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Drug eruptions: is your patient's rash dangerous or benign? Photo-illustrated guide helps you identify easily treated reactions, spot 'red flags' of serious conditions.

your patient who is taking psychotropics suddenly develops a rash. Rapidly identifying the cause is crucial to your decision to either stop the drug and risk decompensation or continue it and deal with the rash.

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Adverse cutaneous drug reactions (ACDRs) develop in 2% to 5% of patients taking psychotropics (1) and can occur with all drug classes. (2) Most "drug eruptions" are benign and easily treated, but they can distress patients and lead to medication nonadherence. Other ACDRs can be disfiguring or life-threatening and require emergent medical treatment.

In this first installment of a 2-part article, we explain how to identify and manage benign ACDRs associated with psychotropics. In part 2, we'll cover serious ACDRs--those that result in persistent or significant disability or are life-threatening (3)--as well as risk-reduction strategies.

Overall strategy

A psychiatric patient with a suspected drug eruption needs to be examined by you and, if necessary, another physician. Identify the lesion by taking a history and performing a physical examination (Box 1, page 44). (4,5) If you are unable to perform this examination, promptly refer the patient to a primary care provider or dermatologist.

Once a rash is identified, determine its cause. Consider nonpharmacologic origins such as:

* infections

* insect bites

* collagen vascular disease

* neoplasms

* exposure to sun, toxins, etc.

If a medication is the prime suspect, search the literature to determine if the drug has been associated with the observed event. Table 1 provides examples of psychotropic drugs and classes associated with 8 common benign rashes. Consider any drug as a possible cause of any reaction, however, even if no published reports have associated a specific drug with a particular reaction. (6)

Look for red flags that may indicate a serious reaction (Table 2). (5,7) Treatment of a serious drug reaction may require care by physicians with training and clinical expertise likely to be beyond the scope of psychiatric practice. However, your responsibility is to ensure that the patient gets a timely--emergent, if indicated--referral so that treatment is not delayed. If an ACDR clearly is benign, follow the guidelines outlined below; otherwise, consult with a dermatologist, infectious diseases clinician, or other appropriate specialist.

Benign rashes

Exanthematous reactions are the most common ACDR. (1) Erythematous macules and papules may initially present on the trunk and spread peripherally within 1 to 2 weeks of a patient's starting psychotropic therapy (Photo 1, page 46). Lesions may become confluent and involve the mucosa, hands, and feet. Differential diagnosis includes infections, collagen vascular diseases, and more serious drug rashes. (1,5,6)

Exanthems usually resolve within 2 weeks after the offending drug is discontinued. (1,6) Because exanthems may resolve without drug discontinuation, (1,8) you could continue treatment with the offending agent if other options are not feasible. (9) Keep in mind, however, that exanthematous reactions may be the presenting symptom of a more serious condition, especially if associated with any of the red flags described in Table 2. If the suspect drug has been associated with a severe reaction, discontinue it permanently. (4) Additional treatments for exanthems include corticosteroids, emollients, and oral antihistamines. (6-8)

Urticaria present as pruritic, blanching erythematous wheals of varying size (Photo 2, page 46). A single lesion will typically last <1 day, but new lesions may continuously arise. Lesions might develop several days after pharmacotherapy begins. Urticaria may be accompanied by angioedema, which can be life-threatening--particularly if it affects the airway. (1,5-7,10)

Urticaria usually is treated with antihistamines. (6,7) A histamine-1 blocker such as hydroxyzine or diphenhydramine--used exclusively or, for severe cases, in combination with a histamine-2 blocker such as ranitidine or cimetidine--may bring relief. (1) Dosage guidelines are based on the severity and distribution of the eruption. If these treatments are not effective, discontinuing the offending drug should resolve the condition. (1,4,11) Resuming the drug can result in anaphylaxis, so warn the patient to never take the offending drug again. (4)

If a patient has unstable vital signs or a rash that affects the airway--or if you believe he or she is at risk for anaphylaxis--emergent treatment is indicated. (1,6) This may include the use of epinephrine and corticosteroids.

Fixed drug eruptions can appear anywhere on the body as single or multiple sharply demarcated, pruritic erythematous macules (Photo 3). They may blister or cause a burning sensation; rarely, a patient may present with constitutional symptoms. Lesions might erupt hours to days after drug exposure. Although this condition usually is benign, consult a dermatologist if the patient exhibits constitutional symptoms or other red flags that may indicate a serious reaction.

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After you discontinue the offending drug, lesions should resolve within several weeks, although there may be residual hyperpigmentation. (6) Depending on the severity of the eruptions, topical corticosteroids or wound care may be indicated. (6,12) Resuming the drug typically will cause the eruptions to reoccur at the same site, potentially with more lesions. (1,5-7)

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Photosensitivity describes phototoxic and photoallergic reactions. A phototoxic response resembles sunburn and is distributed in areas exposed to the sun. This can present as erythema, edema, and skin tenderness (Photo 4).

Delayed hypersensitivity response is a photoallergic reaction. This reaction may be pruritic and appear after sunlight exposure as eczematous, bullous, vesicular, or urticarial lesions 1 to 2 weeks after the drug is started. Photoallergic lesions may extend beyond sun-exposed areas. Phototesting can confirm this diagnosis. (1,5,13,14)

Treat a phototoxic reaction as you would sunburn. Topical soothing agents should bring relief in 1 to 2 days. (15) Instruct patients to use sunscreen and avoid the sun while taking the psychotropic. (1,15) You may need to discontinue the medication if lesions persist. (1)

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Managing a photoallergic response entails avoiding the sun or discontinuing the offending agent. (14,16) For both phototoxic and photoallergic reactions, consider consulting a dermatologist if the above measures do not resolve the rash. (1)

Acne lesions present as papules or pustules, typically on the arms, legs, face, chest, or back (Photo 5). (1) Comedones generally are not present.

Treatment options include benzoyl peroxide, antibiotics, and topical retinoids. (1,12,17) If these measures are insufficient, or if your patient finds the eruption distressing, discontinuing the offending drug usually resolves the condition. (12)

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Pigmentation changes. Blue, gray, or brown discoloration resulting from changes in melanin deposition can affect skin, hair, and nails, particularly in sun-exposed areas (Photo 6). Consider in the differential diagnosis other conditions that causes skin pigmentation changes such as:

* hematochromatosis

* Addison's disease. (1,2,7,12,18-20)

Drug-related pigmentation changes usually resolve once the drug is discontinued, but resolution may take years. (1) Cosmetics may help mask skin discoloration. A dermatologic consultation may not be necessary. (1)

Laser treatment has successfully improved pigmentation changes associated with imipramine without the patient discontinuing the offending drug. (21) Pigmentation changes associated with chlorpromazine have resolved when the drug was replaced by haloperidol (22) or phenothiazines, used individually or in combination. (23)

Alopecia is diffuse nonscarring hair loss (Photo 7, page 49). Anagen effluvium results in rapid hair loss, as seen with chemotherapeutic agents. Telogen effluvium may not occur until months after a drug is started. Frequently, patients experience only partial hair thinning. Differential diagnosis includes:

* infection

* collagen vascular disease

* iron deficiency. (1,24)

Although alopecia is usually considered benign, patients may find it distressing. Improvement usually occurs within several months after the offending medication is discontinued. (1,25) The benefits of continuing a medication associated with alopecia may outweigh the risks; discuss this with the patient.

Psoriasis presents as pruritic erythematous patches with scale (Photo 8, page 49). Psoriasis may appear at the beginning of drug therapy, or pharmacotherapy may worsen preexisting disease. (2,26)

You can treat psoriasis by withdrawing the offending drug. Ultraviolet light has been used to treat drug-related psoriasis; (27) other treatments include topical corticosteroids and antipsoriatics. Consultation with a dermatologist is recommended. (1)

Restarting a medication

By accurately identifying a rash and quickly determining its cause, you may avoid unnecessarily discontinuing a patient's stabilizing medication (Box 2). If you need to discontinue a drug that is causing an ACDR, try to wait 2 weeks before initiating another drug. If this is not possible, cross-tapering a different medication from another class may diminish the risk of drug-rash relapse. To decrease the risk of drug-related rash, follow the manufacturer's dosing recommendations (28) and use the lowest effective dose.

Explain to patients the potential risks of new medications. Teach them how to identify the red flags that indicate a serious rash and what to do if they appear. (3)

Educate office and hospital staff about specifics pertaining to drug rashes to help ensure that:

* vital information gets to you immediately

* evaluation and treatment can start promptly.

References

1. Kimyai-Asadi A, Harris JC, Nousari HC. Critical overview: adverse cutaneous reactions to psychotropic medications. J Clin Psychiatry 1999;60(10):714-25.

2. MacMorran WS, Krahn LE. Adverse cutaneous reactions to psychotropic drugs. Psychosomatics 1997;38(5):413-22.

3. Edwards IR, Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet 2000;356(9237):1255-9.

4. Babu KS, Belgi G. Management of cutaneous drug reactions. Curr Allergy Asthma Rep 2002;2(1):26-33.

5. Shear NH, Knowles SR, Sullivan JR, Shapiro L. Cutaneous reactions to drugs. In: Freedburg IM, Eisen AZ, Wolff K, et al, eds. Fitzpatrick's dermatology in general medicine. 6th ed. New York, NY: McGraw-Hill; 2003:1330-7.

6. Nigen S, Knowles SR, Shear NH. Drug eruptions: approaching the diagnosis of drug-induced skin diseases. J Drugs Dermatol 2003;3:278-99.

7. Chosidow OM, Stern RS, Wintroub BU. Cutaneous drug reactions. In: Kasper DL, Braunwald E, Fauci AS, et al, eds. Harrisons's principles of internal medicine. 16th ed. New York, NY: McGraw-Hill; 2005:318-24.

8. Odom RB, James WD, Berger TG. Contact dermatitis and drug eruptions. In: Andrew's diseases of the skin: clinical dermatology. 9th ed. Philadelphia, PA: W.B. Saunders Co.; 2000:95-145.

9. Rojeau JC, Stern RS. Medical progress: severe adverse cutaneous reactions to drugs. N Engl J Med 1994;331(19):1272-85.

10. Breathnach SM. Adverse cutaneous reactions to drugs. Clin Med 2002;2(1):15-9.

11. du Vivier A, McKee PH, Stoughton RB. Drug and toxic eruptions of the skin. In: du Vivier A, McKee PH, Stoughton RB. Atlas of clinical dermatology. Philadelphia, PA: W.B. Saunders Co.; 1986:14.1-14.18.

12. Warnock JK, Morris DW. Adverse cutaneous reactions to mood stabilizers. Am J Clin Dermatol 2003;4(1):21-30.

13. Mann SC, Walker MM. Leukocytoclastic vasculitis secondary to trazodone treatment. J Am Acad Dermatol 1984;10(4):669-70.

14. Hearn R. Recognition and management of cutaneous photosensitivity. Practitioner 2005;249(1671):418-32.

15. Moore DE. Drug-induced cutaneous photosensitivity: incidence, mechanism, prevention, and management. Drug Saf 2002;25(5):345-72.

16. Crowson AN, Brown TJ, Magro CM. Progress in the understanding of the pathology and pathogenesis of cutaneous drug eruptions. Am J Clin Dermatol 2003;4(6):407-28.

17. Remmer HI. Successful treatment of lithium-induced acne. J Clin Psychiatry 1986;47(1):48.

18. Warnock JK, Morris DW. Adverse cutaneous reactions to antidepressants. Am J Clin Dermatol 2002;3(5):329-39.

19. Warnock JK, Morris DW. Adverse cutaneous reactions to antipsychotics. Am J Clin Dermatol 2002;3(9):629-36.

20. Physicians desk reference. 61st ed. Montvale, NJ: Thomson PDR; 2007.

21. Atkin DH, Fitzpatrick RE. Laser treatment of imipramine-induced hyperpigmentation. J Am Acad Dermatol 2000;43(1 Pt 1):77-80.

22. Thompson TR, Lal S, Yassa R, Gerstein W. Resolution of chlorpromazine-induced pigmentation with haloperidol substitution. Acta Psychiatr Scand 1988;78(6):763-5.

23. Bloom D, Krishnan B, Thavundayil JX, Lal S. Resolution of chlorpromazine-induced cutaneous pigmentation following substitution with levomepromazine or other neuroleptics. Acta Psychiatr Scand 1993;87(3):223-4.

24. Mercke Y, Sheng H, Khan T, Lippmann S. Hair loss in psychopharmacology. Ann Clin Psychiatry 2000;12(1):35-42.

25. Warnock JK. Psychotropic medication and drug-related alopecia. Psychosomatics 1999;32(2):149-52.

26. Gupta AK, Knowles SR, Gupta MA, et al. Lithium therapy associated with hidradenitis suppurativa: case report and review of the dermatologic side effects of lithium. J Am Acad Dermatol 1995; 32(2 part 2):382-6.

27. Osborne SF, Stafford L, Orr KD. Paroxetine-associated psoriasis. Am J Psychiatry 2002;59(12):2113.

28. Wong IC, Mawer GE, Sander JW. Factors influencing the incidence of lamotrigine-related skin rash. Ann Pharmacother 1999;33(10):1037-42.

J.J. Skonicki, MD

Resident

Julia K. Warnock, MD, PhD

Professor of psychiatry

Director, clinical research

Department of psychiatry

University of Oklahoma Health Sciences Center

Tulsa

Box 1 Is your patient's rash drug-related?

When a patient presents with a suspected adverse cutaneous drug reaction, take a history to determine the rash onset, timing, relationship between symptoms and drug ingestion, associated symptoms, and history of previous drug reactions. Ask your patient:

* What are your symptoms?

* How did the rash look initially?

* How has it changed?

* Have you used any new soaps, perfumes, cosmetics, medications, or supplements, or been exposed to insects, foliage, or someone with an illness?

Next, perform a physical examination. In addition to the photos and descriptions in this article (Table 3), review up-to-date textbooks, journal articles, and online resources to aid identification. Look for rashes that affect the mucosa and for lymphadenopathy or signs of internal organ involvement. Seek laboratory abnormalities, including elevated creatinine, positive fecal occult blood test, or hematuria. These and other red flags may indicate a serious rash that requires urgent treatment (Table 2). Consultation with a dermatologist may be indicated.

Box 2 Case study: Is anticonvulsant to blame for painful red lesions?

While visiting the psychiatry clinic to complete paperwork, a patient receiving lamotrigine for bipolar disorder asks the office staff to tell her doctor she has a new rash on her face and in her mouth. Mrs. L, age 52, has been on the same lamotrigine dose (200 mg/d) for >1 year and was also taking lansoprazole (dosage unknown); loratadine, 10 mg/d; bupropion, 300 mg/d; quetiapine, 200 mg/d; clonazepam, 0.5 mg bid; atorvastatin, 10 mg/d; valsartan, 160 mg/ d; and gabapentin, 300 mg/d. She has had no recent medication changes. Mrs. L leaves the office after finishing the paperwork.

Because lamotrigine carries an FDA "black-box" warning about serious, potentially life-threatening rashes, the psychiatrist attempts to contact Mrs. L immediately as soon as she learns of her symptoms. By phone, Mrs. L describes painful red lesions on her face and sores in her mouth that began the day before. She says she isn't sure if these lesions have gotten worse. She denies having fever, chills, muscle aches, arthralgia, cough, neck stiffness, shortness of breath, or any other constitutional symptoms.

The psychiatrist tells Mrs. L she may be having a serious skin reaction to lamotrigine and instructs her to stop taking the drug and visit the ER immediately. She also explains that abruptly stopping lamotrigine might cause a relapse of Mrs. L's bipolar disorder.

The ER physician examines Mrs. L, diagnoses herpes zoster, and prescribes the antiviral famciclovir, 500 mg tid for 7 days, and hydrocodone/acetaminophen, 7.5 mg/500 mg, as needed for pain. Three days later, Mrs. L sees the psychiatrist for a follow-up visit and resumes taking lamotrigine. She has no further complications.

Related Resources

* Dermatology Image Atlas. www.dermatlas.org.

* American Academy of Dermatology. www.aad.org.

Drug Brand Names

Alprazolam * Xanax

Amitriptyline * Elavil

Aripiprazole * Abilify

Atorvastatin * Lipitor

Bupropion * Wellbutrin

Carbamazepine * Tegretol

Chlorpromazine * Thorazine

Cimetidine * Tagamet

Citalopram * Celexa

Clomipramine * Anafranil

Clonazepam * Klonopin

Desipramine * Norpramin

Dexmethylphenidate * Focalin

Diphenhydramine * Benadryl

Duloxetine * Cymbalta

Escitalopram * Lexapro

Eszopiclone * Lunesta

Famciclovir * Famvir

Fluoxetine * Prozac

Fluvoxamine * Luvox

Gabapentin * Neurontin

Haloperidol * Haldol

Hydrocodone/acetaminophen * Vicodin

Hydroxyzine * Atarax

Imipramine * Tofranil

Lamotrigine * Lamictal

Lansoprazole * Prevacid

Loratadine * Claritin

Methylphenidate * Ritalin

Mirtazapine * Remeron

Olanzapine * Zyprexa

Oxcarbazepine * Trileptal

Paroxetine * Paxil

Quetiapine * Seroquel

Ranitidine * Zantac

Risperidone * Risperdal

Sertraline * Zoloft

Thioridazine * Mellaril

Thiothixene * Navane

Topiramate * Topamax

Trazodone * Desyrel

Valproic acid * Depakote

Valsartan * Diovan

Venlafaxine * Effexor

Zaleplon * Sonata

Ziprasidone * Geodon

Zolpidem * Ambien

Disclosures

Dr. Skonicki reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Dr. Warnock receives research/grant support from Boehringer Ingelheim, Forest Pharmaceuticals, and Wyeth Pharmaceuticals.

RELATED ARTICLE: Bottom Line

Discontinuing a medication that is causing a rash is generally an appropriate step but might not always be necessary and may exacerbate psychiatric illness. Look for red flags that indicate a serious reaction such as constitutional symptoms, facial or mucous membrane involvement, and skin tenderness or blistering. Try to wait 2 weeks before restarting pharmacotherapy in a patient who has developed a rash, or cross-taper a different medication from another class.
Table 1 Benign rashes associated with psychotropics*

Rash                     Suspect drugs/classes

Exanthematous reactions  Any drug
Urticaria                Any drug
Fixed drug eruption      Any drug
Photosensitivity         Alprazolam, antipsychotics, bupropion,
                         carbamazepine, citalopram, eszopiclone,
                         fluoxetine, oxcarbazepine, paroxetine,
                         sertraline, topiramate, TCAs, valproic acid,
                         zaleplon, zolpidem
Acneiform eruptions      Antidepressants (most), aripiprazole,
                         clonazepam, eszopiclone, lamotrigine, lithium,
                         oxcarbazepine, quetiapine, risperidone,
                         topiramate, zaleplon, zolpidem
Pigmentation changes     Amitriptyline, carbamazepine, citalopram,
                         clomipramine, desipramine, eszopiclone,
                         fluoxetine, lamotrigine, paroxetine,
                         phenothiazines, sertraline, SGAs (most),
                         thioridazine, thiothixene, topiramate,
                         venlafaxine, zaleplon
Alopecia                 Aripiprazole, carbamazepine, citalopram,
                         clonazepam, dexmethylphenidate, duloxetine,
                         escitalopram, eszopiclone, fluoxetine,
                         fluvoxamine, haloperidol, lamotrigine,
                         lithium, methylphenidate, mirtazapine,
                         olanzapine, oxcarbazepine, paroxetine,
                         risperidone, sertraline, trazodone, TCAs,
                         valproic acid, venlafaxine, zaleplon,
                         ziprasidone
Psoriaform eruptions     Carbamazepine, fluoxetine, lithium, olanzapine,
                         oxcarbazepine, paroxetine, valproic acid

* Suspect any drug with any reaction
SGAs: second-generation antipsychotics; TCAs: tricyclic antidepressants
Source: For reference citations, see this article on
CurrentPsychiatry.com

Table 2 Red flags: Warning signs of a serious drug rash

Constitutional symptoms: fever, sore throat, malaise, arthralgia,
  lymphadenopathy, cough
Erythroderma
Facial or mucous membrane involvement
Skin tenderness or blistering, particularly if there is full-thickness
  epidermal detachment
Purpura

Source: References 5,7

Table 3 Dermatologic glossary

Angioedema: a vascular reaction involving the deep dermis or
  subcutaneous or sub-mucosal tissue that results in localized swelling
Comedones: noninflammatory acne lesions; also called 'blackheads'
Effluvium, anagen: hair shedding during the growth phase of the hair
  cycle
Effluvium, telogen: hair shedding during the resting phase of the hair
  cycle
Erythema: skin redness
Macule: a discolored skin lesion that is not elevated above the surface
Papule: a small, circumscribed, superficial, solid elevation of the skin
  <1 cm in diameter
Purpura: red or purple skin discolorations caused by bleeding underneath
  the skin
Pustule: a visible collection of pus within or beneath the epidermis
Wheal: a smooth, slightly elevated area that appears redder or paler
  than surrounding skin, is often accompanied by severe itching, and
  usually disappears within a few hours

Source: Dorland's illustrated medical dictionary, 30th ed. Philadelphia,
PA: Saunders; 2003
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Author:Skonicki, J.J.; Warnock, Julia K.
Publication:Current Psychiatry
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Date:Mar 1, 2008
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