Background Dealing with the opioid crisis, medical doctors are keen to learn how to best treat opioid dependency in patients with chronic non-cancer pain. Opioid replacement therapy is commonly used, but success rates vary widely. Since many patients still experience severe withdrawal symptoms, additional interventions are necessary. Objective To review the effectiveness of interventions in the treatment of withdrawal symptoms during opioid tapering or acute withdrawal in patients with long-term non-cancer pain. Methods A systematic review was conducted in Embase.com, MEDLINE, Web of Science, PsycINFO, and Cochrane CENTRAL register of trials. Studies eligible for inclusion were (non-)randomized controlled trials in adults with long-term opioid prescriptions for non-cancer pain. Included trials had to compare a non-opioid intervention to placebo, usual care, no treatment, or non-opioid drug and had to report on withdrawal symptoms as an outcome. Study quality was assessed with the 2.0 Cochrane risk of bias (RoB) tool. Evidence quality was rated following the GRADE approach. Results One trial (n = 21, some concerns regarding RoB) compared Varenicline to placebo. There was no statistically significant between-group reduction of withdrawal symptoms (moderate-quality evidence). Conclusions Evidence from clinical trials on interventions reducing withdrawal symptoms is scarce. Based on one trial with a small sample size, no firm conclusion can be drawn. Meanwhile, doctors are in dire need for therapeutic options to tackle withdrawal symptoms while tapering patients with prescription opioid dependence. We hope this review draws attention to this unfortunate research gap so that future research can provide doctors with answers.