1. Background
Pain is a major public health issue throughout the world and represents a major clinical, social, and economic problem (1, 2). Labor pain is one of the most acute pains that women experience during their lives (3). The psychological effects of severe pain should not be ignored, especially when they are associated with adverse maternal or fetal outcomes.
There are different methods of pain relief used during labor with different side effects and efficacies. One of the most common methods is the inhalation of 50% nitrous oxide (4, 5). Nitrous oxide is an odorless, tasteless, inhaled analgesic (6) that has been found to be an effective analgesic for many women that is safe for both mothers and babies (4). Use of nitrous oxide during labor began in the late 1800s, and Minnitt in England introduced equipment for self-administration in 1934. Nitrous oxide is usually run through a mouth mask intermittently, starting about 30 seconds before each contraction (7, 8). Inhalation of 50% nitrous oxide can significantly decrease anxiety without clinically significant side effects, and its effects are quickly reversible upon discontinuation of inhalation (8, 9).
Pethidine or meperidine hydrochloride was the first synthetic opioid, synthesized in 1932 (9). Systemic pethidine is routinely used throughout the UK for labor analgesia (10, 11). However, systemic opioids lead to some complications for mothers (12, 13) and babies (14). Since pethidine passes through the placenta, pethidine may accumulate in the fetal circulation (8), causing early neonatal respiratory depression and behavioral and feeding problems for up to six weeks after delivery (14).
2. Objectives
In present study, we aimed to assess the safety of using inhaled 50% nitrous oxide as an analgesic during labor in comparison to intramuscular pethidine among women undergoing normal vaginal delivery.
3. Methods
This study was a randomized clinical trial conducted in Alavi hospital (Ardabil, Iran) in 2015. One hundred pregnant women who were in the initial phase of labor were enrolled in study. The sample size was calculated with a confidence of 95% and a power of 80%.
3.1. Patient Selection
The inclusion criteria for this study were the commencement of spontaneous labor pain along with appropriate maternal and fetal indications for vaginal delivery. The exclusion criteria were the presence of a personality disorder, an addiction, a complicated pregnancy, diabetes mellitus, macrosomia, chronic obstructive pulmonary disease, an unconfident fetal heart rate, valvular heart disease, an upper respiratory tract infection or sinus obstruction, a history of asthma, and contraindications for Entonox and pethidine usage.
By using random numbers, the subjects were randomly allocated into two groups, with one group using Entonox and the other receiving an intramuscular injection of 0.5 mg/kg of pethidine for pain relief.
3.2. Ethics Declaration
The study was reviewed and approved by the Ardabil University of Medical Science Ethics Committee. Information about the study was given comprehensively to all patients. Informed consent was obtained from all patients according to the University Ethical Committee. This study has been registered at www.irct.ir with the code IRCT 201503244256N6.
3.3. Data Collection
A questionnaire to collect information about the patients’ demographic characteristics, their severity of pain, the duration of the first and second stage of labor, the duration and interval of uterine contractions, any neonatal and maternal complications, and the side effects of drugs was completed by the researcher through the intervention.
Patients were taught to use an Entonox face mask at the beginning of uterine contractions and to continue deep inspirations at times when there was pain and cramps. Use of Entonox could be started or cut at any moment during labor according to the needs and preferences of the woman.
The pethidine group received an intramuscular injection of 0.5 mg/kg of pethidine. If a patient’s pain rated higher than 5 VAS, 0.25 mg/kg of pethidine was injected.
Each patient’s parturient pain scored was evaluated according to their VAS score, which was graded from 0 to 10 (0 = no pain and 10 = severe and intolerable pain) once before any analgesic administrations and twice at 30 and 60 minutes after analgesic administration using a structured questionnaire and a subjective labor pain scale (visual-analogue scale).
The vital signs of all parturient were monitored. The main outcomes (pain score, duration of the first and second phase of the labor, and Apgar scores at one and five minutes) were recorded prospectively by one person with one technique. For comparison studies between the two groups, a cervical dilatation of four to five cm was considered the signal of the start of the active phase of labor.
3.4. Statistical Analysis
The results were reported as mean ± standard deviation (SD) for the quantitative variables and percentages for the categorical variables. The groups were compared using a t-test for the continuous variables and a chi-squared test for the categorical variables. A P value ≤ 0.05 was considered to be statistically significant. All the statistical analyses were performed using SPSS version 15.0 (SPSS Inc., Chicago, IL, USA) for windows.
4. Results
Of the 107 pregnant women were enrolled in this study, seven were excluded by the exclusion criteria.
The majority of women in this study were in the 21 - 30-year age range. The mean maternal age was 26.2 and 27.2 in the Entonox and pethidine groups, respectively. The demographic data of the participants is summarized in Table 1.
Table 1. The Frequency Distribution of the Demographic Characteristics of the Pregnant Women in the Intervention Groupsa
| Characteristics | Entonox (n = 50) | Pethidine (n = 50) | Total Number | P Value |
|---|---|---|---|---|
| Age, y | ||||
| < 20 | 16 (32) | 9 (18) | 4 (4) | |
| 21 - 30 | 29 (58) | 34 (68) | 63 (63) | |
| 31 - 40 | 5 (10) | 7 (14) | 12 (12) | |
| Habitant | 0.099 | |||
| Village | 13 (26) | 16 (32) | 29 (29) | |
| City | 37 (74) | 34 (68) | 71 (71) | |
| Level of Education | 0.002 | |||
| Illiterate | 1 (2) | 1 (2) | 2 (2) | |
| Junior and Senior High School | 27 (54) | 29 (58) | 56 (56) | |
| Diploma and University | 22 (44) | 20 (40) | 42 (42) | |
| Gestation (weeks), mean ± SD | 38.86 ± 2.95 | 38.36 ± 2.11 | NS |
aValues are expressed as No. (%) unless otherwise indicated.
The average pain scores 30 minutes after intervention in the Entonox and pethidine groups were 3.94 ± 1.4 and 5.6 ± 1.1, respectively, (P = 0.001), but there was not a significant difference in the severity of the pain between the two groups 60 minutes after intervention (P > 0.05). No significant differences were seen in the duration and interval of uterine contractions, maternal complications, Apgar score, and in the duration of the first and second stage of labor between the two studied groups (P > 0.05). An analysis of the pooled risk differences showed that none of the side effects investigated were significantly different between the two groups except for mouth dryness, which was significantly higher in the nitrous oxide users (P = 0.044) (Table 2).
Table 2. Descriptive Data of the Entonox and Pethidine Subjects
| Characteristics | Entonox | Pethidine | P Value |
|---|---|---|---|
| Duration | |||
| First stage, hour | 3.15 ± 1.65 | 3.65 ± 1.76 | 0.124 |
| Second stage, minute | 33.7 ± 13.2 | 31.6 ± 7.5 | 0.124 |
| VAS mean score | |||
| Before analgesia | 7.38 ± 2 | 7.3 ± 1.1 | 0.812 |
| 30 minutes after analgesia | 3.94 ± 1.4 | 5.6 ± 1.1 | 0.044 |
| 60 minutes after analgesia | 5.06 ± 1.4 | 4.7 ± 1.1 | 0.592 |
| Systolic blood pressure | |||
| Before analgesia | 113.33 ± 12.64 | 114.32 ± 8.52 | 0.185 |
| After analgesia | 115.67 ± 9.12 | 114.39 ± 8.21 | 0.067 |
| Duration of uterine contractions | |||
| Before analgesia | 39.32 ± 9.12 | 38.82 ± 7.21 | 0.12 |
| After analgesia | 40.32 ± 6.12 | 41.32 ± 5.45 | 0.08 |
| Interval of uterine contractions | |||
| Before analgesia | 120.72 ± 32.61 | 129.35 ± 8.66 | 0.34 |
| After analgesia | 123.37 ± 46.47 | 118.39 ± 3.67 | 0.09 |
| Apgar score | |||
| First minute | 9 ± 0.1 | 8 ± 9 | 0.465 |
| Fifth minute | 9.91 ± 0.4 | 9.88 ± 0.2 | 0.598 |
5. Discussion
Nitrous oxide has low solubility in blood and is transported in a solution without binding to protein. Nitrous oxide takes effect rapidly (15) because it spreads rapidly through the lining of the arterial alveolar membrane and is excreted unchanged mainly through the lungs (6). As a result, the effects of nitrous oxide are quickly reversible upon the discontinuation of therapy (16). The recovery time from the effects of nitrous oxide sedation is faster than that of intravenous analgesia (6).
The analgesic effect of pethidine starts within 10 - 20 minutes and lasts two to four hours after being administered intramuscularly (17). The rate of use of parental opioids was between 39% and 56% in various hospital obstetrics units in the United States (10). However, many studies have suggested that intramuscular pethidine may be ineffective at relieving labor pain and that their use may even be unethical and medically incorrect (18, 19).
In this study, pain severity, which was defined according to a patient’s VAS score, was significantly lower in patients who received nitrous oxide 30 minutes after intervention, but there was not a significant difference in the severity of pain between the patients in the two groups 60 minutes after intervention.
Research has shown that 80% or more of a 100-mg dose of pethidine administered intramuscularly is absorbed over six hours with a mean time of maximum plasma concentration of approximately 24 minutes. With intramuscularly administered pethidine, analgesia may persist for two to four hours following intramuscular, intravenous, or subcutaneous administration (12).
With an intramuscular pethidine injection, appropriate levels of pethidine still exist in the plasma 60 minutes after intervention. In contrast, Entonox consumption requires more cooperation from patients. With the progression of labor and the exacerbation of pain, participants’ cooperation with Entonox use decreases, which might increase a patient’s 60-minute pain score compared to their 30-minute score.
No significant changes in the maternal cardiorespiratory parameters were noted with either of the two analgesics. Associated factors and transplacental transmission of the analgesic from mother to fetus can affect the Apgar scores of the babies at birth. The ideal analgesic is one that has no adverse effect on the fetus. In our study, the Apgar scores of the babies at birth were satisfactory, and no significant difference was observed between infant complications and Apgar scores in the two groups.
Abdollahi et al. concluded that intravenous paracetamol was more effective than intramuscular pethidine at relieving labor pain in normal vaginal deliveries (19).
Pasha et al. showed that the use of 50% nitrous oxide caused less labor pain, favorable expectations and experiences, and also greater maternal satisfaction compared with a control group that did not receive gas (20).
An analysis of the pooled risk differences showed that none of the side effects investigated were significantly different between the two groups except mouth dryness, which was significantly higher in nitrous oxide users.
As a result, inhaled nitrous oxide seems to give better pain relief in the short term compared to a single dose of pethidine. Since Entonox is more convenient to administer, it is also regarded as safe for both mothers and neonates.
