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The present study explored efficient and exclusive analgesic effects of iboga-analogs in formalin-induced mouse via acute pain model. Novel iboga derivatives namely iboga-alcohol, iboga-amide, iboga-methylamide and iboga ester-exo were administered intraperitoneally to evaluate the anti-nociceptive, anti-inflammatory and neuromodulatory effects. Pain assessment was done by paw diameter, paw licking and tail immersion tests. Locomotor activity and anxiety-like behavior were determined by open field test and elevated plus maze. Inflammatory mediators, neurotransmitters and neurotrophic factors were measured from isolated serum, paw tissue and spinal segment. Iboga-analogs significantly reduced paw diameters. Decreased tail flick latency reversed in iboga-alcohol and methyl-amide particularly. Restricted locomotion was also significantly reversed in iboga-alcohol, iboga-amide, and iboga-methyl amide. Anxiolytic behaviour was obtained in the iboga-alcohol, iboga-amide and methyl-amide treated groups. Paw Substance P, CGRP, COX-2 and p65 nuclear translocation; serum IL-6 & TNF-α levels were significantly decreased in the iboga-alcohol treated group. Iboga-alcohol reversed the downregulation of GABA, Dopamine, and elevation of Substance P, NK1R and Glutamate. HRMS analysis confirmed the passage of all iboga-analogs in the brain. Iboga-analogs overturned the depleted BDNF whereas, GDNF elevation was further exaggerated. Taken together, these novel iboga-analogs, particularly iboga-alcohol, executed effective anti-nociception and prevented neuroinflammation. They warrant further clinical applications in acute pain situations.