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Case Reports in Psychiatry
Volume 2013 (2013), Article ID 617251, 5 pages
Linezolid Is Associated with Serotonin Syndrome in a Patient Receiving Amitriptyline, and Fentanyl: A Case Report and Review of the Literature
1Department of Psychiatry, Mental Health Services, Athalassa Psychiatric Hospital, 1452 Nicosia, Cyprus
2Department of Clinical Therapeutics, National and Kapodistrian University of Athens, Alexandra Hospital, 80 Vas. Sofias Avenue, 11528 Athens, Greece
Received 21 January 2013; Accepted 6 February 2013
Academic Editors: J. S. Brar and D. E. Dietrich
Copyright © 2013 Lampros Samartzis et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
We report a unique case of an adverse interaction between the oxazolidinone antibiotic linezolid, the tricyclic antidepressant amitriptyline and the opioid analgesic fentanyl in a 68-year-old woman with advanced ischemic peripheral arterial disease and sepsis, under empirical antibiotic treatment. We also summarize the current relevant literature as identified via PubMed, EMBASE, and PsycINFO as well as reference sections of selected articles.
Ms. B, a 68-year-old woman, presented at our outpatient clinic with intense lower foot pain and fever since a week. Clinical examination revealed the 3 first phalanges of the left foot painful, cyanotic, and swollen in the absence of palpable pulsus at the ventral and dorsal tibial arteries with concomitant fever (38.5°C) and tachycardia (110 bpm). A complete blood count showed elevated total number of white blood cells (21 × 109/L), consisted of 93% from neutrophil granulocytes. She was admitted to our hospital due to sepsis and possible diagnosis of infection of the ischemic left foot. Anamnestic history included advanced peripheral ischemic disease, diabetes mellitus type II, arterial hypertension, and major depression. The patient was receiving treatment with fentanyl transdermal patch 25 μg/h every 72 h since 10 days and amitriptyline 25 mg BD for depression. The low dose of amitriptyline 25 mg BD was maintained due to its antidepressant [1, 2] as well as analgesic effects on chronic pain [3–5] and especially painful diabetic limb [6–12]. During her stay in the medical ward, she was treated with empirical antibiotics including cloxacillin, 3rd generation beta-lactams, and aminoglycosides with an initial general improvement. However, at the 10th day patient had a new onset of high fever (38.7°C) and linezolid 600 mg every 12 hours was added to the treatment regimen and cloxacillin was stopped. Within the first 24 hours of antibiotic change treatment, the patient had a rapid clinical deterioration manifesting symptomatology of restlessness, diaphoresis, tremor, shivering, myoclonus, and high fever (40°C), as well as gradual mental status disorders with disorientation, confusion, and coma. The patient was intubated due to severe respiratory difficulties according to the criteria of our clinic, and transferred to the intensive care unit. Brain computerized tomography and lumbar puncture (LP) for the exclusion of central neural system (CNS) infection were unremarkable. The constellation of the above neurological and mental state features in the presence of serotonergic medication [13–15] and the abstinence of other CNS pathology leads to the diagnosis of serotonin syndrome according to the diagnostic criteria of Hunter [16, 17] and Sternbach . The first signs of improvement appeared a few hours after the interruption of linezolid and amitriptyline. Withdrawal of sedation and ventilator weaning took place 48 hours later. The patient gradually regained her consciousness and orientation to person, location, and time, as expected in the opposite order in which she lost orientation in the beginning of the confusion state .
Amitriptyline is a tricyclic antidepressant (TCA), a drug category that is believed to act through boosting of serotonin and norepinephrine neurotransmission via blockade of serotonin and norepinephrine reuptake pumps , as well as via desensitizing both 5-H and beta-adrenergic receptors. Tertiary amineTCAs, such asamitriptyline, imipramine, and clomipramine, are more potent inhibitors of serotonin reuptake than secondary amine TCAs, such as nortriptyline or desipramine, therefore theoretically more prone to be involved in the development of serotonin syndrome.
Fentanyl is an synthetic opioid analgesic, which is characterised by high lipid solubility and therefore it easily penetrates the central nervous system (CNS), where it acts through binding to μ-opioid receptors (mu receptors) resulting in inhibition of pain neurotransmission [20–22]. Fentanyl belongs to the phenylpiperidine subcategory of opioid substances, as do methadone, pethidine (meperidine), tramadol, propoxyphene, and dextromethorphan. Phenylpiperidine opioids are considered to have mild serotonin-reuptake inhibition (SRI) properties and therefore a higher possibility, for involvement in serotonin syndrome development . The nonphenylpiperidine opioids, such as buprenorphine, codeine, morphine, and oxycodone, were not reported to show SRI properties . Interestingly, there is a report of paradoxical reaction regarding fentanyl use in the treatment of serotonin syndrome , which had been induced by coadministration of the selective serotonin reuptake inhibitor (SSRI) fluoxetine and the reversible inhibitor of monoamine oxidase A (MAO-A) moclobemide.
Linezolid is an oxazolidinone category antibiotic that is believed to act through early inhibition of protein synthesis via binding to the 23S portion of the 50S ribosomal bacterial rRNA subunit [26, 27] inducing conformational structural changes and preventing tRNA to enter and functionally bind to the ribosome  therefore inhibiting mRNA translation. Linezolid is a totally synthetic compound that was initially synthesized as a reversible MAO inhibitor class antidepressant .
Serotonin syndrome usually consisted of a constellation of neurological and mental state symptoms and commonly diagnosed according to the widely accepted criteria of Sternbach and/or Hunter [14, 16, 17, 30], as summarised in Table 1. Symptoms usually improve with the withdrawal of the predisposing drug agents plus supportive care, as there is no specific evidence-based treatment of the syndrome . Cyproheptadine is a H1 histamine receptor antagonist as well as a nonspecific serotonin receptor antagonist  which may have a role in serotonin syndrome treatment in a usual dose of 8 mg via the nasogastric tube.
The development of the serotonin syndrome has been reported as an interaction of linezolid plus almost every category of antidepressant medication. Interactions have been found with the selective serotonin reuptake inhibitors (SSRIs) as citalopram [29, 33–39], escitalopram , paroxetine , fluoxetine [41, 42], sertraline [43–45], with tryptophan, a precursor of serotonin , with noradrenaline and specific serotonergic agents (NaSSA) as mirtazapine , with serotonin 2 antagonist/reuptake inhibitor (SARI) as trazodone , the azapirone category anxiolytic buspirone that is a serotonin 1A partial agonist and serotonin stabilizer , the dual serotonin and noradrenaline reuptake inhibitors (SNRIs) as the antidepressants venlafaxine [36, 48–51] and duloxetine , and the tricyclic antidepressant (TCA) imipramine . Although amitriptyline [14, 53–56] and fentanyl [57–64] have been both involved in serotonin syndrome, no case has been reported involving their combination.
To the knowledge of the authors, this is the first case of serotonin syndrome reported in a patient receiving this common three-drug combination.
Fentanyl is primarily metabolized via CYP-P450-3A4 isoenzyme system by oxidative dealkylation to the main metabolite norfentanyl which is inactive .
Amitriptyline is metabolised via CYP-P450-1A2 isoenzyme by demethylation to form the active metabolite nortriptyline  and via CYP-P450-2D6 by hydroxylation to form inactive metabolites , but there is also data showing that demethylation via CYP-P450-3A4 plays an important role in its metabolism [67–69]. Therefore a pharmacokinetic interaction between fentanyl and amitriptyline could not be excluded. Nevertheless, in our case, coadministration of amitriptyline and fentanyl did not reveal any symptomatic interaction, as the serotonin syndrome was induced only after the addition of linezolid to the treatment regimen.
Linezolide is metabolised via oxidation procedure in a way independent of cytochrome P450 (CYP-450); consequently there is no possible pharmacokinetic mechanism of interaction between linezolide and other medication metabolized through CYP450 pathways .
Also, the serotonin syndrome pathophysiological mechanism does not include idiosyncratic, neither idiopathic nor pharmacokinetic drug reactions, but it is considered to be a predictable and preventable pharmacodynamic consequence of the excess of serotonergic agonism in CNS and peripheral serotonergic receptors .
We suggest that physicians avoid use of linezolid in patients receiving combination of amitriptyline and fentanyl due to possible serotonin syndrome induction.
- G. Guaiana, C. Barbui, and M. Hotopf, “Amitriptyline for depression,” Cochrane Database of Systematic Reviews, no. 3, Article ID CD004186, 2007.
- C. Barbui and M. Hotopf, “Amitriptyline v. the rest: still the leading antidepressant after 40 years of randomised controlled trials,” British Journal of Psychiatry, vol. 178, pp. 129–144, 2001.
- M. E. Lynch, “Antidepressants as analgesics: a review of randomized controlled trials,” Journal of Psychiatry and Neuroscience, vol. 26, no. 1, pp. 30–36, 2001.
- J. Sawynok, M. J. Esser, and A. R. Reid, “Antidepressants as analgesics: an overview of central and peripheral mechanisms of action,” Journal of Psychiatry and Neuroscience, vol. 26, no. 1, pp. 21–29, 2001.
- M. Botney and J. L. Fields, “Amitriptyline potentiates morphine analgesia by a direct action on the central nervous system,” Annals of Neurology, vol. 13, no. 2, pp. 160–164, 1983.
- H. M. Bryson and M. I. Wilde, “Amitriptyline. A review of its pharmacological properties and therapeutic use in chronic pain states,” Drugs and Aging, vol. 8, no. 6, pp. 459–476, 1996.
- V. Bril, “Treatments for diabetic neuropathy,” Journal of the Peripheral Nervous System, vol. 17, supplement 2, pp. 22–27, 2012.
- V. Bril, J. England, G. M. Franklin et al., “Evidence-based guideline: treatment of painful diabetic neuropathy. Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation,” Physical Medicine and Rehabilitation, vol. 3, no. 4, pp. 345e1–352e21, 2011.
- W. E. Cayley Jr., “Antidepressants for the treatment of neuropathic pain,” American Family Physician, vol. 73, no. 11, pp. 1933–1936, 2006.
- J. D. Joss, “Tricyclic antidepressant use in diabetic neuropathy,” Annals of Pharmacotherapy, vol. 33, no. 9, pp. 996–1000, 1999.
- D. J. Kopsky and J. M. Keppel Hesselink, “High doses of topical amitriptyline in nuropathic pain: two cases and literature review,” Pain Pract, vol. 12, pp. 148–153, 2012.
- M. B. Max, M. Culnane, and S. C. Schafer, “Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood,” Neurology, vol. 37, no. 4, pp. 589–596, 1987.
- D. Taylor, C. Paton, and S. Kapur, The Maudsley Prescribing Guidelines in Psychiatry, Wiley, Cornwall, UK, 2012.
- H. Sternbach, “The serotonin syndrome,” American Journal of Psychiatry, vol. 148, no. 6, pp. 705–713, 1991.
- M. Shameen and D. Taylor, “Serotonin syndrome,” Psychiatric Bulletin, vol. 23, pp. 742–747, 1999.
- E. J. C. Dunkley, G. K. Isbister, D. Sibbritt, A. H. Dawson, and I. M. Whyte, “The hunter serotonin toxicity criteria: simple and accurate diagnostic decision rules for serotonin toxicity,” QJM, vol. 96, no. 9, pp. 635–642, 2003.
- E. W. Boyer and M. Shannon, “Current concepts: the serotonin syndrome,” New England Journal of Medicine, vol. 352, no. 11, pp. 1112–1120, 2005.
- P. R. Casey and B. Kelly, Fish's Clinical Psychopathology: Signs and Symptoms in Psychiatry, Royal College of Psychiatrists, Glasgow, UK, 2007.
- S. M. Stahl, Essential Psychopharmacology, Neuroscientific Basis and Practical Applications, Cambridge University Press, New York, NY, USA, 3rd edition, 2008.
- S. Imai, M. Narita, A. Ozeki et al., “Difference in tolerance to anti-hyperalgesic effect and its molecular mechanisms between chronic treatment with morphine, fentanyl and oxycodone in a chronic pain-like state,” Nihon Shinkei Seishin Yakurigaku Zasshi, vol. 28, no. 5-6, pp. 169–176, 2008.
- R. B. R. Muijsers and A. J. Wagstaff, “Transdermal fentanyl: an updated review of its pharmacological properties and therapeutic efficacy in chronic cancer pain control,” Drugs, vol. 61, no. 15, pp. 2289–2307, 2001.
- G. Subramanian and D. M. Ferguson, “Conformational landscape of selective μ-opioid agonists in gas phase and in aqueous solution: the fentanyl series,” Drug Design and Discovery, vol. 17, no. 1, pp. 55–67, 2000.
- E. E. Codd, R. P. Shank, J. J. Schupsky, and R. B. Raffa, “Serotonin and norepinephrine uptake inhibiting activity of centrally acting analgesics: structural determinants and role in antinociception,” Journal of Pharmacology and Experimental Therapeutics, vol. 274, no. 3, pp. 1263–1270, 1995.
- P. K. Gillman, “Monoamine oxidase inhibitors, opioid analgesics and serotonin toxicity,” British Journal of Anaesthesia, vol. 95, no. 4, pp. 434–441, 2005.
- M. Chambost, L. Liron, D. Peillon, and C. Combe, “Serotonin syndrome during fluoxetine intoxication in a patient using moclobemide,” Canadian Journal of Anesthesia, vol. 47, no. 3, pp. 246–250, 2000.
- J. A. Paladino, “Linezolid: an oxazolidinone antimicrobial agent,” American Journal of Health-System Pharmacy, vol. 59, no. 24, pp. 2413–2425, 2002.
- H. B. Fung, H. L. Kirschenbaum, and B. O. Ojofeitimi, “Linezolid: an oxazolidinone antimicrobial agent,” Clinical Therapeutics, vol. 23, no. 3, pp. 356–391, 2001.
- D. N. Wilson, F. Schluenzen, J. M. Harms, A. L. Starosta, S. R. Connell, and P. Fucini, “The oxazolidinone antibiotics perturb the ribosomal peptidyl-transferase center and effect tRNA positioning,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 36, pp. 13339–13344, 2008.
- R. J. DeBellis, O. P. Schaefer, M. Liquori, and G. A. Volturo, “Linezolid-associated serotonin syndrome after concomitant treatment with citalopram and mirtazepine in a critically ill bone marrow transplant recipient,” Journal of Intensive Care Medicine, vol. 20, no. 6, pp. 351–353, 2005.
- J. J. Taylor, J. W. Wilson, and L. L. Estes, “Linezolid and serotonergic drug interactions: a retrospective survey,” Clinical Infectious Diseases, vol. 43, no. 2, pp. 180–187, 2006.
- P. J. Perry and C. A. Wilborn, “Serotonin syndrome vs neuroleptic malignant syndrome: a contrast of causes, diagnoses, and management,” Annals of Clinical Psychiatry, vol. 24, no. 2, pp. 155–162, 2012.
- A. Graudins, A. Stearman, B. Chan, and K. Kulig, “Treatment of the serotonin syndrome with cyproheptadine,” Journal of Emergency Medicine, vol. 16, no. 4, pp. 615–619, 1998.
- M. McClean, J. C. Walsh, and F. Condon, “Serotonin syndrome in an orthopaedic patient secondary to linezolid therapy for MRSA infection,” Irish Journal of Medical Science, vol. 180, no. 1, pp. 285–286, 2011.
- R. A. Lorenz, A. M. Vandenberg, and E. A. Canepa, “Serotonergic antidepressants and linezolid: a retrospective chart review and presentation of cases,” International Journal of Psychiatry in Medicine, vol. 38, no. 1, pp. 81–90, 2008.
- A. C. Go, L. K. Golightly, G. R. Barber, and M. A. Barron, “Linezolid interaction with serotonin reuptake inhibitors: report of two cases and incidence assessment,” Drug Metabolism and Drug Interactions, vol. 25, no. 1, pp. 41–47, 2010.
- L. Bergeron, M. Boulé, and S. Perreault, “Serotonin toxicity associated with concomitant use of linezolid,” Annals of Pharmacotherapy, vol. 39, no. 5, pp. 956–961, 2005.
- L. Bernard, R. Stern, D. Lew, and P. Hoffmeyer, “Serotonin syndrome after concomitant treatment with linezolid and citalopram,” Clinical Infectious Diseases, vol. 36, no. 9, p. 1197, 2003.
- N. Tahir, “Serotonin syndrome as a consequence of drug-resistant infections: an interaction between linezolid and citalopram,” Journal of the American Medical Directors Association, vol. 5, no. 2, pp. 111–113, 2004.
- R. Y. Hachem, K. Hicks, A. Huen, and I. Raad, “Myelosuppression and serotonin syndrome associated with concurrent use of linezolid and selective serotonin reuptake inhibitors in bone marrow transplant recipients,” Clinical Infectious Diseases, vol. 37, no. 1, pp. e8–11, 2003.
- C. L. Wigen and M. B. Goetz, “Serotonin syndrome and linezolid,” Clinical Infectious Diseases, vol. 34, no. 12, pp. 1651–1652, 2002.
- M. Steinberg and A. K. Morin, “Mild serotonin syndrome associated with concurrent linezolid and fluoxetine,” American Journal of Health-System Pharmacy, vol. 64, no. 1, pp. 59–62, 2007.
- C. R. Thomas, M. Rosenberg, V. Blythe, and W. J. Meyer, “Serotonin syndrome and linezolid,” Journal of the American Academy of Child and Adolescent Psychiatry, vol. 43, no. 7, p. 790, 2004.
- S. Lavery, H. Ravi, W. W. McDaniel, and Y. R. Pushkin, “Linezolid and serotonin syndrome,” Psychosomatics, vol. 42, no. 5, pp. 432–434, 2001.
- V. Sahiner and S. O. Erden Aki, “Serotonin syndrome associated with linezolid use: a case report,” Türk Psikiyatri Dergisi, vol. 20, no. 4, pp. 398–402, 2009.
- D. B. Clark, M. R. Andrus, and D. C. Byrd, “Drug interactions between linezolid and selective serotonin reuptake inhibitors: case report involving sertraline and review of the literature,” Pharmacotherapy, vol. 26, no. 2, pp. 269–276, 2006.
- A. Colomar Ferrá, P. Ventayol Bosch, and J. M. Raurich, “Serotonin syndrome due to interaction between linezolid, tryptophan, and metoclopramide,” Medicina Intensiva, vol. 33, no. 7, pp. 360–361, 2009.
- E. K. Morrison and A. S. Rowe, “Probable drug-drug interaction leading to serotonin syndrome in a patient treated with concomitant buspirone and linezolid in the setting of therapeutic hypothermia,” International Journal of Clinical Pharmacology and Therapeutics, vol. 37, no. 5, pp. 610–613, 2012.
- L. W. Mason, K. S. Randhawa, and E. C. Carpenter, “Serotonin toxicity as a consequence of linezolid use in revision hip arthroplasty,” Orthopedics, vol. 31, no. 11, p. 1140, 2008.
- D. G. Miller and E. O. Lovell, “Antibiotic-induced serotonin syndrome,” Journal of Emergency Medicine, vol. 40, no. 1, pp. 25–27, 2011.
- S. Packer and S. A. Berman, “Serotonin syndrome precipitated by the monoamine oxidase inhibitor linezolid,” American Journal of Psychiatry, vol. 164, no. 2, pp. 346–347, 2007.
- S. L. Jones, E. Athan, and D. O'Brien, “Serotonin syndrome due to co-administration of linezolid and venlafaxine,” Journal of Antimicrobial Chemotherapy, vol. 54, no. 1, pp. 289–290, 2004.
- T. B. Strouse, T. N. Kerrihard, C. A. Forscher, and P. Zakowski, “Serotonin syndrome precipitated by linezolid in a medically ill patient on duloxetine,” Journal of Clinical Psychopharmacology, vol. 26, no. 6, pp. 681–683, 2006.
- R. A. Bodner, T. Lynch, L. Lewis, and D. Kahn, “Serotonin syndrome,” Neurology, vol. 45, no. 2, pp. 219–223, 1995.
- R. Lane and D. Baldwin, “Selective serotonin reuptake inhibitor-induced serotonin syndrome: review,” Journal of Clinical Psychopharmacology, vol. 17, no. 3, pp. 208–221, 1997.
- K. Nisijima, M. Shimizu, T. Abe, and T. Ishiguro, “A case of serotonin syndrome induced by concomitant treatment with low-dose trazodone and amitriptyline and lithium,” International Clinical Psychopharmacology, vol. 11, no. 4, pp. 289–290, 1996.
- N. K. Perry, “Venlafaxine-induced serotonin syndrome with relapse following amitriptyline,” Postgraduate Medical Journal, vol. 76, no. 894, pp. 254–256, 2000.
- S. Ailawadhi, K. W. Sung, L. A. Carlson, and M. R. Baer, “Serotonin syndrome caused by interaction between citalopram and fentanyl,” Journal of Clinical Pharmacy and Therapeutics, vol. 32, no. 2, pp. 199–202, 2007.
- A. A. Alkhatib, K. A. Peterson, and A. K. Tuteja, “Serotonin syndrome as a complication of fentanyl sedation during esophagogastroduodenoscopy,” Digestive Diseases and Sciences, vol. 55, no. 1, pp. 215–216, 2010.
- S. Y. Giese and R. Neborsky, “Serotonin syndrome: potential consequences of Meridia combined with Demerol or Fentanyl,” Plastic and Reconstructive Surgery, vol. 107, no. 1, pp. 293–294, 2001.
- S. Gollapudy, V. Kumar, and M. S. Dhamee, “A case of serotonin syndrome precipitated by fentanyl and ondansetron in a patient receiving paroxetine, duloxetine, and bupropion,” Journal of Clinical Anesthesia, vol. 24, no. 3, pp. 251–252, 2012.
- R. Kirschner and J. W. Donovan, “Serotonin syndrome precipitated by fentanyl during procedural sedation,” Journal of Emergency Medicine, vol. 38, no. 4, pp. 477–480, 2010.
- S. Ozkardesler, T. Gurpinar, M. Akan et al., “A possible perianesthetic serotonin syndrome related to intrathecal fentanyl,” Journal of Clinical Anesthesia, vol. 20, no. 2, pp. 143–145, 2008.
- M. Reich and D. Lefebvre-Kuntz, “Serotoninergic antidepressants and opiate analgesics: a sometimes-painful association. A case report,” Encephale, vol. 36, supplement 2, pp. D119–D123, 2010.
- R. Rastogi, R. A. Swarm, and T. A. Patel, “Case scenario: opioid association with serotonin syndrome: implications to the practitioners,” Anesthesiology, vol. 115, no. 6, pp. 1291–1298, 2011.
- D. E. Feierman and J. M. Lasker, “Metabolism of fentanyl, a synthetic opioid analgesic, by human liver microsomes: role of CYP3A4,” Drug Metabolism and Disposition, vol. 24, no. 9, pp. 932–939, 1996.
- S. M. Stahl, Essential Psychopharmacology: the Prescriber's Guide, Cambridge University Press, New York, NY, USA, 2009.
- K. Venkatakrishnan, D. J. Greenblatt, L. L. Von Moltke, J. Schmider, J. S. Harmatz, and R. I. Shader, “Five distinct human cytochromes mediate amitriptyline N-demethylation in vitro: dominance of CYP 2C19 and 3A4,” Journal of Clinical Pharmacology, vol. 38, no. 2, pp. 112–121, 1998.
- O. V. Olesen and K. Linnet, “Metabolism of the tricyclic antidepressant amitriptyline by cDNA-expressed human cytochrome P450 enzymes,” Pharmacology, vol. 55, no. 5, pp. 235–243, 1997.
- P. Ghahramani, S. W. Ellis, M. S. Lennard, L. E. Ramsay, and G. T. Tucker, “Cytochromes P450 mediating the N-demethylation of amitriptyline,” British Journal of Clinical Pharmacology, vol. 43, no. 2, pp. 137–144, 1997.