Expert Review ajog.

org

Pharmacologic and nonpharmacologic options for

pain relief during labor: an expert review
Sivan Zuarez-Easton, MD; Offer Erez, MD; Noah Zafran, MD; Julia Carmeli, MD; Gali Garmi, MD; Raed Salim, MD

Introduction
Labor pain is among the most severe types of physical pain that women may experience Pain is a central feature of parturition in
during their lifetime. Thus, pain relief is an essential part of medical care during child- humans, and its relief is an essential part
birth. Epidural analgesia is considered to be the most efficient method of pain relief of medical care during labor and de-
during labor. Nevertheless, patient preferences, contraindications, limited availability, livery.1 The perception of pain during
and technical failure may require the use of alternative pain reliving methods during labor labor is highly individual: although some
including systemic pharmacologic agents, and nonpharmacologic methods. women can cope with labor pain on their
Nonpharmacologic methods for pain alleviation during vaginal birth have become popular own, others require some form of inter-
over the years, either as a complement to pharmacologic agents or at times as the principal vention that could be nonpharmacologic,
therapy. Methods such as relaxation techniques (ie, yoga, hypnosis, and music), manual systemic pharmacologic, and/or epidural.
techniques (ie, massage, reflexology, and shiatsu), acupuncture, birthing ball, and trans- Currently, epidural analgesia is regarded
cutaneous electrical nerve stimulation are considered safe, although the evidence sup- as the leading and most effective treat-
porting their effectiveness for pain relief is not as robust as it is for pharmacologic agents. ment for labor and delivery pain.2 How-
Systemic pharmacologic agents are mostly administered by inhalation (nitrous oxide) or ever, this method has an 8.5% failure
through the parenteral route. These agents include opioids such as meperidine, nalbu- rate,3 and its downsides include costs,
phine, tramadol, butorphanol, morphine, and remifentanil, and non-opioid agents such as prolonged labor, reduction in women’s
parenteral acetaminophen and nonsteroidal anti-inflammatory drugs. Systemic pharma- sense of control and their participation in
cologic agents suggest a diverse armamentarium of medication for pain management the labor process, and can involve adverse
during labor. Their efficacy in treating pain associated with labor varies, and some continue effects such as intrapartum fever, dural
to be used even though they have not been proven effective for pain relief. In addition, the puncture, and postpartum headache.2,3
maternal and perinatal side effects differ markedly among these agents. There is a relative The use of nonpharmacologic and
abundance of data regarding the effectiveness of analgesic drugs compared with epidural, pharmacologic agents to provide relief
but the data regarding comparisons among the different types of alternative analgesic from labor pain, has a rich history. Until
agents are scarce, and there is no consistency regarding the drug of choice for women who the early 1900s, most children were
do not receive epidural pain management. This review aims to present the available data delivered at home, and pain during labor
regarding the effectiveness of the different methods of relieving pain during labor other was managed mainly with non-
than epidural. The data presented are mainly based on recent level I evidence regarding pharmacologic methods.4 Starting from
pharmacologic and nonpharmacologic methods for pain relief during labor. the mid-1800s, there are records indi-
cating the use of pharmacologic agents to
Key words: acupuncture, aromatherapy, birthing ball, chemical nociceptive mediators, attenuate labor pain. Initially, chloroform
complementary and alternative medicine, GB 21 acupressure, hypnosis, Iyengar yoga, as a volatile gas, was used to treat labor
labor pain, level I evidence, massage, mindfulness, music, myometrial ischemia, nitrous pain, and was even adopted by Queen
oxide, non-opioid agents, opioids, pain relief, patient-controlled analgesia, perineal Victoria in England, leading to it being
structures distention, referral pain, Qi, reflexology, shiatsu, sterile water injection, referred to as “chloroform à la reine.”
transcutaneous electrical nerve stimulation, warm packs, yoga Currently, a wide variety of non-
pharmacologic interventions and phar-
macologic agents are used to alleviate
maternal pain in labor. This review will
From the Department of Obstetrics and Gynecology, Emek Medical Center, Afula, Israel (Drs Zuarez- present recent level I evidence regarding
Easton, Zafran, Garmi, and Salim); Department of Obstetrics and Gynecology, Wayne State pharmacologic and nonpharmacologic
University, Detroit, MI (Dr Erez); Department of Obstetrics and Gynecology, Soroka University options for pain relief during the process
Medical Center, Beer Sheva, Israel (Dr Erez); The Ruth and Bruce Rappaport Faculty of Medicine, of labor.
Technion, Haifa, Israel (Drs Zafran, Garmi, and Salim); Department of Anesthesiology, Emek Medical
Center, Afula, Israel (Dr Carmeli); and Department of Obstetrics and Gynecology, Holy Family
Hospital, Nazareth, Israel (Dr Salim). Physiology of labor pain
Received Feb. 24, 2023; revised March 6, 2023; accepted March 7, 2023. Labor pain is considered to be a physi-
The authors report no conflict of interest. ological response to a natural biological
Corresponding author: Raed Salim, MD. r.salim@hfhosp.org process.5 Average scores of pain during
0002-9378/$36.00
ª 2023 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ajog.2023.03.003 labor are reported to be higher than
those associated with bone fracture,

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sciatic, or dental pains (Figure 1).6 Pain

FIGURE 1
may occur because of: (1) myometrial
ischemia during uterine contractions;
Comparison of pain scores between women during labor and other
(2) cervical, vaginal, and perineal
patients
stretching; and (3) distention of other
perineal structures, particularly
throughout the second stage of labor.7,8
Pain is most intense during uterine
contractions. Myometrial ischemia and
related myometrial cellular breakdown,
owing to constriction of the arteries
supplying the myometrium during re-
petitive contractions, can initiate the
release of mediators that may stimulate
chemoreceptors. Such mediators include
bradykinin, acetylcholine, serotonin,
histamine, and potassium ions.8 In
addition, prostaglandins, leukotrienes,
substance P, and lactic acid may also
serve as chemical nociceptive mediators
to play a role in labor pain.9
The type of pain changes as labor
progresses. During the first stage of la-
bor, visceral pain usually predominates.
Nociceptive stimuli from the cervix,
uterus, adnexa, and pelvic ligaments are
transmitted mainly by sympathetic fibers
to the posterior nerve root ganglia at T10
- L1. This pain is a classic referred pain
because it is transmitted from one part of
the body (cervix, uterus, adnexa, and
pelvic ligaments) and projects sensations
to other parts, such as, the lower
abdomen and back (Figure 2).7 As with
other forms of visceral pain, this referred
pain is slowly transmitted, poorly The pain rating index (PRI) represents the sum of the rank values for all words chosen from 20 sets of
confined, and is frequently radiated to pain descriptions using the McGill Pain Questionnaire obtained from women during labor and from
the abdomen, lower back, and rectum.9 patients in general hospital clinics and an emergency department. From Melzack R. The myth of
During the late first stage and early painless childbirth [The John J. Bonica Lecture]. Pain. 1984;19(4):321e337.4 Copy right 1984. This
second stage of labor, distention and figure has been reproduced with permission of the International Association for the study of Pain
traction on the pelvic organs become the (IASP).
Zuarez-Easton. Pharmacologic and nonpharmacologic options for pain relief during labor. Am J Obstet Gynecol 2023.
predominant source of pain. This pain
stimulus is transmitted predominantly
by the pudendal nerves through the
sacral plexus to the posterior nerve root stretching of and pressure on the adnexa, conceptual elements that influence a
ganglia at spinal levels S2 to S4.8 This rectum, urinary bladder, urethra, woman’s interpretation of noxious sen-
pain is very intense and sharp and is lumbosacral plexus roots, and skeletal sory stimuli in the central nervous sys-
localized mainly to the perineum, muscle spasm.8,9 tem throughout labor.11 An important
the anus, the lower part of the sacrum, Pain during labor and its relief are factor that affects pain sensation in
the thighs, and the lower portion of the emotional experiences. Therefore, women and selection of analgesia, is
legs.9,10 The second stage of labor, while intervention directed at emotional fac- their sense of control over their body and
the fetus descends, induces pain owing to tors may lead to a dramatic decrease in the labor process.12 Understanding the
distention of the perineal structures.7,8 perceived pain.10 Indeed, Chapman et al multidimensional characteristics of
Throughout labor, additional pain suggested that there is an extensive pain, along with the individuality of pain
stimuli may be transmitted owing to the variation of distinctive emotional, experience, is essential, because these
traction of parietal peritoneum, motivational, cultural, social, and factors affect preferences and responses

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labor. Nevertheless, high levels of patient

FIGURE 2
satisfaction and the infrequent incidence
Transmission of labor pain. Labor pain has a visceral component and a of adverse events associated with the use
somatic component of complementary and alternative med-
icine during labor, have led professional
societies, including The American Col-
lege of Obstetrics and Gynecology,17 The
European Board and College of Obstet-
rics and Gynecology,18 and the World
Health Organization,19 to acknowledge
its utility as an adjunct to pharmacologic
agents, to alleviate pain during labor
upon maternal request. The most
frequent complementary and alternative
medicine modalities used during labor
are reviewed below:

1. Relaxation techniques (breathing ex-

ercises, yoga, music, hypnosis, and
mindfulness): Relaxation techniques
comprise a wide range of in-
terventions that aim to relax the body
and reduce blood pressure and
breathing rate, resulting in a sense of
increased wellbeing. Several relaxa-
tion methods have been studied,
including breathing exercises, yoga,
music, hypnosis, and mindfulness.20
Noxious impulses from the uterus and cervix follow afferent sensory-nerve A systematic review of randomized,
fibers that accompany sympathetic nerves, traveling through the paracervical region and the pelvic quasi-randomized, and cluster trials
and hypogastric plexus to enter the lumbar sympathetic chain and the dorsal horn of the spinal cord (15 trials including 1731 women)
through the white rami communicantes of the T10, T11, T12, and L1 spinal nerves. Noxious im- examined the effect of mind-body
pulses from the vagina and perineum travel via the pudendal nerve to enter the spinal cord at S2 to relaxation techniques for pain relief
S4. Reprinted with permission from Eltzschig HK, Lieberman ES, Camann WR. Regional anesthesia during labor. The results showed that
and analgesia for labor and delivery. N Eng J Med 2003;348(4):319e332.136 Copyright 2003 relaxation, yoga, and music may assist
Massachusetts Medical Society. All rights reserved. in pain reduction, but the level of
Zuarez-Easton. Pharmacologic and nonpharmacologic options for pain relief during labor. Am J Obstet Gynecol 2023. evidence is low. Insufficient data exist
to determine the role of mindfulness
and audio analgesia, according to this
to pain management interventions in women’s narratives, a positive effect of review.20 Of note, most included tri-
women12 and serve as the basis for complementary and alternative medi- als did not explore the rate of adverse
nonpharmacologic or pharmacologic cines on the subjective experiences of outcomes associated with these in-
pain relief.8 pregnancy and childbirth. This is terventions. A recent randomized
emphasized by the fact that worldwide, controlled trial (RCT) that compared
Nonpharmacologic methods for pain nearly 73% of women use at least 1 yoga and meditation during preg-
relief nonpharmacologic method for pain re- nancy and labor with routine care
Nonpharmacologic methods for pain lief during labor.14e16 The reported found these methods effective in
relief are popular with women in labor, leading methods are breathing tech- reducing pain and fear, and
either as a complement to pharmaco- niques (48%), position changes (40%), increasing a sense of self-confidence
logic agents or, at times, as the principal hands-on techniques (eg, massage) and coping-skills devopment.21
analgesic treatment. Studies have shown (22%), and mental strategies (eg, relax- Moreover, among primigravids who
a positive impact of nonpharmacologic ation) (21%).14e16 did not receive analgesia during labor,
complementary and alternative medi- Currently, there is little high-quality the practice of Iyengar yoga (focusing
cine approaches on the subjective evidence supporting the efficacy of on strength, balance, breathing, and
experience of pregnancy and child- complementary and alternative medi- alignment of body postures) during
birth.13 It is evident from observing cine as an analgesic method during the third trimester was associated

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FIGURE 3
Comparison of Self-hypnosis vs control
Outcome 1 use of pharmacologic pain relief/anesthesia. From Madden et al23 with permission.
Zuarez-Easton. Pharmacologic and nonpharmacologic options for pain relief during labor. Am J Obstet Gynecol 2023.
with a reduction in labor pain and
anxiety.22
The efficacy of preparing for labor
using hypnosis, with or without intra-
partum use, was examined in a system-
atic review of RCTs and quasi-RCTs. The
results showed that women in the hyp-
nosis group were less likely to use phar-
macologic analgesia than women in the
control group (average risk ratio [RR],
0.73; 95% confidence interval [CI],
0.57e0.94; 8 trials; 2916 women).
Nevertheless, the quality of evidence was
considered very low owing to
inconsistencies in hypnosis timing and
techniques (Figure 3).23
An integrative review including 22
studies of pain intensity during labor
found that 14 of the included studies
reported a statistically significant pain
reduction in women who listened to
music during labor. Other studies have
shown promising trends indicating that
music may help alleviate pain during
labor.24
An RCT that examined the effects of
cognitive behavioral methods via
selected virtual reality videos and clas-
sical music on pain during the active
MAY 2023 American Journal of Obstetrics & Gynecology
Expert Review
phase of labor found that all forms of
cognitive behavioral modalities used in
the study, resulted in pain reduction.25
2. Manual techniques (massage, reflex-
ology, shiatsu, warm and cold packs):
These techniques consist of a wide
range of soft tissue manipulations,
such as body massage, reflexology,
and shiatsu, as well as applying warm
or cold packs to the back, abdomen,
or perineum. According to a sys-
tematic review of RCTs,26 thermal
manual methods (ie, warm packs and
massage) may reduce pain and
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FIGURE 4
The effect of massage (A) and worm packs (B) on pain sensation during labor (from Smith et al26 with permission)

Zuarez-Easton. Pharmacologic and nonpharmacologic options for pain relief during labor. Am J Obstet Gynecol 2023.

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increase emotional comfort, though

FIGURE 5
the level of evidence was low. Mas-
sage was found to reduce pain
Transmission of pain signal from the uterus and birth canal to the brain
measured using self-reported pain
(dotted red line) is blocked by the TENS stimulation (Blue line)
scales, throughout the first stage of
labor compared with usual care
(standardized mean difference
[SMD], 0.81; 95% CI, 1.06
to 0.56; 6 trials; 362 women). In the
second (SMD, 0.98; 95% CI, 2.23
to 0.26; 124 women), and third stages
of labor (SMD, 1.03; 95%
CI, 2.17 to 0.11; 122 women) the
effect was not significant (Figure 4,
A). Warm packs had a prominent
effect on pain reduction during the
second stage of labor (SMD, 1.49;
95% CI, 2.85 to 0.13; 2 trials; 128
women). Labor duration was short-
ened by over an hour among women
who received warm packs vs usual
care (MD, 66.15 min; 95%
CI, 91.83 to 40.47; 2 trials; 128
women; very low-quality evidence),
(Figure 4, B).26
3. Acupuncture: Acupuncture, an
element of traditional Chinese medi-
cine, involves the insertion of fine
needles into different areas of the body TENS, Transcutaneous Electrical Nerve Stimulation.
to address imbalances of energy (in Zuarez-Easton. Pharmacologic and nonpharmacologic options for pain relief during labor. Am J Obstet Gynecol 2023.
form of qi). Acupressure uses the same
paradigm as acupuncture but involves
the therapist using his or her hands RCTs (1586 women) evaluating the group (mean difference, 1.70
and fingers to stimulate body points, effectiveness of acupressure as an points; 95% CI, 2.20 to 1.20).30
rather than needles.27 A recent large adjunct to standard care during labor 5. Transcutaneous electrical nerve
meta-analysis including 28 trials reported significant pain reduction stimulation (TENS): TENS com-
(3960 women), 13 reporting results on compared with sham acupressure plus prises the application of electrical
acupuncture and 15 on acupressure as standard care and standard care alone. currents to the surface of skin, lead-
a treatment for labor pain was pub- No adverse events were reported.28 ing to pain reduction by multiple
lished. Acupuncture may increase mechanisms, including blocking of
satisfaction with pain reduction (RR, A recent RCT comparing the effect of pain signal transmission and release
2.38; 95% CI, 1.78e3.19; 1 trial; GB21 acupressure (located in the middle of endorphins (Figure 5).31 The
150 women; moderate-certainty evi- of the shoulder muscle) vs sham pressure application of TENS during labor
dence), and possibly lessens the ne- and a control group that received usual leads to reduction of dorsal horns
cessity for pharmacologic analgesia care found that the reduction in pain was nerve sensitization and glial
(RR, 0.75; 95% CI, 0.63e0.89; 2 trials; higher in the GB21 group compared with activation by elevation of gamma-
261 women, moderate-certainty the sham and control groups (P¼.001).29 aminobutyric acid and glycine con-
evidence) compared with sham centration and reduction in maternal
acupuncture. Another study showed 4. Birthing ball: A birthing ball is a large pain sensation during labor.32,33 A
that acupressure slightly reduced pain exercise ball that women in labor sit meta-analysis of RCTs (3348 women)
intensity compared with the com- on to perform movements such as evaluated TENS effectiveness in
bined control (standard care or rocking and pelvic rotation to help reducing labor pain compared with
light touch) (SMD, 0.42; 95% reduce pain. A meta-analysis of 7 other therapies and found that TENS
CI, 0.65 to 0.18; 2 trials; RCTs reported that labor pain was reduced pain intensity significantly
322 women; moderate-certainty evi- significantly decreased in the birthing (pooled RR, 1.52; 95% CI,
dence).27 Another meta-analysis of 13 ball group compared with the control 1.35e1.70). Of note, several trials

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TABLE 1
Nonpharmacologic methods for pain relief
Methods
Iyengar yoga
Massage
First stage of labor
Second stage of labor
Third stage of labor
Warm packs during the second stage of
labor
Acupuncture
Satisfaction with pain reduction
Necessity for pharmacologic analgesia
Birthing ball decrease in labor pain
Transcutaneous electrical nerve stimulation
reducing labor pain
Aromatherapy pain reduction during labor
Data presented for the effect on pain during labor compared with routine care.
CI, confidence interval; RR, risk ratio.
Zuarez-Easton. Pharmacologic and nonpharmacologic options for pain relief during labor. Am J Obstet Gynecol 2023.
included in this meta-analysis had a
high risk of bias, and the average
score of the trials using the Cochrane
Risk of Bias Tool indicated low
quality evidence.34 A recent RCT that
compared TENS with routine
obstetrical care during the first stage
of labor showed significantly lower
pain scores and shorter duration of
the active phase of labor among
women who received TENS.35 Báez-
Suárez et al36 compared different
TENS programs during the active
phase of labor and showed that high
frequencies and high pulse widths
were superior at decreasing pain in-
tensity. Research on the impact of
TENS on pain intensity during labor
is in progress, as an additional RCT
examining the effect of TENS on la-
bor is currently being conducted.37
6. Sterile water injection: The method
involves intradermal and subdermal
injection of sterile water. The mech-
anism of action lies on the theory of
S1252 American Journal of Obstetrics & Gynecology MAY 2023
Statistical effect
average RR, 0.73; 95% CI, 0.57e0.94
Standardized mean difference 0.81
(1.06 to 0.56)
Standardized mean difference 0.98
(2.23 to 0.26)
Standardized mean difference 1.03
(2.17 to 0.11)
Standardized mean difference 1.49
(2.85 to 0.13)
RR, 2.38; 95% CI, 1.78e3.19
RR, 0.75; 95% CI, 0.63e0.89
mean difference, 1.70 points; 95% CI,
2.20 to 1.20
pooled RR, 1.52; 95% CI, 1.35e1.70
unstandardized mean difference, 1.75;
95% CI, 1.13e2.37
gate control.38 Several regimens are
described in clinical practice.39 A
systematic review of 7 double-blind
RCTs (766 women) regarding the
use of intracutaneous or subcutane-
ous sterile water injection for intra-
partum pain relief was published.
Control groups received placebo
(saline) injection. All trials reported a
greater reduction in pain in women
who received sterile water injection,
although the authors concluded that
little robust evidence was found to
support the use of sterile water for
low-back or any other labor pains.40
A recent meta-analysis including 9
trials (2102 participants) compared
Visual Analogue Scale (VAS) scores
between a sterile water injection
group and a control group. Sterile
water injection resulted in signifi-
cantly lower VAS scores 30e45, 60,
and 90 minutes after intervention. At
10 minutes after intervention, VAS
scores were similar. Subdermal
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injection resulted in significantly
better pain relief than intradermal
injection at 10 minutes after the
intervention only.41 Another RCT
that aims to evaluate the efficacy of
sterile water injection is ongoing.42
7. Aromatherapy: Aromatherapy uses
essential oils that release volatile,
fragrant organic compounds and are
obtained by distillation of plant mate-
rial. Oils can be used for body
massaged or inhaled via vapor infusion
or a burner. The mechanism of action
is unknown. A meta-analysis including
27 studies (2566 women) found that
aromatherapy was associated with sig-
nificant pain reduction during vaginal
birth (unstandardized mean difference,
1.75; 95% CI, 1.13e2.37). The greatest
effect was at 8 to 10 cm of cervix dila-
tion. Publication bias was not reported
(P¼.113).43
Table 1 summarizes the efficacy of
different nonpharmacologic methods
for pain relief during labor, compared
with usual care.
Pharmacologic pain relief during labor
Pharmacologic options for pain relief
during labor can be divided according to
route of administration, systemic and
regional (epidural). In this section we
will focus on systemic pharmacologic
agents only.
8. Inhaled nitrous oxide (N2O): N2O
has been used worldwide for labor
analgesia for several decades.44 Its
analgesic effect is achieved by stimu-
lation of neuronal release of endog-
enous opioid peptides (dynorphins)
and activation of postsynaptic
opioid receptors (Figure 6).45 The
commonly used blend is a combina-
tion of 50% N2O with 50% oxygen
taken by a self-administered facial
mask. The parturient attaches the
mask to her nose and mouth. With
inhalation, a demand valve opens to
allow gas delivery, which closes with
exhalation (Figure 7). Correct timing
of inhalation is essential because
analgesic effect takes 30 to 60 sec-
onds. N2O is rapidly cleared from the
blood of the mother and the
ajog.org Expert Review

FIGURE 6 FIGURE 7
Nitrous oxide inhalation during Mechanism of action of nitrous oxide inhalation for labor analgesia
labor

Use of nitrous oxide for labor analgesia. The

source of the nitrous oxide is a potable inhalation
system (A), connected by a tube (B) to the
inhalation mask (C). The system is operated by
the patient according to her need for pain control
to allow autonomy and self-control during the
labor process.
Zuarez-Easton. Pharmacologic and nonpharmacologic op-
tions for pain relief during labor. Am J Obstet Gynecol 2023.

newborn, which makes it safe to use

throughout labor.46 It does not in-
fluence labor progress, mode of de-
livery, or neonatal outcome.44,47,48
When given in a 1:1 mix with oxy-
gen, N2O has a good safety pro-
file.47,49 Adverse effects associated
with N2O use, such as nausea, dizzi-
ness, and drowsiness, have been re-
ported.48,49 Furthermore N2O is a
greenhouse gas and is considered an
environmental pollutant.50
The efficacy of N2O-mediated anal-
gesia is unclear, owing to a lack of high-
quality studies. A systematic review
regarding the administration of N2O for
labor pain concluded that N2O inhala-
tion improved satisfaction in women
despite having a negligible analgesic ef-
fect. The same study reported that N2O
had a comparable or marginally greater
analgesic effect than systemic opioid
boluses, and was less effective in relieving
pain compared with an epidural or
remifentanil patientecontrolled anal-
gesia.44 A recently published RCT,51
compared the efficacy of intravenous
(IV) meperidine and inhaled N2O for
intrapartum pain relief among
Emmanouli DE (2020). Mechanisms of action of nitrous oxide. In K Gupta, D Emmanouil, A Sethi
(Eds.), Nitrous Oxide in Pediatric Dentistry: A Clinical Handbook (pp. 78-105). Springer Nature.
Zuarez-Easton. Pharmacologic and nonpharmacologic options for pain relief during labor. Am J Obstet Gynecol 2023.
multiparous, term, singleton gestations. 9. Opioids: Opioids are commonly used
The results showed that pain intensity for pain relief during labor, as they
after 20 to 30 minutes of analgesic are widely available, easy to use and
administration, as assessed by VAS score, are of low cost. Their main advantage
was comparable between the groups is that they produce analgesia with
(primary outcome). The mean VAS milder effect on sensation and pro-
scores that were between 7 and 8 in both prioception. Opioids are classified
groups at baseline, and at 20e30 mi- into 3 groups: (1) natural- obtained
nutes after analgesia administration, from the poppy plant and include
suggests that neither technique provided morphine, codeine, and papaverine
adequate analgesia. Secondary out- (Figure 8, A); (2) semisynthetic that
comes, which included rate of additional are minor modification of the
analgesic use, labor length, mode of de- morphine molecule including heroin
livery, breastfeeding, satisfaction, and (diamorphine), dihydromorphone,
maternal and neonatal adverse effects, and thebaine derivatives (eg, etor-
were similar between the groups. The phine, buprenorphine) (Figure 8, B);
authors concluded that pain intensity and (3) synthetic including mor-
and adverse effects were comparable phinan series (eg, levorphanol,
between the 2 analgesic methods.51 butorphanol), diphenylpropylamine

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Expert Review
FIGURE 8
Structure of opioids medications used for labor analgesia
Opioids are divided into natural (A); semisynthetic (B); and synthetic (C).
Zuarez-Easton. Pharmacologic and nonpharmacologic options for pain relief during labor. Am J Obstet Gynecol 2023.
series (eg, methadone), benzomor-
phan series (eg, pentazocine), and
phenylpiperidine series (eg, meperi-
dine, fentanyl, sufentanil, alfentanil,
remifentanil) (Figure 8, C). The
semisynthetic and the synthetic
groups exert morphine-like effects
through their ability to bind to
different opioid receptors.52 The ef-
fect of opioids in the neuroaxis is
mediated through the opioid re-
ceptors. There are 3 main receptors,
mu (m), kappa (k) and delta (d).52
Their main physiological effects and
the receptor opioid agonist are
S1254 American Journal of Obstetrics & Gynecology MAY 2023
detailed in Table 2. The opioid re-
ceptors are distributed throughout
the central nervous system including
brain structures (ie, thalamus, nu-
cleus raphe, locus coeruleus and
limbic system), and at the dorsal
horn of the spinal cord where their
action is pre- and postsynaptic
(Figure 9). Given systemically, opi-
oids act through all sites simulta-
neously with the supraspinal systems
being the most sensitive.53
Opioid use during labor is associated
with maternal side effects including
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nausea, vomiting, pruritus, sedation,
and respiratory depression.54e56 In
addition, opioids cross the placenta and
may lead to reduced fetal heart rate
variability, reduced baseline fetal heart
rate, neonatal respiratory depression,
lower Apgar scores, neurobehavioral al-
terations, and decreased early breast-
feeding.55,56 The neonatal effects are
dose- and time-dependent, as respira-
tory depression is described more often
when pethidine (meperidine) is given
repeatedly before delivery. Similarly, a
large dose of pethidine depresses the
Apgar score in 1 and 5 minutes.
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Neurobehavioral studies found that
newborns of mothers who received
pethidine are sleepier, less likely to suck,
and slow to base breastfeeding.57
Naloxone, a specific opioid antagonist
that blocks the actions of opioids on
cells, is usually used postpartum to treat
neonates with cardiorespiratory or
neurologic depression, who are exposed
to opioids before birth. Nevertheless, a
systematic review of RCTs reported that
the evidence is insufficient to determine
whether naloxone confers any significant
benefit to neonates with intrauterine
exposure to opioid. Furthermore, the
authors stated that because of safety
concerns, it may be appropriate to limit
its use to RCTs only.58 Furthermore,
parenteral opioids seem to have little
effect on maternal pain scores during
labor. There is uncertainty as to which
opioids have greater analgesic effects and
how they should be administered,
whether as boluses or by patient-
controlled analgesia.54,56
10. Systemic opioid boluses: The dosage
and effect duration of the major
opioids that are currently in clinical
use are presented in Table 3.
Meperidine is the most frequently
used systemic opioid. Meperidine is
administered intravenously (IV) or
intramuscularly (IM) with typical dos-
ages of 25 to 50 mg IV and 50 to 100 mg
IM. Onset of action is 5 to 10 minutes
when administrated IV and up to 45
minutes when injected IM. Given
parenterally, its effect last for 2 to 4
hours.2,59 Meperidine is metabolized to
an active, long-acting metabolite called
normeperidine. Normeperidine has a
prolonged half-life in adults and a half-
life of up to 72 hours in neonates.2,59
The neonatal adverse effect of meperi-
dine is time- and dose-dependent. Ne-
onates who are born less than an hour or
>4 hours after meperidine administra-
tion have a low chance of developing
respiratory depression, whereas neo-
nates who are born 2 to 3 hours
following meperidine injection are
frequently affected with it.60 IV meperi-
dine is less effective in relieving pain and
discomfort during labor compared with
Expert Review
TABLE 2
Subtypes of opioid receptors52
Receptor type Physiological response Receptor agonist
Mu (m) Analgesia Morphine
Miosis Fentanyl
Bradycardia Sufentanil
Sedation Meperidine
Respiratory depression
Decreased gastrointestinal transit
Kappa (k) Analgesia Buprenorphine
Sedation Pentazocine
Respiratory depression
Diuresis
Psychotomimesis
Delta (d) Analgesia Prodynorphin
Endomorphins
Enkephalins
Zuarez-Easton. Pharmacologic and nonpharmacologic options for pain relief during labor. Am J Obstet Gynecol 2023.
epidural analgesia and is associated labor. Rate of maternal adverse effects
with more adverse effects.61e63 Data (particularly nausea and vomiting) are
regarding comparisons with other types higher with tramadol use.64,65
of analgesics are scarce. Fentanyl is a fast-onset and short-
Nalbuphine and butorphanol are acting synthetic opioid, especially with
mixed agonisteantagonists and are,
thus, associated with less neonatal res-
piratory depression.2 FIGURE 9
Morphine is less commonly used for Mechanism of action of systemic
pain relief during labor because the dose opioids
needed to achieve a sedative effect carries
a higher risk for maternal and neonatal
side effects.56 Fentanyl and remifentanil
are used for pain relief during labor but
owing to their short duration of action
they are more suitable for patient-
controlled analgesia use.49
Tramadol a synthetic analog of co-
deine, inhibits norepinephrine and se-
rotonin reuptake and binds to m-opioid
receptors, resulting in inhibitory effect
on pain transmission in the spinal cord.
Several studies showed that tramadol
provides effective analgesia without
maternal and neonatal respiratory
depression that are related to opioid
use.52,64.65 Tramadol seems to be a less Schäfer, M. (2011). Mechanisms of action of
efficient pain reliever compared with opioids. In A. Evers, M. Maze, & E. Kharasch
intramuscular meperidine; nevertheless, (Eds.), Anesthetic Pharmacology: Basic Princi-
more women reported sleepiness with ples and Clinical Practice (pp. 493-508).
meperidine use. Request for additional Cambridge: Cambridge University Press.
analgesia, cesarean delivery rate, and the doi:10.1017/CBO9780511781933.032 with
Apgar scores are comparable between permission.
the 2 agents.52 When compared with Zuarez-Easton. Pharmacologic and nonpharmacologic op-
intravenous acetaminophen, both pro- tions for pain relief during labor. Am J Obstet Gynecol 2023.
vide comparable analgesia during active
MAY 2023 American Journal of Obstetrics & Gynecology S1255
Expert Review ajog.org

TABLE 3
Dosage and kinetics of opioids in the management of pain during labor2,59,86
Elimination half-life
Drug Dosage and route of delivery Onset Duration (maternal)
Meperidine 25e50 mg IV IV e 5 min 2e4 h 2e3 h
50e1000 mg IM IM e 30e45 min
Fentanyl 50e100 mg (every h); Alternatively, as PCA, IV 2e4 min 30e60 min 3h
load 50 mg then 10e25 mg Q 10e12 min
Remifentanil 0.15e0.5 mg/kg Q 2 min as PCA 20e90 s 3e4 min 9e10 min
Morphine 2e5 mg IV; IV- 10 min 1e3 h 2h
5e10 mg IM IM- 30 min
Nalbuphine 10e20 mg IV/SQ/IM I.V 2e3 min 2e4 h 2e5 h
SQ/IM 15 min
Butorphanol 1e2 mg IV/IM IV 5e10 min 4e6 h 2e5 h
IM 30e60 min
IM, intramuscularly; IV, intravenously; PCA, patient-controlled analgesia; Q, every; SQ, subcutaneous.
Zuarez-Easton. Pharmacologic and nonpharmacologic options for pain relief during labor. Am J Obstet Gynecol 2023.

intravenous administration (Table 2).2
This drug can also be administrated
nasally and carries less risk of maternal
adverse effects, including sedation,
nausea, vomiting, and pruritus, than
meperidine. One of its major advan-
tages is that unlike meperidine or
morphine fentanyl, it hardly crosses the
placenta, although, there are reports
on neonatal respiratory depression
following its administration. Fentanyl
and remifentanil are used for pain relief
during labor but because of their short
duration of action they are more suit-
able for patient-controlled analgesia
use.49
11. Patient-controlled analgesia using
opioids: Opioids given via patient-
controlled analgesia offer the op-
portunity to deliver continuous
pain relief, similar to epidural
analgesia. The patient-preferred
dose is administered by pressing a
button, leading to a feeling of pain
control.66 One of the first investi-
gated options for patient-controlled
analgesia during labor was fentanyl
patientecontrolled analgesia. A
small RCT that included 20 pri-
miparous women who were ran-
domized to receive fentanyl
patientecontrolled analgesia or
epidural bupivacaine found that
epidural analgesia was more
effective at providing pain relief;
however, satisfaction was compara-
ble between the groups. Apgar
scores, cord artery pH, neuro-
behavioral scores, and naloxone re-
quirements were also comparable.67
Meperidine and remifentanil represent
the “old” and “new” opioids, respectively,
that have been compared with fentanyl
patientecontrolled analgesia. An RCT
compared meperidine, remifentanil, and
fentanyl patientecontrolled analgesia for
labor analgesia and found that remi-
fentanil provided better analgesia, but
only for the first hour, and was
associated with more sedation and itch-
ing.68 Remifentanil patientecontrolled
analgesia may offer better pain relief and
fewer fetal adverse effects compared
with other intravenous opioid analgesics
owing to its unique pharmacologic ef-
fects.69 Volikas et al compared remi-
fentanil patientecontrolled analgesia
with meperidine patientecontrolled
analgesia in a double-blind RCT. Partu-
rients in the remifentanil group had
significantly lower pain scores than pa-
tients in the meperidine group. The trial
was terminated early owing to concern for
poor Apgar scores in the meperidine
group.70
A recent meta-analysis of RCTs com-
paring remifentanil patientecontrolled
analgesia and epidural analgesia (10 trials,
3086 women) reported that pain relief
during labor was similar between the 2
groups. Use of remifentanil patiente
controlled analgesia significantly reduced
the incidence of maternal fever; however, it
was associated with a higher rate of respi-
ratory depression. Apgar scores <7 at 5
minutes were similar.71 The ultrashort
half-life of remifentanil makes it attractive
for intrapartum use particularly through-
out the second stage of labor because
there is little concern regarding accumu-
lation and undesired neonatal adverse
effects. The rate of conversion from
remifentanil patientecontrolled analgesia
to epidural analgesia is lower than it is for
other opioids and ranges between 5%
and 14%.72,73
The clinical use of remifentanil
patientecontrolled analgesia is limited
because of safety concerns, despite its
efficacy in reducing labor pain.74 The
potential adverse effects include pruri-
tus, nausea and vomiting, maternal
hypoxia,75 respiratory arrest, and cardiac
arrest.76 Melber et al77 reported that,
among 5740 patients who received
remifentanil patientecontrolled anal-
gesia for labor pain, there was a moder-
ate rate of maternal hypoxia (oxygen
saturation <94% in 27.3% [1415/5189
documented cases]), without require-
ment for ventilation or cardiopulmo-
nary resuscitation. The rate of neonatal
cardiopulmonary resuscitation

S1256 American Journal of Obstetrics & Gynecology MAY 2023

ajog.org
performed in relation to remifentanil use
was 0.3% (13/4559 documented cases),
and the rate of supplemental oxygen use
was 7.6% (248/3261 documented
cases).77 Despite these observations, the
recommendation that 1:1 nursing care
should be provided to increase the
chance of detecting respiratory depres-
sion2,74 limits extensive implementation
of remifentanil patientecontrolled
analgesia as a routine choice for labor
analgesia.78
12. Acetaminophen: The fact that
opioid use is associated with
maternal and neonatal adverse ef-
fects led to the search for other op-
tions for intrapartum analgesia.
Intravenous acetaminophen is an
effective, low-cost option for post-
operative pain relief,78 and its IV use
has been proven to be safe with no
need for special monitoring.79,80 IV
acetaminophen 1000 mg for labor
analgesia has been studied in several
trials.79e83 It provides modest pain
reduction compared with placebo81
and similar effectiveness compared
with IV opioids,79,80,82,83 with fewer
maternal adverse effects.71,72,74
13. Nonsteroidal Anti-Inflammatory
Drugs (NSAIDs): NSAIDs inhibit
prostaglandin production which
reduces the inflammatory response
and subsequent pain. Classically,
their effect is anti-inflammatory,
analgesic, and antipyrexial. In
comparison with opioids, they were
found to be less satisfying with pain
relief during labor.84 NSAIDs are
not in general use for labor analgesia
mainly owing to their potential ef-
fect on the ductus arteriosus
closure.84
Healthcare role
Labor pain is often described as one of
the most painful experiences in a wom-
an’s life. Pain perception is subjective and
influenced by many factors.2,6 When the
pain is associated with intention and
progress, the woman experiences more
positive emotions and requires less
analgesia.85 Positive childbirth experi-
ence is one that accomplishes the wom-
an’s previous personal and sociocultural
Expert Review
beliefs and expectations, including giv- considered safe. Their effectiveness may
ing birth to a healthy baby in a safe vary on an individual basis, however, and
environment. A competent clinical staff the evidence supporting their efficacy,
who gives the parturient the option to particularly in the advance staged of labor,
ask questions, and to be given answers is is weaker than that for other methods.
strongly recommended to improve Furthermore, there is not much evidence
overall childbirth experience. Putting the to support the use of one method over the
patient in the center and involving her in other, and the choice is usually individual
decision making may improve maternal and subject to availability.
experience and her satisfaction from la- The effectiveness of systemic phar-
bor analgesia.19 macologic agents delivered by a non-
epidural route in preventing pain during
Conclusion labor is restricted. RCTs comparing the
Increasing number of women are now effectiveness of systemic opioid boluses
opting for pain relief methods that allow with non-opioid agents such as N2O and
them maximal control and participation acetaminophen showed similar efficacy
in the labor process. In such patients, and fewer adverse effects. In view of that,
along with those who are not eligible to when systemic boluses are the desig-
receive epidural analgesia, the use of nated option, women and providers have
nonpharmacologic or systemic pharma- the choice to limit opioid use. Women
cologic analgesia to alleviate labor pain who are interested in efficient conten-
is a reasonable alternative. Non- tious pain relief, and epidural analgesia is
pharmacologic options are attractive and not an option, can be offered
GLOSSARY

GB21 (Gallbladder 21) is one of the points of gall bladder meridian, which is
located on the shoulder half way between the rotator cuff (the acromion) and the
seventh cervical vertebrae. In traditional Chinese medicine, pressing this point is
thought to relieve labor pain.

Qi is believed to be a vital energy, circulating in the body through pathways named
meridians. In traditional Chinese medicine, symptoms of various illnesses are
believed to be caused by disrupted, blocked, and unbalanced qi movement
through meridians and treatment involves correcting those imbalances.

Gate control theory of pain is a model proposed by Melzack and Wall, suggesting
that inhibitory interneurons located in the substantia gelatinosa of the spinal dorsal
horn act as “gate control” units for nociceptive signals entering from the periphery
to the central nervous system areas. The ‘gate’ is where pain signals can pass
through to the brain (gate is open) to perceive the pain, or will be blocked (gate is
closed) and the sensation of pain will not be perceived.

Referred pain is when pain perceived in one part of the body, other than the site of
the involved origin or stimulus.

Iynger Yoga is a type of yoga as exercise, with a focus on the structural alignment
of the body. It differs from other types of yoga in (1) the precision in alignment of
body postures, rather than self-explored postures, (2) the sequence of postures
and the longer stay in each posture to enable muscle to relax and lengthen and (3)
the use of props (such as belts, cushions and benches) to achieve the desired
postures.

Reflexology, is a form of alternative medicine in which gentle pressure is applied
on points on the feet, ears, and hands to produce an effect elsewhere in the body.
Pain may be reduced by gentle manipulation or pressing certain parts of the foot.

Shiatsu, is a form of bodywork that originated in Japan. Literally it means “finger
pressure”. The shiatsu therapist uses finger pressure along energy paths to relieve
pain and tension in the body.
MAY 2023 American Journal of Obstetrics & Gynecology S1257
Expert Review
remifentanil patientecontrolled anal- 13. Mitchell DM. Women’s use of complemen-
gesia during first and second stages of tary and alternative medicine in pregnancy:
narratives of transformation. Complement Ther
labor owing to the short half-life of Clin Pract 2016;23:88–93.
remifentanil. Boluses delivered in a 14. Declercq ER, Sakala C, Corry MP,
dosage between 0.15 and 0.5 mg/kg with Applebaum S, Herrlich A. Major survey findings
1 to 5-minute lockout, appears to be the of listening to mothers(SM) III: pregnancy and
most efficacious patient-controlled birth: report of the third national U.S. survey of
women’s childbearing experiences. J Perinat
analgesia regimen. Even then, close Educ 2014;23:9–16.
monitoring for respiratory depression is 15. Kalder M, Knoblauch K, Hrgovic I,
required. Further studies addressing the Münstedt K. Use of complementary and alter-
efficacious nonpharmacologic methods native medicine during pregnancy and delivery.
that meet expectations of most women Arch Gynecol Obstet 2011;283:475–82.
16. Öztürk R, Emi Nov A, Ertem G. Use of
and wishes from labor analgesia and the complementary and alternative medicine in
optimal remifentanil patientecontrolled pregnancy and labour pain: a cross-sectional
analgesia dose for labor analgesia, are study from turkey. BMC Complement Med
still required. - Ther 2022;22:332.
17. ACOG Committee Opinion No. 766 sum-
mary: approaches to limit intervention during la-
bor and birth. Obstet Gynecol 2019;133:406–8.
REFERENCES 18. Savona-Ventura C, Mahmood T. The role of
1. Shipman P. Why is human childbirth so traditional complementary physical interventions
painful? Am Sci 2013;101:426–9. in obstetrics - a scientific review commissioned
2. Committee on Practice Bulletins—Obstet- by the European Board And College of Obstet-
rics. Practice Bulletin No. 177: obstetric anal- rics and Gynaecology (EBCOG). Eur J Obstet
gesia and anesthesia. Obstet Gynecol Gynecol Reprod Biol 2022;279:84–7.
2017;129:e73–89. 19. WHO recommendations: intrapartum care
3. Bucstain C, Garmi G, Zafran N, Zuarez- for a positive childbirth experience. Geneva:
Easton S, Carmeli J, Salim R. Risk factors and World Health Organization; 2018.
peripartum outcomes of failed epidural: a pro- 20. Smith CA, Levett KM, Collins CT, Armour M,
spective cohort study. Arch Gynecol Obstet Dahlen HG, Suganuma M. Relaxation tech-
2017;295:1119–25. niques for pain management in labour.
4. Narayan MC. Culture’s effects on pain Cochrane Database Syst Rev 2018;3:
assessment and management. Am J Nurs CD009514.
2010;110:38–47. 21. Yilmaz Esencan T, Rathfisch G. Effects of
5. Supporting healthy and normal physiologic yoga and meditation on the birth process. Altern
childbirth: a consensus statement by ACNM, Ther Health Med 2023;29:6–14.
MANA, and NACPM. J Perinat Educ 2013;22: 22. Rahayu B, Ariningtyas RE. Reduction of
14–8. anxiety and pain in primigravida mothers with
6. Aksoy H, Yücel B, Aksoy U, Acmaz G, modified Iyengar yoga: a clinical study.
Aydin T, Babayigit MA. The relationship between J Ayurveda Integr Med 2022;14:100584.
expectation, experience and perception of la- 23. Madden K, Middleton P, Cyna AM,
bour pain: an observational study. Springerplus Matthewson M, Jones L. Hypnosis for pain
2016;5:1766. management during labour and childbirth.
7. McDonald JS. Pain of childbirth. In: Cochrane Database Syst Rev 2016;2016:
Loeser JD, ed. Bonica’s management of pain, CD009356.
3rd ed. Philadelphia, PA: Lippincott Williams & 24. McCaffrey T, Cheung PS, Barry M, Punch P,
Wilkins; 2001. p. 1388–414. Dore L. The role and outcomes of music listening
8. Lowe NK. The pain and discomfort of labor for women in childbirth: an integrative review.
and birth. J Obstet Gynecol Neonatal Nurs Midwifery 2020;83:102627.
1996;25:82–92. 25. Gür EY, Apay SE. The effect of cognitive
9. Brownridge P. The nature and consequences behavioral techniques using virtual reality on
of childbirth pain. Eur J Obstet Gynecol Reprod birth pain: a randomized controlled trial.
Biol 1995;59:S9–15. Midwifery 2020;91:102856.
10. Chapman CR, Nakamura Y. A passion of 26. Smith CA, Levett KM, Collins CT,
the soul: an introduction to pain for conscious- Dahlen HG, Ee CC, Suganuma M. Massage,
ness researchers. Conscious Cogn 1999;8: reflexology and other manual methods for pain
391–422. management in labour. Cochrane Database
11. Chapman CR, Gavrin J. Suffering and its Syst Rev 2018;3:CD009290.
relationship to pain. J Palliat Care 1993;9:5–13. 27. Smith CA, Collins CT, Levett KM, et al.
12. Thomson G, Feeley C, Moran VH, Downe S, Acupuncture or acupressure for pain manage-
Oladapo OT. Women’s experiences of phar- ment during labour. Cochrane Database Syst
macological and non-pharmacological pain relief Rev 2020;2:CD009232.
methods for labour and childbirth: a qualitative 28. Chen Y, Xiang XY, Chin KHR, et al.
systematic review. Reprod Health 2019;16:71. Acupressure for labor pain management: a
S1258 American Journal of Obstetrics & Gynecology MAY 2023
ajog.org
systematic review and meta-analysis of ran-
domized controlled trials. Acupunct Med
2021;39:243–52.
29. Torkiyan H, Sedigh Mobarakabadi S,
Heshmat R, Khajavi A, Ozgoli G. The effect of
GB21 acupressure on pain intensity in the first
stage of labor in primiparous women: a ran-
domized controlled trial. Complement Ther Med
2021;58:102683.
30. Grenvik JM, Rosenthal E, Wey S, et al.
Birthing ball for reducing labor pain: a systematic
review and meta-analysis of randomized
controlled trials. J Matern Fetal Neonatal Med
2022;35:5184–93.
31. Sluka KA, Walsh D. Transcutaneous elec-
trical nerve stimulation: basic science mecha-
nisms and clinical effectiveness. J Pain 2003;4:
109–21.
32. Johnson M. Transcutaneous electrical nerve
stimulation: mechanisms, clinical application
and evidence. Rev Pain 2007;1:7–11.
33. Huang J, Yang C, Zhao K, et al. Trans-
cutaneous electrical nerve stimulation in rodent
models of neuropathic pain: a meta-analysis.
Front Neurosci 2022;16:831413.
34. Thuvarakan K, Zimmermann H,
Mikkelsen MK, Gazerani P. Transcutaneous
electrical nerve stimulation as A pain-relieving
approach in labor pain: a systematic review
and meta-analysis of randomized controlled tri-
als. Neuromodulation 2020;23:732–46.
35. Njogu A, Qin S, Chen Y, Hu L, Luo Y. The
effects of transcutaneous electrical nerve stim-
ulation during the first stage of labor: a ran-
domized controlled trial. BMC Pregnancy
Childbirth 2021;21:164.
36. Báez-Suárez A, Martín-Castillo E, García-
Andújar J, García-Hernández JÁ, Quintana-
Montesdeoca MP, Loro-Ferrer JF. Evaluation of
different doses of transcutaneous nerve stimu-
lation for pain relief during labour: a randomized
controlled trial. Trials 2018;19:652.
37. Dias NT, Santos PR, Cândido TA,
Pinto RMC, Resende APM, Pereira-Baldon VS.
Effects of the addition of transcutaneous elec-
trical stimulation to non-pharmacological mea-
sures in labor pain: study protocol for a
randomized controlled trial. Trials 2022;23:44.
38. Zeilhofer HU, Wildner H, Yévenes GE. Fast
synaptic inhibition in spinal sensory processing
and pain control. Physiol Rev 2012;92:
193–235.
39. Mårtensson LB, Hutton EK, Lee N, Kildea S,
Gao Y, Bergh I. Sterile water injections for
childbirth pain: an evidenced based guide to
practice. Women Birth 2018;31:380–5.
40. Derry S, Straube S, Moore RA, Hancock H,
Collins SL. Intracutaneous or subcutaneous
sterile water injection compared with blinded
controls for pain management in labour.
Cochrane Database Syst Rev 2012;1:
CD009107.
41. Huang CY, Lo SF, Chou SH, Shih CL.
Analgesic effects of sterile water injection in the
management of low back pain during labor: a
systematic review and meta-analysis. Int J
Gynaecol Obstet 2022;159:642–50.
ajog.org
42. Lee N, Gao Y, Mårtensson LB, Callaway L,
Barnett B, Kildea S. Sterile water injections for
relief of labour pain (the Saturn trial): study pro-
tocol for a randomised controlled trial. Trials
2022;23:155.
43. Shaterian N, Pakzad R, Fekri SD, Abdi F,
Shaterian N, Shojaee M. Labor pain in different
dilatations of the cervix and Apgar scores
affected by aromatherapy: a systematic review
and meta-analysis. Reprod Sci 2022;29:
2488–504.
44. Likis FE, Andrews JC, Collins MR, et al.
Nitrous oxide for the management of labor pain:
a systematic review. Anesth Analg 2014;118:
153–67.
45. Emmanouil DE, Quock RM. Advances in
understanding the actions of nitrous oxide.
Anesth Prog 2007;54:9–18.
46. Klomp T, van Poppel M, Jones L, Lazet J, Di
Nisio M, Lagro-Janssen ALM. Inhaled analgesia
for pain management in labour. Cochrane
Database Syst Rev 2012;9:CD009351.
47. Zafirova Z, Sheehan C, Hosseinian L. Up-
date on nitrous oxide and its use in anesthesia
practice. Best Pract Res Clin Anaesthesiol
2018;32:113–23.
48. Rosen MA. Nitrous oxide for relief of labor
pain: a systematic review. Am J Obstet Gynecol
2002;186:S110–26.
49. Sharpe EE, Rollins MD. Beyond the
epidural: alternatives to neuraxial labor anal-
gesia. Best Pract Res Clin Anaesthesiol
2022;36:37–51.
50. Lew V, McKay E, Maze MazeM. Past, pre-
sent, and future of nitrous oxide. Br Med Bull
2018;125:103–19.
51. Zuarez-Easton S, Zafran N, Garmi G,
Dagilayske D, Inbar S, Salim R. Meperidine
compared with nitrous oxide for intrapartum
pain relief in multiparous patients: a randomized
controlled trial. Obstet Gynecol 2023;141:4–10.
52. Williams J. Basic opioid Pharmacology. Rev
Pain 2008;1:2–5.
53. Pasternak GW. Opiate pharmacology and
relief of pain. J Clin Oncol 2014;32:1655–61.
54. Jones L, Othman M, Dowswell T, et al. Pain
management for women in labour: an overview
of systematic reviews. Cochrane Database Syst
Rev 2012;2012:CD009234.
55. Nanji JA, Carvalho B. Pain management
during labor and vaginal birth. Best Pract Res
Clin Obstet Gynaecol 2020;67:100–12.
56. Smith LA, Burns E, Cuthbert A. Parenteral
opioids for maternal pain management in labour.
Cochrane Database Syst Rev 2018;6:
CD007396.
57. Reynolds F. The effects of maternal labour
analgesia on the fetus. Best Pract Res Clin
Obstet Gynaecol 2010;24:289–302.
58. Moe-Byrne T, Brown JVE, McGuire W.
Naloxone for opioid-exposed newborn infants.
Cochrane Database Syst Rev 2018;10:
CD003483.
59. Markley JC, Rollins MD. Non-neuraxial labor
analgesia: options. Clin Obstet Gynecol
2017;60:350–64.
60. Olofsson C, Ekblom A, Ekman-Ordeberg G,
Granström L, Irestedt L. Analgesic efficacy of
intravenous morphine in labour pain: a reap-
praisal. Int J Obstet Anesth 1996;5:176–80.
61. Evron S, Ezri T. Options for systemic labor
analgesia. Curr Opin Anaesthesiol 2007;20:
181–5.
62. Sheiner E, Shoham-Vardi I, Sheiner EK, et al.
A comparison between the effectiveness of
epidural analgesia and parenteral pethidine
during labor. Arch Gynecol Obstet 2000;263:
95–8.
63. Philipsen T, Jensen NH. Maternal opinion
about analgesia in labour and delivery. A com-
parison of epidural blockade and intramuscular
pethidine. Eur J Obstet Gynecol Reprod Biol
1990;34:205–10.
64. Kaur Makkar J, Jain K, Bhatia N, Jain V, Mal
Mithrawal S. Comparison of analgesic efficacy of
paracetamol and tramadol for pain relief in active
labor. J Clin Anesth 2015;27:159–63.
65. Monisha N, Poomalar GK. Comparison of
intravenous paracetamol infusion versus intra-
muscular tramadol as labor analgesia: a ran-
domized control trial. Arch Gynecol Obstet
2023;307:755–62.
66. Mann C, Ouro-Bang’na F, Eledjam JJ. Pa-
tient-controlled analgesia. Curr Drug Targets
2005;6:815–9.
67. Nikkola EM, Ekblad UU, Kero PO,
Alihanka JJ, Salonen MA. Intravenous fentanyl
PCA during labour. Can J Anaesth 1997;44:
1248–55.
68. Douma MR, Verwey RA, Kam-Endtz CE,
van der Linden PD, Stienstra R. Obstetric anal-
gesia: a comparison of patient-controlled
meperidine, remifentanil, and fentanyl in labour.
Br J Anaesth 2010;104:209–15.
69. Ohashi Y, Baghirzada L, Sumikura H,
Balki M. Remifentanil for labor analgesia: a
comprehensive review. J Anesth 2016;30:
1020–30.
70. Volikas I, Male D. A comparison of
pethidine and remifentanil patient-controlled
analgesia in labour. Int J Obstet Anesth
2001;10:86–90.
71. Lei X, Yu Y, Li M, et al. The efficacy and
safety of remifentanil patient-controlled versus
epidural analgesia in labor: a meta-analysis and
systematic review. PLoS One 2022;17:
e0275716.
72. Van de Velde M, Carvalho B. Remifentanil for
labor analgesia: an evidence-based narrative re-
view. Int J Obstet Anesth 2016;25:66–74.
73. Schnabel A, Hahn N, Broscheit J, et al.
Remifentanil for labour analgesia: a meta-
MAY 2023 American Journal of Obstetrics & Gynecology
Expert Review
analysis of randomised controlled trials. Eur J
Anaesthesiol 2012;29:177–85.
74. Karol D, Weiniger CF. Update on non-
neuraxial labor analgesia. Curr Anesthesiol Rep
2021;11:348–54.
75. Stocki D, Matot I, Einav S, Eventov-
Friedman S, Ginosar Y, Weiniger CF.
A randomized controlled trial of the efficacy and
respiratory effects of patient-controlled intrave-
nous remifentanil analgesia and patient-
controlled epidural analgesia in laboring
women. Anesth Analg 2014;118:589–97.
76. Bartsch E, Park AL, Young J, Ray JG, Tu K.
Pharmacological pain relief and fear of childbirth
in low risk women: secondary analysis of the
RAVEL study. BMC Pregnancy Childbirth
2018;18:1.
77. Melber AA, Jelting Y, Huber M, et al. Remi-
fentanil patient-controlled analgesia in labour:
six-year audit of outcome data of the RemiPCA
SAFE Network (2010-2015). Int J Obstet Anesth
2019;39:12–21.
78. Shatalin D, Weiniger CF, Buchman I,
Ginosar Y, Orbach-Zinger S, Ioscovich A. A 10-
year update: national survey questionnaire of
obstetric anesthesia units in Israel. Int J Obstet
Anesth 2019;38:83–92.
79. Abdollahi MH, Mojibian M, Pishgahi A, et al.
Intravenous paracetamol versus intramuscular
pethidine in relief of labour pain in primigravid
women. Niger Med J 2014;55:54–7.
80. Elbohoty AE, Abd-Elrazek H, Abd-El-
Gawad M, Salama F, El-Shorbagy M, Abd-El-
Maeboud KH. Intravenous infusion of
paracetamol versus intravenous pethidine as
an intrapartum analgesic in the first stage of
labor. Int J Gynaecol Obstet 2012;118:
7–10.
81. Zutshi V, Rani KU, Marwah S, Patel M. Effi-
cacy of intravenous infusion of acetaminophen
for intrapartum analgesia. J Clin Diagn Res
2016;10:QC18–21.
82. Anter ME, Abdel Attey Saleh S, Shawkey
Allam S, Mohamed Nofal A. Efficacy and safety
of intravenous paracetamol in management of
labour pains in a low resource setting: a ran-
domized clinical trial. J Matern Fetal Neonatal
Med 2022;35:6320–8.
83. Ankumah NE, Tsao M, Hutchinson M, et al.
Intravenous acetaminophen versus morphine
for analgesia in labor: a randomized trial. Am J
Perinatol 2017;34:38–43.
84. Othman M, Jones L, Neilson JP. Non-opioid
drugs for pain management in labour. Cochrane
Database Syst Rev 2012;7:CD009223.
85. Buckingham G, Maronge E, Walker KF. Pain
relief in maternity care and the role of the ob-
stetric anaesthetist. Obstet Gynaecol Reprod
Med 2023;33:49–53.
86. Ryan-Haddad A. Options in analgesia dur-
ing labor. US Pharm 2006;11:HS44–52.
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