Intraoperative nitrous oxide inhalation to prevent chronic postsurgical pain in video-assisted thoracoscopic surgery: a prospective observational cohort study

Introduction

Chronic postsurgical pain (CPSP) is a significant clinical problem that negatively affects recovery and quality of life after surgery. CPSP is defined as chronic pain that develops or increases in intensity after a surgical procedure and persists beyond the healing process, i.e., at least 3 months after the surgery (1). Due to the location of the incision and the necessity of an indwelling thoracic tube, thoracic surgery is considered to be one of the most painful operations (2), with an overall chronic pain incidence of up to 65% (3). The incidence of chronic pain in the third and sixth months after thoracic lobectomy is 57% and 47%, respectively (4,5). Within 3–6 months after thoracic surgery, the proportion of patients using opioids is as high as 31% (6). Therefore, the prevention of CPSP in thoracic surgery is receiving increasing attention.

The mechanism of CPSP may be related to local trauma, inflammatory reactions and neuropathic pain (7) and involves multiple peripheral and central signalling and modulatory pathways regulated by genes, epigenetics, and psychosocial, perioperative, and gene-environmental interactions (8,9). Some animal and clinical trials have shown that nitrous oxide (N₂O) may produce long-term analgesic effect, and genetic susceptibility may further enhance this effect of N₂O administration (10-12). Evidence has shown that N₂O is a protective factor against chronic postoperative pain in Asian populations with variants in the methylenetetrahydrofolate reductase gene in nonthoracic surgery (13). However, it remains unclear whether this effect also exists in thoracic surgery.

The primary objective of this study was to test the hypothesis that N₂O inhalation during anaesthesia is associated with a lower incidence of chronic pain 6 months after video-assisted thoracoscopic surgery (VATS) in a Chinese population. The impact of N₂O inhalation on postsurgical pain at 3 months and neuropathic pain were also discussed. Our study also provides prospective epidemiological data on CPSP related to thoracic surgery in the Chinese population, as such data are relatively inadequate. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-556/rc) (14).

Methods

Study design

This prospective cohort study was approved by the Ethical Committee of Peking Union Medical College Hospital (Ethical Committee No. JS-2409), Beijing, China (Chairperson Prof. Zhaohui Zhu) on June 23, 2020. The Ethical Committee waived the need for written informed consent due to the observational nature of our study, and verbal consent was attained through verbal questionnaire. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). The study design, outcome variables, and analysis plan were selected prior to surgery.

Study population

Participants aged 18 years and older who underwent elective VATS at Peking Union Medical College Hospital (PUMCH) were eligible. The medical center stopped supplying N₂O on February 18, 2021. Thus, two groups of participants were recruited by time sequence, with the N₂O group consecutively recruited from November 1, 2020, to January 31, 2021, and the control group consecutively recruited from March 1, 2021, to May 31, 2021.

Exclusion criteria included pre-operative chronic pain and opioid usage ≥3 months, contraindications to the use of N₂O, sensory dysfunction, delayed incision healing, uniportal surgery or the absence of a drainage tube. Patients who received a second operation within 6 months and those who refused or were unable to receive our telephone follow-up were also excluded.

Exposure, confounders and endpoints

The primary exposure factor in our study was N₂O inhalation (50–65%) during general anaesthesia, while patients with no N₂O inhalation during anaesthesia represented the control group.

Factors that may have causal relationships with CPSP were regarded as potential confounders in our analysis. Based on clinical experiences and previous studies, we adjusted for the confounding effects of age, sex, body mass index (BMI), American Society of Anaesthesiologists (ASA) score, history of smoking and allergy, blood types, presence of comorbidities, status of employment and marriage, incision length, surgery duration, perioperative chemotherapy, surgery type (wedge resection or lobectomy), intraoperative blood loss, intercostal nerve block, duration of chest tube drainage, malignancy of tumours, length of stay, intraoperative use of nonsteroidal anti-inflammatory drugs (NSAIDs), acute pain on postoperative day 1 (POD 1) and at discharge, patient-controlled analgesia (PCA), pre- and postoperative white blood cell (WBC) counts, preoperative haemoglobin (Hb) level and usage of opioids after discharge. Dosage range of intraoperative fentanyl was 4–6 mcg/kg and remifentanil application were 0.05–0.1 mcg/kg/h (15). Postoperative multi-model analgesia was applied according to patients’ requirement, either PCA or single intravenous usage of 5 mg oxycodone.

A verbal questionnaire as well as a standard operating procedure was written a priori and followed by specialized personnel who completed the telephone follow-up 6 months after surgery. Verbal consent was attained at the beginning of the telephone interview. During the interview, patients were asked if they currently felt pain around or related to the incision site. If the pain had developed since the operation and no other causes existed, the presence of CPSP was recorded. The pain intensity was measured by the numeric rating scales (NRS), and characteristics of neuropathic pain was defined by a score of ≥2 on the neuropathic pain screening scale (ID-PAIN). Opioid consumption was recorded if patients claimed to take opioids after discharge.

The primary endpoint in our study was CPSP as judged by the patient’s complaint of incision-related pain at the 6-month telephone follow-up. Secondary endpoints included chronic pain 3 months after surgery and the presence of neuropathic CPSP at 3 or 6 months.

Statistical analysis

On our pre-experimental basis, 33% of patients reported CPSP at 6 months after surgery, and the enrolment of ≥649 patients attained 90% power to detect a relative risk reduction of 30% with a type I error of 0.05.

The basic characteristics of patients with and without N₂O inhalation were tabulated and compared using Student’s t-test and the Mann-Whitney U-test for continuous variables and using the χ² test for categorical variables. A P value less than 0.1 was considered a significant difference. The potential association between N₂O inhalation and primary or secondary endpoints was analyzed using multivariable odds ratios (ORs) and 95% confidence intervals (CIs) that were adjusted for age, sex, BMI, surgery duration, intraoperative NSAIDS, opioid consumption after discharge, ASA score, duration of chest tube drainage, PCA, intercostal nerve block, NRS at discharge, preoperative Hb and WBC, employment and marital status using multivariable logistic regression or multivariable linear regression.

We assessed the differences in outcomes in 4 subgroups (age, sex, surgery type, and intercostal nerve block) by adding a treatment-by-subgroup interaction term to the multivariate regression. We also explored the association between patient characteristics and several endpoints using the stepwise method of multivariate logistic regression models and linear regression models.

Data analysis was conducted using R version 4.2.0 (R Foundation for Statistical Computing, Vienna, Austria). A 2-sided P value less than 0.05 was considered statistically significant.

Results

A total of 1,142 patients received VATS in our medical centre during the previously designed time period, of whom 859 met our selection criteria. Twenty-six (3.1%) patients could not be contacted despite multiple attempts. The remaining 833 patients were interviewed by telephone, among whom 400 (48.0%) patients received N₂O during anaesthesia and 433 (52.0%) did not receive N₂O inhalation (Figure 1).

Figure 1 Flow chart for patients enrolment. VATS, video-assisted thoracoscopic surgery; PUMCH, Peking Union Medical College Hospital; N₂O, nitrous oxide.

Baseline and surgical characteristics

The mean age was 56.3 years, with 66.4% of female patients and 58.1% of patients aged ≥60 years. Over 80% of patients were classified as ASA II (Table 1). The average operation time was 1.7 hours, and the average length of stay was 6.4 days (Table 2). A total of 419 (50.3%) patients underwent intercostal nerve block, and 162 (19.4%) patients underwent PCA after surgery. At the 6-month follow-up, 387 (46.5%) patients developed CPSP, of whom 79 (20.4%) complained of moderate to severe pain with NRS ≥3, and 158 (40.8%) developed neuropathic pain (Table 3).

The baseline age and sex showed no significant difference between the two groups. Patients in the N₂O group had lower ASA scores, less duration of chest tube drainage and lower pain severity at discharge. More patients received PCA after surgery, and fewer patients received intercostal nerve block in the N₂O group. Preoperative Hb and WBC were slightly lower in the N₂O group, with no clinical significance. Furthermore, there were more patients with full-time employment and fewer patients who were married in the exposed group.

N₂O inhalation and CPSP

A total of 160 (40.0%) patients in the N₂O group and 227 (52.4%) patients in the control group reported CPSP at 6 months after surgery. After univariate analysis, N₂O inhalation was negatively associated with CPSP (OR =0.76; 95% CI: 0.66–0.89; P<0.001). N₂O inhalation was independently associated with CPSP (OR =0.65; 95% CI: 0.48–0.89; P=0.007) (Table 4). N₂O inhalation was found to decrease the odds of CPSP at 3 months after surgery (OR =0.72; 95% CI: 0.52–0.99; P=0.045) (Table 5), as well as neuropathic pain (OR =0.44; 95% CI: 0.30–0.63; P<0.001) (Table 6).

Subgroup analyses for CPSP indicated significant interaction in the sex subgroup suggesting that N₂O inhalation reduced the risk of CPSP more in females than in males (OR =0.57; 95% CI: 0.38–0.83, P for interaction =0.04) (Figure 2). There were no significant interaction effects in the subgroups of age, surgery type and intercostal nerve block.

Figure 2 Odds ratios for chronic postsurgical pain associated with the use of N₂O in selected subgroups. OR, odds ratio; N₂O, nitrous oxide.

Risk factors for CPSP

A higher NRS score at discharge and previous coronary artery disease were risk factors for 6-month CPSP, while N₂O inhalation and full-time employment were protective factors (Table 7). For the 3-month CPSP, a higher NRS score at discharge, prolonged duration of drainage and female sex were risk factors, while full-time employment, opioid consumption and perioperative chemotherapy were protective factors (Table 7). Regarding the development of neuropathic pain, N₂O, intraoperative use of NSAIDs and opioid consumption were protective factors, while female sex, history of smoking and higher NRS at discharge were associated with higher odds of neuropathic pain (Table 7).

Discussion

In our study, chronic pain in thoracoscopy surgeries remains common, with an overall incidence of CPSP 46.5% 6 months after surgery, and one-fifth of them experienced moderate to severe pain, which is consistent with previous studies (4,5). We observed a reduction in CPSP occurrence in our center, whereas the incidence of CPSP was 64.5% in a retrospective case-control study in PUMCH in 2009, in which most patients received thoracotomy (16).

Our study confirms that N₂O administration may have protective effects on CPSP in thoracoscopic surgeries, reducing the incidence of CPSP by 35% at 6 months. The same remains true when exploring the association between N₂O and CPSP at 3 months, suggesting that the result is rather stable. Furthermore, the administration of N₂O reduced the severity of CPSP at 6 months. Intraoperative inhalation of N₂O also reduced the incidence of neuropathic pain after surgery, in accordance with a previous study showing that a single 50% N₂O exposure induced a persistent reduction in hyperalgesia-allodynia in a rat neuropathic pain model (17).

The analgesic mechanisms of N₂O include activating TWIK-related K⁺ channel 1 potassium channels on first-order neurons, blocking voltage-dependent calcium channels to attenuate neuronal excitability, attenuating postsynaptic glutamatergic receptor activation, and possibly blocking voltage-dependent sodium channels in the ascending pathway. In the descending pathway, N₂O induces the release of endogenous opioid ligands and stimulates norepinephrine release. In addition, N₂O may mediate epigenetic changes by inhibiting methionine synthase (18).

Consistent with our findings, in the ENIGMA (evaluation of N₂O in the gas mixture for anaesthesia) randomized controlled trial (11), 640 Hong Kong patients with noncardiac surgery lasting more than 2 hours were subjected to N₂O-based or N₂O-free general anaesthesia. After multivariate analysis, N₂O reduced the risk of postoperative chronic pain (OR =0.43; 95% CI: 0.23–0.83; P=0.01). The ENIGNA-II trials (13) further confirmed this relationship in a predesigned subgroup analysis of 909 patients, in which N₂O reduced the risk of postoperative chronic pain in Asian populations [relative risk (RR) =0.70; 95% CI: 0.50–0.98; P=0.03], probably due to specific polymorphisms in the tetrahydrofolate reductase system in Asian populations, which may be more sensitive to the inhibitory effect of N₂O on the methyl donor activity of methionine synthase, thereby inhibiting DNA synthesis related to chronic postoperative pain and reducing neural plasticity, central nervous sensitivity and neuroinflammation (19,20).

Subgroup analysis showed that intraoperative N₂O was more significant in preventing CPSP in female patients than in male patients, suggesting that more administration of N₂O should be considered in female patients. There were no significantly different impacts of N₂O in the young or older populations, in cases of lobectomy or wedge section and in patients with or without intercostal nerve block.

Although previous research showed that younger age is a risk factor for CPSP after lobectomy (21-23), we did not find any significant impact of age while exploring risk factors for CPSP. Being female is generally considered to be associated with a higher incidence of CPSP (4). In our study, female sex was found to be a risk factor for neuropathic pain and CPSP at 3 months after surgery but was not associated with CPSP at 6 months. Studies suggest that marriage, full-time employment, drinking and smoking may show protective effects in breast surgery (24), whereas our study suggested that a full-time job was a protective factor against CPSP at both 3 and 6 months after surgery and that smoking was a risk factor for neuropathic pain. Postoperative acute pain shares the same molecular mechanism, including peripheral and central sensitization, and is a widely recognized independent risk factor for CPSP (24-27). The findings of this study are consistent with those in previous studies. Although intercostal nerve block reduces the severity of pain at discharge (28,29), there is no clinical evidence of its preventing CPSP. Delayed removal of the thoracic drainage tube is a risk factor for CPSP at 3 months, in accordance with a previous study (30,31). Although NSAIDs have no proven efficacy against neuropathic pain (32), the combination of opioids with NSAIDs produces synergistic analgesic effects on neuropathic pain (33), and intraoperative usage of NSAIDs was a protective factor against neuropathic pain in our research. Interestingly, coronary heart disease was a risk factor for chronic pain, which had no relevant research evidence to explain this phenomenon. This result may be attributed to fewer options regarding pain-control methods in patients with coronary heart disease, as NSAID use is relatively contraindicated in such patients. Perioperative chemotherapy was a protective factor in our study, in contrast with a prior investigation (6), and these findings still need further research and testing.

Although our study included a relatively large sample of patients to evaluate the effect of N₂O on CPSP, there are several limitations. First, this was a single-centre observational study with no randomization, and several components of multimodal analgesia including paracetamol, thoracic epidural, thoracic paravertebral block, or local anesthesia infiltration, were not routinely used in our institution. The exposed and control groups were chosen by time period, which eliminated the confounding of anaesthesiologists’ subjective choice on analgesics but also led to some confounding factors that cannot be adjusted, such as the surgeon’s choice of patients, surgical technical improvements and the season. We collected as much baseline information as possible to attenuate the difference. Second, the endpoints were mainly obtained through telephone follow-up. Pain and NRS scores were evaluated by patients’ subjective answers and may not have been precise or were influenced by physiological and psychological states (34), which we did not explore in this study. Nevertheless, our predesigned standard operating procedure and brief verbal questionnaire enabled nearly all participants to cooperate, including uneducated and elderly patients, ensuring the generalizability of the data. Third, we did not include uniportal VATS, which exhibited a significantly lower incidence of post-thoracotomy pain syndrome (35). To some extent, the generalisability of the study was limited (36). Finally, we did not adjust the subgroup analyses for multiple testing, and this may have increased the type I error. Therefore, the results need to be interpreted with caution.

Conclusions

In summary, in this prospective cohort of patients who underwent thoracoscopic surgery, intraoperative inhalation of N₂O was found to be significantly associated with decreased chronic postoperative pain. This rotective effect was more obvious in female patients. Considering the CPSP in thoracoscopic surgery patients, perioperative analgesia could be improved by administrating N₂O and applying multimodal analgesia with the combination of different anesthesia methods.

Acknowledgments

We would like to thank all the clinical practitioners who took the time to participate in this research. We would also like to thank the presentation of the manuscript in Research Square.

Funding: This work was supported by National High Level Hospital Clinical Research Funding (No. 2022-PUMCH-B-007).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-556/rc

Data Sharing Statement: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-556/dss

Peer Review File: Available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-556/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://jtd.amegroups.com/article/view/10.21037/jtd-24-556/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the Ethical Committee of Peking Union Medical College Hospital (Ethical Committee No. JS-2409), Beijing, China (Chairperson Prof. Zhaohui Zhu) on June 23, 2020. The Ethical Committee waived the need for written informed consent due to the observational nature of the study, and verbal consent was attained through verbal questionnaire.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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