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Codeine

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Collated from PsychonautWiki, TripSit, Pharmacology, DrugCentral. Where sources differ (e.g. dosing), Compare shows them side by side.

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OpioidSubstituted morphinansHabit-formingDepressantCommonPW

Also known as Codeine, Lean, Purple Drank, SyrupPW

Fatal overdose may occur when opiates are combined with other depressants such as benzodiazepines, barbiturates, gabapentinoids, thienodiazepines, alcohol or other GABAergic substances.[1] It is strongly discouraged to combine these substances, particularly in common to heavy doses.PW

Addiction potentialPW
moderately addictive with a high potential for abuse
ToxicityPW
low toxicity; potentially lethal when mixed with depressants like alcohol or benzodiazepines
TolerancePW
full tolerance develops with prolonged and repeated use; half after 3 - 7 days; baseline after 1 - 2 weeks
Cross-tolerancePW
opioids

Oral

Route dataPsychonautWiki

Dose
WeakerStronger
ThresholdLightCommonStrongHeavy
30 mg50–100 mg100–150 mg150–200 mg200 mg+
0250 mg
LightCommonStrongHeavy
Duration
ShorterLonger
Onset30–45 minutes
Come-up1–2 hours
Peak3–5 hours
Offset2–4 hours
Total3–6 hours
OnsetCome-upPeakOffset

Caution / uncertainPW

MAOIsNitrousPCPStimulants

🧬 Receptor activityDC

TargetActionAffinitySource
Delta-type opioid receptor (OPRD1)Agonist4.28 KiDRUGCENTRAL
Kappa-type opioid receptor (OPRK1)Agonist4.59 KiDRUGCENTRAL
Mu-type opioid receptor (OPRM1)Agonist6.14 KiDRUGCENTRAL
Opioid receptor (Oprd1)—8 IC50DRUGCENTRAL
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Mechanism of actionPH

Although the exact mechanism of action of codeine is still unknown, it is generally thought to be mediated through the agonism of opioid receptors, particularly the mu-opioid receptors. Morphine was previously postulated to contribute to the analgesic effect of codeine due to the O-demethylation of codeine to morphine by CYP2D6. Particularly, CYP2D6 poor metabolizer did not experience the analgesic effect of codeine. However, this is unlikely to be the main mechanism of action of codeine as only 5% of codeine is metabolized to morphine. Other hypotheses also postulate that codeine-6-glucuronide, the main metabolite of codeine, mediates the analgesic effect of codeine as it not only has an affinity to the mu receptors as codeine but also can be metabolized to morphine-6-glucuronide, which was observed to be more potent than morphine. Binding to the mu receptors by codeine activates the G-proteins Gα<sub>i</sub>, causing a decrease in intracellular cAMP and Ca<sup>2+</sup> level. This causes hyperpolarization of nociceptive neurons, thus imparing the transmission of pain signals.
Codeine causes suppression of the cough reflex by a direct effect on the cough center in the medulla of the brain and appears to exert a drying effect on respiratory tract mucosa and to increase viscosity of bronchial secretions.

PharmacodynamicsPH

**General effects** Codeine is a weak narcotic pain reliever and cough suppressant that is similar to morphine and hydrocodone. A small amount of ingested codeine is converted to morphine in the body. Codeine increases tolerance to pain, reducing existing discomfort. In addition to decreasing pain, codeine also causes sedation, drowsiness, and respiratory depression. **Antitussive activity** This drug has shown antitussive activity in clinical trials and has been effective in cough secondary to tuberculosis and insomnia due to coughing. Codeine suppresses the cough reflex through a direct effect on the cough center in the medulla. **Effects on intestinal motility** Codeine may reduce intestinal motility through both a local and possibly central mechanism of action. This may possibly lead to constipation. The chronic use of opioids, including codeine sulfate, may lead to obstructive bowel disease, particularly in patients with underlying disorders of intestinal motility. **Effects on the central nervous system** Codeine phosphate is an opioid analgesic with uses similar to those of morphine, but is much less potent as an analgesic. Its primary site of action is at the _mu_ opioid receptors distributed throughout the central nervous system. The sedative activities of codeine are less potent than those of morphine. Codeine may cause respiratory system depression by the activation of μ-opioid receptors at specific sites in the central nervous system. **Effects on blood pressure** This drug poses an increased risk of compromised ability to maintain blood pressure due to peripheral vasodilation and other mechanisms. **Effects on chronic cancer pain and other types of pain** Codeine is an opioid analgesic with similar indications to those of morphine, however, is much less potent in its pain alleviating properties. Its primary action takes place at the mu opioid receptors, which are distributed throughout the central nervous system. The average duration of action is about 4 hours. Regular dosing of opioid analgesics such as codeine in patients with severe cancer pain has been well documented to improve symptoms,.

Pharmacokinetics

Half-lifePH

Plasma half-lives of codeine and its metabolites have been reported to be approximately 3 hours.
Radioimmunoassay (RIA) was used to determine several pharmacokinetic parameters of codeine in man, including the relative bioavailability after oral and intramuscular administration. The study followed a crossover design in 6 healthy, young (18 to 21 yr), male volunteers. Three subjects received 65 mg codeine phosphate orally in an analgesic mixture which also contained aspirin, phenacetin, and caffeine. At the same time a similar group received an equivalent dose of codeine phosphate in a single intramuscular injection. Two weeks later the study was repeated so that each group received the alternate treatment. Plasma samples were collected at various times after drug administration, and codeine concentrations were determined by a specific RIA procedure. The procedure can detect less than 50 pg of codeine. Following intramuscular administration, peak plasma concentrations (194 to 340 ng/ml) were observed between 0.25 to 1 hr; after oral dosing, peak codeine plasma concentrations (102 to 140 ng/ml) appeared within 0.75 to 1 hr. The mean plasma t1/2 and volume of distribution of codeine following intramuscular injection were 3.32 hr and 5.1 L/kg, respectively. Oral, relative to intramuscular, bioavailability of codeine, based on areas under the codeine plasma curves, was 42% to 71% (mean, 53%).
Assuming a rate of hair growth of 1 cm/month, the mean hair elimination half-life of /codeine was 0.61 months (95% CI, 0.54-0.69)/ ... .
The elimination half-life of codeine is 2.5 to 3.5 hours with a clinical duration of 4 to 8 hours because of active metabolites.
Codeine is metabolized rapidly by the tissues of humans, dogs, & rats. Metabolic alteration followed by rapid urinary excretion begins a few minutes after im injection & after a slight delay following oral admin. About one-half an ordinary dose is eliminated within 6 hr & all within 24 hr.

AbsorptionPH

**Absorption** Codeine is absorbed from the gastrointestinal tract. The maximum plasma concentration occurs 60 minutes after administration. **Food Effects** When 60 mg codeine sulfate was given 30 minutes post-ingestion of a high high-calorie meal, there was no significant change in the absorption of codeine. **Steady-state concentration** The administration of 15 mg codeine sulfate every 4 hours for 5 days lead to steady-state concentrations of codeine, morphine, morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G) within 48 hours.
About 90% of the total dose of codeine is excreted by the kidneys. Approximately 10% of the drug excreted by the kidneys is unchanged codeine. The majority of the excretion products can be found in the urine within 6 hours of ingestion, and 40-60 % of the codeine is excreted free or conjugated, approximately 5 to 15 percent as free and conjugated morphine, and approximately 10-20% free and conjugated norcodeine.
Apparent volume of distribution: about 3-6 L/kg, showing an extensive distribution of the drug into tissues.
Renal clearance of codeine was 183 +/- 59 ml min-1 in a clinical study. Renal impairment may decrease codeine clearance [LABEL].
Oral absorption of codeine is good, but there is a significant first-pass effect. The Vd is 2.6 L/kg, and there is a minimal protein binding. The onset os analgesic effect is 30 to 60 minutes, and antitussive effect is 1 to 2 hours. Peak effect is reached in 2 to 4 hours. ... Between 3% and 16% is excreted unchanged in the urine, and 90% of the absorbed dose if excreted via the kidney.
Postmortem samples from 14 cases of suspected heroin overdose were subjected to a preliminary systematic toxicological analysis in order to highlight the presence of unknown exogenous compounds (e.g., drugs of abuse, alcohol) that may have played a role in the mechanism of death. This analysis unveiled histories of poly-drug use in seven of the cases under investigation. Moreover, the concentrations of morphine and codeine in the brain were also investigated, and the results were compared with the data obtained from the blood specimens. The concentration of morphine in blood ranged from 33 to 688 ng/mL, while the concentration of codeine ranged from 0 to 193 ng/mL. However, in the brain, the concentration of morphine was found to be between 85 and 396 ng/g, while the levels of codeine ranged from 11 to 160 ng/g. The codeine/morphine ratio in the blood ranged from 0.043 to 0.619; however, in the brain, the same ratio was found to be between 0.129 and 0.552. In most cases, a significantly higher codeine/morphine ratio was found in the brain, suggesting the accumulation of codeine in brain tissue due its high lipophilicity as compared with morphine.

MetabolismPH

Approximately 70 to 80% of the ingested dose of codeine is metabolized in the liver by conjugation with glucuronic acid to _codeine-6­ glucuronide_ (C6G) and by O-demethylation to _morphine_ (about 5-10%) and N-demethylation to _norcodeine_ (about 10%) respectively. UDP-glucuronosyltransferase (UGT) 2B7 and 2B4 are the major metabolic enzymes mediating the glucurodination of codeine to the metabolite, _codeine 6 glucuronide_. Cytochrome P450 2D6 is the major enzyme responsible for the transformation of codeine to morphine and P450 3A4 is the main enzyme mediating the conversion of codeine to _norcodeine_. Morphine and norcodeine are then further metabolized by conjugation with glucuronic acid. The glucuronide metabolites of morphine are _morphine-3-glucuronide_ (M3G) and_ morphine-6-glucuronide _(M6G). Morphine and M6G have been proven to have analgesic activity in humans. The analgesic activity of C6G in humans is not known at this time. Norcodeine and M3G are generally not considered to have analgesic properties.
Codeine is metabolized in the liver by glucuronidation to codeine-6-glucuronide, by O-demethylation to morphine via CYP2D6, and by N-demethylation to norcodeine via CYP3A, all active metabolites. There is genetic polymorphism od CYP2D6. .. Poor /CYP2D6/ metabolizers have decreased analgesic effectiveness by inhibiting conversion of codeine to morphine. Concomitant administration with CYP2D6 inducers may result in increased metabolism and clearance of drug and also produce decreased clinical efficacy. Examples of CYP2D6 inducers include dexamethasone and rifampin.
... Results confirm biotransformation of codeine to ... normorphine in rodents.
Cytochrome P450 2D6 (CYP2D6) is a member of the cytochrome P450 (CYP) superfamily involved in the biotransformation of drugs and substances of abuse encountered in clinical toxicology. Among the CYP superfamily, the CYP2D6 gene is considered as the most polymorphic as more than 105 different alleles have been identified so far. CYP2D6 genetic polymorphisms have the potential to affect the toxicity of their substrates. This review will focus specifically on CYP2D6 genetic polymorphisms and their relevance for poisoning due to amphetamines, opioid analgesics and antidepressants in humans. PubMed (up to August 2013) was searched with the following selection criteria: 'CYP2D6 AND (toxicology OR poisoning OR intoxication OR overdose)'. Of the 454 citations retrieved, only 46 papers dealt with the impact of CYP2D6 polymorphisms on poisoning due to amphetamines, opioid analgesics and antidepressants. ... Opioid analgesics. CYP2D6 ultra-rapid metabolizers are more likely to experience the adverse effects of codeine and tramadol. Opioid analgesics that do not rely on CYP2D6 for therapeutic activity, such as morphine and hydromorphone, may therefore be a better alternative to codeine and tramadol, with the limitation that these drugs have their own set of adverse reactions. ... Either poor or extensive/ultra-rapid CYP2D6 metabolizers may be exposed to toxic effects of amphetamines, opioid analgesics and antidepressants. In these three categories, the level of evidence is substance dependent, with differences within the same pharmacological class.
Opioid analgesics are commonly prescribed for acute and chronic pain, but are subject to abuse. Consequently, toxicology testing programs are frequently implemented for both forensic and clinical applications. Understanding opioid metabolism and disposition is essential for assessing risk of toxicity and, in some cases, providing additional information regarding risk of therapeutic failure. Opioids significantly metabolized by the cytochromeP450 (CYP450) enzyme system maybe subject to drug-drug interactions, including codeine, hydrocodone, oxycodone, fentanyl, meperidine, methadone, buprenorphine, and tramadol. CYP2D6 metabolism is polymorphic, and pharmacogenetic testing has been investigated for codeine, tramadol, oxycodone, and hydrocodone. CYP2B6 pharmacogenetic testing of methadone may reduce the risk of cardiac toxicity associated with the S-enantiomer. Opioids metabolized primarily by uridine 5'-diphospho-glucuronsyltransferase (UGT) enzymes include morphine, hydromorphone, dihydrocodeine, oxymorphone, levorphanol, and tapentadol. Parent and metabolite disposition is described for blood, oral fluid, and urine. Parent drug is most commonly detected in blood and oral fluid, whereas metabolites typically predominate in urine. Oral fluid/blood ratios exceed 1 for most opioids, making this an excellent alternative matrix for testing of this drug class. Metabolites of codeine, hydrocodone, and oxycodone are commercially available, and knowledge of metabolism is necessary for correct interpretation.
For more Metabolism/Metabolites (Complete) data for CODEINE (7 total), please visit the HSDB record page.

Protein bindingPH

7-25% bound to plasma proteins.

Plan when to take Codeine — see where onset, peak and comedown land on the clock

Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.