Hydrocodone

Claim in safety — inconclusiveinconclusiveworking →

Autopsy findings in opioid-related deaths characteristically include pulmonary edema and congestion with frothy watery fluid in the airwayssupported

Pulmonary edema/congestion are key autopsy findings. 2017.003

Opioid use disorder caused 53,774 U.S. deaths in 2024 and affected 3.7% of adultssupported

Opioid use disorder affected ~3.7% of US adults (9.4M) in 2022 and caused 53,774 deaths in 2024. jama.2025.26348

Paulozzi et al. established that opioid analgesic poisoning deaths — driven substantially by hydrocodone prescribing — exceeded heroin and cocaine deaths combined by 2002partially supported

Opioid analgesic poisoning listed in 5528 deaths in 2002 - more than heroin or cocaine. pds.1276

Opioids subsequently became responsible for more deaths than suicide and motor vehicle crashes.supported

Opioid analgesics now responsible for more deaths than both suicide/motor vehicle crashes or cocaine/heroin combined. es9

Evidence-based treatment for opioid use disorder includes buprenorphine-naloxone (partial agonist substitution therapy), methadone (full agonist substitution), and naltrexone (antagonist-based relapse prevention).supported

Reviews medications for OUD, withdrawal, and overdose reversal. jama.2025.26348

Farrar et al. found that only approximately 44.5% of chronic non-cancer pain patients maintained pain level and opioid dose stability over 12 months on extended-release opioids, reflecting the clinical reality of tolerance development.supported

Patient-level analysis of FDA data from 3,192 patients on ER oxycodone/hydrocodone: ~44.5% maintained pain and opioid dose stability at 12 months. j.pain.0000000000002331

The hydrocodone-alcohol interaction operates through dual mechanisms: pharmacodynamic (additive CNS and respiratory depression) and pharmacokinetic (40% ethanol increases hydrocodone ER Cmax by approximately 135% and shortens Tmax from 6.16 to 2.43 hours)supported

40% alcohol increased AUC by 20% and Cmax from 46.3 to 109 ng/mL, shortened tmax to 2.43 h. cpaa.s70831

Claim in safety — not_supportednot supportedworking →

Fields et al. found that alprazolam and diazepam co-ingestion significantly decreased hydrocodone blood concentrations in postmortem cases — likely through CYP3A4 competition — while deaths still occurred, indicating synergistic CNS toxicity at lower drug concentrations than would be expected for either drug alonesupported

Alprazolam + diazepam significantly decreased median hydrocodone concentrations by 48% but deaths still occurred at lower concentrations, suggesting synergistic toxicity. 1556-4029.12807

Claim in safety — inconclusiveinconclusiveworking →

Claim in safety — inconclusiveinconclusiveworking →

Claim in safety — inconclusiveinconclusiveworking →

CYP2D6 ultra-rapid metabolizer status — excessive hydromorphone formation may produce disproportionate opioid effects at standard dosessupported

CYP2D6 variability is a major cause of opioid efficacy and safety differences. Applicable to other CYP2D6-metabolized opioids including hydrocodone. clpt.2013.254

Pregnancy — neonatal opioid withdrawal syndrome (NOWS) is documented with in-utero opioid exposure; maternal pharmacokinetic data during pregnancy are limitedsupported

Hydrocodone, oxycodone, and codeine are the most prescribed opioids but have major pharmacology knowledge gaps in maternal and pediatric populations. phar.70024

Concurrent benzodiazepine or CNS depressant use — synergistic respiratory depression; substantially elevated overdose mortality risksupported

Alprazolam + diazepam significantly decreased median hydrocodone concentrations by 48% but deaths still occurred at lower concentrations, suggesting synergistic toxicity. 1556-4029.12807

Concurrent benzodiazepine or CNS depressant use — synergistic respiratory depression; substantially elevated overdose mortality risksupported

Benzodiazepines when combined with opioids produce significant respiratory depression. 0897190013515001

A pharmacologically critical distinction defines hydrocodone's mechanism: the parent compound has moderate MOR affinity (Ki = 19.8 nM), but CYP2D6-mediated O-demethylation yields hydromorphone (Ki ≈ 0.6 nM), approximately 33-fold more potent at MORsupported

Hydrocodone Ki = 19.8 nM at mu receptor (rat brain homogenates with 3H-DAMGO). Hydromorphone Ki = 0.6 nM. Many opioids may exert their pharmacological actions predominantly through metabolites. pmid:1851921

Hosseinnejad et al. demonstrated in a postcesarean cohort that plasma hydromorphone concentration — not plasma hydrocodone — was predictive of pain relief, directly establishing the metabolite as a principal mediator of analgesic efficacy.supported

plasma hydromorphone, not hydrocodone, was predictive of pain relief. jalm.2018.026070

Hydrocodone undergoes extensive hepatic first-pass metabolism via two primary CYP-mediated pathways:supported

To determine the Michaelis-Menten kinetics of hydrocodone metabolism to its O- and N-demethylated products, hydromorphone and norhydrocodone, to determine the individual cytochrome p450 enzymes involved. pmid:14998425

Hydrocodone undergoes extensive hepatic first-pass metabolism via two primary CYP-mediated pathways:supported

Hydrocodone undergoes cytochrome P-450 (CYP)-mediated metabolism involving the CYP3A4 and CYP2D6 isozymes. j.clinthera.2015.08.007

Hydrocodone undergoes extensive hepatic first-pass metabolism via two primary CYP-mediated pathways:supported

Hydrocodone is metabolized by cytochrome P450 (CYP) 2D6 into hydromorphone and by CYP3A4 into norhydrocodone. bku051

CYP3A4 (N-demethylation) → norhydrocodone — the major metabolic pathway by mass. Norhydrocodone is considered pharmacologically inactive or weakly active. Mean urinary norhydrocodone mole fraction: approximately 49% of total metabolite outputsupported

Mean hydrocodone, hydromorphone and norhydrocodone mole fractions were 0.39, 0.12 and 0.49, respectively. bku051

CYP2D6 (O-demethylation) → hydromorphone — a minor pathway by mass (approximately 12% of urinary drug and metabolites) but pharmacologically significant due to hydromorphone's 33-fold greater MOR affinitysupported

Mean hydrocodone, hydromorphone and norhydrocodone mole fractions were 0.39, 0.12 and 0.49, respectively. bku051

Claim in pharmacology — inconclusiveinconclusiveworking →

Poor metabolizers exhibit substantially reduced hydromorphone formation and correspondingly reduced analgesiasupported

Individuals with absent (poor metabolizers) or reduced (intermediate metabolizers) CYP2D6 enzyme activity have lower concentrations of highly potent active metabolites of tramadol, hydrocodone, and codeine. jamanetworkopen.2025.58299

Poor metabolizers exhibit substantially reduced hydromorphone formation and correspondingly reduced analgesiasupported

CYP2D6 bioactivates hydrocodone, tramadol, codeine, and oxycodone to active metabolites providing analgesic activity. Reduced CYP2D6 activity may be associated with poor pain control. jamanetworkopen.2025.23543

Claim in pharmacology — inconclusiveinconclusiveworking →

CYP3A4 and CYP3A5 genotype does not significantly predict pain relief from hydrocodone.supported

CYP2D6 is responsible for metabolizing hydrocodone; rate of hydromorphone formation was dependent on the genotype of CYP2D6 and plasma hydromorphone, not hydrocodone, was predictive of pain relief. jalm.2018.026070

Claim in pharmacology — inconclusiveinconclusiveworking →

Hydrocodone metabolism is dominated by two CYP-mediated oxidative pathways characterized in human liver microsomes:supported

To determine the Michaelis-Menten kinetics of hydrocodone metabolism to its O- and N-demethylated products, hydromorphone and norhydrocodone, to determine the individual cytochrome p450 enzymes involved. pmid:14998425

CYP3A4: N-demethylation → norhydrocodone — the quantitatively major pathway. Norhydrocodone accounts for approximately 49% of total urinary drug and metabolites in a large-scale clinical sample (n = 76,924 specimens). Norhydrocodone is considered pharmacologically inactive or weakly active at MOR.supported

Mean hydrocodone, hydromorphone and norhydrocodone mole fractions were 0.39, 0.12 and 0.49, respectively. bku051

CYP2D6: O-demethylation → hydromorphone — the quantitatively minor but pharmacologically dominant pathway. Hydromorphone accounts for approximately 12% of urinary drug and metabolites but possesses 33-fold greater MOR affinity than the parent compound.supported

Mean hydrocodone, hydromorphone and norhydrocodone mole fractions were 0.39, 0.12 and 0.49, respectively. bku051

Parent hydrocodone accounts for approximately 39% of total urinary output.supported

Mean hydrocodone, hydromorphone and norhydrocodone mole fractions were 0.39, 0.12 and 0.49, respectively. bku051

Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →

Poor metabolizers exhibit substantially reduced hydromorphone formation, resulting in diminished analgesia and increased risk of inadequate pain control.supported

Individuals with absent (poor metabolizers) or reduced (intermediate metabolizers) CYP2D6 enzyme activity have lower concentrations of highly potent active metabolites of tramadol, hydrocodone, and codeine. jamanetworkopen.2025.58299

Poor metabolizers exhibit substantially reduced hydromorphone formation, resulting in diminished analgesia and increased risk of inadequate pain control.supported

CYP2D6 bioactivates hydrocodone, tramadol, codeine, and oxycodone to active metabolites providing analgesic activity. Reduced CYP2D6 activity may be associated with poor pain control. jamanetworkopen.2025.23543

Claim in pharmacokinetic-detail — inconclusiveinconclusiveworking →

CYP3A4 and CYP3A5 genotype does not significantly predict pain relief from hydrocodone.supported

CYP2D6 is responsible for metabolizing hydrocodone; rate of hydromorphone formation was dependent on the genotype of CYP2D6 and plasma hydromorphone, not hydrocodone, was predictive of pain relief. jalm.2018.026070

Phase 3 trials of suzetrigine (VX-548), a novel NaV1.8 inhibitor, used hydrocodone bitartrate 5 mg/acetaminophen 300 mg as the reference arm in bunionectomy and abdominoplasty pain, with VX-548 demonstrating non-inferior efficacysupported

Phase 3 trials comparing VX-548 (suzetrigine) vs. hydrocodone bitartrate/acetaminophen and placebo in bunionectomy and abdominoplasty pain. VX-548 significantly reduced pain vs. placebo; non-inferior to hydrocodone/APAP. aln.0000000000005460

By 2011, HCPs had become the most-prescribed drug class in the United States, with 136.7 million prescriptions dispensed annuallysupported

Hydrocodone topped all prescriptions with 136.7 million prescriptions in 2011. es9

The United States accounted for approximately 99% of global hydrocodone consumption.supported

US consumes ~99% of world's hydrocodone supply. 2332-2780-1600078

Paulozzi et al. established in 2006 that opioid analgesic poisoning deaths had exceeded heroin and cocaine deaths combined by 2002partially supported

Opioid analgesic poisoning listed in 5528 deaths in 2002 - more than heroin or cocaine. pds.1276

Opioids subsequently became responsible for more deaths than suicide and motor vehicle crashessupported

Opioid analgesics now responsible for more deaths than both suicide/motor vehicle crashes or cocaine/heroin combined. es9

Shen et al. documented HCP use declining from 55% to 40% among older breast cancer patients, with compensatory prescribing shifts to other opioidssupported

Hydrocodone use declined from 55% to 40% after rescheduling; non-hydrocodone opioid use increased from 43% to 50%. curroncol32110593

Yan et al. recorded significant reductions in dental hydrocodone prescribingsupported

Dentists frequently prescribe hydrocodone. 2014 DEA rescheduling to Schedule II introduced restricted prescribing; changed dental prescribing of opioids. 23800844221102830

Cavallari et al. demonstrated in a randomized trial that CYP2D6-guided opioid management improves postoperative pain control, and Nahid et al. linked CYP2D6 phenotype to emergency department utilization among opioid-treated patientssupported

Individuals with absent (poor metabolizers) or reduced (intermediate metabolizers) CYP2D6 enzyme activity have lower concentrations of highly potent active metabolites of tramadol, hydrocodone, and codeine. jamanetworkopen.2025.58299

Bertoch et al. conducted two Phase 3 randomized clinical trials comparing suzetrigine, a novel NaV1.8 inhibitor, against hydrocodone bitartrate 5 mg/acetaminophen 300 mg as the active comparator in bunionectomy and abdominoplasty painsupported

Phase 3 trials comparing VX-548 (suzetrigine) vs. hydrocodone bitartrate/acetaminophen and placebo in bunionectomy and abdominoplasty pain. aln.0000000000005460

Cooper et al. conducted a randomized, double-blind, placebo-controlled trial comparing analgesic efficacy of naproxen sodium versus hydrocodone/acetaminophen in acute postsurgical dental painsupported

Compared single dose naproxen sodium 440 mg against hydrocodone plus acetaminophen 10/650 mg in post-impaction surgery pain. 00325481.2021.2008180

Chumpitazi et al. evaluated hydrocodone/acetaminophen for pediatric laceration repair in a randomized trial, extending the evidence base for hydrocodone use in pediatric populations.supported

Measured effect of hydrocodone/acetaminophen elixir in reducing pain and anxiety in children undergoing sutured laceration repair in the emergency department. prs.0000000000006383

Farrar et al. conducted a harmonization analysis of FDA patient-level data from abuse-deterrent oxycodone and hydrocodone studies, finding that only approximately 44.5% of 3,192 chronic non-cancer pain patients maintained pain level and opioid dose stability over 12 monthssupported

Patient-level analysis of FDA data from 3,192 patients on ER oxycodone/hydrocodone: ~44.5% maintained pain and opioid dose stability at 12 months. j.pain.0000000000002331

This finding challenges the premise of long-term opioid efficacy maintenance and is consistent with the broader Cochrane assessment by Noble et al. that long-term opioid therapy for chronic non-cancer pain produces sustained benefit in only a minority of patients.supported

Cochrane review (26 studies, 4,893 participants). Many patients discontinue long-term opioids due to adverse events (22.9% oral) or insufficient pain relief (10.3%). 14651858.cd006605.pub2

Cavallari et al. conducted a randomized clinical trial of CYP2D6-guided opioid management in postoperative pain controlsupported

Individuals with absent (poor metabolizers) or reduced (intermediate metabolizers) CYP2D6 enzyme activity have lower concentrations of highly potent active metabolites of tramadol, hydrocodone, and codeine. jamanetworkopen.2025.58299

At the receptor level, hydrocodone's MOR Ki of 19.8 nM ranks it below hydromorphone (0.6 nM), fentanyl, and buprenorphine, but above codeine and tramadol (both > 100 nM).supported

Experiments were conducted to obtain Ki values for 19 approved opioid drugs using a single binding assay in a cell membrane preparation expressing recombinant human MOR. Hydrocodone falls in the Ki=1-100 nM range. j.yrtph.2010.12.007

At the receptor level, hydrocodone's MOR Ki of 19.8 nM ranks it below hydromorphone (0.6 nM), fentanyl, and buprenorphine, but above codeine and tramadol (both > 100 nM).supported

Hydrocodone Ki = 19.8 nM at mu receptor (rat brain homogenates with 3H-DAMGO). Hydromorphone Ki = 0.6 nM. pmid:1851921

The critical difference is magnitude: codeine has negligible intrinsic MOR activity (Ki > 100 nM) and functions almost entirely as a prodrug for morphine, whereas hydrocodone retains moderate MOR affinity (Ki = 19.8 nM) and produces pharmacological effects even in CYP2D6 poor metabolizers — though with reduced analgesic efficacy.supported

Individuals with absent (poor metabolizers) or reduced (intermediate metabolizers) CYP2D6 enzyme activity have lower concentrations of highly potent active metabolites of tramadol, hydrocodone, and codeine. jamanetworkopen.2025.58299

Murphy et al. compared rates of mortality and serious adverse effects among commonly prescribed opioid analgesicssupported

Epidemic of prescription opioid overdose and mortality parallels dispensing rates; evaluation of comparative mortality rates among commonly prescribed opioids including hydrocodone. s40264-018-0660-4

Piper et al. documented trends in medical opioid use from 2006–2016, capturing the peak and decline of hydrocodone prescribing.supported

Nationwide examination of opioid distribution patterns 2006-2016. j.amepre.2018.01.034

The United States accounts for approximately 99% of global consumptionsupported

US consumes ~99% of world's hydrocodone supply. 2332-2780-1600078

Hydrocodone ((4R,4aR,7aR,12bS)-9-methoxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-7-one) is a semi-synthetic morphinan opioid and full μ-opioid receptor (MOR) agonist with moderate receptor affinity (Ki = 19.8 nM)supported

Hydrocodone Ki = 19.8 nM at mu receptor (rat brain homogenates with 3H-DAMGO). pmid:1851921

FDA in 1943, hydrocodone became the most-prescribed drug in the United States by 2011, with 136.7 million annual prescriptionssupported

Hydrocodone topped all prescriptions with 136.7 million prescriptions in 2011. es9

Hydrocodone activates MOR with a Ki of 19.8 nM in rat brain homogenates, placing it in the moderate-affinity range alongside oxycodone and methadonepartially supported

Experiments were conducted to obtain Ki values for 19 approved opioid drugs using a single binding assay in a cell membrane preparation expressing recombinant human MOR. Hydrocodone falls in the Ki=1-100 nM range. j.yrtph.2010.12.007

Clinical pharmacogenomics data confirm that plasma hydromorphone — not plasma hydrocodone — predicts analgesic efficacy, establishing the metabolite as a principal mediator of therapeutic effect.supported

plasma hydromorphone, not hydrocodone, was predictive of pain relief. jalm.2018.026070

Chen et al. established a Ki of 19.8 nM using rat brain homogenates with ³H-DAMGO as the radioligandsupported

Hydrocodone Ki = 19.8 nM at mu receptor (rat brain homogenates with 3H-DAMGO). pmid:1851921

Volpe et al. confirmed this positioning using recombinant human MOR, placing hydrocodone in the Ki = 1–100 nM range — alongside oxycodone, methadone, and fentanyl — rather than among the high-affinity opioids (hydromorphone, buprenorphine, sufentanil; Ki < 1 nM) or the low-affinity agents (codeine, tramadol; Ki > 100 nM).supported

Experiments were conducted to obtain Ki values for 19 approved opioid drugs using a single binding assay in a cell membrane preparation expressing recombinant human MOR. Hydrocodone falls in the Ki=1-100 nM range. j.yrtph.2010.12.007

Hydromorphone, produced via CYP2D6-mediated O-demethylation, has a MOR Ki of approximately 0.6 nM — 33-fold greater affinity than the parent compoundsupported

Hydrocodone Ki = 19.8 nM at mu receptor (rat brain homogenates with 3H-DAMGO). Hydromorphone Ki = 0.6 nM. pmid:1851921

The methoxy group at C-3 is the defining structural distinction between hydrocodone and hydromorphone: O-demethylation by CYP2D6 removes this methyl ether, yielding the free phenol of hydromorphone and dramatically increasing MOR affinity from 19.8 nM to approximately 0.6 nMsupported

Hydrocodone Ki = 19.8 nM at mu receptor... Hydromorphone Ki = 0.6 nM. Many opioids may exert their pharmacological actions predominantly through metabolites. pmid:1851921