nalbuphine and Kidney-Failure--Chronic

End-stage renal disease chronic itch is a frequent symptom that bothers patients with advanced stages of chronic kidney disease. The pathogenesis of the chronic itch symptom is complex and not yet fully understood and includes many metabolic, immunologic, and neurogenic factors. A significant burden of the disease results in decreased quality of life with sleep impairment, depressive symptoms, and increased mortality of affected individuals. No treatment of choice is available; topical therapy (emollients), phototherapy (UV-B), and systemic therapy (antiepileptics, opioid agonists, and antagonists) provide significant relief in varying percentages of patients.

Topics: Amines; Analgesics, Opioid; Anticonvulsants; Antipruritics; Chronic Disease; Cyclohexanecarboxylic Acids; Emollients; Gabapentin; gamma-Aminobutyric Acid; Humans; Kidney Failure, Chronic; Nalbuphine; Narcotic Antagonists; Pregabalin; Pruritus; Quality of Life; Renal Dialysis; Severity of Illness Index; Ultraviolet Therapy

Uremic pruritus is a common and deleterious condition among hemodialysis (HD) patients. Central gating of μ/κ opiate circuitry plays an important role in mediating and countering pruritogenic sensation. The objective of this study was to assess the safety and pharmacokinetics (PK) of the mixed μ-antagonist/κ-agonist nalbuphine, administered orally as nalbuphine HCl extended release (ER) tablets in HD patients, and explore its effect on pruritus.. In this open-label multiple escalating dose study, 15 HD patients with pruritus and 9 matched healthy subjects were enrolled. Nalbuphine HCl ER dose was escalated from 30 mg QD to 240 mg BID over 15 days. A full PK profile was obtained under dialysis and non-dialysis conditions as a function of dose. Clearance during dialysis was determined by sampling dialysate and arterial/venous blood during dialysis. Pruritus severity was assessed twice daily using a Visual Analog Scale (VAS). Safety monitoring included extensive monitoring of EKG, blood pressure, and pulse oximetry.. In HD patients, nalbuphine concentration peaked within 4-9 hours and attained steady state within 2-3 days, with no significant accumulation. Mean half-life was 14.2 hours, mean Cmax and AUCtau ranged between 13 and 83 ng/mL and 118 and 761 ng∙h/mL, respectively, with exposure increasing in a nearly dose-proportional fashion. Exposure in HD patients was about 2-fold higher than in healthy subjects. There was no meaningful difference between exposure on dialysis and non-dialysis days with 1% or less of the dose removed by dialysis. Nalbuphine suppressed itch in a dose-dependent manner, reducing mean VAS score from 4.0 to 1.2 at 180 mg and 0.4 at 240 mg.. Nalbuphine HCl ER tablets can be safely administered to HD patients without dose adjustment up to 240 mg BID and may hold promise in treating uremic pruritus.

Topics: Administration, Oral; Adult; Aged; Analysis of Variance; Area Under Curve; Case-Control Studies; Delayed-Action Preparations; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nalbuphine; Patient Safety; Pruritus; Reference Values; Renal Dialysis; Risk Assessment; Severity of Illness Index; Treatment Outcome; Visual Analog Scale