Use of Donepezil in Patients with Delirium (but without Dementia)

By: Lunbao (Jerry) Huang, Pharm.D. Candidate c/o 2013

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Donepezil, brand name Aricept®, is an acetylcholinesterase inhibitor indicated as monotherapy for Alzheimer’s disease, the most common form of dementia.  Cholinergic deficiency in the cortex and basal forebrain contributes to cognitive deficits in these patients.  Donepezil reversibly, noncompetitively inhibits centrally active acetylcholinesterase, the enzyme responsible for hydrolysis of acetylcholine.  This results in increased concentrations of acetylcholine available for synaptic transmission in the central nervous system.  As opposed to the chronic, slow mental digressions of Alzheimer’s disease, delirium is an acute state of sudden severe confusion and rapid changes in brain function that are brought on by physical or mental illness.  Many disorders cause delirium, including conditions that deprive the brain of oxygen or vital nutrients.  Anticholinergic drugs can cause delirium in patients, thus the theory of increasing acetylcholine in the brain using acetylcholinesterase inhibitors to reverse this effect. Yet, since donepezil is only indicated for Alzheimer’s disease and not for delirium, more studies were needed to evaluate the effectiveness of this treatment.

In 2004, Kobayashi et al. reported a case of a 68-year-old man with a history mixed-type delirium caused by a right basal forebrain vascular lesion after surgery for craniopharyngioma.¹  Magnetic resonance imaging showed hemorrhagic infarcts in the brain.  Treatment with antipsychotics, antidepressants, and hypnotics resulted in little improvement for this patient.  Donepezil administration dramatically improved his intractable delirium after 19 days of treatment; however, this was followed by amnestic symptoms.  Therefore, the clinical evidence suggests that there is a correlation between delirium and efficacy of donepezil treatment, which supports the hypocholinergic theory of delirium.

Within the same year, another case reported by Slatkin et al. describes successful treatment with an  acetylcholinesterase inhibitor on a 55-year-old woman with advanced ovarian cancer, severe pain, and hypoactive delirium caused by an increase in her opioid dosage.²  Intravenous physotigmine, an acetylcholinesterase inhibitor, was administered, which resulted in drastic improvements of her myoclonus and delirium. The improvement was maintained during the administration of oral donezepril, which is another acetylcholinesterase inhibitor.

Liptzin et al. performed a relatively small study of 80 patients in a randomized, double-blind, placebo-controlled trial on using donepezil to treat delirium.³  Each participant was evaluated before surgery and then received either donepezil or placebo for 14 days before surgery and 14 days afterward. Postoperative delirium was assessed using Delirium Symptom Interview, Confusion Assessment Method, daily medical record, nurse-observation reviews, and DSM-IV diagnostic criteria.  Subsyndromal delirium was also assessed for each participant.  There were no significant differences found between the donepezil and placebo groups.  When delirium was present, it lasted only one day.  This may suggest that postoperative delirium was not a major problem in this population of relatively young and cognitively-intact elderly patients undergoing elective orthopedic surgery.

Similar results were seen in a pilot randomized trail in 2011by Marcantonio et al.⁴ The study looked at 16 patients randomly placed in two groups to receive either donepezil or placebo.  Treatment began at 24 hours, preoperatively or postoperatively. Daily treatment continued for 30 days or until side effects or clinical situations required termination of treatment.  The donepezil treatment group experienced more adverse effects and had no significant improvements in delirium presence or severity.  Overall, sufficient evidence was not found to warrant a definitive Phase III trial.

Outcomes of a later randomized, double-blind, placebo-controlled trial done by Sampson et al. suggested a consistent trend towards possible benefit from donepezil treatment for patients with postoperative delirium after elective total hip replacement.⁴  This study consisted of 33 patients with 19 patients placed on donepezil, and 14 on placebo.  Donepezil was well tolerated with no serious adverse events; however, the drug did not significantly reduce the incidence of delirium or length of hospital stay.  These unsatisfactory results may be due to an insufficient number of study participants to meet adequate power; a larger sample size may be required for a more definitive trial.

To date, previous studies are insufficient to suggest that donepezil is effective in treating delirium.  Most studies investigated postoperative delirium, which some suggest is reversible and does not require preventative therapy.  Patient cases do however suggest a benefit with giving donepezil in delirium.  This is an interesting prospect and a bigger, well-designed study is required to attain a definite answer.

SOURCES:

1. Kobayashi K, Higashima M, Mutou K et al. Severe delirium due to basal forebrain vascular lesion and efficacy of donepezil. Prog Neuropsychopharmacol Biol Psychiatry. 2004;28(7):1189—94.
2. Slatkin N, Rhiner M. Treatment of opioid-induced delirium with acetylcholinesterase inhibitors: a case report. J Pain Symptom Manage. 2004;27(3):268—73.
3. Liptzin B, Laki A, Garb JL, et al. Donepezil in the prevention and treatment of post-surgical delirium. Am J Geriatr Psychiatry. 2005;(12):1100—6.
4. Sampson EL, Raven PR, Ndhlovu PN, et al. A randomized, double-blind, placebo-controlled trial of donepezil hydrochloride for reducing the incidence of postoperative delirium after elective total hip replacement. Int J Geriatr Psychiatry. 2007;22(4):343—9.
5. Marcantonio ER, Palihnich K, Appleton P, et al. Pilot randomized trial of donepezil hydrochloride for delirium after hip fracture. J Am Geriatr Soc. 2011;59(2):S282—8.