A common dilemma faced by all animal bioethics committees arises when exceptions are proposed to the use of analgesics in painful procedures. The committee and researcher must weigh the possible confounding effects of including additional drugs (analgesics) in their treatment regimen against the moral obligation to perform humane research. Often neglected in these considerations are the potential confounding effects of unrelieved pain and consistency with pain-relieving practices in human medicine. In this review, we summarize what is currently known regarding the molecular and physiologic effects of pain and analgesics in common animal models used across several therapeutic areas. This work is intended to help provide guidance and assurance that a comprehensive approach has been taken when contemplating how pain relief will be applied in animal research protocols.