The United States is currently in the midst of an opioid epidemic that has led to previously unforeseen opioid misuse, abuse, and death. A major emphasis is being placed on reducing the exposure patients have to opioids, whenever possible, in an effort to hopefully reduce the risk of dependency, addiction, and overdose. However, opioid alternatives must be chosen carefully to ensure efficacy, safety, and availability for patients within the community. Non-opioid medications and modalities can reliably be used to treat not only opioid naive patients, keeping them opioid naive if possible, but also patients with opioid use disorders. Unfortunately, robust randomized controlled trials comparing non-opioid alternatives to opioids are lacking. Therefore, this review provides recommendations for best practices regarding improving pain management via the use of novel alternatives in the emergency department, medical wards and outpatient setting.