Abstract
Methadone maintenance therapy (MMT) is commonly used in the treatment of opioid dependence. Several small-scale reports have suggested that methadone may lead to nonobstructive dilatation of the common bile duct (CBD). We present the first large study to retrospectively evaluate this hypothesis in asymptomatic patients with chronic hepatitis on long-term MMT. Methods: Charts of all adult patients with chronic hepatitis with and without MMT between 2002 and 2007 at Beth Israel Medical Center were reviewed. Data collected included age, gender, CBD size, presence of cirrhosis, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, and dose and duration of methadone use. Patients with a history of pancreatitis and cholecystectomy were excluded. Results: CBD size in the MMT group (n=215) was significantly increased compared to controls (n=108; 5.87 mm vs 3.79 mm; P<.0001). CBD dilatation (CBD ≥8 mm) was seen in 26.1% and 2.78% of MMT and control groups, respectively (P<.0001), and was significantly associated with duration of methadone use (P=.01), but not with methadone dose (P=.83). Multivariate logistic regression showed that patients on MMT are 17.5 times more likely to develop CBD dilatation (odds ratio, 17.5). Conclusion: Chronic MMT is associated with CBD dilatation and should be considered in the differential diagnosis of asymptomatic CBD dilatation. Less invasive studies such as magnetic resonance cholangiopancreatography or endoscopic ultrasound should be considered over endoscopic retrograde cholangiopancreatography in patients without clinical or laboratory evidence suggesting biliary obstruction.
Keywords: Dilatation, bile ducts, methadone, endoscopic retrograde cholangiopancreatography
Methadone is a synthetic opioid commonly used in the treatment of opioid dependence and chronic pain. Opiate agonists have long been applied as adjuncts during hepatobiliary iminodiacetic acid cholescintigraphy, presumably to increase sphincter of Oddi tone and improve gallbladder visualization.1,2 A small prospective trial of 36 methadone maintenance therapy (MMT) patients found 3 patients with asymptomatic common bile duct (CBD) dilatation (CBD ≥8 mm), which was attributed to the chronic use of opiate drugs.3 Although opiate analgesics have been thought to increase intrabiliary pressure through spasms of the sphincter of Oddi,4,5 a small endoscopic retrograde cholangiopancreatography study of 6 MMT patients demonstrated no evidence of biliary obstruction with sustained CBD dilatation.6 These patients had asymptomatic CBD dilatation that was thought unlikely to be related to sphincter of Oddi dysfunction.6 Previous data regarding CBD dilatation in MMT patients are based upon several small studies and anecdotal reports.3,6,7 We conducted a retrospective study of 215 asymptomatic MMT patients with chronic hepatitis B virus (HBV) and/or chronic hepatitis C virus (HCV) without radiologic evidence of CBD obstruction, compared to age- and gender-matched controls.
Methods
Charts of all adult patients with chronic HBV and/or HCV infection seen at gastroenterology and infectious disease clinics at Beth Israel Medical Center in New York from 2002 to 2007 were retrospectively reviewed. Patients with a history of pancreatitis, cholecystectomy, gallstones, or CBD obstruction were excluded from the study. Data collected included age, gender, CBD size (via ultrasound, computerized tomography, or magnetic resonance imaging), and presence of liver cirrhosis (via biopsy and/or imaging studies), as well as methadone dose and duration. Laboratory values collected included the levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total bilirubin (TBi). A study group of 215 MMT patients was compared to a control group of 108 patients without MMT, matched by age and gender.
Statistical analysis of the data included t-test analysis and nonparametric analysis for continuous variables, chi-square test and Fisher exact test for categorical variables, and multivariate logistic regression analysis for the predicted values. This study was approved by the Institutional Review Board at our medical center.
Results
The patient population consisted of a total of 215 HCV and/or HBV patients (70% males; mean age, 47.3±7.3 years) from the study group and 108 HCV and/or HBV patients (71.3% males; mean age, 49.6±8.7 years) from the control group (Table 1). The mean CBD size in the study group was significantly larger than that of the control group (5.87 mm vs 3.79 mm; P<.0001). CBD dilatation (CBD ≥8 mm) was seen in 26.1% of the study group and 2.78% of the control group, respectively (P<.0001). A normal CBD (CBD ≤4 mm) was seen in 55.3% and 89.8% of the study and control groups, respectively (P<.0001; Table 2). A statistically significant association was seen between the duration of methadone intake and CBD dilatation (average duration of 33 months for CBD ≥8 mm vs 23 months for CBD ≤4 mm; P=.01).
Table 1.
General Characteristics of Hepatitis Patients With and Without Methadone Maintenance Therapy (MMT)
| Variables* | Study (MMT) group | Control group | P-value |
|---|---|---|---|
| Age (years) | 47.3±7.3 | 49.6±8.7 | NS |
| Gender (male/female) | 151/64 | 77/31 | NS |
| Alkaline phosphatase (U/L) | 128±74 | 98±42 | .004 |
| Total bilirubin (mg/dL) | 1.30±0.65 | 0.68±0.69 | .001 |
| Cirrhosis (%) | 43 | 81 | <.0001 |
| Common bile duct diameter (mm) | 5.87 | 3.79 | <.0001 |
| Aspartate amino-transferase (U/L) | 68±47 | 52±40 | .004 |
| Alanine aminotransferase (U/L) | 54±41 | 55±44 | NS |
Mean±standard deviation; NS=no significance.
Table 2.
Distribution of Common Bile Duct Size Within the Study and Control Groups
| Common bile duct diameter (mm) | ≤4 (normal) | 5–7 (borderline) | ≥8 (dilatation) |
|---|---|---|---|
| Study group, N (%) | 119 (55.3%) | 40 (18.6%) | 56 (26.1%) |
| Control group, N (%) | 97 (89.8%) | 8 (7.4%) | 3 (2.8%) |
| P-value | <.0001 | <.0001 | <.0001 |
No statistically significant association was observed between methadone dose and CBD dilatation for the study group of 215 patients (P=.83; Table 3). However, in the subgroup of methadone patients with a CBD between 6 mm and 12 mm, there was a positive trend toward increased methadone dose and average CBD size. Multivariate logistic regression showed that patients on chronic methadone are 17.5 times more likely to have CBD dilatation (CBD ≥8 mm; odds ratio, 17.5). No association was seen between chronic methadone use and pancreatic duct dilatation (data not shown).
Table 3.
Correlation of Common Bile Duct Size With Methadone Dose and Duration
| Common bile duct diameter (mm) | Mean duration of methadone use (months) | Average dose of methadone use (mg/day) |
|---|---|---|
| ≤4 (normal) | 23 | 100 |
| ≥8 (dilatation) | 33 | 110 |
| P-value | .01 | .83 |
The laboratory data analysis for the study group compared to the control group demonstrated similar levels of ALT (54±41 U/L vs 55±44 U/L), but higher levels of AST (68±47 U/L vs 52±40 U/L; P=.004), ALP (128±74 U/L vs 98±42 U/L; P=.004), and TBi (1.3±0.65 mg/dL vs 0.68±0.69 mg/dL; P=.001) in the study group (Table 1). No patients in the study or control group recorded biliary symptoms, including right upper quadrant pain, fever, or jaundice. Liver cirrhosis was more common in the control group (43% for the study group vs 81% for the control group; P<.0001). Fifty-five of the 215 (25.6%) patients in the study group had AIDS with a CD4 count of less than 200. Nineteen of these 55 (35%) patients had CBD dilatation (CBD =8 mm), which was consistent with the incidence of CBD dilatation in the MMT group (34%). Patients with AIDS on MMT did not have a higher incidence of CBD dilatation than MMT patients without AIDS.
Discussion
Our study demonstrated that chronic methadone therapy is associated with CBD dilatation and is an independent risk factor for CBD dilatation (odds ratio, 17.5). Although the exact mechanism of how methadone may lead to CBD dilatation remains unknown, this study shows that 26.1% of MMT patients had a CBD of at least 8 mm in contrast to only 2.8% of controls.
One possible explanation may be related to the well-known polymorphism of mu-2 receptors, which are located within the smooth muscles of CBD tissue.8-10 The polymorphic nature of mu-2 receptors may determine the character of the interaction of methadone and/or its metabolites with the CBD surface and smooth muscles.
Another possible explanation may be related to the metabolism of methadone and the concentration of methadone metabolites. The concentration of methadone in bile may be less than 10% compared to that of the portal system, whereas the biliary concentration of methadone metabolites (such as pyrroline and pyrrolidine) varies greatly from subject to subject.9,11,12 The physiologic activity of these metabolites on the CBD may explain the variability of CBD dilatation.
Prior studies have described and studied the initial increase in CBD pressure related to CBD and sphincter of Oddi constriction after opioid use in nonintravenous drug use patients.2,4,13,14 This effect has been used to improve the visualization of the gallbladder and CBD during hepatobiliary iminodiacetic acid cholescintigraphy.1,2,15 Such an effect is presumed to act locally and does not depend upon central opioid function.4 Chronic methadone use, however, has been thought to decrease resting sympathetic nerve activity on smooth muscles, leading to the association of CBD dilatation and duration of MMT.10 Thus, chronic methadone use may lead to CBD dilatation through the combined local opioid effect and decrease of resting sympathetic nerve activity of CBD smooth muscles.
The asymptomatic increase of average AST level (68±47 U/L), TBi level (1.3±0.65 mg/dL), and ALP level (128±74 U/L) in the study group compared to the control group may indirectly point toward intermittent sphincter of Oddi hypertension. Chronic suppression of the sympathetic nervous system related to MMT may lead to unopposed action of parasympathetic signals on the sphincter of Oddi, leading to sphincter hypertension.10 Further evaluation with biliary manometry may be required to further confirm this hypothesis. The higher proportion of patients with liver cirrhosis in the control group may also contribute to the differences in laboratory values. Although there was a slight increase in the number of patients with chronic hepatitis B in the study group, no significant aminotransferase elevation was seen in the group.
The confounding effect of HIV-related cholan-giopathy was considered, given the higher percentage of patients co-infected with HIV or AIDS in the study group relative to the control group. However, the correlation between CBD size and methadone use persisted even after correcting for the presence of a CD4 count of less than 200 (AIDS).
Summary
This study demonstrates a significant association between asymptomatic CBD dilatation and chronic MMT. Our data suggest that chronic methadone use be included in the differential diagnosis of asymptomatic CBD dilatation. Less invasive studies such as magnetic resonance cholangiopancreatography or endoscopic ultrasound should be considered in this group. More invasive interventions such as endoscopic retrograde cholangiopan-creatography should be limited to patients with clinical or laboratory evidence of biliary obstruction.
Contributor Information
Henry C. Bodenheimer, Jr, Dr. Bodenheimer, Jr serves as Chairman of Medicine at Beth Israel Medical Center in New York, New York.
Jerome H. Siegel, Dr. Siegel is Director of Therapeutic Endoscopy.
Albert D. Min, Dr. Min is Director of Hepatitis Research and Program Director of GI Fellowship.
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