Frequency and Intensity of Pain Related to Thyroid Nodule Fine-Needle Aspiration Cytology

Abstract

Background:

Quality of life is an important issue in endocrine tumors because of the high prevalence of benign tumors and the indolent course of most malignant tumors.

Objective:

To evaluate the frequency and the intensity of pain and anxiety in patients undergoing thyroid nodule fine-needle aspiration cytology (FNAC) and to identify factors associated with pain.

Methods:

Single center prospective study in the setting of a one-stop outpatient diagnostic clinic for thyroid nodules. Pain was evaluated using a 100-mm visual analogue scale (VAS) immediately following (VAS¹) and 30 minutes after (VAS²) FNAC and was considered significant if ≥30. Anxiety symptoms were assessed prior to FNAC using a self-report measure questionnaire: the state form of Spielberger State-Trait Anxiety Inventory (STAI, form Y-A). FNAC was performed with a 25-gauge needle and a moderate aspiration and two passes for each nodule.

Results:

Two hundred eighteen consecutive patients (163 females, 55 males; mean age 53 years, range 12–84 years) undergoing FNAC of one to three nodules were included. VAS¹ was ≥30 in 24% of the patients and VAS² was ≥30 in 13% of the patients. Independent significant factors correlated to a VAS¹ of ≥30 were age under 25 years and the number of nodules being biopsied. Independent significant factors correlated to a VAS² of ≥30 were VAS¹ ≥30 and female sex. No correlation was found between pain and nodule size or nodule depth, nor the duration of application of the eutectic mixture of local anesthetics (EMLA) patch prior to FNAC. The mean STAI score for anxiety was 37±12. The average STAI score was significantly higher in women (39) than in men (33; p=0.01). There was no significant correlation between STAI score and age under 25 years, previous FNAC, number of nodules biopsied, or acetaminophen administration, but the STAI score was significantly correlated to VAS¹ and VAS².

Conclusions:

FNAC-related pain is frequent and correlates with the number of nodules biopsied, age under 25 years, female sex, and anxiety.

Introduction

T he prevalence of palpable thyroid nodules in the general population is estimated at 4%–7%, but ultrasound reveals thyroid nodules in up to 50% of the population (1). Fine-needle aspiration cytology (FNAC) is used to diagnose thyroid cancer, which only represents 5% of all thyroid nodules (2,3). Quality of life and care-related pain is an important issue in medicine but particularly for thyroid tumors because of the high prevalence of benign tumors and because of the very high survival rate of patients with thyroid cancers (4,5). Even though complications are rare, FNAC is an invasive procedure that may cause pain and generate anxiety. The prevalence and the intensity of pain and anxiety induced by FNAC have, to our knowledge, never been evaluated. Some authors advocate the use of lidocaine/prilocaine cream or of needle-free delivery of lidocaine in order to decrease FNAC-related pain, whereas others find local anesthesia useless (6 –8). Current recommendations for the prevention of pain, available for most procedures in the oncology setting, do not include thyroid FNAC (9).

The aim of this study was to evaluate the frequency and intensity of pain in patients undergoing thyroid nodule FNAC and to identify factors such as anxiety associated with the severity of pain in order to plan an effective prevention strategy.

Patients and Methods

Patients

This was a single center prospective study, including all consecutive patients seen in our one-stop clinic between December 2010 and June 2011. Approval from our Institutional Review Board was obtained. The one-stop clinic is a dedicated facility where patients with a thyroid nodule are seen by an endocrinologist, then in the same day undergo ultrasound-guided FNAC with real-time microscopic analysis providing the results and then, if necessary, a surgical consultation. FNAC is performed with a 25-gauge needle with slight aspiration of 0.1 to 1 mL suction and two passes for each nodule. An eutectic mixture of local anesthetic (EMLA) patch, an anesthetic agent, is applied to the skin of the neck of all patients before FNAC. After FNAC, patients may receive 1 g of acetaminophen at the physician's discretion.

In this study, pain was evaluated using a 100 mm visual analogue scale (VAS) procedure immediately following (VAS¹) and 30 minutes after (VAS²). A VAS was considered significant if it was ≥30. The VAS assesses pain globally and rates the unpleasantness of the pain experience (how disturbing it is) between two end points labeled “not bad at all” (VAS of 0) and “the most unpleasant feeling imaginable” (VAS of 100).

Starting in January 2011, anxiety symptoms were also assessed immediately following the application of the EMLA patch prior to FNAC. Anxiety was measured using the State form of the French adaptation of the Spielberger State-Trait Anxiety Inventory (STAI) (10,11). The STAI-State anxiety is a self-report measure that assesses an individual's current or transient level of anxiety. Extensive reliability and validity data have been obtained for the STAI, and the instrument has been widely used in the clinical and medical population, including cancer patients. The STAI-State Anxiety Inventory is a 20-item scale. Each item is scored from 1 to 4 according to its intensity. The global score ranges from 20 to 80; a higher score indicates a higher level of anxiety. In cases of anxiety, questionnaires with less than 16 completed items were discarded from statistical analyses. For questionnaires with more than 16 completed items, we calculated the total score by substituting missing data with the mean score of the individual patient. Given that the STAI has only been validated in adults, only patients above the age of 18 years were considered for the anxiety analysis.

Statistical analysis

Quantitative data are expressed as mean and standard deviation, and qualitative data are expressed in percentage. Means were compared using a Student t test, and qualitative data were compared using a chi-square test.

Risk factors associated with a pain ≥30 were analyzed by using univariate and multivariate logistic regression. The two-sided significance level was set at 0.05. Analyses were performed using the SAS statistical software (SAS Institute Inc., Cary, NC), version 9.1.

Results

Patients and FNAC

Two hundred eighteen consecutive patients (163 females, 55 males) with a mean age of 53 years (range, 12–84 years) were included. Eighty-four (39%) patients had previously undergone FNAC for a thyroid nodule (n=74), a breast abnormality (n=8), or both (n=2).

The mean size of the thyroid nodules was 26±12 mm (range: 8–80 mm). FNAC was performed on one nodule only in 160 (73%) patients, on two nodules in 52 (24%) patients, and on three nodules in six (3%) patients. Mean depth of the nodule from the skin level was 10±4 mm (range, 3–26 mm).

The mean interval of time between the patient's arrival at the clinic and the application of the EMLA was 54±30 minutes (range, 0–221 minutes). The mean interval of time between EMLA application and FNAC was 63±28 minutes (range, 5–160 minutes). The time between EMLA application and FNAC was less than 60 minutes in 103 (47%) patients. FNAC was classified as benign in 239 nodules (85%), malignant in nine nodules (3%), suspicious in 31 nodules (11%), and indeterminate in three nodules (1%).

Pain score

VAS¹ immediately after the FNAC was ≥10 for 99 (45%) patients, of which 52 patients (24%) had a VAS¹ of ≥30. Ninety-one (42%) patients had a VAS² 30 minutes after the FNAC of ≥10; among these, 29 patients (13%) had a VAS² ≥30.

Among the 52 patients with a VAS¹ ≥30, 21 patients (40%) still had a VAS² ≥30. Eight of the 29 patients with VAS² ≥30 did not have significant pain during FNAC (VAS¹ <30).

Acetaminophen was administered in 43 patients (22 patients with a VAS¹ ≥30 and 21 with a VAS¹ <30). Fourteen (63%) of the 22 patients with a VAS¹ ≥30 had a VAS² ≥30 despite acetaminophen treatment.

Factors associated with VAS scores ≥30

Factors associated with VAS scores ≥30 are shown in Tables 1 and 2.

Table 1.

Factors Correlated with a Score of 30 or Higher When Pain Is Assessed Using the Visual Analogue Scale Immediately After Fine-Needle Aspiration Cytology

		Univariate analysis		Multivariate analysis
	VAS ¹ ≥30 n/total (%)	OR [95% CI]	p	OR [95% CI]	p
Sex
Male	9/55 (16)	1
Female	43/163 (26)	1.8 [0.8–2.2]	0.14
Extreme age (young)
≥25 years	45/206 (22)	1		1
<25 years	7/12 (58)	5.0 [1.5–16.5]	0.009	6.1 [1.8–20.8]	0.004
Previous FNAC
No	26/134 (19)	1
Yes	26/84 (31)	1.8 [0.98–3.5]	0.07
Site of the previous FNAC
Thyroid	25/75 (33)	1
Breast	1/9 (11)	0.3 [0.03–2.4]	0.26
Maximal size of nodules		1.007 [0.98–1.03]	0.60
No. of biopsied nodules
1	30/160 (19)	1		1
2 or 3	22/58 (38)	2.6 [1.4–5.1]	0.006	2.9 [1.5–5.8]	0.002
Depth of the nodule (18 missing)
≤10 mm	35/127 (28)	1
>10 mm	13/73 (18)	0.6 [0.3–1.2]	0.12
Time between arrival and FNAC
<180 min	48/209 (23)	1
≥180 min	4/9 (40)	2.7 [0.7–10.4]	0.15
Time between EMLA and FNAC
≤60 min	22/114 (19)	1
>60 min	29/103 (28)	1.6 [0.9–3.1]	0.12
Cytopathological results
Benign	44/183 (24)	1
Suspicious	5/24 (21)	0.8 [0.3–2.4]
Malignant	3/8 (38)	1.9 [0.4–8.3]
Indeterminate	0/3 (0)	Not calculable	0.59

VAS, visual analogue scale; VAS¹, pain assessed by VAS immediately after FNAC; EMLA, eutectic mixture of local anesthetics; FNAC, fine-needle aspiration cytology; OR, odds ratio; CI, confidence interval.

Table 2.

Factors Correlated with a Score of 30 or Higher When Pain Is Assessed Using the Visual Analogue Scale 30 Minutes After Fine-Needle Aspiration Cytology

		Univariate analysis		Multivariate analysis
	VAS ² ≥30 n/total (%)	OR [95% CI]	p	OR [95% CI]	p
Sex
Male	1/55 (2)	1		1
Female	28/163 (17)	11.2 [1.5–84.0]	0.02	10.6 [1.3–83.8]	0.02
Extreme age (young)
≥25 years	26/206 (13)	1
<25 years	3/12 (25)	2.3 [0.6–9.1]	0.20
Previous FNAC
No	13/134 (10)	1
Yes	16/84 (19)	2.2 [0.98–4.8]	0.07
Site of the previous FNAC
Thyroid	16/75 (22)	1
Breast	0/9 (0)	Not evaluable	0.97
Maximal size of nodules		0.97 [0.93–1.00]	0.15
No. of biopsied nodules
1	18/160 (11)	1
2 or 3	11/58 (19)	1.8 [0.8–4.2]	0.14
Depth of the nodule (18 missing)
≤10 mm	18/127 (14)	1
>10 mm	7/73 (10)	0.6 [0.3–1.6]	0.38
Time between arrival and FNAC
<180 min	27/209 (13)	1
≥180 min	2/9 (22)	1.9 [0.4–9.7]	0.34
Time between EMLA and FNAC
≤60 min	13/114 (11)	1
>60 min	16/103 (16)	1.4 [0.7–3.1]	0.37
Cytopathological results^a
Benign	26/183 (14)	1	0.78
Suspicious	2/24 (8)	0.9 [0.1–7.3]
Malignant	1/8 (13)	0.5 [0.1–2.5]
Indeterminate	0/3 (0)	Not evaluable
VAS¹ (during FNAC)
<30	8/166 (5)	1		1
≥30	21/52 (40)	13.4 [5.4–32.9]	<0.0001	13.0 [5.2–32.8]	<0.001

Per patient results.

VAS², pain assessed by VAS 30 minutes after FNAC.

Independent significant factors correlated to a VAS¹ ≥30 were age less than 25 years old and the number of nodules biopsied. A VAS¹ ≥30 was more frequent in patients who had had a previous FNAC as compared with patients who never had FNAC, although the difference was not significant. No correlation was found between pain (during FNAC or 30 minutes after) and the two operators that performed the FNAC (PHV, SA; p=0.40 and p=0.22, respectively).

Independent significant factors correlated to a VAS² ≥30 were a VAS¹ ≥30 and female sex.

STAI and VAS

The mean STAI score for anxiety, available in 138 (63%) patients, was 37±12 (range, 20–70). Nine patients (7%) had a STAI score under 40 and a mean VAS¹ of 19±26 (range 0–60). The average STAI score was significantly higher in women (39) than in men (33; p=0.01). There was no significant correlation between STAI score and age <25, previous FNAC, number of biopsied nodules, or acetaminophen administration.

The STAI score was significantly correlated to VAS¹ (r ²=0.20, p=0.02) and to VAS² (r ²=0.16, p=0.05).

Discussion

FNAC for thyroid nodules is routine, but it remains an invasive procedure and management of care-related pain is a concern. This study is the first to assess the frequency of FNAC-related pain despite the use of EMLA and to identify factors associated with pain severity.

Pain was frequent in our study. Twenty-four percent of the patients experienced significant pain (VAS ≥30) just after FNAC, and 13% of the patients had pain 30 minutes after FNAC. The VAS we used for measuring pain is a commonly used and validated scale that has been available for more than 25 years (12). It is the most recommended unidimensional scale in pain measurement (13) and very practical when used as a visual analogue scale (14). Thirty out of 100 mm on the VAS is the cut-off recommended to distinguish mild from moderate to severe pain for which pain prevention and pain treatment should be taken into consideration according to the National Comprehensive Cancer Network clinical practice guidelines in oncology (15).

Depending on the procedure, medical care–related pain may vary; for example, a quick and intense pain for lumbar puncture and mild pain for breast biopsies (16,17). These data are differently analyzed, however, and do not allow a strict comparison of the procedures. Pain is, however, not only related to the complexity of the procedures. It is indeed related to the patients' own history, with pain being more frequent and/or or more intense in the case of previous painful medical procedures or repeated stimulation leading to a rapid sensitization (18,19). This process is, for example, well known in the pediatric setting (20).

Independent factors related to pain during the procedure were age <25 years and multiple nodules targeted by FNAC. Previous FNAC also tended to be related to pain during the procedure, although the relationship was not statistically significant. A VAS¹ ≥30 was observed in 58% of the patients under the age of 25 years and in 22% of older patients. A VAS¹ ≥30 was also observed in 19% of patients having one nodule biopsied and in 38% of patients having more than one nodule biopsied. A more aggressive attitude for pain prevention should therefore be adopted when FNAC is performed for more than one nodule, and it could include not only medication, but also hypnosis (21 –23). The association between younger age and an increased prevalence of pain is unusual. This may be associated with an increased level of anxiety in this age group, but our data did not show a correlation between pain and anxiety in young patients.

Independent factors related to pain 30 minutes after FNAC were the presence of pain right after the FNAC and female sex. A VAS² ≥30 was indeed observed in 40% of patients with a VAS¹ ≥30 and in 5% only of the patients with a VAS¹ <30. A VAS² ≥30 was observed in 17% of the females and only 2% of the males. In light of this data, the main strategy to prevent pain 30 minutes after FNAC is to prevent its occurrence during FNAC. Furthermore, sex is a new issue in pain management driven by improvement in the knowledge of functional pain syndromes that are sex related. Pain threshold and pain tolerance are indeed lower in women than in men, leading to increased pain driven by physiological and hormonal mechanisms (24). This relationship has not been established in procedural pain, but it should deserve more attention because it can modulate pain prevention strategies. One previously published study on FNAC of thyroid nodules also showed a higher frequency of pain in women (7).

The anxiety scores in our patients were comparable to the French general population (11,25). Anxiety in our patients was lower (mean, 37) than that measured in a one-stop clinic for breast tumor diagnosis (mean, 48), or in a group of hematology-oncology patients undergoing bone-marrow aspiration (mean, 43.3) (26). In a group of French women with intermediate to high risk of breast cancer undergoing magnetic resonance imaging, mean anxiety, as assessed by the STAI, was also higher than in our study (mean, 42), even though no invasive procedure was performed (27). This may be explained by a lower perception of cancer risk in our patients, although anxiety may be related both to the diagnostic outcome and to the procedure itself.

As expected, pain was correlated with anxiety, and anxiety was more frequent in women, even if the link between acute pain and anxiety is still a matter of debate and may be linked more often to an increased awareness rather than true anxiety (28,29). This is important because detecting anxiety may also help to define a subset of patients for whom there should be an increased focus on pain prevention. These patients with a high pre-existing anxiety level could benefit from techniques to lower both pain and anxiety such as nonpharmacological therapies (virtual reality, relaxation, music, hypnosis) or short-acting anxiolytic drugs (30). However, no impact of anxiety treatment alone on procedural pain has been shown. Better pre-examination information has also failed to show any advantage in lowering pain or anxiety in other procedures such as liver biopsy (31).

Our study is limited by the number of patients and especially by the number of patients under the age of 25 years, the number of patients undergoing FNAC of multiple nodules, the number of STAI evaluations, and the absence of VAS evaluation before FNAC. Furthermore, 20% of the patients were given acetaminophen, a potential confounding factor. Giving acetaminophen was associated with pain. But, if acetaminophen is to be considered as a strategy to prevent FNAC induced pain, it must be administered at least 30 minutes before FNAC to be effective. A way to improve our practice would be to give acetaminophen at the same time as the EMLA is applied.

We routinely use EMLA application before performing FNAC. EMLA is effective in diffusing in the first millimeters of the skin, and its efficacy is maximal 60 minutes after its application (32). A double-blind, placebo-controlled clinical trial showed a decrease in pain scores in patients undergoing FNAC after EMLA application (7). However, we did not find any correlation between pain and the interval of time between EMLA application and FNAC, even in patients for whom EMLA could not be effective because of too short an exposure time. EMLA may not be the best way to prevent pain though. Pain during FNAC is often experienced when the needle crosses the thyroid capsule at a depth where the EMLA cannot be effective, and many patients experience a radiating pain diffusing to the ears, a characteristic thyroid pain. EMLA application should therefore not be considered as mandatory.

We perform two passages with a 25-gauge needle for each nodule, which is a standard technique. The use of 27-gauge needles might be associated with less pain. However, their use may be associated with an increase in indeterminate cytology results. Some authors advocate a core biopsy rather than FNAC in cases of previous suspicious cytology results (33,34). In these cases, the prevention of pain, if correlated to the size of the needle, would be a major issue.

In conclusion, significant FNAC-related pain occurred in about one fourth of the patients. The main factors related to pain were the number of nodules targeted by FNAC during a single procedure, age <25 years, female sex, and anxiety. Given these results, and in order to implement our pain prevention strategy, acetaminophen could be proposed on a routine basis 60 minutes before a biopsy, especially in patients with more than one nodule, women, young adults, and anxious patients. The efficacy of EMLA to prevent pain remains to be proven. Adequate management by pharmacological treatments or nonpharmacological techniques of pre-FNAC anxiety should be evaluated. Team training in nonpharmacological pain treatment such as hypno-analgesia may be beneficial in this setting.

Footnotes

Disclosure Statement

The authors declare that no competing financial interests exist regarding the research reported.

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