Apparent tolerance to the acute effect of nicotine results in part from distribution kinetics.

Persons exposed to nicotine develop tolerance to many of its effects. When heart rate and forearm venous blood concentration are plotted against time after intravenous administration of nicotine, a greater increase in heart rate is seen for a given nicotine concentration during the rising phase of nicotine concentrations than during the decreasing phase. This could be due to acute tolerance or to more rapid distribution of drug to effect site (brain) than to venous blood. To distinguish between these possibilities, six rabbits were given nicotine intravenously. Blood samples were taken from the internal jugular vein (reflecting brain concentration), and the femoral vein and artery. Brain concentrations peaked before femoral venous concentrations. Seven men received intravenous infusions of nicotine. Peripheral venous blood concentrations and cardiovascular responses were measured. Heart rate peaked before venous concentrations. A physiological kinetic model, fit to the rabbit data, was scaled to humans and used to predict "brain" concentrations in them. Heart rate and predicted brain concentrations peaked simultaneously. We conclude that the rapid development of tolerance to the cardioaccelerating effect of nicotine can be attributed, at least in part, to its distribution kinetics.

Pharmacokinetics of recombinant human luteinizing hormone after intravenous, intramuscular, and subcutaneous administration in monkeys and comparison with intravenous administration of pituitary human luteinizing hormone.

To assess the pharmacokinetics of recombinant human LH (rhLH) in monkeys, we measured serum LH levels after single iv injection and after single and repeated doses by the im or sc route. A single iv bolus of 400 IU/kg rhLH or pituitary hLH (phLH) in six cynomolgus monkeys resulted in parallel concentration-time curves. The initial and terminal half-lives of rhLH (0.8 and 11 h) were comparable to those of phLH (0.6 and 10 h). The serum levels of phLH were consistently higher due to the fact that the immunological dose of phLH was higher. Administration of increasing iv doses of rhLH (10, 63, and 400 IU/kg) to six monkeys showed that the pharmacokinetics are linear over this dose range. The total clearance for the two higher doses was 0.03 L/h.kg. Systemic bioavailability was 50% after a single sc injection of 400 IU/kg and 61% after a single im injection of the same dose. The peak concentration (180 IU/L) after im injection was reached after 2.7 h. This was higher and sooner than after sc injection (110 IU/L after 5.3 h). The terminal half-life by both routes was similar to that seen after iv injection (11 h). Daily sc or im administration of 63 IU/kg for 7 days confirmed these findings. There was no accumulation of rhLH. Some monkeys developed antibodies, especially after repeated administration. They were excluded from the analysis. No significant local or systemic adverse events occurred.

Serum concentrations and effects of (+/-)-nicardipine compared with nifedipine in a population of healthy subjects.

The dihydropyridine calcium antagonist (+/-)-nicardipine shares some of the pharmacologic properties of the dihydropyridine prototype nifedipine. To compare them, serum concentrations and cardiovascular effects of 10 mg nifedipine and 20 mg (+/-)-nicardipine were evaluated at 1, 2, and 3 hours after oral intake in a randomized, crossover, single-blind study involving 79 healthy volunteers. (+/-)-Nicardipine serum concentrations were much lower than those of nifedipine, indicating a greater hepatic first-pass metabolism of (+/-)-nicardipine. There was a significant correlation between serum concentrations of both drugs. The frequency distributions of nifedipine and (+/-)-nicardipine AUC (0-3), heart rate increase, and mean arterial pressure decrease showed no bimodality. This does not confirm the proposed polymorphism of nifedipine oxidation. Concentration-effect plots indicate that (+/-)-nicardipine is more potent than nifedipine but shows comparable efficacy in blood pressure reduction.

Central analgesic effects of desipramine, fluvoxamine, and moclobemide after single oral dosing: a study in healthy volunteers.

The antinociceptive effect of three antidepressants with different postulated modes of action, 75 mg desipramine, 225 mg fluvoxamine, and 450 mg moclobemide, was evaluated after single oral dosing in a randomized, double-blind, placebo-controlled crossover study in 10 healthy volunteers. Experimental pain thresholds (polysynaptic R-III reflex and subjective pain rating) were monitored over 23 hours. Compared with placebo, all drugs induced significant subjective pain threshold increases (maximal increase: desipramine, +20%; fluvoxamine, +17%; moclobemide, +13%). However, only desipramine (maximal increase, +25%) and moclobemide (maximal increase, +14%) displayed a significative effect on R-III threshold. Antidepressants thus exert an antinociceptive effect after a single oral dose. The level of their action apparently relies on the postulated mode of action.

Central analgesic effect of acetaminophen but not of aspirin.

The central nervous system effect of acetaminophen (paracetamol) and acetylsalicylic acid was investigated in healthy volunteers according to a crossover, double-blind, and placebo-controlled design. Ten subjects received, by intravenous route, a placebo, 1 gm acetaminophen, and 1 gm acetylsalicylic acid. Analgesia was assessed by measurement of the subjective pain threshold and the objective nociceptive flexion reflex threshold in response to selective transcutaneous electrical stimulations. A close correlation was observed between subjective and objective pain thresholds. Acetaminophen increased both thresholds for more than 4 hours (24% and 23% of baseline value at 120 minutes, respectively; p less than 0.001, ANOVA). In contrast, acetylsalicylic acid had no noticeable effect on either threshold. These findings show that acetaminophen-induced analgesia is centrally mediated, in contrast to aspirin. The time delay between plasma concentration kinetics and acetaminophen analgesic effect is another argument in favor of its direct action on the central nervous system.

Clinical pharmacology of recombinant human follicle-stimulating hormone. III. Pharmacokinetic-pharmacodynamic modeling after repeated subcutaneous administration.

OBJECTIVE: To investigate the respective role of the pharmacokinetic and of the pharmacodynamic characteristics in individual variability and to reassess the time course and the informative value of FSH pharmacodynamic markers by applying a combined pharmacokinetic-pharmacodynamic modeling analysis. DESIGN: After a 1-week SC administration of 150 IU/d of recombinant human FSH (Gonal-F; Laboratoires Serono, Aubonne, Switzerland) to 12 healthy down-regulated female volunteers, inhibin and E2 serum level and total follicular volume were recorded at preset times during 2 weeks. RESULTS: Good correlations were obtained between inhibin maximal levels and maximal total follicular volumes and between E2 maximal serum level increases and maximal total follicular volumes. In contrast, no correlation was found between maximal serum concentration of FSH and any of the recorded effects. Pharmacodynamic effects started to increase significantly later than FSH serum concentration, especially for E2 serum level and total follicular volume. Inhibin serum level was the first pharmacodynamic marker to increase. A full pharmacokinetic-pharmacodynamic model was developed to determine the relationship between drug concentrations and FSH pharmacological effects. This approach provides a better understanding of the concentration-effect relationship and should allow a rational design for recombinant human FSH dose regimen. The average equilibration half-life between serum concentrations and theoretical effect-compartment concentrations is approximately 2 days for inhibin and approximately 4 days for E2, indicating that inhibin serum levels are tracking FSH concentrations more closely than E2 serum levels. CONCLUSIONS: [1] Recombinant human FSH alone is effective to stimulate ovarian follicular development and steroidogenesis in women pretreated with a GnRH agonist despite complete LH suppression; [2] there is a large interindividual variability in the response to recombinant human FSH; [3] this variability is mainly related to ovarian sensitivity to FSH rather than difference in pharmacokinetics; [4] inhibin is an early index of follicular development, further supporting its role as a putative tool to monitor FSH therapy; and [5] a slow stepwise increase in FSH dose is recommended if FSH overexposure and excessive ovarian stimulation are to be minimized. These observations suggest that recombinant human FSH will in the near future replace urinary human FSH in the clinics.

Clinical pharmacology of recombinant human luteinizing hormone: Part I. Pharmacokinetics after intravenous administration to healthy female volunteers and comparison with urinary human luteinizing hormone.

OBJECTIVE: To assess the pharmacokinetics after i.v. administration of a recombinant human LH and to compare them to those of a reference hMG preparation containing urinary human LH. DESIGN: Prospective, dose-escalating, cross-over study. SETTING: Phase I clinical research environment. PATIENT(S): Twelve healthy pituitary down-regulated females. INTERVENTION(S): Subjects received single i.v. doses of 300, 10,000, and 40,000 IU of recombinant human LH, followed by a single i.v. dose of 300 IU of hMG, all separated by 1 week. MAIN OUTCOME MEASURE(S): Pharmacokinetic parameters. RESULTS: For both preparations, LH serum levels were well described by similar biexponential models. The pharmacokinetics of recombinant human LH were linear over the 300 to 40,000 IU range. After a rapid distribution phase with an initial half-life of 1 hour, both recombinant human LH and urinary human LH were eliminated with a terminal half-life of 10-12 hours. Total serum clearance was 1.7 L/h with < 4% and 30% of the dose being eliminated in the urine for recombinant human LH and urinary human LH, respectively. The volume of distribution at steady-state was approximately 10 L. Irrespective of the dose, recombinant human LH was well tolerated. CONCLUSION(S): The pharmacokinetics of recombinant human LH are linear with dose and similar to those of urinary human LH.

Clinical pharmacology of recombinant human luteinizing hormone: Part II. Bioavailability of recombinant human luteinizing hormone assessed with an immunoassay and an in vitro bioassay.

OBJECTIVE: To assess the single-dose pharmacokinetics of a recombinant human LH preparation administered by the i.v., i.m., and s.c. route. DESIGN: Prospective, randomized cross-over study. SETTING: Phase I clinical research environment. PATIENT(S): Twelve healthy pituitary down-regulated females. INTERVENTION(S): Subjects received single i.v., i.m., and s.c. doses of 10,000 IU of recombinant human LH, each separated by 1 week. MAIN OUTCOME MEASURE(S): Pharmacokinetic parameters. RESULT(S): After single i.v. administration, the pharmacokinetics were described by a two-compartment model, after i.m. or s.c. administration, by a one-compartment model with zero order absorption and a lag time. Using the immunoassay, after i.v. administration initial half-life was 1 hour and terminal half-life was 10 hours (half-life was prolonged after extravascular administration, suggesting rate-limiting absorption). Total serum clearance was 2.6 L/h, and steady, state volume of distribution was 14 L. Observed Cmax, after i.m. and s.c. administration, was 43 IU/L with median tmax of 9 hours (i.m.) and 5 hours (s.c.). Bioavailability was 0.54 (i.m.) and 0.56 (s.c.). The pharmacokinetics of LH are comparable using an in vitro bioassay. CONCLUSION(S): The terminal half-life of recombinant human LH is around 12 hours and is slightly prolonged after extravascular administration. The pharmacokinetics are similar after i.m. and s.c. injection, and one-half the administered dose is available systemically.

Clinical pharmacology of recombinant human follicle-stimulating hormone (FSH). I. Comparative pharmacokinetics with urinary human FSH.

OBJECTIVE: To assess and compare the pharmacokinetics of recombinant human FSH with those of a reference preparation of urinary human FSH. DESIGN: Urinary human FSH and recombinant human FSH (Metrodin and Gonal-F; Laboratoires Serono, Aubonne, Switzerland) were administered in a balanced, random order, crossover sequence as a single i.v. dose of 150 or 300 IU separated by 1 week of washout to 12 pituitary down-regulated, healthy female volunteers. Serum FSH concentrations were measured by an immunoradiometric assay (IRMA) and by an in vitro rat granulosa cell aromatase bioassay. Urine FSH concentrations were measured by IRMA. RESULTS: The mean concentration-time profiles after 150 IU of urinary human FSH and recombinant human FSH were superimposed, and the mean profile after 300 IU of recombinant human FSH was double that of the 150 IU dose. The data for both FSH preparations were well described by a biexponential equation. Total clearance of the preparations was comparable, judging from immunoassay and bioassay data (0.5 and 0.15 L/h, respectively). Based on the immunoassay, renal clearance of urinary human FSH was 0.1 L/h, whereas for recombinant human FSH it was slightly lower at 0.07 L/h, indicating that less than one fifth of the administered dose was excreted in the urine. Immunoassay showed that the two preparations were similar in terms of initial and terminal half-lives (2 and 17 hours, respectively). The volumes of distribution at steady state (11 L) were similar. The results of the in vitro bioassay confirmed this pharmacokinetic analysis. Just after i.v. administration, an initial decrease in the serum bioassay:immunoassay ratio was observed because of dilution of urinary human FSH or of recombinant human FSH in the residual endogenous FSH pool. Then the ratio increased progressively with time, suggesting either metabolic selection or activation of both types of injected human FSH toward forms with greater in vitro bioactivity. The bioassay:immunoassay ratio returned to baseline by day 7. CONCLUSION: The results obtained in this study indicate that the following [1] the pharmacokinetic characteristics of recombinant human FSH are similar to those of urinary human FSH; [2] the terminal half-life of human FSH is approximately 1 day; [3] after a single i.v. injection of human FSH a progressive increase in FSH bioassay: immunoassay ratio is observed; and [4] clinical use of recombinant human FSH could follow protocols and treatment regimens currently applied to urinary human FSH.

Clinical pharmacology of recombinant human follicle-stimulating hormone. II. Single doses and steady state pharmacokinetics.

OBJECTIVE: To assess the single-dose pharmacokinetics of a recombinant human FSH preparation (Gonal-F; Laboratoires Serono, Aubonne, Switzerland), administered by i.v., IM, and SC routes and its pharmacokinetics at steady state after multiple dosing by the SC route. DESIGN: Twelve healthy down-regulated female volunteers received in random order three single doses of recombinant human FSH (150 IU, i.v., IM, and SC), with each administration separated by 1 week. The volunteers then received multiple recombinant human FSH doses by the SC route (150 IU one time per day) for 7 days. Follicle-stimulating hormone concentrations were measured by an immunoradiometric assay and an in vitro granulosa cell aromatase bioassay. RESULTS: After a single administration, the pharmacokinetics of recombinant human FSH were well-described by a two-compartment model after i.v. administration and by a one-compartment model with first order absorption after IM or SC administration. The mean total clearance of FSH was approximately 0.6 L/h, and renal clearance accounted for one tenth of the total elimination after i.v. administration. The distribution half-life was close to 2 hours. The terminal half-life was nearly 1 day when estimated either by modeling the i.v. data set or from analysis of the terminal phase of the steady state pharmacokinetic curve or from the time taken to reach steady state after repeated SC administrations. After single IM and SC injection, two thirds of the administered dose was available systemically. The cumulation factor for repeated SC administration was approximately 3 when steady state was reached. The in vitro bioassay data confirmed these estimations. The temporal evolution of the bioassay:immunoassay ratio suggests either metabolic selection or activation of recombinant human FSH toward forms with greater in vitro bioactivity. CONCLUSION: The estimation of the elimination half-life of approximately 1 day indicates that the maximal effect of a given dose of recombinant human FSH administered daily cannot be observed until 3 to 4 days of repeated administration. This indicates that, on a pure pharmacokinetic basis, physicians should wait at least 4 days to assess the efficacy of a given dose of recombinant human FSH and that they should not modify dosage too frequently.

Pharmacokinetic and pharmacodynamic interactions between recombinant human luteinizing hormone and recombinant human follicle-stimulating hormone.

OBJECTIVE: To assess the pharmacokinetics of a recombinant human LH preparation and its pharmacokinetic and pharmacodynamic interactions with recombinant human follicle-stimulating hormone (FSH). DESIGN: Prospective, randomized cross-over study. SETTING: Phase I clinical research environment. PATIENT(S): Twelve healthy pituitary down-regulated females. INTERVENTION(S): Subjects received 150 IU of s.c. recombinant human LH and FSH, either alone or in combination, followed by recombinant human LH and FSH once daily for 7 days. MAIN OUTCOME MEASURE(S): Pharmacokinetic parameters, ovarian follicle development. RESULT(S): No pharmacokinetic interaction between recombinant human LH and FSH was observed, with no significant difference in baseline-corrected maximal observed concentration over baseline, area under the concentration-time curve from t = 0 to t = 24 hours, or time to maximal concentration after single doses alone or in combination. After daily administration, the mean accumulation ratio was 1.6 for LH and 2.9 for FSH, with absorption and terminal phase half-life estimates of 4 and 11 hours for LH and 8 and 16 hours for FSH, respectively. Combined administration of FSH and LH for 7 days was effective in stimulating ovarian follicular development and steroidogenesis, with large interindividual variability related to ovarian sensitivity. CONCLUSION(S): A new recombinant human LH preparation has a low accumulation ratio at steady-state and no pharmacokinetic or pharmacodynamic interactions with recombinant human FSH.

Objective assessment of clonidine analgesia in man and influence of naloxone.

Experimental data indicate that clonidine can induce marked analgesia. We characterized this effect in healthy volunteers and investigated possible links with the opioid peptide system by means of naloxone antagonism. According to a cross-over, double-blind, placebo-controlled design, 10 subjects received oral and i.v. placebo or clonidine (0.2 mg p.o.) or clonidine and naloxone (2.8 mg i.v. in 5 h). Analgesia was assessed by measurement of the subjective pain threshold (visual analog scale) and the objective nociceptive flexion reflex (R III) threshold after transcutaneous electrical stimulations. A correlation was observed between subjective and objective thresholds (r: 0.78). Oral clonidine alone or with naloxone increased subjective and objective pain thresholds for at least 4 hours (p less than 0.01, ANOVA). Naloxone tended to reinforce clonidine analgesia. Only moderate and well tolerated side-effects were observed.

[The effect of rate of administration of isradipine on the hemodynamic response]. / Influence de la vitesse d'administration sur la réponse hémodynamique de l'isradipine.

As the magnitude of drug response may depend on its input rate, we investigated the rate of administration-effect relationship of the new dihydropyridine isradipine. Ten healthy volunteers received (double-blind and cross-over) isradipine 1 mg i.v. (5 min), 5 mg solution, 5 mg tablet, 10 mg sustained release, and placebo. Blood pressure and heart rate were recorded for 24 h. A single dose of slow-release formulation isradipine does not induce significant hemodynamic effects in healthy subjects. The maximal BP fall was comparable with either i.v., solution, and conventional tablet administration. This is due to a stronger heart rate counter-regulation, linked to rapid isradipine administration. These results imply that slow input rates of isradipine are more effective in lowering blood pressure.

[Absence of polymorphism in individual response to the dihydropyridines nifedipine and (+/-)-nicardipine]. / Absence de polymorphisme dans la réponse individuelle aux dihydropyridines nifédipine et (+/-)-nicardipine.

Nifedipine, the dihydropyridine calcium channel antagonist prototype, is characterized by wide variability of its hepatic first-pass metabolism and individual response. This could be due to a new genetic polymorphism of drug metabolism, and this hypothesis was investigated in a randomized and cross-over population study in normal volunteers (n = 80). The kinetics and effects of an oral dose of nifedipine (10 mg) and (+/-)-nicardipine (20 mg), a second generation derivative with presumed different biotransformation routes, were evaluated at 0, 1, 2 and 3 h. The two drugs displayed a similar pharmacodynamic profile in terms of heart rate and blood pressure. The observed frequency distributions showed no asymmetry or bimodality suggesting polymorphism. The frequency of headaches and flushes were 21/80 and 19/80 respectively for nifedipine and (+/-)-nicardipine. At the doses administered nifedipine and (+/-)-nicardipine show the same efficacy. This study does not confirm the presence of polymorphism in the response to these dihydropyridines.

Pharmacodynamic model of tolerance: application to nicotine.

The authors propose a model of pharmacodynamic response that, when integrated with a pharmacokinetic model, allows characterization of the development of functional tolerance. The model may be conceived of in several equivalent ways; one of these sees tolerance as a result of (noncompetitive) antagonism of agonist effect by a hypothetical substance (e.g., metabolite) produced by a first-order process, driven by agonist concentration. Tolerance thus lags behind, and is approximately proportional to, agonist concentrations. Two new parameters quantifying tolerance are introduced: kantO, which describes the elimination kinetics of the antagonist and determines the rate of development and disappearance of tolerance, and Cant50, which determines the magnitude of tolerance that can be achieved. The model was tested in eight volunteers on data produced after three sequences of paired i.v. administrations of nicotine separated by different intervals of time. Blood concentrations of nicotine and heart rate were measured. The proposed tolerance model was fitted to the nicotine data. The estimate of kantO suggests a half-life of development and regression of tolerance of 35 min, and the estimate of Cant50 suggests that tolerance, at its full development, causes an approximately 80% reduction of initial (nontolerant) effect. This model provides a quantitative pharmacokinetic-pharmacodynamic description of the development of acute tolerance that also carries physiologic meaning. The quantitative information provided by this model may improve understanding of the temporal patterns of drug abuse and complications thereof.

[Central analgesic effect of paracetamol]. / L'effet analgésique central du paracétamol.

Although biochemical data suggest a direct effect of paracetamol on the CNS, its mode of action is still poorly understood. We investigated the central impact of paracetamol compared to acetylsalicylate in response to transcutaneous electrical nerve stimulation in man. Healthy volunteers received i.v. paracetamol, acetylsalicylic acid, and placebo. Analgesia was assessed by measurement of objective (R-III reflex) and subjective (VAS) pain thresholds. A close correlation was observed between both objective and subjective thresholds. Paracetamol raised the objective and subjective thresholds. In contrast, acetylsalicylic acid had no noticeable effect on either threshold. These data demonstrate a central analgesic effect of paracetamol.

[Central analgesic effects of antidepressant drugs with various mechanisms of action: desipramine, fluvoxamine and moclobemide]. / Effet analgésique central d'antidépresseurs à mode d'action distinct: désipramine, fluvoxamine et moclobémide.

Analgesic properties of antidepressants are not yet well established. The aim of this study was to investigate the analgesic effect of three antidepressants after single oral dose administration to healthy volunteers. The late spinal R-III reflex threshold (objective pain threshold) and the subjective pain threshold (numerical categorical scale) were markers of analgesic effect. Desipramine induced significant increases in both thresholds. Fluvoxamine and moclobemide also exerted a significant analgesic effect, although displaying distinct patterns depending on the analgesic marker considered. Antidepressants exert a central analgesic effect independent of their antidepressive effect and, depending on their mode of action, already detectable at spinal level.

Serum concentration-effect relationship of (+/-)-nicardipine and nifedipine in elderly hypertensive patients.

The concentration-effect relationships of (+/-)-nicardipine and nifedipine have been investigated in hypertensive geriatric patients. Following a parallel group, randomised, double blind trial design, they received either slow release nifedipine 20 mg b.d. (n = 9) or slow release (+/-)-nicardipine 50 mg b.d. (n = 10) for 7 days. On Days 1 and 7 serum (+/-)-nicardipine and nifedipine, blood pressure and heart rate were measured 6 and 12 h after drug administration. (+/-)-Nicardipine showed significant cumulation (ca 2 x) without a corresponding decrease in blood pressure or increase in heart rate. Concentration-effect plots indicated that (+/-)-nicardipine was more potent than nifedipine but that it showed apparently comparable efficacy in reducing the blood pressure. Compared to young healthy volunteers, both drugs had a more pronounced effect in elderly patients.

Pharmacokinetic-pharmacodynamic modeling of the effects of clonidine on pain threshold, blood pressure, and salivary flow.

Although clonidine analgesia appears to be mediated by the same central alpha 2-adrenoceptors that mediate its hypotensive effect, it is short-lasting when compared to the fall in blood pressure. This has been investigated by combined pharmacokinetic-pharmacodynamic analysis in 10 healthy volunteers who received (double-blind and crossover) clonidine 200 micrograms orally + placebo i.v. and clonidine orally + naloxone i.v. (2.8 mg/5 h). Analgesia was assessed by measuring the subjective (VAS) and objective (RIII) pain thresholds after transcutaneous electrical stimulations of the sural nerve; the mean arterial blood pressure (MAP), salivary flow (SF), and plasma clonidine concentrations were also monitored. A combined pharmacokinetic (first order absorption - 1 compartment) - pharmacodynamic (linear) model, including a hypothetical effect compartment with and without tolerance, were fitted to the data. Clonidine and clonidine + naloxone increased subjective and objective pain thresholds for 4 h. The concentration-effect plot for MAP showed distinct hysteresis. The t1/2s for effect compartment equilibration were 29 and 42 min for clonidine + naloxone and clonidine. The concentration-effect curves for RIII had the same shape as MAP but the starting hysteresis suddenly collapsed, suggesting acute tolerance. The best fit was obtained with a model where the linear relationship between concentration in the effect compartment and analgesia changed acutely after the third hour. The short-lived analgesia was probably related to an acute change in pain sensitivity induced by food, suggesting that it is not mediated solely by the alpha 2-adrenoceptors responsible for hypotension.

[Analgesic effects of an oral dose of clonidine]. / Effet analgésique d'une dose orale de clonidine.

Experimental data and anecdotal clinical observations have shown that clonidine, an alpha 2-agonist, has a marked analgesic effect. We investigated clonidine-induced analgesia in response to nociceptive stimuli. On 2 different days 7 normal volunteers received either placebo or clonidine (200 micrograms) orally according to a cross-over, double-blind, randomized, placebo-controlled design. Analgesia was assessed by measurement of the subjective (VAS) and objective (R III reflex) pain thresholds. A close correlation was observed between subjective and objective pain thresholds (r = 0.88, y = 0.2 + 1.2 x). Clonidine increased the objective threshold by 21% (+6.2 mA, SEM 2.4) and the subjective threshold by 10% (+2.4 mA, SEM 1.3). Drug effect was rapid (peak between 90 and 120 min) and overall analgesia lasted up to 4 hours. Side effects were a moderate fall in blood pressure, sedation and dryness of the mouth. A single oral dose of clonidine induces significant analgesia. These results suggest that clonidine is potentially a worthwhile drug for pain treatment which deserves further clinical investigation.