INTRODUCTION
Many drugs have been reported to cause acute pancreatitis (azathioprine, thiazides, sulfonamides, furosemide, estrogens and tetracycline) 1. Pancreatitis is a rare side effect induced by codeine, considering the widespread consumption of this drug, but there have been a handful of published cases of pancreatitis due to treatment with codeine 2-6.
CLINICAL CASE
We report the case of a 42-year-old man who was admitted in emergency room in February of 2004 as he complained of epigastric pain and vomiting without fever. He had taken an amoxicillin plus clavulanic acid (500/125 mg) pill and an acetaminophen plus codeine (500/30 mg) tablet for an upper respiratory tract infection 2,5,6 an hour ago. Physical examination was normal. He was treated with metamizol and pantoprazol. A few minutes after he received intravenous doses of both drugs, he suffered from a maculo-papular and itching eruption with facial angioedema.
Laboratory tests were as follows: full blood count, serum creatinine and urea and electrolites were normal. Serum amylase 562 U/l (normal < 120 U/l), GOT 81 U/l (normal < 18 U/l), GPT 32 U/l (normal < 22 U/l), G-GT 142 U/l (normal < 26 U/l), alcaline fosfatase 76 U/l (normal < 170 U/l) and total bilirrubine 1,8 mg/dl (normal < 1 mg/dl). Ecographic study made at admission was normal and only showed cholecystectomy that had been performed in 2000 due to severe biliar pancreatitis. Endoscopic study was also normal. Serological tests for B-hepatic, Echo, Parotiditis and Coxsackie viruses showed no evidence of recent infection 5. There was no history of alcohol consumption. All the parameters were normalized 2,5 while he stayed at hospital. A diagnosis of pancreatitis and an adverse reaction by metamizol and pantoprazol were made.
He was sent to our department for drug study. Study with the involved drugs was made and previously written consent was obtained from the patient before conducting provocation tests.
Quantification of specific-IgE antibodies to betalactams (benzylpenicilloyl BPO, amoxicillin and ampicillin) by RAST was negative. Skin prick and intradermal tests were performed with PPL (penicilloyl-polylysine), MDM (minor determinant mixture), penicillin G, amoxicillin, ampicillin, cefoxitin, amoxicillin plus clavulanic acid and metamizol. All of them were negative.
Oral challenge tests were carried out with amoxicillin plus clavulanic acid, pantoprazol, acetaminophen and metamizol without adverse reaction.
Oral challenge test was not performed with codeine due to ethical and medical reasons. A new exposure to codeine would have been able to provoke serious complications and even a situation beyond medical control. Moreover this drug was not essential for the patient because there were many alternative drugs 7.
DISCUSSION
Drug-induced pancreatitis is considered to be rare. However the exclusion of other possible etiological factors combined with the coincidence in time with the intake of codeine makes this drug suspect as causative agent. The likely underlying pathophysiological mechanism is codeine-induced spasm of the sphincter of Oddi combined with disfunction of the same sphincter related to a previous cholecystectomy. The former (spasm of the sphincter of Oddi) has been demonstrated by subcutaneous injection with therapeutic doses of morphine and codeine 5. Constriction occurs within five minutes and lasts for at least two hours. Despite these findings, there are no recorded cases of opiate induced sphincter of Oddi spasm resulting in pancreatitis. On the other hand, a pancreatitis has been reported to occur in association with secondary sphincter of Oddi disfunction, which is related to biliary calculi in more than 90 % of cases 4. Patients who have had a cholecystectomy often suffer (around 60 %) from fibrosis or smooth muscle hyperplasia, which eventually may lead to stenosis, increasing sphincter of Oddi pressure or spasm. It is possible that codeine ingestion in cholecystectomized patients could also result in a rise in biliary and/or pancreatic sphincter pressure, either by exacerbating an already pre-existing sphincter of Oddi disease or as consequence of reduced storage capacity of the biliary tract in these subjects. Probably in cases of transient distal common bile duct obstrucction, the gallbladder, that acts as a reservoir for bile, is able to accommodate the stagnant bile and, thus, will temporarily decompress the biliary tract. Tanaka et al evaluated patients who had intrabiliary pressure measured before and after cholecystectomy, and demonstrated that intrabiliary pressure increased if the sphincter of Oddi pressure was risen using intravenous morphine, only once the gallbladder had been removed. It is possible that both mechanisms (exacerbated spasm in the sphincter of Oddi and reduced bile storage capacity) combined their effects after codeine ingestion to initiate an episode of acute pancreatitis.
This is the case of our patient, as he had been performed cholecystectomy four years ago and we think that codeine ingestion led to acute pancreatitis in him. So, previous cholecystectomy seems to predispose to codeine induced pancreatitis 4-6.
We conclude that codeine is a widely used drug, both in over the counter and prescribed preparations, so that acute pancreatitis should be considered as a possible side effect of this compound, especially for patients who have had a cholecystectomy 5.
Therefore, allergy departments should be aware of other possible sources of adverse reactions different from the traditional immunological ones usually considered in allergy.
