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DEA NFLIS-Drug Category -> Narcotic Analgesics

DEA Schedule II Controlled Substance

Pharmaceuticals -> Synthetic Cannabinoids or Psychoactive Compounds

Pharmaceuticals -> Listed in ZINC15

Soluble in acetone, ethyl acetate, chloroform

Soluble in ethanol

7.97e-01 g/L

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

FDA approved drugs -> Active ingredient

FDA approved drugs -> Active ingredient

Pharmaceuticals

198 °C

MP: 219-220 °C /Hydrocodone hydriodide/

MP: 250-225 °C /Hydrocodone methiodide/

198 °C

Danger

H302 (97.7%): Harmful if swallowed [Warning Acute toxicity, oral]

P233, P260, P261, P264, P270, P271, P272, P273, P280, P284, P301+P317, P302+P352, P304+P340, P321, P330, P333+P317, P342+P316, P362+P364, P391, P403, and P501 (click each P-code to see the statement)

Aggregated GHS information provided per 43 reports by companies from 3 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Danger

H225: Highly Flammable liquid and vapor [Danger Flammable liquids]

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. 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, naloxone, and naltrexone, and their respective salts, but including the following. Hydrocodone (DEA Code Number: 9193) is included on this list.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including hydrocodone bitartrate approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act. /Hydrocodone bitartrate/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including hydrocodone polistirex approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act. /Hydrocodone polistirex/

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary. Use water spray to cool unopened containers.

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

Store at 25 °C (77 °F); excursions permitted between 15-30 °C (59-86 °F). Dispense in tight, light-resistant container, as defined by the USP.

Conditions for safe storage, including any incompatibilities: Keep container tightly closed in a dry and well-ventilated place. Containers which are opened must be carefully resealed and kept upright to prevent leakage. Recommended storage temperature -20 °C

Hydrocodone bitartrate is affected by light. Hydrocodone bitartrate preparations should be stored in tight, light-resistant containers at 15-30 °C.

ACCIDENTAL RELEASE MEASURES. Personal precautions, protective equipment and emergency procedures: Wear respiratory protection. Avoid breathing vapours, mist or gas. Ensure adequate ventilation. Remove all sources of ignition. Evacuate personnel to safe areas. Beware of vapours accumulating to form explosive concentrations. Vapours can accumulate in low areas.; Environmental precautions: Prevent further leakage or spillage if safe to do so. Do not let product enter drains. Discharge into the environment must be avoided.; Methods and materials for containment and cleaning up: Contain spillage, and then collect with an electrically protected vacuum cleaner or by wet-brushing and place in container for disposal according to local regulations.

SRP: At the time of review, regulatory criteria for small quantity disposal are subject to significant revision, however, household quantities of waste pharmaceuticals may be managed as follows: Mix with wet cat litter or coffee grounds, double bag in plastic, discard in trash.

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.

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.

Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product.

Precautions for safe handling; Avoid contact with skin and eyes. Avoid inhalation of vapour or mist. Use explosion-proof equipment.Keep away from sources of ignition - No smoking.Take measures to prevent the build up of electrostatic charge.

Respiratory protection: Where risk assessment shows air-purifying respirators are appropriate use a full-face respirator with multipurpose combination (US) or type ABEK (EN 14387) respirator cartridges as a backup to engineering controls. If the respirator is the sole means of protection, use a full-face supplied air respirator. Use respirators and components tested and approved under appropriate government standards such as NIOSH (US) or CEN (EU).

Body Protection: Complete suit protecting against chemicals, Flame retardant antistatic protective clothing. The type of protective equipment must be selected according to the concentration and amount of the dangerous substance at the specific workplace.

Skin protection: Handle with gloves.

Eye/face protection: Face shield and safety glasses Use equipment for eye protection tested and approved under appropriate government standards such as NIOSH (US) or EN 166(EU).

/FATAL/ There is limited data on postmortem oxycodone concentrations, consisting of three published reports with a total of 11 cases, many of which were polypharmacy cases. This report presents the results of a review of autopsy and coroner's reports from 10 counties for the years 2000 and 2001 to locate cases with oxycodone or hydrocodone exposure as a leading cause of death. Eighty-eight cases were located. Twenty-four deaths were attributed to oxycodone alone. Mean and median postmortem oxycodone blood concentrations were 1.23 mg/L and 0.43 mg/L, respectively. The range was 0.12 to 8.0 mg/L, with 13 cases (54%) < or = 0.5 mg/L. Seventeen deaths were attributed to hydrocodone alone. Mean and median postmortem hydrocodone blood concentrations were 0.53 mg/L and 0.40 mg/L, respectively. The range was 0.12 to 1.6 mg/L, with 11 cases (65%) < or = 0.5 mg/L. There were seven cases where the cause of death was attributed to the effects of a combination of hydrocodone and oxycodone. Mean oxycodone and hydrocodone blood concentrations were 0.34 mg/L and 0.14 mg/L, respectively. Forty cases involved polysubstance overdoses with significant involvement of other drugs and ethanol. Mean oxycodone and hydrocodone blood concentrations were 0.18 mg/L and 0.29 mg/L, respectively. The list of other substances involved was extensive but included ethanol, amitriptyline, methadone, codeine, propoxyphene, and acetaminophen. The findings of this study report oxycodone values associated with a fatality at blood concentrations lower than previously reported. This may represent enhanced information because of the larger sample group. Hydrocodone values associated with a fatality were similar to previously published values.

Immediate treatment includes support of cardiorespiratory function and measures to reduce drug absorption. Vomiting should be induced mechanically, or with syrup of ipecac, if the patient is alert (adequate pharyngeal and laryngeal reflexes). Oral activated charcoal (1 g/kg) should follow gastric emptying. The first dose should be accompanied by an appropriate cathartic. If repeated doses are used, the cathartic might be included with alternate doses as required. Hypotension is usually hypovolemic and should respond to fluids. Vasopressors and other supportive measures should be employed as indicated. A cuffed endo-tracheal tube should be inserted before gastric lavage of the unconscious patient and, when necessary, to provide assisted respiration. Meticulous attention should be given to maintaining adequate pulmonary ventilation. In severe cases of intoxication, peritoneal dialysis, or preferably hemodialysis may be considered. Naloxone, a narcotic antagonist, can reverse respiratory depression and coma associated with opioid overdose. Naloxone hydrochloride 0.4 mg to 2 mg is given parenterally. Since the duration of action of hydrocodone may exceed that of the naloxone, the patient should be kept under continuous surveillance and repeated doses of the antagonist should be administered as needed to maintain adequate respiration. (L1712)

Hydrocodone may potentiate the effects of other opiate agonists, general anesthetics, tranquilizers, sedatives and hypnotics, tricyclic antidepressants, monoamine oxidase inhibitors, alcohol, and other CNS depressants.

Concurrent use of anticholinergic agents with hydrocodone may produce paralytic ileus.

Some tranquilizers, especially phenothiazines, may antagonize opiate agonist analgesia. /Opiate agonists/

...Using the mouse radiant heat tail-flick nociception model, /investigators/ observed potent analgesia with hydrocodone. In contrast, ibuprofen as a single drug was inactive in this model of moderate to severe pain, perhaps reflecting its limited analgesic potential. Despite the inactivity of ibuprofen alone in this model, the inclusion of ibuprofen with hydrocodone markedly enhanced the analgesic response. Dose-response studies revealed a 50% effective dose for hydrocodone alone in mice of 11 mg/kg, SC. Inclusion of a fixed ibuprofen dose with the various hydrocodone doses shifted the 50% effective dose value almost seven-fold to the left to 1.6 mg/kg, SC, despite the lack of effect of ibuprofen alone in this model. Using a fixed hydrocodone:ibuprofen ratio (1:40) also revealed a marked four-fold shift to 2.6 mg/kg, SC. These findings suggest a synergistic interaction between ibuprofen and hydrocodone in a noninflammatory pain model. Opioids are frequently used in combination with nonsteroidal antiinflammatory drugs clinically. These studies demonstrate strong interactions between ibuprofen and hydrocodone, implying synergy between the two drugs, which may help explain their utility when given together.

To describe the potential for interaction between opioids and serotonergic antidepressants leading to the development of serotonin syndrome (SS), mechanism of the interaction, and the spectrum of SS in elderly residents of a long-term care facility. Case series. Long-term care facility (LTCF) in California. Four elderly LTCF residents treated with serotonergic antidepressants including selective serotonin reuptake inhibitor (SSRI) or mirtazapine and opioids. Signs and symptoms suggestive of SS. /Investigators/ describe 4 cases of probable SS among elderly residents of a LTCF. The spectrum of serotonin toxicity ranged from visual hallucinations, muscle rigidity, myoclonus, or hypertension in patients taking an opiate with an SSRI to lethargy, hypotension, and hypoxia in a patient taking tramadol and mirtazapine. While many can benefit from coadministration of serotonergic antidepressants and opioids, it appears that some individuals are at increased risk for SS. Since SS is a clinical diagnosis, heightened clinician awareness of the possibility of SS among patients receiving SSRI or mirtazapine in combination with opioids may lead to earlier detection and avoidance of potentially lethal consequences.

Despite wide scale use for many decades, hydrocodone by itself has not been convincingly linked to instances of clinically apparent acute liver injury. However, when combined with acetaminophen, hydrocodone combinations have become a common cause of acetaminophen acute liver injury. The typical history is of a patient who began taking more than the prescribed number of pills over several days, attempting to achieve more of an opiate effect and leading secondarily and unintentionally to an overdose of acetaminophen. Because of their potential for hepatotoxicity, opioid combinations in which the dose of acetaminophen is greater than 325 mg per tablet or capsule were discontinued.

TERRESTRIAL FATE: Based on a classification scheme(1), an estimated Koc value of 1,100(SRC), determined from a structure estimation method(2), indicates that hydrocodone is expected to have low mobility in soil(SRC). The pKa of hydrocodone is 8.23(3), indicating that this compound will exist partially 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 of the neutral species of hydrocodone from moist soil surfaces is not expected to be an important fate process(SRC) given an estimated Henry's Law constant of 6.4X10-12 atm-cu m/mole(SRC), using a fragment constant estimation method(5). Hydrocodone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2). Hydrocodone is not biodegraded in wastewater treatment plants(6), suggesting that biodegradation is not an important environmental fate process in soil(SRC).

AQUATIC FATE: Based on a classification scheme(1), an estimated Koc value of 1,100(SRC), determined from a structure estimation method(2), indicates that hydrocodone is expected to adsorb to suspended solids and sediment(SRC). Volatilization from water surfaces of the neutral species is not expected(3) based upon an estimated Henry's Law constant of 6.8X10-12 atm-cu m/mole(SRC), developed using a fragment constant estimation method(4). A pKa of 8.23(5) indicates hydrocodone 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(6), an estimated BCF of 12(SRC), from an estimated log Kow of 2.16(2) and a regression-derived equation(2), suggests the potential for bioconcentration in aquatic organisms is low(SRC). Hydrocodone is not biodegraded in wastewater treatment plants(7), suggesting that biodegradation is not an important environmental fate process in water(SRC).

ATMOSPHERIC FATE: According to a model of gas/particle partitioning of semivolatile organic compounds in the atmosphere(1), hydrocodone, which has an estimated vapor pressure of 1.2X10-7 mm Hg at 25 °C(SRC), determined from a fragment constant method(2), will exist in both the vapor and particulate phases in the ambient atmosphere. Vapor-phase hydrocodone is degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals(SRC); the half-life for this reaction in air is estimated to be 1 hr(SRC), calculated from its rate constant of 1.8X10-10 cu cm/molecule-sec at 25 °C(SRC) that was derived using a structure estimation method(3). Particulate-phase hydrocodone may be removed from the air by wet and dry deposition(SRC). Hydrocodone absorbs UV light at wavelengths 280 nm(4) and, therefore, is not expected to be susceptible to direct photolysis by sunlight since sunlight consists of wavelengths above 290 nm(SRC).

EXPERIMENTAL: Two mothers who were taking an acetaminophen and hydrocodone combination product donated pumped milk for analysis of hydrocodone. Their infants received an estimated 3.1% and 3.7% of the maternal weight-adjusted dosage, but the absolute hydrocodone dosages were 8.58 ug/kg per day and 3.07 ug/kg per day because of the differences in the dosages ingested by their mothers. Moderate dosages of hydrocodone appear acceptable during breastfeeding, but more data are needed to determine the maximum safe dosage for nursing mothers. Neonates and preterm infants may be more susceptible than older infants to adverse effects of hydrocodone and its metabolites in breast milk.

IDENTIFICATION AND USE: Hydrocodone bitartrate (HD) is a phenanthrene-derivative opiate agonist antitussive and analgesic agent. HUMAN EXPOSURE AND TOXICITY: Serious overdose with hydrocodone is characterized by respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdosage, apnea, circulatory collapse, cardiac arrest and death may occur. A 3-year-old child died of the combined effects of a bacterial superinfection and a relative overdose of hydrocodone prescribed for a cough due to a presumed viral respiratory tract infection. Poison center rates of abuse and misuse were highest for hydrocodone at 3.75 per 100,000 population, followed by oxycodone at 1.81 per 100,000 population. DAWN emergency department (ED) data illustrate a similar pattern of abuse with most mentions involving hydrocodone and oxycodone. Poison center data indicate that people aged 18 to 25 had the highest rates of abuse. DAWN reported the majority of ED mentions among 35 to 44-year-olds. ANIMAL STUDIES: LD50 in rats was 150 mg/kg for sc administration and 375 mg/kg when given orally. HB was evaluated in rats (25/sex/group) and in rabbits (20 females/group) given daily po doses of 0 (Vehicle), 10, 33 and 100 mg/kg and 0 (Vehicle), 5.3, 16 and 48 mg/kg, respectively. Female rats were dosed gestation days (DGs) 7-17 and Cesarean-sectioned (CS) on DG 21 and female rabbits were dosed DGs 6-18 and CS on DG 29. Toxicokinetics was evaluated in the range-finding studies for both species at 0.5. 1, 2, 4, 6, 16 and 24 hr postdosage on the first and last days of dose administration. Survival was not affected in either species. Exaggerated pharmacological effects of HB and reduced body weight gain and absolute and relative feed consumption values were observed at all dosage levels in both studies. Rodent fetal body weights were reduced and a reduction in the number of ossifications sites for the caudal vertebrae, hindlimb phalanges and metatarsals occurred in the 100 mg/kg group. The number of late resorptions was increased in the 48 mg/kg group; no other CS parameters were affected and no gross, visceral or skeletal malformations attributed to HB. The maternal NOAELs were less than 10 mg/kg and 5.3 mg/kg for the rat and rabbit studies, respectively. The developmental NOAELs were 16 and 33 mg/kg for the rat and rabbit studies, respectively.

Signs and Symptoms of Overdose

Hydrocodone acts as a weak agonist at OP1, OP2, and OP3 opiate receptors within the central nervous system (CNS). Hydrocodone primarily affects OP3 receptors, which are coupled with G-protein receptors and function as modulators, both positive and negative, 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 such as hydrocodone also inhibit the release of vasopressin, somatostatin, insulin, and glucagon. 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.

Symptoms of overdose include respiratory depression (a decrease in respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), extreme somnolence progressing to stupor or coma, skeletal muscle flaccidity, dizziness, ringing in the ears, confusion, blurred vision, eye problems, cold and clammy skin, and sometimes bradycardia and hypotension. In severe overdose, apnea, circulatory collapse, cardiac arrest and death may occur.

Hydrocodone was detected, not quantified in secondary effluent samples from nine municipal sewage plants in the region of Stuttgart, Germany(1). The compound was detected at 1.47 ug/L in effluent from a sewage treatment plant in Stuttgart, Germany(2). Hydrocodone influent and effluent concentrations were 70 and 8.6 ng/L, respectively, at the 26th Ward wastewater treatment plant, Jamaica Bay, NY, an 88% removal efficiency(3).

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. 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, naloxone, and naltrexone, and their respective salts, but including the following. Hydrocodone (DEA Code Number: 9193) is included on this list.

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including hydrocodone bitartrate approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act. /Hydrocodone bitartrate/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including hydrocodone polistirex approved on the basis of safety and effectiveness by FDA under sections 505 and 507 of the Federal Food, Drug, and Cosmetic Act. /Hydrocodone polistirex/

R - Respiratory system

QR - Respiratory system

Hydrocodone binds to the mu opioid receptor (MOR) with the highest affinity followed by the delta opioid receptors (DOR). Hydrocodone's agonist effect at the MOR is considered to contribute the most to its analgesic effects. Both MOR and DOR are Gi/o coupled and and produces its signal through activation of inward rectifier potassium (GIRK) channels, inhibition of voltage gated calcium channel opening, and decreased adenylyl cyclase activity. In the dorsal horn of the spinal cord, activation of pre-synaptic MOR on primary afferents the inhibition of calcium channel opening and increased activity of GIRK channels hyperpolarizes the neuron and prevents release of neurotransmitters. Post-synaptic MOR can also prevent activation of neurons by glutamate through the aforementioned mechanisms. Hydrocodone can also produce several actions in the brain similarly to other opioids. Activation of MOR in the periaquaductal gray (PAG) inhibits the GABAergic tone on medulo-spinal neurons. This allows these neurons, which project to the dorsal horn of the spinal cord, to suppress pain signalling in secondary afferents by activating inhibitory interneurons. MOR can also inhibit GABAergic neurons in the ventral tegmental area, removing the inhibitory tone on dopaminergic neurons in the nucleus accumbens and contributing to the activation of the brain's reward and addiction pathway. The inhibitory action or MOR likely contributes to respiratory depression, sedation, and suppression of the cough reflex. Activation of DOR may contribute to analgesia through the above mechanisms but has not been well studied.

Hydrocodone is a semi-synthetic opioid agonist with relative selectivity for the mu-opioid receptor, although it can interact with other opioid receptors at higher doses. Hydrocodone acts as an agonist binding to and activating opioid receptors in the brain and spinal cord, which are coupled to G-protein complexes and modulate synaptic transmission through adenylate cyclase. The pharmacological effects of hydrocodone including analgesia, euphoria, respiratory depression and physiological dependence are believed to be primarily mediated via u opioid receptors.

The half-life of elimination reported for hydrocodone is 7-9 h.

The mean terminal half-life (t1/2) was similar for all HYSINGLA ER dose strengths ranging from 7 to 9 hours.

Half-life was determined to be 3.8 +/- 0.3 hrs.

The elimination half-life of hydrocodone is reportedly about 3.8 hours in healthy adults.

Hydrocodone undergoes oxidative O-demethylation to form [hydromorphone], a more potent active metabolite. Though hydromorphone is active it is not present in sufficient quantities to contribute significantly to hydrocodone's therapeutic effects. Both hydrocodone and hydromorphone form 6-α- and 6-β-hydroxy metabolites through 6-ketoreduction. The hydroxy metabolites and hydromorphone can form glucuronide conjugates. Hydrocodone also undergoes oxidative N-demthylation to norhydrocodone. O-demethylation is primarily catalyzed by CYP2D6 while N-demethylation is primarily CYP3A4.

Like other phenanthrene derivatives, hydrocodone is probably metabolized in the liver and excreted mainly in urine. Metabolism of hydrocodone includes O-demethylation, N-demethylation, and 6-keto reduction.

Hydrocodone exhibits a complex pattern of metabolism including O-demethylation, N-demethylation and 6-keto reduction to the corresponding 6-alpha- and 6-beta-hydroxymetabolites.

Following the administration of codeine 30 mg by mouth to 2 healthy subjects, hydrocodone, norhydrocodone, 6 alpha-hydrocodol, and 6 beta-hydrocodol in addition to known metabolites were detected in urine.

Pharmacokinetic drug-drug interactions with codeine, dihydrocodeine, hydrocodone, oxycodone, and buprenorphine are reviewed in this column. These compounds have a very similar chemical structure to morphine. Unlike morphine, which is metabolized chiefly through conjugation reactions with uridine diphosphate glucuronosyl transferase (UGT) enzymes, these five drugs are metabolized both through oxidative reactions by the cytochrome P450 (CYP450) enzyme and conjugation by UGT enzymes. There is controversy as to whether codeine, dihydrocodeine, and hydrocodone are actually prodrugs requiring activation by the CYP450 2D6 enzyme or UGT enzymes. Oxycodone and buprenorphine, however, are clearly not prodrugs and are metabolized by the CYP450 2D6 and 3A4 enzymes, respectively. Knowledge of this metabolism assists in the understanding for the potential of drug-drug interactions with these drugs. ...

Two similar cases are reported here in which Tussionex, a preparation containing hydrocodone and phenyltoloxamine, caused or contributed to death. Toxicological analyses revealed a high concentration ratio of hydromorphone to hydrocodone in the bile in both cases. It is postulated that the finding of hydromorphone is due to the metabolism of hydrocodone.

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HYDROCODONE

Established Pharmacologic Class [EPC] - Opioid Agonist

Mechanisms of Action [MoA] - Opioid Agonists

Hydrocodone is an Opioid Agonist. The mechanism of action of hydrocodone is as an 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.

The absolute bioavailability of hydrocodone has not been characterized due to lack of an IV formulation. The liquid formulations of hydrocodone have a Tmax of 0.83-1.33 h. The extended release tablet formulations have a Tmax of 14-16 h. The Cmax remains dose proportional over the range of 2.5-10 mg in liquid formulations and 20-120 mg in extended release formulations. Administration with food increases Cmax by about 27% while Tmax and AUC remain the same. Administration with 40% ethanol has been observed to increase Cmax 2-fold with an approximate 20% increase in AUC with no change in Tmax. 20% alcohol produces no significant effect.

Most hydrocodone appears to be eliminated via a non-renal route as renal clearance is substantially lower than total apparent clearance. Hepatic metabolism may account for a portion of this, however the slight increase in serum concentration and AUC seen in hepatic impairment indicates a different primary route of elimination.

The apparent volume of distribution ranges widely in published literature. The official FDA labeling reports a value of 402 L. Pharmacokinetic studies report values from 210-714 L with higher values associated with higher doses or single dose studies and lower values associated with lower doses and multiple dose studies. Hydrocodone has been observed in human breast milk at levels equivalent to 1.6% of the maternal dosage. Only 12 of the 30 women studied had detectable concentrations of hydromorphone at mean levels of 0.3 mcg/kg/day.

Official FDA labeling reports an apparent clearance of 83 L/h. Pharmacokinetic studies report values ranging from 24.5-58.8 L/h largely dependent on CYP2D6 metabolizer status.

HYSINGLA ER is a single-entity extended-release formulation of hydrocodone that yields a gradual increase in plasma hydrocodone concentrations with a median Tmax of 14 - 16 hours noted for different dose strengths. Peak plasma levels may occur in the range of 6 -30 hours after single dose HYSINGLA ER administration. Systemic exposure (AUC and Cmax) increased linearly with doses from 20 to 120 mg. Both Cmax and AUC increased slightly more than dose proportionally.

Hydrocodone is well absorbed from the GI tract. Following oral administration of a single 10-mg dose of hydrocodone to adult males in one study, a mean peak serum hydrocodone concentration of 23.6 ng/mL occurred after 1.3 hours. Following oral administration, antitussive action is maintained for 4-6 hours.

This is a /DEA:/ Schedule II controlled substance.

... semisynthetic opioid antitussive and analgesic

MEDICATION (VET)

MEDICATION

Analgesics, Opioid; Antitussive Agents; Narcotics

Use (kg) in USA (2002): 28600

Morphine; 4,5alpha-epoxy-3-methoxy-17-methylmorphinan-6alpha-ol (dihydrocodeine); codeine; 4,5alpha-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one (oxycodone); 7,8-didehydro-4,5alpha-epoxy-3-methoxy-17-methylmorphinan-6-one (codeinone); 7,8-didehydro-4,5alpha-epoxy-3,6alpha-dimethoxy-17-methylmorphinan (methylcodeine); 4,5alpha-epoxy-3,6alpha-dimethoxy-17-methylmorphinan (tetrahydrothebaine); diphenylmethanone (benzophenone); 6,7,8,14-tetrahydro-4,5alpha-epoxy-3,6-dimethoxy-17-methylmorphinan (thebaine); (5alpha)-3,6-dimethoxy-17-methyl-6,7-didehydro-4,5-epoxymorphinan (dihydrothebaine); (5alpha)-3-hydroxy-17-methyl-4,5-epoxymorphinan-6-one (hydromorphone) /hydrocodone hydrogen tartrate 2.5-hydrate/

... Synthetic alkaloid, 7,8-dihydrocodeinone, is prepared ... By catalytic rearrangement of codeine or by controlled hydrolysis & oxidation of dihydrothebaine. /Hydrocodone bitartrate, NF/

For the synthesis of hydrocodone, codeine is catalytically rearranged by heating with palladium or platinum in alcoholic or aqueous acidic solution.

Industrial preparation from dihydrocodeine: K. Pfister, M. Tishler, United States of America patent 2715626 (1955 to Merck & Co.).

HYSINGLA ER (hydrocodone bitartrate) extended-release tablets 20 mg are round, green-colored, bi-convex tablets printed with "HYD 20" and are supplied in child-resistant closure, opaque plastic bottles of 60 (NDC 59011-271-60).

HYSINGLA ER (hydrocodone bitartrate) extended-release tablets 30 mg are round, yellow-colored, bi-convex tablets printed with "HYD 30" and are supplied in child-resistant closure, opaque plastic bottles of 60 (NDC 59011-272-60).

HYSINGLA ER (hydrocodone bitartrate) extended-release tablets 40 mg are round, grey-colored, bi-convex tablets printed with "HYD 40" and are supplied in child-resistant closure, opaque plastic bottles of 60 (NDC 59011-273-60).

HYSINGLA ER (hydrocodone bitartrate) extended-release tablets 60 mg are round, beige-colored, bi-convex tablets printed with "HYD 60" and are supplied in child-resistant closure, opaque plastic bottles of 60 (NDC 59011-274-60).

For more Formulations/Preparations (Complete) data for HYDROCODONE (51 total), please visit the HSDB record page.

Hydrocodone induces side effects similar to codeine and morphine and has an appreciable abuse and dependence potential.

Hydrocodone preparations are subject to control under the Federal Controlled Substances Act of 1970 as schedule III (C-III) drugs when available as a fixed-combination preparation in a concentration of 15 mg or less per dosage unit or 5 mL combined with a therapeutic amount of one or more non-opiate drugs or with a fourfold or greater quantity of isoquinolone opium alkaloid.

Hydrocodone bitartrate and hydrocodone polistirex are currently commercially available only in combination products.