if you place your code that calls the popup in a function the you can set the onblur event of the field. This will fire your code when oever the focus is lost on your field.
crmForm.all.yourField.onblur = yourfunction;
You could use the JavaScript attachEvent method instead but there is nothing on onblur I'm pretty sure anyway so you shouldn't be overwriting existing events.
crmForm.all.yourField.attachEvent('onblur', yourfunction);
You could place some code in yourFunciton to check if the value has changed and only run if it has.
if(crmForm.all.yourField.DataValue != crmForm.all.yourField.DefaultValue){
// Load your popup
}
MSCRM Bing'd -
http://bingsoft.wordpress.com