Somatostatin: still a pharmaceutical defense weapon against post-ERCP pancreatitis? A 30-year story

The question of whether post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) can be prevented by drugs is a story that dates back to 1984 [1], and is still going strong, with conflicting and mostly unsatisfactory results. During these 30 years, many drugs have been tested, with mechanisms of action that, theoretically or in animal studies, include inhibition of the exocrine pancreatic secretion or reduction of the enzyme content in the gland, prevention of the activation of intrapancreatic enzymes, control of the inflammatory reaction cascade, or reduction of sphincter of Oddi post-procedure hypertension. However, studies in which a particular drug demonstrated efficacy in preventing PEP at a given dosage and/or route of administration have rarely been followed by confirmatory trials, with similar designs, on larger series of patients. As a consequence, most endoscopists in the ERCP field believe that expertise and technique, including post-procedure pancreatic stenting, more than pharmacological prophylaxis, play a major role in preventing the complication.

Among the compounds tested to date, only nonsteroidal anti-inflammatory drugs (NSAIDs), used for the first time by Murray et al. in 2003 [2], have been repeatedly confirmed over time as effective in preventing PEP. This was documented by a recent randomized, placebo-controlled trial on the rectal administration of indomethacin in a large series of patients [3], and guidelines issued by the European Society of Gastrointestinal Endoscopy (ESGE) do in fact recognize NSAIDs as being effective [4] [5].

Somatostatin was the first drug to be assessed for the prevention of PEP since the 1980 s, and to date, unlike almost all other drugs except for NSAIDs, it is still regularly tested in studies, with a number of published studies confirming its efficacy even in the past few years [6] [7] [8] [9]. To my knowledge, 29 clinical trials and 4 meta-analyses [10] [11] [12] [13] that evaluated the efficacy of somatostatin for the prevention of PEP have been published, and it is still the most widely investigated drug in the field of pharmacological prevention of this complication.

Why was somatostatin the first drug to be investigated and why has it been considered to prevent PEP for so long? Together with its longer-acting synthetic analog octreotide, somatostatin affects the exocrine function of the pancreas, both directly, by reducing the production and secretion of digestive enzymes, and indirectly, by inhibiting secretin and cholecystokinin production. One of the mechanisms by which the exocrine pancreatic secretion is inhibited is related to a reduction of amino acid uptake by human pancreatic acinar cells, which is the first step in pancreatic protein synthesis and secretion [14]. Both somatostatin and octreotide significantly lessen the drop in plasma amino acid concentration induced by secretin or cerulein stimulation, and this effect seems to be dose dependent.

In addition to their antisecretory effects, both drugs act on the cytokine cascade [15]. An experimental study suggested that somatostatin analogs may induce apoptosis in pancreatic acinar cells, to reduce the inflammatory reaction during acute pancreatitis [16]. Somatostatin also reduces the motility of the sphincter of Oddi, whereas octreotide stimulates sphincter hypertension; the exact reason for these different physiological effects is still not known. Somatostatin can relax the sphincter of Oddi in patients with acute nonbiliary pancreatitis [17]. Hypertension of the sphincter of Oddi and edema of the papilla of Vater are possible mechanisms of PEP, by leading to pancreatic duct obstruction.

Considering all of these mechanisms of action, the use of somatostatin and octreotide to prevent PEP has a reasonable scientific basis. However, overall, the literature suggests that somatostatin is more likely to reduce its frequency, whereas octreotide does not.

The latest meta-analysis, in 2010, which assessed the effects of somatostatin and octreotide in 3818 patients enrolled in, respectively, 10 and 7 randomized clinical trials [13], confirmed the effectiveness of somatostatin in the prevention of PEP, at either a high dosage (3 mg given as an infusion over 12 hours) or a lower dose (250 µg) injected as a bolus, whereas octreotide was effective only at a high dose. Somatostatin was also effective in patients at higher risk for PEP. Therefore, the story of octreotide in the prophylaxis of this complication should be considered a question of the past, and ESGE guidelines do not, in fact, recommend it.

Since the last meta-analysis, four subsequent studies on somatostatin published between 2012 and 2014 still produced conflicting results: two showed it was effective at a high dose given by continuous infusion in one study [7] or in association with diclofenac [6], whereas in the other two studies it was not effective [8] [9]. On the basis of these data, the updated ESGE guidelines for prevention of PEP, issued in 2014, suggest the use of prophylactic somatostatin only in selected cases, whereas the previous guidelines (2010) did not recommend prophylactic somatostatin in average risk patients undergoing ERCP.

The study by Bai et al. [18] in the current issue of Endoscopy again suggests a beneficial effect of a bolus intravenous injection of 250 µg somatostatin immediately before ERCP followed by 250 µg/hour intravenous infusion for 11 hours. This multicenter, randomized, controlled trial examined a large series of 900 patients (445 in the somatostatin group and 455 controls).

The sample size is one of the most important biases affecting most published trials, because the low incidence of PEP (overall mean rate 5 %, low risk cases 2 %) requires large numbers of patients to give significant and convincing results. To halve an estimated standard PEP rate of 5 % (as reported in most studies for nonselected patients) or 12 % (as reported in general for high risk patients), a study with 80 % power and an 0.05 alpha error needs respectively 906 or 356 patients in each arm.

To calculate the sample size, the study by Bai et al. considered an intermediate mean incidence of 8 % pancreatitis, including standard and high risk patients, and aimed at reducing this to 3 % (more than 50 % reduction), this being similar to the rate reported for post-procedure pancreatic stenting. Unlike most of the other recently published studies, this trial enrolled an adequate number of patients, so it provides convincing data about the efficacy of the drug tested. The reported overall rate of post-procedure pancreatitis was 5.8 %, with 7.5 % in the control group and 4.0 % for somatostatin; the difference was statistically significant.

The overall rate of pancreatitis seems a bit higher than that reported in most studies for a nonselected population, but the case series included a large proportion of patients at high risk (88.2 %), and this helps to explain the rate in the control group. On the other hand, considering only those patients at high risk of post-procedure pancreatitis, the 7.3 % reported in untreated patients is lower than the figures in the literature. Somatostatin was not effective in this subgroup, which confirms previous studies. The authors, once again, used prolonged intravenous infusion of the hormone after a single pre-ERCP bolus, and confirmed the positive results reported in most earlier studies.

The main disadvantage of somatostatin, compared with NSAIDs, is that it requires continuous intravenous infusion for up to 12 hours in order to be effective; this is expensive and is therefore not cost effective for the prevention of PEP in a standard risk population whose post-procedure pancreatitis rate is about 2 % – 3 %. Unfortunately, a single-dose bolus intravenous injection, which would be more appealing in terms of cost-effectiveness and practicality in the outpatient setting, was not effective. In contrast, NSAIDs are cheap and have the advantage of requiring only a single bolus dose, so they are cost effective in all cases.

Should we continue to search for an effective pharmacological prophylaxis as an alternative to NSAIDs? In high risk patients, who have a mean risk of post-procedure pancreatitis of 10 % or more, the search for effective pharmacological prophylaxis is still justified; in these cases the pancreatitis appears to be unrelated to the operator’s experience and endoscopic technique, and is only prevented by a pancreatic stent, which does not eliminate the risk altogether and may not be feasible in all cases, or may be risky if attempted after the procedure and fails [19]. Moreover, although NSAIDs have demonstrated effectiveness, pancreatitis is still a problem in 3 % – 5 % of cases in the studies with the best results.

We probably do still need to establish the best dosage regimen for somatostatin, bearing in mind that if the pancreas is profoundly depleted of the intracellular enzyme before the procedure, the local damage induced by enzyme activation could be markedly reduced; this can only be achieved by starting hormone administration at least 24 hours before the ERCP, and not immediately before or after, as has been done in all studies to date. However, though this strategy has already been adopted – with conflicting results – it is not practical and very likely not feasible in most endoscopic centers that perform ERCP procedures on a day-case basis. Nevertheless, it should be taken into consideration when designing future studies of PEP prophylaxis using somatostatin.

• References

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