Lower back pain is one of the leading causes of disability in the world. The aim of this study was to evaluate the effect of supplementation of dexmedetomidine and neostigmine with lidocaine 1.5% and triamcinolone for epidural block in increasing the duration of analgesia among patients suffering from chronic low back pain. In this double-blind, randomized clinical trial, 33 patients with chronic low back pain were included in three groups of 11 patients for epidural blockage. Triamcinolone (40 mg/ml) was added to lidocaine 1.5% solution (2 cc/segment) for all three groups. In group N, neostigmine was used at a dose of 1 mg (mg), followed by group D (dexmedetomidine 35 μg [0.5 μg/kg]), and grou [ND (neostigmine 0.5 mg, and 35 μg dexmedetomidine, all of which were added to the triamcinolone and lidocaine solution in each group. Medications were injected into the epidural space using an interlaminar approach. Subsequently, scores of pain and duration of analgesia were recorded in questionnaires and analysed using SPSS version 23. One month after the injections, pain scores recorded in the N group were 7.6±1.4, followed by 5.88±1.2 in group D and 5.42 ±1.1 in group ND. Therefore, the pain scores were significantly higher in the neostigmine group than the other two groups (p = 0.02), but no significant difference was found between the two groups that received dexmedetomidine and a combination of dexmedetomidine + neostigmine. Three months after the injections, there was a significant difference in pain scores between the two groups (P = 0.01). Both neostigmine and dexmedetomidine were capable of reducing the pain of patients with chronic low back pain after epidural block. However, neostigmine’s impact is lower compared to dexmedetomidine. The combination of the two drugs also reduced the pain scores of the patients after the intervention.