Ruling out Delirium: Therapeutic Principles of Withdrawing and Changing Medications

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Ruling out delirium: Therapeutic principles of withdrawing and changing medications

Jill Kauer, PharmD, MSPhr, BCPP

s. M, age 71, was diagnosed tribute to delirium and should be evaluated with Alzheimer’s disease sev- to determine if they can be discontinued eral months ago and her clinical in a patient with symptoms consistent M 1 presentation and Mini-Mental Status Exam with delirium. score of 22 indicates mild dementia. In addi- Consider withdrawing or replacing tion to chronic medications for hypertension, medications that are strongly implicated Ms. M has been taking lorazepam, 1 mg, in causing delirium with another medica- Vicki L. Ellingrod, 3 times daily, for >15 years for unspecified tion for the same indication with a lower PharmD, FCCP anxiety. potential for precipitating or exacerbating Department Editor Ms. M becomes more confused at home delirium. Benzodiazepines and opioids are over the course of a few days, and her daugh- medications most clearly associated with ter brings her to her primary care physician for an increased risk for delirium,3 although evaluation. Recognizing that benzodiazepines medications with significant anticholiner- can contribute to delirium, the physician dis- gic properties have been associated with continues lorazepam. Three days later, Ms. M’s increased severity of delirium in patients confusion worsens, and she develops nausea with and without underlying demen- and a tremor. She is taken to the local emer- tia4 and are consistently cited as common gency department where she is admitted for causes of drug-induced delirium.1,2 Table 15 benzodiazepine withdrawal and diagnosed (page 42) lists medications that are known with a urinary tract infection. to be anticholinergic. The 2015 Updated Beers Criteria for Potentially Inappropriate Because dementia is a strong risk factor Medication Use in Older Adults added non- for developing delirium,1 withdrawing or benzodiazepine receptor agonist hypnotics changing medications to rule out delirium in patients with mild dementia, such as Practice Points Ms. M, is a common clinical scenario. • Medications strongly implicated in Although delirium often is multifactorial, causing delirium should be withdrawn medications are frequent predisposing or switched. and precipitating factors and contribute • Take into account dosage and duration of Savvy Psychopharmacology to approximately 12% to 39% of delirium treatment, medication half-life, nature of is produced in partnership 1,2 with the College cases. A recently initiated medication is withdrawal symptoms, and care setting of Psychiatric more likely to be a precipitant for delirium; when determining how fast to taper a and Neurologic however, long-term medications can con- medication. Pharmacists cpnp.org Dr. Kauer is Clinical Assistant Professor, College of Pharmacy, University • More aggressive tapering over 2 or 3 mhc.cpnp.org (journal) of Iowa, Iowa City, Iowa. days can be considered for inpatients, Disclosure while gradual tapering might be necessary The author reports no financial relationship with any company whose to ensure safety in outpatients. products are mentioned in this article or with manufacturers of Current Psychiatry competing products. Vol. 16, No. 2 41 Savvy Psychopharmacology

Table 1 Table 2 Medications with significant Half-lives of commonly used anticholinergic activity benzodiazepines and opioids Markedly anticholinergic Elimination Medication class medications Medication half-life Anticholinergics Atropine Benzodiazepines Benztropine Scopolamine Diazepam 44 to 48 hours (active Trihexyphenidyl metabolite: 100 hours) Urinary indications: Chlordiazepoxide 7 to 28 hours (active Darifenacin metabolite: 14 to 95 hours) Flavoxate Oxybutynin Clonazepam 17 to 60 hours Clinical Point Tolterodine Temazepam 4 to 18 hours Gastrointestinal: Taper opioids as Dicyclomine Lorazepam Approximately 12 hours Hyoscyamine quickly and as safely Alprazolam Approximately 11 hours Propantheline as possible, with (16 hours in geriatric Antidepressants Amitriptyline patients) a recommended Desipramine Opioids reduction of ≤20% Doxepin Imipramine Methadone 9 to 87 hours per day to prevent Nortriptyline Protriptyline Fentanyl 20 to 27 hours withdrawal Trimipramine (transdermal patch) Antiemetics Promethazine Antihistamines Brompheniramine Oxycodone Approximately 4 hours Chlorpheniramine Hydrocodone 3 to 4 hours Clemastine Clomipramine Morphine 2 to 4 hours Dimenhydrinate Diphenhydramine Codeine Approximately 3 hours Hydroxyzine Hydromorphone 2 to 3 hours Meclizine Pyrilamine Source: Lexicomp Antipsychotics Chlorpromazine Clozapine Thioridazine Skeletal muscle Orphenadrine relaxants to taper and the best strategy for doing

Source: Reference 5 so depends on a number of factors and requires clinical judgement. When determining how quickly to withdraw a potentially offending medication in a patient (ie, zolpidem, zaleplon, and eszopiclone) as with suspected delirium, clinicians should medications to avoid in patients who have consider: Discuss this article at dementia because of adverse CNS effects.6 www.facebook.com/ These drugs also would be appropriate Dosage and duration of treatment. CurrentPsychiatry targets for withdrawal or modification Consider tapering and discontinuing in patients with mild dementia and sus- benzodiazepines in a patient who is taking pected delirium. more than the minimal scheduled dosages In general, there are no firm rules for for ≥2 weeks, especially after 8 weeks of how to taper and discontinue potentially scheduled treatment. Consider tapering Current Psychiatry 42 February 2017 deliriogenic medications, as both the need opioids in a patient taking more than the Savvy Psychopharmacology

Table 3 Related Resources Withdrawal symptoms of • Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines deliriogenic medications in primary care. CNS Drugs. 2009;23(1):19-34. Medication Withdrawal • U.S. Department of Veterans Affairs; Department of Defense. class symptoms Effective treatments for PTSD: helping patients taper from benzodiazepines. www.va.gov/PAINMANAGEMENT/docs/ Benzodiazepines Anxiety OSI_6_Toolkit_Taper_Benzodiazepines_Clinicians.pdf. Delirium • U.S. Department of Veterans Affairs; Department of Defense. Depressed mood Tapering and discontinuing opioids. www.healthquality. Diaphoresis va.gov/guidelines/Pain/cot/OpioidTaperingFactSheet23 Insomnia May2013v1.pdf. Irritability Nausea Drug Brand Names Psychomotor agitation Acetaminophen/codeine • Hydromorphone • Dilaudid Psychosis Tylenol No. 3 Hydroxyzine • Atarax, Vistaril Clinical Point Seizures Alprazolam • Xanax Hyoscyamine • Levsin Tachycardia Amitriptyline • Elavil Imipramine • Tofranil Generally, potentially Tinnitus Atropine • AtroPen Lorazepam • Ativan Tremor Benztropine • Cogentin Meclizine • Antivert deliriogenic Brompheniramine • J-Tan PD Methadone • Dolophine Opioids Anxiety/irritability Chlordiazepoxide • Librium Morphine • MS Contin medications can Diaphoresis Chlorpheniramine • Nortriptyline • Pamelor be discontinued Diarrhea Chlor-Trimeton Orphenadrine • Norflex Joint/muscle pain Chlorpromazine • Thorazine Oxybutynin • Ditropan without tapering if Lacrimation Clemastine • Tavist Oxycodone • Oxycontin, Nausea Clomipramine • Anafranil Roxicodone taken on a non-daily, Piloerection Clonazepam • Klonopin Promethazine • Phenergan as-needed basis Pupillary dilation Clozapine • Clozaril Propantheline • Restlessness Darifenacin • Enablex Pro-Banthene Rhinorrhea Desipramine • Norpramin Protriptyline • Vivactil Sneezing Diazepam • Valium Pyrilamine • Ru-Hist-D Tremor Dicyclomine • Bentyl Scopolamine • Transderm Dimenhydrinate • Scop Vomiting Dramamine Temazepam • Restoril Yawning Diphenhydramine • Benadryl Thioridazine • Mellaril Anticholinergics Agents with anticholinergic Doxepin • Sinequan Tolterodine • Detrol effects may be associated Eszopiclone • Lunesta Trihexyphenidyl • Artane with additional withdrawal Fentanyl (transdermal patch) • Trimipramine • Surmontil symptoms depending on Duragesic Zaleplon • Sonata the action of the drug at Flavoxate • Urispas Zolpidem • Ambien, Hydrocodone • Hysingla, Edluar, Intermezzo non-muscarinic receptors, Zohydro but anticipated symptoms of cholinergic rebound include: Agitation Diarrhea Headache deliriogenic medications can be discontin- Nausea Restlessness ued without tapering if they are taken on a Sweating non-daily, as-needed basis. Vomiting The half-life of a medication determines both the onset and duration of withdrawal symptoms. Withdrawal occurs earlier minimal scheduled dosage for more than when discontinuing medications with a few days. When attempting to rule out short elimination half-lives (usually within delirium, taper opioids as quickly and 1 to 2 days) and might not emerge until 3 as safely possible, with a recommended to 8 days after discontinuation for medi- reduction of ≤20% per day to prevent with- cations with a half-life >24 hours. Many Current Psychiatry drawal symptoms. In general, potentially resources suggest switching to an agent Vol. 16, No. 2 43 Savvy Psychopharmacology

with a longer half-life when tapering and considered, particularly when high dos- discontinuing benzodiazepines or opioids ages have been prescribed, to minimize to provide a smoother withdrawal (Table 2, patient discomfort. page 42). When ruling out delirium in patients with mild dementia, particularly Care setting. When tapering and discon- in a geriatric patient with reduced medica- tinuing a medication, regularly monitor tion clearance, avoid switching to a longer- patients for withdrawal symptoms; slow acting benzodiazepine or opioid because or temporarily stop the taper if withdrawal this could prolong delirium symptoms. symptoms occur. Because close monitoring is easier in an inpatient vs an outpatient care Nature of withdrawal symptoms. In setting, more aggressive tapering over 2 to 3 patients with suspected delirium, taper- days generally can be considered, although Clinical Point ing over weeks or months—often rec- more gradual tapering might be prudent to Because close ommended for sedative-hypnotics and ensure safety of outpatients. opioids—is not a realistic option; how- monitoring is easier ever, stopping the medication abruptly can References 1. Inouye SK. Delirium in older persons. N Engl J Med. during inpatient lead to intolerable withdrawal symptoms 2006;354(11):1157-1165. care, more aggressive (Table 3, page 43). Avoiding withdrawal 2. Alagiakrishnan K, Wiens CA. An approach to drug induced delirium in the elderly. Postgrad Med J. 2004;80(945):388-393. from benzodiazepines is particularly impor- tapering over 2 to 3 3. Clegg A, Young JB. Which medications to avoid in people at tant because of the potential for severe com- risk of delirium: a systematic review. Age Aging. 2010;40(1): days generally can be plications, including seizures and delirium, 23-29. 4. Han L, McCusker J, Cole M, et al. Use of medications with considered and possibly death. Withdrawal seizures anticholinergic effect predicts clinical severity of delirium are especially common with alprazolam symptoms in older medical inpatients. Arch Intern Med. 2001;161(8):1099-1105. because of its short half-life, so addi- 5. Carnahan RM, Lund BC, Perry PJ, et al. The Anticholinergic tional caution is warranted when taper- Drug Scale as a measure of drug-related anticholinergic burden: associations with serum anticholinergic activity. J Clin ing and discontinuing this medication. Pharmacol. 2006;46(12):1481-1486. Withdrawal from opioids or anticholiner- 6. American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American Geriatrics Society 2015 Updated Beers Criteria gics generally is not life-threatening, but for Potentially Inappropriate Medication Use in Older Adults. J a brief taper of these medications can be Am Geriatr Soc. 2015;63(11):2227-2246.

Current Psychiatry 44 February 2017