Background: Histamine-1 (H1) antihistamines are widely used for the treatment of allergic diseases. These drugs have a similar aromatic ring and amine structure with that of local anesthetics, and proved having a prominent sodium channel blocking activity. Therefore, we performed a dose-response study to test the local analgesic effects ofH1 antihistamines in a rat model. Material and methods: In study 1, eight H1 antihistamines were subcutaneous injected to the shaved dorsal skin to screen the local analgesic effect in S.D. rats (6 rats in each group). The inhibition of the cutaneous trunci muscle reflex to pinpricks with No. 15 Von Frey filament was quantitatively evaluated. No response to six pinpricks was defined as 100% maximum possible effect. Two of the most potent H1 antihistamines were then chosen in study 2 for further dose-response studies, and compared with two clinically used local anesthetics: lidocaine and bupivacaine. Moreover, in study 3, we compared the antinociceptive duration of test drugs at ED25、ED50 and ED75 doses. Result: On an equimolar basis, we found doxylamine and pheniramine possessed potent local analgesic effect. The rank of potency was as following rank: bupivacaine > doxylamine ≒ lidocaine > pheniramine. The ranking of anesthetic durations were: doxylamine > pheniramine ≒ bupivacaine > lidocaine Conclusion: Both doxylamine and pheniramine are potent infiltrative analgesics. The potencies are weaker than that of bupivacaine but similar to that of lidocaine. Moreover, doxylamine had a long duration of drug effect.