JDDG 2015

CME-Article
Submitted: 15.8.2014 DOI: 10.1111/ddg.12522

Accepted: 10.9.2014
Conflict of interest
None.
Clinical management of pruritus
Sonja Ständer 1, Claudia Summary

Zeidler 1, Nina Magnolo1, Ulrike The care of patients with chronic pruritus as a symptom of a wide variety of under-
Raap2, Thomas Mettang3, lying diseases continues to confront dermatologists with diagnostic and therapeutic
Andreas E. Kremer4, Elke challenges. However, a structured history and a physical examination may already
Weisshaar5, Matthias Augustin6 substantially help in narrowing down the number of potential differential diagno-
(1) Competence Center Chronic ses. Apart form reducing the intensity of pruritus, identification and appropriate
Pruritus, Department of Dermatology,

treatment of the underlying disease are important needs of patients. If these goals
University Hospital Muenster, Germany doesn’t lead to improvement of itch, current guidelines provide a number of topical
(2) Department of Dermatology, and systemic therapies for symptomatic treatment. Various skin lesions (for examp-
Allergology, and Venereology, Medical le, xerosis caused by irritant substances, secondary scratch lesions) prompt patients
School Hannover Germany to consult a dermatologist, but most cases require an interdisciplinary therapeutic
(3) Department of Internal Medicine, DKD approach to identify potential internal medicine, neurologic, or psychosomatic as-
Helios Hospital, Wiesbaden, Germany pects. Although great strides have been made in basic research, specific therapies
(4) Department of Internal Medicine 1, are still rare, and a precise knowledge of the legal framework for the implementation
Gastroenterology, Pneumology, and of guidelines (for example, off-label use) is essential.
Endocrinology, Friedrich-Alexander- This CME article gives an overview of the causes of and treatment options for chronic
University, Erlangen, Germany pruritus and discusses both advances in basic research as well as progress in clinical
(5) Department of Clinical Social knowledge.
Medicine, Occupational and
Environmental Dermatology, University
Hospital Heidelberg, Germany Introduction
(6) Competence Center for Research on
Health Care Provision in Dermatology Pruritus can be divided into an acute and a chronic form (duration ≥6 weeks)
(CVderm), and Medical Care (IVDP), [1]. This classification is not based on pathophysiologic considerations, but rather
University Medical Center Hamburg- on criteria for optimal patient care. Chronic pruritus requires further diagno-
Eppendorf, Hamburg, Germany stic evaluation (see below). This definition is primarily based on case reports of
patients with paraneoplastic pruritus who were diagnosed with lymphoma rela-
Section Editor tively shortly after the onset of pruritus (6–12 weeks). Moreover, women with
Prof. Dr. D. Nashan, Dortmund pregnancy-related intrahepatic cholestasis should be evaluated as early as possible
to minimize any risk for the unborn child. Based on international consensus, a
threshold of six weeks has been set for the definition of chronic pruritus requiring
diagnostic workup. This differs significantly from the definition of chronic pain
(≥ 6 months).
The care of patients with chronic pruritus (CP) requires interdisciplinary co-
The care of patients with chronic operation that, depending on diagnostic findings, comorbidities, age, and the-
pruritus requires interdisciplinary rapeutic goals, involves dermatologists, internists, general practitioners, pain
cooperation. therapists, neurologists, gynecologists, pediatricians, experts in psychosomatic
medicine, and psychiatrists (Table 1). A strict differentiation of the individual
© 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1302 101
CME Article
Table 1 Interdisciplinary care for chronic pruritus patients.
Symptoms Specialist
Generalized pruritus with dysesthesia Neurologist, psychosomatic
medicine specialist
Psychological cofactors or comorbidities Psychiatrist, psychosomatic
including delusional parasitosis medicine specialist
Localized neuropathic pruritus Radiologist (MRI), orthopedic
surgeon, neurologist
Localized genitoanal pruritus Gynecologist, proctologist, internist
(frequently sorbitol intolerance)
Pruritus during pregnancy Gynecologist, internist
forms of CP from other disease entities is not always possible – or attempted –

leading to interdisciplinary overlaps. For example, patients with delusional pa-
rasitosis often prioritize pruritus and demand diagnostic evaluation of potential
organic correlates. These patients will hardly benefit form antipruritic treatment,
but rather require psychiatric care. In other forms of CP, when symptoms occur
independent of the underlying disease, a specialist cares for the patient in coope-
ration with the general practitioner or dermatologist (for example, CP despite
successful therapy of Sézary syndrome). Despite the high incidence (7 %) and
prevalence (17–25.5 %) of CP in Germany [2], it is currently impossible to com-
prehensively establish specialized outpatient clinics, necessitating adequate care
to rely on close cooperation between primary health care providers and experts at
the few specialized national pruritus centers. Current guidelines [1] have proven
helpful in providing quick initial access to the topic. To complement these guide-
lines, the objective of this review article is to present the practical aspects of CP
patient care.
Underlying disorders as cause for pruritus
Chronic pruritus may be caused by a multitude of underlying diseases [1], whose

Psychosomatic pruritus continues to respective prevalence varies greatly, which is why not all pruritogenic disorders
represent a diagnostic problem. occur similarly frequently. Somatoform pruritus remains a diagnostic problem,
as clear criteria have not been defined. Therefore, its prevalence is probably much
lower than presumed (Figure 1). Among dermatoses, some are almost always as-
sociated with CP.
Dermatoses
CP is associated with many dermatoses, including inflammatory and infecti-

ous skin diseases, autoimmune, genetic, and pregnancy-related disorders as well
as neoplasms. The onset of pruritus usually coincides with the onset of typical
skin lesions, however, in “invisible” dermatoses, its clinical presentation may be
without apparent skin lesions. The clinical picture of a pruritic dermatosis may
be disguised by scratch marks, for example, lichenification or pruriginous variant
of atopic d
ermatitis, thus delaying the diagnosis. Differentiation of scratch marks
102 © 2015 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2015/1302
CME Article
Figure 1 Percentage of various underlying diseases according to the database of

the Competence Center Chronic Pruritus (KCP) in Muenster, Germany. In 33.5 % of
patients, CP is caused by a dermatosis; in 7.8 %, by a systemic disease; in 9.2 %, by
neuropathy; in 1.2 %, by a somatoform disorder. In 40.2 % of patients, there is more
than one underlying disease (multifactorial pruritus); no cause was found in 8.1 % of
individuals.
from primary dermatoses by the dermatologist is therefore an essential task in the

care of CP patients. Patients referred from other specialists should therefore always
undergo clinical and/or histologic evaluation of skin lesions.
Frequently occurring in early childhood, atopic dermatitis is almost always
Other inflammatory skin diseases as- accompanied by CP. Urticaria is another dermatosis almost always marked by pru-
sociated with severe CP include lichen ritus; here, however, scratch lesions are rare. With a prevalence of 2 % in Europe,
planus, lichen sclerosis et atrophicus, psoriasis vulgaris is a common skin disorder, accompanied by pruritus in 67–84 %
especially in the genital region, ery- of cases [1]. Other inflammatory skin diseases associated with severe CP include
throdermic cutaneous T-cell lymphoma lichen planus, lichen sclerosis et atrophicus, especially in the genital region, ery-
(mycosis fungoides, Sézary syndrome), throdermic cutaneous T-cell lymphoma (mycosis fungoides, Sézary syndrome), and
and Grover’s disease, the latter fre- Grover’s disease, the latter frequently showing inconspicuous flat erythematous
quently showing inconspicuous flat papules on the trunk. Without being the primary symptom, CP may also occur
erythematous papules on the trunk. in drug-induced eruptions or allergic contact dermatitis. In elderly patients, dry
skin and exsiccation dermatitis are the most frequent causes of CP. Occasionally,
chronic pruriginous scratch marks may disguise autoimmune dermatoses such as
bullous pemphigoid (Figure 2), mostly in patients ≥60 years, or Duhring’s disease
in younger individuals. Scabies is an infectious dermatosis usually causing acute,
occasionally chronic pruritus, that should be considered in the differential diag-
nosis, particularly when evaluating patients living in nursing homes or whenever
more than one family member is affected. In rare cases, genetic diseases such as
neurofibromatosis may cause CP. Pregnancy-associated dermatoses inducing CP
include, for example, atopic eruption of pregnancy (AEP), polymorphic eruption
of pregnancy (PEP), and gestational pemphigoid.
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Figure 2 Patient with bullous pemphigoid (subepidermal blister on the lateral

hand, positive direct immunofluorescence) and papular prurigo (initially present).
Systemic disorders
In systemic disorders, pruritus primarily Both localized and generalized CP is a frequent symptom in a variety of systemic
presents without any specific primary disorders [1, 3]. In systemic disorders, pruritus primarily presents without any spe-
skin lesions. Over time, however, cific primary skin lesions. Over time, however, secondary lesions, such as excoria-
secondary lesions, such as excoriations tions and nodular prurigo, arise as a result of scratching. The most common syste-
and nodular prurigo, arise as a result of mic causes of CP are chronic renal failure as well as hepatobiliary and hematologic
scratching. disorders. While chronic renal failure leads to CP in approximately 25–50 % of all
cases, irrespective of the underlying primary condition, CP is not a typical symptom
in acute renal failure or renal diseases without compromised renal function. Patients
undergoing peritoneal or hemodialysis are affected at comparable frequencies [4].
While almost all hepatobiliary diseases may lead to pruritus, it is most com-
mon in cholestatic disorders such as primary biliary cirrhosis, primary sclerosing
cholangitis, mechanical biliary obstruction in choledocholithiasis or biliary duct
tumors, and drug-induced cholestasis. Approximately 25–80 % of affected pati-
ents have CP [1]. Non-cholestatic conditions associated with CP include chronic
viral hepatitis C, alcohol-induced liver damage, and cirrhosis of any etiology. Mo-
reover, CP is the major symptom of intrahepatic cholestasis of pregnancy, usually
occurring during the 3rd trimester. Acute liver failure, however, is usually not cha-
racterized by pruritus [1].
With respect to hematooncologic disorders, especially myeloproliferative di-
seases such as polycythemia vera, essential thrombocythemia, chronic myelofibro-
sis, and hypereosinophilic syndrome as well as lymphoproliferative disorders such
as Hodgkin’s disease and non-Hodgkin lymphoma are pruritic [5].
More rarely, pruritus occurs in patients with endocrinologic diseases such as
hypo- or hyperthyroidism, primary or secondary hyperparathyroidism, and diabe-
tes mellitus. Malassimilation disorders such as lactose intolerance, chronic inflam-
matory bowel disease, gluten-sensitive enteropathy, and anorexia nervosa may, in
up to 20 % of cases, be associated with CP. All of these conditions are frequently
marked by iron deficiency, which itself may cause CP.
CME Article
Differential diagnostic considerations in CP patients should also include para-

sites, HIV and parvovirus B19 [3]. Only very rarely do solid tumors cause localized
or generalized pruritus. On the other hand, drug-induced pruritus (without rash)
is an important differential diagnosis [6], primarily caused by opioids, ACE inhibi-
tors, statins, penicillin, chloroquine, and hydroxyethyl starch infusions.
Thus, numerous differential diagnoses have to be considered and frequently
require an interdisciplinary approach.
Neuropathic pruritus
Neuropathic pruritus occurs in appro- Neuropathic pruritus occurs in approximately 9 % of CP patients and is not
ximately 9 % of CP patients and is not always caused by skin-related disorders. Various diseases such as notalgia pares-
always caused by skin-related disorders. thetica, postherpetic neuralgia, or brachioradial pruritus are considered neuro-
pathic, although their exact differentiation from neuropathic pain is not always
straightforward, as all of these entities may show neuropathic pain, other forms of
dysesthesia, and peripheral nerve hypersensitivity as well [1].
Small fiber neuropathy (SFN) is a disease of the thin myelinated and unmye-
linated cutaneous nerves. The initial stages of SFN usually predominantly pre-
sents with pain, which is why patients often primarily consult a neurologist. The
diagnosis is made on the basis of a skin biopsy and subsequent analysis of the
intraepidermal nerve fiber density. Diabetes mellitus has been described as a major
cause of SFN; others include Gougerot-Sjögren syndrome, Lupus erythematodes,
sarcoidosis, and Fabry’s disease [7].
Brachioradial pruritus (BRP) is a rare form of pruritus affecting the dorso-
lateral side of the forearms. Several reports have linked this condition to cervical
lesions or spinal neoplasms [8]. Thus, even the smallest lesions detectable on MRI
may already affect respective afferent nerve fibers.
History and clinical examination
A questionnaire (in German) is available A questionnaire (in German) is available for the structured assessment of CP symptoms
for the structured assessment of CP [9]. For follow-up documentation, the Dermatology Life Quality Index (DLQI) and
symptoms. intensity scales, such as a visual analog or numeric rating scales, have proven useful.
History taking should focus on CP-associated diseases temporally related to the
onset of CP symptoms and moreover include secondary psychosomatic symptoms
caused by CP that may necessitate additional psychosomatic care. Clinical examina-
tion includes the visual inspection of the entire integument including mucous mem-
branes, genital region, scalp, and nails. Skin color, morphology, distribution pattern,
and additional signs of a potential systemic disease should be documented, as well as
all primary and secondary lesions [1]. This should be followed by a general physical
examination (liver, lungs, kidneys) and lymph node palpation. Based on the results
of the clinical assessment, patients are classified into the following clinical groups:
 Group I: specific lesions corresponding to a dermatosis
 Group II: pruritus without any lesions (normal skin)
 Group III: pruritus with predominantly secondary scratch lesions such as
papules, nodules, and excoriations
Following a detailed history, a thorough clinical examination may provide

another crucial piece of the puzzle with respect to the diagnosis and classification
in CP patients.
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Table 2 Useful lab tests and procedures in the differential diagnostic workup of systemic causes in chronic pruritus without
primary skin lesions.
Differential diagnoses Lab workup Procedures

Chronic renal failure Creatinine, blood urea nitrogen (optional c alcium, Abdominal ultrasound (possibly renal
phosphate and parathyroid hormone) biopsy)
Hepatobiliary ALT, AP, γGT, bilirubin (optional biliary salts, Abdominal ultrasound (possibly MRCP,
disorders anti-HCV) ERCP, liver biopsy)
Hematooncologic CBC with differential, LDH, ESR, ferritin Abdominal ultrasound, chest x-ray (possibly
disorders CT, bone marrow/lymph node biopsy)
Endocrinologic TSH, calcium, phosphate, glucose (optional fT3 , Ultrasound of parathyroid glands, thyroid
disorders fT4 , parathyroid hormone, HbA1c, urine 5-HIES)
Malassimilation CBC with differential (optional vitamin B12, folic Esophagogastroduodenoscopy (possibly
syndromes acid) with biopsy)
Infectious diseases Differential blood count, stool analysis for pa –
rasites/eggs (optional IgE, anti-HIV)
Solid tumors Stool guaiac test Abdominal ultrasound, chest x-ray (possibly
CT, esophagogastroduodenoscopy)
Adverse drug reaction – –
Abbr.: ALT, alanine aminotransferase; AP, alkaline phosphatase; ESR, erythrocyte sedimentation rate; CT, compu-
ted tomography; γGT, γ-glutamyl transferase; HCV, hepatitis C virus; HIV, human immunodeficiency virus; 5-HIES,
5-hydroxyindoleacetic acid; IgE, immunoglobuline E; TSH, thyroid-stimulating hormone; MRCP, magnet resonance
cholangiopancreaticography; ERCP, endoscopic retrograde cholangiopancreaticography
Biopsy
A biopsy should always be performed Skin biopsies play a pivotal role in the diagnostic workup of CP. Apart from the
in prurigo patients to exclude a derma- evaluation of obscure skin lesions, a biopsy should always be performed in prurigo
tosis not readily visible underneath the patients to exclude a dermatosis not readily visible underneath the scratch marks.
scratch marks. Here, bullous pemphigoid or lichen planus are commonly found [1]. For neuro-
pathic pruritus and small fiber neuropathy, analysis of intraepidermal nerve fiber
density should be performed in a biopsy from the affected area or the lateral lower
leg (analysis at the KCP Laboratory, Muenster, Germany).
Rational laboratory workup
Due to the vast number of potential Due to the vast number of potential causes of CP, a systematic approach and inter-
causes of CP, a systematic approach and disciplinary assessment strategies are vital aspects in the evaluation of a possible
interdisciplinary assessment strategies trigger. In case of pruritus on normal skin, systemic disorders should be considered
are vital aspects in the evaluation of a [1], and running only a few lab tests may already provide important diagnostic
possible trigger. clues (Table 2). Elevated creatinine and blood urea nitrogen levels indicate kidney
disease; ALT, alkaline phosphatase, γGT, and bilirubin are used to identify hepa-
tobiliary diseases [1]. In high-risk patients, HCV and HBV antibodies should be
determined; for cholestasis of pregnancy, fasting bile acids and GPT.
A complete blood count, lactate dehydrogenase, and erythrocyte sedimentati-
on rate should be determined in patients with suspected hematooncologic disorders
or night sweats, weight loss, and B symptoms. Microcytic anemia warrants the
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analysis of ferritin and transferrin saturation to detect iron deficiency, whereas in

macrocytic anemia, low vitamin B 12 or folic acid levels may be due to insufficient
supply or malassimilation. Eosinophilia and elevated IgE levels point to parasitosis.
Especially in case of perianal pruritus, stool sampling may helpful in search for
parasites and their eggs. In all cases of generalized pruritus of unknown origin, an
HIV infection should be ruled out serologically.
With respect to thyroid dysfunction, thyroid-stimulating hormone (TSH) and
– in case of abnormal values – free T3 and T4, should be analyzed. If hyperpa-
rathyroidism is suspected, calcium, phosphate, and serum levels of intact parathy-
roid hormone should be measured. While workup for carcinoid includes serum
chromogranin A and 5-hydroxyindoleacetic acid in 24-hour urine, evaluation of
diabetes warrants the analysis of fasting glucose levels and HbA1c as well as glu-
cose tolerance testing. If intestinal bleeding (for example, from a gastrointestinal
tumor) is suspected, a stool guaiac test, even if it is only moderately sensitive, may
be considered.
Diagnostic procedures
Apart from lab tests, additional diagno- Apart from lab tests, additional diagnostic procedures are warranted in case of
stic procedures are warranted in case clinical and serologic suspicion of a systemic disorder (Table 2). Abdominal ul-
of clinical and serologic suspicion of a trasound should be performed by internists or respective specialists if chronic renal
systemic disorder. failure or a hepatobiliary disease is suspected. In case of cholestasis of unknown
origin, primary sclerosing cholangitis or bile duct tumors ought to be ruled out
by magnetic resonance (MRCP) or endoscopic retrograde cholangiopancreatico-
graphy (ERCP). Biopsies of the respective organ may be warranted. Abdominal
ultrasound and chest x-ray may be indicated in the workup of hematooncologic di-
seases, and may be combined with lymph node or bone marrow biopsies. Thyroid
disorders should be evaluated by ultrasound or nuclear imaging techniques. In case
of malabsorption syndromes or a positive guaiac test, the patient ought to undergo
further endoscopic workup. For hormone-producing tumors, scintigraphic scans
or PET-CT may be helpful. As solid tumors only very rarely cause generalized or
localized pruritus, CT or MRI scans are generally not recommended in the wor-
kup of CP of unknown etiology [3]. Nevertheless, follow-up at regular intervals is
warranted, as the onset of CP may precede the diagnosis of an underlying disease
by several years, as has been described for polycythemia vera.
Therapeutic algorithm
S2k guidelines for chronic pruritus [1] S2k guidelines for chronic pruritus [1] recommend a stepwise approach to CP tre-
recommend a stepwise approach to atment (Table 3). It is important to bear in mind, though, that these are merely
CP treatment (Table 3). It is important general recommendations. Patient age, comorbidities, and diagnostic results have
to bear in mind, though, that these are to be taken into account. Antihistamines may be used as first-line therapy, yet
merely general recommendations. Pati- only for histamine-responsive disorders. For example, CP in diabetes mellitus, he-
ent age, comorbidities, and diagnostic patobiliary disorders, or lymphomas does not respond to antihistamines. As to
results have to be taken into account. these cases, there are specific recommendations for the next therapeutic step. Since
these recommendations are rather comprehensive, we refer to the aforementioned
guidelines. In CP caused by chronic renal failure, for example, the anticonvulsant
gabapentin is recommended at a dose of 100–300 mg QD or three times per week;
alternatively, pregabalin at a dose of 25–75 mg. In addition to administration of
anticonvulsants, antidepressants and the opioid receptor antagonist naloxone in
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Table 3 Stepwise treatment of chronic pruritus according to [1].
Step Principle Example

1 Diagnosis and treatment of an underlying disease, Chemotherapy of lymphoma,
discontinuation of pruritus-inducing medication discontinuation of allopurinol
Basic dermatologic therapy Discontinuation of irritant substances,
recommendations for topical therapy
Non-sedating antihistamines, possibly topical corticosteroids Not effective for non-dermatologic forms
(exception: aquagenic pruritus)
2 Evidence-based therapy: recommendations based on trials for Rifampicin, naltrexone, and sertraline for
individual forms cholestatic pruritus
3 Symptomatic treatment: principle of interruption of pruritus Antidepressants, capsaicin
induction and conduction, based on case series, expert opinion
CP patients, new potential therapeutic options have recently been clinically ob-
served. For example, marked relief of brachioradial pruritus could be achieved
by the application of an adhesive patch containing 8% capsaicin for 60 minutes
[10]. Internationally, various randomized controlled trials are currently underway
investigating novel substances for atopic dermatitis, cutaneous T-cell lymphoma,
or prurigo nodularis (for example, neurokinin-1 receptor antagonists).
Economic/efficient prescription practice
Both the topical and systemic pharma- Both the topical and systemic pharmaceutical therapy of CP is characterized by
ceutical therapy of CP is characterized particularities that pose a challenge in dermatologic offices and outpatient depart-
by particularities that pose a challenge ments. Among topical substances, some have to be prescribed by a doctor, others
in dermatologic offices and outpatient do not. Moreover, some preparations are not considered pharmaceuticals including
departments. medicinal products and cosmetics. A considerable number of agents used in syste-
In the interest of guideline-oriented mic pruritus therapy are not approved for this indication. In the interest of guide-
CP patient care, thorough knowledge line-oriented CP patient care, thorough knowledge of the numerous drug-related
of the numerous drug-related legal legal requirements within framework of the German Statutory Health Insurance
requirements within framework of the System (GKV) is indispensable.
German Statutory Health Insurance Pivotal points thereof are subsumed below.
System (GKV) is indispensable.
Economic/efficient action and prescription
Volume 5 of the German Social Security Code (SGB) entitles the contracted
physician to prescribe approved drugs and medicinal products. This freedom

to prescribe is, however, impacted by additional regulations, among those the
frequently cited “Wirtschaftlichskeitsgebot” (the imperative to prescribe econo-
mically/efficiently), which is part of a complex decision-making algorithm for the
prescription of pharmaceutical agents (Figure 3). The basic principle of economic
drug prescription (article 12, SGB V) states that benefits have to be sufficient,
appropriate, and cost-effective, and must not exceed what is necessary.
Moreover, article 9 section 2 of the pharmaceuticals directives (AMR) states:
1. If a therapeutic goal may be reached by different but equally effective the-
rapeutic alternatives, the most economic/efficient alternative regarding daily
therapy costs and treatment duration has to be chosen.
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Figure 3 Algorithm for appropriate drug prescription in a dermatologic office setting according to [11].
2. If different yet equally effective formulations for a certain therapeutic goal are
available, the most cost-efficient formulation has to be chosen.
3. When prescribing pharmaceuticals, offered by different companies, that have
the same active ingredient, efficacy, and formulation, an alternative as inex-
pensive as possible should be chosen.
4. When prescribing pharmaceuticals, low-priced imported alternatives shall be
considered.
5. Therefore, if only an expensive medication allows for humane treatment, pre-
scription of that particular medication is warranted.
In addition to these general principles, other directives of the German Federal

Joint Committee (GBA), especially pharmaceuticals directives, relate to the abo-
ve-mentioned efficiency imperative.
Economic/efficiency standards are also issued by the various Associations of
Statutory Health Insurance (SHI) Physicians (KVs). With respect to care of CP
patients, the following are of relevance:
 Exclusion of OCT drugs from prescription at the expense of SHIs
 Exclusion of “non-economic/efficient” drugs (formerly known as “negative list”),
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 “Therapeutic guidelines“ of the GBA,

 Benchmarks of the KVs,
 Discount agreements.
Exclusion of OTC drugs from prescription at the expense of SHIs
Effective April 1, 2004, OTC drugs cannot be prescribed at the expense of SHIs,
exceptions being stated in the OTC list of the GBA. Exceptions relevant for der-
matology/CP are shown below in Table 4.
Table 4 Approved exceptions to the exclusion of OTC drugs from reimbursement

by SHIs according to article 34, section 1, subsection 2, SGB V (OTC overview, refer
to addendum 1 of the pharmaceuticals directive [AMR]).
Legal provisions of article 12, section 1 to 10 of the directive along with this ad-
dendum regulate under which circumstances pharmaceuticals that cannot be
prescribed at the expense of SHIs may still be prescribed as exceptions. In this
context, the regulations provided in other sections of the AMR are not applicable.
Severe diseases and their respective standard medications include:
 Topical anesthetics and/or antiseptics, only for patient-administered treat-
ment of severe generalized bullous diseases of the skin, such as epidermolysis
bullosa hereditaria; pemphigus.
 Antihistamines
– only in emergency kits for patients with bee, wasp, or hornet venom allergies:
– only for the treatment of severe recurrent urticaria:
– only for severe persistent pruritus:
– only for the treatment of severe allergic rhinitis, if topical nasal application of
corticosteroids is insufficient.
 Pharmaceuticals containing sodium cromoglicate (orally) only for sympto-
matic treatment of systemic mastocytosis.
 Urea-containing formulations with a urea content of at least 5 %, only for
proven ichthyosis, if no other therapeutic options are indicated.
Non-economic/efficient drugs according to addendum 3 of the

pharmaceuticals directive (formerly known as “negative list”)
Overview of prescription restrictions and exclusions due to other regulations (ar-

ticle 34, section 1, subsection 6, and section 3, SGB V) as well as guidelines for the
economic/efficient prescription of non-reimbursable pharmaceuticals for children
under the age of 12 years and adolescents with retardation under the age of 18 years.
The health care provider may prescribe respective pharmaceuticals on a case-by-
case basis if medically warranted (article 31, section 1, subsection 4, Social Security
Code (SGB) V, article 16, section 5, pharmaceuticals directive (AM-RL) (Table 5).
Table 5 None-economic Drugs.
15. Topical antihistamines

- exception: children
No prescription, due to legal regulations, of alimemazine, mepyramine [2].
Restricted prescription of prescription drugs according to this guideline [4].
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For CP, only one section (section 15) is relevant, although guidelines do not recom-
mend topical antihistamines for this indication.
“Therapeutic guidelines“ of the GBA
The GBA issues therapeutic recommendations, according to article 92, section 2,

subsection 7 of the SGB V, for the economic/efficient prescription of pharmaceuti-
cals and may thus restrict their prescription/SHI reimbursement. In these recom-
mendations, drugs are evaluated regarding:
 the extent of therapeutic benefit, also in relation to other drugs and therapeutic
options,
 therapeutic benefit with respect to costs and economic efficiency,
 medical necessity and usefulness
With respect to dermatologic, especially atopic, diseases, addendum 4 cont-

ains comprehensive therapeutic recommendations regarding the active ingredients
listed in Table 6.
Table 6 Therapeutic Recommendations of GBA.
Ingredient Source Indications evaluated in the

recommendations
Pimecrolimus Federal gazette 2004 No. 2, Mild to moderate atopic
(e.g. Elidel®) Jan 6, 2004, page 68 dermatitis
Tacrolimus Federal gazette 2004 No. 2, Moderate to severe atopic
(e.g. Protopic®) Jan 6, 2004, page 68 dermatitis
Complete list available at: www.g-ba.de/downloads/83-691-270/AM-RL-IV-The-
rapie_2011-10-13.pdf
SHIs have increasingly initiated recourse proceedings for “other damages”

in case of non-compliance with these recommendations. Thus, knowledge of and
strict adherence to these recommendations are advisable.
Off-label use
Off-label use (OLU) is the prescription of a approved pharmaceuticals outside their

approved indications. In general, SHIs do not reimburse any off-label use. Excep-
tions stated in the pharmaceuticals directive are:
 Positive recommendation from the expert panel of the German Federal Insti-
tute for Drugs and Medicinal Products (BfArM) AND
 Recognition by the manufacturer of the respective off-label use as intended use
AND
 Integration of the recommendation into the pharmaceuticals directive by the
GBA (addendum 6, part A).
Important: For any off-label use not regulated in this directive, jurisdiction
of the Federal Social Court remains unaffected with respect to the prescription in
individual cases. This basically includes all dermatologic indications. Under the
following circumstances, the Federal Social Court (court decision from March 19,
2002, docket number B 1 KR 37/00 R) has granted off-label use of non-approved
pharmaceuticals at the expense of SHIs:
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1. A severe disease, life-threatening or associated with a severe sustained effect

on quality of life (QoL). Thus, QoL assessment and documentation are recom-
mended in CP patients.
2. There is no equivalent alternative approved therapy available; approved drugs
have previously been tried but proven either less effective or associated with
adverse reactions.
3. Successful treatment is to be expected: the pharmaceutical is currently under-
going a phase III trial, an application for approval has been filed, or efficiency
has been proven in controlled trials and the drug is a standard in CP therapy
(see guidelines).
In the treatment of pruritus, off-label If the health care provider considers the prerequisites for off-label use fulfil-
use plays a paramount role. led, written approval for reimbursement should be obtained from the respective SHI
company. In case of approval, the drug may be prescribed. However, if the drug is
prescribed prior to obtaining written approval by the SHI, the healthcare provider
risks facing recourse proceedings aimed at determining whether or not there was
off-label use. If the insurance company does not approve reimbursement or if the
physician decides not to file a respective application, he may prescribe the drug at
the patient’s expense, who may then try to get reimbursed by his insurance company.
Benchmarks in the prescription of antipruritic drugs
In the past, the volume of all prescriptions provided the basis for the legally regulated
benchmark agreement between German SHI companies and the various Associations
of SHI Physicians (KVs). The German Healthcare Structure Act (VSG) 2012, article
106, section 5e, has suspended the benchmarks in their prior form. Instead, following
the first transgression, no legal recourse claim will be filed against the respective doc-
tor. Moreover, the law states that the amount to be reimbursed by the physician – in
case of future transgressions – may only be determined for the review period follo-
wing consultation by the KV. Thus, legal recourse claims may de facto only be filed
for prescriptions during the review period following the consultation, i.e. from 2016.
Discount agreements
Rabattverträge sind vom Gesetzgeber als Steuerungsinstrument dann vom Apothe-

ker exklusiv abgegeben werden müssen.
This may also affect antipruritic medications. As SHIs usually negotiate dis-
count agreements for a large number of drugs per manufacturer, economic effects
are due to the resulting mix. Without the physician’s knowledge, a single drug
may thus still be more expensive than a comparable drug or the benchmark. The
pharmacist, however, is required to distribute the discounted drug, rendering the
frequently useful aut-idem rule ineffective. Here again, the physician is not infor-
med about the substitution, either, while still bearing full medical responsibility.
Practical consequences
What counts: cost or benefit?

The German Social Security Code clearly answers the frequently asked question with
respect to cost vs. benefit: “If only an expensive medication allows for humane treat-
ment, prescription of that particular medication is unequivocally warranted” (article
70, section 2, SGB V). Thus, the therapeutic benefit outweighs the therapeutic costs.
CME Article
Consequences for daily practice

 Economic efficiency of pruritus therapy is based on the relation between costs
incurred and therapeutic benefit.
 Economic efficiency should always be assessed from a defined perspective, if
possible, from the perspective of the society as a whole.
 Quality of pruritus therapy significantly contributes to its economic efficiency.
The cost of care of qualified pruritus  The cost of care of qualified pruritus therapy is justified by the benefits generated.
therapy is justified by the benefits  According to the German Social Security Code, benefits of pruritus therapy
generated. are prioritized over costs.
Summary
Chronic pruritus is an interdisciplinary symptom that, due to its clinical mani-
festation, is usually first presented to a dermatologist. It poses diagnostic and the-
rapeutic challenges. Despite its complexity, however, a detailed medical history
and thorough clinical examination may already reduce the number of potential
differential diagnoses. Apart from basic lab analysis, further lab workup and dia-
gnostic procedures as well as referrals to other specialists are based on these initial
findings. Identification and treatment of the underlying disease should always be
the primary goal. Drug-induced pruritus always has to be considered, especially in
view of increasing patient age and polypharmaceutic treatment. Based on diagno-
stic results, specific treatment of the underlying disease, along with symptomatic
antipruritic (topical or systemic) treatment should be implemented. Here, the regu-
latory framework for prescriptions, especially off-label use, has to be taken into ac-
count. In recent years, basic research and clinical knowledge as well as therapeutic
options for CP have been continuously expanded and improved. Current studies
are expected to lead to future approval of novel antipruritic therapies. Thus, up-
to-date basic knowledge with respect to CP is imperative in everyday dermatologic
and general practice and enables targeted and optimal patient care.
References
1 Ständer S, Darsow U, Mettang T et al. S2k-Leitlinie chronischer Pruritus. J Dtsch Der-
matol Ges 2012,10: S1–S27.
2 Matterne U, Apfelbacher CJ, Vogelgsang L et al. Incidence and determinants of chron-
ic pruritus: a population-based cohort study. Acta Derm Venereol 2013; 93: 532–7.
3 Kremer AE, Feramisco J, Reeh PW et al. Receptors, cells and circuits involved in pruri-
tus of systemic disorders. Biochim Biophys Acta 2014;1842: 869–92.
4 Mettang T, Kremer AE. Uremic pruritus. Kidney Int 2014 Jan 8. [Epub ahead of print].
5 Yosipovitch G. Chronic pruritus: a paraneoplastic sign. Dermatol Ther 2010; 23:
590–6.
6 Reich A, Ständer S, Szepietowski JC. Drug-induced pruritus: a review. Acta Derm Ve-
Correspondence to
nereol 2009; 89: 236–44.
7 Misery L, Bodere C, Genestet S et al. Small-fibre neuropathies and skin: news and per-
Prof. Dr. med. Sonja Ständer spectives for dermatologists. Eur J Dermatol 2014; 24: 147–53.
Kompetenzzentrum Chronischer 8 Marziniak M, Phan NQ, Raap U et al. Brachioradial pruritus as a result of cervical spine
Pruritus (KCP) pathology: the results of a magnetic resonance tomography study. J Am Acad Derma-
Klinik für Hautkrankheiten tol 2011; 65: 756–62.
University Hospital Muenster 9 Weisshaar E, Ständer S, Gieler U et al. Entwicklung eines deutschsprachigen Frage-
bogens zur Erfassung von chronischem Pruritus (AGP-Fragebogen): Hintergrund und
Von-Esmarch-Strasse 58 erste Ergebnisse. Hautarzt 2011, 62: 914–27.
D-48149 Muenster 10 Zeidler C, Lüling H, Dieckmann A et al. Capsaicin 8% cutaneous patch – a promising
Germany treatment for brachioradial pruritus? Br J Dermatol 2014 Oct 29. doi: 10.1111/bjd.13501.
[Epub ahead of print].
E-mail: sonja.staender@ 11 Augustin M. Sachgerechte Off-label-Verordnung in der Praxis. Hautarzt 2013; 64:
uni-muenster.de 728–35.
CME Article
Questions for DDA certification

1. What is the incidence and c) fasting bile acids, GPT ralized, sudden-onset pruritus that
prevalence of chronic pruritus in d) GPT, AP, bilirubine started 2 months prior, and ask for
Germany? e) GGT, GPT your opinion. Which assumption is
a) incidence 1 %, prevalence 3–8 % incorrect?
b) incidence 5 %, prevalence 5–10 % a) Diabetes mellitus may cause
c) incidence 7 %, prevalence 17–25 % 6. Which of the following statements pruritus.
d) incidence 7 %, prevalence 5–10 % is incorrect with regard to the diagno- b) Statins may cause pruritus.
e) incidence 10 %, prevalence 40 % stic evaluation for pruritus associated c) Beta-blockers may cause pruritus.
with chronic renal failure? d) Allopurinol may cause pruritus.
a) diagnostic skin biopsy if prurigo is e) Arterial hypertension may cause
2. Which of the following is not a present pruritus.
frequent medical cause of chronic b) prescription of ketotifen to be reim-
pruritus? bursed by the SHI
a) chronic renal failure c) initiation of gabapentin following 10. For the patient described in
b) primary biliary cirrhosis application to the SHI question #9, which measures are
c) polycythemia vera d) initiation of topical lipid therapy appropriate in cooperation with the
d) type II diabetes mellitus e) exclusion of diabetes as a pruritic caregiving internist?
e) gastroesophageal reflux cofactor a) Discontinuation of all drugs (not
only pruritic) for at least 12 weeks.
b) Treatment for scabies, the most
3. How is small-fiber neuropathy
7. Which of the following statements common cause of pruritus in elderly
diagnosed in addition to medical patients.
is correct?
history taking? c) Detailed medical history taking and
a) Diagnostic evaluation of chronic
a) measurement of intraepidermal discontinuation of the medication
pruritus should not be initiated
nerve fiber density which had been started shortly
earlier then one year after onset.
b) measurement of serum levels of sub- before the onset of pruritus.
b) Chronic pruritus is defined by a
stance P d) Treatment with sedatives, as pruritus
duration of six weeks or longer.
c) magnetic resonance imaging of the can usually not be treated after a
c) Nephrogenic pruritus is associated
cervical spinal column duration of two months.
with hemo- but not peritoneal dialy-
d) measurement of direct immunoflu- e) Skin swabs, as diabetes may lead to
sis.
orescence furunculosis associated with genera-
d) In psoriatic patients, pruritus is tre-
e) corneometer examination lized pruritus.
atment-associated.
e) Pruritus does not occur in women of
60 years or older
4. Which of the following
dermatoses is usually not pruritic?
Liebe Leserinnen und Leser,
a) bullous pemphigoid
8. Which substance is not der Einsendeschluss an die DDA für
b) urticaria factitia
recommended for short-term topical diese Ausgabe ist der 18. March 2015.
c) atopic eczema
itch alleviation? Die richtige Lösung zum Thema
d) scabies
a) Glycerin „Urticaria“ in Heft 11 ( November 2014)
e) lupus erythematosus
b) Camphor ist: (1b, 2c, 3d, 4e, 5d, 6d, 7c, 8b, 9c,
c) Polidocanol (Syn.: Thesit) 10c).
5. Which lab values should be d) Menthol
Bitte verwenden Sie für Ihre Einsen-
determined for the diagnosis of e) Lidocaine
dung das aktuelle Formblatt auf der
pregnancy-associated cholestasis? folgenden Seite oder aber geben Sie
a) lactate dehydrogenase, erythrocyte Ihre Lösung online unter http://jddg.
sedimentation rate 9. A patient with hypertension,
akademie-dda.de ein.
b) fasting bile acids, alkaline hyperuricemia, diabetes mellitus and
phosphatase (AP) hyperlipidemia presents with gene-

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CME-Article

Submitted: 15.8.2014 DOI: 10.1111/ddg.12522

Clinical management of pruritus

Sonja Ständer 1, Claudia Summary

Table 1 Interdisciplinary care for chronic pruritus patients.

forms of CP from other disease entities is not always possible – or attempted –

Underlying disorders as cause for pruritus

Chronic pruritus may be caused by a multitude of underlying diseases [1], whose

CP is associated with many dermatoses, including inflammatory and infecti-

Figure 1 Percentage of various underlying diseases according to the database of

from primary dermatoses by the dermatologist is therefore an essential task in the

Figure 2 Patient with bullous pemphigoid (subepidermal blister on the lateral

Differential diagnostic considerations in CP patients should also include para-

History and clinical examination

Following a detailed history, a thorough clinical examination may provide

Differential diagnoses Lab workup Procedures

Rational laboratory workup

analysis of ferritin and transferrin saturation to detect iron deficiency, whereas in

Table 3 Stepwise treatment of chronic pruritus according to [1].

Step Principle Example

Economic/efficient prescription practice

In addition to these general principles, other directives of the German Federal

 “Therapeutic guidelines“ of the GBA,

Exclusion of OTC drugs from prescription at the expense of SHIs

Table 4 Approved exceptions to the exclusion of OTC drugs from reimbursement

Non-economic/efficient drugs according to addendum 3 of the

Overview of prescription restrictions and exclusions due to other regulations (ar-

Table 5 None-economic Drugs.

15. Topical antihistamines

“Therapeutic guidelines“ of the GBA

The GBA issues therapeutic recommendations, according to article 92, section 2,

With respect to dermatologic, especially atopic, diseases, addendum 4 cont-

Table 6 Therapeutic Recommendations of GBA.

Ingredient Source Indications evaluated in the

SHIs have increasingly initiated recourse proceedings for “other damages”

Off-label use (OLU) is the prescription of a approved pharmaceuticals outside their

1. A severe disease, life-threatening or associated with a severe sustained effect

Benchmarks in the prescription of antipruritic drugs

Rabattverträge sind vom Gesetzgeber als Steuerungsinstrument dann vom Apothe-

What counts: cost or benefit?

Consequences for daily practice

Questions for DDA certification

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