Psychocutaneous Disease

Psychocutaneous disease

Pharmacotherapy and psychotherapy

Helena Kuhn, MD,a Constance Mennella, DO,b Michelle Magid, MD,c,d,e Caroline Stamu-O’Brien, MD,f and George Kroumpouzos, MD, PhDa,g,h Providence, Rhode Island; Austin, Galveston, and Round Rock, Texas; New York, New York; Sao~ Paulo, Brazil; and South Weymouth, Massachusetts

Learning objectives After completing this learning activity, participants should be able to discuss how to establish a working alliance with the patient who has psychocutaneous disease and most effectively involve the psychiatrist in management; list psychiatric medications used in psychocutaneous disorders; and describe effective psychotherapies for psychocutaneous diseases. Disclosures Editors The editors involved with this CME activity and all content validation/peer reviewers of the journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Authors The authors involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). Planners The planners involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s). The editorial and education staff involved with this journal-based CME activity have reported no relevant financial relationships with commercial interest(s).

Building a strong therapeutic alliance with the patient is of utmost importance in the management of psychocutaneous disease. Optimal management of psychocutaneous disease includes both pharmacotherapy and psychotherapy. This article reviews psychotropic medications currently used for psychocutaneous disease, including antidepressants, antipsychotics, mood stabilizers, and anxiolytics, with a discussion of relevant dosing regimens and adverse effects. Pruritus management is addressed. In addition, basic and complex forms of psychotherapy, such as cognitive-behavioral therapy and habit-reversal training, are described. ( J Am Acad Dermatol 2017;76:795-808.)

Key words: antidepressant; antipsychotic; cognitive-behavioral therapy; drug; management; pruritus; psychocutaneous; psychotherapy.

ost patients with psychocutaneous disease and effectively communicate the connection be- refuse psychiatric intervention, leaving tween mind and skin.1 Rapport develops over the M management exclusively to the dermatol- course of several office visits in which the patient ogist. A direct and empathic approach helps elicit feels, with good reason, that the physician is an ally in relevant psychiatric information from the patient to their struggle to cure the disease.2 A psychiatry formulate a diagnostically driven management plan. referral approached with sensitivity may be success- It is important for the dermatologist to identify ful.2 When patient is resistant to pursuing psychiatric psychosocial factors and psychiatric comorbidity, treatment, the dermatologist should support the

From the Department of Dermatologya and the Division of Accepted for publication November 3, 2016. Child/Adolescent Psychiatry,b Alpert Medical School of Brown Reprints not available from the authors. University, Providence; Departments of Psychiatry at Dell Med- Correspondence to: George Kroumpouzos, MD, PhD, Rhode Island ical School,c University of Texas at Austin, University of Texas Hospital, 593 Eddy Street, APC 10, Providence, RI 02903. E-mail: Medical Branch at Galveston,d Texas A&M Health Science [email protected]. Center,e Round Rock, and New York University Medical School,f 0190-9622/$36.00 New York; Department of Dermatology,g Medical School of Ó 2016 by the American Academy of Dermatology, Inc. Jundiaı, S~ao Paulo; and GK Dermatology, PC,h South http://dx.doi.org/10.1016/j.jaad.2016.11.021 Weymouth. Date of release: May 2017 Funding sources: None. Expiration date: May 2020 Conflicts of interest: None declared.

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imbalance) may occur if they are stopped or tapered Abbreviations used: too quickly.7 Treatment should be continued for a AED: antiepileptic drug minimum of 6 months after therapeutic response.5 CBT: cognitive-behavioral therapy EPS: extrapyramidal symptoms Selective serotonin reuptake inhibitors (SSRIs) and FDA: US Food and Drug Administration tricyclic antidepressants (TCAs) are the most HRT: habit-reversal training commonly used classes of antidepressants in OCRD: obsessive-compulsive and related disorder SSRI: selective serotonin reuptake inhibitor psychodermatology. TCA: tricyclic antidepressant SSRIs. SSRIs (Table I) are the most common class of antidepressants because of their favorable safety profile.6 These medications primarily affect serotonin, although this is a simplified version of how they 12 patient with a nonjudgmental stance, provide indi- work. Effective dosing for psychocutaneous con- cated psychotropic medication (the dermatologist ditions has not been established. As a general rule, it is typical for obsessive-compulsive and related should be aware of commonly used psychotropic 8 agents and their adverse effects),3 and encourage disorders (OCRD) to require higher dosing. The evaluation with a psychiatrist as a supplement to, and most common adverse effects include gastrointes- not as a replacement for, the therapeutic tinal distress (eg, nausea), insomnia, weight changes, 1 and sexual dysfunction (eg, anorgasmia or reduced relationship. 7 There are data supporting the effectiveness of libido). When starting an antidepressant of any class psychotherapy in psychocutaneous disease.4 These in a patient \25 years old, it is important to monitor therapies are described below. for suicide-related events because these medications have been found to be associated with thoughts PHARMACOTHERAPY about suicide and suicide attempts but not 13 Key points completed suicide. This is true particularly at the d Selective serotonin reuptake inhibitors are start of treatment (ie, the first 2 months). If the first commonly used to treat anxiety, depression, SSRI fails, a second SSRI option can be instituted 14 obsessive-compulsive, and somatic symptom before switching to another class of antidepressant. and related disorders TCAs. TCAs (Table II) are an older class of d Tricyclic antidepressants can be used in antidepressants that act on serotonin and norepi- 5 neuropathic pain and obsessive-compulsive nephrine. To a great extent, TCAs have been and related disorders; doxepin is a potent replaced by SSRIs because TCAs are more sedating antipruritic tricyclic antidepressant and have a broad spectrum of adverse effects. However, they have more antihistaminic properties, Antidepressants which serves useful for pruritic complaints and Antidepressants are approved for the treatment of insomnia.5 A few of the TCAs are notable for use in depression and variants of anxiety including, panic psychodermatology. Doxepin carries the most anti- disorder and posttraumatic stress disorder. The onset histaminergic properties, making it a potent oral and of effect for all antidepressants, regardless of class, is topical antipruritic agent for psychogenic pruritus 4 to 6 weeks at a therapeutic dose.5 Dosing recom- and prurigo nodularis, respectively.15 Typically, the mendations include starting low and titrating slowly. dosage of TCA used to treat pruritus is lower than the As a general guideline, one may consider starting at typical antidepressant dosage. There are case reports half the minimum effective dose and titrating up- of reduction of excoriation and pruritus with dox- wards every 14 days. Higher dosing does not hasten epin 30 mg/day.19 Another common TCA used in the effect, but rather puts the patient at greater risk of OCRD, including body dysmorphic disorder, is clo- adverse effects.6 If there is no improvement after an mipramine.20,21 Other TCAs have received approval adequate trial of $6 weeks, or if the medication is not by the US Food and Drug Administration for in- tolerated, one should switch to a different medica- dications such as neuropathic pain.16 When a TCA is tion. If there is partial improvement, titrating the dose used as analgesic, the dosage required tends to be is ideal. No class of antidepressant has been shown less than the dosage required for its antidepressant to be more efficacious than another in the treatment effect; amitriptyline (25-50 mg at bedtime) is of depression.7 Of note, no antidepressant carries an frequently used for pain control.3 indication for a specific psychocutaneous condition. Of the TCAs, nortriptyline has the most favorable Antidepressants are not addictive, but a discontinu- side effect proﬁle, with mortality rates similar to ation symptom (eg, flu-like symptoms, insomnia, or those of SSRIs, and nortriptyline should be

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For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved. Starting dose to target dose (mg/ AEs day) Notes Monitoring/interactions Most common uses* Fluoxetine Mildly activating, 10-40 (for depression and Longest half-life of SSRIs; no No routine monitoring MDD, OCD, panic disorder, y sexual AEs SSRD ) and 10-80 mg (for discontinuation symptoms bulimia nervosa, PMDD, z OCRD ) trichotillomania, and excoriation disorder Sertraline Mildly sedating, 25-100 (for depression and Effective in chronic anxiety No routine monitoring MDD, OCD, panic disorder, sexual AEs SSRD) and 25-200 mg (for PTSD, social anxiety OCRD) disorder, PMDD, and GAD Citalopram Sexual AEs 10-40 (for depression, SSRD, Cardiac risk in doses [40 mg Maximum dose 40 mg, consider MDD, OCD, panic disorder, and OCRD) electrocardiography for PTSD, and GAD higher doses Escitalopram Sexual AEs 5-10 (for depression and SSRD) Purified isomer of citalopram; No routine monitoring MDD, GAD, OCD, panic and 5-20 mg (for OCRD) few drug interactions disorder, and PTSD Paroxetine Sedating, sexual 20-50 (for depression) and Second shortest half-life of No routine monitoring MDD, GAD, OCD, panic AEs, and weight 20-60 (for OCRD) SSRIs; prone to disorder, PTSD, social gain discontinuation symptoms; anxiety disorder, and higher risk of drug PMDD interactions Fluvoxamine Sedating, less 50-150 (for depression) and Shortest half-life of SSRIs; prone No routine monitoring OCD and social anxiety x sexual AEs 50-300 (for OCRD) to discontinuation disorder symptoms; most drug interactions of SSRIs

This table highlights the most common medications and is not an all-inclusive summary. AE, Adverse effect; GAD, generalized anxiety disorder; MDD, major depressive disorder; OCD, obsessive-compulsive disorder; OCRD, obsessive-compulsive and related disorder; PMDD, premenstrual dysphoric disorder; PTSD, posttraumatic stress disorder; SSRD, somatic symptom and related disorder; SSRI, selective serotonin reuptake inhibitor. *Conditions in bold indicate that treatment is approved by the US Food and Drug Administration. y SSRDs include somatic symptom disorder, illness anxiety disorder, conversion disorder, factitious disorder, psychological factors affecting medical conditions, other SSRD, and unspecified SSRDs. z OCRDs include obsessive-compulsive disorder, body dysmorphic disorder, hoarding, trichotillomania (hair pulling disorder), excoriation (skin picking) disorder, substance-induced OCRD, OCRD caused by another medical condition, other specified OCRD, and unspecified OCRD. al et Kuhn x Only the extended release form of fluvoxamine has been approved by the US Food and Drug Administration for the treatment of social anxiety disorder. 797 798 une al et Kuhn

Table II. Tricyclic antidepressants5,15-18

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For personal use only. No other uses without permission. Copyright ©2017. Elsevier Inc. All rights reserved. Medication Adverse events dose (mg/day) Notes Monitoring/interactions Most common uses* Clomipramine High anticholinergic effects, high 25-150 (for depression) Most serotoninergic TCA ECG in women [40 and OCD, BDD, and sedation, moderate orthostatic and 25-250 (for OCRDs) men [30 years of age trichotillomania hypotension, high conduction or those with preexisting abnormalities, and weight gain cardiac disease; high risk of lethality in overdose y Doxepin Anticholinergic effects, high 25-300 (for depression Most antihistaminergic and As above Insomnia, MDD, MDD sedation, less orthostatic and OCRDs) anticholinergic; effective in with psychosis, pruritic hypotension, and fewer treating pruritic skin condition skin disease, and conduction abnormalities because of these properties excoriation Amitriptyline High anticholinergic effects, high 10-150 (for depression Helpful in insomnia because of As above MDD, neuropathic pain, sedation, moderate orthostatic and SSRD) sedating effect fibromyalgia, and hypotension, and high headache conduction abnormalities Imipramine Anticholinergic effects, moderate 50-200 (for depression) As above MDD, enuresis, and sedation, most orthostatic panic disorder hypotension, and high conduction abnormalities Desipramine Fewer anticholinergic effects, less 50-200 (for depression) Monitor weight and BMI As above MDD and chronic pain sedation, moderate orthostatic hypotension, and moderate conduction abnormalities Nortriptyline Moderate anticholinergic effects, 25-100 (for depression) Monitor plasma drug levels; best As above MDD and chronic pain moderate sedation, least TCA for use in elderly orthostatic hypotension, and fewer conduction abnormalities

This table highlights the most common medications and is not an all-inclusive summary. BMI, Body mass index; BDD, body dysmorphic disorder; ECG, electrocardiogram; MDD, major depressive disorder; OCD, obsessive-compulsive disorder; OCRD, obsessive-compulsive and related JA disorder. M A

*Conditions in bold indicate that treatment is approved by the US Food and Drug Administration. CAD y Silenor (Pernix Therapeutics, Morristown, NJ). D M ERMATOL AY 2017 JAM ACAD DERMATOL Kuhn et al 799 VOLUME 76, NUMBER 5 considered for use in the elderly.17,22 With the dose in order to increase tolerability and allow for exception of nortriptyline, therapeutic blood moni- adverse effect monitoring.3,5 There is a risk of toring is not required for TCAs. The most frequent dizziness, sedation, and hypotension with most adverse effects result from anticholinergic proper- antipsychotics, which can be minimized with slow ties, causing dry mouth, constipation, dizziness, titration.5 Patients should be carefully monitored for tachycardia, blurred vision, and urinary retention.5 EPS, because these can become permanent and They are contraindicated in persons with preexisting profoundly disabling.3,5,23 In addition, in elderly conduction defects and should be used cautiously in patients with dementia, antipsychotics increase the those with preexisting heart disease.5 These medi- risk of stroke and transient ischemic attacks.29 cations are also lethal in overdose and ought to be Finally, psychotropic medications can produce a used carefully in suicidal patients or those with wide spectrum of cutaneous adverse effects, history of suicide. including exanthematous eruptions, skin pigmenta- Other antidepressants. Mirtazapine (7.5-30 mg tion changes, photosensitivity, urticaria, and at bedtime) is a noradrenergic and selective seroto- pruritus.30 nergic antidepressant.5 Because it can cause heavy sedation and weight gain, it is commonly used in Typical antipsychotics geriatric and terminal illness populations. Bupropion Pimozide is the most commonly used ﬁrst- XL (150-300 mg every morning) is a selective generation antipsychotic in psychoder- norepinephrine and dopamine reuptake inhibitor.5 matology. The effective dose for psychocutaneous It has fewer sexual adverse events and is activating. It conditions ranges from 2 to 6 mg/day.3 Careful is helpful for depressed patients with fatigue and titration is key to safe usage, with most authors poor motivation.5 recommending a starting dose of 1 mg/day, followed by slow 0.5- to 1-mg uptitration every 2 weeks until 3,23 ANTIPSYCHOTIC AGENTS there is an adequate treatment response. Once Key points improvement is noted, the clinically effective dosage should be maintained for 1 month, then slowly d Antipsychotc agents can be used in delu- tapered by 1 mg every 1 to 2 weeks.3,23 Most patients sional infestation, dermatitis artefacta, and require 5 to 6 months for induction, treatment, and olfactory reference syndrome, and as taper.3 Adverse effects of pimozide are uncommon at augmentation therapy in treatment- the doses used in dermatology. EPS include stiffness resistant obsessive-compulsive and related and akathisia, a feeling of inner restlessness.3,23 EPS disorders can be treated with diphenhydramine 25 mg or d Pimozide is a frequently used typical anti- benztropine 1 to 2 mg, but it is recommended that psychotic in psychodermatology; atypical patients are switched to a second-generation antipsy- antipsychotics used include risperidone, chotic if EPS occur.3 Pimozide can cause QTc prolon- olanzapine, quetiapine, aripiprazole, and gation with subsequent arrhythmias, and an ziprasidone electrocardiogram is recommended for patients with Antipsychotic agents (Table III) work by blocking a history of arrhythmias or cardiac conduction abnor- dopamine receptors in the central nervous system. mality.3 However, controversy exists regarding the They are used to treat delusional and psychotic need for an electrocardiogram with doses\10 mg/day disorders by decreasing the excess dopamine neuro- in young and otherwise healthy individuals.3,31 The transmission believed to drive delusions.23,24 Typical long-term use of pimozide can result in tardive (first-generation) antipsychotics block the dopamine dyskinesia, which is potentially irreversible.3,23 (D2) receptor, and are associated with distressing extrapyramidal side effects, such as dystonia and Atypical antipsychotics parkinsonism. Atypical (second- and third- Risperidone. Risperidone is primarily used for 3,23,32 generation) antipsychotics are both dopamine (D2) the treatment of delusional infestation. The and serotonin (5-HT2) receptor antagonists. There is medication is generally started at 0.5 mg at bedtime, a decreased incidence of extrapyramidal symptoms with the dose increased every few weeks up to 4 mg/ (EPS) because of the preferential 5-HT2 receptor day on a twice daily schedule until clinical improve- 23 3 activity. ment is observed. It retains a high level of D2 Psychocutaneous disorders can be effectively antagonism and therefore can cause hyperprolacti- managed with relatively small doses of antipsy- nemia, manifested by galactorrhea, amenorrhea, and chotic medications. It is recommended to initiate sexual dysfunction.25,26 Risperidone can prolong the therapy at a low dose, and to gradually increase the QT interval and should be used with caution in

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Psychocutaneous Starting dose to disorders with reported Medication* Adverse events maximum dose Notes Monitoring/interactions benefit Pimozide Severe EPS, QTc prolongation, and 1-10 mg/day Risk of tardive dyskinesia with ECG recommended with a history DI and DA anticholinergic effects long-term use of arrhythmias or cardiac conduction abnormality Risperidone Moderate EPS, moderate risk of 0.5 mg at bedtime May initially cause sedation but Parameters of MetS (ie, weight, DI, DA, ORS, TTM, QTc prolongation, moderate risk resolves within a few days blood pressure, glucose, and and BDD of MetS, hyperprolactinemia, to 6 mg/day lipid profiles) should be and sexual dysfunction monitored Olanzapine Very sedating, increased risk of 2.5 mg at bedtime d As above DI, DA, TTM, and BDD weight gain, and significant risk to of MetS 20 mg/day Quetiapine Very sedating, increased risk of 50-600 mg at Useful for elderly population and As above DI, TTM, and BDD weight gain, moderate risk of bedtime treatment resistant patients MetS, and less risk of CVA in elderly Aripiprazole Least sedating, decreased risk of 2-30 mg/day Can be used as augmentation Less risk of MetS, but consider DI, neurotic excoriations, weight gain, less risk of CVA in agent in depression at lower monitoring ORS, TTM, and BDD elderly, and may cause agitation doses Ziprasidone Less weight gain and moderate 20-80 mg twice Slightly less efficacious As above DI risk of QTc prolongation daily antipsychotic

This table highlights the most common medications and is not an all-inclusive summary. BDD, Body dysmorphic disorder; CVA, cerebrovascular accident; DA, dermatitis artefacta; DI, delusional infestation; ECG, electrocardiogram; EPS, extrapyramidal symptoms; MetS, metabolic syndrome; ORS, olfactory reference syndrome; TTM, trichotillomania.

*Listed medications have not been approved by the US Food and Drug Administration for the specific psychocutaneous indication. JA M A CAD D M ERMATOL AY 2017 JAM ACAD DERMATOL Kuhn et al 801 VOLUME 76, NUMBER 5 patients with a history of conduction abnormality or nervosa and binge eating disorder.37 Lithium is concomitant use of medications that may prolong indicated in poor impulse control, and patients with the QT interval.3 Anticholinergic adverse effects of skin picking disorder can benefit from it. Its use is risperidone are minimal, and although it may initially limited by its broad spectrum of cutaneous adverse cause sedation, this generally resolves within the first effects, including triggering/worsening psoriasis.38 few days of use.3,25,26 Olanzapine. Olanzapine has one of the highest Anxiolytic agents incidences of weight gain but is overall well-toler- Antianxiolytic agents can alleviate distress.5 They ated.3,25,26 Dosing for psychocutaneous conditions is can be classified into benzodiazepines and non- not well established; therefore, low doses are rec- benzodiazepines. Benzodiazepines (Table IV) ommended.3 The major adverse effect of olanzapine should be limited to 3- to 4-week courses to avoid is metabolic syndrome, which increases cardiovas- potential for abuse and dependence.3,23,39 They tend cular risk if left untreated.25,26 Weight, blood pres- to be sedating, and should be used cautiously in sure, glucose, and lipid profiles should be monitored patients with sleep apnea. Withdrawal symptoms, during therapy.25,26 including depression, seizures, psychotic episodes, Quetiapine. Quetiapine is particularly useful for and autonomic system disturbances, can be avoided the elderly and treatment-resistant patients.3,23 Again, by using a taper.23 Withdrawal symptoms must be dermatologic dosing is not well established, so low distinguished from the rebound phenomenon (rest- doses are advised.3,23 Common adverse effects lessness, anxiety, or insomnia).40 include weight gain, somnolence, mild anticholinge- Hydroxyzine, a nonbenzodiazepine anxiolytic, ric effects, and orthostatic hypotension.3,25,26 has sedating and anticholinergic effects (Table IV).5 Aripiprazole. Aripiprazole is a third-generation Buspirone (15-60 mg/day), a nonbenzodiazepine, antipsychotic, its great strength being the relatively nonsedating anxiolytic, has a delayed onset of action low incidence of metabolic disturbances, anticholin- (2-4 weeks).4 It has no addictive properties and is a geric effects, EPS, and tardive dyskinesia.23,25 It has safe option when long-term therapy is required.41 been successful in the treatment of delusional SSRIs, such as paroxetine, sertraline, fluoxetine, infestation and neurotic excoriations.23 citalopram, and escitalopram, are effective in chronic Ziprasidone. Ziprasidone, another third- anxiety at the dosages indicated for depression generation antipsychotic, has also been successful (Table I).3,5 Low-dose doxepin and venlaxafine in the treatment of delusional infestation.27 It has no extended release can also be helpful in chronic anticholingeric effects and low likelihood of sedative anxiety. adverse effects and metabolic syndrome, but is more likely than other atypical antipsychotics to increase Hypnotic agents QT interval.28 Sleep restoration is imperative in increasing a patient’s functionality and coping with stress. MOOD STABILIZERS AND ANXIOLYTIC, Zolpidem (5-10 mg orally at bedtime) acts as a partial HYPNOTIC, AND MISCELLANEOUS benzodiazepine but may lead to confusion and 42,43 AGENTS tolerance. Zaleplon (5-20 mg/day) and suvorex- Key point ant (5-20 mg/day) have fewer cognitive adverse 42-44 d Mood stabilizers and anxiolytic and hypno- effects. Eszopiclone (1-3 mg/day) and ramelteon tic agents have an important place in the (8 mg/day) are indicated for long-term use in 42,45 therapeutic armamentarium for psychocuta- insomnia. neous conditions Miscellaneous agents Mood stabilizers N-acetylcysteine (1200-3000 mg/day) is a Mood-stabilizing agents, such as antiepileptic promising new treatment for trichotillomania drugs (AEDs) and lithium carbonate are approved and excoriation disorder.46,47 It is an over-the- for bipolar disorder.33 AEDs may be of benefit in self- counter glutamate modulator that is generally well inflicting dermatoses.34 The use of lamotrigine (12.5- tolerated. 300 mg/day) was effective in skin picking disorder in 1 study35 but not better than placebo in a subsequent PRURITUS MANAGEMENT one.36 Gabapentin, another anticonvulsant, can be Key points used in anxiety and pruritus control (discussed d Management of pruritus in the patient with below). Topiramate was endorsed as an antibinge psychocutaneous disease requires an indi- and antipurge agent, and can be used in both bulimia vidualistically tailored approach

Table IV. Treatment of acute anxiety*3-5,23,39,40

Maximum Onset of Elimination Daily dose y Medication action time (hrs) dosing (mg) (mg/day) Common adverse effects Notes Clonazepam Slow 30-40 0.25-2 daily/ 4 Somnolence, depression, Long duration of effect; less twice daily abnormal coordination, risk of rebound anxiety; and ataxia no active metabolites, therefore easier to taper off Diazepam Slow 30-100 2-10 twice or 40 Drowsiness, fatigue, Long duration of effect; less three times muscle weakness, risk of rebound anxiety daily and ataxia Lorazepam Intermediate 10-20 0.5-1 twice or 6 Sedation, dizziness, Safe in hepatic impairment; three times weakness, and no hepatic metabolism daily unsteadiness Alprazolam Fast 12-15 0.25-0.5 twice 4 Drowsiness, light- Highest potential for abuse, or three headedness, depression, dependence, and times daily headache, dry mouth, rebound anxiety; use with constipation, diarrhea, extreme caution confusion, and insomnia Hydroxyzine Intermediate 20 25-50 three or 600 Drowsiness and dry Used mostly in the United four times mouth States; no potential for daily dependence or withdrawal; anti-itch benefit

This table highlights the most common medications and is not an all-inclusive summary. *Adapted from Kotara et al.5 yClonazepam is approved by the US Food and Drug Administration for the treatment of panic disorder; other medications listed are approved for anxiety.

d Psychotropic drug use has expanded the peripheral nerve fibers by depleting substance P.54 therapeutic options in challenging cases Higher concentrations (0.075-0.1%) are more effec- 55 Pruritus is the presenting symptom in up to half of tive. Pramoxine and mixtures of lidocaine and 48 prilocaine cream have been shown to be effective patients with psychiatric disease. Traditional 49,56,57 treatments for itch target the histamine pathway. in neuropathic, facial, and anogenital itch. More recently, neuroactive medications, such as Other antipruritic medications. Topical corti- neuroleptics, antidepressants, and opioid receptor costeroids and calcineurin inhibitors are not directly modulators, have been used successfully in the antipruritic but relieve pruritus through their antiinﬂammatory effect.57 Calcineurin inhibitors are management of pruritus, particularly in chronic or 57 generalized cases. These medications are thought to particularly useful in anogenital pruritus. Doxepin affect the nonhistaminic pathways of itch transmis- can relieve localized itch in patients with atopic dermatitis and contact dermatitis, but has not been sion and central nervous system modulation. They 49,58 are particularly useful in itch that is of neuropathic or efficacious in other causes of itch. psychogenic origin.49-51 Topical and systemic therapies for pruritus are highlighted in Tables V and VI, Systemic therapies respectively. Phototherapy. Chronic pruritus has improved with several types of phototherapy.48 Generalized Topical therapies pruritus of unknown origin has improved with Coolants. When applied to skin, menthol pro- narrowband ultraviolet B light phototherapy, while duces a cooling sensation. It relieves itch by acti- aquagenic pruritus and prurigo nodularis were vating thermosensitive ion channels that produce the successfully treated with psoralen plus ultraviolet A cool sensation and k-opioid receptors.49,50 light phototherapy.62 Anesthetics. Capsaicin is used in neuropathic Oral antihistamines. Oral antihistamines are itch.52,53 It works primarily by desensitizing helpful in treating urticaria and acute itch.49-51 First-

Table V. Topical treatment of pruritus

Medication Concentration Adverse effects Types of pruritus with reported benefit Menthol49,50 1-5% Irritating at concentrations [5% Acute itch; itch that responds to cold Capsaicin52-55 0.025-0.1% Transient burning sensation Neuropathic itch, notalgia paresthetica, brachioradial pruritus, postherpetic neuralgia, PN, UP, pruritus ani, aquagenic pruritus, and pruritus associated with AD Pramoxine49,56* 1%, 2.5% Irritation and xerosis Pruritus associated with eczematous dermatitis, anogenital itch, neuropathic itch, and UP Lidocaine49,57 2.5-5% Irritation and other reactions Neuropathic itch Prilocaine49,57 2.5% As above; methemoglobinemia in Postburn itch, anogenital itch, and PN pediatric patients (rare) Corticosteroids57 Various Skin atrophy, striae, telangiectasia, Pruritus associated with skin folliculitis inflammation Calcineurin inhibitors57 Pimecrolimus 1% Transient stinging or burning Pruritus associated with AD, contact sensation with application dermatitis, and facial and anogenital itch Tacrolimus 0.03% or 0.1% As above As above Doxepin58* 5% Avoid in children; 20-25% risk of Pruritus associated with AD, LSC, and sedation contact dermatitis Other medications Naltrexone59 1% Well-tolerated Pruritus associated with AD and other inflammatory skin conditions Polidocanol60 3% Stinging, itch, irritation Pruritus associated with AD, contact dermatitis, psoriasis, and idiopathic pruritus N-palmitoylethanolamine61 Well-tolerated Pruritus associated with AD, PN, LSC, and UP Aprepitant61 Nausea, vertigo, drowsiness PN, paraneoplastic and drug-induced pruritus, Sezary syndrome, and UP

AD, Atopic dermatitis; FDA, US Food and Drug Administration; LSC, lichen simplex chronicus; PN, prurigo nodularis; UP, uremic pruritus. *Approved by the US Food and Drug Administration for the treatment of pruritus. generation antihistamines help with nocturnal itch.57 of generalized pruritus, including psychogenic Data are lacking to support the efficacy of antihista- pruritus.24,49,51,64,65 The antipruritic effect may be mines for pruritic conditions beyond urticaria; mediated by downregulation of the excitatory 65 however, clinical gestalt suggests that the reduction postsynaptic 5-HT3 receptor. Mirtazapine has in pruritus is likely caused by a mild anxiolytic effect been effective in various types of pruritus,49-51 and associated with sedation.49,50 has a good effect in nocturnal itch in patients with Neuroleptics. Gabapentin and pregabalin, struc- generalized pruritus.57 The TCAs doxepin and tural analogues of the neurotransmitter g-aminobutyric amitriptyline are frequently utilized in neuropathic acid, are commonly used for neuropathic pain/itch, and psychogenic itch,49-52 but have not been studied including scalp dysesthesia, notalgia paresthetica, in controlled trials. Doxepin, the most potent anti- brachioradial pruritus, prurigo nodularis, and posther- histamine available, can help with neuropathic and petic neuralgia.49,51,52,63 They are thought to inhibit psychogenic itch but results in significant seda- calcium channels in the dorsal root ganglion and spinal tion.49-52 cord, thereby increasing the threshold for neuronal Opioid modulators. Antipruritic effects can be excitation by pruritic stimuli.63 These medications are achieved by blocking the opioid receptor or of slow onset and may require $4 weeks before clinical activating the k-opioid receptor. Naltrexone is the effects plateau.63 prototype receptor antagonist.49,66 It reduces Antidepressants. SSRIs, such as paroxetine, ﬂu- pruritus in several skin conditions,23 especially voxamine, and sertraline, can improve various types prurigo nodularis,67 and has been effective in

Table VI. Systemic treatment of pruritus

Types of pruritus with reported Medication Dosing Adverse effects benefit Phototherapy48,62 Takes 1-2 months Sunburn reactions Chronic itch (narrowband UVB and PUVA) Antihistamines49-51,57 Variable depending on Sedation, drowsiness, dry Pruritus associated with medication mouth, and confusion urticaria and nocturnal itch Neuroleptics49,51,52,63 Gabapentin 100-800 mg three times daily Somnolence, dizziness, Postherpetic neuralgia, (maximum 3600 mg/day) fatigue, weight gain, and psychogenic itch, blurred vision neuropathic itch, UP Pregabalin 50-100 mg three times daily As above; gradual taper to As above; aquagenic itch (maximum 600 mg/day) prevent withdrawal symptoms Antidepressants24,49-52,57,64,65 Paroxetine 20-50 mg daily Sedation, dry mouth, and Psychogenic pruritus, UP, CP, sexual dysfunction and paraneoplastic itch Mirtazapine 7.5-30 mg at bedtime Drowsiness, dizziness, dry As above; nocturnal itch in mouth, constipation, generalized pruritus increased appetite/weight gain, and vision changes Doxepin 25-300 mg at bedtime Drowsiness, dizziness, Neuropathic and psychogenic hypotension, dry mouth, itch urinary retention, and cardiotoxicity Amitriptyline 10-150 mg daily, or divided As above Neuropathic and psychogenic itch Opioid receptor modulators23,49,51,57,66-70 Naltrexone ( antagonist) 12.5-50 mg daily GI distress and hepatoxicity UP, CP, intractable itch, AD, PN, trichotillomania, self- injury, and neurotic excoriations Butorphanol (k agonist, 1-4 mg at bedtime (inhaled) GI distress, drowsiness, and Intractable pruritus associated antagonist) dizziness with inflammatory skin disease, non-Hodgkin lymphoma, CP, and opioid use

AD, Atopic dermatitis; CP, cholestatic pruritus; PN, prurigo nodularis; PUVA, psoralen plus ultraviolet light A phototherapy; UP, uremic pruritus; UVB, ultraviolet B light phototherapy. trichotillomania, cutaneous self-injury, and neurotic Anxiolytics. Anxiety may incite or worsen excoriations.68,69 However, its use is limited by symptoms of pruritus. Anxiolytics, such as benzo- its adverse effects and high cost.57 It is also diazapines and SSRIs, can help reduce itch in contraindicated in patients with acute hepatitis patients with an anxious or obsessive-compulsive or liver failure, and during pregnancy and diathesis. lactation.49,66 Antipsychotics. Antipsychotics can help in psy- PSYCHOTHERAPY chogenic pruritus and pruritus that has a predomi- Key points nantly impulsive quality.51 Medications, such as d Conducting a psychological assessment chlorpromazine, risperidone, and olanzapine, are and establishing a physicianepatient thera- often used to augment treatment with an antidepres- peutic alliance improves the outcome of sant or anxiolytic regimen. Olanzapine monotherapy psychotherapy has successfully treated itching related to self- d There is a plethora of psychotherapeutic mutilation in patients who have failed other modalities but scarce evidence on their pharmacotherapies.71 comparative efficacy

The psychologic evaluation of the dermatology Habit-reversal training. Habit-reversal training patient is crucial, and should include an assessment (HRT) aims at replacing an old habit (a recurrent, whether a referral to psychiatry and/or psychology is often subconscious or automatic pattern of warranted. Patients with psychodermatological is- behavior) with a new, more desirable one.80 HRT is sues often beneﬁt from psychotherapy. The most the criterion standard for treatment of body-focused common psychological interventions and psycho- repetitive behaviors,81,82 and may also be helpful in therapies are described below. atopic dermatitis, lichen simplex chronicus, pruritus ani, and prurigo nodularis.83 HRT includes 3 main components: awareness training, competing Basic therapies response training, and social support.84 Awareness Psychoeducation. Providing psychoeducation training involves the patient describing the old habit increases patients’ understanding of their condition, (ie, skin picking or hair pulling), along with its improves treatment adherence, and reduces distress, antecedents (ie, triggers/warnings signs before the anxiety, shame, and depression associated with the habit occurs, such as looking in a mirror or stroking disease.72 Support groups, in which patients share the hair). Once the patient is made fully aware of the their problem and provide mutual support for each behavior, its antecedents, and its consequences, other, can provide such education and improve breaking the habit becomes much more possible. quality of life.4,73 Competing response training includes teaching the Self-help. Self-help (computer- or literature- patient behaviors that are physically impossible to do based) covers a variety of interventions, including in alongside the old habit (eg, fisting hand with the psychoeducation (providing patients with reading thumb tucked). Social support involves finding a material about their illness), speciﬁc coping tech- friend/family member who can gently make the niques, and self-guided CBT (see below).74 patient aware when he/she is engaging in an old Relaxation. Most psychocutaneous diseases can habit and praise the patient for correctly using be precipitated or exacerbated by stress.4 Relaxation competing behaviors.84 Other helpful interventions techniques are used to help cope with stress. They include stimulus control (eg, covering mirrors, wear- consist of guided imagery, mindfulness, muscle ing gloves, or wearing shorter hairstyles).84 Despite relaxation, avoidance of food indulgence and dehy- positive results, CBT and HRT carry a significant risk dration, aerobic and water exercise, yoga, and of relapse, and their efficacy varies across patients.85 meditation.4,72 Hypnotherapy. Hypnotherapy uses the power Social skills training. Social skills training of suggestion to change habits and thoughts.4,24,86 By helps patients cope with others’ reactions to their tapping into the subconsciousness to reveal an appearance and develop effective strategies to event, comment, or situation, one can resolve it. manage social situations.72 It also helps patients Hypnosis can reduce stress and promote deep elicit more positive feedback from others in social relaxation, can help deal with childhood issues, interactions, and therefore develop a more positive and treat anxiety and depression. Skin disorders sense of self.75 that may benefit from hypnosis include, among others, acne excoriee, delusional infestation, glosso- Complex therapies dynia, and trichotillomania.4,24 CBT. CBT helps alter dysfunctional thought pat- Biofeedback. Biofeedback involves measuring terns (cognitive) or actions (behavioral) that lead to and providing auditory and visual feedback of bodily skin damage or psychological distress.24 CBT places processes including blood pressure, heart rate, a strong emphasis on ‘‘examining the evidence,’’ and galvanic skin response (sweating), muscle tension, replacing inaccurate thoughts with more accurate and skin temperature.4 Patients are taught tech- ones.76 For example, in a patient with skin picking niques that enable them to control the above disorder, the CBT therapist may challenge a patient involuntary functions, which helps manage stress. who believes that he/she can ‘‘pick just a little and Skin diseases improved by biofeedback include, then stop’’ by asking the patient to provide evidence among others, eczema, psoriasis, hyperhidrosis, of a time that he/she was able to pick for\5 minutes. pain syndromes and Raynaud syndrome.4,24,86 CBT is typically conducted once a week for a total of Other interventions. Family-based therapy 12 to 20 weeks. Although preliminary results can be promotes parental responsibility for treatment seen early into treatment, [20 sessions may be adherence, and has been helpful in eating disor- necessary for long-term results.77 CBT is of signifi- ders.87,88 Motivational interviewing seeks to improve cant benefit in OCRDs and somatic symptom a patient’s ambivalence to treatment and resistance disorders.38,78,79 to change, and transform ambivalence into positive

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