Abstract: Twelve RCTs with a total of 585 participants were included. Six trials were double-blinded, placebo-controlled studies, and the other six trials were of less adequate methodology. Most trials were small and had high rates of dropout. Eleven of the 12 included trials described the effects of antioxidants on chronic abdominal pain in chronic pancreatitis. Pain as measured on a visual analogue scale (VAS, scale range 0 to 10) after one to six months was less in the antioxidant group than in the control group (mean difference (MD) -0.33, 95% confidence interval (CI) -0.64 to -0.02, P value 0.04, moderate-quality evidence). The number of pain-free participants was not statistically significantly different (risk ratio (RR) 1.73, 95% CI 0.95 to 3.15, P value 0.07, low-quality evidence). More adverse events were observed in the antioxidant group, both in the parallel trials (RR 4.43, 95% CI 1.60 to 12.29, P value 0.0004, moderate-quality evidence) and in the cross-over trials (RR 5.80, 95% CI 1.56 to 21.53, P value 0.0009, moderate-quality evidence). Adverse events occurred in 16% of participants and were mostly mild (e.g. headache, gastrointestinal complaints), but were sufficient to make participants stop antioxidant use. Other important outcomes such as use of analgesics, exacerbation of pancreatitis and quality of life were rarely reported. One trial from 1991 evaluated the effects of antioxidants on acute pain during exacerbation of chronic pancreatitis and found that a significantly higher proportion of participants in the antioxidant group experienced pain relief. This trial was conducted more than 25 years ago and has not been reproduced since that time. Therefore, additional trials are needed before reliable conclusions can be drawn. Current evidence shows that antioxidants can reduce pain slightly in patients with chronic pancreatitis. The clinical relevance of this small reduction is uncertain, and more evidence is needed. Adverse events in one of six patients may prevent the use of antioxidants. Effects of antioxidants on other outcome measures, such as use of analgesics, exacerbation of pancreatitis and quality of life remain uncertain because reliable data are not available.

Plain-language summary: This review summarises the evidence from randomised trials on the effects of antioxidants in chronic pancreatitis. Antioxidants are substances that prevent damage to cells caused by toxic byproducts of oxygen in the body. Levels of these byproducts are increased in chronic pancreatitis. Antioxidants constitute a large group that contains many natural and man-made products. Examples include vitamin C, vitamin E, flavonoids (present in tea and cocoa) and many specialised medications. We found 12 randomised trials on this topic. The quality of these trials was mixed, and many had small sample sizes and high rates of dropout. Evidence shows that antioxidants may reduce pain in patients with chronic pancreatitis, but the reported reduction in pain was small. Whether this small decrease really had an impact on patients' complaints is not clear. Given the methodological problems of these trials, a strong conclusion could not be drawn. Use of antioxidants resulted in adverse effects in about 16% of study participants. Most adverse effects were mild, such as headache, nausea and constipation. However, participants who developed these adverse effects tended to stop using antioxidant medication. Other outcomes important for decision making such as use of analgesics, rate of exacerbation of pancreatitis and quality of life, were not very well reported. Therefore, we were unable to reach conclusions on these outcomes.