Introduction
Spine surgery is considered one of the most painful surgeries, often necessitating increased and prolonged postoperative analgesic use [1]. While opioids remain highly effective for pain management, their use is associated with numerous significant adverse effects, including nausea, vomiting, constipation, respiratory depression, opioid-induced hyperalgesia, and addiction [2,3]. Moreover, prescription opioids are often cited as a major contributor to the ongoing opioid epidemic in the United States [4]. Therefore, considerable efforts have been undertaken to minimize the perioperative use of opioids.
Although intraoperative pain management has traditionally relied on opioid administration, multimodal analgesic approaches have emerged as effective alternatives to reduce or even eliminate opioid use. These approaches incorporate commonly used medications such as acetaminophen and non-steroidal anti-inflammatory drugs, along with gabapentinoids, antidepressants, muscle relaxants, and regional anesthesia techniques, including nerve blocks [3]. Opioid-sparing anesthesia aims to optimize pain control while minimizing opioid use, reserving opioids for breakthrough pain as needed. In contrast, opioid-free anesthesia (OFA) refers to anesthetic management that completely omits the use of opioids. In spine surgery, spinal anesthesia theoretically offers several advantages over general anesthesia, including greater efficacy, lower cost, improved safety, and better postoperative cognitive outcomes [5]. When feasible, completely avoiding opioids may enhance postoperative recovery; however, inadequate pain control can significantly hinder recovery. Therefore, the risks and benefits of OFA must be carefully evaluated on an individual basis.
In a literature review, Taylor et al. [5] reported a reduction in postoperative complications with opioid-sparing techniques in spine surgery; however, the findings on pain control were inconclusive. Similarly, a meta-analysis by Feenstra et al. [6] evaluating OFA found the existing literature to be inconclusive, and notably, spine surgery was not analyzed as a separate subgroup. To our knowledge, no systematic review of randomized controlled trials (RCTs) has specifically evaluated the effects of completely opioid-free analgesia in spine surgery. A 2023 systematic review and meta-analysis published in the European Spine Journal examined opioid-free analgesia; however, this study permitted a dose of short-acting opioids during induction in the so-called opioid-free group [7]. Therefore, the present systematic review and meta-analysis of RCTs aimed to compare pain control and complications between opioid-free and opioid-based anesthesia in spine surgery.
Materials and Methods
Prior to the formal literature search, this systematic review and meta-analysis was registered in the Prospero database (ID: CRD42024578723) in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines [8]. The only deviation from the original Prospero protocol was the inclusion of multimodal OFA, rather than limiting the analysis to strictly unimodal non-opioid anesthesia, due to insufficient numbers of RCTs focused solely on unimodal non-opioid anesthesia. A systematic search of PubMed, Web of Science, and Embase was conducted on January 1, 2025, without restriction on the start date. Key words used in the search included “opioid-free,” “regional anesthesia,” and “spine surgery.” The detailed search strategies for each database are provided in Supplement 1.
Studies were included if they met the following criteria: (1) RCTs, (2) comparison of opioid-based versus OFA, (3) spine surgery patient population, (4) inclusion of multimodal analgesic approaches, and (5) reporting of postoperative outcomes. Exclusion criteria included cohort studies, case-control studies, case reports, literature reviews, systematic reviews, meta-analyses, cadaver and animal studies, non-full-text manuscripts, non-English publications, studies involving opioid-sparing anesthesia, and procedures unrelated to spine surgery. Although opioid-sparing anesthesia aims to reduce overall opioid consumption, it does not permit a direct comparison between opioid-based and completely OFA, and was therefore excluded.
Studies identified through the initial search were imported into Covidence and de-duplicated. Two reviewers independently screened titles and abstracts, followed by full-text screening based on the pre-defined eligibility criteria. Any discrepancies were resolved through discussion between the reviewers. Data extraction was performed by one reviewer and then confirmed by the second reviewer.
Continuous data were reported as mean and standard deviation, while categorical data were summarized as frequencies and proportions. Reported outcomes included patient-reported pain scores (Numerical Rating Scale [NRS] and Visual Analog Scale [VAS]), patient-reported pain-free period, requirement for rescue analgesia, total postoperative opioid consumption, and incidence of postoperative nausea/vomiting (PONV). Data reported as median and interquartile range were converted to mean and standard deviation using established statistical methods described in the literature [9]. Postoperative opioid consumption presented in terms of intravenous (IV) fentanyl was converted to oral morphine equivalents based on standard conversion ratios [10].
Statistical analysis was performed using RevMan web (https://revman.cochrane.org). Interstudy heterogeneity was assessed using the Higgins and Thompson I2 statistic. Continuous variables were pooled as mean differences (MDs) and confidence intervals (CIs), while categorical variables were pooled as risk ratios (RRs) and CIs. The fixed effect and random effects models were applied depending on the characteristics of the outcomes, such as the number of studies, sample sizes, and heterogeneity amongst studies [11].
Sensitivity analysis was performed using the leave-one-out method, which entails repeating the pooled analysis after sequential exclusion of one study at a time. This approach was employed to identify potential outliers and to assess the robustness and reliability of the overall analysis.
Risk of bias assessment was conducted using the Cochrane Risk of Bias 2 (RoB 2) tool (Cochrane, London, UK) [12]. The assessment was initially performed by one reviewer and independently verified by a second reviewer to ensure accuracy and consensus.
Results
Study selection
A total of 3,065 studies were identified through the initial database search. After the removal of 1,689 duplicates, 1,376 records underwent title and abstract screening. Of these, 54 full-text articles were assessed for eligibility (Supplement 2). Ultimately, eight RCTs met the inclusion criteria and were included in this review [13–20] (Table 1).
Surgeries
Of the included studies, two specifically evaluated cervical spine procedures—either anterior cervical discectomy and fusion (ACDF) or anterior cervical discectomy and arthroplasty [14,16]. Three studies focused exclusively on lumbar spine surgeries, including laminectomy or discectomy procedures [18–20]. The remaining three studies examined thoracolumbar surgeries: one evaluated 1–2 level posterior thoracolumbar fusion, one investigated surgical correction of adolescent idiopathic scoliosis, and one included a broader cohort undergoing various thoracolumbar surgeries [15,17,21].
Postoperative pain levels (VAS)
Three studies compared postoperative pain levels using the VAS in the post-anesthesia care unit (PACU) (Fig. 2) [17–19]. Pooled analysis demonstrated that the opioid-free group had lower VAS scores in the PACU (MD, −18.22; 95% CI, −63.41 to 26.97; p=0.08) than the opioid-based group, although the difference was not statistically significant. Only two of the three studies demonstrated effects in the same direction, contributing to a high heterogeneity (I2=100%). Sensitivity analysis using the leave-one-out method did not demonstrate robustness; removal of either Jellish et al. [18] in 1996 or Kamel et al. [17] in 2024 continued to yield non-significant results (Supplement 3).
Rescue analgesia usage
Two RCTs compared the percentage of patients requiring rescue analgesia in the postoperative period (Fig. 3) [19,20]. Pooled analysis demonstrated that the opioid-free group had a significantly lower risk of rescue analgesia usage in the PACU compared to the opioid-based group (RR, 0.34; 95% CI, 0.20 to 0.56; p<0.00001). At 24 hours postoperatively, the opioid-free group showed a lower risk of rescue analgesia use (RR, 1.06; 95% CI, 0.81 to 1.40; p=0.30), although the difference was not statistically significant. Heterogeneity was low for PACU data, and sensitivity analysis confirmed robustness of the findings. However, the 24-hour results were not robust, as exclusion of either study did not consistently favor either the opioid-free or opioid-based group (Supplement 4).
Postoperative pain-free period
Three RCTs compared the duration of the postoperative pain-free period between groups (Fig. 4) [15,17,18]. Pooled analysis showed that the opioid-free group experienced a significantly longer pain-free period compared to the opioid-based group (MD, 3.36 hours; 95% CI, −3.05 to 9.78; p=0.02). Although all three studies demonstrated effects in the same direction, variation in the magnitude of effect led to high heterogeneity (I2=98%). Moreover, sensitivity analysis revealed that the significance of the pooled result was dependent on the inclusion of Rani et al. [14] (2024); its removal led to loss of statistical significance between the two treatment groups (Supplement 5).
Postoperative pain (NRS)
Three RCTs compared postoperative pain levels at 24 hours using the NRS (Fig. 5) [15,16,21]. Pooled analysis demonstrated that the opioid-free group reported significantly lower NRS scores compared to the opioid-based group (MD, −0.79; 95% CI, −1.26 to −0.32; p=0.001). Heterogeneity was low, and sensitivity analysis confirmed the robustness of these findings (Supplement 6).
Total rescue analgesia consumption
Two studies compared total postoperative rescue analgesia consumption within the first 48 hours (Fig. 6) [15,21]. Pooled analysis demonstrated that the opioid-free group required significantly less rescue analgesia than the opioid-based group (MD, −4.28 mg morphine; 95% CI, −6.72 to −1.83; p=0.0006). Heterogeneity was low, and sensitivity analysis confirmed the robustness of the results (Supplement 7).
Postoperative nausea/vomiting
Five RCTs compared the incidence of PONV (Fig. 7) [14,17,19–21]. Pooled analysis demonstrated that the opioid-free group had a significantly lower risk of PONV compared to the opioid-based group (RR, 0.56; 95% CI, 0.46 to 0.69; p<0.00001). Heterogeneity was low, and sensitivity analysis confirmed the robustness of these findings (Supplement 8).
Discussion
Despite growing evidence on the side effects of opioids, eliminating them from perioperative use remains challenging due to persistent concerns about inadequate pain relief. However, this meta-analysis of RCTs demonstrates that OFA yields outcomes that are comparable or superior to those of opioid-based anesthesia across most measured endpoints. Patients in the opioid-free groups experienced significantly lower pain scores, longer pain-free periods, reduced incidence of PONV, lower frequency of rescue analgesia in the PACU, and reduced total rescue analgesia postoperatively. Although VAS scores were lower in the opioid-free group, the difference did not reach statistical significance. Notably, the only outcome without a clear advantage was the likelihood of requiring rescue analgesia within 24 hours postoperatively, which was similar in the two groups. These findings may be attributed to the well-documented adverse effects of opioids, including opioid-induced hyperalgesia, nausea, and vomiting [2,3]. Additionally, the growing sophistication and efficacy of multimodal non-opioid analgesic regimens likely contributed to the favorable outcomes observed in the opioid-free cohorts.
Pain and rescue analgesia
Opioids have historically been an integral part of comprehensive pain management. The World Health Organization analgesic ladder, widely adopted as the standard of care for managing cancer-related pain, recommends the initiation of opioid therapy for moderate pain, typically defined as a 4/10 pain score on the NRS [22]. However, even this long-standing framework has come under scrutiny. As advancements in cancer therapy have transformed many terminal cancers into chronic, manageable conditions, there is increasing interest in minimizing opioid use through multimodal approaches [23].
Evidence from cohort studies and retrospective reviews has shown that opioid-free management can be non-inferior to opioid-based management in certain surgical procedures, such as ear, nose, and throat surgeries [24]. A systematic review and meta-analysis of thoracic surgery further demonstrated that OFA was superior to opioid-inclusive anesthesia [25]. Similarly, a meta-analysis of RCTs on bariatric surgery found that OFA was associated with lower pain scores, although postoperative opioid consumption remained equivalent between groups [26]. The findings of the present meta-analysis in certain spine surgeries are consistent with this growing body of literature, suggesting that OFA may offer comparable or improved clinical outcomes across a range of surgical specialties. There is growing interest in minimizing opioid use across a wide variety of surgical populations, and these results are encouraging and support a broader adoption of OFA in clinical practice.
Nausea and vomiting
PONV can prolong hospital stay and increase costs, along with the risk of serious complications such as aspiration, dehydration, electrolyte disturbances, and wound disruption [27,28]. Opioid use is a well-established risk factor for PONV [2], which helps explain the significantly lower incidence observed in the OFA group in this meta-analysis. Similar reductions in PONV have been reported in other surgical contexts, including bariatric surgery and intermediate to major non-cardiac surgeries [26,29]. Reducing opioids should help reduce the risk of PONV in patients undergoing spine surgery as well.
Opioid-free versus opioid sparing
While this meta-analysis focused strictly on OFA, there may be a significant role for opioid-sparing regimens. These approaches could potentially minimize the side effects of opioids while preserving their analgesic benefits. However, when possible, OFA may remain the ideal goal. In an RCT of colorectal oncologic surgery comparing opioid-based, opioid-sparing, and OFA, the opioid-free group demonstrated the most favorable outcomes [30].
Practice and policy
Current clinical practice guidelines state that opioids can be used to treat acute pain (lasting less than 1 month) following severe trauma or invasive surgeries, but only when the potential benefits outweigh the associated risks [4]. The guidelines also recommend that for less severe conditions, such as low back pain or dental pain, the usage of non-opioid alternatives should be maximized before considering opioids. These findings suggest that the scope of conditions managed with first-line non-opioid therapies could be expanded to include invasive spine surgeries.
In parallel, multiple laws and policy initiatives have been enacted to limit opioid prescribing and dispensing. One such example is the NOPAIN Act, signed into law in 2022, which encourages physicians to prescribe non-opioid alternatives to reduce prescription opioid misuse [31]. The results of this study may further support such policies by demonstrating that opioids may not be necessary during anesthesia for spine surgery.
Limitations and future directions
This study is limited by the scope and quality of the existing literature. Only eight RCTs met the inclusion criteria, and the small number of studies limits the overall robustness of the results. Furthermore, many of these studies looked at different outcomes. For several outcomes—particularly at defined postoperative time points—only two or three RCTs contributed data. There was also some redundancy in outcome measures, such as the use of both NRS and VAS for pain scoring. Furthermore, most of the included RCTs focused on less invasive spinal procedures, such as ACDFs, single-level lumbar fusion, or laminectomy. These procedures typically require less intensive postoperative analgesia compared to more invasive multi-level spinal fusions, which limits the generalizability of the results to more complex procedures. Future research should include larger, high-quality RCTs that assess a broader range of outcomes across multiple postoperative time points, especially in the context of more extensive spinal procedures. Additionally, an interesting area for further investigation would be a direct comparison of opioid-free versus opioid-sparing anesthesia in spine surgery. This could help determine whether opioid-sparing approaches offer a favorable balance between maintaining analgesic efficacy and reducing opioid-related adverse effects.
Conclusions
OFA appears to be highly effective in certain spine surgeries, demonstrating potentially superior or equivalent outcomes compared to opioid-based anesthesia. While additional studies—particularly involving more invasive spinal procedures—are needed to strengthen the generalizability of these findings, current evidence supports the use of OFA in appropriate clinical contexts. Future studies should compare OFA to opioid-sparing strategies in patients undergoing spine surgery.
Key Points
Opioid-free anesthesia (OFA) is a potential alternative to opioid-based anesthesia to reduce opioid-related adverse effects such as respiratory depression, hyperalgesia, and addiction.
This systematic review suggests that OFA may provide comparable or better postoperative pain control and reduce the need for rescue analgesia.
OFA is associated with lower rates of postoperative nausea and vomiting.
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