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Effects of intermittent hemodialysis on buprenorphine and norbuprenorphine plasma concentrations in chronic pain patients treated with transdermal buprenorphine
European Journal of Pain 10 (2006) 743–748 www.EuropeanJournalPain.com
Effects of intermittent hemodialysis on buprenorphine and norbuprenorphine plasma concentrations in chronic pain patients treated with transdermal buprenorphine Jo¨rg Filitz a, Norbert Griessinger a, Reinhard Sittl a, Rudi Likar b, Ju¨rgen Schu¨ttler a, Wolfgang Koppert a,* a
Department of Anesthesiology, University Hospital Erlangen, Krankenhausstrasse 12, D-91054 Erlangen, Germany b Department of Anesthesiology, LKH Klagenfurt, A-9020 Klagenfurt, Austria Received 21 June 2005; received in revised form 28 November 2005; accepted 2 December 2005 Available online 19 January 2006
Abstract The present study was designed to study the impact of intermittent hemodialysis on the disposition of the partial agonist buprenorphine and its metabolite norbuprenorphine during therapy with transdermal buprenorphine in chronic pain patients with endstage kidney disease. Ten patients (mean age 63 years) who had received transdermal buprenorphine for at least 1 week, were asked to provide blood samples immediately before and after hemodialysis. Blood samples were analysed for buprenorphine and its metabolite norbuprenorphine. The median buprenorphine plasma concentrations were found to be 0.16 ng/ml before and 0.23 ng/ml after hemodialysis. A significant correlation between plasma levels and administered doses was observed (Spearman R = 0.74; P < 0.05). In three patients norbuprenorphine plasma levels were detected. No differences in pain relief before and after hemodialysis were observed. This investigation shows no elevated buprenorphine and norbuprenorphine plasma levels in patients with renal insufficiency receiving transdermal buprenorphine up to 70 lg/h. Furthermore, hemodialysis did not affect buprenorphine plasma levels, leading to stable analgesic effects during the therapy. 2005 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. Keywords: Chronic pain; Opioid therapy; Transdermal buprenorphine; Norbuprenorphine; Renal failure; Intermittent hemodialysis
1. Introduction Moderate to severe pain is frequently experienced by patients with chronic kidney disease. In a prospective cohort study of 205 hemodialysis patients a significant pain problem was determined in more than 50% of these patients (Davison, 2003). ‘Strong’ opioids are used for the initial treatment of moderate to severe pain, or if * Corresponding author. Tel.: +49 9131 853 3296; fax: +49 9131 853 39191. E-mail address: [email protected] (W. Koppert).
pain control is inadequate with a weaker opioid. However, the use of opioids in patients with general and end-stage renal disease is often associated with an increased occurrence of side events: Most of the currently used opioid analgesics have active metabolites, the excretion of which depends on the glomerular filtration rate (GFR) (Chan and Matzke, 1987). Thus, side events from both parent compound and metabolites are increased by renal insufficiency and consequently a dose adjustment is recommended for several agents in this class (Kurella et al., 2003). On the other hand, opioids are often removed by hemodialysis or continuous
1090-3801/$32 2005 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpain.2005.12.001
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J. Filitz et al. / European Journal of Pain 10 (2006) 743–748
renal replacement therapy leading to uncertain analgesic effects (Bastani and Jamal, 1997; Dean, 2004; Izzedine et al., 2002). The present study was designed to study the disposition of the partial agonist buprenorphine and its Ndealkylated metabolite norbuprenorphine in patients with end-stage kidney disease receiving transdermal buprenorphine. Furthermore, the impact of hemodialysis on buprenorphine and norbuprenorphine plasma concentrations and analgesic effects was investigated.
2. Methods 2.1. Subjects The study was conducted by the Department of Anesthesiology, Division of Pain, and the Department IV of Internal Medicine, at the University Hospital Erlangen. Ten patients were included in the study according to the following criteria: (1) age between 18 and 80 years; (2) either sex; (3) suffering from renal impairment combined with any other non-critical illness and being dependant on intermittent hemodialysis; (4) need for a pain therapy according to step 3 of the WHO analgesic ladder (strong opioid, eventually combined with a non-opioid analgesic or an adjuvant drug). All subjects were familiarized with the study protocol prior to participation and gave their written informed consent. The study was performed in accordance with the declaration of Helsinki and approved by the Ethics Committee of the Medical Faculty of the University of Erlangen-Nuremberg. 2.2. Study protocol and medication After enrolment in the study the opioid therapy was switched to buprenorphine. The patients received an initial dosage of transdermal buprenorphine (Transtec, Gruenenthal GmbH, Aachen, Germany) of about 50% of the equipotent opioid dose the patients received before inclusion in the study (Sittl et al., 2003). Transdermal buprenorphine was then increased stepwise until the average pain score as measured by using a numeric rating scale (NRS; with 0 as ‘no pain’ and 10 as ‘worst imaginable pain’) was below 4. The specific buprenorphine patch used for the study includes a matrix technology to ensure the continuous slow release of buprenorphine into the systemic circulation. The patch contains buprenorphine in total loading doses of 20, 30, and 40 mg incorporated into the adhesive polymer matrix designed to release buprenorphine at a steady, controlled rate over 72 h at dosages of 35, 52.5, or 70 lg/h. This corresponds to an administered daily dose of buprenorphine of 0.8, 1.2, and 1.6 mg, respectively. Therapeutic plasma concentrations are
achieved with the transdermal delivery system after approximately 24 h (Sittl et al., 2003). Buprenorphine sublingual tablets 0.2 mg were provided as rescue medication. Patients were asked to report the investigator if they experienced any disturbing symptoms or any side-effects like nausea and vomiting, sweating, constipation, dizziness or somnolence. Patients who could not tolerate the medication were excluded from the study. Since a steady-state after transdermal buprenorphine is reached during the second patch (Sittl and Likar, 2005), patients had to apply transdermal buprenorphine for at least one week to ensure steady-state levels of plasma buprenorphine before taking blood samples for analysis. Pain ratings and the total amount of rescue medication in a 12-h interval following the hemodialysis were compared with a similar interval the day before hemodialysis. After completing the study each patient was free to continue the pain therapy with buprenorphine or to switch back to the opioid treatment the patient received before enrolment in the study. 2.3. Hemodialysis On the day of the study, all patients underwent a standard hemodialysis treatment using either a F6 HPS dialyzer (Fresenius Medical Care AG, Bad Homburg, Germany) or a Diacap-a-Polysulfon (LO PS 12) dialyzer (Braun Medizintechnologie GmbH, Melsungen, Germany). Both dialyzers are low-flux-dialyzers and consist of a polysulfon membrane. Technical data of both dialyzers are almost identical. The effective surface area is 1.3 m2 (F6 HPS) and 1.2 m2 (LO PS 12), respectively. The Ultrafiltration Coefficient is 13 (F6 HPS) and 7.9 (LO PS 12). In general, dialysate flow was 500 ml/min and the blood flow was held at 200–300 ml/min so that the range of urea-clearance was 186–243 ml/min (F6 HPS) and 183–233 ml/min (LO PS 12), respectively. 2.4. Quantification of buprenorphine and norbuprenorphine Blood samples (10 ml EDTA each) were taken directly before and 10–20 min. after hemodialysis. A standard centrifuge for cell-separation was used to process the blood samples. The separated plasma was stored in a deep freeze at 70C immediately until the samples were completed for later analysis in the laboratories of Gruenenthal GmbH, Department of Pharmacokinetics. Quantification of buprenorphine and its metabolite norbuprenorphine was accomplished using liquid chromatography with tandem mass spectrometry (Ceccato et al., 2003). The LC system consisted of an Agilent Model 1100 Series liquid chromatograph and the mass spectrometer was an Applied Biosystems API 4000 Triple Quadrupole instrument equipped with a TurboIon
J. Filitz et al. / European Journal of Pain 10 (2006) 743–748
Spray interface. The MS/MS transitions 468.2/468.2 and 414.1/414.1 for buprenorphine and norbuprenorphine (collision energy, 47 eV) were monitored. Plasma (0.1 ml) was spiked with Deuterium-labelled internal standards and extracted using tert butyl methyl ether. After extraction the analytes were separated by gradient elution on a Synergi 4l Hydro-RP 80A 75 · 2 mm column (Phenomenex, Aschaffenburg, Germany) using acetonitrile/tetrahydrofuran with 0.1% formic acid as solvent. The retention time was 3.8 min for buprenorphine and 3.4 min for norbuprenorphine. The calibration curve was linear in the range from 0.025 to 6 and 0.05 to 12 ng/ml for buprenorphine and norbuprenorphine, respectively. Accuracy and precision of backcalculated quality control standards were within ±10%. 2.5. Statistical procedures
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Table 1 Morphometric and demographic data of the patients Patient no.
Age (years)
Weight (kg)
Extracted volume (l)
Main cause of pain
1
67
74
3.0
2
76
75
2.7
3
71
54
1.8
4
68
60
2.1
5 6
30 74
74 62
1.7 1.3
7 8 9 10
51 59 68 59
54 62 72 62
4.0 1.2 3.6 1.2
Peripheral vascular disease Peripheral vascular disease/osteoporosis Peripheral vascular disease Peripheral vascular disease/osteoarthritis Visceral pain due to ascites Peripheral polyneuropathy/ osteoarthritis Renal osteodystrophy Peripheral vascular disease Peripheral vascular disease Peripheral vascular disease
Buprenorphine and norbuprenorphine plasma concentrations as well as pain ratings before and after the hemodialysis were compared using the Wilcoxon-test, correlations were calculated using the Spearman R coefficient. Incidences of side effects were analyzed using Fisher exact tests. Significance levels throughout this study were P 6 0.05; all data were presented as means ± SD or median and 25–75% percentile ranges. The STATISTICA software package (Statsoft, Tulsa, NC) was used for statistical analyses.
Buprenorphine (ng/ml)
1
0.5
0.1
Median 0.05
Before hemodialysis
3. Results
3.1. Buprenorphine and norbuprenorphine plasma levels The median buprenorphine plasma concentrations were 0.16 ng/ml (0.10–0.52 ng/ml) before and 0.23 ng/ml (0.12–0.56 ng/ml) after hemodialysis (P = 0.07, Fig. 1). A significant correlation was found between administered buprenorphine dose and buprenorphine plasma concentrations (Spearman R = 0.74, P < 0.05; Fig. 2).
Fig. 1. Buprenorphine plasma concentrations before and immediately after hemodialysis. Filled circles represent samples in which detectable norbuprenorphine concentrations were determined. 1.0
0.8
Buprenorphine (ng/ml)
Ten patients with an average age of 62.3 ± 13.7 years (mean ± SD, range 30–76 years) were enrolled in this study. Their demographic data and pain diagnoses are shown in Table 1. All patients suffered from moderate to severe chronic pain, mostly due to peripheral vascular disease, musculoskeletal disorders, or peripheral polyneuropathy caused by diabetes or peripheral vascular disease (Table 1). Prior to the day of blood sampling, stable analgesia was achieved in all patients, without a need for a continuing use of rescue medication. Three patients experienced moderate side-effects, mainly nausea and sweating. None of the patients had to be excluded from the study because of intolerable side-effects.
After hemodialysis
0.6
0.4
0.2
0.0 17.5
35
52.5
70
Dose (µg/h) Fig. 2. Correlation between administered buprenorphine dose and buprenorphine plasma concentrations before hemodialysis. Spearman R = 0.74, P < 0.05. Filled circles represent samples in which detectable norbuprenorphine concentrations were determined.
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Table 2 Buprenorphine dose, buprenorphine and norbuprenorphine plasma concentrations Patient no.
Buprenorphine dose (lg/h)
Buprenorphine concentration (ng/ml)
Norbuprenorphine concentration (ng/ml)
Before HD
After HD
Before HD
After HD
1 2 3 4 5 6 7 8 9 10
52.5 17.5 52.5 35.0 70.0 70.0 52.5 52.5 35.0 70.0
0.128 0.104 0.521 0.095 0.516 0.200 0.104 0.820 0.069 0.937
0.131 0.157 0.667 0.116 0.518 0.131 0.111 0.574 0.113 1.114
0.112 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 0.444 <0.05 0.798
0.062 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 0.500 <0.05 0.934
Seven out of 10 patients did not show detectable norbuprenorphine plasma concentrations, i.e. plasma levels were below 0.05 ng/ml before as well as after hemodialysis. In the other three patients norbuprenorphine plasma concentrations were found to be lower than the concentrations of the mother compound (Table 2). 3.2. Pain ratings and rescue medication Pain ratings before and after hemodialysis were found to be unaffected by hemodialysis (NRS 2.4 ± 0.5 vs. 2.3 ± 0.7, before and after hemodialysis, respectively, n.s.). There was no need for a rescue medication. After study end all patients decided to continue buprenorphine therapy.
4. Discussion Decline in renal function – whether from a pathological reason or simply due to increasing age of the individual – is an important issue in the pharmacological management of many illnesses as it directly interferes with efficacy and safety of the applied drugs. It is an even more important issue in view of the increasing numbers of elderly, multi-morbid patients who often develop chronic pain conditions and require effective analgesic treatments, i.e. opioids. However, impaired or absent renal function in patients treated with opioids may lead to plasma accumulation of either the mother compound or its metabolites as was shown for morphine (Chauvin et al., 1987; Sear et al., 1989), codeine (Guay et al., 1988), meperidine (Szeto et al., 1977) and propoxyphene (Giacomini et al., 1980; for review, see Dean, 2004). To avoid possible toxic accumulation of an opioid or its metabolites, the doses of the analgesics have to be carefully adjusted in these patients, which complicates pain therapy as it may lead to an unsure predictability of analgesic effects. Buprenorphine is a partial l-receptor agonist and an antagonist at j-receptors, which is 30–50 times more
potent than morphine (Sittl et al., 2005). In our study, buprenorphine was applied via a transdermal delivery system. Transdermal application of buprenorphine offers several advantages over the parenteral and oral routes of administration. Buprenorphine is slowly and continuously released into the systemic circulation, resulting in a relatively constant plasma concentration over a known period. Problems associated with oral drug formulations, such as poor absorption from the gastrointestinal tract, hepatic first-pass metabolism, and low and variable bioavailability, may be avoided. Thus, transdermal buprenorphine is particularly useful for patients who are not able to swallow properly or who have gastrointestinal disorders or preexisting nausea or vomiting. It was shown before to be an effective analgesic regimen against chronic, severe pain (Likar et al., 2003; Sittl et al., 2003). As any other opioid, buprenorphine is metabolised mainly in the liver, but also by the gut wall (Rance and Shillingford, 1976, 1977), producing the major metabolite norbuprenorphine (N-desalkyl-buprenorphine) and several glucuronides of less importance. Elimination of buprenorphine occurs independently from the application route predominantly (2/3) via the gastrointestinal tract with the faeces containing mainly unchanged buprenorphine and only to a lesser extent via the urine (1/3), which contains conjugates of the mother compound and norbuprenorphine (Cone et al., 1984; Hand et al., 1990). Renal impairment is thus not expected to cause increased plasma accumulation of the mother compound (Bullingham et al., 1984; Summerfield et al., 1985), but could lead to an increased plasma concentration of norbuprenorphine as the bulk of this metabolite is excreted via the urine. This was confirmed by Hand et al., who also found no differences in clearance or mean elimination half-life of buprenorphine comparing healthy patients and patients with renal impairment, but found norbuprenorphine plasma levels to be increased fourfold in patients with renal impairment (Hand et al., 1990). No significant correlation between
J. Filitz et al. / European Journal of Pain 10 (2006) 743–748
plasma concentrations of buprenorphine and norbuprenorphine were observed in this study. This is in contrast to our study, in which no detectable amounts of norbuprenorphine were determined in most patients and, if measurable, norbuprenorphine plasma concentrations were observed (3 patients), the plasma concentrations were always found to be lower than the plasma levels of the mother compound buprenorphine. These different findings might be caused by the different routes and amounts of delivered buprenorphine: Hand et al. administered buprenorphine via a continuous intravenous infusion of 161 lg/h (median in 20 patients, range 87–230 lg/h) for 30 h (median, range 2–565 h) (Hand et al., 1990), while buprenorphine doses in our study did not exceed 70 lg/h. Thus, the application rate might be of major importance for the appearance of detectable norbuprenorphine plasma concentrations in patients with renal failure. However, since the limited number of patients in our study further research is warranted to investigate this correlation. Nevertheless, even the higher norbuprenorphine plasma concentrations found by Hand et al. did not exert significant pharmacological activities because of the lower receptor affinity and the lower potency of norbuprenorphine as compared to buprenorphine. In the present study, buprenorphine plasma levels before and after intermittent hemodialysis were compared. Previous studies have shown that some opioids are removed by hemodialysis (Dean, 2004), while other opioids are poorly dialyzed (methadone) (Furlan et al., 1999) or only dialyzed when using certain types of filters (fentanyl) (Bastani and Jamal, 1997; Joh et al., 1998). The results of the present observation showed no significant differences in buprenorphine plasma levels before and after hemodialysis, i.e. buprenorphine was not removed by hemodialysis in a clinically relevant manner. Like with buprenorphine, also norbuprenorphine plasma levels were stable during hemodialysis. The observed slight increase in the plasma concentrations of buprenorphine and norbuprenorphine after hemodialysis could be attributed the generally decreased plasma volume after hemodialysis. Therefore, no dose-adjustment seems to be necessary during intermittent hemodialysis in patients receiving transdermal buprenorphine with an application rate used in our study. These findings were confirmed by the fact that significant correlations between transdermal buprenorphine doses and corresponding plasma concentrations are still present in renal failure, indicating a largely unaffected metabolism with no accumulation of buprenorphine when using this dosages. We conclude that transdermal buprenorphine therapy with an application rate used in our study is a efficient and safe treatment option in chronic pain patients undergoing intermittent hemodialysis. None of the patients suffered from a relapse in pain or required add-on pain medication, indicating that
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transdermal buprenorphine exerts unchanged analgesia during and after hemodialysis. Buprenorphine plasma levels in these patients are unaffected by hemodialysis, and neither buprenorphine nor the metabolite norbuprenorphine seem to accumulate, resulting in no need for any dose adjustment of transdermal buprenorphine in patients treated with intermittent hemodialysis. However, further studies are warranted to investigate buprenorphine plasma levels in patients with endstage renal failure receiving higher buprenorphine dosages.
Acknowledgements The study was supported by the Gruenenthal Research Department, Aachen, Germany. We thank Dr. S. Rieß and Dr. C. Klein (Dept. of Anesthesiology) and Dr. G. Sandner and the nursing staff (Dept. IV of Internal Medicine) for their assistance. Furthermore, the authors thank N. Kohl and J. Weiher (Gruenenthal GmbH) for skilful technical assistance.
References Bastani B, Jamal JA. Removal of morphine but not fentanyl during haemodialysis [letter]. Nephrol Dial Transplant 1997;12:2802–4. Bullingham RE, O’Sullivan G, McQuay HJ, Poppleton P, Rolfe M, Weir L, et al. Mandatory sublingual buprenorphine for postoperative pain. Anaesthesia 1984;39:329–34. Ceccato A, Klinkenberg R, Hubert P, Streel B. Sensitive determination of buprenorphine and its N-dealkylated metabolite norbuprenorphine in human plasma by liquid chromatography coupled to tandem mass spectrometry. J Pharm Biomed Anal 2003;32:619–31. Chan GL, Matzke GR. Effects of renal insufficiency on the pharmacokinetics and pharmacodynamics of opioid analgesics. Drug Intell Clin Pharm 1987;21:773–83. Chauvin M, Sandouk P, Scherrmann JM, Farinotti R, Strumza P, Duvaldestin P. Morphine pharmacokinetics in renal failure. Anesthesiology 1987;66:327–31. Cone EJ, Gorodetzky CW, Yousefnejad D, Buchwald WF, Johnson RE. The metabolism and excretion of buprenorphine in humans. Drug Metab Dispos 1984;12:577–81. Davison SN. Pain in hemodialysis patients: prevalence, cause, severity and management. Am J Kidney Dis 2003;42:1239–47. Dean M. Opioids in renal failure and dialysis patients. J Pain Symptom Manage 2004;28:497–504. Furlan V, Hafi A, Dessalles MC, Bouchez J, Charpentier B, Taburet AM. Methadone is poorly removed by haemodialysis. Nephrol Dial Transplant 1999;14:254–5. Giacomini KM, Gibson TP, Levy G. Effect of hemodialysis on propoxyphene and norpropoxyphene concentrations in blood of anephric patients. Clin Pharmacol Ther 1980;27:508–14. Guay DR, Awni WM, Findlay JW, Halstenson CE, Abraham PA, Opsahl JA, et al. Pharmacokinetics and pharmacodynamics of codeine in end-stage renal disease. Clin Pharmacol Ther 1988;43:63–71. Hand CW, Sear JW, Uppington J, Ball MJ, McQuay HJ, Moore RA. Buprenorphine disposition in patients with renal impairment: single and continuous dosing, with special reference to metabolites. Brit J Anaesth 1990;64:276–82.
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Izzedine H, Launay-Vacher V, Abbara C, Aymard G, Bassilios N, Deray G. Pharmacokinetics of tramadol in a hemodialysis patient. Nephron 2002;92:755–6. Joh J, Sila MK, Bastani B. Nondialyzability of fentanyl with highefficiency and high-flux membranes [letter]. Anesth Analg 1998;86:447. Kurella M, Bennett WM, Chertow GM. Analgesia in patients with ESRD: a review of available evidence. Am J Kidney Dis 2003;42:217–28. Likar R, Griessinger N, Sadjak A, Sittl R. Transdermal buprenorphine for treatment of chronic tumor and non-tumor pain. Wien Med Wochenschr 2003;153:317–22. Rance MJ, Shillingford JS. The metabolism of phenolic opiates by rat intestine. Xenobiotica 1977;7:529–36. Rance MJ, Shillingford JS. The role of the gut in the metabolism of strong analgesics. Biochem Pharmacol 1976;25:735–41. Sear JW, Hand CW, Moore RA, McQuay HJ. Studies on morphine disposition: influence of renal failure on the kinetics of morphine and its metabolites. Brit J Anaesth 1989;62:28–32.
Sittl R, Griessinger N, Likar R. Analgesic efficacy and tolerability of transdermal buprenorphine in patients with inadequately controlled chronic pain related to cancer and other disorders: a multicenter, randomized, double-blind, placebo-controlled trial. Clin Ther 2003;25:150–68. Sittl R, Likar R. Transdermal buprenorphine (Transtec) for pain control. In: Likar R, Sittl R, Budd K, editors. Practice of transdermal pain therapy. Bremen: UNI-MED Science Medical Publishing; 2005. p. 68–81. Sittl R, Likar R, Poulsen Nautrop B. Equipotent doses of transdermal fentanyl and transdermal buprenorphine in patients with cancer and noncancer pain: results of a retrospective cohort study. Clin Ther 2005;27:225–37. Summerfield RJ, Allen MC, Moore RA, Sear JW, McQuay HJ. Buprenorphine in end stage renal failure. Anaesthesia 1985;40:914. Szeto HH, Inturrisi CE, Houde R, Saal S, Cheigh J, Reidenberg MM. Accumulation of normeperidine, an active metabolite of meperidine, in patients with renal failure of cancer. Ann Intern Med 1977;86:738–41.
Effects of intermittent hemodialysis on buprenorphine and norbuprenorphine plasma concentrations in chronic pain patients treated with transdermal buprenorphine Jo¨rg Filitz a, Norbert Griessinger a, Reinhard Sittl a, Rudi Likar b, Ju¨rgen Schu¨ttler a, Wolfgang Koppert a,* a
Department of Anesthesiology, University Hospital Erlangen, Krankenhausstrasse 12, D-91054 Erlangen, Germany b Department of Anesthesiology, LKH Klagenfurt, A-9020 Klagenfurt, Austria Received 21 June 2005; received in revised form 28 November 2005; accepted 2 December 2005 Available online 19 January 2006
Abstract The present study was designed to study the impact of intermittent hemodialysis on the disposition of the partial agonist buprenorphine and its metabolite norbuprenorphine during therapy with transdermal buprenorphine in chronic pain patients with endstage kidney disease. Ten patients (mean age 63 years) who had received transdermal buprenorphine for at least 1 week, were asked to provide blood samples immediately before and after hemodialysis. Blood samples were analysed for buprenorphine and its metabolite norbuprenorphine. The median buprenorphine plasma concentrations were found to be 0.16 ng/ml before and 0.23 ng/ml after hemodialysis. A significant correlation between plasma levels and administered doses was observed (Spearman R = 0.74; P < 0.05). In three patients norbuprenorphine plasma levels were detected. No differences in pain relief before and after hemodialysis were observed. This investigation shows no elevated buprenorphine and norbuprenorphine plasma levels in patients with renal insufficiency receiving transdermal buprenorphine up to 70 lg/h. Furthermore, hemodialysis did not affect buprenorphine plasma levels, leading to stable analgesic effects during the therapy. 2005 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. Keywords: Chronic pain; Opioid therapy; Transdermal buprenorphine; Norbuprenorphine; Renal failure; Intermittent hemodialysis
1. Introduction Moderate to severe pain is frequently experienced by patients with chronic kidney disease. In a prospective cohort study of 205 hemodialysis patients a significant pain problem was determined in more than 50% of these patients (Davison, 2003). ‘Strong’ opioids are used for the initial treatment of moderate to severe pain, or if * Corresponding author. Tel.: +49 9131 853 3296; fax: +49 9131 853 39191. E-mail address: [email protected] (W. Koppert).
pain control is inadequate with a weaker opioid. However, the use of opioids in patients with general and end-stage renal disease is often associated with an increased occurrence of side events: Most of the currently used opioid analgesics have active metabolites, the excretion of which depends on the glomerular filtration rate (GFR) (Chan and Matzke, 1987). Thus, side events from both parent compound and metabolites are increased by renal insufficiency and consequently a dose adjustment is recommended for several agents in this class (Kurella et al., 2003). On the other hand, opioids are often removed by hemodialysis or continuous
1090-3801/$32 2005 European Federation of Chapters of the International Association for the Study of Pain. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.ejpain.2005.12.001
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J. Filitz et al. / European Journal of Pain 10 (2006) 743–748
renal replacement therapy leading to uncertain analgesic effects (Bastani and Jamal, 1997; Dean, 2004; Izzedine et al., 2002). The present study was designed to study the disposition of the partial agonist buprenorphine and its Ndealkylated metabolite norbuprenorphine in patients with end-stage kidney disease receiving transdermal buprenorphine. Furthermore, the impact of hemodialysis on buprenorphine and norbuprenorphine plasma concentrations and analgesic effects was investigated.
2. Methods 2.1. Subjects The study was conducted by the Department of Anesthesiology, Division of Pain, and the Department IV of Internal Medicine, at the University Hospital Erlangen. Ten patients were included in the study according to the following criteria: (1) age between 18 and 80 years; (2) either sex; (3) suffering from renal impairment combined with any other non-critical illness and being dependant on intermittent hemodialysis; (4) need for a pain therapy according to step 3 of the WHO analgesic ladder (strong opioid, eventually combined with a non-opioid analgesic or an adjuvant drug). All subjects were familiarized with the study protocol prior to participation and gave their written informed consent. The study was performed in accordance with the declaration of Helsinki and approved by the Ethics Committee of the Medical Faculty of the University of Erlangen-Nuremberg. 2.2. Study protocol and medication After enrolment in the study the opioid therapy was switched to buprenorphine. The patients received an initial dosage of transdermal buprenorphine (Transtec, Gruenenthal GmbH, Aachen, Germany) of about 50% of the equipotent opioid dose the patients received before inclusion in the study (Sittl et al., 2003). Transdermal buprenorphine was then increased stepwise until the average pain score as measured by using a numeric rating scale (NRS; with 0 as ‘no pain’ and 10 as ‘worst imaginable pain’) was below 4. The specific buprenorphine patch used for the study includes a matrix technology to ensure the continuous slow release of buprenorphine into the systemic circulation. The patch contains buprenorphine in total loading doses of 20, 30, and 40 mg incorporated into the adhesive polymer matrix designed to release buprenorphine at a steady, controlled rate over 72 h at dosages of 35, 52.5, or 70 lg/h. This corresponds to an administered daily dose of buprenorphine of 0.8, 1.2, and 1.6 mg, respectively. Therapeutic plasma concentrations are
achieved with the transdermal delivery system after approximately 24 h (Sittl et al., 2003). Buprenorphine sublingual tablets 0.2 mg were provided as rescue medication. Patients were asked to report the investigator if they experienced any disturbing symptoms or any side-effects like nausea and vomiting, sweating, constipation, dizziness or somnolence. Patients who could not tolerate the medication were excluded from the study. Since a steady-state after transdermal buprenorphine is reached during the second patch (Sittl and Likar, 2005), patients had to apply transdermal buprenorphine for at least one week to ensure steady-state levels of plasma buprenorphine before taking blood samples for analysis. Pain ratings and the total amount of rescue medication in a 12-h interval following the hemodialysis were compared with a similar interval the day before hemodialysis. After completing the study each patient was free to continue the pain therapy with buprenorphine or to switch back to the opioid treatment the patient received before enrolment in the study. 2.3. Hemodialysis On the day of the study, all patients underwent a standard hemodialysis treatment using either a F6 HPS dialyzer (Fresenius Medical Care AG, Bad Homburg, Germany) or a Diacap-a-Polysulfon (LO PS 12) dialyzer (Braun Medizintechnologie GmbH, Melsungen, Germany). Both dialyzers are low-flux-dialyzers and consist of a polysulfon membrane. Technical data of both dialyzers are almost identical. The effective surface area is 1.3 m2 (F6 HPS) and 1.2 m2 (LO PS 12), respectively. The Ultrafiltration Coefficient is 13 (F6 HPS) and 7.9 (LO PS 12). In general, dialysate flow was 500 ml/min and the blood flow was held at 200–300 ml/min so that the range of urea-clearance was 186–243 ml/min (F6 HPS) and 183–233 ml/min (LO PS 12), respectively. 2.4. Quantification of buprenorphine and norbuprenorphine Blood samples (10 ml EDTA each) were taken directly before and 10–20 min. after hemodialysis. A standard centrifuge for cell-separation was used to process the blood samples. The separated plasma was stored in a deep freeze at 70C immediately until the samples were completed for later analysis in the laboratories of Gruenenthal GmbH, Department of Pharmacokinetics. Quantification of buprenorphine and its metabolite norbuprenorphine was accomplished using liquid chromatography with tandem mass spectrometry (Ceccato et al., 2003). The LC system consisted of an Agilent Model 1100 Series liquid chromatograph and the mass spectrometer was an Applied Biosystems API 4000 Triple Quadrupole instrument equipped with a TurboIon
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Spray interface. The MS/MS transitions 468.2/468.2 and 414.1/414.1 for buprenorphine and norbuprenorphine (collision energy, 47 eV) were monitored. Plasma (0.1 ml) was spiked with Deuterium-labelled internal standards and extracted using tert butyl methyl ether. After extraction the analytes were separated by gradient elution on a Synergi 4l Hydro-RP 80A 75 · 2 mm column (Phenomenex, Aschaffenburg, Germany) using acetonitrile/tetrahydrofuran with 0.1% formic acid as solvent. The retention time was 3.8 min for buprenorphine and 3.4 min for norbuprenorphine. The calibration curve was linear in the range from 0.025 to 6 and 0.05 to 12 ng/ml for buprenorphine and norbuprenorphine, respectively. Accuracy and precision of backcalculated quality control standards were within ±10%. 2.5. Statistical procedures
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Table 1 Morphometric and demographic data of the patients Patient no.
Age (years)
Weight (kg)
Extracted volume (l)
Main cause of pain
1
67
74
3.0
2
76
75
2.7
3
71
54
1.8
4
68
60
2.1
5 6
30 74
74 62
1.7 1.3
7 8 9 10
51 59 68 59
54 62 72 62
4.0 1.2 3.6 1.2
Peripheral vascular disease Peripheral vascular disease/osteoporosis Peripheral vascular disease Peripheral vascular disease/osteoarthritis Visceral pain due to ascites Peripheral polyneuropathy/ osteoarthritis Renal osteodystrophy Peripheral vascular disease Peripheral vascular disease Peripheral vascular disease
Buprenorphine and norbuprenorphine plasma concentrations as well as pain ratings before and after the hemodialysis were compared using the Wilcoxon-test, correlations were calculated using the Spearman R coefficient. Incidences of side effects were analyzed using Fisher exact tests. Significance levels throughout this study were P 6 0.05; all data were presented as means ± SD or median and 25–75% percentile ranges. The STATISTICA software package (Statsoft, Tulsa, NC) was used for statistical analyses.
Buprenorphine (ng/ml)
1
0.5
0.1
Median 0.05
Before hemodialysis
3. Results
3.1. Buprenorphine and norbuprenorphine plasma levels The median buprenorphine plasma concentrations were 0.16 ng/ml (0.10–0.52 ng/ml) before and 0.23 ng/ml (0.12–0.56 ng/ml) after hemodialysis (P = 0.07, Fig. 1). A significant correlation was found between administered buprenorphine dose and buprenorphine plasma concentrations (Spearman R = 0.74, P < 0.05; Fig. 2).
Fig. 1. Buprenorphine plasma concentrations before and immediately after hemodialysis. Filled circles represent samples in which detectable norbuprenorphine concentrations were determined. 1.0
0.8
Buprenorphine (ng/ml)
Ten patients with an average age of 62.3 ± 13.7 years (mean ± SD, range 30–76 years) were enrolled in this study. Their demographic data and pain diagnoses are shown in Table 1. All patients suffered from moderate to severe chronic pain, mostly due to peripheral vascular disease, musculoskeletal disorders, or peripheral polyneuropathy caused by diabetes or peripheral vascular disease (Table 1). Prior to the day of blood sampling, stable analgesia was achieved in all patients, without a need for a continuing use of rescue medication. Three patients experienced moderate side-effects, mainly nausea and sweating. None of the patients had to be excluded from the study because of intolerable side-effects.
After hemodialysis
0.6
0.4
0.2
0.0 17.5
35
52.5
70
Dose (µg/h) Fig. 2. Correlation between administered buprenorphine dose and buprenorphine plasma concentrations before hemodialysis. Spearman R = 0.74, P < 0.05. Filled circles represent samples in which detectable norbuprenorphine concentrations were determined.
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Table 2 Buprenorphine dose, buprenorphine and norbuprenorphine plasma concentrations Patient no.
Buprenorphine dose (lg/h)
Buprenorphine concentration (ng/ml)
Norbuprenorphine concentration (ng/ml)
Before HD
After HD
Before HD
After HD
1 2 3 4 5 6 7 8 9 10
52.5 17.5 52.5 35.0 70.0 70.0 52.5 52.5 35.0 70.0
0.128 0.104 0.521 0.095 0.516 0.200 0.104 0.820 0.069 0.937
0.131 0.157 0.667 0.116 0.518 0.131 0.111 0.574 0.113 1.114
0.112 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 0.444 <0.05 0.798
0.062 <0.05 <0.05 <0.05 <0.05 <0.05 <0.05 0.500 <0.05 0.934
Seven out of 10 patients did not show detectable norbuprenorphine plasma concentrations, i.e. plasma levels were below 0.05 ng/ml before as well as after hemodialysis. In the other three patients norbuprenorphine plasma concentrations were found to be lower than the concentrations of the mother compound (Table 2). 3.2. Pain ratings and rescue medication Pain ratings before and after hemodialysis were found to be unaffected by hemodialysis (NRS 2.4 ± 0.5 vs. 2.3 ± 0.7, before and after hemodialysis, respectively, n.s.). There was no need for a rescue medication. After study end all patients decided to continue buprenorphine therapy.
4. Discussion Decline in renal function – whether from a pathological reason or simply due to increasing age of the individual – is an important issue in the pharmacological management of many illnesses as it directly interferes with efficacy and safety of the applied drugs. It is an even more important issue in view of the increasing numbers of elderly, multi-morbid patients who often develop chronic pain conditions and require effective analgesic treatments, i.e. opioids. However, impaired or absent renal function in patients treated with opioids may lead to plasma accumulation of either the mother compound or its metabolites as was shown for morphine (Chauvin et al., 1987; Sear et al., 1989), codeine (Guay et al., 1988), meperidine (Szeto et al., 1977) and propoxyphene (Giacomini et al., 1980; for review, see Dean, 2004). To avoid possible toxic accumulation of an opioid or its metabolites, the doses of the analgesics have to be carefully adjusted in these patients, which complicates pain therapy as it may lead to an unsure predictability of analgesic effects. Buprenorphine is a partial l-receptor agonist and an antagonist at j-receptors, which is 30–50 times more
potent than morphine (Sittl et al., 2005). In our study, buprenorphine was applied via a transdermal delivery system. Transdermal application of buprenorphine offers several advantages over the parenteral and oral routes of administration. Buprenorphine is slowly and continuously released into the systemic circulation, resulting in a relatively constant plasma concentration over a known period. Problems associated with oral drug formulations, such as poor absorption from the gastrointestinal tract, hepatic first-pass metabolism, and low and variable bioavailability, may be avoided. Thus, transdermal buprenorphine is particularly useful for patients who are not able to swallow properly or who have gastrointestinal disorders or preexisting nausea or vomiting. It was shown before to be an effective analgesic regimen against chronic, severe pain (Likar et al., 2003; Sittl et al., 2003). As any other opioid, buprenorphine is metabolised mainly in the liver, but also by the gut wall (Rance and Shillingford, 1976, 1977), producing the major metabolite norbuprenorphine (N-desalkyl-buprenorphine) and several glucuronides of less importance. Elimination of buprenorphine occurs independently from the application route predominantly (2/3) via the gastrointestinal tract with the faeces containing mainly unchanged buprenorphine and only to a lesser extent via the urine (1/3), which contains conjugates of the mother compound and norbuprenorphine (Cone et al., 1984; Hand et al., 1990). Renal impairment is thus not expected to cause increased plasma accumulation of the mother compound (Bullingham et al., 1984; Summerfield et al., 1985), but could lead to an increased plasma concentration of norbuprenorphine as the bulk of this metabolite is excreted via the urine. This was confirmed by Hand et al., who also found no differences in clearance or mean elimination half-life of buprenorphine comparing healthy patients and patients with renal impairment, but found norbuprenorphine plasma levels to be increased fourfold in patients with renal impairment (Hand et al., 1990). No significant correlation between
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plasma concentrations of buprenorphine and norbuprenorphine were observed in this study. This is in contrast to our study, in which no detectable amounts of norbuprenorphine were determined in most patients and, if measurable, norbuprenorphine plasma concentrations were observed (3 patients), the plasma concentrations were always found to be lower than the plasma levels of the mother compound buprenorphine. These different findings might be caused by the different routes and amounts of delivered buprenorphine: Hand et al. administered buprenorphine via a continuous intravenous infusion of 161 lg/h (median in 20 patients, range 87–230 lg/h) for 30 h (median, range 2–565 h) (Hand et al., 1990), while buprenorphine doses in our study did not exceed 70 lg/h. Thus, the application rate might be of major importance for the appearance of detectable norbuprenorphine plasma concentrations in patients with renal failure. However, since the limited number of patients in our study further research is warranted to investigate this correlation. Nevertheless, even the higher norbuprenorphine plasma concentrations found by Hand et al. did not exert significant pharmacological activities because of the lower receptor affinity and the lower potency of norbuprenorphine as compared to buprenorphine. In the present study, buprenorphine plasma levels before and after intermittent hemodialysis were compared. Previous studies have shown that some opioids are removed by hemodialysis (Dean, 2004), while other opioids are poorly dialyzed (methadone) (Furlan et al., 1999) or only dialyzed when using certain types of filters (fentanyl) (Bastani and Jamal, 1997; Joh et al., 1998). The results of the present observation showed no significant differences in buprenorphine plasma levels before and after hemodialysis, i.e. buprenorphine was not removed by hemodialysis in a clinically relevant manner. Like with buprenorphine, also norbuprenorphine plasma levels were stable during hemodialysis. The observed slight increase in the plasma concentrations of buprenorphine and norbuprenorphine after hemodialysis could be attributed the generally decreased plasma volume after hemodialysis. Therefore, no dose-adjustment seems to be necessary during intermittent hemodialysis in patients receiving transdermal buprenorphine with an application rate used in our study. These findings were confirmed by the fact that significant correlations between transdermal buprenorphine doses and corresponding plasma concentrations are still present in renal failure, indicating a largely unaffected metabolism with no accumulation of buprenorphine when using this dosages. We conclude that transdermal buprenorphine therapy with an application rate used in our study is a efficient and safe treatment option in chronic pain patients undergoing intermittent hemodialysis. None of the patients suffered from a relapse in pain or required add-on pain medication, indicating that
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transdermal buprenorphine exerts unchanged analgesia during and after hemodialysis. Buprenorphine plasma levels in these patients are unaffected by hemodialysis, and neither buprenorphine nor the metabolite norbuprenorphine seem to accumulate, resulting in no need for any dose adjustment of transdermal buprenorphine in patients treated with intermittent hemodialysis. However, further studies are warranted to investigate buprenorphine plasma levels in patients with endstage renal failure receiving higher buprenorphine dosages.
Acknowledgements The study was supported by the Gruenenthal Research Department, Aachen, Germany. We thank Dr. S. Rieß and Dr. C. Klein (Dept. of Anesthesiology) and Dr. G. Sandner and the nursing staff (Dept. IV of Internal Medicine) for their assistance. Furthermore, the authors thank N. Kohl and J. Weiher (Gruenenthal GmbH) for skilful technical assistance.
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