Nitrous Oxide to Reduce Wound Care–Related Pain in Adults: A Systematic Review and Meta-Analysis

Abstract

Significance:

As an essential procedure, wound care comes with acute pain, which is short but high in intensity, causing patients to fear and affecting subsequent treatment. Nitrous oxide (N₂O) is used to relieve pain related to wound care; however, evidence regarding its application is conflicting. Thus, this systematic review and meta-analysis was performed to evaluate the efficacy of N₂O in wound care–related pain.

Recent Advances:

Randomized controlled trials that investigated the effect of N₂O in adults undergoing wound care were systematically searched from PubMed, Embase, the Cochrane Library, Web of Science, Scopus, and ClinicalTrials.gov up to February 2023. The primary outcome was the pain score. Secondary outcomes included patients’ satisfaction and side effects.

Critical Issues:

Through screening the 265 identified articles, seven and six studies were finally included in the systematic review and meta-analysis, respectively. Pooled analysis suggested that there was no significant difference in reducing wound care–related pain between the N₂O group and the control group (mean difference [MD], −0.02, 95% confidence interval [CI], −1.46, 1.42; p = 0.98, I ² = 96%). Subgroup analyses indicated that there was a significant difference in favor of N₂O for burns, not for ulcers, and N₂O was superior to oxygen and similar to topical or intravenous anesthesia. There was no significant difference in patients’ satisfaction or the incidence of side effects between groups.

Future Directions:

This review suggests that N₂O might be effective for pain management in patients undergoing wound care. Caution must be taken when interpreting these results due to the high risk of biased methods in the included studies.

Ziyang Wang

SCOPE AND SIGNIFICANCE

Wound care is an essential part of clinical practice, and the healing of wounds directly affects the quality of life. However, wound care often comes with acute pain, which is short but high in intensity, causing patients to fear and affecting subsequent treatment. Several studies investigated the effect of nitrous oxide (N₂O) in conscious patients undergoing wound care and no consistent conclusion was made. Patients started inhaling N₂O 2–3 min before the onset of wound care and did not stop until the procedure were completed. Therefore, this review provides a thorough appraisal of the effectiveness of N₂O in patients undergoing wound care.

TRANSLATIONAL RELEVANCE

The relief of wound care–related pain is of the utmost importance, given the high incidence of acute pain in hospitals. Opioids remain the mainstay of treatment for moderate and severe pain, with side effects of respiratory depression, constipation, and itching. N₂O as an inhalation analgesic and sedative anesthetic has the characteristics of noninvasive and rapid clinical effect, and it might also be combined with other analgesics, which could be largely superior to the currently used single-method analgesia. In the future, medical workers should carefully choose the safest and the most effective analgesic methods based on patient needs and wound conditions in wound care.

CLINICAL RELEVANCE

This systematic review and meta-analysis suggested that N₂O might reduce wound care–related pain, especially in patients with burns. It can be used as a safe and readily available noninvasive substitute when intravenous or topical anesthesia is not suitable or contraindicated in wound care. More large-scale randomized controlled trials are needed to evaluate the efficacy of N₂O in patients undergoing wound care in the future.

INTRODUCTION

Procedural pain is caused by wound dressing change and debridement.¹ Debridement refers to the removal of nonviable material, foreign bodies, and poorly healing tissue from the wound. It remains an important adjunct to good wound care and is highly valued by surgeons for the removal of tissue with the highest bacterial count, reliable cultures, and identification of osteomyelitis.² However, the primary risk of debridement is pain, which is acute and lasts for a short time, and the pain intensity is particularly high, causing patients to fear wound care and subsequent treatment. Studies have pointed out that several routine procedures are the main sources of pain.

A survey indicated that in a French university hospital, 64% of hospitalized patients reported pain during daily minor procedures.³ Pain as an unpleasant sensory and emotional experience relates to actual or potential tissue damage and has become the fifth vital sign after respiration, temperature, pulse, and blood pressure.⁴ As a strong and lasting source of stress, pain seriously affects patients’ sleep and appetite, increases the high metabolism caused by trauma, causes anxiety, anger, depression, and other adverse psychological reactions, and leads to physical and psychological fatigue, which harms wound treatment and healing.^5,6

The most commonly used analgesic procedures include intravenous anesthesia, local anesthesia, and oral analgesics. However, the insufficient analgesic efficacy and obvious side effects of drugs with long postanesthetic recovery may delay healing and reduce patients’ compliance.⁷ In addition, most drugs used in general anesthesia often cause respiration and circulation repression in patients. Dependence and tolerance to anesthetic drugs may also occur.⁸ N₂O appears to be an available method in minor procedures owing to its simple operation and mild side effects. As an inhalation analgesic and sedative anesthetic, it has the characteristics of noninvasive, rapid, and good clinical effect, and it is widely used internationally for acute pain.^9
–11

In recent years, several studies investigated the effect of N₂O in conscious patients undergoing wound care such as dressing change and debridement. Patients started inhaling N₂O 2–3 min before the onset of wound care and the N₂O inhalation did not stop until the surgical procedure was completed. At present no consistent conclusion on the efficacy of N₂O in wound care–related pain was made. When trials reach divergent conclusions, a systematic quantitative review of the original clinical trials is a helpful method of assessing the evidence. Therefore, we performed a systematic review and meta-analysis to compare the efficacy of N₂O with other analgesic methods in patients undergoing wound care.

METHODS

This systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines¹² (Supplementary material Table S1 and Supplementary Data S1). The protocol was prospectively registered in the PROSPERO register of systematic reviews (registration number CRD 42023425552), available at https://www.crd.york.ac.uk/PROSPERO/. We made no significant amendments to the original protocol. No formal ethical approval was required.

Search strategy

To define the most appropriate keywords and create an exhaustive search strategy, the search strategy was piloted and refined based on updated Cochrane guidelines.¹³ We systematically searched PubMed, Embase, the Cochrane Library, Web of Science, Scopus, and the ClinicalTrials.gov up to February 2023 using the MeSH terms and appropriate corresponding keywords: “Nitrous Oxide,” “Laughing Gas,” “Nitrogen Protoxide,” “Dressing Change,” “Debridement,” and “Wound Dressing.” Then, the references of included studies were screened manually to identify additional references. PROSPERO register of systematic reviews was also searched for ongoing or recently completed reviews. No language or temporal limit was applied. The literature search, study inclusion and exclusion criteria, and data extraction were performed by two authors independently.

Eligibility criteria

Inclusion criteria followed the participants, interventions, comparators, outcomes, and study design (PICOS) framework.¹⁴ Participants: Studies had to be conducted on adults and were focused on wound care (i.e., dressing change and debridement) at whatever wound site (i.e., trunk and limbs). Intervention: N₂O inhalation aimed at reducing pain induced by wound care. Comparators: Placebo or other analgesic methods. Outcomes: Included trials had to examine outcomes of patient-reported pain intensity, and secondary outcomes at least following one of the endpoints: patient satisfaction, side effects, and duration of the procedure. Study Design: Interventional studies were included (i.e., clinical trials, controlled clinical trials, and randomized controlled trials). Proceedings, research protocols, and gray literature were excluded.

Meta-analysis was based on trials identified in the systematic review. A separate meta-analysis was performed for each analgesic intervention as long as it involved at least two included studies. No meta-analysis will be conducted if there were fewer than two included studies on the intervention.

Screening and data extraction

Two researchers independently screened the title and abstract of identified studies using Endnote X9 (Thomson Scientific, USA), removed duplicates, and reviewed the full text of the potentially relevant studies. Data on study characteristics (first author, year of publication, country, interventions, controls, adjuvant analgesics, and main outcomes), sample characteristics (number, gender, age, and wound types), narrative summary of findings, and quantitative results were independently extracted by two researchers and entered into an excel data collection form. We would contact the original author by e-mail if data needed clarification or were not presented in the article. Any disagreement or uncertainty regarding eligibility and data extraction was resolved by a third assessor.

Risk of bias and certainty of evidence

Risk of bias was assessed by two independent researchers using the revised Cochrane Collaboration Risk of Bias Tool to examine potential bias from the randomization process, allocation concealment, performance and detection bias, missing outcome data, measurement of the outcome, and selection of reported results for all randomized trials.¹⁵ The certainty of the evidence of meta-analysis comparisons was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. The GRADE approach considers study limitations, indirectness, inconsistency, imprecision, and publication bias to rate the certainty of the evidence.¹⁶

Primary and secondary outcomes

Patients’ perception of wound care pain was the primary outcome, defined as pain during wound care or the overall experience of wound care–related pain.

When no point of time was specified, we classified it as pain during the procedure. When pain was assessed at several time points, we only extracted pain score immediately after the procedure. The primary outcome was expressed using the mean on a visual analog scale (VAS) or numeral rating scale (NRS) of 0–10 with standard deviation (SD). Conversion was applied when necessary (e.g., when expressing the pain as mean on 0–100 or median). All other wound care–related outcomes reported across studies were marked as secondary outcomes. The definition for each outcome above was the same as that used in each included study.

Data synthesis

All analyses were completed in Review Manager software (version 5.3; Nordic Cochrane Center, Cochrane Collaboration). The differences were shown as the risk ratio (RR) with 95% confidence interval (CI) of the dichotomous outcome and the weighted mean difference (MD) with 95% CI of the continuous outcome. Where possible, heterogeneity was assessed by reporting 95% prediction intervals and the I ² statistic. I ² values of 0–49.9%, 50–74.9%, and >75% were, respectively, considered to have low, moderate, and high heterogeneity.¹⁷ Contrary to the estimated pooled mean effect size, the prediction interval represents the dispersion of the effects. Statistical significance was considered p < 0.05. When there were >10 studies included in the meta-analysis, meta-regression was conducted. Publication bias was appraised by visually examining a funnel plot when ≥10 trials were available.¹⁸

Sensitivity analysis

Sensitivity analysis involved exploring the role of outliers and influential studies, conducting by omitting one study at a time, and investigating the impact of individual studies on the overall pooled estimate.

Subgroup analysis

The following subgroup analyses were performed to explore heterogeneity in the meta-analysis estimates. These included different wound types (burns or ulcers), different comparators (placebo, intravenous anesthesia, or topical anesthesia), and different time points (during or after procedure).

RESULTS

Overall, the search strategy rendered 265 articles; 184 studies were screened at the title and abstract phase and 11 full texts were assessed. Four studies did not meet the inclusion criteria and were excluded; thus, seven studies^19

–25 were included in the systematic review. One²⁴ article included in the systematic review was not eligible for inclusion in the meta-analysis, as N₂O was used both in the intervention group and in the control group. Therefore, six studies^{19

–23,25} were finally included in the meta-analytic process (Fig. 1).

Figure 1.

Flow chart of study selection.

Study characteristics

The included studies were published between 2008 and 2020, with sample sizes ranging from 30 to 240; 330 patients were included in the intervention arm and 211 patients were in the control arm. The included trials were conducted in five countries: two in France,^19,20 two in China,^21,24 one in Brazil,²² one in Switzerland,²³ and one in Iran.²⁵ All participants of studies contained males and females. All the included studies were randomized controlled trials, of which four^20,21,24,25 were parallel and three^19,22,23 were crossover design. Three trials^19,20,23 were open label, two^22,24 were single blinded, and two^21,25 were double blinded.

Two trials included multiple groups, of which one trial¹⁹ included N₂O group, morphine group, and morphine plus N₂O group, and the other trial²⁵ included N₂O group, gabapentin group, ketamine group, and dexmedetomidine group. Two trials^21,22 compared N₂O with oxygen, and four trials compared N₂O with other analgesic methods (local anesthesia^20,23 and intravenous anesthesia^19,25). The study setting was in the clinic in one trial²³ and in the burn center in one trial,²⁴ and the remaining^19

–22,25 were at the hospital. The wound types included burns^21,22,24,25 and ulcers.^19,20,23 The characteristics and outcomes of included studies are presented in Table 1.

Table 1.

Characteristics of included randomized controlled trials

		Participants
Author	Country	No. of Patients (N/C)	Sex (M/F)	Age (Years)	Wound Types	Intervention	Control	Adjuvant Analgesics	Outcomes
Paris et al 2008¹⁹	France	34/34	M/F	84 (53/96)	Ulcers	N₂O–oxygen mixture was inhaled 5 min before and during painful procedure	Morphine chlorhydrate was administered subcutaneously 30 min before painful procedure	None	Pain score (VAS: 0–10) Side effects; Duration of procedure
Claeys et al 2011²⁰	France	20/21	M/F	N group: 78(57–87); C group: 77(51–89)	Ulcers	N₂O–oxygen mixture (NOOM) inhalation 3 min before the procedure	Lidocaine–prilocaine cream (LPC) application 30 min before the procedure	None	Pain score (VAS: 0–10) Satisfaction; Ramsay scale; Side effects
Li et al 2013²¹	China	180/60	M/F	N group: 30 ± 11; C group: 30 ± 13	Burns	65% N₂O /O₂ inhalation	Oxygen inhalation	None	Pain score (VAS: 0–10) Side effects;
Vale et al 2016²²	Brazil	15/15	M/F	36.27	Burns	65% N₂O /O₂ inhalation	Oxygen inhalation	Fentanyl 0.0005% administered by intravenous pump infusion on-demand	Pain score (VAS: 0–10); Satisfaction; Side effects; Duration of procedure
Traber et al 2017²³	Switzerland	21/21	M/F	75.62 ± 13.55	Ulcers	50% N₂O /O₂ inhalation	Topical analgesia with 5% lidocaine/prilocaine cream	None	Pain score (VAS: 0–10); Side effects; Satisfaction; Duration of procedure
Li et al 2019²⁴	China	35/35	M/F	18–65	Burns	50% N₂O /O₂ inhalation	Titrated with N₂O /O₂ inhalation	None	Pain score (NRS: 0–10); Anxiety level (NRS); Side effects
Chaghazardi et al.2020²⁵	Iran	25/25	M/F	34.64 ± 7.47 (21–52)	Burns	Entonox inhalation	Intravenous ketamine	None	Pain score (VAS: 0–10); Ramsay scale; Side effects

N group, nitrous oxide group; C group, control group.

Risk of bias and quality of evidence

One trial was classified as having low risk of bias, four provided some concerns, and two were classified as high risk of bias. Bias due to blinding of participants and personnel, blinding of outcome assessment, and allocation concealment were of the greatest concern. The risk of bias and details for judgment of bias are shown in Figure 2 and Supplementary material Table S2, respectively. The quality of evidence was low for pain scores and moderate for other outcomes, as presented in Table 2. Publication bias was not conducted due to the limited number of included studies.

Figure 2.

Risk of bias assessment.

Table 2.

Summary of GRADE evidence profile

Outcome	No. of Studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Publication bias	Effect size	Certainty	Importance
Outcome	No. of Studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Publication bias	(95% CI)	Certainty	Importance
Pain score	6	RCT	Serious^a	Serious^b	Not Serious	Not Serious	Undetected	MD −0.11	Low	Critical
Pain score	6	RCT	Serious^a	Serious^b	Not Serious	Not Serious	Undetected	(−1.38, 1.15)	Low	Critical
Degree of satisfaction	3	RCT	Not Serious	Not Serious	Not Serious	Not Serious	Undetected	MD 0.98	Moderate	Important
Degree of satisfaction	3	RCT	Not Serious	Not Serious	Not Serious	Not Serious	Undetected	(0.78, 1.23)	Moderate	Important
Side effects	5	RCT	Not Serious	Not Serious	Not Serious	Not Serious	Undetected	RR 1.31	Moderate	Important
Side effects	5	RCT	Not Serious	Not Serious	Not Serious	Not Serious	Undetected	(0.76, 2.26)	Moderate	Important
Incidence of nausea and vomiting	4	RCT	Not Serious	Not Serious	Not Serious	Serious^c	Undetected	RR 0.95	Moderate	Important
Incidence of nausea and vomiting	4	RCT	Not Serious	Not Serious	Not Serious	Serious^c	Undetected	(0.40, 2.22)	Moderate	Important

GRADE, quality of evidence grade; CI, confidence interval; RCT, randomized controlled trial; RR, risk ratio; SMD, standardized mean difference.

Data reported as downgraded because of some concerns of bias.

Substantial heterogeneity (I ² = 97%) was found.

Data reported as downgraded because of wide CI or inadequate studies.

Primary outcome

Seven studies in the systematic review explored patients’ perception of wound care–related pain, of which two^19,20 assessed pain immediately after the procedure, and five^21

–25 explored overall pain experience. Two studies^24,25 assessed pain at several time points. Different tools were used to assess wound care–related pain, including the VAS^{19

–23,25} and NRS.²⁴ Three trials^21,22,25 explored the wounding dressing, two^20,23 were debridement, and two^19,24 referred to all the wound care–related pain. VAS results were not analyzed in one study,¹⁹ as incomplete data were available. Ultimately, the pain score was available in five studies.^20

–23,25

Pooled analysis suggested that there was no significant difference in reducing wound care–related pain between the N₂O group and the control group (MD, −0.02; 95% CI, −1.46, 1.42; p = 0.98; Fig. 3), with significant heterogeneity (I ² = 96%). Sensitivity analysis was conducted by omitting one study in each turn, and heterogeneity was significantly changed when Claeys et al.’s study²⁰ was excluded (p = 0.002; I ² = 0%). Subgroup analyses were performed to examine the influence of different wound types, control groups, and time points on the pain score.

Figure 3.

Forest plot for the pain score.

There was a significant difference in favor of N₂O for burns^21,22,25 (MD, −0.68; 95% CI, −1.10, −0.26; p = 0.002, I ² = 0%), whereas there was no significant difference for ulcers^20,23 (MD, 0.81; 95% CI, −1.02, 2.64; p = 0.39; I ² = 84%; Fig. 4). Pooled analysis showed that in reducing wound care–related pain, the effect of N₂O was superior to oxygen^21,22 (MD, −0.91; 95% CI, −1.53, −0.29; p = 0.004; I ² = 0%), and was similar to topical anesthesia^20,23 (MD, 0.81; 95% CI, –1.02, 2.64; p = 0.39; I ² = 84%) and intravenous anesthesia²⁵ (MD, –0.48; 95% CI, −1.06, 0.10; Fig. 5). In addition, the pain score during the procedure in the N₂O group^21
–23,25 (MD, −1.62; 95% CI, −6.80, 3.57; p = 0.54; I ² = 100%) was not significantly different from that in the control group, while the pain score post procedure in the N₂O group was significantly lower than that in the control group^21
–23,25 (MD, −0.65; 95% CI, −1.06, −0.24; p = 0.002, I ² = 0%; Fig. 6).

Figure 4.

Forest plot of subgroup analysis for pain score by different wound types.

Figure 5.

Forest plot of subgroup analysis for pain score by different controls.

Figure 6.

Forest plot of subgroup analysis for pain score by different time points.

Secondary outcomes

Satisfaction

The degree of patients’ satisfaction was reported in three trials^20,22,23 with 100 patients. There was no significant difference between the N₂O group and the control group (RR, 0.98; 95% CI, 0.78, 1.23; p = 0.87; I ² = 0%; Supplementary material Fig. S1).

Side effects

Five studies^19

–22,25 reported the overall incidence of side effects, and pooled analysis showed that N₂O did not increase the incidence of side effects compared with other analgesic methods (RR, 1.31; 95% CI, 0.76, 2.26; p = 0.34; I ² = 0%; Supplementary material Fig. S2). Data for nausea and vomiting were available from four trials.^19,21,22,25 Pooled analysis showed no significant difference between groups (RR, 0.95; 95% CI, 0.40, 2.22; p = 0.90; I ² = 0%, Supplementary material Fig. S3).

Duration of the procedure

The mean duration of the procedure was available in three trials^19,22,23 in the systematic review. The mean time was significantly shorter for N₂O versus morphine¹⁹ (16.7 min versus 20 min, P < 0.001), or N₂O versus fentanyl²² (38.8 min versus 43.33 min), and was similar when N₂O versus lidocaine/prilocaine cream²³ (29.48 min versus 28.43 min, p = 0.82).

DISCUSSION

To the best of our knowledge, this was the first systematic review and meta-analysis aimed to investigate the efficacy of N₂O in adults undergoing wound care–related pain. In addition to placebo (oxygen), our review identified four analgesic techniques in the control group, including fentanyl, morphine, ketamine, and lidocaine/prilocaine cream. The evidence accumulated in this study suggested that N₂O could provide better analgesia than oxygen and similar analgesia to other analgesic methods and relieve pain with shorter duration of procedure and mild side effects during the process of wound care.

Wound care is the process of removing dressings, debridement, medication, and bandage for wounds. It is the foundation of wound healing, widely used in burns, ulcers, trauma, and surgical wounds. Efforts are directed at techniques that facilitate wound healing, prevent infection, promote comfort, and meanwhile, maintain optimal function and minimize deformities.²⁶ However, the whole treatment process is often not feasible due to the limited potency of the analgesic method, especially in patients when extensive or deep wound debridement is intended. It is also known that insufficient pain control is a significant predictor of impaired quality of life.^27,28 Therefore, the availability of a potent analgesic method is critical to the overall success of painful wound care not only because of patient comfort and optimal treatment but also because painful process of debridement and dressing change would jeopardize patients’ adherence to further therapy.

Our findings showed that N₂O was not significantly different from other analgesic methods in reducing wound care–related pain, suggesting that N₂O might provide adequate analgesia for adults. Subgroup analyses showed that compared with the control group, N₂O had a better analgesic effect on burns,^21,22,25 and a significantly lower immediate postprocedure pain score.^21
–23,25 A possible explanation could be that, in addition to pain relief, N₂O has sedative and antianxiety properties, so it may increase the patient’s pain threshold, resulting in lower immediate postprocedure pain score.²¹ In pooled analysis of two trials for ulcers, the effect of N₂O is similar to 5% lidocaine/prilocaine cream during the procedure.^20,23

Traber et al.²³ described that a plausible explanation could be that the oil-in-water-based character of lidocaine/prilocaine cream might be able to macerate the wound and thus allow more effective and deeper debridement with a lower level of pain for the patient. On the other hand, Stahl et al.²⁹ found the vasoconstrictive effects of lidocaine/procaine cream, which may exacerbate ulcer progression. The 50% N₂O/O₂ would precipitate its analgesic properties systemically with no topical activity on the wound itself, and can be regarded as an effective substitute when intravenous or topical anesthesia is not suitable or contraindicated in wound care.

Opioids remain the mainstay of treatment for moderate and severe pain. However, the incidence of side effects can be as high as 76–92% in patients with acute pain, such as respiratory depression, constipation, and itching.^8,30 One of the biggest problems faced in wound care is that patients may undergo frequent procedures. Thus, patients need to undergo intravenous anesthesia every other day, or even daily, with prolonged fasting and long periods of postanesthetic recovery.³¹

The consequences may be malnutrition and delayed wound healing. Dependence and tolerance to analgesics may also occur.³² Differed from opioids, N₂O remained intact in airway reflexes and had no negative effect on respiration. The primary effects of N₂O are exerted in the central nervous system, with analgesic action on supraspinal GABA (γ-aminobutyric acid) inhibition and spinal GABA activation.³³ Studies reported that N₂O, as an NMDA (N-methyl-D-aspartic acid) antagonist, could be able to inhibit opioid-induced postoperative hyperalgesia and decrease consumption of opioids.^34,35

The duration of procedure was reported in three included trials^19,22,23 in this review. The mean time was significantly shorter for N₂O versus morphine (16.7 min vs. 20 min; p < 0.001), or N₂O versus fentanyl (38.8 min vs. 43.33 min), and was similar when N₂O versus lidocaine/prilocaine cream (29.48 min vs. 28.43 min; p = 0.82). Mraovic et al.³⁶ found that adding N₂O to isoflurane anesthesia significantly shortened the recovery time of patients undergoing laparoscopic assisted vaginal hysterectomy. This property has a positive effect on promoting patients’ recovery, shortening hospital stays, reducing economic burden, and improving satisfaction.

The above characteristics suggested that N₂O was better suited for patients who cannot tolerate the side effects of opioids or needed rapid and frequent analgesia. Alternatively, N₂O might also be combined with other analgesics, which could be largely superior to the currently used single-method analgesia. In the future, medical workers should carefully choose the safest and most effective analgesic methods based on patient needs and wound conditions in wound care. It is noteworthy that anesthesia is responsible for approximately 1% of N₂O emissions in the atmosphere, which is substantial. Hence, N₂O should be used by trained people and attention should ideally be paid to scavenge it properly.

Limitations

Two trials included in this systematic review and meta-analysis were at high risk of bias. The main areas of bias were the blinding setting and allocation concealment, because of the different characteristics of N₂O and other analgesics. In addition, some of our results may be limited by the low number of trials available for subgroup analyses, which needs larger sample trials in the future so as to increase the reliability of results. In addition, one study²¹ included minor patients older than 16 years and we believed that adolescents older than 16 years had complete communication skills and the ability to express their own perception. Furthermore, the overall high risk of bias in the studies, the ratio of N₂O to oxygen, the analgesic drugs used in the control group, the severity of the wound, and the operators were all factors contributing to the significant heterogeneity among the included trials.

CONCLUSION

This systematic review and meta-analysis highlights the effectiveness of N₂O in reducing wound care–related pain. N₂O has rapid onset and may represent a safe and readily available noninvasive substitute when intravenous or topical anesthesia is not suitable or contraindicated in wound care. Caution must be taken when interpreting these results, due to the high risk of biased methods in the included studies and the heterogeneity observed across studies.

TAKE HOME MESSAGES

Insufficient pain control is a sign of impaired quality of life.

Regarding the successful performance of wound care, the effectiveness, cost, and patient compliance are the three key factors for clinical decision-making.

The findings suggested that N₂O might be effective in patients undergoing wound care. However, when interpreting these results, caution must be taken due to the high risk of biased methods in the included studies.

Footnotes

ACKNOWLEDGMENTS AND FUNDING SOURCES

This study was supported by clinical medical science and technology innovation project of Jinan (Grant number: 202019025). The funders had no role in the conduct of the research.

AUTHOR CONFIRMATION

As the submitting author, L.T. confirms to have written consent from all authors to submit the article and that all authors accept complete responsibility for the contents of the article. This article has not been previously published.

AUTHOR DISCLOSURE AND GHOSTWRITING

The authors have no financial interests to disclose. The content of this article was thoroughly written by the authors. No ghostwriter was used to write this article.

ABOUT THE AUTHORS

Ziyang Wang is a third-year master’s degree student at Weifang Medical University. Fei Wang is Deputy Chief Physician of Anesthesiology Department at PLA 960^th Hospital, People’s Republic of China. Xiaochen Jiang, Weifeng Wang, Yihui Xing, Xueling Qiu, and Chenxi Sun are second-year master’s degree students majoring in nursing. Lu Tang is Head Nurse of Stomatology Department at PLA 960^th Hospital, People’s Republic of China.

SUPPLEMENTARY MATERIAL

Supplementary Figure S1

Supplementary Figure S2

Supplementary Figure S3

Supplementary Table S1

Supplementary Table S2

Supplementary Data S1

Abbreviations and Acronyms

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