Population pharmacokinetic (PK) and pharmacokinetic- pharmacodynamic (PK-PD) models were used to quantify the exposure-response (E-R) relationship between nalbuphine exposure and 2 widely used rating scales for itch: the Numerical Rating Scale for the subject’s ‘average’ itch experience (NRS-AV) and the Worst Itch (WI-NRS), with 24-hour recall. Simulations based on the model E-R relationship were used to support dose selection for future clinical investigations and were evaluated with a target of reducing the 7-day average of the 24-hour WI-NRS by at least 30% from baseline in the majority of the analysis population. Data from two clinical trials (NCT02373215: 9 healthy subjects; NCT02174419: 62 subjects with PN), in patients with Prurigo Nodularis (PN) with moderate to severe itch who received treatment with either of 2 doses of Nalbuphine ER versus placebo, were used for the analysis. A two-compartment PK model with serial zero and first-order oral absorption was used to describe drug exposure. A sigmoidal maximum effect (Emax) model with a placebo effect was used to model the itch response endpoints (NRS-AV, WI-NRS). The PK/PD model adequately predicted the exposure-related reduction in both NRS-AV and WI-NRS over time with approximately 63% and 27% of Emax, respectively. Exposures associated with 80% of Emax were achieved in about 78% of the patients at 162 mg BID compared to 35% at 81 mg BID. Simulated dose-response indicated that 108 and 162 mg BID doses result in the highest proportion of patients achieving at least a 30% reduction in NRS-AV and WI-NRS, respectively.