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Pain Sensation During Colposcopy and Cervical Biopsy, with or without Local Anesthesia: a
Randomized Trial
Running title: Pain experience during colposcopy
Mari Kiviharju MD1*, Ilkka Kalliala MD, PhD 1, Pekka Nieminen MD, PhD 1, Tadek Dyba MSc 2,
Annika Riska MD, PhD 1 and Maija Jakobsson MD, PhD 1
1 Obstetrics and Gynecology, University of Helsinki and University Central Hospital, Helsinki,
Finland
2 Public Health – Cancer Policy Support, Institute for Health and Consumer Protection, European
Commission, DG Joint Research Centre, Ispara, Italy
Source(s) of financial support: Helsinki University Research Grant
Conflict of interest statement: None of the authors have any potential conflicts of interest
to be disclosed.
Separate word counts for the précis 22 , abstract 254, and text 2821(body of text excluding
references, figures, and tables)
2 figures, 4 tables
IRB status: The study protocol was approved by the ethical board of Helsinki University Hospital
(292/13/03/03/2012)
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Précis: Injection of a local anesthetic for colposcopy is less painful than biopsies without local
anesthesia, and local anesthesia decreases the pain perceived.
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Abstract
Objective: This study was performed to determine whether an injection of a local anesthetic is more
painful than a cervical punch biopsy without local anesthesia.
Methods: The study was a randomized controlled trial, conducted at the Helsinki University Central
Hospital. It consisted of 204 women referred for colposcopic assessments. Half of them were
randomized to receive local anesthesia before their cervical punch biopsies. After the injection of
the local anesthetic, the cervical punch biopsy, and the endocervical curettage, the women scored
their actual pain using a 10-cm Visual Analog Scale (VAS).
To measure the difference in VAS scores between two groups a linear regression model was used.
Binomial regression model was applied for comparing the probability of experiencing unbearable
pain between the groups. Applying modeling approach allowed also for proper adjustment for other
potential risk factors.
Results: The mean VAS score for the injection of the local anesthetic was 2.7, the VAS score for
the cervical punch biopsy without local anesthesia was 3.5, and the difference was 0.8 (p=0.017,
95% CI; 0.1-1.5). The mean VAS for the biopsy with local anesthesia was 0.8, which was
significantly lower than the mean VAS for the biopsy without local anesthesia (difference 2.7,
p=<0.001, 95% CI; 2.2-3.3). The RR for experiencing unbearable pain was 0.6 (p=0.03, 95% CI;
0.3-0.9) for the injection of local anesthetic vs. the biopsy without local anesthesia.
Conclusions: Injection of a local anesthetic for colposcopy is less painful than biopsies without
local anesthesia, and local anesthesia decreases the pain perceived.
Key words: colposcopy, biopsy, pain, local anesthetic, rct, CIN, pain relief.
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Introduction
Cervical cancer is the third most common cancer worldwide for females [1]. Cervical
cancer develops via precursor lesions (CIN, cervical intraepithelial neoplasia) caused by persistent
human papillomavirus (HPV) infection. Epithelial cellular changes are detected by cytological
screenings or HPV-tests. Depending on the country, one to five percent of the cytologically
screened patients are sent to colposcopic procedure. In the procedure, the changes are evaluated
with light microscopy and biopsies are taken. Discomfort and pain associated with colposcopy often
cause women to experience anxiety and fear [2], which may influence the attendance and
compliance rates for these procedures. Similarly, pain related anxiety may increase pain perception
[3]. These factors may affect a woman’s cooperation in a colposcopy, and prevent the colposcopist
from achieving representative biopsies. Oral ibuprofen, topical benzocaine, topical benzocaine
spray, topical xylocaine, and topical xylocaine spray do not decrease pain in comparison to placebos
[4-7]. Forced coughing is used to reduce women’s discomfort and pain, with inconsistent results [8-
10]. Furthermore, only one small prospective randomized pilot trial about the efficacy of local
anesthesia has been published, where 56 women were randomized to receive a 1% lidocaine
injection or no injection before taking the biopsies. The injection has a statistically significant
reduction in the pain scores measured using the VAS [11].
In Finland, local anesthesia has not traditionally been used during colposcopies and
cervical punch biopsies due to the general belief that the injection of local anesthetic is as painful as
the biopsy itself. Clinical practice guidelines, nationally or internationally, do not, to the best of our
knowledge, suggest pain relief during colposcopy and punch biopsies either [12,13]. In addition, a
comparison between the VAS for the injection and VAS for the biopsy without local anesthesia has
not been reported.
Our main objective was to study whether the injection of a local anesthetic is more painful
than a cervical punch biopsy without a local anesthetic, and whether a woman’s anxiety or other
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factors have a significant effect on the pain experience. As a secondary outcome, we studied the
effects of a local anesthetic on the pain experienced during punch biopsies and endocervical
curettage.
Methods
We performed a prospective randomized cohort study at the Helsinki University Hospital
colposcopy clinic, a unit conducting 3500 colposcopies annually, between November of 2012 and
September of 2013. From among the clinic’s regular patient flow, consecutive women were
randomized in a 1:1 ratio to receive local anesthesia or no anesthesia during colposcopies and punch
biopsies. The group allocations were made using computer generated random numbers, which were
placed in serially numbered envelopes by a person not involved in the study. The participants were
enrolled and assigned to the interventions by the operator. The sealed envelopes were opened
preceding the operation. Cervical cytology, HPV (human papillomavirus) test, cervical punch
biopsies, and endocervical curettage samples were taken routinely, according to clinical judgment
and Finland’s Current Care Guidelines [12].
We calculated the required sample size, assuming that at least a 1.3 cm difference in the
mean VAS scores between the groups would lead to a clinically significant difference [14] between
the groups. Assuming a difference of 1.3 cm, two-sided alpha-error of 0.05, and standard deviation
of 3.2, recruiting 96 women to both groups would result in sufficient statistical power for the test
[15]. To account for possible loss due to follow-up and data-managing errors, we decided to include
just over 200 consecutive women who required colposcopies with cervical punch biopsies to
achieve this.
Primarily, 272 women were referred to the study. Written informed consent was obtained
from each woman. Women who were under the age of 18, pregnant, suspected to have cancer,
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declined to participate, or allergic to the anesthetic were excluded. After these exclusions, 204
women remained in the study, but the information on six study subjects was lost during the data
gathering. The final study population was therefore comprised of 198 women; 99 in both study
groups (Fig. 1). However, part of the VAS scores was missing from four study subjects.
Fig 1.
Before the randomization, the patients evaluated their own experiences of their pain
thresholds (low, normal, or high) and patients own estimation how intensive pain would be during
colposcopy (anticipated pain). The study subjects also filled out the Beck’s Anxiety Inventory
(BAI) questionnaire [16], and the age, parity, initial cytology leading to colposcopy, and Reid´s
colposcopy index [17] were recorded. We assumed that the more distressed the women were about
the examination, the more likely they were to perceive severe pain during the colposcopy; the BAI
is a questionnaire specifically designed to discriminate anxious subjects [16].
During the course of the colposcopy, cervical cytology was routinely taken, acetic acid was
applied to the cervix to evaluate acetowhitening, and the clinical assessment was based on Reid’s
colposcopic index. Local anesthesia was administrated by an injection (1.8 ml) of 3% prilocaine
and felypressin (30 mg/ml + 0.54 μg/ml) with a 27 G dental needle (0.4 x 35 mm) to all four
quadrants of the cervix for those patients randomized to receive local anesthesia during the
procedure. After approximately two minutes, the biopsies were taken with a biopsy instrument,
resulting in biopsies approximately 3 to 4 mm in size (Fig. 2). In the other group, the biopsies were
taken in a similar way, but without local anesthesia. The biopsies were taken from the most severe
lesions, based on clinical judgement, and endocervical curettage was performed whenever it was
deemed necessary by the clinician. During the procedure, we recorded the pain experienced by
using a 10-cm VAS-ruler (primary outcome measure) in the following steps: 1) injection of the
local anesthetic (the group receiving local anesthesia only), 2) the first cervical punch biopsy, and
3) the endocervical curettage (when needed). The pain VAS is a continuous scale
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comprised of a line, usually 10 centimeters (100 mm) in length, anchored by 2
verbal descriptors, 0= no pain at all and 10=worst imaginable pain. During the
course of the colposcopy, the women were verbally informed about all of the steps of the procedure,
including the injection and the biopsies. All of the participants were able to quit participating in the
study at any time.
The differences in the VAS values between the randomization groups were evaluated using
three categories: 1) injection of local anesthetic vs. biopsy without local anesthesia, 2) biopsy with
vs. without local anesthesia, and 3) endocervical curettage with vs. without local anesthesia. The
number of women reporting unbearable pain (VAS of 5 or more) was recorded, separately in each
category.
To determine the difference between the groups in experiencing the pain a linear
regression was applied [15] with a response variable representing VAS-difference in cm. In order to
control for the variables, which can potentially influence the level of pain, all the models were
adjusted for age, parity, initial cervical cytology (normal vs. abnormal smear), histological
diagnosis at the appointment, Reid´s colposcopic index, pain threshold, and BAI-score.
Additionally, to compare whether the probability of experiencing unbearable pain differed between
the groups a binomial model was applied [18]. The results from fitting this model are presented as
the ratio between the probabilities of experiencing severe pain between the two groups, after
adjusting for the same explanatory variables as in the linear regression. Whenever a covariate
reached the level of p<0.10 in any multivariate model, we tested them for possible interaction.
Whenever the effect modification was statistically significant (p<0.05), we have presented the
results stratified according to that variable. The fit of all models was checked based on Pearson’s
chi-squared statistics [18]. All the models used for getting the presented results are presented fitted.
All statistical tests used were two-sided and were performed with STATA software (StataCorp
2011, Stata Statistical Software: release 12.1, College Station, TX, USA).
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The study protocol was approved by the ethical board of the Helsinki University
Hospital (292/13/03/03/2012). This study was registered at Controlled Trials (www.controlled-
trials.com) (SRCTN20548888).
Role of the funding source
The funding for this research was provided by a Helsinki University Research Grant. The
corresponding author had final responsibility for the decision to submit for publication.
Results
The study groups had an equal number of patients (n = 99) (Fig.1, Table 1). The mean pain
score for the injection of the local anesthetic was 2.7, and the pain score for the cervical punch
biopsy without local anesthesia was 3.5 (Table 2). The linear modeling for the VAS difference in
cm between the groups presented a statistically significant difference in each procedure category
(Table 3). Adjusting for the confounding factors (age, parity, initial cytology leading to colposcopy,
histology, pain threshold, and BAI) did not markedly change the results. In addition, the model
based effect between the curettage after injection vs. the curettage without anesthesia was modified
by the pain threshold. The VAS pain values were significantly higher in the group without
anesthesia, among the women with both high and low pain thresholds. However, the women with
the low pain thresholds had higher VAS values than the women with high pain thresholds. This
suggests that the pain threshold significantly modified the effects of the local anesthesia during
endocervical curettage.
The model based risk ratios (relative risks) for unbearable pain (VAS score of 5 or more) are
presented in Table 4. The probability of experiencing unbearable pain was significantly lower in the
group with anesthesia during all procedures. Additionally, the risk for unbearable pain caused by
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the biopsy with anesthesia was almost halved (RR = 0.6, CI; 0.3-0.9), compared to the pain caused
by the injection of local anesthetic. Furthermore, the risk for unbearable pain during the biopsy with
anesthesia was one-tenth (RR = 0.1, CI; 0.0-0.3) of that experienced during the biopsy without local
anesthesia.
Discussion
The injection of local anesthetic was significantly less painful than obtaining the biopsies
without local anesthesia, and almost twice as many women experienced unbearable pain when the
biopsies were taken without local anesthesia. Additionally, local anesthesia was, in this setting,
effective in reducing the experienced pain in every studied aspect; the biopsies and endocervical
curettage were significantly less painful when performed under local anesthesia.
This was a prospective randomized study, in which all of the women were recruited and
treated in one hospital as part of the daily routine, suggesting that the results were, to a great extent,
directly applicable to daily practice. The study cohort size met the statistical criteria set based on the
enrollment, and was therefore large enough to reveal possible statistically significant differences.
To study the effects of anxiety and interpersonal variation in pain perception, we recorded and
adjusted the results for the woman’s anxiety levels (BAI), and the individual’s own expectations of
their pain threshold. In addition, the results were adjusted for age and parity, which can, at least in
theory, independently explain the interpersonal differences in the pain experiences. The results were
also adjusted for the variables (possibly) capable of altering the extent of the treatment procedure
(RCI, cervical cytology, and histological diagnosis); thus, enabling more reliable statistical
comparisons and clinically more relevant conclusions.
One limitation of this study was the awareness of receiving the local anesthetic, which alone
could decrease the pain and result in lower VAS scores in the group. Altogether, 45 women did not
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want to participate in the study. Some of them wanted to receive local anesthesia anyway, whereas a
smaller number did not want, under any circumstances, to receive local anesthesia. This possible
selection bias might influence our results, since the most sensitive and probably the most anxious
women did not participate. However, in case the most “pain-prone” women were excluded from the
final study population, the selection bias described above would have diluted rather than
exaggerated our results, if we assume that the effects of the local anesthesia would be the same in
this subpopulation as it was in the study population. Furthermore, the results were indeed adjusted
for experienced anxiety and pain threshold, but neither variable was statistically significant in
explaining the experienced pain in the main outcome.
As in any studies of the sensation of pain, one limitation was the VAS. It is a subjective
method, and several factors beyond the scope of our study setting, during the patient´s and
physician´s interactions, might well influence it. Comparing the VAS-scores between the patients
has its weaknesses, but the best possible setting in theory, studying the same woman twice with and
without local anesthesia, is practically impossible. The first sensation of pain for the women in the
local anesthesia group was the needle stick, which might have had an influence on the sensation or
tolerance of the pain when the biopsies were taken. The other group perceived pain for the first time
when the biopsies were taken, which might influence the comparisons between the groups during
the biopsies and endocervical curettage, but not during our main objective of comparing the pain
between the injection and biopsy without anesthesia.
Our results regarding the secondary outcomes, the differences in pain perception between
the groups during the biopsies, were comparable to the results of Oyama et al. 2003 who used
lidocaine (we used prilocaine) [11]. The injection VAS scores were higher in our study (our VAS
mean was 3.7 vs. Oyama’s VAS mean of 1.5), but the cervical biopsy VAS scores with the
anesthesia were smaller in our study (our mean was 0.8 vs. Oyama’s mean of 1.2). However, the
study by Oyama et al. was smaller, with only 29 women in each group, which may have resulted in
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a larger variability in the mean scores. No conclusions should be drawn here regarding the possible
differences in efficacy between the lidocaine and prilocaine, because this comparison is well
beyond the scope of this study. However, prilocaine with felypressin causes fewer side effects than
lidocaine, when used for large loop excisions in the transformation zone [19].
The statistical significance does not, however, always mean clinical significance. The
differences detected here in the VAS scores between the injection of the local anesthetic and biopsy
without local anesthesia (mean VAS difference 0.8) may not be considered to be clinically
significant, since no scientific evidence of VAS scores that are acceptable in gynecological
procedures, and no specific cut off points exist (where pain relief is always suggested). The VAS
score differences recorded here were unanimously lower after the local anesthesia, suggesting that
the injection of the anesthetic was definitely not more painful than the biopsy itself. Additionally,
an unbearable pain experience was more common among the women who did not receive local
anesthesia.
An abnormal result in the cervical cytology can itself cause anxiety [20]. In addition, the
fear of pain or severe disease, or an assumption of discomfort during the examination, may cause
concerns among the women, and even lead to a refusal of the examination. It is therefore crucial to
minimize a woman´s discomfort during painful interventions, as much as possible. As an alternative
method, forced coughing has been shown to be as effective as local anesthesia with lidocaine in
pain relief [8,10]. In a study by Schmid et al [8], forced coughing is preferred to anesthetic injection
as time saving procedure. Coughing is based on a physician´s good clinical and psychological
skills, as well as a thorough knowledge of the process of colposcopy. Therefore, this effect varies
between different patients and physicians. Additionally, the target of the biopsy is likely to move
during coughing, which can challenge the biopsy procedure. Colposcopy is usually performed to
evaluate the possibility of a malignant disease, and it is extremely important to have the best
biopsies possible. Issues regarding a patient’s safety during any procedure might well favor a “drug-
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avoiding” approach whenever suitable. Therefore, the local anesthetic has to be safe, and caution
should be used to prevent an intravenous injection. In a Cochrane review, no serious side effects
were observed in the trials reporting the use of local anesthesia in a colposcopy procedure [21].
Conclusions
The purpose of colposcopy is to investigate abnormal cervical cytology, and define the
further interventions. The injection of the local anesthetic was less painful than the biopsy without
local anesthesia. Furthermore, the women who received local anesthesia reported lower VAS values
when the biopsies were taken, and experienced significantly less unbearable pain, regardless of the
comparison in question. The injection of local anesthesia is a procedure that is easy to learn, repeat,
and is similar in each patient, unlikely to be affected by the physician’s personality between
patients, and at least, in theory, more likely to result in representative biopsies and a proper
diagnosis when compared to forced coughing. Based on these data, during a colposcopy, local
anesthesia should, at least, be offered, since it is safe, significantly reduces the perceived pain
throughout the procedure, and, most of all, the injection of the local anesthetic seems to be
significantly less painful than taking biopsies without local anesthesia.
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Acknowledgements
The authors would like to thank Professor Jorma Paavonen for his constructive comments,
and Maarit Mentula M.D., PhD for the randomization.
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Disclosure statement
None of the authors have any potential conflicts of interest to be disclosed.
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Abbreviations
BAI, Beck anxiety inventory; VAS, 10-cm visual analog scale; HPV, human
papilloma virus; CIN, cervical intraepithelial neoplasia; RCI, Reid colposcopy index.
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