Breakthrough pain associated with a reduction in serum buprenorphine 1
concentration during dialysis 2
3
Ali Reza Salili1, 2, Anne B. Taegtmeyer1, Daniel Müller3, Roswitha Skendaj4, Andreas 4
W. Jehle5 5
6
1Department of Clinical Pharmacology and Toxicology, University and University 7
Hospital Basel;; 2Medical University Department of the University of Basel, 8
Kantonsspital Aarau;; 3Institute of Clinical Chemistry, University Hospital Zürich;;
9
4Insitute of Clinical Chemistry, University Hospital Basel;; 5Clinic for Transplantation 10
Immunology & Nephrology, University Hospital Basel, Switzerland
11 12
Correspondence 13
Anne B. Taegtmeyer: anne.taegtmeyer@usb.ch 14
15
Introduction:
16
Buprenorphine is a potent µ−opioid receptor agonist and κ−opioid receptor 17
antagonist. It is licensed for the treatment of moderate to severe chronic pain in 18
particular in cases where non-opioid analgesics and weak opioids have proven 19
ineffective [1]. Buprenorphine is preferentially used in patients with impaired renal 20
function because it is mainly non-renally (70-90%) eliminated [2, 3, 4].
21 22
Due to its high lipophilicity (volume of distribution = 430 L) and plasma protein 23
binding capacity (96% bound to alpha and beta-globulin) buprenorphine is excreted 24
slowly via faeces (68%) and urine (27%) [5]. It primarily undergoes N-dealkylation by 25
CYP3A4 to norbuprenorphine and glucuronidation by UGT-isoenzymes (mainly 26
UGT1A1 and 2B7) to buprenorphine 3β-O-glucuronide [5]. Norbuprenorphine is an 27
active metabolite, but its analgesic potency is reduced compared to its parent 28
compound by a factor of 50. Data from in vitro and animal studies show 29
buprenorphine glucuronides to be pharmacologically active and possibly contributive 30
to the overall pharmacology of buprenorphine [6]. The elimination of buprenorphine 31
follows a complex bi- or triexponentional model probably due to its complex 32
distribution within the body, including the reabsorption from the gastrointestinal tract 33
(enterohepatic circulation) and a slow diffusion from fat tissue. In addition, the mode 34
of administration (transdermal or oral) has an impact on buprenorphine`s 35
pharmacokinetic properties [7]. For these reasons and also depending on the assay 36
used to quantify buprenorphine in serum, different half-lives for buprenorphine have 37
been determined. This range varies from 3 to 44 hours [7]. Because of the long-
38
lasting and variable binding-time to receptors, the duration of action does not 39
correlate directly with serum concentration or half-life of buprenorphine.
40
In a study of the pharmacokinetics of buprenorphine and norbuprenorphine in 41
patients with severely impaired renal function, no differences in pharmacokinetic 42
parameters compared to patients with normal renal function were observed for 43
buprenorphine, however there was a median four-fold increase in norbuprenorphine 44
concentrations [8]. In another study the effect of hemodialysis on the 45
pharmacokinetics of transdermal buprenorphine up to a dose of 70 µg/h was 46
investigated [9]. No differences in plasma buprenorphine or norbuprenorphine 47
concentrations were observed after dialysis. Buprenorphine is therefore considered 48
to be the opiate of choice and is licensed for patients undergoing haemodialysis. The 49
effect of higher buprenorphine doses and of hypoalbuminaemia on buprenorphine`s 50
pharmacokinetic behaviour is not known.
51 52
Case description
53
An 80 year old patient (108 kg) who received buprenorphine to control bronchial 54
tumour-associated pain complained of increased pain towards the end of his three 55
hour haemodialysis sessions which took place three times per week. Clinically the 56
patient had diabetic nephropathy, and type 2 diabetes mellitus had been diagnosed 57
13 years previously. He was dialysed with a high-flux filter (FX-80, Fresenius Medical 58
Care AG&Co. KGaA, Bad Homburg, Germany). His medical history also included 59
chronic obstructive pulmonary disease and diabetic retinopathy. A 60
hypoalbuminaemia of 23 g/l (reference range: 35 – 52 g/l) was measured on routine 61
monitoring. His medication consisted of transdermal buprenorphine (Transtec® 140 62
µg/h or 3360 µg/day), sublingual buprenorphine (Temgesic® 400 µg) every 4 hours 63
as required and paroxetine (Deroxat® 20 mg/d).
64
It was not clear in this case whether the breakthrough pain after dialysis might be 65
related to a fall in buprenorphine or norbuprenorphine concentrations or related to the 66
psychological stress of dialysis. We suspected though, that due to 67
hypoalbuminaemia, the patient might have a high unbound buprenorphine and 68
norbuprenorphine concentration and that these unbound fractions might be 69
dialysable. Rather than empirically increase the buprenorphine dose, we decided to 70
determine total and free buprenorphine and norbuprenorphine plasma concentrations 71
before and after a single dialysis session.
72 73
A total of 4 samples were taken: one pair of arterial and venous blood samples 74
shortly after the beginning and another pair towards the end of hemodialysis.
75
Samples were stored frozen at -20°C until analysis in the laboratories of the Institute 76
of Clinical Chemistry, University Hospital Zürich. Total burprenorphine and 77
norbuprenorphine was measured after protein precipitation by a fully validated LC-
78
MS/MS method using deuterated internal standards on a TSQ Quantum Access Max 79
(Thermo Fisher Scientific, Reinach, Switzerland). Chromatography was performed on 80
an Uptisphere C18 column (125x2mm, 5µm particle size). As mobile phases, 10 mM 81
ammonium acetate in water + 0.1% formic acid (mobile phase A) and 10 mM 82
ammonium acetate in methanol/acetonitrile 50/50 + 0.1% formic acid (mobile phase 83
B) were used. Within-day imprecision was <5.1% for buprenorphine and <10% for 84
norbuprenorphine. Between-day imprecision was <4.6% for buprenorphine and <
85
7.8% for norbuprenorphine. The lower limit of quantification (LLOQ) was 0.05 µg/L for 86
both, buprenorphine and norbuprenorphine. Using the post-column infusion method, 87
no significant matrix effect could be detected. To assure quality, regular participation 88
at an external quality assurance scheme, provided by Arvecon GmbH (Walldorf, 89
Germany) is mandatory. Free buprenorphine and free norbuprenorphine were 90
measured using the same method after ultrafiltration of 1 ml plasma for 1h at 1000 x 91
g with Centricon centrifugal filter units with a mass cut-off of 30’000 Da (Merck 92
Millipore, Schaffhausen, Switzerland).Buprenorphine glucuronide metabolites were 93
not measured. Due to the limited sample volume available for analysis, all 94
measurements were done only once.
95
On the day of sampling the patient was under continuous treatment with Transtec®
96
140 µg/h without oral administration of Temgesic®. The day before, the patient had 97
additionally received 2.4 mg sublingual buprenorphine.
98 99
The arterial total and free buprenorphine concentrations were higher than the venous 100
concentrations at both time points (Figure). The free fraction of buprenorphine was 101
higher than expected in normal subjects (32% instead of 4% as expected with a 102
protein binding capacity of 96%). This finding was most probably due to the 103
hypoalbuminaemia of 23 g/l. The free buprenorphine concentration (active fraction) 104
decreased rapidly and significantly during dialysis from 2.4 µg/l before dialysis to 105
<0.1 µg/l after dialysis. The half-life of buprenorphine (administered as Transtec®) for 106
this patient during dialysis was 11 h, compared to 30 h without dialysis [1].
107 108
Discussion:
109
Although no significant changes in pre- and post-hemodialysis total serum 110
concentrations of buprenorphine and its active metabolite norbuprenorphine at a 111
dose of 70 µg/h were found in a previous study [9], we found that in this case – 112
where buprenorphine was dosed at >140 µg/h and in the presence of 113
hypoalbuminaemia – buprenorphine and norburpenorphine are dialysable.
114
Buprenorphine and norbuprenorphine are lipophilic and highly protein-bound but 115
have molecular weights of 467 and 413 Dalton respectively, which means that the 116
free fractions are highly dialysable.
117
To our knowledge, no previous data regarding dialysability of dose-rates greater than 118
70 µg/h are available (PubMed and Embase search). The high free fraction seen in 119
our case may have been due to a combination of hypoalbuminaemia and saturation 120
of the buprenorphine and norbuprenorphine protein binding sites. As a consequence, 121
the free buprenorphine plasma concentration decreased significantly during 122
hemodialysis and is the likeliest explanation for the gap in analgesia which occurred 123
towards the end of and after dialysis. To prevent the occurrence of pain during and/or 124
after hemodialysis, a supplementary dose of buprenorphine sublingual (Temgesic®) 125
should be taken into consideration at the beginning of dialysis, especially in the 126
presence of significant hypoalbuminaemia.
127
128
Conclusions 129
In this case of high buprenorphine requirements and hypoalbuminaemia, the 130
concentration of pharmacologically active free buprenorphine fell significantly during 131
dialysis and was associated with breakthrough pain during and after dialysis.
132
Clinicians should be aware that some patients may require extra buprenorphine 133
doses during dialysis to prevent significant falls in the concentration of active drug.
134
135
Conflict of interest statement 136
The authors declare that they do not have any financial disclosures or conflicts of 137
interest in relation to this work. The results presented in this paper have not been 138
published previously in whole or part.
139 140 141 142 143 144 145
References:
146
1. Product Information CH: Transtec™ Transdermales Matrix Pflaster, Gruenthal 147
Pharma AG, Glarus Sued, Switzerland.
148
149
2. Davis MP. Twelve reasons for considering buprenorphine as a frontline analgesic 150
in the management of pain. J Support Oncol. 2012 Nov-Dec;;10(6):209-19.
151 152
3. Böger RH. Renal impairment: a challenge for opioid treatment? The role of 153
buprenorphine. Palliat Med. 2006;;20 Suppl 1:s17-23.
154 155
4. Murtagh FE, Chai MO, Donohoe PM, Higginson LJ. The use of opioid analgesia in 156
end-stage renal disease patients managed without dialysis: recommendations for 157
practice. J. Pain Palliat Care Pharmacother. 2007;;21(2):5-16.
158
159
5. Huang P, Kehner GB, Cowan A, Liu-Chen LY: Comparison of pharmacological 160
activities of buprenorphine and norbuprenorphine: norbuprenorphine is a potent 161
opioid agonist. Journal of Pharmacology and Experimental Therapeutics. 297, Nr. 2, 162
Mai 2001, S. 688–95.
163
164
6. Brown SM, Holtzmann M, Kim T, Kharash ED: Buprenorphine metabolites, 165
buprenorphine-3-glucuronide and norbuprenorphine-3-glucuronide, are biologically 166
active. Anesthesiology, 2011 Dec;; 115(6):1251-60 167
168
7. Elkader A, Sproule B: Buprenorphine: clinical pharmacokinetics in the treatment of 169
opioid dependence. In: Clin Pharmacokinet. 44, Nr. 7, 2005, S. 661–80.
170 171
8. Hand CW, Sear JW, Uppington J, Ball MJ, McQuay HJ, Moore RA. Buprenorphine 172
disposition in patients with renal impairment: single and continuous dosing, with 173
special reference to metabolites. Br J Anaesth. 1990 Mar;;64(3):276-82 174
175
9. Filitz J, Griessinger N, Sittl R, Likar R, Schüttler J, Koppert W. Effects of 176
intermittent hemodialysis on buprenorphine and norbuprenorphine plasma 177
concentrations in chronic pain patients treated with transdermal buprenorphine.Eur J 178
Pain. 2006 Nov;;10(8):743-8.
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Figure: Panels A – D show the measured arterial (A and B) and venous (C and D) 196
serum concentration of buprenorphine (total and free) and norbuprenorphine (total 197
and free) shortly after the start (0h) and near the end (3h) of hemodialysis.
198 199
200
0.0 2.0 4.0 6.0 8.0 10.0 12.0
0 3
Buprenorphine (µg/l)
Total Free
0.0 2.0 4.0 6.0 8.0 10.0 12.0
0 3
Norbuprenorphine (µg/l)
0.0 2.0 4.0 6.0 8.0 10.0 12.0
0 3
Buprenorphine (µg/l)
0.0 2.0 4.0 6.0 8.0 10.0 12.0
0 3
Norbuprenorphine (µg/l)
A B
C D
Time after dialysis start (h) Time after dialysis start (h)
Time after dialysis start (h) Time after dialysis start (h)
