The concept of multimodal analgesia is the current trend for pain management. There is now evidence that both hyperalgesia after tissue injury and the development of opiate tolerance involve activation of the NMDA receptors and subsequent central sensitization . Combination analgesic chemotherapy besides targeting multiple analgesic pathways simultaneously , reduces the incidence of side effects by blocking the cascade of dysfunctional cellular regulation due to the release of neurotrophic factors . In this prospective , double blinded , randomized controlled clinical study we investigated the effect of two intrathecal NMDA receptor antagonists , magnesium and ketamine , in potentiating spinal ropivacaine fentanyl analgesia and their effect on the neurotrophic factors . Seventy five patients ASA І and ІІ male patients undergoing elective surgery below the umbilicus were randomly allocated to 3 equally sized groups . All groups received intrathecal 10 mg ropivacaine (1%) + 25 μg fentanyl citrate , with the addition of 50 mg preservative free magnesium sulphate to group І , 5 mg preservative free ketamine to group ІІ and 3 ml of preservative free 0.9% sodium chloride to group ІІІ . The addition of intrathecal magnesium sulphate (50mg) significantly prolonged the duration of spinal analgesia to 183 [29] minutes , (p<0.05%) , compared to 82 [7] minutes in the ketamine group and 70 [4] minutes in the placebo group . The mean values of postoperative plasma levels of nerve growth factor ( NGF ) and brain derived neurotrophic factor (BDNF ) showed a significant decrease both in the magnesium group ( 42 [19] ng/ml and 1707 [526] ng/ml respectively , p < 0.001 ) and the ketamine group ( 51 [28] ng/ml and 2467 [1132] ng/ml respectively , p < 0.001 ) compared to the placebo group ( 82 [36] ng/ml and 3413 [1106] ng/ml repectively , p < 0.001 ) , and to the preoperative values with no associated increase in side effects . There were no significant differences among the three groups as regards the onset time of sensory and motor block . There were no significant group difference in the median visual analogue score (VAS) except at 5 minutes , 10 minutes , 75 minutes and 90 minutes time interval , where it was significantly lower in the magnesium group compared to the ketamine and placebo group ( p < 0.001 ) . In Conclusion: In patients undergoing orthopaedic lower extremity surgery , the addition of intrathecal non-competitive NMDA receptor antagonists; magnesium sulphate (50mg) or ketamine (5mg) to spinal anaesthesia induced by ropivacaine (10mg 1%) and fentanyl (25μg) as a part of a combined spinal-epidural technique significantly prolonged the mean (SD) duration of analgesia in the magnesium group compared to ketamine and placebo groups with no associated increase in side effects . The mean values of postoperative plasma levels of NGF and BDNF showed a significant decrease in both the magnesium and ketamine group (p <0.001) compared to the control groups and to the preoperative values which correlated well with the duration of analgesia.