Use of Pregabalin in the Management of Chronic Uremic Pruritus

Transcription

1 776 Journal of Pain and Symptom Management Vol. 45 No. 4 April 2013 Clinical Note Use of Pregabalin in the Management of Chronic Uremic Pruritus Linda Shavit, MD, Tal Grenader, MD, Meyer Lifschitz, MD, and Itzchak Slotki, MD Division of Adult Nephrology (L.S., M.L., I.S.) and The Oncology Institute (T.G.), Shaare Zedek Medical Center, Jerusalem, Israel Abstract Context. Uremic pruritus (UP) affects many patients suffering from chronic kidney disease (CKD) and has a negative impact on quality of life and survival. It has become increasingly evident that central transmission and sensitization processes similar to those observed in chronic pain are important mechanisms of pruritus. Objectives. To test the potential role of pregabalin in reducing the intensity of UP in CKD patients. Methods. We prospectively collected data on CKD patients who suffered from severe intractable pruritus. Patients were asked to record the intensity of pruritus on a visual analogue scale. Results. Twelve patients were studied. The average pretreatment pruritus score was and decreased to , , and after one, four, and 24 weeks of treatment, respectively (P < 0.05). The positive effect of pregabalin was demonstrated during the first week of therapy in six patients. Most patients required 25 mg a day. Pregabalin was well tolerated, with somnolence and dizziness developing in two patients. Conclusion. We demonstrated dramatic improvement of long-standing UP after the initiation of pregabalin. We suggest that pregabalin can be used safely in CKD but careful titration of the dose is required to obtain an optimal response and minimize the possible adverse effects. J Pain Symptom Manage 2013;45:776e781. Ó 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. Key Words Pregabalin, chronic renal failure, uremic pruritus, symptom control Introduction Uremic pruritus (UP) is a common and distressing problem in patients with advanced Address correspondence to: Linda Shavit, MD, Adult Nephrology Unit, Shaare Zedek Medical Center, P.O. Box 3235, Jerusalem 91031, Israel. lshavit@szmc.org.il Accepted for publication: March 10, Ó 2013 U.S. Cancer Pain Relief Committee. Published by Elsevier Inc. All rights reserved. chronic kidney disease (CKD) or end-stage kidney disease. The prevalence of UP varies widely among studies and seems to have declined over the last 30 years (from 85% in the 1970s and 50%e60% in the 1980s to 22% in the 2000s). 1 It has become increasingly evident that central transmission and sensitization processes similar to those observed in chronic pain are important mechanisms in the pathogenesis of chronic pruritus. 2 Pruritus may arise from /$ - see front matter

2 Vol. 45 No. 4 April 2013 Pregabalin in the Management of UP 777 a diminished threshold of perception and abnormalities of nerve terminals and fibers that are commonly found in hemodialysis patients. 3 Therefore, we hypothesized that a drug designed as a potent therapy for neuropathic pain also might have a favorable effect on UP. Pregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. It binds to the a2d subunit of the voltage-dependent calcium channel in the central nervous system and reduces calcium influx into nerve terminals. Pregabalin also decreases the release of neurotransmitters such as glutamate, noradrenaline, and substance P and inhibits the release of calcitonin gene-related peptide, a mediator of itching. 4 We routinely use pregabalin for the treatment of neuropathic pain in patients on hemodialysis. In addition to neuropathic pain, several of our patients have complained of severe chronic pruritus, and after pregabalin treatment, significant improvement in the intensity of pruritus was observed. This study presents the prospectively collected data on these patients. Methods Patient Population We prospectively collected data on adult hemodialysis patients and on patients from the nephrology outpatient clinic, with CKD Stage III or IV. All hemodialysis patients received outpatient treatment using B. Braun CE0123 machines (B. Braun Melsungen AG, Melsungen, Germany). The dialysis sessions were for four hours each three times per week. Polysulfone hollow fiber dialyzers (polysulfone membranes; B. Braun Melsungen AG) and bicarbonate-based dialysate were used throughout the study. The blood flow rate varied between 200 and 300 ml/minute but was kept constant for a given patient. Study Protocol Patients with severe pruritus unresponsive to antihistamines and local moisturizers were eligible to receive pregabalin (LyricaÒ; Pfizer, Berlin, Germany). These patients were asked to record the severity of their pruritus on a visual analogue scale (VAS) before the initiation of pregabalin therapy and weekly thereafter. The VAS was a 10 cm horizontal line marked from 0 (denoting no itch) to 10 (denoting the severest itch). Patients were excluded if they suffered from allergy to pregabalin, any acute illness, liver cirrhosis, decompensated heart failure, inability to give informed consent, or poor compliance. The initial dose was 25 mg administered orally thrice weekly at the end of the hemodialysis session. If no improvement in symptoms was observed by the end of the first week of therapy, the dose was increased to 25 mg/day and, subsequently, to 50 mg/day. Study participants were followed for 24 weeks. Adverse effects classified by severity and possible relation to the study medicine were recorded. The following demographic and clinical characteristics were recorded prospectively: age, gender, history of heart failure, coronary artery disease, cause of end-stage renal disease, diabetes, hypertension, hyperlipidemia, peripheral vascular disease, cerebral vascular accident, time and duration of dialysis, predialysis and postdialysis weights, interdialytic weight gain, and pre- and postdialysis systolic and diastolic blood pressures. Medications, including antihypertensive agents, lipid-lowering agents, antihistamines, and local moisturizers, and values of the most recent monthly laboratory studies (hemoglobin, divalent ions, parathyroid hormone [PTH], creatinine, blood urea nitrogen, sodium, potassium, lipid profile, total protein, albumin, liver enzymes, adequacy of dialysis expressed as Kt/V, C-reactive protein, thyroid-stimulating hormone, iron, transferrin, and ferritin) also were recorded. The study was approved by the Institutional Review Board of Shaare Zedek Medical Center, and all participants gave informed consent. Study End Points and Statistical Analyses The primary end point was a reduction in the VAS of $50% during the first two weeks of pregabalin administration. VAS scores were expressed as mean SD, and post-treatment values were compared with baseline scores using one-way analysis of variance, with differences reported as significant if P < All analyses were conducted using SPSS software version 17 (SPSS, Inc., Chicago, IL).

3 778 Shavit et al. Vol. 45 No. 4 April 2013 Results Ten patients on chronic hemodialysis and two patients with Stage IV CKD (estimated glomerular filtration rate 15e30 ml/minute/ 1.73 m 2 ) were included. Dialysis regimen, diet, and chronic medications were kept constant during the study period. Baseline clinical and laboratory characteristics are presented in Table 1. The average age was 72 9 years, and half of our patients were male. The average duration of hemodialysis was months. A high prevalence of diabetes, hypertension, and cardiovascular disease was noted. All participants suffered from severe long-lasting pruritus, with an average VAS of , and had been treated unsuccessfully with different antihistamines and topical moisturizers. Average plasma calcium, phosphorus, and PTH were within the recommended range ( mg/dl, mg/dl, and pg/ml, respectively). No features of malnutrition, severe anemia, or inadequate dialysis were detected (plasma albumin g/dl, hemoglobin g/dl, and Kt/V , respectively). The effect of pregabalin on VAS scores is shown in Fig. 1. The average pretreatment VAS was and decreased to , , and after one, four, and 24 weeks of treatment, respectively (P < 0.05). The positive effect of pregabalin was demonstrated during the first week of therapy in six patients; one patient improved with a dose of 25 mg thrice a week, eight patients responded to 25 mg daily, and three patients required 50 mg daily. Pregabalin was generally well tolerated but somnolence and dizziness developed in two patients. These symptoms promptly improved when the drug was administered before bedtime. During the follow-up period, two patients discontinued pregabalin of their own volition but restarted the drug a few days later because of a relapse of pruritus. Discussion Our study demonstrated a dramatic improvement in chronic severe UP after the initiation of pregabalin therapy. All our patients suffered from disabling pruritus, with an average VAS of , and all were previously treated unsuccessfully with different Table 1 Baseline Clinical and Laboratory Characteristics (n ¼ 12) Characteristics Mean SD Age (years) 72 9 Male (n) 6 Weight (kg) Duration of hemodialysis (months) Pruritus score before pregabalin therapy Use of oral antihistamines and/or 12 topical therapy (n) CHF (n) 3 Systemic hypertension (n) 6 Diabetes mellitus (n) 5 Cardiovascular disease (n) 5 Peripheral vascular disease (n) 1 Phosphate binders (n) Calcium carbonate 5 Sevelamer hydrochloride 4 Lanthanum carbonate 2 Other medications (n) 3 Cinacalcet hydrochloride 2 ACE inhibitors/angiotensin II 1 receptor blockers Statins 5 Laboratory results Plasma sodium (meq/l) Plasma potassium (meq/l) Plasma calcium (mg/dl) Plasma phosphorus (mg/dl) Plasma PTH (pg/ml) Plasma urea nitrogen (mg/dl) Plasma creatinine (mg/dl) Kt/V Plasma TSH (reference range 0.3e5.0) (miu/l) Plasma albumin (g/dl) Plasma total cholesterol (mg/dl) Plasma triglycerides (mg/dl) CRP (reference range 0.3e5.0) (mg/dl) Hemoglobin (g/dl) Iron (reference range 49e181) (mcg/dl) Transferrin (reference range 200e400) (mcg/dl) Ferritin (reference range 24e336) (ng/ml) Liver enzymes (IU/L) AST (GOT) (reference range 17e59) ALT (GPT) (reference range 21e70) GGT (reference range 15e73) Alkaline phosphatase (reference range 38e130) CHF ¼ congestive heart failure; ACE ¼ angiotensin-converting enzyme; PTH ¼ parathyroid hormone; TSH ¼ thyroid-stimulating hormone; CRP ¼ C-reactive protein; AST (GOT) ¼ aspartate aminotransferase (glutamic oxaloacetic transaminase); ALT (GPT) ¼ alanine aminotransferase (glutamic pyruvic transaminase); GGT ¼ gamma-glutamyl transpeptidase. antihistamines and topical therapy. Pregabalin had a rapid and impressive effect in more than 60% of the study patients, whereas the remainder required higher doses and up to four weeks to obtain an optimal clinical response.

4 Vol. 45 No. 4 April 2013 Pregabalin in the Management of UP 779 Pruritus score Week -1 Week 1 Week 4 Week 24 Fig. 1. Effect of pregabalin administration on pruritus score. Patients recorded the severity of their pruritus on a visual analogue scale (10 cm horizontal line marked from 0 [no itch] to 10 [severest itch]). The average pretreatment pruritus score was and decreased to , , and after one, four, and 24 weeks of treatment, respectively (P < 0.05). Are our findings biologically plausible and supported by pathogenic mechanisms? The mechanism of UP is unknown, but several hypotheses have been proposed to explain the pathogenesis. The prevailing explanation until recently was excess PTH because UP seemed to be most severe in patients with marked secondary hyperparathyroidism and resolved after parathyroidectomy. 5 However, subsequent data did not confirm this theory, and, indeed, our patients had PTH levels within the target range. 6 Similarly, the concept of precipitated calcium phosphate crystals in the setting of elevated serum calcium and phosphate levels as a trigger of UP could not be sustained. 7 Additional suggested causes include xerosis, 8 involvement of the peripheral nervous 9 or opioid systems, 10 mast cells and autacoids (histamine and serotonin), and derangements of the immune system. 11 Activity of the nervous system also may play an important role in the mechanism of UP. 9 It has become increasingly evident that central transmission and sensitization processes similar to those observed in chronic pain also are important mechanisms in the pathogenesis of chronic pruritus. 2 Pruritus may arise from a diminished threshold of perception and abnormalities of nerve terminals and fibers that are commonly found in hemodialysis patients. 3 Therefore, drugs such as pregabalin, designed as potent therapies for neuropathic pain, would be predicted to have a favorable effect on UP. Pregabalin is very similar to gabapentin regarding the structure and mechanism of action. Like gabapentin, pregabalin binds to the a2d subunit of the voltage-dependent calcium channel in the central nervous system. This reduces calcium influx into the nerve terminals. Pregabalin also decreases the release of neurotransmitters such as glutamate, noradrenaline, and substance P. 4 Pregabalin seems to have an advantage over gabapentin in terms of its more rapid response to stressful symptoms. Gabapentin recently was shown to be safe and effective in the treatment of chronic UP in hemodialysis patients. 12 Both central and peripheral mechanisms could explain this effect. Gabapentin, like pregabalin, inhibits the release of calcitonin gene-related peptide, which is a mediator of itching, from primary afferent neurons through an increase of g-aminobutyric acid in the spinal cord. 4 Moreover, gabapentin may modify the central perception of itch by modulation of m-opioid receptors. 13 Two recent case reports showed the efficacy of pregabalin in the treatment of chronic severe non-up. One of them demonstrated its efficacy in a patient with cetuximab-related itch and the other reported three patients with a 15- to 25-year history of generalized severe itch, which was related to polycythemia vera in two of them. 14,15 The itch intensity, as rated by VAS, was eight points in all patients. After multiple treatment failures, pregabalin was commenced at a dose of 75 mg twice daily and increased to 150 mg twice daily, resulting in a more than 70% reduction of itch. 14 While this manuscript was being prepared, a report showing similar findings to ours in a group of hemodialysis patients with intractable pruritus was published, thus strengthening the hypothesis that pregabalin is a useful drug in the treatment of this distressing symptom. 16 Pregabalin is generally well tolerated, and our patients had minimal or no side effects. However, the drug is eliminated primarily by renal excretion and, therefore, the dose should be adjusted in patients with reduced renal function. 17 The recommended dose for hemodialysis patients is 25e75 mg/day. Pregabalin does not bind to plasma proteins and is fully dialyzable because of its small molecular size. Thus, hemodialysis patients may require supplemental dosing after dialysis to maintain plasma pregabalin concentrations within the desired range. 17 Pregabalin has no significant pharmacokinetic drug interactions, and the adverse reactions most frequently leading to

5 780 Shavit et al. Vol. 45 No. 4 April 2013 discontinuation of therapy are dizziness (4%) and somnolence (3%). We observed a doseresponse effect in our patients and, therefore, we suggest a careful titration of dose to obtain the best response while minimizing adverse effects. Illustrative Case A 67-year-old woman who had end-stage kidney disease as a result of familial Mediterranean fever had been treated by chronic hemodialysis since Her medical history was remarkable for hypothyroidism, idiopathic interstitial lung disease, and hearing loss. In addition, she suffered from intermittent severe pruritus for over four years. Her dialysis dose was optimal, and serum PTH and phosphorus were well controlled in the recommended ranges. In addition, she underwent recurrent dermatologic evaluation and received different therapies including topical emollients, topical steroids, and oral antihistamines. Despite these measures, she continued to suffer from severe pruritus (VAS of 10, denoting the severest itch) that led to insomnia and skin excoriations. Pregabalin at a dose of 25 mg/day induced significant improvement in her symptoms during the first week of therapy. She did develop somnolence, which resolved with bedtime administration of the drug. The patient expressed her gratitude for being able to sleep undisturbed by pruritus for the first time in years. Limitations and Future Directions Our study has some limitations. First, it was observational and uncontrolled and, therefore, we cannot rule out known or unknown confounding factors as an explanation for our results. Second, pregabalin was used in a limited patient population. However, the multitude of currently available treatments for the relief of UP attests to their, at best, modest success. 18 Therefore, it is hard to overestimate the importance of any potentially effective therapy for this distressing condition, which has a negative impact on the quality of life and overall survival. 19 In summary, our promising results represent a launching pad for a sufficiently powered, randomized, placebo-controlled trial to define the exact role of pregabalin in the management of UP. Disclosures and Acknowledgments No funding was received for this study, and the authors declare no conflicts of interest. References 1. Mettang T, Fischer FP, Kuhlmann U. [Uremic pruritus. Pathophysiologic and therapeutic concepts]. [in German]. Dtsch Med Wochenschr 1996; 121:1025e Stander S, Schmelz M. Chronic itch and paind similarities and differences. Eur J Pain 2006;10: 473e Johansson O, Hilliges M, Stahle-Backdahl M. Intraepidermal neuron-specific enolase (NSE)- immunoreactive nerve fibres: evidence for sprouting in uremic patients on maintenance hemodialysis. Neurosci Lett 1989;99:281e Fehrenbacher JC, Taylor CP, Vasko MR. Pregabalin and gabapentin reduce release of substance P and CGRP from rat spinal tissues only after inflammation or activation of protein kinase C. Pain 2003;105:133e Massry SG, Popovtzer MM, Coburn JW, et al. Intractable pruritus as a manifestation of secondary hyperparathyroidism in uremia. Disappearance of itching after subtotal parathyroidectomy. N Engl J Med 1968;279:697e Stahle-Backdahl M, Hagermark O, Lins LE, et al. Experimental and immunohistochemical studies on the possible role of parathyroid hormone in uraemic pruritus. J Intern Med 1989;225:411e Blachley JD, Blankenship DM, Menter A, Parker TF III, Knochel JP. Uremic pruritus: skin divalent ion content and response to ultraviolet phototherapy. Am J Kidney Dis 1985;5:237e Morton CA, Lafferty M, Hau C, et al. Pruritus and skin hydration during dialysis. Nephrol Dial Transplant 1996;11:2031e Zakrzewska-Pniewska B, Jedras M. Is pruritus in chronic uremic patients related to peripheral somatic and autonomic neuropathy? Study by R-R interval variation test (RRIV) and by sympathetic skin response (SSR). Neurophysiol Clin 2001;31: 181e Peer G, Kivity S, Agami O, et al. Randomised crossover trial of naltrexone in uraemic pruritus. Lancet 1996;348:1552e Fusaro M, Munaretto G, Spinello M, Gallieni M. Regression of uraemic pruritus by cyclosporin treatment in a haemodialysis patient. Nephrol Dial Transplant 2004;19:1338e Gunal AI, Ozalp G, Yoldas TK, et al. Gabapentin therapy for pruritus in haemodialysis patients: a randomized, placebo-controlled, double-blind trial. Nephrol Dial Transplant 2004;19:3137e3139.

6 Vol. 45 No. 4 April 2013 Pregabalin in the Management of UP Yoon MH, Choi JI, Jeong SW. Spinal gabapentin and antinociception: mechanisms of action. J Korean Med Sci 2003;18:255e Ehrchen J, Stander S. Pregabalin in the treatment of chronic pruritus. J Am Acad Dermatol 2008;58:S36eS Porzio G, Aielli F, Verna L, et al. Efficacy of pregabalin in the management of cetuximab-related itch. J Pain Symptom Manage 2006;32:397e Aperis G, Paliouras C, Zervos A, Arvanitis A, Alivanis P. The use of pregabalin in the treatment of uraemic pruritus in haemodialysis patients. J Ren Care 2010;36:180e Randinitis EJ, Posvar EL, Alvey CW, et al. Pharmacokinetics of pregabalin in subjects with various degrees of renal function. J Clin Pharmacol 2003; 43:277e Wikstrom B. Itchy skinda clinical problem for haemodialysis patients. Nephrol Dial Transplant 2007;22(Suppl 5):v3ev Kuypers DR. Skin problems in chronic kidney disease. Nat Clin Pract Nephrol 2009;5:157e170.