Codeine

Nervous system

Patients with migraine who use daily codeine or other opioids can be more susceptible to chronic daily headaches; this is evident in opiate overuse. In a pilot questionnaire study of 32 patients who used codeine or other opioids for control of their bowel motility after colectomy, chronic daily headaches occurred in those who were misusing opioids, but only if they had pre-existing migraine [ ]. The study had significant limitations, including the small sample size, diagnosis by means of a mailed questionnaire, a short duration of overuse of opioids, and the fact that it was uncontrolled.

Twelve cases of analgesic-related headache have been reported in children aged 6–16 years, half of whom were taking paracetamol in combination with codeine [ ]. Headaches occurred on at least 4 days per week and analgesic withdrawal led to symptom resolution in 50% and some improvement in the other cases.

Sensory systems

Reduced pupil size has been related to plasma codeine concentration [ ].

Pancreas

Acute pancreatitis has been attributed to codeine [ ], in one case in a patient taking co-codamol (paracetamol plus codeine) [ ].

• A 20-year-old woman, who had previously taken paracetamol without adverse effects, took paracetamol 1 g and codeine 60 mg for a headache. After 3 hours she developed severe upper abdominal pain radiating to the back. The abdominal pain resolved within 24 hours of the administration of phloroglucinol and tiemonium. Her serum amylase activity was raised 3-fold and the serum lipase 15-fold. Other biochemical parameters, abdominal ultrasound, and an MRI scan were normal. Contrast-enhanced computed tomography showed pancreatic edema.

The previous use of paracetamol without adverse reactions supports the theory that the reaction was linked to the addition of codeine.

Four other cases of acute pancreatitis related to codeine have been reported [ ].

• A 65-year-old man presented with severe abdominal pain 90 minutes after taking codeine and low-dose paracetamol. Serum amylase and lipase were significantly raised. Liver function tests were moderately abnormal. Abdominal ultrasound and CT scan showed edematous pancreatitis. Endoscopic retrograde cholangiography showed a papilla with a spastic appearance and an abnormal bile duct. He recovered completely, but 3 months later took codeine and paracetamol after a hemorrhoidectomy; abdominal pain recurred 1 hour later and acute pancreatitis was confirmed.

• A 26-year-old woman developed abdominal pain 2 days after taking codeine for a respiratory tract infection. Three hours later she complained of epigastric pain and vomiting. Her serum amylase and lipase were raised. Her symptoms resolved and the diagnosis was mild idiopathic pancreatitis. One week later she took codeine for similar respiratory symptoms. Two hours later she developed similar symptoms and a CT scan showed an enlarged and heterogeneous pancreas, with necrosis of the tail of the pancreas involving the left kidney. She responded to conservative treatment.

• A 53-year-old woman developed severe central abdominal and epigastric pain 90 minutes after taking codeine for migraine. Pancreatic amylase, lipase, and liver function tests were mildly raised. Abdominal ultrasound was consistent with acute pancreatitis.

• A 57-year-old woman developed severe abdominal pain 2 hours after taking codeine. She had had two similar episodes in the past, once with loperamide and once with codeine. An abdominal CT scan showed edematous acute pancreatitis.

In three of these cases unintentional rechallenge with codeine resulted in recurrence of the symptoms, and the diagnosis was confirmed radiologically and biochemically. All the patients had previously had a cholecystectomy, suggesting that this may increase the likelihood of codeine-induced pancreatitis. The authors speculated that codeine could cause a rise in biliary and/or pancreatic sphincter pressure in cholecystectomized patients, either by exacerbating pre-existing disease of the sphincter of Oddi or as a consequence of reduced storage capacity of the biliary tract, initiating acute pancreatitis. They cautioned that codeine-associated acute pancreatitis can be misconstrued—it may seem as if patients are taking codeine for pancreatic pain when in fact the codeine is producing the pain.

Skin

Rashes have been attributed to codeine.

• A 72-year-old man developed a generalized maculopapular rash 12 hours after taking co-codamol (codeine 10 mg plus paracetamol 500 mg) [ ]. The lesions persisted for 7 days, became scaly, and disappeared. He later reported a similar skin condition after having taken a combination of acetylsalicylic acid, codeine, and caffeine. Patch tests gave a positive result for codeine, suggesting a type IV allergic reaction.

• A 58-year-old man developed a maculopapular rash on the dorsal aspects of the hand and upper body 6 days after taking codeine as an analgesic for hemoptysis secondary to tuberculosis; on withdrawal of codeine, the rash subsided after 48 hours [ ].

Two reports have highlighted the importance of using an oral provocation test and not a patch test to determine if codeine is the causative agent in non-urticarial skin lesions [ , ].

• A 58-year-old man developed a pruritic rash on the body and face, with periorbital swelling 3 hours after taking codeine 20 mg, acetylcysteine 600 mg, and acetylsalicylic acid 500 mg. An oral provocation test over 2 hours with codeine phosphate (1 mg, 4 mg, and 8 mg) precipitated a pruritic scarlatiniform rash for 24 hours, with swelling of the arms, starting 7 hours after the 8 mg dose. A rechallenge test confirmed the effect of codeine. Throughout this period, histamine release tests (CAST-ELISA with codeine) were negative.

• A 57-year-old patient presented with generalized malaise, fever, pruritus, and palpebral and labial angioedema 6 hours after taking a tablet containing paracetamol 500 mg, saccharin 10 mg, and codeine phosphate 30 mg. There was complete resolution in 8 hours, after treatment with prednisolone, hydroxyzine, and metamizole. Later a patch test with 1% codeine and an oral provocation test with paracetamol were both negative. Following an oral provocation test with codeine 5 mg, the patient developed similar symptoms.