7,8-Didehydro-4,5-epoxy-3-methoxy-17-methyl-morphinan-6-ol,(5 alpha, 6 alpha)-

Biological Agents -> Plant Toxins

Pharmaceutical

DEA NFLIS-Drug Category -> Narcotic Analgesics

DEA Schedule II Controlled Substance

Pharmaceuticals -> Used in Switzerland

Pharmaceuticals -> Metabolite of Morphine

Pharmaceuticals -> Listed in ZINC15

Pharmaceuticals -> Synthetic Cannabinoids or Psychoactive Compounds

log Kow = 1.19

1.19

Orthorhombic crystals from water, dilute alcohol, ether

Colorless or white crystals or powder

less than 1 mg/mL at 70 °F (NTP, 1992)

soluble in water

Soluble in water

Slightly soluble in water

Soluble in ethyl ether, benzene, chloroform, toluene; very soluble in ethanol; insoluble in petroleum ether

Soluble in alcohol and chloroform

Breast Feeding; Lactation; Milk, Human; Analgesics, Opioid; Narcotics; Antitussive Agents

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Antitussives

482 °F at 22 mmHg (sublimes) (NTP, 1992)

BP: 250 °C at 22 mm Hg

Danger

H302 (93.4%): Harmful if swallowed [Warning Acute toxicity, oral]

P203, P260, P261, P263, P264, P264+P265, P270, P271, P272, P280, P301+P317, P302+P352, P304+P340, P305+P354+P338, P317, P318, P319, P321, P330, P333+P317, P362+P364, P403+P233, P405, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 61 reports by companies from 9 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Warning

H302: Harmful if swallowed [Warning Acute toxicity, oral]

DEA schedule II controlled substance

Regulation (EC) No 178/2002 (amended)

Status: Active Update: 29-06-2022 https://echa.europa.eu/registration-dossier/-/registered-dossier/19207

Codeine: Does not have an individual approval but may be used under an appropriate group standard

SYMPTOMS: Symptoms of exposure to this compound may include gastrointestinal distress, nausea, vomiting, constipation; dizziness; palpitations; drowsiness; pruritis; restlessness, excitement; vertigo; and mydrasis. Larger doses result in muscle weakness; tremors; miosis (pinpoint pupils); delirium; coma; and convulsions with possible development of central nervous system and respiratory depression which may result in death. Body temperature and blood pressure may fall. Sensitivity reactions and pulmonary edema (fitting the description of "heroin lung") have been reported. Chronic symptoms may include miosis and rapid mood changes. Excessive use may lead to physical dependence and tolerance.

Schedule I shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. Unless specifically excepted or unless listed in another schedule, any of the following opium derivatives, its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation. /Acetyldihydrocodeine, Codeine methylbromide, Codeine-N-Oxide, Nicocodeine/[Table#4367]

Schedule II shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. Substances, vegetable origin or chemical synthesis. Unless specifically excepted or unless listed in another schedule, any of the following substances whether produced directly or indirectly by extraction from substances of vegetable origin, or independently by means of chemical synthesis, or by a combination of extraction and chemical synthesis: (1) Opium and opiate, and any salt, compound, derivative, or preparation of opium or opiate excluding apomorphine, thebaine-derived butorphanol, dextrorphan, nalbuphine, nalmefene, naloxegol, naloxone, and naltrexone, and their respective salts, but including the following. Codeine (DEA Code Number: 9050) is included on this list.

Schedule II shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. ... Opiates. Unless specifically excepted or unless in another schedule any of the following opiates, including its isomers, esters, ethers, salts and salts of isomers, esters and ethers whenever the existence of such isomers, esters, ethers, and salts is possible within the specific chemical designation, dextrorphan and levopropoxyphene excepted: Dihydrocodeine (DEA Code Number: 9120) is included on this list. /Dihydrocodeine/

Schedule III shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. ... Narcotic drugs. Unless specifically excepted or unless listed in another schedule: (1) Any material, compound, mixture, or preparation containing any of the following narcotic drugs, or their salts calculated as the free anhydrous base or alkaloid, in limited quantities as set forth below: (i) Not more than 1.8 grams of codeine per 100 milliliters or not more than 90 milligrams per dosage unit, with an equal or greater quantity of an isoquinoline alkaloid of opium. DEA Code Number: 9803.

For more FDA Requirements (Complete) data for CODEINE (8 total), please visit the HSDB record page.

CDC Guideline for Prescribing Opioids for Chronic Pain - United States, 2016; This guideline provides recommendations for primary care clinicians who are prescribing opioids for chronic pain outside of active cancer treatment, palliative care, and end-of-life care. The guideline addresses 1) when to initiate or continue opioids for chronic pain; 2) opioid selection, dosage, duration, follow-up, and discontinuation; and 3) assessing risk and addressing harms of opioid use. CDC developed the guideline using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework, and recommendations are made on the basis of a systematic review of the scientific evidence while considering benefits and harms, values and preferences, and resource allocation. CDC obtained input from experts, stakeholders, the public, peer reviewers, and a federally chartered advisory committee. It is important that patients receive appropriate pain treatment with careful consideration of the benefits and risks of treatment options. This guideline is intended to improve communication between clinicians and patients about the risks and benefits of opioid therapy for chronic pain, improve the safety and effectiveness of pain treatment, and reduce the risks associated with long-term opioid therapy, including opioid use disorder, overdose, and death.[Dowell D et al; Morbidity and Mortality Weekly Report (MMWR) 65 (1):1-49 (2016); Available from, as of March 22, 2016: http://www.cdc.gov/mmwr/volumes/65/rr/rr6501e1.htm]

DHHS/NIDA; Research Monograph Series 52: Testing Drugs for Physical Dependence Potential and Abuse Liability (1984) DHHS Pub No. (ADM)87-1332

DHHS/NIDA; Research Monograph Series 54: Mechanisms of Tolerance and Dependence (1984) DHHS Pub No. (ADM)88-1330

DHHS/NIDA; Research Monograph Series 56: Etiology of Drug Abuse: Implications for Prevention (1987) DHHS Pub No. (ADM)87-1335

For more Special Reports (Complete) data for CODEINE (12 total), please visit the HSDB record page.

CODEINE is incompatible with bromides, iodides and salts of heavy metals. (NTP, 1992). It is an amine. Amines are chemical bases. They neutralize acids to form salts plus water. These acid-base reactions are exothermic. The amount of heat that is evolved per mole of amine in a neutralization is largely independent of the strength of the amine as a base. Amines may be incompatible with isocyanates, halogenated organics, peroxides, phenols (acidic), epoxides, anhydrides, and acid halides. Flammable gaseous hydrogen is generated by amines in combination with strong reducing agents, such as hydrides.

EYES: First check the victim for contact lenses and remove if present. Flush victim's eyes with water or normal saline solution for 20 to 30 minutes while simultaneously calling a hospital or poison control center. Do not put any ointments, oils, or medication in the victim's eyes without specific instructions from a physician. IMMEDIATELY transport the victim after flushing eyes to a hospital even if no symptoms (such as redness or irritation) develop.

Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide. /Codeine monohydrate/

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary. /Codeine monohydrate/

To fight fire, use alcohol foam.

Keep container tightly closed in a dry and well-ventilated place. Recommended storage temperature 2 - 8 °C /Codeine monohydrate/

Codeine sulfate tablets should be stored in well-closed, light-resistant containers at a temperature less than 40 °C, preferably between 15-30 °C.

ACCIDENTAL RELEASE MEASURES: Personal precautions, protective equipment and emergency procedures: Use personal protective equipment. Avoid dust formation. Avoid breathing vapors, mist or gas. Ensure adequate ventilation. Avoid breathing dust; Environmental precautions: Do not let product enter drains; Methods and materials for containment and cleaning up: Pick up and arrange disposal without creating dust. Sweep up and shovel. Keep in suitable, closed containers for disposal. /Codeine monohydrate/

SMALL SPILLS AND LEAKAGE: Should a spill occur while you are handling this chemical, FIRST REMOVE ALL SOURCES OF IGNITION, then you should dampen the solid spill material with 60-70% ethanol and transfer the dampened material to a suitable container. Use absorbent paper dampened with 60-70% ethanol to pick up any remaining material. Seal the absorbent paper, and any of your clothes, which may be contaminated, in a vapor-tight plastic bag for eventual disposal. Solvent wash all contaminated surfaces with 60-70% ethanol followed by washing with a soap and water solution. Do not reenter the contaminated area until the Safety Officer (or other responsible person) has verified that the area has been properly cleaned.

SRP: Expired or waste pharmaceuticals shall carefully take into consideration applicable DEA, EPA, and FDA regulations. It is not appropriate to dispose by flushing the pharmaceutical down the toilet or discarding to trash. If possible return the pharmaceutical to the manufacturer for proper disposal being careful to properly label and securely package the material. Alternatively, the waste pharmaceutical shall be labeled, securely packaged and transported by a state licensed medical waste contractor to dispose by burial in a licensed hazardous or toxic waste landfill or incinerator.

Product: Offer surplus and non-recyclable solutions to a licensed disposal company; Contaminated packaging: Dispose of as unused product. /Codeine monohydrate/

SRP: At the time of review, criteria for land treatment or burial (sanitary landfill) disposal practices are subject to significant revision. Prior to implementing land disposal of waste residue (including waste sludge), consult with environmental regulatory agencies for guidance on acceptable disposal practices.

Precautions for safe handling: Avoid contact with skin and eyes. Avoid formation of dust and aerosols. Further processing of solid materials may result in the formation of combustible dusts. The potential for combustible dust formation should be taken into consideration before additional processing occurs. Provide appropriate exhaust ventilation at places where dust is formed. /Codeine monohydrate/

Appropriate engineering controls: Handle in accordance with good industrial hygiene and safety practice. Wash hands before breaks and at the end of workday. /Codeine monohydrate/

Gloves must be inspected prior to use. Use proper glove removal technique (without touching glove's outer surface) to avoid skin contact with this product. Dispose of contaminated gloves after use in accordance with applicable laws and good laboratory practices. Wash and dry hands. /Codeine monohydrate/

SRP: Local exhaust ventilation should be applied wherever there is an incidence of point source emissions or dispersion of regulated contaminants in the work area. Ventilation control of the contaminant as close to its point of generation is both the most economical and safest method to minimize personnel exposure to airborne contaminants. Ensure that the local ventilation moves the contaminant away from the worker.

RECOMMENDED RESPIRATOR: Where the neat test chemical is weighed and diluted, wear a NIOSH-approved half face respirator equipped with an organic vapor/acid gas cartridge (specific for organic vapors, HCl, acid gas and SO2) with a dust/mist filter. (NTP, 1992)

Eye/face protection: Safety glasses with side-shields conforming to EN166. Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU). /Codeine monohydrate/

Skin protection: Handle with gloves. /Codeine monohydrate/

Body Protection: Complete suit protecting against chemicals. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace. /Codeine monohydrate/

Respiratory protection: For nuisance exposures use type P95 (US) or type P1 (EU EN 143) particle respirator. For higher level protection use type OV/AG/P99 (US) or type ABEK-P2 (EU EN 143) respirator cartridges. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU). /Codeine monohydrate/

Naloxone antagonizes most effects of codeine. Protect the airway as Naloxone may induce vomiting. Naloxone has a shorter duration of action than codeine; repeated doses may be needed. Protect the patient's airway and support ventilation and perfusion. Meticulously monitor and maintain, within acceptable limits, the patient's vital signs, blood gases, serum electrolytes, etc. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which in many cases, is more effective than emesis or lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient's airway when employing gastric emptying or charcoal. (L1712)

Drugs that depress CNS and respiratory function may have additive effects when combined with opioids. Withdrawal symptoms may be precipitated in dependent patients who are given naloxone or other opioid antagonists. Concomitant use of codeine and quinidine results in reduced analgesic effect because CYP2D6 inhibition prevents conversion of codeine to morphine. Other drugs that inhibit CYP2D6 may also produce this effect. Drugs that induce CYP2D6 and CYP3A may increase codeine conversion to morphine, with impaired analgesic control.

Because opiate agonists may potentiate the effects of other CNS depressants including other opiate agonists, general anesthetics, tranquilizers, sedatives and hypnotics, and alcohol, opiate agonists should be used with great caution and in reduced dosage when used in conjunction with such drugs. Some tranquilizers, especially phenothiazines, may antagonize opiate agonist analgesia. /Opiate agonists/

Opiate agonists may potentiate the effects of tricyclic antidepressants and monoamine oxidase (MAO) inhibitors, including procarbazine hydrochloride; therefore, opiate agonists should be used with great caution and in reduced dosage when used in conjunction with such drugs. Virtually all the reported incidents of opiate agonist interaction with MAO inhibitors have occurred in patients receiving meperidine. ... If an opiate agonist is required in patients receiving MAO inhibitors, a sensitivity test should be performed with small increments of morphine administered over a period of several hours while the patient is kept under close medical observation. /Opiate agonists/

Withdrawal symptoms may occur in patients receiving opiate agonists concomitantly with opiate antagonists (e.g., naloxone, naltrexone) or opiate partial agonists (e.g., buprenorphine, butorphanol, nalbuphine, pentazocine). Partial agonists should not be administered in patients receiving opiate agonists as they may reduce the analgesic effect and/or precipitate withdrawal symptoms. /Opiate agonists/

For more Interactions (Complete) data for CODEINE (17 total), please visit the HSDB record page.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 700(SRC), determined from a structure estimation method(2), indicates that codeine is expected to have low mobility in soil(SRC). The pKa of codeine is 8.21(3), indicating that this compound will exist almost entirely in the cation form in the environment and cations generally adsorb more strongly to soils containing organic carbon and clay than their neutral counterparts(4). Volatilization from moist soil is not expected because the compound exists as a cation and cations do not volatilize. Codeine is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 5.5X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Biodegradation data in soil were not available(SRC, 2016).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 700(SRC), determined from a structure estimation method(2), indicates that codeine is expected to adsorb to suspended solids and sediment(SRC). A pKa of 8.21(3) indicates codeine will exist almost entirely in the cation form at pH values of 5 to 9 and, therefore, volatilization from water surfaces is not expected to be an important fate process(SRC). According to a classification scheme(4), an estimated BCF of 3(SRC), from its log Kow of 1.19(5) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Biodegradation data in water were not available(SRC, 2016).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), codeine, which has an estimated vapor pressure of 5.5X10-9 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), is expected to exist solely in the particulate phase in the ambient atmosphere. Particulate-phase codeine may be removed from the air by wet and dry deposition(SRC). Codeine is affected by light(4) and, therefore, may be susceptible to direct photolysis by sunlight(SRC).

Skin Sensitizer - An agent that can induce an allergic reaction in the skin.

Constipation is one of the most common adverse effects of codeine. Most patients report some constipation following the initiation of therapy or increases in dose. With continued exposure, constipation remains a persistent harmful effect of the drug. Increased fluid intake and stool softeners are often recommended to patients to mitigate this unwanted effect. Nausea/vomiting is another common adverse effect, but it generally diminishes within days to weeks of continued codeine exposure. Anti-emetic therapies in both oral and rectal formulations are readily available for treatment.

Oral, Intramuscular. Well absorbed following oral administration with a bioavailability of approximately 90%. Maximum plasma concentration occurs 60 minutes post-administration. Food does not effect the rate or extent of absorption of codeine.

IDENTIFICATION AND USE: Codeine occurs as colorless or white crystals or powder. Codeine is an opiate, a component of opium, and an opioid agonist used as an analgesic, antitussive, and antidiarrheal agent. It commonly is given in combination with aspirin, acetaminophen, or other agents. It may also be used in veterinary care as an analgesic and antitussive. HUMAN EXPOSURE AND TOXICITY: Toxic doses of codeine may produce exhilaration, excitement, seizures, delirium, hypotension, miosis, slow pulse, tachycardia, narcosis, flushed facies, tinnitus, lassitude, muscular weakness, and circulatory collapse or respiratory paralysis. Cardiovascular side effects, ataxia, and headache have been observed in cases of accidental exposure. Respiratory arrest, coma, and death have occurred in young children receiving oral codeine doses of 5-12 mg/kg. Codeine should not be prescribed to children due to its poor analgesic effect and risk of opioid toxicity and oversedation. All opioid analgesics are metabolized by the liver and should be used with caution in patients with hepatic disease because increased bioavailability after oral administration of cumulative effects may occur. In patients with asthma or pulmonary emphysema, the indiscriminate use of antitussives may precipitate respiratory insufficiency. One case of opiate toxicity resulting in neonatal death has been reported in the nursing infant of a mother receiving codeine; genetic testing of the mother indicated that she was an ultrarapid metabolizer of codeine. First trimester use in 563 cases was associated with: respiratory malformations, genitourinary tract defects other than hypospadias, Down's syndrome, tumors, umbilical hernia, and inguinal hernia. After 2522 exposures to codeine anytime in pregnancy, the following were noted: hydrocephaly, pyloric stenosis, umbilical hernia, inguinal hernia. Chronic codeine-containing syrup abuse may be associated with disruptions in brain white matter (WM) integrity. These WM microstructural deficits may be linked to higher impulsivity in chronic codeine-containing syrup users. 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. ANIMAL STUDIES: Codeine given intravenously to rabbits has in most instances reduced ocular pressure but occasionally has produced small rise. Hamsters and mice were gavaged with up to 300 or 150 mg/kg twice daily respectively. Decreased fetal weight was found at maternally toxic doses but no teratogenicity. Pregnant hamsters injected on day 8 subcutaneously with 73 to 360 mg/kg produced 6 to 8 percent cranioschisis in the offspring. In mice, codeine exposure during gestation failed to increase the incidence of major fetal malformations even at the highest dose (300 mg/kg, bid) which produced a significant increase in the percentage of resorptions per litter. The 300 mg/kg dose was also associated with a significant decrease in average fetal body weight per litter, and 19% mortality among pregnant females. Embryo/fetal development of the hamster was sensitive to codeine administered at a maternally nontoxic dose of 50 mg/kg, twice daily. At that dose, fetal body weight was significantly reduced while all parameters of maternal toxicity indicated no effect.There was no evidence of carcinogenic activity of codeine in male or female rats exposed to 400, 800, or 1,600 ppm of codeine for 2 years. There was no evidence of carcinogenic activity of codeine in male or female mice exposed to 750, 1,500, or 3,000 ppm of codeine for 2 years.

Deaths related to opioid toxicity have increased in the past decades, and a significant proportion of the increase derives from accidental overdoses. Opioid overdose is characteristically associated with a triad of abnormally slow respiration (apnea), decreased consciousness (coma), and pinpoint pupils (miosis). Codeine has a narrow therapeutic index, with a dose of 500 to 1000 mg usually proving fatal, though codeine-dependent individuals have been reported to use as much as 1536 mg daily.

Opiate receptors are coupled with G-protein receptors and function as both positive and negative regulators of synaptic transmission via G-proteins that activate effector proteins. Binding of the opiate stimulates the exchange of GTP for GDP on the G-protein complex. As the effector system is adenylate cyclase and cAMP located at the inner surface of the plasma membrane, opioids decrease intracellular cAMP by inhibiting adenylate cyclase. Subsequently, the release of nociceptive neurotransmitters such as substance P, GABA, dopamine, acetylcholine and noradrenaline is inhibited. Opioids also inhibit the release of vasopressin, somatostatin, insulin and glucagon. Codeine's analgesic activity is, most likely, due to its conversion to morphine. Opioids close N-type voltage-operated calcium channels (OP2-receptor agonist) and open calcium-dependent inwardly rectifying potassium channels (OP3 and OP1 receptor agonist). This results in hyperpolarization and reduced neuronal excitability.

Schedule I shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. Unless specifically excepted or unless listed in another schedule, any of the following opium derivatives, its salts, isomers, and salts of isomers whenever the existence of such salts, isomers, and salts of isomers is possible within the specific chemical designation. /Acetyldihydrocodeine, Codeine methylbromide, Codeine-N-Oxide, Nicocodeine/[Table#4367]

Schedule II shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. Substances, vegetable origin or chemical synthesis. Unless specifically excepted or unless listed in another schedule, any of the following substances whether produced directly or indirectly by extraction from substances of vegetable origin, or independently by means of chemical synthesis, or by a combination of extraction and chemical synthesis: (1) Opium and opiate, and any salt, compound, derivative, or preparation of opium or opiate excluding apomorphine, thebaine-derived butorphanol, dextrorphan, nalbuphine, nalmefene, naloxegol, naloxone, and naltrexone, and their respective salts, but including the following. Codeine (DEA Code Number: 9050) is included on this list.

Schedule II shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. ... Opiates. Unless specifically excepted or unless in another schedule any of the following opiates, including its isomers, esters, ethers, salts and salts of isomers, esters and ethers whenever the existence of such isomers, esters, ethers, and salts is possible within the specific chemical designation, dextrorphan and levopropoxyphene excepted: Dihydrocodeine (DEA Code Number: 9120) is included on this list. /Dihydrocodeine/

Schedule III shall consist of the drugs and other substances, by whatever official name, common or usual name, chemical name, or brand name designated, listed in this section. Each drug or substance has been assigned the DEA Controlled Substances Code Number set forth opposite it. ... Narcotic drugs. Unless specifically excepted or unless listed in another schedule: (1) Any material, compound, mixture, or preparation containing any of the following narcotic drugs, or their salts calculated as the free anhydrous base or alkaloid, in limited quantities as set forth below: (i) Not more than 1.8 grams of codeine per 100 milliliters or not more than 90 milligrams per dosage unit, with an equal or greater quantity of an isoquinoline alkaloid of opium. DEA Code Number: 9803.

For more FDA Requirements (Complete) data for CODEINE (8 total), please visit the HSDB record page.

R05DA04

R - Respiratory system

QR - Respiratory system

R05DA04

**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,.

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_i, causing a decrease in intracellular cAMP and Ca²⁺ 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.

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.

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.

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CODEINE ANHYDROUS

Mechanisms of Action [MoA] - Full Opioid Agonists

Established Pharmacologic Class [EPC] - Opioid Agonist

Codeine anhydrous is an Opioid Agonist. The mechanism of action of codeine anhydrous is as a Full Opioid Agonist.

Compounds with activity like OPIATE ALKALOIDS, acting at OPIOID RECEPTORS. Properties include induction of ANALGESIA or NARCOSIS.

Agents that suppress cough. They act centrally on the medullary cough center. EXPECTORANTS, also used in the treatment of cough, act locally.

Agents that induce NARCOSIS. Narcotics include agents that cause somnolence or induced sleep (STUPOR); natural or synthetic derivatives of OPIUM or MORPHINE or any substance that has such effects. They are potent inducers of ANALGESIA and OPIOID-RELATED DISORDERS.

**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.

Analgesics, Opioid; Antitussive Agents; Narcotics

Codeine (DEA Code Number: 9050) is a Schedule II controlled substance.

Schedule II Controlled Substance: (A) The drug or other substance has a high potential for abuse; (B) The drug or other substance has a currently accepted medical use in treatment in the United States or a currently accepted medical use with severe restrictions; and (C) Abuse of the drug or other substances may lead to severe psychological or physical dependence.

Codeine is an opiate, a component of opium, and an opioid agonist used as an analgesic, antitussive, and antidiarrheal agent. In Europe, codeine has been used in an illicit synthetic opioid mixture including hydrocodone and dihydrocodeine, called Brown.

For more Uses (Complete) data for CODEINE (6 total), please visit the HSDB record page.

Use (kg; approx.) in Germany (2009): >2500

Codeine is extracted from opium (concentration in opium 0.7 to 2.5%, depending on the source), but mostly prepared by methylation of morphine in a phase transfer reaction.

Although some codeine is obtained from opium directly, the quantity is not sufficient to meet the extensive use of this alkaloid as a valuable medicinal agent. Much more codeine is used than morphine. This need is met by making it by partial synthesis from morphine. The process involves methylating the phenolic OH of the latter with phenyltrimethylammonium hydroxide. Dry morphine is dissolved in a solution of potassium hydroxide in absolute alcohol, the methylating agent added, and the solution heated. After cooling, water is added, the solution is acidified with sulfuric acid, the dimethylaniline product separated, and the alcohol removed by distillation. Treatment with caustic soda solution precipitates the codeine, while any unreacted morphine is held in solution by the sodium hydroxide. The crude codeine is purified by crystallization as the sulfate.

Grade: Technical, NF

Codeine Phosphate, USP, and Codeine Sulfate, USP, are available primarily in combination with antihistamine (chlorpheniramine), expectorant (guaifenesin), decongestant (phenylephrine), and other combinations of drugs ...

Terpin Hydrate, USP, Codeine Elixir, NF, contains 10 mg codeine in each 5 ml (limit for nonprescription use).

Available commercially as the free base monohydrate or as the hydrobromide or hydrochloride salts.

Derivatives: dihydrocodeine; hydrocodone; oxycodone

Pharmaceuticals -> Animal Drugs -> Approved in Taiwan

Pharmaceuticals -> Anaesthetics -> Antitussives