Chronic pruritus of unknown origin (CPUO) is a highly prevalent and burdensome disease that is reported to range from 7% to 46% of the elderly across various different countries, although its diagnosis is not limited to the elderly1. There is a high burden associated with CPUO, with about half of patients reporting severe to very severe itching, and it is significantly associated with impaired sleep, depression, and anxiety, which further exacerbates itch. Despite this, treatment of CPUO can be especially challenging and there is no single FDA-approved treatment. Patients can often suffer from pruritus for many years, undergo extensive diagnostics, and are inadequately treated2–4.
The pathogenesis of CPUO is not well defined. CPUO is a diagnosis of exclusion for patients with >6 weeks of pruritus and no identified cause, or with multiple potential causes, of which the primary cause cannot be determined4. Patients often present with seemingly normal skin with secondary skin changes such as excoriations and nonspecific dermatitis. Recent studies have implicated several causes of CPUO that may work synergistically, including age-related loss of barrier function, systemic immunosenescence with low-grade inflammation, and neural sensory changes.
In the elderly, skin thinning leads to skin barrier dysfunction and reduced reconstitution after damage, leading to loss of fluid retention causing the skin to become more susceptible to pruritus5. Immunosenescence, characterized by a loss of T helper type (Th)-1 cell-driven immune activity and a paradoxical increase in Th2 immune activity in the skin, leads to elevated downstream cytokines IL-4, IL-13, and IL-316, which trigger IgE serum levels, peripheral and tissue eosinophilia, decreased dermal Langerhans cells, and CD8 lymphopenia in CPUO patients compared with age-matched controls7,8. This immune dysregulation further disrupts the epithelial skin barrier and causes more inflammation. Additional nerve damage acquired during the aging process may also result in neuronal degeneration of nonhistaminergic neural pathways involved in itch, resulting in impaired itch signaling and hypersensitization to itch stimuli9. These factors may have a cumulative effect that further exacerbates the patient’s chronic pruritus.
Although the treatment of CPUO is especially challenging, given that much of its pathogenesis is still unknown, patients can still vastly benefit when given the appropriate treatment. Here, we thoroughly review the literature on the various therapeutics for CPUO, with a focus on each therapy’s mechanism of action, effectiveness, dosage, and safety profile to educate providers on the various different treatments that are available and promising. In addition, we provide a therapy ladder (Table 1) to help guide clinical decision-making for optimal management.
Table 1 -
Therapeutic ladder for treating CPUO itch of severe, moderate, and mild intensity.
|Intensity Level of CPUO
||ð-opioid agonists and ð-opioid antagonists
||Antidepressants + gabapentin
||Topical ketamine, amitriptyline, and lidocaine
||Serotonin receptor antagonists
CPUO indicates chronic pruritus of unknown origin; JAK, Janus kinase; NK-1, neurokinin-1.
Topical immunomodulators, namely tacrolimus and pimecrolimus, can be used to reduce itch because of their anti-inflammatory and antipruritic properties10. Tacrolimus and pimecrolimus are calcineurin inhibitors; specifically, their itch-reducing properties can be attributed to the modulation of transient receptor potential vanilloid subtype 1 (TRPV1), which is a nonselective cation channel that is found on peripheral C sensory nerve fibers11,12. Studies have found that topical administration of these calcineurin inhibitors can reduce itch within 48 hours of the first application and continue to promote antipruritic effects with frequent use12. The most reported adverse effect is stinging upon application; however, this sensation typically resolves after numerous administrations11,12. An advantage to using calcineurin inhibitors as opposed to topical corticosteroids is that their side effect profile is more limited and continued use does not result in symptoms of local breakdown such as atrophy13. A thin layer of topical cream or ointment can be applied up to twice a day.
Other topical therapies that have demonstrated anti-itch properties and are used for the treatment of CPUO are coolants such as menthol and phenol. Menthol is a cyclic terpene alcohol that occurs naturally from plants. As the class name suggests, its primary mechanism of action is the activation of the nonselective cation channel, transient receptor potential cation channel subfamily M member 8, to elicit a cooling sensation11. Namely, it is presumed that the activation of A delta cutaneous fibers and spinal B5-I inhibitory interneurons promote the anti-itch response from menthol application14. Because of their broad mechanism of action, menthol and comparably phenols can be utilized in CPUO. As CPUO is common in the elderly population, menthol-enriched moisturizers that contain ceramides can also be beneficial to this subset of patients because they can alleviate the itch associated with asteatosis14. Coolants are overall safe to use and well-tolerated, and patients can use them for long periods14. However, the use of coolants to relieve itch is limited by their short duration of relief, which necessitates frequent reapplication14. Furthermore, in some patients, coolants have been reported to aggravate itch15.
Local anesthetics, such as lidocaine, pramoxine, and polidocanol, are topical agents that can mitigate itch in CPUO14. The mechanism of action of local anesthetics is impulse inhibition of sensory nerves, such as unmyelinated C nerve fibers, to prevent the sensations of pain and itch11,16. They are thought to diminish nerve transmission by blockade of N-methyl-d-aspartate receptor and sodium channels14. Local anesthetics have been found to decrease pruritus in several itchy etiologies, such as uremic pruritus, atopic dermatitis, contact dermatitis, and psoriasis14. Pramoxine is often used with ceramides and/or oatmeal to provide rapid and long-lasting relief17,18. A topical gel containing 4% strontium may also be used to reduce nonhistaminergic itch and is superior to topical hydrocortisone and diphenhydramine19. Recently, a formulation containing 4% strontium with ceramides has been reported to be effective for old age itch (unpublished data). A retrospective study reported that a topical formulary containing ketamine, amitriptyline, and lidocaine was efficacious at reducing itch in many pruritic conditions, namely neuropathic itch and prurigo nodularis14,20. Some side effects reported with topical anesthetics include mild skin irritation consisting of edema, pallor, and erythema; in addition, there is a small risk of systemic toxicity in certain patients21,22.
Derived from chili peppers, capsaicin is a substance that has also been used to attenuate itchy sensations and can be a topical therapy choice in the setting of CPUO11. Similar to the antipruritic mechanism of action seen in calcineurin inhibitors, capsaicin also activates TRPV114. The activation of TRPV1 potentiates nerves to release and deplete neuropeptides; in particular, neuropeptide substance P (SP) has been found to be associated with itch and is one of the molecules that is inactivated by capsaicin14. SP mediates itch through both vasodilation and histamine release by mast cells14. Although capsaicin is effective in chronic pruritus and neuropathic itch, it may have poor compliance among the elderly and those applying on large body areas because of an intense, transient burning sensation upon application11.
CPUO may be topically treated with creams containing cannabinoids. Cannabinoid receptors were found to be expressed on cutaneous nerve fibers; therefore, the use of cannabinoid agonists was thought to be potentially therapeutic in decreasing itch. Dvorak et al23 found that cannabinoid receptor agonists reduced histamine-associated itch. One study reported that the topical application of an emollient cream containing N-palmitoyl ethanolamine (PEA), a cannabinoid receptor CB2 agonist, reduced itch on average by 86.4% in patients with refractory, chronic pruritus of various etiologies11,24; another open-label study evaluated PEA-containing cream in atopic dermatitis patients and reported decreased pruritus with a tolerance of 92%25. Since then, there have been several new formulations of topical cannabinoid oils for itch, including endocannabinoids such as anandamide, phytocannabinoids, and synthetic cannabinoids26,27. Xerosis is also reported to be reduced in 81% of patients28. However, a randomized, single-blinded study conducted on 100 chronic pruritus patients found no significant difference between PEA-containing lotion and vehicle in reducing pruritus, which may be attributed to the hydrophobic nature of cannabinoids hampering percutaneous absorption. A few patients also reported minor side effects such as stinging, scaling, and reddening28,29. Therefore, more clinical trials are needed to validate the efficacy and safety profile of cannabinoids in reducing CPUO.
Gabapentin and pregabalin are antiepileptic agents commonly used to treat neuropathic pruritus and can be used to treat CPUO, due to CPUO’s association with underlying neural sensory changes. They may be especially helpful in the absence of immunosenescence30. The exact antipruritic mechanism of these antiepileptics is unknown; multiple hypotheses have been proposed. First, both are γ-aminobutyric acid analogs whose primary effect is binding and inhibition of voltage-dependent calcium ion channels in the dorsal horn of the spinal cord and dorsal root ganglion. Secondly, they may also modulate both central and peripheral μ-opioid receptors31,32.
An open-label study of 22 patients found a daily dose of pregabalin 150 mg led to a significant decrease in itch after 4 weeks of treatment32. Another study on the efficacy of pregabalin in CPUO found that pruritus was improved in 7 of 10 patients, and corresponded to a decrease in C-fiber nerve sensitivity to electrical stimulation33. A case series found treating CPUO patients with gabapentin 300 mg/d with the daily incremental increase to 1800 mg/d during the next few weeks led to the excellent response and complete control of itch within a month31,34.
Both gabapentin and pregabalin are generally well-tolerated, with the most common adverse side effects of sedation, fatigue, dizziness, and weight gain. It may also be helpful to administer the dosage in the evening when patients most frequently experience severe itch35. Rarely, gabapentin may cause pancytopenia, cholestasis, hypersensitivity syndrome, and dyskinesia34. Pregabalin works faster than gabapentin and does not bind to plasma proteins, making it safe to use in patients with low plasma protein and hepatic failure32.
Serotonin receptor antagonists
Mirtazapine is a dual noradrenergic and serotonergic antidepressant with antihistaminergic properties. It is believed to centrally reduce itch through α2-adrenergic receptors and 5-HT2 and 5-HT3 receptors36. Mirtazapine reduces itch in many chronic pruritic conditions, including CPUO. Side effects include weight gain and sedation, although sedative effects may help promote sleep in patients who suffer from sleep deprivation due to pruritus37. It is given once daily due to its long half-life with a dose as low as 15 mg38.
Other serotonin inhibitors, such as selective serotonin reuptake inhibitors, have also been found to reduce the chronic itch. While selective serotonin reuptake inhibitors primarily target 5-HT receptors, they may also target central opioid receptors as an antipruritic mechanism of action. They also inhibit CYP2D6 hepatic isoenzyme, which is involved in the activation of other opioid pruritogens39. One open-label 2-arm study consisting mostly of patients with CPUO found paroxetine and fluvoxamine to have antipruritic effects, with 68% of patients experiencing reduced itch40. Another randomized, controlled trial found paroxetine significantly reduced itch compared with a placebo. Side effects included nausea, which usually ceased after a few days and could be ameliorated with ondansetron39.
Opioid antagonists and agonists
For more severe forms of CPUO, κ-opioid agonists and μ-opioid antagonists may help attenuate pruritus. Naltrexone and naloxone are μ-opioid antagonists used to treat several different types of chronic pruritus, including CPUO. In general, they do not cause physical dependence and have no abuse potential. They are generally well-tolerated, although nausea may occur in predominantly young and female populations41. Rarely, opioid withdrawal symptoms are present42.
Intranasal butorphanol, a κ-opioid agonist and μ-opioid antagonist, may also be therapeutic for CPUO43,44. In a recent case series, 8 out of 12 CPUO patients treated with butorphanol had an improvement in itch45. However, side effects include nausea, lightheadedness, and lethargy, which in some cases is significant enough to discontinue treatment43,44. New κ-opioid agonists with a good safety profile such as difelikefalin was recently approved for intravenous administration in uremic pruritus and may be effective for CPUO itch when an oral formulation is approved46.
Dronabinol is a cannabinoid found efficacious in treating generalized pruritus, especially in systemic diseases such as cholestatic pruritus and uremic pruritus. Cannabinoids have been found to inhibit mast cell degranulation and histamine release, and also depolarize nerve fibers through activation of cannabinoid receptor 1 and inhibition of transient receptor potential ion channels, which modulate itch47. Excitation of cannabinoid receptor 1 also markedly enhances skin barrier function48,49.
Immunosuppressive agents have been found to be particularly effective in CPUO patients with elevated Th2 differentiation
Methotrexate is commonly used in several inflammatory and pruritic skin conditions such as atopic dermatitis and psoriasis. Its anti-inflammatory properties may prove beneficial for CPUO, where low-grade inflammation is present. Methotrexate has been found to be very effective in reducing complex severe pruritus, particularly in elderly patients with multiple comorbidities50. Side effects are rare in low doses, although abnormal liver function tests, nausea, gastrointestinal complaints, and myelosuppression may occur. Routine monitoring is required50,51.
Azathioprine is a synthetic purine analog that works at the level of DNA as an s-phase inhibitor. As lymphocytes lack a salvage pathway and rely on the de novo synthesis of purines, they are particularly susceptible to azathioprine resulting in the inhibition of T-cell proliferation52. A retrospective review of 97 patients showed azathioprine to be efficacious in the treatment of CPUO. However, side effects are common, with 65% of patients experiencing adverse effects and 33% necessitating complete drug withdrawal53.
Although there is limited literature on the use of cyclosporine for CPUO, it is used to suppress pruritus in a variety of diseases, as it’s a pan T-cell immunosuppressant54. Cyclosporine may be therapeutic for CPUO patients, in which elevated expression of IL-31 cytokines and decreased fluid retention in the skin is present55.
Neurokinin-1 receptor antagonists
The proinflammatory neuropeptide SP and its receptor, neurokinin-1 receptor (NK1R) are known to be important mediators of nonhistaminergic pruritus56. NK1R is found at various levels of the itch signaling pathway, including the skin, spinal cord, trigeminal ganglion, and in brain areas associated with and activated by itch57,58.
The first approved NK1R antagonist, aprepitant, has been reported to have antipruritic effects in refractory brachioradial pruritus, cutaneous T-cell lymphomas, tumors, and a variety of other conditions59,60. A proof-of-concept study, in which 8 out of 20 patients had CPUO, found that treatment with aprepitant 80 mg decreased itch from a visual analog scale score of 8.4–4.9 in 1 week57. As a CYP3A4 inhibitor and CYP2C9 inducer, aprepitant can have drug-drug interactions with CYP3A4 and CYP2C9 substrates, causing major adverse effects. Commonly known drugs that interact with aprepitant are dexamethasone (infections and mental disturbances), oxycodone (respiratory depression and sedation), coumarin derivatives (lower international normalized ratio), and hormonal contraceptives (decreased efficacy)61.
Serlopitant is another NK1R inhibitor explored for potential therapeutic value for CPUO. A large phase II trial of 368 patients with chronic pruritus, over half of which had CPUO, found that both 1 mg and 5 mg of serlopitant once daily for 6 weeks were associated with reduced pruritus intensity on a visual analog scale compared with placebo. Unfortunately, a phase 3 trial for CPUO itch failed to reach its end points56.
As more evidence points towards type 2 inflammation as a mechanism for CPUO, with a paradoxical decrease in type 1 inflammation, there has been a heightened interest in therapies that target Th2-associated cytokines such as IL-4, 13, and 31. For example, IL-31 has been found to be significantly increased in the serum of CPUO patients6. Therefore, monoclonal antibodies targeting these Th2 cytokines may block them from exerting further downstream effects that lead to CPUO6,62.
Several studies have examined Dupilumab, an anti-IL-4Rα monoclonal antibody, as a potential therapeutic for CPUO. A retrospective case series found that dupilumab had anti-itch efficacy in 15 patients with CPUO63. Another case series found that dupilumab provided complete resolution of pruritus in 12 out of 20 patients, with an overall itch reduction of 7.5564. Both studies found that dupilumab was well-tolerated among patients65,66. Currently, dupilumab is undergoing phase 3 clinical trials for the treatment of adults with CPUO67.
IL-31 is another Th2 cytokine that has been implicated in the pathology of several chronic pruritic inflammatory skin conditions and chronic pruritic diseases with absence or subtle skin inflammation62,68,69. Similarly, a recent study found the presence of IL-31 was significantly elevated in CPUO patients, suggesting it may play a role in the pathogenesis of the disease. IL-31 binds to its receptor and activates the Janus kinase (JAK)/signal transducers and activators of transcription, phosphatidylinositol-3 kinase/protein kinase b, and mitogen-activated protein signaling pathways, which induce proinflammatory cytokines and chemokines, regulate cell proliferation, and stimulate dorsal root ganglia sensory neurons62. IL-31 also affects keratinocyte differentiation, leading to further dysregulation of skin barrier function70. Therefore, anti-IL-31 biologics may reduce itch in individuals with CPUO62.
As IL-31 has been coined the itchy cytokine and has a role in multitudes of itchy conditions, blocking this cytokine may have a potential role for CPUO itch. The successful antipruritic effect of IL-31 receptor antagonist monoclonal antibody nemolizumab in atopic eczema and prurigo nodularis may suggest that this drug would have a beneficial effect on CPUO. Its safety profile seems very good with few adverse events that include gastrointestinal symptoms71.
Vixarelimab is another drug targeting the IL-31 itch cascade as it is an inhibitor of the IL-31 receptor subunit oncostatin M receptor-β72. A recent unpublished exploratory phase II study found that it did not significantly decrease CPUO compared with a placebo. More research is needed to determine its therapeutic potential in CPUO. No significant adverse events have been reported with vixarelimab as of yet73,74.
Janus kinase inhibitors
As described above, several Th2 cytokines such as IL-4, IL-13, and IL-31 activate the JAK-signal transducer activator of the transcription pathway, which leads to the transcription of proinflammatory cytokines and growth factors that mediate itch. JAK signaling is increased in pruriceptive neurons and JAK inhibitors have been found to have neuromodulatory properties that may attenuate itch75. JAK inhibitors such as tofacitinib, baracitinib, abrocitinib, and upadacitinib have potent antipruritic properties and have demonstrated efficacy in several pruritic diseases mainly in atopic dermatitis and psoriasis63,64,76–78.
In particular, tofacitinib has been investigated for its therapeutic effects in CPUO and found to improve pruritus in CPUO patients. Oetjen et al75 found oral tofacitinib provided marked improvement of itch with rapid onset of relief in contrast to other immunosuppressive therapies. In addition, a case series of 5 rheumatoid arthritis patients with refractory CPUO reported a significant decrease in itch score levels after taking oral tofacitinib 5 mg twice daily, with excoriations markedly improved after treatment79. As the FDA issued a black box warning on their use due to serious side effects such as blood clotting and infections, they should be cautiously used, particularly in the elderly with CPUO, and the authors suggest they should not be used for prolonged periods75,79,80.
Protecting skin barrier function
Xerosis is a common instigator of itch in the geriatric population due to the epidermal barrier becoming increasingly dysfunctional with advancing age81. Many of the nonpharmacological measures recommended for CPUO in the elderly focuses on maintaining skin barrier integrity, which increases the moisture content in the stratum corneum and decreases allergy invasion and subsequent dermatitis82.
One such method involves the use of emollients, which have long been a mainstay for pruritus treatment. Many moisturizers contain biochemical agents normally found in healthy skin such as lipids, urea, lactic acid, and amino acids, which maintain skin barrier integrity and reduce irritation83–85. When a deficiency occurs in pruritic skin, restoration of levels may be obtained through the application of these emollients, thus improving the epidermal barrier. Colloid oatmeal-based products and daily oatmeal baths also improve moisturization and skin barrier function in patients with xerosis, particularly in the elderly18.
In particular, urea has demonstrated efficacy in the treatment of pruritus. Urea is a physiological molecule normally found on the skin. At low concentrations, it acts as an emollient (filling the gaps between keratinocytes) and as a humectant (drawing water from the dermis into the epidermis)86,87. Urea may also regulate filaggrin gene expression necessary for proper barrier function maintenance87,88. At higher concentrations, urea works by acting as a keratolytic in the setting of xerosis. Urea is applied topically in concentrations from 5% to 12% (low concentration). One study of 10% urea cream in patients with old age xerosis demonstrated a significant, progressive clinical improvement of xerosis and pruritus in all 20 patients89. Adverse effects include contact dermatitis, irritation, redness, and burning85,90, though there were no side effects reported in the Lacarrubba and colleagues study, suggesting a high tolerability profile.
Another important aspect of protecting the integrity of the skin is pH balance. Normal skin pH is in the 4–6 range and maintains barrier homeostasis and stratum corneum integrity90,91. Increased skin pH is associated with barrier dysfunction in atopic dermatitis92. Therefore, the therapeutic range for similar itchy conditions should be slightly acidic. Topical emollients and leave-on products may restore natural pH levels, though the implications in humans have not been fully elucidated yet through clinical trials. Alkaline cleansers can increase skin pH and should be avoided.
Phototherapy with narrow-band ultraviolet B (NB-UVB) is used for both dermatologic and systemic causes of pruritus refractory to topical treatment93. The suspected mechanism involves both anti-inflammatory and neuromodulatory effects including apoptosis of keratinocytes, effector T-cell populations, and Langerhans cells through reactive oxygen species94; increasing tolerance of regulatory T cells95; decreasing histamine and inflammatory cytokine release96,97; modulating signals of the endogenous opioid system98; and altering nerve fiber density in the skin99.
Phototherapy is an involved process requiring treatments ~3 times per week for 3 months. The prescription regimen for phototherapy is dependent on the underlying condition as well as the patient’s skin type. Side effects include paradoxical itching in the first 2–3 weeks of therapy as well as erythema, edema, blistering, headache, and nausea with increased risk for nonmelanoma skin cancers100.
Although there have been no large, randomized, controlled trials investigating the antipruritic effects of phototherapy, there have been several retrospective studies. A retrospective chart review of 67 patients diagnosed with CPUO showed remission in 70% of patients after receiving NB-UVB phototherapy with no serious adverse side effects101. In another retrospective review of phototherapy in geriatric patients, of 12 patients with generalized pruritus, 80% achieved significant improvement with NB-UVB (excluding 2 patients who did not receive at least 8 sessions.)102 Erythema occurred in 20% of patients. However, therapeutic relief did require many sessions, with the number of sessions ranging from 12 to 108 with an average of 44.
Overall, phototherapy is an effective treatment for generalized pruritus and is safe in the geriatric population, though the inconvenience of this modality should be considered when recommended by the clinician.
Acupuncture is an increasingly popular complementary and alternative medicine and has been used in traditional Asian medicine to treat itch for over 2500 years103. Placebo-controlled studies have found that acupuncture can reduce itch from a variety of causes, including histamine-induced acute itch, uremic pruritus, atopic dermatitis, and neurogenic pruritus104–108. The mechanism of action is thought to involve the stimulation and activation of brain areas involved in itch processing and signaling, such as the insula, putamen, premotor, and prefrontal cortical areas. For electroacupuncture, electrical stimulation to affective or adjacent dermatomes may also exert an antipruritic effect by stimulating κ-opioid receptors109. Acupuncture is usually safe, with the most common adverse events cited as dizziness, local pain, and bruising or hematomas at needle-placement sites110.
Psychological interventions have been shown to be effective in the treatment of chronic itch. Habit Reversal Training in combination with techniques to restructure cognition can help attenuate the itch-scratch cycle by raising awareness of the dysfunctional behavior (in this case, scratching,) and practicing a competing behavior to replace it111–113. Stress is also known to correlate with chronic itch, and as such relaxation techniques (progressive muscle relaxation and autogenic training) can have beneficial effects on chronic itch patients, particularly if they are susceptible to auto-suggestions113–116. Other cognitive-behavioral therapies originally developed for the treatment of chronic pain (acceptance and commitment therapy and mindfulness-based stress reduction) may have similar success when applied to chronic itch, although further evaluation is needed113,117–120.
Although prevalent and debilitating for many patients, CPUO remains an underrecognized and underdiagnosed condition. Many patients often suffer for years with refractory chronic itch and providers often have difficulty finding treatments that may provide therapeutic relief. However, an increased interest in CPUO and itch therapy has resulted in a breakthrough of various treatment options for CPUO patients. From traditional antipruritic treatments such as cooling agents, analgesics, and neuromodulators (GABAergic drugs, κ-opioid agonists, and μ-opioid antagonists) to novel therapies on the horizon such as monoclonal antibodies and JAK inhibitors, providers are now armed with a plethora of therapeutics for CPUO itch. As additional clinical trials and studies are underway with new targeted treatments for chronic pruritus, CPUO patients stand to benefit. Further research is still needed to elucidate the pathogenesis of CPUO and the role of the various treatments, as well as specific guidelines with therapeutic ladders for the large unmet need of treating CPUO.
Sources of funding
National Institute of Arthritis and Musculoskeletal and Skin Diseases (5R21AR078940-02).
Conflicts of interest disclosure
G. Y. conducted clinical trials or received honoraria for serving as a member of the Scientific Advisory Board and consultant for Pfizer, TREVI, Regeneron, Sanofi, Galderma, Novartis, Bellus, Kiniksa, and Eli Lilly, and received research funds from Pfizer, Leo, Sanofi, Regeneron, Eli Lilly, and Novartis. The remaining authors declare that they have no financial conflict of interest with regard to the content of this report.
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