Abstract Background Long-term prescription of opioids by healthcare professionals has been linked to poor individual patient outcomes and high resource utilization. Supportive strategies in this population regarding acute healthcare settings may have substantial impact. Methods We performed a systematic review and meta-analysis of primary studies. The studies were included according to the following criteria: 1) age 18 and older; 2) long-term prescribed opioid therapy; 3) acute healthcare setting presentation from a complication of opioid therapy; 4) evaluating a supportive strategy; 5) comparing the effectiveness of different interventions; 6) addressing patient or healthcare related outcomes. We performed a qualitative analysis of supportive strategies identified. We pooled patient and system related outcome data for each supportive strategy. Results A total of 5664 studies were screened and 19 studies were included. A total of 9 broad categories of supportive strategies were identified. Meta-analysis was performed for the “supports for patients in pain” supportive strategy on two system-related outcomes using a ratio of means. The number of emergency department (ED) visits were significantly reduced for cohort studies (n = 6, 0.36, 95% CI [0.20–0.62], I² = 87%) and randomized controlled trials (RCTs) (n = 3, 0.71, 95% CI [0.61–0.82], I² = 0%). The number of opioid prescriptions at ED discharge was significantly reduced for RCTs (n = 3, 0.34, 95% CI [0.14–0.82], I² = 78%). Conclusion For patients presenting to acute healthcare settings with complications related to long-term opioid therapy, the intervention with the most robust data is “supports for patients in pain”.