Acute or chronic pain is a major source of impairment in quality of life and affects a substantial part of the population. To date, pain is alleviated by a limited range of treatments with significant toxicity, increased risk of misuse and inconsistent efficacy, owing, in part, to lack of specificity and/or unfavorable pharmacokinetic properties. Thanks to the unique properties of nanoscaled drug carriers, nanomedicine may enhance drug biodistribution and targeting, thus contributing to improved bioavailability and lower off-target toxicity. After a brief overview of the current situation and the main critical issues regarding pain alleviation, this review will examine the most advanced approaches using nanomedicine of each drug class, from the preclinical stage to approved nanomedicines.