Antipruritic treatment with systemic μ-opioid receptor antagonists: A review

Antipruritic treatment with systemic m-opioid receptor antagonists: A review Ngoc Quan Phan, MD,a Jeffrey D. Bernhard, MD,b,c Thomas A. Luger, MD,a and Sonja Sta¨nder, MDa ¨ nster, Germany; Worcester, Massachusetts; and Rochester, New York Mu During the past two decades, systemic -opioid receptor antagonists (MORA) have been used in the treatment of various forms of chronic pruritus. In a number of case reports, case series, and controlled trials, treatment with MORA has demonstrated considerable antipruritic effects. In double-blind controlled studies, significant antipruritic relief has been achieved by MORA in cholestatic pruritus, chronic urticaria, and atopic dermatitis. In case reports and case series, antipruritic efficacy of MORA has been reported in prurigo nodularis, mycosis fungoides, postburn pruritus, aquagenic pruritus, hydroxyethyl starch-induced pruritus, and pruritus of unknown origin. However, most of the evidence remains anecdotal, the design of these trials varies, and comparison of results is difficult. In this review we aim to present an overview of these reports and to assess the evidence for the antipruritic action of the drugs naloxone, nalmefene, and naltrexone, which are currently in use for the treatment of chronic pruritus of different origins. We will also evaluate recommendations for the use of MORA in daily medical practice. ( J Am Acad Dermatol 2010;63:680-8.) Key words: atopic dermatitis; itch; opioid receptor antagonist; pruritus; sensory nerve fibers; therapy.

P

ruritus is a symptom associated with a wide variety of systemic and dermatologic diseases and is often refractory to treatment. As a result, it becomes chronic and more severe as sensitization mechanisms in the peripheral and/or central nervous system come into play.1,2 Development of safe and effective antipruritic drugs continues to remain a challenging task. The -opioid receptor (MOR) antagonists (MORA) are of interest because there is a rational theory about how they work and because efficacy has been demonstrated in case series and controlled trials.3

METHODS We conducted a literature research for reports on MORA in the treatment of chronic pruritus and itchy conditions. We searched different electronic databases (MEDLINE, Ovid, and DIMDI) using the free From the Competence Center Pruritus, Department of Dermatology, University Hospital Mu¨nstera; University of Massachusetts Medical Schoolb; and Logical Images Inc, Rochester.c Funding sources: None. Conflicts of interest: None declared. Reprint requests: Sonja Sta¨nder, MD, Competence Center Pruritus, Department of Dermatology, University Clinics Mu¨nster, VonEsmarch-Strasse 58, D-48149 Mu¨nster, Germany. E-mail: sonja. [email protected]. Published online May 12, 2010. 0190-9622/$36.00 ª 2009 by the American Academy of Dermatology, Inc. doi:10.1016/j.jaad.2009.08.052

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Abbreviations used: MOR: -opioid receptor MORA: -opioid receptor antagonists RCT: randomized controlled trial

text key words ‘‘naltrexone,’’ ‘‘nalmefene,’’ ‘‘naloxone,’’ ‘‘opioid receptor antagonist,’’ ‘‘pharmacology,’’ ‘‘pruritus,’’ ‘‘itch,’’ and their combinations. Search was done without language restriction. Manufacturers of drugs and authors of articles were not contacted. In addition, we included information from current data sheets for the substances.

RESULTS Online search yielded a total of 318 reports from 1979 to 2009 containing the key words mentioned above. We included 58 clinical articles mainly reporting on chronic pruritus and some examples in acute pruritus. Case reports and studies on morphine-induced pruritus were excluded. The main topics addressed in these studies were the pharmacology of opioid receptor antagonists, their neuronal mechanism, and their clinical antipruritic potency. Pharmacology of MORA: Metabolism and excretion MORA were originally developed for treatment of heroin dependence and to reverse symptoms of postanesthetic depression, narcotic overdose, and

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opioid intoxication such as respiratory depression, opioid withdrawal reactions such as severe lightsedation, and hypotension. Naloxone, an allyl derheadedness, disturbed body image, depersonalizaivate of noroxymorphone, was synthesized in 1960.4 tion, anxiety, paresthesias, and hallucinations have It has low oral bioavailability and thus requires been reported to occur.20-23,25,29-31 These adverse parenteral administration. After subcutaneous or effects have been attributed to the presence of intravenous administration, it undergoes first-pass increased levels of endogenous opioids in some metabolism in the liver to yield naloxone glucuropruritic conditions such as hepatic cholestasis.23 Severe cardiovascular side nide, which is subsequently effects such as pulmonary excreted by the kidney. With CAPSULE SUMMARY edema, cardiovascular instaa plasma half-life of only 1 to bility, ventricular tachycar2 hours,4,5 its duration of acThe -opioids appear to stimulate itch in tion is short, making it necdia, and ventricular several clinical settings, such as essary to repeat the dose fibrillation have been mainly cholestatic pruritus. The -opioid frequently or administer it reported in the context of receptor antagonists (MORA) interfere as a continuous infusion. treatment of postoperative with this activity. Naltrexone, a derivative of narcotic overdose and intoxMore than 550 patients with pruritus oxymorphone developed in ication in patients with opiwho have received MORA have been 1963, is an orally active, longoid dependence, possibly as reported in the medical literature. acting, competitive antagoa result of abrupt reversal of nist at MOR.6,7 After oral opioid effects. To diminish MORA can be recommended as secondadministration, naltrexone is side effects, some authors line treatment in cholestatic pruritus. rapidly absorbed,8,9 and unsuggest gradual introduction MORA cannot be recommended for dergoes extensive first-pass of naltrexone or nalmefene treatment of uremic pruritus. metabolism in the liver with with slowly increasing rapid reduction to the major doses.27 Nausea can be easily metabolite 6b-naltrexol.9,10 Naltrexone and its metabolites remain in the circulation for up to 48 hours Table I. Side effects of -opioid receptor and are excreted by renal clearance.8,10-12 The anantagonist therapy with naloxone, naltrexone, or tagonist potency of naltrexone is about 12 to 17 times nalmefene greater than that of nalorphine and twice that of naloxone.6 Common side effects18-27 Nalmefene (6-desoxy-6-methylene-naltrexone), a Gastrointestinal Nausea,* vomiting,* diarrhea,* chemical analogue of naltrexone, was synthesized heartburn, loss of appetite, in 1975.13,14 It is a potent, orally active opioid intermittent abdominal pain antagonist at -, k-, and d-opioid receptors.15-17 Cardiovascular Dizziness,* hypertension, hypotension, pulmonary Nalmefene has longer-lasting plasma concentrations edema, vasodilatation, and greater oral bioavailability than naltrexone.13,15 cardiovascular instability, Administered via oral, intravenous, intramuscular, or ventricular tachycardia, subcutaneous routes, nalmefene is rapidly absorbed ventricular fibrillation with therapeutic plasma and brain concentrations Neurologic Fatigue,* headache,* reached within 5 to 15 minutes. It is metabolized in lightheadedness,* anxiety, the liver primarily by glucuronide conjugation.15,18,19 nightmares, hallucinations, Currently, nalmefene is only available in the United depression, depersonalization, States, but not in Europe. disturbed body image, d

d

d

d

Side effects MORA do not cause physical dependence and have no abuse potential. In general, naloxone, naltrexone, and nalmefene appear to have a favorable risk-to-benefit ratio with comparable occurrence of identical side effects (Table I). All MORA are usually well tolerated with dose-dependent side effects generally limited to the first 2 weeks of treatment.15,18-27 Interestingly, female and younger subjects are more likely to report nausea.28 Rarely,

Musculoskeletal system Allergic

paresthesias, tremor, fever, chills Myalgia, arthralgia

Urticaria, rhinitis, angioedema, dyspnea Opioid Light-headedness, disturbed body withdrawal-like image, depersonalization, reactions20-23,25,29-31 anxiety, paresthesias, hallucinations *Frequent appearance.

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Fig 1. Neuronal mechanism of antipruritic effect of -opioid receptor (MOR) antagonists (MORA). Pain-transmitting dorsal horn neurons (blue) and pruritoceptive dorsal horn neurons (red ) run parallel in dorsal horn of spinal cord. They are connected by opioid-sensitive interneurons (IN ). Activated IN may suppress pruritus transmission in pruritoceptive neurons. A, Opioids target MOR on pain-transmitting neurons and IN, inducing neuronal inactivity and analgesia. As a consequence, inhibitory effect of IN on pruriceptive neurons is abrogated, clinically resulting in itch perception. B, MORA inhibit activation of MOR and reconstitute thereby suppression of itch. DRG, Dorsal root ganglion; presynaptic neuron (itch neuron: black, pain neuron: orange), postsynaptic neuron (itch neuron: red, pain neuron: blue).

managed by oral metoclopramide.20 Interestingly, Neuberger and Jones31 reported on a patient with hallucinations and intense nausea under naltrexone treatment, which could be counteracted by slow infusion of naloxone (0.002 g/kg/min up to 0.2 g/kg/min) followed by administration of naltrexone. However, after long-term administration of naloxone, side effects of subsequent naltrexone therapy may be increased, possibly as a result of MOR up-regulation.27 In high dosages of up to 300 g, naltrexone has the capacity to produce transient dose-related hepatocellular injury resulting in elevation of serum transaminases and to evoke thrombocytopenic purpura.32,33 In patients treated for chronic pruritus with MORA, neither elevation of liver enzymes nor thrombocytopenic purpura was observed.20 In patients with liver diseases, the clearance of nalmefene was significantly reduced in comparison with patients without liver diseases,34 but no dosage adjustment is recommended (Baker Norton Pharmaceuticals Inc, Miami, FL, datasheet nalmefene). Endogenous opioids and opioid antagonists influence immune functions.35 Naloxone enhances T-lymphocyte proliferation, increases T-helper cell 1 but decreases T-helper cell 2 cytokine production, and worsens inflammatory responses in animals possibly by blocking endogenous -agonist opioids.36 Interestingly, a recent study reported that naloxone reduces endothelial barrier disruption caused by morphine.37 The role of opioid receptors in the human immunoregulatory system awaits further elucidation.

Contraindications to MORA therapy Naltrexone and nalmefene are contraindicated in patients with acute hepatitis, liver failure, severe liver insufficiency, and marginal evidence of hepatocellular injury. In cirrhosis, metabolism of naltrexone into 6b-naltrexol is disturbed leading to reduced effective circulating concentrations.38 Furthermore, naloxone, naltrexone, and nalmefene must not be given to drug addicts or to patients receiving opioid analgetics or opioid-containing medicines such as cough, cold, and antidiarrheal preparations. Patients with a history of opioid dependence and pre-existent cardiac diseases should be monitored carefully.18 None of these agents should be used in children or in pregnant or breast-feeding women. Neuronal mechanism of the antipruritic effect Clinical and experimental observations have demonstrated that pruritus can be evoked or intensified by endogenous or exogenous opioids.39-43 It is generally agreed that opioids activate spinal -, k-, and d-opioid receptors, which induce analgesia often combined with induction of pruritus.2,44 Reversing the opioid effects by administration of MORA results in inhibition of pruritus. Neuronal communication between pain- and itch-transmitting neurons underlies this mechanism (Fig 1). Itch and pain neurons in the spinal cord are connected by opioid-sensitive interneurons that can inhibit the pruritus transmission.1,2 Suppression of the activity of these interneurons by opioids results in clinically relevant itch sensation. The findings of experimental

Chronic urticaria24,69,70

Atopic dermatitis20,24,29,60,70,71

Psoriasis vulgaris20,29,60

Nalmefene (once 10 mg, once 20 mg)24 Nalmefene (20 mg/d, po, single dose)70 Nalmefene (once 10 mg, once 20 mg)24 Nalmefene (20 mg/d, po, single dose)70 Nalmefene (10 mg/d, po)29 Naltrexone (25 mg, po)71 Nalmefene (10 mg twice daily, po)29

Prurigo nodularis, macular amyloidosus, lichen amyloidosus20,59,60

-

Lichen simplex20,60

-

Mycosis fungoides20,27,60

-

Cutaneous B-cell lymphoma20,60

-

Study design

n

Comparator

RCT

21

Placebo

RCT

20

Placebo

RCT

59

Placebo

RCT

19

Placebo

RCT RCT RCT

7 11 12

Placebo Placebo Placebo

MORA in case reports (dosage, maximal duration of treatment)

Study design

n

CR

1

Naltrexone (50-150 mg/d po, 3 mo)60 Naltrexone (50 mg/d po, 6 wk-12 mo)20

OLT

16

OLT

4

Naltrexone (50 mg/d po)20 Naltrexone (50-150 mg/d po)60 Naltrexone (50-150 mg/d po, up to 3 y)60 Naltrexone (50 mg/d po)20 Butorphanol (1 mg/d intranasal)59 Naltrexone (50-100 mg/d po; 1 wk)60 Naltrexone (50 mg/d po)20 Naltrexone (50-150 mg/d po, 1 mo)60 Naltrexone (50 mg po)20 Naloxone (0.2 mg sc every 3-4 h) followed by Naltrexone (50 mg/d po twice)27 Naltrexone (100 mg/d po, 1 mo)60 Naltrexone (50 mg/d po)20

OLT

1

OLT

1

OLT

34

OLT CR

18 2

OLT

2

OLT OLT

1 4

OLT CR

4 1

OLT

3

OLT

1

CR, Case report; MORA, -opioid receptor antagonists; OLT, open-label trial; po, by mouth (oral); RCT; randomized controlled trial; sc, subcutaneously. *Considerable relief: [50% of patients responded or [50% pruritus reduction.

Significant relief24,70 Considerable relief69 Significant relief24,71 Considerable relief20,60 No significant relief29,70 Considerable relief20 No significant relief29 No improvement60 Considerable relief20,59,60

Considerable relief60 No improvement20 Considerable relief20,27,60

No improvement20,60

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Naloxone (1.6 mg/h for 4 h, once)69

Antipruritic effect: relief of itch*

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Diagnosis

MORA in double-blind, placebo-controlled studies

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Table II. Antipruritic effect of -opioid receptor antagonists in dermatologic diseases

MORA in controlled studies (dosage)

Diagnosis

Uremic pruritus20,25,26,52-54,60

Cholestatic pruritus 20-23,30,31,45,48,59-68

Study design

Naltrexone (50 mg/d po, 2 wk)53 Naltrexone (50 mg/d po, 4 wk)25 Naltrexone (50 mg/d po, 1 wk)26 Naltrexone (50 mg/d po, 1 wk)54 Naloxone (0.2 g/kg/min for 24 h, 2 d)21 Naloxone (single infusion of 2 mg)48

RCT

Naloxone (0.2 g/kg/min for 24 h, 1-2 d)63 Nalmefene (20 mg twice daily po, 2 mo)61 Naltrexone (50 mg/d po, 1 wk)67 Naltrexone (50 mg/d po, 2 wk)66

CT single blind

Naltrexone (50 mg/d po, 4 wk)62

Hydroxyl-ethyl starch-induced pruritus20,60

-

-

MORA in case reports (dosage, maximal duration of treatment)

Study design

CR

RCT

52 Loratadine Naloxone (single infusion of 0.8 mg)52 23 Placebo Naltrexone (50-150 mg/d po)60

RCT

15 Placebo

Naltrexone (50 mg/d po, 3 wk)20

OLT

RCT

4 Placebo

RCT

29 Placebo

Naloxone (0.8 mg/d, sc, 2 d)45

CR

RCT

20 Placebo

Naloxone (0.2 g/kg/min, IV, 2 d, followed by Nalmefene 80 mg/d po)64 Nalmefene (30-120 mg po, twice daily, 2-26 mo)22 Nalmefene (20-40 mg thrice daily, po, 6 mo)65 Naltrexone (50 mg/d po, 1 wk)30 Naltrexone (50-150 mg/d po)60 Naltrexone (50 mg/d po, 9 mo)20 Naltrexone (25 mg/d po, 12 mo)23 Naloxone (0.2 g/kg/min, IV, followed by Naltrexone (150 mg/d po, 3 mo)31 Naltrexone (25 mg twice daily)68 Butorphanol (1 mg/d intranasal)59 Naltrexone (50 mg/d po, 3-6 mo)20 Naltrexone (50 mg/d po, 5 mo)20 Naltrexone (25 mg/d po, 3 mo)73 Naltrexone (50 mg/d po, 5 mo)20 Naltrexone (50-150 mg/d po)60

CR

8 Placebo

RCT

11 Placebo

RCT

34 Placebo

RCT

20 Placebo

RCT

16 Placebo

OLT

OLT OLT CS

n

Effect*

1 Significant relief26 4 Complete relief52 2 Considerable relief20,54,60 No significant relief25,53 1 Significant relief21,61-63,66,67 1 Significant relief in placebononresponders48 14 Complete relief23,31,45 11 Considerable relief20,22,30,59,60,64,65, 5

OLT

3

OLT

1

CR

1

CR

1

CR CR

1 1

OLT

2 Weak relief20

OLT CR OLT OLT

1 Complete relief73 1 Considerable relief20 4 Considerable relief20,60 2

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-

Comparator

J AM ACAD DERMATOL

Pruritus in diabetes mellitus20 Aquagenic pruritus20,73

n

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Table III. Antipruritic effect of -opioid receptor antagonists in systemic diseases

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59,60,69

Pruritus of unknown origin20,

Non-Hodgkin lymphoma59

Postburn pruritus72

CR, Case report; CS, case series; CT, controlled trial; IV, intravenous; MORA, -opioid receptor antagonists; OLT, open-label trial; po, by mouth (oral); RCT; randomized controlled trial; sc, subcutaneously. *Considerable relief: [50% of patients responded or [50% pruritus reduction.

1 CR

19 Considerable relief59,60 5 No significant relief20 OLT OLT

1 Complete relief69 CR

1 Considerable relief59 CR

Naloxone (50-100 mg/d po, 2 wk)72 Butorphanol (3-4 mg/d intranasal)59 Naloxone (1.6 mg/ h for 4 h, IV, once)69 Naltrexone (50-150 mg/d po)60 Naltrexone (50-100 mg/d po, 3 mo)20 Butorphanol (1 mg/d intranasal)59

CS

15 Considerable relief72

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studies that different MORA may significantly diminish pruritus is in agreement with the neuronal mechanisms mentioned above.40,45-48 In human beings, pruritus induced by cutaneous injection of different neuropeptides and neurotransmitters such as histamine,46,47 substance P,49 serotonin,50 and acetylcholine51 could be completely suppressed by naloxone and naltrexone. Clinical antipruritic effect of MORA Chronic pruritus is a clinical symptom occurring in a heterogeneous group of diseases. Several studies with varying study designs have reported on the efficacy of MORA in the treatment of pruritus associated with many different diseases (Tables II and III). The first studies carried out in the early 1980s reported that acute opioid-induced pruritus, for example, pruritus occurring after injection of the synthetic analgesic butorphanol39 or pruritus after epidural or intrathecal analgesia with morphine,3,55-57 could be quickly reversed by MORA. In subsequent studies of patients with chronic pruritus, MORA were demonstrated to have considerable antipruritic effects in most, although not in all, subjects (Tables II and III). However, randomized controlled trials (RCTs) exist only for single diseases such as cholestatic pruritus, chronic urticaria, and atopic dermatitis. Single-arm trials, case series, and case reports have reported variable responses in other indications such as psoriasis vulgaris and atopic dermatitis. Importantly, in one study, patients with cholestatic pruritus were divided into two groups according to their reaction to placebo: placebo responders (pruritus improved on placebo) and placebo nonresponders. Interestingly, only patients defined as placebo nonresponders experienced itch improvement under naloxone, possibly reflecting the contribution of elevated opioid levels to pruritus.48 This finding might explain the failure of treatment in a great number of individuals. Further studies should consider the difference in pruritus relief from naloxone experienced by placebo responders versus placebo nonresponders. In general, treatment with MORA is a symptomatic therapy combating only itch symptoms, so that after discontinuation of the therapy spontaneous exacerbation of pruritus can be expected.20 Tachyphylaxis Tachyphylaxis, ie, loss of efficacy despite unchanged therapy, has been reported to occur infrequently under long-term MORA therapy with variable latency between 4 weeks and 9 months.20,22,27,30 The antipruritic effect can be re-established by increasing

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the dose or interrupting administration of MORA for 2 to 3 weeks.20,27,30 Tachyphylaxis may result from an up-regulation of receptors after long-term stimulation.58 Conclusions and perspectives MORA have been used in the treatment of pruritus associated with a broad variety of pruritic dermatologic and systemic diseases. Published studies include a total of more than 550 patients treated with MORA. Several RCTs have reported significant improvement of pruritus in cholestatic pruritus,20-23,30,31,45,48,59-68 chronic urticaria,24,69,70 and atopic dermatitis.20,24,29,60,70,71 In case series and case reports, MORA were also described to have efficacy in chronic therapy-refractory pruritus such mycosis funas prurigo nodularis,20,59,60 20,27,60 postburn pruritus,72 aquagenic prurigoides, tus,20,73 hydroxyethyl starch-induced pruritus,20,60 and pruritus of unknown origin.20,59,60,69 However, RCTs are pending. In view of the side effects and costs, MORA can only be recommended as secondline treatment in these conditions. Results of RCTs with MORA in uremic pruritus are conflicting (Table III). Given the current level of evidence, MORA cannot be recommended for treatment of uremic pruritus. Of special interest in uremic pruritus is a new class of k-opioid agonists that also exert antipruritic effect on central afferent neurons.74 Methylnaltrexone, a peripherally acting MORA, was recently approved by the Food and Drug Administration for the treatment of opioidinduced constipation in patients with advanced illness (eg, cancer, AIDS) receiving palliative care.75 Interestingly, clinical and laboratory studies performed during the development of methylnaltrexone have indicated that peripheral opioid receptors mediate certain effects, including nausea, vomiting, and pruritus.75 In one small, double-blind, randomized, placebo-controlled study, oral methylnaltrexone decreased morphine-induced itching.76 This result suggests that methylnaltrexone may be another therapeutic alternative in chronic pruritus targeting opioid receptors. Methylnaltrexone appears to have a beneficial side-effect profile but elucidation of its mechanism and RCTs remain to be done. k-Opioid receptor agonists Activation of spinal k-opioid receptors is also known to inhibit pruritus, therefore, it was expected that k-opioid receptor agonists would be able to reduce pruritus clinically. Butorphanol is a k-opioid receptor agonist and a weak MOR antagonist with minimal or absent abuse potential.77 This

pharmacologic profile suggests that it could be an effective antipruritic. In experimental animal models, butorphanol reduced morphine-induced itch.78 Several clinical studies have shown that butorphanol is effective in alleviating acute opioidinduced itch.79 In a case series of patients with chronic pruritus of various types, intranasal butorphanol spray had an antipruritic effect with a low rate of side effects59 (Tables II and III). In chronic cholestatic pruritus butorphanol spray was also reported to reduce itching in selected patients.80 However, controlled studies have to be performed. Nalfurafine is a newly developed, selective k-opioid receptor agonist. In one RCT it had potent antipruritic effects in hemodialysis patients with uremic pruritus.74 It may be speculated that nalfurafine will also show efficacy in other types of pruritus.

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