Psychosomatics 45:361-363, August 2004
© 2004 The Academy of Psychosomatic Medicine
Delirium From the COX-2 Inhibitor Refecoxib
Sunanda Muralee, M.D.,
Daniel Bober, D.O., and
Rajesh Tampi, M.D., M.S., New Haven, Conn.
Key Words: delirium • Alzheimer's disease
TO THE EDITOR: We report a case of delirium caused by the COX-2 inhibitor refecoxib in a patient with Alzheimer's disease. To our knowledge, this is the first report of such a case. We are aware of only one previously reported case of delirium due to the COX-2 inhibitor refecoxib, but it occured in an elderly patient who did not have Alzheimer's disease.1 Alzheimer's disease is a chronic and progressive neurodegenerative disorder causing impairments in memory, activities of daily living, and behaviors. It is the most common form of dementia, with a prevalence of 6% to 8% in individuals 65 years and older.2 The prevalence of this disorder doubles every 5 years after the age of 60, so that in a population 85 years of age and older, the prevalence is between 33% and 50%.3 In 1997, an estimated 2.32 million people in the United States had Alzheimer's disease. It is predicted that the prevalence of this condition would increase to 8.64 million by 2047.4
Delirium is a common problem in patients with preexisting Alzheimer's disease. The prevalence of delirium superimposed on Alzheimer's disease ranges from 22% to 25%.5,6 It is unclear whether the delirium simply unmasks a previously unrecognized dementing illness or if it leads to a worsening of cognitive function, thereby increasing the chances of developing dementia. One prospective study found that in a group of 51 patients in the community, 14 patients were diagnosed as having a dementing illness immediately after the symptoms of delirium had subsided.6 In the next 2 years, 28 more patients were diagnosed with dementia. Common causes of delirium in Alzheimer's disease are infections, the stress of surgery, the death of a spouse, a change in residence, and severe pain, especially from herpes zoster infection.6 Medications are commonly implicated in the development of delirium. Common classes of medications causing delirium include sedative-hypnotics such as benzodiazepines, antihistamines, antipsychotics, anticholinergics, cardiovascular drugs, and pain medications, including narcotics and nonsteroidal anti-inflamatory drugs.6–10 Although the exact pathogenic mechanisms underlying delirium are still unclear, it is thought that several pathophysiological mechanisms exist, including deficits in cholinergic transmission, decreased cerebral metabolism, and an inflammatory response.11,12
Case Report
Ms. A was an 82-year-old widowed Hispanic woman who was admitted to the inpatient geriatric psychiatry unit of a major tertiary care hospital for increasing agitation, aggression, paranoid delusions, and poor self-care. The history obtained from the patient's family indicated that over the past 2 years her memory—both short term and long term—had deteriorated. During this period, her ability to take care of her basic and instrumental activities of daily living had also become impaired. Two weeks before her admission to the hospital, Ms. A had become very irritable and was aggressive with her family members. She was also paranoid and thought that someone was hiding in her house and that this person wanted to harm her. She was not eating or sleeping well, and her compliance with her medications was poor. Her family took her to her primary care physician, who gave Ms. A 25 mg/day of oral controlled-release paroxetine, assuming a diagnosis of depression. Her mental status became worse after she started taking paroxetine. She stopped eating and would not let her family care for her. She was fearful that something bad was going to happen to her. On the day of her admission to the hospital, Ms. A was agitated and aggressive. She tried to break a window to frighten away the intruder who she thought was living in her house. As her family did not know how to take care of her in this agitated state, they decided to bring her to the hospital.
Ms. A was initially brought to the emergency room of a tertiary care hospital. At the emergency room, a workup for delirium was performed. It included a CBC with differential; blood urea nitrogen, creatinine, electrolyte, vitamin B12, and folate levels; liver function tests; thyroid function tests; a Venereal Disease Research Laboratory test; iron studies; a urine analysis and cultures; an ECG; and a chest X-ray. A computerized tomography (CT) scan of her head without contrast was also obtained in the emergency room. Other than a decrease in potassium (3.4 meq/liter) and hemoglobin (9.5 g/dl) levels, with decreased hematocrit (29.5%) and increased ferritin levels, the rest of the laboratory data were within normal limits. The chest X-ray was also normal. The CT scan of Ms. A's head showed diffused volume loss, along with a lacunar infarct and periventricular white matter disease. From the emergency room, Ms. A was transferred to the geriatric psychiatric unit for further management of her behaviors.
Ms. A's medical history was significant for glaucoma, peripheral vascular disease, and osteoarthritis. There was no surgical history. Other than the 2-year history of worsening cognitive function and the 2-week history of agitation, aggression, and paranoid delusions, there was no other psychiatric history. Her medications at the time of admission to the hospital included controlled-release paroxetine, presantine, latanoprost, and pilocarpine opthalmic solutions. She did not have any known drug allergies. There was no family history of dementia, delirium, or any other known psychiatric disorders.
Based on her history, a physical examination, and laboratory data, Ms. A was given a diagnosis of Alzheimer's disease with delusions and behavioral disturbance and iron-deficient anemia. At the time of admission to the hospital, Ms. A was very agitated. She was expressing paranoid delusions that someone was trying to hurt her. She was also not eating or sleeping well. In view of these symptoms, the controlled-release paroxetine that she was taking was discontinued. She was given oral olanzapine, 2.5 mg at bedtime, and oral trazodone, 50 mg at bedtime as needed. She was also given oral ferrous sulfate, 325 mg b.i.d., for the treatment of iron-deficient anemia and oral ducosate sodium, 100 mg/day, for the prevention of constipation due to the ferrous sulfate. Over the next few days, her mental status improved. She was calmer, and her sleep and appetite were improving.
Ms. A had severe osteoarthritis in her hands and feet, which were not being treated at the time of admission. Therefore, a rheumatology consultation was obtained. The rheumatologist recommended giving her an oral COX-2 inhibitor, refecoxib, at 12.5 mg/day, along with oral protonix, 40 mg/day, to prevent gastric irritation. She tolerated the first two doses of refecoxib well. After the third dose of refecoxib, she became very agitated and started having visual and auditory hallucinations. She became more paranoid and aggressive. She was also calling out loudly and was not redirectable. Her oral dose of olanzapine was increased to a maximum of 20 mg at bedtime over the next few days. This did not decrease her level of agitation. She continued to have hallucinations, was aggressive, was having fluctuating levels of consciousness, and was not sleeping or eating well. Her oral dose of trazodone was increased to 200 mg at bedtime with no benefit. Divalproex sodium was added to her medication regimen, and it was titrated to an oral dosage of 250 mg in the morning and 500 mg at bedtime. These changes in medications did not cause any improvement in the symptoms of agitation or psychosis.
As this presentation was more consistent with the onset of delirium than agitation/psychosis due to Alzheimer's disease, a workup for delirium was initiated. This included a physical examination and blood and urine examinations. These were all within normal limits except for the presence of severe osteoarthritis and iron-deficient anemia. We performed a literature search to see if there were any case reports of delirium due to refecoxib because the Physicians Desk Reference (accessed through Micromedex) did not indicate delirium as a side effect of refecoxib. We found one case report in which an elderly woman without Alzheimer's disease had episodes of delirium due to celecoxib and refecoxib at different times. We decided to discontinue the refecoxib and see if the agitation, paranoid delusions, hallucinations, and sleep disturbance improved. Within the next 2 to 3 days, the symptoms improved dramatically. Ms. A's mental state improved to such an extent that we were able to decrease her dose of oral olanzapine to 10 mg at bedtime and send her home with a visiting nurse follow-up. She was also provided with outpatient follow-up with a psychiatrist at our geriatric assessment center.
Six months after Ms. A was discharged, she remained well and was receiving outpatient psychiatric follow-up. She was tolerating her medications well. She continued to take oral olanzapine, 10 mg at bedtime, oral divalproex sodium, 250 mg in the morning and 500 mg at bedtime, and oral trazodone, 200 mg at bedtime, along with presantine, ferrous sulfate, docusate sodium, latanoprost, and pilocarpine eyedrops. She was not given donepezil because her family was not keen for her to be taking this medication.
Discussion
The exact mechanism by which analgesic medications such as nonsteroidal anti-inflamatory drugs cause delirium is still unclear. Some reports suggest that some of the nonsteroidal anti-inflamatory drugs cause delirium because they have indolic moieties. These moieties are similar to serotonin, which by itself can cause delirium.10 On the other hand, COX-2 inhibitors do not have any such indolic moieties, and hence, it is unclear as to how this class of medication causes delirium. The long-term effects of delirium include worsening of cognitive and functional abilities, rehospitalization, admission to a skilled nursing facility, and death. Among these effects, the risk of mortality is even higher in patients who have delirium superimposed on a dementing illness.13 For this reason, it is the duty of clinicians to be aware of the risk factors for the development of delirium, especially in the cognitively impaired elderly. This will prevent undue suffering to patients and their families and also prevent the unnecessary loss of life.
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