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The Cutting Edge |

Efficacy of Gabapentin in the Management of Pruritus of Unknown Origin FREE

P. D. Yesudian, MRCP; N. J. E. Wilson, FRCP
[+] Author Affiliations

Section Editor: George J. Hruza, MD
Assistant Section Editor: Michael P. Heffernan, MD
Assistant Section Editor: Summer R. Youker, MD

More Author Information
Arch Dermatol. 2005;141(12):1507-1509. doi:10.1001/archderm.141.12.1507.
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Published online

Generalized pruritus is a distressing symptom that can occur in several dermatologic and systemic disorders.1 Generalized pruritus of unknown origin is that which affects patients without any underlying dermatologic or systemic disorder and is unassociated with rash. It most commonly occurs in older patients and persists for long periods, from months to years. In many cases, the itching may be due to reduced water content of the skin, without overt dryness. Failure of the normal processing of the itching sensation along the course of central and peripheral sensory pathways may also play a role.2

CASE 1

An 80-year-old man was initially seen with generalized itching of longer than 12 months’ duration. It was intermittent but affected him daily. There was no associated rash, and the itching had increased in severity during a few months. He had undergone treatment with emollients, topical corticosteroids, and oral antihistamines, without much benefit. His medical history included ischemic heart disease, asbestosis, and peripheral vascular disease, for which he was taking simvastatin, furosemide, and clopidogrel hydrogen sulfate. Treatment with each medication had been stopped for at least 3 months to ascertain whether this would relieve the itching, without any change. There was no personal or family history of atopy. Physical examination revealed no abnormality in the skin.

He was examined using routine hematologic (complete blood cell count) and biochemical tests (liver function tests and serum urea nitrogen and electrolyte profiles), the results of which were all normal. His serum creatinine level was marginally elevated at 1.8 mg/dL (162 μmol/L) (reference range, 0.6-1.5 mg/dL [50-130 μmol/L]). Chest x-ray films showed pleural plaques in both hemithoraces that were suggestive of asbestosis; they were confirmed by computed tomography of the chest and by a restrictive pattern on spirometry. Results of iron studies revealed a low serum iron level at 36 μg/dL (6.5 μmol/L) (reference range, 73-179 μg/dL [13-32 μmol/L]), although the transferrin level and total iron-binding capacity were normal. His total IgE level was elevated at 3019 IU/L (reference range, <100 IU/L).

Treatment was started with 1% menthol in aqueous cream and supplemental oral ferrous fumarate to increase the iron level. Although the iron level normalized within 8 weeks, there was no improvement in the itching. Sedative antihistamine therapy (50 mg of hydroxyzine hydrochloride at bedtime) and nonsedative antihistamine therapy (180 mg of fexofenadine hydrochloride once daily) also conferred no benefit. A course of broadband UV-B treatment was started, but the patient could not tolerate it because of increased itching within 2 hours of each phototherapy session. An empirical course of prednisolone (30 mg/d), tapered and stopped within 3 weeks, also had no effect on the pruritus.

CASE 2

A 72-year-old man had a 2-year history of generalized itching unassociated with rash. It routinely prevented him from sleeping through the night. He had tried different emollient creams without improvement. His medical history included asthma, interstitial pulmonary fibrosis, and hiatus hernia, for which he was taking aminophylline and using inhaler devices. On physical examination, no rash was evident. His complete blood cell count was normal, except for an eosinophil count of 2400/μL (reference range, 0-400/μL). Results of liver function tests, serum urea nitrogen and electrolyte profiles, iron studies, and autoantibody screens were normal. The IgE level was elevated at 169 IU/L (reference range, <100 IU/L). Chest x-ray films showed bilateral basal fibrosis, and spirometry demonstrated a restrictive pattern, suggestive of interstitial fibrosis.

Treatment with oral antihistamines (25 mg of hydroxyzine hydrochloride at bedtime) and 1% menthol in aqueous cream was not effective in relieving itching. Treatment with topical corticosteroids, emollients, and oral cetirizine hydrochloride (10 mg once daily) also did not improve his symptoms. Broadband UV-B therapy 3 times a week for 6 weeks, a reducing course of oral prednisolone for 8 weeks, oral dothiepin hydrochloride for 10 weeks, and 2 mg of ketotifen fumarate twice daily for 4 months also had no effect.

Treatment of generalized pruritus of unknown origin can be challenging, and topical and systemic agents have been used successfully. Topical agents include coolants (menthol),3 anesthetic agents (a eutectic mixture of local anesthetics),4 antihistamines (doxepin hydrochloride),5 corticosteroids,6 and substance P depletors (capsaicin).7 Most patients, however, will require systemic agents such as antihistamines (histamine1 and histamine2 receptor antagonists), dothiepin, paroxetine hydrochloride, prednisolone, opioid antagonists (naltrexone hydrochloride), and antiserotoninergic medication.810 There are anecdotal reports of the usefulness of anesthetic agents such as propofol11 and lidocaine hydrochloride.12 Our patients did not respond to topical or oral medications that are normally used in treating generalized pruritus of unknown origin.

Recently, gabapentin, an antiepileptic agent, has been reported to be an effective antipruritic agent in brachioradial pruritus.13,14 It has been suggested that gabapentin may be useful in chronic itching that is unresponsive to other treatments.15

In our patients, we started gabapentin therapy at a dose of 300 mg/d on day 1, increasing it to 600 mg/d and 900 mg/d on days 2 and 3, respectively. Thereafter, the dosage was increased to 1800 mg/d during the next 3 to 4 weeks, titrating the dose to symptom control. Both patients had an excellent response, with complete control of the itching within the first month. They have continued with a maintenance dosage (based on symptom control) of gabapentin and have remained symptom free for longer than 9 months, with no adverse effects due to the medication.

Pruritus is a distinct sensation that evokes a desire to scratch. It is transmitted by C fibers that end in specialized receptors localized on the multimodal endings close to the dermoepidermal junction. These fibers synapse in a specific class of dorsal horn neurons and ascend up the spinal cord in the lateral spinothalamic tract. Supraspinal processing of the itching sensation is attributed to activation of the anterior cingulate cortex, supplementary motor area, and inferior parietal lobe in the brain, with a left hemisphere predominance.16 Different pharmacological mediators of the itching sensation have been proposed, including histamine phosphate, prostaglandin E1, serotonin (5-HT), substance P, opioid peptides, calcitonin gene–related peptide, IL-2, and tryptase.2 Specific inhibitors of these mediators have been shown to alleviate itching to varying degrees. A recent study8 demonstrated the efficacy of paroxetine (a selective serotonin reuptake inhibitor) in treating generalized pruritus by its binding to serotonin transporters on presynaptic nerve endings. This prevents neural reuptake of serotonin, which initially increases the amount of serotonin in the synapse. With prolonged reuptake inhibition, the postsynaptic 5-HT receptors are downgraded, and serotonin release is decreased. Opioid receptors also play a part in pruritus by means of peripheral and central mechanisms. Administration of morphine sulfate, an opioid agonist, causes intense pruritus in most patients.17 Opioid receptor antagonists in experimental mice have been shown to be effective in preventing scratching in response to itching.18

Gabapentin is an antiepileptic drug that has been used in different conditions associated with chronic pain19 and, recently, in pruritic disorders.13,14 It has a novel molecular structure, and although its precise mechanism of action is unknown, various hypotheses have been proposed to explain it. Its primary effect is inhibition of voltage-dependent calcium ion channels located in the spinal cord (with particular high density in the superficial laminae of the dorsal horn), inhibiting the release of excitatory neurotransmitters. Gabapentin neither acts directly on the γ-aminobutyric acid receptor nor affects the reuptake of γ-aminobutyric acid. It increases the synthesis of γ-aminobutyric acid from glutamate by altering the activity of glutamic acid decarboxylase in neurological tissue.20 Its effect on pruritus may be central and peripheral. Gabapentin is known to secondarily inhibit calcitonin gene–related peptide (a mediator of itching) release from primary afferent neurons through a primary increase of γ-aminobutyric acid in the spinal cord.21 Furthermore, it has been hypothesized that opioid receptors are involved in the mechanism of action of gabapentin.22 Although not directly agonistic or antagonistic to the opioid receptors, modulation of the μ-opioid receptors may affect the central perception of itching. Opioid peptides also have a peripheral action, potentiating itching due to other agents.

Gabapentin is well absorbed orally and does not inhibit or induce hepatic enzyme function. Because of the pharmacokinetics of gabapentin, drug interactions are unlikely.23 The initial dosage of gabapentin is 300 mg/d and can be increased up to 1200 mg 3 times a day. It has a high toxicity ratio, minimizing the chance of adverse effects with even very high overdoses.14 Gabapentin treatment should not be discontinued abruptly but rather tapered gradually, as discontinuation can lead to withdrawal-related adverse effects.24 The most common adverse effect is sedation. Rarely, it can cause pancytopenia, cholestasis, hypersensitivity syndrome, and dyskinesia. We recommend gabapentin treatment for patients with generalized pruritus of unknown origin that is unresponsive to the usual treatment modalities.

Correspondence: N. J. E. Wilson, FRCP, Department of Dermatology, The Royal Liverpool and Broadgreen University Hospitals NHS Trust, Thomas Drive, Liverpool L14 3LB, England (Niall.Wilson@rlbuht.nhs.uk).

Accepted for Publication: December 24, 2004.

Author Contributions:Study concept and design: Yesudian and Wilson. Drafting of the manuscript: Yesudian. Critical revision of the manuscript for important intellectual content: Wilson. Administrative, technical, and material support: Yesudian. Study supervision: Wilson.

Financial Disclosure: None.

Submissions

Clinicians, residents, and fellows are invited to submit cases of challenges in management and therapeutics to this section. Cases should follow the established pattern. Manuscripts should be prepared double-spaced with right margins nonjustified. Pages should be numbered consecutively with the title page separated from the text (see “Instructions for Authors”). Clinical photographs, photomicrographs, and illustrations must be sharply focused and submitted as separate JPG files with each file numbered with the manuscript number (eg, Fig 1_DCE00000.jpg). Material must be accompanied by the required copyright transfer statement (see “Instructions for Authors”). Preliminary inquires regarding submissions for this feature may be submitted to George J. Hruza, MD (ghruza@aol.com). Manuscripts should be submitted electronically to archdermatol@jama-archives.org. Please indicate in your e-mail that the manuscript is a submission to The Cutting Edge.

Kantor  GRLookingbill  DP Generalized pruritus and systemic disease J Am Acad Dermatol 1983;9375- 382
PubMed Link to Article
Greaves  MWWall  PD Pathophysiology of itching Lancet 1996;348938- 940
PubMed Link to Article
Bromm  BScharein  EDarsow  URing  J Effects of menthol and cold on histamine-induced itch and skin reactions in man Neurosci Lett 1995;187157- 160
PubMed Link to Article
Shuttleworth  DHill  SMarks  RConnelly  DM Relief of experimentally induced pruritus with a novel eutectic mixture of local anaesthetic agents Br J Dermatol 1988;119535- 540
PubMed Link to Article
Drake  LAMillikan  LEDoxepin Study Group, The antipruritic effect of 5% doxepin cream in patients with eczematous dermatitis Arch Dermatol 1995;1311403- 1408
PubMed Link to Article
Yosipovitch  GSzolar  CHui  XYMaibach  H High-potency topical corticosteroid rapidly decreases histamine-induced itch but not thermal sensation and pain in human beings J Am Acad Dermatol 1996;35118- 120
PubMed Link to Article
Anand  P Capsaicin and menthol in the treatment of itch and pain: recently cloned receptors provide the key Gut 2003;521233- 1235
PubMed Link to Article
Zylicz  ZKrajnik  Mvan Sorge  AACostantini  M Paroxetine in the treatment of severe non-dermatological pruritus: a randomized, controlled trial J Pain Symptom Manage 2003;261105- 1112
PubMed Link to Article
Peer  GKivity  SAgami  O  et al.  Randomised crossover trial of naltrexone in uraemic pruritus Lancet 1996;3481552- 1554
PubMed Link to Article
Schworer  HHartmann  HRamadori  G Relief of cholestatic pruritus by a novel class of drugs: 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists: effectiveness of ondansetron Pain 1995;6133- 37
PubMed Link to Article
Borgeat  AWilder-Smith  OHMentha  G Subhypnotic doses of propofol relieve pruritus associated with liver disease Gastroenterology 1993;104244- 247
PubMed
Fishman  SMCaneris  OAStojanovic  MPBorsook  D Intravenous lidocaine for treatment-resistant pruritus Am J Med 1997;102584- 585
PubMed Link to Article
Bueller  HABernhard  JDDubroff  LM Gabapentin treatment for brachioradial pruritus [letter] J Eur Acad Dermatol Venereol 1999;13227- 228
PubMed Link to Article
Winhoven  SMCoulson  IHBottomley  WW Brachioradial pruritus: response to treatment with gabapentin [letter] Br J Dermatol 2004;150786- 787
PubMed Link to Article
Scheinfeld  N The role of gabapentin in treating diseases with cutaneous manifestations and pain Int J Dermatol 2003;42491- 495
PubMed Link to Article
Yosipovitch  GGreaves  MWSchmelz  M Itch Lancet 2003;361690- 694
PubMed Link to Article
Fischer  HBScott  PV Spinal opiate analgesia and facial pruritus [letter] Anaesthesia 1982;37777- 778
PubMed Link to Article
Inagaki  NNakamura  NNagao  MKawasaki  HNagai  H Inhibition of passive cutaneous anaphylaxis-associated scratching behavior by μ-opioid receptor antagonists in ICR mice Int Arch Allergy Immunol 2000;123365- 368
PubMed Link to Article
Rose  MAKam  PC Gabapentin: pharmacology and its use in pain management Anaesthesia 2002;57451- 462
PubMed Link to Article
Bennett  MISimpson  KH Gabapentin in the treatment of neuropathic pain Palliat Med 2004;185- 11
PubMed Link to Article
Fehrenbacher  JCTaylor  CPVasko  MR Pregabalin and gabapentin reduce release of substance P and CGRP from rat spinal tissues only after inflammation or activation of protein kinase C Pain 2003;105133- 141
PubMed Link to Article
Yoon  MHChoi  JJeong  SW Spinal gabapentin and antinociception: mechanisms of action J Korean Med Sci 2003;18255- 261
PubMed
Singh  DKennedy  DH The use of gabapentin for the treatment of postherpetic neuralgia Clin Ther 2003;25852- 889
PubMed Link to Article
Norton  JW Gabapentin withdrawal syndrome Clin Neuropharmacol 2001;24245- 246
PubMed Link to Article

Figures

Tables

References

Kantor  GRLookingbill  DP Generalized pruritus and systemic disease J Am Acad Dermatol 1983;9375- 382
PubMed Link to Article
Greaves  MWWall  PD Pathophysiology of itching Lancet 1996;348938- 940
PubMed Link to Article
Bromm  BScharein  EDarsow  URing  J Effects of menthol and cold on histamine-induced itch and skin reactions in man Neurosci Lett 1995;187157- 160
PubMed Link to Article
Shuttleworth  DHill  SMarks  RConnelly  DM Relief of experimentally induced pruritus with a novel eutectic mixture of local anaesthetic agents Br J Dermatol 1988;119535- 540
PubMed Link to Article
Drake  LAMillikan  LEDoxepin Study Group, The antipruritic effect of 5% doxepin cream in patients with eczematous dermatitis Arch Dermatol 1995;1311403- 1408
PubMed Link to Article
Yosipovitch  GSzolar  CHui  XYMaibach  H High-potency topical corticosteroid rapidly decreases histamine-induced itch but not thermal sensation and pain in human beings J Am Acad Dermatol 1996;35118- 120
PubMed Link to Article
Anand  P Capsaicin and menthol in the treatment of itch and pain: recently cloned receptors provide the key Gut 2003;521233- 1235
PubMed Link to Article
Zylicz  ZKrajnik  Mvan Sorge  AACostantini  M Paroxetine in the treatment of severe non-dermatological pruritus: a randomized, controlled trial J Pain Symptom Manage 2003;261105- 1112
PubMed Link to Article
Peer  GKivity  SAgami  O  et al.  Randomised crossover trial of naltrexone in uraemic pruritus Lancet 1996;3481552- 1554
PubMed Link to Article
Schworer  HHartmann  HRamadori  G Relief of cholestatic pruritus by a novel class of drugs: 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists: effectiveness of ondansetron Pain 1995;6133- 37
PubMed Link to Article
Borgeat  AWilder-Smith  OHMentha  G Subhypnotic doses of propofol relieve pruritus associated with liver disease Gastroenterology 1993;104244- 247
PubMed
Fishman  SMCaneris  OAStojanovic  MPBorsook  D Intravenous lidocaine for treatment-resistant pruritus Am J Med 1997;102584- 585
PubMed Link to Article
Bueller  HABernhard  JDDubroff  LM Gabapentin treatment for brachioradial pruritus [letter] J Eur Acad Dermatol Venereol 1999;13227- 228
PubMed Link to Article
Winhoven  SMCoulson  IHBottomley  WW Brachioradial pruritus: response to treatment with gabapentin [letter] Br J Dermatol 2004;150786- 787
PubMed Link to Article
Scheinfeld  N The role of gabapentin in treating diseases with cutaneous manifestations and pain Int J Dermatol 2003;42491- 495
PubMed Link to Article
Yosipovitch  GGreaves  MWSchmelz  M Itch Lancet 2003;361690- 694
PubMed Link to Article
Fischer  HBScott  PV Spinal opiate analgesia and facial pruritus [letter] Anaesthesia 1982;37777- 778
PubMed Link to Article
Inagaki  NNakamura  NNagao  MKawasaki  HNagai  H Inhibition of passive cutaneous anaphylaxis-associated scratching behavior by μ-opioid receptor antagonists in ICR mice Int Arch Allergy Immunol 2000;123365- 368
PubMed Link to Article
Rose  MAKam  PC Gabapentin: pharmacology and its use in pain management Anaesthesia 2002;57451- 462
PubMed Link to Article
Bennett  MISimpson  KH Gabapentin in the treatment of neuropathic pain Palliat Med 2004;185- 11
PubMed Link to Article
Fehrenbacher  JCTaylor  CPVasko  MR Pregabalin and gabapentin reduce release of substance P and CGRP from rat spinal tissues only after inflammation or activation of protein kinase C Pain 2003;105133- 141
PubMed Link to Article
Yoon  MHChoi  JJeong  SW Spinal gabapentin and antinociception: mechanisms of action J Korean Med Sci 2003;18255- 261
PubMed
Singh  DKennedy  DH The use of gabapentin for the treatment of postherpetic neuralgia Clin Ther 2003;25852- 889
PubMed Link to Article
Norton  JW Gabapentin withdrawal syndrome Clin Neuropharmacol 2001;24245- 246
PubMed Link to Article

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