Approval for this report (1210-CR) was provided by the local Human Ethical Committee and institutional review board (Chairperson Hassan Al-Dhibi) on 27 February 2012 and consent for publication was granted by the patients.
We report five patients who developed severe epigastric pain as a consequence of sphincter of Oddi spasm after oral premedication with a single low dose of paracetamol/codeine combination. Patients were scheduled for ophthalmic surgical procedures (two for cataract and three for glaucoma surgery) under local anaesthetic block.
All patients were women in the age range of 38 to 56 years. Two patients were moderately obese (BMI = 43.3 and 31.6) and had a history of dyspepsia but the rest had a normal build (BMI = 20 to 25). The third patient had a recent history of upper respiratory tract infection (not on any medication), whereas the fourth had a previous history of kidney stone with no recent change but was asymptomatic and not on any treatment. None of the patients had a history of a known allergy to any drug or food or was taking any herbal medication. One patient was taking ophthalmic drops (acetazolamide three drops 6 hourly in the affected eye), whereas another one was taking acetazolamide 250 mg orally every 8 h. Preoperative routine urine analysis and blood examination did not reveal infection in any patient, and chest radiograph (done in four patients) and ECG were within normal limits. The only common factor among the patients was a history of laparoscopic cholecystectomy in the previous 3 to 7 years secondary to chronic cholelithiasis. All cholecystectomies were performed under general anaesthesia and the average duration of surgery was 40 to 60 min but further details about the surgeon's variability or operative conditions could not be determined as the patients came from remote areas without any written previous medical records.
All patients had fasted 6 h for solids and 2 h for liquids (water). They were premedicated 2 h before the expected time of surgery with two tablets of Revacod (The Arab Pharmaceutical Manufacturing Co. Ltd, Amman, Jordan) and ranitidine 150 mg orally. Each tablet of Revacod contained paracetamol 500 mg and codeine 10 mg.
The patients started complaining of moderate-to-severe epigastric pain after 1 to 1.5 h of premedication. The pain was continuous, piercing in nature and radiating to the whole abdomen. They were unable to pinpoint the exact location of the pain. All patients had a history of epigastric pain and intolerance to fatty meal before cholecystectomy but none had residual epigastric pain or food intolerance after surgery. The episode had some similarity to previous gall bladder attacks, but the patients were unable to match the severity and nature of pain with their pain of cholecystitis before cholecystectomy. The severity of pain ranged 5 to 8 on verbal analogue scale (VAS) of 0 to 10. No patient had any recent history of diarrhoea or constipation. Abdominal palpation did not exacerbate the pain and auscultation did not reveal hyperactivity of peristaltic movements. All patients had some nausea but no vomiting. They were anxious and restless but the vital signs were stable and the ECG was negative for myocardial ischaemia or infarction.
Initially heartburn secondary to stress-related hyperacidity was suspected in the first two patients and they were treated with 30 ml of oral antacid suspension (aluminum hydroxide, magnesium hydroxide and simethicone), but showed no improvement in their symptoms. By this time, a provisional diagnosis of spasm of the sphincter of Oddi was made and meperidine (pethidine) 50 mg intravenously was given in titrated doses (starting with 20 mg supplemented by 10 mg every 5 min) for symptomatic pain relief. A gradual but progressive improvement was noted in pain relief (VAS = 1 to 3), but it took 1 to 2 h for the patients to return to normal condition. Neither patient had a recurrence of the pain.
The remaining three patients were treated with naloxone 0.1 to 0.4 mg in titrated doses (starting with 0.04 to 0.1 mg) and the response was proportional to the dose. Faster and better relief was achieved at higher doses. Complete relief was seen in all patients by 15 to 20 min. One patient needed an additional dose of 0.1 mg naloxone after 25 to 30 min because of mild recurrent pain (VAS = 2). All patients were followed up for 24 h, but none had experienced any further pain.
When sphincter of Oddi spasm/dysfunction is suspected, it is important to differentiate their abdominal pain from other serious conditions such as cancer of the pancreas or bile ducts, peptic ulcer disease, renal stones or stones in the cystic ducts. In some cases, heart conditions such as angina or ischaemia can cause pain that seems to be coming from the abdomen, but all our patients were relatively young or middle age and none had a history of any such condition in the recent past. The laboratory work, chest radiograph and ECG were also negative for any serious pathological condition. The onset time of pain was 1 to 1.5 h after oral intake of codeine, which corresponds to the onset time of the clinical action of this drug.
Morphine is well known to cause the spasm of the sphincter of Oddi1 and result in pain. Codeine is a pro-drug and is converted to morphine and codeine-6 glucuronide in the liver after oral intake. It is used for the treatment of mild-to-moderate pain and also as a cough suppressant, and it is useful as part of premedication for the procedures performed under local anaesthesia to avoid excessive coughing during surgery.2
Previous cholecystectomy is known to be a predisposing factor for the spasm of the sphincter of Oddi after morphine sedation.3 As codeine is also metabolised to morphine, we suspected it to be responsible for spasm of this sphincter and pain. This series confirms a similar case report in which a single low dose of paracetamol/codeine (500 mg/30 mg) has resulted in acute abdomen.4
The biliary system has a rich supply of pain fibres.5 The pain from the sphincter of Oddi is probably not due to the spasm itself but to the resultant increased pressure in the bile duct.6 Reduced bile storage capacity after cholecystectomy may lead to a faster distension of the bile duct and results in severe pain. Severe and prolonged spasm may lead to acute pancreatitis.7
The exact mechanism of spasm of the sphincter of Oddi in cholecystectomised patients is not clear but it may be because of disruption of the inhibitory nerve fibres of the sphincter.8 We know that cholecystokinin (CCK) is a peptide hormone which is normally synthesised by the mucosa of the small intestine and secreted in the duodenum after a fatty meal to stimulate the digestion of fats and proteins. It causes the gall bladder to contract and the sphincter of Oddi to relax at the same time to allow the bile and pancreatic juice to be released into duodenum. It is likely that gall bladder and sphincter of Oddi function are coordinated by nerve fibres that pass from the gall bladder to the sphincter of Oddi via the cystic duct. Cholecystectomy, probably by dividing these nerves, may result in altered response to CCK and failure to relax.9
High doses of opioids are used intraoperatively and postoperatively, but this kind of pain is not common in those patients. This may be due to the masking effect of the anaesthetic or surgical pain. A small preoperative dose may be enough to cause spasm of the sphincter of Oddi and result in pain.
We treated our first two patients with pethidine, having both antispastic and analgesic properties, because of its ability to relieve biliary spasm,8 but we noted slow and incomplete relief. Naloxone, demonstrated a prompt and clear response in a dose-dependent manner in the remaining three patients.
We conclude that premedication with a single dose of codeine is likely to cause the spasm of the sphincter of Oddi in patients with previous cholecystectomy. The pain may be relieved with pethidine to some extent but appears highly responsive to naloxone, which normally aggravates most other pains. Naloxone serves both diagnostic and therapeutic purposes. Opioids may not be the drugs of choice for premedication in patients with previous cholecystectomy.
Assistance with the letter: none declared.
Financial support and sponsorship: none declared.
Conflicts of interest: none declared.
1. Butler KC, Selden B, Pollack CV Jr. Relief by naloxone of morphine-induced spasm of the sphincter of Oddi in a postcholecystectomy patient. J Emer Med
2. Tsunezuka Y, Sato H, Tsukioka T, et al. The role of codeine phosphate premedication in fibre-optic bronchoscopy under insufficient local anaesthesia and midazolam sedation. Respir Med
3. Anthony MH, Ho MD. Previous cholecystectomy and choledochal sphincter spasm after morphine sedation. Can J Anesth
4. Torres D, Parrinello G, Trapanese C, Licata G. Sudden severe abdominal pain after a single low dose of paracetamol/codeine in a cholecystectomized patient: learning from a case report. Am J Ther
5. Britton J, Bickerstaff KI, Savage A. Morris PJ, Malt RA. Benign diseases of the biliary tract. Oxford text book of surgery
. New York:Oxford University press; 1994. 1209–1239.
6. Chuttani R, Carr-Locke DL. Pathphysiology of the sphincter of Oddi. Surg Clin N Am
7. Hastier P, Buckley MJ, Peten EP, et al.
A new source of drug induced acute pancreatitis: codeine. Am J Gastroenterol
8. Rolny P, Funch-Jensen P, Kruse A, Thommessen P. Effect of cholecystectomy on the relationship between hydrostatic common bile duct pressure and sphincter of Oddi motility. Endoscopy
9. Luman W, Williams AJ, Pryde A, et al. Influence of cholecystectomy on sphincter of Oddi motility. Gut