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Hydrocodone

PubChem CID
5284569
Structure
Hydrocodone_small.png
Hydrocodone_3D_Structure.png
Molecular Formula
Synonyms
  • HYDROCODONE
  • Dihydrocodeinone
  • Hydrocodon
  • Hydrocone
  • Hydroconum
Molecular Weight
299.4 g/mol
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Dates
  • Create:
    2005-03-26
  • Modify:
    2025-01-11
Description
Hydrocodone is a morphinane-like compound that is a semi-synthetic opioid synthesized from codeine. It has a role as a mu-opioid receptor agonist, an opioid analgesic and an antitussive. It is an organic heteropentacyclic compound and a morphinane-like compound. It derives from a hydride of a morphinan.
Hydrocodone is a DEA Schedule II controlled substance. Substances in the DEA Schedule II have a high potential for abuse which may lead to severe psychological or physical dependence.
Hydrocodone is a synthetic opioid derivative of codeine. It is commonly used in combination with [acetaminophen] to control moderate to severe pain. Historically, hydrocodone has been used as a cough suppressant although this has largely been replaced by [dextromethorphan] in current cough and cold formulations. Hydrocodone's more potent metabolite, [hydromorphone] has also found wide use as an analgesic and is frequently used in cases of severe pain. The FDA first approved Hydrocodone for use as part of the cough suppressant syrup Hycodan in March of 1943.
See also: Hydrocodone Bitartrate (has salt form); Benzhydrocodone Hydrochloride (is active moiety of); Hydrocodone hydrochloride (is active moiety of).

1 Structures

1.1 2D Structure

Chemical Structure Depiction
Hydrocodone.png

1.2 3D Conformer

2 Names and Identifiers

2.1 Computed Descriptors

2.1.1 IUPAC Name

(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
Computed by Lexichem TK 2.7.0 (PubChem release 2021.10.14)

2.1.2 InChI

InChI=1S/C18H21NO3/c1-19-8-7-18-11-4-5-13(20)17(18)22-16-14(21-2)6-3-10(15(16)18)9-12(11)19/h3,6,11-12,17H,4-5,7-9H2,1-2H3/t11-,12+,17-,18-/m0/s1
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.3 InChIKey

LLPOLZWFYMWNKH-CMKMFDCUSA-N
Computed by InChI 1.0.6 (PubChem release 2021.10.14)

2.1.4 SMILES

CN1CC[C@]23[C@@H]4[C@H]1CC5=C2C(=C(C=C5)OC)O[C@H]3C(=O)CC4
Computed by OEChem 2.3.0 (PubChem release 2024.12.12)

2.2 Molecular Formula

C18H21NO3
Computed by PubChem 2.2 (PubChem release 2021.10.14)

2.3 Other Identifiers

2.3.1 CAS

2.3.3 Deprecated CAS

1037-91-8, 1469752-80-4, 50678-79-0, 9007-52-7
1469752-80-4, 50678-79-0, 9007-52-7

2.3.4 European Community (EC) Number

2.3.5 UNII

2.3.6 ChEBI ID

2.3.7 ChEMBL ID

2.3.8 DEA Code Number

9193 (DEA schedule II controlled substance)

2.3.9 DrugBank ID

2.3.10 DSSTox Substance ID

2.3.11 HMDB ID

2.3.12 KEGG ID

2.3.13 Metabolomics Workbench ID

2.3.14 NCI Thesaurus Code

2.3.15 Nikkaji Number

2.3.16 NSC Number

2.3.17 PharmGKB ID

2.3.18 Pharos Ligand ID

2.3.19 RXCUI

2.3.20 Wikidata

2.3.21 Wikipedia

2.4 Synonyms

2.4.1 MeSH Entry Terms

  • Codinovo
  • Dicodid
  • Dihydrocodeinone
  • Hycodan
  • Hycon
  • Hydrocodeinonebitartrate
  • Hydrocodon
  • Hydrocodone
  • Hydrocodone Bitartrate
  • Hydrocodone Tartrate (1:1), Hydrate (2:5)
  • Hydrocon
  • Robidone

2.4.2 Depositor-Supplied Synonyms

3 Chemical and Physical Properties

3.1 Computed Properties

Property Name
Molecular Weight
Property Value
299.4 g/mol
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
XLogP3-AA
Property Value
2.2
Reference
Computed by XLogP3 3.0 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Donor Count
Property Value
0
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Hydrogen Bond Acceptor Count
Property Value
4
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Rotatable Bond Count
Property Value
1
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Exact Mass
Property Value
299.15214353 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Monoisotopic Mass
Property Value
299.15214353 Da
Reference
Computed by PubChem 2.2 (PubChem release 2021.10.14)
Property Name
Topological Polar Surface Area
Property Value
38.8 Ų
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Heavy Atom Count
Property Value
22
Reference
Computed by PubChem
Property Name
Formal Charge
Property Value
0
Reference
Computed by PubChem
Property Name
Complexity
Property Value
509
Reference
Computed by Cactvs 3.4.8.18 (PubChem release 2021.10.14)
Property Name
Isotope Atom Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Atom Stereocenter Count
Property Value
4
Reference
Computed by PubChem
Property Name
Undefined Atom Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Defined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Undefined Bond Stereocenter Count
Property Value
0
Reference
Computed by PubChem
Property Name
Covalently-Bonded Unit Count
Property Value
1
Reference
Computed by PubChem
Property Name
Compound Is Canonicalized
Property Value
Yes
Reference
Computed by PubChem (release 2021.10.14)

3.2 Experimental Properties

3.2.1 Physical Description

Solid

3.2.2 Color / Form

Prisms from alcohol
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 886

3.2.3 Melting Point

198 °C
PhysProp
198 °C
Haynes, W.M. (ed.). CRC Handbook of Chemistry and Physics. 95th Edition. CRC Press LLC, Boca Raton: FL 2014-2015, p. 3-302
MP: 219-220 °C /Hydrocodone hydriodide/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 827
MP: 250-225 °C /Hydrocodone methiodide/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 827

3.2.4 Flash Point

9.7 °C (49.5 °F) - closed cup
Sigma-Aldrich; Material Safety Data Sheet for Hydrocodone solution, Product Number: H-003, Version 5.4 (Revision Date 05/07/2015). Available from, as of August 3, 2015: https://www.sigmaaldrich.com/safety-center.html

3.2.5 Solubility

O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 886
Soluble in ethanol
Haynes, W.M. (ed.). CRC Handbook of Chemistry and Physics. 95th Edition. CRC Press LLC, Boca Raton: FL 2014-2015, p. 3-302
7.97e-01 g/L

3.2.6 LogP

1.2

3.2.7 Stability / Shelf Life

Stable under recommended storage conditions.
Sigma-Aldrich; Material Safety Data Sheet for Hydrocodone solution, Product Number: H-003, Version 5.4 (Revision Date 05/07/2015). Available from, as of August 3, 2015: https://www.sigmaaldrich.com/safety-center.html

3.2.8 Optical Rotation

Specific optical rotation = -203 deg at 25 °C/D ( c = 0.41 in CHCL3)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 886

3.2.9 Decomposition

When heated to decomposition it emits toxic fumes of /nitrogen oxide/.
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2799

3.2.10 Dissociation Constants

pKa = 8.23
Volpi A, Toffoli F; Bull Chim Farm 118: 594-609 (1979)

3.2.11 Collision Cross Section

167.4 Ų [M+H]+ [CCS Type: TW; Method: Major Mix IMS/Tof Calibration Kit (Waters)]

172.49 Ų [M+Na]+

168.06 Ų [M+H]+

S61 | UJICCSLIB | Collision Cross Section (CCS) Library from UJI | DOI:10.5281/zenodo.3549476

3.2.12 Other Experimental Properties

Crystals; melting point 185-186 °C, decomposes; specific optical rotation: -130 deg at 27 °C/D (ce = 2.877 g ub 100 mL water); very sol in water /Hydrocodone hydrochloride/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 886
Fine white crystals or crystalline powder; mp 118-128 °C; one g dissolves in 16 mL water, in 150 g 95% ethanol; insoluble in ether, chloroform; pH: about 3.6 (2% aqueous solution) /Hydrocodone bitartrate hemipentahydrate/
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 886

3.3 Chemical Classes

Pharmaceutical

3.3.1 Drugs

Pharmaceuticals -> Listed in ZINC15
S55 | ZINC15PHARMA | Pharmaceuticals from ZINC15 | DOI:10.5281/zenodo.3247749
Pharmaceuticals -> Synthetic Cannabinoids or Psychoactive Compounds
S58 | PSYCHOCANNAB | Synthetic Cannabinoids and Psychoactive Compounds | DOI:10.5281/zenodo.3247723
3.3.1.1 Human Drugs
Breast Feeding; Lactation; Milk, Human; Analgesics, Opioid; Narcotics; Antitussive Agents
Human drug -> Prescription
Human drug -> Active ingredient (HYDROCODONE POLISTIREX)
Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

3.3.2 Endocrine Disruptors

Potential endocrine disrupting compound
S109 | PARCEDC | List of 7074 potential endocrine disrupting compounds (EDCs) by PARC T4.2 | DOI:10.5281/zenodo.10944198

4 Spectral Information

4.1 1D NMR Spectra

4.1.1 13C NMR Spectra

1 of 2
Instrument Name
Jeol PS-100
Copyright
Copyright © 2002-2024 Wiley-VCH Verlag GmbH & Co. KGaA. All Rights Reserved.
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2 of 2
Instrument Name
Varian NV-14
Copyright
Copyright © 2002-2024 Wiley-VCH Verlag GmbH & Co. KGaA. All Rights Reserved.
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4.2 Mass Spectrometry

4.2.1 GC-MS

1 of 2
Source of Spectrum
Mass Spectrometry Committee of the Toxicology Section of the American Academy of Forensic Sciences
Copyright
Copyright © 2012-2024 John Wiley & Sons, Inc. Portions provided by AAFS, Toxicology Section. All Rights Reserved.
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2 of 2
Source of Spectrum
Mass Spectrometry Committee of the Toxicology Section of the American Academy of Forensic Sciences
Copyright
Copyright © 2012-2024 John Wiley & Sons, Inc. Portions provided by AAFS, Toxicology Section. All Rights Reserved.
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4.2.2 MS-MS

1 of 6
View All
Spectra ID
Ionization Mode
Positive
Top 5 Peaks

300.16357 100

199.08586 34.67

213.09396 10.32

241.0919 9.26

183.08472 7.82

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2 of 6
View All
Spectra ID
Ionization Mode
Positive
Top 5 Peaks

171.0803 100

128.062 83.11

141.0698 71.88

153.0698 67.06

199.0752 62.58

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4.2.3 LC-MS

1 of 9
View All
Authors
Otto J, Stravs M, Schymanski E, Singer H, Department of Environmental Chemistry, Eawag
Instrument
Q Exactive Orbitrap Thermo Scientific
Instrument Type
LC-ESI-QFT
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
15 (nominal)
Fragmentation Mode
HCD
Column Name
XBridge C18 3.5um, 2.1x50mm, Waters
Retention Time
3.2 min
Precursor m/z
300.1594
Precursor Adduct
[M+H]+
Top 5 Peaks

300.1592 999

199.0747 2

285.1349 1

Thumbnail
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License
CC BY
2 of 9
View All
Authors
Otto J, Stravs M, Schymanski E, Singer H, Department of Environmental Chemistry, Eawag
Instrument
Q Exactive Orbitrap Thermo Scientific
Instrument Type
LC-ESI-QFT
MS Level
MS2
Ionization Mode
POSITIVE
Ionization
ESI
Collision Energy
30 (nominal)
Fragmentation Mode
HCD
Column Name
XBridge C18 3.5um, 2.1x50mm, Waters
Retention Time
3.2 min
Precursor m/z
300.1594
Precursor Adduct
[M+H]+
Top 5 Peaks

300.1593 999

199.0752 29

243.1015 15

241.0858 9

257.1174 5

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License
CC BY

4.2.4 Other MS

Other MS
MASS: 60616 (NIST/EPA/MSDC Mass Spectral database, 1990 version)

4.3 UV Spectra

Maximum uv absorption: 280 nm (e = 1310)
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 886
UV: 151 (Absorption Spectra in the UV and Visible Region, Academic Press, New York)
Lide, D.R., G.W.A. Milne (eds.). Handbook of Data on Organic Compounds. Volume I. 3rd ed. CRC Press, Inc. Boca Raton ,FL. 1994., p. V4: 3441

4.4 IR Spectra

4.4.1 ATR-IR Spectra

Instrument Name
Bio-Rad FTS
Technique
ATR-Film (MeCl2) (DuraSamplIR II)
Source of Spectrum
Forensic Spectral Research
Source of Sample
Alltech Associates, Inc., Grace Davison Discovery Sciences
Catalog Number
Free base of 01806
Lot Number
Free base of 4091
Copyright
Copyright © 2009-2024 John Wiley & Sons, Inc. All Rights Reserved.
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4.5 Other Spectra

Intense mass spectral peaks: 59 m/z, 96 m/z, 185 m/z, 242 m/z, 299 m/z
Pfleger, K., H. Maurer and A. Weber. Mass Spectral and GC Data of Drugs, Poisons and their Metabolites. Parts I and II. Mass Spectra Indexes. Weinheim, Federal Republic of Germany. 1985., p. 523

6 Chemical Vendors

7 Drug and Medication Information

7.1 Drug Indication

Hydrocodone is indicated for the management of acute pain, sometimes in combination with [acetaminophen] or [ibuprofen], as well as the symptomatic treatment of the common cold and allergic rhinitis in combination with decongestants, antihistamines, and expectorants.

7.2 LiverTox Summary

Hydrocodone is a semisynthetic, moderately potent, orally available opioid that, in combination with acetaminophen, is widely used for treatment of acute or chronic pain, and in combination with antihistamines or anticholinergics used to treat cough. Hydrocodone by itself has not been linked to serum enzyme elevations during therapy or to clinically apparent liver injury, but the combination with acetaminophen has been linked to many cases of acute liver failure due to unintentional overdose with acetaminophen.

7.3 Drug Classes

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

7.4 FDA Approved Drugs

7.5 FDA Orange Book

7.6 Drug Labels

Active ingredient and drug

7.7 Clinical Trials

7.7.1 ClinicalTrials.gov

7.8 DEA Drug and Chemical Information

Hydrocodone

(Trade Names:Vicodin®, Lortab®, Lorcet-HD®, Hycodan®, Vicoprofen®)

7.8.1 DEA Controlled Substances

Substance
Hydrocodone
DEA Controlled Substances Code Number
9193
Controlled Substances Act Schedule
Schedule II - Substances in the DEA Schedule II have a high potential for abuse which may lead to severe psychological or physical dependence.

7.9 Therapeutic Uses

Analgesics, Opioid; Antitussive Agents; Narcotics
National Library of Medicine's Medical Subject Headings. Hydrocodone. Online file (MeSH, 2014). Available from, as of December 18, 2014: https://www.nlm.nih.gov/mesh/2014/mesh_browser/MBrowser.html
HYSINGLA ER is indicated for the management of pain severe enough to require daily, around-the-clock, long-term opioid treatment and for which alternative treatment options are inadequate. Because of the risks of addiction, abuse, and misuse with opioids, even at recommended doses, and because of the greater risks of overdose and death with extended-release opioid formulations, reserve HYSINGLA ER for use in patients for whom alternative treatment options (e.g., non-opioid analgesics or immediate-release opioids) are ineffective, not tolerated, or would be otherwise inadequate to provide sufficient management of pain. HYSINGLA ER is not indicated as an as-needed analgesic.
NIH; DailyMed. Current Medication Information for HYSINGLA ER- hydrocodone bitartrate tablet, extended release (Updated: February 2015). Available from, as of September 4, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b7d23ac2-e776-9f62-3290-c64c2d6eb353
Extended-release capsules of hydrocodone bitartrate are used for the relief of pain that is severe enough to require long-term, daily, around-the-clock use of an opiate analgesic. Because of the risks of addiction, abuse, and misuse associated with opiates, even at recommended dosages, and because of the greater risks of overdose and death associated with extended-release opiate formulations, extended-release hydrocodone bitartrate should be reserved for use in patients for whom alternative treatment options (e.g., nonopiate analgesics or immediate-release opiates) are inadequate or not tolerated. Extended-release hydrocodone bitartrate is not indicated for use on an as-needed ("prn") basis.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2124
Hydrocodone bitartrate and hydrocodone polistirex are used in combination with other antitussives or expectorants for the symptomatic relief of nonproductive cough. Since the cough reflex may be a useful physiologic mechanism that clears the respiratory passages of foreign material and excess secretions and may aid in preventing or reversing atelectasis, cough suppressants should not be used indiscriminately.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2769
VET: Hydrocodone is recommended in treatment of the harsh, dry, and nonproductive cough associated and bronchitis and bronchiectasis in the dog. It is also indicated for alleviation of coughing associated with chronic pulmonary emphysema and in some stages of mitral valvular insufficiency in the older dog.
The Royal Society of Chemistry. Foreign Compound Metabolism in Mammals. Volume 6: A Review of the Literature Published during 1978 and 1979. London: The Royal Society of Chemistry, 1981., p. 677

7.10 Drug Warnings

/BOXED WARNING/ Cytochrome P450 3A4 Interaction: The concomitant use of HYSINGLA ER with all cytochrome P450 3A4 inhibitors may result in an increase in hydrocodone plasma concentrations, which could increase or prolong adverse drug effects and may cause potentially fatal respiratory depression. In addition, discontinuation of a concomitantly used cytochrome P450 3A4 inducer may result in an increase in hydrocodone plasma concentration. Monitor patients receiving HYSINGLA ER and any CYP3A4 inhibitor or inducer.
NIH; DailyMed. Current Medication Information for HYSINGLA ER- hydrocodone bitartrate tablet, extended release (Updated: February 2015). Available from, as of September 4, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b7d23ac2-e776-9f62-3290-c64c2d6eb353
/BOXED WARNING/ Neonatal Opioid Withdrawal Syndrome: Prolonged use of HYSINGLA ER during pregnancy can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized and treated, and requires management according to protocols developed by neonatology experts. If opioid use is required for a prolonged period in a pregnant woman, advise the patient of the risk of neonatal opioid withdrawal syndrome and ensure that appropriate treatment will be available
NIH; DailyMed. Current Medication Information for HYSINGLA ER- hydrocodone bitartrate tablet, extended release (Updated: February 2015). Available from, as of September 4, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b7d23ac2-e776-9f62-3290-c64c2d6eb353
/BOXED WARNING/ Accidental Ingestion Accidental ingestion of even one dose of HYSINGLA ER, especially by children, can result in a fatal overdose of hydrocodone.
NIH; DailyMed. Current Medication Information for HYSINGLA ER- hydrocodone bitartrate tablet, extended release (Updated: February 2015). Available from, as of September 4, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b7d23ac2-e776-9f62-3290-c64c2d6eb353
/BOXED WARNING/ Life-Threatening Respiratory Depression: Serious, life-threatening, or fatal respiratory depression may occur with use of HYSINGLA ER. Monitor for respiratory depression, especially during initiation of HYSINGLA ER or following a dose increase. Instruct patients to swallow HYSINGLA ER tablets whole; crushing, chewing, or dissolving HYSINGLA ER tablets can cause rapid release and absorption of a potentially fatal dose of hydrocodone.
NIH; DailyMed. Current Medication Information for HYSINGLA ER- hydrocodone bitartrate tablet, extended release (Updated: February 2015). Available from, as of September 4, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b7d23ac2-e776-9f62-3290-c64c2d6eb353
For more Drug Warnings (Complete) data for HYDROCODONE (32 total), please visit the HSDB record page.

7.11 Reported Fatal Dose

... 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....
Spiller HA; J Forensic Sci 48 (2): 429-31 (2003)

7.12 Drug Tolerance

Hydrocodone preparations should be given in the smallest effective dose and as infrequently as possible to minimize the development of tolerance and physical dependence. Reduced dosage is indicated in debilitated or poor-risk patients, in very young or very old patients, adn in patients receiving other CNS depressants.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2769

8 Pharmacology and Biochemistry

8.1 Pharmacodynamics

Hydrocodone inhibits pain signaling in both the spinal cord and brain. Its actions in the brain also produce euphoria, respiratory depression, and sedation.

8.2 MeSH Pharmacological Classification

Antitussive Agents
Agents that suppress cough. They act centrally on the medullary cough center. EXPECTORANTS, also used in the treatment of cough, act locally. (See all compounds classified as Antitussive Agents.)
Analgesics, Opioid
Compounds with activity like OPIATE ALKALOIDS, acting at OPIOID RECEPTORS. Properties include induction of ANALGESIA or NARCOSIS. (See all compounds classified as Analgesics, Opioid.)
Narcotics
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. (See all compounds classified as Narcotics.)

8.3 FDA Pharmacological Classification

FDA UNII
6YKS4Y3WQ7
Active Moiety
HYDROCODONE
Pharmacological Classes
Established Pharmacologic Class [EPC] - Opioid Agonist
Pharmacological Classes
Mechanisms of Action [MoA] - Opioid Agonists
FDA Pharmacology Summary
Hydrocodone is an Opioid Agonist. The mechanism of action of hydrocodone is as an Opioid Agonist.

8.4 ATC Code

R - Respiratory system

R05 - Cough and cold preparations

R05D - Cough suppressants, excl. combinations with expectorants

R05DA - Opium alkaloids and derivatives

R05DA03 - Hydrocodone

8.5 Absorption, Distribution and Excretion

Absorption
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.
Route of Elimination
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.
Volume of Distribution
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.
Clearance
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.
NIH; DailyMed. Current Medication Information for HYSINGLA ER- hydrocodone bitartrate tablet, extended release (Updated: February 2015). Available from, as of September 4, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b7d23ac2-e776-9f62-3290-c64c2d6eb353
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.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2770
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.
Anderson PO et al; Breastfeed Med 2 (1): 10-4 (2007)
... As part of an ongoing study, the hair of admitted opiate users was analyzed for hydrocodone and hydromorphone, as well as codeine, morphine, and 6-acetylmorphine in order to determine if there was any correlation between self-reported frequency of opiate intake and the concentration of drug detected in hair. The hairs were confirmed using gas chromatography-mass spectrometry following screening by enzyme linked immunosorbent assay (ELISA). Twenty-four hair specimens collected from volunteers showed the presence of hydrocodone (130-15,933 pg/mg); four of those also contained hydromorphone (59-504 pg/mg). The specimens were also analyzed for morphine, codeine, and 6-acetylmorphine. Hair specimens from five self-reported codeine users showed concentrations of hydrocodone between 592 and 15,933 pg/mg. In addition, codeine was present at concentrations of 575-20,543 pg/mg, but neither morphine nor hydromorphone were present in any of those hair specimens. ...
Moore C et al; J Anal Toxicol 30 (6): 353-9 (2006)

8.6 Metabolism / Metabolites

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.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2770
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.
Physicians Desk Reference 65th ed. PDR Network, LLC, Montvale, NJ. 2011, p. 575
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.
SWEETMAN, S.C. (ed.) Martindale-The Complete Drug Reference. 36th ed. London: The Pharmaceutical Press, 2009., p. 1005
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. ...
Armstrong SC, Cozza KL; Psychosomatics 44 (6): 515-20 (2003)
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.
Park JI et al; J Forensic Sci 27 (1): 223-4 (1982)
Hydrocodone has known human metabolites that include Hydromorphone and Norhydromorphone.
S73 | METXBIODB | Metabolite Reaction Database from BioTransformer | DOI:10.5281/zenodo.4056560
Hepatic and also in intestinal mucosa. Half Life: 1.25-3 hours

8.7 Biological Half-Life

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.
NIH; DailyMed. Current Medication Information for HYSINGLA ER- hydrocodone bitartrate tablet, extended release (Updated: February 2015). Available from, as of September 4, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b7d23ac2-e776-9f62-3290-c64c2d6eb353
Half-life was determined to be 3.8 +/- 0.3 hrs.
Physicians Desk Reference 65th ed. PDR Network, LLC, Montvale, NJ. 2011, p. 575
The elimination half-life of hydrocodone is reportedly about 3.8 hours in healthy adults.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2770

8.8 Mechanism of Action

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.
NIH; DailyMed. Current Medication Information for HYSINGLA ER- hydrocodone bitartrate tablet, extended release (Updated: February 2015). Available from, as of September 4, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b7d23ac2-e776-9f62-3290-c64c2d6eb353

8.9 Human Metabolite Information

8.9.1 Cellular Locations

Membrane

8.9.2 Metabolite Pathways

8.10 Transformations

9 Use and Manufacturing

9.1 Uses

EPA CPDat Chemical and Product Categories
The Chemical and Products Database, a resource for exposure-relevant data on chemicals in consumer products, Scientific Data, volume 5, Article number: 180125 (2018), DOI:10.1038/sdata.2018.125
This is a /DEA:/ Schedule II controlled substance.
21 CFR 1308.12(b) (USDEA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of March 20, 2008: https://www.ecfr.gov
... semisynthetic opioid antitussive and analgesic
Thomson Health Care Inc.; Physicians' Desk Reference 62 ed., Montvale, NJ 2008, p. 1112
MEDICATION (VET)
MEDICATION
Analgesics, Opioid; Antitussive Agents; Narcotics
National Library of Medicine's Medical Subject Headings. Hydrocodone. Online file (MeSH, 2014). Available from, as of December 18, 2014: https://www.nlm.nih.gov/mesh/2014/mesh_browser/MBrowser.html

Use (kg) in USA (2002): 28600

Consumption (g per capita) in the USA (2002): 0.101

Calculated removal (%): 9.7

For relief of moderate to moderately severe pain. Also used for the symptomatic relief of nonproductive cough, alone or in combination with other antitussives or expectorants.

9.1.1 Use Classification

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients
Pharmaceuticals
S72 | NTUPHTW | Pharmaceutically Active Substances from National Taiwan University | DOI:10.5281/zenodo.3955664

9.2 Methods of Manufacturing

... Synthetic alkaloid, 7,8-dihydrocodeinone, is prepared ... By catalytic rearrangement of codeine or by controlled hydrolysis & oxidation of dihydrothebaine. /Hydrocodone bitartrate, NF/
Osol, A. and J.E. Hoover, et al. (eds.). Remington's Pharmaceutical Sciences. 15th ed. Easton, Pennsylvania: Mack Publishing Co., 1975., p. 1040
For the synthesis of hydrocodone, codeine is catalytically rearranged by heating with palladium or platinum in alcoholic or aqueous acidic solution.
Ullmann's Encyclopedia of Industrial Chemistry. 6th ed.Vol 1: Federal Republic of Germany: Wiley-VCH Verlag GmbH & Co. 2003 to Present, p. V9 619 (2003)
Industrial preparation from dihydrocodeine: K. Pfister, M. Tishler, United States of America patent 2715626 (1955 to Merck & Co.).
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Whitehouse Station, NJ: Merck and Co., Inc., 2006., p. 827

9.3 Impurities

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/
Council of Europe, European Directorate for the Quality of Medicines. European Pharmacopoeia, 5th Ed., Supplement 5.7; Strasbourg, France, p.5023 (2006)

9.4 Formulations / Preparations

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).
NIH; DailyMed. Current Medication Information for HYSINGLA ER- hydrocodone bitartrate tablet, extended release (Updated: February 2015). Available from, as of September 4, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b7d23ac2-e776-9f62-3290-c64c2d6eb353
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).
NIH; DailyMed. Current Medication Information for HYSINGLA ER- hydrocodone bitartrate tablet, extended release (Updated: February 2015). Available from, as of September 4, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b7d23ac2-e776-9f62-3290-c64c2d6eb353
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).
NIH; DailyMed. Current Medication Information for HYSINGLA ER- hydrocodone bitartrate tablet, extended release (Updated: February 2015). Available from, as of September 4, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b7d23ac2-e776-9f62-3290-c64c2d6eb353
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).
NIH; DailyMed. Current Medication Information for HYSINGLA ER- hydrocodone bitartrate tablet, extended release (Updated: February 2015). Available from, as of September 4, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b7d23ac2-e776-9f62-3290-c64c2d6eb353
For more Formulations/Preparations (Complete) data for HYDROCODONE (51 total), please visit the HSDB record page.

9.5 General Manufacturing Information

Hydrocodone induces side effects similar to codeine and morphine and has an appreciable abuse and dependence potential.
Friderichs E et al; Ullmann's Encyclopedia of Industrial Chemistry 7th ed. (2008). NY, NY: John Wiley & Sons; Analgesics and Antipyretics. Online Posting Date: July 15, 2007
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.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2135
Hydrocodone bitartrate and hydrocodone polistirex are currently commercially available only in combination products.
McEvoy, G.K. (ed.). American Hospital Formulary Service. AHFS Drug Information. American Society of Health-System Pharmacists, Bethesda, MD. 2007., p. 2751

10 Identification

10.1 Analytic Laboratory Methods

GENERAL SAMPLE, SPECTROPHOTOMETRY @ 280 NM; GENERAL SAMPLE, GAS CHROMATOGRAPHY.
Sunshine, I. (ed.). CRC Handbook of Analytical Toxicology. Cleveland: The Chemical Rubber Co., 1969., p. 56
Analyte: hydrocodone bitartrate; matrix: chemical identification; procedure: infrared absorption spectrophotometry with comparison to standards /hydrocodone bitartrate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 30/The National Formulary, NF 25; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p.2289 (2007)
Analyte: hydrocodone bitartrate; matrix: chemical identification; procedure: ultraviolet absorption spectrophotometry with comparison to standards /hydrocodone bitartrate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 30/The National Formulary, NF 25; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p.2289 (2007)
Analyte: hydrocodone bitartrate; matrix: chemical purity; procedure: liquid chromatography with detection at 280 nm and comparison to standards /hydrocodone bitartrate/
U.S. Pharmacopeia. The United States Pharmacopeia, USP 30/The National Formulary, NF 25; Rockville, MD: U.S. Pharmacopeial Convention, Inc., p.2289 (2007)
For more Analytic Laboratory Methods (Complete) data for HYDROCODONE (13 total), please visit the HSDB record page.

10.2 Clinical Laboratory Methods

LC/MS/MS determination in plasma.
O'Neil, M.J. (ed.). The Merck Index - An Encyclopedia of Chemicals, Drugs, and Biologicals. Cambridge, UK: Royal Society of Chemistry, 2013., p. 886
Determination of hydrocodone and metabolites in urine using selected ion recording with methane chemical ionization.
Cone EJ, Darwin WD; Biomed Mass Spectrom 5 (4): 291-5 (1978)
Analyte: hydrocodone; matrix: blood, bile; procedure: high-performance liquid chromatography with ultraviolet detection at 210 nm combined with fluorescence detection at 220 nm (excitation) and 370 nm (emission)
Crump KL et al; J Anal Toxicol 18: 208-212 (1994). As cited in: Lunn G; HPLC and CE Methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)
Analyte: hydrocodone; matrix: urine; procedure: high-performance liquid chromatography with ultraviolet detection at 210 nm and 235 nm; limit of detection: 300 ng/mL
Binder SR et al; J Chromatogr 473: 325-341 (1989). As cited in: Lunn G; HPLC and CE Methods for Pharmaceutical Analysis. CD-ROM. New York, NY: John Wiley & Sons (2000)
For more Clinical Laboratory Methods (Complete) data for HYDROCODONE (6 total), please visit the HSDB record page.

11 Safety and Hazards

11.1 Hazards Identification

11.1.1 GHS Classification

1 of 2
View All
Pictogram(s)
Irritant
Health Hazard
Environmental Hazard
Signal
Danger
GHS Hazard Statements

H302 (97.6%): Harmful if swallowed [Warning Acute toxicity, oral]

H317 (100%): May cause an allergic skin reaction [Warning Sensitization, Skin]

H334 (100%): May cause allergy or asthma symptoms or breathing difficulties if inhaled [Danger Sensitization, respiratory]

H400 (97.6%): Very toxic to aquatic life [Warning Hazardous to the aquatic environment, acute hazard]

Precautionary Statement Codes

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

(The corresponding statement to each P-code can be found at the GHS Classification page.)

ECHA C&L Notifications Summary

Aggregated GHS information provided per 42 reports by companies from 2 notifications to the ECHA C&L Inventory. Each notification may be associated with multiple companies.

Information may vary between notifications depending on impurities, additives, and other factors. The percentage value in parenthesis indicates the notified classification ratio from companies that provide hazard codes. Only hazard codes with percentage values above 10% are shown.

11.1.2 Hazard Classes and Categories

Acute Tox. 4 (97.6%)

Skin Sens. 1 (100%)

Resp. Sens. 1 (100%)

Aquatic Acute 1 (97.6%)

11.2 Fire Fighting

11.2.1 Fire Fighting Procedures

Advice for firefighters: Wear self-contained breathing apparatus for firefighting if necessary. Use water spray to cool unopened containers.
Sigma-Aldrich; Material Safety Data Sheet for Hydrocodone solution, Product Number: H-003, Version 5.4 (Revision Date 05/07/2015). Available from, as of August 3, 2015: https://www.sigmaaldrich.com/safety-center.html
Suitable extinguishing media: Use water spray, alcohol-resistant foam, dry chemical or carbon dioxide.
Sigma-Aldrich; Material Safety Data Sheet for Hydrocodone solution, Product Number: H-003, Version 5.4 (Revision Date 05/07/2015). Available from, as of August 3, 2015: https://www.sigmaaldrich.com/safety-center.html

11.3 Accidental Release Measures

11.3.1 Cleanup Methods

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.
Sigma-Aldrich; Material Safety Data Sheet for Hydrocodone solution, Product Number: H-003, Version 5.4 (Revision Date 05/07/2015). Available from, as of August 3, 2015: https://www.sigmaaldrich.com/safety-center.html

11.3.2 Disposal Methods

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.

11.3.3 Preventive Measures

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.
Sigma-Aldrich; Material Safety Data Sheet for Hydrocodone solution, Product Number: H-003, Version 5.4 (Revision Date 05/07/2015). Available from, as of August 3, 2015: https://www.sigmaaldrich.com/safety-center.html
Appropriate engineering controls: Avoid contact with skin, eyes and clothing. Wash hands before breaks and immediately after handling the product.
Sigma-Aldrich; Material Safety Data Sheet for Hydrocodone solution, Product Number: H-003, Version 5.4 (Revision Date 05/07/2015). Available from, as of August 3, 2015: https://www.sigmaaldrich.com/safety-center.html
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.
Sigma-Aldrich; Material Safety Data Sheet for Hydrocodone solution, Product Number: H-003, Version 5.4 (Revision Date 05/07/2015). Available from, as of August 3, 2015: https://www.sigmaaldrich.com/safety-center.html

11.4 Handling and Storage

11.4.1 Storage Conditions

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.
NIH; DailyMed. Current Medication Information for HYSINGLA ER- hydrocodone bitartrate tablet, extended release (Updated: February 2015). Available from, as of September 4, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b7d23ac2-e776-9f62-3290-c64c2d6eb353
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
Sigma-Aldrich; Material Safety Data Sheet for Hydrocodone solution, Product Number: H-003, Version 5.4 (Revision Date 05/07/2015). Available from, as of August 3, 2015: https://www.sigmaaldrich.com/safety-center.html
Hydrocodone bitartrate is affected by light. Hydrocodone bitartrate preparations should be stored in tight, light-resistant containers at 15-30 °C.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2770

11.5 Exposure Control and Personal Protection

11.5.1 Personal Protective Equipment (PPE)

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).
Sigma-Aldrich; Material Safety Data Sheet for Hydrocodone solution, Product Number: H-003, Version 5.4 (Revision Date 05/07/2015). Available from, as of August 3, 2015: https://www.sigmaaldrich.com/safety-center.html
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.
Sigma-Aldrich; Material Safety Data Sheet for Hydrocodone solution, Product Number: H-003, Version 5.4 (Revision Date 05/07/2015). Available from, as of August 3, 2015: https://www.sigmaaldrich.com/safety-center.html
Skin protection: Handle with gloves.
Sigma-Aldrich; Material Safety Data Sheet for Hydrocodone solution, Product Number: H-003, Version 5.4 (Revision Date 05/07/2015). Available from, as of August 3, 2015: https://www.sigmaaldrich.com/safety-center.html
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).
Sigma-Aldrich; Material Safety Data Sheet for Hydrocodone solution, Product Number: H-003, Version 5.4 (Revision Date 05/07/2015). Available from, as of August 3, 2015: https://www.sigmaaldrich.com/safety-center.html

11.6 Stability and Reactivity

11.6.1 Hazardous Reactivities and Incompatibilities

Incompatible materials: Acids, Oxidizing agents, Alkali metals, Strong oxidizing agents, Strong acids, Acid chlorides, Acid anhydrides, Reducing agents, Strong reducing agents, Phosphorus halides
Sigma-Aldrich; Material Safety Data Sheet for Hydrocodone solution, Product Number: H-003, Version 5.4 (Revision Date 05/07/2015). Available from, as of August 3, 2015: https://www.sigmaaldrich.com/safety-center.html

11.7 Regulatory Information

DEA Controlled Substances
DEA schedule II controlled substance

11.7.1 FDA Requirements

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.
21 CFR 1308.12(a) (b) (1) (USFDA); U.S. National Archives and Records Administration's Electronic Code of Federal Regulations. Available from, as of March 4, 2015: https://www.ecfr.gov
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/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of March 6, 2015: https://www.fda.gov/cder/ob/
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/
DHHS/FDA; Electronic Orange Book-Approved Drug Products with Therapeutic Equivalence Evaluations. Available from, as of March 6, 2015: https://www.fda.gov/cder/ob/

12 Toxicity

12.1 Toxicological Information

12.1.1 Toxicity Summary

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.
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.

12.1.2 USGS Health-Based Screening Levels for Evaluating Water-Quality

Chemical
Hydrocodone
Chemical Classes
Pharmaceutical
Reference
Smith, C.D. and Nowell, L.H., 2024. Health-Based Screening Levels for evaluating water-quality data (3rd ed.). DOI:10.5066/F71C1TWP

12.1.3 Hepatotoxicity

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.

Hydrocodone, like other opiates, is metabolized in the liver by the P450 microsomal oxidizing enzyme system, and levels can be significantly affected by either inhibitors of CYP 3A4 (which increase levels and can lead to toxicity) or inducers of the enzyme (which decrease levels and can affect efficacy).

Likelihood score: E (unlikely cause of clinically apparent liver injury).

References on the safety and potential hepatotoxicity of hydrocodone are given in the Overview section of the Opioids.

Drug Class: Opioids

12.1.4 Carcinogen Classification

Carcinogen Classification
No indication of carcinogenicity to humans (not listed by IARC).

12.1.5 Health Effects

Medical problems can include congested lungs, liver disease, tetanus, infection of the heart valves, skin abscesses, anemia and pneumonia. Death can occur from overdose.

12.1.6 Effects During Pregnancy and Lactation

◉ Summary of Use during Lactation

Hydrocodone is an opioid narcotic. Benzhydrocodone is a hydrocodone prodrug that is rapidly converted into hydrocodone in the gastrointestinal tract. Maternal use of oral opioids during breastfeeding can cause infant drowsiness, which may progress to rare but severe central nervous system depression. Newborn infants seem to be particularly sensitive to the effects of even small dosages of narcotic analgesics. If hydrocodone is required by the mother of a newborn, it is not a reason to discontinue breastfeeding; however, once the mother's milk comes in, it is best to provide pain control with a nonnarcotic analgesic and limit maternal intake of oral hydrocodone to 2 to 3 days at a maximum dosage of 30 mg daily with close infant monitoring. If the baby shows signs of increased sleepiness (more than usual), difficulty breastfeeding, breathing difficulties, or limpness, a physician should be contacted immediately.

◉ Effects in Breastfed Infants

The 18-day-old infant of a breastfeeding mother became groggy and "slept for most of the day" while the mother was taking 20 mg of oral hydrocodone combined with 1300 mg of acetaminophen every 4 hours for painful nipple candidiasis and mastitis. The mother decreased her dose by one-half and the infant apparently no longer experienced grogginess or hypersomnolence.[3] The infant's symptoms were probably due to the maternal hydrocodone.

A 5-week-old breastfed infant became cyanotic and required mouth-to-mouth resuscitation and intubation. The infant's urine was positive for opioids and the infant responded positively to naloxone; the level of consciousness improved over 2 days and extubation was accomplished. The infant's mother admitted to taking a hydrocodone-acetaminophen combination product and methadone that had been prescribed for migraine headache before she was breastfeeding.[4] The infant's symptoms were probably due to the maternal opiate use.

◉ Effects on Lactation and Breastmilk

Narcotics can increase serum prolactin.[5] However, the prolactin level in a mother with established lactation may not affect her ability to breastfeed.

◈ What is hydrocodone?

Hydrocodone is an opioid medication that has been used to treat pain. Opioids are sometimes called narcotics. Some commonly used hydrocodone products also contain other medications, such as acetaminophen. Brand names for these combination products include Lortab®, Norco®, and Vicodin®. For more information on acetaminophen, please see our fact sheet: https://mothertobaby.org/fact-sheets/acetaminophen-pregnancy/.Sometimes when people find out they are pregnant, they think about changing how they take their medication, or stopping their medication altogether. However, it is important to talk with your healthcare providers before making any changes to how you take your medication. Your healthcare providers can talk with you about the benefits of treating your condition and the risks of untreated illness during pregnancy.If you have been taking hydrocodone regularly or have a dependency or opioid use disorder, you should not stop taking the medication suddenly. Stopping an opioid medication suddenly could cause you to go into withdrawal. It is not known if or how withdrawal might affect a pregnancy. It is suggested that any reduction in hydrocodone be done slowly, and under the direction of your healthcare provider.

◈ I am taking hydrocodone, but I would like to stop taking it before getting pregnant. How long does the drug stay in my body?

People eliminate medication at different rates. In healthy adults, it takes up to 24 hours, on average, for most of the hydrocodone to be gone from the body.

◈ I take hydrocodone. Can it make it harder for me to get pregnant?

It is not known if using hydrocodone could make it harder to get pregnant. The results from a limited number of studies on the use of opioids during pregnancy are mixed and do not clearly show if opioids could make it harder to get pregnant.

◈ Does taking hydrocodone increase the chance of miscarriage?

Miscarriage is common and can occur in any pregnancy for many different reasons. There are no published studies that have looked at the link between the use of hydrocodone and the chance of miscarriage. Some studies on the use of other opioids suggest an increased chance of miscarriage while other studies do not.

◈ Does taking hydrocodone increase the chance of birth defects?

Every pregnancy starts out with a 3-5% chance of having a birth defect. This is called the background risk. It is not known if taking hydrocodone during pregnancy increases the chance of birth defects. Two studies reported that taking hydrocodone in the first trimester increased the chance of heart defects. One of the studies also reported a small increased chance of spina bifida (an opening in the spine and spinal cord) and gastroschisis (an opening in the wall of the abdomen). However, the number of pregnancies exposed to hydrocodone in these studies was small and these studies have not found a specific pattern of birth defects caused by hydrocodone. Two other studies on hydrocodone did not find an increased chance of birth defects. It is possible that other factors, such as other exposures, a combination of exposures, or the condition causing the pain could have been responsible for the birth defects reported. Based on the published information, if there is an increased chance of birth defects with opioid use in pregnancy, it is likely to be small.

◈ Does taking hydrocodone in pregnancy increase the chance of other pregnancy-related problems?

One study found that people who used hydrocodone and other opioids in pregnancy were more likely to have babies that were born smaller than expected. However, the people in this study who used opioids were also more likely to smoke cigarettes during pregnancy, which can also cause babies to be born small.Studies involving people who often use some opioids during their pregnancy have found an increased chance for pregnancy-related problems, including poor growth of the baby, low levels of amniotic fluid (fluid that surrounds baby in uterus), stillbirth, preterm delivery (birth before week 37), and C-section. This is more commonly reported in those who are taking heroin or who are using prescribed opioid medication in greater amounts or for longer than recommended by their healthcare provider. Use of an opioid close to the time of delivery can result in withdrawal symptoms in the baby (see the section of this fact sheet on neonatal abstinence syndrome).

◈ Will my baby have withdrawal (neonatal abstinence syndrome) if I continue to take hydrocodone?

Neonatal abstinence syndrome (NAS) is the term used to describe withdrawal symptoms in newborns from opioid medication(s) that a person takes during pregnancy. NAS symptoms can include irritability, crying, sneezing, stuffy nose, poor sleep, extreme drowsiness (very tired), yawning, poor feeding, sweating, tremors, seizures, vomiting, and diarrhea. Most often, symptoms of NAS appear 2 days after birth and may last more than 2 weeks. The chance that NAS will occur depends on the length of time and/or the dose of opioid taken during pregnancy, if other medications were also taken, if baby was born preterm, and/or size of the baby at birth. If opioids were taken in pregnancy, it is important to let your baby’s healthcare providers know so that they can check for symptoms of NAS and provide the best care for your newborn.Studies have reported a risk for neonatal abstinence syndrome (NAS) with some opioids; however, not all medications in this class have been studied. Based on what we know about the chance of NAS with other opioids, it is likely that hydrocodone also has a chance for NAS. Because information is limited, it is not known if the chance is higher or lower with hydrocodone than with other, better studied opioids.

◈ Does taking hydrocodone in pregnancy affect future behavior or learning for the child?

It is not known if hydrocodone increases the chance for behavior or learning issues. Some studies on opioids as a general group have found more problems with learning and behavior in children exposed to opioids for a long period of time during pregnancy. It is hard to tell if this is due to the medication exposure or other factors that may increase the chances of these problems.

◈ What if I have an opioid use disorder?

Studies find that people who are pregnant and take opioids in higher doses or for longer than recommended by their healthcare providers (i.e. misuse or “abuse” opioids) have an increased chance for pregnancy problems. These include poor growth of the baby, stillbirth, preterm delivery, and need for a C-section.

◈ What screenings or tests are available to see if my pregnancy has birth defects or other issues?

Prenatal ultrasounds can be used to screen for some birth defects. Ultrasound can also be used to monitor the growth of the pregnancy. Talk with your healthcare provider about any prenatal screenings or testing that are available to you. There are no tests available during pregnancy that can tell how much effect there could be on future behavior or learning.

◈ Hydrocodone and breastfeeding:

Speak to your healthcare provider about your pain and medications that may be used while you are breastfeeding. While the amounts of hydrocodone that get into breast milk are very small, some babies might have problems with those small amounts. Talk with your healthcare provider or a MotherToBaby specialist about your specific medication, as information on breastfeeding might change based on your specific situation such as the age of your baby, the dose of medication, and other factors.The use of some opioids in breastfeeding might cause babies to be very sleepy and have trouble latching on. Some opioids can cause trouble with breathing. If you are using any opioid, talk to your healthcare provider about how to use the least amount for the shortest time and how to monitor (watch) your baby for any signs of concern. Contact the baby’s healthcare provider immediately if your baby has any problems such as increased sleepiness (more than usual), trouble feeding, trouble breathing, or limpness. Be sure to talk to your healthcare provider about all your breastfeeding questions.

◈ If a male takes hydrocodone, could it affect fertility or increase the chance of birth defects?

It is not known if hydrocodone could affect male fertility (ability to get partner pregnant) or increase the chance of birth defects above the background risk. Use or misuse of opioids in general has been shown to lower fertility in males. In general, exposures that fathers or sperm donors have are unlikely to increase risks to a pregnancy. For more information, please see the MotherToBaby fact sheet Paternal Exposures at https://mothertobaby.org/fact-sheets/paternal-exposures-pregnancy/.

12.1.7 Exposure Routes

Oral. Well absorbed from the gastrointestinal tract.

12.1.8 Symptoms

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.

12.1.9 Acute Effects

12.1.10 Toxicity Data

LD50: 85.7mg/kg (Parenteral-subcutaneous, Mouse) (A308)
A308: Wishart DS, Knox C, Guo AC, Cheng D, Shrivastava S, Tzur D, Gautam B, Hassanali M: DrugBank: a knowledgebase for drugs, drug actions and drug targets. Nucleic Acids Res. 2008 Jan;36(Database issue):D901-6. Epub 2007 Nov 29. PMID:18048412

12.1.11 Treatment

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)
L1712: RxList: The Internet Drug Index (2009). http://www.rxlist.com/

12.1.12 Interactions

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.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2770
Concurrent use of anticholinergic agents with hydrocodone may produce paralytic ileus.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2770
Some tranquilizers, especially phenothiazines, may antagonize opiate agonist analgesia. /Opiate agonists/
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2113
...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.
Kolesnikov YA et al; Anesth Analg 97 (6): 1721-3 (2003)
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.
Gnanadesigan N et al; J Am Med Dir Assoc 6 (4): 265-9 (2005)

12.1.13 Antidote and Emergency Treatment

Emergency and supportive measures. 1. Maintain an open airway and assist ventilation if necessary. Administer supplemental oxygen. Treat coma, seizures, hypotension, and noncardiogenic pulmonary edema if they occur. /Opiates and opioids/
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 312
Specific drugs and antidotes. 1. Naloxone is a specific opioid antagonist with no agonist properties of its own; large doses may be given safely. ... Caution: The duration of effect of naloxone (1-2 hours) is shorter than that of many opioids. Therefore, do not release a patient who has awakened after naloxone treatment until at least 3-4 hours has passed since the last dose of naloxone. In general, if naloxone was required to reverse opioid-induced coma, it is safer to admit the patient for at least 6-12 hours of observation. 2. Nalmefene is an opioid antagonist with a longer duration of effect (3-5 hours). ... /Opiates and opioids/
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 312
Decontamination. Administer activated charcoal orally if conditions are appropriate. Gastric lavage is not necessary after small to moderate ingestions if activated charcoal can be given promptly. ... /Opiates and opioids/
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 312
Enhanced elimination. Because of the very large volumes of distribution of the opioids and the availability of an effective antidotal treatment, there is no role for enhanced elimination procedures. /Opiates and opioids/
OLSON, K.R. (Ed). Poisoning and Drug Overdose, Sixth Edition. McGraw-Hill, New York, NY 2012, p. 312
For more Antidote and Emergency Treatment (Complete) data for HYDROCODONE (7 total), please visit the HSDB record page.

12.1.14 Human Toxicity Excerpts

/HUMAN EXPOSURE STUDIES/ 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.
Anderson PO et al; Breastfeed Med 2 (1): 10-4 (2007)
/SIGNS AND SYMPTOMS/ 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.
Physicians Desk Reference 65th ed. PDR Network, LLC, Montvale, NJ. 2011, p. 575
/SIGNS AND SYMPTOMS/ Respiratory depression and, to a lesser degree circulatory depression (including orthostatic hypotension) are the chief hazards of opiate agonist therapy. Respiratory arrest, shock, and cardiac arrest have occurred. Rapid iv administration of opiate agonists increases the incidence of these serious adverse effects. /Opiate agonists/
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2112
/CASE REPORTS/ 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. This case illustrates the importance of evaluating the effects of prescribed medication in assessing the cause and mechanism of death in children dying suddenly of presumed natural disease.
Morrow PL, Faris EC; Am J Forensic Med Pathol 8 (1): 60-3 (1987)
For more Human Toxicity Excerpts (Complete) data for HYDROCODONE (18 total), please visit the HSDB record page.

12.1.15 Non-Human Toxicity Excerpts

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Hydrocodone was evaluated for carcinogenic potential in mice. In a two-year bioassay in mice, doses up to 200 mg/kg in males and 100 mg/kg in females were administered orally and no treatment-related neoplasms were observed (exposure is equivalent to 3.5-fold and 3.0-fold, respectively, the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons).
NIH; DailyMed. Current Medication Information for HYSINGLA ER- hydrocodone bitartrate tablet, extended release (Updated: February 2015). Available from, as of September 4, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b7d23ac2-e776-9f62-3290-c64c2d6eb353
/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ Hydrocodone was evaluated for carcinogenic potential in rats. In a two-year bioassay in rats, doses up to 25 mg/kg in males and females were administered orally and no treatment-related neoplasms were observed (exposure is equivalent to 0.2-fold the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons).
NIH; DailyMed. Current Medication Information for HYSINGLA ER- hydrocodone bitartrate tablet, extended release (Updated: February 2015). Available from, as of September 4, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b7d23ac2-e776-9f62-3290-c64c2d6eb353
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ No effect on fertility or general reproductive performance was seen with oral administration of hydrocodone to male and female rats at doses up to 25 mg/kg/day (approximately 0.06-fold and 0.08-fold, respectively, the human hydrocodone dose of 120 mg/day based on AUC exposure comparisons).
NIH; DailyMed. Current Medication Information for HYSINGLA ER- hydrocodone bitartrate tablet, extended release (Updated: February 2015). Available from, as of September 4, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b7d23ac2-e776-9f62-3290-c64c2d6eb353
/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Hydrocodone Bitartrate (HB), an opioid analgesic indicated for control of moderate to severe pain, was tested for developmental toxicity in two species by ICH guidelines for NDA submission. HB was evaluated in CDN rats (25/sex/group) and in NZW 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 Caesarean-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. Based on these data, HB, USP, should not be identified as a selective developmental toxicant in the rat or rabbit.
York RG et al; Reprod Toxicol 17 (4): 507 (2003)
/GENOTOXICITY/ Hydrocodone was genotoxic in the mouse lymphoma assay in the presence of rat S9 metabolic activation but not in the absence of rat metabolic activation. However, hydrocodone was not genotoxic in the mouse lymphoma assay with or without human S9 metabolic activation. There was no evidence of genotoxic potential with hydrocodone in an in vitro bacterial reverse mutation assay with Salmonella typhimurium and Escherichia coli with or without metabolic activation or in an in vivo mouse bone marrow micronucleus test with or without metabolic activation.
NIH; DailyMed. Current Medication Information for HYSINGLA ER- hydrocodone bitartrate tablet, extended release (Updated: February 2015). Available from, as of September 4, 2015: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=b7d23ac2-e776-9f62-3290-c64c2d6eb353

12.1.16 Non-Human Toxicity Values

LD50 Rat sc 150 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2799
LD50 Mouse sc 86 mg/kg
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 2799
LD50 Rat oral 375 mg/kg /Dihydrocodeinone bitartrate/
Lewis, R.J. Sr. (ed) Sax's Dangerous Properties of Industrial Materials. 11th Edition. Wiley-Interscience, Wiley & Sons, Inc. Hoboken, NJ. 2004., p. 1307

12.1.17 Populations at Special Risk

... Neonates and preterm infants may be more susceptible than older infants to adverse effects of hydrocodone and its metabolites in breast milk.
Anderson PO et al; Breastfeed Med 2 (1): 10-4 (2007)
Safety and efficacy of hydrocodone bitartrate as an antitussive agent have not been established in children younger than 6 years of age. The extended-release preparation containing hydrocodone polistirex and chlorpheniramine polistirex is contraindicated in children younger than 6 years of age. The extended-release preparation should be used with caution in children 6 years of age or older due to the risk of respiratory depression. The risk of potentially fatal respiratory depression is increased with overdosage or concomitant use of other respiratory depressants. Because of the dose-dependent respiratory-depressant effects of opiates, potential benefits and risks of hydrocodone therapy should be carefully considered in pediatric patients, especially those with conditions that may impede adequate respiration (e.g., croup).
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2770
Hydrocodone should be used with caution in geriatric or debilitated patients. Hydrocodone should also be used with caution in patients with head injury, other intracranial lesions, or preexisting increased intracranial pressure, since opiate agonists may increase CSF pressure and markedly exaggerate these conditions; in addition, adverse CNS effects of the drug may obscure the clinical course of the underlying condition. The drug should also be used with caution in patients who have undergone thoracotomies or lapaRotomies, since suppression of the cough reflex may lead to retention of secretions postoperatively in these patients.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2769
In patients with asthma or pulmonary emphysema, indiscriminate use of antitussives may precipitate respiratory insufficiency resulting from increased viscosity of bronchial secretions and suppression of the cough reflex. Tolerance and physical dependence may occur following prolonged administration of hydrocodone preparations.
American Society of Health-System Pharmacists 2015; Drug Information 2015. Bethesda, MD. 2015, p. 2769
For more Populations at Special Risk (Complete) data for HYDROCODONE (10 total), please visit the HSDB record page.

12.1.18 Protein Binding

Hydrocodone is 36% bound to plasma proteins.

12.2 Ecological Information

12.2.1 Environmental Fate / Exposure Summary

Hydrocodone's production and administration as an analgesic and antitussive may result in its release to the environment through various waste streams. If released to air, an estimated vapor pressure of 1.2X10-7 mm Hg at 25 °C indicates hydrocodone will exist in both the vapor and particulate phases in the atmosphere. Vapor-phase hydrocodone will be degraded in the atmosphere by reaction with photochemically-produced hydroxyl radicals; the half-life for this reaction in air is estimated to be 1 hour. Particulate-phase hydrocodone will be removed from the atmosphere by wet and dry deposition. Hydrocodone absorbs UV light at wavelengths 280 nm and, therefore, is not expected to be susceptible to direct photolysis by sunlight since sunlight consists of wavelengths above 290 nm. If released to soil, hydrocodone is expected to have low mobility based upon an estimated Koc of 1,100. The pKa of hydrocodone is 8.23, 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. Volatilization from moist soil surfaces is not expected to be an important fate process based upon an estimated Henry's Law constant of 6.4X10-12 atm-cu m/mole. Hydrocodone is not expected to volatilize from dry soil surfaces based upon its vapor pressure. Hydrocodone is not biodegraded in wastewater treatment plants, suggesting that biodegradation is not an important environmental fate process in soil or water. If released into water, hydrocodone is expected to adsorb to suspended solids and sediment based upon the estimated Koc. Volatilization of the neutral species from water surfaces is not expected to be an important fate process based upon this compound's estimated Henry's Law constant. The pKa indicates hydrocodone will exist partially 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. An estimated BCF of 12 suggests the potential for bioconcentration in aquatic organisms is low. Hydrolysis is not expected to be an important environmental fate process since this compound lacks functional groups that hydrolyze under environmental conditions (pH 5 to 9). Occupational exposure to hydrocodone may occur through inhalation and dermal contact with this compound at workplaces where hydrocodone is produced or used. Monitoring data indicate that the general population may be exposed to hydrocodone via ingestion of drinking water. Exposure to hydrocodone among the general population may be extended to those administered the drug, an opiate. Exposure may also occur via illicit use as it has an appreciable abuse and dependence potential. (SRC)

12.2.2 Artificial Pollution Sources

Hydrocodone's production and use as a analgesic and antitussive(1) may result in its release to the environment through various waste streams(SRC).
(1) O'Neil MJ, ed; The Merck Index. 15th ed. Cambridge, UK: Royal Society of Chemistry, p. 886 (2013)

12.2.3 Environmental Fate

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).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Feb 19, 2015: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) Volpi A, Toffoli F; Bull Chim Farm 118: 594-609 (1979)
(4) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)
(5) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(6) Mohle E, Metzger JW; Amer Chem Soc, Div Environ Chem., Preprints Ext Abst., 219th ACS Natl Mtg., 40: 114-6 (2000)
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).
(1) Swann RL et al; Res Rev 85: 17-28 (1983)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Feb 19, 2015: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
(4) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(5) Volpi A, Toffoli F; Bull Chim Farm 118: 594-609 (1979)
(6) Franke C et al; Chemosphere 29: 1501-14 (1994)
(7) Mohle E, Metzger JW; Amer Chem Soc, Div Environ Chem., Preprints Ext Abst., 219th ACS Natl Mtg., 40: 114-6 (2000)
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).
(1) Bidleman TF; Environ Sci Technol 22: 361-367 (1988)
(2) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Feb 19, 2015: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(3) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)
(4) O'Neil MJ, ed; The Merck Index. 15th ed., Cambridge, UK: Royal Society of Chemistry, p. 886 (2013)

12.2.4 Environmental Biodegradation

AEROBIC: Hydrocodone was apparently formed from dihydrocodeine, following addition of the latter at a concn of 10 ug/L to an activated sludge inoculum (diluted 1:5, 0.8 g/L dry solids) incubated under batch reactor conditions(1). Following a 3-day lag, the concentration of hydrocodone after 70 hours rose to 0.7 ug/L(1).
(1) Mohle E, Metzger JW; Amer Chem Soc, Div Environ Chem., Preprints Ext Abst., 219th ACS Natl Mtg., 40: 114-6 (2000)

12.2.5 Environmental Abiotic Degradation

The rate constant for the vapor-phase reaction of hydrocodone with photochemically-produced hydroxyl radicals has been estimated as 1.8X10-10 cu cm/molecule-sec at 25 °C(SRC) using a structure estimation method(1). This corresponds to an atmospheric half-life of about 1 hour at an atmospheric concentration of 5X10+5 hydroxyl radicals per cu cm(1). Hydrocodone is not expected to undergo hydrolysis in the environment due to the lack of functional groups that hydrolyze under environmental conditions(2). Hydrocodone absorbs UV light at wavelength 280 nm(3) and, therefore, is not expected to be susceptible to direct photolysis by sunlight since sunlight consists of wavelengths above 290 nm(SRC).
(1) Meylan WM, Howard PH; Chemosphere 26: 2293-99 (1993)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 7-4, 7-5 (1990)
(3) O'Neil MJ, ed; The Merck Index. 15th ed., Cambridge, UK: Royal Society of Chemistry, p. 886 (2013)

12.2.6 Environmental Bioconcentration

An estimated BCF of 12 was calculated in fish for hydrocodone(SRC), using an estimated log Kow of 2.16(1) and a regression-derived equation(1). According to a classification scheme(2), this BCF suggests the potential for bioconcentration in aquatic organisms is low(SRC).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Feb 19, 2015: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm/
(2) Franke C et al; Chemosphere 29: 1501-14 (1994)

12.2.7 Soil Adsorption / Mobility

Using a structure estimation method based on molecular connectivity indices(1), the Koc of hydrocodone can be estimated to be 1,100(SRC). According to a classification scheme(2), this estimated Koc value suggests that hydrocodone is expected to have low mobility in soil. 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). Hydrocodone was 28.0% and 76.7% absorbed to a carbonaceous resin and a coconut shell-based absorbant, respectively, in a drinking water treatment study using Lake Mead water, Nevada(5). Hydrocodone concentrations were shown to decrease with increasing salinity in a test conducted in an estuary in Jamaica Bay, Long Island, NY(6).
(1) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Feb 19, 2015: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm
(2) Swann RL et al; Res Rev 85: 17-28 (1983)
(3) Volpi A, Toffoli F; Bull Chim Farm 118: 594-609 (1979)
(4) Doucette WJ; pp. 141-188 in Handbook of Property Estimation Methods for Chemicals. Boethling RS, Mackay D, eds. Boca Raton, FL: Lewis Publ (2000)
(5) Rossner A et al; Water Res 43: 3787-96 (2009)
(6) Benotti MJ, Brownawell BJ; Environ Sci Technol 41: 5795-802 (2007)

12.2.8 Volatilization from Water / Soil

The Henry's Law constant for hydrocodone is estimated as 6.4X10-12 atm-cu m/mole(SRC) using a fragment constant estimation method(1). This Henry's Law constant indicates that hydrocodone is expected to be essentially nonvolatile from water and soil surfaces(2). Hydrocodone is not expected to volatilize from dry soil surfaces(SRC) based upon an estimated vapor pressure of 1.2X10-7 mm Hg(SRC), determined from a fragment constant method(3).
(1) Meylan WM, Howard PH; Environ Toxicol Chem 10: 1283-93 (1991)
(2) Lyman WJ et al; Handbook of Chemical Property Estimation Methods. Washington, DC: Amer Chem Soc pp. 15-1 to 15-29 (1990)
(3) US EPA; Estimation Program Interface (EPI) Suite. Ver. 4.1. Nov, 2012. Available from, as of Feb 19, 2015: https://www.epa.gov/oppt/exposure/pubs/episuitedl.htm

12.2.9 Environmental Water Concentrations

SURFACE WATER: Hydrocodone was been detected in surface and sewage water samples(1,2). Hydrocodone was detected at a concentration range of 6-13 ng/L in the Las Vegas Bay of Lake Mead, Nevada, sampling conducted between 1997 and 1999(3).
(1) Heberer T; Toxicol Lett 131: 5-17 (2002)
(2) Daughton CG; Rev Environ Contam Toxicol 210: 59-110 (2011)
(3) Snyder SA et al; Amer Chem Soc, ACS Symp Ser 2001, 791(Pharmaceuticals and Personal Car Products in the Environment): 116-39 (2001)

12.2.10 Effluent Concentrations

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).
(1) Mohle E, Metzger JW; Amer Chem Soc, Div Environ Chem., Preprints Ext Abst., 219th ACS Natl Mtg., 40: 114-6 (2000)
(2) Diaz-Cruz S, Barcelo D; Handb Environ Chem 5: 227-60 (2004)
(3) Benotti MJ, Brownawell BJ; Environ Sci Technol 41: 5795-802 (2007)

12.2.11 Milk Concentrations

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.
Anderson PO et al; Breastfeed Med 2 (1): 10-4 (2007)

12.2.12 Other Environmental Concentrations

Hydrocodone was produced as a degradation product of dihydrocodeine, following addition of the latter at a concentration of 10 ug/L to an activated sludge inoculum (diluted 1:5, 0.8 g/L dry solids) incubated under batch reactor conditions(1). The presence of hydrocodone in wastewater treatment plant biosolids can result in environmental release through land application(2). In simulated drinking water treatment processes, hydrocodone was 24% removed from spiked samples(3).
(1) Mohle E, Metzger JW; Amer Chem Soc, Div Environ Chem., Preprints Ext Abst., 219th ACS Natl Mtg., 40: 114-6 (2000)
(2) Xia K et al; J Environ Qual 34: 91-104 (2005)
(3) Westerhoff P et al; Environ Sci Technol 39: 6649-63 (2005)

12.2.13 Probable Routes of Human Exposure

Occupational exposure to hydrocodone may occur through inhalation and dermal contact with this compound at workplaces where hydrocodone is produced or used. Monitoring data indicate that the general population may be exposed to hydrocodone via ingestion of drinking water. Exposure to hydrocodone among the general population may be extended to those administered the drug, an opiate(SRC). Because hydrocodone induces side effects similar to codeine and morphine, exposure may also occur via illicit use as it has an appreciable abuse and dependence potential(1).
(1) Friderichs E et al; Analgesics, Centrally Acting. Ullmann's Encyclopedia of Industrial Chemistry. 7th ed. (1999-2015). New York, NY: John Wiley & Sons. Online Posting Date: 15 Oct 2011

12.2.14 Body Burden

/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.
Spiller HA; J Forensic Sci 48 (2): 429-31 (2003)

13 Associated Disorders and Diseases

14 Literature

14.1 Consolidated References

14.2 NLM Curated PubMed Citations

14.3 Springer Nature References

14.4 Thieme References

14.5 Chemical Co-Occurrences in Literature

14.6 Chemical-Gene Co-Occurrences in Literature

14.7 Chemical-Disease Co-Occurrences in Literature

15 Patents

15.1 Depositor-Supplied Patent Identifiers

15.2 WIPO PATENTSCOPE

15.3 Chemical Co-Occurrences in Patents

15.4 Chemical-Disease Co-Occurrences in Patents

15.5 Chemical-Gene Co-Occurrences in Patents

16 Interactions and Pathways

16.1 Chemical-Target Interactions

16.2 Drug-Drug Interactions

16.3 Drug-Food Interactions

  • Avoid alcohol. Profound CNS depression, including sedation, respiratory depression, coma, and death may occur.
  • Take with or without food. Cmax and AUC are not altered by food in a clinically significant way.

16.4 Pathways

17 Biological Test Results

17.1 BioAssay Results

18 Taxonomy

The LOTUS Initiative for Open Natural Products Research: frozen dataset union wikidata (with metadata) | DOI:10.5281/zenodo.5794106

19 Classification

19.1 MeSH Tree

19.2 NCI Thesaurus Tree

19.3 ChEBI Ontology

19.4 KEGG: ATC

19.5 KEGG: Target-based Classification of Drugs

19.6 KEGG: Drug Groups

19.7 WHO ATC Classification System

19.8 FDA Pharm Classes

19.9 ChemIDplus

19.10 IUPHAR / BPS Guide to PHARMACOLOGY Target Classification

19.11 ChEMBL Target Tree

19.12 UN GHS Classification

19.13 EPA CPDat Classification

19.14 Drug Enforcement Administration (DEA) Classification

19.15 NORMAN Suspect List Exchange Classification

19.16 CCSBase Classification

19.17 EPA DSSTox Classification

19.18 LOTUS Tree

19.19 EPA Substance Registry Services Tree

19.20 MolGenie Organic Chemistry Ontology

20 Information Sources

  1. BindingDB
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  12. European Chemicals Agency (ECHA)
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  16. CCSbase
    CCSbase Classification
    https://ccsbase.net/
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    Hydrocodone
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    https://www.norman-network.com/nds/SLE/
  18. ChEBI
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  27. DailyMed
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  29. Mother To Baby Fact Sheets
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  33. Japan Chemical Substance Dictionary (Nikkaji)
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  35. Natural Product Activity and Species Source (NPASS)
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    https://www.whocc.no/copyright_disclaimer/
  47. Wikidata
  48. Wikipedia
  49. Medical Subject Headings (MeSH)
    LICENSE
    Works produced by the U.S. government are not subject to copyright protection in the United States. Any such works found on National Library of Medicine (NLM) Web sites may be freely used or reproduced without permission in the U.S.
    https://www.nlm.nih.gov/copyright.html
  50. PubChem
  51. GHS Classification (UNECE)
  52. EPA Substance Registry Services
  53. MolGenie
    MolGenie Organic Chemistry Ontology
    https://github.com/MolGenie/ontology/
  54. PATENTSCOPE (WIPO)
  55. NCBI
CONTENTS