Intravenous lidocaine is as effective as epidural bupivacaine in reducing ileus duration, hospital stay, and pain after open colon resection: a randomized clinical trial.

BACKGROUND: Both postoperative epidural analgesia and intravenous (IV) infusion of local anesthetic have been shown to shorten ileus duration and hospital stay after colon surgery when compared with the use of systemic narcotics alone. However, they have not been compared directly with each other. METHODS: Prospective, randomized clinical trial was conducted comparing the 2 treatments in open colon surgery patients. Before induction of general anesthesia, patients were randomized either to epidural analgesia (bupivacaine 0.125% and hydromorphone 6 microg/mL were started at 10 mL/hr within 1 hr of the end of surgery) or IV lidocaine (1 mg/min in patients < 70 kg, 2 mg/min in patients > or = 70 kg). Markers of return of bowel function, length of stay, postoperative pain scores, systemic analgesic requirements, and adverse events were recorded and compared between the 2 groups in an intent-to-treat analysis. RESULTS: Study enrollment took place from April 2005 to July 2006. Twenty-two patients were randomized to IV lidocaine therapy and 20 patients to epidural therapy. No statistically significant differences were found between groups in time to return of bowel function or hospital length of stay. The median pain score difference was not statistically significant. No statistically significant differences were found in pain scores for any specific postoperative day or in analgesic consumption. CONCLUSIONS: No differences were observed between groups in terms of return of bowel function, duration of hospital stay, and postoperative pain control, suggesting that IV infusion of local anesthetic may be an effective alternative to epidural therapy in patients in whom epidural anesthesia is contraindicated or not desired.

Effects of topiramate on methamphetamine-induced changes in attentional and perceptual-motor skills of cognition in recently abstinent methamphetamine-dependent individuals.

Methamphetamine-dependent individuals often cite the need to maintain enhanced cognitive performance and attention as a reason for continuing or relapsing to drug-taking. Further, methamphetamine addicts might not comply with taking a potentially therapeutic medication if it had a profound effect on these cognitive processes. Topiramate, a sulfamate-substituted fructopyranose derivative, has been suggested as a putative therapeutic medication for treating methamphetamine dependence. Examination of topiramate's effects on cognitive performance and attention is a clinically and scientifically important component of understanding its potential therapeutic profile. In 10 male and female individuals who met DSM-IV criteria for methamphetamine dependence, we examined the effects of low (50 mg b.i.d.)- and high (100 mg b.i.d.)-dose topiramate - in both the presence and absence of low (15 mg)- and high (30 mg)-dose intravenous methamphetamine--on cognitive performance, attention, and concentration on the rapid visual information processing task and the digit symbol substitution test. Intravenous methamphetamine enhanced cognitive performance, attention, and concentration among recently withdrawn methamphetamine addicts--an effect that hitherto had not been well characterized. Topiramate's cognitive effects were mixed and rather paradoxical, with a tendency to improve attention and concentration both alone and in the presence of methamphetamine while worsening psychomotor retardation. No deleterious interaction occurred between topiramate and methamphetamine on any of these cognitive processes. While clinical studies with topiramate should prepare participants for possible psychomotor retardation, the cognitive effects profile observed would not likely present an important obstacle to compliance in motivated patients. Topiramate's complicated cognitive effects among methamphetamine addicts need more comprehensive examination.

Kinetic and cardiovascular effects of acute topiramate dosing among non-treatment-seeking, methamphetamine-dependent individuals.

Previously, we have shown that orally administered topiramate, a sulfamate-substituted fructopyranose derivative, appears to accentuate rather than diminish some aspects of methamphetamine-induced positive subjective mood and cognitive performance. One possible mechanism by which this might occur would be for topiramate to increase plasma methamphetamine level. Such an effect also would be expected to enhance methamphetamine-induced hemodynamic response. We, therefore, studied -- in the same experiment from which the previous findings originated -- the effects of topiramate on the kinetic profile and hemodynamic response to methamphetamine. In a 27-day inpatient study, 10 methamphetamine-dependent individuals participated in a double-blind, placebo-controlled, cross-over design, with oral doses of topiramate (0, 100, and 200 mg) administered as a pretreatment before intravenous doses of methamphetamine (0, 15, and 30 mg). The 3x3 factorial combination of topiramate and methamphetamine resulted in a sequence of the nine treatments administered to each subject in an order determined by a 9x9 Latin Square design. Methamphetamine alone was associated with prototypical increases in hemodynamic response that were not altered in the presence of topiramate. While there was no significant kinetic interaction between topiramate and methamphetamine, there was a non-significant trend for topiramate to increase plasma methamphetamine level. No significant adverse events were reported. The combination of topiramate and methamphetamine at pharmacologically relevant doses appears to be safe. Larger laboratory studies with chronic dosing regimens are needed to establish whether or not there is a kinetic interaction between topiramate and methamphetamine.

Effects of acute topiramate dosing on methamphetamine-induced subjective mood.

Clinical studies have shown that topiramate, a sulphamate-substituted fructopyranose derivative, might be an efficacious treatment for alcohol dependence, smoking cessation within an alcohol-dependent population, and cocaine dependence. Mechanistically, topiramate's therapeutic effects have been hypothesized to be due to inhibition of cortico-mesolimbic dopamine function, the primary substrate that governs the acquisition, maintenance, and reinstatement of goal-directed behaviour towards seeking abused drugs. Predicated on this hypothesis, we tested in 10 methamphetamine-dependent individuals (three females) whether low- or high-dose (15 or 30 mg i.v.) methamphetamine-induced positive subjective effects and reinforcement can be antagonized by low- or high-dose (100 or 200 mg orally) topiramate using a placebo-controlled, cross-over, factorial design. Methamphetamine administration was associated with orderly, prototypical, and significant increases on measures of stimulation, euphoria, craving, and reinforcement; however, some dysphoric symptoms also emerged. Topiramate alone showed a non-significant trend towards mild reductions in positive mood and reinforcement; yet topiramate appeared to accentuate the appreciation of methamphetamine-induced stimulation and euphoria significantly, but not craving or reinforcement. The experimental combination of topiramate and methamphetamine appeared to be safe and well tolerated, with few adverse events. Acute dosing with up to 200 mg topiramate appears to enhance, rather than attenuate, the positive subjective effects of methamphetamine. Perhaps this indicates a partial inhibition of methamphetamine's reinforcing effects. Thus, testing chronically administered or higher doses, or both, of topiramate would be necessary to determine conclusively whether or not it can attenuate the positive subjective and reinforcing effects of methamphetamine.

Effects of repeated-dose isradipine on the abuse liability of cocaine.

Despite preclinical studies suggesting that isradipine may antagonize the abuse liability of cocaine, pretreatment with sustained-release isradipine did not reduce euphoric mood in cocaine-using volunteers. This double-blind, within-subject, crossover laboratory study determined whether maximal dose-loading with isradipine could antagonize effects of cocaine in 12 cocaine-dependent research volunteers administered intravenous cocaine doses (0, 0.325, and 0.65 mg/kg) on different days after 5 days of treatment with isradipine or placebo. Isradipine dose was 30 mg sustained release nightly plus 15 mg immediate release 2 hr before cocaine infusion. Cocaine produced dose-related increases in cocaine's subjective effects and a behavioral measure of reinforcement. Isradipine enhanced, rather than antagonized, subjective effects, indicating that isradipine does not antagonize cocaine's abuse liability in dependent research volunteers.

Isradipine decreases the hemodynamic response of cocaine and methamphetamine results from two human laboratory studies: results from two human laboratory studies.

BACKGROUND: Massive hypertensive crises relating to cerebrovascular accidents such as strokes or ruptured aneurysms, or cardiovascular dysfunction and toxicity, are an important cause of morbidity and mortality associated with cocaine or methamphetamine use. Experimentally administered, pharmacologically effective doses of cocaine and methamphetamine may serve as a model for studying the effects of these drugs on hemodynamic response and for examining the potential utility of the antihypertensive and dihydropyridine-class calcium channel antagonist isradipine to block these effects. We therefore examined, in two separate experiments of similar design conducted contemporaneously, the hemodynamic effects of cocaine or methamphetamine in the presence and absence of isradipine. METHODS: In both experiments (total N = 31), isradipine pretreatment was provided to cocaine- or methamphetamine-dependent male and female subjects before intravenous administration of low and high doses of cocaine (0.325 or 0.650 mg/kg) or methamphetamine (15 or 30 mg), respectively, on separate test days. RESULTS: Both cocaine and methamphetamine administration produced predicted elevations in blood pressure (with peak response between 1 and 3 min after infusion). Apart from tachycardia, no arrhythmias were reported. Isradipine significantly reduced stimulant-associated increases in all measures of blood pressure except pulse pressure, but tended to enhance the effects of these drugs on heart rate. CONCLUSIONS: Clinical studies are needed to determine whether isradipine is therapeutically efficacious in preventing hypertensive crises and the associated cerebrovascular and cardiovascular sequelae in cocaine- or methamphetamine-dependent individuals. As there is no established pharmacotherapy for treating cocaine or methamphetamine dependence, identification of a medication that reduces the harmful medical consequences of these drugs would be scientifically and clinically important.

Effects of isradipine on cocaine-induced changes in cognitive performance in recently abstinent cocaine-dependent individuals.

Recently abstinent cocaine-dependent individuals, compared with healthy controls, appear more likely to exhibit deficits in cognitive performance and attention. Individuals with such cognitive deficits might be less able to avail themselves of rehabilitative or relapse-prevention efforts. Pharmacotherapy that reduces the impairment in cognitive performance among cocaine-dependent individuals would be a useful clinical tool. Preclinical and human studies suggest that the dihydropyridine-class calcium-channel antagonist, isradipine, can enhance neurocognitive function in some neuropsychiatric disorders. Isradipine, presumably by increasing cerebral blood flow and its actions at various neurotransmitter systems, might, therefore, ameliorate the impairment in cognitive performance and attention seen in cocaine addicts and enhance the expected modest improvement in performance during acute cocaine-taking in these same individuals. Among 12 male and female cocaine-dependent individuals, we examined the effects of low and high doses of intravenous cocaine (0, 0.325, and 0.650 mg/kg) on cognitive performance and attention in both the presence and absence of isradipine (0 or 30 mg sustained release each evening prior to testing, plus 0 or 15 mg immediate release each morning 2 h before the cocaine or placebo cocaine infusion and on the day of testing). Intravenous cocaine produced a modest increase in cognitive performance and attention. Isradipine, both with and without cocaine, had no effect on these same parameters. Hence, cocaine-taking by cocaine-dependent individuals produces little improvement in cognitive performance and attention in either the presence or absence of isradipine.

Acute intravenous low- and high-dose cocaine reduces quantitative global and regional cerebral blood flow in recently abstinent subjects with cocaine use disorder.

Cocaine-induced hypoperfusion, a risk factor for ischemic stroke, has not been fully characterized during experimental drug-taking among individuals with cocaine use disorder. We sought to examine cocaine's dose-dependent, time-related effects on cerebral blood flow. In a double-blind, randomized human laboratory study with a counterbalanced order of drug administration, 31 male and female subjects with cocaine use disorder were divided into two groups receiving either (a) low-dose cocaine (0.325 mg/kg intravenously) or placebo (N=15) or (b) high-dose cocaine (0.650 mg/kg intravenously) or placebo (N=16). The different dose conditions were administered on test days separated by a rest period of >or=48 h. Cerebral blood flow was assessed quantitatively using H(2)O(15) positron emission tomography. Experimentally administered low- and high-dose cocaine conditions versus their corresponding placebo conditions were associated with global and regional hypoperfusion. The trend for high- versus low-dose cocaine to be associated with greater hypoperfusion achieved statistical significance only for the dopamine-rich sublobar and midbrain regions. Cocaine's hypoperfusion effects were maximal at 8 mins after infusion (i.e., at about the expected peak of intravenous cocaine levels) and had mostly dissipated by 32 mins after infusion. Although hypoperfusion occurred throughout the brain, the left hemispheric dopamine-rich sublobar region was the most severely affected. Cocaine-induced cerebral hypoperfusion is associated with the time course of its pharmacological effects, and dopamine-rich areas, particularly in the left hemisphere, may be most vulnerable. Increasingly larger doses of cocaine may be associated with greater risk for ischemic stroke.

Effects of isradipine on methamphetamine-induced changes in attentional and perceptual-motor skills of cognition.

RATIONALE: While the effects of d-amphetamine in increasing performance have been established, there is a paucity of information on the effects of methamphetamine on cognition in drug-naive subjects, and no published information on the effects of intravenous methamphetamine administration in dependent individuals. The dihydropyridine-class calcium channel antagonist, isradipine, has been posited as a putative treatment to prevent methamphetamine-associated hypertensive crisis and its sequelae. Yet, isradipine's effects on cognitive performance in methamphetamine-dependent individuals are not known. OBJECTIVE: Since individuals whose dependence on methamphetamine is attributable to the need to enhance performance may be loath to take a cognition-impairing medication, even for the treatment of life-threatening hypertensive crisis, it would be important to determine isradipine's effects on performance. METHODS: We therefore examined in a blinded, placebo-controlled, crossover design the cognitive effects of low and high doses of intravenous methamphetamine (15 mg and 30 mg, respectively) in both the presence and absence of isradipine. RESULTS: Intravenous d-methamphetamine produced dose-dependent increases in attention, concentration, and psychomotor performance. Isradipine, both with and without methamphetamine, had a modest effect to decrease attention. CONCLUSION: Our results do not support the further testing of isradipine as a medication for improving the cognitive impairments that have been associated with chronic methamphetamine use.

Kinetic and cardiovascular comparison of immediate-release isradipine and sustained-release isradipine among non-treatment-seeking, cocaine-dependent individuals.

The authors sought to determine whether sustained-release (SR) isradipine provided comparable systemic availability to that of immediate-release (IR) isradipine in non-treatment-seeking, cocaine-dependent individuals. This information could be used to design a rational dosage regimen for additional isradipine clinical trials in the treatment of stimulant dependence and related neurovascular disorders. Eight male volunteers who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for cocaine dependence participated in a randomized, double-blind, crossover study. Subjects received a 15-mg dose of an IR isradipine formulation and a 30-mg dose of an SR isradipine formulation, separated by a 2-day interval. Vital signs and blood sampling for isradipine serum levels were performed before and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 8, 10, 12, and 24 h after each isradipine dose administration. Neither the 15-mg dose of IR isradipine nor the 30-mg dose of SR isradipine produced significant adverse effects on cardiovascular parameters, but the IR formulation was more likely to produce marked short-term decreases in pressor response. Significant intersubject variability in serum concentrations and pharmacokinetic parameters occurred for both formulations. The relative bioavailability of the SR formulation was 55.5% of that of the IR formulation. Both formulations cumulatively may deliver about the same amount of drug, but IR isradipine achieves a higher peak concentration than SR isradipine. The more favorable cardiovascular profile of SR isradipine would, however, make it more appropriate as an investigational medication for the treatment of stimulant dependence and related neurovascular disorders.

Effects of isradipine on cocaine-induced subjective mood.

We hypothesized that in humans, as in animals, isradipine, a dihydropyridine-class calcium channel antagonist, would antagonize cocaine's rewarding effects, based on preclinical evidence that isradipine inhibits cocaine-mediated increases in mesolimbic dopamine (DA), thereby reducing cocaine's abuse liability. Confirmation of our hypothesis would make isradipine a promising medication for treating cocaine dependence. Eighteen male and female volunteers (mean age, 32.6 years) who met Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria for cocaine dependence participated in a double-blind, placebo-controlled, crossover study. Subjects received placebo or sustained-release (SR) low-dose or high-dose isradipine (15 or 30 mg), plus placebo or low-dose or high-dose cocaine HCl (0.325 or 0.650 mg/kg), for 9 treatment sessions separated by a 2-day interval. Standardized assessments of abuse liability, including a choice procedure to determine preference for cocaine with and without isradipine over monetary incentives, were conducted at scheduled intervals. Cocaine administration produced dose-related prototypic increases in stimulant-related effects, including euphoria, and drug preference over monetary incentives. Isradipine lacked any stimulant or abuse liability effects or the propensity to elicit craving, and it did not antagonize any of cocaine's stimulant-related effects associated with its abuse liability. In conclusion, SR isradipine (up to 30 mg) does not antagonize cocaine's rewarding effects in cocaine-dependent individuals. While higher isradipine doses may have been more effective at antagonizing cocaine reward, we could not test such doses due to the risk of serious adverse events. Also, isradipine-mediated inhibition of mesolimbic DA release may be an ineffective treatment of cocaine dependence.