Case Report Dextromethorphan- Induced Methadone Interaction Delirium and Possible

~E. LotHch et M. The Americae~ Joure~al of Geriatric Phar~rlacotherapy

Case Report Dextromethorphan- Induced Delirium and Possible Methadone Interaction

Francis E. Lotrich, MD, PhD, Jules Rosen, MD, and Bruce G. Pollock, MD, PhD

Deportmen: of Psychiotry, Wessern £sychiosrlc Institute ond C/in£, University of Pittsburgh/He@co/Center, Pittsburgh, Per~ns//vclnicl

ABSTRACT Introduction: Dextromethorphan is a commonly used antitussive agent that can be purchased over the counter. It is metabolized primarily by the cytochrorne P450 (CYP) 2D6 isozyme. Methadone has been found m inhibit CYP2 D6, indicating a potential for interaction with dextromethorphan. Case summary: An 8S-year-old woman was evaluated for delirium, hypersomnia, confusion, lethargy, impaired concentration, and poor food intake. Symptoms resolved soon after discontinuing dextromethorphan. Discussion: Vulnerability to delirium was potentially caused by coadministration ofrnethadone, which can inhibit the CYP2 D6 isozyme. Conclusion: Evaluation of delirium should include close investigation of the patient's medications for potential interactions with dextromethorphan. (Am J Geriatr Pharre, acother. 2005;3:1~20) Copyright © 2005 Excerpta Medica, Inc.

INTRODUCTION dextromethorphan overdose in 19675 Methadone is Dextromethorphan is a commonly used antitussive increasingly used for pain control in the elderly and in agent that can be purchased over the counter. Some of palliative care settings. 6,7 It is reportedly taken by-10% the preparations of which it is a component include of patients receiving palliative care. 6 Methadone has Contac Severe Cold and Flu Caplets®, * Guaifenex been found m inhibit CYP2D6, s,9 indicating a poten DM®, t Robitussin DM®, ~ TheraFlu®,~ Triaminic tial for interaction with dextromethorphan. Cough Liqttid®,~ and Vicks 44 Cough Relief®. II Dex- We report the case of an elderly woman with tromethorphan is metabolized primarily by the dextrornethorphan induced delirium. To our knowl cytochrome P450 (CYP) 2D6 isozyme. 1~ Notably, edge, there are no previously published reports of a dextromethorphan is an N-methyl-D-aspartate (NMDA) possible adverse interaction between dextromethor- antagonist at high concentrations, s,4 similar to keta phan and methadone. mine and phenylcyclohexylpiperidine, 2 other NMDA antagonists. Psychosis was first reported as an effect of CASE SUMMARY An 83 year old white woman was referred for psychi *Trademark of GlaxoSmithKline~ Research Triangle Park~ North attic evaluation after a 5 month period ofhypersomuia, Carolina. confusion, and poor food intake following a brief hos- tTrademark of KV Pharmaceutical Company, St. Louis, Missouri. pitalization for pneumonia. Several days after hospital tTrademark of WyethPharmaceuticals, Philadelphia, Pennsylvania. STrademark of Novartis Consmner Health, Inc., Parsippany, New discharge, she became very confused and started falling Jersey. down. Before this, the patient was described as having IITradcmark of Procter & Gamble, Chlchmati, Ot~o. been highly functional, both physically and mentally,

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Copyright @ 2005 Excerpts Medica~ Inc Volume 3 * Number I March 2005 17 The America~ ]our~M o3eG¢ria~ric Pharmaco~her~py ~E. Lotrich et M.

and she socialized actively. During rehospitalization, including imaging and electroencephalography, were mild hyponatremia (serum sodium level, 132 mEq/L) considered but deferred pending other interventions. was detected and identified as the probable cause of Normal results were obtained on the following bio her confusion. This was addressed by changing the pa chemical parameters: complete blood count, sodium tient's prescription for sertraline to escitalopram. Her (138 mEq/mL), potassium, thyroid-stimulating hor- confusion did not resolve, and she was discharged to a mone, vitamin Bl> glucose, and liver enzymes. Con nursing home, where she remained unable to care for sistent with some dehydration, the blood urea nitro herself for the ensuing 5 months. gen level was elevated (28 mg/dL). Urine cultures The patient's medical history was notable for chronic were negative. obstructive pulmonary disease, depression with anxiety, Because the patient denied any current back pain and diabetes mellitus, atrial fibrillation, spinal stenosis, and showed no evidence of pain, her methadone dose was gastroesophageal reflux disease. Her depression had decreased. She had no increase in pain at a methadone reportedly been successfully treated with sertraline. No dosage of 7.5 rag/d; however, her mental status was other psychiatric history was reported by her family, unchanged. Dextromethorphan was then discontinued although a niece indicated possible past dependent per without worsening of cough. After 1 week, the patient sonality features. The patient's diabetes was managed was increasingly alert, was eating better, and sponta without medication. There was no history of seizures, neously reported feeling less confusion. She was able to loss of consciousness, loss of bowel or bladder control, state all 7 days of the week in reverse order without or cerebrovascular accident. Multiple narcotics had been cuing. After 2 weeks, she was able to recall 3 of 3 prescribed in the past for pain related to spinal stenosis, objects at 5 minutes without hesitation. After several and the patient had most recently been receiving weeks, her mood and affect continued to be bright, she methadone 20 mg/d and hydrocodone/acetaminophen continued to recall 3 of 3 objects without difficulty, she tablets as needed. After her nursing home admission, could recite the days of the week backwards without the patient's primary care physician had reduced the difficulty, and she had returned to her baseline func methadone dose to 10 mg/d without any improve tional status and level of socializing before hospitaliza ment in her mental status. Other medications included tion for pneumonia. The methadone dose was further escitalopram, ipratropium bromide, metoclopramide, tapered and the drug was discontinued at 2 months. metolazone, and warfarin. Combination guaifenesin/ dextromethorphan 600 mg/30 mg BID had been ini- DISCUSSION tiated for cough related to pneumonia at the time of This elderly patient exhibited a fairly abrupt change in the patient's hospitalization 5 months earlier. Although mental status after her hospitalization for pneumonia. there was no record of persistent cough, this medica- As with many elderly patients, she had multiple comor- tion had not been discontinued. bidities and was receiving multiple medications. She On initial evaluation at the nursing home, the patient remained confused and lethargic during 5 months in appeared lethargic. She confirmed that she had poor the nursing home, and had a presumptive diagnosis of appetite, hypersomnia, sadness, hopelessness, and a pas dementia. Mental status testing clearly showed greater sive wish to die. Her mood was sad, although she could impairment of the patient's attention than of her mere smile appropriately on occasion. There was no evidence ory, suggesting that delirium played some part in her of thought disorder, hallucinations, or delusions. How confusion. The role of delirium was further supported ever, she exhibited intermittent episodes of staring for by the acute onset of symptoms after pneumonia. 10 seconds at a time, a behavior that was spontaneously Notably, discontinuation of dextromethorphan quickly reported by her family. On mental status examination, resulted in improved mental status and mood. Blood the patient's memory was moderately impaired, as she levels of dextromethorphan and methadone were not could recall 1 of 3 objects at 3 minutes and the other 2 obtained, nor was CYP activity assessed; therefore, a with cuing. Her attention, on the other hand, was conclusive inference about the etiology of the patient's markedly impaired, as indicated by her inability to state delirium could not be made. However, the onset and any days of the week in reverse order despite cuing and resolution of confusion were clearly temporally related multiple trials, although she was able to recite the days to the initiation and discontinuation of dextromethor in their normal sequence without difficulty. phan. The role of this agent in the patient's delirium No focal neurologic deficits were noted on a limited was rated as probable on the Naranjo Adverse Drug physical examination. Further neurologic evaluations, Reaction Probability Scale. l° This case highlights the

18 E.E. Lotrich et M. The American Journal of Geriatric Phar,nacotherapy

need for a high index of suspicion when assessing delir potentially increasing dextromethorphan levels; the list inm in elderly patients, particularly with respect to may be extensive, including fluoxetine, paroxetine, potential drug interactions and adverse drug effects. cimetidine, hydroxyzine, and quinidine. ~° Several Web Dextromethorphan is normally well tolerated at the sites listing inhibitors of and snbstrates for CYP2D6 are usual doses. No interactions between dextromethor- now available for reference (eg, www.drug-interactions. phan and the patient's other medications are noted in corn). As dextromethorphan, methadone, and many of Physidans" Desk Referencell or medication interaction these other medications are used in the elderly and in software such as ePocrates Rx 4.0 (ePocrates Inc., San palliative care settings, prescribers should be aware of Mateo, California). Furthermore, despite methadone the potential for drug interactions. being a known CYP2D6 inhibitor, to our knowledge adverse interactions with dextromethorphan have not CONCLUSIONS been reported previously. In fact, there were no reports In general, clinicians evaluating mental status changes of delirium in a study in 10 medically healthy adult in the elderly should conduct a careful review of medi males aged 21 to 55 years who were receiving metha- cations to determine whether each is, in fact, necessary. done maintenance therapy and were challenged with They also should look for changes in medications that dextromethorphan. 12 That study did report a strong coincide temporally with the onset of confusion. In relationship between the dextromethorphan dose and addition, they should recognize that the elderly may adverse effects, primarily sedation and "feeling high." have increased vulnerability to adverse effects related to Notably, over the counter products containing dextro numerous medications and that not all potential inter methorphan are increasingly abused at high doses for actions have yet been reported. In the case reported their dissociative like effects. 13,14 here, it appears that the interaction between dextro The patient in the present case may have been at methorphan and methadone resulted in unrecognized increased risk for dextromethorphan-induced deliri- delirium. Delirium had a profound effect in terms of um, as concomitant methadone can significantly inhib the patient's social functioning and general health, and it CYP2D6 activity. 8,9 Moreover, in older patients, incurred the costs of nursing home placement. Caution NMDA receptors may be decreased 15 and sensitivity to is therefore warranted when coprescribing dextro- glutamaterglc antagonism may be increased. 16 Other methorphan and medications that inhibit CYP2D6, factors that may have contributed to potential vulnera particularly in potentially vulnerable elderly patients. bility in this patient include possible mild baseline dementia, some dehydration, and use of a selective REFERENCES seromnin renptake inhibitor. Dextromethorphan can 1. Kerry NL, Somogyi AA, Boclmer F, /Vlikus G. The role indirectly increase seromnin in the brain stem, and of CYP2D6 in primary and secondary oxidative metab- serotonin syndrome has been reported when this olism of dextromethorphan: In vitro studies using hu drug was coprescribed with antidepressants. 17 There man liver microsomes. Br J Clin l)harmacol. 1994;38: fore, particular caution is recommended with anti- 243-248. depressants that inhibit CYP2D6, such as fluoxetine 2. 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19 The America~ Jour~M of Geriatric Pharmacorherapy tqE.Lotrich et M.

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Address correspondence to: Francis E. Lotrich, MD, PhD, Western Psychiatric Institute and Clinic, 3811 Ohara Street, Pittsburgh, PA 15213. E mail: [email protected]