<p>Older adults are at increased risk of loneliness, social isolation and use of analgesics such as over-the-counter (OTC) medications and opioids. While evidence suggest that loneliness and social isolation may influence patterns of pain medication use, longitudinal studies remain limited. Data from the Health and Retirement Study (2014–2022) were analysed for 9,454 US adults aged 50+. Continuous-time multistate Markov models examined how social isolation and loneliness were associated with the likelihood of transitioning between states of medication use, non-use, and death whilst controlling for sociodemographic and health-related factors. Loneliness was associated with higher risks of initiating both opioids (HR = 1.19, 95%CI: 1.03–1.37) and OTC (HR = 1.12, 95%CI: 1.01–1.25). Conversely, social isolation was not associated with transitions into opioid use, but it was associated with a reduced likelihood of initiating OTC medication (HR = 0.85, 95%CI: 0.77–0.95). Neither factor was associated with medication discontinuation. Loneliness and social isolation are thus differentially related to pain medication transitions in older adults; whereas loneliness may contribute to increased likelihood of initiating medication use, social isolation relates to lower OTC uptake. These findings highlight the need to consider subjective and objective social connection as critical components of safer pain management in older adults.</p>