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Jennifer M Hah,1 Heather Hilmoe,2 Peter Schmidt,2 Rebecca McCue,2 Jodie Trafton,3,4 Debra Clay,2 Yasamin Sharifzadeh,2 Gabriela Ruchelli,2 Tina Hernandez Boussard,5 Stuart Goodman,6 James Huddleston,7 William J Maloney,7 Frederick M Dirbas,8 Joseph Shrager,9 John G Costouros,7 Catherine Curtin,10 Sean C Mackey,1 Ian Carroll1 1Division of Pain Medicine, Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, Stanford, CA, USA; 2Stanford Systems Neuroscience and Pain Lab, Stanford University, Stanford, CA, USA; 3Department of Psychiatry and Behavioral Sciences, Stanford University, Palo Alto, CA, USA; 4VA Program Evaluation and Resource Center, VHA Office of Mental Health Operations, Palo Alto, CA, USA; 5Department of Medicine, Department of Biomedical Data Science, Stanford University, Stanford, CA, USA; 6Department of Orthopaedic Surgery and (by Courtesy) Bioengineering, Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA; 7Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USA; 8Department of General Surgery, Stanford University, Stanford, CA, USA; 9Division of Thoracic Surgery, Stanford University, Stanford, CA, USA; 10Division of Hand and Plastic Surgery, Department of Orthopaedic Surgery, Stanford University, Stanford, CA, USACorrespondence: Jennifer M HahDivision of Pain Medicine, Department of Anesthesiology, Perioperative, and Pain Medicine, Stanford University, 1070 Arastradero Road, Suite 200, Palo Alto, CA 94304, USATel +1 650-736-9415Fax +1 650-725-9642Email jhah@stanford.eduBackground: Preoperative patient-specific risk factors may elucidate the mechanisms leading to the persistence of pain and opioid use after surgery. This study aimed to determine whether similar or discordant preoperative factors were associated with the duration of postoperative pain and opioid use.Methods: In this post hoc analysis of a randomized, double-blind, placebo-controlled trial of perioperative gabapentin vs active placebo, 410 patients aged 18– 75 years, undergoing diverse operations underwent preoperative assessments of pain, opioid use, substance use, and psychosocial variables. After surgery, a modified Brief Pain Inventory was administered over the phone daily up to 3 months, weekly up to 6 months, and monthly up to 2 years after surgery. Pain and opioid cessation were defined as the first of 5 consecutive days of 0 out of 10 pain or no opioid use, respectively.Results: Overall, 36.1%, 19.8%, and 9.5% of patients continued to report pain, and 9.5%, 2.4%, and 1.7% reported continued opioid use at 3, 6, and 12 months after surgery. Preoperative pain at the future surgical site (every 1-point increase in the Numeric Pain Rating Scale; HR 0.93; 95% CI 0.87– 1.00; P=0.034), trait anxiety (every 10-point increase in the Trait Anxiety Inventory; HR 0.79; 95% CI 0.68– 0.92; P=0.002), and a history of delayed recovery after injury (HR 0.62; 95% CI 0.40– 0.96; P=0.034) were associated with delayed pain cessation. Preoperative opioid use (HR 0.60; 95% CI 0.39– 0.92; P=0.020), elevated depressive symptoms (every 5-point increase in the Beck Depression Inventory-II score; HR 0.88; 95% CI 0.80– 0.98; P=0.017), and preoperative pain outside of the surgical site (HR 0.94; 95% CI 0.89– 1.00; P=0.046) were associated with delayed opioid cessation, while perioperative gabapentin promoted opioid cessation (HR 1.37; 95% CI 1.06– 1.77; P=0.016).Conclusion: Separate risk factors for prolonged post-surgical pain and opioid use indicate that preoperative risk stratification for each outcome may identify patients needing personalized care to augment universal protocols for perioperative pain management and conservative opioid prescribing to improve long-term outcomes.Keywords: persistent postsurgical pain, persistent postoperative opioid use, chronic opioid use after surgery, chronic pain after surgery

Acute postoperative pain is associated with the development of persistent postsurgical pain, but it is unclear which aspect is most estimable.To identify patient clusters based on acute pain trajectories, preoperative psychosocial characteristics associated with the high-risk cluster, and the best acute pain predictor of remote outcomes.A secondary analysis of the Stanford Accelerated Recovery Trial randomized, double-blind clinical trial was conducted at a single-center, tertiary, referral teaching hospital. A total of 422 participants scheduled for thoracotomy, video-assisted thoracoscopic surgery, total hip replacement, total knee replacement, mastectomy, breast lumpectomy, hand surgery, carpal tunnel surgery, knee arthroscopy, shoulder arthroplasty, or shoulder arthroscopy were enrolled between May 25, 2010, and July 25, 2014. Data analysis was performed from January 1 to August 1, 2018.Patients were randomized to receive gabapentin (1200 mg, preoperatively, and 600 mg, 3 times a day postoperatively) or active placebo (lorazepam, 0.5 mg preoperatively, inactive placebo postoperatively) for 72 hours.A modified Brief Pain Inventory prospectively captured 3 surgical site pain outcomes: average pain and worst pain intensity over the past 24 hours, and current pain intensity. Within each category, acute pain trajectories (first 10 postoperative pain scores) were compared using a k-means clustering algorithm. Fifteen descriptors of acute pain were compared as predictors of remote postoperative pain resolution, opioid cessation, and full recovery.Of the 422 patients enrolled, 371 patients (≤10% missing pain scores) were included in the analysis. Of these, 146 (39.4%) were men; mean (SD) age was 56.67 (11.70) years. Two clusters were identified within each trajectory category. The high pain cluster of the average pain trajectory significantly predicted prolonged pain (hazard ratio [HR], 0.63; 95% CI, 0.50-0.80; P .001) and delayed opioid cessation (HR, 0.52; 95% CI, 0.41-0.67; P .001) but was not a predictor of time to recovery in Cox proportional hazards regression (HR, 0.89; 95% CI, 0.69-1.14; P = .89). Preoperative risk factors for categorization to the high average pain cluster included female sex (adjusted relative risk [ARR], 1.36; 95% CI, 1.08-1.70; P = .008), elevated preoperative pain (ARR, 1.11; 95% CI, 1.07-1.15; P .001), a history of alcohol or drug abuse treatment (ARR, 1.90; 95% CI, 1.42-2.53; P .001), and receiving active placebo (ARR, 1.27; 95% CI, 1.03-1.56; P = .03). Worst pain reported on postoperative day 10 was the best predictor of time to pain resolution (HR, 0.83; 95% CI, 0.78-0.87; P .001), opioid cessation (HR, 0.84; 95% CI, 0.80-0.89; P .001), and complete surgical recovery (HR, 0.91; 95% CI, 0.86-0.96; P .001).This study has shown a possible uniform predictor of remote postoperative pain, opioid use, and recovery that can be easily assessed. Future work is needed to replicate these findings.ClinicalTrials.gov Identifier: NCT01067144.

Importance Guidelines recommend using gabapentin to decrease postoperative pain and opioid use, but significant variation exists in clinical practice. Objective To determine the effect of perioperative gabapentin on remote postoperative time to pain resolution and opioid cessation. Design, Setting, and Participants A randomized, double-blind, placebo-controlled trial of perioperative gabapentin was conducted at a single-center, tertiary referral teaching hospital. A total of 1805 patients aged 18 to 75 years scheduled for surgery (thoracotomy, video-assisted thoracoscopic surgery, total hip replacement, total knee replacement, mastectomy, breast lumpectomy, hand surgery, carpal tunnel surgery, knee arthroscopy, shoulder arthroplasty, and shoulder arthroscopy) were screened. Participants were enrolled from May 25, 2010, to July 25, 2014, and followed up for 2 years postoperatively. Intention-to-treat analysis was used in evaluation of the findings. Interventions Gabapentin, 1200 mg, preoperatively and 600 mg, 3 times a day postoperatively or active placebo (lorazepam, 0.5 mg) preoperatively followed by inactive placebo postoperatively for 72 hours. Main Outcomes and Measures Primary outcome was time to pain resolution (5 consecutive reports of 0 of 10 possible levels of average pain at the surgical site on the numeric rating scale of pain). Secondary outcomes were time to opioid cessation (5 consecutive reports of no opioid use) and the proportion of participants with continued pain or opioid use at 6 months and 1 year. Results Of 1805 patients screened for enrollment, 1383 were excluded, including 926 who did not meet inclusion criteria and 273 who declined to participate. Overall, 8% of patients randomized were lost to follow-up. A total of 202 patients were randomized to active placebo and 208 patients were randomized to gabapentin in the intention-to-treat analysis (mean [SD] age, 56.7 [11.7] years; 256 (62.4%) women and 154 (37.6%) men). Baseline characteristics of the groups were similar. Perioperative gabapentin did not affect time to pain cessation (hazard ratio [HR], 1.04; 95% CI, 0.82-1.33; P = .73) in the intention-to-treat analysis. However, participants receiving gabapentin had a 24% increase in the rate of opioid cessation after surgery (HR, 1.24; 95% CI, 1.00-1.54; P = .05). No significant differences were noted in the number of adverse events as well as the rate of medication discontinuation due to sedation or dizziness (placebo, 42 of 202 [20.8%]; gabapentin, 52 of 208 [25.0%]). Conclusions and Relevance Perioperative administration of gabapentin had no effect on postoperative pain resolution, but it had a modest effect on promoting opioid cessation after surgery. The routine use of perioperative gabapentin may be warranted to promote opioid cessation and prevent chronic opioid use. Optimal dosing and timing of perioperative gabapentin in the context of specific operations to decrease opioid use should be addressed in further research. Trial Registration clinicaltrials.gov Identifier:NCT01067144

This article summarizes the current evidence for the use of gabapentinoids in the perioperative setting and provides useful clinical recommendations regarding dosing, timing, and choice of agent.