Pearls of Wisdom: What Caused This Man's Loss of Consciousness?
A 62-year-old man was admitted to the hospital with a 3-day history of fatigue, dyspnea, fever, and cough. The patient had a history of chronic lymphocytic leukemia that had been treated with chemotherapy 3 months prior. The patient had been taking valproic acid, 1500 mg/day, for 3 years for posttraumatic generalized seizures.
Upon admission, the patient was alert and oriented but was hypoxemic (partial pressure of oxygen, 56 mm Hg). A radiograph confirmed the presence of bilateral inferior-lobe pneumonia.
Triple therapy with ceftriaxone, clarithromycin, and voriconazole was initiated. Oral codeine, 25 mg, 3 times a day, for cough was also prescribed.
Four days into his hospitalization, the patient’s level of consciousness deteriorated into unconsciousness. Naloxone improved his level of consciousness promptly and dramatically.
What caused the change in level of consciousness?
A. Valproic acid, 1500 mg/day, that the patient had been receiving for 3 years.
B. Clarithromycin administered in the hospital to treat pneumonia.
C. Codeine, 25 mg, 3 times a day, administered in the hospital for cough.
D. Ceftriaxone administered in the hospital for pneumonia.
What is the correct answer?
(Answer and discussion on next page)
Louis Kuritzky, MD, has been involved in medical education since the 1970s. Drawing upon years of clinical experience, he has crafted each year for almost 3 decades a collection of items that are often underappreciated by clinicians, yet important for patients. These “Pearls of Wisdom” often highlight studies that may not have gotten traction within the clinical community and/or may have been overlooked since their time of publishing, but warrant a second look.
Now, for the first time, Dr Kuritzky is sharing with the Consultant360 audience. Sign up today to receive new advice each week.
Answer: Codeine, 25 mg, 3 times a day, administered in the hospital for cough.
Because the potential drug interactions involving the cytochrome P450 system are not commonly encountered, some clinicians tend to think they are more theoretic than real. In an earlier Pearls of Wisdom we presented the case of an infant death also related to the culprit in this case: codeine.
Codeine has no inherent analgesic activity. Rather, about 10% of codeine is metabolized to morphine, from which its analgesic effect derives. Metabolism of codeine to morphine occurs by way of the cytochrome P450 2D6 isoenzyme (CYP2D6). The 3 general categories of CYP2D6 metabolism are as follows: slow metabolizers or nonmetabolizers; rapid metabolizers (normal); and ultrarapid metabolizers (marked enhancement of CYP2D6 activity).
_______________________________________________________________________________________________________________________________________________________________________
RELATED CONTENT
What Makes a Drug a Narcotic?
Opioid Analgesics for Persistent Pain in the Older Patient
_______________________________________________________________________________________________________________________________________________________________________
We do not typically have occasion to determine the CYP2D6 status of our patients. This particular patient was an ultrarapid metabolizer, but it was unknown until he encountered a consequence because of multiple pathways that lead to morphine intoxication.
What Caused This Man’s Coma? CYP2D6 Ultrametabolizer + CYP3A4 Blockade1
Since the patient was receiving a low therapeutic dose of codeine, we would not expect opioid narcosis, except that his ultrametabolizer status markedly increased the amount of morphine derived from codeine. At the same time, medications he was receiving to treat his pneumonia (eg, voriconazole, clarithromycin) are cytochrome P450 3A4 isoenzyme (CYP3A4) inhibitors. Why does that matter? Because normally, any codeine not metabolized to morphine by CYP2D6 is metabolized to inactive metabolites through CYP3A4, which in this case was being blocked, leaving an unusual residual amount of codeine available to be further metabolized into morphine. Finally, morphine generated by conversion of codeine is normally excreted renally. This patient’s renal failure allowed accumulation of an already elevated level of morphine.
Codeine is not inherently a “bad” opioid. Rather, clinicians need to be aware of various metabolizer status categories, and that the 2 poles of metabolism require our awareness: nonmetabolizers or slow metabolizers will not achieve analgesia from codeine, because they are unable to convert enough codeine into morphine to have the desired effect. Ultrametabolizers may convert codeine into morphine with sufficient hyperefficiency that a patient may experience toxicity, as was the situation in the case presented here.
What’s the “Take Home”?
Although codeine is a generally functional analgesic, clinicians must be wary of drug interactions: inhibitors of CYP3A4 will delay the metabolism of codeine into inactive metabolites. Inducers of CYP2D6 (or hereditary ultrametabolizer status) can lead to morphine toxicity by exaggerated conversion of typical therapeutic doses of codeine into morphine.
Reference:
1. Gasche Y, Daali Y, Fathi M, et al. Codeine intoxication associated with ultrarapid CYP2D6 metabolism. N Engl J Med. 2004;351(27):2827-2831.