What drugs can cause delirium? A comprehensive pharmacological guide

Approximately 15 to 50% of older adults experience delirium during a hospital stay, and medications are a common reversible cause. Understanding what drugs can cause delirium is crucial for patients, caregivers, and healthcare providers to mitigate the risk of this acute and serious confusional state.

Quick Summary

A wide range of drug classes, including anticholinergics, opioids, and sedatives, can induce or worsen delirium. Vulnerability increases with age, polypharmacy, and existing cognitive impairment, making careful medication review and monitoring essential for prevention and management.

Key Points

• Anticholinergic Medications: Drugs like Benadryl, TCAs, and certain GI and bladder medications commonly cause delirium, especially in older adults due to their effects on acetylcholine.

• Opioid Analgesics: High-dose opioids such as morphine, fentanyl, and meperidine are significant causes of delirium, particularly in the elderly and those with advanced illnesses.

• Benzodiazepines and Hypnotics: Sedatives like lorazepam (Ativan) and zolpidem (Ambien) can induce delirium directly, and abrupt withdrawal can also be a trigger.

• Vulnerable Populations: Advanced age, pre-existing dementia, and polypharmacy are major risk factors that increase an individual's susceptibility to drug-induced delirium.

• Delirium vs. Dementia: Delirium is an acute, fluctuating state affecting attention, while dementia is a chronic, gradual decline primarily affecting memory. Delirium can be superimposed on dementia.

• Non-Pharmacological Management: Prevention and treatment should prioritize non-drug approaches, including early mobility, sensory aids, promoting sleep, and frequent reorientation.

• Comprehensive Medication Review: The most effective management strategy is identifying and discontinuing or reducing the dose of the offending medication, which is part of a detailed medication review.

Delirium is a serious, acute state of confusion and altered awareness that can develop rapidly over hours or days. It is a medical emergency that can lead to adverse health outcomes, particularly in older adults. While delirium can arise from many underlying conditions, medications are a frequent and often preventable cause. The effects of drugs on the brain, particularly on neurotransmitter systems like acetylcholine and dopamine, are a key mechanism. A detailed review of a patient's medication list is a critical step in both preventing and managing drug-induced delirium.

Anticholinergic Medications

Anticholinergic drugs are notorious for causing delirium, especially in older adults who are more sensitive to their effects. They work by blocking the neurotransmitter acetylcholine, which is vital for cognitive function. The 'anticholinergic load' from multiple medications can significantly increase the risk.

Common anticholinergic culprits include:

• Antihistamines: First-generation antihistamines like diphenhydramine (Benadryl) and meclizine (Antivert), often found in over-the-counter sleep aids and cold remedies, have strong anticholinergic properties.
• Tricyclic Antidepressants (TCAs): Older antidepressants such as amitriptyline (Elavil), imipramine, and doxepin are known for their potent anticholinergic effects.
• Gastrointestinal and Bladder Medications: Drugs like dicyclomine (Bentyl) and oxybutynin (Ditropan), used for irritable bowel syndrome or urinary incontinence, possess anticholinergic activity.
• Antipsychotics: Some antipsychotics, like chlorpromazine (Thorazine) and olanzapine (Zyprexa), have anticholinergic effects that can contribute to delirium.

Opioids and Other Pain Medications

Opioid analgesics are a common cause of delirium, especially in higher doses or when introduced rapidly. Untreated pain can also trigger delirium, so there is a need to balance adequate pain management with the risk of delirium. The risk can be dose-dependent.

Pain medications linked to delirium include:

• Opioids: Morphine, fentanyl, meperidine (Demerol), oxycodone, and hydrocodone are frequently implicated. Meperidine, in particular, should be avoided in older adults due to the accumulation of a toxic metabolite.
• Other Analgesics: Tramadol has been associated with an increased risk of delirium.

Sedatives, Anesthetics, and Psychiatric Medications

Several other classes of drugs that affect the central nervous system can cause delirium. They may disrupt the balance of neurotransmitters, particularly in vulnerable individuals.

Key medication classes and examples:

• Benzodiazepines: These medications, such as lorazepam (Ativan) and alprazolam (Xanax), can cause delirium, especially in the elderly. Abrupt withdrawal from benzodiazepines can also precipitate a dangerous withdrawal delirium.
• Hypnotics (Sleep Aids): Medications like zolpidem (Ambien) and doxylamine (Unisom) are sedatives that can contribute to delirium.
• Antidepressants: While TCAs are high-risk, some Selective Serotonin Reuptake Inhibitors (SSRIs) like citalopram and paroxetine have been linked to delirium, partly due to the risk of hyponatremia.
• Anticonvulsants: Certain anticonvulsants, including carbamazepine (Tegretol), gabapentin (Neurontin), and valproic acid (Depakote), have been linked to delirium.
• Anesthetics: Intravenous anesthetics like ketamine and inhalational anesthetics have been associated with delirium, especially in the postoperative period.

Other Medication Classes

Beyond the primary culprits, many other drugs can contribute to delirium, especially in patients with complex medical conditions or multiple prescriptions.

• Corticosteroids: Steroids such as prednisone can induce delirium.
• Cardiac Medications: Digoxin, certain antiarrhythmics, and some antihypertensive medications have been reported to cause delirium.
• Antibiotics and Antivirals: Acyclovir, ciprofloxacin, levofloxacin, and vancomycin are among the antibiotics and antivirals associated with delirium.
• Parkinson's Disease Medications: Dopamine agonists, including amantadine, pramipexole, and ropinirole, can cause psychosis and delirium.

Risk Factors and Vulnerable Populations

Certain individuals are more susceptible to medication-induced delirium. It is a multifactorial condition, with drugs often acting as a precipitating factor in a vulnerable person.

• Advanced Age: Older adults are at a significantly higher risk due to age-related changes in brain function, metabolism, and higher rates of multimorbidity.
• Polypharmacy: The use of multiple medications increases the risk of drug-drug interactions and cumulative side effects, which can trigger delirium. One study found using six or more drugs was associated with persistent delirium.
• Cognitive Impairment: Pre-existing dementia or other cognitive issues are major risk factors for developing delirium.
• Severe Illness or Hospitalization: Patients in the Intensive Care Unit (ICU) or those recovering from surgery are at high risk.
• Dehydration and Electrolyte Imbalances: These physiological disturbances can worsen the effects of medications and contribute to delirium.

Delirium vs. Dementia: Key Differences

While symptoms can overlap, distinguishing delirium from dementia is crucial for proper treatment. Delirium is acute and often reversible, whereas dementia is a chronic, progressive condition.

Feature	Delirium	Dementia
Onset	Sudden, over hours or days.	Gradual, over months or years.
Course	Fluctuating throughout the day; symptoms may worsen at night ('sundowning').	Relatively stable, with occasional periods of worsening.
Attention	Impaired ability to focus, sustain, or shift attention; easily distracted.	Generally intact in early stages; declines in later stages.
Awareness	Reduced or clouded state of awareness.	Generally alert until later stages.
Hallucinations	Common, often visual and frightening.	Less common, may occur in conditions like Lewy body dementia.
Reversibility	Often reversible with identification and treatment of the underlying cause.	Usually irreversible and progressive.

Prevention and Management Strategies

Preventing medication-induced delirium starts with careful prescribing and risk assessment, particularly in high-risk patients like older adults.

Non-pharmacological interventions are the first-line approach:

• Medication Review: Systematically assess and minimize the use of high-risk drugs, especially those with anticholinergic properties.
• Sensory Aids: Ensure patients use glasses or hearing aids to improve their interaction with the environment.
• Reorientation: Provide calendars and clocks, and frequently reorient the patient to their time, place, and situation.
• Promote Sleep-Wake Cycle: Keep rooms well-lit during the day and dark and quiet at night to normalize circadian rhythms.
• Early Mobility: Encourage physical activity to prevent complications.
• Family Involvement: Involve family members to provide comfort and reassurance in a calm setting.

Pharmacological management:

• Treat the Root Cause: Focus on treating the underlying medical issue (e.g., an infection) rather than just the delirium symptoms.
• Symptom Management: For severe agitation or hallucinations that pose a safety risk, short-term, low-dose antipsychotics (e.g., haloperidol, risperidone) may be used.
• Avoid Benzodiazepines (except for withdrawal): Benzodiazepines can worsen delirium, and their use should be limited to specific situations like alcohol or benzodiazepine withdrawal.

Conclusion

A wide array of medications can cause or exacerbate delirium, with anticholinergics, opioids, and sedatives being particularly high-risk. Vulnerable populations, especially the elderly and those with polypharmacy or existing cognitive impairment, require careful monitoring and proactive management. The cornerstone of managing drug-induced delirium is identifying and discontinuing the causative agent, supported by crucial non-pharmacological strategies. By understanding what drugs can cause delirium, healthcare providers and caregivers can significantly improve patient outcomes and prevent this potentially devastating condition. A good resource for understanding the distinction between delirium and other memory disorders is available from the Mayo Clinic News Network.

Sources

• American Addiction Centers
• American Journal of Psychiatry (Psychiatry Online)
• ATS Journals (American Journal of Respiratory and Critical Care Medicine)
• BioMed Central (BMC Geriatrics, BPS Medicine)
• Center to Advance Palliative Care (CAPC)
• Clearbrook Treatment Centers
• Cornerstone of Recovery
• FPnotebook
• Johns Hopkins Medicine
• McKnight's Long-Term Care News
• MedlinePlus
• MSD Manuals
• Nature (Scientific Reports)
• Neurological Research and Practice
• Oxford Academic (Age and Ageing, Postgraduate Medical Journal)
• Psychiatry Online
• PubMed (NIH)
• ScienceDirect.com
• Vanderbilt University Medical Center (VUMC)
• YouTube

Frequently Asked Questions

What is the primary cause of medication-induced delirium?

The primary cause is often a disruption of neurotransmitter systems in the brain, particularly an overactivity of the dopaminergic system and an underactivity of the cholinergic system, frequently caused by anticholinergic or psychoactive drugs.

Are over-the-counter medications safe for people at risk of delirium?

No, many over-the-counter medications, especially those containing first-generation antihistamines like diphenhydramine (Benadryl) and meclizine (Antivert), have significant anticholinergic effects that can trigger delirium in susceptible individuals, such as older adults.

How does polypharmacy increase the risk of delirium?

Polypharmacy, or the use of multiple medications, increases the risk of delirium through complex drug-drug interactions, cumulative sedative effects, and a higher overall 'anticholinergic load.' It can also be a marker for patients with multiple comorbidities who are more susceptible.

Can psychiatric medications, like antidepressants, cause delirium?

Yes, certain psychiatric medications can cause delirium. Tricyclic antidepressants are well-known culprits due to their anticholinergic effects, and some SSRIs and SNRIs can also be linked, sometimes due to side effects like hyponatremia.

Is delirium different from dementia?

Yes, they are distinct conditions. Delirium has a sudden onset, a fluctuating course, and primarily affects attention and awareness, whereas dementia has a gradual onset, a progressive course, and primarily affects memory. However, a person with dementia is at a much higher risk of developing delirium.

What is the first step in managing drug-induced delirium?

The first and most effective step is to identify and stop or reduce the dosage of the offending medication. This is typically done alongside non-pharmacological interventions like reorientation and family support.

Can opioids cause delirium even when used correctly for pain?

Yes, even when used for legitimate pain management, opioids can cause delirium, especially in susceptible individuals like the elderly or those with advanced cancer. Healthcare providers must balance adequate pain control with monitoring for adverse cognitive effects.

What is 'sundowning' and how does it relate to delirium?

'Sundowning' refers to the worsening of confusion and agitation in the late afternoon or evening, a common fluctuating symptom of delirium. It's often associated with a disruption of the sleep-wake cycle.