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Hydroxyzine (Atarax®) and Risk of QT Interval Prolongation and Torsades de Pointes

On June 6, 2016 Health Canada released a warning that hydroxyzine has been associated with QT interval prolongation and torsade de pointes (TdP) which may lead to dizziness, palpitations, syncope, seizures, and sudden cardiac death (SCD) http://healthycanadians.gc.ca/recall-alert-rappel-avis/hc- sc/2016/58758a-eng.php.1 Both the FDA2 and European Agency (EMA)3 have released similar warnings.

Hydroxyzine (ATARAX) is now contraindicated in patients with a history of: 1 - QTP (QT prolongation) and/or TdP (including congenital long QT syndromes) - Family history of sudden cardiac death - History of cardiac arrhythmias - Significant electrolyte imbalance (hypokalemia, hypomagnesemia, hypocalcemia) - Significant bradycardia - Concomitant use of other QT/QTc-prolonging drugs or inhibitors of hydroxyzine metabolism

If use cannot be avoided, hydroxyzine should be used for as short a duration as possible and at the lowest effective dose up to a maximum daily oral dose of 100 mg in adults and 50 mg in the elderly (in divided doses).1 Periodic electrocardiography should be considered.4

What are these recommendations based on? Studies in animals and human cells have shown that hydroxyzine has the potential to block hERG channels and other types of cardiac channels, resulting in a potential risk of QT interval prolongation and cardiac arrhythmia. This potential risk was confirmed by clinical and post-marketing data (61 case reports). Most cases had other risk factors that could have been contributory, as listed above.1,3 The CredibleMeds® website and QTdrugs list has categorized hydroxyzine as a drug with conditional risk of TdP https://crediblemeds.org/new-drug-list/ .4

How does this apply to patients with Chronic Kidney Disease (CKD)? CKD itself has been associated with prolonged QTc interval.5 A prospective electrocardiographic study of 179 patients undergoing hemodialysis found that 49% of patients had a prolonged QT interval (QTc > 440 ms).5,6 The risk of SCD is 4 to 20 times higher in CKD patients compared to the general population and increases proportionally as kidney function declines.5,6 It is estimated that SCD is accountable for approximately 27% of all-cause mortality in patients.5 Patients with CKD, especially those receiving hemodialysis, are exposed to many potential risk factors for arrhythmia such as; rapid electrolyte and fluid shifts, electrolyte abnormalities, uremic cardiomyopathy, sympathetic over activity, autonomic dysregulation and inflammation.5

Hydroxyzine is commonly used for the treatment of pruritus in patients with CKD despite a lack of supporting data. , such as hydroxyzine, have limited efficacy for treating uremic pruritus, in which is not a major trigger.7–11 Any reported benefit is likely related to decreased perception of pruritus due to sedation.7–11 Considering questionable efficacy and high risk patient population, hydroxyzine is not recommended for treatment of uremic pruritus.

How should uremic pruritus be treated? Evidence to support specific therapies for uremic pruritus is limited. Most studies are retrospective or small open-label prospective studies in hemodialysis patients, which often use a cross-over design. Many uncontrolled studies showing positive results were not reproduced in controlled studies. In addition, positive effects reported as statistically significant may not be clinically relevant. Recommended treatments based on small RCTs include: aggressive use of moisturizing cream12–14, topical agents for localized pruritus (capsaicin cream15,16, pramoxine17) and systemic agents (gabapentin18–21, pregablain22, doxepin23,24).7–11,25,26 [See Figure 1]

Figure 1: Stepwise approach to Uremic Pruritus7-11, 65, 66

Optimize elements of CKD care most relevant to pruritus: - Dialysis adequacy - Correct hyperparathyroidism and serum phosphorus and calcium levels Rule out other causes of pruritus such as: - Dermatologic (atopic eczema, psoriasis, , lichen planus, scabies, bed bugs) - Hyperthyroidism Check: - Cholestatis - Enzymes - Hematologic (iron deficiency, lymphoma, hemochromatosis, polycythemia vera) - TSH - Neurologic (stroke, MS, brain tumor/abscess, post-herpetic) - Ferritin - Solid tumors - Psychiatric disorder (OCD, substance abuse) - HIV 65,66 - Drug induced : , ACE inhibitors, SSRIs, contrast media, drug , anti-neoplastic agents (epidermal growth factor inhibitors, kinase inhibitors, BRAF inhibitors, and MEK inhibitors)

Non -Pharmacologic Measures: - Patient education on importance of avoiding or minimizing scratching

- Keep finger nails trimmed - Use gentle soap (e.g. Dove®, Cetaphil®)

- Apply soap only to underarms and groin/perineum (except if other areas visibly dirty) - Avoid excessive bathing or bathing in hot water – use only lukewarm water. Gently pat skin dry. - Eliminate wool or irritating clothing

- Aggressive skin moisturization with topical emollient cream (NOT lotion) BID and after bathing (e.g. Glaxal base® [MRP], Urea cream[MRP], Eucerin Complete Repair™, CeraVe®, Lac-Hydrin®, Cetaphil®, Petrolatum 50g, 100g, 450g (60g) ointment [Vaseline®]) NIHB only covers: Barriere cream® , Prevex cream®

- Baby oil (chilled to 10–15°C/un-chilled) applied to affected area for 15-20 min at least once daily.[OTC,X NIHB, X MRP] -

Generalized Itchiness Localized Itchiness 100-300 mg po 3x/wk to qHS, - Pramoxine HCL 1% cream BID (e.g. Aveeno® or Gold [OTC,X NIHB, X MRP] titrate as tolerated. [ PC, NIHB, X MRP] Bond® Medicated Anti- cream) (Consider 25-75 mg qHS if no response - *Topical steroids - apply BID PRN (ointment for thick, X PC, X MRP, NIHB limited use for neuropathic pain) lichenified lesions; low agents preferred on face to gabapentin – [ PC, NIHB] INADEQUATE and intertriginous areas) [OTC, MRP] Oral antihistamines [limited benefit] CONTROL ▪ Low potency – hydrocortisone 1% cream - 25 mg PO QID PRN, titrate ▪ Medium potency – betamethasone valerate 0.1% as tolerated. May prolong QT with excessive cream [Betaderm®] doses [> 400 mg per day] – (Conditional risk) - *Camphor 0.5%, menthol 0.5% in 1% [ PC, NIHB, X MRP] [OTC,  NIHB, MRP] hydrocortisone cream *Lack of controlled studies, used anecdotally.

Consider acupuncture for those interested - Topical capsaicin 0.025% cream applied sparingly

BID-QID [OTC, NIHB. X MRP] INADEQUATE CONTROL

Other

Consult Dermatology for differential diagnosis/UVB light

If noSummary contraindication of Treatments consider : 10 mg PO HS; titrate by 10-25 mg weekly to a maximum of 50 mg PO HS as tolerated. N.B. Can prolong QT (Conditional Risk) [ NIHB, Pharmacare, X MRP] Summary of Treatments Trial of agent with limited/lower quality evidence: [ PC, NIHB, X MRP], desloratidine[OTC, NIHB, X PC/MRP], [ PC, NIHB, X MRP], etc.(Check TdP risk) Summary of Treatments

- Aggressive skin moisturization with emollient cream considered first-line treatment as dry skin (xerosis) is common in this population. - Lotions have higher water to lipid content, which is not well absorbed therefore it evaporates and may dry skin further. Creams preferred as they provide a layer of oil to lock moisture in.

Level -1 Evidence Advantages Disadvantages Topical (localized areas) Capsaicin 0.025% cream 2 RCTs15,16 -No serious adverse - Initial burning on applied sparingly BID- - Placebo controlled reactions application QID - Cross-over design -OTC - Onset 2-4 wks -Covered by NIHB - Do not apply to open sores Pramoxine HCL 1% BID 1 RCT17 -Well tolerated - Not covered by NIHB (Aveeno Anti-Itch - Placebo controlled -OTC cream®, Gold Bond - Double blinded Medicated Anti-Itch cream®) Systemic Gabapentin 100 to 300 4 RCTs18–21 - May be useful 2nd line - , dizziness, mg po 3x/wk to qHS (6) - Placebo controlled agent and fatigue - 2 were cross-over -Covered by NIHB and - Onset 3 -8 weeks design Pharmacare (Part 1) Pregabalin 75 mg twice 1 RCT22 - For those who don’t - Not covered by weekly or 25-75 mg qHS - Placebo controlled respond or tolerate pharmacare - Double blinded gabapentin - NIHB – limited use for neuropathic pain 23 Doxepin 10-50 mg po hs; 1 RCT - Strong anti-H1 - side titrate by 10-25 mg - Placebo controlled histaminic activity effects are common weekly - Cross-over design - Possible 3rd line agent (e.g. drowsiness, - Double blinded - Covered by NIHB and constipation) 1 RCT vs pregabalin24 Pharmacare (Part 1) - TCA – conditional risk - Single blinded of TdP 4

Other treatments - Chilled or un-chilled baby oil (10–15°C) applied to affected area for 15-20 min at least once daily.27,28

- Menthol +/- camphor added to topical emollients may relieve itch – lack of controlled studies.11 o E.g. Camphor 0.5%, menthol 0.5% in 1% hydrocortisone cream

- Topical steroids (applied BID PRN)- used anecdotally for localized itchiness.10 Ointment for thick, lichenified lesions. Low potency agents preferred on face and intertriginous areas.10 o Low potency – hydrocortisone 1% cream29 o Medium potency – betamethasone valerate 0.1% cream – [Betaderm®] (suitable for intermittent long term use)29

- Hydroxyzine, doxepin and diphenhydramine are often used for treatment of all types of pruritus without supporting data from RCTs – other than urticaria. Efficacy likely due to effect.7,9,11 Hydroxyzine should be avoided for reasons discussed previously. Doxepin can prolong QT (Conditional TdP Risk).4 Diphenhdramine may prolong QT with excessive doses (> 400 mg per day) – conditional TdP risk.4

- Acupuncture/Acupressure o A Cochrane review30 found that manual acupressure may provide short-term relief of CKD symptoms such as pruritus, however studies were of low quality. No conclusion could be made for acupuncture due to low quality evidence with high risk of bias. Safety of acupuncture was not assessed due to incomplete reporting of acupuncture-related harm. o In the only RCT with a placebo control group, acupuncture was performed by inserting a 1-inch, 34-gauge acupuncture needle at Quchi (LI11) which was left in place for 1 hour, 3 times weekly.31 Mean pruritus scores (via 45 point questionnaire) in the active intervention group decreased by 56% at three months. o Possible option for those who are interested in acupuncture.

- Phototherapy o Meta-analysis from 1991, which included 3 small RCTs, found that UVB phototherapy was effective for treatment of uremic pruritus. 32 o More recent RCT of narrowband UVB phototherapy did not show significant benefit compared to control (UVA phototherapy). Possibly underpowered, as it only included 18 patients.33 o Long-term effects unknown; possible increased risk of skin cancer.7,8 o Narrow band UVB light therapy - not covered by MB Health (cost is $17/treatment)

Limited Evidence

Drug Efficacy Comments Sertraline 25-75 mg po daily Modest benefit in 1 small - Conditional risk of TdP 4 prospective, non-RCT34 and 1 - May be useful for concomitant small retrospective review.35 depression/ disorder Desloratidine 5 mg po Modest benefit (43% reduction in - OTC 3 times/week VAS score) in small open-label, - Covered by NIHB cross-over trial versus gabapentin.36 Montelukast 10 mg po daily One small RCT (n=14) crossover - Pharmacare Part II EDS for study showed modest asthma only improvement in pruritus (35% - Limited use benefit (prior reduction in VAS score).10,37 approval required) for use in asthma only Mirtazapine 15 mg po daily qHS Case reports, mostly non- - Possible risk of TdP 4 uremic/chronic pruritus11,38,39 Cromolyn Sodium Benefit found in 1 small RCT (DB, - Nalcrom® 100 mg capsule - Orally 135 mg TID PC) using oral cromolyn sodium 40 (Sanofi-Aventis) indicated for - Topical cream 4% and another small RCT (DB, PC) treatment of food using topical cream.41 - No marketed topical product Omega-3 fatty acids 1 g po tid One small RCT crossover trial Common side effects: burping, showed some benefit.42 indigestion, altered taste.42 Turmeric 500 mg (22.1 mg 1 small RCT vs placebo showed Generally well tolerated. curcumin) PO TID modest benefit (57% decrease in Reported side effects: dyspepsia, pruritus score vs 31% decrease diarrhea, gastroesophageal with placebo).43 reflux, , and vomiting44 Not Recommended

Drug Comments Hydroxyzine - Small (n=23) randomized crossover trial comparing hydroxyzine 10- mg po HS to Avena sativa (oatmeal) lotion and diluted vinegar.45 There was no statistically significant difference in uremic pruritus intensity between treatments. There was a 30% reduction in VAS score from baseline with hydroxyzine and diluted vinegar and a 40% reduction with Avena sativa. Gamma-Linolenic acid8,10 - No product found (Topical) Tacrolimus ointment - 3 small single center studies with conflicting results7,10 - Case reports and animal studies reporting rare associations with malignancies (lymphoma, skin cancer). FDA black box warning that use be limited to those who have failed other therapies and to treatment periods of less than 6 weeks.7,10 Naltrexone (mu-receptor - 2 studies with conflicting results.46,47 ) Nalfurafine (kappa- - Preliminary data with positive results although and receptor agonist) constipation were common, studies ongoing with kappa-receptor . 7 - Not available in Canada. Activated Charcoal9,10 - Limited evidence suggesting efficacy but not practical. Would need to give 23 x 260 mg capsules to make up a 6 g daily dose. - May bind to and needs to be spaced apart from other medications. Pentoxifylline 600 mg IV 3x/wk - Possibly effective in patients refractory to gabapentin and UVB phototherapy but poorly tolerated.48 Thalidomide - One small RCT in refractory uremic pruritus showed moderate improvement. 49 - Common side effects include sedation, peripheral neuropathy and thromboembolism.50 - Peripheral neuropathy has occurred in approximately 20% of patients, at doses of 25 mg per day or more, within the first year of treatment. Symptoms may progress to muscle weakness, hypotonia, cramps and/or tendon reflex decline. It can be detected early using nerve conduction studies.50 - 2 small prospective studies showing no benefit.8–10 - Known risk of TdP4 Zinc sulfate - 1 small RCT (TB, PC) using zinc sulfate 220 mg po daily in 36 HD pts x 4 wks. Benefit reported but not statistically significant.51 Another small RCT (DB, PC) using 220 mg po BID showed modest benefit (52% reduction in VAS score) vs. placebo.52 Nicotinamide - 1 RCT (DB, PC)53 found to be ineffective

Evidence for Treatment of Uremic Pruritus

Study (y) UP treatment No. Level of Design Efficacy Mean worst of Evidence VAS score/10 pts (% response itch reduction) Topical Treatments Okada and Emollients 20 2 NR with control Yes 3.5 (85) Matsumoto et group al (2004)12 Morton et al Emollients 21 2 Prospective Yes 5.0 (48) (1996)13 Cohort Szepietowski et Emollients 19 2 Prospective Yes 6.2 (80) al (2005)14 cohort Tarng et al Capsaicin 0.025% 17 1 RCT PC Yes NA (39) (1996)15 Cross-over Makhlough et Capsaicin 0.03% 34 1 RCT DB PC Yes NA (84) al. (2010)16 Cross-over Weisshaar et al Capsaicin 11 2 Case Control No NA (2003)54 0.05% Breneman et al Capsaicin 0.025% 21 2 Open-Label Yes NA (1992)55 Prospective Breneman et al Capsaicin 0.025% 5 2 Prospective, DB Yes NA (1992)55 Randomized Vehicle controlled Young et al Pramoxine 1% 27 1 RCT DB PC Yes 5.5 (61) (2009)17 Gabapentin/Pregabalin Gunal et al Gabapentin 25 1 RCT DB PC Yes 7.9 (85) (2004)18 300 mg 3x/wk Cross-over Naini et al Gabapentin 34 1 RCT DB PC Yes 7.2 (79) (2007)19 400 mg 2x/wk Tol et al Gabapentin 14 1 RCT PC Yes 7.6 (83) (2010)20 300 mg 3x/wk Cross-over Nofal et al Gabapentin 54 1 RCT PC Yes 7.63 (76) (2016)21 100-300 mg 3x/wk Single blinded Amirkhanlou et Gabapentin 100 mg 52 1 RCT DB vs. Yes NA (88) al (2016)56 daily Razeghi et al Gabapentin 34 2 DB PC Yes VAS 100 (2009)57 100 mg 3x/wk Single-arm 100 (94) Cross-over Marquez et al Gabapentin 19 2 Quasi- No 5.95 (23) (2012)36 300 mg 3x/wk to randomized, OL, daily Cross-over vs. desloratidine Rayner et al Gabapentin 40 2 Step-wise OL Yes NA (77.5) (2012)58 100 mg 3x/wk- ordered daily, up to 900 mg daily Hassan et al. Gabapentin 30 2 Retrospective Yes NA (2015)59 100 mg q 2 days Cohort Manenti et al Gabapentin 6 3 Case series Yes 8.2 (83) (2005)60 100 mg 3-4x/wk Yue et al. Pregabalin 179 1 RCT DB PC vs. Yes 8 (83) (2015)22 75 mg 2x/wk ondansetron Aperis et al. Pregabalin 16 2 Open Label Yes 7.4 (77) (2010)61 25 mg/day Shavit et al. Pregabalin 12 2 Open Label Yes 9.7 (69) (2013)62 25 mg 3x/wk to 50 mg/day Rayner et al. Gabapentin 100- 79 2 Open Label Yes NA (2012)58 900 mg/d or 100- Prospective 400 mg per HD VS Cohort Pregabalin 25-150 mg/d or 25 mg per HD Solak et al. Gabapentin 300 mg 29 1 RCT Yes No difference (2012)63 per HD 3x/wk VS Cross-over between groups pregabalin 75 mg/d Antihistamines/Mast-cell Stabilizers Pour-Reza- Doxepin 24 1 RCT PC Yes NA Gholi et al. 10 mg po BID Cross-over Complete (2007)23 resolution in 58% of pts Foroutan N et Doxepin 10 mg po 72 1 RCT vs pregabalin Yes D 7.1 (41) al. (2016)24 daily to BID or No Placebo arm Pr 7.5 (72) Pregabalin 50 mg Single blinded eod to daily Marquez et al Desloratidine 19 2 Quasi- Yes 5.95 (43) (2012)36 5 mg 3 x weekly randomized, open-label, cross- over vs. gabapentin Nasrollahi A et Montelukast 10 mg 14 1 RCT PC Yes NA (35.7) al. (2007)37 daily Cross-over Vessal et al.40 Cromolyn Sodium 40 1 RCT, DB, PC Yes 8.68 (89.6) (2010) 135 mg po TID Feily et al.41 Cromolyn Sodium 60 1 RCT, DB, PC Yes 2.5/5 (88) 4% (topical) BID Other Chan et al Sertraline 25-75 17 2 Retrospective Yes 7.47 (67) (2013)35 mg daily review Shakiba et al Sertraline 50 mg 19 2 Prospective, Yes NA (2012)34 daily before/after Ghanei E et al. Fish oil 1 g capsule 22 1 RCT PC DB Yes NA (68) (2012)42 (180 mg EPA/120 Cross-over mg DHA) TID

Levels of evidence: Level Evidence 1 One or more randomized, controlled clinical trials 2 Nonrandomized clinical trials, prospective observational studies, cohort studies, retrospective studies, case- control studies 3 One or more published case reports

Resources

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2. FDA. Safety Information - Vistaril (hydroxyzine pamoate) capsules and oral suspension. http://www.fda.gov/safety/medwatch/safetyinformation/ucm405005.htm. Accessed August 17, 2016.

3. European Medicines Agency - Human medicines - Hydroxyzine. http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals/Hydroxyzine/ human_referral_prac_000043.jsp&mid=WC0b01ac05805c516f. Accessed August 17, 2016.

4. Woosley R, Romero K. QTdrug list. In: CredibleMeds. 1822 Innovation Park Dr., Oro Valley, AZ 85755: AZCERT, Inc. https://crediblemeds.org/healthcare-providers/. Accessed August 17, 2016.

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6. Pun PH. The interplay between CKD, sudden cardiac death, and ventricular arrhythmias. Adv Chronic Kidney Dis. 2014;21(6):480-488.

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9. Manenti L, Tansinda P, Vaglio A. Uraemic pruritus: clinical characteristics, pathophysiology and treatment. Drugs. 2009;69(3):251-263.

10. BC Renal Agency. Symptom Management Resources: Pruritus. http://www.bcrenalagency.ca/health-professionals/clinical-resources/pharmacy-formulary. Accessed August 17, 2016.

11. Yosipovitch G, Bernhard JD. Clinical practice. Chronic pruritus. N Engl J Med. 2013;368(17):1625- 1634.

12. Okada K, Matsumoto K. Effect of skin care with an emollient containing a high water content on mild uremic pruritus. Ther Apher Dial Off Peer-Rev J Int Soc Apher Jpn Soc Apher Jpn Soc Dial Ther. 2004;8(5):419-422.

13. Morton CA, Lafferty M, Hau C, Henderson I, Jones M, Lowe JG. Pruritus and skin hydration during dialysis. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc. 1996;11(10):2031- 2036.

14. Szepietowski JC, Reich A, Szepietowski T. Emollients with endocannabinoids in the treatment of uremic pruritus: discussion of the therapeutic options. Ther Apher Dial Off Peer-Rev J Int Soc Apher Jpn Soc Apher Jpn Soc Dial Ther. 2005;9(3):277-279.

15. Tarng DC, Cho YL, Liu HN, Huang TP. Hemodialysis-related pruritus: a double-blind, placebo- controlled, crossover study of capsaicin 0.025% cream. Nephron. 1996;72(4):617-622. 16. Makhlough A, Ala S, Haj-Heydari Z, Kashi Z, Bari A. Topical capsaicin therapy for uremic pruritus in patients on hemodialysis. Iran J Kidney Dis. 2010;4(2):137-140.

17. Young TA, Patel TS, Camacho F, et al. A pramoxine-based anti-itch lotion is more effective than a control lotion for the treatment of uremic pruritus in adult hemodialysis patients. J Dermatol Treat. 2009;20(2):76-81.

18. Gunal AI, Ozalp G, Yoldas TK, Gunal SY, Kirciman E, Celiker H. Gabapentin therapy for pruritus in haemodialysis patients: a randomized, placebo-controlled, double-blind trial. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc. 2004;19(12):3137-3139.

19. Naini AE, Harandi AA, Khanbabapour S, Shahidi S, Seirafiyan S, Mohseni M. Gabapentin: a promising drug for the treatment of uremic pruritus. Saudi J Kidney Dis Transplant Off Publ Saudi Cent Organ Transplant Saudi Arab. 2007;18(3):378-381.

20. Tol H, Atalay H, Güney İ, et al. The Effects of Gabapentin Therapy on Pruritus, Quality of Life, Depression and Sleep Quality in Pruritic Hemodialysis Patients. Balk Med J. 2010;2010(2). http://dergipark.ulakbim.gov.tr/bmj/article/view/5000060337. Accessed September 13, 2016.

21. Nofal E, Farag F, Nofal A, Eldesouky F, Alkot R, Abdelkhalik Z. Gabapentin: A promising therapy for uremic pruritus in hemodialysis patients: A randomized-controlled trial and review of literature. J Dermatol Treat. April 2016:1-5.

22. Yue J, Jiao S, Xiao Y, Ren W, Zhao T, Meng J. Comparison of pregabalin with ondansetron in treatment of uraemic pruritus in dialysis patients: a prospective, randomized, double-blind study. Int Urol Nephrol. 2015;47(1):161-167.

23. Pour-Reza-Gholi F, Nasrollahi A, Firouzan A, Esfahani EN, Farrokhi F. Low-dose doxepin for treatment of pruritus in patients on hemodialysis. Iran J Kidney Dis. 2007;1(1):34-37.

24. Foroutan N, Etminan A, Nikvarz N, Abadi MSS. Comparison of pregabalin with doxepin in the management of uremic pruritus: a randomized single blind . Hemodial Int Symp Home Hemodial. July 2016.

25. Matsuda KM, Sharma D, Schonfeld AR, Kwatra SG. Gabapentin and pregabalin for the treatment of chronic pruritus. J Am Acad Dermatol. May 2016. doi:10.1016/j.jaad.2016.02.1237.

26. Lau T, Leung S, Lau W. Gabapentin for uremic pruritus in hemodialysis patients: a qualitative . Can J Kidney Health Dis. 2016;3:14-016-0107-8. eCollection 2016.

27. Lin T-C, Lai Y-H, Guo S-E, et al. Baby oil therapy for uremic pruritus in haemodialysis patients. J Clin Nurs. 2012;21(1-2):139-148. doi:10.1111/j.1365-2702.2011.03906.x.

28. Karadag E, Kilic SP, Karatay G, Metin O. Effect of baby oil on pruritus, sleep quality, and quality of life in hemodialysis patients: pretest-post-test model with control groups. Jpn J Nurs Sci JJNS. 2014;11(3):180-189. doi:10.1111/jjns.12019.

29. Regier L. Topical Corticosteroids. In: RxFiles Drug Comparison Charts. 10th ed. Saskatoon, SK: Saskatoon Health Region; 2016. http://www.rxfiles.ca/rxfiles/. Accessed August 11, 2016.

30. Acupuncture and related interventions for symptoms of chronic kidney disease - Kim - 2016 - The - Wiley Online Library. http://onlinelibrary.wiley.com.uml.idm.oclc.org/doi/10.1002/14651858.CD009440.pub2/full. Accessed September 16, 2016. 31. Che-yi C, Wen CY, Min-Tsung K, Chiu-Ching H. Acupuncture in haemodialysis patients at the Quchi (LI11) acupoint for refractory uraemic pruritus. Nephrol Dial Transplant. 2005;20(9):1912-1915. doi:10.1093/ndt/gfh955.

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33. Ko M-J, Yang J-Y, Wu H-Y, et al. Narrowband ultraviolet B phototherapy for patients with refractory uraemic pruritus: a randomized controlled trial. Br J Dermatol. 2011;165(3):633-639. doi:10.1111/j.1365-2133.2011.10448.x.

34. Shakiba M, Sanadgol H, Azmoude HR, Mashhadi MA, Sharifi H. Effect of sertraline on uremic pruritus improvement in ESRD patients. Int J Nephrol. 2012;2012:363901.

35. Chan KY, Li CW, Wong H, et al. Use of sertraline for -refractory uremic pruritus in renal palliative care patients. J Palliat Med. 2013;16(8):966-970.

36. Marquez D, Ramonda C, Lauxmann JE, et al. Uremic pruritus in hemodialysis patients: treatment with desloratidine versus gabapentin. J Bras Nefrol Orgao Of Soc Bras E Lat-Am Nefrol. 2012;34(2):148-152.

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40. Vessal G, Sagheb MM, Shilian S, Jafari P, Samani SM. Effect of oral cromolyn sodium on CKD- associated pruritus and serum tryptase level: a double-blind placebo-controlled study. Nephrol Dial Transplant Off Publ Eur Dial Transpl Assoc - Eur Ren Assoc. 2010;25(5):1541-1547. doi:10.1093/ndt/gfp628.

41. Feily A, Dormanesh B, Ghorbani AR, et al. Efficacy of topical cromolyn sodium 4% on pruritus in uremic nephrogenic patients: a randomized double-blind study in 60 patients. Int J Clin Pharmacol Ther. 2012;50(7):510-513.

42. Ghanei E, Zeinali J, Borghei M, Homayouni M. Efficacy of omega-3 fatty acids supplementation in treatment of uremic pruritus in hemodialysis patients: a double-blind randomized controlled trial. Iran Red Crescent Med J. 2012;14(9):515-522.

43. Pakfetrat M, Basiri F, Malekmakan L, Roozbeh J. Effects of turmeric on uremic pruritus in end stage renal disease patients: a double-blind randomized clinical trial. J Nephrol. 2014;27(2):203-207.

44. Jellin JM, ed. TURMERIC Monograph. In: Natural Medicines Comprehensive Database. Stockton, CA: Therapeutic Research Faculty; 1995. http://naturaldatabase.therapeuticresearch.com.uml.idm.oclc.org/home.aspx?cs=&s=ND. Accessed October 6, 2016.

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