Thread: codeine

A 65-year-old man with chronic lymphocytic leukemia is hospitalized for pneumonia. There is no history of smoking or pulmonary disease. His treatment consists of ceftriaxone and clarithromycin; supportive therapy with fluids and oxygen; and, codeine, 25 mg, 3 times daily, for cough. Over the next 2 days, his fever resolves, but his level of consciousness rapidly deteriorates. Arterial blood gas measurements indicate a PaO2 of 56 mm Hg and a PaCO2 of 64 mm Hg. Administration of naloxone results in dramatic improvement in his level of consciousness, and his respiratory failure resolves.

Which of the following is the best explanation for this patient's apparent sensitivity to oral codeine?

A Ceftriaxone–codeine drug interaction
B Critical-illness myopathy
C Genetic variation in CYP2D6
D Underlying chronic obstructive pulmonary disease (COPD)

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the answer is C
CYP2D6 is a drug-oxidizing enzyme and is dysfunctional in 7% of white and black Americans. This genetic condition results in reduced metabolism of certain drugs, but the clinical consequences depend on other routes of drug elimination. Other individuals may have two or more copies of the CYP2D6 gene, resulting in rapid metabolism of the target drug. CYP2D6 metabolizes a number of drugs including antiarrhythmic drugs, β-blockers, selective serotonin reuptake inhibitors, and codeine. Codeine is activated and metabolized by CYP2D6 into morphine and then undergoes glucuronidation. Life-threatening intoxication can develop over a matter of days in patients who have multiple functional alleles of CYP2D6, resulting in ultra-rapid metabolism of opioids such as codeine into morphine.

There are no known interactions between ceftriaxone and codeine. The patient does not have a history of chronic obstructive pulmonary disease and therefore is not susceptible to the loss of respiratory drive that occurs in patients with chronic obstructive pulmonary disease on administration of oxygen. Finally, the patient's history is not indicative of critical-illness myopathy. Critical-illness myopathy is a form of acute muscle injury associated with sepsis and multiple organ failure and does not respond to administration of naloxone.