ORIGINAL ARTICLE
Renal function and symptoms/adverse effects in opioid-treated patients with cancer € m3, P. Sjøgren1,4, O. Ekholm5, L. Christrup6, A. Davies7, S. Kaasa8,9, G. P. Kurita1,2, S. Lundstro 10,11 P. Klepstad and O. Dale11 1
Department of Oncology, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark Multidisciplinary Pain Centre, Department of Neuroanaesthesiology, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark 3 Stockholms Sjukhem Foundation and Department of Oncology Pathology, Karolinska Institute, Stockholm, Sweden 4 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 5 National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark 6 Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 7 Royal Surrey County Hospital, Guildford, UK 8 Department of Oncology, Trondheim University Hospital, St. Olav Hospital, Trondheim, Norway 9 European Palliative Care Research Centre, DMF, Norwegian University of Science and Technology, Trondheim, Norway 10 Department of Intensive Care Medicine, St Olavs University Hospital, Trondheim, Norway 11 Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway 2
Correspondence G. P. Kurita, Section of Palliative Medicine, Dept 4111, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark E-mail: [email protected] Conflicts of interest The authors have declared no conflicts of interest. Funding This study was supported by European Palliative Care Research Collaborative 6th EU Framework Programme and Norwegian Research Council. Submitted 6 January 2015; accepted 2 March 2015; submission 19 June 2014. Citation €m S, Sjøgren P, Ekholm O, Kurita GP, Lundstro Christrup L, Davies A, Kaasa S, Klepstad P, Dale O. Renal function and symptoms/adverse effects in opioid-treated patients with cancer. Acta Anaesthesiologica Scandinavica 2015 doi: 10.1111/aas.12521
Background: Renal impairment and the risk of toxicity caused by accumulation of opioids and/or active metabolites is an underinvestigated issue. This study aimed at analysing if symptoms/ adverse effects in opioid-treated patients with cancer were associated with renal function. Methods: Cross-sectional multicentre study (European Pharmacogenetic Opioid Study, 2005–2008), in which 1147 adult patients treated exclusively with only one of the most frequently reported opioids (morphine/oxycodone/fentanyl) for at least 3 days were analysed. Fatigue, nausea/vomiting, pain, loss of appetite, constipation and cognitive dysfunction were assessed (EORTC QLQ-C30). Glomerular filtration rate (GFR) was estimated using Cockcroft–Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI Creatinine) equations. Results: Mild to severe low GFR was observed among 40–54% of patients. CG equation showed that patients with mild and moderate/severe low GFR on morphine treatment had higher odds of having severe constipation (P < 0.01) than patients with normal GFR. In addition, patients with moderate/severe low GFR on morphine treatment were more likely to have loss of appetite (P = 0.04). No other significant associations were found. Conclusion: Only severe constipation and loss of appetite were associated with low GFR in patients treated with morphine. Oxycodone and fentanyl, in relation to the symptoms studied, seem to be safe as used and titrated in routine cancer pain care.
Acta Anaesthesiologica Scandinavica 59 (2015) 1049–1059 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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Editorial comment: what this article tells us
In patients with cancer-related pain treated with morphine, severe constipation and loss of appetite were associated with low glomerular filtration rate. This association was not found for oxycodone and fentanyl. Patients with cancer often have some degree of renal impairment related to treatment and/or disease.1,2 Concerns regarding the use of opioids in patients with renal impairment have been raised because of the risk of toxicity caused by accumulation of active metabolites or the parent drug.3–5 Therefore, opioid type, its pharmacological properties, and excretion may also give rise to development of symptom/adverse effects. Despite the fact that it seems to be obvious that renal function should be assessed before initiating treatment with opioids, there are reports of inadequate assessment of renal function as well as lack of consensus regarding opioid dose adjustment according to the severity of renal failure.6 Recommendations of the optimal type of opioid to be used in renal impairment do exist, however they are based on knowledge regarding the physiochemical properties of the opioids rather than clinical trials.4,7 Opioids have multiple adverse effects, but an important research question is to what extent renal function/impairment contributes to the development of these symptoms/adverse effects. Thus, this study aimed to analyse whether symptoms/adverse effects are associated with renal function in patients with cancer in opioid treatment. Methods Study design and sample Data were retrieved from the multinational and cross-sectional European Pharmacogenetic Opioid Study (EPOS), in which 2294 adult patients on systemic opioids for at least 3 days to manage moderate or severe pain caused by advanced cancer were included. Patients with communication problems were excluded. The inclusion of patients took place from July 2005 to April 2008.8 Local ethics committees approved the protocol (Regional Medical Research Ethics Committee, Central Norway Health Authority, Protocol ref-
erence number: 119-03, approved 27.09.03) and written informed consent was obtained from all patients. For the present study, we selected patients taking exclusively one of the three most frequently used opioids: morphine (n = 581), oxycodone (n = 298), and fentanyl (n = 268). Other patients were treated with other types of opioids or with more than one opioid. This requirement was different from previous EPOS publications regarding associations between clinical variables and opioid pharmacology.3,5,9 The final sample consisted of 1147 patients, who had available data regarding weight, height, serum concentrations of opioid/metabolites, and creatinine. Assessment 1. The symptoms/adverse effects were selfassessed according to European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQC30), (http://groups.eortc.be/qol/eortc-qlqc30). It includes the symptoms fatigue, nausea and vomiting, pain, appetite, constipation, and cognitive dysfunction.10 Scores were transformed into 0–100 scales. Patients with a score of 33 or more on the symptoms scales were considered to have the specific symptom/adverse effect and it was considered severe when the score was 66 or more. In addition, patients with scores of 67 or less on the cognition scale were considered to have cognitive dysfunction and it was considered severe when the score was 34 or less.11,12 2. Renal function was assessed by an estimate of glomerular filtration rate (GFR), which was calculated by using the Cockcroft–Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI Creatinine) equations published by the National Kidney Foundation.13 CF equation’s constants Acta Anaesthesiologica Scandinavica 59 (2015) 1049–1059
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RENAL FUNCTION AND OPIOID EFFECTS
included were 1.23 for males of any age, and 1.05 for females of any age14 and the estimate was adjusted for body surface area.15 Cut-offs applied were adapted from the KDOQI Clinical Practice Guidelines for Chronic Kidney Disease 2002,16 which are the current figures presented by the National Kidney Foundation,13 and classified in ≥ 90 ml/min/1.73 m2 for normal GFR, 60–89 ml/min/1.73 m2 for mild low GFR, 30–59 ml/min/1.73 m2 for moderate low GFR, and 15–29 ml/min/ 1.73 m2 for severe low GFR. Mild to severe low GFR will be considered as renal impairment in this study. 3. Serum samples were analysed for concentrations of serum creatinine, opioids, and their main metabolites. Blood samples for all patients were drawn at the clinical assessment and in less than 1 h before the administration of the scheduled opioid medication (through samples). For patients receiving transdermal, continuously subcutaneous or intravenous opioids blood samples were drawn in the morning (7:00–12:00 h). Blood samples were centrifuged at 2500 9g for 10 min, and the serum was separated and transferred to two cryo-tubes (opioid/metabolites analysis and confirmatory analysis). The cryo-tubes were stored at 80°C until shipment to the Medical Faculty Norwegian University of Science and Technology, Norway, for quantification of opioids and metabolites.3,17–21
Statistical analysis To evaluate the association between opioids/ metabolites serum concentrations and renal function according to opioid type, non-parametric Kruskal–Wallis test was applied. Two models of multiple regression analyses were performed as follows: (1) to examine the associations between opioids/metabolites serum concentrations and symptoms, and (2) renal function and severe symptoms/adverse effects by opioid group and GFR equations. In the first model adjusting for sex, age, renal function, and use of other medications (antidepressants, anticonvulsants, hypnotics, corticosteroids, and chemotherapy among others) was done, while in the second model, adjusting for the same variables except renal
function was done. Odds ratios (OR) and confidence intervals (95% CI) were calculated using SAS version 9.1 (SAS Institute Inc., Cary, NC, USA). Significance level was P < 0.05. Results Sample general characteristics Sample characteristics are shown in Table 1. In this sample, 51% of patients were treated with morphine. Moderate or severe low GFR was observed in 11–15% of the patients treated with morphine, 14–16% treated with oxycodone, and 14–22% of the patients treated with fentanyl depending on the equation applied (Table 2). A concurrent kidney disease was recorded in a small number of patients (< 5% of total sample). Associations between dose, serum concentrations of opioids and their metabolites, and renal function The mean dose was decreased at lower GFR estimated by the three equations for the morphine group (P < 0.01). The same trend was observed in the oxycodone and fentanyl groups, but the numbers did not reach statistical significance (Table 3). Morphine, oxycodone, and fentanyl serum concentrations did not differ significantly according to renal function using any one of the equations. The mean serum concentrations of the metabolites M3G and M6G were higher in patients with moderate/severe low GFR compared with patients with mild low and normal GFR, according to the three equations. Higher noroxycodone mean serum concentrations were also observed in association with moderate/ severe low GRF, but only expressed by CG equation. Significantly higher levels of oxymorphone mean serum concentrations were also observed, but because they were associated with both normal renal function and moderate/severe low GFR, the nature of the association is not clear (Table 3). Associations between serum concentrations of opioids and their metabolites and symptoms/adverse effects Patients with higher levels of morphine serum concentrations (≥ 41.89 nmol/l) were more
Acta Anaesthesiologica Scandinavica 59 (2015) 1049–1059 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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Table 1 Study sample characteristics by opioid treatment. Characteristics All (n, %) Sex (n, %) Men Women Age (n, %) 18–39 years 40–49 years 50–59 years 60–69 years 70–79 years ≥ 80 years Department (n, %) Palliative care unit/hospice General oncology ward Surgical ward Outpatient clinic Cancer type (n, %) Breast Female reproductive organs Gastrointestinal Head and neck Haematologic Lung Pancreatic Prostate Sarcoma Skin Urologic Kidney disease (n, %) Karnofsky Performance Status (mean, SD)
Morphine
Oxycodone
Fentanyl
581
100
298
100
268
100
304 277
52 48
157 141
53 47
127 141
47 53
27 76 123 189 127 39
5 13 21 33 22 7
19 35 74 90 64 16
6 12 25 30 22 5
10 27 59 74 74 24
4 10 22 28 28 9
190 241 15 135
33 41 3 23
69 159 10 60
23 54 3 20
89 95 11 73
33 35 4 27
88 39 121 18 40 109 5 75 14 10 32 24 62.4
15 7 21 3 7 19 1 13 2 2 6 4 17.4
19 8 17 2 8 13 1 14 2 2 7 2 14.8
32 29 65 13 23 25 10 25 8 5 22 14 58.2
12 11 24 5 9 9 4 9 3 2 8 5 16.6
likely to have severe constipation (OR: 1.73; 95% CI: 1.13–2.65; P < 0.001) and severe cognitive dysfunction (OR: 1.77; 95% CI: 1.13–2.78; P = 0.01) than patients with lower morphine serum concentrations (< 41.89 nmol/l). Furthermore, patients with higher M3G serum concentrations (≥ 1262.20 nmol/l) were more likely to have severe cognitive dysfunction (OR: 1.63; 95% CI: 1.03–2.56; P = 0.04) than patients with lower M3G serum concentrations. Patients with higher oxycodone serum concentrations (> 99.58 nmol/l) were more likely to report severe fatigue (OR: 1.70; 95% CI: 1.04–2.78; P = 0.03) than patients with lower oxycodone serum concentrations. Fentanyl and the metabolites norfentanyl, noroxycodone, and M6G were not associated with any of the six symptoms.
55 24 51 6 24 40 4 42 5 5 21 7 66.4
Associations between opioids, renal function, and symptoms/adverse effects The multiple logistic regressions have shown significant associations only with GFR estimates by CG equation. These results demonstrated that patients with moderate/severe and mild renal impairment in morphine treatment had higher odds of having severe constipation (OR: 1.91, 95% CI: 1.08–3.37 and OR: 1.80, 95% CI: 1.18–2.75, respectively) compared with patients with normal renal function. Further, loss of appetite in patients with moderate/severe renal impairment in morphine treatment was also noted (P = 0.04; Table 4). No other significant associations were observed. Acta Anaesthesiologica Scandinavica 59 (2015) 1049–1059
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RENAL FUNCTION AND OPIOID EFFECTS
Table 2 Distribution of patients by opioid treatment and glomerular filtration rate (GFR) estimated by Cockroft–Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI Creatinine) equations. Morphine GFR CG Normal Mild low Moderate low Severe low Total MDRD Normal Mild low Moderate low Severe low Total CKD-EPI Creatinine Normal Mild low Moderate low Severe low Total
Oxycodone
Fentanyl
n
%
n
%
n
%
294 198 81 8 581
51.0 34.0 14.0 1.0 100.0
143 106 46 3 298
48.0 36.0 15.0 1.0 100.0
123 85 51 9 268
46.0 32.0 19.0 3.0 100.0
355 178 60 5 598
59.4 29.8 10.0 0.8 100.0
182 85 38 5 310
58.7 27.4 12.3 1.6 100.0
164 70 31 7 272
60.3 25.7 11.4 2.6 100.0
332 198 62 6 598
55.5 33.1 10.4 1.0 100.0
169 96 40 5 310
54.5 31.0 12.9 1.6 100.0
147 80 37 8 272
54.0 29.4 13.6 2.9 100.0
Normal: ≥ 90 ml/min/1.73 m2; mild low: 60–89 ml/min/1.73 m2; moderate low: 30–59 ml/min/1.73 m2; severe low: 15–29 ml/min/1.73 m2.
Discussion Precautions of the administration of opioids – especially morphine – in cancer patients with impaired renal function have been the major message from guidelines and expert opinions.4,7,22 Therefore, in our study, it is surprising to observe that only slightly more patients with potential renal impairment were treated with fentanyl or oxycodone compared with morphine. This indicates that the guidelines are generally not followed or known,4,7,22 which corresponds with reports of physicians’ poor awareness of renal function in relation to opioid prescription.6 A recent systematic literature review regarding the use of opioids in cancer patients with renal impairment could only identify 15 studies reporting on clinical outcomes.4 All studies, eight prospective observational trials and seven retrospective studies, were judged of low quality. Morphine is by far the most investigated opioid drug; however, the findings indicating that morphine metabolites have a role in causing adverse effects in renal failure were not consistent.4 Thus, the recent evidence-based
European Association for Palliative Care (EAPC) guidelines for the use of opioids in patients with cancer only state that ‘in patients with significant renal function impairment defined as GFR < 30 ml/min opioids should be used with caution’.22 It seems that the physicians involved in the treatment of the patients in the present study follow this recommendation, since a decrease in the opioid dose was noted according to the lower levels of GFR. In our study, it is noteworthy and of clinical importance that the three equations to estimate GRF resulted in very few differences and a substantial sample of patients with cancer on opioid treatment also demonstrated relatively small differences regarding symptoms/adverse effects when treated with different opioid drugs. The use of the different equations to estimate GFR and assess renal function is still under debate.13,23–25 There are questions regarding accuracy in populations without kidney disease and ethnic subgroups. In addition, because of creatinine clearance measurements, CG formula’s accuracy is less reliable in edema, cachexia, low protein levels, and acute renal failure, which occur frequently in patients with
Acta Anaesthesiologica Scandinavica 59 (2015) 1049–1059 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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Table 3 Mean and median of dose and serum concentrations of opioid treatment, metabolites of opioids according to glomerular filtration rate (GFR) estimated by Cockroft–Gault (CG), Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI Creatinine) equations. Dose in mg* Opioid/metabolite CG Morphine
GFR
Mean (SD)
Median (min–max)
Normal Mild low Moderate/severe low
206 (479.2) 166 (669.6) 101 (109.0) P < 0.01
100 (10–6600) 80 (10–9090) 60 (10–480)
M3G
Normal Mild low Moderate/severe low
M6G
Normal Mild low Moderate/severe low
Oxycodone
Normal Mild low Moderate/severe low
Oxymorphone
Normal Mild low Moderate/severe low
Noroxycodone
Normal Mild low Moderate/severe low
Fentanyl
Normal Mild low Moderate/severe low
Norfentanyl
Normal Mild low Moderate/severe low
MDRD Morphine
Serum concentrations (nmol/l)
Normal Mild low Moderate/severe low
M3G
Normal Mild low Moderate/severe low
M6G
Normal Mild low Moderate/severe low
Oxycodone
Normal Mild low Moderate/severe low
138 (188.5) 100 (126.1) 94 (104.4) P = 0.06
1.6 (1.2) 1.7 (1.5) 1.4 (1.1) P = 0.17
215 119 128 P
Renal function and symptoms/adverse effects in opioid-treated patients with cancer € m3, P. Sjøgren1,4, O. Ekholm5, L. Christrup6, A. Davies7, S. Kaasa8,9, G. P. Kurita1,2, S. Lundstro 10,11 P. Klepstad and O. Dale11 1
Department of Oncology, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark Multidisciplinary Pain Centre, Department of Neuroanaesthesiology, Rigshospitalet Copenhagen University Hospital, Copenhagen, Denmark 3 Stockholms Sjukhem Foundation and Department of Oncology Pathology, Karolinska Institute, Stockholm, Sweden 4 Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 5 National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark 6 Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark 7 Royal Surrey County Hospital, Guildford, UK 8 Department of Oncology, Trondheim University Hospital, St. Olav Hospital, Trondheim, Norway 9 European Palliative Care Research Centre, DMF, Norwegian University of Science and Technology, Trondheim, Norway 10 Department of Intensive Care Medicine, St Olavs University Hospital, Trondheim, Norway 11 Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Trondheim, Norway 2
Correspondence G. P. Kurita, Section of Palliative Medicine, Dept 4111, Rigshospitalet, Blegdamsvej 9, 2100 Copenhagen, Denmark E-mail: [email protected] Conflicts of interest The authors have declared no conflicts of interest. Funding This study was supported by European Palliative Care Research Collaborative 6th EU Framework Programme and Norwegian Research Council. Submitted 6 January 2015; accepted 2 March 2015; submission 19 June 2014. Citation €m S, Sjøgren P, Ekholm O, Kurita GP, Lundstro Christrup L, Davies A, Kaasa S, Klepstad P, Dale O. Renal function and symptoms/adverse effects in opioid-treated patients with cancer. Acta Anaesthesiologica Scandinavica 2015 doi: 10.1111/aas.12521
Background: Renal impairment and the risk of toxicity caused by accumulation of opioids and/or active metabolites is an underinvestigated issue. This study aimed at analysing if symptoms/ adverse effects in opioid-treated patients with cancer were associated with renal function. Methods: Cross-sectional multicentre study (European Pharmacogenetic Opioid Study, 2005–2008), in which 1147 adult patients treated exclusively with only one of the most frequently reported opioids (morphine/oxycodone/fentanyl) for at least 3 days were analysed. Fatigue, nausea/vomiting, pain, loss of appetite, constipation and cognitive dysfunction were assessed (EORTC QLQ-C30). Glomerular filtration rate (GFR) was estimated using Cockcroft–Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI Creatinine) equations. Results: Mild to severe low GFR was observed among 40–54% of patients. CG equation showed that patients with mild and moderate/severe low GFR on morphine treatment had higher odds of having severe constipation (P < 0.01) than patients with normal GFR. In addition, patients with moderate/severe low GFR on morphine treatment were more likely to have loss of appetite (P = 0.04). No other significant associations were found. Conclusion: Only severe constipation and loss of appetite were associated with low GFR in patients treated with morphine. Oxycodone and fentanyl, in relation to the symptoms studied, seem to be safe as used and titrated in routine cancer pain care.
Acta Anaesthesiologica Scandinavica 59 (2015) 1049–1059 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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Editorial comment: what this article tells us
In patients with cancer-related pain treated with morphine, severe constipation and loss of appetite were associated with low glomerular filtration rate. This association was not found for oxycodone and fentanyl. Patients with cancer often have some degree of renal impairment related to treatment and/or disease.1,2 Concerns regarding the use of opioids in patients with renal impairment have been raised because of the risk of toxicity caused by accumulation of active metabolites or the parent drug.3–5 Therefore, opioid type, its pharmacological properties, and excretion may also give rise to development of symptom/adverse effects. Despite the fact that it seems to be obvious that renal function should be assessed before initiating treatment with opioids, there are reports of inadequate assessment of renal function as well as lack of consensus regarding opioid dose adjustment according to the severity of renal failure.6 Recommendations of the optimal type of opioid to be used in renal impairment do exist, however they are based on knowledge regarding the physiochemical properties of the opioids rather than clinical trials.4,7 Opioids have multiple adverse effects, but an important research question is to what extent renal function/impairment contributes to the development of these symptoms/adverse effects. Thus, this study aimed to analyse whether symptoms/adverse effects are associated with renal function in patients with cancer in opioid treatment. Methods Study design and sample Data were retrieved from the multinational and cross-sectional European Pharmacogenetic Opioid Study (EPOS), in which 2294 adult patients on systemic opioids for at least 3 days to manage moderate or severe pain caused by advanced cancer were included. Patients with communication problems were excluded. The inclusion of patients took place from July 2005 to April 2008.8 Local ethics committees approved the protocol (Regional Medical Research Ethics Committee, Central Norway Health Authority, Protocol ref-
erence number: 119-03, approved 27.09.03) and written informed consent was obtained from all patients. For the present study, we selected patients taking exclusively one of the three most frequently used opioids: morphine (n = 581), oxycodone (n = 298), and fentanyl (n = 268). Other patients were treated with other types of opioids or with more than one opioid. This requirement was different from previous EPOS publications regarding associations between clinical variables and opioid pharmacology.3,5,9 The final sample consisted of 1147 patients, who had available data regarding weight, height, serum concentrations of opioid/metabolites, and creatinine. Assessment 1. The symptoms/adverse effects were selfassessed according to European Organization for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQC30), (http://groups.eortc.be/qol/eortc-qlqc30). It includes the symptoms fatigue, nausea and vomiting, pain, appetite, constipation, and cognitive dysfunction.10 Scores were transformed into 0–100 scales. Patients with a score of 33 or more on the symptoms scales were considered to have the specific symptom/adverse effect and it was considered severe when the score was 66 or more. In addition, patients with scores of 67 or less on the cognition scale were considered to have cognitive dysfunction and it was considered severe when the score was 34 or less.11,12 2. Renal function was assessed by an estimate of glomerular filtration rate (GFR), which was calculated by using the Cockcroft–Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI Creatinine) equations published by the National Kidney Foundation.13 CF equation’s constants Acta Anaesthesiologica Scandinavica 59 (2015) 1049–1059
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RENAL FUNCTION AND OPIOID EFFECTS
included were 1.23 for males of any age, and 1.05 for females of any age14 and the estimate was adjusted for body surface area.15 Cut-offs applied were adapted from the KDOQI Clinical Practice Guidelines for Chronic Kidney Disease 2002,16 which are the current figures presented by the National Kidney Foundation,13 and classified in ≥ 90 ml/min/1.73 m2 for normal GFR, 60–89 ml/min/1.73 m2 for mild low GFR, 30–59 ml/min/1.73 m2 for moderate low GFR, and 15–29 ml/min/ 1.73 m2 for severe low GFR. Mild to severe low GFR will be considered as renal impairment in this study. 3. Serum samples were analysed for concentrations of serum creatinine, opioids, and their main metabolites. Blood samples for all patients were drawn at the clinical assessment and in less than 1 h before the administration of the scheduled opioid medication (through samples). For patients receiving transdermal, continuously subcutaneous or intravenous opioids blood samples were drawn in the morning (7:00–12:00 h). Blood samples were centrifuged at 2500 9g for 10 min, and the serum was separated and transferred to two cryo-tubes (opioid/metabolites analysis and confirmatory analysis). The cryo-tubes were stored at 80°C until shipment to the Medical Faculty Norwegian University of Science and Technology, Norway, for quantification of opioids and metabolites.3,17–21
Statistical analysis To evaluate the association between opioids/ metabolites serum concentrations and renal function according to opioid type, non-parametric Kruskal–Wallis test was applied. Two models of multiple regression analyses were performed as follows: (1) to examine the associations between opioids/metabolites serum concentrations and symptoms, and (2) renal function and severe symptoms/adverse effects by opioid group and GFR equations. In the first model adjusting for sex, age, renal function, and use of other medications (antidepressants, anticonvulsants, hypnotics, corticosteroids, and chemotherapy among others) was done, while in the second model, adjusting for the same variables except renal
function was done. Odds ratios (OR) and confidence intervals (95% CI) were calculated using SAS version 9.1 (SAS Institute Inc., Cary, NC, USA). Significance level was P < 0.05. Results Sample general characteristics Sample characteristics are shown in Table 1. In this sample, 51% of patients were treated with morphine. Moderate or severe low GFR was observed in 11–15% of the patients treated with morphine, 14–16% treated with oxycodone, and 14–22% of the patients treated with fentanyl depending on the equation applied (Table 2). A concurrent kidney disease was recorded in a small number of patients (< 5% of total sample). Associations between dose, serum concentrations of opioids and their metabolites, and renal function The mean dose was decreased at lower GFR estimated by the three equations for the morphine group (P < 0.01). The same trend was observed in the oxycodone and fentanyl groups, but the numbers did not reach statistical significance (Table 3). Morphine, oxycodone, and fentanyl serum concentrations did not differ significantly according to renal function using any one of the equations. The mean serum concentrations of the metabolites M3G and M6G were higher in patients with moderate/severe low GFR compared with patients with mild low and normal GFR, according to the three equations. Higher noroxycodone mean serum concentrations were also observed in association with moderate/ severe low GRF, but only expressed by CG equation. Significantly higher levels of oxymorphone mean serum concentrations were also observed, but because they were associated with both normal renal function and moderate/severe low GFR, the nature of the association is not clear (Table 3). Associations between serum concentrations of opioids and their metabolites and symptoms/adverse effects Patients with higher levels of morphine serum concentrations (≥ 41.89 nmol/l) were more
Acta Anaesthesiologica Scandinavica 59 (2015) 1049–1059 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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Table 1 Study sample characteristics by opioid treatment. Characteristics All (n, %) Sex (n, %) Men Women Age (n, %) 18–39 years 40–49 years 50–59 years 60–69 years 70–79 years ≥ 80 years Department (n, %) Palliative care unit/hospice General oncology ward Surgical ward Outpatient clinic Cancer type (n, %) Breast Female reproductive organs Gastrointestinal Head and neck Haematologic Lung Pancreatic Prostate Sarcoma Skin Urologic Kidney disease (n, %) Karnofsky Performance Status (mean, SD)
Morphine
Oxycodone
Fentanyl
581
100
298
100
268
100
304 277
52 48
157 141
53 47
127 141
47 53
27 76 123 189 127 39
5 13 21 33 22 7
19 35 74 90 64 16
6 12 25 30 22 5
10 27 59 74 74 24
4 10 22 28 28 9
190 241 15 135
33 41 3 23
69 159 10 60
23 54 3 20
89 95 11 73
33 35 4 27
88 39 121 18 40 109 5 75 14 10 32 24 62.4
15 7 21 3 7 19 1 13 2 2 6 4 17.4
19 8 17 2 8 13 1 14 2 2 7 2 14.8
32 29 65 13 23 25 10 25 8 5 22 14 58.2
12 11 24 5 9 9 4 9 3 2 8 5 16.6
likely to have severe constipation (OR: 1.73; 95% CI: 1.13–2.65; P < 0.001) and severe cognitive dysfunction (OR: 1.77; 95% CI: 1.13–2.78; P = 0.01) than patients with lower morphine serum concentrations (< 41.89 nmol/l). Furthermore, patients with higher M3G serum concentrations (≥ 1262.20 nmol/l) were more likely to have severe cognitive dysfunction (OR: 1.63; 95% CI: 1.03–2.56; P = 0.04) than patients with lower M3G serum concentrations. Patients with higher oxycodone serum concentrations (> 99.58 nmol/l) were more likely to report severe fatigue (OR: 1.70; 95% CI: 1.04–2.78; P = 0.03) than patients with lower oxycodone serum concentrations. Fentanyl and the metabolites norfentanyl, noroxycodone, and M6G were not associated with any of the six symptoms.
55 24 51 6 24 40 4 42 5 5 21 7 66.4
Associations between opioids, renal function, and symptoms/adverse effects The multiple logistic regressions have shown significant associations only with GFR estimates by CG equation. These results demonstrated that patients with moderate/severe and mild renal impairment in morphine treatment had higher odds of having severe constipation (OR: 1.91, 95% CI: 1.08–3.37 and OR: 1.80, 95% CI: 1.18–2.75, respectively) compared with patients with normal renal function. Further, loss of appetite in patients with moderate/severe renal impairment in morphine treatment was also noted (P = 0.04; Table 4). No other significant associations were observed. Acta Anaesthesiologica Scandinavica 59 (2015) 1049–1059
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ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
RENAL FUNCTION AND OPIOID EFFECTS
Table 2 Distribution of patients by opioid treatment and glomerular filtration rate (GFR) estimated by Cockroft–Gault (CG), Modification of Diet in Renal Disease (MDRD), and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI Creatinine) equations. Morphine GFR CG Normal Mild low Moderate low Severe low Total MDRD Normal Mild low Moderate low Severe low Total CKD-EPI Creatinine Normal Mild low Moderate low Severe low Total
Oxycodone
Fentanyl
n
%
n
%
n
%
294 198 81 8 581
51.0 34.0 14.0 1.0 100.0
143 106 46 3 298
48.0 36.0 15.0 1.0 100.0
123 85 51 9 268
46.0 32.0 19.0 3.0 100.0
355 178 60 5 598
59.4 29.8 10.0 0.8 100.0
182 85 38 5 310
58.7 27.4 12.3 1.6 100.0
164 70 31 7 272
60.3 25.7 11.4 2.6 100.0
332 198 62 6 598
55.5 33.1 10.4 1.0 100.0
169 96 40 5 310
54.5 31.0 12.9 1.6 100.0
147 80 37 8 272
54.0 29.4 13.6 2.9 100.0
Normal: ≥ 90 ml/min/1.73 m2; mild low: 60–89 ml/min/1.73 m2; moderate low: 30–59 ml/min/1.73 m2; severe low: 15–29 ml/min/1.73 m2.
Discussion Precautions of the administration of opioids – especially morphine – in cancer patients with impaired renal function have been the major message from guidelines and expert opinions.4,7,22 Therefore, in our study, it is surprising to observe that only slightly more patients with potential renal impairment were treated with fentanyl or oxycodone compared with morphine. This indicates that the guidelines are generally not followed or known,4,7,22 which corresponds with reports of physicians’ poor awareness of renal function in relation to opioid prescription.6 A recent systematic literature review regarding the use of opioids in cancer patients with renal impairment could only identify 15 studies reporting on clinical outcomes.4 All studies, eight prospective observational trials and seven retrospective studies, were judged of low quality. Morphine is by far the most investigated opioid drug; however, the findings indicating that morphine metabolites have a role in causing adverse effects in renal failure were not consistent.4 Thus, the recent evidence-based
European Association for Palliative Care (EAPC) guidelines for the use of opioids in patients with cancer only state that ‘in patients with significant renal function impairment defined as GFR < 30 ml/min opioids should be used with caution’.22 It seems that the physicians involved in the treatment of the patients in the present study follow this recommendation, since a decrease in the opioid dose was noted according to the lower levels of GFR. In our study, it is noteworthy and of clinical importance that the three equations to estimate GRF resulted in very few differences and a substantial sample of patients with cancer on opioid treatment also demonstrated relatively small differences regarding symptoms/adverse effects when treated with different opioid drugs. The use of the different equations to estimate GFR and assess renal function is still under debate.13,23–25 There are questions regarding accuracy in populations without kidney disease and ethnic subgroups. In addition, because of creatinine clearance measurements, CG formula’s accuracy is less reliable in edema, cachexia, low protein levels, and acute renal failure, which occur frequently in patients with
Acta Anaesthesiologica Scandinavica 59 (2015) 1049–1059 ª 2015 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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G. P. KURITA ET AL.
Table 3 Mean and median of dose and serum concentrations of opioid treatment, metabolites of opioids according to glomerular filtration rate (GFR) estimated by Cockroft–Gault (CG), Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI Creatinine) equations. Dose in mg* Opioid/metabolite CG Morphine
GFR
Mean (SD)
Median (min–max)
Normal Mild low Moderate/severe low
206 (479.2) 166 (669.6) 101 (109.0) P < 0.01
100 (10–6600) 80 (10–9090) 60 (10–480)
M3G
Normal Mild low Moderate/severe low
M6G
Normal Mild low Moderate/severe low
Oxycodone
Normal Mild low Moderate/severe low
Oxymorphone
Normal Mild low Moderate/severe low
Noroxycodone
Normal Mild low Moderate/severe low
Fentanyl
Normal Mild low Moderate/severe low
Norfentanyl
Normal Mild low Moderate/severe low
MDRD Morphine
Serum concentrations (nmol/l)
Normal Mild low Moderate/severe low
M3G
Normal Mild low Moderate/severe low
M6G
Normal Mild low Moderate/severe low
Oxycodone
Normal Mild low Moderate/severe low
138 (188.5) 100 (126.1) 94 (104.4) P = 0.06
1.6 (1.2) 1.7 (1.5) 1.4 (1.1) P = 0.17
215 119 128 P
