Since both morphine and tadalafil have been proven to exert some of their analgesic activity through modulation of the NO-cGMP pathway, the aim of the current study is to evaluate the pharmacologic interaction between tadalafil and morphine in order to decrease the dose of morphine and subsequently its side effects. The assessment was carried out through isobolographic analysis relative to ED50s of both morphine and tadalafil obtained by tail-flick test on BALB/c mice. Morphine and tadalafil ED50s calculated from the dose-response curves were 8303 µg/kg and 2080 µ/kg, respectively. The experimental ED50 values of morphine and tadalafil in their mixture were 4800 µ/kg and 1210 µ/kg, respectively. Those results showed an additive interaction between morphine and tadalafil presented by a total fraction value for the mixture of 1160 µ/kg. This outcome can be interpreted by the fact that both drugs share common pathways namely, NO-cGMP and opioid receptors. As a conclusion, morphine and tadalafil combination showed an additive effect against acute pain, which is mediated through the central nervous system, thus providing a rationale for combining them in order to decrease morphine dose and thus minimizing its side effect.