A reduction in opioid use may reduce the incidence and severity of opioid-related side effects. However, no published studies have demonstrated this relationship. In a prospective, placebo-controlled, randomized trial of analgesia for laparoscopic cholecystectomy, we validated an opioid-related symptom distress scale (SDS) questionnaire and clinically meaningful events (CMEs). A total of 193 patients completed the SDS questionnaire every 24 h after discharge for 7 days. This analysis was based on data from Day 1 only. The SDS assessed 12 common opioid-related symptoms, including nausea, vomiting, and difficulty passing urine, by 3 ordinal measures: frequency, severity, and bothersomeness. Patients with responses of "frequently" to "almost constantly," "moderate" to "very severe," or "quite a bit" to "very much bothered" were considered to have a CME. A detailed postoperative recovery survey of patient functional status and experience of adverse effects was used to validate the SDS. Validation measures in the recovery survey were categorized as nonspecific (e.g., level of normal activities) and specific (e.g., number of times vomited in 24 h, minutes of nausea in 24 h, and ability to void normally). SDS scores and CMEs for nausea, vomiting, and difficulty passing urine were strongly associated with three related validation measures from the recovery survey: minutes of nausea within 24 h, number of times vomited within 24 h, and ability to void normally, respectively (P < 0.0001). There was also a strong association between SDS scores and CMEs for nausea, vomiting, and voiding and general recovery validation measures, although the association was significantly weaker than that for symptom-specific validation measures. CMEs for nausea, vomiting, and voiding showed a high specificity and lower sensitivity with directly assessed responses. The SDS questionnaire and CMEs are valid tools for assessing postoperative opioid-related symptoms after laparoscopic cholecystectomy. Symptoms defined as CMEs through the SDS may be more sensitive than those identified by direct assessment.