This document discusses the pathophysiology and management of pruritus (itch). It summarizes that pruritus can be caused by multiple pathways, including histamines, proteases, opioids, interleukin-31, vanilloids, neurotrophins, and substance P. Pruritus is classified into categories including dermatological diseases, systemic diseases, neurological diseases, and psychiatric diseases. Treatment involves targeting the specific components and pathways causing pruritus, such as proteases, cytokines, neurotrophin-induced pathways, and substance P. Non-pharmacological treatments like cognitive therapy are also used for psychogenic pruritus.

1. PATHOPHYSIOLOGY OF PRURITUS
AND ITS MANANGEMENT
MODERATOR:
DR. PUNEET BHARGAVA

2. INTRODUCTION
• Pruritus or itch refers to an uncomfortable
sensation and emotional experience
associated with an actual or perceived
disturbance to the skin that provokes the
desire to scratch

6. HISTAMINES
• prototypic pruritogen

7. PROTEASE PATHWAY
• binds to protease-activated receptors (PAR) to stimulate
cutaneous mechanical-sensitive C-fibers
• The protease pathway plays an important role in itch
transmission in AD and probably also in other chronic
pruritic conditions
• the management of pruritus is to target the specific
components in the protease pathway, which consists of
PAR-2 and endogenous proteases.
• These endogenous proteases includes serine proteases,
such as mast cell tryptase26,27 and kallikreins28, and
cysteine proteases, such as Cathepsin S29

8. Opioid system
• that an excess of mu-opioid receptor activity
in comparison to kappa-opioid receptor
activity results in pruritus and stimulation of
the kappa-opioid receptor was found to inhibit
mu-receptor effects both centrally and
peripherally
• cholestasis, uraemia and dermatologic
diseases

9. Interleukin-31
• higher levels of IL-31 have been found in the
lesions of patients with AD and prurigo
nodularis.
• IL-31 may exert its pruritogenic effect by
directly binding to its receptors on cutaneous
nerve fibres

10. Vanilloids
• endogenous and exogenous agents that possess the ability to
activate transient receptor potential vanilloid (TRPV) ion
channels either directly or indirectly
• Activation of TRPV1 results in excitation and subsequent
desensitisation of C-fibres through depletion of
neuropeptides, a mechanism which has been utilised to
alleviate pain and itch
• Mediate histamine-induced itch via activation of
phospholipase A2 and 12-lipoxygenase
• A/w chronic pruritic diseases, particularly those of
neuropathic origin

11. Neurotrophins
• Neuropeptides that regulate the growth and function of nerve
cells
• Neurotrophin is nerve growth factor (NGF), whose main
sources are keratinocytes and mast cells.
• NGF has been shown to result in proliferation of nerve fibres
and upregulation of neuropeptides, such as substance P. In AD
lesions, higher levels of NGF have been found in keratinocytes
in the epidermal basal and spinous layers, and increased
density of NGF receptors, known as tropomyosin-related
kinase A (Trk A), have been noted in the epidermis and upper
dermis.
• The level of NGF in the stratum corneum also correlated with
the severity of itching and eruptions in AD.
• Increased NGF and TrkA immunoreactivities have been
detected in prurigo nodularisand pruritic psoriatic lesions

12. Substance P-Neurokinin Receptor
• neuropeptide mediating itch and neurogenic inflammation.
• It is a tachykinin that binds to neurokinin receptors (NKR) 1 to
3 but has the highest affinity for NKR-1.
• NKR-1 is expressed in the central nervous system and the skin
and NKR-1-expressing neurons in the superficial dorsal horn
of the spinal cord were found to be involved in itch
transmission
• Sezary syndrome, erythrodermic cutaneous T-cell lymphoma,
metastatic sarcoma and breast carcinoma, erlotinib-induced
itch, and chronic refractory pruritus

13. OTHERS
• lysophosphatidic acid (LPA) functioned as a pruritogen in the
sera of patients with cholestatic liver disease
• Mas-related G-protein-coupled receptors (Mrgprs), a family of
G protein-coupled receptors expressed exclusively in
peripheral sensory neurons,function as receptors in
chloroquine-induced itch
• Acetylcholine is the main neurotransmitter in the autonomic
nervous system, and may have a role in mediating pruritus.
Elevated expression of acetylcholine has been found in the
skin of AD patients
• Cannabinoids also have role in histamine-induced itch and
vasodilatation in healthy volunteers

14. • functional Toll-like receptor 7 (TLR7) was
found to be expressed in C-fibre sensory
neurons and was important in mediating itch
induced by nonhistaminergic pruritogens in
mice
• Role in human isn’t well established

16. CLASSIFICATION OF PRURITUS
• For differential diagnostic purposes, a
classification of 6 categories of pruritus is
proposed
• Category I: Dermatological diseases
• Category II: Systemic diseases including diseases
of pregnancy and drug-induced pruritus
• Category III: Neurological
• Category IV: Psychiatric / psychosomatic diseases.
• Category V: Mixed overlapping and coexistence of
several diseases
• Category VI: Undetermined origins.

17. DERMATOLOGICAL DISEASES
• Pruritus is the most common accompanying symptom
of many dermatological diseases
• Inflammatory diseases [e.g. atopic dermatitis (AD),
psoriasis, urticaria]
• infectious diseases (mycotic, bacterial and viral
infections, scabies, pediculosis, insect bites, folliculitis),
• autoimmune diseases (e.g. dermatitis herpetiformis,
bullous dermatoses),
• neoplastic disorders (cutaneous T-cell lymphoma,
cutaneous B-cell lymphoma, and leukemic infiltrates),
• genodermatoses (e.g. ichthyosis vulgaris, Netherton
syndrome)

18. MECHANISM OF PRURITUS
• Pruritus is generated in the epidermis and
papillary dermis on nociceptors of
unmyelinated C-fibers

20. T/T OF DERMATOLOGICAL PRURITUS

22. PRURITUS FROM SYSYTEMIC DISEASES
• Pruritus are renal insufficiency, cholestasis, lymphoma,
polycythemia vera, solid tumors, and many others. Diseases
of pregnancy and drug-induced pruritus are also divided
into this group.
–
–
–
–
–
–
Primary biliary cirrhosis
CRF
Dialysis
Hodgkin’s disease
Non Hodgkin’s disease
Polycyathemia Vera
– 80%
--15-49%
--90%
-- 30%
-- 15%
--30-50%

23. • The mechanism underlying systemic pruritus is multifactorial
• Pathogenesis of uremic pruritus
– an immune-system derangement that results in a proinflammatory
state
– an imbalance of the endogenous opioidergic system
– a neuropathic mechanism
– interleukin-2 serum levels were elevated in patients with uremic
pruritus.
• Lysophosphatidic acid (LPA) and autotoxin (an enzyme that produces LPA)
were identified as a potent pruritogen in pruritus of cholestasis
• Cytokines (such as interleukin-6 and interleukin-8) are found to be closely
related to pathophysiology of pruritus of lymphoma.

25. Neurological Pruritus
Neurological or neuropathic pruritus terms as pruritus arising from diseases
or disorders of the central or peripheral nervous system by nerve damage,
nerve compression, and nerve irritation.
Common peripheral neuropathic pruritic diseases are postherpetic
neuralgia (PHN), brachioradial pruritus (BP), Notalgia paraesthetica,
keloid, and burn scars.
Central neuropathic pruritic diseases include spinal tumors, CreutzfeldtJakob disease and multiple sclerosis.
The itch sensation in most cases is chronic, persistent, and always
accompanied with painful qualities (burning, stinging, biting, piercing, or
tingling) and sensory damage (experienced as parasthesia, hyperesthesia,
or hypothesia) in the affected areas.
Mechanisms are incompletely understood. Some of the proposed
mechanisms include itch associated with local nerve damage; central
neuronal deprivation of afferent input, and central hypersensitivity of
nerve fibers.

26. • Therapeutic options for neuropathic itch are sparse.
• Neuroleptic drugs were proven to be effective in
neuropathic pain, such as gabapentin and pregabalin
Botulinium toxin A injection has been reported to be
successful for notalgia paresthetica and PHN neuropathic
pain. Clinical efficacy and side effects need to be assessed
in further studies.
Novel drugs (Anti-NGF antibodies, TrkA inhibitors) targeting
neurotrophin-induced pruritus pathway may be useful in
neurological pruritus therapy.

27. Pruritus with Psychiatric /
Psychosomatic Diseases
•
In some circumstances, chronic pruritus is indeed unrelated to skin diseases, and
the skin lesions are simply secondary to scratching behavior and are highly
associated with mental state.
Psychiatric pruritus is considered psychiatric in origin, which is characterized as an
excessive impulse to scratch, gouge, or pick at normal skin.
•
•
Clinically, it has long been recognized that both acute stress (stressful life events)
and chronic psychoemotional stress can precipitate or exacerbate pruritus and the
scratching response.
Gupta et al, found a direct correlation between depression and pruritus severity in
patients with AD, psoriasis, and chronic idiopathic urticaria (CIU). And, a close
association between pruritus severity and anger in CIU was also showed.

28. • Stress activates the nervous system in a number of ways.
• SP-NKR1 pathway has been shown to be activated in response to stressful
stimuli, both in the central and peripheral nervous system.
• SP is an important pruritogen in the induction and maintenance of
pruritus by binding to NKR1. And, a correlation between pruritus intensity
and number of SP-positive nerves in lesional skin of psoriasis patients was
observed.
• Interestingly, the Beck's Depression Inventory (BDI) score of the patients
positively correlated with the number of SP and NKR1-positive cells in
lesional skin.
• These indicate that stress and depression may influence pruritus via
substance P and NKR1.
• The noradrenergic system, which is highly relevant to emotional reaction,
was found to play a role in itch transmission. Descending noradrenergic
system exerts a tonic inhibition of itch transmission in the spinal cord
mediated by α-adrenoceptors.

30. •
•
•
Pharmacological treatment
•
Non-Pharmacological treatment
Tricyclic anti-depressant (TCA), such
as doxepin, amitriptyline, and
trimipramine, has additional antihistaminic effects and is of benefit in
dermatological conditions such as
urticaria and pruritus.
Neuroleptic medications are useful
for the treatment of delusions of
parasitosis, and the current drug of
choice is pimizode.
New anti-psychotics (e.g. risperidone)
are effective for psychotic syndrome
and have a much safer adverse effect
profile.
•
•
•
Cognitive therapy
Behavior therapy
Combined therapy

31. Pruritus from Mixed Overlapping and
Coexistence of Several Diseases
• Patients, especially elderly patients with
chronic pruritus, always have multifactorial
origins, among which, metabolic, endocrine,
or hematological disturbances are most
common
• Dry skin, reduced sweating, decreased
production of sebum, thicker stratum
corneum, impaired skin barrier also
contributes to itching.

32. Pruritus of Undetermined Origin
• Chronic pruritus with no detection of the underlying origin after
completion of diagnostic tests is called PUO, which accounts for up
to 45% of all cases.
• Subclinical or subsided diseases are common reasons for PUO, and
an association of as-yet unrelated diseases with pruritic conditions
should be considered
• General principles should be followed before non-specific topical or
oral anti-pruritus therapy (anti-histamine, corticosteroids). Opioid
antagonists (naltrexone hydrochloride), and SSRIs were found to be
effective treatment of severe PUO and gabapentin is recommended
for treatment of PUO unresponsive to the usual treatment
modalities

33. • THANK YOU