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Ruling out delirium: Therapeutic principles of withdrawing and changing medications
 

Ms. M, age 71, was diagnosed with Alzheimer’s disease several months ago and her clinical presentation and Mini-Mental Status Exam score of 22 indicates mild dementia. In addition to chronic medications for hypertension, Ms. M has been taking lorazepam, 1 mg, 3 times daily, for >15 years for unspecified anxiety.

Ms. M becomes more confused at home over the course of a few days, and her daughter brings her to her primary care physician for evaluation. Recognizing that benzodiazepines can contribute to delirium, the physician discontinues lorazepam. Three days later, Ms. M’s confusion worsens, and she develops nausea and a tremor. She is taken to the local emergency department where she is admitted for benzodiazepine withdrawal and diagnosed with a urinary tract infection.

Because dementia is a strong risk factor for developing delirium,1 withdrawing or changing

medications to rule out delirium in patients with mild dementia, such as Ms. M, is a common clinical scenario. Although delirium often is multifactorial, medications are frequent predisposing and precipitating factors and contribute to approximately 12% to 39% of delirium cases.1,2 A recently initiated medication is more likely to be a precipitant for delirium; however, long-term medications can contribute to delirium and should be evaluated to determine if they can be discontinued in a patient with symptoms consistent with delirium.1

 

Consider withdrawing or replacing medications that are strongly implicated in causing delirium with another medication for the same indication with a lower potential for

precipitating or exacerbating delirium. Benzodiazepines and opioids are medications most clearly associated with an increased risk for delirium,3 although medications with significant anticholinergic properties have been associated with increased severity of delirium in patients with and without underlying dementia4 and are consistently cited as common causes of drug-induced delirium.1,2 Table 15 lists medications that are known to be anticholinergic. The 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults added non-benzodiazepine receptor agonist hypnotics (ie, zolpidem, zaleplon, and eszopiclone) as medications to avoid in patients who have dementia because of adverse CNS effects.6 These drugs also would be appropriate targets for withdrawal or modification in patients with mild dementia and suspected delirium.
 

 

 

 

In general, there are no firm rules for how to taper and discontinue potentially deliriogenic medications, as both the need to taper and the best strategy for doing so depends on a number of factors and requires clinical judgement. When determining how quickly to withdraw a potentially offending medication in a patient with suspected delirium, clinicians should consider:

Dosage and duration of treatment. Consider tapering and discontinuing benzodiazepines in a patient who is taking more than the minimal scheduled dosages for ≥2 weeks, especially after 8 weeks of scheduled treatment. Consider tapering opioids in a patient taking more than the minimal scheduled dosage for more than a few days. When attempting to rule out delirium, taper opioids as quickly and as safely possible, with a recommended reduction of ≤20% per day to prevent withdrawal symptoms. In general, potentially deliriogenic medications can be discontinued without tapering if they are taken on a non-daily, as-needed basis.

The half-life of a medication determines both the onset and duration of withdrawal symptoms. Withdrawal occurs earlier when discontinuing medications with short

elimination half-lives (usually within 1 to 2 days) and might not emerge until 3 to 8 days after discontinuation for medications with a half-life >24 hours. Many resources suggest switching to an agent with a longer half-life when tapering and discontinuing benzodiazepines or opioids to provide a smoother withdrawal (Table 2). When ruling out delirium in patients with mild dementia, particularly in a geriatric patient with reduced medication clearance, avoid switching to a longer-acting benzodiazepine or opioid because this could prolong delirium symptoms.

Nature of withdrawal symptoms. In patients with suspected delirium, tapering over weeks or
months—often recommended for sedative-hypnotics and opioids—is not a realistic option; however, stopping the medication abruptly can lead to intolerable withdrawal symptoms (Table 3). Avoiding withdrawal from benzodiazepines is particularly important because of the potential for severe complications, including seizures and delirium, and possibly death. Withdrawal seizures are especially common with alprazolam because of its short half-life, so additional caution is warranted when tapering and discontinuing this medication. Withdrawal from opioids or anticholinergics generally is not life-threatening, but a brief taper of these medications can be considered, particularly when high dosages have been prescribed, to minimize patient discomfort.

Care setting. When tapering and discontinuing a medication, regularly monitor patients for withdrawal symptoms; slow or temporarily stop the taper if withdrawal symptoms occur. Because close monitoring is easier in an inpatient vs an outpatient care setting, more aggressive tapering over 2 to 3 days generally can be considered, although more gradual tapering might be prudent to ensure safety of outpatients.

 

 

 

Related Resources

  • Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs. 2009;23(1):19-34.
  • U.S. Department of Veterans Affairs; Department of Defense. Effective treatments for PTSD: helping patients taper from benzodiazepines. www.va.gov/PAINMANAGEMENT/docs/OSI_6_Toolkit_Taper_Benzodiazepines_Clinicians.pdf.
  • U.S. Department of Veterans Affairs; Department of Defense. Tapering and discontinuing opioids. www.healthquality.va.gov/guidelines/Pain/cot/OpioidTaperingFactSheet23May2013v1.pdf.

Drug Brand Names
Acetaminophen/codeine Tylenol No. 3
Alprazolam Xanax
Amitriptyline Elavil
Atropine AtroPen
Benztropine Cogentin
Brompheniramine J-Tan PD
Chlordiazepoxide Librium
Chlorpheniramine Chlor-Trimeton
Chlorpromazine Thorazine
Clemastine Tavist
Clomipramine Anafranil
Clonazepam Klonopin
Clozapine Clozaril
Darifenacin Enablex
Desipramine Norpramin
Diazepam Valium
Dicyclomine Bentyl
Dimenhydrinate Dramamine
Diphenhydramine Benadryl
Doxepin Sinequan
Eszopiclone Lunesta
Fentanyl (transdermal patch) Duragesic
Flavoxate Urispas
Hydrocodone Hysingla, Zohydro
Hydromorphone Dilaudid
Hydroxyzine Atarax, Vistaril
Hyoscyamine Levsin
Imipramine Tofranil
Lorazepam Ativan
Meclizine Antivert
Methadone Dolophine
Morphine MS Contin
Nortriptyline Pamelor
Orphenadrine Norflex
Oxybutynin Ditropan
Oxycodone Oxycontin, Roxicodone
Promethazine Phenergan
Propantheline Pro-Banthene
Protriptyline Vivactil
Pyrilamine Ru-Hist-D
Scopolamine Transderm Scop
Temazepam Restoril
Thioridazine Mellaril
Tolterodine Detrol
Trihexyphenidyl Artane
Trimipramine Surmontil
Zaleplon Sonata
Zolpidem Ambien, Edluar, Intermezzo

References

1. Inouye SK. Delirium in older persons. N Engl J Med. 2006;354(11):1157-1165.
2. Alagiakrishnan K, Wiens CA. An approach to drug induced delirium in the elderly. Postgrad Med J. 2004;80(945):388-393.
3. Clegg A, Young JB. Which medications to avoid in people at risk of delirium: a systematic review. Age Aging. 2010;40(1):23-29.
4. Han L, McCusker J, Cole M, et al. Use of medications with anticholinergic effect predicts clinical severity of delirium symptoms in older medical inpatients. Arch Intern Med. 2001;161(8):1099-1105.
5. Carnahan RM, Lund BC, Perry PJ, et al. The Anticholinergic Drug Scale as a measure of drug-related anticholinergic burden: associations with serum anticholinergic activity. J Clin Pharmacol. 2006;46(12):1481-1486.
6. American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2015;63(11):2227-2246.

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Dr. Kauer is Clinical Assistant Professor, College of Pharmacy, University of Iowa, Iowa City, Iowa.

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Dr. Kauer is Clinical Assistant Professor, College of Pharmacy, University of Iowa, Iowa City, Iowa.

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Ms. M, age 71, was diagnosed with Alzheimer’s disease several months ago and her clinical presentation and Mini-Mental Status Exam score of 22 indicates mild dementia. In addition to chronic medications for hypertension, Ms. M has been taking lorazepam, 1 mg, 3 times daily, for >15 years for unspecified anxiety.

Ms. M becomes more confused at home over the course of a few days, and her daughter brings her to her primary care physician for evaluation. Recognizing that benzodiazepines can contribute to delirium, the physician discontinues lorazepam. Three days later, Ms. M’s confusion worsens, and she develops nausea and a tremor. She is taken to the local emergency department where she is admitted for benzodiazepine withdrawal and diagnosed with a urinary tract infection.

Because dementia is a strong risk factor for developing delirium,1 withdrawing or changing

medications to rule out delirium in patients with mild dementia, such as Ms. M, is a common clinical scenario. Although delirium often is multifactorial, medications are frequent predisposing and precipitating factors and contribute to approximately 12% to 39% of delirium cases.1,2 A recently initiated medication is more likely to be a precipitant for delirium; however, long-term medications can contribute to delirium and should be evaluated to determine if they can be discontinued in a patient with symptoms consistent with delirium.1

 

Consider withdrawing or replacing medications that are strongly implicated in causing delirium with another medication for the same indication with a lower potential for

precipitating or exacerbating delirium. Benzodiazepines and opioids are medications most clearly associated with an increased risk for delirium,3 although medications with significant anticholinergic properties have been associated with increased severity of delirium in patients with and without underlying dementia4 and are consistently cited as common causes of drug-induced delirium.1,2 Table 15 lists medications that are known to be anticholinergic. The 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults added non-benzodiazepine receptor agonist hypnotics (ie, zolpidem, zaleplon, and eszopiclone) as medications to avoid in patients who have dementia because of adverse CNS effects.6 These drugs also would be appropriate targets for withdrawal or modification in patients with mild dementia and suspected delirium.
 

 

 

 

In general, there are no firm rules for how to taper and discontinue potentially deliriogenic medications, as both the need to taper and the best strategy for doing so depends on a number of factors and requires clinical judgement. When determining how quickly to withdraw a potentially offending medication in a patient with suspected delirium, clinicians should consider:

Dosage and duration of treatment. Consider tapering and discontinuing benzodiazepines in a patient who is taking more than the minimal scheduled dosages for ≥2 weeks, especially after 8 weeks of scheduled treatment. Consider tapering opioids in a patient taking more than the minimal scheduled dosage for more than a few days. When attempting to rule out delirium, taper opioids as quickly and as safely possible, with a recommended reduction of ≤20% per day to prevent withdrawal symptoms. In general, potentially deliriogenic medications can be discontinued without tapering if they are taken on a non-daily, as-needed basis.

The half-life of a medication determines both the onset and duration of withdrawal symptoms. Withdrawal occurs earlier when discontinuing medications with short

elimination half-lives (usually within 1 to 2 days) and might not emerge until 3 to 8 days after discontinuation for medications with a half-life >24 hours. Many resources suggest switching to an agent with a longer half-life when tapering and discontinuing benzodiazepines or opioids to provide a smoother withdrawal (Table 2). When ruling out delirium in patients with mild dementia, particularly in a geriatric patient with reduced medication clearance, avoid switching to a longer-acting benzodiazepine or opioid because this could prolong delirium symptoms.

Nature of withdrawal symptoms. In patients with suspected delirium, tapering over weeks or
months—often recommended for sedative-hypnotics and opioids—is not a realistic option; however, stopping the medication abruptly can lead to intolerable withdrawal symptoms (Table 3). Avoiding withdrawal from benzodiazepines is particularly important because of the potential for severe complications, including seizures and delirium, and possibly death. Withdrawal seizures are especially common with alprazolam because of its short half-life, so additional caution is warranted when tapering and discontinuing this medication. Withdrawal from opioids or anticholinergics generally is not life-threatening, but a brief taper of these medications can be considered, particularly when high dosages have been prescribed, to minimize patient discomfort.

Care setting. When tapering and discontinuing a medication, regularly monitor patients for withdrawal symptoms; slow or temporarily stop the taper if withdrawal symptoms occur. Because close monitoring is easier in an inpatient vs an outpatient care setting, more aggressive tapering over 2 to 3 days generally can be considered, although more gradual tapering might be prudent to ensure safety of outpatients.

 

 

 

Related Resources

  • Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs. 2009;23(1):19-34.
  • U.S. Department of Veterans Affairs; Department of Defense. Effective treatments for PTSD: helping patients taper from benzodiazepines. www.va.gov/PAINMANAGEMENT/docs/OSI_6_Toolkit_Taper_Benzodiazepines_Clinicians.pdf.
  • U.S. Department of Veterans Affairs; Department of Defense. Tapering and discontinuing opioids. www.healthquality.va.gov/guidelines/Pain/cot/OpioidTaperingFactSheet23May2013v1.pdf.

Drug Brand Names
Acetaminophen/codeine Tylenol No. 3
Alprazolam Xanax
Amitriptyline Elavil
Atropine AtroPen
Benztropine Cogentin
Brompheniramine J-Tan PD
Chlordiazepoxide Librium
Chlorpheniramine Chlor-Trimeton
Chlorpromazine Thorazine
Clemastine Tavist
Clomipramine Anafranil
Clonazepam Klonopin
Clozapine Clozaril
Darifenacin Enablex
Desipramine Norpramin
Diazepam Valium
Dicyclomine Bentyl
Dimenhydrinate Dramamine
Diphenhydramine Benadryl
Doxepin Sinequan
Eszopiclone Lunesta
Fentanyl (transdermal patch) Duragesic
Flavoxate Urispas
Hydrocodone Hysingla, Zohydro
Hydromorphone Dilaudid
Hydroxyzine Atarax, Vistaril
Hyoscyamine Levsin
Imipramine Tofranil
Lorazepam Ativan
Meclizine Antivert
Methadone Dolophine
Morphine MS Contin
Nortriptyline Pamelor
Orphenadrine Norflex
Oxybutynin Ditropan
Oxycodone Oxycontin, Roxicodone
Promethazine Phenergan
Propantheline Pro-Banthene
Protriptyline Vivactil
Pyrilamine Ru-Hist-D
Scopolamine Transderm Scop
Temazepam Restoril
Thioridazine Mellaril
Tolterodine Detrol
Trihexyphenidyl Artane
Trimipramine Surmontil
Zaleplon Sonata
Zolpidem Ambien, Edluar, Intermezzo

 

Ms. M, age 71, was diagnosed with Alzheimer’s disease several months ago and her clinical presentation and Mini-Mental Status Exam score of 22 indicates mild dementia. In addition to chronic medications for hypertension, Ms. M has been taking lorazepam, 1 mg, 3 times daily, for >15 years for unspecified anxiety.

Ms. M becomes more confused at home over the course of a few days, and her daughter brings her to her primary care physician for evaluation. Recognizing that benzodiazepines can contribute to delirium, the physician discontinues lorazepam. Three days later, Ms. M’s confusion worsens, and she develops nausea and a tremor. She is taken to the local emergency department where she is admitted for benzodiazepine withdrawal and diagnosed with a urinary tract infection.

Because dementia is a strong risk factor for developing delirium,1 withdrawing or changing

medications to rule out delirium in patients with mild dementia, such as Ms. M, is a common clinical scenario. Although delirium often is multifactorial, medications are frequent predisposing and precipitating factors and contribute to approximately 12% to 39% of delirium cases.1,2 A recently initiated medication is more likely to be a precipitant for delirium; however, long-term medications can contribute to delirium and should be evaluated to determine if they can be discontinued in a patient with symptoms consistent with delirium.1

 

Consider withdrawing or replacing medications that are strongly implicated in causing delirium with another medication for the same indication with a lower potential for

precipitating or exacerbating delirium. Benzodiazepines and opioids are medications most clearly associated with an increased risk for delirium,3 although medications with significant anticholinergic properties have been associated with increased severity of delirium in patients with and without underlying dementia4 and are consistently cited as common causes of drug-induced delirium.1,2 Table 15 lists medications that are known to be anticholinergic. The 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults added non-benzodiazepine receptor agonist hypnotics (ie, zolpidem, zaleplon, and eszopiclone) as medications to avoid in patients who have dementia because of adverse CNS effects.6 These drugs also would be appropriate targets for withdrawal or modification in patients with mild dementia and suspected delirium.
 

 

 

 

In general, there are no firm rules for how to taper and discontinue potentially deliriogenic medications, as both the need to taper and the best strategy for doing so depends on a number of factors and requires clinical judgement. When determining how quickly to withdraw a potentially offending medication in a patient with suspected delirium, clinicians should consider:

Dosage and duration of treatment. Consider tapering and discontinuing benzodiazepines in a patient who is taking more than the minimal scheduled dosages for ≥2 weeks, especially after 8 weeks of scheduled treatment. Consider tapering opioids in a patient taking more than the minimal scheduled dosage for more than a few days. When attempting to rule out delirium, taper opioids as quickly and as safely possible, with a recommended reduction of ≤20% per day to prevent withdrawal symptoms. In general, potentially deliriogenic medications can be discontinued without tapering if they are taken on a non-daily, as-needed basis.

The half-life of a medication determines both the onset and duration of withdrawal symptoms. Withdrawal occurs earlier when discontinuing medications with short

elimination half-lives (usually within 1 to 2 days) and might not emerge until 3 to 8 days after discontinuation for medications with a half-life >24 hours. Many resources suggest switching to an agent with a longer half-life when tapering and discontinuing benzodiazepines or opioids to provide a smoother withdrawal (Table 2). When ruling out delirium in patients with mild dementia, particularly in a geriatric patient with reduced medication clearance, avoid switching to a longer-acting benzodiazepine or opioid because this could prolong delirium symptoms.

Nature of withdrawal symptoms. In patients with suspected delirium, tapering over weeks or
months—often recommended for sedative-hypnotics and opioids—is not a realistic option; however, stopping the medication abruptly can lead to intolerable withdrawal symptoms (Table 3). Avoiding withdrawal from benzodiazepines is particularly important because of the potential for severe complications, including seizures and delirium, and possibly death. Withdrawal seizures are especially common with alprazolam because of its short half-life, so additional caution is warranted when tapering and discontinuing this medication. Withdrawal from opioids or anticholinergics generally is not life-threatening, but a brief taper of these medications can be considered, particularly when high dosages have been prescribed, to minimize patient discomfort.

Care setting. When tapering and discontinuing a medication, regularly monitor patients for withdrawal symptoms; slow or temporarily stop the taper if withdrawal symptoms occur. Because close monitoring is easier in an inpatient vs an outpatient care setting, more aggressive tapering over 2 to 3 days generally can be considered, although more gradual tapering might be prudent to ensure safety of outpatients.

 

 

 

Related Resources

  • Lader M, Tylee A, Donoghue J. Withdrawing benzodiazepines in primary care. CNS Drugs. 2009;23(1):19-34.
  • U.S. Department of Veterans Affairs; Department of Defense. Effective treatments for PTSD: helping patients taper from benzodiazepines. www.va.gov/PAINMANAGEMENT/docs/OSI_6_Toolkit_Taper_Benzodiazepines_Clinicians.pdf.
  • U.S. Department of Veterans Affairs; Department of Defense. Tapering and discontinuing opioids. www.healthquality.va.gov/guidelines/Pain/cot/OpioidTaperingFactSheet23May2013v1.pdf.

Drug Brand Names
Acetaminophen/codeine Tylenol No. 3
Alprazolam Xanax
Amitriptyline Elavil
Atropine AtroPen
Benztropine Cogentin
Brompheniramine J-Tan PD
Chlordiazepoxide Librium
Chlorpheniramine Chlor-Trimeton
Chlorpromazine Thorazine
Clemastine Tavist
Clomipramine Anafranil
Clonazepam Klonopin
Clozapine Clozaril
Darifenacin Enablex
Desipramine Norpramin
Diazepam Valium
Dicyclomine Bentyl
Dimenhydrinate Dramamine
Diphenhydramine Benadryl
Doxepin Sinequan
Eszopiclone Lunesta
Fentanyl (transdermal patch) Duragesic
Flavoxate Urispas
Hydrocodone Hysingla, Zohydro
Hydromorphone Dilaudid
Hydroxyzine Atarax, Vistaril
Hyoscyamine Levsin
Imipramine Tofranil
Lorazepam Ativan
Meclizine Antivert
Methadone Dolophine
Morphine MS Contin
Nortriptyline Pamelor
Orphenadrine Norflex
Oxybutynin Ditropan
Oxycodone Oxycontin, Roxicodone
Promethazine Phenergan
Propantheline Pro-Banthene
Protriptyline Vivactil
Pyrilamine Ru-Hist-D
Scopolamine Transderm Scop
Temazepam Restoril
Thioridazine Mellaril
Tolterodine Detrol
Trihexyphenidyl Artane
Trimipramine Surmontil
Zaleplon Sonata
Zolpidem Ambien, Edluar, Intermezzo

References

1. Inouye SK. Delirium in older persons. N Engl J Med. 2006;354(11):1157-1165.
2. Alagiakrishnan K, Wiens CA. An approach to drug induced delirium in the elderly. Postgrad Med J. 2004;80(945):388-393.
3. Clegg A, Young JB. Which medications to avoid in people at risk of delirium: a systematic review. Age Aging. 2010;40(1):23-29.
4. Han L, McCusker J, Cole M, et al. Use of medications with anticholinergic effect predicts clinical severity of delirium symptoms in older medical inpatients. Arch Intern Med. 2001;161(8):1099-1105.
5. Carnahan RM, Lund BC, Perry PJ, et al. The Anticholinergic Drug Scale as a measure of drug-related anticholinergic burden: associations with serum anticholinergic activity. J Clin Pharmacol. 2006;46(12):1481-1486.
6. American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2015;63(11):2227-2246.

References

1. Inouye SK. Delirium in older persons. N Engl J Med. 2006;354(11):1157-1165.
2. Alagiakrishnan K, Wiens CA. An approach to drug induced delirium in the elderly. Postgrad Med J. 2004;80(945):388-393.
3. Clegg A, Young JB. Which medications to avoid in people at risk of delirium: a systematic review. Age Aging. 2010;40(1):23-29.
4. Han L, McCusker J, Cole M, et al. Use of medications with anticholinergic effect predicts clinical severity of delirium symptoms in older medical inpatients. Arch Intern Med. 2001;161(8):1099-1105.
5. Carnahan RM, Lund BC, Perry PJ, et al. The Anticholinergic Drug Scale as a measure of drug-related anticholinergic burden: associations with serum anticholinergic activity. J Clin Pharmacol. 2006;46(12):1481-1486.
6. American Geriatrics Society 2015 Beers Criteria Update Expert Panel. American Geriatrics Society 2015 Updated Beers Criteria for Potentially Inappropriate Medication Use in Older Adults. J Am Geriatr Soc. 2015;63(11):2227-2246.

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