Background

Pruritus (itching) is a common and often distressing symptom near the end of life.  The itch sensation may arise from stimulation of the skin itch receptor via unmyelinated C fibers, or itch may arise as a central phenomenon without skin involvement (e.g. opioid induced pruritus).  Although histamine causes pruritus, many patients with pruritis show no signs of histamine release.  Besides histamine, serotonin, prostaglandins, kinins, proteases and physical stimuli have all been implicated as mediators of pruritus.

Common Causes

• Dermatological (dryness, wetness, irritation, eczema, psoriasis)
• Metabolic (hepatic failure, renal failure, hypothyroidism)
• Hematologic (iron deficiency, polycythemia, thrombocytosis, leukemia, lymphoma)
• Drugs (opioids, aspirin, drug reactions)
• Infectious (scabies, lice, candida)
• Allergy (urticaria, contact dermatitis, drug reactions)
• Psychogenic
• The Itch-Scratch Cycle – scratching leads to cellular damage which results in more itching.

Management:  Beyond eliminating the cause whenever possible, symptomatic strategies include:

• Moisturizers:  Dryness (xerosis) is very common and may exacerbate other causes. The mainstay of treatment is skin hydration.  Note: Most OTC preparations only have small amounts of moisturizer—they are mostly water. Serious dryness requires emollients and moisturizers (such as petroleum jelly) that patients find oily or greasy. Nevertheless, they may be applied after bathing, over damp skin, with a superficial covering. An older fashion remedy is immersion in an oatmeal bath (e.g. Aveeno).
• Cooling agents (e.g. Calamine and/or Menthol in aqueous cream, 0.5%-2%) are mildly antipruritic. They may act as a counterirritant or anesthetic. A more direct way to anesthetize the skin is with the eutectic mixture of local anesthetics lidocaine and prilocaine (EMLA cream). Simple application of cold compresses may also be helpful.
• Antihistamines may be helpful in relieving itch when associated with histamine release. Morphine causes non-immune mediated histamine release from mast cells. Although there is not much supporting research, many report benefits of combining H1 and H2 receptor subtype antihistamines. These may have central effects as well as peripheral antihistaminergic effects.  Doxepin (10-30 mg PO at bedtime), a tricyclic antidepressant, is a very potent antihistamine and may help in more refractory cases.
• Topical steroids may be helpful in the presence of skin inflammation. These are best applied in ointment rather than cream formulations to alleviate dryness. Systemic steroids have been used in refractory cases.
• Topical tacrolimus has shown benefit in reducing pruritus related to rashes from atopic dermatitis, genitoanal pruritus, and prurigo nodularis. 
• Antidepressants: A systematic review of 35 studies showed benefit from initiation of antidepressants in most studies, with overall good tolerability. While their effectiveness may be a class effect, studies included in the systematic review suggested that paroxetine and mirtazapine were effective for paraneoplastic pruritus; sertraline, amitriptyline, and doxepin were effective for pruritus related to chronic kidney disease; and sertraline was effective for pruritus related to cholestasis.    
• Ondansetron and other 5HT3 antagonists have demonstrated benefit for patients with opioid-induced, cholestasis-induced, and renally-induced pruritus.
• Cholestyramine appears to benefit patients with cholestatic pruritus.
• Gabapentin and pregabalin have shown benefit in a variety of forms of refractory chronic pruritus including uremic pruritus, neuropathic pruritus, and itch of unknown origin. There is not conclusive evidence to support their use for opioid-induced pruritus or cholestatic pruritus.
• Opioid Antagonists:  Continuous infusions of IV naloxone at low doses (e.g. 0.25-1 ug/kg/hr) has the largest body of data supporting its use in adult and pediatric patients with opioid induced pruritus without inducing opioid withdrawal.  Small studies suggest a potential role for methylnaltrexone in opioid-induced pruritus. Mixed agonist-antagonist opioids (pentazocine, nalbuphine, buprenorphine) may also reduce opioid-induced pruritus.

References

1. Fleisher A, Michaels JR. Pruritus. Berger A, Portenoy RK, Weissman DE, eds. In: Principles & Practice of Supportive Oncology. Philadelphia PA: Lippincott-Raven Publishers; 1998: pp245-250.
2. Krajnik M, Zylicz Z. Understanding pruritis in systemic disease. J Pain Symp Manage. 2001; 21:151-168.
3. Kouwenhoven, Tessa A., Peter CM van de Kerkhof, and Marijke Kamsteeg. “Use of oral antidepressants in patients with chronic pruritus: A systematic review.” Journal of the American Academy of Dermatology 77.6 (2017): 1068-1073.
4. Ständer S, Schürmeyer-Horst F, Luger TA, Weisshaar E. Treatment of pruritic diseases with topical calcineurin inhibitors. Ther Clin Risk Manag. 2006;2(2):213-218. doi:10.2147/tcrm.2006.2.2.213
5. Wilde MI, Markham A.  Ondansetron: a review of its pharmacology and preliminary clinical findings in novel applications. Drugs.1996; 52:773-794.
6. Zylicz Z, Smits C, Chem D, Krajnik M.  Paroxetine for pruritis in advanced cancer. J Pain Symptom Manage. 1998; 16:121-124.
7. Davis MP, Frandsen JL, et al.  Mirtazipine for pruritus.  J Pain Symptom Manage 2003; 25: 288-91.
8. Matsuda, Kazuki M., et al. “Gabapentin and pregabalin for the treatment of chronic pruritus.” Journal of the American Academy of Dermatology 75.3 (2016): 619-625.
9. Kumar K, Singh SI. Neuraxial opioid-induced pruritus: An update. J Anaesthesiol Clin Pharmacol. 2013;29(3):303-307. doi:10.4103/0970-9185.117045
10. Wolfhagen FH, Sternieri E, et al.  Oral naltrexone treatment for cholestatic pruritus: a double blind, placebo-controlled study.  Gastroenterology 1997;113: 1264-69.
11. Miller JL, Hagemann TM.  Use of pure opioid antagonists of opioid induced pruritus.  American Journal of Health-System Pharmacy 2011; 68: 1419-1425.

Version History:  This Fast Fact was originally edited by David E Weissman MD.  2^nd Edition published August 2005; 3^rd Edition May 2015. A more substantive content updated occurred in August 2020 by Dr. Andrew W Kamell for the 4^th Edition .