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ORIGINAL ARTICLE

4218T/C polymorphism associations with post-cesarean patient-


controlled epidural fentanyl consumption and pain perception
W. Xie1,†, W. Zhuang2,†, L. Chen2 , W. Xie1, C. Jiang1 and N. Liu1
1
Department of Anesthesiology, Quanzhou First Hospital, Quanzhou, China
2
Department of Anesthesiology, Huian Hospital, Quanzhou, China

Correspondence Background: The utilization of intrathecal opioids is an effica-


L. Chen, Department of Anesthesiology, Huian cious component of post-cesarean section pain management.
Hospital, Quanzhou, China
Given that growing evidence indicates that calcitonin gene-related
E-mail: chenlin1chenlin@126.com
and
peptide (CGRP) plays a key role in the development of peripheral
W. Xie, Department of Anesthesiology, sensitization and is associated with enhanced pain, we hypothe-
Quanzhou First Hospital, Quanzhou, China sized that CGRP 4218T/C polymorphism is associated with the
E-mail: wenqinxie@126.com variability in fentanyl consumption for post-cesarean analgesia.
Methods: We recruited 548 patients who presented for elective

Contributed equally. cesarean delivery, and used polymerase chain reaction-restriction
fragment length polymorphism (PCR-RFLP) method to analyze
Conflict of interest
The authors report no conflict of interest.
CGRP 4218T/C polymorphism. We examined the association of
CGRP 4218T/C polymorphism and post-operative fentanyl con-
Submitted 3 October 2017; accepted 29 sumption for analgesia as well as adverse reactions to fentanyl in
October 2017; submission 23 June 2017. those patients who received cesarean section surgeries.
Results: We found that the CGRP 4218T/C polymorphism has a
Citation significant effect on pain perception, analgesic requirement, and
Xie W, Zhuang W, Chen L, Xie W, Jiang C, Liu
nausea and vomiting for the first 24 h after cesarean delivery in
N. 4218T/C polymorphism associations with
post-cesarean patient-controlled epidural
patients who received PCEA fentanyl. Individuals with the C/C
fentanyl consumption and pain perception. genotype had more pain, required more PCEA fentanyl, and expe-
Acta Anaesthesiologica Scandinavica 2017 rienced a lower incidence of nausea and vomiting.
Conclusion: These results indicated that patients with C/C geno-
doi: 10.1111/aas.13040 type may have reduced sensitivity to fentanyl analgesia and/or
increased pain perception, and were more willing to use PCEA
fentanyl to manage their pain.

Editorial comment
In this cohort undergoing cesarean section, polymorphism for the specific calcitonin gene-related
peptide (CGRP 4218T/C) was determined, along with reported post-operative pain and epidural
fentanyl consumption. Those with the C/C genotype appeared to have more pain and opioid
consumption compared to those with the T/T or T/C genotype.

Adequate interaction between mother and and available for the needs of infant. However,
infant during the early post-delivery period is with the rising rate of cesarean section in
psychologically important to the new mother China, effective pain management after
and is substantially involved in the develop- cesarean section is still a great challenge, with
ment of the infant.1 Thus, post-cesarean section the respective of accelerated post-operative
analgesia needs to provide effective pain con- recovery and rapid discharge, as well as patient
trol while allowing the mother to remain active satisfaction.2,3

Acta Anaesthesiologica Scandinavica (2017)


ª 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd 1

An international journal of anaesthesiology, intensive


care, pain, and critical emergency medicine
W. XIE ET AL.

The utilization of intrathecal opioids is an effi- polymorphism and post-operative fentanyl con-
cacious component of post-cesarean section pain sumption for analgesia as well as adverse reac-
management.4–6 While low-dose morphine has tions to fentanyl in those patients who received
been the gold standard in post-cesarean section cesarean section surgeries.
pain management,7–9 it suffers from late onset of
action10,11 and high frequency of side
Materials and Methods
effects.12,13 In contrast, fentanyl is one of the
most commonly used intrathecal lipophilic opi-
Participants
oids. It exhibits a rapid onset and relatively
short duration of action10 and has become a A total of 548 patients were recruited in our
well-accepted practice in the management of study. Patients were recruited from Quanzhou
labor analgesia. However, numerous studies First Hospital during a period from January
have shown that poor analgesic effects of opioid 2015 to December 2016. Enrolled patients were
drugs are attributed to certain genetic polymor- all American Society of Anesthesiologists physi-
phisms.14–16 Similarly, significant differences in cal status I, Han Chinese women who presented
the sensitivity to fentanyl among patients are a for elective cesarean delivery at ≥37 weeks of
major issue in clinical therapy. While recent gestation. The inclusion criteria were: age 25–
studies have shown that CYP3A4*1G genetic 35 years; ability to comprehend and operate the
polymorphism contributes to the variability in patient-controlled analgesia (PCA) pump; abil-
CYP3A activity and response to fentanyl,17,18 it ity to comprehend and describe pain score by
is still unclear whether other human genetic the 0–10 verbal/visual analog scales; no history
polymorphisms contribute to the clinical effec- of drug dependence or recreational drug use.
tiveness of fentanyl. The exclusion criteria were: have at least one
One that deserves investigation is the genetic medical condition (e.g. diabetes mellitus, hyper-
polymorphism of calcitonin gene-related peptide tension, etc.); contraindication to spinal anesthe-
(CGRP). Calcitonin gene-related peptide sia and/or allergy to opioids or any of the drugs
(CGRP) is a 37-amino acid peptide found pri- to be given intraoperatively. This study was
marily in the C and Ad sensory fibers arising approved by the ethics committee of Quanzhou
from the dorsal root and trigeminal ganglia, as First Hospital. All patients received consent
well as the central nervous system.19–21 Grow- form and signed it before enrollment.
ing evidence indicates that CGRP plays a key
role in the development of peripheral sensitiza-
Anesthetic procedure
tion and is associated with enhanced pain.22,23
Recent studies showed that blocking the Before the initiation of anesthesia, we collected
function of CGRP can alleviate migraine. baseline noninvasive blood pressure, heart rate,
Furthermore, CGRP 4218T/C contributes to respiratory rate, and oxygen saturation using
post-operative fentanyl consumption in cancer pulse oximetry. Mandatory intravenous access
patients as well as adverse reactions to fentanyl. was established before surgery. Venous blood
However, whether CGRP 4218T/C is involved in (3 ml) was then collected and stored. Before the
the analgesic effects of post-cesarean section fen- induction of anesthesia, all patients were given
tanyl is still not fully understood. Thus, the pre- 0.5 l lactated Ringer’s solution for pre-hydra-
sent study examined the hypothesis that CGRP tion. Spinal anesthesia was induced with a 27-
4218T/C polymorphism is associated with the gauge Whitacre spinal needle inserted at the
variability in fentanyl consumption for post- L3–L4 level in the right lateral position of
cesarean analgesia. patients. After free flow of cerebrospinal fluid
To this end, we recruited patient who pre- was achieved, 0.5% hyperbaric bupivacaine
sented for elective cesarean delivery, and used (2 ml) was injected intrathecally, supplemented
polymerase chain reaction-restriction fragment with fentanyl (25 lg). The patients, surgeons,
length polymorphism (PCR-RFLP) method to anesthetists, or other medical staff who partici-
analyze CGRP 4218T/C polymorphism. We pated in the study were all blind to the
examined the association of CGRP 4218T/C genotypes of the patients. Sensory block was
Acta Anaesthesiologica Scandinavica (2017)
2 ª 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
CGRP 4218T/C IN PAIN MANAGEMENT

assessed bilaterally by loss of cold sensation. available for women with signs of central ner-
The surgery was initiated when the block was vous system or respiratory system depression.
detected at T4 level. Hypotension was treated
with 5–10 mg of intravenous ephedrine. Intra-
Genotyping method
venous ondansetron (4 mg), metoclopramide
(10 mg), and dexamethasone (4 mg) were Venous blood was collected with heparin anti-
routinely given before the end of surgery. The coagulant. Conventional phenol/chloroform
duration of surgery was recorded. method was used to extract DNA. Polymerase
chain reaction-restriction fragment length poly-
morphism (PCR-RFLP) method was used to
Post-operative analgesia
analyze CGRP 4218T/C polymorphism. We used
After surgery, all patients were treated with Premier 5.0 to design primers, the sequences of
patient controlled epidural analgesia (PCEA) which were shown as follows: F: 5-GGA
using the Wechsler electronic pump. The regi- AGAAGCAAA GACCAGGA-3; R: 5-CTGCAAG
men was set as follows: 2.5 lg/ml fentanyl; AACAATTCCCACA-3. PCR products were then
demand dose = 2 ml, lockout interval = 10 min, digested with Alu I enzyme. For the wild
background infusion = 2 ml/h. The concentra- homozygote (T/T), three bands of 202 bp,
tion of fentanyl ranging 2–3 lg/ml is routinely 169 bp, and 106 bp were presented. For the
used for pain management after surgery.24,25 heterozygote (T/C), four bands of 371 bp,
During the first 24 h post-operatively (the time 202 bp, 169 bp, and 106 bp were presented. For
of arrival at recovery was defined as time 0), no the mutant homozygote (C/C), two bands of
other supplemental analgesics were given. Data 371 bp and 106 bp were presented.
related to patients’ age, weight, height, body
mass index, history of previous cesarean deliv-
Statistical analysis
ery, duration of surgery, and pain scores (0–10
visual analog scale) at time 0, 4, 8, 12, 16, 20, We excluded data from patients when there was
and 24 h were recorded. The total amount of a failure to establish a free flow of cerebrospinal
fentanyl over the first 24 post-operative hours fluid after three attempts or failure to establish a
was recorded; requests and boluses received complete block of T4 after 30 min. Data from
served as a surrogate to the overall pain experi- patients with complications such as hemorrhage
ence. necessitating additional procedures or surgery
The side effects were also recorded at time 0, necessitating more than 120 min of operating
4, 8, 12, 16, 20, and 24 h, including nausea time were also excluded from analysis.
(severity scale of 0–3: 0 = none, 1 = mild, 2 = In this study, we first treated genotypes includ-
moderate, 3 = severe), vomiting (the number of ing homozygous (T/T), heterozygous (T/C), and
episodes of retching with or without expulsion homozygous (C/C) as independent variables. The
of fluids from the stomach), pruritus (severity sample size (521 subjects) exhibits a power of
scale of 0–3: 0 = none, 1 = mild, 2 = moderate, 82% to detect an additive genetic effect corre-
3 = severe), central nervous system depression sponding to a 10% change in total fentanyl
(asleep and difficult to rouse with a moderately intake of the baseline genotype T/T at a 5% level
loud auditory stimulus (i.e., calling out patients’ of significance. The normality of numerical vari-
names) or glabellar tap), and respiratory depres- ables were assessed within each genotype group
sion (a rate of less than 8 and/or shallow breath- using Shapiro-Wilk test, and expressed using the
ing and/or oxygen saturation of <90% on room mean and standard deviation (SD). The signifi-
air as indicated by pulse oximetry). Women with cant differences between the three genotypes for
more than mild nausea and/or vomiting were numerical variables were then assessed using
treated with 10 mg intravenous metoclopramide one-way analysis of variance (ANOVA) when
and 4 mg intravenous ondansetron. Women with they were normally distributed. For numerical
severe pruritus were offered intravenous nalox- variables with skewed distributions, the
one (0.04–0.1 mg). Intravenous naloxone (0.04– Kruskal–Wallis rank sum test was then used. To
0.1 mg) and supplemental oxygen by mask were assess the association between the genotypes and
Acta Anaesthesiologica Scandinavica (2017)
ª 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd 3
W. XIE ET AL.

the categorical variables, the Pearson chi-square data from these 27 patients were excluded. Data
test was used. The genotypes for the CGRP from the remaining 521 patients were included
4218T/C polymorphism were tested for depar- and analyzed in this study. We found that there
tures from Hardy–Weinberg equilibrium using a are 351 (67.3%) patients carrying the wild
likelihood ratio test. The call rate of the polymor- homozygote (T/T), 128 (24.5%) patients carrying
phism was used as a measure of genotyping per- the mutant heterozygote (T/C), and 42 (8.0%)
formance. An ANOVA with repeated measures patients carrying the mutant homozygote (C/C).
was used for pain scores and fentanyl consump- The call rate of genotyping was 99.4% (518 of
tion with genotypes as between-subjects factor, 521). The allelic frequencies for the T and C
and time as within-subjects factor. For the analy- alleles were 79.6% and 20.4%, respectively. We
sis of side effects, the area under curve described did not find any significant differences in the
by the severity scores was used to analyze the demographic and baseline clinical parameters
overall severity of these side effects over the between the three genotypic groups. In addi-
whole duration of study. To compare total fen- tion, there was also no difference in the dura-
tanyl consumption among genotypes, the Wil- tion of surgery among the three genotypic
coxon rank sum test was performed. To explore groups.
the variables that were associated with total fen-
tanyl consumption, a multivariate regression
Fentanyl consumption
analysis with a stepwise model-selection proce-
dure using the Akaike information criterion was We found that there was a significant difference
used.26 All analyses were performed with SPSS in the total consumption of PCEA fentanyl
18.0. The differences were statistically significant among the three genotypic groups (P = 0.016;
only when P < 0.05. Fig. 1A). Furthermore, all three genotypic
groups exhibited a similar pattern of consump-
tion, with the lowest average doses at 12–16 h.
Results
However, at the 4, 8, and 12 h after the surgery,
the consumption of PCEA fentanyl in the C/C
Demographic and clinical Characteristic
group was significantly higher than the T/T
The demographic and clinical Characteristic group (Tukey test, P < 0.05; Fig. 1B). No failed
results were summarized in Table 1. Generally, PCEA demands were reported throughout the
a total of 548 women patients were enrolled in study.
the present study. Two patients encountered
technical failure. Five patients had complete
Pain scores
block failure, and 14 patients encountered par-
tial block failure. Intraoperative complications In general, pain scores remained low in all three
such as hemorrhage were developed in six genotypic groups. However, there was a signifi-
patients. As a result, these patients required cant difference in the total pain scores among
more than 120 min of operating time. Therefore, the three genotypic groups (P = 0.041; Fig. 2A).

Table 1 Clinical characteristics of the study population.

TT (n = 351) TC (n = 128) CC (n = 42) P value

Age (years) 26.8  3.8 27.1  3.8 26.9  3.6 0.86


Weight (kg) 64.2  7.8 64.5  8.1 64.4  8.2 0.78
Height (cm) 156.1  4.8 155.8  4.9 155.9  5.2 0.69
BMI (kg/m²) 27.4  3.5 27.2  2.9 27.6  2.8 0.77
Previous C-sec, 0 : >1 311 : 40 111 : 17 37 : 5 0.15
Surgery Duration (min) 51.2  13.5 53.5  18.8 52.7  16.9 0.22

Data are expressed as mean  SD.

Acta Anaesthesiologica Scandinavica (2017)


4 ª 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
CGRP 4218T/C IN PAIN MANAGEMENT

Fig. 1. Patient-controlled epidural analgesia (PCEA) fentanyl (mean  SD) consumption (lg/kg) (A) in total and (B) across time after surgery in
each genotype. *Significant difference between CC and TT (P < 0.05). No difference between TC and TT.

Fig. 2. Pain perception in patients. (A) Pain severity and (B) pain scores (mean  SD) across time after surgery in each genotype. *Significant
difference between CC and TT (P < 0.05). No difference between TC and TT.

Furthermore, similar with the pattern of con- present study. The C/C group exhibited signifi-
sumption of PCEA fentanyl, at the 4, 8, and cantly lower incidence of vomiting compared to
12 h after the surgery, pain scores in the C/C the other two groups. There was no significant
group was significantly higher than the T/T difference between the T/T and T/C groups.
group (Tukey test, P < 0.05; Fig. 2B). We found that a total of 188 patients (36.1%)
developed pruritus. Additionally, there was no
difference among the three genotypic groups.
Side effects
Furthermore, there was no difference in the
The results of side effects were summarized in severity scores for pruritus over the first 24 h
Table 2. We found that the overall incidence of among the three genotypic groups. In the pre-
nausea was low. The C/C group exhibited sig- sent study, no women needed intravenous
nificantly lower incidence of nausea compared naloxone treatment for pruritus. We also did not
to the other two groups. There was no signifi- find any patients with respiratory or central ner-
cant difference between the T/T and T/C groups. vous system depression.
The C/C group also experienced the lowest
severity scores for nausea over the first 24 h.
Risk factors of the consumption of PCEA
Also, there was no significant difference
fentanyl
between the T/T and T/C groups in severity
scores for nausea. Similar to nausea, the overall We next conducted multivariate regression to
incidence of vomiting remained low in the evaluate the risk factors that were related to the

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ª 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd 5
W. XIE ET AL.

Table 2 Summary of side effects

TT (n = 351) TC (n = 128) CC (n = 42) P value

Nausea (n) 25 6 1 0.02


Vomiting (n) 17 3 1 0.02
Pruritus (n) 105 19 6 0.01
Nausea Score over 24 h 0.03 (0–5) 0.01 (0–3.5) 0.01 (0–0.9) 0.03
Medium (Min–Max)
Pruritus Score over 24 h 0.5 (0–10) 0.27 (0–10) 0.01 (0–5) 0.04
Medium (Min–Max)

consumption of PCEA fentanyl (Table 3). With C/C genotype exhibits low sensitivity to the
adjustments for age, height, weight, duration of analgesic effect of PCEA fentanyl. Our findings
the operation, and previous cesarean delivery, seem consistent with previous clinical studies in
we found that C-allele-containing genotypes the patients after cancer surgeries. Additionally,
was associated with a significantly high con- our results indicated that physiologic changes
sumption of PCEA fentanyl (OR = 2.29, 95% during pregnancy did not alter the association of
CI: 1.66–5.77, P = 0.031; Table 3). the genotype with pain perception and analgesic
consumption.
Calcitonin gene-related peptide is a type of
Discussion
neuropeptide widely distributed in both the
The present study was designed to exam the role peripheral and central nervous system. Studies
of CGRP 4218T/C in post-operative fentanyl con- have shown that CGRP plays a critical role in
sumption and pain perception as well as adverse nociceptive information transmission, generation
reactions in patients who received cesarean sec- of hyperalgesia in the spinal cord, and pain
tion surgeries. We reported that CGRP 4218T/C modulation.27,28 A recent study has reported the
polymorphism was associated with the variabil- effects of CGRP 4218T/C polymorphism on
ity in fentanyl consumption for post-cesarean the analgesic effects of intravenous fentanyl in
analgesia. Specifically, we reported that women the patients after cancer surgeries.29 Adding to
with the C/C genotype consumed higher amount this literature, the results of our study indicated
of PCEA fentanyl and exhibited higher pain that the CGRP 4218T/C polymorphism had a sig-
scores than other genotypic groups. With adjust- nificant influence on post-cesarean section
ments for age, height, weight, duration of the epidural fentanyl consumption for analgesia and
operation, and previous cesarean delivery, we pain perception. These studies together sug-
reported that C-allele-containing genotype was gested that CGRP 4218T/C polymorphism may
associated with a significantly high consumption be involved in modulation of fentanyl analgesia
of PCEA fentanyl. These results suggested that regardless of administration regimen.
Multiple factors may influence the post-opera-
tive analgesic effects of opioids in clinical
Table 3 Risk factors of the consumption of PCEA fentanyl.
settings. These factors include individual differ-
PCEA fentanyl ences in the sensitivity to pain, the metabolism
Clinical characteristics OR (95% CIs) P rate of analgesics, and specific opioid drug
TC/CC vs. TT 2.29 (1.66–5.77) 0.031 mechanisms.8,9 Furthermore, multiple genetic
Age 1.75 (1.14–2.57) 0.019 factors may together have influences on the
Weight 0.74 (0.38–1.43) 0.285 post-operative analgesic effects of opioids. For
Height 0.99 (0.57–1.68) 0.921 example, previous studies have shown that
BMI percentiles 1.00 (0.99–1.05) 0.650 A118G single nucleotide polymorphism of
Previous C-sec 1.32 (0.67–2.66) 0.491
human l-opioid receptor gene plays a critical
Surgery duration 1.68 (0.84–3.32) 0.135
role in pain perception and patient-controlled
intravenous morphine consumption for
Acta Anaesthesiologica Scandinavica (2017)
6 ª 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
CGRP 4218T/C IN PAIN MANAGEMENT

post-cesarean analgesia.30 However, others have However, the clinical impact contributed by this
reported that the analgesic requirements of genetic variation in acute post-operative pain
patients receiving sufentanil and ropivacaine management and in the prevention of the devel-
through PCEA after cesarean section were not opment of chronic pain is still not clear. There-
associated with A118G polymorphism of l- fore, future studies would be necessary to
opioid receptor gene.31 These results suggested examine it. This line of research will not only
that the role of genetic factors in post-operative be important for investigating the role of genetic
analgesic effects of opioids may depend on polymorphisms in the influence of effects of opi-
specific opioid drug mechanisms. Adding to this oids, but also for the development of effective
line of research, we reported that CGRP 4218T/C post-operative pain management strategies.
polymorphism is also critical for the post-opera-
tive analgesic effects of fentanyl. However,
Acknowledgments
future studies will be necessary to exam
whether CGRP 4218T/C polymorphism is signifi- None.
cantly involved in modulation of the post-opera-
tive analgesic effects of other opioids.
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Acta Anaesthesiologica Scandinavica (2017)


8 ª 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd