Background: The indications for initiating long-term opioid treatment (L-TOT) for chronic non-cancer pain (CNCP) are often unclear and associated with problematic use. This study aimed at evaluating the efficacy of stabilizing opioid therapy followed by a sequential opioid tapering off program in CNCP patients. Methods: A randomized clinical trial with a medications stabilization period (Phase 1) was followed by an opioid tapering off program (Phase 2). In Phase 2, patients were randomized to Control Group (stable treatment) or Taper off Group (sequential opioid dose reduction) and assessed at baseline, after stabilization and up to 6 months. Primary outcomes: measures of cognitive function; secondary outcomes: pain, sleep, rest, quality of life, depression, anxiety, opioid misuse and opioid withdrawal symptoms. Results: In all, 274 patients were screened; 75 were included, out of which 40 dropped out before Phase 2. Those who succeeded Phase 1 (n = 35) had weak/moderate improvements of psychomotor function (p = 0.020), sleeping hours (p = 0.031), opioid withdrawal symptoms (p = 0.019), measures of quality of life (p ≤ 0.043) and opioid misuse scores (p = 0.003). In Phase 2, patients in Taper off Group (n = 15) experienced stable pain intensity and felt significantly more rested at third assessment than the Control Group (n = 20). Conclusions: The opioid tapering off program was not successful due to the vast number of dropouts. Phase 1 was associated with weak to moderate improvements on psychomotor function, sleeping, opioid withdrawal symptoms, quality of life and reduced risk of opioid misuse. In the intervention group of Phase 2, pain intensity was stable and patients felt more rested. Significance: This trial showed that sequential tapering off L-TOT in CNCP patients may be an unfeasible approach. However, improvements after opioid treatment stabilization were achieved and stable pain intensity in those tapered off may encourage the development of more refined programs.