Clinical benefits of ketorolac in adults undergoing lumbar spinal surgery

Ketorolac, whether used alone or with other analgesics, markedly lessens postoperative pain and opioid use after lumbar spinal surgery without substantially increasing nausea or vomiting. However, its impact on hospital stay is modest.

Lumbar degenerative diseases (like spinal stenosis and disc herniation) often elicit severe compression of the lumbar nerve roots, causing substantial radicular pain. In case of serious symptoms, surgical treatments (like fusion surgery and minimally invasive decompression) are sometimes imperative. But, they are associated with post-surgical issues, including back pain and radicular pain. Such pain may arise from muscle ischemia, muscle dissection, or injury to spinal nerve branches during surgery. Poor pain management can hinder early postoperative mobility and recovery. It can also escalate the likelihood of complexities such as chronic spinal pain syndrome and lower limb venous thrombosis.

Current postoperative pain management often relies heavily on opioids, which are effective in relieving pain. However, their use is linked with detrimental effects, including nausea, vomiting, and the likelihood of sustained dependence. The overuse of opioids poses a growing public health issue, particularly amid the ongoing opioid crisis. Research indicates that opioid use for acute post-surgical distress can inadvertently lead to long-term addiction. Therefore, it is prudent to optimize pain control while minimizing opioid consumption to boost postoperative recovery.

Ketorolac, an NSAID with opioid-sparing effects, is commonly employed for postoperative pain alleviation. Multiple randomized controlled trials (RCTs) have explored its use alone or with other analgesics like bupivacaine, morphine, and paracetamol in lumbar surgery. Variations in study design, patient demographics, and dosing regimens have led to inconsistent results, making it challenging to establish standardized pain management protocols.

Rationale behind research

The lack of clear guidelines for ketorolac in multimodal pain management highlights the need for a comprehensive review of existing evidence.

Objective

This systematic review and meta-analysis sought to assess ketorolac's efficacy and safety in lumbar spinal surgery, providing evidence-based insights to optimize pain control, reduce opioid reliance, and improve patient outcomes.

Literature search

A systematic search was carried out in databases including Cochrane Library, China National Knowledge Infrastructure (CNKI), Elton B. Stephens Company (EBSCO), Embase, Medline, PubMed, VIP, WanFang, and Web of Science from inception to May 2023. Keywords and MeSH terms like “analgesia” “ketorolac” “lumbar surgery” “spinal surgery” and “postoperative pain” were used. Reference lists of relevant studies and reviews were also hand-searched, with the process repeated to identify additional eligible studies. In July 2024, the final search was completed, ascertaining that the review incorporated the most current data at the time of the assessment.

Inclusion criteria

Study design should be an RCT

Volunteers should be those who underwent lumbar spinal surgery

Intervention should be ketorolac (either alone or in conjunction with other pain relievers) compared to control interventions (other pain relievers alone without ketorolac or placebo, like saline)

Exclusion criteria

• Animal studies
• Papers not issued in English or Chinese
• Studies with less than 10 candidates per group
• Non-randomized studies
• Studies with limited information (e.g., missing key outcome measures, ambiguous intervention details, or inadequate demographic data)
• Studies focusing on distinct patient cohorts (e.g., pediatrics or surgeries other than lumbar spinal surgery) or evaluating unrelated interventions (e.g., non-ketorolac pain relievers) and outcomes not aligned with the review's focus.

Data extraction

Baseline information, including sample size, first author, country, age, gender, administration (method and timing), surgery (duration and type) for both groups, was extracted from the original studies. Data acquisition was independently executed by two investigators, with discrepancies settled through consensus. The corresponding author was contacted to procure additional data when needed.

Data and statistical analysis

Researchers analyzed continuous outcomes (like visual analog scale [VAS] scores, length of hospitalization, postoperative morphine use). This was done using mean difference (MD) or standard mean difference (SMD) along with 95% confidence intervals (CI). SMD was applied for outcomes measured on different scales. Dichotomous outcomes (e.g., adverse effects) were assessed using risk ratio (RR) with 95% CI.

A random-effects model was picked for addressing anticipated heterogeneity in study designs, populations, and interventions, while a fixed-effect model was reserved for homogeneous studies. Utilizing the Q-test and I² statistic, with I² thresholds of 25%, 50%, and 75% (signifying low, moderate, and high heterogeneity respectively), an assessment of statistical heterogeneity was done.

Subgroup analyses explored heterogeneity sources, focusing on timing (preoperative, intraoperative, postoperative) and dosage of ketorolac, which may influence its efficacy in pain management and hospital stay duration.

Risk of bias and quality assessment

Publication-related bias was inspected via Begg’s and Egger’s tests, along with a funnel plot. However, this assessment was not carried out for outcomes with less than 10 studies due to restricted test power. At P < 0.05, statistical significance was set. Analyses were executed via OpenMeta-Analyst software with R as the statistical engine.

The methodological standards of each RCT were determined with the help of the Jadad Scale. This scale evaluated randomization (0–2 points), blinding (0–2 points), and dropouts/withdrawals (0–1 point). A score of 1 was granted for each element if appropriately conducted and reported. The Jadad score ranged from 0 to 5 points, with a score ≤2 denoting low quality and ≥3 denoting high quality. The Jadad scale was chosen for its simplicity, efficiency, and focus on key elements like randomization and blinding. Although the Cochrane Risk of Bias tool is more detailed, the Jadad scale was preferred for its balance of rigor and practicality.

Study outcomes

The primary outcomes assessed were:

• VAS pain score at 0 to 6 hours, 6 to 12 hours, and 12 to 24 hours
• Postoperative morphine requirements 
• The secondary outcomes assessed were:
• Length of hospitalization (days)
• Side effects

Key findings

Overall, 13 RCTs involving a total of 938 participants were included. The studies exhibited a high level of methodological integrity. Notably, 3 studies scored 5, 6 studies scored 4, and 4 studies scored 3 on the Jadad scale. The main findings were as follows:

• Pain Reduction: The heterogeneity was found to be low in the 12–24-hour period, with an I2 of 13%, reflecting uniform results across the studies.

(a) 0–6 hours: Ketorolac markedly ameliorated pain, with a MD of −1.42 (95% CI: −2.03 to −0.80). This exceeded the minimal clinically important difference (MCID) of 1.2 to 2.0 points on the VAS, signifying substantial pain improvement.

(b) 6–12 hours: Pain reduction remained significant with a MD of −0.58 (95% CI: −0.80 to −0.35), although it was below the MCID threshold.

(c) 12–24 hours: Ketorolac continued to show remarkable pain alleviation with a MD of −0.48 (95% CI: −0.68 to −0.28). However, this decrease was also beneath the MCID threshold.

• Postoperative Morphine Requirement: There was a drastic decrease in postoperative morphine needs (SMD = −1.83; 95% CI: −3.42 to −0.23), although there was considerable heterogeneity among the studies (I2 = 93%).
• Length of Stay: Ketorolac administration led to a substantial reduction in the length of hospital stay (MD = −0.45 days; 95% CI: −0.74 to −0.16). However, the abatement of less than half a day (0.45 days) may have minimal practical value in clinical settings.
• Opioid-Sparing Effect: Ketorolac successfully attenuated opioid use following surgery, supporting its role as part of multimodal analgesia for lumbar spinal surgery.
• Safety Profile: No significant escalation in common adverse effects was noted, suggesting that ketorolac has a favorable safety profile.

In conclusion, this study supports the use of ketorolac as an effective analgesic for addressing postoperative pain following lumbar spinal surgery. The meta-analysis of 13 RCTs with 932 participants revealed that ketorolac, whether used alone or in combination with other analgesics, markedly reduced pain scores in the first 12 hours after surgery, with the most substantial pain relief witnessed in the first 6 hours. The reduction in pain during the 6–12 hour and 12–24 hour periods was statistically significant, though the clinical significance of the latter reductions fell below the MCID.

Ketorolac’s opioid-sparing effect is a key finding, as it markedly diminished the need for postoperative morphine, a crucial factor in minimizing opioid-related side effects and dependency. The study showed that ketorolac offered prominent reductions in postoperative morphine dependency, with a SMD of −1.83, although there was substantial heterogeneity in the results. Sensitivity analyses helped diminish this variability by excluding certain outlier studies, leading to more consistent findings. Ketorolac was efficient across various doses and administration times (preoperative, intraoperative, and postoperative), indicating its versatility in multimodal pain management strategies.

The study also highlighted that ketorolac was linked with a shorter length of stay in the hospital, reducing hospital resource utilization and potentially lowering healthcare costs. The mean reduction in length of stay was 0.45 days, which, while not substantial in terms of clinical recovery, could have implications for resource optimization in surgical settings. Despite the higher direct drug costs linked with ketorolac, its overall cost-effectiveness was supported by the reduction in opioid use, leading to lower overall hospital costs and a quicker recovery process.

Regarding safety, ketorolac did not markedly escalate the incidence of common postoperative adverse effects, such as nausea, vomiting, pruritus, or constipation, when compared to other analgesics. However, it may still predispose patients to more serious complications, including acute kidney injury, gastrointestinal bleeding, and anaphylaxis, particularly in those with pre-existing renal conditions or gastrointestinal risk factors. The study suggests that monitoring kidney function and taking precautions, such as co-administering proton pump inhibitors in high-risk patients, could help mitigate these risks.

Thus, ketorolac proves to be a valuable therapeutic agent in postoperative pain control following lumbar spinal surgery, offering clinically meaningful pain relief and reducing the reliance on opioids. However, its use must be meticulously analyzed, particularly in high-risk patients, due to the potential for serious adverse effects. Future studies should expand on the current evidence to yield a clearer understanding of its safety profile across diverse patient groups and surgical settings. This will facilitate more accurate risk–benefit assessments and assist in refining guidelines for its safe use in postoperative care. Furthermore, upcoming investigations must concentrate on standardizing protocols and probing ideal dosing strategies.