Lower prevalence of gastroesophageal reflux disease in patients with noncardiac chest pain on opiates: a cross-sectional study

Lower prevalence of gastroesophageal reflux disease in patients with noncardiac chest pain on... SUMMARY Opiates can cause heartburn and spastic esophageal dysmotility but their role in noncardiac chest pain (NCCP) is not known. Our aim was to characterize opiate effects on esophageal function using esophageal pH monitoring and high-resolution manometry (HREM) in these patients. We performed a cross sectional study of opiate users with NCCP who underwent HREM and esophageal pH study from 2010 to 2017 using opiate nonusers as a comparison group. Demographic data, symptoms, opiate use, endoscopic findings, esophageal pH study parameters, and HREM data were abstracted. Thirty three patients with NCCP on opiates were compared to 144 opiate non-users. Compared to opiate nonusers, opiate users had lower total acid exposure (2.3% vs. 3%, P = 0.012), lower upright acid exposure (1.2% vs. 3.1%, P = 0.032) and lower DeMeester score (6.5 vs. 12.7, P = 0.016). Opiate users also had higher lower esophageal sphincter integrated relaxation pressure (LES-IRP) (7.0 mm Hg [2.2, 11.7] vs. 3.7 mm Hg [1.1, 6.2] P = 0.011) and greater mean distal contractile integral (DCI) (2575 mm.Hg.s.cm [1134, 4466] vs. 1409 mm.Hg.s.cm [796, 3003] P = 0.03) than opiate non-users. The prevalence of hypertensive motility disorders (15.2% vs. 11.1%) and achalasia (12.1% vs. 2.1%) was higher in opiate users (P = 0.039) but did not reach significance on multivariate analysis. In patients presenting with NCCP, opiate users had lower esophageal acid exposure compared to opiate nonusers. This might be due to higher LES pressures preventing reflux and higher DCI leading to more rapid acid esophageal clearance. STUDY HIGHLIGHTS WHAT IS CURRENT KNOWLEDGE: Opiates are associated with spastic esophageal disorders on HREM. Opiates are known to cause gastroesophageal reflux symptoms. The role of opiates in noncardiac chest pain has not been defined. WHAT IS NEW HERE: There was lower prevalence of pathologic esophageal acid exposure in patients with noncardiac chest pain using opiates. INTRODUCTION Opiate use and misuse has increased dramatically in United States over the last two decades and has reached epidemic proportions. In 2016, a total of 61,862,364 patients had at least one prescription for opioids filled at a rate of 19.1 patients per 100 persons.1 Although they are highly effective agents for pain relief, they can lead to a variety of gastrointestinal side effects such as nausea, vomiting, abdominal pain, bloating, heartburn, acid reflux, anorexia, delayed digestion, and constipation, which are grouped under the term ‘opioid-induced bowel dysfunction.’2 These effects are mediated by binding to μ-, δ-, and κ-opioid receptors, which are distributed in the stomach, small intestine, and colon.3 The side effects of opiates on stomach and colon have been extensively studied but their effects on esophagus are not well described and coming to attention only recently due to increasing use of opiates.4–11 Opiates appear to increase basal lower esophageal sphincter (LES) pressure and cause incomplete relaxation of LES and spastic esophageal peristalsis.10 Most of these studies were done in normal volunteers or patients presenting with dysphagia. However, none of the studies have reported on effect of opiates on esophageal function in patients presenting with noncardiac chest pain (NCCP). NCCP is defined as the presence of pain resembling angina in the absence of evidence of any coronary artery disease.12 It is a common presenting symptom with up to 25% mean annual prevalence.13 The most common cause of NCCP is gastroesophageal reflux disease (GERD) followed by esophageal motility disorders.12 Therefore, these patients are referred for evaluation of esophageal function with esophageal manometry and ambulatory esophageal pH monitoring. Since a proportion of these patients are on opiates, we hypothesized that patients with NCCP on opiates have a higher prevalence of spastic motility disorders as well as GERD. Therefore, our aim was to characterize the effect of opiates on esophageal function using high-resolution esophageal manometry (HREM) and esophageal pH monitoring in these patients with NCCP. METHODS Subjects This is a retrospective cross-sectional study of patients referred to our gastrointestinal physiology laboratory for evaluation of NCCP between January 1st 2010 and January 31st 2017. Inclusion criteria were all patients who had a HREM, esophageal pH monitoring, and upper endoscopy. Prior to the referral, these patients had a cardiac etiology was ruled out after evaluation by a cardiologist or by noninvasive cardiac stress testing or coronary angiogram. Data regarding demographics including age, gender, and race, additional esophageal symptoms such as regurgitation, heartburn and dysphagia and relevant medication use (acid suppressants, antidepressants, opiates, calcium channel blockers, and nitrates) were obtained. The study subjects were on opiates at the time of esophageal function tests and opiate non-users served as the comparison group. Specific type of opiate and indication for its use were also abstracted. HREM HREM was completed using a HREM solid-state catheter with 36 circumferential sensors spaced at 1 cm intervals (Medtronics, 710 Medtronic Parkway, Minneapolis, MN 55,432-5604 USA). The patients were typically advised to hold calcium channel blockers and nitrates for 24 hours prior to the procedure but not opiates or anticholinergic medications. All HREM studies were performed using a standard technique in a supine position after at least 4 hours of fasting. The catheter was placed transnasally, positioned to record from hypopharynx to the stomach with at least three intragastric sensors and maintained in this position throughout the study. The study protocol consisted of a period of catheter acclimation, baseline sphincter pressure assessment over a 30 second period; followed by ten water swallows given in 30 second intervals. HREM tracings were assessed using the Manoview analysis software (Medtronics, 710 Medtronic Parkway, Minneapolis, MN 55,432-5604 USA). Chicago classification version 3.0 was used to classify peristaltic patterns and diagnose motility disorders.14 All HREM tracings were reviewed for the study purposes. Ambulatory esophageal pH monitoring Esophageal pH monitoring was performed using either 24-hour catheter-based system (Versaflex catheter, Medtronics) or 48-hour wireless bravo probe (Medtronic, Minneapolis, MN, USA). The patients were instructed to hold proton pump inhibitors (PPI) 5 days before and H2 receptor antagonists 48 hours before pH testing. The following pH parameters were analyzed using AccuView reflux software: total acid exposure, supine and upright acid exposure, symptom index (SI), symptom sensitivity index (SSI), and symptom association probability (SAP). The cutoff for abnormal parameters was total acid exposure of more than 5.5%, upright acid exposure of more than 8.2% and supine acid exposure of more than 3%.15 In the case of 48-hour testing, parameters from the worst day were used for analysis. A total pH time less than 4 ≥ 5.5% of the time was considered diagnostic for pathologic esophageal acid exposure. Statistical analysis Data are presented as mean ± standard deviation, median [25th, 75th percentiles] or frequency (percent). Univariable analysis was performed to assess differences between subjects using opiates and those not using opiates. Analysis of variance (ANOVA) or the nonparametric Kruskal–Wallis tests were used to compare continuous variables and Pearson's chi-square tests were used for categorical factors. Based on esophageal motility patterns, patients were divided in four groups for statistical analysis: first group with achalasia (all types) and esophagogastric junction (EGJ) outflow obstruction, second group with the hypertensive disorders: distal esophageal spasm (DES) and jackhammer esophagus; third group with the hypotensive disorders: absent contractility, ineffective esophageal motility (IEM) and fragmented peristalsis. Finally, the fourth group included normal HREM. Multivariable logistic regression analysis was performed to assess association between opiate use and abnormal HREM and esophageal pH monitoring while adjusting for potential confounders. Opiate use was included in all models and other factors considered for inclusion were demographics, social factors, symptoms, and medications. Final multivariable models were chosen using an automated stepwise variable selection method performed on 1000 bootstrap samples; factors with inclusion rates of at least 50% were included in the models. All analyses were performed using SAS (version 9.4, The SAS Institute, Cary, NC) and a P < 0.05 was considered statistically significant. RESULTS There were 33 patients who were on opiates at the time of study and 144 patients in the control group. Average age was 54.2 ± 12.9 years, 67% of patients were female, and 89.6% were white. The opiates prescribed were as follows: oxycodone in 13 patients, tramadol in 8, hydrocodone in 7, codeine in 2, hydromorphone in 1, tapendadol in 1, and fentanyl in one patient. The indications for opioid prescription were chronic low back pain in 8 patients, degenerative joint disease in 8, chronic abdominal pain in 4, chronic pelvic pain in1, NCCP in 3, postoperative pain in 2, rheumatoid arthritis related joint pain in 2, headaches in 1, chronic cough in 1, and chronic pain syndrome in 3 patients. The median morphine equivalent daily dose (MEDD) was 30 mg/day, with a range of 7.5–150 mg/day. The baseline characteristics of both groups were comparable; no statistically significant differences were found regarding age, gender, race, smoking status, and alcohol use (Table 1). Opiate users were more likely to have dysphagia in addition to NCCP (48.5% vs. 29.2%, P = 0.033) and to be on antidepressants, calcium channel blockers, gabapentin, and/or pregabalin. The frequency of other concomitant esophageal symptoms (regurgitation and heartburn) and use of acid suppressant medications did not differ (Table 1). Table 1 Patient general characteristics. Factor  Opiate nonusers (N = 144)  Opiate users (N = 33)  P-value  Age at HREM (years)  54.0 ± 13.3  55.2 ± 10.9  0.62†  Female gender  95 (66.0)  24 (72.7)  0.46‡  White race  128 (91.4)  27 (81.8)  0.10‡  Never smoker  85 (59.0)  17 (51.5)  0.18‡  Never alcohol use  60 (41.7)  17(51.5)  0.071‡  Heartburn  71 (49.3)  15 (45.5)  0.69‡  Regurgitation  54 (37.5)  11 (33.3)  0.65‡  Dysphagia  42 (29.2)  16 (48.5)  0.033‡  Abnormal upper endoscopic findings  46 (31.9)  11 (33.3)  0.87‡  Medications  Gabapentin and/or pregabalin  5(3.5)  5(15.2)  0.009‡  Calcium channel blockers  24(16.7)  13(39.4)  0.004‡  Nitrates  8(5.6)  4(12.1)  0.18‡  Proton Pump Inhibitor use  99(68.8)  27(81.8)  0.13‡  Histamine receptor antagonist use  12(8.3)  6(18.2)  0.091‡  Antidepressants  39(27.1)  16(48.5)  0.017‡  Factor  Opiate nonusers (N = 144)  Opiate users (N = 33)  P-value  Age at HREM (years)  54.0 ± 13.3  55.2 ± 10.9  0.62†  Female gender  95 (66.0)  24 (72.7)  0.46‡  White race  128 (91.4)  27 (81.8)  0.10‡  Never smoker  85 (59.0)  17 (51.5)  0.18‡  Never alcohol use  60 (41.7)  17(51.5)  0.071‡  Heartburn  71 (49.3)  15 (45.5)  0.69‡  Regurgitation  54 (37.5)  11 (33.3)  0.65‡  Dysphagia  42 (29.2)  16 (48.5)  0.033‡  Abnormal upper endoscopic findings  46 (31.9)  11 (33.3)  0.87‡  Medications  Gabapentin and/or pregabalin  5(3.5)  5(15.2)  0.009‡  Calcium channel blockers  24(16.7)  13(39.4)  0.004‡  Nitrates  8(5.6)  4(12.1)  0.18‡  Proton Pump Inhibitor use  99(68.8)  27(81.8)  0.13‡  Histamine receptor antagonist use  12(8.3)  6(18.2)  0.091‡  Antidepressants  39(27.1)  16(48.5)  0.017‡  Statistics presented as mean ± standard deviation, Median [P25, P75] or N (column %). P-values: †ANOVA, ‡Pearson's chi-square test. HREM, high-resolution esophageal manometry. View Large Table 1 Patient general characteristics. Factor  Opiate nonusers (N = 144)  Opiate users (N = 33)  P-value  Age at HREM (years)  54.0 ± 13.3  55.2 ± 10.9  0.62†  Female gender  95 (66.0)  24 (72.7)  0.46‡  White race  128 (91.4)  27 (81.8)  0.10‡  Never smoker  85 (59.0)  17 (51.5)  0.18‡  Never alcohol use  60 (41.7)  17(51.5)  0.071‡  Heartburn  71 (49.3)  15 (45.5)  0.69‡  Regurgitation  54 (37.5)  11 (33.3)  0.65‡  Dysphagia  42 (29.2)  16 (48.5)  0.033‡  Abnormal upper endoscopic findings  46 (31.9)  11 (33.3)  0.87‡  Medications  Gabapentin and/or pregabalin  5(3.5)  5(15.2)  0.009‡  Calcium channel blockers  24(16.7)  13(39.4)  0.004‡  Nitrates  8(5.6)  4(12.1)  0.18‡  Proton Pump Inhibitor use  99(68.8)  27(81.8)  0.13‡  Histamine receptor antagonist use  12(8.3)  6(18.2)  0.091‡  Antidepressants  39(27.1)  16(48.5)  0.017‡  Factor  Opiate nonusers (N = 144)  Opiate users (N = 33)  P-value  Age at HREM (years)  54.0 ± 13.3  55.2 ± 10.9  0.62†  Female gender  95 (66.0)  24 (72.7)  0.46‡  White race  128 (91.4)  27 (81.8)  0.10‡  Never smoker  85 (59.0)  17 (51.5)  0.18‡  Never alcohol use  60 (41.7)  17(51.5)  0.071‡  Heartburn  71 (49.3)  15 (45.5)  0.69‡  Regurgitation  54 (37.5)  11 (33.3)  0.65‡  Dysphagia  42 (29.2)  16 (48.5)  0.033‡  Abnormal upper endoscopic findings  46 (31.9)  11 (33.3)  0.87‡  Medications  Gabapentin and/or pregabalin  5(3.5)  5(15.2)  0.009‡  Calcium channel blockers  24(16.7)  13(39.4)  0.004‡  Nitrates  8(5.6)  4(12.1)  0.18‡  Proton Pump Inhibitor use  99(68.8)  27(81.8)  0.13‡  Histamine receptor antagonist use  12(8.3)  6(18.2)  0.091‡  Antidepressants  39(27.1)  16(48.5)  0.017‡  Statistics presented as mean ± standard deviation, Median [P25, P75] or N (column %). P-values: †ANOVA, ‡Pearson's chi-square test. HREM, high-resolution esophageal manometry. View Large On HREM, these patients had significantly higher LES integrated relaxation pressure (IRP) and were more likely to have an IRP greater than 15. The basal LES pressure was also higher in the opiate group, but did not reach statistical significance. Even after excluding patients with achalasia, mean LES IRP remained higher in opiate group (6.1 mm Hg [1.9, 10.8] versus 3.7 mm Hg [1.1, 6], P = 0.027). There was a moderately weak correlation between MEDD and IRP in opiate users (rho = 0.36, 95 CI [0.02, 0.63]; P = 0.038). In addition, opiate users had greater average distal contractile integral (DCI) and shorter distal latency (Table 2). The prevalence of hypertensive peristalsis (15.2% vs. 11.1%) and achalasia or EGJ outflow obstruction (12.1% vs. 2.1%) was higher among opiate users (P = 0.039) (Table 2). The prevalence of various esophageal motility disorders in both groups is presented in Table 3. Table 2 Esophageal function testing. Factor  No opiates (N = 144)  Opiates (N = 33)  P-value  HREM findings  Basal LES pressure (mmHg)  23.0 [12.9,33.5]  24.8 [15.4,36.4]  0.54†  Mean LES-IRP (mmHg)  3.7 [1.1,6.2]  7.0 [2.2,11.7]  0.011†  LES-IRP > 15 (mmHg)  5(3.5)  6(18.2)  0.002‡  Contractile front Velocity (cm/s)  3.4 [2.7,4.3]  3.5 [3.1,4.9]  0.20†  Mean DCI (mm.Hg.s.cm)  1409 [796,3003]  2575 [1134,4466]  0.030†  Distal Latency (sec)  6.7 [6.0,7.7]  6.0 [5.2,6.8]  0.018†  Normal per Chicago classification  101 (70.1)  21 (63.6)    Hypotensive disorders¶  24 (16.7)  3 (9.1)  0.039§  Hypertensive disorders¶  16 (11.1)  5 (15.2)    Achalasia or EGJ outflow obstruction¶  3 (2.1)  4 (12.1)    Esophageal pH monitoring  Total acid exposure ≥5.5% time  56 (38.9)  6 (18.2)  0.025§  Total acid exposure time (%)  3.0 [0.65,9.1]  2.3 [0.20,5.1]  0.012†  Upright acid exposure time (%)  3.1 [0.90,8.1]  1.2 [0.20,5.4]  0.032†  Supine acid exposure time (%)  0.60 [0.00,5.8]  0.60 [0.00,3.1]  0.35†  DeMeester Score  12.7 [3.4,28.8]  6.5 [0.30,18.0]  0.016†  SI for chest pain > 50%  12 (8.3)  2 (6.1)  0.66§  SSI for chest pain > 10%  3 (2.6)  3 (10.0)  0.068§  SAP for chest pain > 95%  6 (5.2)  3 (10.0)  0.33§  Factor  No opiates (N = 144)  Opiates (N = 33)  P-value  HREM findings  Basal LES pressure (mmHg)  23.0 [12.9,33.5]  24.8 [15.4,36.4]  0.54†  Mean LES-IRP (mmHg)  3.7 [1.1,6.2]  7.0 [2.2,11.7]  0.011†  LES-IRP > 15 (mmHg)  5(3.5)  6(18.2)  0.002‡  Contractile front Velocity (cm/s)  3.4 [2.7,4.3]  3.5 [3.1,4.9]  0.20†  Mean DCI (mm.Hg.s.cm)  1409 [796,3003]  2575 [1134,4466]  0.030†  Distal Latency (sec)  6.7 [6.0,7.7]  6.0 [5.2,6.8]  0.018†  Normal per Chicago classification  101 (70.1)  21 (63.6)    Hypotensive disorders¶  24 (16.7)  3 (9.1)  0.039§  Hypertensive disorders¶  16 (11.1)  5 (15.2)    Achalasia or EGJ outflow obstruction¶  3 (2.1)  4 (12.1)    Esophageal pH monitoring  Total acid exposure ≥5.5% time  56 (38.9)  6 (18.2)  0.025§  Total acid exposure time (%)  3.0 [0.65,9.1]  2.3 [0.20,5.1]  0.012†  Upright acid exposure time (%)  3.1 [0.90,8.1]  1.2 [0.20,5.4]  0.032†  Supine acid exposure time (%)  0.60 [0.00,5.8]  0.60 [0.00,3.1]  0.35†  DeMeester Score  12.7 [3.4,28.8]  6.5 [0.30,18.0]  0.016†  SI for chest pain > 50%  12 (8.3)  2 (6.1)  0.66§  SSI for chest pain > 10%  3 (2.6)  3 (10.0)  0.068§  SAP for chest pain > 95%  6 (5.2)  3 (10.0)  0.33§  Statistics presented as mean ± standard deviation, Median [P25, P75] or N (column %). P-values: §ANOVA, †Kruskal-Wallis test, ‡Pearson's chi-square test. DCI, distal contractile integral; EGJ, esophagogastric Junction; LES, lower esophageal sphincter; IRP, integrated relaxation pressure; HREM, high-resolution esophageal manometry; SI, symptom index; SSI = symptom sensitivity index; SAP, symptom association probability. ¶Hypotensive disorders: absent contractility, ineffective esophageal motility, fragmented peristalsis. ¶Hypertensive disorders: distal esophageal spasm, Jackhammer esophagus. ¶Achalasia includes type I, II, and III. View Large Table 2 Esophageal function testing. Factor  No opiates (N = 144)  Opiates (N = 33)  P-value  HREM findings  Basal LES pressure (mmHg)  23.0 [12.9,33.5]  24.8 [15.4,36.4]  0.54†  Mean LES-IRP (mmHg)  3.7 [1.1,6.2]  7.0 [2.2,11.7]  0.011†  LES-IRP > 15 (mmHg)  5(3.5)  6(18.2)  0.002‡  Contractile front Velocity (cm/s)  3.4 [2.7,4.3]  3.5 [3.1,4.9]  0.20†  Mean DCI (mm.Hg.s.cm)  1409 [796,3003]  2575 [1134,4466]  0.030†  Distal Latency (sec)  6.7 [6.0,7.7]  6.0 [5.2,6.8]  0.018†  Normal per Chicago classification  101 (70.1)  21 (63.6)    Hypotensive disorders¶  24 (16.7)  3 (9.1)  0.039§  Hypertensive disorders¶  16 (11.1)  5 (15.2)    Achalasia or EGJ outflow obstruction¶  3 (2.1)  4 (12.1)    Esophageal pH monitoring  Total acid exposure ≥5.5% time  56 (38.9)  6 (18.2)  0.025§  Total acid exposure time (%)  3.0 [0.65,9.1]  2.3 [0.20,5.1]  0.012†  Upright acid exposure time (%)  3.1 [0.90,8.1]  1.2 [0.20,5.4]  0.032†  Supine acid exposure time (%)  0.60 [0.00,5.8]  0.60 [0.00,3.1]  0.35†  DeMeester Score  12.7 [3.4,28.8]  6.5 [0.30,18.0]  0.016†  SI for chest pain > 50%  12 (8.3)  2 (6.1)  0.66§  SSI for chest pain > 10%  3 (2.6)  3 (10.0)  0.068§  SAP for chest pain > 95%  6 (5.2)  3 (10.0)  0.33§  Factor  No opiates (N = 144)  Opiates (N = 33)  P-value  HREM findings  Basal LES pressure (mmHg)  23.0 [12.9,33.5]  24.8 [15.4,36.4]  0.54†  Mean LES-IRP (mmHg)  3.7 [1.1,6.2]  7.0 [2.2,11.7]  0.011†  LES-IRP > 15 (mmHg)  5(3.5)  6(18.2)  0.002‡  Contractile front Velocity (cm/s)  3.4 [2.7,4.3]  3.5 [3.1,4.9]  0.20†  Mean DCI (mm.Hg.s.cm)  1409 [796,3003]  2575 [1134,4466]  0.030†  Distal Latency (sec)  6.7 [6.0,7.7]  6.0 [5.2,6.8]  0.018†  Normal per Chicago classification  101 (70.1)  21 (63.6)    Hypotensive disorders¶  24 (16.7)  3 (9.1)  0.039§  Hypertensive disorders¶  16 (11.1)  5 (15.2)    Achalasia or EGJ outflow obstruction¶  3 (2.1)  4 (12.1)    Esophageal pH monitoring  Total acid exposure ≥5.5% time  56 (38.9)  6 (18.2)  0.025§  Total acid exposure time (%)  3.0 [0.65,9.1]  2.3 [0.20,5.1]  0.012†  Upright acid exposure time (%)  3.1 [0.90,8.1]  1.2 [0.20,5.4]  0.032†  Supine acid exposure time (%)  0.60 [0.00,5.8]  0.60 [0.00,3.1]  0.35†  DeMeester Score  12.7 [3.4,28.8]  6.5 [0.30,18.0]  0.016†  SI for chest pain > 50%  12 (8.3)  2 (6.1)  0.66§  SSI for chest pain > 10%  3 (2.6)  3 (10.0)  0.068§  SAP for chest pain > 95%  6 (5.2)  3 (10.0)  0.33§  Statistics presented as mean ± standard deviation, Median [P25, P75] or N (column %). P-values: §ANOVA, †Kruskal-Wallis test, ‡Pearson's chi-square test. DCI, distal contractile integral; EGJ, esophagogastric Junction; LES, lower esophageal sphincter; IRP, integrated relaxation pressure; HREM, high-resolution esophageal manometry; SI, symptom index; SSI = symptom sensitivity index; SAP, symptom association probability. ¶Hypotensive disorders: absent contractility, ineffective esophageal motility, fragmented peristalsis. ¶Hypertensive disorders: distal esophageal spasm, Jackhammer esophagus. ¶Achalasia includes type I, II, and III. View Large Table 3 Distribution of esophageal motility disorders by opiate use. HREM diagnosis  Opiate nonusers (N = 144)  Opiate users (N = 33)  Achalasia type I  0 (0.0%)  0 (0%)  Achalasia type II  2 (1.3%)  1 (3.0%)  Achalasia type III  0 (0.0%)  1 (3.0%)  EGJ outflow obstruction  1 (0.6%)  2 (6.0%)  Distal esophageal spasm  6 (4.1%)  3 (9.0%)  Jackhammer esophagus  10 (6.9%)  2 (6.0%)  Absent contractility  1 (0.6%)  0 (0.0%)  Ineffective esophageal motility  22 (15.2%)  3 (9.0%)  Fragmented peristalsis  1 (0.6%)  0 (0.0%)  Normal  101 (70.1%)  21 (63.6%)  HREM diagnosis  Opiate nonusers (N = 144)  Opiate users (N = 33)  Achalasia type I  0 (0.0%)  0 (0%)  Achalasia type II  2 (1.3%)  1 (3.0%)  Achalasia type III  0 (0.0%)  1 (3.0%)  EGJ outflow obstruction  1 (0.6%)  2 (6.0%)  Distal esophageal spasm  6 (4.1%)  3 (9.0%)  Jackhammer esophagus  10 (6.9%)  2 (6.0%)  Absent contractility  1 (0.6%)  0 (0.0%)  Ineffective esophageal motility  22 (15.2%)  3 (9.0%)  Fragmented peristalsis  1 (0.6%)  0 (0.0%)  Normal  101 (70.1%)  21 (63.6%)  Statistics presented as N (column %). EGJ, esophagogastric junction; HREM, high resolution esophageal manometry. View Large Table 3 Distribution of esophageal motility disorders by opiate use. HREM diagnosis  Opiate nonusers (N = 144)  Opiate users (N = 33)  Achalasia type I  0 (0.0%)  0 (0%)  Achalasia type II  2 (1.3%)  1 (3.0%)  Achalasia type III  0 (0.0%)  1 (3.0%)  EGJ outflow obstruction  1 (0.6%)  2 (6.0%)  Distal esophageal spasm  6 (4.1%)  3 (9.0%)  Jackhammer esophagus  10 (6.9%)  2 (6.0%)  Absent contractility  1 (0.6%)  0 (0.0%)  Ineffective esophageal motility  22 (15.2%)  3 (9.0%)  Fragmented peristalsis  1 (0.6%)  0 (0.0%)  Normal  101 (70.1%)  21 (63.6%)  HREM diagnosis  Opiate nonusers (N = 144)  Opiate users (N = 33)  Achalasia type I  0 (0.0%)  0 (0%)  Achalasia type II  2 (1.3%)  1 (3.0%)  Achalasia type III  0 (0.0%)  1 (3.0%)  EGJ outflow obstruction  1 (0.6%)  2 (6.0%)  Distal esophageal spasm  6 (4.1%)  3 (9.0%)  Jackhammer esophagus  10 (6.9%)  2 (6.0%)  Absent contractility  1 (0.6%)  0 (0.0%)  Ineffective esophageal motility  22 (15.2%)  3 (9.0%)  Fragmented peristalsis  1 (0.6%)  0 (0.0%)  Normal  101 (70.1%)  21 (63.6%)  Statistics presented as N (column %). EGJ, esophagogastric junction; HREM, high resolution esophageal manometry. View Large On esophageal pH monitoring, patients on opiates were less likely to have abnormal esophageal acid exposure compared to non-users (18.2% vs. 38.9% P = 0.025) (Table 2). Consequently, DeMeester score, total acid exposure time (2.3% vs. 3.0%) and upright acid reflux time (1.2% vs. 3.1%) were significantly lower in the opiate group. The symptom association indices did not differ significantly in the two groups. Among opiate users, 22 of 33 patients had normal endoscopic appearance of the esophagus. The abnormal esophageal findings in the remaining 11 patients were: grade A esophagitis in 3, grade B esophagitis in 2, Barrett's esophagus in 2, resistance at EGJ in 2, dilated esophageal lumen in 1 and ringed esophagus in one. Among opiate nonusers, reflux esophagitis was seen in 25 patients, Barrett's esophagus in 9, strictures in 4, dilated esophageal lumen in 2, ringed appearance in 3, ulcers in 3 and normal upper endoscopy in 98 patients. The prevalence of abnormal esophageal findings was similar between groups (Table 1). Among opiate nonusers, 43 of 144 (29.8%) patients underwent gastric emptying testing while in the opiate group, 11 of 33 (33.3%) patients underwent testing. The prevalence of delayed gastric emptying was 2.7% and 3.0% of those tested respectively (P = 0.73). On multivariable analysis, opiate users were three times less likely to have abnormal esophageal acid exposure compared to opiate nonusers (Table 4). Opiate use was not associated with abnormal HREM findings in general (P = 0.99). Similarly, on subgroup analysis, opiate use did not reach statistical significance for hypertensive disorders, achalasia, and EGJ outflow obstruction (P = 0.15). Table 4 Multivariable logistic regression of the effect of opiates on esophageal function tests. Use of opiates  OR (95% CI)  P-value  Abnormal pH monitoring  0.33 (0.12, 0.91)  0.032  Abnormal HREM  0.99 (0.42, 2.4)  0.99  Hypotensive peristaltic disorders  0.47(0.13, 1.7)  0.26  Hypertensive peristaltic disorders  0.81(0.25, 2.7)  0.73  Hypertensive peristalsis, achalasia and EGJ outflow obstruction in HREM  2.1 (0.77, 5.6)  0.15  Use of opiates  OR (95% CI)  P-value  Abnormal pH monitoring  0.33 (0.12, 0.91)  0.032  Abnormal HREM  0.99 (0.42, 2.4)  0.99  Hypotensive peristaltic disorders  0.47(0.13, 1.7)  0.26  Hypertensive peristaltic disorders  0.81(0.25, 2.7)  0.73  Hypertensive peristalsis, achalasia and EGJ outflow obstruction in HREM  2.1 (0.77, 5.6)  0.15  CI, confidence interval; EGJ, esophagogastric junction; HREM, high-resolution esophageal manometry; OR, odds ratio. View Large Table 4 Multivariable logistic regression of the effect of opiates on esophageal function tests. Use of opiates  OR (95% CI)  P-value  Abnormal pH monitoring  0.33 (0.12, 0.91)  0.032  Abnormal HREM  0.99 (0.42, 2.4)  0.99  Hypotensive peristaltic disorders  0.47(0.13, 1.7)  0.26  Hypertensive peristaltic disorders  0.81(0.25, 2.7)  0.73  Hypertensive peristalsis, achalasia and EGJ outflow obstruction in HREM  2.1 (0.77, 5.6)  0.15  Use of opiates  OR (95% CI)  P-value  Abnormal pH monitoring  0.33 (0.12, 0.91)  0.032  Abnormal HREM  0.99 (0.42, 2.4)  0.99  Hypotensive peristaltic disorders  0.47(0.13, 1.7)  0.26  Hypertensive peristaltic disorders  0.81(0.25, 2.7)  0.73  Hypertensive peristalsis, achalasia and EGJ outflow obstruction in HREM  2.1 (0.77, 5.6)  0.15  CI, confidence interval; EGJ, esophagogastric junction; HREM, high-resolution esophageal manometry; OR, odds ratio. View Large DISCUSSION Due to the widespread use of opiates, there is greater attention on the effects of opiates on gastrointestinal motility. Opiates have been linked to nausea, vomiting, abdominal pain, bloating, heartburn, acid reflux, anorexia, delayed gastric emptying, and constipation.2 Nonetheless, there are limited data on their effect on NCCP and esophageal function. In this study, opiate users had lower total and upright esophageal acid exposure and lower DeMeester score on esophageal pH monitoring. Opiate users were also three times less likely to have pathologic acid exposure compared to opiate nonusers. Opiates were also associated with higher prevalence of spastic features on HREM such as higher LES-IRP, greater mean DCI, and shorter distal latency. Opiates have contradictory physiological effects on GERD. On one hand, opiates cause increased LES tone,10 reduction in transient LES relaxation,9 and decreased gastric secretions which offer protection against GERD,16 and on the other hand, they impair effective esophageal peristalsis and delay gastric emptying,17 which worsens GERD. Traditional thinking is that opiates cause regurgitation and heartburn. In a study on patients with noncancer pain on chronic opiates, GERD symptoms were reported in up to 33% of the patients.18 This was independent of the dose or duration of use of opiates. In another study of over 50,000 individuals, opium users were 1.7 times more likely to have GERD symptoms than opium non-users.19 In gastroparetic patients, chronic opiate use was associated with greater severity of heartburn, regurgitation, acid taste in the mouth and chest discomfort.20 However, prior studies looking at effect of opiates on objective evidence of GERD are lacking. In one study of 8 healthy subjects and 8 patients with GERD, pH recordings were obtained for 30 min after administration of intravenous morphine.9 Morphine reduced markedly the rate of transient LES relaxations, which resulted in decrease in number of reflux episodes and in esophageal acid exposure.9 This duration of pH monitoring is short to make any meaningful inference. Contrary to the popular belief, we found that opiates are associated with reduced esophageal acid exposure. Why is this so? It might be hypothesized that higher LES-IRP and higher basal LES pressure reduce reflux episodes in patients on opiates. Besides, the greater DCI may enhance the esophageal acid clearance mechanism. Another thing to ponder upon is that even though GERD is mainly a clinical diagnosis, heartburn and regurgitation are not 100% sensitive or specific for a definitive diagnosis of GERD. In one study, reflux disease questionnaire had a 62% sensitivity and 67% specificity for diagnosis of GERD.21 In another prospective study comparing GERD questionnaire to 48 hour Bravo study, sensitivity of the questionnaire was 71% (95% CI, 61–80%) and specificity was 39% (95% CI, 29–51%) for identifying acid reflux in patients off acid suppression.22 Thus, symptoms alone are not sufficient to make a diagnosis of GERD and this disconnect may explain the discrepancy between our study findings and those of the studies reporting GERD symptoms in patients on opiates. Even though there was a higher prevalence of achalasia, EGJ outflow obstruction, and hypertensive disorders in opiate users than nonusers, multivariable analysis did not reveal any association between opiate use and esophageal motility disorders, which may be due to Type II error. In a retrospective cohort of 121 chronic opiate users, patients who were on opiates at the time of the study had esophageal motility findings similar to ours: higher LES-IRP, shorter distal latency and greater prevalence of spastic motility disorders, specifically EGJ outflow obstruction and achalasia type III.10 Another study on 15 opioid users undergoing conventional manometry noted incomplete LES relaxation, simultaneous contractions and high amplitude/velocity.4 In a case series of patients on opiates who underwent HREM, all 5 patients had EGJ outflow obstruction or achalasia.11 Other studies evaluated the acute effects of intravenous opiates on esophageal motility. Two of these studies found reduction in basal LES pressure5,6 but remaining studies reported increased basal LES tone and decreased swallow induced relaxation.7–9 The exact mechanism of the effect of opiates on the esophagus is not well established. In general, opiates interfere with the releases of excitatory neurotransmitters such as acetyl choline, which leads to an overall inhibitory effect.23 However, opioids can also lead to spasm of smooth muscle. In vitro studies in guinea pig ileal muscle showed that morphine causes contraction of the circular muscle by reducing the amount of nitric oxide released.24 Morphine also appears to have a direct myogenic effect on isolated sphincter and small intestinal muscle contraction.25,26 In animals, opioid receptors have been identified in the esophageal body and LES27 and similar mechanisms may explain the opiate effects on the human esophagus. The main strength of this study is a comprehensive assessment of esophageal function with HREM, esophageal pH monitoring, upper endoscopy, and negative cardiac evaluation in all the study subjects. Baseline characteristics were comparable between the two groups and the association between opiate use and lower esophageal acid exposure remained significant after multivariable analysis. Nevertheless, this study has limitations. Since it is a small group of patients, we could not assess if there are any differences based on duration and dosage. Also different opiates have differing effects on gastrointestinal function28 and this study was not powered to assess this finding. Since this is a retrospective study, it is difficult to draw cause–effect relationships. Third, this represents a highly select group of patients seen in a tertiary referral center, which may restrict the generalizability of the findings. Despite these limitations, we consider our data on the effects of opiates on esophageal function worthwhile to share in view of the alarming opioid epidemic in United States. In conclusion, opiates are associated with reduced prevalence of pathologic acid reflux in NCCP patients. Although the clinical significance of these data is unclear, it is essential to assess for opiate use in all patients presenting with NCCP. Finally, this study opens the door for further research to study the clinical impact of opiates on esophageal function depending on the type, duration and dose used. Notes Specific author contributions: Study concept and design: Juan D. Gomez Cifuentes, Prashanthi N. Thota; Acquisition of data: Juan D. Gomez Cifuentes; Analysis and interpretation of data: Juan D. Gomez Cifuentes, Prashanthi N. Thota, Rocio Lopez; Drafting of the manuscript: Juan D. Gomez Cifuentes; Drafting and critical revision of the manuscript: Prashanthi N. Thota; Study supervision: Prashanthi N. Thota; Critical revision of the manuscript for important intellectual content: Rocio Lopez; Statistical analysis: Rocio Lopez. Guarantor of the article: Prashanthi N.Thota. Disclosures: Grant Support: None. Financial disclosures: None. Conflicts of interest: None. References 1 https://www.cdc.gov/drugoverdose/pdf/pubs/CDC_2017_Surveillance-Report_DataSummary_presentation.pdf. Surveillance Report Highlights from the Annual Surveillance Report of Drug-Related Risks and Outcomes United States, 2017. 2 Bell T J, Panchal S J, Miaskowski C et al.   The prevalence, severity, and impact of opioid-induced bowel dysfunction: results of a US and European patient survey (PROBE 1). Pain Med  2009; 10: 35– 42. Google Scholar CrossRef Search ADS PubMed  3 Sternini C, Patierno S, Selmer I S et al.   The opioid system in the gastrointestinal tract. Neurogastroenterol Motil  2004; 16: 3– 16. Google Scholar CrossRef Search ADS PubMed  4 Kraichely R E, Arora A S, Murray J A. Opiate-induced oesophageal dysmotility. Aliment Pharmacol Ther  2010; 31: 601– 6. Google Scholar CrossRef Search ADS PubMed  5 Mittal R K, Frank E B, Lange R C et al.   Effects of morphine and naloxone on esophageal motility and gastric emptying in man. Digest Dis Sci  1986; 31: 936– 42. Google Scholar CrossRef Search ADS PubMed  6 Penagini R, Bartesaghi B, Zannini P et al.   Lower oesophageal sphincter hypersensitivity to opioid receptor stimulation in patients with idiopathic achalasia. Gut  1993; 34: 16– 20. Google Scholar CrossRef Search ADS PubMed  7 Penagini R, Picone A, Bianchi P A. Effect of morphine and naloxone on motor response of the human esophagus to swallowing and distension. Am J Physiol  1996; 271: G675– 80. Google Scholar PubMed  8 Dowlatshahi K, Evander A, Walther B et al.   Influence of morphine on the distal oesophagus and the lower oesophageal sphincter—a manometric study. Gut  1985; 26: 802– 6. Google Scholar CrossRef Search ADS PubMed  9 Penagini R, Bianchi P A. Effect of morphine on gastroesophageal reflux and transient lower esophageal sphincter relaxation. Gastroenterology  1997; 113: 409– 14. Google Scholar CrossRef Search ADS PubMed  10 Ratuapli S K, Crowell M D, DiBaise J K et al.   Opioid-induced esophageal dysfunction (OIED) in patients on chronic opioids. Am J Gastroenterol  2015; 110: 979– 84. Google Scholar CrossRef Search ADS PubMed  11 González E S, Bellver V O, Jaime F C D, Cortés J A O, Gil V G. Opioid-induced lower esophageal sphincter dysfunction. J Neurogastroenterol Motil  2015; 21: 618– 20. Google Scholar CrossRef Search ADS PubMed  12 Yamasaki T, Fass R. Noncardiac chest pain: diagnosis and management. Curr Opin Gastroenterol  2017; 33: 293– 300. Google Scholar CrossRef Search ADS PubMed  13 Locke G R 3rd, Talley N J, Fett S L et al.   Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology  1997; 112: 1448– 56. Google Scholar CrossRef Search ADS PubMed  14 Kahrilas P J, Bredenoord A J, Fox M et al.   The Chicago Classification of esophageal motility disorders, v3.0. Neurogastroenterol Motil  2015; 27: 160– 74. Google Scholar CrossRef Search ADS PubMed  15 Jamieson J R, Stein H J, DeMeester T R et al.   Ambulatory 24-h esophageal pH monitoring: normal values, optimal thresholds, specificity, sensitivity, and reproducibility. Am J Gastroenterol  1992; 87: 1102– 11. Google Scholar PubMed  16 Feldman M, Walsh J H, Taylor I L. Effect of naloxone and morphine on gastric acid secretion and on serum gastrin and pancreatic polypeptide concentrations in humans. Gastroenterology  1980; 79: 294– 8. Google Scholar PubMed  17 Camilleri M, Malagelada J R, Stanghellini V et al.   Dose-related effects of synthetic human beta-endorphin and naloxone of fed gastrointestinal motility. Am J Physiol  1986; 251: G147– 54. Google Scholar PubMed  18 Tuteja A K, Biskupiak J, Stoddard G J et al.   Opioid-induced bowel disorders and narcotic bowel syndrome in patients with chronic non-cancer pain. Neurogastroenterol Motil  2010; 22: 424– e96, e96. Google Scholar CrossRef Search ADS PubMed  19 Islami F, Nasseri-Moghaddam S, Pourshams A et al.   Determinants of gastroesophageal reflux disease, including hookah smoking and opium use—a cross-sectional analysis of 50,000 individuals. PLoS One  2014; 9: e89256. Google Scholar CrossRef Search ADS PubMed  20 Jehangir A, Parkman H P. Chronic opioids in gastroparesis: relationship with gastrointestinal symptoms, healthcare utilization and employment. World J Gastroenterol  2017; 23: 7310– 20. Google Scholar CrossRef Search ADS PubMed  21 Dent J, Vakil N, Jones R et al.   Accuracy of the diagnosis of GORD by questionnaire, physicians and a trial of proton pump inhibitor treatment: the Diamond Study. Gut  2010; 59: 714– 21. Google Scholar CrossRef Search ADS PubMed  22 Lacy B E, Chehade R, Crowell M D. A prospective study to compare a symptom-based reflux disease questionnaire to 48-h wireless pH monitoring for the identification of gastroesophageal reflux (revised 2-26-11). Am J Gastroenterol  2011; 106: 1604– 11. Google Scholar CrossRef Search ADS PubMed  23 Camilleri M, Lembo A, Katzka D A. Opioids in gastroenterology: treating adverse effects and creating therapeutic benefits. Clin Gastroenterol Hepatol  2017; 15: 1338– 49. Google Scholar CrossRef Search ADS PubMed  24 Lénárd L, Halmai V, Barthó L. Morphine contracts the guinea pig ileal circular muscle by interfering with a nitric oxide mediated tonic inhibition. Digestion  1999; 60: 562– 6. Google Scholar CrossRef Search ADS PubMed  25 Hirning L D, Porreca F, Burks T F. Mu, but not kappa, opioid agonists induce contractions of the canine small intestine ex vivo. Eur J Pharmacol  1985; 109: 49– 54. Google Scholar CrossRef Search ADS PubMed  26 Zhou P, Li T, Su R, Gong Z. Effects of thienorphine on contraction of the guinea pig sphincter of Oddi, choledochus and gall bladder. Eur J Pharmacol  2014; 737: 22– 28. Google Scholar CrossRef Search ADS PubMed  27 Rattan S, Goyal R K. Identification and localization of opioid receptors in the opossum lower esophageal sphincter. J Pharmacol Exp Ther  1983; 224: 391– 7. Google Scholar PubMed  28 Jeong I D, Camilleri M, Shin A et al.   A randomised, placebo-controlled trial comparing the effects of tapentadol and oxycodone on gastrointestinal and colonic transit in healthy humans. Aliment Pharmacol Ther  2012; 35: 1088– 96. Google Scholar PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Diseases of the Esophagus Oxford University Press

Lower prevalence of gastroesophageal reflux disease in patients with noncardiac chest pain on opiates: a cross-sectional study

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The International Society for Diseases of the Esophagus
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© The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus.
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1120-8694
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1442-2050
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10.1093/dote/doy053
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Abstract

SUMMARY Opiates can cause heartburn and spastic esophageal dysmotility but their role in noncardiac chest pain (NCCP) is not known. Our aim was to characterize opiate effects on esophageal function using esophageal pH monitoring and high-resolution manometry (HREM) in these patients. We performed a cross sectional study of opiate users with NCCP who underwent HREM and esophageal pH study from 2010 to 2017 using opiate nonusers as a comparison group. Demographic data, symptoms, opiate use, endoscopic findings, esophageal pH study parameters, and HREM data were abstracted. Thirty three patients with NCCP on opiates were compared to 144 opiate non-users. Compared to opiate nonusers, opiate users had lower total acid exposure (2.3% vs. 3%, P = 0.012), lower upright acid exposure (1.2% vs. 3.1%, P = 0.032) and lower DeMeester score (6.5 vs. 12.7, P = 0.016). Opiate users also had higher lower esophageal sphincter integrated relaxation pressure (LES-IRP) (7.0 mm Hg [2.2, 11.7] vs. 3.7 mm Hg [1.1, 6.2] P = 0.011) and greater mean distal contractile integral (DCI) (2575 mm.Hg.s.cm [1134, 4466] vs. 1409 mm.Hg.s.cm [796, 3003] P = 0.03) than opiate non-users. The prevalence of hypertensive motility disorders (15.2% vs. 11.1%) and achalasia (12.1% vs. 2.1%) was higher in opiate users (P = 0.039) but did not reach significance on multivariate analysis. In patients presenting with NCCP, opiate users had lower esophageal acid exposure compared to opiate nonusers. This might be due to higher LES pressures preventing reflux and higher DCI leading to more rapid acid esophageal clearance. STUDY HIGHLIGHTS WHAT IS CURRENT KNOWLEDGE: Opiates are associated with spastic esophageal disorders on HREM. Opiates are known to cause gastroesophageal reflux symptoms. The role of opiates in noncardiac chest pain has not been defined. WHAT IS NEW HERE: There was lower prevalence of pathologic esophageal acid exposure in patients with noncardiac chest pain using opiates. INTRODUCTION Opiate use and misuse has increased dramatically in United States over the last two decades and has reached epidemic proportions. In 2016, a total of 61,862,364 patients had at least one prescription for opioids filled at a rate of 19.1 patients per 100 persons.1 Although they are highly effective agents for pain relief, they can lead to a variety of gastrointestinal side effects such as nausea, vomiting, abdominal pain, bloating, heartburn, acid reflux, anorexia, delayed digestion, and constipation, which are grouped under the term ‘opioid-induced bowel dysfunction.’2 These effects are mediated by binding to μ-, δ-, and κ-opioid receptors, which are distributed in the stomach, small intestine, and colon.3 The side effects of opiates on stomach and colon have been extensively studied but their effects on esophagus are not well described and coming to attention only recently due to increasing use of opiates.4–11 Opiates appear to increase basal lower esophageal sphincter (LES) pressure and cause incomplete relaxation of LES and spastic esophageal peristalsis.10 Most of these studies were done in normal volunteers or patients presenting with dysphagia. However, none of the studies have reported on effect of opiates on esophageal function in patients presenting with noncardiac chest pain (NCCP). NCCP is defined as the presence of pain resembling angina in the absence of evidence of any coronary artery disease.12 It is a common presenting symptom with up to 25% mean annual prevalence.13 The most common cause of NCCP is gastroesophageal reflux disease (GERD) followed by esophageal motility disorders.12 Therefore, these patients are referred for evaluation of esophageal function with esophageal manometry and ambulatory esophageal pH monitoring. Since a proportion of these patients are on opiates, we hypothesized that patients with NCCP on opiates have a higher prevalence of spastic motility disorders as well as GERD. Therefore, our aim was to characterize the effect of opiates on esophageal function using high-resolution esophageal manometry (HREM) and esophageal pH monitoring in these patients with NCCP. METHODS Subjects This is a retrospective cross-sectional study of patients referred to our gastrointestinal physiology laboratory for evaluation of NCCP between January 1st 2010 and January 31st 2017. Inclusion criteria were all patients who had a HREM, esophageal pH monitoring, and upper endoscopy. Prior to the referral, these patients had a cardiac etiology was ruled out after evaluation by a cardiologist or by noninvasive cardiac stress testing or coronary angiogram. Data regarding demographics including age, gender, and race, additional esophageal symptoms such as regurgitation, heartburn and dysphagia and relevant medication use (acid suppressants, antidepressants, opiates, calcium channel blockers, and nitrates) were obtained. The study subjects were on opiates at the time of esophageal function tests and opiate non-users served as the comparison group. Specific type of opiate and indication for its use were also abstracted. HREM HREM was completed using a HREM solid-state catheter with 36 circumferential sensors spaced at 1 cm intervals (Medtronics, 710 Medtronic Parkway, Minneapolis, MN 55,432-5604 USA). The patients were typically advised to hold calcium channel blockers and nitrates for 24 hours prior to the procedure but not opiates or anticholinergic medications. All HREM studies were performed using a standard technique in a supine position after at least 4 hours of fasting. The catheter was placed transnasally, positioned to record from hypopharynx to the stomach with at least three intragastric sensors and maintained in this position throughout the study. The study protocol consisted of a period of catheter acclimation, baseline sphincter pressure assessment over a 30 second period; followed by ten water swallows given in 30 second intervals. HREM tracings were assessed using the Manoview analysis software (Medtronics, 710 Medtronic Parkway, Minneapolis, MN 55,432-5604 USA). Chicago classification version 3.0 was used to classify peristaltic patterns and diagnose motility disorders.14 All HREM tracings were reviewed for the study purposes. Ambulatory esophageal pH monitoring Esophageal pH monitoring was performed using either 24-hour catheter-based system (Versaflex catheter, Medtronics) or 48-hour wireless bravo probe (Medtronic, Minneapolis, MN, USA). The patients were instructed to hold proton pump inhibitors (PPI) 5 days before and H2 receptor antagonists 48 hours before pH testing. The following pH parameters were analyzed using AccuView reflux software: total acid exposure, supine and upright acid exposure, symptom index (SI), symptom sensitivity index (SSI), and symptom association probability (SAP). The cutoff for abnormal parameters was total acid exposure of more than 5.5%, upright acid exposure of more than 8.2% and supine acid exposure of more than 3%.15 In the case of 48-hour testing, parameters from the worst day were used for analysis. A total pH time less than 4 ≥ 5.5% of the time was considered diagnostic for pathologic esophageal acid exposure. Statistical analysis Data are presented as mean ± standard deviation, median [25th, 75th percentiles] or frequency (percent). Univariable analysis was performed to assess differences between subjects using opiates and those not using opiates. Analysis of variance (ANOVA) or the nonparametric Kruskal–Wallis tests were used to compare continuous variables and Pearson's chi-square tests were used for categorical factors. Based on esophageal motility patterns, patients were divided in four groups for statistical analysis: first group with achalasia (all types) and esophagogastric junction (EGJ) outflow obstruction, second group with the hypertensive disorders: distal esophageal spasm (DES) and jackhammer esophagus; third group with the hypotensive disorders: absent contractility, ineffective esophageal motility (IEM) and fragmented peristalsis. Finally, the fourth group included normal HREM. Multivariable logistic regression analysis was performed to assess association between opiate use and abnormal HREM and esophageal pH monitoring while adjusting for potential confounders. Opiate use was included in all models and other factors considered for inclusion were demographics, social factors, symptoms, and medications. Final multivariable models were chosen using an automated stepwise variable selection method performed on 1000 bootstrap samples; factors with inclusion rates of at least 50% were included in the models. All analyses were performed using SAS (version 9.4, The SAS Institute, Cary, NC) and a P < 0.05 was considered statistically significant. RESULTS There were 33 patients who were on opiates at the time of study and 144 patients in the control group. Average age was 54.2 ± 12.9 years, 67% of patients were female, and 89.6% were white. The opiates prescribed were as follows: oxycodone in 13 patients, tramadol in 8, hydrocodone in 7, codeine in 2, hydromorphone in 1, tapendadol in 1, and fentanyl in one patient. The indications for opioid prescription were chronic low back pain in 8 patients, degenerative joint disease in 8, chronic abdominal pain in 4, chronic pelvic pain in1, NCCP in 3, postoperative pain in 2, rheumatoid arthritis related joint pain in 2, headaches in 1, chronic cough in 1, and chronic pain syndrome in 3 patients. The median morphine equivalent daily dose (MEDD) was 30 mg/day, with a range of 7.5–150 mg/day. The baseline characteristics of both groups were comparable; no statistically significant differences were found regarding age, gender, race, smoking status, and alcohol use (Table 1). Opiate users were more likely to have dysphagia in addition to NCCP (48.5% vs. 29.2%, P = 0.033) and to be on antidepressants, calcium channel blockers, gabapentin, and/or pregabalin. The frequency of other concomitant esophageal symptoms (regurgitation and heartburn) and use of acid suppressant medications did not differ (Table 1). Table 1 Patient general characteristics. Factor  Opiate nonusers (N = 144)  Opiate users (N = 33)  P-value  Age at HREM (years)  54.0 ± 13.3  55.2 ± 10.9  0.62†  Female gender  95 (66.0)  24 (72.7)  0.46‡  White race  128 (91.4)  27 (81.8)  0.10‡  Never smoker  85 (59.0)  17 (51.5)  0.18‡  Never alcohol use  60 (41.7)  17(51.5)  0.071‡  Heartburn  71 (49.3)  15 (45.5)  0.69‡  Regurgitation  54 (37.5)  11 (33.3)  0.65‡  Dysphagia  42 (29.2)  16 (48.5)  0.033‡  Abnormal upper endoscopic findings  46 (31.9)  11 (33.3)  0.87‡  Medications  Gabapentin and/or pregabalin  5(3.5)  5(15.2)  0.009‡  Calcium channel blockers  24(16.7)  13(39.4)  0.004‡  Nitrates  8(5.6)  4(12.1)  0.18‡  Proton Pump Inhibitor use  99(68.8)  27(81.8)  0.13‡  Histamine receptor antagonist use  12(8.3)  6(18.2)  0.091‡  Antidepressants  39(27.1)  16(48.5)  0.017‡  Factor  Opiate nonusers (N = 144)  Opiate users (N = 33)  P-value  Age at HREM (years)  54.0 ± 13.3  55.2 ± 10.9  0.62†  Female gender  95 (66.0)  24 (72.7)  0.46‡  White race  128 (91.4)  27 (81.8)  0.10‡  Never smoker  85 (59.0)  17 (51.5)  0.18‡  Never alcohol use  60 (41.7)  17(51.5)  0.071‡  Heartburn  71 (49.3)  15 (45.5)  0.69‡  Regurgitation  54 (37.5)  11 (33.3)  0.65‡  Dysphagia  42 (29.2)  16 (48.5)  0.033‡  Abnormal upper endoscopic findings  46 (31.9)  11 (33.3)  0.87‡  Medications  Gabapentin and/or pregabalin  5(3.5)  5(15.2)  0.009‡  Calcium channel blockers  24(16.7)  13(39.4)  0.004‡  Nitrates  8(5.6)  4(12.1)  0.18‡  Proton Pump Inhibitor use  99(68.8)  27(81.8)  0.13‡  Histamine receptor antagonist use  12(8.3)  6(18.2)  0.091‡  Antidepressants  39(27.1)  16(48.5)  0.017‡  Statistics presented as mean ± standard deviation, Median [P25, P75] or N (column %). P-values: †ANOVA, ‡Pearson's chi-square test. HREM, high-resolution esophageal manometry. View Large Table 1 Patient general characteristics. Factor  Opiate nonusers (N = 144)  Opiate users (N = 33)  P-value  Age at HREM (years)  54.0 ± 13.3  55.2 ± 10.9  0.62†  Female gender  95 (66.0)  24 (72.7)  0.46‡  White race  128 (91.4)  27 (81.8)  0.10‡  Never smoker  85 (59.0)  17 (51.5)  0.18‡  Never alcohol use  60 (41.7)  17(51.5)  0.071‡  Heartburn  71 (49.3)  15 (45.5)  0.69‡  Regurgitation  54 (37.5)  11 (33.3)  0.65‡  Dysphagia  42 (29.2)  16 (48.5)  0.033‡  Abnormal upper endoscopic findings  46 (31.9)  11 (33.3)  0.87‡  Medications  Gabapentin and/or pregabalin  5(3.5)  5(15.2)  0.009‡  Calcium channel blockers  24(16.7)  13(39.4)  0.004‡  Nitrates  8(5.6)  4(12.1)  0.18‡  Proton Pump Inhibitor use  99(68.8)  27(81.8)  0.13‡  Histamine receptor antagonist use  12(8.3)  6(18.2)  0.091‡  Antidepressants  39(27.1)  16(48.5)  0.017‡  Factor  Opiate nonusers (N = 144)  Opiate users (N = 33)  P-value  Age at HREM (years)  54.0 ± 13.3  55.2 ± 10.9  0.62†  Female gender  95 (66.0)  24 (72.7)  0.46‡  White race  128 (91.4)  27 (81.8)  0.10‡  Never smoker  85 (59.0)  17 (51.5)  0.18‡  Never alcohol use  60 (41.7)  17(51.5)  0.071‡  Heartburn  71 (49.3)  15 (45.5)  0.69‡  Regurgitation  54 (37.5)  11 (33.3)  0.65‡  Dysphagia  42 (29.2)  16 (48.5)  0.033‡  Abnormal upper endoscopic findings  46 (31.9)  11 (33.3)  0.87‡  Medications  Gabapentin and/or pregabalin  5(3.5)  5(15.2)  0.009‡  Calcium channel blockers  24(16.7)  13(39.4)  0.004‡  Nitrates  8(5.6)  4(12.1)  0.18‡  Proton Pump Inhibitor use  99(68.8)  27(81.8)  0.13‡  Histamine receptor antagonist use  12(8.3)  6(18.2)  0.091‡  Antidepressants  39(27.1)  16(48.5)  0.017‡  Statistics presented as mean ± standard deviation, Median [P25, P75] or N (column %). P-values: †ANOVA, ‡Pearson's chi-square test. HREM, high-resolution esophageal manometry. View Large On HREM, these patients had significantly higher LES integrated relaxation pressure (IRP) and were more likely to have an IRP greater than 15. The basal LES pressure was also higher in the opiate group, but did not reach statistical significance. Even after excluding patients with achalasia, mean LES IRP remained higher in opiate group (6.1 mm Hg [1.9, 10.8] versus 3.7 mm Hg [1.1, 6], P = 0.027). There was a moderately weak correlation between MEDD and IRP in opiate users (rho = 0.36, 95 CI [0.02, 0.63]; P = 0.038). In addition, opiate users had greater average distal contractile integral (DCI) and shorter distal latency (Table 2). The prevalence of hypertensive peristalsis (15.2% vs. 11.1%) and achalasia or EGJ outflow obstruction (12.1% vs. 2.1%) was higher among opiate users (P = 0.039) (Table 2). The prevalence of various esophageal motility disorders in both groups is presented in Table 3. Table 2 Esophageal function testing. Factor  No opiates (N = 144)  Opiates (N = 33)  P-value  HREM findings  Basal LES pressure (mmHg)  23.0 [12.9,33.5]  24.8 [15.4,36.4]  0.54†  Mean LES-IRP (mmHg)  3.7 [1.1,6.2]  7.0 [2.2,11.7]  0.011†  LES-IRP > 15 (mmHg)  5(3.5)  6(18.2)  0.002‡  Contractile front Velocity (cm/s)  3.4 [2.7,4.3]  3.5 [3.1,4.9]  0.20†  Mean DCI (mm.Hg.s.cm)  1409 [796,3003]  2575 [1134,4466]  0.030†  Distal Latency (sec)  6.7 [6.0,7.7]  6.0 [5.2,6.8]  0.018†  Normal per Chicago classification  101 (70.1)  21 (63.6)    Hypotensive disorders¶  24 (16.7)  3 (9.1)  0.039§  Hypertensive disorders¶  16 (11.1)  5 (15.2)    Achalasia or EGJ outflow obstruction¶  3 (2.1)  4 (12.1)    Esophageal pH monitoring  Total acid exposure ≥5.5% time  56 (38.9)  6 (18.2)  0.025§  Total acid exposure time (%)  3.0 [0.65,9.1]  2.3 [0.20,5.1]  0.012†  Upright acid exposure time (%)  3.1 [0.90,8.1]  1.2 [0.20,5.4]  0.032†  Supine acid exposure time (%)  0.60 [0.00,5.8]  0.60 [0.00,3.1]  0.35†  DeMeester Score  12.7 [3.4,28.8]  6.5 [0.30,18.0]  0.016†  SI for chest pain > 50%  12 (8.3)  2 (6.1)  0.66§  SSI for chest pain > 10%  3 (2.6)  3 (10.0)  0.068§  SAP for chest pain > 95%  6 (5.2)  3 (10.0)  0.33§  Factor  No opiates (N = 144)  Opiates (N = 33)  P-value  HREM findings  Basal LES pressure (mmHg)  23.0 [12.9,33.5]  24.8 [15.4,36.4]  0.54†  Mean LES-IRP (mmHg)  3.7 [1.1,6.2]  7.0 [2.2,11.7]  0.011†  LES-IRP > 15 (mmHg)  5(3.5)  6(18.2)  0.002‡  Contractile front Velocity (cm/s)  3.4 [2.7,4.3]  3.5 [3.1,4.9]  0.20†  Mean DCI (mm.Hg.s.cm)  1409 [796,3003]  2575 [1134,4466]  0.030†  Distal Latency (sec)  6.7 [6.0,7.7]  6.0 [5.2,6.8]  0.018†  Normal per Chicago classification  101 (70.1)  21 (63.6)    Hypotensive disorders¶  24 (16.7)  3 (9.1)  0.039§  Hypertensive disorders¶  16 (11.1)  5 (15.2)    Achalasia or EGJ outflow obstruction¶  3 (2.1)  4 (12.1)    Esophageal pH monitoring  Total acid exposure ≥5.5% time  56 (38.9)  6 (18.2)  0.025§  Total acid exposure time (%)  3.0 [0.65,9.1]  2.3 [0.20,5.1]  0.012†  Upright acid exposure time (%)  3.1 [0.90,8.1]  1.2 [0.20,5.4]  0.032†  Supine acid exposure time (%)  0.60 [0.00,5.8]  0.60 [0.00,3.1]  0.35†  DeMeester Score  12.7 [3.4,28.8]  6.5 [0.30,18.0]  0.016†  SI for chest pain > 50%  12 (8.3)  2 (6.1)  0.66§  SSI for chest pain > 10%  3 (2.6)  3 (10.0)  0.068§  SAP for chest pain > 95%  6 (5.2)  3 (10.0)  0.33§  Statistics presented as mean ± standard deviation, Median [P25, P75] or N (column %). P-values: §ANOVA, †Kruskal-Wallis test, ‡Pearson's chi-square test. DCI, distal contractile integral; EGJ, esophagogastric Junction; LES, lower esophageal sphincter; IRP, integrated relaxation pressure; HREM, high-resolution esophageal manometry; SI, symptom index; SSI = symptom sensitivity index; SAP, symptom association probability. ¶Hypotensive disorders: absent contractility, ineffective esophageal motility, fragmented peristalsis. ¶Hypertensive disorders: distal esophageal spasm, Jackhammer esophagus. ¶Achalasia includes type I, II, and III. View Large Table 2 Esophageal function testing. Factor  No opiates (N = 144)  Opiates (N = 33)  P-value  HREM findings  Basal LES pressure (mmHg)  23.0 [12.9,33.5]  24.8 [15.4,36.4]  0.54†  Mean LES-IRP (mmHg)  3.7 [1.1,6.2]  7.0 [2.2,11.7]  0.011†  LES-IRP > 15 (mmHg)  5(3.5)  6(18.2)  0.002‡  Contractile front Velocity (cm/s)  3.4 [2.7,4.3]  3.5 [3.1,4.9]  0.20†  Mean DCI (mm.Hg.s.cm)  1409 [796,3003]  2575 [1134,4466]  0.030†  Distal Latency (sec)  6.7 [6.0,7.7]  6.0 [5.2,6.8]  0.018†  Normal per Chicago classification  101 (70.1)  21 (63.6)    Hypotensive disorders¶  24 (16.7)  3 (9.1)  0.039§  Hypertensive disorders¶  16 (11.1)  5 (15.2)    Achalasia or EGJ outflow obstruction¶  3 (2.1)  4 (12.1)    Esophageal pH monitoring  Total acid exposure ≥5.5% time  56 (38.9)  6 (18.2)  0.025§  Total acid exposure time (%)  3.0 [0.65,9.1]  2.3 [0.20,5.1]  0.012†  Upright acid exposure time (%)  3.1 [0.90,8.1]  1.2 [0.20,5.4]  0.032†  Supine acid exposure time (%)  0.60 [0.00,5.8]  0.60 [0.00,3.1]  0.35†  DeMeester Score  12.7 [3.4,28.8]  6.5 [0.30,18.0]  0.016†  SI for chest pain > 50%  12 (8.3)  2 (6.1)  0.66§  SSI for chest pain > 10%  3 (2.6)  3 (10.0)  0.068§  SAP for chest pain > 95%  6 (5.2)  3 (10.0)  0.33§  Factor  No opiates (N = 144)  Opiates (N = 33)  P-value  HREM findings  Basal LES pressure (mmHg)  23.0 [12.9,33.5]  24.8 [15.4,36.4]  0.54†  Mean LES-IRP (mmHg)  3.7 [1.1,6.2]  7.0 [2.2,11.7]  0.011†  LES-IRP > 15 (mmHg)  5(3.5)  6(18.2)  0.002‡  Contractile front Velocity (cm/s)  3.4 [2.7,4.3]  3.5 [3.1,4.9]  0.20†  Mean DCI (mm.Hg.s.cm)  1409 [796,3003]  2575 [1134,4466]  0.030†  Distal Latency (sec)  6.7 [6.0,7.7]  6.0 [5.2,6.8]  0.018†  Normal per Chicago classification  101 (70.1)  21 (63.6)    Hypotensive disorders¶  24 (16.7)  3 (9.1)  0.039§  Hypertensive disorders¶  16 (11.1)  5 (15.2)    Achalasia or EGJ outflow obstruction¶  3 (2.1)  4 (12.1)    Esophageal pH monitoring  Total acid exposure ≥5.5% time  56 (38.9)  6 (18.2)  0.025§  Total acid exposure time (%)  3.0 [0.65,9.1]  2.3 [0.20,5.1]  0.012†  Upright acid exposure time (%)  3.1 [0.90,8.1]  1.2 [0.20,5.4]  0.032†  Supine acid exposure time (%)  0.60 [0.00,5.8]  0.60 [0.00,3.1]  0.35†  DeMeester Score  12.7 [3.4,28.8]  6.5 [0.30,18.0]  0.016†  SI for chest pain > 50%  12 (8.3)  2 (6.1)  0.66§  SSI for chest pain > 10%  3 (2.6)  3 (10.0)  0.068§  SAP for chest pain > 95%  6 (5.2)  3 (10.0)  0.33§  Statistics presented as mean ± standard deviation, Median [P25, P75] or N (column %). P-values: §ANOVA, †Kruskal-Wallis test, ‡Pearson's chi-square test. DCI, distal contractile integral; EGJ, esophagogastric Junction; LES, lower esophageal sphincter; IRP, integrated relaxation pressure; HREM, high-resolution esophageal manometry; SI, symptom index; SSI = symptom sensitivity index; SAP, symptom association probability. ¶Hypotensive disorders: absent contractility, ineffective esophageal motility, fragmented peristalsis. ¶Hypertensive disorders: distal esophageal spasm, Jackhammer esophagus. ¶Achalasia includes type I, II, and III. View Large Table 3 Distribution of esophageal motility disorders by opiate use. HREM diagnosis  Opiate nonusers (N = 144)  Opiate users (N = 33)  Achalasia type I  0 (0.0%)  0 (0%)  Achalasia type II  2 (1.3%)  1 (3.0%)  Achalasia type III  0 (0.0%)  1 (3.0%)  EGJ outflow obstruction  1 (0.6%)  2 (6.0%)  Distal esophageal spasm  6 (4.1%)  3 (9.0%)  Jackhammer esophagus  10 (6.9%)  2 (6.0%)  Absent contractility  1 (0.6%)  0 (0.0%)  Ineffective esophageal motility  22 (15.2%)  3 (9.0%)  Fragmented peristalsis  1 (0.6%)  0 (0.0%)  Normal  101 (70.1%)  21 (63.6%)  HREM diagnosis  Opiate nonusers (N = 144)  Opiate users (N = 33)  Achalasia type I  0 (0.0%)  0 (0%)  Achalasia type II  2 (1.3%)  1 (3.0%)  Achalasia type III  0 (0.0%)  1 (3.0%)  EGJ outflow obstruction  1 (0.6%)  2 (6.0%)  Distal esophageal spasm  6 (4.1%)  3 (9.0%)  Jackhammer esophagus  10 (6.9%)  2 (6.0%)  Absent contractility  1 (0.6%)  0 (0.0%)  Ineffective esophageal motility  22 (15.2%)  3 (9.0%)  Fragmented peristalsis  1 (0.6%)  0 (0.0%)  Normal  101 (70.1%)  21 (63.6%)  Statistics presented as N (column %). EGJ, esophagogastric junction; HREM, high resolution esophageal manometry. View Large Table 3 Distribution of esophageal motility disorders by opiate use. HREM diagnosis  Opiate nonusers (N = 144)  Opiate users (N = 33)  Achalasia type I  0 (0.0%)  0 (0%)  Achalasia type II  2 (1.3%)  1 (3.0%)  Achalasia type III  0 (0.0%)  1 (3.0%)  EGJ outflow obstruction  1 (0.6%)  2 (6.0%)  Distal esophageal spasm  6 (4.1%)  3 (9.0%)  Jackhammer esophagus  10 (6.9%)  2 (6.0%)  Absent contractility  1 (0.6%)  0 (0.0%)  Ineffective esophageal motility  22 (15.2%)  3 (9.0%)  Fragmented peristalsis  1 (0.6%)  0 (0.0%)  Normal  101 (70.1%)  21 (63.6%)  HREM diagnosis  Opiate nonusers (N = 144)  Opiate users (N = 33)  Achalasia type I  0 (0.0%)  0 (0%)  Achalasia type II  2 (1.3%)  1 (3.0%)  Achalasia type III  0 (0.0%)  1 (3.0%)  EGJ outflow obstruction  1 (0.6%)  2 (6.0%)  Distal esophageal spasm  6 (4.1%)  3 (9.0%)  Jackhammer esophagus  10 (6.9%)  2 (6.0%)  Absent contractility  1 (0.6%)  0 (0.0%)  Ineffective esophageal motility  22 (15.2%)  3 (9.0%)  Fragmented peristalsis  1 (0.6%)  0 (0.0%)  Normal  101 (70.1%)  21 (63.6%)  Statistics presented as N (column %). EGJ, esophagogastric junction; HREM, high resolution esophageal manometry. View Large On esophageal pH monitoring, patients on opiates were less likely to have abnormal esophageal acid exposure compared to non-users (18.2% vs. 38.9% P = 0.025) (Table 2). Consequently, DeMeester score, total acid exposure time (2.3% vs. 3.0%) and upright acid reflux time (1.2% vs. 3.1%) were significantly lower in the opiate group. The symptom association indices did not differ significantly in the two groups. Among opiate users, 22 of 33 patients had normal endoscopic appearance of the esophagus. The abnormal esophageal findings in the remaining 11 patients were: grade A esophagitis in 3, grade B esophagitis in 2, Barrett's esophagus in 2, resistance at EGJ in 2, dilated esophageal lumen in 1 and ringed esophagus in one. Among opiate nonusers, reflux esophagitis was seen in 25 patients, Barrett's esophagus in 9, strictures in 4, dilated esophageal lumen in 2, ringed appearance in 3, ulcers in 3 and normal upper endoscopy in 98 patients. The prevalence of abnormal esophageal findings was similar between groups (Table 1). Among opiate nonusers, 43 of 144 (29.8%) patients underwent gastric emptying testing while in the opiate group, 11 of 33 (33.3%) patients underwent testing. The prevalence of delayed gastric emptying was 2.7% and 3.0% of those tested respectively (P = 0.73). On multivariable analysis, opiate users were three times less likely to have abnormal esophageal acid exposure compared to opiate nonusers (Table 4). Opiate use was not associated with abnormal HREM findings in general (P = 0.99). Similarly, on subgroup analysis, opiate use did not reach statistical significance for hypertensive disorders, achalasia, and EGJ outflow obstruction (P = 0.15). Table 4 Multivariable logistic regression of the effect of opiates on esophageal function tests. Use of opiates  OR (95% CI)  P-value  Abnormal pH monitoring  0.33 (0.12, 0.91)  0.032  Abnormal HREM  0.99 (0.42, 2.4)  0.99  Hypotensive peristaltic disorders  0.47(0.13, 1.7)  0.26  Hypertensive peristaltic disorders  0.81(0.25, 2.7)  0.73  Hypertensive peristalsis, achalasia and EGJ outflow obstruction in HREM  2.1 (0.77, 5.6)  0.15  Use of opiates  OR (95% CI)  P-value  Abnormal pH monitoring  0.33 (0.12, 0.91)  0.032  Abnormal HREM  0.99 (0.42, 2.4)  0.99  Hypotensive peristaltic disorders  0.47(0.13, 1.7)  0.26  Hypertensive peristaltic disorders  0.81(0.25, 2.7)  0.73  Hypertensive peristalsis, achalasia and EGJ outflow obstruction in HREM  2.1 (0.77, 5.6)  0.15  CI, confidence interval; EGJ, esophagogastric junction; HREM, high-resolution esophageal manometry; OR, odds ratio. View Large Table 4 Multivariable logistic regression of the effect of opiates on esophageal function tests. Use of opiates  OR (95% CI)  P-value  Abnormal pH monitoring  0.33 (0.12, 0.91)  0.032  Abnormal HREM  0.99 (0.42, 2.4)  0.99  Hypotensive peristaltic disorders  0.47(0.13, 1.7)  0.26  Hypertensive peristaltic disorders  0.81(0.25, 2.7)  0.73  Hypertensive peristalsis, achalasia and EGJ outflow obstruction in HREM  2.1 (0.77, 5.6)  0.15  Use of opiates  OR (95% CI)  P-value  Abnormal pH monitoring  0.33 (0.12, 0.91)  0.032  Abnormal HREM  0.99 (0.42, 2.4)  0.99  Hypotensive peristaltic disorders  0.47(0.13, 1.7)  0.26  Hypertensive peristaltic disorders  0.81(0.25, 2.7)  0.73  Hypertensive peristalsis, achalasia and EGJ outflow obstruction in HREM  2.1 (0.77, 5.6)  0.15  CI, confidence interval; EGJ, esophagogastric junction; HREM, high-resolution esophageal manometry; OR, odds ratio. View Large DISCUSSION Due to the widespread use of opiates, there is greater attention on the effects of opiates on gastrointestinal motility. Opiates have been linked to nausea, vomiting, abdominal pain, bloating, heartburn, acid reflux, anorexia, delayed gastric emptying, and constipation.2 Nonetheless, there are limited data on their effect on NCCP and esophageal function. In this study, opiate users had lower total and upright esophageal acid exposure and lower DeMeester score on esophageal pH monitoring. Opiate users were also three times less likely to have pathologic acid exposure compared to opiate nonusers. Opiates were also associated with higher prevalence of spastic features on HREM such as higher LES-IRP, greater mean DCI, and shorter distal latency. Opiates have contradictory physiological effects on GERD. On one hand, opiates cause increased LES tone,10 reduction in transient LES relaxation,9 and decreased gastric secretions which offer protection against GERD,16 and on the other hand, they impair effective esophageal peristalsis and delay gastric emptying,17 which worsens GERD. Traditional thinking is that opiates cause regurgitation and heartburn. In a study on patients with noncancer pain on chronic opiates, GERD symptoms were reported in up to 33% of the patients.18 This was independent of the dose or duration of use of opiates. In another study of over 50,000 individuals, opium users were 1.7 times more likely to have GERD symptoms than opium non-users.19 In gastroparetic patients, chronic opiate use was associated with greater severity of heartburn, regurgitation, acid taste in the mouth and chest discomfort.20 However, prior studies looking at effect of opiates on objective evidence of GERD are lacking. In one study of 8 healthy subjects and 8 patients with GERD, pH recordings were obtained for 30 min after administration of intravenous morphine.9 Morphine reduced markedly the rate of transient LES relaxations, which resulted in decrease in number of reflux episodes and in esophageal acid exposure.9 This duration of pH monitoring is short to make any meaningful inference. Contrary to the popular belief, we found that opiates are associated with reduced esophageal acid exposure. Why is this so? It might be hypothesized that higher LES-IRP and higher basal LES pressure reduce reflux episodes in patients on opiates. Besides, the greater DCI may enhance the esophageal acid clearance mechanism. Another thing to ponder upon is that even though GERD is mainly a clinical diagnosis, heartburn and regurgitation are not 100% sensitive or specific for a definitive diagnosis of GERD. In one study, reflux disease questionnaire had a 62% sensitivity and 67% specificity for diagnosis of GERD.21 In another prospective study comparing GERD questionnaire to 48 hour Bravo study, sensitivity of the questionnaire was 71% (95% CI, 61–80%) and specificity was 39% (95% CI, 29–51%) for identifying acid reflux in patients off acid suppression.22 Thus, symptoms alone are not sufficient to make a diagnosis of GERD and this disconnect may explain the discrepancy between our study findings and those of the studies reporting GERD symptoms in patients on opiates. Even though there was a higher prevalence of achalasia, EGJ outflow obstruction, and hypertensive disorders in opiate users than nonusers, multivariable analysis did not reveal any association between opiate use and esophageal motility disorders, which may be due to Type II error. In a retrospective cohort of 121 chronic opiate users, patients who were on opiates at the time of the study had esophageal motility findings similar to ours: higher LES-IRP, shorter distal latency and greater prevalence of spastic motility disorders, specifically EGJ outflow obstruction and achalasia type III.10 Another study on 15 opioid users undergoing conventional manometry noted incomplete LES relaxation, simultaneous contractions and high amplitude/velocity.4 In a case series of patients on opiates who underwent HREM, all 5 patients had EGJ outflow obstruction or achalasia.11 Other studies evaluated the acute effects of intravenous opiates on esophageal motility. Two of these studies found reduction in basal LES pressure5,6 but remaining studies reported increased basal LES tone and decreased swallow induced relaxation.7–9 The exact mechanism of the effect of opiates on the esophagus is not well established. In general, opiates interfere with the releases of excitatory neurotransmitters such as acetyl choline, which leads to an overall inhibitory effect.23 However, opioids can also lead to spasm of smooth muscle. In vitro studies in guinea pig ileal muscle showed that morphine causes contraction of the circular muscle by reducing the amount of nitric oxide released.24 Morphine also appears to have a direct myogenic effect on isolated sphincter and small intestinal muscle contraction.25,26 In animals, opioid receptors have been identified in the esophageal body and LES27 and similar mechanisms may explain the opiate effects on the human esophagus. The main strength of this study is a comprehensive assessment of esophageal function with HREM, esophageal pH monitoring, upper endoscopy, and negative cardiac evaluation in all the study subjects. Baseline characteristics were comparable between the two groups and the association between opiate use and lower esophageal acid exposure remained significant after multivariable analysis. Nevertheless, this study has limitations. Since it is a small group of patients, we could not assess if there are any differences based on duration and dosage. Also different opiates have differing effects on gastrointestinal function28 and this study was not powered to assess this finding. Since this is a retrospective study, it is difficult to draw cause–effect relationships. Third, this represents a highly select group of patients seen in a tertiary referral center, which may restrict the generalizability of the findings. Despite these limitations, we consider our data on the effects of opiates on esophageal function worthwhile to share in view of the alarming opioid epidemic in United States. In conclusion, opiates are associated with reduced prevalence of pathologic acid reflux in NCCP patients. Although the clinical significance of these data is unclear, it is essential to assess for opiate use in all patients presenting with NCCP. Finally, this study opens the door for further research to study the clinical impact of opiates on esophageal function depending on the type, duration and dose used. Notes Specific author contributions: Study concept and design: Juan D. Gomez Cifuentes, Prashanthi N. Thota; Acquisition of data: Juan D. Gomez Cifuentes; Analysis and interpretation of data: Juan D. Gomez Cifuentes, Prashanthi N. Thota, Rocio Lopez; Drafting of the manuscript: Juan D. Gomez Cifuentes; Drafting and critical revision of the manuscript: Prashanthi N. Thota; Study supervision: Prashanthi N. Thota; Critical revision of the manuscript for important intellectual content: Rocio Lopez; Statistical analysis: Rocio Lopez. Guarantor of the article: Prashanthi N.Thota. Disclosures: Grant Support: None. Financial disclosures: None. Conflicts of interest: None. References 1 https://www.cdc.gov/drugoverdose/pdf/pubs/CDC_2017_Surveillance-Report_DataSummary_presentation.pdf. Surveillance Report Highlights from the Annual Surveillance Report of Drug-Related Risks and Outcomes United States, 2017. 2 Bell T J, Panchal S J, Miaskowski C et al.   The prevalence, severity, and impact of opioid-induced bowel dysfunction: results of a US and European patient survey (PROBE 1). Pain Med  2009; 10: 35– 42. Google Scholar CrossRef Search ADS PubMed  3 Sternini C, Patierno S, Selmer I S et al.   The opioid system in the gastrointestinal tract. Neurogastroenterol Motil  2004; 16: 3– 16. Google Scholar CrossRef Search ADS PubMed  4 Kraichely R E, Arora A S, Murray J A. Opiate-induced oesophageal dysmotility. Aliment Pharmacol Ther  2010; 31: 601– 6. 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Effect of morphine on gastroesophageal reflux and transient lower esophageal sphincter relaxation. Gastroenterology  1997; 113: 409– 14. Google Scholar CrossRef Search ADS PubMed  10 Ratuapli S K, Crowell M D, DiBaise J K et al.   Opioid-induced esophageal dysfunction (OIED) in patients on chronic opioids. Am J Gastroenterol  2015; 110: 979– 84. Google Scholar CrossRef Search ADS PubMed  11 González E S, Bellver V O, Jaime F C D, Cortés J A O, Gil V G. Opioid-induced lower esophageal sphincter dysfunction. J Neurogastroenterol Motil  2015; 21: 618– 20. Google Scholar CrossRef Search ADS PubMed  12 Yamasaki T, Fass R. Noncardiac chest pain: diagnosis and management. Curr Opin Gastroenterol  2017; 33: 293– 300. Google Scholar CrossRef Search ADS PubMed  13 Locke G R 3rd, Talley N J, Fett S L et al.   Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology  1997; 112: 1448– 56. Google Scholar CrossRef Search ADS PubMed  14 Kahrilas P J, Bredenoord A J, Fox M et al.   The Chicago Classification of esophageal motility disorders, v3.0. Neurogastroenterol Motil  2015; 27: 160– 74. Google Scholar CrossRef Search ADS PubMed  15 Jamieson J R, Stein H J, DeMeester T R et al.   Ambulatory 24-h esophageal pH monitoring: normal values, optimal thresholds, specificity, sensitivity, and reproducibility. Am J Gastroenterol  1992; 87: 1102– 11. Google Scholar PubMed  16 Feldman M, Walsh J H, Taylor I L. Effect of naloxone and morphine on gastric acid secretion and on serum gastrin and pancreatic polypeptide concentrations in humans. Gastroenterology  1980; 79: 294– 8. Google Scholar PubMed  17 Camilleri M, Malagelada J R, Stanghellini V et al.   Dose-related effects of synthetic human beta-endorphin and naloxone of fed gastrointestinal motility. Am J Physiol  1986; 251: G147– 54. Google Scholar PubMed  18 Tuteja A K, Biskupiak J, Stoddard G J et al.   Opioid-induced bowel disorders and narcotic bowel syndrome in patients with chronic non-cancer pain. Neurogastroenterol Motil  2010; 22: 424– e96, e96. Google Scholar CrossRef Search ADS PubMed  19 Islami F, Nasseri-Moghaddam S, Pourshams A et al.   Determinants of gastroesophageal reflux disease, including hookah smoking and opium use—a cross-sectional analysis of 50,000 individuals. PLoS One  2014; 9: e89256. Google Scholar CrossRef Search ADS PubMed  20 Jehangir A, Parkman H P. Chronic opioids in gastroparesis: relationship with gastrointestinal symptoms, healthcare utilization and employment. World J Gastroenterol  2017; 23: 7310– 20. Google Scholar CrossRef Search ADS PubMed  21 Dent J, Vakil N, Jones R et al.   Accuracy of the diagnosis of GORD by questionnaire, physicians and a trial of proton pump inhibitor treatment: the Diamond Study. Gut  2010; 59: 714– 21. Google Scholar CrossRef Search ADS PubMed  22 Lacy B E, Chehade R, Crowell M D. A prospective study to compare a symptom-based reflux disease questionnaire to 48-h wireless pH monitoring for the identification of gastroesophageal reflux (revised 2-26-11). Am J Gastroenterol  2011; 106: 1604– 11. Google Scholar CrossRef Search ADS PubMed  23 Camilleri M, Lembo A, Katzka D A. Opioids in gastroenterology: treating adverse effects and creating therapeutic benefits. Clin Gastroenterol Hepatol  2017; 15: 1338– 49. Google Scholar CrossRef Search ADS PubMed  24 Lénárd L, Halmai V, Barthó L. Morphine contracts the guinea pig ileal circular muscle by interfering with a nitric oxide mediated tonic inhibition. Digestion  1999; 60: 562– 6. Google Scholar CrossRef Search ADS PubMed  25 Hirning L D, Porreca F, Burks T F. Mu, but not kappa, opioid agonists induce contractions of the canine small intestine ex vivo. Eur J Pharmacol  1985; 109: 49– 54. Google Scholar CrossRef Search ADS PubMed  26 Zhou P, Li T, Su R, Gong Z. Effects of thienorphine on contraction of the guinea pig sphincter of Oddi, choledochus and gall bladder. Eur J Pharmacol  2014; 737: 22– 28. Google Scholar CrossRef Search ADS PubMed  27 Rattan S, Goyal R K. Identification and localization of opioid receptors in the opossum lower esophageal sphincter. J Pharmacol Exp Ther  1983; 224: 391– 7. Google Scholar PubMed  28 Jeong I D, Camilleri M, Shin A et al.   A randomised, placebo-controlled trial comparing the effects of tapentadol and oxycodone on gastrointestinal and colonic transit in healthy humans. Aliment Pharmacol Ther  2012; 35: 1088– 96. Google Scholar PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of International Society for Diseases of the Esophagus. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Diseases of the EsophagusOxford University Press

Published: May 26, 2018

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