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Doxepin cream is not effective in reducing itch in burn scar patients: A multicenter triple-blind randomized clinical crossover trial
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Available online at www.sciencedirect.com
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Doxepin cream is not effective in reducing itch in burn scar patients: A multicenter triple-blind randomized clinical crossover trial K.A.A. Kwa a,b, * , C.M. Legemate c,d,e , A. Pijpe a, A. Meij-de Vries a, E. Middelkoop a,d,e , M.E. van Baar c,e,f, R.S. Breederveld a,b , M.K. Nieuwenhuis e,g, ** a
Burn Center, Red Cross Hospital, Beverwijk, The Netherlands Department of Traumasurgery, Leiden University Medical Center, Leiden, The Netherlands c Burn Center Maasstad Hospital, Rotterdam, The Netherlands d Amsterdam UMC, Free University Amsterdam, Department of Plastic, Reconstructive and Hand Surgery, Amsterdam Movement Sciences, Amsterdam, The Netherlands e Association of Dutch Burn Centers, The Netherlands f Department of Public Health Erasmus MC, Rotterdam, The Netherlands g Burn Center, Martini Hospital, Groningen, The Netherlands b
article info
abstract
Article history:
Objective: To evaluate the effect of doxepin hydrochloride 5% cream on reducing pruritus in
Accepted 13 November 2019
burn scar patients compared to a placebo cream.
Available online xxx
Method: We conducted a multicenter triple-blind randomized clinical placebo-controlled crossover trial in which burn patients 18 years with an itch intensity 3 on a Visual Analogue
Keywords: Itch Pruritus burn* Doxepin Antihistamines
Scale (VAS) were randomized between a doxepin-placebo or placebo-doxepin treatment protocol. Patients used each cream during two weeks with a wash-out period of one week in between. Primary outcome was change in itch intensity in two weeks’ time using the VAS. Secondary outcome included the impact of itch (Burn Itch Questionnaire). Other parameters were the use of hydrating cream, silicon treatment, pressure garments, and other antipruritic medication. Results: Twenty-seven patients were included. The change in itch intensity (VAS) was not different during the doxepin and placebo period (p=0.994); neither the doxepin cream nor placebo cream reduced itch intensity. However, based on the Burn Itch Questionnaire, we observed a statistically significant decrease in itch intensity and improvement in impact scores in both treatment groups, but no difference in the degree of reduction between the groups. Conclusion: Doxepin cream was not effective in reducing pruritus in our burn patient study population. © 2019 Elsevier Ltd and ISBI. All rights reserved.
Abbreviations: AE, adverse event; BIQ, Burn Itch Questionnaire; IQR, Inter Quartile Range; MIC, minimal important change; POSAS, Patient and Observer Scar Assessment Scale; SD, standard deviation; TBSA, total body surface area; VAS, Visual Analogue Scale. * Corresponding author at: Red Cross Hospital, Burn Center, Vondellaan 13, 1942 LE Beverwijk, The Netherlands. ** Corresponding author at: Martini Hospital, Burn Center, Van Swietenplein 1, 9728 NT Groningen, The Netherlands. E-mail addresses: [email protected] (K.A.A. Kwa), [email protected] (C.M. Legemate), [email protected] (A. Pijpe), [email protected] (A. Meij-de Vries), [email protected] (E. Middelkoop), [email protected] (M.E. van Baar), [email protected] (R.S. Breederveld), [email protected] (M.K. Nieuwenhuis). https://doi.org/10.1016/j.burns.2019.11.006 0305-4179/© 2019 Elsevier Ltd and ISBI. All rights reserved.
Please cite this article in press as: K.A.A. Kwa, et al., Doxepin cream is not effective in reducing itch in burn scar patients: A multicenter triple-blind randomized clinical crossover trial, Burns (2019), https://doi.org/10.1016/j.burns.2019.11.006
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Introduction
Pruritus occurs in 67 87% of the burn patients [1 3] and can have a negative effect on their quality of life [4 7]. Although the pathophysiology of pruritus is not fully understood, the role of histamine release is well described [8,9]. Therefore, the standard of care treatment against pruritus is oral antihistamines [2,10]. Unfortunately, antihistaminic agents have a limited effect as only 20% of patients experience complete relief [2]. Doxepin hydrochloride 5% cream is a topical antihistaminic agent used for the treatment of pruritus caused by eczema with a greater antihistaminic potency than other antihistaminic agents [11,12]. Three studies by Demling et al. examined the effect of doxepin cream on itch in burn patients. These all showed a significant improvement of pruritus [13 15]. However, these studies had several limitations. Only patients with spontaneously healed burn wounds were included and the studies that described the scar age of the patients only included patients with burn scars less than one year old. Moreover, none of the studies used a placebo-controlled group. There is a need for better treatment against pruritus in burn patients, as is also expressed by the Dutch Society of Burn survivors. Therefore, we performed a randomized clinical trial to evaluate whether doxepin cream was more effective in reducing pruritus than an oral antihistamine [16]. This trial showed an equal decrease in both treatment arms and thus there was no superior effect of doxepin cream in the reduction of pruritus in burn patients. However, the level of evidence was limited due to a premature ending of the study because of the high demands of the trial (multipele checkups, frequent application of study cream, and refrainment from driving were frequently mentioned), and a superior effect of doxepin cream in the reduction of pruritus in burn patients could not be ruled out. To examine the full potential of doxepin cream in patients with burn scars, we designed and conducted a second clinical trial taking into account the limitations of the first study. The objective of this study was to evaluate the effect of doxepin hydrochloride 5% cream on reducing pruritus in burn scar patients compared to a placebo cream.
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2.
Methods
2.1.
Study design
Our study was a multicenter triple-blind randomized clinical placebo-controlled crossover trial. Patients were randomized to receive treatment according to the schedule presented in Fig. 1, either doxepin-placebo or placebo-doxepin. An allocation sequence was developed using mixed randomization. The sequence was generated by someone not involved in data acquisition using www.randomization.com. Treatment allocation, concealed using sequentially numbered opaque sealed envelopes [17], was described as either A B or B-A whereby only the distributing pharmacists knew which letter referred to which cream. Thus, researchers, physicians as well as the patients were blinded. Unblinding took place after statistical analysis was completed. The study was conducted according to the principles of the Declaration of Helsinki (Ethics manual World Association 2nd edition 2009) and in accordance with the Medical Research Involving Human Subjects Act (WMO). The study was approved by the Medical Research Ethics Committee Noord-Holland (NL59341.094.16), and was registered in the Netherlands Trial Registry (NTR number NTR6413).
2.2.
Participants
Patients were recruited from the outpatient clinics in the three burn centers in the Netherlands. Inclusion criteria were: age 18 years, healed burns, a 3 score on the Visual Analogue Scale (VAS) for itch intensity at time of enrolment and a total body surface area (TBSA) that itched not exceeding 10%. Exclusion criteria were: patients who were unable to give informed consent, unable to understand and fill in itch intensity scores and questionnaires, patients with a cutaneous or systematic disease that causes itch and patients with any disease or condition associated with adverse effects using doxepin cream. The estimated effect size for the sample size calculation was based on the study by Demling [15]. The calculated total sample size with an a level of 0.05, a power of 80% and an anticipated dropout rate of 25% was 27 patients.
Fig. 1 – Study design.
Please cite this article in press as: K.A.A. Kwa, et al., Doxepin cream is not effective in reducing itch in burn scar patients: A multicenter triple-blind randomized clinical crossover trial, Burns (2019), https://doi.org/10.1016/j.burns.2019.11.006
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2.3.
Study procedure
The active product doxepin (Xepin 5% cream, Bioglan AB, Malmö, Sweden) and the placebo vehicle cream (Bioglan AB, Malmö, Sweden) looked identical and were put in 25g plastic tubes labeled with the prescribed date of use. The duration of the study was five weeks. Patients used the first prescribed cream for two weeks, followed by a wash-out period of one week and subsequently used the other cream for another two weeks. Every patient was contacted after 2 3weeks to verify the use of the right cream by reminding them to switch to the second cream. Patients were required to use each cream at least once daily for two consecutive weeks with a maximum of four times a day. The area that itched the most was designated as the study area. Patients were allowed to wear pressure garments, use hydrating cream and continue other medications against itch. Patients were not allowed to start with other medications against itch simultaneously with the start of the study.
2.4.
Study outcomes
2.4.1.
Primary outcome
Our primary outcome was the difference in change in itch intensity after two weeks of treatment between doxepin and placebo cream (D(Day)1 vs D14 and D22 vs D35) as measured by the VAS. The anchor on the far left side of the 100mm scale indicated ‘no itch’ and on the far right side ‘worst itch imaginable’. Patients were required to put a mark on the scale to indicate the itch intensity they experienced. The VAS was assessed on a daily basis in a patient journal during the period they used the study cream. In addition, the journal contained daily questions regarding the use of other anti-pruritic medication, hydrating cream, pressure garments and the experience of adverse events (AE) (Appendix A).
2.4.2.
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Scar Assessment Scale) which consists of a Patient and an Observer Scale [19]. The item ‘vascularity’ and the overall impression score of the Observer and Patient part were compared to the VAS itch score at the start to assess whether there was a correlation between scar quality and itch. The POSAS was assessed at W0.
2.6.
Statistical analysis
Normality of continuous data was tested with the Shapiro Wilk test and by inspecting the frequency distributions (histograms). Homogeneity of variances was tested using the Levene’s test. Data were analyzed according to the intentionto-treat protocol. The baseline characteristics and outcome data are described with mean and standard deviation (SD) (parametric data) or medians and interquartile range (IQR) or first quartile third quartile (non-parametric data). For categorical data, percentage was calculated. Mean differences in itch scores were analyzed using the paired t-test for parametric data and the Wilcoxon test for non-parametric data. The Pearson correlation analysis was performed to assess linear relationships between two continuous variables. The course of the itch-scores in time during the doxepin and placebo periods was evaluated using line charts. Exploratory generalized linear mixed model analysis was used to assess the effect of the intervention on VAS itch intensity (with a random intercept on id and adjusted for the baseline values D1 and D22) and to assess the influence of possible relevant covariates (sequence of treatment, age, sex, grafted burns or use of hydrating cream). A p-value of<0.05 was taken as a threshold for statistical significance. Data were analyzed using the IBM Statistical Package for the Social Sciences (SPSS) version 24.
3.
Results
3.1.
Study population
Secondary outcome
The secondary outcome was the assessment of the impact of itch measured with the Burn Itch Questionnaire (BIQ). Van Loey et al. validated the BIQ for three separate subscales which include: (1) burn severity, (2) sleep interference and (3) daily life [18]. The 22 items were scored on a 10-point scale (0=no itch to 9=most severe itch) or a 10-point Likert Scale (0=totally disagree to 9=totally agree). The itch intensity score from the BIQ was used as a second itch intensity score as it measures itch experienced in the last week/day instead of only on the same day as with the VAS. The patient filled out the BIQ before start of the study at week 0 (W0), at the end of week two after the use of the first prescribed cream (W2) and at the end of week five after the use of the second prescribed cream (W5) (Appendix A).
A total number of 27 patients was included between June 2017 and March 2018. Thirteen patients started with doxepin cream and fourteen patients started with the placebo cream. One patient switched back to the first cream on her own initiative after the second cream did not relieve the itch and the first prescribed cream did. The first cream turned out to be doxepin. This patient did not show up on follow up appointments, and was therefore lost to follow-up after the start of the use of the second prescribed cream. One other patient quit the study prematurely due to increase of itch after the use of what turned out to be the doxepin cream. This patient did provide study data (Fig. 2).
2.5.
3.2.
Other parameters
The following patient parameters were derived from the patients electronic medical record: age, sex, cause of burn, percentage TBSA burned, location of burn, time till complete wound healing, percentage TBSA that itched, skin grafting (yes/no), duration of itch, comorbidities, and allergies. We also assessed scar quality using the POSAS (Patient and Observer
Patient and clinical characteristics
Our study population consisted of 11 men and 16 women (Table 1). The mean age was 40.4 (SD 15.5) years. The median percentage TBSA of the study area was 1.5 (IQR, 1.2). The causes of burn injuries were flame (51.9%), scald (18.5%), contact (11.1%), chemical (14.8%) and grease (3.7%). The study areas were located on the leg (44.4%), arm (37.0%), head (11.1%) and
Please cite this article in press as: K.A.A. Kwa, et al., Doxepin cream is not effective in reducing itch in burn scar patients: A multicenter triple-blind randomized clinical crossover trial, Burns (2019), https://doi.org/10.1016/j.burns.2019.11.006
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Fig. 2 – Flowchart.
trunk (7.4%). Four patients were using antipruritic medication (e.g. Promethazine, Clemastine) before start of the study. The mean vascularity score of the observer part of the POSAS was 3.7 (SD 1.5). The mean overall impression score of the Observer part was 3.8 (SD 1.1). There was no correlation between the vascularity and the itch score using the VAS at day 1 (r= 0.358, p=0.093). There was also no correlation between
Table 1 – Patient characteristics. Patient characteristics (n=27) Male (%) Age in years Time to wound healing study area in days Scar age in days Duration of itch in days Days since start of itch after burn %TBSA burned %TBSA skin grafted %TBSA study area %TBSA study area skin grafted
40.7 40.4 15.5 36.3 17.1 148, 75 508 78, 30 350 45, 18 143 4.2, 1.5 9.0 1.0, 0 2.5 1.5, 0.8 2.0 0.5, 0 1.5
Values are presented in either percentages, means standard deviation or median with first quartile third quartile. TBSA=Total Body Surface Area, BIQ= Burn Itch Questionnaire.
the overall impression score of the patient and the itch score using the VAS at day 1 (r=0.043, p=0.845).
3.3.
Itch scores using VAS
There was no difference between the doxepin and placebo group in the mean itch intensity change using the VAS (p=0.994) (Fig. 3). Both treatments showed a small but not statistically significant decrease in itch intensity over two weeks’ time. Doxepin treatment (n=20) decreased from 3.39 (SD 2.45) to 2.88 (SD 2.72) (p=0.335) and placebo treatment (n=20) decreased from 3.82 (SD 2.44) to 2.88 (SD 2.80) (p=0.115). There was no difference in baseline itch score between the group starting with doxepin (3.41 SD 2.56) or the group starting with placebo cream (3.94 SD 2.44) (p=0.440). Seven measurements in the VAS daily journal were missing in each arm due to the following reasons: stopped using one of the creams during the study at some point (n=3), lost their journal (n=2), incomplete VAS scores in the journals (n=3), and lost-to-follow-up (n=1). Exploratory generalized linear mixed model analysis did not reveal an effect of doxepin treatment on itch intensity (VAS) (b 0.104, p=0.384). There were no confounders or effect modifiers. Itch at baseline was independently associated with the outcome (b 0.514, p<0.01).
Please cite this article in press as: K.A.A. Kwa, et al., Doxepin cream is not effective in reducing itch in burn scar patients: A multicenter triple-blind randomized clinical crossover trial, Burns (2019), https://doi.org/10.1016/j.burns.2019.11.006
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(4%), drowsiness (4%), and the formation of small wounds (4%). The experienced AE’s during placebo treatment were the formation of small wounds (12%), dry skin (12%), increase in itch (4%), and drowsiness (4%).
3.6.
Fig. 3 – VAS Itch scores change between start and end of use of doxepin and placebo over two weeks’ time. Values are presented as mean with standard deviation. *Within group analysis: Paired Samples t-test. **Between group analysis: Paired Samples t-test.
3.4.
Itch score and impact of itch using BIQ
There was no significant difference between the doxepin and placebo group in mean itch intensity change (p=0.600). Both treatments showed a significant decrease in itch intensity between start and end of each cream. Doxepin treatment (n=25) decreased itch from 6.0 [4.0 7.0] to 4.0 [1.0 6.0] (p=0.003) and placebo treatment (n=24) decreased itch from 6.0 [4.0 7.0] to 5.0 [2.3 5.8] (p=0.002). There was no significant difference between both treatments in the scores on the domains ‘itch severity’ (p=0.492), ‘sleep interference’ (p=0.924) or ‘daily life’ (p=0.917). Both treatments showed a significant decrease in BIQ scores in the domains ‘itch severity’ and ‘sleep interference’, but not in the domain ‘daily life’ (Table 2).
3.5.
Adverse events
There were two serious adverse events in one patient, both not deemed related to the study medication. One patient with a history of psychiatric diseases and admissions was admitted on the psychiatric ward twice during the study period. Adverse events were experienced by 7 and 4 patients in the doxepin and placebo treatment arm (p=0.453), respectively. The experienced AE’s during the doxepin treatment were an increase in itch (12%), tight/irritated skin (12%), mild rash (8%), dry skin
Other treatments
Two patients were using an oral antihistaminic agent during the whole study period. Two other patients used an oral antihistaminic agent sporadically (2 4 times) during the study period. Eight patients were using hydrating cream, and two patients had silicon treatment during the study period. There were seven patients who wore pressure garments throughout their whole study period.
4.
Discussion
Our study assessed whether doxepin cream was effective in reducing itch in burn scar patients compared to a placebo cream. Our results showed no difference between the doxepin and placebo group in the mean itch intensity change using either the VAS or the BIQ. The lack of change in itch intensity in the doxepin group is in contrast to studies performed by Demling et al. who showed a significant decrease in itch with patients using doxepin cream [14,15]. This discrepancy may be due to differences in included patients. In our study we included patients with skin grafted burns and patients with relatively old scars, while Demling et al. only included patients with spontaneously healed burns and scars less than one year old. The antihistaminic effect might not be as effective in patients with skin grafted burns or older scars. Mechanisms other than histamine release also play a role in the pathogenesis of itch in burn scar patients [20 23]. Thus, doxepin might be effective in a selective group of patients, namely those with young burn scars in which histamine is more involved in the pathogenesis of itch and a stronger antihistaminic agent is indicated. We were not able to compare younger versus older scars, because our power analysis did not take into account this distinction. In contrast to the VAS scores derived from the daily journal, the BIQ itch intensity score did show a statistically significant decrease of itch with both treatments. It is debatable which instrument assesses the effectiveness of treatment best. In our previous study [16] we noticed that the daily assessment of itch scores led to highly variable scores as itch can vary per day and during the day. This was also the case in this study. Therefore,
Table 2 – Secondary outcomes: change in BIQ itch impact domains scores between the start and end of the use of the creams and between the groups. p-Value
Doxepin n BIQ BIQ BIQ a
itch severity sleep interference daily life
23 25 25
Pre 5.0 [3.5 6.5] 3.5 [1.5 6.0] 1.8 [0.0 3.0]
Post
within
3.3 [1.3 5.0] 2.0 [0.0 4.0] 0.8 [0.0 3.0]
a
0.006 0.013a 0.295a
Placebo n 22 24 24
Pre 4.5 [3.5 6.5] 3.8 [1.4 6.1] 1.9 [0.0 3.1]
Post 4.0 [1.2 5.0] 2.1 [0.0 3.8] 0.6 [0.3 2.1]
p-Value
p-Value
within
between
a
0.006 0.005a 0.106a
0.492a 0.924a 0.917a
Values are presented as median with interquartile range (Q1 Q3). Wilcoxon Signed Ranks test.
Please cite this article in press as: K.A.A. Kwa, et al., Doxepin cream is not effective in reducing itch in burn scar patients: A multicenter triple-blind randomized clinical crossover trial, Burns (2019), https://doi.org/10.1016/j.burns.2019.11.006
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the use of the BIQ itch score, which assesses itch experienced in the past week/day, might be more adequate and reliable. This would mean that both the doxepin as well as the placebo cream led to a decrease in itch intensity. The reduction of itch intensity with the placebo treatment was less than with the doxepin cream. However, this difference was not significant. A placebo effect is possibly effective here, which is not uncommon in studies comparing active substance cream to placebo cream in reducing itch [24,25]. The decrease in itch intensity scores derived from the BIQ is accompanied by a decrease in BIQ scores of the subscales’ itch severity’ and ‘sleep interference’, but not ‘daily life’. A decrease in these scores indicates less impact of itch on life. These results correspond with the results of our previous study in which itch significantly decreased and BIQ scores improved [16]. The POSAS items ‘vascularity’ and ‘general impression’ did not show a correlation with itch at the start of the study. Earlier studies showed that erythema, which is said to be caused by an increase in vascularity that is more apparent in an active scar, corresponded with a higher itch score [14,15]. This was not evident from our study, possibly due to the relative older scars in our population. The most notable adverse event of antihistaminic agents is somnolence [26]. In our study, somnolence was only reported in two patients, of which one patient reported it during the use of the placebo cream. This is in contrast to both Demling’s studies in which somnolence occurred in 10 15% of patients using doxepin cream [14,15], and in contrast to our recent study [16] in which 50% of patients reported somnolence. The latter was possibly due to priming of patients in this study (i.e. patients were asked whether they experienced somnolence on a daily basis). Another possible explanation for the difference in reported somnolence between our study and previous studies could be the total dosage of doxepin cream that the study patients received. Our study area was relatively small, with a median of 1.5% TBSA, while Demling’s was 13% [15] and 5% [14]. In addition, Demling’s patients were required to use the cream four times a day, while our patients were required to use the cream once a day with a maximum of four times a day. Another adverse event mentioned in our study were skin problems, including dry or irritated/tight skin. While an irritated or ‘tight skin’ was reported by three patients, two patients specifically reported a mild rash. This is a known side effect described with the use of doxepin cream, especially in chronic users [27]. Our study protocol we described that we wanted to determine the Minimal Important Change (MIC), which is the smallest change in treatment outcome (itch intensity score) that a patient would identify as relevant. However, due to missing data we only had 36 measurements of 20 patients to determine the MIC, while analysis requires data of at least 50 measurements [28]. Therefore, we decided it was not justified to determine the MIC of the itch score. We do believe it is valuable to determine a MIC for itch in burn patients to know the clinical relevance of combatting itch and to evaluate study outcomes. We recommend that to determine the MIC in burn patients, an adequate sample size calculation should be made, taking into account a loss to follow up. Our study has several strengths. First, we used a randomized crossover design which was suitable for our study population since we expected a chronic and stable situation
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regarding itch intensity over five weeks’ time. Due to this design fewer patients were required and each patient served as his/her own control, which limits the influence of confounding variables. Second, we used a placebo arm to account for the placebo effect which allows detection of the effects of the treatment itself, and strengthens the study design. Third, our patients, outcome assessors and statistical analysts were blinded, thereby preventing potentially biased estimates of treatment effects. Our study also has some limitations. First, we did not make a distinction between patients with different ages of scars or the length of time they experienced itch, which resulted in a heterogeneous study population. The mechanism of pruritus is complex and to a large extent unknown. The pathophysiology in burn patients in the burn scar maturation phase versus patients whose burn scars have matured might be different. In the acute phase, histamine release plays an important role in itch sensation, while in the maturated phase, neurological factors might play a role [8,9,22]. Unfortunately, our sample size did not allow to make a distinction between these two groups. Second, patients were allowed to apply the cream 1 4 times a day, but we did not assess how often the patients actually used the cream on a daily basis. Thus, an underestimation of the effect of doxepin due to underuse cannot be excluded. It might be that the patients did not need to apply the cream more often, because the itch was relieved enough. However, it could also be that patients did not use the maximum number of applications of cream due to inconvenience, for instance the seven patients who wore pressure garments, or due to lack of effort. Either way, that would make doxepin cream as a treatment not suitable for this patient population. Finally, for our secondary outcome on itch intensity we used the BIQ score taken at baseline as a control for both treatment periods. However, as we did not detect a difference between the VAS itch scores at the first days of starting either cream and our multivariate analysis did not show an effect of sequence, we believe this has not affected our results. In conclusion, based on our findings doxepin cream is not effective in reducing itch in burn patients in our study population compared to a placebo cream. Thus, we do not recommended to use doxepin cream as a standard treatment of itch in burn patients. However, doxepin might be indicated in a selective group of patients with younger and more superficial burn scars in which histamine plays a more significant role in the presence of itch. Future studies of pruritus treatment in burn patients should take these distinctions into account.
Declarations of interest None.
Source of funding The study was funded by the Dutch Burns Foundation (reference number 11.101), which had no involvement in the collection, analysis and interpretation of data, writing the report and decision to submit the article for publication.
Please cite this article in press as: K.A.A. Kwa, et al., Doxepin cream is not effective in reducing itch in burn scar patients: A multicenter triple-blind randomized clinical crossover trial, Burns (2019), https://doi.org/10.1016/j.burns.2019.11.006
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Acknowledgement We gratefully acknowledge the research nurses Nicole Trommel and Matthea Stoop for their contribution to this study. Furthermore, we thank the department of Clinical Pharmacy, specifically Marinus van Hulst, hospital pharmacist for their help in conducting the study.
Appendix A. Study assessment schedule
Timepoint 0 Baseline data Burns Itch Questionnaire POSAS VAS itching Side effects Use of other medication Use of escape moisturizer Use of pressure garments
Daily 1 14
X X
Day 14
Daily 22 35
X
At 5 6 weeks X
X X X X
X X X
X
X
X
X
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[10] Zachariah JR, Rao AL, Prabha R, Gupta AK, Paul MK, Lamba S. Post burn pruritus–a review of current treatment options. Burns 2012;38(5):621 9. [11] Bernstein JE, Whitney DH, Soltani K. Inhibition of histamineinduced pruritus by topical tricyclic antidepressants. J Am Acad Dermatol 1981;5(5):582 5. [12] Richelson E. Tricyclic antidepressants and histamine H1 receptors. Mayo Clin Proc 1979;54(10):669 74. [13] Demling RHDL, Nelson RD. Pruritus and burn wounds. Wounds 2002;14(1):1 13. [14] Demling RHD. L. Topical doxepin signifanctly decrease itching and erythema in the healed burn wound. Wounds 2002;14 (9):334 9. [15] Demling RHD. L. Topical doxepin significantly decreases itching and erythema in the chronically pruritic burn scar. Wounds 2003;15(6):1 8. [16] Kwa Kaap A, Middelkoop E, Van Baar ME, Niemeijer AS, Breederveld RS, Nieuwenhuis , et al. Comparing doxepin cream to oral antihistamines for the treatment of itch in burn patients: a multi-center triple-blind randomized controlled trial. Burns Open 2019;3(4):135 40. [17] Doig GS, Simpson F. Randomization and allocation concealment: a practical guide for researchers. J Crit Care 2005;20(2)187 91 discussion 91-3. [18] Van Loey NE, Hofland HW, Hendrickx H, Van de Steenoven J, Boekelaar A, Nieuwenhuis MK. Validation of the burns itch questionnaire. Burns 2016;42(3):526 34. [19] van der Wal MB, Tuinebreijer WE, Bloemen MC, Verhaegen PD, Middelkoop E, van Zuijlen PP. Rasch analysis of the Patient and Observer Scar Assessment Scale (POSAS) in burn scars. Qual Life Res 2012;21(1):13 23. [20] Ahuja RB, Gupta GK. A four arm, double blind, randomized and placebo controlled study of pregabalin in the management of post-burn pruritus. Burns 2013;39(1):24 9. [21] Cheng B, Liu HW, Fu XB. Update on pruritic mechanisms of hypertrophic scars in postburn patients: the potential role of opioids and their receptors. J Burn Care Res 2011;32(4): e118 25. [22] Goutos I. Neuropathic mechanisms in the pathophysiology of burns pruritus: redefining directions for therapy and research. J Burn Care Res 2013;34(1):82 93. [23] Goutos I, Eldardiri M, Khan AA, Dziewulski P, Richardson PM. Comparative evaluation of antipruritic protocols in acute burns. The emerging value of gabapentin in the treatment of burns pruritus. J Burn Care Res 2010;31(1):57 63. [24] Wu J, Xu R, Zhan R, Luo G, Niu X, Liu Y, et al. Effective symptomatic treatment for severe and intractable pruritus associated with severe burn-induced hypertrophic scars: A prospective, multicenter, controlled trial. Burns 2016;42(5):1059 66. [25] Drake LA, Fallon JD, Sober A. Relief of pruritus in patients with atopic dermatitis after treatment with topical doxepin cream. The Doxepin Study Group. J Am Acad Dermatol 1994;31(4):613 6. [26] Church MK, Maurer M, Simons FE, Bindslev-Jensen C, van Cauwenberge P, Bousquet J, et al. Risk of first-generation H(1)antihistamines: a GA(2)LEN position paper. Allergy 2010;65 (4):459 66. [27] Shelley WB, Shelley ED, Talanin NY. Self-potentiating allergic contact dermatitis caused by doxepin hydrochloride cream. J Am Acad Dermatol 1996;34(1):143 4. [28] De Vet HCW, Terwee CB, Mokkink LB, Knol DL. Sample size for reliability studies. In: De Vet HCW, editor. Measurement in medicine. Cambridge University Press; 2011. p. 126 8.
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Available online at www.sciencedirect.com
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Doxepin cream is not effective in reducing itch in burn scar patients: A multicenter triple-blind randomized clinical crossover trial K.A.A. Kwa a,b, * , C.M. Legemate c,d,e , A. Pijpe a, A. Meij-de Vries a, E. Middelkoop a,d,e , M.E. van Baar c,e,f, R.S. Breederveld a,b , M.K. Nieuwenhuis e,g, ** a
Burn Center, Red Cross Hospital, Beverwijk, The Netherlands Department of Traumasurgery, Leiden University Medical Center, Leiden, The Netherlands c Burn Center Maasstad Hospital, Rotterdam, The Netherlands d Amsterdam UMC, Free University Amsterdam, Department of Plastic, Reconstructive and Hand Surgery, Amsterdam Movement Sciences, Amsterdam, The Netherlands e Association of Dutch Burn Centers, The Netherlands f Department of Public Health Erasmus MC, Rotterdam, The Netherlands g Burn Center, Martini Hospital, Groningen, The Netherlands b
article info
abstract
Article history:
Objective: To evaluate the effect of doxepin hydrochloride 5% cream on reducing pruritus in
Accepted 13 November 2019
burn scar patients compared to a placebo cream.
Available online xxx
Method: We conducted a multicenter triple-blind randomized clinical placebo-controlled crossover trial in which burn patients 18 years with an itch intensity 3 on a Visual Analogue
Keywords: Itch Pruritus burn* Doxepin Antihistamines
Scale (VAS) were randomized between a doxepin-placebo or placebo-doxepin treatment protocol. Patients used each cream during two weeks with a wash-out period of one week in between. Primary outcome was change in itch intensity in two weeks’ time using the VAS. Secondary outcome included the impact of itch (Burn Itch Questionnaire). Other parameters were the use of hydrating cream, silicon treatment, pressure garments, and other antipruritic medication. Results: Twenty-seven patients were included. The change in itch intensity (VAS) was not different during the doxepin and placebo period (p=0.994); neither the doxepin cream nor placebo cream reduced itch intensity. However, based on the Burn Itch Questionnaire, we observed a statistically significant decrease in itch intensity and improvement in impact scores in both treatment groups, but no difference in the degree of reduction between the groups. Conclusion: Doxepin cream was not effective in reducing pruritus in our burn patient study population. © 2019 Elsevier Ltd and ISBI. All rights reserved.
Abbreviations: AE, adverse event; BIQ, Burn Itch Questionnaire; IQR, Inter Quartile Range; MIC, minimal important change; POSAS, Patient and Observer Scar Assessment Scale; SD, standard deviation; TBSA, total body surface area; VAS, Visual Analogue Scale. * Corresponding author at: Red Cross Hospital, Burn Center, Vondellaan 13, 1942 LE Beverwijk, The Netherlands. ** Corresponding author at: Martini Hospital, Burn Center, Van Swietenplein 1, 9728 NT Groningen, The Netherlands. E-mail addresses: [email protected] (K.A.A. Kwa), [email protected] (C.M. Legemate), [email protected] (A. Pijpe), [email protected] (A. Meij-de Vries), [email protected] (E. Middelkoop), [email protected] (M.E. van Baar), [email protected] (R.S. Breederveld), [email protected] (M.K. Nieuwenhuis). https://doi.org/10.1016/j.burns.2019.11.006 0305-4179/© 2019 Elsevier Ltd and ISBI. All rights reserved.
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1.
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Introduction
Pruritus occurs in 67 87% of the burn patients [1 3] and can have a negative effect on their quality of life [4 7]. Although the pathophysiology of pruritus is not fully understood, the role of histamine release is well described [8,9]. Therefore, the standard of care treatment against pruritus is oral antihistamines [2,10]. Unfortunately, antihistaminic agents have a limited effect as only 20% of patients experience complete relief [2]. Doxepin hydrochloride 5% cream is a topical antihistaminic agent used for the treatment of pruritus caused by eczema with a greater antihistaminic potency than other antihistaminic agents [11,12]. Three studies by Demling et al. examined the effect of doxepin cream on itch in burn patients. These all showed a significant improvement of pruritus [13 15]. However, these studies had several limitations. Only patients with spontaneously healed burn wounds were included and the studies that described the scar age of the patients only included patients with burn scars less than one year old. Moreover, none of the studies used a placebo-controlled group. There is a need for better treatment against pruritus in burn patients, as is also expressed by the Dutch Society of Burn survivors. Therefore, we performed a randomized clinical trial to evaluate whether doxepin cream was more effective in reducing pruritus than an oral antihistamine [16]. This trial showed an equal decrease in both treatment arms and thus there was no superior effect of doxepin cream in the reduction of pruritus in burn patients. However, the level of evidence was limited due to a premature ending of the study because of the high demands of the trial (multipele checkups, frequent application of study cream, and refrainment from driving were frequently mentioned), and a superior effect of doxepin cream in the reduction of pruritus in burn patients could not be ruled out. To examine the full potential of doxepin cream in patients with burn scars, we designed and conducted a second clinical trial taking into account the limitations of the first study. The objective of this study was to evaluate the effect of doxepin hydrochloride 5% cream on reducing pruritus in burn scar patients compared to a placebo cream.
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2.
Methods
2.1.
Study design
Our study was a multicenter triple-blind randomized clinical placebo-controlled crossover trial. Patients were randomized to receive treatment according to the schedule presented in Fig. 1, either doxepin-placebo or placebo-doxepin. An allocation sequence was developed using mixed randomization. The sequence was generated by someone not involved in data acquisition using www.randomization.com. Treatment allocation, concealed using sequentially numbered opaque sealed envelopes [17], was described as either A B or B-A whereby only the distributing pharmacists knew which letter referred to which cream. Thus, researchers, physicians as well as the patients were blinded. Unblinding took place after statistical analysis was completed. The study was conducted according to the principles of the Declaration of Helsinki (Ethics manual World Association 2nd edition 2009) and in accordance with the Medical Research Involving Human Subjects Act (WMO). The study was approved by the Medical Research Ethics Committee Noord-Holland (NL59341.094.16), and was registered in the Netherlands Trial Registry (NTR number NTR6413).
2.2.
Participants
Patients were recruited from the outpatient clinics in the three burn centers in the Netherlands. Inclusion criteria were: age 18 years, healed burns, a 3 score on the Visual Analogue Scale (VAS) for itch intensity at time of enrolment and a total body surface area (TBSA) that itched not exceeding 10%. Exclusion criteria were: patients who were unable to give informed consent, unable to understand and fill in itch intensity scores and questionnaires, patients with a cutaneous or systematic disease that causes itch and patients with any disease or condition associated with adverse effects using doxepin cream. The estimated effect size for the sample size calculation was based on the study by Demling [15]. The calculated total sample size with an a level of 0.05, a power of 80% and an anticipated dropout rate of 25% was 27 patients.
Fig. 1 – Study design.
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2.3.
Study procedure
The active product doxepin (Xepin 5% cream, Bioglan AB, Malmö, Sweden) and the placebo vehicle cream (Bioglan AB, Malmö, Sweden) looked identical and were put in 25g plastic tubes labeled with the prescribed date of use. The duration of the study was five weeks. Patients used the first prescribed cream for two weeks, followed by a wash-out period of one week and subsequently used the other cream for another two weeks. Every patient was contacted after 2 3weeks to verify the use of the right cream by reminding them to switch to the second cream. Patients were required to use each cream at least once daily for two consecutive weeks with a maximum of four times a day. The area that itched the most was designated as the study area. Patients were allowed to wear pressure garments, use hydrating cream and continue other medications against itch. Patients were not allowed to start with other medications against itch simultaneously with the start of the study.
2.4.
Study outcomes
2.4.1.
Primary outcome
Our primary outcome was the difference in change in itch intensity after two weeks of treatment between doxepin and placebo cream (D(Day)1 vs D14 and D22 vs D35) as measured by the VAS. The anchor on the far left side of the 100mm scale indicated ‘no itch’ and on the far right side ‘worst itch imaginable’. Patients were required to put a mark on the scale to indicate the itch intensity they experienced. The VAS was assessed on a daily basis in a patient journal during the period they used the study cream. In addition, the journal contained daily questions regarding the use of other anti-pruritic medication, hydrating cream, pressure garments and the experience of adverse events (AE) (Appendix A).
2.4.2.
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Scar Assessment Scale) which consists of a Patient and an Observer Scale [19]. The item ‘vascularity’ and the overall impression score of the Observer and Patient part were compared to the VAS itch score at the start to assess whether there was a correlation between scar quality and itch. The POSAS was assessed at W0.
2.6.
Statistical analysis
Normality of continuous data was tested with the Shapiro Wilk test and by inspecting the frequency distributions (histograms). Homogeneity of variances was tested using the Levene’s test. Data were analyzed according to the intentionto-treat protocol. The baseline characteristics and outcome data are described with mean and standard deviation (SD) (parametric data) or medians and interquartile range (IQR) or first quartile third quartile (non-parametric data). For categorical data, percentage was calculated. Mean differences in itch scores were analyzed using the paired t-test for parametric data and the Wilcoxon test for non-parametric data. The Pearson correlation analysis was performed to assess linear relationships between two continuous variables. The course of the itch-scores in time during the doxepin and placebo periods was evaluated using line charts. Exploratory generalized linear mixed model analysis was used to assess the effect of the intervention on VAS itch intensity (with a random intercept on id and adjusted for the baseline values D1 and D22) and to assess the influence of possible relevant covariates (sequence of treatment, age, sex, grafted burns or use of hydrating cream). A p-value of<0.05 was taken as a threshold for statistical significance. Data were analyzed using the IBM Statistical Package for the Social Sciences (SPSS) version 24.
3.
Results
3.1.
Study population
Secondary outcome
The secondary outcome was the assessment of the impact of itch measured with the Burn Itch Questionnaire (BIQ). Van Loey et al. validated the BIQ for three separate subscales which include: (1) burn severity, (2) sleep interference and (3) daily life [18]. The 22 items were scored on a 10-point scale (0=no itch to 9=most severe itch) or a 10-point Likert Scale (0=totally disagree to 9=totally agree). The itch intensity score from the BIQ was used as a second itch intensity score as it measures itch experienced in the last week/day instead of only on the same day as with the VAS. The patient filled out the BIQ before start of the study at week 0 (W0), at the end of week two after the use of the first prescribed cream (W2) and at the end of week five after the use of the second prescribed cream (W5) (Appendix A).
A total number of 27 patients was included between June 2017 and March 2018. Thirteen patients started with doxepin cream and fourteen patients started with the placebo cream. One patient switched back to the first cream on her own initiative after the second cream did not relieve the itch and the first prescribed cream did. The first cream turned out to be doxepin. This patient did not show up on follow up appointments, and was therefore lost to follow-up after the start of the use of the second prescribed cream. One other patient quit the study prematurely due to increase of itch after the use of what turned out to be the doxepin cream. This patient did provide study data (Fig. 2).
2.5.
3.2.
Other parameters
The following patient parameters were derived from the patients electronic medical record: age, sex, cause of burn, percentage TBSA burned, location of burn, time till complete wound healing, percentage TBSA that itched, skin grafting (yes/no), duration of itch, comorbidities, and allergies. We also assessed scar quality using the POSAS (Patient and Observer
Patient and clinical characteristics
Our study population consisted of 11 men and 16 women (Table 1). The mean age was 40.4 (SD 15.5) years. The median percentage TBSA of the study area was 1.5 (IQR, 1.2). The causes of burn injuries were flame (51.9%), scald (18.5%), contact (11.1%), chemical (14.8%) and grease (3.7%). The study areas were located on the leg (44.4%), arm (37.0%), head (11.1%) and
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Fig. 2 – Flowchart.
trunk (7.4%). Four patients were using antipruritic medication (e.g. Promethazine, Clemastine) before start of the study. The mean vascularity score of the observer part of the POSAS was 3.7 (SD 1.5). The mean overall impression score of the Observer part was 3.8 (SD 1.1). There was no correlation between the vascularity and the itch score using the VAS at day 1 (r= 0.358, p=0.093). There was also no correlation between
Table 1 – Patient characteristics. Patient characteristics (n=27) Male (%) Age in years Time to wound healing study area in days Scar age in days Duration of itch in days Days since start of itch after burn %TBSA burned %TBSA skin grafted %TBSA study area %TBSA study area skin grafted
40.7 40.4 15.5 36.3 17.1 148, 75 508 78, 30 350 45, 18 143 4.2, 1.5 9.0 1.0, 0 2.5 1.5, 0.8 2.0 0.5, 0 1.5
Values are presented in either percentages, means standard deviation or median with first quartile third quartile. TBSA=Total Body Surface Area, BIQ= Burn Itch Questionnaire.
the overall impression score of the patient and the itch score using the VAS at day 1 (r=0.043, p=0.845).
3.3.
Itch scores using VAS
There was no difference between the doxepin and placebo group in the mean itch intensity change using the VAS (p=0.994) (Fig. 3). Both treatments showed a small but not statistically significant decrease in itch intensity over two weeks’ time. Doxepin treatment (n=20) decreased from 3.39 (SD 2.45) to 2.88 (SD 2.72) (p=0.335) and placebo treatment (n=20) decreased from 3.82 (SD 2.44) to 2.88 (SD 2.80) (p=0.115). There was no difference in baseline itch score between the group starting with doxepin (3.41 SD 2.56) or the group starting with placebo cream (3.94 SD 2.44) (p=0.440). Seven measurements in the VAS daily journal were missing in each arm due to the following reasons: stopped using one of the creams during the study at some point (n=3), lost their journal (n=2), incomplete VAS scores in the journals (n=3), and lost-to-follow-up (n=1). Exploratory generalized linear mixed model analysis did not reveal an effect of doxepin treatment on itch intensity (VAS) (b 0.104, p=0.384). There were no confounders or effect modifiers. Itch at baseline was independently associated with the outcome (b 0.514, p<0.01).
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(4%), drowsiness (4%), and the formation of small wounds (4%). The experienced AE’s during placebo treatment were the formation of small wounds (12%), dry skin (12%), increase in itch (4%), and drowsiness (4%).
3.6.
Fig. 3 – VAS Itch scores change between start and end of use of doxepin and placebo over two weeks’ time. Values are presented as mean with standard deviation. *Within group analysis: Paired Samples t-test. **Between group analysis: Paired Samples t-test.
3.4.
Itch score and impact of itch using BIQ
There was no significant difference between the doxepin and placebo group in mean itch intensity change (p=0.600). Both treatments showed a significant decrease in itch intensity between start and end of each cream. Doxepin treatment (n=25) decreased itch from 6.0 [4.0 7.0] to 4.0 [1.0 6.0] (p=0.003) and placebo treatment (n=24) decreased itch from 6.0 [4.0 7.0] to 5.0 [2.3 5.8] (p=0.002). There was no significant difference between both treatments in the scores on the domains ‘itch severity’ (p=0.492), ‘sleep interference’ (p=0.924) or ‘daily life’ (p=0.917). Both treatments showed a significant decrease in BIQ scores in the domains ‘itch severity’ and ‘sleep interference’, but not in the domain ‘daily life’ (Table 2).
3.5.
Adverse events
There were two serious adverse events in one patient, both not deemed related to the study medication. One patient with a history of psychiatric diseases and admissions was admitted on the psychiatric ward twice during the study period. Adverse events were experienced by 7 and 4 patients in the doxepin and placebo treatment arm (p=0.453), respectively. The experienced AE’s during the doxepin treatment were an increase in itch (12%), tight/irritated skin (12%), mild rash (8%), dry skin
Other treatments
Two patients were using an oral antihistaminic agent during the whole study period. Two other patients used an oral antihistaminic agent sporadically (2 4 times) during the study period. Eight patients were using hydrating cream, and two patients had silicon treatment during the study period. There were seven patients who wore pressure garments throughout their whole study period.
4.
Discussion
Our study assessed whether doxepin cream was effective in reducing itch in burn scar patients compared to a placebo cream. Our results showed no difference between the doxepin and placebo group in the mean itch intensity change using either the VAS or the BIQ. The lack of change in itch intensity in the doxepin group is in contrast to studies performed by Demling et al. who showed a significant decrease in itch with patients using doxepin cream [14,15]. This discrepancy may be due to differences in included patients. In our study we included patients with skin grafted burns and patients with relatively old scars, while Demling et al. only included patients with spontaneously healed burns and scars less than one year old. The antihistaminic effect might not be as effective in patients with skin grafted burns or older scars. Mechanisms other than histamine release also play a role in the pathogenesis of itch in burn scar patients [20 23]. Thus, doxepin might be effective in a selective group of patients, namely those with young burn scars in which histamine is more involved in the pathogenesis of itch and a stronger antihistaminic agent is indicated. We were not able to compare younger versus older scars, because our power analysis did not take into account this distinction. In contrast to the VAS scores derived from the daily journal, the BIQ itch intensity score did show a statistically significant decrease of itch with both treatments. It is debatable which instrument assesses the effectiveness of treatment best. In our previous study [16] we noticed that the daily assessment of itch scores led to highly variable scores as itch can vary per day and during the day. This was also the case in this study. Therefore,
Table 2 – Secondary outcomes: change in BIQ itch impact domains scores between the start and end of the use of the creams and between the groups. p-Value
Doxepin n BIQ BIQ BIQ a
itch severity sleep interference daily life
23 25 25
Pre 5.0 [3.5 6.5] 3.5 [1.5 6.0] 1.8 [0.0 3.0]
Post
within
3.3 [1.3 5.0] 2.0 [0.0 4.0] 0.8 [0.0 3.0]
a
0.006 0.013a 0.295a
Placebo n 22 24 24
Pre 4.5 [3.5 6.5] 3.8 [1.4 6.1] 1.9 [0.0 3.1]
Post 4.0 [1.2 5.0] 2.1 [0.0 3.8] 0.6 [0.3 2.1]
p-Value
p-Value
within
between
a
0.006 0.005a 0.106a
0.492a 0.924a 0.917a
Values are presented as median with interquartile range (Q1 Q3). Wilcoxon Signed Ranks test.
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the use of the BIQ itch score, which assesses itch experienced in the past week/day, might be more adequate and reliable. This would mean that both the doxepin as well as the placebo cream led to a decrease in itch intensity. The reduction of itch intensity with the placebo treatment was less than with the doxepin cream. However, this difference was not significant. A placebo effect is possibly effective here, which is not uncommon in studies comparing active substance cream to placebo cream in reducing itch [24,25]. The decrease in itch intensity scores derived from the BIQ is accompanied by a decrease in BIQ scores of the subscales’ itch severity’ and ‘sleep interference’, but not ‘daily life’. A decrease in these scores indicates less impact of itch on life. These results correspond with the results of our previous study in which itch significantly decreased and BIQ scores improved [16]. The POSAS items ‘vascularity’ and ‘general impression’ did not show a correlation with itch at the start of the study. Earlier studies showed that erythema, which is said to be caused by an increase in vascularity that is more apparent in an active scar, corresponded with a higher itch score [14,15]. This was not evident from our study, possibly due to the relative older scars in our population. The most notable adverse event of antihistaminic agents is somnolence [26]. In our study, somnolence was only reported in two patients, of which one patient reported it during the use of the placebo cream. This is in contrast to both Demling’s studies in which somnolence occurred in 10 15% of patients using doxepin cream [14,15], and in contrast to our recent study [16] in which 50% of patients reported somnolence. The latter was possibly due to priming of patients in this study (i.e. patients were asked whether they experienced somnolence on a daily basis). Another possible explanation for the difference in reported somnolence between our study and previous studies could be the total dosage of doxepin cream that the study patients received. Our study area was relatively small, with a median of 1.5% TBSA, while Demling’s was 13% [15] and 5% [14]. In addition, Demling’s patients were required to use the cream four times a day, while our patients were required to use the cream once a day with a maximum of four times a day. Another adverse event mentioned in our study were skin problems, including dry or irritated/tight skin. While an irritated or ‘tight skin’ was reported by three patients, two patients specifically reported a mild rash. This is a known side effect described with the use of doxepin cream, especially in chronic users [27]. Our study protocol we described that we wanted to determine the Minimal Important Change (MIC), which is the smallest change in treatment outcome (itch intensity score) that a patient would identify as relevant. However, due to missing data we only had 36 measurements of 20 patients to determine the MIC, while analysis requires data of at least 50 measurements [28]. Therefore, we decided it was not justified to determine the MIC of the itch score. We do believe it is valuable to determine a MIC for itch in burn patients to know the clinical relevance of combatting itch and to evaluate study outcomes. We recommend that to determine the MIC in burn patients, an adequate sample size calculation should be made, taking into account a loss to follow up. Our study has several strengths. First, we used a randomized crossover design which was suitable for our study population since we expected a chronic and stable situation
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regarding itch intensity over five weeks’ time. Due to this design fewer patients were required and each patient served as his/her own control, which limits the influence of confounding variables. Second, we used a placebo arm to account for the placebo effect which allows detection of the effects of the treatment itself, and strengthens the study design. Third, our patients, outcome assessors and statistical analysts were blinded, thereby preventing potentially biased estimates of treatment effects. Our study also has some limitations. First, we did not make a distinction between patients with different ages of scars or the length of time they experienced itch, which resulted in a heterogeneous study population. The mechanism of pruritus is complex and to a large extent unknown. The pathophysiology in burn patients in the burn scar maturation phase versus patients whose burn scars have matured might be different. In the acute phase, histamine release plays an important role in itch sensation, while in the maturated phase, neurological factors might play a role [8,9,22]. Unfortunately, our sample size did not allow to make a distinction between these two groups. Second, patients were allowed to apply the cream 1 4 times a day, but we did not assess how often the patients actually used the cream on a daily basis. Thus, an underestimation of the effect of doxepin due to underuse cannot be excluded. It might be that the patients did not need to apply the cream more often, because the itch was relieved enough. However, it could also be that patients did not use the maximum number of applications of cream due to inconvenience, for instance the seven patients who wore pressure garments, or due to lack of effort. Either way, that would make doxepin cream as a treatment not suitable for this patient population. Finally, for our secondary outcome on itch intensity we used the BIQ score taken at baseline as a control for both treatment periods. However, as we did not detect a difference between the VAS itch scores at the first days of starting either cream and our multivariate analysis did not show an effect of sequence, we believe this has not affected our results. In conclusion, based on our findings doxepin cream is not effective in reducing itch in burn patients in our study population compared to a placebo cream. Thus, we do not recommended to use doxepin cream as a standard treatment of itch in burn patients. However, doxepin might be indicated in a selective group of patients with younger and more superficial burn scars in which histamine plays a more significant role in the presence of itch. Future studies of pruritus treatment in burn patients should take these distinctions into account.
Declarations of interest None.
Source of funding The study was funded by the Dutch Burns Foundation (reference number 11.101), which had no involvement in the collection, analysis and interpretation of data, writing the report and decision to submit the article for publication.
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Acknowledgement We gratefully acknowledge the research nurses Nicole Trommel and Matthea Stoop for their contribution to this study. Furthermore, we thank the department of Clinical Pharmacy, specifically Marinus van Hulst, hospital pharmacist for their help in conducting the study.
Appendix A. Study assessment schedule
Timepoint 0 Baseline data Burns Itch Questionnaire POSAS VAS itching Side effects Use of other medication Use of escape moisturizer Use of pressure garments
Daily 1 14
X X
Day 14
Daily 22 35
X
At 5 6 weeks X
X X X X
X X X
X
X
X
X
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Please cite this article in press as: K.A.A. Kwa, et al., Doxepin cream is not effective in reducing itch in burn scar patients: A multicenter triple-blind randomized clinical crossover trial, Burns (2019), https://doi.org/10.1016/j.burns.2019.11.006