Electrospray LC-MS method with solid-phase extraction for accurate determination of morphine-, codeine-, and ethylmorphine-glucuronides and 6-acetylmorphine in urine.

A method for the identification and quantification of morphine-3-glucuronide, codeine-6-glucuronide, ethylmorphine-6-glucuronide, and 6-acetylmorphine in human urine based on solid-phase extraction (SPE) and electrospray ionization liquid chromatography-mass spectrometry (LC-MS) was validated for use as a confirmation procedure in combination with immunochemical screening for opiates. Three deuterium-labelled analogues were used as internal standards: morphine-3-glucuronide-d3, codeine-d3, and 6-acetylmorphine-d3. Fifty-microliter aliquots of urine were prepared by SPE using 30-mg Oasis HLB cartridges. The chromatographic system consisted of a 2.0 x 100-mm C18 column and the gradient elution buffers used acetonitrile and 25 mmol/L formic acid. The protonated molecular ions were monitored in the selected ion monitoring mode together with one qualifier ion for each analyte. The interassay variability was less than 10% at the reporting limit 30 ng/mL for 6-acetylmorphine and 300 ng/mL for the other analytes. The method was validated by comparison with a reference gas chromatographic (GC)-MS method using authentic urine samples. The two methods agreed completely regarding identified analytes, and for the quantitative results there were slightly lower levels when measuring glucuronides directly as compared to total determination after hydrolysis by GC-MS. This result was to be expected because the free compounds are not measured with the LC-MS method. This study concludes that the presented LC-MS method is robust and reliable, and suitable for use as a confirmation method in clinical urine drug testing for opiates.

Establishing standardised methods for comparing aqueous droplet inhalers.

Aerosol inhalers are widely used to deliver drug directly to the respiratory system in patients with respiratory disease. Currently available nebulisers only deliver a proportion of the loaded or charged dose to the patient. The proportion of the charged dose received by the patient can be considered as the inhalable dose and is that part of the dose generated during inhalation and breathed in by the patient. As such, it is important to fully characterise the performance of new nebuliser brands to assess the proportion of the charged dose actually delivered to the patient. Despite the large variety of nebulisers, driver units and formulations currently on the market, often little is known about the performance of new nebulisers in terms of inhalable dose under a variety of breathing patterns and with different drug formulations. The results presented here highlight the variation in performance in terms of inhalable dose and droplet distribution of a breath-enhanced jet nebuliser when tested with a number of formulations and under different breathing patterns. Based on the results presented here we propose that a standard protocol for evaluating the performance of established and developmental nebulisers should include breathing patterns appropriate to the intended use and a variety of test formulations to capture those currently available for nebulisation.

Ketobemidone is a substrate for cytochrome P4502C9 and 3A4, but not for P-glycoprotein.

The role of the major drug-metabolizing cytochrome P450 (CYP) enzymes as well as P-glycoprotein (PGP) was investigated in the disposition of ketobemidone in vitro. Formation of norketobemidone from ketobemidone was studied and compared with the activities of 11 major CYP enzymes in human liver microsomes. The formation of norketobemidone from ketobemidone (1 microM) correlated best with CYP2C9 activity, measured as losartan oxidation (rs = 0.82, n = 19, p < 0.001), but there was also a strong correlation with CYP3A4 activity. Additionally, a good correlation was observed with CYP2C19, CYP2C8 and CYP2B6 at a ketobemidone concentration of 50 microM. Inhibition studies confirmed the involvement of CYP2C9 and CTP3A4 in the formation of norketobemidone. The formation rate of norketobemidone was three times higher in the CYP2C9*1*1 genotype group compared with the CYP2C9*1*2, CYP2C9*1*3 and CYP2C9*3*3 genotypes (p < 0.01). Treatment with verapamil as a PGP inhibitor did not affect the transport of ketobemidone in Caco-2 cells, indicating that PGP is not involved. The data suggest that CYP2C9 and CYP3A4 play a major role in the formation of norketobemidone at clinically relevant concentrations.

In vitro comparison of nebulised budesonide (Pulmicort Respules) and beclomethasone dipropionate (Clenil per Aerosol).

This study compared the in vitro performance of two inhaled corticosteroid products for nebulisation, Pulmicort Respules(budesonide 0.5 mg/mL) and Clenil) per Aerosol (beclomethasone dipropionate (BDP) 0.4 mg/mL). Each product was used in combination with three different nebulisers (2 mL/test, 5 min run time) and the dose to the lungs was determined according to standard methods. The shape of the suspended particles in each product was studied using scanning electron microscopy (SEM). Overall, a higher fine particle dose was achieved with Pulmicort Respules versus Clenil per Aerosol, with estimated dose to the lungs of 8-14 and 3-6% of nominal dose, respectively. SEM showed that budesonide particles were small, typically approximately 2-3 microm in diameter, whereas those of BDP were needle-shaped and up to approximately 10 microm long. The more favourable particle shape and size of suspended budesonide may explain the higher fine particle dose with Pulmicort Respules versus Clenil per Aerosol.

High-performance liquid chromatographic method for determination of amodiaquine, chloroquine and their monodesethyl metabolites in biological samples.

A high-performance liquid chromatographic method for determination of amodiaquine (AQ), desethylamodiaquine (DAQ), chloroquine (CQ) and desethylchloroquine (DCQ) in human whole blood, plasma and urine is reported. 4-(4-Dimethylamino-1-methylbutylamino)-7-chloroquinoline was used as internal standard. The drugs and the internal standard were extracted into di-isopropyl ether as bases and then re-extracted into an acidic aqueous phase with 0.1 M phosphate buffer at pH 4.0 for AQ samples and at pH 2.5 for CQ filter paper samples. A C(18) column was used and the mobile phase consisted of methanol-phosphate buffer (0.1 M, pH 3)-perchloric acid (250: 747.5:2.5, v/v). The absorbance of the drugs was monitored at 333 nm and no endogenous compound interfered at this wavelength. The limit of quantification in whole blood, plasma and urine was 100 nM for AQ and DAQ (sample size 100 microliter) as well as for CQ and DCQ in blood samples dried on filter paper. For 1000 microliter AQ and DAQ samples, the limit of quantification was 10 nM in all three biological fluids. The within-assay and between-assay coefficients of variations were always <10% at the limits of quantification. Plasma should be preferred for the determination of AQ and DAQ since use of whole blood may be associated with stability problems.

Pharmacokinetics and non-analgesic effects of S- and R-ketamines in healthy volunteers with normal and reduced metabolic capacity.

OBJECTIVE: There is a growing interest in low-dose ketamine as an analgesic agent in different intractable pain conditions. Due to its narrow therapeutic window, well-defined pharmacokinetic parameters are essential for its successful use in these situations. Arterial data for ketamine or its enantiomers have not been reported before. The metabolic pathways involved in the metabolism of S- and R-ketamines are not known. METHODS: Ten healthy male volunteers received 7 mg infusions of R- and S-ketamine-hydrochloride in a randomised order over 30 min on 2 separate days. Six were extensive metabolisers, two were poor metabolisers of debrisoquine (CYP2D6) and two were poor metabolisers of mephenytoin (CYP2C19). Arterial and venous concentrations and non-analgesic side effects were measured. RESULTS: Subjective side effects were mild but more pronounced for S- than for R-ketamine. There were no salient differences between the subjects with reduced and normal metabolic capacity in pharmacokinetic parameters or in side effects. Volumes of distribution and mean residence times were 40% smaller for arterial than for venous data. The mean clearance of R-ketamine, 0.020 l min(-1) kg(-1), was slightly but significantly lower than of S-ketamine, 0.024 l min(-1) kg(-1). CONCLUSIONS: There are large differences between arterial and venous data in the pharmacokinetic parameters that are heavily dependent on distribution processes. Parameters mainly reflecting elimination, such as clearance and area under the concentration time curve, are unchanged. The choice of sampling site could be important when computer-controlled infusions are used.

Inhibition of cytochrome P4502D6 activity with paroxetine normalizes the ultrarapid metabolizer phenotype as measured by nortriptyline pharmacokinetics and the debrisoquin test.

BACKGROUND: The ultrarapid metabolizer phenotype of the cytochrome P4502D6 (CYP2D6) enzyme has been considered a relevant cause of nonresponse to antidepressant drug therapy. Prescribing high doses of antidepressants to such patients leads to high concentrations of potentially toxic metabolites and an increased risk for adverse reactions. Normalization of the metabolic status of ultrarapid metabolizers by inhibition of CYP2D6 activity could offer a clinically acceptable method to successfully treat such patients with antidepressants. METHODS: Five ultrarapid metabolizers with a CYP2D6 gene duplication or triplication were treated with 25 mg nortriptyline twice a day for 3 consecutive weeks, alone during the first week and concomitantly with the CYP2D6 inhibitor paroxetine 10 mg or 20 mg twice a day, respectively, during the second and third weeks. After the third week, nortriptyline was discontinued and the subjects were treated with paroxetine 20 mg twice a day during the fourth study week. At the end of each study week, the steady-state pharmacokinetic parameters of nortriptyline or paroxetine were determined within the dose interval. In addition, the CYP2D6 phenotype was determined by debrisoquin (INN, debrisoquine) test at baseline and at the end of each study phase. Treatment-related adverse events were recorded during drug administration and for 1 week thereafter. RESULTS: All 5 subjects had very low (subtherapeutic) nortriptyline concentrations after 7 days' treatment with nortriptyline only. Addition of paroxetine 10 mg twice a day to the nortriptyline regimen resulted in a change in all individuals to the "normal" extensive debrisoquine metabolizer phenotype, and therapeutic plasma nortriptyline concentrations were achieved in 4 of 5 subjects after a 3 times mean increase in nortriptyline trough concentration (P =.0011). Doubling the paroxetine dose caused a 15 times mean increase in paroxetine trough concentration (P <.001), indicating strong inhibition by paroxetine of its own metabolism. The high paroxetine concentrations in 2 subjects caused them to have the poor debrisoquine metabolizer phenotype and resulted in a further increase in plasma nortriptyline trough concentration (P =.0099). A strong correlation (rank correlation coefficient [r(s)] = 0.89; P <.0001) was observed between paroxetine and nortriptyline trough concentrations. Paroxetine also significantly decreased the fluctuation of nortriptyline concentrations within the dose interval. One subject discontinued the study after the second study week because of adverse effects; otherwise, the study drugs were well tolerated. CONCLUSIONS: Paroxetine, with a daily dosage from 20 to 40 mg, is an effective tool in normalizing the metabolic status of CYP2D6 ultrarapid metabolizers.

Plasma concentrations of haloperidol are related to CYP2D6 genotype at low, but not high doses of haloperidol in Korean schizophrenic patients.

AIMS: This study was carried out to evaluate the influence of CYP2D6 genotype on the steady state plasma concentrations of haloperidol and reduced haloperidol in Korean schizophrenic patients. METHODS: One hundred and twenty Korean schizophrenic patients treated with various, clinically determined, doses of haloperidol (range 3-60, median 20 mg day-1) during monotherapy were recruited. CYP2D6 genotypes were determined by analysis of the CYP2D6*10 allele using allele-specific PCR and the CYP2D6*5 allele by long-PCR. Steady state plasma concentrations of haloperidol and reduced haloperidol were analysed by h.p.l.c. RESULTS: Twenty-three (19.2%), 60 (50.0%), 1 (0.8%), 33 (27.5%) and 3 patients (2.5%) possessed the CYP2D6 genotypes *1/*1, *1/*10, *1/*5, *10/*10 and *10/*5, respectively. The allele frequencies of CYP2D6*1, *10 and *5 were 44.6%, 53.8% and 1.7%, respectively. Significant relationships between dose and plasma concentrations of haloperidol (linear; r2 = 0.60, P < 0.0001) and reduced haloperidol (quadratic equation; r(2) = 0.67) were observed. Overall, the concentrations normalized for dose (C/D) of haloperidol were significantly different between the CYP2D6*1/*1, *1/*10 and *10/*10 genotype groups (one-way ANOVA; P = 0.028). No significant differences between the genotype groups were found with respect to the C/D of reduced haloperidol (P = 0.755). However, in patients with daily doses less than 20 mg, significant differences in the C/D of haloperidol (P = 0.003), but not of reduced haloperidol, were found between the three major genotype groups. In patients with doses higher than 20 mg, no differences were found between the genotype groups for either haloperidol or reduced haloperidol. 68 patients (57%) used benztropine, an antimuscarinic agent. All four patients with a *5 allele (one together with *1 and three with *10) were found to use benztropine. The patients homozygous for the *1 allele seemed to need less benztropine than the patients with one or two mutated alleles (Fisher's exact test; P = 0.036). CONCLUSIONS: The dose-corrected steady state plasma concentrations of haloperidol, but not of reduced haloperidol, were significantly different between the CYP2D6*1/*1, *1/*10 and *10/*10 genotype groups when doses lower than 20 mg haloperidol were given. No differences were found at higher doses. These results suggest the involvement of CYP2D6 in the metabolism of haloperidol at low doses of haloperidol (< 20 mg daily), while another enzyme, probably CYP3A4, contributes at higher doses.

Determination of LSD in urine with high-performance liquid chromatography--mass spectrometry.

A rapid, specific, and sensitive high-performance liquid chromatography/mass spectrometry method has been developed for routine determination of lysergic acid diethylamide (LSD) in urine. It includes sample purification by extraction into an organic solvent and back-extraction to an acetate buffer, reversed-phase high-performance liquid chromatography, and detection with a single quadrupole mass spectrometer equipped with an atmospheric pressure ionization electrospray interface. Trideuterated LSD was used as internal standard. The limit of detection was 0.02 ng/mL and the calibration curve was linear from 0.05 to 10 ng/mL. Within-and between-day coefficients of variation were 3.5% and 4.0% respectively and extraction recovery was 91%.

Determination of ketobemidone and its metabolites in plasma and urine using solid-phase extraction and liquid chromatography-mass spectrometry.

The authors developed a sensitive, specific, and rapid liquid chromatography--mass spectrometry (LC-MS) method for determining ketobemidone and its major metabolites in plasma and urine. The method involves a solid-phase extraction, high-performance liquid chromatography (HPLC), and electrospray mass spectrometry. The limit of quantification for ketobemidone and norketobemidone was 3 nmol/L. Recovery rates for ketobemidone and norketobemidone were 84.8% and 81.1%, respectively. Coefficients of variation (CV) ranged from 2.8 % to 9.5%. The method was used to determine ketobemidone and its major metabolites in clinical samples from relevant patient groups.

Risperidone metabolism in relation to CYP2D6*10 allele in Korean schizophrenic patients.

OBJECTIVE: Risperidone is known to be biotransformed to its active metabolite, 9-hydroxyrisperidone, by the polymorphic CYP2D6 in Caucasians. This study aimed to investigate the relationship between the CYP2D6*10 allele and the plasma levels of risperidone and 9-hydroxyrisperidone in Korean schizophrenic patients. METHODS: Eighty-two Korean schizophrenic patients in monotherapy with oral doses of risperidone from 1 mg/day to 8 mg/day (mean +/- SD 4.3 +/- 1.9, median 4) participated in this study. Plasma concentrations of risperidone and 9-hydroxyrisperidone were analyzed using high-performance liquid chromatography. The CYP2D6*10 allele, which contains C188T mutation in exon 1, was identified using allele-specific polymerase chain reaction amplification. RESULTS: Seventeen of 82 patients were homozygous for CYP2D6*1, 22 for *10, while the remaining 43 patients were heterozygous for these alleles. The plasma levels of risperidone and 9-hydroxyrisperidone ranged from 1.0 nM to 168 nM and 6.2 nM to 235 nM, respectively. The median concentrations/dose (C/Ds) (range) of risperidone in CYP2D6*1/*1, *1/*10, and *10/*10 groups were 1.7 (0.2-7.9), 2.6 (0.3-27.1), and 6.7 nM/mg (2.4-21.0), respectively. There was a statistically significant difference among the three genotypes (Kruskal-Wallis test, P<0.001). For 9-hydroxyriperidone, the corresponding median C/Ds were 13.1 (3.3-25.4), 11.9 (4.2-30.8), and 13.6 nM/mg (6.5-52.8), respectively, with no significant difference between the genotypes (P=0.54). The medians of the ratios between risperidone and 9-hydroxyrisperidone concentrations were 0.13 (0.01-0.93), 0.28 (0.01-2.77), and 0.46 nM/mg (0.05-1.28) in *1/*1, *1/*10, and *10/*10 genotypes, respectively, and they were significantly different (P=0.004). The active moieties (sum of the C/Ds of risperidone and 9-hydroxyrisperidone) were not significantly different between the genotypes (P=0.063). CONCLUSION: In Korean schizophrenic patients, the metabolism of risperidone is dependent on CYP2D6, and the CYP2D6*10 allele is important for the regulation of the activity of this enzyme. There were no significant differences in the plasma concentration of parent drug plus its active metabolite between the genotypes. This suggests that the clinical significance of this polymorphism is limited. Our study confirms previous studies on risperidone metabolism in Caucasians.

Rapid and simple determination of indinavir in serum, urine, and cerebrospinal fluid using high-performance liquid chromatography.

A method for analysis of indinavir in serum, cerebrospinal fluid, and urine was developed. The method is based on liquid-liquid extraction followed by high performance liquid chromatography with UV detection. The method has a shorter analysis time than previously published methods, and it is sensitive enough to measure levels in all three fluids under routine clinical conditions. The method is linear up to 32 micromol/L, the limit of detection is 0.01 micromol/L, and recovery of the method is 86%. The interassay coefficient of variation at 2.0 micromol/L was 2.8%, and no internal standard is needed. Over 700 clinical samples have been analyzed by this method, and concomitant antiviral drugs do not interfere with the assay. Paroxetin and dipyridamol are the only two compounds encountered to elute with retention times similar to that of indinavir. Examples of chromatograms and a pharmacokinetic curve are given. The method is well suited for routine therapeutic drug monitoring as well as for pharmacokinetic studies for research purposes.

Ketobemidone may alter busulfan pharmacokinetics during high-dose therapy.

The authors report a possible interaction between ketobemidone and busulfan during myeloablative treatment of a patient with acute myeloid leukemia. At the time of admission, the patient was receiving ketobemidone 1,000 mg/d as analgesic for a rectal fissure. The patient started conditioning prior to bone marrow transplantation with busulfan (1 mg/kg x 4 for 4 days). High busulfan plasma concentrations were observed after the first dose and the next doses were reduced to 0.7 mg/kg. The kinetics of both drugs revealed that an increase in ketobemidone concentration was followed by an increase in busulfan levels. Substituting ketobemidone with morphine resulted in a decrease in busulfan concentration despite increasing the dose once more to 1 mg/kg.

Determination of ribavirin in serum using highly selective solid-phase extraction and high-performance liquid chromatography.

A rapid assay for determination of ribavirin in serum using solid-phase extraction (SPE), high-performance liquid chromatography (HPLC), and UV-detection was developed. The SPE uses phenylboronic acid columns with an approximately 100% recovery for ribavirin. The concentration-peak area relation was linear (r > 0.995), from 1 to 64 microM in 100 microL serum. The limit of detection was 0.1 microM. The intraassay CV was 3.2% at treatment levels (9.7 microM) and 11.5% at 0.4 microM. The method is used to monitor patients undergoing ribavirin treatment for hepatitis C (HCV). Samples from HCV-infected patients with and without renal dysfunction have been analyzed without interference of endogenous compounds. It is concluded that the method is useful for routine therapeutic drug monitoring.

Indinavir-based treatment of HIV-1 infected patients: efficacy in the central nervous system.

OBJECTIVE: To study the pharmacokinetic properties and clinical efficacy of the HIV-1 protease inhibitor (PI) indinavir in the central nervous system (CNS). DESIGN: Twenty-five consecutive HIV-1 infected patients on combination therapy that included indinavir, had cerebrospinal fluid (CSF) and plasma samples taken on 32 different occasions, at different times after indinavir administration. CSF and viral load data obtained from these treated patients were compared with those from 36 untreated HIV-1 infected patients of similar immunological and demographic pre-treatment status. METHODS: Concentrations of indinavir were measured in CSF and plasma by high-pressure liquid chromatography with ultraviolet light detection and the data were used in pharmacokinetic modelling. RESULTS: The concentration of indinavir in plasma varied with time over a dose interval by about two orders of magnitude, whereas the concentration in CSF was relatively stable. The median concentration of indinavir in CSF was 210 nmol/l, which is above the 95% inhibitory concentration in vitro. Findings from the pharmacokinetic modelling indicate that indinavir is actively transported out of the CSF (P <0.001 compared with a passive transport-only model). In the PI-treated group there was a reduction in viral load to below 50 copies/ml in most subjects and a normalization of the CSF cell content and IgG-index. CONCLUSIONS: This study has shown that one PI, indinavir, is present in the CSF at therapeutic concentrations, and is likely to contribute to the antiretroviral activities observed within the CNS.

A simple HPLC method for simultaneous determination of mycophenolic acid and mycophenolic acid glucuronide in plasma.

A reversed-phase high-performance liquid chromatographic method for the simultaneous determination of mycophenolic acid and its metabolite, mycophenolic acid glucuronide, is presented herein. Sample purification is limited to protein precipitation with acetonitrile. The analytes were separated on a C18 column with a mobile phase containing 30% acetonitrile and a 40 mm phosphoric acid buffer at pH 2.1 and measured with UV-detection at 215 nm.

Lamotrigine drug interactions in a TDM material.

Using therapeutic drug monitoring (TDM) data from our laboratory, we have studied the concentration/dose relationship for lamotrigine and the influence of drug interactions in clinical practice. One hundred forty-nine lamotrigine samples from 104 adult patients were included in the study. The samples were collected as steady-state trough values, 9-16 hours after dose intake. Concomitant drug treatment was specified on the analysis request form. Lamotrigine serum concentrations were determined by high-performance liquid chromatography (HPLC). In 20 patients in monotherapy, the concentration/dose (C/D) ratio was 65 (range: 50-84) nmol/L/mg (mean and 95% confidence interval, antilog from lognormal distribution). In 37 patients with concomitant carbamazepine treatment, the C/D ratio was less than half that of the patients in monotherapy; 31 (2146) nmol/L/mg, and in 14 patients with phenytoin, it was even lower; 17 (13-23) nmol/L/mg. Valproic acid significantly increased the C/D to 251 (200-320) nmol/L/mg in 13 patients. Triple therapy with valproic acid and either carbamazepine or phenytoin (23 patients) yielded a C/D slightly above that of monotherapy, whereas a few patients on phenobarbital had a C/D slightly below that of monotherapy. The within-group C/D variation was comparatively small. The C/D ratio in a mixed lamotrigine TDM material shows a widespread intra- and interindividual variation, which can largely be explained by pharmacokinetic interactions with concomitantly used antiepileptic drugs. These results support the use of TDM in lamotrigine therapy.

Effect of codeine on oro-cecal transit time in Chinese healthy volunteers in comparison with Caucasian subjects.

OBJECTIVES: To evaluate the effect of codeine on oro-cecal transit time (OCTT) in Chinese subjects. METHODS: OCTT was measured with the hydrogen breath test in 12 Chinese healthy volunteers on two occasions: after placebo and after a single oral dose of codeine 50 mg. Codeine and its metabolites in urine were measured by HPLC. The Results of this study were compared with those previously obtained from Caucasian subjects. RESULTS AND CONCLUSION: The mean OCTT increased significantly after a single oral dose of codeine 50 mg [2.6 (1.2) h] compared with placebo [1.9 (0.6) h] in the Chinese subjects (P = 0.05). The increase in OCTT after codeine was similar in the Caucasian [0.9 (0.8) h] and in the Chinese subjects [0.7 (0.9) h]. However, the Chinese subjects had a significantly longer OCTT after placebo [1.9 (0.6) h] compared with the Caucasian subjects [1.3 (0.6) h, P < 0.05], possibly due to different environmental factors.

The analgesic effect of racemic ketamine in patients with chronic ischemic pain due to lower extremity arteriosclerosis obliterans.

BACKGROUND: Ketamine in sub-dissociative doses has been shown to have analgesic effects in various pain conditions, including neuropathic and phantom-limb pain, where conventional treatment has often failed. Chronic ischemic pain due to lower extremity arteriosclerosis obliterans often responds poorly to analgesics, and the pain-generating mechanisms are not well understood. METHODS: Eight patients with rest pain in the lower extremity due to arteriosclerosis obliterans were given sub-dissociative doses of 0.15, 0.30, or 0.45 mg/kg racemic ketamine and morphine 10 mg as a 5-min infusion on four separate days in a cross-over, double-blind, randomised protocol. Plasma levels of (S)- and (R)-ketamine and their nor-metabolites were analysed with an enantioselective high-performance liquid chromatography (HPLC) method. Pain levels were evaluated with a visual analogue scale (VAS). RESULTS: Individual pain levels were highly variable during and after all the infusions but the pooled pain levels showed a dose-dependent analgesic effect of ketamine with a transient but complete pain relief in all the patients at the highest dose (0.45 mg/kg). Side-effects, mainly disturbed cognition and perception, were pronounced and dose-dependent. Morphine 10 mg had an analgesic peak at 20 min and 5/8 patients had complete pain relief. These 3 patients also had high baseline pain scores, indicating a higher analgesic potency for the 0.30 and 0.45 mg/kg ketamine doses than for morphine 10 mg. CONCLUSION: We have demonstrated a potent dose-dependent analgesic effect of racemic ketamine in clinical ischemic pain. Due to a narrow therapeutic window, this analgesic effect is probably best utilised in combination with other analgesics.