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Capsaicin-induced pain and sensitisation in the postpartum period
British Journal of Anaesthesia, 122 (1): 103e110 (2019) doi: 10.1016/j.bja.2018.09.026 Advance Access Publication Date: 16 November 2018 Obstetric Anaesthesia
Capsaicin-induced pain and sensitisation in the postpartum period L. M. Street1, L. Harris2, R. S. Curry2 and J. C. Eisenach2,* 1
Department of Obstetrics and Gynecology, Augusta University, Augusta, GA, USA and 2Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, USA
*Corresponding author. E-mail: [email protected]
Abstract Background: Recovery from Caesarean delivery in women and surgical nerve injury in animals after delivery is more rapid than expected, an effect reversed in animals by spinal injection of an oxytocin receptor antagonist. We hypothesised that endogenous modulation of acute pain is altered postpartum. Methods: Endogenous inhibition of acute pain in a conditioned pain modulation paradigm or endogenous sensitisation by topical capsaicin was tested in women who were breastfeeding 10e14 days after Caesarean delivery and age-matched controls (n¼80 total: 20 per group and 20 per test). The study was powered to detect a difference in area of hyperalgesia after capsaicin of 33%. Capsaicin-evoked pain was recorded in women, and capsaicin-evoked mechanical hypersensitivity was measured in rats 48 h after delivery and in age-matched female and male animals. Results: There was no effect of the postpartum period in the endogenous sensitisation assay in women, and the conditioned pain modulation assay failed to produce analgesia in either group. Postpartum women, however, reported less intense pain than controls at the end of topical capsaicin exposure (1.3 [1.4] vs 2.0 [2.0] on 0e10 verbal scale), and acute hypersensitivity after capsaicin was less in postpartum than control rats (withdrawal threshold 25 [15] vs 3.6 [1] g). Conclusions: These results agree with a recent report that oxytocin may desensitise the transient receptor potential for vanilloid-1 channel, although other explanations, including hormone effects, are possible. These results do not, however, support the inhibition of capsaicin-evoked spinal sensitisation in the postpartum period. Clinical trial registration: NCT01843517. Keywords: Caesarean delivery; hyperalgesia; nerve injury; oxytocin; postoperative pain; postpartum period
Editor’s key points Recovery from Caesarean delivery in women is more rapid than expected, so the authors hypothesised that endogenous modulation of acute pain is altered postpartum. There was no effect of the postpartum period on endogenous sensitisation, but women reported less
intense capsaicin-evoked pain and rats had less acute hypersensitivity after capsaicin. There was no postpartum difference in pain experience to acute phasic heat stimuli and experimentally induced hypersensitivity in new mothers who are breastfeeding, but capsaicin-evoked pain was reduced. The mechanisms of this postpartum analgesic effect are not clear, but may involve oxytocin-induced desensitisation of pain-related ion channels.
Editorial decision: 28 September 2018; Accepted: 28 September 2018 © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved. For Permissions, please email: [email protected]
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In two large prospective studies, we observed that persistent pain after Caesarean delivery is rarer than one would anticipate.1 This reflects a more rapid recovery of pain in the initial postoperative weeks compared with other surgical procedures,2,3 although this is not a universal finding.4 In animals, surgery-induced mechanical hypersensitivity dissipates more quickly in the early postpartum period.5 A better understanding of the mechanisms for this speedier recovery could lead to new treatments to speed recovery after surgery. Peripheral and central oxytocin release increases at the time of delivery and persists during lactation.6 In animals, recovery from hypersensitivity after surgery in the postpartum period is temporarily reversed by intrathecally injected antagonists of oxytocin action,7 suggesting a role for oxytocin in modulating pain neurotransmission directly through reduced sensitisation or enhanced inhibition. The primary goal of the current study was to determine whether endogenous pain sensitisation or inhibition was altered in postpartum women compared with an age-matched control group. A previous study found no difference in the measure of sensitisation (temporal summation) in women during the third trimester and in the postpartum period, but that study did not include a non-obstetric control group.8 Endogenous pain inhibition can be induced by exposure to noxious conditioning stimuli in what is termed conditioned pain modulation (CPM), and this effect is increased by peripherally administered oxytocin.9 The strength of preoperative CPM is inversely related to the risk of persistent pain after injury,10 so oxytocin might speed recovery after surgery by increasing endogenous inhibition. A previous study showed no difference in CPM in women between the postpartum period and during pregnancy, but the method used failed to induce CPM at either time.8 Oxytocin could also speed recovery from pain by reducing the nociceptor input from the periphery. Peripherally administered oxytocin reduces pain to acute noxious heat stimuli in some studies,11 but not in others.12 In mice, oxytocin diminishes the behavioural response to capsaicin and desensitises the transient receptor potential for vanilloid-1 (TRPV-1) ion channel.13 The secondary goals of this study were to determine whether pain responses to heat or capsaicin are reduced in postpartum women, and capsaicin-evoked hypersensitivity is reduced in postpartum animals. Both acute and chronic stress can exacerbate chronic pain and enhance pain intensity ratings from experimental pain.14 Caesarean delivery could increase stress because it is a major surgery and women are under social stress in the care of a newborn. For this reason, the final goal of the current study was to test whether perceived stress differed between postpartum women and age-matched controls, and was related to experience of nociception and strength of endogenous inhibition or sensitisation.
Methods Animal studies Studies were approved by the Institutional Animal Care and Use Committee at Wake Forest University (Winston-Salem, NC, USA). Twelve female and six male Sprague-Dawley rats were obtained from Harlan Industries (Indianapolis, IN, USA). Pregnant animals were obtained at 10e15 days gestation and singly housed until delivery, and then housed with their pups. Non-pregnant rats were pair housed with the same sex under
a standard 12:12 h lightedark (light from 6 a.m. to 6 p.m.) cycle in a separate, specific pathogen-free facility, and provided with food and water ad libitum. The rats were acclimated to paw withdrawal testing on three separate days before the study. These data were not used for analysis. The animals were placed in plastic chambers atop a mesh surface and were acclimated to the behavioural test room for 30 min. Calibrated von Frey filaments (Touch Test Sensory Probes; Stoelting, Wood Dale, IL, USA) were applied to the plantar hind paw until the filament bent. Paw withdrawal response was defined as a brisk withdrawal of the hind paw within 5 s of filament application at bending force. Paw withdrawal threshold was calculated using an upedown method, as described.15 On the day of study, the rats were briefly anaesthetised with isoflurane (3.5 vol%), and capsaicin 100 mg in 50 ml saline was injected subcutaneously on the dorsal aspect of the right hind paw. Anaesthesia was provided because pain in humans from intraplantar capsaicin injection is intense for several minutes, and this pain is inescapable in the animal model. Paw withdrawal threshold was determined before and at 30, 60, and 120 min after capsaicin injection. The technician determining paw withdrawal threshold could not be effectively blinded to the study group, as each group had distinctive appearance that could not be hidden. Randomisation was not performed, as the purpose was to determine the differences between conditions (postpartum compared with virgin). Reporting of the animal study adheres to the Animal Research: Reporting of In Vivo Experiments guidelines.
Human studies After the Institutional Review Board approval, adult women (ASA physical status 1, 2, or 3) in hospital after singleton vaginal delivery from uncomplicated pregnancy and who planned breastfeeding were recruited from a single centre (Maya Angelou Women’s Health & Wellness Center, Novant Health Forsyth Medical Center, Winston-Salem, NC, USA). We excluded patients who did not understand English. The trial was registered before enrolment of the first subject (NCT01843517). The purpose of the study was explained, questions were answered, and all patients gave written informed consent. The subjects were allowed to choose whether to be tested for endogenous facilitation with topical capsaicin or endogenous analgesia in the cold water CPM paradigm. Choice was provided because one of these (capsaicin) required over 1 h more time in the research unit, and we wanted to provide flexibility to these new mothers who were breastfeeding. Subject characteristics, medical history, and relevant obstetric information were recorded. For each obstetric subject, a control woman (nulliparous or not breastfeeding and whose youngest child was 2 yr or older) was recruited through advertisements in the community, matching for age, height, race, and ethnicity. We excluded subjects with history of chronic pain or chronic analgesic use. In addition, we excluded subjects in the obstetric group who took pain medication within 4 h of the study visit, or who had an average pain of >3 on a 0e10 numeric rating scale in the 24 h period before the study visit. Subjects reported to the Clinical Research Unit at Wake Forest Baptist Medical Center (Winston-Salem, NC, USA) for a single study visit. Postpartum women were studied 10e14 days after delivery. In these women, we recorded the average pain for the preceding 24 h on a 0e10 numeric rating scale,
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time since last pain medication, and time since last breastfeeding. All subjects completed the following surveys: Edinburgh Postnatal Depression Scale,16 Perceived Stress Scale,17 and the Insomnia Severity Index.18 Figure 1 displays the flow of patients through the capsaicin and CPM arms; the testing which was common (noxious heat stimulus response); and, in the two arms, experimental procedures and outcome measures.
the worst imaginable pain or unpleasantness. Stimuli were presented in the first block in ascending order to expose the subjects to the range of intensities and accustom them to rating pain. In the second block, the probe was moved to a different skin area (to avoid sensitisation), and each subject received these same six temperature stimuli, but in random order. Pain ratings from this second block of stimuli were used for analysis.
Pain testing
Capsaicin-evoked sensitisation
Acute noxious heat stimuli were delivered via a commercially available Food and Drug Administration-approved device (TSA-II; Medoc, Ramat Yishai, Israel). Thermal stimuli from 41 to 49 C were applied via a 16 16 mm Peltier-controlled thermode strapped to the volar aspect of the forearm. The surface of the thermode was maintained at 35 C between stimuli. Every subject received the same two blocks of stimuli. In the first block, the probe temperature was increased at a rate of 6 C s1 to either 41, 43, 44, 45, 47, or 49 C, maintained at this temperature for 5 s, and then decreased to 35 C at 6 C s1. Stimuli were separated by 30 s. Within 5 s after each stimulus, the subject was asked to report the intensity and then the unpleasantness of pain on a 0e10 verbal scale, with 0 representing no pain or unpleasantness at all and 10 representing
Central sensitisation was induced by a combination of topical heat and capsaicin, as described.19 In brief, a 4 cm2 Peltiercontrolled thermode was applied to the volar aspect of the forearm and maintained at 45 C for 5 min during which subjects rated pain intensity every minute. We then removed the thermode and applied capsaicin (0.075% cream; Bioglan Pharmaceuticals, Malvern, PA, USA) to the site of previous heating, covering the cream with an occlusive dressing for 30 min during which the subjects rated pain every 5 min. At 40 min after the removal of the capsaicin cream, the application site was heated to 40 C for 5 min (rekindling). Skin temperature on the volar forearm was maintained at 30 C with a heating lamp throughout the experiment. Areas of mechanical hyperalgesia to probing with a 225 mN von Frey filament and
Fig 1. Subject flow, experimental procedures, and outcome measures. Postpartum women chose between capsaicin and conditioned pain modulation testing, and in each arm of the study, matched controls were recruited. As indicated, six postpartum women withdrew before the study. (a) Women in both arms of the study rated pain to thermal stimuli of various temperatures applied to the forearm, and data were combined within groups (postpartum or control) across both arms of the study. (b) In the capsaicin arm, heat was applied to the forearm for 5 min, capsaicin cream was then applied to this area under an occlusive dressing for 30 min, and 45 min later the area was reheated for 5 min. Areas of hypersensitivity, the primary outcome measures, were tested after the initial heating, after capsaicin application, and after the second heating. Verbal pain intensity scores (shown as red blocks on the timeline), the secondary outcome measures, were obtained every minute during the initial heating and every 5 min during capsaicin cream application. (c) In the conditioned pain modulation arm, pain rating to the test stimulus, a 5 s, 49 C heating, was obtained before and during the conditioned pain stimulus, placing the foot in cold water, and the strength of conditioned pain modulation determined as the difference between these pain ratings.
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of mechanical allodynia to brushing with a cotton wisp were determined, as described,20 at the end of the initial 5 min heating, just after the removal of the capsaicin cream, and at the end of the rekindling heating.
2016 (Microsoft Corporation, Redmond, WA, USA), or R version 3.2 (R Foundation for Statistical Computing, Vienna, Austria) and RStudio version 0.98.501 (RStudio, Inc., Boston, MA, USA).
Results Conditioned pain modulation CPM was induced, as described,21 using a conditioning stimulus of placing a foot in a container of circulating water maintained at 10 C for 90 s. Pain intensity and unpleasantness scores to the test stimulus (5 s; 49 C stimulus on the volar forearm) were obtained ~1 min before and 30 s after immersion of the foot in the cold water. The strength of CPM was determined as the change in pain intensity rating to the test stimulus during the conditioning stimulus compared with before the conditioning stimulus.
Primary outcomes For rat studies, the primary outcome was paw withdrawal threshold; the study was powered before experimentation to observe a 40% difference between groups in withdrawal threshold over 30e120 min after capsaicin injection, a moderate effect size consistent with manipulations that alter this paradigm in mechanistic studies.22 For human studies of the thermal pain stimulus response, the primary outcome was the area under the pain intensityestimulus temperature curve; the study was powered to detect a 12% difference in this area between postpartum and control groups, an effect size observed with pharmacological interventions of approved analgesics.23 For capsaicin-evoked hypersensitivity, the primary outcome was the area of hyperalgesia; the study was powered to detect a 33% difference in this area between groups, an effect size observed with pharmacological interventions of approved analgesics.24,25 The primary outcome for the CPM study was the strength of CPM; the study was powered to detect a difference of 55% in CPM strength between groups. Secondary analyses examined correlations in each group between level of perceived stress and outcomes, and whether pain from sustained heat or topical capsaicin differed between groups in the capsaicin sensitisation paradigm.
Animal studies All animals were used in the analysis, and all pregnant rats delivered at term. Baseline withdrawal threshold did not differ between groups and capsaicin-evoked hypersensitivity in all animals. There was no sex difference in capsaicin effect in control male and female animals, but both groups differed from postpartum animals (Fig. 2).
Human studies From May 2013 through November 2017, 46 postpartum women and 40 matched controls were recruited. Six postpartum women who initially consented withdrew consent before the day of the study visit. Of the 40 control women, 22 were nulliparous. For the controls who were parous, the age of their youngest child was 4 (3) yr (range: 2e12 yr). Table 1 compares the subject characteristics and questionnaire score responses of the postpartum and control groups. One control subject and no postpartum subjects had an Edinburgh Postnatal Depression Scale score >13 indicative of likely depression. The Perceived Stress Scale scores were within the normative range (13.7 [6.6]) for American women aged 18e29 yr.26 One postpartum and one control subject met the criteria for severe clinical insomnia, and one postpartum subject met the criteria for moderate clinical insomnia. There was a difference in race within the postpartum group in those choosing the capsaicin or the CPM study (Online Supplement 1), and the same race distribution was successfully obtained in the matched controls. Table 2 compares the postpartum groups for obstetric variables, noting no differences between
Statistical analysis Unless otherwise indicated, data are presented as mean (standard deviation) or median (first and third quartiles). Rat-paw withdrawal threshold data were normally distributed in the log domain, and log values are depicted and were used for analysis by two-way repeated measures analysis of variance (ANOVA). In the clinical study, the groups were compared for subject characteristics, questionnaires, area under the pain intensityestimulus temperature curve (calculating area >41 C), and strength of CPM using Student’s t-test or ManneWhitney U-test, as appropriate. The groups were compared for areas of hyperalgesia and allodynia, and to pain intensity response to sustained heat and to capsaicin application over time by twoway repeated measures ANOVA with random effect for subject intercept. The relationships between perceived stress scale score or time since breastfeeding and pain outcomes were tested by Spearman’s correlation. A P-value <0.05 was considered significant. Primary outcomes and analyses were defined a priori. Each secondary analysis was tested with a P<0.05 criterion for significance, and was considered by definition to be exploratory. Analyses were performed using Microsoft Excel
Fig 2. Paw withdrawal threshold after intra-plantar capsaicin in rats. Paw withdrawal threshold after intra-plantar injection of capsaicin just after Time 0 in rats (n¼6 per group). Data are mean (standard deviation). *P<0.05 compared with control female or male animals.
Capsaicin-evoked pain is reduced postpartum
Table 1 Subject characteristics and questionnaire scores. Patient characteristics and questionnaires Variable
Postpartum
Control
Age (yr) Height (cm) Weight (kg) Race
21e37 165 (6) 92 (22) White (28)/ black (12) Hispanic (2) 3.8 (3.3)
19e39 166±(7) 80±(21) White (28)/ black (12) Hispanic (2) 5.1 (3.7)
14 (7.9) 5.5 (4.9)
12 (6.3) 5.3 (4.9)
Ethnicity Edinburgh Postnatal Depression Scale Perceived Stress Scale Insomnia Severity Index
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P¼0.290] or hyperalgesia (F[1, 38]¼2.076; P¼0.158) between the postpartum and control groups.
Sustained heat and capsaicin-evoked pain During the 5 min 45 C heat application, pain scores increased in both groups, but the groups did not differ in intercept B¼e0.33 ([95% confidence interval (CI): e0.95 to 0.28]; P¼0.291, or slope B¼e0.06 [95% CI: e0.20 to 0.09]; P¼0.461 (Fig. 5, left panel)). Pain scores increased more during the 30 min topical capsaicin application, and the postpartum group exhibited a smaller slope that differed from control in slope of change over this time (group time B¼e0.045 [95% CI: e0.07 to e0.02]; P¼0.002; Fig. 5, right panel).
Conditioned pain modulation Table 2 Postpartum groups. *CPM, conditioned pain modulation; data presented as mean±(standard deviation), median (first, third quartiles) or ranges XeY. No differences between groups Variable
Capsaicin
CPM*
Gravida Parity Gestational age (weeks) Duration of first-stage labour (h) Duration of second-stage labour (h) Neonatal weight (g) Degree of perineal laceration (0/1/2/3/4)
2 (1.75, 4) 1 (0, 2) 39 (1.5) 9.4 (11) 0.7 (1.1)
2 (1, 4) 1 (0, 2) 40 (1.1) 11 (8.4) 1.1 (1.3)
3360 (510) 7/7/5/0/1
3390 (570) 9/7/4/0/0
We did not demonstrate CPM in either postpartum or control group. Pain intensity rating from the 49 C test stimulus was numerically decreased during the cold water conditioning stimulus, although not significant in either group (8% in control group; 1% in postpartum group), and these pain ratings did not differ between groups (Supplementary Fig. S1a). As shown in Supplementary Figure S1b, there was a wide variability in change in pain intensity rating from the test stimulus during the conditioning stimulus. A slight majority of the subjects in each group showed a decrease in pain intensity during the conditioning stimulus, but this proportion did not differ between groups.
Relationship to perceived stress
Pain intensity and unpleasantness scores did not differ between the postpartum and control groups (Fig. 3). Pain intensity and unpleasantness ratings were highly correlated (Pearson r¼0.93) and did not differ by group. The primary outcome, area under the pain intensity vs stimulus temperature curve, did not differ between the postpartum and control (6.4 [6.1] and 6.1 [4.9], respectively; P¼0.16) groups, nor did the area under the pain unpleasantness vs stimulus temperature curve (7.5 [6.4] for postpartum vs 6.6 [4.4] for control; P¼0.07).
Perceived stress was not different between groups (Table 1), although there was considerable individual variability within each group. Neither group (Pearson correlation P¼0.61 for the postpartum group and P¼0.44 for the control group) nor the entire population (Pearson correlation P¼0.96) demonstrated a significant correlation between perceived stress and area under the pain intensity vs stimulus temperature curve. Similarly, neither group nor the entire population demonstrated a significant correlation between perceived stress and strength of CPM within individuals (Pearson correlation P¼0.71 for the postpartum group, P¼0.61 for the control group, and P¼0.50 for the entire population). Finally, neither group nor the entire population demonstrated a significant correlation between perceived stress and capsaicin-evoked hyperalgesia or allodynia (for hyperalgesia and allodynia Pearson correlation P¼0.40 and P¼0.38 for the postpartum group, P¼0.43 and P¼0.38 for the control group, and P¼0.41 and P¼0.19 for the entire population).
Capsaicin-evoked sensitisation
Discussion
All subjects completed the study through reheating after capsaicin. Areas of hyperalgesia and allodynia from heat, capsaicin application, and reheating are shown in Figure 4. There was no statistically significant group by condition (initial heat, capsaicin, and reheating) interaction on allodynia (F[2, 38]¼1.03; P¼0.337) or hyperalgesia (F[2, 38]¼0.586; P¼0.559). The main effect of condition showed a statistically significant difference in allodynia (F[2, 38]¼62.5; P<0.001) and hyperalgesia (F[2, 76]¼126.748; P<0.001) at the different time points. The main effect of group showed that there was no statistically significant difference in allodynia (F[1, 38]¼1.154;
We report that the postpartum period was associated with reduced behavioural responses to capsaicin in rats and humans, but not with differences in area of hypersensitivity in humans, or in pain intensity or unpleasantness to acute heat stimuli. There are no studies in rodents of capsaicin testing within the postpartum period. Intra-plantar injection of capsaicin in rodents produces a few minutes of guarding or licking behaviour followed by longer periods of mechanical hypersensitivity.27,28 In those studies, capsaicin was injected in awake, restrained animals, whereas for ethical reasons we provided anaesthesia, preventing us from observing
subjects choosing to participate in the capsaicin or CPM arms of the study. The time from last breastfeeding to beginning pain testing was 59 (44, 130) min.
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Fig 3. Pain experience to acute heat stimuli in women. Pain intensity (left) and unpleasantness (right) on a 0e10 numeric rating scale in response to 5 s stimuli on the forearm skin at temperatures ranging from 41 to 49 C in postpartum (blue) and age-matched control (pink) women. Data are mean (standard deviation), n¼40 per group. The groups did not differ in the primary outcome of the area under the pain intensity or unpleasantness/temperature curve.
spontaneous behaviours in the first minutes after injection. Mechanical hypersensitivity, our primary outcome, was reduced in postpartum animals compared with control males and females.
Fig 4. Areas of hypersensitivity in the topical capsaicin/heat paradigm. Areas of mechanical hyperalgesia to von Frey filament testing (circles) and mechanical allodynia to brushing with a cotton wisp (squares) in postpartum women (blue) or controls (pink). Values are mean (standard deviation), n¼20 per group. There was an effect of time, but not of group or a group*condition interaction. The data were analysed using categorical fixed effects and not linear or curvilinear contrasts, and the plot is for display only.
There are no studies in postpartum women using capsaicin testing. Temporal summation, another measure of central sensitisation, did not differ in women during the third trimester of pregnancy compared with repeat testing in the postpartum period, although no non-obstetric control was included.8 Contrary to our hypothesis, capsaicin-evoked sensitisation was not decreased in postpartum women compared with controls. Several interpretations of this lack of difference are possible. The hypothesis could simply be wrong. The initial degree of sensitisation from stimuli in the postpartum period may be unaffected, whereas the duration of sensitisation may be shortened, consistent with clinical observations that pain in the first few days after Caesarean delivery is similar to that after other major surgery, but subsequent recovery is more rapid after Caesarean delivery.2 We powered our study to examine sensitisation, as increased area of hypersensitivity surrounding the surgical wound carries increased risk for persistent pain after surgery.29,30 This study was underpowered to test the observed 15e20% reduction in area of hypersensitivity in postpartum women compared with controls. We considered a 33% difference between groups as clinically meaningful in our power analysis, as systemic and intrathecal drugs, which produce acute analgesia in patients with chronic pain, reduce the area of hyperalgesia after capsaicin by this amount.31e33 We showed no difference between groups in pain ratings across a range of suprathreshold noxious heat stimuli, similar to a lack of difference in threshold to heat pain between women during their third trimester compared with postpartum.8 The lack of reduction in acute nociception in the postpartum period is consistent with similar intensity of pain
Capsaicin-evoked pain is reduced postpartum
Fig 5. Pain intensity during sustained heat and with topical capsaicin. Pain intensity on a 0e10 numeric rating scale for every minute for 5 min during sustained heating of the skin on the forearm to 45 C (left panel), or every 5 min for 30 min thereafter when the heat was removed and topical capsaicin applied to the skin. Postpartum women in blue and control women in pink. The diameter of the circle directly reflects the number of subjects with that value. The lines and shaded areas represent linear regressions for each group in each condition with 95% confidence limits, n¼20 per group. Groups differ in pain report in response to capsaicin, but not to heat.
in the initial days after Caesarean delivery compared with other surgery.2 The strength of CPM did not differ between the study groups in the current study, just as it did not differ in women tested at third trimester and postpartum.8 In both studies, however, a CPM effect was not observed in either group or at either time, so neither study was able to test the hypothesis that CPM was altered in the postpartum period. We based our CPM paradigm on a previous report,21 and replicated pain ratings to test stimuli before the conditioning stimulus. We note that the strength of CPM is highly variable and failure not uncommon.34 In rodents, oxytocin binds to the TRPV-1 ion channel, minimally stimulates the channel, but effectively desensitises it to subsequent stimulation.13 In addition, co-administration of oxytocin with intra-cutaneous capsaicin reduces acute pain behaviours in mice. We observed a two-fold reduction in hypersensitivity from capsaicin injection in rats in the postpartum period compared with controls, and less pain in postpartum women during topical capsaicin exposure compared with controls. The women did not rate heat pain less in the postpartum period. TRPV-1 is thought to mediate heat sensation, but this is not inconsistent with possible desensitisation of the TRPV-1 channel, as there are redundant channels that signal noxious heat.35 We interpret the reduction in capsaicin-evoked pain in women in the postpartum period to reflect increased oxytocin exposure of peripheral nerves, although it is conceivable that the effect could reflect peripheral or central actions of other compounds of hormones, such as prolactin, that are increased in the postpartum period. Breastfeeding is associated with a doubling in circulating oxytocin in the first 20 min of suckling,36 and a 36% increased concentration in mothers who breastfeed compared with those who bottle-feed.6
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This study has several limitations. The CPM paradigm failed, so we cannot comment on endogenous inhibition produced by this mechanism. The analysis of pain during capsaicin application was prompted by research that appeared after completion of the study,13 and should be considered exploratory. We did not measure blood oxytocin concentrations, so we cannot comment on the relationship between this measure and pain during capsaicin exposure. Finally, the study rests on the assumption that the same systems that alter the time course of recovery from a major surgical injury also modify the experience and modulation of acute experimental pain. In conclusion, pain experience to acute phasic heat stimuli and experimentally induced hypersensitivity do not differ between new mothers who are breastfeeding their infants and age-matched controls. Capsaicin-evoked pain, however, is reduced in these mothers, consistent with a preclinical report suggesting that oxytocin desensitises the TRPV-1 ion channel.13 These data generate new hypotheses regarding the mechanisms behind quicker recovery from postoperative pain in the obstetric setting.
Authors’ contributions Study design: all authors. Patient recruitment: L.M.S., L.H., R.S.G. Data collection: L.H., R.S.G. Data analysis: J.C.E. Writing of first draft of manuscript: J.C.E. Review and editing of manuscript: L.M.S., L.H., R.S.G.
Acknowledgements The authors thank T.T. Houle, Department of Anesthesiology and Perioperative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA for his help in statistical analyses. The authors gratefully acknowledge the use of the services and facilities of the clinical research unit, funded by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant award number UL1TR001420.
Declaration of interest J.C.E. consults to Adynxx (San Francisco, CA, USA) regarding preclinical and clinical analgesic development of analgesics. Adynxx is developing non-oxytocin agents to speed recovery from surgery, but does not use the methods described in this manuscript and did not participate in this work or the manuscript. The remaining authors declare no conflicts of interest.
Funding National Institutes of Health (R37 GM48085) to J.C.E.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.bja.2018.09.026.
References 1. Eisenach JC, Pan P, Smiley RM, Lavand’homme P, Landau R, Houle TT. Resolution of pain after childbirth. Anesthesiology 2013; 118: 143e51
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2. Houle TT, Miller S, Lang JE, et al. Day-to-day experience in resolution of pain after surgery. Pain 2017; 158: 2147e54 3. Booth JL, Sharpe EE, Houle TT, et al. Patterns of recovery from pain after Cesarean delivery. Pain 2018; 159: 2088e96 4. Weibel S, Neubert K, Jelting Y, et al. Incidence and severity of chronic pain after caesarean section: a systematic review with meta-analysis. Eur J Anaesthesiol 2016; 33: 853e65 5. Aschenbrenner CA, Houle TT, Gutierrez S, Eisenach JC. Modeling individual recovery after peripheral nerve injury in rats and the effects of parturition. Anesthesiology 2014; 121: 1056e67 6. Grewen KM, Davenport RE, Light KC. An investigation of plasma and salivary oxytocin responses in breast- and formula-feeding mothers of infants. Psychophysiology 2010; 47: 625e32 7. Gutierrez S, Liu B, Hayashida K, Houle TT, Eisenach JC. Reversal of peripheral nerve injury-induced hypersensitivity in the postpartum period: role of spinal oxytocin. Anesthesiology 2013; 118: 152e9 8. Carvalho B, Granot M, Sultan P, Wilson H, Landau R. A longitudinal study to evaluate pregnancy-induced endogenous analgesia and pain modulation. Reg Anesth Pain Med 2016; 41: 175e80 9. Goodin BR, Anderson AJ, Freeman EL, Bulls HW, Robbins MT, Ness TJ. Intranasal oxytocin administration is associated with enhanced endogenous pain inhibition and reduced negative mood states. Clin J Pain 2015; 31: 757e67 10. Yarnitsky D, Crispel Y, Eisenberg E, et al. Prediction of chronic post-operative pain: pre-operative DNIC testing identifies patients at risk. Pain 2008; 138: 22e8 11. Paloyelis Y, Krahe C, Maltezos S, Williams SC, Howard MA, Fotopoulou A. The analgesic effect of oxytocin in humans: a double-blind, placebo-controlled cross-over study using laser-evoked potentials. J Neuroendocrinol 2016; 28: 1e10. https://doi.org/10.1111/jne.12347 12. Zunhammer M, Geis S, Busch V, Eichhammer P, Greenlee MW. Pain modulation by intranasal oxytocin and emotional picture viewingda randomized double-blind fMRI study. Sci Rep 2016; 6: 31606 13. Nersesyan Y, Demirkhanyan L, Cabezas-Bratesco D, et al. Oxytocin modulates nociception as an agonist of painsensing TRPV1. Cell Rep 2017; 21: 1681e91 14. Banik RK, Brennan TJ. Trpv1 mediates spontaneous firing and heat sensitization of cutaneous primary afferents after plantar incision. Pain 2009; 141: 41e51 15. Chaplan SR, Bach FW, Pogrel JW, Chung JM, Yaksh TL. Quantitative assessment of tactile allodynia in the rat paw. J Neurosci Methods 1994; 53: 55e63 16. Cox JL, Holden JM, Sagovsky R. Detection of postnatal depression. Development of the 10-item Edinburgh postnatal depression scale. Br J Psychiatry 1987; 150: 782e6 17. Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J Health Soc Behav 1983; 24: 385e96 18. Bastien CH, Vallieres A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med 2001; 2: 297e307 19. Petersen KL, Rowbotham MC. A new human experimental pain model: the heat/capsaicin sensitization model. Neuroreport 1999; 10: 1511e6 20. Eisenach JC, Hood DD, Curry R. Preliminary efficacy assessment of intrathecal injection of an American
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formulation of adenosine in humans. Anesthesiology 2002; 96: 29e34 Nahman-Averbuch H, Granovsky Y, Coghill RC, Yarnitsky D, Sprecher E, Weissman-Fogel I. Waning of “conditioned pain modulation”: a novel expression of subtle pronociception in migraine. Headache 2013; 53: 1104e15 Gear RW, Aley KO, Levine JD. Pain-induced analgesia mediated by mesolimbic reward circuits. J Neurosci 1999; 19: 7175e81 Sverrisdottir E, Foster DJ, Upton RN, et al. Modelling concentration-analgesia relationships for morphine to evaluate experimental pain models. Eur J Pharm Sci 2015; 66: 50e8 Eisenach JC, Hood DD, Curry R. Intrathecal, but not intravenous, clonidine reduces experimental thermal or capsaicin-induced pain and hyperalgesia in normal volunteers. Anesth Analg 1998; 87: 591e6 Dirks J, Petersen KL, Rowbotham MC, Dahl JB. Gabapentin suppresses cutaneous hyperalgesia following heatcapsaicin sensitization. Anesthesiology 2002; 97: 102e7 Cohen S, Williamson G. Perceived stress in a probability sample of the United States. Newbury Park, CA: Sage; 1988 Gilchrist HD, Allard BL, Simone DA. Enhanced withdrawal responses to heat and mechanical stimuli following intraplantar injection of capsaicin in rats. Pain 1996; 67: 179e88 Lariviere WR, Wilson SG, Laughlin TM, et al. Heritability of nociception. III. Genetic relationships among commonly used assays of nociception and hypersensitivity. Pain 2002; 97: 75e86 Eisenach JC. Preventing chronic pain after surgery: who, how, and when? Reg AnesthPain Med 2006; 31: 1e3 Kaasa T, Romundstad L, Roald H, Skolleborg K, Stubhaug A. Hyperesthesia one year after breast augmentation surgery increases the odds for persistent pain at four years. A prospective four-year follow-up study. Scand J Pain 2010; 1: 75e81 Eisenach JC, Hood DD, Curry R, Tong CY. Alfentanil, but not amitriptyline, reduces pain, hyperalgesia, and allodynia from intradermal injection of capsaicin in humans. Anesthesiology 1997; 86: 1279e87 Eisenach JC, Hood DD, Curry R. Relative potency of epidural to intrathecal clonidine differs between acute thermal pain and capsaicin-induced allodynia. Pain 2000; 84: 57e64 Eisenach JC, Curry R, Hood DD. Dose response of intrathecal adenosine in experimental pain and allodynia. Anesthesiology 2002; 97: 938e42 Kennedy DL, Kemp HI, Ridout D, Yarnitsky D, Rice ASC. Reliability of conditioned pain modulation: a systematic review. Pain 2016; 157: 2410e9 Vandewauw I, De Clercq K, Mulier M, et al. A TRP channel trio mediates acute noxious heat sensing. Nature 2018; 555: 662e6 Jonas K, Johansson LM, Nissen E, Ejdeback M, RansjoArvidson AB, Uvnas-Moberg K. Effects of intrapartum oxytocin administration and epidural analgesia on the concentration of plasma oxytocin and prolactin, in response to suckling during the second day postpartum. Breastfeed Med 2009; 4: 71e82
Handling editor: H.C. Hemmings Jr
Capsaicin-induced pain and sensitisation in the postpartum period L. M. Street1, L. Harris2, R. S. Curry2 and J. C. Eisenach2,* 1
Department of Obstetrics and Gynecology, Augusta University, Augusta, GA, USA and 2Department of Anesthesiology, Wake Forest School of Medicine, Winston-Salem, NC, USA
*Corresponding author. E-mail: [email protected]
Abstract Background: Recovery from Caesarean delivery in women and surgical nerve injury in animals after delivery is more rapid than expected, an effect reversed in animals by spinal injection of an oxytocin receptor antagonist. We hypothesised that endogenous modulation of acute pain is altered postpartum. Methods: Endogenous inhibition of acute pain in a conditioned pain modulation paradigm or endogenous sensitisation by topical capsaicin was tested in women who were breastfeeding 10e14 days after Caesarean delivery and age-matched controls (n¼80 total: 20 per group and 20 per test). The study was powered to detect a difference in area of hyperalgesia after capsaicin of 33%. Capsaicin-evoked pain was recorded in women, and capsaicin-evoked mechanical hypersensitivity was measured in rats 48 h after delivery and in age-matched female and male animals. Results: There was no effect of the postpartum period in the endogenous sensitisation assay in women, and the conditioned pain modulation assay failed to produce analgesia in either group. Postpartum women, however, reported less intense pain than controls at the end of topical capsaicin exposure (1.3 [1.4] vs 2.0 [2.0] on 0e10 verbal scale), and acute hypersensitivity after capsaicin was less in postpartum than control rats (withdrawal threshold 25 [15] vs 3.6 [1] g). Conclusions: These results agree with a recent report that oxytocin may desensitise the transient receptor potential for vanilloid-1 channel, although other explanations, including hormone effects, are possible. These results do not, however, support the inhibition of capsaicin-evoked spinal sensitisation in the postpartum period. Clinical trial registration: NCT01843517. Keywords: Caesarean delivery; hyperalgesia; nerve injury; oxytocin; postoperative pain; postpartum period
Editor’s key points Recovery from Caesarean delivery in women is more rapid than expected, so the authors hypothesised that endogenous modulation of acute pain is altered postpartum. There was no effect of the postpartum period on endogenous sensitisation, but women reported less
intense capsaicin-evoked pain and rats had less acute hypersensitivity after capsaicin. There was no postpartum difference in pain experience to acute phasic heat stimuli and experimentally induced hypersensitivity in new mothers who are breastfeeding, but capsaicin-evoked pain was reduced. The mechanisms of this postpartum analgesic effect are not clear, but may involve oxytocin-induced desensitisation of pain-related ion channels.
Editorial decision: 28 September 2018; Accepted: 28 September 2018 © 2018 British Journal of Anaesthesia. Published by Elsevier Ltd. All rights reserved. For Permissions, please email: [email protected]
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In two large prospective studies, we observed that persistent pain after Caesarean delivery is rarer than one would anticipate.1 This reflects a more rapid recovery of pain in the initial postoperative weeks compared with other surgical procedures,2,3 although this is not a universal finding.4 In animals, surgery-induced mechanical hypersensitivity dissipates more quickly in the early postpartum period.5 A better understanding of the mechanisms for this speedier recovery could lead to new treatments to speed recovery after surgery. Peripheral and central oxytocin release increases at the time of delivery and persists during lactation.6 In animals, recovery from hypersensitivity after surgery in the postpartum period is temporarily reversed by intrathecally injected antagonists of oxytocin action,7 suggesting a role for oxytocin in modulating pain neurotransmission directly through reduced sensitisation or enhanced inhibition. The primary goal of the current study was to determine whether endogenous pain sensitisation or inhibition was altered in postpartum women compared with an age-matched control group. A previous study found no difference in the measure of sensitisation (temporal summation) in women during the third trimester and in the postpartum period, but that study did not include a non-obstetric control group.8 Endogenous pain inhibition can be induced by exposure to noxious conditioning stimuli in what is termed conditioned pain modulation (CPM), and this effect is increased by peripherally administered oxytocin.9 The strength of preoperative CPM is inversely related to the risk of persistent pain after injury,10 so oxytocin might speed recovery after surgery by increasing endogenous inhibition. A previous study showed no difference in CPM in women between the postpartum period and during pregnancy, but the method used failed to induce CPM at either time.8 Oxytocin could also speed recovery from pain by reducing the nociceptor input from the periphery. Peripherally administered oxytocin reduces pain to acute noxious heat stimuli in some studies,11 but not in others.12 In mice, oxytocin diminishes the behavioural response to capsaicin and desensitises the transient receptor potential for vanilloid-1 (TRPV-1) ion channel.13 The secondary goals of this study were to determine whether pain responses to heat or capsaicin are reduced in postpartum women, and capsaicin-evoked hypersensitivity is reduced in postpartum animals. Both acute and chronic stress can exacerbate chronic pain and enhance pain intensity ratings from experimental pain.14 Caesarean delivery could increase stress because it is a major surgery and women are under social stress in the care of a newborn. For this reason, the final goal of the current study was to test whether perceived stress differed between postpartum women and age-matched controls, and was related to experience of nociception and strength of endogenous inhibition or sensitisation.
Methods Animal studies Studies were approved by the Institutional Animal Care and Use Committee at Wake Forest University (Winston-Salem, NC, USA). Twelve female and six male Sprague-Dawley rats were obtained from Harlan Industries (Indianapolis, IN, USA). Pregnant animals were obtained at 10e15 days gestation and singly housed until delivery, and then housed with their pups. Non-pregnant rats were pair housed with the same sex under
a standard 12:12 h lightedark (light from 6 a.m. to 6 p.m.) cycle in a separate, specific pathogen-free facility, and provided with food and water ad libitum. The rats were acclimated to paw withdrawal testing on three separate days before the study. These data were not used for analysis. The animals were placed in plastic chambers atop a mesh surface and were acclimated to the behavioural test room for 30 min. Calibrated von Frey filaments (Touch Test Sensory Probes; Stoelting, Wood Dale, IL, USA) were applied to the plantar hind paw until the filament bent. Paw withdrawal response was defined as a brisk withdrawal of the hind paw within 5 s of filament application at bending force. Paw withdrawal threshold was calculated using an upedown method, as described.15 On the day of study, the rats were briefly anaesthetised with isoflurane (3.5 vol%), and capsaicin 100 mg in 50 ml saline was injected subcutaneously on the dorsal aspect of the right hind paw. Anaesthesia was provided because pain in humans from intraplantar capsaicin injection is intense for several minutes, and this pain is inescapable in the animal model. Paw withdrawal threshold was determined before and at 30, 60, and 120 min after capsaicin injection. The technician determining paw withdrawal threshold could not be effectively blinded to the study group, as each group had distinctive appearance that could not be hidden. Randomisation was not performed, as the purpose was to determine the differences between conditions (postpartum compared with virgin). Reporting of the animal study adheres to the Animal Research: Reporting of In Vivo Experiments guidelines.
Human studies After the Institutional Review Board approval, adult women (ASA physical status 1, 2, or 3) in hospital after singleton vaginal delivery from uncomplicated pregnancy and who planned breastfeeding were recruited from a single centre (Maya Angelou Women’s Health & Wellness Center, Novant Health Forsyth Medical Center, Winston-Salem, NC, USA). We excluded patients who did not understand English. The trial was registered before enrolment of the first subject (NCT01843517). The purpose of the study was explained, questions were answered, and all patients gave written informed consent. The subjects were allowed to choose whether to be tested for endogenous facilitation with topical capsaicin or endogenous analgesia in the cold water CPM paradigm. Choice was provided because one of these (capsaicin) required over 1 h more time in the research unit, and we wanted to provide flexibility to these new mothers who were breastfeeding. Subject characteristics, medical history, and relevant obstetric information were recorded. For each obstetric subject, a control woman (nulliparous or not breastfeeding and whose youngest child was 2 yr or older) was recruited through advertisements in the community, matching for age, height, race, and ethnicity. We excluded subjects with history of chronic pain or chronic analgesic use. In addition, we excluded subjects in the obstetric group who took pain medication within 4 h of the study visit, or who had an average pain of >3 on a 0e10 numeric rating scale in the 24 h period before the study visit. Subjects reported to the Clinical Research Unit at Wake Forest Baptist Medical Center (Winston-Salem, NC, USA) for a single study visit. Postpartum women were studied 10e14 days after delivery. In these women, we recorded the average pain for the preceding 24 h on a 0e10 numeric rating scale,
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time since last pain medication, and time since last breastfeeding. All subjects completed the following surveys: Edinburgh Postnatal Depression Scale,16 Perceived Stress Scale,17 and the Insomnia Severity Index.18 Figure 1 displays the flow of patients through the capsaicin and CPM arms; the testing which was common (noxious heat stimulus response); and, in the two arms, experimental procedures and outcome measures.
the worst imaginable pain or unpleasantness. Stimuli were presented in the first block in ascending order to expose the subjects to the range of intensities and accustom them to rating pain. In the second block, the probe was moved to a different skin area (to avoid sensitisation), and each subject received these same six temperature stimuli, but in random order. Pain ratings from this second block of stimuli were used for analysis.
Pain testing
Capsaicin-evoked sensitisation
Acute noxious heat stimuli were delivered via a commercially available Food and Drug Administration-approved device (TSA-II; Medoc, Ramat Yishai, Israel). Thermal stimuli from 41 to 49 C were applied via a 16 16 mm Peltier-controlled thermode strapped to the volar aspect of the forearm. The surface of the thermode was maintained at 35 C between stimuli. Every subject received the same two blocks of stimuli. In the first block, the probe temperature was increased at a rate of 6 C s1 to either 41, 43, 44, 45, 47, or 49 C, maintained at this temperature for 5 s, and then decreased to 35 C at 6 C s1. Stimuli were separated by 30 s. Within 5 s after each stimulus, the subject was asked to report the intensity and then the unpleasantness of pain on a 0e10 verbal scale, with 0 representing no pain or unpleasantness at all and 10 representing
Central sensitisation was induced by a combination of topical heat and capsaicin, as described.19 In brief, a 4 cm2 Peltiercontrolled thermode was applied to the volar aspect of the forearm and maintained at 45 C for 5 min during which subjects rated pain intensity every minute. We then removed the thermode and applied capsaicin (0.075% cream; Bioglan Pharmaceuticals, Malvern, PA, USA) to the site of previous heating, covering the cream with an occlusive dressing for 30 min during which the subjects rated pain every 5 min. At 40 min after the removal of the capsaicin cream, the application site was heated to 40 C for 5 min (rekindling). Skin temperature on the volar forearm was maintained at 30 C with a heating lamp throughout the experiment. Areas of mechanical hyperalgesia to probing with a 225 mN von Frey filament and
Fig 1. Subject flow, experimental procedures, and outcome measures. Postpartum women chose between capsaicin and conditioned pain modulation testing, and in each arm of the study, matched controls were recruited. As indicated, six postpartum women withdrew before the study. (a) Women in both arms of the study rated pain to thermal stimuli of various temperatures applied to the forearm, and data were combined within groups (postpartum or control) across both arms of the study. (b) In the capsaicin arm, heat was applied to the forearm for 5 min, capsaicin cream was then applied to this area under an occlusive dressing for 30 min, and 45 min later the area was reheated for 5 min. Areas of hypersensitivity, the primary outcome measures, were tested after the initial heating, after capsaicin application, and after the second heating. Verbal pain intensity scores (shown as red blocks on the timeline), the secondary outcome measures, were obtained every minute during the initial heating and every 5 min during capsaicin cream application. (c) In the conditioned pain modulation arm, pain rating to the test stimulus, a 5 s, 49 C heating, was obtained before and during the conditioned pain stimulus, placing the foot in cold water, and the strength of conditioned pain modulation determined as the difference between these pain ratings.
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of mechanical allodynia to brushing with a cotton wisp were determined, as described,20 at the end of the initial 5 min heating, just after the removal of the capsaicin cream, and at the end of the rekindling heating.
2016 (Microsoft Corporation, Redmond, WA, USA), or R version 3.2 (R Foundation for Statistical Computing, Vienna, Austria) and RStudio version 0.98.501 (RStudio, Inc., Boston, MA, USA).
Results Conditioned pain modulation CPM was induced, as described,21 using a conditioning stimulus of placing a foot in a container of circulating water maintained at 10 C for 90 s. Pain intensity and unpleasantness scores to the test stimulus (5 s; 49 C stimulus on the volar forearm) were obtained ~1 min before and 30 s after immersion of the foot in the cold water. The strength of CPM was determined as the change in pain intensity rating to the test stimulus during the conditioning stimulus compared with before the conditioning stimulus.
Primary outcomes For rat studies, the primary outcome was paw withdrawal threshold; the study was powered before experimentation to observe a 40% difference between groups in withdrawal threshold over 30e120 min after capsaicin injection, a moderate effect size consistent with manipulations that alter this paradigm in mechanistic studies.22 For human studies of the thermal pain stimulus response, the primary outcome was the area under the pain intensityestimulus temperature curve; the study was powered to detect a 12% difference in this area between postpartum and control groups, an effect size observed with pharmacological interventions of approved analgesics.23 For capsaicin-evoked hypersensitivity, the primary outcome was the area of hyperalgesia; the study was powered to detect a 33% difference in this area between groups, an effect size observed with pharmacological interventions of approved analgesics.24,25 The primary outcome for the CPM study was the strength of CPM; the study was powered to detect a difference of 55% in CPM strength between groups. Secondary analyses examined correlations in each group between level of perceived stress and outcomes, and whether pain from sustained heat or topical capsaicin differed between groups in the capsaicin sensitisation paradigm.
Animal studies All animals were used in the analysis, and all pregnant rats delivered at term. Baseline withdrawal threshold did not differ between groups and capsaicin-evoked hypersensitivity in all animals. There was no sex difference in capsaicin effect in control male and female animals, but both groups differed from postpartum animals (Fig. 2).
Human studies From May 2013 through November 2017, 46 postpartum women and 40 matched controls were recruited. Six postpartum women who initially consented withdrew consent before the day of the study visit. Of the 40 control women, 22 were nulliparous. For the controls who were parous, the age of their youngest child was 4 (3) yr (range: 2e12 yr). Table 1 compares the subject characteristics and questionnaire score responses of the postpartum and control groups. One control subject and no postpartum subjects had an Edinburgh Postnatal Depression Scale score >13 indicative of likely depression. The Perceived Stress Scale scores were within the normative range (13.7 [6.6]) for American women aged 18e29 yr.26 One postpartum and one control subject met the criteria for severe clinical insomnia, and one postpartum subject met the criteria for moderate clinical insomnia. There was a difference in race within the postpartum group in those choosing the capsaicin or the CPM study (Online Supplement 1), and the same race distribution was successfully obtained in the matched controls. Table 2 compares the postpartum groups for obstetric variables, noting no differences between
Statistical analysis Unless otherwise indicated, data are presented as mean (standard deviation) or median (first and third quartiles). Rat-paw withdrawal threshold data were normally distributed in the log domain, and log values are depicted and were used for analysis by two-way repeated measures analysis of variance (ANOVA). In the clinical study, the groups were compared for subject characteristics, questionnaires, area under the pain intensityestimulus temperature curve (calculating area >41 C), and strength of CPM using Student’s t-test or ManneWhitney U-test, as appropriate. The groups were compared for areas of hyperalgesia and allodynia, and to pain intensity response to sustained heat and to capsaicin application over time by twoway repeated measures ANOVA with random effect for subject intercept. The relationships between perceived stress scale score or time since breastfeeding and pain outcomes were tested by Spearman’s correlation. A P-value <0.05 was considered significant. Primary outcomes and analyses were defined a priori. Each secondary analysis was tested with a P<0.05 criterion for significance, and was considered by definition to be exploratory. Analyses were performed using Microsoft Excel
Fig 2. Paw withdrawal threshold after intra-plantar capsaicin in rats. Paw withdrawal threshold after intra-plantar injection of capsaicin just after Time 0 in rats (n¼6 per group). Data are mean (standard deviation). *P<0.05 compared with control female or male animals.
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Table 1 Subject characteristics and questionnaire scores. Patient characteristics and questionnaires Variable
Postpartum
Control
Age (yr) Height (cm) Weight (kg) Race
21e37 165 (6) 92 (22) White (28)/ black (12) Hispanic (2) 3.8 (3.3)
19e39 166±(7) 80±(21) White (28)/ black (12) Hispanic (2) 5.1 (3.7)
14 (7.9) 5.5 (4.9)
12 (6.3) 5.3 (4.9)
Ethnicity Edinburgh Postnatal Depression Scale Perceived Stress Scale Insomnia Severity Index
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P¼0.290] or hyperalgesia (F[1, 38]¼2.076; P¼0.158) between the postpartum and control groups.
Sustained heat and capsaicin-evoked pain During the 5 min 45 C heat application, pain scores increased in both groups, but the groups did not differ in intercept B¼e0.33 ([95% confidence interval (CI): e0.95 to 0.28]; P¼0.291, or slope B¼e0.06 [95% CI: e0.20 to 0.09]; P¼0.461 (Fig. 5, left panel)). Pain scores increased more during the 30 min topical capsaicin application, and the postpartum group exhibited a smaller slope that differed from control in slope of change over this time (group time B¼e0.045 [95% CI: e0.07 to e0.02]; P¼0.002; Fig. 5, right panel).
Conditioned pain modulation Table 2 Postpartum groups. *CPM, conditioned pain modulation; data presented as mean±(standard deviation), median (first, third quartiles) or ranges XeY. No differences between groups Variable
Capsaicin
CPM*
Gravida Parity Gestational age (weeks) Duration of first-stage labour (h) Duration of second-stage labour (h) Neonatal weight (g) Degree of perineal laceration (0/1/2/3/4)
2 (1.75, 4) 1 (0, 2) 39 (1.5) 9.4 (11) 0.7 (1.1)
2 (1, 4) 1 (0, 2) 40 (1.1) 11 (8.4) 1.1 (1.3)
3360 (510) 7/7/5/0/1
3390 (570) 9/7/4/0/0
We did not demonstrate CPM in either postpartum or control group. Pain intensity rating from the 49 C test stimulus was numerically decreased during the cold water conditioning stimulus, although not significant in either group (8% in control group; 1% in postpartum group), and these pain ratings did not differ between groups (Supplementary Fig. S1a). As shown in Supplementary Figure S1b, there was a wide variability in change in pain intensity rating from the test stimulus during the conditioning stimulus. A slight majority of the subjects in each group showed a decrease in pain intensity during the conditioning stimulus, but this proportion did not differ between groups.
Relationship to perceived stress
Pain intensity and unpleasantness scores did not differ between the postpartum and control groups (Fig. 3). Pain intensity and unpleasantness ratings were highly correlated (Pearson r¼0.93) and did not differ by group. The primary outcome, area under the pain intensity vs stimulus temperature curve, did not differ between the postpartum and control (6.4 [6.1] and 6.1 [4.9], respectively; P¼0.16) groups, nor did the area under the pain unpleasantness vs stimulus temperature curve (7.5 [6.4] for postpartum vs 6.6 [4.4] for control; P¼0.07).
Perceived stress was not different between groups (Table 1), although there was considerable individual variability within each group. Neither group (Pearson correlation P¼0.61 for the postpartum group and P¼0.44 for the control group) nor the entire population (Pearson correlation P¼0.96) demonstrated a significant correlation between perceived stress and area under the pain intensity vs stimulus temperature curve. Similarly, neither group nor the entire population demonstrated a significant correlation between perceived stress and strength of CPM within individuals (Pearson correlation P¼0.71 for the postpartum group, P¼0.61 for the control group, and P¼0.50 for the entire population). Finally, neither group nor the entire population demonstrated a significant correlation between perceived stress and capsaicin-evoked hyperalgesia or allodynia (for hyperalgesia and allodynia Pearson correlation P¼0.40 and P¼0.38 for the postpartum group, P¼0.43 and P¼0.38 for the control group, and P¼0.41 and P¼0.19 for the entire population).
Capsaicin-evoked sensitisation
Discussion
All subjects completed the study through reheating after capsaicin. Areas of hyperalgesia and allodynia from heat, capsaicin application, and reheating are shown in Figure 4. There was no statistically significant group by condition (initial heat, capsaicin, and reheating) interaction on allodynia (F[2, 38]¼1.03; P¼0.337) or hyperalgesia (F[2, 38]¼0.586; P¼0.559). The main effect of condition showed a statistically significant difference in allodynia (F[2, 38]¼62.5; P<0.001) and hyperalgesia (F[2, 76]¼126.748; P<0.001) at the different time points. The main effect of group showed that there was no statistically significant difference in allodynia (F[1, 38]¼1.154;
We report that the postpartum period was associated with reduced behavioural responses to capsaicin in rats and humans, but not with differences in area of hypersensitivity in humans, or in pain intensity or unpleasantness to acute heat stimuli. There are no studies in rodents of capsaicin testing within the postpartum period. Intra-plantar injection of capsaicin in rodents produces a few minutes of guarding or licking behaviour followed by longer periods of mechanical hypersensitivity.27,28 In those studies, capsaicin was injected in awake, restrained animals, whereas for ethical reasons we provided anaesthesia, preventing us from observing
subjects choosing to participate in the capsaicin or CPM arms of the study. The time from last breastfeeding to beginning pain testing was 59 (44, 130) min.
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Fig 3. Pain experience to acute heat stimuli in women. Pain intensity (left) and unpleasantness (right) on a 0e10 numeric rating scale in response to 5 s stimuli on the forearm skin at temperatures ranging from 41 to 49 C in postpartum (blue) and age-matched control (pink) women. Data are mean (standard deviation), n¼40 per group. The groups did not differ in the primary outcome of the area under the pain intensity or unpleasantness/temperature curve.
spontaneous behaviours in the first minutes after injection. Mechanical hypersensitivity, our primary outcome, was reduced in postpartum animals compared with control males and females.
Fig 4. Areas of hypersensitivity in the topical capsaicin/heat paradigm. Areas of mechanical hyperalgesia to von Frey filament testing (circles) and mechanical allodynia to brushing with a cotton wisp (squares) in postpartum women (blue) or controls (pink). Values are mean (standard deviation), n¼20 per group. There was an effect of time, but not of group or a group*condition interaction. The data were analysed using categorical fixed effects and not linear or curvilinear contrasts, and the plot is for display only.
There are no studies in postpartum women using capsaicin testing. Temporal summation, another measure of central sensitisation, did not differ in women during the third trimester of pregnancy compared with repeat testing in the postpartum period, although no non-obstetric control was included.8 Contrary to our hypothesis, capsaicin-evoked sensitisation was not decreased in postpartum women compared with controls. Several interpretations of this lack of difference are possible. The hypothesis could simply be wrong. The initial degree of sensitisation from stimuli in the postpartum period may be unaffected, whereas the duration of sensitisation may be shortened, consistent with clinical observations that pain in the first few days after Caesarean delivery is similar to that after other major surgery, but subsequent recovery is more rapid after Caesarean delivery.2 We powered our study to examine sensitisation, as increased area of hypersensitivity surrounding the surgical wound carries increased risk for persistent pain after surgery.29,30 This study was underpowered to test the observed 15e20% reduction in area of hypersensitivity in postpartum women compared with controls. We considered a 33% difference between groups as clinically meaningful in our power analysis, as systemic and intrathecal drugs, which produce acute analgesia in patients with chronic pain, reduce the area of hyperalgesia after capsaicin by this amount.31e33 We showed no difference between groups in pain ratings across a range of suprathreshold noxious heat stimuli, similar to a lack of difference in threshold to heat pain between women during their third trimester compared with postpartum.8 The lack of reduction in acute nociception in the postpartum period is consistent with similar intensity of pain
Capsaicin-evoked pain is reduced postpartum
Fig 5. Pain intensity during sustained heat and with topical capsaicin. Pain intensity on a 0e10 numeric rating scale for every minute for 5 min during sustained heating of the skin on the forearm to 45 C (left panel), or every 5 min for 30 min thereafter when the heat was removed and topical capsaicin applied to the skin. Postpartum women in blue and control women in pink. The diameter of the circle directly reflects the number of subjects with that value. The lines and shaded areas represent linear regressions for each group in each condition with 95% confidence limits, n¼20 per group. Groups differ in pain report in response to capsaicin, but not to heat.
in the initial days after Caesarean delivery compared with other surgery.2 The strength of CPM did not differ between the study groups in the current study, just as it did not differ in women tested at third trimester and postpartum.8 In both studies, however, a CPM effect was not observed in either group or at either time, so neither study was able to test the hypothesis that CPM was altered in the postpartum period. We based our CPM paradigm on a previous report,21 and replicated pain ratings to test stimuli before the conditioning stimulus. We note that the strength of CPM is highly variable and failure not uncommon.34 In rodents, oxytocin binds to the TRPV-1 ion channel, minimally stimulates the channel, but effectively desensitises it to subsequent stimulation.13 In addition, co-administration of oxytocin with intra-cutaneous capsaicin reduces acute pain behaviours in mice. We observed a two-fold reduction in hypersensitivity from capsaicin injection in rats in the postpartum period compared with controls, and less pain in postpartum women during topical capsaicin exposure compared with controls. The women did not rate heat pain less in the postpartum period. TRPV-1 is thought to mediate heat sensation, but this is not inconsistent with possible desensitisation of the TRPV-1 channel, as there are redundant channels that signal noxious heat.35 We interpret the reduction in capsaicin-evoked pain in women in the postpartum period to reflect increased oxytocin exposure of peripheral nerves, although it is conceivable that the effect could reflect peripheral or central actions of other compounds of hormones, such as prolactin, that are increased in the postpartum period. Breastfeeding is associated with a doubling in circulating oxytocin in the first 20 min of suckling,36 and a 36% increased concentration in mothers who breastfeed compared with those who bottle-feed.6
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This study has several limitations. The CPM paradigm failed, so we cannot comment on endogenous inhibition produced by this mechanism. The analysis of pain during capsaicin application was prompted by research that appeared after completion of the study,13 and should be considered exploratory. We did not measure blood oxytocin concentrations, so we cannot comment on the relationship between this measure and pain during capsaicin exposure. Finally, the study rests on the assumption that the same systems that alter the time course of recovery from a major surgical injury also modify the experience and modulation of acute experimental pain. In conclusion, pain experience to acute phasic heat stimuli and experimentally induced hypersensitivity do not differ between new mothers who are breastfeeding their infants and age-matched controls. Capsaicin-evoked pain, however, is reduced in these mothers, consistent with a preclinical report suggesting that oxytocin desensitises the TRPV-1 ion channel.13 These data generate new hypotheses regarding the mechanisms behind quicker recovery from postoperative pain in the obstetric setting.
Authors’ contributions Study design: all authors. Patient recruitment: L.M.S., L.H., R.S.G. Data collection: L.H., R.S.G. Data analysis: J.C.E. Writing of first draft of manuscript: J.C.E. Review and editing of manuscript: L.M.S., L.H., R.S.G.
Acknowledgements The authors thank T.T. Houle, Department of Anesthesiology and Perioperative Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA for his help in statistical analyses. The authors gratefully acknowledge the use of the services and facilities of the clinical research unit, funded by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant award number UL1TR001420.
Declaration of interest J.C.E. consults to Adynxx (San Francisco, CA, USA) regarding preclinical and clinical analgesic development of analgesics. Adynxx is developing non-oxytocin agents to speed recovery from surgery, but does not use the methods described in this manuscript and did not participate in this work or the manuscript. The remaining authors declare no conflicts of interest.
Funding National Institutes of Health (R37 GM48085) to J.C.E.
Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.bja.2018.09.026.
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