Opioids remain the most common analgesic tool for the surgeon, owing to their cost-effectiveness in both the inpatient and outpatient setting. Aside from these attributes, opioids have significant side effects that are associated with morbidity and mortality. Specifically, obese patients, patients with sleep apnea, and the elderly may be at an increased risk of experiencing sedation and respiratory depression in response to opioids. Opioid reduction strategies prove useful for decreasing total opioid dose and, in turn, their associated adverse effects. Such strategies may include adjuvant nonopioid analgesics such as α-2 agonists, gabapentinoids, and N-methyl-D-aspartate receptor agonists as well as local, regional, or neuraxial anesthesia and modification of surgical technique where possible for operative patients. Patients may also present to surgeons while taking chronic opioids, including high-dose opioids and opioid agonist/antagonists. These clinical scenarios are associated with extreme challenges in postoperative analgesic management. With all opioid prescribing, other sedative medications should be limited or avoided as the risk for additive sedation is significant. This review aims to describe systematic methods to reduce opioid side effects and identify specific risk-reduction strategies within each risk group.