Chemical Abstracts Service Registry Number: 76-57-3. (Phosphate hemihydrate form 41444-62-6)
Formal Names: BRON, Methylmorphine
Informal Names: AC/DC, Barr, C, Captain Cody, Co-Dine, Cody, Coties, Cough Syrup, Down, Homebake, Karo, Lean, Lean & Dean, Nods, Schoolboy, Syrup, T-3s. With glutethimide: Doors & 4, 4 Doors, Hits, Loads, Packets, Pancakes & Syrup, Sets, 3s & 8s
Type: Depressant (opiate class). See page 22
Federal Schedule Listing: Schedule II, III, V controlled substance, depending on product formulation (DEA no. 9050)
USA Availability: Prescription and nonprescription
Pregnancy Category: C
Uses. Codeine was discovered in 1832 by French chemist Pierre-Jean Robi-quet. Typically it is derived from the more potent drug morphine, which, depending on dosage route (oral, injection), is considered about 3 to 12 times stronger than codeine. After codeine is administered, body chemistry transforms it back into morphine; thus employer drug screens on someone who used a codeine cough remedy can be positive for morphine. Basically codeine is a prodrug, a substance having little medicinal effect itself but that the body transforms into a useful drug—in this case, morphine. Although scientists have long believed that codeine's therapeutic effects come from morphine, as the twenty-first century began, one group of researchers reported that persons whose bodies cannot properly convert codeine into morphine can nonetheless experience medical benefit from codeine itself.
Codeine is administered for sedation and to stop diarrhea, coughs, and pain. The substance is considered one of the best cough medicines, although research in the 1990s indicated the drug has little ability to control coughs from colds. Some people take the drug regularly to diminish chronic pain. One study of the drug's ability to ease pain after tonsillectomy found its effectiveness comparable to morphine, but another tonsillectomy study found codeine no more effective than acetaminophen (Tylenol and similar products). Research examining pain from a wide variety of causes, ranging from cancer to backache, found no more discomfort relief from a combination dose of codeine and acetaminophen than from combining hydrocodone and ibuprofen. Such findings probably indicate simply that various kinds of pain relievers work adequately for various discomforts, with codeine often being as good as the other drugs.
Some regular codeine users take it to reduce anxiety, and some simply find the substance's effects pleasant. A clinical test of codeine found no antide-pressant action, but people who use codeine for a long time tend to be depressed and may be taking that drug to medicate themselves for depression— so if they have access to antidepressants they may have less interest in codeine. Codeine cough syrups may include stimulants and other ingredients that persons find pleasant, increasing the syrups' appeal.
Drawbacks. Codeine can promote sleepiness, abdominal cramps, constipation, urinary retention, nausea, and breathing impairment. A case report tells of a massive dose followed by several days of hallucinations and paranoia in a person already prone to psychiatric problems. After taking a dose, people should avoid operating dangerous machinery until they know the drug is not hindering their ability to do so. When 70 professional army drivers in Finland were tested in a driving simulator after taking 50 mg of codeine, they ran off the roadway more frequently than when they were under the influence of alcohol. Elderly persons who take codeine have an increased likelihood of hip fracture, presumably because the substance makes them woozy and more likely to fall. Codeine has been known to cause pancreatitis, particularly if the victim's gallbladder has been surgically removed, but this effect is considered unusual. Medical personnel refrain from administering the drug through intravenous injection because that route can lower blood pressure and blood oxygen to fatal levels.
In two studies researchers found that people taking codeine felt few sensations from the drug and had normal performance on assorted tests of physical and mental functioning. Those findings, however, may be related to dosages given by experimenters; higher dosages might well produce different results.
Abuse factors. Codeine abuse can be troublesome enough that persons need treatment to break the addiction. Some cases have required hospitalization. Nonetheless, prevalence of codeine addiction was disputed in 1989 by two authorities who carefully examined past reports of addiction: Little scientific research had been done on the topic, and most had involved persons already addicted to morphine. As morphine addicts will use codeine as a stopgap to hold off a withdrawal syndrome when their main drug is unavailable, their responses to codeine are not necessarily representative of a general population's reactions. In addition, codeine cough syrups may contain a substantial percentage of alcohol, so heavy use of such a product can involve a further confounding factor of alcoholism. The 1989 authorities concluded that verifiable accounts of people being addicted primarily to codeine (rather than mainly to some other drug, with codeine on the side) were unusual.
Dependence with codeine can develop; withdrawal symptoms are like those of morphine withdrawal, but milder. A study of rheumatism patients receiving codeine found that quite a few needed higher doses to control pain as months went by, but the increase was caused by decline of their physical condition rather than development of tolerance.
The same study noted that almost no patients abused the drug, and of those few who did, all abused other substances as well. That finding is consistent with many observations of other drugs having abuse potential; only a small minority of users misuse them, and this minority is prone to problems with more than one substance. People having a bad relationship with codeine tend to have bad relationships with alcohol, marijuana, and (less commonly) heroin. One study found that almost half the patients requesting treatment for codeine cough syrup addiction engaged in sexual conduct putting them at risk for AIDS, conduct illustrating a multiproblem lifestyle in which codeine abuse was simply one aspect. Background checks of deceased Los Angeles-area codeine abusers revealed almost 66% had attempted suicide, had a prior overdose on some drug, had been hospitalized for psychiatric problems, had been in physical fights, and had an alcohol problem (87% had an alcohol-related arrest record). So codeine may be only one of several problems in such lives.
Not all drug abuse is illicit. Sometimes people develop an abusive relationship with a drug that is supplied to them through legitimate medical channels. Swedish researchers compared the use of codeine in that country to the use of propoxyphene, an opioid related to methadone. Those investigators found that doctors in two of Sweden's largest cities typically tended to prescribe codeine to middle-aged females and that in one of those cities codeine was used the most in poor areas of town and was often associated with taking benzodiazepines frequently (in experiments the benzodiazepine diazepam lengthened the time that a codeine dose lasted, while codeine interfered with diazepam—suggesting that a codeine user would have to take more diazepam to get benzodiazepine sensations, consistent with the Swedish findings of increased benzodiazepine consumption among codeine users). Those kinds of codeine usage characteristics were not found for propoxyphene in the Swedish research even though both drugs would have opiate-type effects; the difference in usage suggests that physicians' customs may have been promoting codeine abuse.
In drug abuse treatment programs codeine has been used successfully to shift addicts from other opiates—so successfully that one group of researchers suggests that codeine maintenance programs might be an alternative to meth-adone maintenance, particularly because codeine produces fewer unwanted effects than methadone.
Drug interactions. The antidepressants fluoxetine (Prozac) and paroxetine interfere with the body's transformation of codeine into morphine; therefore, persons taking those antidepressants are considered less likely to develop codeine abuse (because they would experience fewer effects from codeine). Although codeine is weaker than morphine, similarities between the two drugs mean that interactions occurring with morphine can be expected to occur with codeine.
Cancer. Laboratory tests find no evidence that the drug causes cell mutations that might lead to cancer. Experimenters gave codeine to rats and mice for two years and looked for evidence of cancer caused by the drug but found none. Although no direct observations have noted codeine causing cancer in rats or mice, computer analysis of data from some experiments indicates that the drug may cause cancer in rodents. The human body produces very small amounts of codeine naturally, and researchers suspect this naturally occurring codeine may deter development of lung cancer; but those natural processes do not mean that doses of the drug would help prevent cancer.
Pregnancy. Whether codeine causes birth defects is unknown. It produced no evidence of malformations when given to pregnant rats and rabbits. Codeine reduced fetal weight in mice and hamsters in one experiment but did not increase the normal rate of defects in mice, nor was a statistically significant change in malformation rate observed in hamsters. Investigators running another mice experiment, however, concluded that codeine does cause assorted malformations. Researchers seeking evidence about various human birth defects examined medical records of 100 to 199 women who used a cough remedy containing codeine and found that none of the offspring had any of the congenital abnormalities being investigated. Suspicion exists that codeine may cause cleft palate and cleft lip in humans, but birth defects are considered unlikely if the drug is used during pregnancy. A pregnant woman who takes codeine can produce an infant who is dependent on that drug and who undergoes a withdrawal syndrome upon birth.
Codeine passes into the milk of nursing mothers, but researchers find its level and that of its metabolite morphine to be acceptable if the woman is using codeine moderately. Nonetheless, nursing mothers are advised to avoid codeine because mechanisms that break down codeine in the body are incompletely formed in newborns, causing them to react more strongly to the drug than older children or adults.
Additional scientific information may be found in:
Eggen, A.E., and M. Andrew. "Use of Codeine Analgesics in a General Population. A Norwegian Study of Moderately Strong Analgesics." European Journal of Clinical Pharmacology 46 (1994): 491-96. Mattoo, S.K., et al. "Abuse of Codeine-Containing Cough Syrups: A Report from India." Addiction 92 (1997): 1783-87. Romach, M.K., et al. "Long-Term Codeine Use Is Associated with Depressive Symptoms." Journal of Clinical Psychopharmacology 19 (1999): 373-76. Rowden, A.M., and J.R. Lopez. "Codeine Addiction." DICP: The Annals of Pharmacotherapy 23 (1989): 475-77. Sproule, B.A., et al. "Characteristics of Dependent and Nondependent Regular Users of Codeine." Journal of Clinical Psychopharmacology 19 (1999): 367-72.
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