Increased injection pain with darbepoetin-a compared to epoetin-b in paediatric dialysis patients

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1 NDT Advance Access published August 5, Nephrol Dial Transplant () 1 of 5 doi:1.193/ndt/gfl79 Original Article Increased injection pain with darbepoetin-a compared to epoetin-b in paediatric dialysis patients Claus Peter Schmitt, Barbara Nau, Christiane Brummer, Joachim Rosenkranz and Franz Schaefer Division of Paediatric Nephrology, University Hospital for Paediatric and Adolescent Medicine, University of Heidelberg, Germany Abstract Background. Darbepoetin-a is applicable at longer injection intervals. Our early experience in children on peritoneal dialysis suggested increased injection pain compared to epoetin-b, possibly due to technical differences or patient anxiety. Methods. To verify a possible difference in the painfulness of the injected fluids per se, we performed a prospective, randomized, double-blind trial in 13 paediatric end-stage renal disease patients. They received three injections of equivalent doses of darbepoetin-a or epoetin-b in. ml saline, using neutral syringes and 7G needles, at week intervals. Pain perception was recorded immediately and after 3 min on a visual analogue scale (VAS, ¼ no pain, 1 ¼ maximal pain; complemented by 5 faces for young children). Results. The patients perceived more intense immediate injection pain with darbepoetin-a than with epoetin-b (5. 1 vs.3., P <.5). This was confirmed by the impression of the parents (5.3 1 vs..9, P <.5) and the nurses (. 1 vs.., P <.5). General injection pain was inversely related to patient age (R ¼.77, P ¼.1). Six patients perceived no or a mild difference in injection pain, whereas 7 subjects reported a markedly higher pain score ( VAS points) with darbepoetin-a. After 3 min, the injection site was largely painless with both drugs. No significant local reactions occurred with either medication (.3.1 vs.3.1 on a 5-score scale). Conclusions. Subcutaneous injections of darbepoetin-a are more painful than those of epoetin-b in the majority of paediatric patients. The observed difference in painfulness is related to the nature of the injected compounds and may limit the subcutaneous applicability of darbepoetin-a in children. Correspondence and offprint requests to: Claus Peter Schmitt, MD, Division of Paediatric Nephrology, University Hospital for Paediatric and Adolescent Medicine, Im Neuenheimer Feld 153, 91 Heidelberg, Germany. claus.peter.schmitt@med.uni-heidelberg.de Keywords: anaemia; darbepoetin-a; epoetin-b; paediatric dialysis; pain perception; subcutaneous injection Introduction Renal anaemia, essentially contributing to reduced quality of life and excessive cardiovascular morbidity in advanced chronic renal failure [1,], can be efficiently treated by administration of human recombinant erythropoietin (Epo). The advent of darbepoetin-a, a modified Epo with two additional glycosylation chains and extra sialic acid residues, has directed clinical interest to the modification of dosing intervals. The plasma disappearance half-life of darbepoetin-a is increased to 3-fold relative to conventional Epo after either subcutaneous or intravenous administration both in adults and children [3,]. The potential advantage of extended dosing is particularly relevant for subcutaneous injection, which is the preferred route of administration in children due to the marked preponderance of peritoneal dialysis (PD) and stable pre-endstage chronic renal failure in this population. Several studies indeed demonstrated that the interval of subcutaneous darbepoetin-a injections can be extended to weeks in dialysis patients and up to weeks in patients with chronic renal failure [5,]. A similar trend was observed in an uncontrolled prospective trial in children [7]. Injections are a major source of distress in children [], which can only partially be alleviated by topical anaesthetics [9,1]. We were thus intrigued by the possibility to reduce the cumulative burden of pain by using darbepoetin-a administered at extended intervals. Our early experience, however, suggested an increased injection pain with darbepoetin-a relative to conventional epoetin-b. Since the reason for the apparent difference in pain perception was unclear, and possibly related to technical differences (needle size or sharpness, injected volume, etc.) or patient ß The Author []. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please journals.permissions@oxfordjournals.org

2 of5 anxiety with the new drug, we performed a prospective randomized double-blind trial to assess the mechanism, severity, duration and overall acceptability of injection pain with darbepoetin-a relative to epoetin-b. Subjects and methods Patients Patients were eligible for the trial if they were treated with erythropoietin for renal anaemia, had stable haemoglobin levels and no neurological disorders potentially interfering with pain perception, and no skin disease at the injection sites. Nineteen paediatric patients were asked to participate in the study. Three families denied due to previous negative experiences with darbepoetin-a, including vomiting and one episode of asthma following subcutaneous injection. Another three patients did not give any specific reasons. The remaining 13 patients treated with chronic PD (n ¼ 1) or haemodialysis (n ¼ 3) agreed to participate and completed the study. The age of the subjects ranged from 3.7 to (mean 13.) years, four patients were female. Prior to the study, four patients had received subcutaneous and three intravenous epoetin-b, and six patients had been treated with subcutaneous darbepoetin-a. The trial was initiated and exclusively designed by the investigators and performed in full compliance with the Declaration of Helsinki and the current EU Good Clinical Practice guidelines for clinical trials. Approval for the study protocol was obtained from the Heidelberg Ethical committee. Written informed consent was obtained from the parents and patients, assent from patients below 7 years of age. Erythropietin preparations Epoetin-b (NeoRecormon Õ, Hoffmann-La Roche AG, Grenzach-Wyhlen, Germany) and darbepoetin-a (Aranesp Õ, Amgen, Munich, Germany) were filled into neutral syringes with 7G needles. Injected volume was. ml; the medication was diluted with solution as required. The injected dose of the alternative drug was calculated to substitute the usual weekly (n ¼ ) or biweekly (n ¼ 7) maintenance dose of the routinely administered compound ( IU epoetin-b ¼ 1 mg darbepoetin-a/week). The mean injected dose of epoetin-b was (range: 71) IU/kg, that of darbepoetin-a..9 ( ) mg/kg body weight. Physiological saline solution was used to dilute the epoetin-b aliquot by 1 7% and the darbepoetin by 5 5% in order to equalize the injected volumes to. ml. The preparing and labelling of the study medication was performed by a single study nurse (C.B.). Study design All patients received in blinded order three injections of equivalent doses of darbepoetin-a or epoetin-b at -week intervals. In the light of our previous experience of increased injection pain with darbepoetin, all patients first received a dose of epoetin-b to prevent a potential drop out bias. The second and third injections were randomized to either epoetin-b followed by darbepoetin or vice versa. Patients, parents and the caregiving nurse performing the injections were blinded as to the nature of the compound injected. Injections were alternately given into the left and right ventral thigh. Blood pressure and blood biochemistry including haemoglobin and platelet count were assessed prior to each injection. Pain assessment Pain perception was recorded by patients, parents and the nurse immediately and 3 min after injection on a visual analogue scale (VAS), consisting of a non-graduated 1 cm horizontal line ranging from ¼ did not hurt at all to 1 ¼ as painful as it could be. For young children, the VAS was complemented by five cartoons with facial expression ranging from neutral to markedly distressed. Scoring was performed by drawing a vertical line. In addition, every patient was asked to describe the nature and duration of their sensations (burning, stabbing or dull pain, itching, numbness). Moreover, parents and the nurses estimated patients needle phobia on a VAS, again consisting of a 1 cm non-graduated, horizontal line ranging from ¼ no fear of injections to 1 ¼ max. needle phobia. The injection site was examined 3 min after each injection by a physician with regard to bleeding, erythema, swelling and blister formation and recorded as a score of 5 points. After the last injection, patients and parents were informed about the order of injections and asked about the general and conditional acceptability of further subcutaneous administration of either drug. Statistical analysis Results are given as mean and SEM or median and range, depending on the mode of distribution of the variable of interest. The mean values of the two epoetin-b injections were used for comparison with the values obtained from the darbepoetin-a injection. Statistical differences were calculated by paired t-test or by Wilcoxon Signed Rank test in the case of non-gaussian distribution. Associations were examined using Spearman Rank Order coefficient. Results C. P. Schmitt et al. The global needle anxiety estimates given by the parent and the nurse in charge of the child averaged.5 ( 1) and 1.3 ( 1) VAS points, respectively, with an intraindividual difference of estimate between the two observers of.3 1. VAS (P ¼ NS). Epoetin-b injections usually caused mild immediate injection pain, with a mean VAS of.3. VAS points reported by patients. Pain perception with epoetin-b was consistent, with small intraindividual differences between the two blinded injections (mean difference.5 3.7,.. and..7 reported by patient, parent and nurse, respectively, P ¼ NS). Darbepoetin-a injections were associated with a significantly greater pain perception by patients than those of epoetin-b (5. 1 vs.3., P <.5) (Figure 1). This was confirmed by the impression

3 Injection pain with darbepoetin-a and epoetin-b 3 of 5 1 Table 1. Characteristics of darbepoetin sensitive patients Darbepoetin sensitive (score difference, n ¼ 7) Darbepoetin insensitive (score difference <, n ¼ ) Pain score Pain score epoetin Pain score darbepoetin. 1.5*. 1. General injection fear score Age (years) Dose epoetin (IU/kg) Dose darbepoetin (mg/kg) Dilution epoetin (%) Dilution darbepoetin (%) 17 3 *P <.1 vs darbepoetin insensitive patients. Epoetin-β Darbepoetin-β Fig. 1. Individual immediate pain perception in patients who received epoetin-b (mean of two injections) and darbepoetin-a. VAS-score ** * Patients Parents' impression Nurse's impression Fig.. Pain perception after subcutaneous injection of epoetin-b (filled columns) and darbepoetin-a (hatched columns) as documented on the VAS by patients, parents and the caregiving nurse. of parents (5.3 1 vs..9, P <.5) and nurses (. 1 vs.., P <.3) (Figure ). Pain perceived with subcutaneous darbepoetin-a injections did not correlate with pain perceived with epoetin-b. Notably, the difference in immediate injection pain was bimodally distributed, with no or mild differences in six, but a very marked difference experienced in seven patients ( VAS points). These two subgroups did not differ with respect to relative erythropoietin dosage or dilution factor. Patients perceiving darbepoetin-a as more painful however tended to be younger and to have increased injection pain (Table 1, Figure 1). The two patients older than Pain score r=.77, P= Age (years) Fig. 3. Overall pain intensity perceived by patients with subcutaneous erythropoietin injections in relation to patient age. The mean value calculated from the pain score reported with darbepoetin-a and from the mean pain score reported with epoetin-b is figured on the y-axis. 1 years of age reported no injection pain with either medication. Most of the patients described acute, burning sensations, one patient reported dull pain. The pain character did not differ between the compounds. After 3 min, the injection site was largely painless after darbepoetin-a (..5) and epoetin-b injections (..5, P ¼ NS), the local reaction score averaged.3.1 on a 5-score scale with each of the drugs. The mean overall pain perception (Figure 3) as well as the pain scores reported with epoetin-b (R ¼., P <.1) and darbepoetin-a (R ¼.57, P ¼.) were inversely related to patient age.

4 of5 After completion of the study, the families were informed about the sequence of injections. Seven patients confirmed that darbepoetin-a was markedly more painful. One child stated that it was slightly more painful, three children that there was no difference, the remaining subjects did not give any retrospective judgement. Four subjects refused any further darbepoetin administration. They belonged to the group of darbepoetin sensitive patients, the difference in immediate pain scores was 5.. Five families indicated acceptance of darbepoetin-a only when the injection interval would be prolonged compared to the present schedule, one family preferred to continue with weekly darbepoetin-a treatment. Discussion This prospective, randomized, double-blind study demonstrates increased painfulness of subcutaneous darbepoetin-a (Aranesp Õ ) compared to epoetin-b injections (NeoRecormon Õ ) in children. The observed difference is not explained by differences in injected volume, needle properties or patient anxieties, and must, therefore be related to the nature of the injected fluids per se. Pain perception is increased in children compared to adults. The psychological stress imposed by repeated venipunctures and injections in chronically ill children is enormous and may result in needle phobia and reduced medical adherence [,11,1]. The general results obtained in this study support this notion: the overall pain perception was closely inversely related to the age of the patients. Moreover, the level of pain observed after epoetin-b injections in our patients was at least -fold higher than that reported by adult dialysis patients using a similar VAS [13,1]. The pronounced difference in pain perception with darbepoetin-a compared to epoetin-b substantiated our initial clinical impression with children switched to darbepoetin-a. Our results are further validated by the excellent agreement in pain estimates given by patients, parents and the caretaking nurse. The estimates given by parents and nurses do not independently validate our findings in children but ensure that the patients understood how to use the scoring system. In addition, since the parents and nurses were also unaware of the nature of the compound injected, their estimates indicate that caregivers are indeed able to correctly assess the pain level perceived by a child. This was not necessarily expected since previous work suggested limited agreement in pain ratings between children, their parents and health care professionals [15]. Our findings are also in keeping with a recent report in children receiving darbepoetin-a for months after previous use of epoetin-a. Eight out of 1 children asked retrospectively to compare injection site pain with the previous medication stated that darbepoetin-a was more painful [7]. This compares well to the 7 out of C. P. Schmitt et al. 13 subjects studied here perceiving darbepoetin-a as much more painful than epoetin-b. The determinants of the marked individual differences in darbepoetin sensitivity are not entirely clear. While general needlephobia was not predictive, young children appeared to be more susceptible to darbepoetin-a-induced injection pain than adolescents and young adults. Differences in the genetic disposition to pain sensitivity may add to the variability observed [1,17]. The results obtained in this limited number of paediatric patients deserve to be reassessed in a well-sized blinded study in adult patients. The meticulous standardization of the preparation and injection procedure and the double-blind design of the study largely ruled out any interference by technical (needle, injected volume) or psychological factors, such as previous adverse experience with one of the drugs or biased pain expectation towards the new drug. Darbepoetin-a was usually diluted with twice as much saline as epoetin-b; this factor should, if anything, have reduced injection pain with darbepoetin-a. Hence, it is highly likely that the difference in perceived pain is related to the specific composition of the two medications. Patients who were particularly sensitive to darbepoetin-a did not differ with respect to erythropoietin dosage or dilution factor but tended to be younger and to have increased fear of injection (Table 1). Several earlier studies demonstrated that differences in the tolerability of recombinant erythropoietin preparations can partially be explained by the type of buffer added. Citrate-buffered epoetin-a caused significantly greater injection pain in adults than phosphate-buffered epoetin-b [13]. Replacement of citrate by phosphate buffer reduced but did not eliminate this difference completely [1]. The pain experienced with epoetin-b was similar [1] or even less compared to physiological saline [13], suggesting that some additives may exert local anaesthetic properties. Based on structural similarities with polidocanol, a strong local anaesthetic, an anaesthetizing activity has been suspected for the carrier compound polysorbate. The epoetin-b preparation used in our study contains polysorbate, phosphate buffer, sodium chloride, calcium chloride, urea and a variety of amino acids at ph 7.. Darbepoetin-a contains polysorbate, phosphate buffer and sodium chloride and is buffered at ph.1. Whether the better subcutaneous tolerability of epoetin-b is due to one of the additives or to the more physiological ph of the solution, remains to be clarified. We did not include comparative erythropoietin-a administration into the trial, since a previous trial already demonstrated increased injection pain compared to epoetin-b, although the citrate buffer has been replaced by phosphate [1]. Increased injection pain experienced with darbepoetin does not necessarily preclude subcutaneous administration; but should be weighed against the potential clinical advantages of this longer acting compound. In the post hoc judgement asked of the families,

5 Injection pain with darbepoetin-a and epoetin-b 5 of 5 we assessed the consideration that the increased injection site pain with darbepoetin-a might be outweighed by the option of a less frequent administration schedule. Four out of 1 families categorically refused any further darbepoetin use; this adds to the three patients who refused to participate in the study based on their previous painful experience with darbepoetin-a. Five families indicated they were willing to use darbepoetin-a if dosing intervals were longer than those required with epoetin-b. In this context, it is of note that at least with subcutaneous injections, erythropoietin-b may also be administered at longer intervals than recommended to date [1]. In conclusion, subcutaneous darbepoetin-a injections are more painful than those of equivalent doses of epoetin-b in children. The difference in injection site pain is unrelated to technical or psychological factors and appears to be related to the composition of the drug. This drawback may limit the subcutaneous applicability of the current darbepoetin preparation in paediatric patients. Acknowledgements. The study was supported by Hoffmann-La Roche AG, Grenzach-Wyhlen, Germany. We are grateful to the nurses of our paediatric dialysis unit for their dedicated support of the study. Conflict of interest statement. None declared. References 1. Jurkovitz CT, Abramson JL, Vaccarino LV, Weintraub WS, McClellan WM. Association of high serum creatinine and anemia increases the risk of coronary events: results from the prospective community-based atherosclerosis risk in communities (ARIC) study. J Am Soc Nephrol 3; 1: Pisoni RL, Bragg-Gresham JL, Young EW et al. Anemia management and outcomes from 1 countries in the Dialysis Outcomes and Practice Patterns Study (DOPPS). Am J Kidney Dis ; : Macdougall IC, Gray SJ, Elston O et al. Pharmacokinetics of novel erythropoiesis stimulating protein compared with epoetin alfa in dialysis patients. J Am Soc Nephrol 1999; 1: Lerner G, Kale AS, Warady BA et al. Pharmacokinetics of darbepoetin alfa in pediatric patients with chronic kidney disease. Pediatr Nephrol ; 17: Brunkhorst R, Bommer J, Braun J et al. Darbepoetin alfa effectively maintains haemoglobin concentrations at extended dose intervals relative to intravenous or subcutaneous recombinant human erythropoietin in dialysis patients. Nephrol Dial Transplant ; 19: Ling B, Walczyk M, Agarwal A, Carroll W, Liu W, Brenner R. Darbepoetin alfa administered once monthly maintains hemoglobin concentrations in patients with chronic kidney disease. Clin Nephrol 5; 3: Geary DF, Keating LE, Vigneux A, Stephens D, Hebert D, Harvey EA. Darbepoetin alfa (Aranesp) in children with chronic renal failure. Kidney Int 5; : Cummings EA, Reid GJ, Finley GA, McGrath PJ, Ritchie JA. Prevalence and source of pain in pediatric inpatients. Pain 199; : Morris KP, Hughes C, Hardy SP, Matthews JN, Coulthard MG. Pain after subcutaneous injection of recombinant human erythropoietin: does Emla cream help? Nephrol Dial Transplant 199; 9: Kleiber C, Sorenson M, Whiteside K, Gronstal BA, Tannous R. Topical anesthetics for intravenous insertion in children: a randomized equivalency study. Pediatrics ; 11: Dahlquist LM, Gil KM, Armstrong FD, DeLawyer DD, Greene P, Wuori D. Preparing children for medical examinations: the importance of previous medical experience. Health Psychol 19; 5: Frank NC, Blount RL, Smith AJ, Manimala MR, Martin JK. Parent and staff behavior, previous child medical experience, and maternal anxiety as they relate to child procedural distress and coping. J Pediatr Psychol 1995; : Granolleras C, Leskopf W, Shaldon S, Fourcade J. Experience of pain after subcutaneous administration of different preparations of recombinant human erythropoietin: a randomized, double-blind crossover study. Clin Nephrol 1991; 3: Veys N, Dhondt A, Lameire N. Pain at the injection site of subcutaneously administered erythropoietin: phosphatebuffered epoetin alpha compared to citrate-buffered epoetin alpha and epoetin beta. Clin Nephrol 199; 9: Singer AJ, Gulla J, Thode HC,Jr. Parents and practitioners are poor judges of young children s pain severity. Acad Emerg Med ; 9: Wiesenfeld-Hallin Z. Sex differences in pain perception. Gend Med 5; : Dionne RA, Bartoshuk L, Mogil J, Witter J. Individual responder analyses for pain: does one pain scale fit all? Trends Pharmacol Sci 5; : Grzeszczak W, Sulowicz W, Rutkowski B et al. The efficacy and safety of once-weekly and once-fortnightly subcutaneous epoetin beta in peritoneal dialysis patients with chronic renal anaemia. Nephrol Dial Transplant 5; : 93 9 Received for publication: 13.. Accepted in revised form: 1.7.