US Pharm. 2022;47(8):43-46.
ABSTRACT: Pruritus is a commonly seen dermatologic symptom that can lead to excessive scratching and substantially impact quality of life. Unfortunately, chronic pruritus is often refractory, which can lead to severe distress. The treatment of pruritus is largely dependent upon the identifiable cause, which may be due to systemic, psychiatric, and neurological conditions, as well as drug and medication intake. This review aims at discussing medication-induced pruritus and the topical and systemic treatment of pruritus.
Pruritus is a common symptom that can be problematic among patients and lead to excessive scratching. Additionally, chronic pruritus has a substantial impact on quality of life that may be comparable to that of pain.1 Pruritus can be caused by various systemic, psychiatric, and neurological conditions, as well as a result of drug and medication intake.2 Pruritus is thought to be the most commonly encountered skin problem in dermatology. A population-based study in France estimated the prevalence of pruritus of 12.4% during a 2-year period.2 This distressing symptom is reported by patients in more than 7 million outpatient visits per year in the United States; of these, 1.8 million visits are by patients aged 65 and older.3 Unfortunately, chronic pruritus is often refractory to therapy, leading to hopelessness and despair in patients. Elderly patients are often faced with severe pruritus due to changes in their skin barrier.
While medication-induced pruritus is the focus of this review, understanding the changes in skin barrier with elderly patients is imperative. A combination of three age-related biological processes can contribute to itching.3 The first is loss of barrier function, for which the retainment of water is the most important function of the skin. With age, the rate of repair and the function of this barrier are reduced. Secondly, immunosenescence is the proinflammatory state of the skin that may contribute to the high frequency of eczematous and other inflammatory skin reactions. Thirdly, age-related neuropathy can contribute to pruritus. Considering these causes of itching can help providers effectively treat pruritus.3
The cause of pruritus should be delineated, and a medical history should detail the severity and location of pruritus. Given there are multiple causes for this distressing syndrome, identifying the cause will help with potential treatment options. Additionally, a detailed medication history should be taken, as medications are a common cause of pruritus. While other causes of pruritus may be prevalent, this review aims to discuss drug-related causes of pruritus, treatment, and the role of the pharmacist.
Pruritus can be attributable to systemic medications and can be classified into three separate categories: pruritus with a transient eruption or with no rash; pruritus due to drug-induced cholestasis; and pruritus with skin eruption or rash.3 It is imperative to obtain a detailed medication list to discern the cause of pruritus. Unfortunately, there are sparse data available on the association of pruritus with many commonly used medications. Many previous studies have evaluated only small case series or have been narrow in scope by focusing on a single healthcare setting or a single drug/drug class.4
In a retrospective study evaluating inpatient, outpatient, and emergency departments, authors assessed those who were on a medication of interest (as defined as associations with pruritus in previous literature) and with a chief complaint of “pruritus” or a diagnosis of “itching” within 3 months of receiving medication of interest.4 Among antimicrobials, higher rates of pruritus are seen with penicillin antibiotics (0.73%) and trimethoprim-sulfamethoxazole (1.06%) versus lower rates for cephalosporins (0.77%), quinolones (0.02%), and tetracyclines (0.05%). In contrast, psychiatric and neurological drugs as a class were associated with the lowest rates of pruritus: 0.1% in tricyclic antidepressants (TCA), 0.03% in selective serotonin reuptake inhibitors (SSRI), 0.05% in antiepileptics drugs (AED), and 0.05% in opioid analgesics.4 Cardiovascular drugs were associated with higher rates of pruritus with 0.69% in angiotensin converting enzyme inhibitors (ACEI), 0.75% in beta blockers, 0.68% in hydrochlorothiazide, 0.62% in amiodarone, and 0.67% in statins. Interestingly, heparin was associated with a high rate of pruritus (1.11%). About half of patients who developed pruritus also developed skin eruption during the same period. Skin eruption with pruritus was highest for patients receiving cephalosporins (52.1%) and opioid analgesics (50.6%).4
In regard to mechanism of itching and medications, penicillin and trimethoprim-sulfamethoxazole are thought to be secondary to inflammatory skin eruptions or cholestatic liver injury.4 Calcium channel blockers, beta blockers, and hydrochlorothiazide are associated with pruritus from skin inflammation, whereas itching with ACEI is associated with elevated levels of bradykinin.4 Statin-induced xerosis cutis has been thought to be the mechanism for which statins cause itching in addition to an impaired barrier function due to decreased lipid distribution in the skin.4 The mechanism of TCAs, SSRIs, and AEDs is through blockade of afferent neural pathways as well as direct action in the central nervous system.4 Heparin’s mechanism of pruritus is potentially due to immunoglobulin E–mediated urticarial reactions, whereas opioids cause pruritus from triggering nonimmunological histamine release in the skin and central nervous system.4
Treatment of Pruritus
As aforementioned, the primary treatment of pruritus is the identification and elimination of the underlying cause, if possible. Such examples include, but are not limited to, treatment of implicated conditions, avoidance of an identified contact allergen, or stopping an offending medication.5 Further general management strategies of pruritus include nonpharmacologic, topical, and systemic therapies.
Nonpharmacologic therapies can have a significant role in symptom reduction. Dry skin can worsen pruritus, so those affected should frequently moisturize affected areas and apply emollients as needed. Patients should avoid drying out their skin by overbathing or overusing soaps and cleansers.5 Warmer temperatures may lower the pruritic threshold, so maintaining a cooler environment, wearing lightweight clothing, and using lukewarm water instead of hot water for bathing or showering may be helpful.5 Stress reduction and behavioral therapy can also be effective means of managing pruritus—patients learn to reduce impetus through distraction and habit alteration.6,7 Finally, physical barriers can be implemented to help break the itch-scratch cycle.
There are a variety of topical therapies that may be implemented in the treatment of pruritus. As aforementioned, moisturizers (i.e., products containing glycerol acetate, urea, petroleum, mineral oil, and glyceryl stearate, as well as lotions) may be effective in reducing pruritus by reducing skin dryness and restoring the natural barrier.8 Beyond this, products that provide a cooling sensation, such as topical menthol, may be useful in low concentrations (less than 5%).5,8,9 Zinc oxide is a common component of topical products, including calamine, and has been shown to be moderately effective for contact dermatitis.5 Camphor can be applied topically and produces a warming sensation as well as a component of anesthesia.5
Topical capsaicin induces release of neuropeptides, such as substance P, from sensory nerves on the skin. This initially causes a burning sensation that resolves after repeated applications. Capsaicin may be more beneficial in pain of neuropathic origin, including notalgia parasthetica and brachioradial pruritus, although it has been studied in an array of other pruritic conditions.5,6,10
Topical steroids are indicated for the relief of itching due to inflammatory dermatoses, such as atopic dermatitis or psoriasis. By reducing the level of local inflammation, topical steroids have been shown to reduce the degree of pruritus.10,11 Given the risk for adverse effects, such as cutaneous atrophy, telangiectasia, and the potential for hypothalamic-pituitary axis suppression, topical steroids should not be used for a prolonged period of time, with some guidelines recommending use for 1 to 3 weeks.5
Other immunomodulators that have been studied are topical calcineurin inhibitors, including tacrolimus and pimecrolimus. While these have predominantly been shown to be effective in the treatment of pruritus from atopic dermatitis, they have also been used for chronic irritative hand dermatitis, graft-versus-host disease, lichen sclerosis, anogenital pruritus, and prurigo nodularis.12-14 Tacrolimus is available as 0.03% and 0.1% ointments, and pimecrolimus is available as a 1% cream—both of these are typically applied twice daily. Similar to capsaicin, these agents are associated with a burning sensation after application, which is thought to be secondary to substance P release.5,10
Local anesthetics, including pramoxine 1%, lidocaine 5%, and lidocaine 2.5%–prilocaine 2.5% eutectic mixture, have been shown to be effective in the treatment of pruritus, including data from a randomized trial in adult hemodialysis patients.15 In addition to relieving pruritus associated with chronic kidney disease (CKD), these agents may also be effective in the treatment of postburn, neuropathic, and paraneoplastic pruritus.5,6 Polidocanol is an anionic surfactant with local anesthetic properties and can be used to treat pruritus in atopic dermatitis, contact dermatitis, and psoriasis.10
Topical antihistamines are commonly prescribed for treatment of pruritus despite only mixed evidence to support use.6,16 Doxepin, a TCA with potent histamine 1 and 2 (H1 and H2) receptor antagonist activity, is the only topical agent with data to support its use in atopic dermatitis as a topical cream.17
Histamine binds to one of four receptor subtypes; however, H1 and H2 receptors are expressed in the skin. Pruritus is transmitted by afferent c-type nerve fibers in the skin, and histamine stimulates these c-type fibers leading to the perception of itch in the central nervous system. Two generations of antihistamines have been utilized for the treatment of pruritus. First-generation antihistamines bind to histamine, muscarinic, alpha adrenergic, and serotonin receptors. However, second-generation antihistamines have an advantage over first-generation antihistamines due to a difference in histamine receptor dissociation rate, duration of action, and central nervous system penetration.18 This difference allows for a longer duration of action, leading to less frequent dosing and a decrease in significant side effects such as drowsiness. When using first-generation antihistamines, such as diphenhydramine or hydroxyzine, administration at night is preferred due to drowsiness. Antihistamines are most commonly used to treat patients with pruritus given the overall safety profile, availability, and affordability. Additionally, large, double-blind, placebo-controlled trials have confirmed that antihistamines greatly reduce the pruritus associated with chronic urticaria and atopic dermatitis.18
Oral antidepressants may treat pruritus due to their impact on serotonin and histamine receptors. The use of oral antidepressants is recommended by the European Guideline for Chronic Pruritus when chronic pruritus is not responsive to other treatments.5 A systemic review evaluating 35 studies assessed the use of fluoxetine, fluvoxamine, paroxetine, sertraline, amitriptyline, nortriptyline, doxepin, and mirtazapine on chronic pruritus.19 In patients treated with SSRIs, including fluoxetine, fluvoxamine, paroxetine, and sertraline, 15% to 70.8% of patients experienced one or more side effects. The most common side effects included drowsiness, vertigo, fatigue, and headache. Additionally, gastrointestinal symptoms and cardiovascular symptoms were reported. Those taking TCAs, including amitriptyline, nortriptyline, and doxepin, experienced drowsiness, dizziness, somnolence, and impaired concentration in 16.2% to 56% of patients. Patients utilizing mirtazapine reported neurologic and gastrointestinal symptoms, as well as drowsiness and somnolence. The authors concluded that the strongest evidence is for use of antidepressants in chronic pruritus due to CKD, cholestasis, and malignancies refractory to conventional therapy.
Opioid Agonists and Antagonists
Opioids that are µ-opioid receptor agonists are known to have potential pruritic adverse effects, sometimes referred to as opioid-induced pruritus (OIP).8,10 Accordingly, OIP can be effectively reversed by µ-opioid antagonists, such as naloxone or naltrexone. Naltrexone has also been shown to improve pruritus in cholestasis, uremia, burns, and atopic dermatitis.20-23 Contrary to µ-opioid receptor agonists, k-opioid agonists reduce pruritus.10 Butorphanol, a k-opioid agonist, has been evaluated in a case series of patients with chronic intractable itch due to inflammatory skin or systemic diseases, administered via the intranasal route.24 Nalfurafine is another k-opioid agonist that has randomized data to support use in pruritus associated with CKD; however, it is not commercially available in the U.S.25
Gabapentin, a structural analogue of the inhibitory neurotransmitter g-aminobutyric acid (GABA), is often used in the treatment of neuropathic pruritus, including brachioradial pruritus and notalgia paresthetica. Although the mechanism is not fully elucidated, it is believed to mitigate nociceptive signaling.10 Gabapentin has also been evaluated in pruritus of CKD in a randomized trial and was found to be effective.26 Pregabalin, another GABA analogue, has also been evaluated in the treatment of pruritus, specifically in chronic and uremic pruritus, and has found to relieve itching.27,28 Pregabalin may be an option in patients who are intolerant to gabapentin.
There is limited clinical evidence to support the use of systemic corticosteroids in the treatment of pruritus. Despite this, they are used to treat pruritus due to inflammatory skin or systemic diseases, such as atopic dermatitis, and there may be utility for the treatment of lymphoma-related pruritus.5,29 In general, it is recommended that systemic steroids should not be used for durations greater than 2 weeks given risk for adverse effects, such as adrenal suppression and rebound disease.5 Typically, prednisone is utilized at doses of 30 mg to 40 mg daily with rare exceptions of pulse dose IV methylprednisolone followed by a taper.5 Ultimately, guidelines recommend systemic corticosteroids be reserved for select severe, refractory cases of pruritus, such as lymphoma-related pruritus.5
Oral immunosuppressants, including cyclosporine, methotrexate, azathioprine, and tacrolimus have been implicated in the treatment of pruritus. Cyclosporine, a calcineurin inhibitor, is considered one of the primary treatment options for moderate-to-severe atopic dermatitis that is refractory to topical treatment and oral antihistamines.30 Its efficacy in this setting has been demonstrated in several prospective studies.31-33 Furthermore, it may have utility in treating pruritus associated with refractory chronic urticaria and dystrophic epidermolysis bullosa.5 Cyclosporine is associated with several side effects, including nephrotoxicity, tremors, paresthesia, nausea, diarrhea, and electrolyte derangements, which may limit its utility.30 Methotrexate is a folate antimetabolite that is effective in the treatment of pruritus associated with psoriasis and severe, refractory atopic dermatitis. A randomized, controlled trial demonstrated similar efficacy of methotrexate and azathioprine in the treatment of severe atopic eczema with 42% of patients experiencing a reduction in severity.34 Common side effects include liver dysfunction, gastrointestinal issues, hematologic abnormalities, pulmonary toxicities, fatigue, and headache.30 Azathioprine is a purine synthesis inhibitor used off-label for the treatment of severe atopic dermatitis. Its use is supported by prospective, randomized trials.34-36 An important consideration with azathioprine use is its metabolism by thiopurine methyltransferase (TPMT), which has varying levels of activity due to different genotypes. It is recommended to assess TMPT activity or genotype to minimize myelosuppression associated with azathioprine.30 Other side effects of azathioprine include gastrointestinal disturbances and liver dysfunction.
Pruritus is commonly seen and can lead to substantial itching and decreased quality of life for patients. Pruritus can be caused by various systemic, psychiatric, and neurological conditions, as well as a result of drug and medication intake. The treatment for chronic pruritus ranges from topical to systemic treatments. Topical treatments may include capsaicin, steroids, analgesics, and antihistamine agents. Systemic treatments may include antihistamines, antidepressants, opioids, neuroleptics, and immunosuppressants. Pharmacists can play a large role in the determination of pruritus causes by thoroughly evaluating active medications and assist with acute and chronic management.
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29. Singer EM, Shin DB, Nattkemper LA, et al. IL-31 is produced by the malignant T-cell population in cutaneous T-cell lymphoma and correlates with CTCL pruritus. J Invest Dermatol. 2013;133(12):2783-2785.30. Megna M, Napolitano M, Patruno C, et al. Systemic treatment of adult atopic dermatitis: a review. Dermatol Ther (Heidelb). 2017;7(1):1-23.
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33. Simon D, Bieber T. Systemic therapy for atopic dermatitis. Allergy. 2014;69(1):46-55.34. Schram ME, Roekevisch E, Leeflang MMG, et al. A randomized trial of methotrexate versus azathioprine for severe atopic eczema. J Allergy Clin Immunol. 2011;128(2):353-359.
35. Berth-Jones J, Takwale A, Tan E, et al. Azathioprine in severe adult atopic dermatitis: a double-blind, placebo-controlled, crossover trial. Br J Dermatol. 2002;147(2):324-330.36. Meggitt SJ, Gray JC, Reynolds NJ. Azathioprine dosed by thiopurine methyltransferase activity for moderate-to-severe atopic eczema: a double-blind, randomised controlled trial. Lancet. 2006;367(9513):839-846.
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