ĸ-Opioid System in Uremic Pruritus J Am Soc Nephrol 16: 3742–3747, Bjorn Wikstrom,* Ryszard Gellert R1 이동영

Uremic pruritis Major impact on the quality of life Increase in morbidity and mortality Only current definitive treatment for uremic pruritus –successful renal transplantation µ-opioid receptor Stimulation: result in itching ĸ-Opioid stimulation: inhibits µ-receptor effects Nalfurafine, a new ĸ-opioid receptor agonist –effective in reducing the scratching behavior induced by an injection of substance P in the mouse model Uremic pruritus : triggered and sustained by the release of substance P This led to the studies : Using nalfurafine in the treatment of uremic pruritus

Materials and Methods

Study Design and Treatments At least 18 yr of age Undergoing routine hemodialysis Uncontrolled pruritus caused only by ESRD Normal hepatic function “Worst itching” visual analogue scale (VAS): – ≥ 8 of 14 times during a 1-wk run-in period At least 3 “worst itching” VAS measurements during the run-in period of 50 mm Average “worst itching” VAS of 25 mm

Parallel-group design Treatment for 4 wk Randomly assigned –Nalfurafine 5 g (n=26) –placebo (n=25) Thrice weekly by intravenous infusion Crossover design Randomly assigned 1:1 to receive for 2 wk –Nalfurafine 5 g –placebo Then crossed over to the other study medication for an 2 wk of therapy Study 1 Study 2

Check the severity of pruritus and the treatment effectiveness every 12 h during the run-in period and throughout the studies The primary end point: “worst itching” Secondary efficacy end points –Responders : Reduction at least 50% in “worst itching” VAS –Itching intensity: 5-point categorical scale : 1 (no itching) ~ 5 (intolerable itching) –Ability to sleep: 5-point categorical scale : 1 (no itching) ~ 5 (cannot sleep due to itching)

Itching intensity compared the efficacy of the study medication with run-in period –Three-point scale: Same, Better, Worse Number of excoriations on the body compared these values with those at run-in using –Three-point scale: Same, Better, Worse

Statistical Analyses The weighted analysis of “worst itching” VAS –study 1 period 1 study 2 –study 1 study 2 Re-categorized variables as follows: –1 : nondisturbing itching ( “0, no itching” or “1, tolerable without scratching”) –0 : disturbing itching ( categories 2 ~ 5 ) –1 : sound sleep ( “0, no itching “or “1, sound sleep with slight itch on retiring”) –0 : sleep disturbed ( categories 2 ~ 5 ) The sum of the re-categorized itching intensity or sleep disturbance variables : assessments of improvement in itching and excoriation and the proportion of responders

Results The reduction of the mean “worst itching” VAS :Naf - Placebo = Δ week Table 1 –Δ Week 2= = 10.6 –Δ Week 4= = 12.3 Table 2 –Δ period 1= = 6.9

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

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 + period 1 study 2

Table 4. Summary statistics of investigators’ assessment of excoriations: Study 1 + period 1 study 2a

Discussion µ-Opioid receptor agonists : elicit itching due to disinhibition of the central itch response as a result of their antinociceptive action ĸ-Agonists : block the itching through a central effect Substance P –another pruritogen, which induce scratching in mice, with and without mast cells –possible cause of antihistamine-resistant pruritus. –Nalfurafine has been shown to inhibit scratching in this model –This effect was reversed when ĸ-receptor antagonist was administered –the anti-pruritic effect of nalfurafine was mediated via the ĸ - receptor

The itch of uremic pruritus: imbalance of endogenous opioids hemodialysis patients – ß-endorphin / dynorphin A ↑ – this ratio increased with the severity of itching. ß-endorphin : µ-receptor agonist Dynorphin A : ĸ-receptor agonist This imbalance can result in overactivity of the µ-opioid receptor and induce pruritus Drug-related adverse events (ADR), –central nervous system: headache, vertigo, and insomnia –gastrointestinal system: nausea and vomiting