Intractable pruritus is encountered frequently

Transcription

1 Brief reports 527 Butorphanol for treatment of intractable pruritus Aerlyn G. Dawn, MD, MBA, a and Gil Yosipovitch, MD a,b Winston-Salem, North Carolina Severe chronic itch and intractable pruritus are encountered frequently by dermatologists. Recent data suggest that generalized pruritus may result from an imbalance between the mu and kappa opioid systems, and kappa-agonists have been shown to inhibit pruritus in both animals and human beings. These findings led us to use butorphanol, a commercially available kappa-opioid agonist and mu-opioid antagonist. We present a case series of 5 patients with intractable pruritus associated with inflammatory skin diseases or systemic diseases who demonstrated rapid and marked improvement when treated with intranasal butorphanol. Because of the small, open-label nature of this study, butorphanol should be investigated further in a larger, randomized controlled trial. ( J Am Acad Dermatol 2006;54: ) Intractable pruritus is encountered frequently by dermatologists. It is defined as a chronic itch state in which the cause cannot be removed or otherwise treated, and in the generally accepted course of medical practice no relief or cure has been found after reasonable efforts. 1 Despite the central role of oral antihistamines in the treatment of itch, these medications are ineffective for most cases of pruritus caused by inflammatory skin diseases and systemic diseases. Without adequate treatment, pruritus can significantly impair patients quality of life; patients have attributed depression, agitation, difficulty concentrating, decreased sexual desire, and decreased sexual function to itch. 2-4 Mu-opioid receptor agonists, such as morphine and endogenous opiates, are known to cause generalized pruritus. 5-8 This has led to the use of mu-opioid antagonists, such as naloxone and naltrexone, for the treatment of pruritus associated with cholestasis, uremia, and dermatologic diseases. However, such mu-antagonists are associated with significant side effects, can be inconvenient to administer, and have been used infrequently by dermatologists. Recent data suggest that generalized pruritus results from an imbalance between the mu and kappa opioid systems. 9 Kappa-opioid receptor stimulation inhibits mu-receptor effects both centrally and peripherally. 6,7,10 This led us to use butorphanol, a From the Departments of Dermatology a and Neurobiology and Anatomy, b Wake Forest University School of Medicine. Funding sources: None. Conflicts of interest: None identified. Reprint requests: Gil Yosipovitch, MD, Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC gyosipov@wfubmc.edu. Published online January 17, /$32.00 ª 2006 by the American Academy of Dermatology, Inc. doi: /j.jaad commercially available kappa-opioid receptor agonist and mu-opioid receptor antagonist in patients with intractable pruritus. No previous report has described the use of butorphanol for treatment of pruritus associated with systemic diseases and inflammatory skin diseases. Given the need for medications that successfully treat severe pruritus and the profound impact that itch can have on patients lives, we propose that the opioid agonist-antagonist analgesic butorphanol may have a role in treating patients with chronic, severe, and intractable pruritus. We report a series of 5 patients with severe pruritus unresponsive to high doses of sedating antihistamines, corticosteroids, and other medications that demonstrated rapid and marked improvement when treated with intranasal butorphanol (Table I). CASE REPORTS Patient 1 was a 35-year-old woman with prurigo nodularis who presented with severe pruritus of 1-year duration. Multiple skin biopsy specimens confirmed prurigo nodularis. A 5-week trial of oral prednisone (40 mg/d) combined with oral antihistamines and a 3-week trial of mirtazapine (15 mg/d) did not reduce the patient s itch. Kenalog injections (40 mg) with cryotherapy every 2 weeks for nearly 3 months improved her prurigo lesions but did not relieve her pruritus. An outside physician prescribed a 3-month trial of dapsone (100 mg/d), which was also ineffective. Continued severe pruritus caused difficulty sleeping and depressed mood. Finally, a 3- month trial of hydroxyzine (up to 150 mg/d) caused drowsiness without relief of pruritus. After starting butorphanol (1 mg every other day), she reported a reduction in itch and improvement in sleep with her first dose and on the days of subsequent butorphanol doses. Her butorphanol dose was titrated up to 1 mg/d, and her pruritus remained well controlled.

2 528 Brief reports JAM ACAD DERMATOL MARCH 2006 Table I. Summary of patients with intractable pruritus treated with butorphanol Patient Age, y Diagnosis Ineffective previous medications Effective butorphanol dose Butorphanol adverse effects 1 35 Prurigo nodularis Prednisone (40 mg/d) 1 mg/d None Mirtazapine (15 mg/d) Kenalog (40 mg IM) with cryotherapy Dapsone (100 mg/d) Hydroxyzine (150 mg/d) 2 50 Primary biliary cirrhosis Naltrexone (20 mg/d) 1 mg/d None 3 94 Idiopathic elderly pruritus Alprazolam (2.5 mg/d) 1 mg/d Nausea Prednisone (20-30 mg/d) Kenalog (40 mg IM) 4 42 Non-Hodgkins lymphoma Pramoxine (1%) with hydrocortisone 3-4 mg/d Abuse (1%) lotion Triamcinolone 0.1% with eucerin Mometasone (0.1% cream) Clobetasol (0.05% cream) Aclometasone (0.05% cream) Diphenhydramine (50 mg 4 times daily) Hydroxyzine (75 mg/d) Mirtazapine (15 mg/d) 5 56 Perforating collagenosis Triamcinolone (0.1% cream) 1 mg/d None Hydroxyzine (75 mg/d) IM, intramuscular. Patient 2 was a 50-year-old woman with primary biliary cirrhosis. She presented with severe pruritus of her palms, soles, and forearms, which was particularly bothersome at night. A 1-week trial of naltrexone (20 mg/d) caused drowsiness and nausea. We then initiated butorphanol (1 mg/d), and she reported immediate improvement of her pruritus and improved sleep after only one dose. Her pruritus continued to be well controlled on 1 mg/d of butorphanol without any adverse effects while awaiting a liver transplant. Patient 3 was a 94-year-old man with a 5-year history of idiopathic elderly pruritus. A 6-month trial of alprazolam (2.5 mg/d) provided no relief. Multiple trials of prednisone (20-30 mg/d, tapered gradually) caused diffuse atrophy and was discontinued. Monthly Kenalog injections (40 mg) for more than a year were also ineffective. We initiated butorphanol (1 mg/d), but the patient developed severe nausea after his first dose. Nevertheless, his pruritus was controlled for 4 days after this single dose. We later determined that the patient had inadvertently taken two inhalations daily (2 mg/d) rather than the prescribed 1 inhalation daily (1 mg/d). The correct dose of 1 mg/d controlled his pruritus but did not eliminate the patient s nausea. He refused to take antiemetic medications and discontinued the butorphanol; consequently, his pruritus returned to its prior intensity. Patient 4 was a 42-year-old woman who presented with severe protracted itch and difficulty sleeping of 1-year duration. Previous trials of topical corticosteroids including pramoxine (1%) with hydrocortisone (1%) lotion, topical triamcinolone 0.1% with Eucerin (Beiersdorf Inc., Wilton, CT), mometasone (0.1% cream), clobetasol (0.05% cream), and aclometasone (0.05% cream) were ineffective. High doses of oral antihistamines including diphenhydramine (50 mg 4 times daily) and hydroxyzine (75 mg/d) also failed to relieve her itch. Further evaluation including chest radiograph, chest computed tomogram, and needle biopsy revealed low-grade non-hodgkin s lymphoma. A 3-week trial of mirtazapine (15 mg/d) did not relieve her pruritus. After starting butorphanol (1 mg/d), she noted significant improvement in her itch and sleep after only one dose. However, she continued to have daytime itch and self-medicated with 4 mg of butorphanol daily for 2 weeks. She denied any history of drug abuse or addiction. Later, she underwent chemotherapy for her lymphoma with 1 month of concurrent butorphanol (3 mg/d). Her pruritus resolved as her cancer regressed, and she no longer required butorphanol. Patient 5 was a 56-year-old man with diabetes and end-stage renal disease who presented with severe pruritus that began after starting hemodialysis. We observed multiple excoriated nodules, particularly on the trunk and upper extremities, and gave him the diagnosis of perforating collagenosis. Trials of triamcinolone (0.1% cream), oral hydroxyzine (75 mg/d), and desloratadine (5 mg/d) did not improve his

3 Brief reports 529 papular lesions or itch. Butorphanol (1 mg/d) significantly improved his itch within 1 day of starting therapy and his pruritus remained well controlled at this dose. DISCUSSION Butorphanol is a potent opioid agonist-antagonist that has a Food and Drug Administrationeapproved indication for management of pain. Intranasal butorphanol has been used in clinical trials for postoperative pain, postepisiotomy pain, musculoskeletal pain, and migraine headaches. This medication is potentially an ideal drug for the treatment of severe pruritus because it possesses both kappa-agonist activity and mu-antagonist activity. It does not treat the underlying cause of pruritus but inhibits itch perception. Previous studies have demonstrated that both epidural and intranasal butorphanol relieve opioid-associated pruritus unresponsive to antihistamines In our series of patients with intractable pruritus, intranasal butorphanol was highly effective. Opiates modify the perception of pruritus via central opioid receptors. Activation of mu-opioid receptors stimulates itch perception, whereas activation of kappa-opioid receptors suppresses itch perception. In animal models, kappa-opioid receptor agonists inhibit pruritus and scratching induced by substance P or histamine. 7,10 In a recent placebocontrolled trial of patients on hemodialysis with severe pruritus, Kumagai et al 9 demonstrated that a novel kappa agonist, nalfurafine (TRK-820), significantly reduced patient-reported itch. Therefore, kappa agonists are a promising treatment for severe itch; however, nalfurafine is not commercially available in the United States. The use of mu-opioid antagonists, naloxone and naltrexone, to treat itch is also supported by controlled clinical trials Metze et al 20 demonstrated that naltrexone was effective for treatment of some cases of severe, intractable pruritus. However, most previous studies demonstrating the efficacy of naloxone and naltrexone for pruritus have been performed in an inpatient setting. Such mu-antagonists are associated with significant side effects including hepatotoxicity, nausea and vomiting, abdominal pain, fatigue, difficulty sleeping, and reversal of analgesia, which often require inpatient treatment. In contrast, dermatologists treat most patients with severe itch as outpatients; therefore, it is essential to find effective antipruritic therapies that can be reasonably administered in an outpatient setting. Unlike naloxone and naltrexone, butorphanol possesses both antagonist action at mu-opioid receptors and agonist activity at kappa-opioid receptors. Furthermore, butorphanol has a favorable side effect profile compared with other opioid antagonists. This was demonstrated by Patient 2 who did not tolerate naltrexone but had excellent results on butorphanol without any adverse events. Both naloxone and naltrexone are associated with reversal of analgesia 21 ; in contrast, intranasal butorphanol reduces pruritus without reversing the analgesic effects of opioid therapy. 13 Activation of the kappaopioid receptor antagonizes various actions mediated by the mu-opioid receptor but does not inhibit analgesic action. Both naloxone and naltrexone are contraindicated in patients physically dependent on opiates and those receiving opioid analgesics or opioid-containing medicines, such as cough, cold, and antidiarrheal therapies. Butorphanol may also precipitate withdrawal in patients who are narcoticdependent. 22 Naltrexone is contraindicated in patients with evidence of liver dysfunction. In contrast, butorphanol can be used safely in patients with hepatic or renal impairment; however, the initial dose should be reduced by half. Additional advantages of butorphanol include its once-daily dosing, intranasal administration, and rapid onset of action. The intranasal formulation allows self-administration by the patient and oncedaily dosing aids patient compliance. In contrast, naloxone has low oral bioavailability that necessitates parenteral administration. The initial recommended dose for intranasal butorphanol is 1 mg (1 spray in one nostril). An initial dose of 2 mg (1 spray in each nostril) may be used in patients who will remain recumbent; however, the incidence of adverse effects is higher at the 2-mg dose. In addition, intranasal butorphanol has a rapid onset of action. Onset of analgesia occurs within 15 minutes, and peak analgesic activity occurs within 1 to 2 hours. As demonstrated by the patients in this brief report, butorphanol provides rapid relief of pruritus as well. All 5 patients achieved significant relief of pruritus within 1 to 3 days of starting the medication. Butorphanol s ease of administration and favorable side effect profile facilitate use in an outpatient dermatology setting. In clinical trials of intranasal butorphanol, the most frequently reported side effects were somnolence (43%), dizziness (19%), and nausea or vomiting (13%). 23 Sedation has been noted at doses of 0.5 mg or more. At doses of 2 mg and higher, patients may also experience psychomotor impairment for up to 2 hours. 24,25 For these reasons, we typically instruct patients to take the medication at bedtime. Sedation and psychomotor impairment may improve sleep quality in patients with severe nocturnal itch, as demonstrated by patients 1, 2, and 4. In long-term trials with intranasal butorphanol, nasal congestion (13%) and insomnia (11%) were also frequently

4 530 Brief reports JAM ACAD DERMATOL MARCH 2006 reported. Like other opioid agonists, butorphanol produces respiratory depression; however, the magnitude of respiratory depression does not increase significantly at higher doses. Butorphanol-induced respiratory depression is reversed by treatment with naloxone. Butorphanol-associated nausea can be significant, as demonstrated by patient 3. Nausea and vomiting have been noted at doses of 1 mg or more. As with other agonist-antagonists with high kappa-opioid receptor affinity, some individuals may experience unpleasant psychomimetic effects. Butorphanol is classified as pregnancy category C and should be used with caution in pregnant and nursing women because the drug crosses the placental barrier and is secreted in breast milk. Butorphanol has minimal abuse potential compared with other medications with opioid-agonist activity; however, it may occasionally lead to abuse and dependence. Patient 4 overused butorphanol. In clinical trials, less than 1% of patients developed physical dependence or tolerance, 23 and there is no evidence of acute physical dependence. 26 Butorphanol s limited addictive potential probably results from its weak agonist activity at the mu-2 receptor, which is primarily responsible for euphoria and physical dependence. 27 Nevertheless, caution should be exercised in patients with a history of drug abuse or with patients receiving the medication continuously for an extended period of time. CONCLUSION Most dermatologists do not prescribe opioid antagonists for pruritus because of their mode of administration and side effects. However, butorphanol has greater potential for use in an outpatient dermatology setting based on its efficacy, ease of administration, and favorable side effect profile. Intranasal butorphanol was highly effective for the treatment of intractable pruritus in our series of patients. Nevertheless, there are many types of itch related to inflammatory skin disease and systemic disease. 5,28 We do not yet know if butorphanol is effective for all types of pruritus, particularly neuropathic itch. It would be of interest to examine the efficacy of butorphanol for different types of pruritus in a large, prospective clinical trial. We would like to thank Nora V. Bergasa, MD, for her suggestion to use butorphanol for pruritus based on her large experience treating patients with liver disease with opiate antagonists. ADDENDUM Institutional review board approval is not required for retrospective case series of this size at our institution. REFERENCES 1. Yosipovitch G, Greaves MW. Definitions of itch. In: Yosipovitch G, Greaves MW, Fleischer AB, McGlone F, editors. Itch: basic mechanisms and therapy. New York: Marcel Dekker; p Yosipovitch G, Goon A, Wee J, Chan YH, Goh CL. The prevalence and clinical characteristics of pruritus among patients with extensive psoriasis. 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