time: 283.5 versus 510.5 min (p < 0.05) 
Multiple dose study: median four-fold increase of norbuprenorphine (p < 0.001) and 15-fold increase for buprenorphine-3-glucuronide in patients with reduced renal function (p < 0.001) 
 Hawi et al. [28] (2015), UK Open-label, single site, cohort study, N = 24; 63%, 15/24 versus 37% 9/24 Haemodialysis patients at stage 5 ESRD with pruritis and matched healthy subjects, gender: 5/24 (20.8%) female, age: 47.9±8.6 years NR Nalbuphine hydrochloride oral, ER 30 mg daily, increasing to 240 mg twice daily over 15 days NR NR Nalbuphine mean Cmax: 29.41 versus 17.79 ng/mL (90% CI: for mean ratio 138%–197%) 
Nalbuphine mean AUC: 273.38 versus 149.23 ng × h/mL (90% CI: for mean ratio 153%–220%) 
 Shyu et al. [45] (1996), USA Open-label, parallel group study, N = 18; 67%, 12/18 versus 33%, 6/18 Volunteer females, gender: 100% (18/18) female, age: 49±7 years Normal renal function, CrCl ≥70, moderately reduced renal function CrCl = 30–60, severely reduced renal function CrCl <30, serum Cr concentration = NR Butorphanol transnasal 1 mg single dose Total adverse events: 52% versus 48% (p = NR) NR Butorphanol elimination half-life: 10.48 h in patients with severely reduced renal function versus 5.75 h in patients with normal renal function 
No increase in the frequency, duration or severity of side effects with worse renal function (p = NR)  correlated with renal clearance of butorphanol (r = 0.563, p = 0.02) 
 Riley et al. [42] (2004), UK Retrospective cohort study, N = 177; reduced versus normal renal function NR Patients with progressive malignant disease, gender = NR, age = NR CrCl = NR, patients who switched from morphine to alternative opioid: serum Cr concentration = 79.5 (range 37–816), patients who remained on morphine: serum Cr concentration = 81 (range 49–246) Range of opioids; morphine oral or “alternative opioids” (opioid, dose, frequency NR) Poor renal function associated with a higher risk of morphine intolerance requiring switching to alternative opioid (p = NR) NR NR 
 Kurita et al. [31] (2015), Norway Retrospective cross-sectional analysis; subset of European Pharmacogenetic Opioid study, N = 1,147; 51%, 587/1,147 versus 49%, 560/1,147 Cancer patients, gender: 49% (559/1,147) female, age = NR Reduced renal function:
  • Mild: eGFR = 60–89

  • Moderate: 30–59

  • Severe: 15–29

  • Normal renal function eGFR ≥90

  • Serum Cr concentration = NR

 
Range of opioids; morphine in 50.7% (581/1,147) of patients, oxycodone in 26.0% (298/1,147) of patients, fentanyl in 23.4% (268/1,147) of patients, (route, dose, and frequency NR) Higher odds of constipation in patients with mild (OR = 1.80, 95% CI: 1.18–2.75), moderate, and severe reduction (OR = 1.91, 95% CI: 1.08–3.37) in renal function compared with normal renal function group NR NR 
Greater incidence of loss of appetite in patients with moderate or severe reduction in renal function (p = 0.04) 
Patients with higher M-3-G serum concentrations (≥1,262.20 nmol/L) were more likely to have severe cognitive dysfunction (OR = 1.63, 95% CI: 1.03–2.56, p = 0.04) 
 Brant et al. [20] (2018), USA Retrospective case-controlled study, N = 225; 20%, 42/225 versus 80%, 183/225 Hospitalised patients who experienced over-sedation due to opioid use, gender: 60% (135/225) female, Age: 61±17.9 years GFR <60, serum Cr concentration >124 Range of opioids; oxycodone, morphine, hydromorphone, hydrocodone, fentanyl, meperidine Comorbid renal disease was a significant predictor of oversedation (aOR 4.22 (95% CI: 1.66–10.70) NR NR 
Range of routes: oral, IV, patient-controlled analgesia (dose NR) 
Observational studies (patients with reduced renal function only) 
 Ishida et al. [29] (2018), USA Retrospective cohort study, N = 140,899 
  • Data from the US Renal Data System on patients receiving chronic maintenance haemodialysis, gender: 49% female, age:

 
NR Range of opioids; lower opioid dose group: daily total MME ≤60, higher opioid dose group: daily total MME >60 Rates of adverse events highest in higher opioid dose group (29 per 100 persons-years) and lower opioid dose group (20 per 100 persons-years) NR NR 
Opioid use associated with higher risk of altered mental status: 
  • No opioid group 63±15 years

  • Lower opioid dose group 61±15 years

  • Higher opioid dose group 57±15 years

 
  • Lower opioid dose group: aHR = 1.28, 95% CI: 1.23–1.34 (p < 0.001)

  • Lower opioid

  • Higher opioid group: aHR = 1.67, 95% CI: 1.56–1.78 (p < 0.001)

  • Opioid use associated with higher risk of falls: dose group: aHR = 1.28, 95% CI: 1.21–1.36 (p < 0.001)

  • Higher opioid group: aHR = 1.45, 95% CI: 1.31–1.61 (p < 0.001)

  • Opioid use associated with higher risk of fracture:

  • Lower opioid dose group: aHR = 1.44, 95% CI: 1.33–1.56 (p < 0.001)

  • Higher opioid group: aHR = 1.65, 95% CI: 1.44–1.89 (p < 0.001)

 
 Chan et al. [22] (2018), Hong Kong Retrospective cross-sectional, N = 253 Patients with advanced chronic kidney disease opting for renal palliative care, patients with pain symptoms: gender: 47% (50/107) female, age: 78.7±10.5 years, patients without pain symptoms: gender: 51% (75/146) female, age: 80.3±7.9 years NR Range of opioids; for patients with significant pain: 3% (2/62) patients required strong opioids and 29% (18/62) required regular non-opioid/weak opioid, doses, and frequency NR Incidence of adverse events: 42% (107/253) NRS pain intensity: NR 
  • Mild (NRS 0–3): 42.1% (45/107)

  • Moderate (NRS 4–6): 47.7% (51/107)

  • Severe (7–10): 10.2% (11/107) CrCl (1–5 mL/min or 0–5 mL/min) was not a statistically significant pain response predictor (aOR 3.033, 95% CI: 0.668–7.712)

 
 Twomey et al. [46] (2006), UK Retrospective case-note review, N = 40 Cancer patients with reduced renal function, gender: 42.5% (17/40) female, age: 72 (range 37–89) years CrCl = NR, serum Cr concentration >150 Range of opioids; 85% (34/400) prescribed opioids. Of these, 53% (18/34) received codeine, morphine sulphate or diamorphine only, 26% (9/34) received oxycodone only, 21% (7/34) received combination of opioids 33% (13/40) of patients developed opioid toxicity NR NR 
Author, year, countryStudy design, sample size (total); reduced versus normal renal functionPatient demographics, gender (reduced vs. normal renal function), age (reduced vs. normal renal function)Patients’ renal function, serum Cr concentrationaOpioid(s) administered: route, formulation, frequency, and doseSafety: opioid-related adverse events for reduced versus normal renal function cohortEfficacy: pain scores for reduced versus normal renal function cohortsOther: serum opioid concentration for reduced versus normal renal function cohorts
Observational studies (reduced vs. normal renal function) 
 Bochner et al. [19] (1990), Australia Observational study, N = 15; reduced versus normal renal function NR Elderly patients: gender = NR, age: 80±11 years, young, healthy patients: gender = NR, age: 27±5 years Elderly patients: CrCl = 10–120, serum Cr concentration = NR, young, healthy patients: CrCl = 90–132, serum Cr concentration = NR Codeine phosphate oral, 30 mg 8-hourly for ≥7 doses NR NR Positive correlation between renal clearance of codeine (r2 = 0.62, p < 0.01), C-6-G (r2 = 0.56, p < 0.01), and CrCl 
Negative correlation between plasma codeine concentration (r2 = 0.89, p < 0.01), C-6-G (r2 = 0.70, p < 0.01), and CrCl 
 Barnes et al. [17] (1985), England Cohort study, N = 18; 50%, 9/18 versus 50%, 9/18 Patients receiving maintenance haemodialysis or normal subjects, gender: 44% (4/9) versus 22% (2/9) female, age: 34.2±4.2 versus 40.8±5.2 years CrCl = NR, serum Cr concentration patients with renal failure = 1,114.7±101.2, serum Cr concentration normal subjects = 82.6±5.9 Dihydrocodeine tartrate oral 60 mg single dose NR NR Mean plasma dihydrocodeine concentrations were significantly higher at 4 and 6 h for patients with renal failure (p < 0.05) 
AUC mean plasma dihydrocodeine at 0–6 h was greater for patients with renal failure (p < 0.05) 
 Darwish et al. [25] (2016), USA Open label, single-dose, parallel group study, N = 55; 75%, 41/55 versus 25%, 14/55 Adults, gender: 53% (29/55) female, age range: 42–82 years (median NR) Normal renal function (CrCl >80), reduced renal function: mild (CrCl >50–80), moderate (CrCl = 30–50), severe (CrCl <30), ESRD (CrCl = NR), serum Cr concentration = NR. Hydrocodone oral ER 45 mg single dose General opioid-related adverse events in groups with reduced renal function: mild (38%), moderate (44%) and severe (33%), ESRD (56%) versus normal renal function (57%, p = NR) NR Hydrocodone Cmax
Reduced renal function: 
  • Mild: 33.4±9.8 ng/mL

  • Moderate: 42.4±11.6 ng/mL

  • Severe: 36.5±12.4 ng/mL

  • ESRD: 31.6±6.8 ng/mL versus Normal renal function: 28.6±5.7 ng/mL (p = NR)

 
 Gould et al. [26] (2016), USA Prospective open-label parallel-group design, N = 9–10/group (total sample size NR); reduced versus normal renal function NR Patients with mild, moderate, or severe hepatic disease, gender = NR, age = NR NR Hydrocodone oral ER 20 mg single dose NR NR Hydrocodone AUC: mild (391±122 ng × h/mL), moderate (547±184 ng × h/mL), severe (487±123 ng × h/mL) reduction in renal function versus normal renal function (343±105 ng × h/mL) 
Hydrocodone Cmax: mild (21.3±5.1 ng/mL), moderate (27.5±7.5 ng/mL), severe (25.8±6.0 ng/mL) reduction in renal function versus normal renal function (18.5±4.4 ng/mL) 
 Hand et al. [27] (1990), England Prospective observational study, single-dose study: N = 15; 60% 9/15 versus 40%, 6/15, multiple-dosing study: N = 20; 40%, 8/20 versus 60%, 12/20 Single dose study: patients undergoing lower abdominal or body surface surgery, gender: 44% (4/9) versus 83% (5/6) female, age: 34.7±13.8 versus 49±16.6 years, multiple dosing study: intensive care unit patients, gender: 25% (2/8) versus 17% (2/12) female, age: 60.3 (range 37–80) versus 60.7 (range 22–80) years Single dose study: renal disease patients, CrCl <5, serum Cr concentration = 420–1,031, normal renal function patients, CrCl = NR, serum Cr concentration = 85–103, multiple dosing study: renal disease patients, CrCl <9, serum Cr concentration >250, normal renal function patients, CrCl = 53–140, serum Cr concentration = 60–124 Single dose study: buprenorphine IV 0.3 mg single dose, multiple-dosing study: loading dose of buprenorphine 0.6 mg IV, then continuous infusion 30 μg/mL NR NR Single dose study: buprenorphine elimination half-life range: 101–560 versus 148–694 min (p = NR) 
Buprenorphine mean residence time: 283.5 versus 510.5 min (p < 0.05) 
Multiple dose study: median four-fold increase of norbuprenorphine (p < 0.001) and 15-fold increase for buprenorphine-3-glucuronide in patients with reduced renal function (p < 0.001) 
 Hawi et al. [28] (2015), UK Open-label, single site, cohort study, N = 24; 63%, 15/24 versus 37% 9/24 Haemodialysis patients at stage 5 ESRD with pruritis and matched healthy subjects, gender: 5/24 (20.8%) female, age: 47.9±8.6 years NR Nalbuphine hydrochloride oral, ER 30 mg daily, increasing to 240 mg twice daily over 15 days NR NR Nalbuphine mean Cmax: 29.41 versus 17.79 ng/mL (90% CI: for mean ratio 138%–197%) 
Nalbuphine mean AUC: 273.38 versus 149.23 ng × h/mL (90% CI: for mean ratio 153%–220%) 
 Shyu et al. [45] (1996), USA Open-label, parallel group study, N = 18; 67%, 12/18 versus 33%, 6/18 Volunteer females, gender: 100% (18/18) female, age: 49±7 years Normal renal function, CrCl ≥70, moderately reduced renal function CrCl = 30–60, severely reduced renal function CrCl <30, serum Cr concentration = NR Butorphanol transnasal 1 mg single dose Total adverse events: 52% versus 48% (p = NR) NR Butorphanol elimination half-life: 10.48 h in patients with severely reduced renal function versus 5.75 h in patients with normal renal function 
No increase in the frequency, duration or severity of side effects with worse renal function (p = NR)  correlated with renal clearance of butorphanol (r = 0.563, p = 0.02) 
 Riley et al. [42] (2004), UK Retrospective cohort study, N = 177; reduced versus normal renal function NR Patients with progressive malignant disease, gender = NR, age = NR CrCl = NR, patients who switched from morphine to alternative opioid: serum Cr concentration = 79.5 (range 37–816), patients who remained on morphine: serum Cr concentration = 81 (range 49–246) Range of opioids; morphine oral or “alternative opioids” (opioid, dose, frequency NR) Poor renal function associated with a higher risk of morphine intolerance requiring switching to alternative opioid (p = NR) NR NR 
 Kurita et al. [31] (2015), Norway Retrospective cross-sectional analysis; subset of European Pharmacogenetic Opioid study, N = 1,147; 51%, 587/1,147 versus 49%, 560/1,147 Cancer patients, gender: 49% (559/1,147) female, age = NR Reduced renal function:
  • Mild: eGFR = 60–89

  • Moderate: 30–59

  • Severe: 15–29

  • Normal renal function eGFR ≥90

  • Serum Cr concentration = NR

 
Range of opioids; morphine in 50.7% (581/1,147) of patients, oxycodone in 26.0% (298/1,147) of patients, fentanyl in 23.4% (268/1,147) of patients, (route, dose, and frequency NR) Higher odds of constipation in patients with mild (OR = 1.80, 95% CI: 1.18–2.75), moderate, and severe reduction (OR = 1.91, 95% CI: 1.08–3.37) in renal function compared with normal renal function group NR NR 
Greater incidence of loss of appetite in patients with moderate or severe reduction in renal function (p = 0.04) 
Patients with higher M-3-G serum concentrations (≥1,262.20 nmol/L) were more likely to have severe cognitive dysfunction (OR = 1.63, 95% CI: 1.03–2.56, p = 0.04) 
 Brant et al. [20] (2018), USA Retrospective case-controlled study, N = 225; 20%, 42/225 versus 80%, 183/225 Hospitalised patients who experienced over-sedation due to opioid use, gender: 60% (135/225) female, Age: 61±17.9 years GFR <60, serum Cr concentration >124 Range of opioids; oxycodone, morphine, hydromorphone, hydrocodone, fentanyl, meperidine Comorbid renal disease was a significant predictor of oversedation (aOR 4.22 (95% CI: 1.66–10.70) NR NR 
Range of routes: oral, IV, patient-controlled analgesia (dose NR) 
Observational studies (patients with reduced renal function only) 
 Ishida et al. [29] (2018), USA Retrospective cohort study, N = 140,899 
  • Data from the US Renal Data System on patients receiving chronic maintenance haemodialysis, gender: 49% female, age:

 
NR Range of opioids; lower opioid dose group: daily total MME ≤60, higher opioid dose group: daily total MME >60 Rates of adverse events highest in higher opioid dose group (29 per 100 persons-years) and lower opioid dose group (20 per 100 persons-years) NR NR 
Opioid use associated with higher risk of altered mental status: 
  • No opioid group 63±15 years

  • Lower opioid dose group 61±15 years

  • Higher opioid dose group 57±15 years

 
  • Lower opioid dose group: aHR = 1.28, 95% CI: 1.23–1.34 (p < 0.001)

  • Lower opioid

  • Higher opioid group: aHR = 1.67, 95% CI: 1.56–1.78 (p < 0.001)

  • Opioid use associated with higher risk of falls: dose group: aHR = 1.28, 95% CI: 1.21–1.36 (p < 0.001)

  • Higher opioid group: aHR = 1.45, 95% CI: 1.31–1.61 (p < 0.001)

  • Opioid use associated with higher risk of fracture:

  • Lower opioid dose group: aHR = 1.44, 95% CI: 1.33–1.56 (p < 0.001)

  • Higher opioid group: aHR = 1.65, 95% CI: 1.44–1.89 (p < 0.001)

 
 Chan et al. [22] (2018), Hong Kong Retrospective cross-sectional, N = 253 Patients with advanced chronic kidney disease opting for renal palliative care, patients with pain symptoms: gender: 47% (50/107) female, age: 78.7±10.5 years, patients without pain symptoms: gender: 51% (75/146) female, age: 80.3±7.9 years NR Range of opioids; for patients with significant pain: 3% (2/62) patients required strong opioids and 29% (18/62) required regular non-opioid/weak opioid, doses, and frequency NR Incidence of adverse events: 42% (107/253) NRS pain intensity: NR 
  • Mild (NRS 0–3): 42.1% (45/107)

  • Moderate (NRS 4–6): 47.7% (51/107)

  • Severe (7–10): 10.2% (11/107) CrCl (1–5 mL/min or 0–5 mL/min) was not a statistically significant pain response predictor (aOR 3.033, 95% CI: 0.668–7.712)

 
 Twomey et al. [46] (2006), UK Retrospective case-note review, N = 40 Cancer patients with reduced renal function, gender: 42.5% (17/40) female, age: 72 (range 37–89) years CrCl = NR, serum Cr concentration >150 Range of opioids; 85% (34/400) prescribed opioids. Of these, 53% (18/34) received codeine, morphine sulphate or diamorphine only, 26% (9/34) received oxycodone only, 21% (7/34) received combination of opioids 33% (13/40) of patients developed opioid toxicity NR NR 

Values are expressed as number (%), mean ± standard deviation, or median (range).

N, sample size; NR, not reported; CrCl, creatinine clearance; Cr, creatinine; GFR, glomerular filtration rate; eGFR, estimated glomerular filtration rate; OR, odds ratio; aOR, adjusted odds ratio; aHR, adjusted hazard ratio; 95% CI, 95% confidence interval; AUC, area under the curve; Cmax, maximum serum concentration; ER, extended release; C-6-G, codeine-6-glucuronide; M-3-G, morphine-3-glucuronide; ESRD, end-stage renal disease; MME, morphine milligramme equivalents; IV, intravenous; NRS, numeric rating scale.

aCrCl reported as mL/min, eGFR reported as mL/min/1.73 m2, and serum creatinine concentration reported as µmol/L.

Risk of Bias in Included Studies

Online supplementary Table 3 summarises the risk of bias for individual studies. Twenty-two studies had a moderate risk of bias [15, 17, 18, 20‒23, 25, 29‒31, 34, 36‒40, 42‒46], and 10 studies had a serious risk of bias [16, 19, 24, 26‒28, 32, 33, 35, 41]. Most studies had a moderate to serious risk of bias due to potential confounding [15, 16, 18, 19, 22, 24‒30, 32, 33, 35‒37, 41‒46], measurement of outcomes [15‒24, 26‒46], and selection of the reported result [15‒20, 22‒46]. Potential bias due to deviations from intended interventions [15, 30, 33‒38, 40, 41, 44‒46] or missing data [15, 24, 26, 27, 29, 30, 34, 37, 40‒42, 45, 46] were not reported in several studies.

Morphine

Fourteen studies examined the analgesic effect of morphine use on clinical outcomes among patients with reduced renal function [15, 16, 21, 23, 24, 30, 34‒36, 38, 39, 41, 43, 44], including 13 studies which compared outcomes between groups with reduced versus normal renal function [15, 16, 23, 24, 30, 34‒36, 38, 39, 41, 43, 44] and one study involving patients with reduced renal function only (Table 1) [21].

Studies Involving Patients with Reduced versus Normal Renal Function

Of the 13 studies comparing outcomes between patients with reduced versus normal renal function [15, 16, 23, 24, 30, 34‒36, 38, 39, 41, 43, 44], three studies reported on safety or efficacy outcomes related to morphine use [15, 23, 30], and the remaining 10 studies reported only on pharmacokinetic data related to morphine use [16, 24, 34‒36, 38, 39, 41, 43, 44].

Safety or Efficacy Outcomes. Three studies reported on safety or efficacy outcomes related to morphine use [15, 23, 30]. A retrospective cohort study involving 6,612 patients undergoing laparoscopic surgery reported that patients with reduced renal function (preoperative estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) had 3.5% lower morphine milligramme equivalent (MME) consumption on the first three postoperative days compared to patients with normal renal function (coefficient −0.035, 95% CI: −0.064-0.005, p = 0.023) [23]. Two retrospective cross-sectional studies involving cancer patients reported a higher incidence of adverse events among patients with reduced compared to renal function [15, 30]. Of these, one study reported a higher incidence of nausea, vomiting, and brain dysfunction among patients with reduced compared to normal renal function (100 vs. 41%; p = 0.01) [15]. Another study identified a greater incidence of loss of appetite in patients with moderate to severe reduction (OR = 2.33, 95% CI, 1.31–4.16; p = 0.02) in renal function (CrCl <60 mL/min), as well as a greater incidence of constipation among patients with mild (OR = 2.16, 95% CI, 1.38–3.39) or a moderate to severe reduction (OR = 1.69, 95% CI, 0.95–3.01; p = 0.003) in renal function compared to patients with normal renal function (Table 1) [30].

Pharmacokinetic Data Outcomes. Ten studies reported on the pharmacokinetic characteristics of morphine among patients with reduced or normal renal function [16, 24, 34‒36, 38, 39, 41, 43, 44]. Linear correlations between CrCl and the clearance of morphine (r = 0.82, p < 0.001) [16] and its metabolites (r ≥ 0.910, p < 0.001) [35], particularly following parenteral administration (subcutaneous route; r = 1.00 for M-3-G and r = 0.99 for M-6-G, p < 0.01) [41] were identified. No outcomes on safety or efficacy were reported in these studies (Table 1).

Fentanyl

Three studies examined the effect of fentanyl use [18, 33, 37], including two studies comparing groups with reduced versus normal renal function [18, 37] and one study involving patients with reduced renal function only (Table 2) [33].

Studies Involving Patients with Reduced versus Normal Renal Function

Two retrospective cross-sectional studies compared groups with reduced versus normal renal function and reported on pharmacokinetic data but not clinical data related to fentanyl use [18, 37].

Pharmacokinetic Data. One study in which patients were given transdermal fentanyl reported that renal insufficiency was associated with an increased metabolic ratio of serum norfentanyl (inactive metabolite of fentanyl) relative to fentanyl, as well as serum norfentanyl concentrations (p = 0.006) [18]. Another study in which patients were given sublingual fentanyl identified that the median duration of fentanyl use was significantly shorter in patients with chronic kidney disease compared to those with normal renal function (42 days 95% CI: 8.2–6.3] versus 66 days [95% CI, 40.0–92.0]; p < 0.001) [37]. No outcomes on safety or efficacy were reported (Table 2) [18, 37].

Studies Involving Patients with Reduced Renal Function Only

One retrospective cross-sectional study reported on the safety and efficacy of subcutaneous fentanyl use among patients with reduced renal function only [33].

Safety or Efficacy Outcomes. Palliative care patients with renal failure (eGFR = 25 [range 4–59] mL/min/1.73 m2) given subcutaneous fentanyl experienced that pain control was completely achieved in 59% (31/53), partially achieved in 26% (14/53), or not achieved in 2% (1/53) of patients (not evaluated in 13% (7/53) of patients) [33].

Hydromorphone

Two studies examined the effect of hydromorphone use [32, 40], including one study comparing outcomes among patients with reduced versus normal renal function [32] and one study involving patients with reduced renal function only (Table 3) [40].

Studies Involving Patients with Reduced versus Normal Renal Function

Safety or Efficacy Outcomes. A retrospective cross-sectional study involved 55 palliative care patients who switched from other opioids (including morphine, coproxamol, fentanyl, and diamorphine) to hydromorphone. Two patients switched to hydromorphone from transdermal fentanyl (doses 75 and 150 microg/h) were given an equivalent oral daily morphine dose of 270 and 540 mg, respectively [32].

Studies Involving Patients with Reduced Renal Function Only

Safety or Efficacy Outcomes. One study involved 52 palliative care patients with eGFR = 41.5 ± 44 mL/min/1.73 m2 given a hydromorphone continuous infusion at 6.5 ± 2 mg per hour reported a graded increase in agitation (p < 0.0001) and cognitive dysfunction (p < 0.002) as the dose or duration of hydromorphone increased [40].

Other Opioids

Thirteen studies examined the effect of other opioids on clinical outcomes among patients with reduced renal function [17, 19, 20, 22, 25‒29, 31, 42, 45, 46], including ten studies comparing outcomes between groups with reduced or normal renal function [17, 19, 20, 25‒28, 31, 42, 45] and three studies involving patients with reduced renal function only (Table 4) [22, 29, 46].

This systematic review identified 32 observational studies reporting on opioid use among patients with reduced renal function. Limited data were available on the safety and efficacy of opioid use in renal disease. Most of the included articles reported on morphine use. The overall quality of the evidence was low, with all studies showing a moderate [15, 17, 18, 20‒23, 25, 29‒31, 34, 36‒40, 42‒46] or serious [16, 19, 24, 26‒28, 32, 33, 35, 41] risk of bias. Due to heterogeneity in study design, opioids given, and outcome variables across studies, a meta-analysis was not possible.

Previous systematic reviews of opioid use in renal insufficiency have focused largely on patients with cancer-related pain, with limited research targeting other contexts such as acute or chronic non-cancer pain. One review from 2011, of 15 observational studies on opioid use in patients with cancer pain and renal insufficiency identified a very low level of direct clinical evidence for opioid choice in cancer patients with kidney disease [11]. No study provided a clear relative risk for the safe use of one opioid compared to another [11]. These conclusions align with the findings of the present review. Our review included additional studies on opioid use in cancer pain and the palliative care context to inform the pharmacokinetic profile of fentanyl [18, 33, 37] in renal impairment. Furthermore, this review included two studies involving hydromorphone use among palliative care patients with kidney disease which suggested hydromorphone use may be associated with improved pain control, but a greater risk of adverse events with increasing dose [32, 40]. This review builds upon the existing literature by highlighting that a paucity of available evidence on the safety and efficacy outcomes related to opioid use in renal disease exists in non-cancer pain as well as cancer-related pain contexts. Thus, further high-quality studies to inform the safe and effective use of opioid analgesics in renal disease are urgently needed.

The findings of this systematic review as well as the other reviews [7, 11] suggest that most of the available evidence informing opioid use in renal disease involves morphine use. Several studies in the present review demonstrated that morphine and its active metabolites accumulate in renal disease [16, 24, 34‒36, 38, 39, 41, 43, 44] and that morphine use may be associated with an increased risk of adverse events among patients with reduced compared to normal renal function [15, 30] The study findings demonstrate that advanced chronic kidney disease, high opioid doses, and prolonged treatment duration are associated opioid toxicity in the context of poor renal clearance. However, patients’ renal function and morphine doses used in these studies are poorly reported. As a result of inconsistent reporting, extrapolation of safety outcomes to this cohort remains a challenge.

There are several limitations to this review. While a rigorous search was conducted across eight databases and reference lists of included studies, the search strategy was limited to articles written in English. Therefore, potentially relevant articles in other languages may not have been identified. The effect of haemodialysis on the clearance and subsequent toxicity associated with opioids and their metabolites was not addressed in this review. The relationship between renal function and incidence of adverse events may not be accurately represented in studies which reported only on the average of a cohort’s renal function, where some patients within the cohort may have normal or reduced kidney function. A meta-analysis was not conducted due to significant heterogeneity between studies. Similarly, the use of chronic kidney disease stage to discuss and compare the use of drugs between studies was not feasible due to heterogeneity in the kidney function units of measure reported. Finally, all studies showed a moderate to serious risk of bias. Thus, the findings of the studies summarised in this review should be interpreted with caution.

There is limited and low-quality evidence to inform the safety and analgesic effect of opioid use in reduced renal function. Currently, morphine remains the opioid for which there is the most evidence available on safety and analgesic effects in the context of renal disease. Contextual information such as dose and expected duration of use has biological plausibility but requires empirical investigation with appropriate methodology. Greater caution and consideration of potential risks and benefits should be applied when using other opioids. Further high-quality studies examining clinical outcomes associated with the use of different opioids and opioid doses in renal disease are warranted.

The authors appreciate the assistance provided by Bernadette Bugeja, David Begley, Antony Kodsi, Joy Tong, Bryan Chong, Brendon Lee, and Kiana Chan for their contributions to the assessment of article eligibility.

An ethics statement is not applicable because this study is based exclusively on published literature.

The authors declare no conflicts of interest.

S.L. and J.P. have received grant funding for an unrelated trial from the AVANT Research Foundation. S.L. is supported by a NHMRC Postgraduate Scholarship and a Prince of Wales Hospital Foundation Grant. These funding sources had no role in the design of the study, data collection and analysis or preparation of the manuscript.

S.L.: study conception, design, data collection, data analysis, and drafting, revision, and approval of final manuscript. M.B.S. and J.P.: study conception, design, data collection, data analysis, and revision and approval of final manuscript. J.W.K., S.F., and K.E.K.: data collection, data analysis, and revision and approval of final manuscript. C.H.Y., K.P., M.A.A., and G.R.: data collection and revision and approval of final manuscript. K.Y.: revision and approval of final manuscript.

The data that support the findings of this study are not publicly available due to ethical restrictions but are available from the corresponding author upon reasonable request.

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