Hydrocodone
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Collated from PsychonautWiki, TripSit, Pharmacology, DrugCentral, DailyMed. Where sources differ (e.g. dosing), Compare shows them side by side.
Also known as Vicodin (with paracetamol), Zohydro ER (extended-release), Norco, vicodin, hydroPW
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
Oral
Route dataPsychonautWiki
| Threshold | Light | Common | Strong | Heavy |
|---|---|---|---|---|
| 3 mg | 5–10 mg | 10–25 mg | 25–40 mg | 40 mg+ |
| Onset | 10–60 minutes |
|---|---|
| Total | 4–8 hours |
Dangerous interactionsPW
Caution / uncertainPW
🧬 Receptor activityDC
| Target | Action | Affinity | Source | |
|---|---|---|---|---|
| Kappa-type opioid receptor (OPRK1) | Agonist | 6.59 Ki | DRUGCENTRAL | TargetKappa-type opioid receptor (OPRK1) ActionAgonist Affinity6.59 Ki SourceDRUGCENTRAL |
| Mu-type opioid receptor (OPRM1) | Agonist | 8.02 Ki | DRUGCENTRAL | TargetMu-type opioid receptor (OPRM1) ActionAgonist Affinity8.02 Ki SourceDRUGCENTRAL |
Mechanism of actionPHDM
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.
PharmacodynamicsPH
Hydrocodone inhibits pain signaling in both the spinal cord and brain. Its actions in the brain also produce euphoria, respiratory depression, and sedation.
Pharmacokinetics
Half-lifePH
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.
AbsorptionPHDM
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.
MetabolismPH
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.
Protein bindingPH
Hydrocodone is 36% bound to plasma proteins.
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External links
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.