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Recent research demonstrated that codeine produced hypoalgesia and morphine produced hyperalgesia against a noxious thermal stimulus in young domestic fowl. The bidirectional effects of these opiate agonists on nociception are inconsistent with the notion that codeine's algesic effects result through in vivo demethylation of codeine to yield morphine. In Experiment 1, the temporal pattern (15,30,60 and 120 min) of codeine (30 mg/kg) effects on thermal nociception and respiration were examined in 15-day-old cockerels. Codeine produced a time-dependent biphasic response: hypoalgesia at 15 min and hyperalgesia at 60 and 120 min. Respiration was depressed by codeine at all test intervals. To assess for opioid specificity, Experiment 2 examined the action of naloxone (5 mg/kg) on the temporal pattern (15 and 60 min) of codeine effects (30 mg/kg) on thermal nociception and respiration. Bidirectional codeine algesic effects were observed at the 15- and 60-min test intervals. Naloxone increased the codeine jump latency scores at the 15-min interval and decreased codeine jump latency scores at the 60-min interval. These results suggest that codeine engages opposed nonopioid-mediated hypoalgesic and opioid-mediated hyperalgesic nociceptive systems in this animal model. Codeine depressed respiration at both the 15- and 60-min test intervals and this respiratory depression was reversed by naloxone. These findings support the notion that codeine respiratory effects are mediated by opioid system activity.
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PMID:Time-dependent codeine hypoalgesia and hyperalgesia in domestic fowl. 157 24

1. Morphine-like analgesic drugs caused depression of twitches of the isolated guinea-pig ileum in response to transmural electrical stimulation. The drugs tested were the narcotic analgesics codeine, diamorphine, fentanyl, morphine, morphine-N-oxide, normorphine, oxymorphone, pethidine, phenazocine and phenoperidine and the analgesic narcotic antagonists nalorphine and pentazocine.2. With the first application of one of these drugs the extent of depression of twitches was proportional to concentration. Except in the case of pethidine, there was no further depression when additional drug was added to the organ bath. With the second application of a drug after washing out the first dose, the depressant effect was less; that is, tolerance developed. With pethidine, the depression of twitches was proportional to concentration and tolerance could not be observed.3. When tolerance had been produced by cumulative addition of these drugs, a concentration was reached at which further addition resulted in increased activity of the ileum.4. With codeine, morphine and normorphine, the twitches were increased in height and regular.5. With diamorphine, fentanyl, oxymorphone, pentazocine, phenazocine and phenoperidine there were increased but irregular responses to transmural stimulation.6. Having reached the concentration at which these effects were observed, washout of the drug resulted in reduction of activity; the twitches became smaller or the irregular responses ceased.7. Readministration of a drug after activity of the ileum had been depressed by withdrawal of that drug resulted in restoration of activity, the ileum being dependent on the presence of the drug for its activity.8. Codeine and nalorphine did not produce as great an increase in activity on readministration to a dependent ileum as did morphine: they seem to act as partial agonists in producing this effect.9. In similar experiments with the isolated urinary bladder of the rat and guinea-pig, morphine was less active in depressing responses to stimulation than it was on the ileum, and tolerance to the drug and dependence on it did not occur.10. These observations have been discussed in relation to analgesic activity, tolerance and dependence in man.
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PMID:Comparison of effect of morphine-like analgesics on transmurally stimulated guinea-pig ileum. 534 30

Codeine and morphine were compared in a double-blind study of postoperative analgesia in 40 patients after intracranial neurosurgery. Eighteen patients received codeine phosphate 60 mg and 18 morphine sulphate 10 mg, both by intramuscular injection; 4 patients (10%) required no analgesia. Both drugs provided analgesia within 20 min of injection but morphine was more effective than codeine beyond 60 min (p = 0.01). Fewer doses of morphine than codeine were required (p = 0.003). Nine patients requested one dose of morphine and 9 two doses. Seven patients required three doses of codeine and 1 patient required four doses. Neither drug caused respiratory depression, sedation, pupillary constriction or unwanted cardiovascular effects. We conclude that, in the doses used, morphine is a safe alternative to codeine for analgesia after neurosurgery and has a more persistent action.
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PMID:A double-blind comparison of codeine and morphine for postoperative analgesia following intracranial surgery. 894 93

Morphine dosage must be carefully adapted in patients with renal failure or severe liver failure. The i.v. route is used for morphine titration in the post anaesthesia care unit (PACU), or for analgesia in children. Systematic (not on demand) intramuscular or subcutaneous morphine must be administered at intervals not longer than 4 hours. Dosage is best determined after i.v. titration in the PACU. Codeine, administered orally, is metabolised into morphine. Codeine has almost no effect in 7% of Caucasians and at least 15% of Asians. Nalbuphine, which has a sedative effect and a short half-life, is mainly used in children. Paracetamol (acetaminophen) is used orally or rectally, most often in combination with codeine. Paracetamol dosage is 60-90 mg.kg-1.d-1, including a 20 mg (orally), or 40 mg (rectally) loading dose. Its therapeutic ratio is low, with a potential hepatic toxicity. Dosage must be lowered in alcoholics or in patients under isoniazide therapy. Non-steroidal anti-inflammatory drugs are powerful antinociceptive agents. Their use must be restricted to the first 5 postoperative days. Their major contraindications are kidney failure, risk of gastrointestinal bleeding, coagulation disorders, allergy. They also have a marked morphine sparing effect and reduce therefore the respiratory depression induced by morphine.
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PMID:[Conventional techniques for analgesia: opioids and non-opioids. Indications, adverse effects and monitoring]. 975 Jul 95

Although codeine is a widely used medication, the problems of codeine abuse and dependence have not been well-studied. This study characterized regular codeine users (using at least 3 days per week for 6 months, excluding those using codeine for the treatment of cancer pain) through a self-completed questionnaire. Recruitment through newspaper advertisements resulted in a total of 339 eligible questionnaires. Thirty-seven percent of subjects met DSM-IV criteria for codeine dependence. Dependent subjects (mean age, 40 +/- 10 years) were using an average of 179 (+/-171) mg of codeine per day. Codeine was predominantly used in the form of combination products with acetaminophen. Dependent subjects identified specific problems causally related to their codeine use such as depression (23%), anxiety (21%), and gastrointestinal disturbances (13%). The dependent subjects reported problems with other drugs more than did nondependent users (alcohol, 57% vs. 26%; cannabis, 23% vs. 5%; sedative/hypnotics, 33% vs. 12%; and heroin, 11% vs. 2%, respectively). Most were taking codeine primarily for a chronic pain problem (81%), although the dependent subjects currently found codeine less effective for treating pain than did the nondependent subjects and were more likely to use codeine for pleasurable effects, to relax, or to prevent withdrawal symptoms. This study showed that dependence is associated with the regular use of codeine. Pain is a key issue with these users; however, they are probably not receiving optimal treatment. There is a need to identify individuals experiencing problems with their codeine use and to develop optimal prevention and treatment strategies.
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PMID:Characteristics of dependent and nondependent regular users of codeine. 1044 Apr 66

A community survey was conducted among long-term (>6 months) users of codeine-containing products to characterize chronic use of these extensively consumed medications. Respondents recruited through newspaper advertisements completed a mailed questionnaire. Three hundred thirty-nine completed questionnaires were obtained, yielding a response rate of 70%. Codeine dependence/abuse as defined by DSM-IV criteria was present in 41% of the respondents. Two thirds of the subjects had sought help for mental health problems, most often depression (70%). Scores on the Symptom Checklist-90 subscales were modestly elevated, particularly on the Depression subscale (1.2 +/- 0.9). Long-term codeine use is strongly associated with dependence. Depression and depressive symptoms are common. These data suggest that dysphoric mood states may be significant in maintaining long-term codeine use.
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PMID:Long-term codeine use is associated with depressive symptoms. 1044 Apr 67

Opioids have been used for analgesia in nearly all civilizations. In paediatrics their use has become widely accepted for combating severe pain, especially postoperative pain and tumour pain. Receptors in the central nervous system are the best known sites of action of opioids, but the existence of peripheral receptors is also probable. The action depends on whether the opioid is more agonist or antagonist and on the peculiarities of physiology in childhood: in the small child a hyperdynamic blood circulation makes resorption faster, and in newborn and premature infants distribution and excretion are influenced by the different composition of the body and the immaturity of liver and kidney. The best known opioid is morphine, and it is the reference substance with which all other opioids are compared. Fentanyl has been used even for the smallest ventilated prematures in recent times, as it is easy to manage and has an early onset of action. Its depressant action on the respiratory centre is an advantage when attempts of spontaneous breathing make mechanical ventilation difficult. Obstinate constipation is the disadvantage of both morphine and fentanyl, and an exacerbation of hyperbilirubinaemia has been seen with fentanyl. Nalbuphine causes a lower degree of respiratory depression. The newer opioids alfentanil and sufentanil have already been used for the relief of paediatric postoperative pain and during mechanical ventilation, but no special advantages of their use are reported. Meperidine has been favoured especially for postoperative pain, although it appears to have no advantages over morphine. Its active metabolite normeperidine may accumulate and cause seizures; meperidine should not be used in prematures or in children with renal dysfunction. There are few publications on the use of piritramide in paediatric pain. Tramadol is widely used for emergencies, as it has the least sedative action; but it has disadvantages in causing nausea and vomiting. Codeine is widely used for its antitussive action. While the necessity of good analgesia for even the smallest infant cannot be overstated, the opioid used must be carefully selected with reference to the age of the child and the pain to be controlled.
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PMID:[Analgesia with opioids in the paediatric patient.]. 1841 33

We have previously reported antitussive effects of naltrindole (NTI), a typical delta opioid receptor antagonist, in a rat model. The ED50 values of NTI by intraperitoneal and peroral injections were 104 microg/kg and 1840 microg/kg, respectively, comparable to those of codeine. Codeine, one of the most reliable centrally acting antitussive drugs, has micro agonist activity and thus the same side effects as morphine, e.g., constipation, dependency, and respiratory depression. Because NTI is a delta opioid antagonist, its derivatives have potential as highly potent antitussives, free from the mu opioid agonist side effects. We attempted to optimize the NTI derivatives to develop novel antitussive agents. On the basis of the studies of structure-antitussive activity relationships of alkyl substituted NTI derivatives, we designed NTI derivatives with extra ring fused structures. As a clinical candidate, we identified a highly potent new compound, (5R,9R,13S,14S)-17-cyclopropylmethyl-6,7-didehydro-4,5-epoxy-5',6'-dihydro-3-methoxy-4'H-pyrrolo[3,2,1-ij]quinolino[2',1':6,7]morphinan-14-ol (5b) methanesulfonate (TRK-850) which was effective even by oral administration (ED50 6.40 microg/kg).
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PMID:Structure-antitussive activity relationships of naltrindole derivatives. Identification of novel and potent antitussive agents. 1863 71

1. A method is described for recording intrathoracic pressure in cats without opening the pleural cavity; active expiratory movements were elicited by inhalation of a constant CO(2)-air mixture for a given time and a study was made of the action of drugs on inspiration and expiration. 2. Morphine and heroine were found to exert a selective depressant action on the central expiratory mechanism, and the slower rate, with relatively unaltered depth, seemed to be due at least partly to the slower rate of emptying the lungs. Codeine had no depressant action on the respiration of decerebrated cats. 3. Larger doses of morphine or heroine had no further depressant effect on rate or depth of breathing after expiration was made passive, unless circulatory depression appeared, and failure of circulation seemed to be the cause of respiratory depression, rather than the reverse relation. In decerebrated animals large doses of morphine and moderate doses of codeine stimulated the spinal cord, and expiration became active, with a faster rate of breathing. The characteristic action of morphine and heroine on the respiration of the cat is apparently limited to a depression of active expiration.
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PMID:THE ACTION OF DRUGS ON RESPIRATION : I. THE MORPHINE SERIES. 1986 13

Codeine is widely prescribed in clinical practice with over the counter (OTC) preparations of codeine freely available for consumption typically as a component of remedies for the common cold/cough. We describe the first reported case of acute confusional state in a previously healthy 14-year-old girl ultimately attributed to inappropriate codeine use. The usage of codeine in the paediatric setting has been highlighted in recent years with many reported deaths--mostly due to respiratory depression. The risks associated with codeine usage may be particularly unnecessary with OTC cough suppressants as evidence of efficacy is absent. Finally, codeine dependence is a common problem among adults and has been reported locally and internationally among adolescents. The combination of lack of efficacy, risk of acute intoxication and dependence, suggests that the use of OTC codeine preparations may be unwarranted.
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PMID:Cough, codeine and confusion. 2670 76


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