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Itraconazole–Fentanyl Interaction in a Cancer Patient

2002; Elsevier BV; Volume: 24; Issue: 3 Linguagem: Inglês

10.1016/s0885-3924(02)00477-3

1873-6513

Sebastiano Mercadante, Patrizia Villari, Patrizia Ferrera,

Epilepsy research and treatment

To the Editor: Recent reports have highlighted the importance of recognizing drug interactions in palliative care and the potential consequences of these interactions in pain management. The following case illustrates a significant drug interaction between itraconazole and fentanyl and methadone, which underlines the need for knowledge and vigilance for clinicians in the palliative care setting. A 67-year-old man with head and neck cancer was admitted to a Pain Relief and Palliative Care Unit as a consequence of irradiation performed two weeks earlier in another institution. He showed signs of dehydration and malnutrition, although laboratory parameters were not particularly altered. A nasogastric tube had been placed because he was not able to swallow. He had a severe oropharyngeal candidiasis and skin lesions on the neck anterior wall causing pain, for which he had been receiving transdermal fentanyl 50 μg/hr for one week, with partial pain relief and moderate somnolence. Intravenous hydration (1200 ml/day of an electrolyte solution and 500 ml of gelatine) and enteral nutritional support were ordered. Oral itraconazole was started in doses of 200 mg twice daily, and ibuprofen and omeprazole were added to the analgesic regimen. The following day, signs of opioid toxicity appeared. Physical examination showed an agitated delirium with frequent episodes of bilateral myoclonus of the muscles in the hand. Renal and liver function were normal. A computed tomography scan was negative for any cerebral involvement. The fentanyl patch was removed and substituted with methadone 7 mg three times a day given through the nasogastric tube. The use of a semi-elementary diet through the nasogastric tube induced diarrhea, bloating, and abdominal distension. Fever complicated the clinical situation. The next day, the case was discussed with the supervisor and it was decided to stop methadone and to provide intravenous morphine 5 mg as needed for pain relief, adding clonazepam 0.3 mg as needed to control myoclonus. Enteral nutrition was discontinued and a catheter from the brachial vein was advanced into the superior cava to start parenteral nutrition. Symptoms progressively subsided and the patient fully recovered two days after. Clonazepam was no longer necessary. In the following days, mucositis improved, fever disappeared, and the patient was able to take some oral fluids. Itraconazole was stopped. The dose of intravenous morphine that allowed an acceptable pain control was converted to transdermal fentanyl 25 μg/hr, with an adequate pain relief and no changes in cognitive function. Seven days after admission, the patient was discharged with a transdermal patch of 25 μg/hr of fentanyl, with adequate symptom control, and a prescription for parenteral nutrition to be continued at home for a subsequent ten days until the complete recovery from dysphagia occurred. On admission, the patient was receiving transdermal fentanyl 50 μg/hr. Ibuprofen was added to avoid further dose increments in the setting of mild partial cognitive impairment. Despite maintaining constant the dose of fentanyl, clear signs of opioid toxicity occurred 24 hours after starting itraconazole. Possible fentanyl overdose was hypothesized. This drug was replaced with methadone, but after consultation between the team members, it was recognized that methadone could potentially interact with itraconazole. Given the stability of the fentanyl dose and the temporal association between opioid toxicity and the addition of itraconazole, it is also possible that a drug interaction between itraconazole and fentanyl was the initial cause of the relative overdose. Switching to methadone could cause the same effect, with similar problems occurring. The literature indicates that methadone poses an intermediate risk for potential drug interaction, and there are few data available for fentanyl.1Bernard S.A. Bruera E. Drug interactions in palliative care.J Clin Oncol. 2000; 18: 1780-1799PubMed Google Scholar For a drug interaction to occur, an inhibitor or an inducer needs a substrate, resulting in a more intense effect or less activity, respectively. The mechanism of enzymatic inhibition can be either competitive or non-competitive. In the former case, as the accomplice drug (inhibitor) tightly binds the heme moiety of the cytochrome P450 isoenzyme, the bullet drug (substrate) will not be transformed. In the latter, non-competitive inhibition occurs when the enzyme is inactivated or modified by the accomplice drug and the original substrate no longer can be metabolized. Fentanyl is metabolized primarily by CYP 3A4 isoenzyme. It is N-dealkylated to norfentanyl. In addition, hydroxypropionyl fentanyl and hydropropionyl norfentanyl are produced by hydroxylation. A reduced clearance of fentanyl, which may result from drug–drug interactions at the CYP 3A4 isoenzyme, could result in a prolonged terminal half-life. Methadone's metabolism is even more complex. In the liver, it predominantly undergoes N-demethylation, which is largely mediated by the CYP3A4 isoenzyme. Other than fentanyl and methadone, CYP3A4 enzyme metabolizes several substrates and is inhibited by macrolides, such as clarithromycin and erythromcycin; antifungals; antidepressants, including fluoxetine, fluvoxamine, and sertraline; oral contraceptives; cimetidine; omeprazole; antiviral agents; and valproid acid. Thus, concomitant administration of these substances results in an increased effect of drugs commonly metabolized by this enzymatic system. Some other drugs, such as carbamazepine, phenytoin, and phenobarbital, have an inductive enzymatic effect, and could result in a decrease of the analgesic effect of methadone or in a withdrawal syndrome. For example, while phenytoin induced opioid withdrawal in patients chronically taking methadone,2Tong T. Pond S.M. Kreek M.J. Phenytoin-induced methadone withdrawal.Ann Int Med. 1981; 94: 349-351Crossref PubMed Scopus (100) Google Scholar fluvoxamine produced higher methadone plasma concentration and adverse effects requiring a reduction in dose.3Bertschy G. Baumann P. Eap C.B. Probable metabolic interaction between methadone and fluvoxamine in addict patients.Ther Drug Monit. 1994; 16: 42-45Crossref PubMed Scopus (86) Google Scholar The extent of inhibition of one drug by another will depend on the affinity each compound has for the enzyme. Azoles, including fluconazole in large dose, itraconazole, and ketoconazole, are known as typical cytochrome CYP 3A4 inhibitors. Specifically, itraconazole and its active metabolite hydroxy-itraconazole may increase serum levels of other substrates.4Virani A. Mailis A. Shapiro L.E. Shear N.H. Drug interactions in human neuropathic pain pharmacotherapy.Pain. 1997; 73: 3-13Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar Thus, a concomitant administration of these drugs could increase the effect of analgesics, such as fentanyl or methadone. Other isoenzymes, such as CYP1A2, CYP2D6, CYP2C9, and CYP2C19, also are involved in fentanyl and methadone metabolism, but to a much lesser degree.5Foster D.J.R. Somogyi A.A. Bochner F. Methadone N-demethylation in human liver microsomes lack of stereoselectivity and involvement of CYP3A4.Br J Pharmacol. 1999; 47: 403-412Crossref Scopus (173) Google Scholar, 6Moody D.E. Alburges M.E. Parker R.J. et al.The involvement of cytochrome P4503A4 in the N-demethylation of 1-alpha-acetylmethadol (laam), norlaam, and methadone.Drug Metab Dispos. 1997; 25: 1347-1353PubMed Google Scholar These systems are characterized by genetic polymorphism and expression variability. All the drugs which inhibit these systems may increase plasma concentration or prolong half-life in patients chronically taking opioids like methadone and fentanyl. Ciprofloxacin, fluvoxamine, venlafaxine, fluoxetine, omeprazole, fluconazole, and desipramine all have been reported to competitively inhibit these systems, although with different patterns.7Herrlin K. Segerdahl M. Gustafsson L. Kalso E. Methadone, ciprofloxacin, and adverse drug reactions.Lancet. 2000; 356: 2069-2070Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar, 8Andersson T. Pharmacokinetics, metabolism and interactions of acid pump inhibitors. Focus on omeprazole, lansoprazole and pantoprazole.Clin Pharmacokinet. 1996; 31: 9-28Crossref PubMed Scopus (353) Google Scholar Ciprofloxacin, a quinolone antibiotic which is a competitive inhibitor of CYP2D6 and CYP3A4, administered in a patient with chronic pain on methadone therapy, caused profound sedation and respiratory depression.7Herrlin K. Segerdahl M. Gustafsson L. Kalso E. Methadone, ciprofloxacin, and adverse drug reactions.Lancet. 2000; 356: 2069-2070Abstract Full Text Full Text PDF PubMed Scopus (89) Google Scholar Most of these pharmacokinetic changes are subclinical.9Cobb M.N. Desai J. Brown L.S. et al.The effect of fluconazole on the clinical pharmacokinetics of methadone.Clin Pharmacol Ther. 1998; 63: 655-662Crossref PubMed Scopus (83) Google Scholar In some circumstances, however, they may have relevant clinical consequences. Low plasma protein levels, decreased volume of distribution, dehydration, and concomitant clinical problems make advanced cancer patients particularly vulnerable to drug interactions. For these reasons, the use of morphine as needed was considered, in our case, to decrease opioid toxicity and possible interaction with itraconazole, while allowing pain control with minimal adverse effects. Morphine metabolism requires glucuronidation; interaction at the CYP is not seen.1Bernard S.A. Bruera E. Drug interactions in palliative care.J Clin Oncol. 2000; 18: 1780-1799PubMed Google Scholar Parenteral support was also useful in maintaining an adequate intake of fluid and calories. After the oropharyngeal improvement allowed the discontinuation of itraconazole, the fentanyl patch could be started again, without producing toxicity. Other possible interactions have to be taken into consideration. Omeprazole is metabolized by CYP2C19 and may inhibit CYP 3A4.4Virani A. Mailis A. Shapiro L.E. Shear N.H. Drug interactions in human neuropathic pain pharmacotherapy.Pain. 1997; 73: 3-13Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar Alternatively, ibuprofen could have produced renal damage, with reduction of opioid elimination. Seventy-five percent of fentanyl is normally excreted in the urine. In addition to the suspected pharmacokinetic interaction, other contributing factors also have to be considered. Previous dehydration, fever, and the loss of fluids may all have contributed, although fluid balance was corrected by giving intravenous electrolyte solutions. Finally, it has been recognized that smoking may induce CYP1A2 enzyme capacity; the patient, however, was not a smoker. An interaction between fentanyl and itraconazole has not been reported previously. Cancer patients receiving multiple drugs are at increased risk for drug interactions that may have relevant clinical consequences. Greater awareness of the potential interactions among the multitude of drugs, including analgesics, which are frequently prescribed in the palliative care setting is needed to avoid otherwise unexplainable and dangerous clinical phenomena.