Tramadol interaction with fluoxetine: An isobolographic analysis

Tramadol, a weak opioid agonist with effects on adrenergic and serotonergic neurotransmission, is used to treat conditions varying from postoperative to chronic malignant pain. Additionally, selective serotonin reuptake inhibitors (SSRIs) are used as adjuvants or prophylactics for the associated residual pain component. The present work evaluates, by isobolographic analysis, the interaction between a combination of racemic (±) tramadol, an opioid agonist, and fluoxetine, an SSRI, using a chemical analgesiometric test (abdominal writhing). Intraperitoneal administration of both tramadol (0.5–20 mg/kg) and fluoxetine (5–40 mg/kg) produced dose‐dependent antinociception. Co‐administration of fixed ratios of ED 50 fractions of fluoxetine and tramadol resulted in an additive effect. However, the least dose of fluoxetine (2.1 mg/kg) and tramadol (0.21 mg/kg) used in fixed ratios for antinociceptive effect individually showed antidepressant activity in a modified Porsolt forced swim test. The interaction studies in the writhing test suggested that such combinations might be devoid of any additional advantage over the individual drug regimen in acute cases of pain with co‐morbidity of depression. Further, the nature of interaction for such combinations in chronic pain models needs further assessment. Drug Dev. Res. 61:79‐85, 2004. © 2004 Wiley‐Liss, Inc.