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Novel Agents for Intractable Itch

C. B. Lynde1; J. N. Kraft, MD2; C. W. Lynde, MD, FRCPC1
1Faculty of Medicine, University of Toronto, Toronto, ON, Canada
2Division of Dermatology, Sunnybrook Hospital, University of Toronto, Toronto, ON, Canada

ABSTRACT

There exists a multitude of medical conditions that cause intractable itch, or pruritus. The successful management of this symptom depends explicitly on establishing the underlying cause. Studies have shown that drugs not traditionally used in the treatment of cutaneous disorders, such as opiate receptor antagonists, antidepressants, and antiepileptics, can provide symptomatic relief of intractable itch. These novel antipruritic agents will be explored in this review.

Key Words: Intractable itch, pruritus, opiate receptor antagonists, antidepressants, anticonvulsants, antihistamine, phototherapy, thalidomide

Dermatologic Disorders
Local Generalized
  • Dermatitis (atopic and contact)
  • Prurigo nodularis
  • Urticaria
  • Insect bites
  • Lichen planus
  • Dermatitis herpetiformis
  • Lichen simplex chronicus
  • Infection (candidiasis, varicella)
  • “Winter itch”
  • Pruritus of senescent skin
  • Infestations (lice, scabies)
  • Drug eruptions (opiates, ASA)
  • Psychogenic states
Table 1: A summary of dermatologic disorders that can cause intractable itch.
Itch, or pruritus, refers to an unpleasant sensation in the skin that provokes scratching. Arguably, all humans experience an itch at some point in their lives. One-fifth of the population is thought to suffer from some form of itch at any given moment.1 The intensity of pruritus ranges from mild to severe, and can have a significant psychosocial impact on patients, by interfering with their sleep and daily activities. Itch is one of the most common symptoms associated with cutaneous disorders that require treatment from dermatologists.

Its management presents a treatment challenge, as many therapies are often tried to no avail.

Causation can sometimes be easily established, such as a primary dermatological disease (e.g., atopic dermatitis, psoriasis, urticaria), underlying renal or hepatic disease, or a drug-induced reaction (e.g., opiates). However, in many cases resolution of the symptom does not follow even after the etiology has been established; this is especially true for chronic disorders.
Tables 1 and 2 summarize dermatologic and systemic disorders that can cause intractable itch.



Pathophysiology

Sytemic Disorders
Endocrine
  • Hyper/ hypothyroidism
  • Diabetes mellitus
Hematologic
  • Iron deficiency anemia
  • Polycythemia rubra vera
  • Hemochromatosis
Hepatic
  • Obstructive biliary disease
  • Cholestatic liver disease of pregnancy
Infectious
  • HIV
  • Hepatitis C
  • Trichinosis
Neoplastic
  • Cutaneous T-cell lymphoma
  • Hodgkin’s/ non-Hodgkin’s lymphoma
  • Leukemia
  • Carcinoid
  • Multiple myeloma
  • Internal malignant tumors (i.e., lung, breast, gastric)
Neurologic
  • Peripheral nerve injuries
  • Post-herpetic neuralgia
  • Psychosis
  • Depression
  • Multiple sclerosis
Renal
  • Chronic renal failure
Miscellaneous
  • Gout
Table 2: A summary of systemic disorders that can cause intractable itch.

The neuropathways responsible for relaying pruritus to the brain are well-known. The itch sensation is carried to the brain by a dedicated subset of nociceptive C neurons. Like the pathways for pain and temperature, the message is relayed to the spinal cord, then crosses the midline and ascends via the lateral spinothalamic tract to the thalamus, and then finally travels to the cerebral cortex.

There are many peripheral mediators of pruritus, which include histamine, cytokines (IL-2), tryptase, substance P, serotonin, and opioid peptides. The most potent from this list is histamine, which is released by dermal mast cells via many triggers (i.e., IgE crosslinking, substance P, complement C5a). This biogenic amine acts mainly as a neurotransmitter and plays a major role in skin reactions associated with urticaria, urticaria pigmentosa, and insect bites. Its role in other skin diseases (e.g., atopic dermatitis) is debatable.

Traditional Topical Agents

Topical agents provide symptomatic relief. However, it must be stressed that successful management depends on establishing the underlying physiologic imbalance.

  • Menthol 1%, compounded in an aqueous cream or in a moisturizer base, sensitizes thermal receptors to cold and is considered a safe remedy that has been used for centuries.
  • Doxepin 5% cream is a topical tricyclic antidepressant that relieves pruritic symptoms associated with atopic dermatitis. Patients being treated with doxepin should be cautioned regarding adverse side-effects, such as systemic absorption and drowsiness.
  • Capsaicin 0.025%-0.3% cream is derived from chili peppers, and triggers the release of substance P from C nociceptors, which desensitizes nerve fibers. Local irritation can result.
  • Topical corticosteroids are only considered when there is a primary dermatosis, due to the potential for local side-effects (i.e., telangiectasia, atrophy, striae).
  • Topical anesthetics are seldom used as they are associated with an increased risk of allergic sensitization.
  • Other topical agents that may be of benefit include: moisturizers, oatmeal-based agents, calamine lotion, aloe and camphor.

Agent Class Examples and Typical Dosing Uses in Literature Strength of
Evidence

Opioid Agonists/ Antagonists
Proposed Mechanism of Action: inhibition of itch transmission based primarily on direct relationship of increased opioidergic tone and pruritus at the spinal level (ì-opioids are pruritic, ê-opioids are antipruritic)

Butorphanol
  • ì-opioid receptor antagonist, ê-opioid receptor agonist
  • 2mg intranasal spray every 4-6 hours
severe opioid-induced pruritus D3
intractable pruritus associated with inflammatory skin diseases or systemic diseases D4
Naltrexone
  • ì-opioid receptor antagonist
  • 50mg po daily
cholestatic pruritus A5
intractable pruritus associated with inflammatory skin diseases or systemic diseases B6, C7
uremic pruritus B8

Antidepressants: Selective Serotonin Reuptake Inhibitors
Proposed Mechanism of Action: reduces pruritus signaling through alteration of neurotransmitter concentrations within the central nervous system (CNS)

Paroxetine
  • 20mg po daily
malignancy D9
polycythemia vera C10
Sertraline
  • 75-100mg po daily

pruritus associated with a variety of underlying conditions (e.g., solid tumors, hematological malignancies, drug-induced pruritus [none opioid induced], paraneoplastic pruritus, and cholestatic pruritus)

A11
Fluoxetine
  • 10mg po daily
cholestatic pruritus B12

Antidepressants: Norepinephrine and Serotonin Enhancer
Proposed Mechanism of Action: reduces pruritus signaling through alteration of neurotransmitter concentrations within the CNS

Mirtazapine
  • 15-45mg po daily
inflammatory skin diseases and severe nocturnal pruritus E13
cholestasis, renal failure and malignancies E14

Anticonvulsants
Proposed Mechanism of Action: blocks neuropathic afferent pathway

Gabapentin
  • 300mg po daily and titrating to effect up to 1800mg po daily over 3-4 weeks
brachioradial pruritus E15, 16
multiple sclerosis - induced itch E17
uremic pruritus A18
cholestatic pruritus - negative effect A19

Glutamic Acid Derivative
Proposed Mechanism of Action: hypnosedative effects (penetrates CNS); direct effects on neural tissue; and immunomodulatory and anti-inflammatory effects (e.g., antagonism of histamine)

Thalidomide
  • 100-200mg po qhs
prurigo nodularis E20
chronic pruritus (psoriasis, eczema, nodular prurigo, senile pruritus and primary biliary cirrhosis) D21

Table 3: Summary of novel agents for intractable itch. A=double-blind study; B=clinical trial =20 subjects; C=clinical trial <20 subjects; D=series =5, <20 subjects; E=anecdotal case reports.

Systemic Agents

Systemic agents are tried if there is a specific indication or if the more conservative measures are ineffective. Antihistamines are predominantly used for treating urticaria, but are otherwise rarely effective for itch. The first generation antihistamines are sedating, but are generally considered to be the most effective when compared with its subsequent counterparts. Due to its potential to affect performance, sedating antihistamines should be administered at night. The addition of successive generations (second or third) may be helpful for daytime relief as they are minimally sedating. Tranquilizers have been used, but they only serve to sedate the patient and do not directly address the pruritic symptoms.

Phototherapy

For patients who are unresponsive to traditional topical or systemic therapies, UV light (UVB or PUVA) may be an option. For example, UVB has been shown to be of benefit in the treatment of pruritus associated with chronic renal disease.2 After 2 weeks of three treatments per week, improvement can be seen. If no improvement is detected following this treatment regimen, phototherapy should be reconsidered. Clinical experience seems to indicate that maintenance therapy is not required.

Novel Agents

In the past, if traditional agents were not effective, dermatologists had few other options. The emergence of a new understanding of the pathophysiology of itch has led to novel uses of existing therapies to treat pruritus, which include opiate receptor antagonists, antidepressants, and antiepileptics. The addition of these drugs to the dermatologist’s therapeutic arsenal provides options to patients who are inadequate responders to traditional agents. Table 3 provides a summary of these unconventional antipruritic agents.

Conclusions

Pruritus is a very common symptom that is associated with many dermatologic and systemic conditions, and can be challenging to treat. Conventional therapies such as topical agents and antihistamines are often not effective. Novel therapies such as opioid antagonists, antidepressants, and anticonvulsants are emerging as promising treatments for intractable itch.

References

  1. Rea JN, Newhouse ML, Halil T. Skin disease in Lambeth. A community study of prevalence and use of medical care. Br J Prev Soc Med 30(2):107-14 (1976 Jun).
  2. Seckin D, Demircay Z, Akin O. Generalized pruritus treated with narrowband UVB. Int J Dermatol 46(4):367-70 (2007 Apr).
  3. Dunteman E, Karanikolas M, Filos KS. Transnasal butorphanol for the treatment of opioid-induced pruritus unresponsive to antihistamines. J Pain Symptom Manage 12(4):255-60 (1996 Oct).
  4. Dawn AG, Yosipovitch G. Butorphanol for treatment of intractable pruritus. J Am Acad Dermatol 54(3):527-31 (2006 Mar).
  5. Wolfhagen FH, Sternieri E, Hop WC, et al. Oral naltrexone treatment for cholestatic pruritus: a double-blind, placebo-controlled study. Gastroenterology 113(4):1264-9 (1997 Oct).
  6. Metze D, Reimann S, Beissert S, et al. Efficacy and safety of naltrexone, an oral opiate receptor antagonist, in the treatment of pruritus in internal disease and dermatological diseases. J Am Acad Dermatol 41(4):533-9 (1999 Oct).
  7. Bigliardi PL, Stammer H, Jost G, et al. Treatment of pruritus with topically applied opiate receptor antagonist. J Am Acad Dermatol 56(6):979-988 (2007 Jun).
  8. Peer G, Kivity S, Agami O, et al. Randomised crossover trial of naltrexone in uraemic pruritus. Lancet 348(9041):1552-4 (1996 Dec 7).
  9. Zylicz Z, Smits C, Krajnik M. Paroxetine for pruritus in advanced cancer. J Pain Symptom Manage 16(2):121-4 (1998 Aug).
  10. Tefferi A, Fonseca R. Selective serotonin reuptake inhibitors are effective in the treatment of polycythemia vera-associated pruritus. Blood 99(7):2627 (2002 Apr 1).
  11. Zylicz Z, Krajnik M, Sorge AA, et al. Paroxetine in the treatment of severe non-dermatological pruritus: a randomized, controlled trial. J Pain Symptom Manage 26(6):1105-12 (2003 Dec).
  12. Browning J, Combes B, Mayo MJ. Long-term efficacy of sertraline as a treatment for cholestatic pruritus in patients with primary biliary cirrhosis. Am J Gastroenterol 98(12):2736-41 (2003 Dec).
  13. Hundley JL, Yosipovitch G. Mirtazapine for reducing nocturnal itch in patients with chronic pruritus: a pilot study. J Am Acad Dermatol 50(6):889-91 (2004 Jun).
  14. Davis MP, Frandsen JL, Walsh D, et al. Mirtazapine for pruritus. J Pain Symptom Manage 25(3):288-91 (2003 Mar).
  15. Bueller HA, Bernhard JD, Dubroff LM. Gabapentin treatment for brachioradial pruritus. J Eur Acad Dermatol Venereol 13(3):227-8 (1999 Nov).
  16. Winhoven SM, Coulson IH, Bottomley WW. Brachioradial pruritus: response to treatment with gabapentin. Br J Dermatol 150(4):786-7 (2004 Apr).
  17. Taylor RS. Multiple sclerosis potpourri. Paroxysmal symptoms, seizures, fatigue, pregnancy, and more. Phys Med Rehabil Clin N Am 9(3):551-9 (1998 Aug).
  18. Gunal AI, Ozalp G, Yoldas TK, et al. Gabapentin therapy for pruritus in haemodialysis patients: a randomized, placebo-controlled, double-blind trial. Nephrol Dial Transplant 19(12):3137-9 (2004 Dec).
  19. Bergasa NV, McGee M, Ginsburg IH, et al. Gabapentin in patients with the pruritus of cholestasis: a double-blind, randomized, placebo-controlled trial. Hepatology 44(5):1317-23 (2006 Nov).
  20. Alfadley A, Al-Hawasawi K, Thestrup-Pedersen K, et al. Treatment of prurigo nodularis with thalidomide: a case report and review of the literature. Int J Dermatol 42(5):372-5 (2003 May).
  21. Daly BM, Shuster S. Antipruritic action of thalidomide. Acta Derm Venereol 80(1):24-5 (2000 Jan-Feb).

In this issue:

  1. Psoriasis as the Marker of Underlying Systemic Disease
  2. Novel Agents for Intractable Itch
  3. Update on Drugs and Drug News - February 2008