It is thus legal to possess codeine without a prescription, provided that it is compounded with at least one other active or inactive ingredient and that the dosage of each tablet, capsule, etc. does not exceed 100 mg or 2.5% concentration in the case of liquid preparations. The exemptions do not to apply to any preparation of codeine designed for injection. United States
In the United States, codeine is regulated by the Controlled Substances Act. Federal law dictates that codeine be a Schedule II controlled substance when used in products for pain-relief that contain codeine alone or more than 80 mg per dosage unit. Codeine without aspirin or acetaminophen (Tylenol) is very rarely available or prescribed in order to discourage abuse. Tablets of codeine in combination with aspirin or acetaminophen (paracetamol) and intended for pain relief are listed as Schedule II, requiring a physical paper-copy (aka triplicate) of the physician ordered prescription. Cough syrups are classed as Schedule III, IV or V, depending on formulation. For example, the acetaminophen/codeine antitussive liquid is a Schedule IV controlled substance.Some states have chosen to reclassify codeine preparations at a more restrictive schedule in order to lower the instances of its abuse. Minnesota, for instance, has chosen to reclassify Schedule V some codeine preparations (e.g. Cheratussin) as a Schedule II controlled substance.Schedule V Controlled Substances
Substances in this schedule have a low potential for abuse relative to substances listed in Schedule IV and consist primarily of preparations containing limited quantities of certain narcotics.
CYP3A4 produces norcodeine, and UGT2B7 conjugates codeine, norcodeine, and morphine to the corresponding 3- and 6-glucuronides. Srinivasan, Wielbo and Tebbett speculate that codeine-6-glucuronide is responsible for a large percentage of the analgesia of codeine, and thus these patients should experience some analgesia. Many of the adverse effects will still be experienced in poor metabolizers. Conversely, between 0.5% and 2% of the population are "extensive metabolizers"; multiple copies of the gene for 2D6 produce high levels of CYP2D6 and will metabolize drugs through that pathway more quickly than others. Some medications are CYP2D6 inhibitors and reduce or even completely block the conversion of codeine to morphine. The best-known of these are two of the selective serotonin reuptake inhibitors, paroxetine (Paxil) and fluoxetine (Prozac) as well as the antihistamine diphenhydramine (Benadryl) and the antidepressant bupropion (Wellbutrin, also known as Zyban). Other drugs, such as rifampicin and dexamethasone, induce CYP450 isozymes and thus increase the conversion rate. CYP2D6 converts codeine into morphine, which then undergoes glucuronidation. Life-threatening intoxication, including respiratory depression requiring intubation, can develop over a matter of days in patients who have multiple functional alleles of CYP2D6, resulting in ultrarapid metabolism of opioids such as codeine into morphine.Studies on codeines analgesic effect are consistent with the idea that metabolism by CYP2D6 to morphine is important, but some studies show no major differences between those who are poor metabolizers and extensive metabolizers.