Identification
- Summary
Dihydrocodeine is an opioid analgesic agent used for the management of pain severe enough to require an opioid analgesic and for which alternative treatments are inadequate.
- Brand Names
- Dvorah, Trezix
- Generic Name
- Dihydrocodeine
- DrugBank Accession Number
- DB01551
- Background
Dihydrocodeine is an opioid analgesic used as an alternative or adjunct to codeine to treat moderate to severe pain, severe dyspnea, and cough.
It is semi-synthetic, and was developed in Germany in 1908 during an international search to find a more effective antitussive agent to help reduce the spread of airborne infectious diseases such as tuburculosis. It was marketed in 1911.
- Type
- Small Molecule
- Groups
- Approved, Illicit
- Structure
Structure for Dihydrocodeine (DB01551)
- Weight
- Average: 301.3801
Monoisotopic: 301.167793607 - Chemical Formula
- C18H23NO3
- Synonyms
- DHC
- Dihydrocodeine
- External IDs
- IDS-ND-008(SECT.2)
- NSC-231319
Pharmacology
- Indication
Dihydrocodeine is used for the treatment of moderate to severe pain, including post-operative and dental pain [2]. It can also be used to treat chronic pain [1], breathlessness and coughing.
In heroin addicts, dihydrocodeine has been used as a substitute drug, in doses up to 2500mg/day to treat addiction. [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014322/]
Reduce drug development failure ratesBuild, train, & validate machine-learning modelswith evidence-based and structured datasets.Build, train, & validate predictive machine-learning models with structured datasets.- Associated Conditions
Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination to treat Pain Combination Product in combination with: Caffeine (DB00201), Acetylsalicylic acid (DB00945) •••••••••••• ••••••• Used in combination to manage Severe pain Combination Product in combination with: Caffeine (DB00201), Acetaminophen (DB00316) •••••••••••• Used in combination to manage Moderate pain Combination Product in combination with: Caffeine (DB00201), Acetaminophen (DB00316) •••••••••••• - Contraindications & Blackbox Warnings
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Possible opioid related side effects include, but are not limited to, drowsiness, nausea, headache, dry mouth, constipation, difficulty passing urine, and mild euphoria.
- Mechanism of action
Dihydrocodeine is metabolized to dihydromorphine -- a highly active metabolite with a high affinity for mu opioid receptors. [3]
- Absorption
Bioavailability is low (approximately 20%) if administered orally. This may be due to poor gastrointestinal absorption. It is also likely due to pre-systemic metabolism by the liver and intestinal wall. [2]
The AUCs after oral and intravenous administration are similar (3203ug/l/h and 3401ug/l/h, respectively). [2]
Time to peak values are 1.6 and 1.8hours for a 30mg and 60mg dose, respectively. The concentrations achieved were 71.8 ug/1 and 146 ug/1, respectively. [2]
- Volume of distribution
The disposition of dihydrocodeine is described as a two compartment model. [2]
- Protein binding
Not Available
- Metabolism
Metabolized in the liver by CYP 2D6 into an active metabolite, dihydromorphine, and by CYP 3A4 into secondary primary metabolite, nordihydrocodeine. A third primary metabolite is dihydrocodeine-6-glucuronide. [1]
The time for mean peak concentration in acid metabolites is 1.76h and 1.98h for a 30 and 60mg dose, respectively. The concentrations achieved were 563 ug/1 and 1476 ug/1, respectively. [2]
- Route of elimination
Renal elimination and urinary excretion. [1]
- Half-life
4h
- Clearance
Plasma clearance is approximately 300ml/min. [2]
The pharmacokinetics of dihydrocodeine and active metabolite dihydromorphine have been reported to be linear. [1]
The decline in plasma dihydrocodeine concentrations after intravenous administration has been described as bi-exponential, with a sleep decline in the initial 2h following administration, followed by a mono-exponential decline thereafter. Clearance was not dose dependent. [2]
- Adverse Effects
Improve decision support & research outcomesWith structured adverse effects data, including: blackbox warnings, adverse reactions, warning & precautions, & incidence rates. View sample adverse effects data in our new Data Library!Improve decision support & research outcomes with our structured adverse effects data.- Toxicity
Not Available
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs Browse all" title="About SNP Mediated Effects/ADRs" id="snp-actions-info" class="drug-info-popup" href="javascript:void(0);">
- Not Available
Interactions
- Drug Interactions Learn More" title="About Drug Interactions" id="structured-interactions-info" class="drug-info-popup" href="javascript:void(0);">
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your software1,2-Benzodiazepine The risk or severity of adverse effects can be increased when Dihydrocodeine is combined with 1,2-Benzodiazepine. Abametapir The serum concentration of Dihydrocodeine can be increased when it is combined with Abametapir. Abatacept The metabolism of Dihydrocodeine can be increased when combined with Abatacept. Abiraterone The metabolism of Dihydrocodeine can be decreased when combined with Abiraterone. Acebutolol The metabolism of Dihydrocodeine can be decreased when combined with Acebutolol. - Food Interactions
- Avoid alcohol. Alcohol can enhance the CNS depressant effects of this drug.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Dihydrocodeine bitartrate 8LXS95BSA9 5965-13-9 ZGSZBVAEVPSPFM-HYTSPMEMSA-N Dihydrocodeine hydrochloride 9073288YPO 36418-29-8 VMZXMTVGOAQUEN-FFHNEAJVSA-N Dihydrocodeine hydroiodide 6D04Y0152T 5965-15-1 COAKEBDIEZAZMT-FFHNEAJVSA-N Dihydrocodeine phosphate 5D9XI60ASE 24204-13-5 HFBYLYCMISIEMM-FFHNEAJVSA-N Dihydrocodeine thiocyanate 442C0H2H3P 84824-87-3 HVXYRJWFMXAVJG-FFHNEAJVSA-N - Active Moieties
Name Kind UNII CAS InChI Key Codeine unknown UX6OWY2V7J 76-57-3 OROGSEYTTFOCAN-DNJOTXNNSA-N - International/Other Brands
- Codidol / Contugesic / Dehace / DF-118 Forte / Dicogesic / Hydrocodin / Remedacen
- Mixture Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Acetaminophen, Caffeine and Dihydrocodeine Bitartrate Dihydrocodeine bitartrate (16 mg/1) + Acetaminophen (325 mg/1) + Caffeine (30 mg/1) Tablet Oral Atland Pharmaceuticals, Llc 2020-01-30 Not applicable US 
Acetaminophen, Caffeine and Dihydrocodeine Bitartrate Dihydrocodeine bitartrate (16 mg/1) + Acetaminophen (325 mg/1) + Caffeine (30 mg/1) Tablet Oral Larken Laboratories Inc. 2016-10-04 Not applicable US Acetaminophen, Caffeine and Dihydrocodeine Bitartrate Dihydrocodeine bitartrate (32 mg/1) + Acetaminophen (712.8 mg/1) + Caffeine (60 mg/1) Tablet Oral Boca Pharmacal, Inc. 2007-04-03 2013-05-23 US Acetaminophen, Caffeine and Dihydrocodeine Bitartrate Dihydrocodeine bitartrate (32 mg/1) + Acetaminophen (712.8 mg/1) + Caffeine (60 mg/1) Tablet Oral Mikart, Inc. 2006-10-06 Not applicable US Acetaminophen, Caffeine, Dihydrocodeine Bitartrate Dihydrocodeine bitartrate (16 mg/1) + Acetaminophen (320.5 mg/1) + Caffeine (30 mg/1) Capsule Oral Mesource Pharmaceuticals 2015-08-05 2017-03-31 US - Unapproved/Other Products
Name Ingredients Dosage Route Labeller Marketing Start Marketing End Region Image Centussin Dhc Dihydrocodeine bitartrate (3 mg/5mL) + Brompheniramine maleate (4 mg/5mL) + Phenylephrine hydrochloride (7.5 mg/5mL) Liquid Oral Centurion Labs 2009-11-24 2016-05-02 US Coldcough Dihydrocodeine bitartrate (7.5 mg/5mL) + Chlorpheniramine maleate (2.0 mg/5mL) + Pseudoephedrine hydrochloride (15 mg/5mL) Syrup Oral Breckenridge Pharmaceutical, Inc. 2003-07-01 2011-08-31 US Coldcough PD Dihydrocodeine bitartrate (3 mg/5mL) + Chlorpheniramine maleate (2 mg/5mL) + Phenylephrine hydrochloride (7.5 mg/5mL) Syrup Oral Breckenridge Pharmaceutical, Inc. 2003-07-01 2011-12-31 US DiHydro CP Dihydrocodeine bitartrate (7.5 mg/5mL) + Chlorpheniramine maleate (2 mg/5mL) + Pseudoephedrine hydrochloride (15 mg/5mL) Syrup Oral Cypress Pharmaceuticals, Inc. 2007-02-15 2011-08-26 US Dihydrocodeine BPM Phenyleph HCl Dihydrocodeine bitartrate (3 mg/5mL) + Brompheniramine maleate (4 mg/5mL) + Phenylephrine hydrochloride (7.5 mg/5mL) Liquid Oral River's Edge Pharmaceuticals, LLC 2010-03-01 2012-02-29 US
Categories
- ATC Codes
- N02AA58 — Dihydrocodeine, combinationsN02AA08 — DihydrocodeineN02AJ02 — Dihydrocodeine and acetylsalicylic acid
- N02AJ — Opioids in combination with non-opioid analgesics
- N02A — OPIOIDS
- N02 — ANALGESICS
- N — NERVOUS SYSTEM
- Drug Categories
- Alkaloids
- Analgesics
- Central Nervous System Agents
- Central Nervous System Depressants
- Cytochrome P-450 CYP2D6 Substrates
- Cytochrome P-450 CYP3A Substrates
- Cytochrome P-450 CYP3A4 Substrates
- Cytochrome P-450 Substrates
- Heterocyclic Compounds, Fused-Ring
- Morphinans
- Morphine Derivatives
- Narcotics
- Natural Opium Alkaloids
- Nervous System
- Opiate Alkaloids
- Opioid Agonist
- Opioids
- Peripheral Nervous System Agents
- Phenanthrenes
- Semi-synthetic Opioids
- Sensory System Agents
- Serotonergic Drugs Shown to Increase Risk of Serotonin Syndrome
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as morphinans. These are polycyclic compounds with a four-ring skeleton with three condensed six-member rings forming a partially hydrogenated phenanthrene moiety, one of which is aromatic while the two others are alicyclic.
- Kingdom
- Organic compounds
- Super Class
- Alkaloids and derivatives
- Class
- Morphinans
- Sub Class
- Not Available
- Direct Parent
- Morphinans
- Alternative Parents
- Phenanthrenes and derivatives / Tetralins / Coumarans / Anisoles / Aralkylamines / Alkyl aryl ethers / Piperidines / Trialkylamines / Secondary alcohols / Cyclic alcohols and derivatives show 4 more
- Substituents
- Alcohol / Alkyl aryl ether / Amine / Anisole / Aralkylamine / Aromatic heteropolycyclic compound / Azacycle / Benzenoid / Coumaran / Cyclic alcohol show 16 more
- Molecular Framework
- Aromatic heteropolycyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- N9I9HDB855
- CAS number
- 125-28-0
- InChI Key
- RBOXVHNMENFORY-DNJOTXNNSA-N
- InChI
- InChI=1S/C18H23NO3/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/h3,6,11-13,17,20H,4-5,7-9H2,1-2H3/t11-,12+,13-,17-,18-/m0/s1
- IUPAC Name
- (1S,5R,13R,14S,17R)-10-methoxy-4-methyl-12-oxa-4-azapentacyclo[9.6.1.0^{1,13}.0^{5,17}.0^{7,18}]octadeca-7,9,11(18)-trien-14-ol
- SMILES
- [H][C@@]12OC3=C4C(C[C@H]5N(C)CC[C@@]14[C@@]5([H])CC[C@@H]2O)=CC=C3OC
References
- Synthesis Reference
Igor Likhotvorik, "Preparation of dihydrocodeine from codeine." U.S. Patent US06887999, issued May 03, 2005.
US06887999- General References
- Ammon S, Hofmann U, Griese EU, Gugeler N, Mikus G: Pharmacokinetics of dihydrocodeine and its active metabolite after single and multiple oral dosing. Br J Clin Pharmacol. 1999 Sep;48(3):317-22. [Article]
- Rowell FJ, Seymour RA, Rawlins MD: Pharmacokinetics of intravenous and oral dihydrocodeine and its acid metabolites. Eur J Clin Pharmacol. 1983;25(3):419-24. [Article]
- Schmidt H, Vormfelde SV, Walchner-Bonjean M, Klinder K, Freudenthaler S, Gleiter CH, Gundert-Remy U, Skopp G, Aderjan R, Fuhr U: The role of active metabolites in dihydrocodeine effects. Int J Clin Pharmacol Ther. 2003 Mar;41(3):95-106. [Article]
- FDA Approved Drug Products: SYNALGOS®-DC (aspirin, caffeine, and dihydrocodeine bitartrate) capsules, for oral use, CIII (Jan 2024) [Link]
- External Links
- KEGG Drug
- D01481
- PubChem Compound
- 5284543
- PubChem Substance
- 46506478
- ChemSpider
- 4447600
- 23088
- ChEBI
- 135276
- ChEMBL
- CHEMBL1595
- ZINC
- ZINC000004215736
- PharmGKB
- PA449322
- Drugs.com
- Drugs.com Drug Page
- Wikipedia
- Dihydrocodeine
Clinical Trials
- Clinical Trials Learn More" title="About Clinical Trials" id="clinical-trials-info" class="drug-info-popup" href="javascript:void(0);">
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- A-S Medication Solutions LLC
- Boca Pharmacal
- Caraco Pharmaceutical Labs
- Leitner Pharmaceuticals LLC
- Mikart Inc.
- Nucare Pharmaceuticals Inc.
- Pamlab LLC
- PD-Rx Pharmaceuticals Inc.
- Pharmedix
- Physicians Total Care Inc.
- West-Ward Pharmaceuticals
- Zerxis Pharmaceuticals
- Dosage Forms
Form Route Strength Tablet Oral Cream Oral; Vaginal Solution / drops Oral Tablet, film coated Oral 120 mg Tablet, film coated Oral 60 mg Tablet, film coated Oral 90 mg Tablet Oral Syrup Oral 0.242 g Solution Oral 242 mg Solution Oral 0.242 g Capsule Oral Liquid Oral Suspension Oral 240 mg Syrup Oral 242 mg Tablet Oral 10 mg Solution / drops Oral 10 mg/g Syrup Oral 200 mg/100g Solution Oral 15 g Solution Oral 30 g Solution / drops Oral 10.25 mg/mL Solution Oral 13.6 mg Tablet Oral 30 mg Syrup Oral - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
Property Value Source melting point (°C) 112.5 °C PhysProp - Predicted Properties
Property Value Source Water Solubility 2.38 mg/mL ALOGPS logP 1.58 ALOGPS logP 1.55 Chemaxon logS -2.1 ALOGPS pKa (Strongest Acidic) 14.15 Chemaxon pKa (Strongest Basic) 9.33 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 4 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 41.93 Å2 Chemaxon Rotatable Bond Count 1 Chemaxon Refractivity 83.64 m3·mol-1 Chemaxon Polarizability 32.8 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter Yes Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.9942 Blood Brain Barrier + 0.9974 Caco-2 permeable + 0.8388 P-glycoprotein substrate Substrate 0.8754 P-glycoprotein inhibitor I Inhibitor 0.5937 P-glycoprotein inhibitor II Non-inhibitor 0.9652 Renal organic cation transporter Inhibitor 0.5676 CYP450 2C9 substrate Non-substrate 0.831 CYP450 2D6 substrate Substrate 0.9143 CYP450 3A4 substrate Substrate 0.7941 CYP450 1A2 substrate Non-inhibitor 0.8554 CYP450 2C9 inhibitor Non-inhibitor 0.9074 CYP450 2D6 inhibitor Inhibitor 0.7395 CYP450 2C19 inhibitor Non-inhibitor 0.7689 CYP450 3A4 inhibitor Non-inhibitor 0.8114 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.957 Ames test Non AMES toxic 0.8074 Carcinogenicity Non-carcinogens 0.9522 Biodegradation Not ready biodegradable 0.9857 Rat acute toxicity 2.9382 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.9058 hERG inhibition (predictor II) Non-inhibitor 0.8246
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 174.8310872 predictedDarkChem Lite v0.1.0 [M-H]- 175.4669872 predictedDarkChem Lite v0.1.0 [M-H]- 177.15668 predictedDeepCCS 1.0 (2019) [M-H]- 174.8310872 predictedDarkChem Lite v0.1.0 [M-H]- 175.4669872 predictedDarkChem Lite v0.1.0 [M-H]- 177.15668 predictedDeepCCS 1.0 (2019) [M+H]+ 174.9010872 predictedDarkChem Lite v0.1.0 [M+H]+ 175.4787872 predictedDarkChem Lite v0.1.0 [M+H]+ 179.5262 predictedDeepCCS 1.0 (2019) [M+H]+ 174.9010872 predictedDarkChem Lite v0.1.0 [M+H]+ 175.4787872 predictedDarkChem Lite v0.1.0 [M+H]+ 179.5262 predictedDeepCCS 1.0 (2019) [M+Na]+ 175.3010872 predictedDarkChem Lite v0.1.0 [M+Na]+ 175.5157872 predictedDarkChem Lite v0.1.0 [M+Na]+ 186.96376 predictedDeepCCS 1.0 (2019) [M+Na]+ 175.3010872 predictedDarkChem Lite v0.1.0 [M+Na]+ 175.5157872 predictedDarkChem Lite v0.1.0 [M+Na]+ 186.96376 predictedDeepCCS 1.0 (2019)
Enzymes
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Vitamin d3 25-hydroxylase activity
- Specific Function
- Cytochromes P450 are a group of heme-thiolate monooxygenases. In liver microsomes, this enzyme is involved in an NADPH-dependent electron transport pathway. It performs a variety of oxidation react...
- Gene Name
- CYP3A4
- Uniprot ID
- P08684
- Uniprot Name
- Cytochrome P450 3A4
- Molecular Weight
- 57342.67 Da
References
- Hutchinson MR, Menelaou A, Foster DJ, Coller JK, Somogyi AA: CYP2D6 and CYP3A4 involvement in the primary oxidative metabolism of hydrocodone by human liver microsomes. Br J Clin Pharmacol. 2004 Mar;57(3):287-97. [Article]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- Unknown
- Actions
- Substrate
- General Function
- Steroid hydroxylase activity
- Specific Function
- Responsible for the metabolism of many drugs and environmental chemicals that it oxidizes. It is involved in the metabolism of drugs such as antiarrhythmics, adrenoceptor antagonists, and tricyclic...
- Gene Name
- CYP2D6
- Uniprot ID
- P10635
- Uniprot Name
- Cytochrome P450 2D6
- Molecular Weight
- 55768.94 Da
References
- Kirkwood LC, Nation RL, Somogyi AA: Characterization of the human cytochrome P450 enzymes involved in the metabolism of dihydrocodeine. Br J Clin Pharmacol. 1997 Dec;44(6):549-55. [Article]
- Schmidt H, Vormfelde Sv, Klinder K, Gundert-Remy U, Gleiter CH, Skopp G, Aderjan R, Fuhr U: Affinities of dihydrocodeine and its metabolites to opioid receptors. Pharmacol Toxicol. 2002 Aug;91(2):57-63. [Article]
- Fromm MF, Hofmann U, Griese EU, Mikus G: Dihydrocodeine: a new opioid substrate for the polymorphic CYP2D6 in humans. Clin Pharmacol Ther. 1995 Oct;58(4):374-82. doi: 10.1016/0009-9236(95)90049-7. [Article]
- Schmidt H, Vormfelde SV, Walchner-Bonjean M, Klinder K, Freudenthaler S, Gleiter CH, Gundert-Remy U, Skopp G, Aderjan R, Fuhr U: The role of active metabolites in dihydrocodeine effects. Int J Clin Pharmacol Ther. 2003 Mar;41(3):95-106. [Article]
Drug created at July 31, 2007 13:10 / Updated at January 22, 2024 17:49