I've found Kayako's eSupport suite to be a nicely finished product that performs well with large volumes of tickets. Ofcourse, it is a bit on the expensive side but for a large scale setup it's preferred.

There's also WHMCS, which is gaining in popularity these days. You might want to check that out as well, it's more of a billing system but has a support system built in as well. It's also priced much lower than Kayako.