Efficacy of Perioperative Pregabalin in Acute and Chronic Post-operative Pain

Article Identification

• Article Title: Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial.
• Citation: Shreedhar S Joshi, A M Jagadeesh. Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial. Annals of Cardiac Anaesthesia. 2013;16(3):180-5.
• DOI/PMID: DOI: 10.4103/0971-9784.114239 | PMID: 23816671

Quick Reference Summary

• Pregabalin administration perioperatively significantly reduced acute post-operative pain scores at rest and during deep breathing at multiple time points post-extubation (P < 0.05) and decreased tramadol consumption by 60% (P < 0.001) in OPCAB patients.
• No significant differences were observed between the pregabalin and control groups regarding sedation levels, extubation times, incidence of nausea, or chronic post-operative pain outcomes.

Core Clinical Question

In adult patients undergoing elective off-pump coronary artery bypass (OPCAB) surgery, does perioperative administration of pregabalin compared to placebo reduce acute post-operative pain and opioid consumption without increasing sedation or delaying extubation?

Background

• Disease or Condition Overview:
  • Off-pump coronary artery bypass (OPCAB) surgery is a common procedure for treating coronary artery disease without the use of cardiopulmonary bypass.
  • Effective pain management post-OPCAB is crucial for patient recovery, reducing complications, and enhancing overall outcomes.
• Prior Data on the Topic:
  • Kehlet H, Holte K. (2001) emphasized the importance of multimodal pain management post-cardiac surgery to minimize opioid-related side effects.
  • Pesonen A et al. (2011) demonstrated that pregabalin reduces opioid consumption by 44% post-cardiac surgery without significant sedation.
• Current Standard of Care:
  • Utilization of multimodal analgesia, including opioids, non-steroidal anti-inflammatory drugs (NSAIDs), and regional epidural analgesia.
  • Challenges include opioid-related side effects and the risks associated with epidural analgesia in anticoagulated patients.
• Knowledge Gaps Addressed by the Study:
  • Limited evidence on the efficacy of pregabalin specifically in the OPCAB population.
  • Unclear impact of pregabalin on chronic post-operative pain following cardiac surgery.
• Study Rationale:
  • To evaluate whether pregabalin can effectively manage acute post-operative pain and reduce opioid consumption without adverse effects in OPCAB patients.
  • To assess the potential of pregabalin in preventing chronic post-operative pain.

Methods Summary

• Study Design: Randomized, double-blind, placebo-controlled trial.
• Setting and Time Period: Conducted at Sri Jayadeva Institute of Cardiovascular Sciences and Research, Bangalore, India. Received: Dec 13, 2012; Accepted: May 14, 2013.
• Population Characteristics:
  • Participants: 40 adult patients (ages 30-65) undergoing elective OPCAB surgery.
  • Inclusion Criteria: Elective OPCAB surgery, age 30-65 years, ASA physical status I-II.
  • Exclusion Criteria: Unstable hemodynamics, use of intra-aortic balloon pump, congestive heart failure, left ventricular ejection fraction <40%, renal/hepatic dysfunction, current use of anticonvulsants, antidepressants, or chronic analgesics.
• Intervention Details:
  • Pregabalin Group: 150 mg pregabalin administered 2 hours before anesthesia induction, followed by 75 mg twice daily for 2 post-operative days.
• Control Group Details:
  • Placebo Group: Placebo capsules administered at the same timings as the pregabalin group.
• Primary and Secondary Outcomes:
  • Primary Outcomes: Acute post-operative pain scores (VAS at rest and deep breath), tramadol consumption.
  • Secondary Outcomes: Sedation scores (RASS), time to extubation, side effects (nausea, vomiting, respiratory depression), and chronic post-operative pain at 1 and 3 months.
• Basic Statistical Analysis Approach:
  • VAS Scores: Mann-Whitney U test.
  • Continuous Variables: ANOVA for repeated measures.
  • Categorical Variables: Chi-square test.
• Sample Size Calculations:
  • Initially 16 per group to detect a 1-point difference in VAS scores with 80% power and 5% significance.
  • Increased to 20 per group to account for a 25% dropout rate.
• Ethics and Funding Information:
  • Institutional Review Board approval obtained.
  • No funding sources declared; no conflicts of interest reported.

Detailed Results

• Participant Flow and Demographics:
  • All 40 patients completed the study.
  • Demographics: Comparable between groups (age, sex, weight, height).
  • Clinical Characteristics: No significant differences in diabetes, hypertension, NYHA class, number of coronary arteries involved, or intraoperative fentanyl consumption.
• Primary Outcome Results:
  • VAS Scores at Rest: Significantly lower in the pregabalin group at 6, 12, 24, and 36 hours post-extubation (P < 0.05).
  • VAS Scores During Deep Breath: Significantly lower in the pregabalin group at 4, 6, 12, 24, and 36 hours post-extubation (P < 0.05).
  • Tramadol Consumption: Reduced by 60% in the pregabalin group compared to control (P < 0.001).
• Secondary Outcome Results:
  • Sedation Scores (RASS): Comparable between groups; no significant differences.
  • Extubation Times: No significant delay in the pregabalin group (447 ± 117 vs. 461 ± 119 minutes; P = 0.7).
  • Incidence of Nausea and Vomiting: Comparable between groups; no significant difference.
  • Chronic Post-operative Pain: No significant difference between groups at 1 and 3 months.
  • Incentive Spirometry: Higher peak inspiratory flow rates in the pregabalin group at 12, 24, and 36 hours post-extubation (P < 0.05).

Authors' Conclusions

• Primary Conclusions:
  • Perioperative pregabalin effectively reduced acute post-operative pain scores at rest and during deep breathing in OPCAB patients.
  • Significant reduction in tramadol consumption was observed in the pregabalin group without causing excessive sedation or delaying extubation.
• Clinical Implications Stated by Authors:
  • Pregabalin can be integrated into perioperative analgesic protocols for OPCAB surgery to enhance pain control and reduce opioid requirements.
• Future Research Recommendations:
  • Larger cohort studies are necessary to assess the impact of pregabalin on chronic post-operative pain.
  • Objective pulmonary function tests should be included to evaluate the effect of improved pain control on pulmonary outcomes.

Critical Analysis

A. Strengths

• Methodological Strengths:
  • Randomized Controlled Design: Minimizes selection bias.
  • Double-Blind: Reduces performance and detection bias.
  • Placebo-Controlled: Provides a clear comparison between intervention and control.
• Internal Validity Considerations:
  • Well-defined inclusion and exclusion criteria enhance the study's internal validity.
  • Use of validated pain (VAS) and sedation (RASS) scales ensures reliable outcome measurements.
• External Validity Considerations:
  • Study population is specific to OPCAB patients, enhancing applicability to similar surgical contexts.
  • Exclusion of patients with severe comorbidities may limit generalizability to broader cardiac surgery populations.

B. Limitations

• Study Design Limitations or Biases:
  • Sample Size: Relatively small (40 patients), limiting the power to detect differences in chronic pain outcomes.
  • Short Follow-Up for Chronic Pain: Only assessed up to 3 months, which may not capture long-term pain trajectories.
• Generalizability Issues:
  • Conducted in a single center in India, which may limit applicability to different healthcare settings and populations.
• Statistical Limitations:
  • Multiple comparisons without adjustment may increase the risk of Type I error.
• Missing Data Handling or Loss to Follow-Up:
  • No significant loss to follow-up reported, but small sample size may still affect the robustness of chronic pain findings.

Literature Review

Introduction

The randomized, double-blind, placebo-controlled trial by Joshi and Jagadeesh (2013) evaluated the efficacy of perioperative pregabalin in managing acute and chronic postoperative pain in patients undergoing off-pump coronary artery bypass (OPCAB) surgery. The study demonstrated that pregabalin significantly reduced acute pain scores and tramadol consumption without adversely affecting sedation levels or extubation times. However, it did not show a significant impact on chronic postoperative pain.

Comparative Analysis

A. Positioning the Current Study in Existing Evidence

• Key Previous Studies:
  • Kehlet H, Holte K. (2001) highlighted the need for multimodal analgesia in cardiac surgery to reduce opioid-related side effects.
  • Pesonen A et al. (2011) conducted a randomized trial showing that pregabalin reduced opioid consumption by 44% post-cardiac surgery without significant sedation.
  • Zhang J, Ho KY, Wang Y. (2011) performed a meta-analysis confirming that pregabalin effectively reduces acute postoperative pain and opioid requirements across various surgical procedures.
• Methodological Quality:
  • The current study aligns with high-quality randomized controlled trials, utilizing blinding and placebo control to ensure robust findings.
  • Compared to earlier studies, the sample size is smaller, potentially limiting the power to detect certain outcomes like chronic pain.
• Guidelines and Consensus Statements:
  • American Society of Anesthesiologists (ASA) Guidelines advocate for multimodal analgesia approaches, including gabapentinoids like pregabalin, to manage post-operative pain effectively.
  • Society of Critical Care Medicine (SCCm) emphasizes the use of adjunctive non-opioid analgesics in ICU settings to minimize opioid-related complications.
• Geographic or Population Differences:
  • Most prior studies were conducted in Western populations, whereas Joshi and Jagadeesh’s study was conducted in India, adding diversity to the existing evidence base.
  • OPCAB-specific data were limited prior to this study, making this research a valuable addition to targeted cardiac surgery analgesia protocols.

B. Comprehensive Synthesis of Findings

• Alignment with Other Recent Data:
  • The current study’s findings of reduced opioid consumption and effective acute pain control are consistent with Pesonen et al. (2011) and Zhang et al. (2011), reinforcing the role of pregabalin in multimodal analgesia.
  • Unlike Pesonen et al., who observed an extension in extubation times, Joshi and Jagadeesh reported no significant delay, likely due to differences in anesthetic protocols aimed at early extubation.
• Strengths and Weaknesses of Referenced Studies:
  • Strengths: Consistent demonstration of pregabalin’s opioid-sparing effects across studies; robust RCT designs.
  • Weaknesses: Variation in dosing regimens, limited long-term follow-up for chronic pain in most studies, and differing surgical populations.
• Clinical Applicability:
  • Integrating pregabalin into OPCAB analgesic protocols aligns with existing guidelines advocating for multimodal approaches.
  • The significant reduction in tramadol use observed supports practices aimed at minimizing opioid-related side effects, such as respiratory depression and sedation.
• Systematic Reviews and Meta-Analyses:
  • Zhang J et al. (2011) concluded that pregabalin is effective in reducing acute postoperative pain and opioid consumption, supporting the findings of Joshi and Jagadeesh.
  • Lahtinen P et al. (2006) identified a chronic pain incidence of 11–24% post-cardiac surgery, highlighting the importance of effective acute pain management to potentially mitigate chronic pain development.
• Cost-Effectiveness or Resource Utilization:
  • While not directly addressed in Joshi and Jagadeesh’s study, pregabalin’s opioid-sparing effects could translate to cost savings by reducing opioid-related side effects and enhancing patient recovery.
• Ongoing Trials:
  • Emerging studies are exploring the long-term benefits of gabapentinoids in various surgical populations, with ongoing trials assessing their role in chronic pain prevention.

C. Gaps and Future Directions

• Unanswered Questions:
  • The impact of pregabalin on chronic post-operative pain remains unclear, necessitating larger, long-term studies.
  • The optimal dosing regimen for balancing analgesic efficacy and side effects in OPCAB patients requires further investigation.
• Areas for Additional Research:
  • Subpopulations: Evaluating pregabalin’s efficacy in diverse patient groups, including those with varying comorbidities.
  • Safety Endpoints: Long-term safety data, particularly concerning cardiovascular outcomes in cardiac surgery patients.
  • Real-World Implementation: Assessing the feasibility and outcomes of integrating pregabalin into routine OPCAB analgesic protocols across different healthcare settings.
  • Combination Therapies: Exploring the synergistic effects of pregabalin with other non-opioid analgesics like NSAIDs or acetaminophen to enhance multimodal analgesia efficacy.

Integration with Clinical Practice Guidelines and Evidence

Integrating Joshi and Jagadeesh’s findings with existing guidelines, such as those from the ASA and SCCm, underscores the potential of pregabalin as a valuable component of multimodal analgesia. The study supports the guidelines’ recommendations by demonstrating significant opioid-sparing effects and effective acute pain control without increasing sedation or delaying extubation. However, the lack of significant impact on chronic pain suggests that pregabalin should be part of a broader, individualized pain management strategy rather than a standalone intervention.

Conclusion

The trial by Joshi and Jagadeesh (2013) contributes valuable evidence supporting the use of perioperative pregabalin in OPCAB surgery patients. The significant reduction in acute pain and tramadol consumption aligns with current multimodal analgesia guidelines, promoting enhanced patient recovery and reduced opioid-related side effects. However, the study highlights the need for further research to elucidate pregabalin’s role in chronic pain prevention and to optimize dosing strategies. Integrating these findings with existing literature reinforces the importance of individualized, evidence-based pain management protocols in improving postoperative outcomes in cardiac surgery patients.

References

• Devlin JW, Skrobik Y, Gélinas C, et al. Clinical Practice Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption in Adult Patients in the ICU. Crit Care Med. 2018;46(9):e825-e841. doi:10.1097/CCM.0000000000003299
• Cattabriga I, Pacini D, Lamazza G, et al. Intravenous paracetamol as adjunctive treatment for postoperative pain after cardiac surgery: a double-blind randomized controlled trial. Eur J Cardio-Thoracic Surg. 2007;32(3):527-531. doi:10.1016/j.ejcts.2007.05.017
• Joshi SS, Jagadeesh AM. Efficacy of perioperative pregabalin in acute and chronic post-operative pain after off-pump coronary artery bypass surgery: a randomized, double-blind placebo controlled trial. Annals of Cardiac Anaesthesia. 2013;16(3):180-5. doi:10.4103/0971-9784.114239

Clinical Application

• Pregabalin can be incorporated into perioperative analgesic protocols for OPCAB patients to effectively reduce acute post-operative pain and significantly decrease opioid consumption, thereby minimizing opioid-related side effects.
• This approach is particularly beneficial for patients at higher risk of opioid-related complications, such as respiratory depression, and can facilitate faster rehabilitation by enhancing pain control without delaying extubation.
• Implementation considerations include ensuring appropriate dosing regimens to balance analgesic efficacy with the risk of side effects, as well as training clinical staff to integrate pregabalin into existing multimodal pain management strategies.

How To Use This Info In Practice

Clinicians should consider integrating perioperative pregabalin into multimodal analgesia regimens for OPCAB surgery patients in alignment with current guidelines, emphasizing its role in reducing acute pain and opioid use while monitoring for any potential side effects to optimize patient outcomes.