Opioid System in Uremic Pruritus: Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Studies

JASN Express. Published on October 26, 2005 as doi: 10.1681/ASN.2005020152

␬-Opioid System in Uremic Pruritus: Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Studies

Bjo¨rn Wikstro¨m,* Ryszard Gellert,† Søren D. Ladefoged,‡ Yasuaki Danda,§ Masahiko Akai,§ Kaoru Ide,§ Midori Ogasawara,§ Yoshiharu Kawashima,§ Koki Ueno,§ Akio Mori,§ and Yuji Ueno§ *Department of Nephrology, Dialysis Unit, University Hospital, Uppsala, Sweden; †Department of Health Care, Institute of Social Medicine, Warsaw Medical University, Warsaw, Poland; ‡Department of Nephrology, Section 5101, Rigshopspitalet, Copenhagen, Denmark; and §Clinical Development Center, Toray Industries, Inc., Chiba, Japan

Uremic pruritus is a very common and frustrating condition for both patients and clinicians because no treatment has been demonstrated to be effective in relieving the itch. In this report, nalfurafine, a new ␬-opioid receptor agonist, was used to treat uremic pruritus in patients who were undergoing routine hemodialysis. Two multicenter, randomized, double-blind, placebo- controlled studies enrolled 144 patients with uremic pruritus to postdialysis intravenous treatment with either nalfurafine or placebo for 2 to 4 wk. A meta-analysis approach was used to assess the efficacy of nalfurafine. Statistically significant were noted in the (0.0003 ؍ and sleep disturbances (P ,(0.0410 ؍ itching intensity (P ,(0.0212 ؍ reductions in worst itching (P were noted (0.0060 ؍ and excoriations (P (0.0025 ؍ nalfurafine group as compared with placebo. Improvements in itching (P for the nalfurafine-treated patients. Nalfurafine showed similar types and incidences of drug-related adverse events as did placebo. Nalfurafine was shown to be an effective and safe compound for use in this severely ill patient population. J Am Soc Nephrol ●: ●●●–●●●, ●●●●. doi: 10.1681/ASN.2005020152

remic pruritus has a major impact on the quality of Materials and Methods life in patients who already have a compromised Study Design and Treatments U lifestyle (1–5). It is, of itself, not a life-threatening Two multicenter, randomized, double-blind, placebo-controlled clin- condition; however, it is known to contribute to an increase in ical studies were performed with the common objective of assessing the morbidity (6) and mortality (7) of uremic patients. The only efficacy and the safety of nalfurafine, as compared with placebo, in the treatment of uremic pruritus. The inclusion and exclusion criteria and current definitive treatment for uremic pruritus is successful the evaluations, methods of evaluations, and times of evaluations were renal transplantation (8). Increasing the dialysis dose as well as the same in both studies. implementing other therapeutic measures to lessen the symp- Patients were males and females who were at least 18 yr of age and toms, some as extraordinary as acupressure, (9) have provided undergoing routine hemodialysis secondary to ESRD and had severe, only limited effectiveness in dialysis patients. uncontrolled pruritus caused only by ESRD. Female patients were not Stimulation of the ␮-opioid receptor in the brain and/or of childbearing potential or were using an acceptable contraceptive peripheral nerve endings by its agonists, such as morphine, can method(s). They had normal hepatic function, and any concurrent result in itching (10–12). ␮-Opioid receptor antagonists can diseases were stable, were not severe, and would not interfere with interpretations of the study results. All patients completed the “worst inhibit itching induced by substance P (13). ␬-Opioid stimula- itching” visual analogue scale (VAS) at least eight of 14 times during a ␮ tion inhibits -receptor effects both centrally and peripherally 1-wk run-in period. Each patient had at least three “worst itching” VAS ␬ (11). Nalfurafine, a new -opioid receptor agonist, was effective measurements during the run-in period of Ն50 mm and an average in reducing the scratching behavior induced by an injection of “worst itching” VAS of Ն25 mm. Excluded were female patients who substance P in the mouse model (13,14). From these findings, it were pregnant, were nursing, or wanted to become pregnant; patients was hypothesized that uremic pruritus could be triggered and whose pruritus occurred only during dialysis; and patients who had sustained by the release of substance P (15). This led to the participated in a clinical trial or received an experimental drug within 30 d of trial start. Patients with a history of drug/alcohol abuse, allergy studies in the treatment of uremic pruritus using nalfurafine. to opioids or other drug allergies, or a psychiatric disorder were excluded. The first study (study 1) was a parallel-group design with the treatment lasting for 4 wk. Seventy-nine patients were randomly assigned in this study, and 74 completed the 4 wk of treatment. Before the run-in Received February 8, 2005. Accepted September 7, 2005. period (baseline), all anti-pruritic medications, except for topical neu- Published online ahead of print. Publication date available at www.jasn.org. tral agents, were discontinued for at least 7 d. After the run-in period in which it was documented that patients had pruritus that required Address correspondence to: Dr. Yuji Ueno, Clinical Development Center, Toray Industries Inc., 8-1, Mihama 1-chome, Urayasu, Chiba 279-8555, Japan. Phone: treatment [itching uncontrolled by current medication(s)/treatment(s)], ϩ81-47-350-6754; Fax: ϩ81-47-350-6769; E-mail: [email protected] the patients were randomly assigned to receive nalfurafine 5 ␮g(n ϭ

26) or placebo (n ϭ 25) thrice weekly by intravenous infusion, imme- included in a FAS data set. With the intention to select comparable data diately after completion of each of their hemodialysis (HD) sessions in from the two studies, only the data from the nalfurafine 5 ␮g and the 4 wk. A follow-up visit was performed 2 wk after administration of the placebo groups were used in these analyses because it allowed pooling final dose of study medication. of the same dose groups, thus increasing the sample sizes. Using only The second study (study 2) was a crossover design in which patients the data from the first 2 wk of treatment in study 1 and the first 2-wk were randomly assigned 1:1 to receive for 2 wk an intravenous infusion treatment period in study 2 was considered appropriate because of of either nalfurafine 5 ␮g or placebo thrice weekly immediately after concerns of the drug carryover effects and regression to the mean. For each of their HD sessions. Before randomization, patients underwent a any missing data, the last observation carried forward approach was 1-wk run-in period to determine their eligibility. At the completion of used. the first treatment period, patients underwent a 3-wk washout period The primary end point (worst itching VAS) was analyzed using an followed by another 1-wk run-in period. Patients then were crossed analysis of covariance model. Treatment, study, and run-in values were over to the other study medication for an additional 2 wk of therapy. used as factors in the model. This corresponds to the model used in the Thirty-four patients were randomly assigned to this study, and 31 individual studies, stratified by study. For the weighted analysis of completed the 4 wk of treatment. “worst itching” VAS in study 1 ϩ period 1 study 2 and study 1 ϩ study The severity of pruritus and the treatment effectiveness were self- 2, the DerSimonian-Laird method (16,17), a random-effects model, was evaluated by the patients every 12 h during the run-in period and used. The DerSimonian estimates were equal to ordinary fixed-effects throughout the studies using a 100-mm VAS to measure the “worst model estimates because the heterogeneity parameter ␶2 was found to itching” during the previous 12 h as the primary end point. At the left be zero. end of the scale (0 mm) was “no itching” and the right end (100 mm) For the secondary efficacy variables, patients’ assessment of itching represented “worst itching ever” with the patient making a vertical line intensity and sleep disturbances were analyzed using analysis of co- between “0” and “100” to denote the severity of itching. Secondary variance models, with treatment, study, and run-in value as factors. For efficacy end points were (1) patient responders as defined by a reduc- analysis purposes, these variables were re-categorized as follows: 1, tion from run-in of at least 50% in “worst itching” VAS, (2) itching nondisturbing itching (originally recorded as “0, no itching” or “1, intensity assessed each evening using a five-point categorical scale tolerable without scratching”), and 0, disturbing itching (originally ranging from 1 (no itching) to 5 (intolerable itching), and (3) ability to recorded as categories 2 through 5 above), or as 1, sound sleep (origi- sleep during the night assessed each morning using a five-point cate- nally recorded as “0, no itching” or “1, sound sleep with slight itch on gorical scale ranging from 1 (no itching) to 5 (cannot sleep because of retiring”), and 0, sleep disturbed (originally recorded as categories 2 itching). through 5 above). In addition, the investigators assessed (1) the itching intensity of the The sum of the re-categorized itching intensity or sleep disturbance patients by direct questioning of the patients using the same five-point variables was used to estimate the number of days with nondisturbing categorical scale used by the patients and compared the efficacy of the itching or to estimate the number of nights with sound sleep within a study medication using a three-point scale (same, better, worse com- study week, respectively. The change from run-in was used for hypoth- pared with run-in) performed at the end of each week of treatment and esis testing. (2) the number of excoriations on the body during run-in and after each Investigators’ assessments of improvement in itching and excoriation 2 wk of therapy and compared these values with those at run-in using and the proportion of responders in each treatment group were ana- a three-point scale (same, better, worse). lyzed using the Cochran-Mantel-Haenszel test stratified for study (with Each dose of double-blind study medication in both studies was modified ridit scores). An overall comparison was performed using administered as an intravenous infusion at a rate of 2 ml/min for 5 min Fisher exact test. using an infusion pump. All doses were administered immediately Two-sided P Ͻ 0.05 was considered to indicate statistical signifi- after conclusion of each HD session. cance. Statistical calculations were performed with SAS software (ver- sion 8.2; SAS Institute, Cary, NC). Ethics The studies were conducted in accordance with the ethical principles Results that have their origins in the Declaration of Helsinki and its amend- Efficacy ment. Both protocols and the representative informed consent forms Using the complete study 1 ϩ study 2 data sets, 86 patients and patient information sheets underwent review and received ap- were treated with nalfurafine, and 58 patients received placebo. proval by the representative ethics committees. All patients were in- In study 1, 26 patients were randomly assigned to nalfurafine 5 formed and had questions answered by the investigators at each study ␮g, and 25 received with placebo. Sixteen patients were ran- site before they provided written informed consent. All patients pro- ␮ vided their written informed consent before having any study-related domly assigned to nalfurafine 5 g and 18 received placebo in procedure performed. the first period of study 2. A total of 42 patients received nalfurafine 5 ␮g as the first medication for 2 wk, and 43 patients started with placebo in the study 1 ϩ period 1 study 2 analysis. Statistical Analyses All demographic and clinical characteristics including the du- The primary end point for each of the clinical trials was reduction in rations of renal disease, dialysis, and pruritus in each study mean “worst itching” VAS from run-in to the end of week 4 (study 1) were comparable. and week 2 (study 2). This end point was prespecified before the initiation of either trial. Likewise, the primary end point for the meta- Evaluation of the mean “worst itching” VAS from the study ϩ analysis was reduction in mean “worst itching” VAS from run-in to 1 period 1 study 2 analysis demonstrated that nalfurafine week 2. reduced the mean “worst itching” VAS from run-in statistically All patients who had received at least one dose of study medication significantly more than placebo (weighted mean difference 9.53 and had at least one assessable “worst itching” VAS measurement were mm; 95% confidence interval 1.42 to 17.64 mm; P ϭ 0.0212; J Am Soc Nephrol ●: ●●●–●●●, ●●●● ␬-Opioid Receptor Agonist Relieved Uremic Pruritus 3

Figure 1. “Worst itching” visual analog scale; 95% confidence interval for the treatment difference.

Figure 1). This is similar to the results from the individual nalfurafine group improved from 0.6 d/wk at the run-in period studies (Tables 1 and 2). Using data from both treatment peri- to 2.2 and 2.8 d at week 1 and week 2, respectively. Also, the ods in the crossover study as a sensitivity analysis, study 1 ϩ number of nights with sound sleep in the nalfurafine group study 2, the reduction of the mean “worst itching” VAS also improved from 1.7 nights/wk at the run-in period to 3.4 and 4.3 reached statistical significance (weighted mean difference 7.29 nights at week 1 and week 2, respectively. mm; 95% confidence interval 0.17 to 14.4 mm; P ϭ 0.0447; The investigators’ assessment of itching demonstrated a sta- Figure 1). tistically significant improvement (P ϭ 0.0025) in favor of nal- Responders were patients with at least a 50% decrease from furafine. The nalfurafine group also had a statistically signifi- baseline in “worst itching” VAS. At the 2-wk time point (study cant improvement (P ϭ 0.0060) in excoriations, as judged by the ϩ 1 period 1 study 2), 15 (36%) of the nalfurafine patients were investigators (Table 4). ϭ responders as compared with 6 (14%) in the placebo group (P Using the meta-analysis approach, it was demonstrated that 0.0226). When several variables (age, gender, height, weight, nalfurafine produced a statistically significantly greater im- smoking status, and alcohol intake) were evaluated to deter- provement in the “worst itching” VAS as compared with pla- mine a characteristic(s) that could be predictive of a responder, cebo after 2 wk of therapy. When the reduction of “worst none was identified. itching” VAS over 4 wk of treatment (study 1) was reviewed, a For patients’ assessment, both number of days with nondis- continued reduction in VAS occurred for the next 2 wk for turbing itching and number of nights with sound sleep were nalfurafine (21.5 mm at 2 wk and 25.8 mm at 4 wk). Although statistically significantly different between groups at week 2, in statistical significance was not demonstrated in this study, the favor of nalfurafine (P ϭ 0.0410 and P ϭ 0.0003, respectively; data suggested that nalfurafine was clinically effective for at Table 3). The number of days with nondisturbing itching in the least 4 wk (Table 1).

Table 1. Summary of “worst itching” VAS (mm) at the end of weeks 2 and 4 in study 1a Table 2. Summary of “worst itching” VAS (mm) at the end of week 2 in period 1 in study 2 Treatment Week n Mean SD Sequence Period n Mean SD Nalfurafine, 5 ␮g Run-in 26 65.3 15.2 Week 2 26 44.9 26.5 Nalfurafine, placebo Run-in 1 16 63.6 10.9 Week 4 26 40.3 27.8 Period 1 16 41.5 20.5 Placebo Run-in 25 65.3 15.0 (nalfurafine) Week 2 25 55.5 21.5 Placebo, nalfurafine Run-in 1 18 61.9 12.6 Week 4 25 52.6 24.0 Period 1 18 48.4 19.1 (placebo) aVAS, visual analog scale. 4 Journal of the American Society of Nephrology J Am Soc Nephrol ●: ●●●–●●●, ●●●●

Table 3. Mean changes from run-in to week 2 in number of days with nondisturbing itching and number of nights with sound sleep: Study 1 ϩ period 1 study 2

Mean Score at Mean Score at Mean P Value Treatment Run-in Ϯ SD Week 2 Ϯ SD Change Ϯ SD (95% CI)a,b

No. of days/wk with nondisturbing itching 0.0410 (0.04 to 1.79) nalfurafine (n ϭ 42) 0.6 Ϯ 1.1 2.8 Ϯ 2.6 2.2 Ϯ 2.2 placebo (n ϭ 43) 0.8 Ϯ 1.2 2.1 Ϯ 2.5 1.4 Ϯ 1.8 No. of nights/wk with sound sleep 0.0003 (0.72 to 2.47) nalfurafine (n ϭ 42) 1.7 Ϯ 2.3 4.3 Ϯ 2.4 2.5 Ϯ 2.0 placebo (n ϭ 43) 2.1 Ϯ 2.4 3.1 Ϯ 2.6 0.9 Ϯ 2.1

aCI, confidence interval. bCompared with placebo.

Table 4. Summary statistics of investigators’ assessment elevations of aspartate aminotransferase and alanine of excoriations: Study 1 ϩ period 1 study 2a transaminase (one patient). All of these ADR were mild and resolved, and treatment was not discontinued. Three pa- Better Same Worse tients who were administered nalfurafine had an SAE and Excoriations n % n % n % three on placebo recorded an SAE, but none of the SAE was considered to be drug related. In addition, there was no Study 1 12 50 12 50 0 0 difference of withdrawal rates between the active treatment ϭ b nalfurafine (n 24 ) groups and placebo groups in both studies. placebo (n ϭ 24c) 31320831 4 Period 1 study 2 ϭ Discussion nalfurafine (n 16) 15 94 1 6 0 0 To date, no treatments have demonstrated efficacy for uremic ϭ b placebo (n 16 ) 12 75 4 25 0 0 pruritus in a rigorously designed (randomized, double-blind, ϩ Study 1 period 1 study 2 placebo-controlled) and carried out clinical study. On the basis ϭ nalfurafine (n 40) 27 68 13 33 0 0 of the data presented, it seems that nalfurafine, a ␬-opioid ϭ placebo (n 40) 15 38 24 60 1 3 receptor agonist, could be the first agent to have demonstrated aP ϭ 0.0060, Cochran-Mantel-Haenszel test stratified for a statistically significant efficacy over placebo for this condition. study, using modified ridit scores, compared with placebo. Efficacy (using the “worst itching” VAS) was confirmed in a bTwo patients were withdrawn prematurely and not recent study (data not shown) that used nalfurafine in patients included in investigators’ assessment of itching. who had uremic pruritus and were undergoing routine hemo- c One patient was withdrawn prematurely and not dialysis. included in investigators’ assessment of itching. This meta-analysis should be regarded as a complement to the analyses of the pivotal study 1 and study 2, because the Safety results were consistent for all analyses (Figure 1). In this very Evaluation of the safety profiles from these two studies as- disturbing condition, an increase of attention and the sensa- sisted in assessment of the clinical utility of nalfurafine. In tion of being treated could be associated with subjective study 1, the incidence of drug-related adverse events (ADR), as improvement (the Bergstrom effect [18]). Even so, the ob- judged by the investigators, was similar between nalfurafine 5 served strong placebo effect was overridden by nalfurafine, ␮g and placebo groups: 17 (65%) of 26 and 13 (52%) of 25, which demonstrates the potent therapeutic effect of this respectively. The most common ADR associated with nal- medication. furafine were headache and nausea in three patients each and That nalfurafine can reduce the itching associated with ure- insomnia, vertigo, and vomiting in two patients each. With the mic pruritus suggests that opioid receptors may play an impor- exception of one case each of severe headache and insomnia, all tant role in the generation and maintenance of itching in this of these ADR were mild to moderate in intensity and resolved. patient population. ␮-Opioid receptor agonists elicit itching Only one patient, who had moderate nausea and vomiting, had from their central nervous system actions (13,19), and this therapy discontinued. Two (8%) patients in the nalfurafine 5 ␮g activity may be due to disinhibition of the central itch response group and six (24%) patients in the placebo group reported at that occurs as a result of their antinociceptive action (20). least one serious adverse event (SAE), but none of the SAE was ␬-Agonists have been shown to block the itching response of considered to be drug related. morphine through a central effect (13,21) while maintaining or In study 2, the incidence of ADR was similar between the enhancing morphine-induced antinociception. This anti-pru- nalfurafine 5 ␮g and placebo groups: 2 (13%) of 16 and 2 ritic effect may be due to a direct effect in one or more areas of (11%) of 18 patients, respectively. The most common ADR the brain and/or a positive feedback from the skin at the level associated with nalfurafine were vertigo (one patient) and of the spinal cord. J Am Soc Nephrol ●: ●●●–●●●, ●●●● ␬-Opioid Receptor Agonist Relieved Uremic Pruritus 5

The itching of uremic pruritus may be caused by another La¨nssjukhuset NA¨ L (Dr. Henrik Mulec, Dr. Kerstin Na¨ttorp), Borås pruritogen, substance P. This chemical has been shown to in- Lasarett (Dr. Sven-Aage Johnsen), Carlanderska Sjukhuset (Dr. Gert duce scratching in mice, with and without mast cells (14). Jensen, Dr. Katarina Gissle´n); Denmark: Rigshospitalet i Copenhagen Antihistamines were not effective in relieving the scratching in (Dr. Preben So¨rensen), Herlev Sygehus (Dr. Arne Ho¨j Nielsen), Cen- tralsygehuset i Holbaeck (Dr. Karsten So¨lling, Dr. Niels Lo¨kkegaard), either setting. These findings suggest that substance P can be a Hillerød Sygehus (Dr. Henrik Daugaard, Dr. Esben Gade-Rasmussen), possible cause of antihistamine-resistant pruritus. Nalfurafine Amtssygehus i Roskilde (Dr. Knud Rasmussen), Aalborg Sygehus Syd has been shown to inhibit scratching in this model. This effect was (Dr. Jakob So¨lling, Dr. Georg Dimcevski); Norway: Regionssykehuset i ␬ reversed when nor-binaltorphimine, a specific -receptor antago- Trondheim (Dr. Cecilia Montgomery-O¨ ien); Finland: Kirurgsjukhuset i nist, was administered, demonstrating that the anti-pruritic effect Helsinki (Dr. Eero Honkanen), Tampere University Hospital (Dr. Jukka of nalfurafine was mediated via the ␬-receptor (13,14). Mustonen, Dr. Ilpo Ala-Houhala). Study 2: Poland: Szpital Praski (Dr. Kumagai et al. (22) showed that the itch of uremic pruritus Janusz Puka); Szpital ZOZ, Milano´wek (Dr. Marek Stopinski); Szpital may be related to an imbalance of endogenous opioids. In their ZOZ, Wołomin (Dr. Stanislaw Niemczyk); Szpital Wojewo´dzki, Ciech- work, hemodialysis patients had increased ratios of ␤-endor- ano´w (Dr. Dorota Daniewska); Szpital Rejonowy, Mako´w Maz (Dr. phin/dynorphin A in serum, as compared with healthy volun- Janusz Grochowski); Szpital Wojewo´dzki, Radom (Dr. Antoni Sokal- teers, and this ratio increased with the severity of itching. ski); Szpital Wojewo´dzki, Wloclawek (Dr. Janusz Ostrowski); Szpital Wojewo´dzki, Plock (Dr. Marek Switalski). Because ␤-endorphin is a ␮-receptor agonist and dynorphin A is a ␬-receptor agonist, it is suggestive that this imbalance can ␮ result in overactivity of the -opioid receptor and induce pru- References ritus. In support of this imbalance hypothesis, Odou et al. (23) 1. Gilchrest BA, Stern RS, Steinman TI, Brown RS, Arndt KA, demonstrated a correlation between pruritus intensity and nal- Anderson WW: Clinical features of pruritus among pa- trexone sensitivity in patients with uremic pruritus. tients undergoing maintenance hemodialysis. Arch Derma- ␮ An explanation for the antagonistic actions of the - and tol 118: 154–156, 1982 ␬ -opioid systems is that although both receptors mediate their 2. Evans RW, Manninen DL, Garrison LP Jr, Hart LG, Blagg action in the same cellular manner, they are located in different CR, Gutman RA, Hull AR, Lowrie EG: The quality of life of types of neurons with direct connections to each other to elicit patients with end-stage renal disease. N Engl J Med 312: their inhibitory/excitatory interactions (24). Because these dif- 553–559, 1985 ferent receptors interact and the ␮-receptor opioid system 3. Balaskas EV, Oreopoulos DG: Uremic pruritus. Dial Trans- seems to play a major role in the pathophysiology of uremic plant 21: 192–244, 1992 pruritus, it seems reasonable that a selective ␬-agonist, such as 4. Robertson KE, Mueller BA: Uremic pruritus. Am J Health Syst Pharm 53: 2159–2170, 1996 nalfurafine, would demonstrate effectiveness in the treatment 5. Goicoechea M, de Sequera P, Ochando A, Andrea C, Cara- of central itching, especially uremic pruritus. melo C: Uremic pruritus: An unresolved problem in he- Evaluation of the adverse events from these two trials demon- modialysis patients. Nephron 82: 73–74, 1999 strates nalfurafine to be well tolerated in the clinical arena. The 6. Barrett BJ, Vavasour HM, Major A, Parfrey PS: Clinical and main events seem to be mediated by the central nervous system psychological correlates of somatic symptoms in patients (headache, vertigo, and insomnia) and the gastrointestinal system on dialysis. Nephron 55: 10–15, 1990 (nausea and vomiting). As all of these adverse events were tran- 7. Carmichael AJ, McHugh MI, Martin AM: Renal itch as an sient and resolved, this indicates that nalfurafine is a safe agent. indicator of poor outcome. Lancet 337: 1225–1226, 1991 Neither addiction nor symptoms of withdrawal were noted in 8. Murphy M, Carmichael AJ: Renal itch. Clin Exp Dermatol these patients and has been confirmed with studies in animals. 25: 103–106, 2000 Nalfurafine seems to be both an effective and a safe agent to be 9. Jedras M, Bataa O, Gellert R, Ostrowski G, Wojtaszek E, Lange J, Oledzka M: Acupressure in the treatment of ure- used in the treatment of uremic pruritus in ESRD patients who are mic pruritus. Dial Transplant 32: 8–10, 2001 undergoing routine hemodialysis. 10. Yosipovitch G, Greaves MW, Schmelz M: Itch. Lancet 361: 690–694, 2003 Acknowledgments 11. Pan ZZ: mu-Opposing actions of the kappa-opioid recep- We thank all of the investigators, nurses, and pharmacists at the tor. Trends Pharmacol Sci 19: 94–98, 1998 participating institutions and the patients who gave consent for these 12. Cousins MJ, Mather LE: Intrathecal and epidural adminis- studies. We also thank Dr. William Cady, who provided advice about tration of opioids. Anesthesiology 61: 276–310, 1984 manuscript preparation; and Yukari Ozaki, Tomoko Nakada, and Ha- 13. Umeuchi H, Togashi Y, Honda T, Nakao K, Okano K, rumi Hirota, who provided clerical support. Tanaka T, Nagase H: Involvement of central mu-opioid The following investigators contributed to these studies. Study 1: system in the scratching behavior in mice, and the sup- Sweden: Akademiska Sjukhuset i Uppsala (Dr. Torbjo¨rn Linde, Dr. pression of it by the activation of kappa-opioid system. Eur Hans Furuland), Karolinska Sjukhuset (Dr. Britta Hylander), Sophia- J Pharmacol 477: 29–35, 2003 hemmet (Dr. Ingela Fehrman-Ekholm, Dr. David Dunge), Huddinge 14. Togashi Y, Umeuchi H, Okano K, Ando N, Yoshizawa Y, Sjukhus, Huddinge (Dr. Peter Bara`ny), Huddinge Sjukhus, So¨der (Dr. Honda T, Kawamura K, Endoh T, Utsumi J, Kamei J, Alberto Gutierrez), Vrinnevi Sjukhus (Dr. Sven-Ingmar Deurell), Uni- Tanaka T, Nagase H: Antipruritic activity of the kappa- versitetssjukhuset i Linko¨ping (Dr. Martin Magnusson), Univer- opioid receptor agonist, TRK-820. Eur J Pharmacol 435: sitetssjukhuset MAS (Dr. Gunnar Sterner), Centralsjukhuset i Karlstad 259–264, 2002 (Dr. Lars Weiss), Universitetssjukhuset i O¨ rebro (Dr. Martin Tidman), 15. Cho YL, Liu HN, Huang TP, Tarng DC: Uremic pruritus: 6 Journal of the American Society of Nephrology J Am Soc Nephrol ●: ●●●–●●●, ●●●●

Roles of parathyroid hormone and substance P. J Am Acad Kishioka S, Woods JH, Naughton NN: Activation of kap- Dermatol 36: 538–543, 1997 pa-opioid receptors inhibits pruritus evoked by subcuta- 16. Whitehead A, Whitehead J: A general parametric approach neous or intrathecal administration of morphine in mon- to the meta-analysis of randomized clinical trials. Stat Med keys. J Pharmacol Exp Ther 305: 173–179, 2003 10: 1665–1677, 1991 22. Kumagai H, Saruta T, Matsukawa S, Utsumi J: Prospects 17. DerSimonian R, Laird N: Meta-analysis in clinical trials. for a novel kappa-opioid receptor agonist, TRK-820, in Control Clin Trials 7: 177–188, 1986 uremic pruritis. In: Itch, Basic Mechanisms and Therapy, 18. Bergstrom J, Alvestrand A, Bucht H, Gutierrez A: Progres- edited by Yosipovitch G, Greaves MW, Fleischer Jr AB, sion of chronic renal failure in man is retarded with more McGlone F, New York, Marcel Dekker Inc, 2004, pp frequent clinical follow-ups and better blood pressure con- 279–286 trol. Clin Nephrol 25: 1–6, 1986 23. Odou P, Azar R, Luyckx M, Brunet C, Dine T: A hypothesis 19. Schmelz M: A neural pathway for itch. Nat Neurosci 4: for endogenous opioid peptides in uraemic pruritus: Role 9–10, 2001 of enkephalin. Nephrol Dial Transplant 16: 1953–1954, 2001 20. Schmelz M: Itch—Mediators and mechanisms. J Dermatol 24. Pan ZZ, Tershner SA, Fields HL: Cellular mechanism for Sci 28: 91–96, 2002 anti-analgesic action of agonists of the kappa-opioid recep- 21. Ko MCH, Lee H, Song MS, Sobczyk-Kojiro K, Mosberg HI, tor. Nature 389: 382–385, 1997