PAIN MEDICINE

Volume 1

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Number 2

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2000

© Blackwell Science, Inc. 1526-2375/00/$15.00/181 181–182

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Oral Ketamine in Hepatocellular Carcinoma

Robert Friedman, MD, Victor Li, MD, Fred Kueppers, MD, and Gary Atkinson, DO

A B S T R A C T

Department of Anesthesiology, Temple University School of Medicine, Philadelphia, PA

Ketamine, an NMDA antagonist, has been used in pain treatment for a number of years. Recent re-ports have suggested its utility in a variety of pain states including post-herpetic neuralgia [1], cancer[2], and postoperative pain [5]. While a variety of neuropsychologic side effects are observed withparenteral ketamine, in oral use these side effects have been less pronounced [2,3]. We report a patientwith severe hepatic disease who developed hallucinations following a 75-mg oral dose of ketamine fortreatment of severe cancer pain unresponsive to morphine.

Case Report

A

59-year-old male with a history of hepatitis Cfor 14 years and hepatocellular carcinoma for

3 years was admitted to our hospital complaining ofabdominal pain secondary to a liver abscess. He hadsevere lung disease, but no longer smoked ciga-rettes. He had stopped drinking 3 years earlier andhad never used illegal drugs. He had allergies topenicillin and IVP dye, but no prior history of psy-chiatric problems.

On the 12th day post admission, the patient hadsevere pain despite surgical drainage of his abscess,treatment with large doses of morphine (4mg sub-cutaneous every 2 hours), and a 100-

m

g fentanylpatch. His mental status as described by the nursingstaff had not been affected by his medications. Hecomplained bitterly about his right upper quadrantpain. He was not receiving any other medicationswith central anti-cholinergic activity, or any benzo-diazepines. Apart from significant elevations (Alka-line phosphatase of 2073, AST of 184, ALT 82, Bi-lirubin of 1.8) in his liver function tests, elevatedalpha-1-antitrypsin levels (an acute phase reactant),and a low hemoglobin (9.8 mg%), the remainder ofhis laboratory tests were within normal limits.

Prior to receiving oral ketamine, the patient hadbeen reported to have periodic confusion to time,but knew his surroundings and his caretakers. Hewas afebrile and normotensive. The patient re-ceived a trial dose of 75 mg of oral ketamine in or-der to improve his pain control. Within 30 minutes,he developed visual hallucinations and paranoid ide-ation stating, “someone was out there trying to killhim.” Vital signs were unchanged. The patient alsonoted that his pain was gone. The patient’s mentalcondition rapidly improved during the next 30 min-utes as he was quieted with reassurance from thenursing staff. Within a few hours the patient’s men-tal status had returned to baseline. The patient wasable to discuss his long-term and short-term caregoals with a recreational therapist he had met be-fore receiving oral ketamine. The patient was notrechallenged with ketamine, and his other medica-tions were continued with no further episodes ofparanoid ideation. Serum levels of ketamine andmetabolites were not measured.

Discussion

The patient was in the terminal stages of liver can-cer, and was debilitated. Changes in mental statusfollowing oral ketamine suggest a reaction morecommonly seen with parenteral ketamine. In viewof his liver cancer and liver function abnormalities,it is possible that his higher-than-expected serumketamine levels were associated with impaired he-

Reprint requests to:

Robert Friedman, MD, Department ofAnesthesiology, Temple University School of Medicine,3401 N. Broad Street, Philadelphia, PA 19140. Tel: (215)707-3326; Fax: (215) 707-8028.

CASE REPORT

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Friedman et al.

patic metabolism of ketamine to its less hallucino-genic metabolites. The hallucinations occurred soonafter receiving the drug and persisted for another 30minutes. In human volunteers who received oral ket-amine, plasma concentrations of ketamine peaked at30 minutes, followed by a norketamine peak at 1hour, which slowly declined over the next 7 hours[6]. Once absorbed, the metabolism of oral ket-amine depends significantly on adequate liver func-tion to first metabolize ketamine to norketamine andthen to 6-hydroxy-norketamine, an inactive metabo-lite excreted by the kidneys [8,9].

When administered orally, ketamine producesanalgesia through its major metabolite, norket-amine, which may also produce fewer psychotomi-metic effects [7]. Volunteers with serum ketaminelevels of less than 50 ng/ml did not develop halluci-nations [4]. Large clinical trials in cancer patientshave shown effective analgesia and a low incidenceof psychological side effects when oral doses of .5mg/kg are used twice daily (2). Other trials reportanalgesia with minimal side effects with eveningdoses of 250 mg to treat intractable neuropathicpain [3]. We used a high dose of oral ketamine (1mg/kg) in this patient because of the severity of hispain. We now begin with a much lower test dose,0.10 mg/kg or .05 mg/kg depending on the pa-tient’s weight. In other cancer patients that we havetreated on morphine, we usually escalate the doseof ketamine by 50% every 8 hours until we get an-algesia or side effects. Most patients we havetreated since do not develop confusion on the lowertest dose and get good relief at doses of 40 to 80mgs (0.5–1.0 mg/kg) every 8 hours when their nar-cotic medication is continued.

In patients with liver disease we usually do notescalate the dose as rapidly. We have treated oneother patient who did well on 40 mg of ketamineevery 8 hours until shortly before she died when,because of liver metastases, her dose was reduced to20 mg every 8 hours with continued benefit and areduction of a “floating feeling.” This patient wasmaintained on her morphine dose. In both casesthe possibility that morphine metabolites were con-tributing to abnormal subjective complaints couldnot be excluded [10].

This case illustrates the need for further studiesto be done on the metabolism of ketamine in popu-

lations in which the drug is likely to be used. Whileketamine levels were not measured in this patient,the time course of his side effects, their persistenceand eventual resolution suggest impaired oral ket-amine metabolism. We suggest caution in provid-ing oral ketamine to patients who have cancer andsignificant hepatic dysfunction. Initial results oforal ketamine treatment of patients with cancer areencouraging. We hope oral ketamine will be morewidely used to control cancer pain if this caution isobserved.

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