Role of Cytochrome P4502B6 Polymorphisms in Ketamine Metabolism and Clearance.

BACKGROUND: At therapeutic concentrations, cytochrome P4502B6 (CYP2B6) is the major P450 isoform catalyzing hepatic ketamine N-demethylation to norketamine in vitro. The CYP2B6 gene is highly polymorphic. The most common variant allele, CYP2B6*6, is associated with diminished hepatic CYP2B6 expression and catalytic activity compared with wild-type CYP2B6*1/*1. CYP2B6.6, the protein encoded by the CYP2B6*6 allele, and liver microsomes from CYP2B6*6 carriers had diminished ketamine metabolism in vitro. This investigation tested whether humans with the CYP2B6*6 allele would have decreased clinical ketamine metabolism and clearance. METHODS: Thirty volunteers with CYP2B6*1/*1, *1/*6, or *6/*6 genotypes (n = 10 each) received a subsedating dose of oral ketamine. Plasma and urine concentrations of ketamine and the major CYP2B6-dependent metabolites were determined by mass spectrometry. Subjects' self-assessment of ketamine effects were also recorded. The primary outcome was ketamine N-demethylation, measured as the plasma norketamine/ketamine area under the curve ratio. Secondary outcomes included plasma ketamine enantiomer and metabolite area under the plasma concentration-time curve, maximum concentrations, apparent oral clearance, and metabolite formation clearances. RESULTS: There was no significant difference between CYP2B6 genotypes in ketamine metabolism or any of the secondary outcome measures. Subjective self-assessment did reveal some differences in energy and level of awareness among subjects. CONCLUSIONS: These results show that while the CYP2B6*6 polymorphism results in diminished ketamine metabolism in vitro, this allelic variant did not affect single, low-dose ketamine metabolism, clearance, and pharmacokinetics in vivo. While in vitro drug metabolism studies may be informative, clinical investigations in general are needed to validate in vitro observations.

Metabotropic glutamate receptor 5 antagonism with fenobam: examination of analgesic tolerance and side effect profile in mice.

BACKGROUND: The metabotropic glutamate receptor 5 noncompetitive antagonist fenobam is analgesic in rodents. Future development of fenobam as an analgesic in humans will require a favorable long-term treatment profile and a lack of significant deleterious side effects. This study aimed to determine whether tolerance to fenobam's analgesic effects developed over 14 days and to assess for side effects in mice. METHODS: Mouse models of pain, locomotor behavior, and coordination were used. Fenobam or vehicle (n = 8 or 11 per group) was administered for 14 days, and analgesic tolerance to fenobam was assessed using the formalin test. Histopathologic examination, hematology, and clinical chemistry analysis after 14-day fenobam administration were also assessed (n = 12 or 9). The effects of fenobam on locomotor activity were assessed in the open field and elevated zero maze (n = 8 or 7). Coordination was assessed using ledge crossing and vertical pole descent tasks (n = 11 or 10). RESULTS: Tolerance to fenobam's analgesic effect did not develop after 14 days. Chronic fenobam administration resulted in statistically significantly less weight gain compared with vehicle control subjects, but did not cause any physiologically or statistically significant hematologic abnormalities, altered organ function, or abnormal histopathology of the liver, brain, or testes. Fenobam administration resulted in a metabotropic glutamate receptor 5-dependent increase in exploratory behavior but does not impair motor coordination at analgesic doses. CONCLUSIONS: Analgesic tolerance to repeat fenobam dosing does not develop. Chronic dosing of up to 14 days is well tolerated. Fenobam represents a promising candidate for the treatment of human pain conditions.

Prediction of Individual Analgesic Response to Intravenous Lidocaine in Painful Diabetic Peripheral Neuropathy: A Randomized, Placebo-controlled, Crossover Trial.

OBJECTIVES: Intravenous lidocaine can alleviate painful diabetic peripheral neuropathy (DPN) in some patients. Whether quantitative sensory testing (QST) can identify treatment responders has not been prospectively tested. MATERIALS AND METHODS: This was a prospective, randomized, double-blind, crossover, placebo-controlled trial comparing intravenous lidocaine to normal saline (placebo) for painful DPN. Thirty-four participants with painful DPN were enrolled and administered intravenous lidocaine (5 mg/kg ideal body weight) or placebo as a 40-minute infusion, after a battery of QST parameters were tested on the dorsal foot, with a 3-week washout period between infusions. RESULTS: Thirty-one participants completed both study sessions and were included in the final analysis. Lidocaine resulted in a 51% pain reduction 60 to 120 minutes after infusion initiation, as assessed on a 0 to 10 numerical rating scale, while placebo resulted in a 33.5% pain reduction (difference=17.6%, 95% confidence interval [CI], 1.9%-33.3%, P=0.03). Neither mechanical pain threshold, heat pain threshold, or any of the other measured QST parameters predicted the response to treatment. Lidocaine administration reduced mean Neuropathic Pain Symptom Inventory paresthesia/dysesthesia scores when compared with placebo by 1.29 points (95% CI, -2.03 to -0.55, P=0.001), and paroxysmal pain scores by 0.84 points (95% CI, -1.62 to -0.56, P=0.04), without significant changes in burning, pressing or evoked pain subscores. DISCUSSION: While some participants reported therapeutic benefit from lidocaine administration, QST measures alone were not predictive of response to treatment. Further studies, powered to test more complex phenotypic interactions, are required to identify reliable predictors of response to pharmacotherapy in patients with DPN.

Somatosensory predictors of response to pregabalin in painful chemotherapy-induced peripheral neuropathy: a randomized, placebo-controlled, crossover study.

Painful chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating and treatment-resistant sequela of many chemotherapeutic medications. Ligands of α2δ subunits of voltage-gated Ca channels, such as pregabalin, have shown efficacy in reducing mechanical sensitivity in animal models of neuropathic pain. In addition, some data suggest that pregabalin may be more efficacious in relieving neuropathic pain in subjects with increased sensitivity to pinprick. We hypothesized that greater mechanical sensitivity, as quantified by decreased mechanical pain threshold at the feet, would be predictive of a greater reduction in average daily pain in response to pregabalin vs placebo. In a prospective, randomized, double-blinded study, 26 patients with painful CIPN from oxaliplatin, docetaxel, or paclitaxel received 28-day treatment with pregabalin (titrated to maximum dose 600 mg per day) and placebo in crossover design. Twenty-three participants were eligible for efficacy analysis. Mechanical pain threshold was not significantly correlated with reduction in average pain (P = 0.97) or worst pain (P = 0.60) in response to pregabalin. There was no significant difference between pregabalin and placebo in reducing average daily pain (22.5% vs 10.7%, P = 0.23) or worst pain (29.2% vs 16.0%, P = 0.13) from baseline. Post hoc analysis of patients with CIPN caused by oxaliplatin (n = 18) demonstrated a larger reduction in worst pain with pregabalin than with placebo (35.4% vs 14.6%, P = 0.04). In summary, baseline mechanical pain threshold tested on dorsal feet did not meaningfully predict the analgesic response to pregabalin in painful CIPN.

Postoperative myocardial injury after major head and neck cancer surgery.

BACKGROUND: Patients with head and neck cancer often have multiple risk factors for coronary artery disease. Yet, little is known about the incidence of postoperative myocardial injury after major head and neck cancer surgery and its clinical relevance. The aim of this study was to determine the risk of postoperative myocardial injury in patients undergoing major head and neck cancer surgery. METHODS: This was a retrospective cohort study of all patients who underwent major head and neck cancer surgery (n = 378) at a single major academic center from April 2003 to July 2008. Peak postoperative troponin I (TnI) concentration was the primary outcome. RESULTS: Of 378 patients who underwent major head and neck cancer surgery, 57 patients (15%) had development of an elevated TnI; 90% of these occurred within the first 24 hours after surgery. Preexisting renal insufficiency (unadjusted OR [OR]: 4.60; 95% CI 1.53-13.82), coronary artery disease (OR: 2.33; 95% CI 1.21-4.50), peripheral vascular disease (OR: 2.83; 95% CI 1.31-6.14), hypertension (OR: 2.22; 95% CI 1.20-4.12), and previous combined chemotherapy and radiation (OR: 2.68; 95% CI 1.04-6.91) were associated with elevated postoperative TnI levels. Patients with elevated TnI levels had a significantly longer length of stay in the hospital (8.5 vs 10.1 days; p = .014) and ICU (3 vs 4.5 days; p = .001) and an 8-fold increased risk of death at 60 days after surgery (adjusted OR: 8.01, 95% CI 2.03-31.56). At 1 year, patients with an abnormal postoperative TnI level were twice as likely to die (OR 1.93; 95% CI 1.02-3.63). CONCLUSIONS: Patients who undergo major head and neck cancer surgery are at significant risk for postoperative myocardial injury, which is a strong predictor of 60-day mortality after surgery. Monitoring of myocardial injury during the first postoperative days, as well as optimizing preventive cardiac care, may be helpful to reduce postoperative mortality rates.