Angina Pain Precipitated by a Continuous Subcutaneous Infusion of Ketamine

Case Report 

A 62-year-old man was diagnosed in June 1999 with a poorly differentiated transitional cell carcinoma of the bladder (T4a). He was treated with radical radiotherapy. His medical history included chronic obstructive pulmonary disease, a subendocardial infarct, angina, and a postoperative pulmonary embolus. He was admitted to the hospital in July 2001 with an extensive left femoral vein thrombosis and tumor recurrence in his lumbosacral spine and lungs. He was anticoagulated orally but while in the hospital he developed a right external iliac vein thrombosis and his warfarin was replaced with low molecular weight heparin. He developed venous gangrene of his right foot and complained of increasing pain. He was transferred to the hospice in early August for symptom control.

On admission to the hospice, the ache in his lower back and sensation of pressure in his swollen thighs were adequately controlled with a continuous subcutaneous infusion of diamorphine (130 mg in 24 hours). He was believed to be approaching death, and, to ease the burden associated with multiple medications, all nonessential medications (including his anti-anginal drugs) were discontinued. Over the next four days, he complained of spasms in both legs and severe allodynia over his lower right leg, which was only partially responsive to diamorphine (totalling 400 mg in 24 hours). The increasing doses of diamorphine resulted in unacceptable drowsiness. The pain did not respond to oral or subcutaneous nonsteroidal anti-inflammatory drugs. A subcutaneous infusion of ketamine (100 mg in 24 hours) was, therefore, commenced and the diamorphine infusion halved (200 mg in 24 hours). Within 24 hours his pain had lessened with fewer spasms and no side effects reported. After 72 hours, the dose of ketamine was increased (150 mg in 24 hours) and the diamorphine further halved (100 mg in 24 hours). This resulted in elimination of the pain and spasms. Fifteen days after commencing the ketamine infusion, the patient complained of anginal pain that responded to sublingual glyceryl trinitrate (GTN). The chest pain increased in frequency and required escalating GTN. Despite recommencing modified-release diltiazem (120 mg twice daily), his angina pain persisted. The ketamine was therefore reduced by 50 mg every 24 hours and stopped three days later, without an increase in his leg pain. He did not complain of any further angina and his leg pain remained well controlled on a stable dose of diamorphine until his death 12 days later.

Comment 

It is common practice to stop medications that are of questionable benefit and a burden in patients with advanced malignant disease and reduced physical functioning.4 In the case we describe, we were able to stop numerous medications, including his anti-anginal medication, without any adverse effects for a period of over two weeks. Unusually in this case, and despite the patient being bed-bound and undergoing little physical exertion, his angina pain returned and increased in severity. After re-introducing the same dose of medication that had previously controlled his angina, he continued to complain of chest pain requiring sublingual GTN. Other possible exacerbating factors of his angina, such as reduced hemoglobin level and hypoxia, were excluded. The ketamine was, therefore, thought to be contributing to his angina and the infusion was discontinued.

We would like to highlight the following points. First, the patient's foot and leg pain did not recur on stopping the ketamine and his opioid requirements remained constant. This would support the theory that ketamine inhibits the “wind-up” phenomenon. Hence, prolonged dosing is not always necessary.5 Second, once the ketamine was stopped, the patient's anginal pain ceased and he no longer required sublingual GTN or the diltiazem. In some patients, ketamine may temporarily increase heart rate and blood pressure by increasing sympathetic nervous system activity, although this may be less common in the severely ill.6 It has also been observed that these cardiovascular effects occur to a lesser degree but are more protracted with intramuscular as compared to intravenous administration.7 We postulate that, in this case, the prolonged subcutaneous infusion of ketamine caused an increase in myocardial demand without a measurable increase in heart rate and blood pressure.

We conclude that ketamine remains a valid treatment option in patients with a history of myocardial ischemia, but we wish to highlight to clinicians the possibility of exacerbating anginal pain. We recommend that when treating patients with ketamine who have a history of angina, any anti-anginal medication should be continued for the duration of the ketamine treatment and that burst therapy should be the mode of administration.