Polytrauma patients often require medications to treat pain, treat agitation, and facilitate painful procedures. Though analgesia will be deferred in obtunded patients in profound shock, reduced-dose opioids or ketamine should be administered to unstable patients with severe pain with good mental status. Agitation commonly complicates polytrauma presentations, and is treated according to the danger it presents to patient and staff. Severe agitation can be effectively managed with dissociative-dose ketamine, which facilitates ongoing resuscitation, including CT. Severely painful procedures can be effectively facilitated by propofol or dissociative-dose ketamine, with continuous attention to ventilation and application of a step-by-step response to hypoventilation.