Background: The opioid epidemic is at epic proportions currently in the United States. Exposure to opioids for surgery and subsequent postoperative pain management is a known risk factor for opioid dependence. In addition, opioids can have a negative impact on multiple aspects including clinical outcomes, length of hospital stay, and overall cost of care. Thus, the greatest effort to reduce perioperative opioid use is necessary and a multimodal pain control (MMPC) has been gaining popularity. However, its efficacy in spine surgery is not well known. We aimed to evaluate the efficacy of a MMPC protocol in patients undergoing lumbar single-level anterior lumbar interbody fusion (ALIF)., Methods: This is a retrospective comparative study. From a prospective, single-surgeon, surgical database, consecutive patients undergoing single-level ALIF with or without subsequent posterior fusion for degenerative lumbar conditions were identified before and after initiation of the MMPC protocol. The MMPC protocol consisted of a preoperative oral regimen of cyclobenzaprine (10 mg), gabapentin (600 mg), acetaminophen (1 g), and methadone (10 mg). Postoperatively they received a bilateral transverse abdominis plane block with 0.5% Ropivacaine prior to extubation. We compared in-hospital opioid consumption between the MMPC and non-MMPC cohorts as well as baseline demographic, the length of hospital stay, cost, and rate of postoperative ileus. Opioid consumption was calculated and normalized to the morphine milligram equivalents (MMEs)., Results: In total, 68 patients in the MMPC cohort and 39 in the non-MMPC cohort were identified. There was no difference in baseline demographics including sex, body mass index, smoking status, or preoperative opioid use between the two groups. Although there was no difference in the MMEs on the day of surgery (58.5 vs. 66.9, P=0.387), cumulative MMEs each day after surgery was significantly lower in the MMPC cohort, with final cumulative MMEs being reduced by 62% (120.2 vs. 314.8, P<0.001). There was no difference in postoperative ileus, length of stay, and hospital costs., Conclusions: The use of a MMPC protocol in patients undergoing single-level ALIF for degenerative conditions reduced opioid consumption starting on the first day after surgery, resulting in a cumulative reduction of 62%., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/jss-20-629). Dr. JLG reports personal fees from Acuity, personal fees from Medtronic, personal fees from DePuy, personal fees from Alphatec, from Stryker, from Acuity, from K2M, from NuVasive, personal fees from Pfizer, outside the submitted work; Dr. CHC 3rd reports personal fees from Alphatec, personal fees from Medtronic, personal fees from NuVasive, personal fees from Alphatec, personal fees from Medtronic, personal fees from Titan, personal fees from SRS Committee, personal fees from NASS Committee, outside the submitted work; Dr. MD reports personal fees from Medtronic, personal fees from NuVasive, outside the submitted work; Dr. RKO 2nd reports personal fees from Medtronic, personal fees from NuVasive, grants from Pfizer, grants from Texas Scottish Rite Hospital, grants from Alan L. & Jacqueline B. Stuart Spine Research, grants from Cerapedics, grants from SRS, grants from Medtronic, grants from OREF, grants from ISSG, outside the submitted work; Dr. JRD 2nd reports personal fees from Medtronic, personal fees from DePuy, other from Federation Of Spine Association, other from SRS, personal fees from Pfizer, outside the submitted work; Dr. SDG reports personal fees from Medtronic, outside the submitted work; Dr. LYC reports personal fees from AO spine, personal fees from Center for Spine Surgery and Research of the University of Southern Denmark, personal fees from University of Louisville Institutional Review Board, grants from Scoliosis Research Society Research, grants from Orthopedic Educational Research Fund, grants from Integra, grants from Pfizer, personal fees from Pfizer, outside the submitted work. The other authors have no conflicts of interest to declare., (2020 Journal of Spine Surgery. All rights reserved.)