ORIGINAL ARTICLE
Antioxidant Therapy for Pain Reduction in Patients With Chronic Pancreatitis A Systematic Review and Meta-analysis Tarun Rustagi, MD* and Basile Njei, MD† Objectives: Oxidative stress is strongly implicated in the pathogenesis of chronic pancreatitis (CP); however, clinical studies evaluating antioxidant therapy (AOT) in the management of CP pain have yielded conflicting results. The aim of this meta-analysis was to evaluate the efficacy of AOT in pain reduction in CP patients. Methods: Two authors independently conducted a comprehensive literature search from inception to December 2013. Relative risk (RR) and 95% confidence intervals (CIs) were calculated using the Mantel-Haenszel and DerSimonian-Laird methods. Results: Eight studies involving 446 patients (234 in AOT and 212 in control group) were included. Overall, CP patients who received AOT had significant reduction in pain compared with the control group (RR, 0.73; 95% CI, 0.58-0.91; P = 0.006). In the subgroup analysis, studies with predominantly alcoholic CP patients (RR, 0.60; 95% CI, 0.47-0.77; P < 0.0001) and studies with mean age of patients 42 years or older (RR, 0.66; 95% CI, 0.49-0.89; P = 0.006) showed significant benefit of AOT over placebo. Conclusions: This is the first meta-analysis to summarize all the available evidence and show benefit of AOT in pain reduction in CP patients. There is a pressing need for well-designed larger studies with longer follow-up to better define the patient and disease factors favoring response, the optimal formulation, and duration of AOT. Key Words: chronic pancreatitis, antioxidants, pain, selenium, methionine, carotene, vitamin, tocopherol, alcoholic (Pancreas 2015;44: 812–818)
C
hronic pancreatitis (CP) is a progressive inflammatory disorder characterized by recurrent episodes of severe abdominal pain that significantly decreases the quality of life.1–6 Affected patients typically experience years of disabling pain, and conventional therapies are often unable to offer satisfactory symptomatic benefit.3–7 Oxidative stress caused by short-lived intracellular reactive oxygen and nitrogen free radicals is a common feature in all forms of CP and results in oxidization of lipids in the cell membrane and proteins, as well as mitochondrial depolarization and DNA fragmentation.8–11 Several studies have shown increased oxidant stress, dietary insufficiency of antioxidants (such as methionine, vitamin C, and selenium), along with reduced antioxidant capacity in CP patients.12–17 Based on these findings, exogenous supplementation with antioxidants or precursors for antioxidant pathways has been examined as a potential therapy for CP in the hope that it might reduce the pain or slow the disease progression. However, clinical trials evaluating the benefits of antioxidant therapy (AOT) From the *Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven; and †Department of Internal Medicine, University of Connecticut Health Center, Farmington, CT. Received for publication June 30, 2014; accepted December 1, 2014. Reprints: Tarun Rustagi, MD, Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar St, 1080 LMP, New Haven, CT 06520-8019 (e‐mail: [email protected]; [email protected]). The authors declare no conflict of interest. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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www.pancreasjournal.com
in the management of CP pain have demonstrated conflicting results, and there is lack of consensus on their efficacy.1,2,18,19 Because some of the studies were limited in patient number, we sought to analytically increase the number of patients for analysis by performing a structured meta-analysis of all eligible studies to assess the overall efficacy of AOT in pain reduction in CP patients.
MATERIALS AND METHODS Search Strategy Two authors (T.R. and B.N.) independently conducted a comprehensive search of the Cochrane library, PubMed, and Scopus from January 1980 to December 2013. Clinical trial databases (www.clinicaltrials.gov) and published proceedings from major hepatology and gastrointestinal meetings in the past 5 years (including Digestive Disease Week, Canadian Digestive Disease Week, United European Gastroenterology Week, American College of Gastroenterology and the AsiaPacific Digestive Week) were also searched. The search terms were as follows: CP, pancreatic inflammation, antioxidant, vitamin, superoxide dismutase, manganese, glutamine, butylated hydroxyanisole, taurine, glutathione, curcumin, catalase, peroxidase, lutein, xanthophylls, zeaxanthin, selenium, riboflavin, zinc, carotenoid, cobalamin, retinol, alpha-tocopherol, ascorbic acid, beta-carotene, carotene, and all medical subject headings terms for pharmacologically active antioxidants. All relevant articles irrespective of language, year of publication, type of publication, or publication status were included. The reference lists of studies of interest were then manually reviewed for additional articles. In the case of studies with incomplete information, the principal authors were contacted to obtain additional data.
Methodological Quality of Included Studies The methodological quality of the trials were assessed using the Jadad scale score, a previously validated instrument that assesses trials based on appropriate randomization, blinding, and description of study withdrawals or dropouts.20 The description of this score is as follows1: whether randomized (yes = 1 point, no = 0)2; whether randomization was described appropriately (yes = 1 point, no = 0)3; double blind (yes = 1 point, no = 0)4; was the double-blinding described appropriately (yes = 1 point, no = 0)5; and whether withdrawals and dropouts were described (yes = 1 point, no = 0). The quality score ranges from 0 to 5 points; a low-quality report score is 2 or less, and a high-quality report score is at least 3.
Outcome Measures Our primary outcome measure was overall incidence reduction of pain in patients with CP who received AOT compared with that in patients who received placebo. In addition to overall outcome measures, subgroup analysis by etiology of Pancreas • Volume 44, Number 5, July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 44, Number 5, July 2015
CP (alcoholic vs nonalcoholic) and age group (
Antioxidant Therapy for Pain Reduction in Patients With Chronic Pancreatitis A Systematic Review and Meta-analysis Tarun Rustagi, MD* and Basile Njei, MD† Objectives: Oxidative stress is strongly implicated in the pathogenesis of chronic pancreatitis (CP); however, clinical studies evaluating antioxidant therapy (AOT) in the management of CP pain have yielded conflicting results. The aim of this meta-analysis was to evaluate the efficacy of AOT in pain reduction in CP patients. Methods: Two authors independently conducted a comprehensive literature search from inception to December 2013. Relative risk (RR) and 95% confidence intervals (CIs) were calculated using the Mantel-Haenszel and DerSimonian-Laird methods. Results: Eight studies involving 446 patients (234 in AOT and 212 in control group) were included. Overall, CP patients who received AOT had significant reduction in pain compared with the control group (RR, 0.73; 95% CI, 0.58-0.91; P = 0.006). In the subgroup analysis, studies with predominantly alcoholic CP patients (RR, 0.60; 95% CI, 0.47-0.77; P < 0.0001) and studies with mean age of patients 42 years or older (RR, 0.66; 95% CI, 0.49-0.89; P = 0.006) showed significant benefit of AOT over placebo. Conclusions: This is the first meta-analysis to summarize all the available evidence and show benefit of AOT in pain reduction in CP patients. There is a pressing need for well-designed larger studies with longer follow-up to better define the patient and disease factors favoring response, the optimal formulation, and duration of AOT. Key Words: chronic pancreatitis, antioxidants, pain, selenium, methionine, carotene, vitamin, tocopherol, alcoholic (Pancreas 2015;44: 812–818)
C
hronic pancreatitis (CP) is a progressive inflammatory disorder characterized by recurrent episodes of severe abdominal pain that significantly decreases the quality of life.1–6 Affected patients typically experience years of disabling pain, and conventional therapies are often unable to offer satisfactory symptomatic benefit.3–7 Oxidative stress caused by short-lived intracellular reactive oxygen and nitrogen free radicals is a common feature in all forms of CP and results in oxidization of lipids in the cell membrane and proteins, as well as mitochondrial depolarization and DNA fragmentation.8–11 Several studies have shown increased oxidant stress, dietary insufficiency of antioxidants (such as methionine, vitamin C, and selenium), along with reduced antioxidant capacity in CP patients.12–17 Based on these findings, exogenous supplementation with antioxidants or precursors for antioxidant pathways has been examined as a potential therapy for CP in the hope that it might reduce the pain or slow the disease progression. However, clinical trials evaluating the benefits of antioxidant therapy (AOT) From the *Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, New Haven; and †Department of Internal Medicine, University of Connecticut Health Center, Farmington, CT. Received for publication June 30, 2014; accepted December 1, 2014. Reprints: Tarun Rustagi, MD, Section of Digestive Diseases, Department of Internal Medicine, Yale University School of Medicine, 333 Cedar St, 1080 LMP, New Haven, CT 06520-8019 (e‐mail: [email protected]; [email protected]). The authors declare no conflict of interest. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
812
www.pancreasjournal.com
in the management of CP pain have demonstrated conflicting results, and there is lack of consensus on their efficacy.1,2,18,19 Because some of the studies were limited in patient number, we sought to analytically increase the number of patients for analysis by performing a structured meta-analysis of all eligible studies to assess the overall efficacy of AOT in pain reduction in CP patients.
MATERIALS AND METHODS Search Strategy Two authors (T.R. and B.N.) independently conducted a comprehensive search of the Cochrane library, PubMed, and Scopus from January 1980 to December 2013. Clinical trial databases (www.clinicaltrials.gov) and published proceedings from major hepatology and gastrointestinal meetings in the past 5 years (including Digestive Disease Week, Canadian Digestive Disease Week, United European Gastroenterology Week, American College of Gastroenterology and the AsiaPacific Digestive Week) were also searched. The search terms were as follows: CP, pancreatic inflammation, antioxidant, vitamin, superoxide dismutase, manganese, glutamine, butylated hydroxyanisole, taurine, glutathione, curcumin, catalase, peroxidase, lutein, xanthophylls, zeaxanthin, selenium, riboflavin, zinc, carotenoid, cobalamin, retinol, alpha-tocopherol, ascorbic acid, beta-carotene, carotene, and all medical subject headings terms for pharmacologically active antioxidants. All relevant articles irrespective of language, year of publication, type of publication, or publication status were included. The reference lists of studies of interest were then manually reviewed for additional articles. In the case of studies with incomplete information, the principal authors were contacted to obtain additional data.
Methodological Quality of Included Studies The methodological quality of the trials were assessed using the Jadad scale score, a previously validated instrument that assesses trials based on appropriate randomization, blinding, and description of study withdrawals or dropouts.20 The description of this score is as follows1: whether randomized (yes = 1 point, no = 0)2; whether randomization was described appropriately (yes = 1 point, no = 0)3; double blind (yes = 1 point, no = 0)4; was the double-blinding described appropriately (yes = 1 point, no = 0)5; and whether withdrawals and dropouts were described (yes = 1 point, no = 0). The quality score ranges from 0 to 5 points; a low-quality report score is 2 or less, and a high-quality report score is at least 3.
Outcome Measures Our primary outcome measure was overall incidence reduction of pain in patients with CP who received AOT compared with that in patients who received placebo. In addition to overall outcome measures, subgroup analysis by etiology of Pancreas • Volume 44, Number 5, July 2015
Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Pancreas • Volume 44, Number 5, July 2015
CP (alcoholic vs nonalcoholic) and age group (
