Standard Topical Ointment or Doxepin against pruritus in burn patients

Pruritus is a common and impairing problem in patients after burn injury, with
prevalence rates up to 87%. Pruritus impairs quality of life by causing stress,
affecting mood and cognition and can give difficulty sleeping. It is associated
with several risk factors. Up to three months post burn, complaints of itch
were predicted by female sex, number of surgical procedures, percentage Total
Body Surface Area burned (%TBSA) and post-traumatic stress symptoms, as
measured by the Impact of Event Scale (IES) two weeks post burn.

The mechanism of pruritus is complex and to a large extent unknown. It involves
both peripheral and central factors. The best described mediator of peripheral
origin is histamine. Histamine is released during acute inflammation and in
granulation tissue (formed as a by-product of collagen production) which might
explain the presence of pruritus in the early phases of wound healing.
Antihistamines, which by agonising histaminic receptors, have therefore been
the standard of care (SOC) in the treatment of pruritus in patients after burn
injury.

Doxepin is a dibenzoxepin tricyclic compound used for the treatment of
depression. In 1994 topical Doxepin hydrochloride 5% was marketed for the
treatment of pruritus due to eczema. The complete working mechanism of Doxepin
is not known, but one of the mechanisms is the antihistaminic effect. Doxepin
has an antihistaminic potent against H1 and H2 receptors, more than 50-800
times higher than other known antihistaminic agents.
In several studies by Demling, Doxepine significantly reduced itch in burn
patients. However, these studies included a subpopulation of burn patients and
no placebo cream was used.

to evaluate whether Doxepin hydrochloride 5% cream versus a placebo cream
significantly reduces pruritus in burn patients by comparing itch scores.

This is a multicentre, double-blind, randomized, placebo-controlled cross-over
trial.

Crossover study: patients will receive both the Doxepin cream as well as the
placebo cream. With which cream they will start will bed decided through
randomisation. Three phases:
1. Two weeks cream A
2. One week: wash out period
3. Two weeks cream B

The treatment period will be five weeks in total. Patients will visit the
outpatient clinic after these 5 weeks. During the two times two week treatment
period, patients are required to keep a diary in which they have to score their
itch, and describe side effects, whether they use pressure garments and other
creams or escape medications. Patients are required to fill in the Burn Itch
Questionnaire after each two-week treatment with a cream and before inclusion
(a total of three times).

Patients might benefit from participating as the expectation is that Doxepin
cream relieves itch. Reported risks for Doxepin hydrochloride 5% cream include
the development of an allergic contact dermatitis and toxicity in case of
topical overdose. Application of Doxepin cream might give some stinging. A
possible side effect is somnolence, especially in the first few days. Several
cases of allergic contact dermatitis have been reported and care should be
taken in long-term users. It is advised Doxepin cream application should be
limited to a TBSA of no more than 10%. In one case-report, a ninety-year-old
woman developed bullous pemphigoid after using Doxepin cream for 20 days for
complaints of itch. The symptoms diminished after doxepin was stopped.
Systemic effects which have been observed with orally administered doxepin
(e.g. depression) are rarely observed with topical Xepin. These may include
anticholinergic reactions (dry mouth, changes in taste, dry eyes, blurred
vision, urinary retention), central nervous system effects other than
drowsiness (headaches, fever, dizziness) and gastro-intestinal effects (nausea,
indigestion, vomiting, diarrhea or constipation)