Labor Pain Mechanisms
Helen Shnol, BSc Nicole Paul, BSc Inna Belfer, MD, PhD Department of Anesthesiology, Molecular Epidemiology of Pain Program University of Pittsburgh, Pennsylvania
Pain is a major socioeconomic and health problem in the world. There is no unique medical term that can encompass the vast reach of the condition, from acute surgery-related presentations to persistent body or site-specific pain. Although nociception is instrumental to survival, understanding of its mechanisms and pathways is still underway. It is crucial not only for “physiological” pain but even more for “pathologic” pain, for example, extremely severe acute and debilitating chronic pain. Severe acute pain is clinically challenging, limits patient mobility, and negatively affects mood. Furthermore, studies show that severe acute pain, for example, postsurgical pain, predicts long-term chronic pain.1 Chronic pain, as defined in the American Society of Anesthesiologists Practice Guidelines for Chronic Pain Management, is “pain of any etiology not directly related to neoplastic involvement, associated with a chronic medical condition or extending in duration beyond the expected temporal boundary of tissue injury and normal healing, and adversely affecting the function or well-being of the individual.”2 In recent years chronic pain has become a global pandemic, with millions suffering every year (Global Industry Analysts Inc. Report, January 10, 2011). In the United States alone, there is a tremendous expenditure of economic and social resources on health care costs, rehabilitation, and lost worker productivity, as well as the emotional and financial burden it places on patients and their families.3 Labor is traditionally regarded as one of the most painful events in a woman’s reproductive history, although its self-description ranges from nonexistent4 to excruciating.5 Such variation in women’s perception of labor pain is an interaction of physiological and biobehavioral processes. Although there are interindividual differences in pain intensity, reported pain experiences can be influenced and modified by REPRINTS: INNA BELFER, MD, PHD, DEPARTMENT OF ANESTHESIOLOGY, MOLECULAR EPIDEMIOLOGY OF PAIN PROGRAM, UNIVERSITY OF PITTSBURGH, 3550 TERRACE ST, SCAIFE HALL A1305, PITTSBURGH, PA 15261. E-MAIL: [email protected] INTERNATIONAL ANESTHESIOLOGY CLINICS Volume 52, Number 3, 1–17 r 2014, Lippincott Williams & Wilkins
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psychological factors (anxiety, depression, pain coping behavior), clinical factors (high-risk pregnancies), and genetic factors that predispose some women to higher pain severity and protect others from severe or persistent pain. There is a growing body of evidence that demonstrates that each group of factors may contribute to the risk for development of chronic pain postpartum and may assist in the prediction of analgesia effectiveness during labor and delivery. Although childbirth is a natural event in the lives of many women, it can result in long-term maternal and fetal morbidity from postpartum depression, chronic pain, and developmental difficulties. Pain (genital, perineal, back, and pelvic girdle) may appear at the very beginning of pregnancy, get worse with pregnancy progression, and stay after delivery for months or years.6 In fact, up to 55.8% of Chinese women reported chronic pain 5 to 11 years after their deliveries.7 With >4 million deliveries annually in the United States alone, even a smaller prevalence of persistent pain carries important public health consequences.8 Like other areas of pain research, there is little consensus on the risk factors associated with the development and persistence of labor-related pain. Elucidation of these factors has significant relevance for clinical practice, as it could identify women who might benefit from novel preventive strategies and allow tailored management of labor-related pain. The aim of this chapter is to describe the clinical characteristics of labor pain, review underlying mechanisms, and discuss risk factors and potential predictors in the development of chronic pain after childbirth.
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Labor-related Pain
Women may experience pain in 1 or several body sites including spine (cervical, thoracic, and lumbar), pelvic, and genital areas, and they may start experiencing it in early pregnancy. Occasional abdominal or pelvic discomfort is a common pregnancy complaint. It may be caused by the expansion of the uterus (accommodation pain), functional ovarian cysts, ligament stretches, pressure from growing fetus, etc. Severe or persistent pain can be a sign of a serious problem (eg, ectopic pregnancy or miscarriage). Yet, in some cases there is no clear medical reason for pain that may persist or even increase during pregnancy. Overall, significant pelvic girdle and/or low back pain occurs in approximately 50% of pregnant women in the months preceding delivery.9,10 The severity of such pain is related to age, number of weeks of pregnancy, passive hip flexion and internal rotation, and swimming. However, the total explained variance of these factors is only 15.9%.9 The severity of backache increases with both increasing age and increasing parity.11 Pain during pregnancy may have significant longterm consequences: a large epidemiological study in 5118 women www.anesthesiaclinics.com
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showed that a higher burden of symptoms such as backache during pregnancy correlated with poorer health status 14 years postpartum.12 Back pain is common during pregnancy, but there is limited information regarding the course of back pain after pregnancy. It is important to develop novel, and improve current, preventive strategies, especially in young multigravida patients.13 Low back pain in parturients is due primarily to anterior sacroiliac joint dysfunction, whereas in the general population it is primarily due to myofascial pain. Thus it is not uncommon to see myofascial trigger points in the parturient as well, and such a patient would benefit from epidural analgesia combined with additional myofascial trigger point analgesia.14 Other pain during labor is caused by contractions of the uterus, by pressure on the cervix, bladder, and bowels by the baby’s head, and by the stretching of the birth canal and vagina. During the first stage of labor (dilatation phase), pain is usually located in the region of the uterus and its adnexae as a result of (a) dilatation of the cervix and lower uterine segment; (b) traction and pressure on the adnexae and parietal peritoneum and the structures they envelop; (c) pressure and stretching of the bladder, urethra, rectum, and other pain-sensitive structures in the pelvis; (d) pressure on one or more roots of the lumbosacral plexus; and (e) reflex skeletal muscle spasms.15–17 Several hypotheses suggest that pain intensity is related to fetal position, ischemia of the uterus, myometrial blood flow, inflammatory processes of the uterine muscles, psychological aspects, and, probably, contractions of the uterus under isometric conditions.18 In general, the increasing intensity of pain commonly observed with dilatation may be partially attributable to a lowered activation threshold in the mechanoreceptors and to chemoreceptor stimulation produced by the uterine contractions.19 These nociceptive stimuli of the dilatation phase are predominantly transmitted to the T10 to L1 posterior nerve root ganglia. As with other types of visceral pain, labor pain may be referred to the abdominal wall, lumbosacral region, iliac crests, gluteal areas, and thighs.20 The onset of perineal pain at the end of the first stage signals the beginning of fetal descent and the second stage of labor.21 At the second stage (pelvic or descent phase) of labor, somatic pain predominates caused by distention and traction on pelvic structures and by distention of the pelvic floor and perineum. Sharp and generally well localized, these stimuli are transmitted through the pudendal nerve through the anterior rami of S2-S4. The intensity of this pain increases with greater cervical dilatation and is positively correlated to the intensity, duration, and frequency of uterine contractions.22 Interestingly, the experienced pain during labor among primiparae is not influenced by fetal weight.23 Previous deliveries, however, appear to correlate positively with pain severity: 21% of grand multiparas rated their pain as intolerable (pain scores 9 to 10) during the second stage of labor compared with 10% of www.anesthesiaclinics.com
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primiparas.24 Accurate estimation of pain during the delivery by the caregivers is important for appropriate pain management; however, some factors, such as birth order and religious practice of the patient, may significantly affect the caregiver’s ability to correctly estimate the pain of the parturient. The wider the cultural gap between the caregiver and the patient, the less accurate the estimate.25 Pain after delivery may linger for several weeks (acute pain) or persist for much longer (chronic postpartum pain). Several factors related to the labor, including induced labor, longer labor, and use of medications during labor, predict postpartum pain.26–28 During breast feeding, nearly all women (96%) report deep pain primarily at 3 sites: lower abdomen, low back, and breast, with associated referred hyperalgesia in 62% of them. The intensity of these pains increased significantly with parity.29 Episiotomy and perineal laceration are strongly associated with the presence of perineal pain during the immediate postpartum period and at 3 months for 11% of women.30 Yet, 75% of women with an intact perineum reported pain 1 day after childbirth, and 38% a week later.31 The reported prevalence of perineal pain, back pain, and pelvic girdle pain that affects recovery from childbirth ranges from 5% to 43% for 6 months after delivery.32 One in 13 women after vaginal delivery in US tertiary care centers suffers from severe acute pain after delivery, and for cesarean delivery the rates were even higher at 1 in 5.8 Cesarean section (CS), as any other surgical injury, can cause severe acute pain due to the damage to a variety of tissues. Activation and sensitization of nociceptors results in primary hyperalgesia, and enhanced responsiveness of pain-transmitting neurons in the central nervous system (central sensitization) results in secondary hyperalgesia.33 In many cases, acute post-CS pain can persist for much longer than the usual healing period, and there is a correlation between higher pain scores in the immediate postoperative period and a higher incidence of chronic post-CS pain.34 A Danish study showed that 12.3% of parturients experienced persistent pain at the end of a followup period ranging from 6 to 18 months; 6% of them reported daily pain, and those having CS under general anesthesia had a higher frequency of persistent pain compared with spinal anesthesia.35 An Asian study showed that there was a 9.2% incidence of chronic pain after 3 months following elective CS under spinal anesthesia.36 Furthermore, a study of Brazilian women found that 67% of women with chronic pelvic pain had a history of CS.37 When comparing the incidence of persistent pain at 1 year after CS versus vaginal delivery, a significant difference was found (18% vs. 10%); however, the intensity of pain was similar and correlated with previous pain, previous back pain, and any chronic disease rather than the mode of delivery.38 Moreover, a large prospective longitudinal study revealed that the severity of acute postpartum pain, but not mode of delivery, increased 2.5 fold the risk for persistent postpartum pain.8 www.anesthesiaclinics.com
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Generally, up to 30% of women have chronic postpartum pain 2 years after delivery, and more than a half of those with low back pain during pregnancy still experience it at 3 months after delivery.39,40 ’
Factors Contributing to Labor Pain and Its Perception
Many factors contribute to interindividual differences in processing and perception of labor pain. Some clinical, physiological, and psychosocial factors are more prominent in one cohort than another because of differences in standard care protocols and patient characteristics. It is important to not only identify but recognize the importance of these differences in clinical research and pain management. In addition, growing evidence demonstrates the role of genetic mechanisms that underlie the variability in human pain, including labor-related pain. Genetic factors may contribute independently and/or through interplay with demographic, psychological, and other environmental factors shaping pain phenotypes such as pain sensitivity, pain severity, frequency, and duration.41,42 They also interact with environmental factors, such as stress or early exposure to acute painful stimuli that can have long-term effects on nociceptive thresholds.43 Physiology of Pain (Nociception)
There are 4 basic processes involved in nociception: transduction, transmission, perception, and modulation.44 Normally, nociceptors (C and A-delta fibers of primary afferent neurons located in somatic and visceral structures) respond to noxious stimulation (mechanical, thermal, or chemical) causing the release of a variety of mediators, depolarization and repolarization of cell membranes, and generation of pain impulse. This signal is then transmitted to the dorsal horn of the spinal cord through release of excitatory neurotransmitters, then to brain stem and thalamus through spinothalamic and the spinoparabrachial ascending pathways, and, finally, to higher levels of the brain. Perception of pain is a conscious multidimensional experience with affective-motivational, sensory-discriminative, emotional, and behavioral components. Cortical areas involved in perception of pain stimuli comprise the reticular system (responsible for the autonomic and motor response to pain), somatosensory cortex (responsible for interpretation of sensations, such as intensity, type, and location of pain), and the limbic system (responsible for the emotional and behavioral responses to pain, such as attention, mood, and motivation). Modulation of pain means changing or inhibiting transmission of pain impulses in the spinal cord, by means of descending pathways that can increase (excitatory pathway) or decrease (inhibitory pathway) pain transmission. The latter involves the release of inhibitory neurotransmitters that block or partially block www.anesthesiaclinics.com
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the transmission of pain impulses producing analgesia. Among them is oxytocin, the best-known birth hormone. Levels of oxytocin gradually increase throughout labor causing uterine contractions, and are highest around the time of birth, when it contributes to mother’s euphoria and stress reduction.45 Demographic Factors and Labor Pain
Demographics play a significant role in the variability in human pain. Sex itself contributes to the difference in pain perception. Both clinical and laboratory pain studies demonstrate that men and women experience pain differently, and women seem to be prone to more severe pain compared with men.46 Moreover, many chronic painful diseases are much more prevalent in female individuals.47 Gender also affects analgesia, although the argument for sex-specific pain management is still in its early stages and needs further evidence.48 Other demographic factors contribute to the variance in pain, including labor pain perception, such as ethnic differences. However, it is unclear whether these differences are due to nociceptive processes per se or to personality-related traits. For example, Jewish and Italian patients more openly express pain than Irish and American patients,49 although they may report similar pain intensity levels. A study comparing KoreanAmerican and Euro-American obstetric patients reported significant differences in the quality of pain especially in the affective type of pain experience and overall evaluation of pain but not in the pain intensity in general between the 2 groups.50 A study from 5 self-reported ethnic groups (Asian, Black, Hispanic, Other, and White) showed that Asian women reported less pain during their labor compared with all other patients.51 Cultural differences also play an important role: sometimes caregivers underestimate labor pain with regard to intensity levels in religious parturients25 or in minorities.52 Younger age, higher education, and poor socioeconomic status have been shown as indicators that a woman would be more likely to perceive labor pain of higher intensity.53 In contrast, women who report lower pain are older, married, have good social support, have given birth previously, and planned/desired the pregnancy.26,27 Psychological Factors and Labor Pain
Affective-emotional factors contribute significantly to the experience of labor pain, both short-term and long-term. Preexisting expectations, level of anxiety, and fear of labor play the most important role. Fear of pain itself is a common reason for requesting a CS that, ironically, may cause more severe acute and chronic postlabor pain.54–56 Fear of delivery just before or during birth has been shown to increase the risk www.anesthesiaclinics.com
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of pain and of a negative childbirth experience.57 Anxiety impacts obstetric pain predicting maximum pain during labor and in the sensory aspects of pain.28 This is in line with earlier findings that anxiety is related to greater pain severity for women but not for men during a laboratory pain task indicating that women with high anxiety levels have a greater tendency for negative interpretations of pain, which would lead to more fear of painful experiences, such as childbirth.58 Exhaustion and sleep deprivation have been shown to decrease the pain perception threshold,59 and this could have contributed to the high pain scores observed during night labor.60 In addition, depression, neuroticism, “unstable emotional feelings,” concern for oneself or one’s baby, and sense of preparedness for and confidence in managing labor pain may influence labor pain independently and/or in combination.17,26 Coping behavior is an additional psychosocial factor influencing pain, and higher pain catastrophizing among female individuals correlates with higher pain scores.61,62 Thus, poor pain coping strategies combined with high maternal anxiety could lead to increased pain and potentially to the need for more risky procedures for delivery. In contrast, positive expectations correlated with better response to labor analgesia; for example, women in labor who experienced better labor analgesia with nitrous oxide had higher positive expectations before receiving nitrous oxide.55 The previous experience of pain also positively correlates with perceived levels of labor pain: women who reported that they had previously experienced significant levels of pain unrelated to childbirth had lower levels of labor pain compared with subjects who reported little experience of pain unrelated to childbirth.63 Overall, modifiable factors that have empirically been shown to influence labor pain and response to labor analgesia include the following: environmental conditions, coping strategies, fear, anxiety, expectations about the experience, and, above all, a woman’s sense of self-efficacy or confidence in her ability to cope.64 The use of cognitive and behavioral techniques such as education and exposure-based strategies with women at risk during pregnancy may help mitigate not only their pain expectations but also their pain experience, thus improving their overall birth experience.28 Pain Sensitivity and Labor Pain
Women have more comorbid mood disorders,65 comorbid physical conditions,66 and overall number of somatic symptoms67 compared with men which may influence their pain sensitivity thresholds and make them prone to experience more severe pain.48 To evaluate these sex differences and the relationship between pain sensitivity and clinical pain, pain researchers have incorporated experimental (evoked) pain tests, also known as Quantitative Sensory Testing (QST), to reproduce www.anesthesiaclinics.com
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clinical pain in a laboratory setting. Pain sensitivity assessment through standardized QST protocols has been extensively used in fibromyalgia patients68,69 and temporomandibular disorder70 to evaluate general and sex-specific pain mechanisms. The QST protocols include assessment of symptomatic and asymptomatic anatomic sites by administration of thermal, mechanical, or chemical stimuli that model the clinical pain studied. Evidence shows that evoked pain scores correlate with clinical pain. For example, women suffering from acute pain after hysterectomy more often had accompanying brush allodynia and pinprick hyperalgesia before surgery compared with women without pain.71 This is in line with previous studies, which have found that preoperative reduced thresholds to experimental pain stimuli in women undergoing C-section are associated with acute postoperative pain.72–74 The link to chronic pain remains uncertain.75 A recent study utilizing QST to predict labor pain and response to epidural analgesia revealed that, consistent with postoperative studies, suprathreshold and tolerance tests appear more useful than the threshold test for predicting labor pain responses76; however, a robust, easy, and quick-to-perform, point-of-care clinical test that accurately and comprehensively predicts labor-related pain has not been adequately elucidated. Furthermore, developing such a test may be more challenging compared with a test for other pain conditions, due to the influence of many social, psychological, and obstetric factors.
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Genetic Mechanisms of Labor Pain and Analgesia
There is growing evidence demonstrating the contribution of genetic factors to pain. QST is also used for dissecting the genetic and environmental contributions to interindividual differences in pain sensitivity and analgesic response. A recent twin study with randomized, double-blind and placebo-controlled design assessed pain sensitivity and analgesic opioid effects with experimental heat and cold pressor pain models along with important covariates including demographic factors, depression, anxiety, and sleep quality. The study detected significant heritability with genetic effects accounting for 12% to 60% of the observed response variance.77 These findings confirm a previous observation that 60% of the variance in cold pressor pain is predicted to be genetically mediated, compared with only 26% of the variance in heat pain.78 A study on female twins using a wide range of noxious stimuli and including models of hyperalgesia and allodynia reported genetic components of 22% to 55% for the majority of painful stimuli, particularly heat pain thresholds.79 Moreover, studies show that genetic factors control distinct clusters of nociception and an observed negative correlation that implies the presence of common pathways acting in opposing directions or in a competitive manner.43 www.anesthesiaclinics.com
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Genetic variations influencing specific pain phenotypes are catalogued in a comprehensive database of knockout mice.80 Numerous candidate genes have been considered for the study of human pain genetics.43 Rare mutations in some of them lead to monogenic rare pain disorders. One of these genes, SCN9A, which encodes the a subunit of the voltage-gated sodium channel Nav1.7, has been identified as an essential and nonredundant requirement for nociception in humans. SCN9A loss-of-function mutations cause total absence of pain perception in affected subjects including the physiological nociceptive response associated with severe tissue damage and injuries.81,82 Interestingly, the affected individuals are able to distinguish sharp from dull stimuli and detect differences in temperature, and their motor reflexes and autonomic responses are also normal, suggesting an absence of peripheral nerve abnormalities. Lack of protective properties in Nav1.7 is of major interest to the pain community as the search for drugs with similar pain-blocking properties remains ongoing.83 Genetic mechanisms underlying common painful diseases and pain in the general population seem to be more complex as multiple genes play a role; they interact with each other and interplay with environmental factors. Most of these genes have been identified in animal models first and then confirmed with human association data,42 although replication of the findings may be challenging because of sample heterogeneity, underpowered study design, population admixture, poor phenotyping, genotyping errors, and statistical analytical mistakes.84 Genetics of pain related to labor is also expected to be multifactorial, although several studies reported “extreme” pain phenotypes in parturient women; for example, 10 of 97 subjects reported that they had never experienced any pain with childbirth, but did not differ significantly from the majority of subjects on a large number of obstetric and psychological factors, which normally affect pain in labor.85 Certain genetic factors influencing labor pain are expected to overlap with those associated with other pain conditions, especially prevalent in women, such as temporomandibular disorder, fibromyalgia, or vulvar vestibulitis. Recent evidence suggesting a role for polymorphisms of genes in the serotoninergic, dopaminergic, and catecholaminergic systems in the pathogenesis of these conditions86 is of high interest for labor pain genetic studies. Another source of potential candidate genes for labor pain comes from the studies on genetic effects on specific components of the nociceptive system that may be modality specific but uniform across pain patient populations. For example, functional variants in the GCH1 gene encoding GTP cyclohydrolase 1 affected mechanical pain sensitivity, but not the response to suprathreshold cold and heat stimuli.87 In addition, genes contributing to stress response and emotional components of pain perception are likely to influence labor pain experience because of its www.anesthesiaclinics.com
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high affective charge. A classic example of these effects is the study of common functional single nucleotide polymorphism (SNP) in the COMT gene encoding catechol-O-methyltransferase, a key enzyme that degrades catecholamines such as dopamine, epinephrine, and norepinephrine.88 Individuals homozygous for the COMT met158 allele showed diminished regional m-opioid system responses to pain compared with heterozygotes, accompanied by higher sensory and affective ratings of pain and a more negative internal affective state.89 Thus, this SNP may underlie interindividual differences in the adaptation and responses to pain and other stressful stimuli. Recent developments in pain genetics research have opened vast opportunities to closely examine the influence of genes and their interactions on obstetric pain phenotypes. However, to date, only a handful of pain genes have been tested for effects on labor-related pain and analgesia, and the data are limited and inconsistent. OPRM1 is an obvious candidate gene as it encodes for the m-opioid receptor, a primary site for endogenous opioid peptides and for opioid analgesics, and has a well-known functional SNP (A118G). In 2004, Landau et al90 found an OPRM1 allele associated with an increased response to b-endorphin present in >30% of healthy parturients. In 2008, the same group conducted 2 double-blinded trials investigating the role of OPRM1 alleles on labor analgesia and demonstrated that the G allele significantly reduced intrathecal fentanyl requirement and increased responsiveness to opioids.91 Similar findings were reported for other pain conditions.92,93 However, recent studies found no association between the OPRM1 allele and the duration of intrathecal fentanyl analgesia in vaginal deliveries or the requirement for supplemental systemic analgesia in Cesarean deliveries,94 or with pain-related behavior during labor.95 The GCH1 gene mentioned above was tested for the effects on laborrelated behavior. It was found that pain-protective haplotype homozygotes arrived to the delivery ward with a more advanced stage of cervical dilation indicating less pain during labor progression (initial dilation of cervix), but more frequently required second-line labor analgesia.96 The b2AR gene encodes the b2-Adrenergic receptor that influences labor, and its genotype affects the incidence of preterm delivery.97 Parturients who express Gln allele at the 27th position of the b2AR had slower and more painful labor, and this functional polymorphism interplayed with ethnicity affecting labor outcomes.98 Labor pain is closely related to labor progress, and mathematical models have been developed to detect subtle effects of patient covariates on the progress and pain of the first stage of labor. These models expanded previous observations on the relationship of several risk factors with the length of time to reach a full cervical dilation that captured the latent and active stages of labor information mathematically in the form of www.anesthesiaclinics.com
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population-based labor curve.99 Generally, slower labor progress is associated with less rapid progression of pain; Asian women and heavier women have slower labor and slower onset of labor pain compared with others.51 The relationship between labor progress and pain may also be controlled by genetic mechanisms that influence the progress of labor. It was shown that parturients who are homozygous for the G allele at SNP rs53576 in the oxytocin receptor gene transitioned to active labor later and thus had slower labor.100 In addition, the COMT TT genotype at SNP rs4633 was associated with slower latent phase labor. Homozygotes for the T allele required approximately 5 hours more to reach full cervical dilation from 3-cm dilated than those with the CC or CT genotype.100 Microarray studies looking on the effects of labor progression on placental gene expression revealed hundreds of differentially expressed transcripts (344 upregulated and 7 downregulated) that involved 15 categories including genes involved in stress response, immune response, cell death, coagulation, and blood vessel development.101 These differentially expressed genes, which are considered to be most closely associated with the inflammatory response during labor, indicate a diversity of gene expression alteration and complexity of labor process. This is in line with earlier findings of the release of proinflammatory cytokines and antiangiogenic factors into the maternal circulation caused by oxidative and inflammatory stress of labor and delivery.102 Oxidative stress, activation of the nuclear factor-kB pathway, tumor necrosis factora, and interleukin 1b all increased in placental tissues after labor, whereas growth factor decreased, and the magnitude of these changes related to the duration of labor. After labor, 55 gene transcripts were upregulated and 35 downregulated.102 It is unclear whether these genes cause the interindividual variability in labor progress and/or labor-related pain. Pharmocogenetics is a new field of research that studies genetic variability in drug metabolism and response. This emerging field is set to retire the “one size fits all” idea within pharmaceutical companies that are limited in drug development for an “average” patient. The wealth of information about human painful conditions and responses to pain medicine has been identified with recent advances in the field of pain genetics and creation of the HapMap international project in 2002,103 which allowed collecting and cataloging genetic variations (SNPs) within the entire human genome. The availability of validated and emerging information about SNPs is expected to explain how inherent differences in different pain cohorts contribute to appropriate or adverse drug reactions, or no response at all. The increased push for tailored medication will not only expand our knowledge of the role of genetics in pharmaceutical agents but also improve patient outcomes in predicting adverse reactions.104 A recent review of genetic studies in drug binding sites (eg, adrenergic receptors, m-d-k-opioid receptors) explored the influence of www.anesthesiaclinics.com
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gene variations on observed variability in therapeutic response to obstetric anesthesia and analgesia.105 The review concluded that genetic variants affect drug responses to an extent that can have relevant implications beyond just the efficacy of a prescribed drug. To date there are no guidelines or recommendations that suggest any pharmacogenetic testing before administering any pain and/or anesthesia-related drug.
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Future Direction
The mechanisms leading to the initiation of normal, premature, or dysfunctional human labor are poorly understood, as animal models are inappropriate, and experimental studies are limited.91 Likewise, the mechanisms underlying interindividual variability in labor pain and response to obstetric anesthesia and analgesia need more investigation. New technologies in determining the pathways contributing to greater pain expression in certain patients or cohorts are now available including sensory testing methodology and genetic approaches. In common with other complex traits and behaviors, there are several levels of genetic complexity underlying labor-related pain phenotypes. First, such phenotypes represent an interactive array of multiple nonindependent intermediate phenotypes. Second, intermediate phenotypes are shaped by multiple interacting genes and environmental exposures, most of which have small individual effects on obstetric pain. Third, many of the contributing genetic loci that we are yet to discover are likely to possess complex genotypic and haplotypic structures with epistatic interactions within a single gene locus.83 Despite the complexity and challenges of genetic studies of human pain, including labor pain, current advances in pain assessment, accurate and affordable genotyping techniques, and novel functional genomics technologies as well as availability of large populations of obstetric patients will probably lead to well-designed genome-wide association and sequencing studies elucidating novel genetic factors and precise genetic mechanisms of severe acute and chronic labor-related pain. Pain at each stage of labor is multifactorial and affected by clinical, psychosocial, demographic, and genetic factors that put some women at greater risk for poor outcomes.106 Prediction of patients at risk based on an individual profile of risk factors and mathematical modeling will allow prevention of pain and pain-related conditions, which is especially important in the case of chronic and persistent postlabor pain. Current guidelines for multimodal or multidisciplinary chronic pain management (eg, combinations of ablative techniques, acupuncture, blocks, pharmacologic management, psychological treatment, etc.2,107) will be replaced in the future with more tailored analgesic therapies in targeted www.anesthesiaclinics.com
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patients. Personalized labor pain medicine based on fully revealed pain mechanisms in the postgenomic era will serve multiple goals including maximization and optimization of pain treatment, minimization or prevention of adverse effects, and, finally improvement of woman’s health and quality of life.
The authors have no conflicts of interest to disclose.
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References
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16. Bonica J, McDonald J. Obstetric Analgesia and Anesthesia. 2nd ed. Malvern: Williams and Wilkins; 1995. 17. Reading A. Testing pain mechanisms in persons in pain. In: Wall P, Melzack R. ed. Textbook of Pain. 3rd ed. Edinburgh: Churchill Livingstone; 1984. 18. Molina FJ, Sola P, Lopez E, et al. Pain in the first stage of labor: relationship with the patient’s position. J Pain Symptom Manage. 1997;13:98–103. 19. Brownridge P. The nature and consequences of childbirth pain. Eur J Obstet Gynecol Reprod Biol. 1995;59:S9–S15. 20. Camorcia M, Capogna G. Epidural levobupivacaine, ropivacaine and bupivacaine in combination with sufentanil in early labour: a randomized trial. Eur J Anaesthesiol. 2003;20:636–639. 21. Fabris LK. Persistent post-partum pain after vaginal birth and cesarean section. PeriodicumBiologorum. 2011;113:239–241. 22. Brown ST, Campbell D, Kurtz A. Characteristics of labour pain at two stages of cervical dilation. Pain. 1989;38:289–295. 23. Klostergaard K. “Labor pain in relation to fetal weight in primiparae”. Eur J Obstet Gynecol. 2001;99:195–198. 24. Ranta P, Joppila P, Joppila R. The intensity of labor pain in grand multiparas. Acta Obstet Gynecol Scand. 1996;75:250–254. 25. Sheiner E, Sheiner EK, Hershkovitz R, et al. Overestimation and underestimation of labor pain. Eur J Obstet Gynecol Reprod Biol. 2000;91:37–40. 26. Dannenbring D, Stevens MJ, House AE. Predictors of childbirth pain and maternal satisfaction. J Behav Med. 1997;20:127–142. 27. Fridh G, Kopare T, Gaston-Johansson F, et al. Factors associated with more intense labor pain. Res Nurs Health. 1988;11:117–124. 28. Lang A, Sorell J, Rodgers C, et al. Anxiety sensitivity as a predictor of labor pain. Eur J Pain. 2006;10:263–270. 29. Holdcroft A, Snidvongs S, Cason A, et al. Pain and uterine contractions during breast feeding in the immediate post-partum period increase with parity. Pain. 2003;104:589–596. 30. Klein MC, Gauthier RJ, Robbins JM. Relationship of episiotomy to perineal trauma and morbidity, sexual dysfunction, and pelvic floor relaxation. Am J Obstet Gynecol. 1994;171:591–598. 31. Macarthur AJ, Macarthur C. Incidence, severity, and determinants of perineal pain after vaginal delivery: a prospective cohort study. Am J Obstet Gynecol. 2004;191: 1199–1204. 32. Wang SM, Dezinno P, Maranets I, et al. Low back pain during pregnancy: prevalence, risk factors, and outcomes. Obstet Gynecol. 2004;104:65–70. 33. Carvalho B, Clark DJ, Angst MS. Local and systemic release of cytokines, nerve growth factor, prostaglandin E2, and substance P in incisional wounds and serum following cesarean delivery. J Pain. 2008;9:650–657. 34. Cancado T, Omais M, Ashmawi H, et al. Chronic pain after cesarean section. Influence of anesthetic/surgical technique and postoperative analgesia. Rev Bras Anestesiol. 2012;62:762–774. 35. Nikolajsen L, Sorensen HC, Jensen TS, et al. Chronic pain following caesarean section. Acta Anaesthesiol Scand. 2004;48:111–116. 36. Song BL, Sia TH, Quek K, et al. Incidence and risk factors for chronic pain after caesarean section under spinal anesthesia. Anaesth Intensive Care. 2009;37:748–752. 37. Almeida ECS, Nogueira FJ, Candido Dos Reis FJ, et al. Cesarean section as a cause of chronic pelvic pain. Int J Gynaecol Obstet. 2002;79:101–104. 38. Kainu JP, Sarvela J, Tiippana E, et al. Persistent pain after caesarean section and vaginal birth: a cohort study. Int J Obstet Anesth. 2010;19:4–9.
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´ttir S, et al. Low back pain, smoking and employment 39. Lı´ndal E, Hauksson A, Arnardo during pregnancy and after delivery - a 3-month follow-up study. J Obstet Gynaecol. 2000;20:263–266. 40. To WW, Wong MW. Factors associated with back pain symptoms in pregnancy and the persistence of pain 2 years after pregnancy. Acta Obstet Gynecol Scand. 2003; 82:1086–1091. 41. Young EE, Lariviere WR, Belfer I. Genetic basis of pain variability: recent advances. J Med Genet. 2012;49:1–9. 42. Belfer I, Shnol H, Finelli P. Molecular genetics of variability in human pain. eLS. 2013. 43. Foulkes T, Wood JN. Pain genes. PLoS Genet. 2008;4:e1000086. 44. McCaffery M, Pasero C. Pain: A Clinical Manual. St Louis, MO: Mosby; 1999. 45. Dawood MY, Raghavan KS, Pociask C, et al. Oxytocin in human pregnancy and parturition. Obstet Gynecol. 1978;51:138–143. 46. Bartley EJ, Fillingim RB. Sex differences in pain: a brief review of clinical and experimental findings. Br J Anaesth. 2013;111:52–58. 47. Fillingim RB, King CD, Ribeiro-Dasilva MC, et al. Sex, gender, and pain: a review of recent clinical and experimental findings. J Pain. 2009;10:447–485. 48. Greenspan JD, Craft RM, LeResche L, et al. Studying sex and gender differences in pain and analgesia: a consensus report. Pain. 2007;132:S26–S45. 49. Zborowski M. Cultural components in response to pain. J Soc Issues. 1952;8:15–35. 50. Lee MC, Essoka G. Patient’s perception of pain: comparison between KoreanAmerican and Euro-American obstetric patients. J Cult Divers. 1998;5:29–37; Spring. 51. Debiec J, Conell-Price J, Evansmith J, et al. Mathematical modeling of the pain and progress of the first stage of nulliparous labor. Anesthesiology. 2009;111: 1093–1110. 52. Winsburg G, Greenlick M. Pain response in Negro and White obstetrical patients. J Health Soc Behav. 1968;9:222–227. 53. Shrestha I, Pradhan N, Sharma J. Factors influencing perception of labor pain among parturient women. Nepal J Obstet Gynaecol. 2013;8:26–30. 54. Saisto T, Halmesma¨ki E. Fear of childbirth can be treated, and cesarean section on maternal request avoided. Acta Obstet Gynecol Scand. 2007;86:1148–1149. 55. Pasha H, Basirat Z, Hajahamadi M, et al. Maternal expectations and experiences of labor analgesia with nitrous oxide. Iran Red Crescent Med J. 2012;14:792–797. 56. Ryding EL. Investigation of 33 women who demanded a cesarean section for personal reasons. Acta Obstet Gynecol Scand. 1993;72:280–285. 57. Wuitchik M, Hesson K, Bakal DA. Perinatal predictors of pain and distress during labor. Birth. 1990;17:186–191. 58. Keogh E, Birkby J. The effect of anxiety sensitivity and gender on the experience of pain. Cogn Emot. 1999;13:813–829. 59. Labrecque G, Karzazi M, Vanier MC. Biological rhythms in pain and analgesia. In: Redfern PH, Lemmers B. ed. Physiology and Pharmacology of Biological Rhythms. New York: Springer-Verlag: 1997;83–90. 60. Aya AGM, Viales N, Mangin R, et al. Chronobiology of labour pain perception: an observational study. Br J Anesth. 2004;93:451–453. 61. Keogh E, Eccleston C. Sex differences in adolescent chronic pain and pain-related coping. Pain. 2006;123:275–284. 62. Keefe FJ, Lefebvre JC, Egert JR, et al. The relationship of gender to pain, pain behavior, and disability in osteoarthritis patients: the role of catastrophizing. Pain. 2000;87:325–334. 63. Niven C, Gusbers K. Do low levels of labour pain reflect low sensitivity to noxious stimulation. Soc Sci Med. 1989;29:585–588. www.anesthesiaclinics.com
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64. Canton D. The nature and management of labor pain: executive summary. Am J Obstet Gynecol. 2002;186:S1–15. 65. Sloan DM, Kornstein SG. Gender differences in depression and response to antidepressant treatment. Psychiatr Clin North Am. 2003;26:581–594. 66. Paykel ES, Brugha T, Fryers T. Size and burden of depressive disorders in Europe. Eur Neuropsychopharmacol. 2005;15:411–423. 67. Von Korff M, Dworkin SF, Le Resche L, et al. An epidemiologic comparison of pain complaints. Pain. 1988;32:173–183. 68. Lautenbacher S, Rollman GB, McCain GA. Multi-method assessment of experimental and clinical pain in patients with fibromyalgia. Pain. 1994;59:45–53. 69. Staud R, Vierck CJ, Cannon RL, et al. Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain. 2001;91:165–175. 70. Sarlani E, Grace EG, Reynolds MA, et al. Evidence for up-regulated central nociceptive processing in patients with masticatory myofascial pain. J Orofac Pain. 2004;18:41–55. 71. Brandsborg B. Pain following hysterectomy: epidemiological and clinical aspects. Dan Med J. 2012;59:1–15. 72. Granot M, Lowenstein L, Yarnitsky D, et al. Postcesarean section pain prediction by preoperative experimental pain assessment. Anesthesiology. 2003;98:1422–1426. 73. Pan PH, Coghill R, Houle TT, et al. Multifactorial preoperative predictors for postcesarean section pain and analgesic requirement. Anesthesiology. 2006;104: 417–425. 74. Strulov L, Zimmer EZ, Granot M, et al. Pain catastrophizing, response to experimental heat stimuli, and post-cesarean section pain. J Pain. 2007;8:273–279. 75. Granot M. Can we predict persistent postoperative pain by testing preoperative experimental pain? Curr Opin Anaesthesiol. 2009;22:425–430. 76. Carvalho B, Zheng M, Aiono-Le Tagaloa L. Evaluation of experimental pain tests to predict labour pain and epidural analgesic consumption. Br J Anaesth. 2013;110:600–606. 77. Angst MS, Phillips NG, Drover DR, et al. Pain sensitivity and opioid analgesia: a pharmacogenomics twin study. Pain. 2012;153:1397–1409. 78. Nielsen CS, Stubhaug A, Price DD, et al. Individual differences in pain sensitivity: genetic and environmental contributions. Pain. 2008;136:21–29. 79. Norbury TA, MacGregor AJ, Urwin J, et al. Heritability of responses to painful stimuli in women: a classical twin study. Brain. 2007;130(pt 11):3041–3049. 80. Lacroix-Fralish ML, Ledoux JB, Mogil JS. The Pain genes database: an interactive web browser of pain related transgenic knockout studies. Pain. 2007;131:e1–e4. 81. Nielsen KB, Nicholas AK, Woods CG, et al. Two novel SCN9A mutations causing insensitivity to pain. Pain. 2009;143:155–158. 82. Goldberg YP, MacFarlane J, MacDonald ML, et al. Loss-of function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations. Clin Genet. 2007;71:311–319. 83. Diatchenko L. Genetic architecture of human pain perception. TIG. 2007;23: 605–613. 84. Belfer I, Dai F. Phenotyping and genotyping neuropathic pain. Curr Pain Headache Rep. 2010;14:204–212. 85. Niven C, Gijsbers K. A study of labour pain using the McGill Pain Questionnaire. Soc Sci Med. 1984;19:1347–1351. 86. Buskila D. Genetics of chronic pain states. Best Pract Res Clin Rheumatol. 2007;21: 535–547. 87. Campbell CM, Edwards RR, Carmona C, et al. Polymorphisms in the GTP cyclohydrolase gene (GCH1) are associated with ratings of capsaicin pain. Pain. 2009; 141:114–118. www.anesthesiaclinics.com
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88. Belfer I, Segall S. COMT genetic variants and pain. Drugs Today (Barc). 2011;47: 457–467. 89. Zubieta JK, Heitzeg MM, Smith YR, et al. COMT val158met genotype affects muopioid neurotransmitter responses to a pain stressor. Science. 2003;299:1240–1243. 90. Landau R, Cahana A, Smiley RM, et al. Genetic variability of mu-opioid receptor in an obstetric population. Anesthesiology. 2004;100:1030–1033. 91. Pervolaraki E, Holden AV. Spatiotemporal patterning of uterine excitation patterns in human labour. BioSystems. 2013;112:63–72. 92. Janicki PK, Schuler G, Francis D, et al. A genetic association study of the functional A118G polymorphism of the human mu-opioid receptor gene in patients with acute and chronic pain. Anesth Analg. 2006;103:1011–1017. 93. Han W, Ide S, Sora I, et al. A possible genetic mechanism underlying individual and interstrain differences in opioid actions: focus on the mu opioid receptor gene. Ann NY Acad Sci. 2004;1025:370–375. 94. Wong CA, McCarthy RJ, Blouin J, et al. Observational study of the effect of muopioid receptor genetic polymorphism on intrathecal opioid labor analgesia and post-cesarean delivery analgesia. Int J Obstet Anesth. 2010;19:246–253. 95. Pettersson FD, Gro ¨nbladh A, Nyberg F, et al. The A118G single-nucleotide polymorphism of human m-opioid receptor gene and use of labor analgesia. Reprod Sci. 2012;19:962–967. 96. Dabo F, Gro ¨nbladh A, Nyberg F, et al. Different SNP combinations in the GCH1 gene and use of labor analgesia. Mol Pain. 2010;6:41–47. 97. Miller RS, Smiley RM, Daniel D, et al. Beta-2 adrenoceptor genotype and progress in term and late preterm active labor. Am J Obstet Gynecol. 2011;205:e1–e7. 98. Reitman E, Conell-Price J, Evansmith J, et al. Beta2-adrenergic receptor genotype and other variables that contribute to labor pain and progress. Anesthesiology. 2011;114:927–939. 99. Friedman E. The graphic analysis of labor. Am J Obstet Gynecol. 1954;68:1568–1575. 100. Terkawi AS, Jackson WM, Thiet M-P, et al. Oxytocin and catechol-O-methyltransferase receptor genotype predict the length of the first stage of labor. Am J Obstet Gynecol. 2012;207:e1–e8. 101. Lee KJ, Shim SH, Kang KM, et al. Global gene expression changes induced in the human placenta during labor. Placenta. 2010;31:698–704. 102. Cindrova-Davies T, Yung HW, Jhons J, et al. Oxidative stress, gene expression, and protein changes induced in the human placenta during labor. Am J Pathol. 2007;171:1168–1179. 103. International HapMap Project. “About the HapMap.” Available at: http:// hapmap.ncbi.nlm.nih.gov/thehapmap.html.en. Accessed May 15, 2013. 104. National Center for Biotechnology Information. “Just the Facts: A Basic Introduction to the Science Underlying NCBI Resources.” NCBI. March 31, 2004. U.S. National Library of Medicine. Available at: http://webcache.googleuser content.com/search?q=cache:2NEC2Svb0jAJ:http://www.biology.uoc.gr/courses/BIO 303_genetiki_anthropou/Material/SNPs.doc%2BJust+the+Facts:+A+Basic+Intro duction+to+the+Science+Underlying+NCBI+Resources+NCBI.+March+31,& hl=en&biw=&bih=&gbv=2&ct=clnk. Accessed May 15, 2013. 105. Landau R. Pharmacogenetic influences in obstetric anaesthesia. Best Pract Res Clin Obstet Gynaecol. 2010;24:277–287. 106. Dabo Pettersson F. Genetics and Labor Pain Behavior. [Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 729]. Uppsala: Acta Universitatis Upsaliensis; 2011:1–62. 107. The American Society of Anesthesiologists Inc. Practice guidelines for chronic pain management. Anesthesiology. 2010;112:1–24.
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Helen Shnol, BSc Nicole Paul, BSc Inna Belfer, MD, PhD Department of Anesthesiology, Molecular Epidemiology of Pain Program University of Pittsburgh, Pennsylvania
Pain is a major socioeconomic and health problem in the world. There is no unique medical term that can encompass the vast reach of the condition, from acute surgery-related presentations to persistent body or site-specific pain. Although nociception is instrumental to survival, understanding of its mechanisms and pathways is still underway. It is crucial not only for “physiological” pain but even more for “pathologic” pain, for example, extremely severe acute and debilitating chronic pain. Severe acute pain is clinically challenging, limits patient mobility, and negatively affects mood. Furthermore, studies show that severe acute pain, for example, postsurgical pain, predicts long-term chronic pain.1 Chronic pain, as defined in the American Society of Anesthesiologists Practice Guidelines for Chronic Pain Management, is “pain of any etiology not directly related to neoplastic involvement, associated with a chronic medical condition or extending in duration beyond the expected temporal boundary of tissue injury and normal healing, and adversely affecting the function or well-being of the individual.”2 In recent years chronic pain has become a global pandemic, with millions suffering every year (Global Industry Analysts Inc. Report, January 10, 2011). In the United States alone, there is a tremendous expenditure of economic and social resources on health care costs, rehabilitation, and lost worker productivity, as well as the emotional and financial burden it places on patients and their families.3 Labor is traditionally regarded as one of the most painful events in a woman’s reproductive history, although its self-description ranges from nonexistent4 to excruciating.5 Such variation in women’s perception of labor pain is an interaction of physiological and biobehavioral processes. Although there are interindividual differences in pain intensity, reported pain experiences can be influenced and modified by REPRINTS: INNA BELFER, MD, PHD, DEPARTMENT OF ANESTHESIOLOGY, MOLECULAR EPIDEMIOLOGY OF PAIN PROGRAM, UNIVERSITY OF PITTSBURGH, 3550 TERRACE ST, SCAIFE HALL A1305, PITTSBURGH, PA 15261. E-MAIL: [email protected] INTERNATIONAL ANESTHESIOLOGY CLINICS Volume 52, Number 3, 1–17 r 2014, Lippincott Williams & Wilkins
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psychological factors (anxiety, depression, pain coping behavior), clinical factors (high-risk pregnancies), and genetic factors that predispose some women to higher pain severity and protect others from severe or persistent pain. There is a growing body of evidence that demonstrates that each group of factors may contribute to the risk for development of chronic pain postpartum and may assist in the prediction of analgesia effectiveness during labor and delivery. Although childbirth is a natural event in the lives of many women, it can result in long-term maternal and fetal morbidity from postpartum depression, chronic pain, and developmental difficulties. Pain (genital, perineal, back, and pelvic girdle) may appear at the very beginning of pregnancy, get worse with pregnancy progression, and stay after delivery for months or years.6 In fact, up to 55.8% of Chinese women reported chronic pain 5 to 11 years after their deliveries.7 With >4 million deliveries annually in the United States alone, even a smaller prevalence of persistent pain carries important public health consequences.8 Like other areas of pain research, there is little consensus on the risk factors associated with the development and persistence of labor-related pain. Elucidation of these factors has significant relevance for clinical practice, as it could identify women who might benefit from novel preventive strategies and allow tailored management of labor-related pain. The aim of this chapter is to describe the clinical characteristics of labor pain, review underlying mechanisms, and discuss risk factors and potential predictors in the development of chronic pain after childbirth.
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Labor-related Pain
Women may experience pain in 1 or several body sites including spine (cervical, thoracic, and lumbar), pelvic, and genital areas, and they may start experiencing it in early pregnancy. Occasional abdominal or pelvic discomfort is a common pregnancy complaint. It may be caused by the expansion of the uterus (accommodation pain), functional ovarian cysts, ligament stretches, pressure from growing fetus, etc. Severe or persistent pain can be a sign of a serious problem (eg, ectopic pregnancy or miscarriage). Yet, in some cases there is no clear medical reason for pain that may persist or even increase during pregnancy. Overall, significant pelvic girdle and/or low back pain occurs in approximately 50% of pregnant women in the months preceding delivery.9,10 The severity of such pain is related to age, number of weeks of pregnancy, passive hip flexion and internal rotation, and swimming. However, the total explained variance of these factors is only 15.9%.9 The severity of backache increases with both increasing age and increasing parity.11 Pain during pregnancy may have significant longterm consequences: a large epidemiological study in 5118 women www.anesthesiaclinics.com
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showed that a higher burden of symptoms such as backache during pregnancy correlated with poorer health status 14 years postpartum.12 Back pain is common during pregnancy, but there is limited information regarding the course of back pain after pregnancy. It is important to develop novel, and improve current, preventive strategies, especially in young multigravida patients.13 Low back pain in parturients is due primarily to anterior sacroiliac joint dysfunction, whereas in the general population it is primarily due to myofascial pain. Thus it is not uncommon to see myofascial trigger points in the parturient as well, and such a patient would benefit from epidural analgesia combined with additional myofascial trigger point analgesia.14 Other pain during labor is caused by contractions of the uterus, by pressure on the cervix, bladder, and bowels by the baby’s head, and by the stretching of the birth canal and vagina. During the first stage of labor (dilatation phase), pain is usually located in the region of the uterus and its adnexae as a result of (a) dilatation of the cervix and lower uterine segment; (b) traction and pressure on the adnexae and parietal peritoneum and the structures they envelop; (c) pressure and stretching of the bladder, urethra, rectum, and other pain-sensitive structures in the pelvis; (d) pressure on one or more roots of the lumbosacral plexus; and (e) reflex skeletal muscle spasms.15–17 Several hypotheses suggest that pain intensity is related to fetal position, ischemia of the uterus, myometrial blood flow, inflammatory processes of the uterine muscles, psychological aspects, and, probably, contractions of the uterus under isometric conditions.18 In general, the increasing intensity of pain commonly observed with dilatation may be partially attributable to a lowered activation threshold in the mechanoreceptors and to chemoreceptor stimulation produced by the uterine contractions.19 These nociceptive stimuli of the dilatation phase are predominantly transmitted to the T10 to L1 posterior nerve root ganglia. As with other types of visceral pain, labor pain may be referred to the abdominal wall, lumbosacral region, iliac crests, gluteal areas, and thighs.20 The onset of perineal pain at the end of the first stage signals the beginning of fetal descent and the second stage of labor.21 At the second stage (pelvic or descent phase) of labor, somatic pain predominates caused by distention and traction on pelvic structures and by distention of the pelvic floor and perineum. Sharp and generally well localized, these stimuli are transmitted through the pudendal nerve through the anterior rami of S2-S4. The intensity of this pain increases with greater cervical dilatation and is positively correlated to the intensity, duration, and frequency of uterine contractions.22 Interestingly, the experienced pain during labor among primiparae is not influenced by fetal weight.23 Previous deliveries, however, appear to correlate positively with pain severity: 21% of grand multiparas rated their pain as intolerable (pain scores 9 to 10) during the second stage of labor compared with 10% of www.anesthesiaclinics.com
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primiparas.24 Accurate estimation of pain during the delivery by the caregivers is important for appropriate pain management; however, some factors, such as birth order and religious practice of the patient, may significantly affect the caregiver’s ability to correctly estimate the pain of the parturient. The wider the cultural gap between the caregiver and the patient, the less accurate the estimate.25 Pain after delivery may linger for several weeks (acute pain) or persist for much longer (chronic postpartum pain). Several factors related to the labor, including induced labor, longer labor, and use of medications during labor, predict postpartum pain.26–28 During breast feeding, nearly all women (96%) report deep pain primarily at 3 sites: lower abdomen, low back, and breast, with associated referred hyperalgesia in 62% of them. The intensity of these pains increased significantly with parity.29 Episiotomy and perineal laceration are strongly associated with the presence of perineal pain during the immediate postpartum period and at 3 months for 11% of women.30 Yet, 75% of women with an intact perineum reported pain 1 day after childbirth, and 38% a week later.31 The reported prevalence of perineal pain, back pain, and pelvic girdle pain that affects recovery from childbirth ranges from 5% to 43% for 6 months after delivery.32 One in 13 women after vaginal delivery in US tertiary care centers suffers from severe acute pain after delivery, and for cesarean delivery the rates were even higher at 1 in 5.8 Cesarean section (CS), as any other surgical injury, can cause severe acute pain due to the damage to a variety of tissues. Activation and sensitization of nociceptors results in primary hyperalgesia, and enhanced responsiveness of pain-transmitting neurons in the central nervous system (central sensitization) results in secondary hyperalgesia.33 In many cases, acute post-CS pain can persist for much longer than the usual healing period, and there is a correlation between higher pain scores in the immediate postoperative period and a higher incidence of chronic post-CS pain.34 A Danish study showed that 12.3% of parturients experienced persistent pain at the end of a followup period ranging from 6 to 18 months; 6% of them reported daily pain, and those having CS under general anesthesia had a higher frequency of persistent pain compared with spinal anesthesia.35 An Asian study showed that there was a 9.2% incidence of chronic pain after 3 months following elective CS under spinal anesthesia.36 Furthermore, a study of Brazilian women found that 67% of women with chronic pelvic pain had a history of CS.37 When comparing the incidence of persistent pain at 1 year after CS versus vaginal delivery, a significant difference was found (18% vs. 10%); however, the intensity of pain was similar and correlated with previous pain, previous back pain, and any chronic disease rather than the mode of delivery.38 Moreover, a large prospective longitudinal study revealed that the severity of acute postpartum pain, but not mode of delivery, increased 2.5 fold the risk for persistent postpartum pain.8 www.anesthesiaclinics.com
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Generally, up to 30% of women have chronic postpartum pain 2 years after delivery, and more than a half of those with low back pain during pregnancy still experience it at 3 months after delivery.39,40 ’
Factors Contributing to Labor Pain and Its Perception
Many factors contribute to interindividual differences in processing and perception of labor pain. Some clinical, physiological, and psychosocial factors are more prominent in one cohort than another because of differences in standard care protocols and patient characteristics. It is important to not only identify but recognize the importance of these differences in clinical research and pain management. In addition, growing evidence demonstrates the role of genetic mechanisms that underlie the variability in human pain, including labor-related pain. Genetic factors may contribute independently and/or through interplay with demographic, psychological, and other environmental factors shaping pain phenotypes such as pain sensitivity, pain severity, frequency, and duration.41,42 They also interact with environmental factors, such as stress or early exposure to acute painful stimuli that can have long-term effects on nociceptive thresholds.43 Physiology of Pain (Nociception)
There are 4 basic processes involved in nociception: transduction, transmission, perception, and modulation.44 Normally, nociceptors (C and A-delta fibers of primary afferent neurons located in somatic and visceral structures) respond to noxious stimulation (mechanical, thermal, or chemical) causing the release of a variety of mediators, depolarization and repolarization of cell membranes, and generation of pain impulse. This signal is then transmitted to the dorsal horn of the spinal cord through release of excitatory neurotransmitters, then to brain stem and thalamus through spinothalamic and the spinoparabrachial ascending pathways, and, finally, to higher levels of the brain. Perception of pain is a conscious multidimensional experience with affective-motivational, sensory-discriminative, emotional, and behavioral components. Cortical areas involved in perception of pain stimuli comprise the reticular system (responsible for the autonomic and motor response to pain), somatosensory cortex (responsible for interpretation of sensations, such as intensity, type, and location of pain), and the limbic system (responsible for the emotional and behavioral responses to pain, such as attention, mood, and motivation). Modulation of pain means changing or inhibiting transmission of pain impulses in the spinal cord, by means of descending pathways that can increase (excitatory pathway) or decrease (inhibitory pathway) pain transmission. The latter involves the release of inhibitory neurotransmitters that block or partially block www.anesthesiaclinics.com
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the transmission of pain impulses producing analgesia. Among them is oxytocin, the best-known birth hormone. Levels of oxytocin gradually increase throughout labor causing uterine contractions, and are highest around the time of birth, when it contributes to mother’s euphoria and stress reduction.45 Demographic Factors and Labor Pain
Demographics play a significant role in the variability in human pain. Sex itself contributes to the difference in pain perception. Both clinical and laboratory pain studies demonstrate that men and women experience pain differently, and women seem to be prone to more severe pain compared with men.46 Moreover, many chronic painful diseases are much more prevalent in female individuals.47 Gender also affects analgesia, although the argument for sex-specific pain management is still in its early stages and needs further evidence.48 Other demographic factors contribute to the variance in pain, including labor pain perception, such as ethnic differences. However, it is unclear whether these differences are due to nociceptive processes per se or to personality-related traits. For example, Jewish and Italian patients more openly express pain than Irish and American patients,49 although they may report similar pain intensity levels. A study comparing KoreanAmerican and Euro-American obstetric patients reported significant differences in the quality of pain especially in the affective type of pain experience and overall evaluation of pain but not in the pain intensity in general between the 2 groups.50 A study from 5 self-reported ethnic groups (Asian, Black, Hispanic, Other, and White) showed that Asian women reported less pain during their labor compared with all other patients.51 Cultural differences also play an important role: sometimes caregivers underestimate labor pain with regard to intensity levels in religious parturients25 or in minorities.52 Younger age, higher education, and poor socioeconomic status have been shown as indicators that a woman would be more likely to perceive labor pain of higher intensity.53 In contrast, women who report lower pain are older, married, have good social support, have given birth previously, and planned/desired the pregnancy.26,27 Psychological Factors and Labor Pain
Affective-emotional factors contribute significantly to the experience of labor pain, both short-term and long-term. Preexisting expectations, level of anxiety, and fear of labor play the most important role. Fear of pain itself is a common reason for requesting a CS that, ironically, may cause more severe acute and chronic postlabor pain.54–56 Fear of delivery just before or during birth has been shown to increase the risk www.anesthesiaclinics.com
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of pain and of a negative childbirth experience.57 Anxiety impacts obstetric pain predicting maximum pain during labor and in the sensory aspects of pain.28 This is in line with earlier findings that anxiety is related to greater pain severity for women but not for men during a laboratory pain task indicating that women with high anxiety levels have a greater tendency for negative interpretations of pain, which would lead to more fear of painful experiences, such as childbirth.58 Exhaustion and sleep deprivation have been shown to decrease the pain perception threshold,59 and this could have contributed to the high pain scores observed during night labor.60 In addition, depression, neuroticism, “unstable emotional feelings,” concern for oneself or one’s baby, and sense of preparedness for and confidence in managing labor pain may influence labor pain independently and/or in combination.17,26 Coping behavior is an additional psychosocial factor influencing pain, and higher pain catastrophizing among female individuals correlates with higher pain scores.61,62 Thus, poor pain coping strategies combined with high maternal anxiety could lead to increased pain and potentially to the need for more risky procedures for delivery. In contrast, positive expectations correlated with better response to labor analgesia; for example, women in labor who experienced better labor analgesia with nitrous oxide had higher positive expectations before receiving nitrous oxide.55 The previous experience of pain also positively correlates with perceived levels of labor pain: women who reported that they had previously experienced significant levels of pain unrelated to childbirth had lower levels of labor pain compared with subjects who reported little experience of pain unrelated to childbirth.63 Overall, modifiable factors that have empirically been shown to influence labor pain and response to labor analgesia include the following: environmental conditions, coping strategies, fear, anxiety, expectations about the experience, and, above all, a woman’s sense of self-efficacy or confidence in her ability to cope.64 The use of cognitive and behavioral techniques such as education and exposure-based strategies with women at risk during pregnancy may help mitigate not only their pain expectations but also their pain experience, thus improving their overall birth experience.28 Pain Sensitivity and Labor Pain
Women have more comorbid mood disorders,65 comorbid physical conditions,66 and overall number of somatic symptoms67 compared with men which may influence their pain sensitivity thresholds and make them prone to experience more severe pain.48 To evaluate these sex differences and the relationship between pain sensitivity and clinical pain, pain researchers have incorporated experimental (evoked) pain tests, also known as Quantitative Sensory Testing (QST), to reproduce www.anesthesiaclinics.com
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clinical pain in a laboratory setting. Pain sensitivity assessment through standardized QST protocols has been extensively used in fibromyalgia patients68,69 and temporomandibular disorder70 to evaluate general and sex-specific pain mechanisms. The QST protocols include assessment of symptomatic and asymptomatic anatomic sites by administration of thermal, mechanical, or chemical stimuli that model the clinical pain studied. Evidence shows that evoked pain scores correlate with clinical pain. For example, women suffering from acute pain after hysterectomy more often had accompanying brush allodynia and pinprick hyperalgesia before surgery compared with women without pain.71 This is in line with previous studies, which have found that preoperative reduced thresholds to experimental pain stimuli in women undergoing C-section are associated with acute postoperative pain.72–74 The link to chronic pain remains uncertain.75 A recent study utilizing QST to predict labor pain and response to epidural analgesia revealed that, consistent with postoperative studies, suprathreshold and tolerance tests appear more useful than the threshold test for predicting labor pain responses76; however, a robust, easy, and quick-to-perform, point-of-care clinical test that accurately and comprehensively predicts labor-related pain has not been adequately elucidated. Furthermore, developing such a test may be more challenging compared with a test for other pain conditions, due to the influence of many social, psychological, and obstetric factors.
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Genetic Mechanisms of Labor Pain and Analgesia
There is growing evidence demonstrating the contribution of genetic factors to pain. QST is also used for dissecting the genetic and environmental contributions to interindividual differences in pain sensitivity and analgesic response. A recent twin study with randomized, double-blind and placebo-controlled design assessed pain sensitivity and analgesic opioid effects with experimental heat and cold pressor pain models along with important covariates including demographic factors, depression, anxiety, and sleep quality. The study detected significant heritability with genetic effects accounting for 12% to 60% of the observed response variance.77 These findings confirm a previous observation that 60% of the variance in cold pressor pain is predicted to be genetically mediated, compared with only 26% of the variance in heat pain.78 A study on female twins using a wide range of noxious stimuli and including models of hyperalgesia and allodynia reported genetic components of 22% to 55% for the majority of painful stimuli, particularly heat pain thresholds.79 Moreover, studies show that genetic factors control distinct clusters of nociception and an observed negative correlation that implies the presence of common pathways acting in opposing directions or in a competitive manner.43 www.anesthesiaclinics.com
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Genetic variations influencing specific pain phenotypes are catalogued in a comprehensive database of knockout mice.80 Numerous candidate genes have been considered for the study of human pain genetics.43 Rare mutations in some of them lead to monogenic rare pain disorders. One of these genes, SCN9A, which encodes the a subunit of the voltage-gated sodium channel Nav1.7, has been identified as an essential and nonredundant requirement for nociception in humans. SCN9A loss-of-function mutations cause total absence of pain perception in affected subjects including the physiological nociceptive response associated with severe tissue damage and injuries.81,82 Interestingly, the affected individuals are able to distinguish sharp from dull stimuli and detect differences in temperature, and their motor reflexes and autonomic responses are also normal, suggesting an absence of peripheral nerve abnormalities. Lack of protective properties in Nav1.7 is of major interest to the pain community as the search for drugs with similar pain-blocking properties remains ongoing.83 Genetic mechanisms underlying common painful diseases and pain in the general population seem to be more complex as multiple genes play a role; they interact with each other and interplay with environmental factors. Most of these genes have been identified in animal models first and then confirmed with human association data,42 although replication of the findings may be challenging because of sample heterogeneity, underpowered study design, population admixture, poor phenotyping, genotyping errors, and statistical analytical mistakes.84 Genetics of pain related to labor is also expected to be multifactorial, although several studies reported “extreme” pain phenotypes in parturient women; for example, 10 of 97 subjects reported that they had never experienced any pain with childbirth, but did not differ significantly from the majority of subjects on a large number of obstetric and psychological factors, which normally affect pain in labor.85 Certain genetic factors influencing labor pain are expected to overlap with those associated with other pain conditions, especially prevalent in women, such as temporomandibular disorder, fibromyalgia, or vulvar vestibulitis. Recent evidence suggesting a role for polymorphisms of genes in the serotoninergic, dopaminergic, and catecholaminergic systems in the pathogenesis of these conditions86 is of high interest for labor pain genetic studies. Another source of potential candidate genes for labor pain comes from the studies on genetic effects on specific components of the nociceptive system that may be modality specific but uniform across pain patient populations. For example, functional variants in the GCH1 gene encoding GTP cyclohydrolase 1 affected mechanical pain sensitivity, but not the response to suprathreshold cold and heat stimuli.87 In addition, genes contributing to stress response and emotional components of pain perception are likely to influence labor pain experience because of its www.anesthesiaclinics.com
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high affective charge. A classic example of these effects is the study of common functional single nucleotide polymorphism (SNP) in the COMT gene encoding catechol-O-methyltransferase, a key enzyme that degrades catecholamines such as dopamine, epinephrine, and norepinephrine.88 Individuals homozygous for the COMT met158 allele showed diminished regional m-opioid system responses to pain compared with heterozygotes, accompanied by higher sensory and affective ratings of pain and a more negative internal affective state.89 Thus, this SNP may underlie interindividual differences in the adaptation and responses to pain and other stressful stimuli. Recent developments in pain genetics research have opened vast opportunities to closely examine the influence of genes and their interactions on obstetric pain phenotypes. However, to date, only a handful of pain genes have been tested for effects on labor-related pain and analgesia, and the data are limited and inconsistent. OPRM1 is an obvious candidate gene as it encodes for the m-opioid receptor, a primary site for endogenous opioid peptides and for opioid analgesics, and has a well-known functional SNP (A118G). In 2004, Landau et al90 found an OPRM1 allele associated with an increased response to b-endorphin present in >30% of healthy parturients. In 2008, the same group conducted 2 double-blinded trials investigating the role of OPRM1 alleles on labor analgesia and demonstrated that the G allele significantly reduced intrathecal fentanyl requirement and increased responsiveness to opioids.91 Similar findings were reported for other pain conditions.92,93 However, recent studies found no association between the OPRM1 allele and the duration of intrathecal fentanyl analgesia in vaginal deliveries or the requirement for supplemental systemic analgesia in Cesarean deliveries,94 or with pain-related behavior during labor.95 The GCH1 gene mentioned above was tested for the effects on laborrelated behavior. It was found that pain-protective haplotype homozygotes arrived to the delivery ward with a more advanced stage of cervical dilation indicating less pain during labor progression (initial dilation of cervix), but more frequently required second-line labor analgesia.96 The b2AR gene encodes the b2-Adrenergic receptor that influences labor, and its genotype affects the incidence of preterm delivery.97 Parturients who express Gln allele at the 27th position of the b2AR had slower and more painful labor, and this functional polymorphism interplayed with ethnicity affecting labor outcomes.98 Labor pain is closely related to labor progress, and mathematical models have been developed to detect subtle effects of patient covariates on the progress and pain of the first stage of labor. These models expanded previous observations on the relationship of several risk factors with the length of time to reach a full cervical dilation that captured the latent and active stages of labor information mathematically in the form of www.anesthesiaclinics.com
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population-based labor curve.99 Generally, slower labor progress is associated with less rapid progression of pain; Asian women and heavier women have slower labor and slower onset of labor pain compared with others.51 The relationship between labor progress and pain may also be controlled by genetic mechanisms that influence the progress of labor. It was shown that parturients who are homozygous for the G allele at SNP rs53576 in the oxytocin receptor gene transitioned to active labor later and thus had slower labor.100 In addition, the COMT TT genotype at SNP rs4633 was associated with slower latent phase labor. Homozygotes for the T allele required approximately 5 hours more to reach full cervical dilation from 3-cm dilated than those with the CC or CT genotype.100 Microarray studies looking on the effects of labor progression on placental gene expression revealed hundreds of differentially expressed transcripts (344 upregulated and 7 downregulated) that involved 15 categories including genes involved in stress response, immune response, cell death, coagulation, and blood vessel development.101 These differentially expressed genes, which are considered to be most closely associated with the inflammatory response during labor, indicate a diversity of gene expression alteration and complexity of labor process. This is in line with earlier findings of the release of proinflammatory cytokines and antiangiogenic factors into the maternal circulation caused by oxidative and inflammatory stress of labor and delivery.102 Oxidative stress, activation of the nuclear factor-kB pathway, tumor necrosis factora, and interleukin 1b all increased in placental tissues after labor, whereas growth factor decreased, and the magnitude of these changes related to the duration of labor. After labor, 55 gene transcripts were upregulated and 35 downregulated.102 It is unclear whether these genes cause the interindividual variability in labor progress and/or labor-related pain. Pharmocogenetics is a new field of research that studies genetic variability in drug metabolism and response. This emerging field is set to retire the “one size fits all” idea within pharmaceutical companies that are limited in drug development for an “average” patient. The wealth of information about human painful conditions and responses to pain medicine has been identified with recent advances in the field of pain genetics and creation of the HapMap international project in 2002,103 which allowed collecting and cataloging genetic variations (SNPs) within the entire human genome. The availability of validated and emerging information about SNPs is expected to explain how inherent differences in different pain cohorts contribute to appropriate or adverse drug reactions, or no response at all. The increased push for tailored medication will not only expand our knowledge of the role of genetics in pharmaceutical agents but also improve patient outcomes in predicting adverse reactions.104 A recent review of genetic studies in drug binding sites (eg, adrenergic receptors, m-d-k-opioid receptors) explored the influence of www.anesthesiaclinics.com
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gene variations on observed variability in therapeutic response to obstetric anesthesia and analgesia.105 The review concluded that genetic variants affect drug responses to an extent that can have relevant implications beyond just the efficacy of a prescribed drug. To date there are no guidelines or recommendations that suggest any pharmacogenetic testing before administering any pain and/or anesthesia-related drug.
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Future Direction
The mechanisms leading to the initiation of normal, premature, or dysfunctional human labor are poorly understood, as animal models are inappropriate, and experimental studies are limited.91 Likewise, the mechanisms underlying interindividual variability in labor pain and response to obstetric anesthesia and analgesia need more investigation. New technologies in determining the pathways contributing to greater pain expression in certain patients or cohorts are now available including sensory testing methodology and genetic approaches. In common with other complex traits and behaviors, there are several levels of genetic complexity underlying labor-related pain phenotypes. First, such phenotypes represent an interactive array of multiple nonindependent intermediate phenotypes. Second, intermediate phenotypes are shaped by multiple interacting genes and environmental exposures, most of which have small individual effects on obstetric pain. Third, many of the contributing genetic loci that we are yet to discover are likely to possess complex genotypic and haplotypic structures with epistatic interactions within a single gene locus.83 Despite the complexity and challenges of genetic studies of human pain, including labor pain, current advances in pain assessment, accurate and affordable genotyping techniques, and novel functional genomics technologies as well as availability of large populations of obstetric patients will probably lead to well-designed genome-wide association and sequencing studies elucidating novel genetic factors and precise genetic mechanisms of severe acute and chronic labor-related pain. Pain at each stage of labor is multifactorial and affected by clinical, psychosocial, demographic, and genetic factors that put some women at greater risk for poor outcomes.106 Prediction of patients at risk based on an individual profile of risk factors and mathematical modeling will allow prevention of pain and pain-related conditions, which is especially important in the case of chronic and persistent postlabor pain. Current guidelines for multimodal or multidisciplinary chronic pain management (eg, combinations of ablative techniques, acupuncture, blocks, pharmacologic management, psychological treatment, etc.2,107) will be replaced in the future with more tailored analgesic therapies in targeted www.anesthesiaclinics.com
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patients. Personalized labor pain medicine based on fully revealed pain mechanisms in the postgenomic era will serve multiple goals including maximization and optimization of pain treatment, minimization or prevention of adverse effects, and, finally improvement of woman’s health and quality of life.
The authors have no conflicts of interest to disclose.
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