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Pharmacological studies of a new analgesic, dl-erythro-1-phenyl-2-(o-chlorophenyl)-2-[4-(p-methoxybenzyl)-1-piperazinyl] ethanol dihydrochloride, in experimental animals.

dl-Erythro-1-phenyl-2-(o-chlorophenyl)-2-[4-(p-methoxybenzyl)-1-piperazinyl] ethanol dihydrochloride showed orally a definite analgesic activity, without producing the significant morphine-like physical dependence liability, and its analgesic potency was about a half that of codeine and far superior to aminopyrine in experimental animals.

Aminopyrine↗

Local histamine release after immunological and non-immunological mast cell degranulation in vivo.

Plasma histamine concentration in the circulation has been proposed as an index of mast cell degranulation occurring in vivo but there are problems with this approach in practice. Local elevations in plasma histamine occur in blood draining the site of antigen challenge in forearm skin. We have compared changes in plasma histamine concentration with time following intradermal injection of antigen, codeine or histamine to produce matched wheal and flare responses in 4 atopic subjects. Less histamine appears to be released after non-immunological challenge.

Adult↗

Is bowel confinement necessary after anorectal reconstructive surgery? A prospective, randomized, surgeon-blinded trial.

PURPOSE: The aim of this study was to assess any differences between the inclusion or omission of medical bowel confinement relative to postoperative morbidity and patient tolerance after anorectal reconstructive surgery. METHODS: Between January 1995 and February 1997 a prospective randomized trial was conducted for patients without stomas who underwent anorectal reconstructive surgery. All patients were randomly assigned either to medical bowel confinement (a clear liquid diet with loperamide 4 mg by mouth three times per day and codeine phosphate 30 mg by mouth four times per day until the third postoperative day) or to a regular diet, beginning the day of surgery. All patients in both groups underwent the identical preoperative oral mechanical preparation, preoperative oral and parenteral antibiotics, and postoperative antibiotics. Wound closure and wound care were identical in both groups. RESULTS: Fifty-four patients (46 females) were prospectively, randomly assigned to medical bowel confinement (n = 27; 50 percent) or a regular diet (n = 27; 50 percent); the mean ages were 51.0 (range, 28-80) and 47.2 (range, 23-87) years, respectively. Indications for surgery were fecal incontinence in 32 patients, complicated fistulas in 17 patients, anal stenosis in 4 patients, a Whitehead deformity in 1 patient, and a chronic unhealed fissure in 1 patient. Fifty-four patients underwent 55 procedures: 32 patients underwent sphincteroplasty, 18 patients underwent transanal advancement flaps, and 5 patients underwent anoplasties. There were no differences between the two groups in the incidence of either septic or urologic complications. Nausea and vomiting were recorded in seven (26 percent) medical bowel confinement and three (11 percent) regular-diet patients. The first postoperative bowel movement occurred at a mean of 3.9 days in the medical bowel confinement group and 2.8 days in the regular diet group (P < 0.05). Fecal impaction occurred in seven (26 percent) of the patients in the medical bowel confinement group and two (7 percent) of the patients in the regular diet group. Hospital charges analysis showed a mean cost of hospitalization of $12,586.00 (range, $3,436.00-$20,375.00) for the medical bowel confinement group and $10,685.00 (range, $3,954.00-$18,574.00) in the regular diet group, representing a mean difference of $1,901.00 (P = 0.06). Mean follow-up was 13 months for both groups (range, 1-24 months in the regular diet group and 2-25 months in the medical bowel confinement group). No statistical difference was shown in the functional outcome of sphincteroplasties between the medical bowel confinement group and the regular diet group. CONCLUSIONS: The outcome of reconstructive anorectal surgery was not adversely affected by the omission of medical bowel confinement. Moreover, cost savings can be achieved by the omission of routine bowel confinement.

Adult↗

Subhypnotic propofol does not treat postoperative vomiting in children after adenotonsillectomy.

PURPOSE: To investigate the efficacy of a subhypnotic dose of propofol to treat vomiting in children after adenotonsillectomy. METHODS: Two hundred and fifty-two children, aged 2-12 yr, underwent a standardized anaesthetic opioid administration, and postoperative care after adenotonsillectomy, adenoidectomy or tonsillectomy. A prospective, double-blinded, placebo-controlled study was performed in 70 of the patients who retched or vomited after surgery and who had intravenous access. Patients were assigned randomly to receive either 0.2 mg.kg-1) propofol (n = 35), or placebo (intralipid 10%, n = 35). RESULTS: The overall incidence of vomiting during the first 18-24 hr was 50%. Of those who had received propofol after the first episode of vomiting, 63% relapsed requiring a rescue antiemetic compared with 57% of those who had received intralipid (P = NS). Of the children who received propofol, 54% experienced pain on injection and 46% were mildly sedated compared with 3% and 11%, respectively, in the placebo group (P < 0.003). CONCLUSION: We conclude that an intravenous bolus of 0.2 mg.kg-1 propofolis not effective in the treatment of postoperative vomiting in children after adenotonsillectomy when a standardized anaesthetic with thiopentone, halothane, nitrous oxide, and 1.5 mg.kg-1 codeine phosphate is used, but it does cause sedation and pain on injection.

Adenoidectomy↗

Hairy root induction of Papaver somniferum var. album, a difficult-to-transform plant, by A rhizogenes LBA 9402.

Two strains of Agrobacterium rhizogenes (15834, LBA 9402) and one Agrobacterium tumefaciens strain [GV 3101 (PMP90RK, p35SGUS-2)] and four culture media were tested and compared for their ability to induce hairy root formation on wounded Papaver somniferum L. hypocotyls. Five weeks after the infection with A. rhizogenes LBA 9402, hairy roots appeared on 80% of the hypocotyls maintained in the hormone-free liquid medium. Six hairy-root cultures were established. Transformation was confirmed by polymerase chain reaction analysis. One clone was analysed for its alkaloid production. The total alkaloid content was higher in the transformed roots (0.46+/-0.06% DW) than in the untransformed roots (0.32+/-0.05% DW). The transformed roots accumulated three times more codeine (0.18+/-0.02% DW) than intact roots (0.05+/-0% DW). Moreover, morphine (0.255+/-0.03% DW) and sanguinarine (0.014+/-0% DW) were found in the liquid culture medium.

Alkaloids↗

[Gordian knot: medication overuse headache].

Overuse of any kind of headache drugs may lead to the development of the medication overuse headache (MOH). Clinical features of MOH depend on the substance class that has been overused. Overuse of analgesics leads to a chronic tension-type like headache, the overuse of triptans to daily migraine-like headache or to the increase of migraine frequency. The delay between the drug overuse and onset of daily headache is shortest for triptans (1.7 years), longer for ergots (2.7 years) and longest for analgesics (4.8 years). Treatment includes withdrawal followed by structured acute therapy and initiation of specific prophylactic treatment for the underlying primary headache. The relapse rate after a successful withdrawal is about 30%. Predictors for relapse are tension-type headache and the overuse of analgesics in combination with codeine, caffeine or opioids.

Analgesics↗

Randomized, clinical trial of bowel confinement vs. laxative use after primary repair of a third-degree obstetric anal sphincter tear.

PURPOSE: Third-degree tears are generally managed by primary anal sphincter repair. Postoperatively, some physicians recommend laxative use, whereas others favor bowel confinement after anorectal reconstructive surgery. This randomized trial was designed to compare a laxative regimen with a constipating regimen in early postoperative management after primary obstetric anal sphincter repair. METHODS: A total of 105 females were randomized after primary repair of a third-degree tear to receive lactulose (laxative group) or codeine phosphate (constipated group) for three days postoperatively. Patients were reviewed at three days and at three months postpartum. Recorded outcome measures were symptomatic and functional outcome and early postoperative morbidity. RESULTS: Forty-nine patients were randomly assigned to the constipated group and 56 patients to the laxative group. The first postoperative bowel motion occurred at a median of four (mean, 4.5 (range, 1-9)) days in the constipated group and at two (mean, 2.5 (range, 1-7)) days in the laxative group (P<0.001). Patients in the constipated group had a significantly more painful first evacuation compared with the laxative group (P<0.001). The mean duration of hospital stay was 3.7 (range, 2-6) days in the constipated group and 3.05 days in the laxative group (range, 2-5; P=0.001). Nine patients in the constipated group complained of troublesome postoperative constipation compared with three in the laxative group (P=0.033). Continence scores, anal manometry, and endoanal ultrasound findings were similar in the two groups at three months postpartum. CONCLUSIONS: Patients in the laxative group had a significantly earlier and less painful bowel motion and earlier postnatal discharge. There was no difference in the symptomatic or functional outcome of repair between the two regimens.

Adult↗

The influence of analgesic drugs in road crashes.

The involvement in road crashes of two classes of drug referred to as analgesics is discussed. Evidence for the effect on traffic safety of each drug group is examined in terms of their behavioural pharmacology and of the available epidemiological data. In the case of the antipyretic analgesics, such as aspirin, there is no evidence to suggest any causative involvement in road crashes. In view of the striking differences in the supply and manner of use of the legal and illegal narcotic analgesics, these are examined separately. The behavioural pharmacology of intravenously administered heroin suggests that any drug induced deficit in driving performance is not due to any effect on psychomotor function, but might be expected from the effect of the drug on mood states. Methadone, as used in treatment schedules for narcotic dependence produces no significant effect on measures of human skills performance. Epidemiological data are contradictory though the suggestion is that the involvement of the narcotic analgesic drugs in road crashes is unlikely to be a source of significant concern. A suggestion is made that a closer examination be undertaken of the involvement in road crashes of the more widely available narcotic drugs codeine and propoxyphene when they are taken together with alcohol.

Accidents, Traffic↗

A comparison of crossover versus parallel-group design in the evaluation of analgesic efficacy after molar extraction.

This study compares the analgesic effects of two standard combinations (Empirin with codeine versus Mersyndol) and placebo as measured by crossover versus parallel-group design. The analgesic results obtained with three groups of 12 to 13 crossed over subjects with two extractions divided into six subgroups of five to seven subjects for each sequence were qualitatively the same and statistically at least as strong as those obtained by analysis of parallel groups of 38 to 42 extractions per group. By both methods the analgesics were statistically significantly more effective than placebo. The difference between the two products was not statistically significant, although the score for Mersyndol was somewhat better by both methods of study. The crossover data did not allow judgments concerning side effects in spite of its greater efficiency in quantifying pain relief.

Acetaminophen↗

The effects of local micro injections of opiates and enkephalins into the forebrain on the electrocorticogram of the rat.

The effects of various opiate compounds have been studied on the electrocorticogram (ECoG) of the rat following local injection into various brain areas. Injections of all compounds studied into both the caudate-putamen and the basal forebrain, in particular the olfactory tubercles, induced changes in the ECoG. Injections of saline vehicle into these areas were ineffective as were injections of morphine into the corpus callosum. Potency was etorphine greater than morphine = codeine greater than thebaine. Naloxone alone was inactive following injection but if combined with morphine markedly attenuated the normal morphine response and reversed the morphine response if injected following morphine. The endogenous opiate compound enkephalin and the synthetic analogue D-ala2-met5-encamide also induced electrocortical changes which were naloxone sensitive. The results are similar to those following systemic administration of opiates. It is possible that the areas studied represent the site of action of systemically applied opiates. It is suggested that the opiates and enkephalins produce their actions by acting at the same site. Since the areas studied are rich in dopaminergic terminals an interaction may exist between dopaminergic and opiate mechanism to bring about the observed changes.

Animals↗

Antitussive activity of some naturally occurring cannabinoids in anesthetized cats.

Experimental cough was elicited in pentobarbital-anesthetized cats by either electrical stimulation of the superior laryngeal nerve or by mechanical stimulation of the tracheal mucosa. Intravenous administration of delta9-tetrahydrocannabinol (THC) effectively reduced the amplitude of the cough response in both these models of experimentally induced cough with ED50 values (AtD50) of 1.84 and 0.78 mg/kg, respectively. This cough suppressant activity of THC was more similar to codeine-PO4 than dextromethorphan-HBr. On the other hand, both cannabinol (CBN) and cannabidiol (CBD) were devoid of antitussive activity at doses as high as 10.0 mg/kg.

Animals↗

Discriminative stimulus effects of enkephalin analogs, EK-209 and EK-399, in rats.

The discriminative stimulus effects of two enkephalin analogs, Tyr-D-Ala-Gly-MePhe-NHNHCOCH2CH3.AcOH (EK-209) and Tyr-D-Met(O)-Gly-EtPhe-NHNHCOCH3.AcOH (EK-399), were assessed in a drug discrimination experiment with rats. The animals were trained to discriminate between the effect of morphine (3 mg/kg s.c.) and saline in a two-lever choice, water reinforced procedure. After the discrimination training had been completed, the animals were used in stimulus generalization tests. A test drug was administered subcutaneously before the test session, and the animals were allowed to select the morphine or saline lever. The animals completely generalized to the effects of codeine, fentanyl and EK-209, but did not generalize completely to the effect of ethylketocyclazocine. After receiving an injection of pentazocine, levallorphan, N-allynormetazocine, or EK-399, the animals pressed the morphine lever, but did not generalize completely to the effects of these drugs. These results suggest that the discriminative stimulus effect of EK-209 is similar to that of morphine, whereas the effect of EK-399 may be different from that of morphine.

Analgesics↗

Pharmacological studies of allergic cough in the guinea pig.

The pharmacological mechanisms of allergic cough in the guinea pig were studied. Actively sensitized guinea pigs were exposed to aerosols of antigen to elicit coughing. In separate experiments, naive guinea pigs were exposed to aerosols of capsaicin to elicit coughing. Both allergic and capsaicin-induced cough were inhibited by loratadine (0.3-10 mg kg-1 p.o.) and chlorpheniramine (0.1-3.0 mg kg-1 p.o.). Neither cimetidine (10 mg kg-1 s.c.), nor thioperamide (3-10 mg kg-1 s.c.), inhibited allergic or capsaicin-induced cough. Codeine (3-30 mg kg-1 p.o.), salbutamol (0.003-3.0 mg kg-1 s.c.) and ipratropium (0.03-1.0 mg kg-1 s.c.) inhibited both allergic and capsaicin-induced cough. Hexamethonium (10 and 30 mg kg-1 s.c.) inhibited allergic, but not capsaicin-induced cough. Allergic and capsaicin-induced cough were unaffected by phenidone (5.0 and 10.0 mg kg-1 s.c.). Indomethacin (5.0 and 10.0 mg kg-1 s.c.) had no effect on allergic cough but slightly inhibited capsaicin-induced cough. We conclude that allergic and capsaicin-induced cough are modulated by histamine H1 receptor and cholinergic mechanisms. Histamine H2 or histamine H3 receptor mechanisms, and lipoxygenase and cyclooxygenase products of arachidonic acid metabolism do not influence allergic and capsaicin-induced cough. Ganglionic mechanisms play a minor role in the production of allergic cough and no role in capsaicin-induced cough.

Administration, Oral↗

Effect of opioid agonist-antagonist interaction on morphine dependence in rats.

Morphine dependence was induced by treatment with morphine-admixed food (0.25mg/g of food) for 7 days. Withdrawal was precipitated by injecting naloxone (0.5mg/kg, s.c.). Rats treated with morphine exhibited body weight loss upon the naloxone injection. When morphine-dependent rats were injected subcutaneously with morphine, codeine, meperidine and pentazocine 30 min before the naloxone injection, these drugs significantly suppressed the naloxone-precipitated loss of body weight in a dose-dependent manner. However, body weight loss induced through coadministration of naloxone and Mr-2266 BS were not suppressed by morphine pretreatment. These results suggest that opioids protect against naloxone-precipitated loss of body weight, and that mu and kappa opiate receptors play an important role in the protection against naloxone-precipitated withdrawal.

Animals↗

Mu receptor binding of some commonly used opioids and their metabolites.

The binding affinity to the mu receptor of some opioids chemically related to morphine and some of their metabolites was examined in rat brain homogenates with 3H-DAMGO. The chemical group at position 6 of the molecule had little effect on binding (e.g. morphine-6-glucuronide Ki = 0.6 nM; morphine = 1.2 nM). Decreasing the length of the alkyl group at position 3 decreased the Ki values (morphine less than codeine less than ethylmorphine less than pholcodine). Analgesics with high clinical potency containing a methoxyl group at position 3 (e.g. hydrocodone, Ki = 19.8 nM) had relatively weak receptor binding, whilst their O-demethylated metabolites (e.g. hydromorphone, Ki = 0.6 nM) had much stronger binding. Many opioids may exert their pharmacological actions predominantly through metabolites.

Animals↗

Persistence of drug experience in rats formerly dependent on phenobarbital or meprobamate.

The rats of groups I, II, III and IV were treated orally with phenobarbital, meprobamate, codeine and vehicle, respectively, for total 21 days, and then drugs were withdrawn. All these rats were given again orally phenobarbital for 5 days starting from 70 days after the withdrawal. In comparison with groups III and IV, groups I and II showed larger weight gain during phenobarbital re-administration and longer-lasting weight loss and an larger increase in body temperature after the termination. These results suggested that the drug experience on sedative-hypnotics persisted over two months after the withdrawal and that did not cross to that of narcotics.

Animals↗

Dental drugs and anaphylactic reactions. Report of a case.

The patient described here experienced an acute anaphylactic reaction after receiving parenteral lidocaine, oral aspirin, codeine, and penicillin following routine dental treatment. The patient had taken all of the drugs previously with no untoward effects. The incidence and mechanisms of drug-induced hypersensitivity reactions are discussed. The importance of monitoring the patient following drug administration, even in the case of a negative medical and drug history, is discussed.

Adult↗

Butorphanol and nalbuphine: a pharmacologic comparison.

The agonist/antagonist analgesics, butorphanol (Stadol) and nalbuphine (Nubain), are being increasingly employed as intravenous sedation agents; nalbuphine will be available in the future as an oral analgesic. The drugs possess numerous pharmacologic similarities and some dissimilarities. Both are equianalgesic (and nalbuphine is equipotent) with morphine parenterally and codeine orally. Their pharmacokinetics are similar; nalbuphine has a longer duration of action. Both may precipitate an abstinence syndrome in narcotic-dependent persons and will probably be associated with low-level drug abuse potential. They are both agonists of the kappa opioid receptor and partial agonists of the mu receptor. Butorphanol is a partial agonist of the sigma receptor responsible for psychotomimetic effects. The incidence of adverse effects is low, sedation being the most common. In cardiac-risk patients, nalbuphine does not increase cardiac work or oxygen requirements; nor do increasing doses of nalbuphine increase the duration of respiratory depression. Both drugs possess plateau respiratory depressant actions.

Anesthesia, Dental↗