ABSTRACT
AIMS: Ketamine analgesia is limited by low intrinsic efficacy compounded by large interindividual variability in drug responses, possibly due to the heterogeneity in drug concentration. The CYP2B6*6 allele is associated with substantially reduced ketamine metabolism in vitro and, therefore, may affect ketamine clearance. Our aims were to examine the impact of the CYP2B6*6 allele on ketamine plasma clearance and on adverse effects in chronic pain patients. METHODS: CYP2B6 genotypes were identified in 49 chronic pain patients who received 24 h continuous subcutaneous infusions of ketamine. Steady-state plasma concentrations of ketamine (Css,k ) and norketamine (Css,nk ) were determined using HPLC. RESULTS: The median plasma clearance of ketamine after 100 mg 24 h(-1) dose was significantly lower in patients with the CYP2B6*6/*6 (21.6 l h(-1) ) and CYP2B6*1/*6 (40.6 l h(-1) ) genotypes compared with patients with the CYP2B6*1/*1 genotype (68.1 l h(-1) , P < 0.001). The ketamine : norketamine plasma metabolic ratio was significantly higher in patients with the CYP2B6*6/*6 genotype than in those with the CYP2B6*1/*6 and the CYP2B6*1/*1 genotypes (P < 0.001). Patients who experienced adverse effects had lower plasma clearance (45.6 l h(-1) ) than those who did not (52.6 l h(-1) , P = 0.04). The CYP2B6*6 genotype and age, and their combined impact explained 40%, 30% and 60% of the variation in Css,k , respectively. Similar results were observed after higher doses. CONCLUSIONS: The CYP2B6*6 allele is associated with a substantial decrease in steady-state ketamine plasma clearance in chronic pain patients. The decreased clearance and resultant higher plasma concentrations may be associated with a higher incidence of ketamine adverse effects.
Subject(s)
Analgesics/adverse effects , Analgesics/pharmacokinetics , Chronic Pain/drug therapy , Cytochrome P-450 CYP2B6/genetics , Ketamine/adverse effects , Ketamine/pharmacokinetics , Adult , Aged , Aged, 80 and over , Analgesics/administration & dosage , Analgesics/therapeutic use , Chronic Pain/blood , Chronic Pain/enzymology , DNA/genetics , Double-Blind Method , Female , Gene Frequency , Genotype , Humans , Ketamine/administration & dosage , Ketamine/therapeutic use , Linear Models , Male , Metabolic Clearance Rate , Middle AgedABSTRACT
A 59-year-old male patient with progressive neuropathic pain secondary to chronic idiopathic axonal polyneuropathy responded poorly to conventional therapies including gabapentin, tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors and opioids. Following continuous intravenous administration of low dose ketamine, an N-methyl-D-aspartic acid receptor antagonist, 20 mg/h for 5 days, almost complete pain relief was obtained without significant side effects. The analgesic effect lasted 10-12 weeks and the ketamine infusion was repeated, with this pattern being maintained for 3.5 years. This supports the growing body of evidence that ketamine may be useful in the management of refractory chronic neuropathic pain. We discuss chronic idiopathic axonal polyneuropathy, neuropathic pain mechanisms, and the use of ketamine in this report.
