J Neurogastroenterol Motil 2024; 30(1): 38-45  https://doi.org/10.5056/jnm22131
Effects of Codeine on Esophageal Peristalsis in Patients With Ineffective Esophageal Motility: Studies Using High-resolution Manometry
Wei-Yi Lei,1 Tso-Tsai Liu,1 Wei-Chuan Chang,2 Chih-Hsun Yi,1 Jui-Sheng Hung,1 Ming-Wun Wong,1,3 Shu-Wei Liang,1 Lin Lin,1 and Chien-Lin Chen1,4*
1Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and School of Medicine, Tzu Chi University, Hualien, Taiwan; 2Department of Medical Research, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan; 3School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan; and 4Institute of Medical Sciences, Tzu Chi University, Hualien, Taiwan
Correspondence to: *Chien-Lin Chen, MD, PhD
Department of Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation and Tzu Chi University, 707, Section 3, Chung-Yang Road, Hualien 970, Taiwan
Tel: +886-3-8561825, E-mail: harry.clchen@msa.hinet.net
Received: August 11, 2022; Revised: February 8, 2023; Accepted: April 2, 2023; Published online: January 30, 2024
© The Korean Society of Neurogastroenterology and Motility. All rights reserved.

cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background/Aims
This study aims to evaluate the effects of acute codeine administration on primary and secondary esophageal peristalsis in patients with ineffective esophageal motility (IEM).
Methods
Eighteen IEM patients (8 women; mean age 37.8 years, range 23-64 years) were enrolled in the study. The patients underwent high-resolution manometry exams, consisting of 10 single wet swallows, multiple rapid swallows, and ten 20 mL rapid air injections to trigger secondary peristalsis. All participants completed 2 separate sessions, including acute administration of codeine (60 mg) and placebo, in a randomized order.
Results
Codeine significantly increased the distal contractile integral (566 ± 81 mmHg∙s∙cm vs 247 ± 36 mmHg∙s∙cm, P = 0.001) and shortened distal latency (5.7 ± 0.2 seconds vs 6.5 ± 0.1 seconds, P < 0.001) for primary peristalsis compared with these parameters after placebo treatment. The mean total break length decreased significantly after codeine treatment compared with the length after placebo (P = 0.003). Codeine significantly increased esophagogastric junction-contractile integral (P = 0.028) but did not change the 4-second integrated relaxation pressure (P = 0.794). Codeine significantly decreased the frequency of weak (P = 0.039) and failed contractions (P = 0.009), resulting in increased frequency of normal primary peristalsis (P < 0.136). No significant differences in the ratio of impaired multiple rapid swallows inhibition and parameters of secondary peristalsis were detected.
Conclusions
In IEM patients, acute administration of codeine increases contraction vigor and reduces distal latency of primary esophageal peristalsis, but has no effect on secondary peristalsis. Future studies are required to further elucidate clinical relevance of these findings, especially in the setting of gastroesophageal reflux disease with IEM.
Keywords: Humans; Manometry; Peristalsis
Introduction

Opioid use for the management of chronic pain is increasing. Opioids exert their effects by binding on the μ, δ, and κ opioid receptors in the central and enteric nervous systems.1,2 Activation of the enteric opioid receptors within the gastrointestinal tract suppresses excitability of the inhibitory neurons, resulting in decreased intestinal secretions, increased sphincter tone, altered visceral sensation, and abnormal coordination of motility.3 Concerns about the adverse effects of chronic opioid use on the gastrointestinal tract are growing. The majority of adverse effects occur in the stomach, small intestine, and colon, and have been widely studied.2,3 However, the effects of opioids on the esophagus have not been widely investigated.

Early studies using conventional manometry demonstrated opioid effects on esophageal motility. These studies showed that opioids impair lower esophageal sphincter (LES) relaxation and increase contraction amplitude and simultaneous waves of the esophageal body.4-6 More recent studies based on the Chicago classification demonstrated that chronic opioid use can lead to esophageal motility dysfunction, including esophagogastric junction outflow obstruction (EGJOO), diffuse esophageal spasms, and type III achalasia.7-12 Opioid-induced esophageal dysfunction may lead to new or worsening esophageal symptoms. Furthermore, impaired deglutitive inhibition during multiple rapid swallows (MRS) is frequently observed in chronic opioid users, suggesting that opioids might interfere with inhibitory signals in the esophagus.10 These esophageal manometric findings led to the description of a disease spectrum termed opioid-induced esophageal dysfunction (OIED).

Ineffective esophageal motility (IEM) characterized by a combination of weak or failed peristalsis and peristaltic breaks may result in poor bolus clearance. According to the latest Chicago classification, the diagnosis of IEM includes more than 70% ineffective peristalsis or ≥ 50% failed swallows.13 Failed rather than weak peristalsis is associated with impaired esophageal clearance, reflux burden, and symptomatic dysphagia.14,15 At present, limited data are available concerning pharmacological interventions to improve esophageal smooth muscle contractility and associated symptoms.

Codeine, a partial opioid agonist with mild analgesic efficacy, may also induce esophageal dysmotility.8,16 Recently, our group demonstrated that acute administration of codeine affects both primary and secondary peristalsis in healthy volunteers.17 However, little is known about the effects of acute administration of opioids on esophageal manometric findings in IEM patients. Therefore, we aim to determine the effects of acute codeine administration on primary and secondary esophageal peristalsis assessed by high-resolution manometry (HRM) in IEM patients.

Materials and Methods

Study Subjects

Eighteen eligible patients with IEM (female 8; mean age 37.8 years, range 23-64 years) were enrolled in the study. Prior to enrollment in the study, all subjects were diagnosed with IEM, based on HRM exams and the previously described criteria.13 Patients were excluded from the study due to esophageal strictures, previous gastrointestinal surgery, the presence of systemic diseases that might affect esophageal motility, chronic use of medications that influence esophageal motility, and recent and chronic use of opioids. One week before the study, drugs that might lead to esophageal dysmotility were discontinued. This study was approved by the Research Ethics Committee (IRB110-175-A), and each subject gave written informed consent before being enrolled in the study.

High-resolution Manometry

After an overnight fast, HRM was performed using a 22-channel catheter with 1 air injection port in the mid-esophagus (MMS). The HRM assembly was inserted via the nasal passage into the esophagogastric portion of the esophagus. The HRM assembly was then positioned so that at least 3 distal sensors were in the stomach to record data from the hypopharynx to the stomach. Before the procedure, the catheter was zeroed to atmospheric pressure. The luminal diameter for the perfusion capillary was 0.4 mm, and the total diameter was 4.7 mm by perfusing with ambient temperature distilled water at 0.15 mL/min. Swallowing events were detected using the most proximal channel of the catheter to differentiate between primary and secondary peristalsis.

Study Protocol

All participants underwent HRM in the motility laboratory in the morning on 2 separate occasions separated by 1 week. Oral administration of 60 mg of codeine or the placebo 45 minutes prior to HRM studies were performed in a random order, as previously reported.17 The crossover design of the study is shown in Figure 1. Primary peristalsis was evaluated using 10 swallows of 5-mL of saline; each swallow was spaced 20 seconds apart. MRS were assessed by steadily injecting 10 mL of water into the mouth with a syringe.18 Each MRS consisted of 5 rapid 2-mL swallows, with ≤ 4 seconds between swallows. Secondary peristalsis was tested using 10 rapid mid-esophageal 20 mL air injections. The participants were allowed to take a dry swallow after each injection to eliminate the retained air within the esophageal lumen and avoid swallow attempts during the next injection.

Figure 1. The design of the study. The study consisted of 2 treatment arms with a 1-week washout period. IEM, ineffective esophageal motility; HRM, high-resolution manometry.

High-resolution Manometry Data Analysis

Analysis of HRM data was performed using Medical Measurement Systems database software (MMS). The manometric findings were reviewed by 2 motility experts, and a diagnosis of esophageal motor disorder based on Chicago classification was made.13 Primary and secondary peristalsis were considered successful if the typical peristaltic pattern of pressure topography was demonstrated on HRM. Primary or secondary peristaltic frequencies (%) were calculated as the number of successful responses divided by the total trials of primary or secondary peristalsis. The evaluated manometric parameters included distal contractile integral (DCI), 4-second integrated relaxation pressure (IRP-4s), distal latency (DL), and LES resting pressure. The parameters were automatically calculated by the data analysis software (MMS, Enschede, The Netherlands). The esophagogastric junction–contractile integral (EGJ-CI) was also measured using the DCI measurement across the esophagogastric junction (EGJ).19 MRS was used to assess the contractile reserve and deglutitive inhibition.18 Analysis of deglutitive inhibition included completeness of esophageal body inhibition and LES relaxation. DCI after MRS was measured immediately after the last MRS swallow to evaluate contractile reserve.18

Statistical Methods

Due to earlier work revealing significant differences in DL and IRP-4s of primary peristalsis and frequency of secondary peristalsis,17 the estimated number of cases was estimated as at least 14 to achieve a power of 80% and α of 0.05. Differences between codeine and the placebo were compared using a paired test and represented as mean ± SEM. Assessment of the normality of data was performed using D’Agostino’s K-squared test. Proportionality between groups was tested using McNemar test. All significance levels were set to P < 0.05. Statistical analyses were performed with SPSS version 22.0 for Windows (IBM Corp, Armonk, NY, USA).

Results

Effects of Codeine on Primary Peristalsis in Ineffective Esophageal Motility Patients

The primary esophageal peristalsis measurements after the administration of codeine or placebo are shown in Table 1. Codeine significantly increased DCI in patients with IEM compared with DCI after placebo (P = 0.001) (Fig. 2A). The mean DL was significantly shortened (P < 0.001) (Fig. 2B) and total break length was significantly decreased (P = 0.003) (Fig. 2C) after treatment with codeine compared with placebo treatment. Codeine significantly increased EGJ-CI compared with placebo (P = 0.028) (Fig. 2D), while no changes in LES parameters, such as IRP-4s (P = 0.794) or basal pressure (P = 0.092), were detected. Codeine also significantly increased the frequency of normal primary contractions (P < 0.136) and decreased the frequency of weak contractions (P = 0.039) and failed contractions (P = 0.009) compared with the contractions after placebo (Fig. 3). No significant differences in upper esophageal sphincter basal pressure were detected between codeine and placebo treatments (P = 0.136). Codeine did not significantly increase the DCI after MRS (550.4 ± 124.5 mmHg∙s∙cm vs 736.7 ± 154.4 mmHg∙s∙cm, P = 0.129) or change the ratio of the normal MRS response (14.4% vs 24.1%, P = 0.220) compared with MRS after placebo. Additionally, there were no significant differences in impaired MRS inhibition between codeine and the placebo (P = 0.321).

Figure 2. Manometric parameters of esophageal primary peristalsis after codeine and placebo adminstration in patients with ineffective esophageal motility. (A) Effects of acute administration of codeine on the distal contractile integral (DCI) of esophageal primary peristalsis. The DCI was significantly higher after codeine compared to the value after placebo. (B) Effects of acute administration of codeine on distal latency (DL) of esophageal primary peristalsis. The DL was significantly lower after codeine compared with the DL after placebo. (C) Effects of acute administration of codeine on the total break length of esophageal primary peristalsis. The total break length of esophageal peristalsis was significantly lower after codeine treatment compared with the length after placebo. (D) Effects of acute administration of codeine on the esophagogastric junction–contractile integral (EGJ-CI) of esophageal primary peristalsis. Codeine significantly increased the EGJ-CI of esophageal peristalsis was significantly higher after codeine treatment compared with the EGJ-CI after placebo treatment.
Figure 3. Effects of acute administration of codeine on the frequency of esophageal primary peristalsis. Codeine significantly increased the frequency of normal primary contraction was significantly higher after codeine treatment, and the frequencies of weak and failed contractions were significantly lower after codeine treatment compared with placebo treatment.

Table 1 . High-resolution Manometric Characteristics of Esophageal Primary Peristalsis After Codeine and Placebo Treatment in Patients With Ineffective Esophageal Motility

CharacteristicsCodeinePlaceboP-value
UES parameters (mmHg)
Basal pressure53.4 (9.3)39.3 (6.5)0.136
LES parameters (mmHg)
Basal pressure23.0 (2.8)17.5 (1.5)0.092
IRP-4s7.9 (1.2)7.6 (0.7)0.794
EGJ-CI (mmHg∙cm)40.7 (5.1)27.8 (3.4)0.028a
Esophageal body parameters
DCI (mmHg∙s∙cm)566.5 (81.2)247.1 (36.0)0.001a
Distal latency (sec)5.7 (0.2)6.5 (0.1)< 0.001a
Total break length (cm)4.6 (1.0)7.4 (0.9)0.003a
Frequency (%)
Normal peristalsis53.9 (8.0)15.0 (3.6)< 0.001a
Weak peristalsis28.3 (7.2)45.6 (5.4)0.039a
Failed peristalsis17.8 (6.5)39.4 (6.7)0.009a
Multiple rapid swallows
Post-MRS DCI (mmHg∙s∙cm)736.7 (154.4)550.4 (124.5)0.129
Contractile reserve (%)24.1 (5.7)14.4 (4.5)0.220
Impaired inhibition (n [%])1 (5.6)0 (0)0.321

aP-value < 0.05 was a requisite for statistical significance.

UES, upper esophageal sphincter; LES, lower esophageal sphincter; IRP-4s, 4-second integrated relaxation pressure; EGJ-CI, esophagogastric junction–contractile integral; DCI, distal contractile integral; MRS, multiple rapid swallows.

Data are presented as mean (SEM).



Effects of Codeine on Secondary Peristalsis in Ineffective Esophageal Motility Patients

Secondary peristalsis measurements after treatment with codeine and placebo are shown in Table 2. The DCI of secondary peristalsis was not different between the codeine and placebo treatments (P = 0.077). The mean values of IRP-4s for secondary peristalsis were similar between codeine and the placebo treatments (P = 0.636). No significant differences in DL (P = 0.877) or total break length (P = 0.979) during air injection were detected between the codeine and placebo treatments. Similarly, the frequencies of triggering secondary peristalsis were similar between codeine and placebo treatments (32.8% vs 28.9%, P = 0.607).

Table 2 . High-resolution Manometric Characteristics of Esophageal Secondary Peristalsis After Treatment With codeine and Placebo in Patients With Ineffective Esophageal Motility

CharacteristicsCodeinePlaceboP-value
LES parameters (mmHg)
IRP-4s7.3 (1.7)6.5 (1.0)0.636
Esophageal body parameters
DCI (mmHg∙s∙cm)329.3 (90.6)176.7 (39.9)0.077a
Distal latency (sec)7.3 (0.6)7.4 (0.8)0.877
Total break length (cm)7.0 (1.0)7.0 (1.0)0.979
Frequency (%)
Successful response32.8 (8.3)28.9 (7.5)0.607

aP-value < 0.05 was a requisite for statistical significance.

LES, lower esophageal sphincter; IRP-4s, 4-second integrated relaxation pressure; DCI, distal contractile integral.

Data are presented as mean (SEM).


Discussion

This study prospectively evaluated the effects of acute codeine administration in patients with IEM. The results demonstrated that codeine significantly increased esophageal body contraction vigor and decreased DL and peristaltic breaks of primary peristalsis in IEM patients. In addition, codeine significantly increased the efficiency of primary peristalsis by increasing the frequency of effective contractions and reducing ineffective peristalsis. Nevertheless, no significant differences in secondary peristalsis were detected between codeine and placebo treatments.

Chronic opioid use is thought to induce esophageal dysfunction by suppressing the excitability of the inhibitory motor neurons, resulting in the loss of the latency gradient, and unchecked tonic contraction of the LES.20 These changes lead to high-amplitude, rapid or simultaneous contractions in the esophageal body and impaired relaxation of the LES. This mechanism of OIED explains a range of manometric abnormalities, including diffuse esophageal spasms, EGJOO, Jackhammer esophagus, and type III achalasia, which have been reported in patients with chronic opioid use.7-12 Moreover, opioids may lead to abnormal contractile patterns during MRS by interfering with inhibitory neural pathways.10

Despite the effects of chronic opioids on esophageal motility, studies evaluating the effects of acute opioid administration on esophageal peristalsis have shown conflicting results. Early studies demonstrated that acute morphine injection reduced swallow-induced LES relaxation and influenced distal esophageal contractility.4,6,21 A recent study utilizing HRM and pressure-flow analysis showed that acute administration of codeine increased bolus resistance at the EGJ in healthy adults, resulting in a manometric pattern mimicking major motility disorders like EGJOO.22 However, Balko et al23 reported that acute fentanyl administration did not increase the incidence of manometric abnormalities. Our recent study demonstrated that acute administration of codeine in healthy volunteers reduced LES relaxation and DL of primary peristalsis as well as increased the frequency of secondary peristalsis, though these metrics did not reach the manometric cut-off values for the diagnosis of peristaltic abnormalities.17 Some of these findings were not consistent with the effects of chronic opioid use previously reported.7-12 These differences may be due to different doses, opioid classes, and modes of drug administration. Additionally, esophageal physiology may be different for acute and chronic opioid use.

A variety of factors determine esophageal contraction amplitude, bolus clearance, and transit, implying that the pathophysiology of IEM is multifactorial and complicated. The neural control of esophageal smooth muscle contractions is modulated by central input from the brain stem and peripheral stimulation from myenteric ganglions in the esophageal wall through vagal afferent nerves.24,25 In our study, although acute codeine administration significantly increased esophageal body contraction vigor, decreased DL, and reduced the ineffective contractions of primary peristalsis, these metrics all fell within the normal range without reaching EGJ outflow or peristaltic disorders defined by the Chicago classification. Similar to our findings, a recent study by Sanchez et al2 retrospectively investigated the effects of opioids on the prevalence of esophageal motility disorders.1 Sanchez et al noted that the prevalence of IEM in chronic opioid users was significantly lower compared with patients who did not use opioids. To the best of our knowledge, our study is the first to prospectively evaluate the effects of opioids on esophageal peristalsis in IEM patients after acute administration of a single dose of codeine. Although the exact pathophysiological mechanisms and clinical significance needs to be clarified, our data suggest that opioids interfere with the inhibitory modulation of the esophagus and, consequently, alter HRM metrics, resulting in provocative effects that overcome the presence of esophageal hypomotility.

Although previous reports showed that opioids impair MRS inhibition,26,27 our study did not demonstrate interference with deglutitive inhibition in response to codeine administration. This difference is likely due to differences in esophageal physiology between acute and chronic drug usage, opioid dose and timing, route of drug administration, and codeine metabolizer phenotypes. In addition, secondary peristalsis is induced by a distention stimulus within the esophageal lumen, resulting in afferent signaling to the swallowing center through the vagal nerve.28 Motor or sensory defects due to changes in vagal function, central mechanisms, and impaired muscle contractility can lead to failure of secondary peristalsis. In the present study, acute codeine administration did not affect the frequency of esophageal secondary peristalsis in response to rapid air injections in patients with IEM. Because rapid air-induced secondary peristalsis is mediated by rapidly adapting mechanoreceptors in the esophageal mucosa, the lack of response in patients with IEM suggests that the peripheral mechanoreceptors or sensorimotor pathway is defective and could not be modulated by acute codeine administration.29 The exact pathophysiology mechanisms of secondary esophageal peristalsis in the context of acute codeine administration need further study.

There are several limitations to our study. First, in the present study, the pressure-flow analysis of the EGJ and esophageal body after acute codeine administration were not evaluated due to limitations of the HRM catheter; the esophageal secondary peristalsis and pressure-flow metrics could not be measured at the same time. Second, while our study demonstrated the association of acute codeine administration with manometric abnormalities, we did not establish causation for this relationship. Future studies with the administration of naloxone to reverse the codeine effects are required to verify the causal relationship and confirm the recovery of opioid-induced esophageal dysmotility. Finally, although we investigated the acute codeine effects on esophageal primary and secondary peristalsis, these effects may not be reproducible in chronic codeine users. Moreover, we did not assess the influence of different opioids or dose-dependent effects. Additional studies including larger populations are needed to investigate the acute and chronic effects of different opioid types and doses on esophageal symptoms and manometric findings.

In conclusion, we demonstrate that acute codeine administration increases contraction vigor and reduces DL of primary esophageal peristalsis in patients with IEM. In addition, codeine use increases the efficiency of primary peristalsis by reducing ineffective peristalsis and increasing effective contractions. In contrast to healthy adults,17 novel evidence from this study demonstrates that the influence of acute codeine administration on primary and secondary peristalsis in patients with IEM is different. Future studies are needed to investigate the clinical implications of the current physiological evidence in patients with IEM.

Acknowledgement

A part of this study was presented at the Digestive Disease Week (DDW Virtual) in 2022.

Financial support

This study was supported by a grant (TCRD111-36) from Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan, and a grant (MOST 109-2314-B-303-011-MY3) from Ministry of Science and Technology, Taiwan.

Conflicts of interest

None.

Author contributions

Chien-Lin Chen and Wei-Yi Lei: study concept and design; Wei-Chuan Chang: statistical analysis; Tso-Tsai Liu, Chih-Hsun Yi, Jui-Sheng Hung, Ming-Wun Wong, Shu-Wei Liang, and Lin Lin: acquisition, analysis, or interpretation of data; Chien-Lin Chen and Wei-Yi Lei: drafting of the manuscript; and Chien-Lin Chen: administrative, technical, or material support, and study supervision. All authors contributed to critical revision of the manuscript for important intellectual content.

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