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Opioid-Induced Respiratory Depression Resulting from Transdermal Fentanyl-Clarithromycin Drug Interaction in a Patient with Advanced COPD

2009; Elsevier BV; Volume: 37; Issue: 6 Linguagem: Inglês

10.1016/j.jpainsymman.2009.02.230

1873-6513

Robert Horton, Claire E.H. Barber,

Pharmacological Receptor Mechanisms and Effects

Concomitant administration of transdermal fentanyl and potent inhibitors of cytochrome P450 has the potential to result in significant respiratory depression and death because of pharmacokinetic drug interaction. A recent case involving near fatal respiratory depression in a patient with chronic obstructive pulmonary disease (COPD) is reported. The patient, a frail 81-year-old man with dementia and advanced COPD requiring home oxygen, had suffered from cervical spondylosis and spinal stenosis for several years. For more than a year, his chronic neck pain was treated with a transdermal fentanyl patch (Duragesic®) at a dosage of 200 ug/hour changed every 48 hours. He was admitted to a tertiary hospital with a five-day history of increased shortness of breath, purulent sputum, unilateral inflammation of his parotid gland, worsening confusion and disorientation. The initial workup revealed leukocytosis and iron deficiency anemia, and he was diagnosed with an acute exacerbation of COPD and parotitis. He was treated with aerosolized salbutamol and ipratropium, oral prednisone and levofloxacin, as well as a 10-day course of intravenous vancomycin and a transfusion of two units of packed cells. He was also continued on his previous dose of fentanyl and oxygen. By hospital Day 12, he had returned to baseline and was being prepared for discharge. In the meanwhile, his Helicobacter pylori serology returned and was positive. He was presumed to have a possible H. pylori gastritis and an associated upper gastrointestinal bleed causing his anemia, and was started on an H. pylori eradication regimen of clarithromycin 500 mg twice a day and metronidazole 250 mg four times daily. Thirty-six hours after receiving the initial dose of clarithromycin, he was found to be unresponsive to verbal or tactile stimuli. He had pinpoint pupils, hypoventilation, profound hypoxemia, and a respiratory rate of two breaths per minute. He was administered 0.4 mg intravenous naloxone and promptly recovered consciousness. His respiratory rate increased to 30 breaths per minute, with associated tachycardia, agitation, and respiratory distress. The fentanyl patch was discontinued and his opioid withdrawal symptoms were managed with supplemental doses of subcutaneous morphine. By the following morning, he was alert and conversive, with normal respiratory rate and oxygen saturation. He denied pain and did not exhibit signs or symptoms of opioid withdrawal. Clarithromycin was discontinued and he subsequently resumed transdermal fentanyl at 50% of his preadmission dose, which was tolerated without significant increase in pain or further evidence of opioid toxicity. He was ultimately discharged without further incident. This case serves as a warning about a known but often underappreciated serious interaction between two widely prescribed drugs: fentanyl and clarithromycin. Adverse outcomes and deaths related to the prescription of transdermal fentanyl in opioid-naïve patients and misuse of fentanyl under other circumstances are well documented.1Martin T.L. Woodall K.L. McLellan B.A. Fentanyl-related deaths in Ontario, Canada: toxicological findings and circumstances of death in 112 cases (2002-2004).J Anal Toxicol. 2006; 30: 603-610Crossref PubMed Scopus (118) Google Scholar, 2Raymond B. Morawiecka I. Transdermal fentanyl (Duragesic): respiratory arrest in adolescents.CMAJ. 2004; 171: 991-992PubMed Google Scholar The aforementioned case outlines the unforeseen development of opioid-induced respiratory depression in a patient on a chronic stable dose of transdermal fentanyl. The development of respiratory depression in an opioid-tolerant patient within 48 hours of the initiation of clarithromycin suggests that the most probable cause was a pharmacokinetic interaction between the potent cytochrome P450 inhibitor clarithromycin and fentanyl. This is further supported by the prior recognition and documentation of this interaction,3Hallberg P. Marten L. Wadelius M. Possible fluconazole-fentanyl interaction—a case report.Eur J Clin Pharmacol. 2006; 62: 491-492Crossref PubMed Scopus (28) Google Scholar, 4U.S. Food and Drug Administration Alert for healthcare professionals: fentanyl transdermal system (marketed as Duragesic).http://www.fda.gov/medwatch/SAFETY/2005/duragesic_ddl.pdfDate: 2005Google Scholar, 5Mercadante S. Villari P. Ferrera P. Itraconazole-fentanyl interaction in a cancer patient.J Pain Symptom Manage. 2002; 24: 284-286Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar the prompt resolution of symptoms with the administration of an opioid antagonist, the absence of other suspect conditions or medications, and the successful reintroduction of fentanyl after clarithromycin was withdrawn. Given these factors, our confidence in this causality, based on accepted criteria,6Cobert B. Biron P. Practical drug safety from A to Z. Jones and Bartlett, Boston2008Google Scholar is greater than 95%. Transdermal fentanyl has been available for more than a decade and is widely used for the treatment of both cancer pain and chronic nonmalignant pain. IMS HEALTH data indicate that more than half a million prescriptions were dispensed from Canadian retail pharmacies in 2007. Prescriptions for clarithromycin, a potent inhibitor of the cytochrome P450 system, topped over 2.1 million for the same time period. In 2005, Janssen, the manufacturer of Duragesic®, in cooperation with the United States Food and Drug Administration (FDA) and Health Canada, issued an important drug warning, including a statement that "concomitant use of transdermal fentanyl with potent cytochrome P450 3A4 inhibitors may cause potentially fatal respiratory depression."4U.S. Food and Drug Administration Alert for healthcare professionals: fentanyl transdermal system (marketed as Duragesic).http://www.fda.gov/medwatch/SAFETY/2005/duragesic_ddl.pdfDate: 2005Google Scholar As with many relatively rare postmarketing adverse effects, the exact incidence of this serious adverse event is not known and rates are difficult to determine because of several factors, including a general underreporting of adverse events by health professionals. Additional cautions and potential pitfalls are outlined in Table 1.Table 1Transdermal Fentanyl: Factors Increasing the Potential for Serious or Life-Threatening Hypoventilation•Concomitant use with potent cytochrome P450 3A4 inhibitors, such as ritonavir, ketoconazole, itraconazole, troleandomycin, clarithromycin, nelfinavir, and nefazodone.•Use in combination with CNS depressants (including other opioids, sedatives or hypnotics, general anesthetics, phenothiazines, tranquilizers), skeletal muscle relaxants, sedating antihistamines, and alcoholic beverages. Additive depressant effects may result.•Fever: fentanyl concentrations could theoretically increase by approximately one-third for patients with a body temperature of 40°C (104°F) because of temperature-dependent increases in fentanyl release from the system and increased skin permeability.•Exposure of the application site to direct external heat sources. All patients should be advised to avoid external heat sources, such as heating pads, electric blankets, heated water beds, heat lamps, hot water bottles, saunas and hot whirlpool spa baths, intensive sunbathing, and so on.CNS=central nervous system.Source: Health Canada Endorsed Important Safety Information on Duragesic (fentanyl transdermal system): http://www.hc-sc.gc.ca/dhpmps/medeff/advisories-avis/prof/2005/duragesic_hpc-cps_e.html Open table in a new tab CNS=central nervous system. Source: Health Canada Endorsed Important Safety Information on Duragesic (fentanyl transdermal system): http://www.hc-sc.gc.ca/dhpmps/medeff/advisories-avis/prof/2005/duragesic_hpc-cps_e.html Lack of physician knowledge regarding pharmacokinetic properties of this preparation has been previously reported.7Welsh J. Reid A. Graham J. et al.Physicians' knowledge of transdermal fentanyl.Palliat Med. 2005; 19: 9-16Crossref PubMed Scopus (9) Google Scholar Despite the 2005 warning, significant adverse events and fatalities associated with the use of transdermal fentanyl continue to be reported, prompting the FDA to issue an updated warning in December 2007.8U.S. Food and Drug Administration FDA issues second safety warning on fentanyl skin patch.http://www.fda.gov/bbs/topics/NEWS/2007/NEW01762.htmlDate: 2007Google Scholar Fentanyl is metabolized in the liver by the cytochrome P450 system, mainly undergoing dealkylation to inactive metabolites by cytochrome P450 3A4.9Tateishi T. Krivoruk Y. Ueng Y.F. et al.Identification of human liver cytochrome P-450 3A4 as the enzyme responsible for fentanyl and sufentanil N-dealkylation.Anesth Analg. 1996; 82: 167-172PubMed Google Scholar Case reports of opioid toxicity from drug-drug interactions because of coadministration of fentanyl and cytochrome P450 inhibitors have been published elsewhere.3Hallberg P. Marten L. Wadelius M. Possible fluconazole-fentanyl interaction—a case report.Eur J Clin Pharmacol. 2006; 62: 491-492Crossref PubMed Scopus (28) Google Scholar, 5Mercadante S. Villari P. Ferrera P. Itraconazole-fentanyl interaction in a cancer patient.J Pain Symptom Manage. 2002; 24: 284-286Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar Several strategies might have been used in this case that could have prevented the adverse outcome. These include, but are not limited to: 1) fentanyl dose reduction with close monitoring for increase in pain or symptoms of opioid toxicity; 2) rotation to alternate opioid not undergoing P450 metabolism; 3) an alternate H. pylori eradication regimen that did not include clarithromycin; and 4) forgoing empiric H. pylori eradication in a patient with multiple comorbidities who might be unlikely to benefit. This case report serves as a cautionary tale. The use of transdermal fentanyl in patients with multiple comorbidities without appreciation of the drug's pharmacokinetic profile and potential for serious drug interactions with commonly used drugs may place patients at increased risk for serious complications.