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The effects of paroxetine and amitriptyline on the upper esophageal sphincter (UES) pressure and its natural history in globus pharyngeus
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Alimentary Tract
The effects of paroxetine and amitriptyline on the upper esophageal sphincter (UES) pressure and its natural history in globus pharyngeus Wen-cong Zhou a,1 , Lin Jia a,b,∗,1 , Dong-yun Chen a , Yao Liu a , Jing Liu b , Shu-man Jiang b , Meng Yang b , Jian Xu c a
Department of Gastroenterology, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, Guangdong Province, China Department of Gastroenterology, Guangzhou Nansha Central Hospital Affiliated to Guangzhou First People’s Hospital, Guangzhou, Guangdong Province, China c Department of Psychology, Guangzhou Nansha Central Hospital, Guangzhou, Guangdong Province, China b
a r t i c l e
i n f o
Article history: Received 20 September 2016 Received in revised form 2 February 2017 Accepted 2 February 2017 Available online xxx Keywords: Antidepressants Globus pharyngeus Natural history UES
a b s t r a c t
Background: Antidepressant agents have been shown to be an effective and safe treatment method for patients with globus. However, there are few clinical trials dedicated to studying the effects of antidepressant agents on the natural history and upper oesophageal sphincter (UES) pressure of treated globus patients. Aims: To evaluate the effect of paroxetine and amitriptyline to prevent relapses in patients with globus, the simultaneous relationship between changes in UES pressure and improvement of globus symptoms were measured. Methods: Globus patients were randomised into amitriptyline, paroxetine and lansoprazole groups for a 6-week treatment period, and follow-up was extended to 12 additional months. Efficacy was evaluated in terms of the Glasgow-Edinburgh Throat Scale (GETS), and UES pressure was measured by standard oesophageal manometry. Results: Paroxetine therapy resulted in a higher withdrawal rate due to symptom relapse (15.9% vs 44.1%, P = 0.01; 15.9% vs 64.7, P = 0.001) than amitriptyline and lansoprazole. Furthermore, globus symptoms were alleviated with the decrease of UES pressure after paroxetine and amitriptyline treatment (r = 0.620, P = 0.02; r = 0.575, P = 0.03) Conclusions: This follow-up study indicates that paroxetine may alter the natural history of globus and can effectively be used for the long-term management of patients with the disease. Apart from the clinical benefits, paroxetine and amitriptyline can potentially decrease UES pressure. © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Globus pharyngeus is a long-lasting recurrent disease, in which patients commonly describe the sensation of a ball being lodged in their throat. Globus sensation is not an uncommon symptom. According to our recent study [1], the overall lifetime prevalence of globus was 21.5%, with a peak age at disease onset of 35–54 years. Although many possible aetiologies for globus have been proposed, its exact pathogenesis remains obscure. In addition to
∗ Corresponding author at: Department of Gastroenterology, Guangzhou First People’s Hospital, Guangzhou Medical University, No. 1 Panfu Road, Guangzhou 510180, Guangdong Province, China. Fax: +86 20 81628809. E-mail address: [email protected] (L. Jia). 1 Wen-cong Zhou and Lin Jia contributed to the work equally and should be regarded as co-first authors.
psychogenic factors, gastroesophageal reflux disease (GERD) [2,3] and hypertonicity of the oesophageal body [4], conflicting reports exist regarding a relationship with increased upper oesophageal sphincter (UES) pressure. Some studies [5–8] have suggested that globus is caused by hypertonicity of UES pressure. Tokashiki et al. [9] found that 13 of the 20 subjects complained of globus at approximately the same time as the UES pressure increased with distal oesophageal acid perfusion; however, Sun et al. [10] failed to demonstrate increased prevalence of UES hypertonicity in patients with globus sensation. While the most appropriate standard medication for globus pharyngeus has not been established, the usual medical care often shows inadequate response [11–13]. However, antidepressant agents are gradually becoming more widely accepted as treatment options. In recent years, antidepressant agents have shown consistent evidence of efficacy on functional gastrointesti-
http://dx.doi.org/10.1016/j.dld.2017.02.008 1590-8658/© 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Zhou W-c, et al. The effects of paroxetine and amitriptyline on the upper esophageal sphincter (UES) pressure and its natural history in globus pharyngeus. Dig Liver Dis (2017), http://dx.doi.org/10.1016/j.dld.2017.02.008
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nal disorders (FGIDs), even for refractory FGIDs [14–16]. According to our previous study, low-dose amitriptyline (AMT) is effective and well-tolerated for globus patients [13]. Paroxetine (PAR) therapy is more efficacious than low-dose AMT therapy in alleviating globus symptoms [12]. Despite several studies in the literature showing the efficacy of antidepressants for the treatment of this disorder, to date, relatively limited data has evaluated the effect of PAR and AMT to prevent relapses in patients with globus. Moreover, little research has been conducted to investigate the effect of antidepressants on oesophageal function. Previously, we reported on the short-term efficacy of PAR and AMT for globus patients. The present study had two goals. First, we aimed to elucidate the natural history of globus patients who demonstrated treatment response after 6 weeks of treatment. Second, we attempted to identify the effect of antidepressants on UES pressure. 2. Materials and methods 2.1. Patients Patients over the age of 18 years of age with the globus sensation of a lump or foreign body in the throat were enrolled from either the department of gastroenterology or Ear, Nose and Throat (ENT) Clinics at Guangzhou Nansha Central Hospital, from September 2014 to August 2016. Globus was diagnosed in accordance with Rome III consensus criteria [17]. Investigations into both the upper GI and laryngo-oesophageal endoscopy were performed for globus in all subjects. The inclusion criteria of endoscopy were normal gastric and oesophagus mucosa without the presence of any organic disease. The exclusion criteria included: (1) age below 18 or above 80 years; (2) use of any proton pump inhibitor (PPI) or histamine type 2 receptor antagonist during the last 2 months; (3) use of tranquilisers or antidepressants that may affect oesophageal motor function; (4) prior foregut surgery or histopathology-based motor disorders; (5) known allergy to lansoprazole (routine treatment, RT), AMT or PAR; (6) severe hepatic or renal dysfunction; (7) prostatic disease; (8) pregnancy or breastfeeding; exclusion criteria related to endoscopy were endoscopy not permitted; gastric or duodenal peptic ulcer; gastroesophageal reflux (GERD); gastric and oesophageal neoplasm; any precancerous gastric and oesophagus lesions; gastric and oesophageal polyp; and hiatal hernia. 2.2. Study design and procedures This was a prospective, randomised controlled trial for globus pharyngeus (clinical trial number: Chi-CTR-TRC-14005097), which was approved by the hospital ethics committee. Prior to the study, written informed consent was obtained, and demographical data, previous medication use and medical histories were collected from all subjects. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki (6th revision, 2008) as reflected in a priori approval by the institution’s human research committee. Recruited outpatients were randomised to treatment with RT, AMT or PAR using a computerised random number generator. The staff generating the list and preparing the opaque sealed envelopes were not involved in any of the data collection. Blinding of participants and observers was not possible due to the nature of the intervention; however, the patients were notified of which medicine they would take after randomisation. Only the study statistician was blinded to the allocation of intervention or control arms. In the RT group, patients were treated with lansoprazole (Takepron; 30 mg/tablet; Takeda Pharmaceutical Company, Osaka, Japan) 30 mg twice daily, one tablet in the morning and another tablet in the afternoon. In the AMT group, patients were treated with AMT (25 mg/tablet; Hunan Dongting Pharmaceutical
Co., Ltd. HuNan, China) 12.5 mg once daily before bedtime. In the PAR group, patients were treated with PAR (Seroxat; 20 mg/tablet; GlaxoSmithKline Pharmaceutical Co., Ltd.) 20 mg once daily before bedtime. The dose of each allowed drug and the duration of treatment with these drugs were recorded in detail. Before and during the last day of treatment, high-resolution manometry and the following questionnaires were performed: GETS, the Pittsburgh Sleep Quality Index and the Hamilton Rating Scale Anxiety/Depression. Patients who responded to treatment at the end of the 6-week treatment trial entered post-treatment follow-up for 12 months without receiving any drug therapy. No rescue medication was provided for this trial. Treatment response [13] was defined as a >50% reduction in the GETS score. The response was calculated as the formula: (|(score at treatment − score at baseline) |/score at baseline) × 100%. The treatment responses of these three groups were calculated separately. Follow-up visits were performed at two-week intervals by phone or a return visit to the treating clinician. At each follow-up visit, the GETS and visual analogue scale (VAS) were administered by investigators. We then evaluated the relapse time in each of these three groups. Relapse was defined as a patient who reported at least five episodes of globus sensation per week, GETS score ≥ score at baseline or VAS ≥ 50. The patient was removed from the study once relapsed, and the time interval of symptom relapse was measured in weeks since the initiation of follow-up. 2.3. Sample size Previously, we reported that the treatment response of low-dose AMT for globus patients was 75%, significantly higher than that of 35.7% in RT groups. Moreover, we performed a preliminary trial before conducting the present study to evaluate the efficacy of PAR for globus patients and found that 80% (16/20) of globus patients showed a treatment response. With a two-sided significance level ˛ = 0.05, a power of 90%, and an estimated loss to follow-up of 10%, the total required sample size of 190 was large enough to provide safety and effectiveness data reflecting the actual reality of treatment with PAR, AMT and RT. 2.4. Evaluation of globus symptoms The severity of globus symptoms was measured by making a mark on the GETS questionnaire [18], which is based on 10 questions, with a maximum possible score of 70. Patients subjectively indicated the severity of their symptoms for each question on a 7point Likert scale, with 0 representing “none” and 7 representing “unbearable”. 2.5. High-resolution manometry protocol After an 8-h fasting period, manometry was performed with the patients in a supine position, using a water-perfused catheter of 4 mm in diameter (Ninbo Maida Medical Device Inc., Ningbo, China). The catheter has 24 channels with recording side-holes. Hole 1, which starts at the most distal point, is 5 cm from hole 2. Holes 2–5 are 1 cm from each other. Side-holes 6–24 are 1.5 cm from each other. The oesophagogastric junction (EGJ) was explored through side-holes 2–5. A 30-s period of basal recording was obtained after positioning the catheter. Later, the patients were asked to swallow 5 ml of water and repeat this for a total of 10 times, separated by 30-s intervals. Lastly, multiple rapid swallows (generally 5 swallows of 2 mL of water spaced at 2- to 3-s intervals) were performed. UES resting pressure, UES residual pressure and lower oesosphageal sphincter (LES) resting pressure were analysed. All tests were performed by a single investigator.
Please cite this article in press as: Zhou W-c, et al. The effects of paroxetine and amitriptyline on the upper esophageal sphincter (UES) pressure and its natural history in globus pharyngeus. Dig Liver Dis (2017), http://dx.doi.org/10.1016/j.dld.2017.02.008
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N=206 Paents screened N=11 Screening failures 4=not meeng inclusion criteria 3=meeng exclusion criteria 4=treatment not permied
N=195 Randomised
N=69 RT group
N=64 AMT group
2=lack of efficacy 1=lost to follow-up
N=62 PAR group
2=Side effect 2=lost to follow-up
1=Side effect 2=lost to follow-up
N=66 Completed therapy
N=60 Completed therapy
N=59 Completed therapy
N=21 Paents treatment success
N=38 Paents treatment success
N=50 Paents treatment success
1=drop-outs before follow-up
N=20 Paents in follow-up phase
N=37 Paents in follow-up phase
2=lost to follow-up 1=Non complaince
N=17 Completed follow-up phase
1=drop-outs before follow-up
2=drop-outs before follow-up
N=48 Paents in follow-up phase
2=lost to follow-up 1=Non complaince
N=34 Completed follow-up phase
3=lost to follow-up 1=Lack of efficacy
N=44 Completed follow-up phase
Fig. 1. Summary of patient distribution throughout the study. A total of 195 eligible participants were recruited to the study, with 69, 64 and 62 assigned to the RT, AMT and PAR groups, respectively. Patients who received ‘treatment success’ at the end of the 6-week treatment trial entered post-treatment follow-up for 12 months without receiving any drug therapy. Treatment response was defined as a >50% reduction in the GETS score. The response was calculated as: (|(score at treatment − score at baseline) |/score at baseline) × 100%. The treatment responses of these three groups were calculated separately.
2.6. Statistical methods Statistical analysis was performed using SPSS 13.0 software (SPSS Inc., Chicago IL, United States), significance was accepted when P-value <0.05. All the analyses were performed on the intention-to-treat (ITT) population, which included all patients who received at least one dose of the study medication. As supportive analyses, the response rate was analysed by ITT and PP, excluding subjects who had protocol deviations with potential impact on the efficacy. Continuous variables at baseline and after treatment are presented as the mean (±SD) and were compared by paired t-test or Mann–Whitney U-test. Continuous variables across groups were analysed using one-way analysis of variance (ANOVA) or the Kruskal–Wallis method, as appropriate. For categorical variables, chi-squared (2) analysis or Fisher’s exact test were used across groups, as appropriate. The Bonferroni test was used for
multiple comparisons. The Spearman’s correlation coefficient was performed to identify the relationship between changes in UES pressure and GETS score after the 6-week treatment period. For the subpopulation of ‘successfully treated patients’, relapse rates during follow-ups across the groups were analysed using the 2 test. A Kaplan–Meier curve analysis was used to calculate the proportion of patients remaining symptom free, and the log-rank test was used to verify differences in survival probability between groups. 3. Results 3.1. Characteristics of the participants Recruitment and allocation of patients are summarised in Fig. 1. One hundred ninety-five patients were randomised for treatment with RT, AMT or PAR, but 10 patients dropped out at different levels
Please cite this article in press as: Zhou W-c, et al. The effects of paroxetine and amitriptyline on the upper esophageal sphincter (UES) pressure and its natural history in globus pharyngeus. Dig Liver Dis (2017), http://dx.doi.org/10.1016/j.dld.2017.02.008
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Table 1 Demographic, efficacy of the subjects n (%). Variable
RT group (n = 69) n (%)
AMT group (n = 64) n (%)
PAR group (n = 62) n (%)
P value
Gender (male/female) Age (year) Symptom duration (month) Treatment response Withdrawal rates GETS Baseline 6-week Baseline HAMA 6-week HAMD Baseline 6-week Baseline PSQI 6-week
23/46 46.7 ± 12.7 22.8 ± 15.4 21 (30.4) 11 (64.7) 10.2 ± 4.3 8.5 ± 4.0 9.7 ± 4.1 8.1 ± 4.1 6.4 ± 2.1 5.6 ± 1.6 7.7 ± 4.5 6.7 ± 4.0
20/44 45.3 ± 14.1 30.8 ± 27.8 38 (59.3)** 15 (44.1) 10.5 ± 3.7 5.4 ± 2.6*,** 9.0 ± 4.3 5.1 ± 2.6*,** 6.0 ± 2.5 5.7 ± 2.9 6.8 ± 4.5 4.2 ± 2.6*,**
22/40 45.3 ± 13.62 20.3 ± 14.5 50 (80.6)***,† 7 (15.9)***,† 11.2 ± 4.8 2.8 ± 1.4*,***,† 10.1 ± 5.1 2.4 ± 1.0*,***,† 7.9 ± 4.2 3.6 ± 1.7*,***,† 8.9 ± 4.8 4.1 ± 2.1*,***
0.881 0.925 0.198 0.001 0.001 0.736 0.001 0.727 0.001 0.110 0.003 0.312 0.008
P < 0.05 was considered statistically significant. GETS: Glasgow Edinburgh Throat Scale. Bonferroni test was used for multiple comparisons. P < 0.0167 was considered statistically significant. * P < 0.05 when compared with baseline. ** P < 0.0167 when RT vs AMT. *** P < 0.0167 when RT vs PAR. † P < 0.0167 when AMT vs PAR.
of the study. Thus, 185 patients completed the 6-week treatment, and 95 patients completed the follow-up phase. The baseline characteristics of enrolled patients who started the trial medications are shown in Table 1. No statistically significant differences were observed among the three groups in regard to age, gender and symptom duration (all P > 0.05). Prior to treatment, no statistical differences were found among the three groups in GETS score, HAMA score, HAMD score and PSQI score (all P > 0.05).
3.2. Short-term efficacy The short-term efficacy of antidepressant agents are also shown in Table 1. A decrease in GETS score was seen in the AMT and PAR groups after the 6-week treatment (10.5 ± 3.7 vs 5.4 ± 2.6, P = 0.001; 11.2 ± 4.8 vs 2.8 ± 1.4, P = 0.001), while there was no evident alteration of that in the RT group (10.2 ± 4.3 vs 8.5 ± 4.0, P = 0.190). At the end of the treatment period, the GETS scores were significantly lower in both the PAR and AMT groups than that in the RT group (2.8 ± 1.4 vs 8.5 ± 4.0, P = 0.001; 5.4 ± 2.6 vs 8.5 ± 4.0, P = 0.001). Furthermore, the GETS score in the PAR group was also lower than that in the AMT group and reached statistical significance (2.8 ± 1.4 vs 5.4 ± 2.6, P = 0.01). The response rates were statistically different in the three treatment groups throughout the study. By ITT analysis, the proportions of responders in the RT, AMT and PAR groups were 30.4% (21/69), 59.3% (38/64) and 80.6% (50/62), respectively. The PAR group showed a higher number of patients who responded to treatment in comparison to the RT and AMT groups (80.6% vs 30.4%, P = 0.001; 80.6% vs 59.3%, P = 0.009). By PP analysis, the proportions of responders in the RT, AMT and PAR groups were 31.8% (21/66), 63.3% (38/60) and 84.7% (50/59), respectively. The PAR group also showed a higher number of patients who responded to treatment in comparison to the RT and AMT groups (84.7% vs 31.8%, P = 0.001; 84.7% vs 63.3%, P = 0.012). Comparison of the 3 groups after 6 weeks of treatment revealed that the HAMA and HAMD scores in the PAR group were significantly lower than the RT and AMT groups (all P < 0.0167). The HAMA and PSQI scores in the AMT group were significantly lower than that in the RT group (5.1 ± 2.6 vs 8.1 ± 4.1, P = 0.003; 4.2 ± 2.6 vs 6.7 ± 4.0, P = 0.109), while there were no significant differences in HAMD scores when comparing the AMT and RT groups, and no difference in PSQI when comparing the AMT and PAR groups after 6 weeks of treatment (all P > 0.0167).
3.3. Follow-up of successfully treated patients In total, 105 patients (20 in the RT group, 37 in the AMT group and 48 the in PAR group) were eligible for follow-up analysis at the end of the study. The follow-up data of patients who responded to treatment from the RT, AMT and PAR groups are presented in Table 1. Considering the overall follow-up period, the withdrawal rate due to symptom relapse was significantly lower in the PAR group when compared with the RT and AMT groups (15.9% vs 64.7%, P = 0.001; 15.9% vs 44.1%, P = 0.001), indicating the loss of the longterm therapeutic effect of RT and AMT. The Kaplan–Meyer curves by treatment group during the follow-up period are shown in Fig. 2. The Kaplan–Meier curves demonstrated that patients who received PAR therapy had a significantly higher probability of being relapsefree when compared with those who received AMT of RT therapy (P = 0.003).
3.4. UES One hundred twenty patients agreed to high-resolution manometry before and during the last day of treatment. The data of oesophageal manometry from the RT, AMT and PAR groups are presented in Table 2. Compared with baseline, the UES pressure (mmHg) after the 6-week treatment period were significantly decreased in the AMT and PAR groups (80.8 ± 27.9 vs 63.1 ± 19.9, P = 0.015; 74.9 ± 25.5 vs 45.6 ± 11.0, P = 0.001), while there was no difference of that in the RT group (80.4 ± 31.1 vs 88.4 ± 26.6, P = 0.380). At the end of the treatment, UES pressures (mmHg) were significantly lower in both the AMT and PAR groups compared to that in the RT group (63.1 ± 19.9 vs 88.4 ± 26.6, P = 0.001; 45.6 ± 11.0 vs 88.4 ± 26.6, P = 0.001). Moreover, UES pressure (mmHg) was also significantly lower in the PAR group than that in the AMT group (45.6 ± 11.0 vs 63.1 ± 19.9, P = 0.013). There were no significant differences among the 3 groups in UES residual pressure and LES pressure after 6 weeks of treatment (all P > 0.05). Meanwhile, a decrease in UES pressure (UES at treatment–UES at baseline) is positively correlated with relief of globus symptoms (GETS score at treatment–GETS score at baseline) and had a statistical significance both in the PAR (r = 0.620, P = 0.02) and AMT (r = 0.575, P = 0.03) groups, but not in the RT group (r = 0.170, P = 0.462).
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Fig. 2. Kaplan–Meyer curve demonstrating the effect of treatment RT, AMT and PAR from the end of treatment to symptom relapse. The blue curve represents PAR, the green one represents AMT and the yellow one represents RT. Censored represents a patient symptom relapsed or lost to follow-up. The log-rank test was used to verify differences in survival probability between groups. Significance was accepted when P-value <0.05.
Table 2 Data of esophageal mamometry.
UES pressure UES residual pressure LES pressure
Baseline 6-week Baseline 6-week Baseline 6-week
RT group (n = 36)
AMT group (n = 43)
PAR group (n = 41)
P value
80.4 ± 31.1 mmHg 88.4 ± 26.6 mmHg 9.9 ± 3.8 mmHg 8.7 ± 3.8 mmHg 20.2 ± 8.0 20.7 ± 8.3
80.8 ± 27.9 mmHg 63.1 ± 19.9 mmHg*,** 11.1 ± 4.8 mmHg 10.7 ± 4.8 mmHg 21.9 ± 8.1 21.1 ± 7.2
74.9 ± 25.5 mmHg 45.6 ± 11.0 mmHg*,***,† 10.3 ± 3.9 mmHg 10.1 ± 3.9 mmHg 18.8 ± 6.4 19.1 ± 6.7
0.735 0.001 0.639 0.277 0.381 0.651
P < 0.05 was considered statistically significant. Bonferroni test was used for multiple comparisons. P < 0.0167 was considered statistically significant. * P < 0.05 when compared with baseline. ** P < 0.0167 when RT vs AMT. *** P < 0.0167 when RT vs PAR. † P < 0.0167 when AMT vs PAR.
3.5. Adverse events All adverse event cases reported among these groups are shown in Table S1 (Supplementary data). No serious adverse events were reported during the study period. The most common treatmentemergent adverse events were sleepiness and dry mouth, and nearly all were mild to moderate. During the treatment period, 2 patients dropped out of the AMT group due to unbearable sleepiness and dizziness, 1 patient dropped out of the PAR group because of troubling sleepiness. Only one patient in each group was withdrawn for safety reasons. 4. Discussion Globus pharyngeus is reportedly experienced by up to 45% of the general population and is responsible for 4% of patients visiting an otolaryngology clinic [19,20]. However, its pathogenesis remains unknown, and there is no standard protocol for diagnosing and managing it. Prior research on potential aetiologies of globus has mainly focused on its psychosomatic origins or the relationship with GERD [9,21]. However, attention is slowly shifting to motor evaluation after the advent of high-resolution manometry and the ability to better define UES. Studies have revealed
that high-resolution manometry increases diagnostic accuracy and detects clinically important abnormalities of the oesophageal function not identified by standard investigations [22,23]. An increasing number of studies have recognised that UES hypertension and abnormalities in UES relaxation may produce the globus sensation symptom [6,8,10,24]. Abnormalities of the UES pressure include the hypertonsic and hypotonsic sphincters and various abnormalities of relaxation. We found that antidepressants led to a decrease in UES pressure and simultaneously improved globus symptoms. These findings were inconsistent with those of the previous study. Globus patients had high pressure in the cricopharyngeal sphincter [7], and Halum et al. [5] found that injecting botulinum toxin into the cricopharyngeal muscle to a globus patient with extremely high UES pressure led to a decrease in the UES pressure and the disappearance of the globus sensation. The underlying mechanism of these antidepressant agents for treating globus with the decrease in UES pressure has been seldom reported. Oesophageal balloon distention can simulate the globulus sensation at low distending thresholds, suggesting that patients with globus demonstrate oesophageal visceral hypersensitivity and aberrant viscerosomatic referral [4]. As a tricyclic antidepressant, low-dose AMT has been widely used in treating FGID, but this is not
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due to the antidepressant effect, as the doses were below the effective doses of the antidepressant [25]. Our previous study found that low-dose AMT could reduce visceral sensitivity, modify the braingut axis and regulate gastrointestinal tract motor functions, which might contribute to the centrally-mediated visceral analgesic properties of AMT [26]. In theory, AMT may decrease UES pressure through reducing the oesophageal visceral hypersensitivity. The upper oesophageal sphincter consists of skeletal muscle, and its primary muscle is the cricopharyngeal part of the inferior pharyngeal constrictor [27]. Cook et al. reported that in response to acute mental stress, UES pressure rose by 31% in globus patients [28]. Our previous investigation found that more than 53% of general globus patients suffered from probable psychological disorders, such as anxiety or depression [29]. PAR, the newer selective serotonin reuptake inhibitor (SSRI), resulted in a significant decrease in HAMA, HAMD and PSQI and was efficacious in improving emotional well-being, quality of life and quality of sleep. However, the underlying mechanisms of PAR’s ability to decrease UES pressure remain unknown, but may be partially attributable to the relief of mental state. The cause of the hyperdynamic UES in patients with globus sensation requires further investigation. Similar to previous conventional 8-channel manometry, caution must be used in measuring UES pressure. In this study, a similar method of pull-through occurred when sensors were passing through the UES area to ensure that the highest pressure was measured. A similar caution was used to avoid the slippage of the sensors from the UES upon swallowing by ensuring that the sensor measuring the highest pressure was still measuring the highest pressure of the region after swallows. However, there is a significant methodological limitation in analysing UES pressure variation. Hyperdynamic respiratory UES pressure changes were prevalent in globus patients [30], and our 24-channel-sensor was slower to respond to a pressure change than the solid-state manometry, diminishing its utility in measuring the UES pressure. The mean GETS score of patients included in this study is approximately 10; thus, it seems that the symptoms were quite moderate in these patients. Deary et al. [18] reported that, of 10 throat symptoms, approximately 70% of globus patients reported no problems (zero scores) with swallowing and no pain respectively, despite having a feeling of something stuck in their throats. Therefore, globus patients only have part of these symptoms. Furthermore, Tang et al. [1] reported that the average GETS score of globus was 7.80 ± 4.09 according to a large, population-based epidemiological study of globus. Even for refractory globus patients, the GETS scores were only 13.41 ± 4.94. Hence, mild symptoms are the most common in globus [2]. To our knowledge, this is the first prospective, randomised controlled trial investigating the natural history of low-dose of AMT and PAR in globus. In previous works, we have demonstrated that AMT and PAR improved globus symptoms after short-term treatment [12,13]. This study advances those findings by demonstrating that patients with globus can show improvement both during and following PAR treatment. Globus pharyngeus appears to be a benign condition; however, several studies have reported that approximately 44–73% of globus patients complained of persistent symptoms without therapeutic intervention [31–33]. After 6 weeks of treatment, 84.7% patients in the PAR group achieved symptom relief, which was significantly greater than that of the AMT (63.3%) and RT(31.8%) groups. The Kaplan–Meyer curves revealed that patients who received PAR therapy had a significantly higher probability of being relapse-free (P = 0.001). PAR can significantly prolong the amount of symptom relief time when compared with AMT and RT. This was associated with a significantly higher withdrawal rate due to symptom relapse in the follow-up period in the
RT and AMT groups, and a significantly higher probability of being symptom-free in the PAR group during overall follow-up. In conclusion, this study shows that PAR was able to protect against the appearance of symptom relapse in globus, as the results obtained with PAR at the end of the treatment period also persisted during the follow-up. Therefore, PAR could effectively be used for the long-term management of patients with globus. Our study also found that globus symptoms are alleviated with the decrease of UES pressure after treatment with antidepressants, and suggested that the possible etiologic factor in globus pharyngeus may be an association with UES hypertension. The current study also has several limitations. First, the singlecentre enrolled population of 206 patients may have led to a component of selection bias. Secondly, the fact that patients and physicians were not blind for this study is a major limitation. In order to reduce these biases, GETS questionnaires, as well as those for PSQI and Hamilton Rating Scale Anxiety/Depression were performed by a single psychiatrist who was blinded to the allocation of intervention or control arms. Furthermore, the staff who were involved in the follow-up period were also blind to the allocation. Third, the sample size of the RT group in the follow-up phase was relatively small. Although the dropout rate of participants was balanced between these 3 groups, the number of dropouts could potentially have had an effect on our findings. It is unknown whether their disease remained controlled appropriately or if they ultimately developed symptom relapse requiring additional operative intervention at a different institution. The results obtained in this study should be further confirmed in a more generalised population and longer follow-up periods. Conflict of interest None declared. Acknowledgement We would like to thank Professor Ming-zhi Xu (from the Guangdong Mental Disorder Research Institute) for his guidance in the use of the anxiety and depression scales. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.dld.2017.02.008. References [1] Tang B, Cai HD, Xie HL, et al. Epidemiology of globus symptoms and associated psychological factors in China. Journal of Digestive Diseases 2016;17:319–24. [2] Hill J, Stuart RC, Fung HK, et al. Gastroesophageal reflux, motility disorders, and psychological profiles in the etiology of globus pharyngis. Laryngoscope 1997;107:1373–7. [3] Zelenik K, Matousek P, Urban O, et al. Globus pharyngeus and extraesophageal reflux: simultaneous pH < 4.0 and pH < 5.0 analysis. Laryngoscope 2010;120:2160–4. [4] Chen CL, Szczesniak MM, Cook IJ. Evidence for oesophageal visceral hypersensitivity and aberrant symptom referral in patients with globus. Neurogastroenterology & Motility 2009;21:1142–96. [5] Halum SL, Butler SG, Koufman JA, et al. Treatment of globus by upper esophageal sphincter injection with botulinum A toxin. Ear, Nose & Throat Journal 2005;84:74. [6] Corso MJ, Pursnani KG, Mohiuddin MA, et al. Globus sensation is associated with hypertensive upper esophageal sphincter but not with gastroesophageal reflux. Digestive Diseases and Sciences 1998;43:1513–7. [7] Watson WC, Sullivan SN. Hypertonicity of the cricopharyngeal sphincter: a cause of globus sensation. Lancet 1974;2:1417–9. [8] Peng L, Patel A, Kushnir V, et al. Assessment of upper esophageal sphincter function on high-resolution manometry: identification of predictors of globus symptoms. Journal of Clinical Gastroenterology 2015;49:95–100. [9] Tokashiki R, Funato N, Suzuki M. Globus sensation and increased upper esophageal sphincter pressure with distal esophageal acid perfusion. European Archives of Oto-Rhino-Laryngology 2010;267:737–41.
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Alimentary Tract
The effects of paroxetine and amitriptyline on the upper esophageal sphincter (UES) pressure and its natural history in globus pharyngeus Wen-cong Zhou a,1 , Lin Jia a,b,∗,1 , Dong-yun Chen a , Yao Liu a , Jing Liu b , Shu-man Jiang b , Meng Yang b , Jian Xu c a
Department of Gastroenterology, Guangzhou First People’s Hospital, Guangzhou Medical University, Guangzhou, Guangdong Province, China Department of Gastroenterology, Guangzhou Nansha Central Hospital Affiliated to Guangzhou First People’s Hospital, Guangzhou, Guangdong Province, China c Department of Psychology, Guangzhou Nansha Central Hospital, Guangzhou, Guangdong Province, China b
a r t i c l e
i n f o
Article history: Received 20 September 2016 Received in revised form 2 February 2017 Accepted 2 February 2017 Available online xxx Keywords: Antidepressants Globus pharyngeus Natural history UES
a b s t r a c t
Background: Antidepressant agents have been shown to be an effective and safe treatment method for patients with globus. However, there are few clinical trials dedicated to studying the effects of antidepressant agents on the natural history and upper oesophageal sphincter (UES) pressure of treated globus patients. Aims: To evaluate the effect of paroxetine and amitriptyline to prevent relapses in patients with globus, the simultaneous relationship between changes in UES pressure and improvement of globus symptoms were measured. Methods: Globus patients were randomised into amitriptyline, paroxetine and lansoprazole groups for a 6-week treatment period, and follow-up was extended to 12 additional months. Efficacy was evaluated in terms of the Glasgow-Edinburgh Throat Scale (GETS), and UES pressure was measured by standard oesophageal manometry. Results: Paroxetine therapy resulted in a higher withdrawal rate due to symptom relapse (15.9% vs 44.1%, P = 0.01; 15.9% vs 64.7, P = 0.001) than amitriptyline and lansoprazole. Furthermore, globus symptoms were alleviated with the decrease of UES pressure after paroxetine and amitriptyline treatment (r = 0.620, P = 0.02; r = 0.575, P = 0.03) Conclusions: This follow-up study indicates that paroxetine may alter the natural history of globus and can effectively be used for the long-term management of patients with the disease. Apart from the clinical benefits, paroxetine and amitriptyline can potentially decrease UES pressure. © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
1. Introduction Globus pharyngeus is a long-lasting recurrent disease, in which patients commonly describe the sensation of a ball being lodged in their throat. Globus sensation is not an uncommon symptom. According to our recent study [1], the overall lifetime prevalence of globus was 21.5%, with a peak age at disease onset of 35–54 years. Although many possible aetiologies for globus have been proposed, its exact pathogenesis remains obscure. In addition to
∗ Corresponding author at: Department of Gastroenterology, Guangzhou First People’s Hospital, Guangzhou Medical University, No. 1 Panfu Road, Guangzhou 510180, Guangdong Province, China. Fax: +86 20 81628809. E-mail address: [email protected] (L. Jia). 1 Wen-cong Zhou and Lin Jia contributed to the work equally and should be regarded as co-first authors.
psychogenic factors, gastroesophageal reflux disease (GERD) [2,3] and hypertonicity of the oesophageal body [4], conflicting reports exist regarding a relationship with increased upper oesophageal sphincter (UES) pressure. Some studies [5–8] have suggested that globus is caused by hypertonicity of UES pressure. Tokashiki et al. [9] found that 13 of the 20 subjects complained of globus at approximately the same time as the UES pressure increased with distal oesophageal acid perfusion; however, Sun et al. [10] failed to demonstrate increased prevalence of UES hypertonicity in patients with globus sensation. While the most appropriate standard medication for globus pharyngeus has not been established, the usual medical care often shows inadequate response [11–13]. However, antidepressant agents are gradually becoming more widely accepted as treatment options. In recent years, antidepressant agents have shown consistent evidence of efficacy on functional gastrointesti-
http://dx.doi.org/10.1016/j.dld.2017.02.008 1590-8658/© 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
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nal disorders (FGIDs), even for refractory FGIDs [14–16]. According to our previous study, low-dose amitriptyline (AMT) is effective and well-tolerated for globus patients [13]. Paroxetine (PAR) therapy is more efficacious than low-dose AMT therapy in alleviating globus symptoms [12]. Despite several studies in the literature showing the efficacy of antidepressants for the treatment of this disorder, to date, relatively limited data has evaluated the effect of PAR and AMT to prevent relapses in patients with globus. Moreover, little research has been conducted to investigate the effect of antidepressants on oesophageal function. Previously, we reported on the short-term efficacy of PAR and AMT for globus patients. The present study had two goals. First, we aimed to elucidate the natural history of globus patients who demonstrated treatment response after 6 weeks of treatment. Second, we attempted to identify the effect of antidepressants on UES pressure. 2. Materials and methods 2.1. Patients Patients over the age of 18 years of age with the globus sensation of a lump or foreign body in the throat were enrolled from either the department of gastroenterology or Ear, Nose and Throat (ENT) Clinics at Guangzhou Nansha Central Hospital, from September 2014 to August 2016. Globus was diagnosed in accordance with Rome III consensus criteria [17]. Investigations into both the upper GI and laryngo-oesophageal endoscopy were performed for globus in all subjects. The inclusion criteria of endoscopy were normal gastric and oesophagus mucosa without the presence of any organic disease. The exclusion criteria included: (1) age below 18 or above 80 years; (2) use of any proton pump inhibitor (PPI) or histamine type 2 receptor antagonist during the last 2 months; (3) use of tranquilisers or antidepressants that may affect oesophageal motor function; (4) prior foregut surgery or histopathology-based motor disorders; (5) known allergy to lansoprazole (routine treatment, RT), AMT or PAR; (6) severe hepatic or renal dysfunction; (7) prostatic disease; (8) pregnancy or breastfeeding; exclusion criteria related to endoscopy were endoscopy not permitted; gastric or duodenal peptic ulcer; gastroesophageal reflux (GERD); gastric and oesophageal neoplasm; any precancerous gastric and oesophagus lesions; gastric and oesophageal polyp; and hiatal hernia. 2.2. Study design and procedures This was a prospective, randomised controlled trial for globus pharyngeus (clinical trial number: Chi-CTR-TRC-14005097), which was approved by the hospital ethics committee. Prior to the study, written informed consent was obtained, and demographical data, previous medication use and medical histories were collected from all subjects. The study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki (6th revision, 2008) as reflected in a priori approval by the institution’s human research committee. Recruited outpatients were randomised to treatment with RT, AMT or PAR using a computerised random number generator. The staff generating the list and preparing the opaque sealed envelopes were not involved in any of the data collection. Blinding of participants and observers was not possible due to the nature of the intervention; however, the patients were notified of which medicine they would take after randomisation. Only the study statistician was blinded to the allocation of intervention or control arms. In the RT group, patients were treated with lansoprazole (Takepron; 30 mg/tablet; Takeda Pharmaceutical Company, Osaka, Japan) 30 mg twice daily, one tablet in the morning and another tablet in the afternoon. In the AMT group, patients were treated with AMT (25 mg/tablet; Hunan Dongting Pharmaceutical
Co., Ltd. HuNan, China) 12.5 mg once daily before bedtime. In the PAR group, patients were treated with PAR (Seroxat; 20 mg/tablet; GlaxoSmithKline Pharmaceutical Co., Ltd.) 20 mg once daily before bedtime. The dose of each allowed drug and the duration of treatment with these drugs were recorded in detail. Before and during the last day of treatment, high-resolution manometry and the following questionnaires were performed: GETS, the Pittsburgh Sleep Quality Index and the Hamilton Rating Scale Anxiety/Depression. Patients who responded to treatment at the end of the 6-week treatment trial entered post-treatment follow-up for 12 months without receiving any drug therapy. No rescue medication was provided for this trial. Treatment response [13] was defined as a >50% reduction in the GETS score. The response was calculated as the formula: (|(score at treatment − score at baseline) |/score at baseline) × 100%. The treatment responses of these three groups were calculated separately. Follow-up visits were performed at two-week intervals by phone or a return visit to the treating clinician. At each follow-up visit, the GETS and visual analogue scale (VAS) were administered by investigators. We then evaluated the relapse time in each of these three groups. Relapse was defined as a patient who reported at least five episodes of globus sensation per week, GETS score ≥ score at baseline or VAS ≥ 50. The patient was removed from the study once relapsed, and the time interval of symptom relapse was measured in weeks since the initiation of follow-up. 2.3. Sample size Previously, we reported that the treatment response of low-dose AMT for globus patients was 75%, significantly higher than that of 35.7% in RT groups. Moreover, we performed a preliminary trial before conducting the present study to evaluate the efficacy of PAR for globus patients and found that 80% (16/20) of globus patients showed a treatment response. With a two-sided significance level ˛ = 0.05, a power of 90%, and an estimated loss to follow-up of 10%, the total required sample size of 190 was large enough to provide safety and effectiveness data reflecting the actual reality of treatment with PAR, AMT and RT. 2.4. Evaluation of globus symptoms The severity of globus symptoms was measured by making a mark on the GETS questionnaire [18], which is based on 10 questions, with a maximum possible score of 70. Patients subjectively indicated the severity of their symptoms for each question on a 7point Likert scale, with 0 representing “none” and 7 representing “unbearable”. 2.5. High-resolution manometry protocol After an 8-h fasting period, manometry was performed with the patients in a supine position, using a water-perfused catheter of 4 mm in diameter (Ninbo Maida Medical Device Inc., Ningbo, China). The catheter has 24 channels with recording side-holes. Hole 1, which starts at the most distal point, is 5 cm from hole 2. Holes 2–5 are 1 cm from each other. Side-holes 6–24 are 1.5 cm from each other. The oesophagogastric junction (EGJ) was explored through side-holes 2–5. A 30-s period of basal recording was obtained after positioning the catheter. Later, the patients were asked to swallow 5 ml of water and repeat this for a total of 10 times, separated by 30-s intervals. Lastly, multiple rapid swallows (generally 5 swallows of 2 mL of water spaced at 2- to 3-s intervals) were performed. UES resting pressure, UES residual pressure and lower oesosphageal sphincter (LES) resting pressure were analysed. All tests were performed by a single investigator.
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N=206 Paents screened N=11 Screening failures 4=not meeng inclusion criteria 3=meeng exclusion criteria 4=treatment not permied
N=195 Randomised
N=69 RT group
N=64 AMT group
2=lack of efficacy 1=lost to follow-up
N=62 PAR group
2=Side effect 2=lost to follow-up
1=Side effect 2=lost to follow-up
N=66 Completed therapy
N=60 Completed therapy
N=59 Completed therapy
N=21 Paents treatment success
N=38 Paents treatment success
N=50 Paents treatment success
1=drop-outs before follow-up
N=20 Paents in follow-up phase
N=37 Paents in follow-up phase
2=lost to follow-up 1=Non complaince
N=17 Completed follow-up phase
1=drop-outs before follow-up
2=drop-outs before follow-up
N=48 Paents in follow-up phase
2=lost to follow-up 1=Non complaince
N=34 Completed follow-up phase
3=lost to follow-up 1=Lack of efficacy
N=44 Completed follow-up phase
Fig. 1. Summary of patient distribution throughout the study. A total of 195 eligible participants were recruited to the study, with 69, 64 and 62 assigned to the RT, AMT and PAR groups, respectively. Patients who received ‘treatment success’ at the end of the 6-week treatment trial entered post-treatment follow-up for 12 months without receiving any drug therapy. Treatment response was defined as a >50% reduction in the GETS score. The response was calculated as: (|(score at treatment − score at baseline) |/score at baseline) × 100%. The treatment responses of these three groups were calculated separately.
2.6. Statistical methods Statistical analysis was performed using SPSS 13.0 software (SPSS Inc., Chicago IL, United States), significance was accepted when P-value <0.05. All the analyses were performed on the intention-to-treat (ITT) population, which included all patients who received at least one dose of the study medication. As supportive analyses, the response rate was analysed by ITT and PP, excluding subjects who had protocol deviations with potential impact on the efficacy. Continuous variables at baseline and after treatment are presented as the mean (±SD) and were compared by paired t-test or Mann–Whitney U-test. Continuous variables across groups were analysed using one-way analysis of variance (ANOVA) or the Kruskal–Wallis method, as appropriate. For categorical variables, chi-squared (2) analysis or Fisher’s exact test were used across groups, as appropriate. The Bonferroni test was used for
multiple comparisons. The Spearman’s correlation coefficient was performed to identify the relationship between changes in UES pressure and GETS score after the 6-week treatment period. For the subpopulation of ‘successfully treated patients’, relapse rates during follow-ups across the groups were analysed using the 2 test. A Kaplan–Meier curve analysis was used to calculate the proportion of patients remaining symptom free, and the log-rank test was used to verify differences in survival probability between groups. 3. Results 3.1. Characteristics of the participants Recruitment and allocation of patients are summarised in Fig. 1. One hundred ninety-five patients were randomised for treatment with RT, AMT or PAR, but 10 patients dropped out at different levels
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Table 1 Demographic, efficacy of the subjects n (%). Variable
RT group (n = 69) n (%)
AMT group (n = 64) n (%)
PAR group (n = 62) n (%)
P value
Gender (male/female) Age (year) Symptom duration (month) Treatment response Withdrawal rates GETS Baseline 6-week Baseline HAMA 6-week HAMD Baseline 6-week Baseline PSQI 6-week
23/46 46.7 ± 12.7 22.8 ± 15.4 21 (30.4) 11 (64.7) 10.2 ± 4.3 8.5 ± 4.0 9.7 ± 4.1 8.1 ± 4.1 6.4 ± 2.1 5.6 ± 1.6 7.7 ± 4.5 6.7 ± 4.0
20/44 45.3 ± 14.1 30.8 ± 27.8 38 (59.3)** 15 (44.1) 10.5 ± 3.7 5.4 ± 2.6*,** 9.0 ± 4.3 5.1 ± 2.6*,** 6.0 ± 2.5 5.7 ± 2.9 6.8 ± 4.5 4.2 ± 2.6*,**
22/40 45.3 ± 13.62 20.3 ± 14.5 50 (80.6)***,† 7 (15.9)***,† 11.2 ± 4.8 2.8 ± 1.4*,***,† 10.1 ± 5.1 2.4 ± 1.0*,***,† 7.9 ± 4.2 3.6 ± 1.7*,***,† 8.9 ± 4.8 4.1 ± 2.1*,***
0.881 0.925 0.198 0.001 0.001 0.736 0.001 0.727 0.001 0.110 0.003 0.312 0.008
P < 0.05 was considered statistically significant. GETS: Glasgow Edinburgh Throat Scale. Bonferroni test was used for multiple comparisons. P < 0.0167 was considered statistically significant. * P < 0.05 when compared with baseline. ** P < 0.0167 when RT vs AMT. *** P < 0.0167 when RT vs PAR. † P < 0.0167 when AMT vs PAR.
of the study. Thus, 185 patients completed the 6-week treatment, and 95 patients completed the follow-up phase. The baseline characteristics of enrolled patients who started the trial medications are shown in Table 1. No statistically significant differences were observed among the three groups in regard to age, gender and symptom duration (all P > 0.05). Prior to treatment, no statistical differences were found among the three groups in GETS score, HAMA score, HAMD score and PSQI score (all P > 0.05).
3.2. Short-term efficacy The short-term efficacy of antidepressant agents are also shown in Table 1. A decrease in GETS score was seen in the AMT and PAR groups after the 6-week treatment (10.5 ± 3.7 vs 5.4 ± 2.6, P = 0.001; 11.2 ± 4.8 vs 2.8 ± 1.4, P = 0.001), while there was no evident alteration of that in the RT group (10.2 ± 4.3 vs 8.5 ± 4.0, P = 0.190). At the end of the treatment period, the GETS scores were significantly lower in both the PAR and AMT groups than that in the RT group (2.8 ± 1.4 vs 8.5 ± 4.0, P = 0.001; 5.4 ± 2.6 vs 8.5 ± 4.0, P = 0.001). Furthermore, the GETS score in the PAR group was also lower than that in the AMT group and reached statistical significance (2.8 ± 1.4 vs 5.4 ± 2.6, P = 0.01). The response rates were statistically different in the three treatment groups throughout the study. By ITT analysis, the proportions of responders in the RT, AMT and PAR groups were 30.4% (21/69), 59.3% (38/64) and 80.6% (50/62), respectively. The PAR group showed a higher number of patients who responded to treatment in comparison to the RT and AMT groups (80.6% vs 30.4%, P = 0.001; 80.6% vs 59.3%, P = 0.009). By PP analysis, the proportions of responders in the RT, AMT and PAR groups were 31.8% (21/66), 63.3% (38/60) and 84.7% (50/59), respectively. The PAR group also showed a higher number of patients who responded to treatment in comparison to the RT and AMT groups (84.7% vs 31.8%, P = 0.001; 84.7% vs 63.3%, P = 0.012). Comparison of the 3 groups after 6 weeks of treatment revealed that the HAMA and HAMD scores in the PAR group were significantly lower than the RT and AMT groups (all P < 0.0167). The HAMA and PSQI scores in the AMT group were significantly lower than that in the RT group (5.1 ± 2.6 vs 8.1 ± 4.1, P = 0.003; 4.2 ± 2.6 vs 6.7 ± 4.0, P = 0.109), while there were no significant differences in HAMD scores when comparing the AMT and RT groups, and no difference in PSQI when comparing the AMT and PAR groups after 6 weeks of treatment (all P > 0.0167).
3.3. Follow-up of successfully treated patients In total, 105 patients (20 in the RT group, 37 in the AMT group and 48 the in PAR group) were eligible for follow-up analysis at the end of the study. The follow-up data of patients who responded to treatment from the RT, AMT and PAR groups are presented in Table 1. Considering the overall follow-up period, the withdrawal rate due to symptom relapse was significantly lower in the PAR group when compared with the RT and AMT groups (15.9% vs 64.7%, P = 0.001; 15.9% vs 44.1%, P = 0.001), indicating the loss of the longterm therapeutic effect of RT and AMT. The Kaplan–Meyer curves by treatment group during the follow-up period are shown in Fig. 2. The Kaplan–Meier curves demonstrated that patients who received PAR therapy had a significantly higher probability of being relapsefree when compared with those who received AMT of RT therapy (P = 0.003).
3.4. UES One hundred twenty patients agreed to high-resolution manometry before and during the last day of treatment. The data of oesophageal manometry from the RT, AMT and PAR groups are presented in Table 2. Compared with baseline, the UES pressure (mmHg) after the 6-week treatment period were significantly decreased in the AMT and PAR groups (80.8 ± 27.9 vs 63.1 ± 19.9, P = 0.015; 74.9 ± 25.5 vs 45.6 ± 11.0, P = 0.001), while there was no difference of that in the RT group (80.4 ± 31.1 vs 88.4 ± 26.6, P = 0.380). At the end of the treatment, UES pressures (mmHg) were significantly lower in both the AMT and PAR groups compared to that in the RT group (63.1 ± 19.9 vs 88.4 ± 26.6, P = 0.001; 45.6 ± 11.0 vs 88.4 ± 26.6, P = 0.001). Moreover, UES pressure (mmHg) was also significantly lower in the PAR group than that in the AMT group (45.6 ± 11.0 vs 63.1 ± 19.9, P = 0.013). There were no significant differences among the 3 groups in UES residual pressure and LES pressure after 6 weeks of treatment (all P > 0.05). Meanwhile, a decrease in UES pressure (UES at treatment–UES at baseline) is positively correlated with relief of globus symptoms (GETS score at treatment–GETS score at baseline) and had a statistical significance both in the PAR (r = 0.620, P = 0.02) and AMT (r = 0.575, P = 0.03) groups, but not in the RT group (r = 0.170, P = 0.462).
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Fig. 2. Kaplan–Meyer curve demonstrating the effect of treatment RT, AMT and PAR from the end of treatment to symptom relapse. The blue curve represents PAR, the green one represents AMT and the yellow one represents RT. Censored represents a patient symptom relapsed or lost to follow-up. The log-rank test was used to verify differences in survival probability between groups. Significance was accepted when P-value <0.05.
Table 2 Data of esophageal mamometry.
UES pressure UES residual pressure LES pressure
Baseline 6-week Baseline 6-week Baseline 6-week
RT group (n = 36)
AMT group (n = 43)
PAR group (n = 41)
P value
80.4 ± 31.1 mmHg 88.4 ± 26.6 mmHg 9.9 ± 3.8 mmHg 8.7 ± 3.8 mmHg 20.2 ± 8.0 20.7 ± 8.3
80.8 ± 27.9 mmHg 63.1 ± 19.9 mmHg*,** 11.1 ± 4.8 mmHg 10.7 ± 4.8 mmHg 21.9 ± 8.1 21.1 ± 7.2
74.9 ± 25.5 mmHg 45.6 ± 11.0 mmHg*,***,† 10.3 ± 3.9 mmHg 10.1 ± 3.9 mmHg 18.8 ± 6.4 19.1 ± 6.7
0.735 0.001 0.639 0.277 0.381 0.651
P < 0.05 was considered statistically significant. Bonferroni test was used for multiple comparisons. P < 0.0167 was considered statistically significant. * P < 0.05 when compared with baseline. ** P < 0.0167 when RT vs AMT. *** P < 0.0167 when RT vs PAR. † P < 0.0167 when AMT vs PAR.
3.5. Adverse events All adverse event cases reported among these groups are shown in Table S1 (Supplementary data). No serious adverse events were reported during the study period. The most common treatmentemergent adverse events were sleepiness and dry mouth, and nearly all were mild to moderate. During the treatment period, 2 patients dropped out of the AMT group due to unbearable sleepiness and dizziness, 1 patient dropped out of the PAR group because of troubling sleepiness. Only one patient in each group was withdrawn for safety reasons. 4. Discussion Globus pharyngeus is reportedly experienced by up to 45% of the general population and is responsible for 4% of patients visiting an otolaryngology clinic [19,20]. However, its pathogenesis remains unknown, and there is no standard protocol for diagnosing and managing it. Prior research on potential aetiologies of globus has mainly focused on its psychosomatic origins or the relationship with GERD [9,21]. However, attention is slowly shifting to motor evaluation after the advent of high-resolution manometry and the ability to better define UES. Studies have revealed
that high-resolution manometry increases diagnostic accuracy and detects clinically important abnormalities of the oesophageal function not identified by standard investigations [22,23]. An increasing number of studies have recognised that UES hypertension and abnormalities in UES relaxation may produce the globus sensation symptom [6,8,10,24]. Abnormalities of the UES pressure include the hypertonsic and hypotonsic sphincters and various abnormalities of relaxation. We found that antidepressants led to a decrease in UES pressure and simultaneously improved globus symptoms. These findings were inconsistent with those of the previous study. Globus patients had high pressure in the cricopharyngeal sphincter [7], and Halum et al. [5] found that injecting botulinum toxin into the cricopharyngeal muscle to a globus patient with extremely high UES pressure led to a decrease in the UES pressure and the disappearance of the globus sensation. The underlying mechanism of these antidepressant agents for treating globus with the decrease in UES pressure has been seldom reported. Oesophageal balloon distention can simulate the globulus sensation at low distending thresholds, suggesting that patients with globus demonstrate oesophageal visceral hypersensitivity and aberrant viscerosomatic referral [4]. As a tricyclic antidepressant, low-dose AMT has been widely used in treating FGID, but this is not
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due to the antidepressant effect, as the doses were below the effective doses of the antidepressant [25]. Our previous study found that low-dose AMT could reduce visceral sensitivity, modify the braingut axis and regulate gastrointestinal tract motor functions, which might contribute to the centrally-mediated visceral analgesic properties of AMT [26]. In theory, AMT may decrease UES pressure through reducing the oesophageal visceral hypersensitivity. The upper oesophageal sphincter consists of skeletal muscle, and its primary muscle is the cricopharyngeal part of the inferior pharyngeal constrictor [27]. Cook et al. reported that in response to acute mental stress, UES pressure rose by 31% in globus patients [28]. Our previous investigation found that more than 53% of general globus patients suffered from probable psychological disorders, such as anxiety or depression [29]. PAR, the newer selective serotonin reuptake inhibitor (SSRI), resulted in a significant decrease in HAMA, HAMD and PSQI and was efficacious in improving emotional well-being, quality of life and quality of sleep. However, the underlying mechanisms of PAR’s ability to decrease UES pressure remain unknown, but may be partially attributable to the relief of mental state. The cause of the hyperdynamic UES in patients with globus sensation requires further investigation. Similar to previous conventional 8-channel manometry, caution must be used in measuring UES pressure. In this study, a similar method of pull-through occurred when sensors were passing through the UES area to ensure that the highest pressure was measured. A similar caution was used to avoid the slippage of the sensors from the UES upon swallowing by ensuring that the sensor measuring the highest pressure was still measuring the highest pressure of the region after swallows. However, there is a significant methodological limitation in analysing UES pressure variation. Hyperdynamic respiratory UES pressure changes were prevalent in globus patients [30], and our 24-channel-sensor was slower to respond to a pressure change than the solid-state manometry, diminishing its utility in measuring the UES pressure. The mean GETS score of patients included in this study is approximately 10; thus, it seems that the symptoms were quite moderate in these patients. Deary et al. [18] reported that, of 10 throat symptoms, approximately 70% of globus patients reported no problems (zero scores) with swallowing and no pain respectively, despite having a feeling of something stuck in their throats. Therefore, globus patients only have part of these symptoms. Furthermore, Tang et al. [1] reported that the average GETS score of globus was 7.80 ± 4.09 according to a large, population-based epidemiological study of globus. Even for refractory globus patients, the GETS scores were only 13.41 ± 4.94. Hence, mild symptoms are the most common in globus [2]. To our knowledge, this is the first prospective, randomised controlled trial investigating the natural history of low-dose of AMT and PAR in globus. In previous works, we have demonstrated that AMT and PAR improved globus symptoms after short-term treatment [12,13]. This study advances those findings by demonstrating that patients with globus can show improvement both during and following PAR treatment. Globus pharyngeus appears to be a benign condition; however, several studies have reported that approximately 44–73% of globus patients complained of persistent symptoms without therapeutic intervention [31–33]. After 6 weeks of treatment, 84.7% patients in the PAR group achieved symptom relief, which was significantly greater than that of the AMT (63.3%) and RT(31.8%) groups. The Kaplan–Meyer curves revealed that patients who received PAR therapy had a significantly higher probability of being relapse-free (P = 0.001). PAR can significantly prolong the amount of symptom relief time when compared with AMT and RT. This was associated with a significantly higher withdrawal rate due to symptom relapse in the follow-up period in the
RT and AMT groups, and a significantly higher probability of being symptom-free in the PAR group during overall follow-up. In conclusion, this study shows that PAR was able to protect against the appearance of symptom relapse in globus, as the results obtained with PAR at the end of the treatment period also persisted during the follow-up. Therefore, PAR could effectively be used for the long-term management of patients with globus. Our study also found that globus symptoms are alleviated with the decrease of UES pressure after treatment with antidepressants, and suggested that the possible etiologic factor in globus pharyngeus may be an association with UES hypertension. The current study also has several limitations. First, the singlecentre enrolled population of 206 patients may have led to a component of selection bias. Secondly, the fact that patients and physicians were not blind for this study is a major limitation. In order to reduce these biases, GETS questionnaires, as well as those for PSQI and Hamilton Rating Scale Anxiety/Depression were performed by a single psychiatrist who was blinded to the allocation of intervention or control arms. Furthermore, the staff who were involved in the follow-up period were also blind to the allocation. Third, the sample size of the RT group in the follow-up phase was relatively small. Although the dropout rate of participants was balanced between these 3 groups, the number of dropouts could potentially have had an effect on our findings. It is unknown whether their disease remained controlled appropriately or if they ultimately developed symptom relapse requiring additional operative intervention at a different institution. The results obtained in this study should be further confirmed in a more generalised population and longer follow-up periods. Conflict of interest None declared. Acknowledgement We would like to thank Professor Ming-zhi Xu (from the Guangdong Mental Disorder Research Institute) for his guidance in the use of the anxiety and depression scales. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.dld.2017.02.008. References [1] Tang B, Cai HD, Xie HL, et al. Epidemiology of globus symptoms and associated psychological factors in China. Journal of Digestive Diseases 2016;17:319–24. [2] Hill J, Stuart RC, Fung HK, et al. Gastroesophageal reflux, motility disorders, and psychological profiles in the etiology of globus pharyngis. Laryngoscope 1997;107:1373–7. [3] Zelenik K, Matousek P, Urban O, et al. Globus pharyngeus and extraesophageal reflux: simultaneous pH < 4.0 and pH < 5.0 analysis. Laryngoscope 2010;120:2160–4. [4] Chen CL, Szczesniak MM, Cook IJ. Evidence for oesophageal visceral hypersensitivity and aberrant symptom referral in patients with globus. Neurogastroenterology & Motility 2009;21:1142–96. [5] Halum SL, Butler SG, Koufman JA, et al. Treatment of globus by upper esophageal sphincter injection with botulinum A toxin. Ear, Nose & Throat Journal 2005;84:74. [6] Corso MJ, Pursnani KG, Mohiuddin MA, et al. Globus sensation is associated with hypertensive upper esophageal sphincter but not with gastroesophageal reflux. Digestive Diseases and Sciences 1998;43:1513–7. [7] Watson WC, Sullivan SN. Hypertonicity of the cricopharyngeal sphincter: a cause of globus sensation. Lancet 1974;2:1417–9. [8] Peng L, Patel A, Kushnir V, et al. Assessment of upper esophageal sphincter function on high-resolution manometry: identification of predictors of globus symptoms. Journal of Clinical Gastroenterology 2015;49:95–100. [9] Tokashiki R, Funato N, Suzuki M. Globus sensation and increased upper esophageal sphincter pressure with distal esophageal acid perfusion. European Archives of Oto-Rhino-Laryngology 2010;267:737–41.
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Please cite this article in press as: Zhou W-c, et al. The effects of paroxetine and amitriptyline on the upper esophageal sphincter (UES) pressure and its natural history in globus pharyngeus. Dig Liver Dis (2017), http://dx.doi.org/10.1016/j.dld.2017.02.008