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PubMed2004

Analgesia: morphine-pathway block in top1 poppies.

The opium poppy is a source of the pharmaceuticals codeine, morphine and their derived analgesics. Here we describe the initial characterization of the poppy mutant known as top1 (for 'thebaine oripavine poppy 1'), which accumulates the morphine and codeine precursors thebaine and oripavine and does not complete their biosynthesis into morphine and codeine. The original discovery of top1 stimulated a re-engineering of the opioid industry in the island state of Tasmania, which grows over 40% of the world's licit opiates, in order to produce thebaine and oripavine efficiently from morphine-free poppy crops to provide precursors for highly effective analgesics and for treatment of opioid addiction.

Analgesics, Opioid↗
PubMed1991

Microbial degradation of the morphine alkaloids. Purification and characterization of morphine dehydrogenase from Pseudomonas putida M10.

The NADP(+)-dependent morphine dehydrogenase that catalyses the oxidation of morphine to morphinone was detected in glucose-grown cells of Pseudomonas putida M10. A rapid and reliable purification procedure involving two consecutive affinity chromatography steps on immobilized dyes was developed for purifying the enzyme 1216-fold to electrophoretic homogeneity from P. putida M10. Morphine dehydrogenase was found to be a monomer of Mr 32,000 and highly specific with regard to substrates, oxidizing only the C-6 hydroxy group of morphine and codeine. The pH optimum of morphine dehydrogenase was 9.5, and at pH 6.5 in the presence of NADPH the enzyme catalyses the reduction of codeinone to codeine. The Km values for morphine and codeine were 0.46 mM and 0.044 mM respectively. The enzyme was inhibited by thiol-blocking reagents and the metal-complexing reagents 1,10-phenanthroline and 2,2'-dipyridyl, suggesting that a metal centre may be necessary for activity of the enzyme.

Alcohol Oxidoreductases↗
PubMed1997

Tramadol: a new centrally acting analgesic.

The pharmacology, pharmacokinetics, efficacy, adverse effects, and dosage and administration of tramadol are reviewed. Tramadol is a synthetic analogue of codeine that binds to mu opiate receptors and inhibits norepinephrine and serotonin reuptake. It is rapidly and extensively absorbed after oral doses and is metabolized in the liver. Analgesia begins within one hour and starts to peak in two hours. In patients with moderate postoperative pain, i.v. or i.m. tramadol is roughly equal in efficacy to meperidine or morphine; for severe acute pain, tramadol is less effective than morphine. Oral tramadol can also be effective after certain types of surgery. Tramadol and meperidine are equally effective in postoperative patient-controlled analgesia. In epidural administration for pain after abdominal surgery, tramadol is more effective than bupivacaine but less effective than morphine. In patients with ureteral calculi, both dipyrone and butylscopolamine are more effective than tramadol. For labor pain, i.m. tramadol works as well as meperidine and is less likely to cause neonatal respiratory depression. Oral tramadol is as effective as codeine for acute dental pain. In several types of severe or refractory cancer pain, tramadol is effective, but less so than morphine; for other types of chronic pain, such as low-back pain, oral tramadol works as well as acetaminophen-codeine. Common adverse effects of tramadol include dizziness, nausea, dry mouth, and sedation. The abuse potential seems low. The recommended oral dosage is 50-100 mg every four to six hours. Tramadol is an effective, if expensive, alternative to other analgesics in some clinical situations.

Analgesics, Opioid↗
PubMedDate not supplied

Simultaneous determination of heroin 6-monoacetylmorphine, morphine, and its glucuronides by liquid chromatography--atmospheric pressure ionspray-mass spectrometry.

A new analytical technique has been developed for the simultaneous determination of heroin, 6-monoacetylmorphine, morphine, morphine-6- and 3-glucuronides, and codeine in serum using liquid chromatography coupled with ionspray mass spectrometry. The analytes and the internal standard, nalorphine, were subjected to solid-phase extraction (SPE) using ethyl SPE columns before chromatography. The chromatographic separation of the analytes was achieved using a normal phase column and a water-methanol-acetonitrile-formic acid mobile phase at a flow rate of 230 microL/min. The mass spectrometer was operated in selected-ion monitoring mode. Under these conditions, the limit of quantitation was 0.5 ng/ml for heroin, 4 ng/ml for 6-monoacetylmorphine, 4 ng/ml for morphine, 1 ng/ml for morphine-3-glucuronide, 4 ng/ml for morphine-6-glucuronide, and 4 ng/mL for codeine. Serum levels of heroin metabolites were determined in C57BL/6 inbred mice after a dose of 20 mg/kg heroin administered subcutaneously. 6-monoacetylmorphine showed a peak concentration of 0.93 micrograms/mL serum at 3 min, whereas morphine and morphine-3-glucuronide achieved their peak concentrations of 9.6 and 2.9 micrograms/mL serum at 10 and 20 min, respectively. Finally, the absence of morphine-6-glucuronide and codeine excluded the possibility of their formation from morphine in this animal model.

Animals↗
PubMed2000

Monitoring opiate use in substance abuse treatment patients with sweat and urine drug testing.

Although urine testing remains the standard for drug use monitoring, sweat testing for drugs of abuse is increasing, especially in criminal justice programs. One reason for this increase is sweat testing may widen the detection window compared to urine testing. Drug metabolites are rapidly excreted in urine limiting the window of detection of a single use to a few days. In contrast, sweat collection devices can be worn for longer periods of time. This study was designed to compare the efficacy of sweat testing versus urine testing for detecting drug use. Paired sweat patches that were applied and removed weekly on Tuesdays were compared to 3-5 consecutive urine specimens collected Mondays, Wednesdays, and Fridays (355 matched sweat and urine specimen sets) from 44 patients in a methadone-maintenance outpatient treatment program. All patches (N = 925) were extracted in 2.5 mL of solvent and analyzed by ELISA immunoassay for opiates (cutoff concentration 10 ng/mL). A subset (N = 389) of patches was analyzed by gas chromatography-mass spectrometry (GC-MS). Urine specimens (N = 1886) were subjected to qualitative analysis by EMIT (cutoff 300 ng/mL). Results were evaluated to (1) determine the identity and relative amounts of opiates in sweat; (2) assess replicability in duplicate patches; (3) compare ELISA and GC-MS results for opiates in sweat; and (4) compare the detection of opiate use by sweat and urine testing. Opiates were detected in 38.5% of the sweat patches with the ELISA screen. GC-MS analysis confirmed 83.4% of the screen-positive sweat patches for heroin, 6-acetylmorphine, morphine, and/or codeine (cutoff concentration 5 ng/mL) and 90.2% of the screen-negative patches. The sensitivity, specificity, and efficiency of ELISA opiate results as compared to GC-MS results in sweat were 96.7%, 72.2%, and 89.5%, respectively. Heroin and/or 6-acetylmorphine were detected in 78.1% of the GC-MS-positive sweat patches. Median concentrations of heroin, 6-acetylmorphine, morphine, and codeine in the positive sweat samples were 10.5, 13.6, 15.9, and 13.0 ng/mL, respectively. Agreement in paired sweat patch test results was 90.6% by ELISA analysis. For the purposes of this comparison of ELISA sweat patch to EMIT urine screening for opiates, the more commonly used urine test was considered to be the reference method. The sensitivity, specificity, and efficiency of sweat patch results to urine results for opiates were 68.6%, 86.1%, and 78.6%, respectively. There were 13.5% false-negative and 7.9% false-positive sweat results as compared to urine tests. Analysis of sweat patches provides an alternate method for objectively monitoring drug use and provides an advantage over urine drug testing by extending drug detection times to one week or longer. In addition, identification of heroin and/or 6-acetylmorphine in sweat patches confirmed the use of heroin in 78.1% of the positive cases and differentiated illicit heroin use from possible ingestion of codeine or opiate-containing foods. However, the percentage of false-negative results, at least in this treatment population, indicates that weekly sweat testing may be less sensitive than thrice weekly urine testing in detecting opiate use.

Adolescent↗
PubMedDate not supplied

Postmortem distribution of heroin metabolites in femoral blood, liver, cerebrospinal fluid, and vitreous humor.

The presence of 6-monoacetylmorphine (6-MAM) is often used to distinguish between heroin (diacetylmorphine) and morphine exposures. 6-MAM, however, is rapidly metabolized to morphine and may not be present in detectable quantities in blood following heroin exposure. Recent studies have shown that 6-MAM may persist in cerebrospinal fluid (CSF) and this specimen may be preferable for establishing heroin exposure. This study reports postmortem distribution of 6-MAM, unconjugated morphine, and codeine in different tissues from 25 deceased individuals. In all cases, 6-MAM was detected in vitreous humor, and in CSF in 16 of the 25 cases (64%). When 6-MAM was detected in blood (13 of 25 cases), the level of 6-MAM in vitreous humor and CSF was higher than in blood, with a mean concentration ratio of 11.3 (range: 1.7-27) for vitreous humor and 6.6 (range: 2.6-17.3) for CSF. 6-MAM was not detected in liver in any of the cases examined. Free morphine levels were highest in liver, followed by blood, CSF, and vitreous humor. The concentration ratios (mean +/- standard deviation) for free morphine in vitreous humor, CSF, and liver to that in blood were 0.36 +/- 0.18, 0.64 +/- 0.27, and 2.99 +/- 2.12, respectively. The liver/blood ratio was consistent with previously reported values for morphine in heart and femoral blood. Codeine levels following heroin overdose were consistently low relative to the morphine concentration. For blood, liver, and CSF, the ratio of codeine to morphine was essentially the same (0.06), whereas the vitreous codeine/morphine concentration ratio was slightly higher (0.19). These results characterize the distribution of heroin metabolites in postmortem tissues. Vitreous humor appears to be a useful specimen for determining 6-MAM and establishing the morphine was derived from heroin.

Aqueous Humor↗
PubMed2001

Scalp nerve blocks decrease the severity of pain after craniotomy.

UNLABELLED: Up to 80% of patients report moderate to severe pain after craniotomy. In this study, we assessed the efficacy of scalp block for decreasing postoperative pain in brain surgery. Thirty patients scheduled for supratentorial craniotomy were enrolled. They were randomly divided into two groups: Ropivacaine (scalp block with 20 mL of ropivacaine 0.75%) and Saline (scalp block with 20 mL of saline 0.9%). Anesthesia was standardized. The scalp block was performed after skin closure and before awakening. Postoperative pain was assessed at 4, 8, 12, 16, 20, 24, and 48 h by using a 10-cm visual analog scale. Analgesia was provided with sub- cutaneous codeine as requested by the patient. Average visual analog scale scores were higher in the Saline group as compared with Ropivacaine (3.7 +/- 2.4 vs 2.0 +/- 1.6; P = 0.036). The total dose of codeine did not differ, nor did the duration of time before the first dose of codeine was required in the Ropivacaine (571 +/- 765 min) versus Saline (319 +/- 409 min; P = 0.17) group. In conclusion, we found that postoperative scalp block decreases the severity of pain after craniotomy and that this effect is long lasting, possibly through a preemptive mechanism. IMPLICATIONS: Up to 80% of patients report moderate to severe pain after craniotomy. This randomized double-blinded study demonstrated that ropivacaine scalp block decreases the severity of pain after supratentorial craniotomy.

Adolescent↗
PubMed1996

Genetic polymorphisms of debrisoquine and S-mephenytoin oxidation metabolism in Chinese populations: a meta-analysis.

Chinese data on the polymorphic metabolism of debrisoquine, metoprolol, codeine and mephenytoin were collected and re-analysed using a meta-analysis method. There were no significant differences in the incidences of poor metabolizer (PM) between the separate series of debrisoquine, metoprolol and codeine, which are the three probe drugs reflecting the same enzyme polymorphism. PMs were detected at low frequencies for debrisoquine (1.20%; 95% confidence interval, CI: 0.67-1.98%), metoprolol (0.72%; CI: 0.29-1.49%) and codeine (0.48%, CI: 0.01-2.68%). The overall estimate of PM was 0.95% (CI: 0.60-1.42%) based on the 2427 determinations of all three probe drugs. The overall mean of PM of mephenytoin was 14.32% (12.26-16.38%) in the 1117 subjects. In summary, the present meta-analysis determined the accurate incidences of the genetic deficiency of S-mephenytoin 4'-hydroxylase (cytochrome P450 2C19) and debrisoquine hydroxylase (cytochrome P450 2D6) in Chinese populations.

China↗
PubMed1995

The dextromethorphan defense: dextromethorphan and the opioid screen.

OBJECTIVE: To determine whether a single oral dose of dextromethorphan produces a falsely positive qualitative urine opioid screen. METHODS: A prospective, randomized, triple-blind, placebo-controlled, crossover exposure study design was used. Twenty adult volunteers participated. All were without routine medications, not pregnant or lactating, without known sensitivity to dextromethorphan, and negative for urine toxicologic screening immediately prior to testing. These volunteers underwent three separate urine Enzyme-Multiplied Immunoassay Technique (EMIT) opioid screens. Each screen was performed six hours after the subject had ingested a single liquid medication, either dextromethorphan, codeine, or placebo. Each volunteer took all three medications randomly, at least 72 hours apart. Half of the volunteers took the standard adult dose of dextromethorphan (20 mg), while the other half ingested twice this amount (40 mg). The amounts of codeine (30 mg) and sucrose placebo (10 mL) remained constant. RESULTS: For these young adults (mean age +/- SD = 30.7 +/- 2.8 years), all urine EMIT assays six hours after ingestion of dextromethorphan, at both dosage levels, were negative for opioids and all other drugs. All assays after codeine and placebo ingestion were positive and negative for opioids, respectively. CONCLUSION: Although dextromethorphan is structurally similar to opioid drugs, the ingestion of a single normal (or even twice normal) dose of dextromethorphan is not likely to produce a falsely positive six-hour urine opioid EMIT screen.

Adult↗
PubMed2001

Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review.

OBJECTIVE: To establish whether cannabis is an effective and safe treatment option in the management of pain. DESIGN: Systematic review of randomised controlled trials. DATA SOURCES: Electronic databases Medline, Embase, Oxford Pain Database, and Cochrane Library; references from identified papers; hand searches. STUDY SELECTION: Trials of cannabis given by any route of administration (experimental intervention) with any analgesic or placebo (control intervention) in patients with acute, chronic non-malignant, or cancer pain. Outcomes examined were pain intensity scores, pain relief scores, and adverse effects. Validity of trials was assessed independently with the Oxford score. DATA EXTRACTION: Independent data extraction; discrepancies resolved by consensus. DATA SYNTHESIS: 20 randomised controlled trials were identified, 11 of which were excluded. Of the 9 included trials (222 patients), 5 trials related to cancer pain, 2 to chronic non-malignant pain, and 2 to acute postoperative pain. No randomised controlled trials evaluated cannabis; all tested active substances were cannabinoids. Oral delta-9-tetrahydrocannabinol (THC) 5-20 mg, an oral synthetic nitrogen analogue of THC 1 mg, and intramuscular levonantradol 1.5-3 mg were about as effective as codeine 50-120 mg, and oral benzopyranoperidine 2-4 mg was less effective than codeine 60-120 mg and no better than placebo. Adverse effects, most often psychotropic, were common. CONCLUSION: Cannabinoids are no more effective than codeine in controlling pain and have depressant effects on the central nervous system that limit their use. Their widespread introduction into clinical practice for pain management is therefore undesirable. In acute postoperative pain they should not be used. Before cannabinoids can be considered for treating spasticity and neuropathic pain, further valid randomised controlled studies are needed.

Analgesics, Non-Narcotic↗
PubMed2004

Opioid-induced mast cell activation and vascular responses is not mediated by mu-opioid receptors: an in vivo microdialysis study in human skin.

UNLABELLED: Activation of mast cells and the systemic release of histamine is a common side effect of opioids. Nevertheless, fentanyl and its derivatives show only a slight activation of mast cells with a subsequent liberation of histamine and tryptase. In this study, we used intradermal microdialysis to assess whether this stimulatory effect of opioids on mast cells depends on the activation of opioid receptors. This new approach allowed us to measure the dose-dependent release of histamine and tryptase from mast cells and the subsequent vascular and sensory effect without systemic side effects in volunteers. The opiate codeine and the synthetic opioids meperidine, fentanyl, alfentanil, sufentanil, remifentanil, buprenorphine, and the opioid antagonist naloxone were tested. Only codeine and meperidine induced mast cell activation with the release of tryptase and histamine, leading to protein extravasation, flare reactions, and itch sensations. Because naloxone did not attenuate these effects, it is unlikely that mu-opioid receptors are involved in the activation of mast cells. IMPLICATIONS: Opioid effects on mast cells were assessed using intradermal microdialysis. Mast cell activation was seen with codeine and meperidine; no other opioid induced degranulation. Therefore, histamine release seen at large concentrations of potent micro agonists is caused by an unspecific effect rather than an activation of opioid receptors.

Adult↗
PubMed2006

A comparison between scalp nerve block and morphine for transitional analgesia after remifentanil-based anesthesia in neurosurgery.

We compared transitional analgesia provided by scalp nerve block (SNB) or morphine after remifentanil-based anesthesia in neurosurgery. Fifty craniotomy patients were randomly divided into two groups: morphine (morphine 0.1 mg x kg(-1) IV after dural closure and an SNB performed with 20 mL of 0.9% saline at the end of surgery) and block (10 mL of 0.9% saline instead of morphine after dural closure and an SNB performed with a 1:1 mixture of bupivacaine 0.5% and lidocaine 2% at the end of surgery). Postoperative pain was assessed at 1, 2, 4, 8, 12, 16, and 24 h using a 10-point numerical rating scale. Analgesia consisted of subcutaneous codeine. Average numerical rating scale scores were similar between the two groups at each time interval. Total codeine dosage was also similar, except at 4 h postoperatively when it was higher in the block group. The delay before administration of the first dose of codeine was not statistically different between groups: 45 min (20-2880) vs 30 min (10-2880), median and range for the block and morphine group, respectively. Postoperative hemodynamics were similar for both groups. The incidence of nausea and vomiting was slightly more frequent in the morphine group, but the occurrence of confusion did not differ between groups. In conclusion, SNB provides a quality of transitional analgesia that is similar to that of morphine with the same postoperative hemodynamic profile.

Adult↗
PubMed1992

Use of indomethacin in the prophylaxis of ureteral colic following extracorporeal shock wave lithotripsy.

Ureteral obstruction leading to pain seems to be related to an increase of renal prostaglandins (PG). We designed a prospective double-blind, placebo controlled protocol for evaluating the effect of indomethacin, a PG-synthetase inhibitor, in the prophylaxis of ureteral colic following extracorporeal shock wave lithotripsy (ESWL). Sixty patients undergoing ESWL were randomized into two groups, group 1 (study group) received 50 mg indomethacin capsule three times daily and group 2 (control group) received multiple-vitamin tablet three times daily. Twenty-four hours urine samples were collected before and three days after ESWL was performed for PGE2 (predominant renal PG) determination. Subjective pain after ESWL was recorded with pain score (0-10 degrees). Oral codein or pethidine injection were available for relieving pain following ESWL. The pain score, analgesic requirement and urinary PGE2 in pre- and post-ESWL were used to compare the two groups. The pain score was 4.00 +/- 0.25 and 3.00 +/- 0.25 in the control and study groups respectively; it had a statistically significant difference (p < 0.01). In control group, 12 and 14 patients required 23 doses of codein and 18 doses of pethidine. In the study group, three and four patients required five doses of codein and eight doses of pethidine. The difference was statistically significant (p < 0.05). In the control group, the mean pre- and post-ESWL urinary PGE2 was 305 +/- 65.8 and 474 +/- 101 micrograms/24-hr respectively. In the study group, the mean pre- and post-ESWL urinary PGE2 was 289 +/- 60.7 and 186 +/- 26.5 micrograms/24-hr respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1981

Excretion of drugs in human breast milk.

The present report briefly discusses some of the morphological, physiological, and compositional aspects of animal and human breast milk and how these characteristics might be important for the accumulation of drugs and foreign compounds. In addition, a study is described confirming the presence of caffeine, codeine, morphine, phenacetin, acetaminophen, and salicylic acid in the breast milk of a lactating mother following oral administration of a combination analgesic containing aspirin, phenacetin, caffeine, and codeine. Although the study is limited to one subject, it has provided critically needed data on the rates of appearance in, and elimination of these drugs from, breast milk. A similar amount of information is presented on phenacetin, also a component of the analgesic mixture, which has not been previously reported to enter human milk. The distribution of these drugs between the slightly more acidic breast milk and the relatively neutral plasma is consistent with their weakly basic, acidic, or relatively neutral properties. In general, the study shows that codeine and morphine milk concentrations are higher than, salicylic acid milk levels are much lower than, and phenacetin, caffeine, and acetaminophen milk concentrations are relatively similar to their respective plasma levels. It is projected, from estimated steady-state milk concentrations of the drugs and their metabolites studied, that very low percentages of the therapeutic dosages (less than 0.7%) would be excreted in mother's milk, too low an amount to be clinically significant to the infant.

Analgesics↗
PubMed2001

Isoquinoline alkaloid production by transformed cultures of Papaver somniferum.

Three clones of transformed cultures of opium poppy (Papaver somniferum L.) were established by infection with Agrobacterium rhizogenes MAFF 03-01724. MAFF clone 1 being capable of forming somatic embryos was selected and its growth and isoquinoline alkaloid production was investigated. The illumination, temperature and nutrient medium composition greatly affected growth, cell morphology and alkaloid accumulation. The MAFF clone 1 cultured in Root Culture medium in the dark at 22 degrees C accumulated a high quantity of sanguinarine (652 micrograms/g dry weight) though the growth was poor (4.4 fold as fresh weight basis after 2 months of culture). The MAFF clone 1 cultured in a quarter macro salt strength Woody Plant medium under 14 h/day light at 22 degrees C developed into plantlets and accumulated significant quantity of codeine (648 micrograms/g dry wt) together with papaverine, noscapine, and sanguinarine. This clone was applied to a rotating drum fermenter (2 L working volume), and ca. 0.3 mg codeine and 0.06 mg sanguinarine were obtained after 4 weeks of culture. One quarter of the codeine produced was found in the culture medium.

Alkaloids↗
PubMed2001

[Preparations of liposomal morphine. Investigation of the interaction of morphine and its derivatives with the dipalmitoyl phosphatidylcholine membrane].

Liposomes composed of the lipids of biological membranes are suitable for drug delivery. To reach a better therapeutical effect it is important to know the properties of interactions between the drug and lipid molecules. From dipalmitoyl phosphatidylcholine (DPPC) using ultrasound small liposomes containing morphine were prepared. The amount of entrapped morphine was determined with spectrophotometry and luminescence spectroscopy. The interaction between the molecules of morphine and its derivates (codeine, N-methyl-morphine, N-methyl-codeine) and the DPPC lipid was studied with differential scanning calorimetry (DSC) and electron spin resonance (ESR) methods. Our studies indicated that the molecules of morphine and its derivates principally interact with the environment of DPPC lipid head groups. Due to the interaction the mobility of head groups decreases especially in case of codeine and N-methylcodeine.

1,2-Dipalmitoylphosphatidylcholine↗
PubMed1991

[Urine checks as a supportive measure with drug abuse patients to supplement current therapy models].

Urine samples of 120 heroin-addicted probands who had to take part in urinanalysis tests were analysed during a 26 months' period. Up to 7 substances (morphine/diamorphie, codeine, cocain, LSD, cannabinoides, barbiturates and amphetamines) were tested. The results were compared to the results of a group of 177 cannabies-smokers. The purpose of this study was to find out in how far urinanalysis tests can change drug-consuming behaviour. More than 80% of the cannabis-smokers showed evidently a decrease of THC-positive urine samples at the end of the investigation period. Only about 13% had positive samples during the whole period. 12 out of 120 heroin-addicted probands (= 10%) had morphine-positive urine samples at the beginning of investigations. For 104 out of 1423 tested samples (46 probands) an unmistakable distinction between morphine/diamorphine- or codeine-intake was not possible because the concentrations found were too low. About 20% of the samples indicated a shift to a substitutional used drug like codeine. Further more a slightly significant increase of cannabis-intake was to be observed.

Follow-Up Studies↗
PubMed1988

Cardiovascular and ventilator effects of vadocaine hydrochloride in urethane-anaesthetized rats and guinea-pigs.

Urethane-anaesthetized rats and guinea-pigs were used to compare the cardiovascular, electrocardiac and ventilator effects of Vadocaine hydrochloride (2',4'-dimethyl-6'-methoxy-3-(2-methylpiperidyl)propionanilide+ ++ hydrochloride, OR K-242-HCl; INN: vadocaine), lidocaine hydrochloride and codeine phosphate. In rats, vadocaine and lidocaine, only at the largest dose tested (64 mumol/kg i.v.), reduced mean arterial pressure (MAP), heart rate (HR) and ventilation rate (VR). Codeine reduced VR dose-dependently, MAP decreased only at the largest dose of 64 mumol/kg, and HR was not affected at the doses tested. In guinea-pigs, neither vadocaine nor lidocaine had any clear effects on MAP. HR was significantly reduced at the doses of 4 and 16 mumol/kg of vadocaine and 16 and 64 mumol/kg of lidocaine. Vadocaine and lidocaine 16 mumol/kg i.v. caused a significant reduction in VR. Lidocaine 64 mumol/kg did not further reduce VR. The electrocardiac effects included prolongation of P-Q interval both in the vadocaine and lidocaine group. Prolongation of Q-Tc, deepening of Q and S, decrease in R amplitude, and inversion of T waves were seen only in the vadocaine group. To induce changes in the P-Q interval, four times less vadocaine than lidocaine was needed. The acute toxic dose of vadocaine in rats ranged from 64 to 100 mumol/kg i.v.; lidocaine and codeine caused no lethalities in rats at the dose range 1-64 mumol/kg i.v. In guinea-pigs, the lethal dose of 64 mumol/kg i.v. produced AV blocks followed by asystole or ventricular fibrillation. At the dose of 64 mumol/kg i.v. of lidocaine 3 guinea-pigs out of 11 died.

Anesthesia↗