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PubMed2001

GC-MS determination of heroin metabolites in meconium: evaluation of four solid-phase extraction cartridges.

A procedure for extraction of heroin and metabolites for gas chromatography-mass spectrometry (GC-MS) analysis of meconium specimens that would allow detection of these analytes at low levels was needed. Solid-phase extraction (SPE) cartridges were therefore evaluated for their effectiveness in sample preparation. Four different types of commercially available extraction cartridges were used. Heroin, 6-monoacetylmorphine (6-MAM), morphine, and codeine were extracted from meconium samples using these SPE cartridges and then simultaneously analyzed using GC-MS. In each case, the extraction efficiency, linearity range, limit of detection (LOD), limit of quantitation (LOQ), between-run precision, and within-run precision were determined. Although satisfactory results were obtained with the four different types of SPE cartridges, best overall performance was observed using Clean Screen columns following the procedures outlined here. LODs as low as 20 ng/g for codeine, 10 ng/g for morphine, and 2.5 ng/g for 6-MAM were obtained, and LOQs as low as 20 ng/g for codeine, 10 ng/g for morphine, and 5 ng/g for 6-MAM were obtained. In all cases linearities were observed (r = > 0.99) for codeine, morphine, and 6-MAM over a wide concentration range (100-2000, 100-2000, and 5-100, respectively). At 50 ng/g codeine and morphine and 10 ng/g 6-MAM, the precision of analysis using these cartridges showed coefficients of variation ranging from 4.75% to 15.5%.

Codeine↗
PubMed2000

Mimicking gene defects to treat drug dependence.

The genetic basis for drug dependence has focused on genes that encode receptors involved in the reinforcing properties of drugs of abuse or that determine drug-taking behavior (e.g. impulsivity, etc.). Pharmacogenetic variations in the patterns of metabolism among individuals can also importantly modulate the risk of drug dependence. Cytochrome P450 drug metabolizing enzymes (CYPs), can activate (e.g. codeine to morphine) or deactivate (e.g. nicotine to cotinine) drugs of abuse. Some CYPs are polymorphic, that is, there are gene mutations which result in individuals with no (null mutations) or decreased enzyme activity (e.g. CYP2D6*10). Individuals with two null mutations appear in the population as phenotypic poor metabolizers. Using in vitro studies, we have identified drugs of abuse that are substrates of the polymorphic enzymes CYP2D6 (codeine, amphetamines, dextromethorphan), CYP2A6 (nicotine) and CYP2C19 (flunitrazepam). In human experimental studies, we have shown that CYP phenotype and genotype affect abuse liability of CYP2D6 metabolized drugs of abuse. In addition, we inhibited CYP2D6 and decreased individuals' risk of dependence experimentally (codeine, dextromethorphan) and treated codeine dependence. In epidemiologic studies CYP2D6 and CYP2A6 null mutations protect individuals from becoming codeine and tobacco dependent, respectively. With respect to CYP2A6, individuals with mutations, smoke fewer cigarettes and can quit more easily. Inhibiting CYP2A6 (e.g. tranylcypromine, methoxsalen) decreases smoking and the activation of procarcinogens. By mimicking these gene defects the risk of dependence can be decreased in individuals and new treatments developed.

Animals↗
PubMed1984

Efficacy and tolerability of glaucine as an antitussive agent.

One hundred and thirty out-patients, affected by acute and chronic cough caused by upper respiratory tract inflammation, took part in two clinical studies aimed at evaluating the efficacy and tolerability of glaucine , a new antitussive agent. The first study involved 90 patients in a double-blind comparative trial of glaucine and codeine: both treatments were administered as a syrup at a dosage of 30 mg 3-times daily for 7 days. The cough suppressant effect of the two treatments was checked by the physician and the patient using a 4-point scale (from absent to severe), and by the patient using a visual analogue scale. Mean scores of the physician's evaluation decreased from 3.0 to 1.10 after codeine and from 3.0 to 0.47 after glaucine (p less than 0.001 between treatments). Mean values of the patients' visual analogue scales decreased from 83 mm to 17 mm after codeine, and from 85 mm to 7 mm after glaucine (p less than 0.001 between treatments). Constipation and nausea were reported by 9 patients on codeine and by no patient on glaucine (p less than 0.01). One patient on codeine was withdrawn from the study after 3 days because of vomiting, constipation and nausea. The second study was an open trial in 40 patients who received glaucine capsules at a dosage of 30 mg 3-times daily for 28 days. The antitussive effect of the treatment was evaluated on the basis of the same criteria as in the first study. The mean score of the physician's evaluation decreased from 3.0 to 0.15 (p less than 0.001); the mean value of the patients' visual analogue scales decreased from 93 mm to 1 mm (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed2001

[Weak opioids].

Weak opioids have been used as analgesics in cancer patients with moderate to severe chronic pain. Codeine is one of the weak opioids which is assigned as a representative analgesic of the 2nd ladder-drugs for the treatment of cancer pain by WHO cancer pain relief programme. Analgesic effect of codeine is recognized when it is administered with 20 mg p.o. or more. Clinical ceiling effect of codeine is seemed to be 200-300 mg/day, although it is described as 600 mg/day in some textbooks. Side effects of codeine are same as those of morphine, therefore, drugs for the side effects should be given to the patients simultaneously when codeine is administered.

Analgesics, Opioid↗
PubMed1991

Poppy seed ingestion as a contributing factor to opiate-positive urinalysis results: the Pacific perspective.

The possible contribution of poppy seed foods to positive opiate urinalysis results, especially from foods available in the Pacific Rim area, has recently become an issue for the U.S. Army Forensic Toxicology Drug Testing Laboratory in Hawaii. To assess the likelihood of this possible contribution, seven different poppy seed food products were consumed by male and female volunteers, and urine specimens were collected at time increments up to either 24 or 72 h. Specimens were evaluated for opiates using Roche Abuscreen radioimmunoassay (RIA), and all RIA positive specimens were analyzed for morphine and codeine using gas chromatography/mass spectrometry (GC-MS). Poppy seed cake, bagels, muffins, and rolls did not contain sufficient quantities of poppy seeds to give rise to opiate positive specimens by U.S. Department of Defense (DOD) GC-MS cutoff levels (morphine = 4000 ng/mL, codeine = 2000 ng/mL), although a number of specimens were positive by National Institute on Drug Abuse (NIDA) cutoff levels (morphine and codeine = 300 ng/mL). However, ingestion of poppy seed streusel or Danish pastry led to confirmed morphine and codeine positive specimens, irrespective of the use of DOD or NIDA confirmation cutoff values. In addition, significant amounts of codeine were observed in a number of these specimens. These findings argue against the unqualified application of previously published quantitative guidelines for eliminating poppy seed ingestion as a possible cause for a positive opiate urinalysis result.

Codeine↗
PubMed1991

Polymorphic metabolism of opioid narcotic drugs: possible clinical implications.

The oxidative metabolism of many drugs is under genetic control. The enzyme responsible for this reaction for this group of drugs is cytochrome P-450IID6. Humans can be classified either as extensive metabolisers or, if lacking this enzyme, poor metabolisers. The incidence of poor metabolisers in caucasian subjects is 7-10%. The hepatic O-demethylation of codeine to morphine, quantitatively a minor metabolic process, represents this type of genetic polymorphism and has been studied in human pharmacokinetic studies, human urinary recovery studies, and in human and rat liver microsome experiments. Based on the current understanding that the analgesic effect of codeine is mediated primarily through morphine, one might anticipate that poor metabolisers would not obtain pain relief from codeine. The clinical significance of this polymorphism to the antidiarrhoeal and antitussive properties of codeine is not known. Others opioids (dihydrocodeine, hydrocodone, oxycodone, and thebaine) are structurally similar to codeine and their metabolism (O-demethylation at the 3 position) might also be under genetic control. Pharmacogenetics may play an important role in explaining the wide variability of the clinical response to many opioid drugs.

Alfentanil↗
PubMed1990

Airway opioid receptors mediate inhibition of cough and reflex bronchoconstriction in guinea pigs.

Effects of opioids and opioid antagonists on citric acid-induced cough and reflex bronchoconstriction have been examined in conscious guinea pigs. Airway reflexes produced by inhaled citric acid are mediated by capsaicin sensitive sensory neurons, and we examined particularly the possibility that inhibitory effects of opioids can be exerted locally in the airway. As expected, systemically administered codeine (1-10 mg/kg), meperidine (3-30 mg/kg) and morphine (1-10 mg/kg) dose-dependently inhibited cough and bronchoconstriction. However, inhalations of nebulized codeine (10-100 mg/ml) and morphine (10-30 mg/ml) also produced these effects. The potency and rapid onset of action of inhaled codeine suggest that it exerted its effects without first being metabolized to morphine. The opioid receptor antagonist naloxone completely (10-100 micrograms/kg), and nalorphine (a mixed agonist/antagonist) (1-3 mg/kg) partly, inhibited codeine's antitussive and antibronchoconstrictor effects. Nalorphine alone (3-30 mg/kg) inhibited citric acid induced reflexes, whereas naloxone was without effect. Prior inhalation of a quaternary opioid receptor antagonist, levallorphan methyl iodide (10 mg/ml), abolished the inhibitory effects of inhaled codeine (30 mg/ml). The present data suggest that inhibition of cough and reflex bronchoconstriction can be produced by opioids, acting on mu and kappa receptors located in the guinea pig tracheobronchial tree. The possible existence in the airways of a unique opioid receptor mediating inhibition of cough (as described in the central nervous system) cannot be excluded.

Animals↗
PubMed1985

[Objectivation of the effect of antitussive agents using tussometry in patients with chronic cough].

The antitussive effect of several antitussive agents has been objectively evaluated in patients with chronic stable cough due to bronchial carcinoma, pulmonary tuberculosis or chronic obstructive lung disease. The patients received the active antitussive drugs or placebo in a double-blind, randomized crossover design. The preparations were administered at 10 p.m. and 2 a.m. on 7 consecutive nights and no antitussive was given for the following 20 hours. Cough frequency and intensity were recorded from 10 p.m. until 6 a.m. The active medications were noscapine (30 mg), dextromethorphan (20 mg), dihydrocodeine (30 mg) and codeine (20, 30 and 60 mg) at 10 p.m. and 2 a.m. Cough frequency and intensity were objectively assessed with a pressure transducer placed over the trachea and recorded on a chartrecorder. Statistical analysis was performed with analysis of variance and multiple range testing. Noscapine, dextromethorphan, dihydrocodeine and codeine (60 mg) significantly (p less than 0.001) reduced the cough frequency compared to placebo. They also produced a greater reduction of cough intensity than placebo, codeine (20 mg) and codeine (30 mg) (p less than 0.001). The duration of action of low-dose codeine (6 hours) was unsatisfactory. Subjective preference for dextromethorphan indicates a psychotropic central nervous action of this drug not assessed by the measuring device. Noscapine was equally well tolerated but more neutral psychologically.

Adult↗
PubMed1984

Gangrene of the upper extremity following intra-arterial injection of drugs. A case report and review of the literature.

A case of inadvertent intra-arterial self-injection of crushed codeine tablets in an 37-year-old man, resulting in gangrene of an upper extremity, is presented. The problem studied was whether the gangrene was caused by the codeine or by one of the excipients found in the tablets. The cause of the gangrene was investigated in an experimental study. Each of the components of the tablet (codeine, lactose, gelatin, carboxymethyl cellulose, calcium stearate, talc, and microcrystalline cellulose) was injected into the femoral arteries of dogs. The results of the study clearly demonstrate that the unique component producing the gangrene was the micro-crystalline cellulose, while the injection of pure codeine was harmless. To date, the only reported deleterious effects of intravascular injection of micro-crystalline cellulose have been pulmonary embolism and granulomatosis. Some examples of drugs that include microcrystalline cellulose are methadone, methaqualone, oxcycodone, acetaminophen, aspirin with codeine, propoxyphene napsylate, meprobamate, and phenobarbital. Recently, the vulnerability of drug addicts who habitually inject drugs into veins to the accidental injection of an artery has been noted, and it seems likely that in the future the problem of intra-arterial injection will increase in severity. The literature of the last 40 years is reviewed, and a list of drugs known to have produced gangrene when injected intra-arterially is cited.

Adult↗
PubMed1983

Antitussive effect of the optical isomers of mu, kappa and sigma opiate agonists/antagonists in the cat.

The optical isomer of mu and kappa opiates, when given i.v., inhibited the cough reflex in the lightly anesthetized cat, the levoisomers being, in general, 2 to 14 times more potent than the dextro-isomers. The optical isomers of the sigma agonist, SKF 10,047, did not show any antitussive activity up to near lethal or lethal doses (5 mg/kg i.v.). Naloxone (1 mg/kg i.v.) did not block or reverse the antitussive effects of (-)- and (+)-codeine but completely antagonized the effects of an ED84 of (-)-, (+)-morphine, (-)-, (+)-methadone, levomethorphan and dextromethorphan. The cough suppressant effects of the kappa opiates were partially blocked by naloxone, (+/-)-ketocyclazocine being more sensitive to the effect of naloxone than (-)-cyclazocine. (-)-SKF 10,047 at 3.0 mg/kg i.v. and the ED16 of (-)-cyclazocine did not inhibit the antitussive effect of codeine but blocked that of morphine, behaving like naloxone. (+)-SKF 10,047 and (+)-cyclazocine did not show in vivo antagonistic effect vs. codeine or morphine. The ED16 of ketocyclazocine partially antagonized codeine but not morphine. The optical isomers of opiates showed good correlation between the in vivo antitussive potencies and their in vitro inhibitory potencies against (-)-codeine binding in homogenates of the guinea-pig medulla. The data confirm the hypothesis that the cough suppressant effects of opiates are mediated by receptors which are less stereoselective and less naloxone-sensitive than the analgesic receptors. The possible involvement of mu and kappa sites as well as their interactions are discussed.

Animals↗
PubMed1981

Maintenance of behavior by ketamine and related compounds in rhesus monkeys with different self-administration histories.

Rhesus monkeys lever-pressed under a fixed-ratio 30 time-out 600 sec schedule of i.v. injection of codeine (0.32 mg/kg/injection) or, in a second group of monkeys, ketamine (1.0 mg/kg/injection). During single session substitutions, the maintenance drug was replaced with saline or doses of various other drugs. At appropriate doses, ketamine maintained responding when substituted for ketamine. Phencyclidine, dexoxadrol and dextrorphan maintained responding when substituted for ketamine but did not maintain responding when substituted for codeine. Cyclazocine and SKF-10,047 (N-allyl-normetazocine) did not maintain responding when substituted for either ketamine or codeine; ethylketazocine did not maintain responding when substituted for ketamine. For those drugs maintained under behavior, fixed-ratio response rate and the number of injection dose and then decreased at higher injection doses. Substituted drugs maintained maximum response rates at the following injection doses: codeine, 0.32 mg/kg; ketamine, 1.0 mg/kg; phencyclidine, 0.03 mg/kg, dexoxadrol, 0.32 mg/kg; and dextrorphan, 1.0 mg/kg. Under only the ketamine maintenance schedule, the rate of responding during the timeout component varied as a function of the substitution dose of ketamine, codeine, phencyclidine and dexoxadrol, with the dose that maintained maximal fixed-ratio rates also engendering the highest rates of timeout responding.

Animals↗
PubMed1998

Improved GC/MS analysis of opiates with use of oxime-TMS derivatives.

An improved gas chromatographic/mass spectrometric (GC/MS) assay is described for the quantitation of codeine and morphine as trimethylsyl (TMS) derivatives. The TMS derivatization of ketone-containing opiates results in the formation of multiple derivatives. Some of these products have retention times close to those of codeine-TMS and morphine-TMS. When the keto-opiates are present in samples assayed for codeine and morphine in urine, they can interfere with the quantitation of these commonly targeted opiates. The assay was improved with the addition of a pre-BSTFA derivatization step, whereby hydroxylamine was used to convert the keto-opiates into the corresponding oxime derivative. These derivatives were then reacted with BSTFA to form the TMS ethers and TMS oxime derivatives. The oxime step enabled production of single derivatives for hydrocodone and hydromorphone. In addition, the retention times for the oxime-TMS derivatives were increased so that they no longer elute near the targeted drugs of codeine and morphine. The addition of the oxime step does not affect the sylation of codeine and morphine, and the accuracy and precision of this assay were unaffected.

Codeine↗
PubMed1988

A double-blind parallel evaluation of the efficacy and safety of a single dose of ketoprofen in cancer pain.

The analgesic effects of single oral doses of ketoprofen 100 and 300 mg, the combination of aspirin 650 mg plus codeine 60 mg, and placebo were compared under double-blind conditions in 160 hospitalized patients with cancer pain. At baseline and at 30 minutes and hourly for 6 hours after treatment, patients evaluated their pain intensity and pain relief. The 100 mg ketoprofen dose was significantly (P less than 0.05) superior to placebo for all 14 derived efficacy parameters; the 300 mg dose was significantly superior to placebo in all assessments except derived onset of relief. Aspirin plus codeine was significantly (P less than 0.05) superior to placebo for nine of the 14 assessments. No statistically significant differences were observed among active treatments for any of the 14 derived parameters. The number of patients with a "good" response was greatest in the ketoprofen 100 mg group (55%); the numbers of good responders in the aspirin plus codeine (37.5%) and the ketoprofen 300 mg (30%) groups were comparable. The three active treatment groups were not significantly different from each other for patient response. The numbers of patients requiring rescue analgesic were significantly (P less than 0.05) lower for both ketoprofen groups, but not for the aspirin plus codeine group, as compared with the placebo group. Twenty-three percent of the 160 patients reported adverse experiences, but there were no significant differences between the treatment groups in the number or type of experience. These results show that ketoprofen is as effective and well tolerated as aspirin plus codeine in relieving cancer pain.

Adult↗
PubMed1992

A conspicuous down-regulating effect of morphine on essential steroid hydroxylation reactions and certain drug N-demethylations.

This study was conducted to explore the potency of morphine to induce reductions of specific cytochrome P450 isoenzyme functions. Male Sprague-Dawley rats were treated with escalating doses (20-125 mg/kg per day) of morphine for 2 weeks in order to study the effects on the following cytochrome P450 catalyzed reactions: 16 alpha-hydroxylation of dehydroepienderosterone (DHA) and progesterone; 17 alpha- and 21-hydroxylation of progesterone; N-demethylation of ethymorphine, codeine and morphine as well as O-dealkylation of ethylmorphine and codeine. 16 alpha-Hydroxylation of DHA and progesterone and 17 alpha-hydroxylation of progesterone decreased to 18, 12 and 10% of control activities, respectively. The N-demethylation of ethylmorphine and codeine decreased to 34 and 43% of control activities, respectively. Morphine treatment had no effect on the 21-hydroxylation reactions or the O-dealkylation of ethylmorphine or codeine. A monoclonal antibody (Mab) against rat liver cytochrome P450 2 c/RLM 5 exerted a 66-73% inhibition of the N-demethylation of ethylmorphine and codeine, respectively, whereas the O-dealkylation reactions were not affected. This Mab inhibited the 16 alpha- and 17 alpha-hydroxylation of DHA and progesterone, whereas the 21-hydroxylation reactions were unaffected. The steroid hydroxylation reactions in rat adrenals were not altered upon morphine treatment. Our data suggest that a major part of the 16 alpha- and 17 alpha-steroid hydroxylations are catalyzed by the same (or closely related) cytochrome(s) P450 as the opioid N-demethylation reactions.

Adrenal Glands↗
PubMed2004

Antitussive effect of Carum copticum in guinea pigs.

Several therapeutic effects including anti-asthma and dyspnea have been described for the seeds of Carum copticum In previous studies the relaxant and anticholinergic (functional antagonism) effects, histamine (H(1)) inhibitory effect of Carum copticum have been demonstrated on guinea pig tracheal chains. In the present study the antitussive effect of this plant was evaluated. The antitussive effects of aerosols of two different concentrations of aqueous and macerated extracts and carvacrol, codeine, and saline were tested by counting the number of coughs produced due to aerosol of citric acid 10 min after exposing animals to aerosols of different solutions (for carvacrol n=5 and for other solutions n=6). The results showed significant reduction of cough number obtained in the presence of both concentrations of aqueous and macerated extracts and codeine (p<0.001 for extracts and p<0.01 for codeine). The cough number obtained in the presence of higher concentration of aqueous and macerated extracts was significantly less than those of lower concentrations (p<0.05 for both extracts). In addition the cough number obtained in the presence of both concentrations of aqueous and macerated extracts was significantly lower than that of codeine (p<0.05 to 0.001). However, carvacrol did not show any antitussive effect. These results indicated an antitussive effect of Carum copticum which was even greater than that of codeine at concentrations used. In addition the antitussive effect of Carum copticum was not due to its main constituent, carvacrol.

Animals↗
PubMed1996

Pharmacokinetic changes in the elderly. Do they contribute to drug abuse and dependence?

The elderly frequently use psychoactive drugs including alcohol (ethanol), benzodiazepines and opioid analgesics, which have a propensity to cause abuse and dependence. Theoretically, the changes in pharmacokinetics of these agents in the elderly may modify their abuse and dependence potential. In the elderly, blood alcohol concentrations following an oral dose are higher, alcohol withdrawal syndrome follows a more severe and protracted clinical course and requires treatment with higher doses of chlordiazepoxide than needed for younger adults. However, there is no direct evidence that supports an increased direct abuse and dependence potential of alcohol because of its altered kinetics in the elderly. In the case of oxidatively metabolised benzodiazepine, both age-related pharmacokinetics and pharmacodynamic changes may increase their clinical effects in the elderly. The hypothesis that benzodiazepines have an increased abuse and dependence potential in the elderly has not been tested. Many of the benzodiazepines (e.g. alprazolam, triazolam and midazolam) are metabolised by the cytochrome P450 (CYP)3A subfamily. The pharmacokinetics of these agents may be modified by inhibition of CYP3A due to concurrently administered medications such as selective serotonin reuptake inhibitors. Unfortunately, data on the direct measures of abuse and dependence potential of benzodiazepines are not available in the elderly. Thus, a conclusive statement on the contribution of age-related pharmacokinetic changes to benzodiazepine abuse and dependence cannot be made at the present time. The clinical effects of codeine do not appear to change with age. Codeine is O-demethylated to its active metabolite morphine by the genetically polymorphic CYP2D6 isozyme. The activity of this isozyme is unaltered by age, gender or smoking habits; however, it is subject to potent inhibition by some of the frequently used medications in the elderly, such as the antidepressants paroxetine and fluoxetine. This may result in an impairment in O-demethylation of codeine to morphine and may lead to a decrease in the abuse and dependence potential of codeine. Conversely, those with a very rapid CYP2D6 catalytic activity may have an increased potential for codeine abuse and dependence. The clinical significance of age-related pharmacokinetic changes should be evaluated within the context of clinical practice. Most physicians are inclined to prescribe lower doses to the elderly, which may offset the potential impact of altered pharmacokinetics on the abuse and dependence potential of psychoactive agents. In summary, the available data are not sufficient for a definitive conclusion on whether the pharmacokinetic changes in the elderly translate to an increase in the abuse and dependence potential of alcohol, benzodiazepines or opioids. In particular, the data on age-associated changes in direct measures of abuse potential of these agents are missing. Future comparative systemic pharmacokinetic-pharmacodynamic studies assessing pertinent outcome measures on abuse and dependence potential of commonly used psychoactive drugs are required to resolve the ongoing controversy on risk factors for drug abuse and dependence in the elderly.

Aged↗
PubMed1985

[The pharmacologic effect of flupirtine, a structurally new analgesic].

The analgesic potency of ethyl-N-[2-amino-6-(4-fluorophenylmethylamino)pyridin-3-yl]carb ama te (flupirtine, D 9998) in mice and rats in Haffner's test, electro-pain test and Randall-Selitto test (inflammation induced pain) lies between the more potent dextromoramide and methadone and the more weakly active pethidine, dextropropoxyphene, codeine, phenacetin and paracetamol. In comparison to codeine flupirtine is up to 4 times more potent, up to 2 times more active than pethidine and 4 times more potent than dextropropoxyphene in the above-mentioned methods. With one exception of inflammation induced pain, where flupirtine shows an activity of about 1 1/2 times that of phenacetin and paracetamol, both analgesics are about 10 to nearly 30 times less active than flupirtine in other above-mentioned tests. In the hot plate test flupirtine is twice as active as codeine and approximately 10 times more active than phenacetin and paracetamol. The weakest analgesic activity of flupirtine is seen in acetic acid test where it is about half as active as codein and approximately as active as dextropropoxyphene. Nevertheless, flupirtine is up to 10 times more potent than phenacetin and paracetamol. The acetic acid test is claimed to be non-specific according to our own experience and to other authors. Flupirtine is enterally absorbed at a higher degree than the other tested centrally acting analgesics. In regard to the results of various analgesic investigations in mice and rats flupirtine can be classified as a medium to strong acting analgesic. The duration of action of flupirtine is comparable to that of codeine. Experiments with flupirtine suggest that there are some convincing criteria for a pronounced central acting component of its analgesic activity. These criteria are the strong efficacy in the hot-plate and Haffner's test, in which only centrally acting analgesics show distinct effects, and the finding that flupirtine increases the pain threshold for vocalisation in rats and mice excluding a pure reflex of the spinal cord. In current experiments concerning the mode of action flupirtine exhibits a distinct central analgesic component of action. In spite of its relatively high analgesic potency which corresponds to that of opiates flupirtine does not show any other signs of opiate properties and other potent analgesics. Thus, flupirtine does not develop tolerance in mice and rats after 19 or 17 days of daily administration.(ABSTRACT TRUNCATED AT 400 WORDS)

Aminopyridines↗
PubMed1976

Antitussive properties of butorphanol.

Butorphanol (levo-N-cyclobutylmethyl-3, 14-dihydroxy morphinan), a potent analgetic agent of the narcotic antagonist type with a low abuse potential in laboratory animals, was evaluated for antitussive activity in unanesthetized guinea-pigs and dogs. Subcutaneously, it was over 100 times more active than codeine, dextromethorphan and dl-pentazocine and about 20 times more active than morphine in the guinea-pig, while in the dog it was 100, 10 and 4 times more active than codeine, dl-pentazocine and morphine, respectively. Orally, butorphanol was 15-20 times more active than either codeine or dextromethrophan in both species. Naloxone reversed the antitussive effects of butorphanol, codeine, morphine and dl-pentazocine while those of dextromethorphan were not antagonized. The antitussive effect of butorphanol and morphine lasted about 4 hr and both compounds were longer acting than codeine. Butorphanol was also shown to be as effective against cough of pathological origin as against experimentally induced cough in the dog.

Animals↗