Hydrocodone/paracetamol was approved for medical use in the United States in 1982.[1] In the United States, it is a schedule II controlled substance.[1] In 2022, it was the 23rd most commonly prescribed medication in the United States, with more than 23million prescriptions.[7][8] It is not available in the United Kingdom,[9] though the combination codeine/paracetamol (co-codamol) is.[10] It is sold under the brand names Vicodin and Norco among others.[1][2]
Uses
Medical
Hydrocodone/paracetamol is a fixed-dose combination consisting of the opioid hydrocodone and the non-opioid analgesic paracetamol. It is indicated for relief of moderate to severe pain of acute, chronic, or postoperative types.[2] Hydrocodone/paracetamol comes in oral solution and tablet formulations; however strength of each component may vary.[1] In October 2014, the Drug Enforcement Administration rescheduled hydrocodone combination drugs from schedule III, to schedule II due to its risk for misuse, abuse, and diversions.[11]
Recreational
Hydrocodone diversion and recreational use have escalated due to its opioid effects.[12] In 2009 and 2010, hydrocodone was the second most frequently encountered opioid in the pharmaceutical industry. In-drug evidence was submitted to U.S. federal state and local forensic laboratories as reported by the Drug Enforcement Administration's National Forensic Laboratory Information System (NFLIS) and System to Retrieve Information from Drug Evidence (STRIDE).[13]
Pregnancy and breastfeeding
Prolonged use of hydrocodone/paracetamol during pregnancy can result in neonatal opioid withdrawal syndrome.[1] Hydrocodone/paracetamol passes into breast milk and may harm the baby.[1]
"Paracetamol has been associated with cases of acute liver failure, at times resulting in liver transplant and death. Most of the cases of liver injury are associated with the use of paracetamol at doses that exceed 4000 milligrams per day, and often involve more than one paracetamol-containing product."[2]
In the US, the label for hydrocodone/paracetamol contains a boxed warning about addiction, abuse, and misuse.[2][1]
Overdose
Hydrocodone: Respiratory depression, extreme somnolence progressing towards coma, muscle limpness, cold and clammy skin, slow heart rate, low blood pressure, abrupt loss of heart function, and death may occur.[2]
Paracetamol: Liver and kidney failure, low blood sugar, and coma may occur.[2]
Absorption/distribution: The oral formulation can be absorbed from the gastrointestinal tract and remain 20–50% bound to plasma proteins.[15] The onset of analgesia is about 20 to 30 minutes with a duration of 4 to 8 hours and t1/2 of 3 to 4 hours.[15] Maximum serum levels are achieved at 1.3 hours.[1]
Metabolism/excretion: It is metabolized to norhydrocodone by cytochrome P450 3A4 and to hydromorphone, also biologically active, by cytochrome P450 2D6.[16][17] For individuals who have a defect in the gene encoding CYP2D6, the clearance of the drug will be lower and less metabolite such as hydromorphone will be formed; however, the effect on analgesia remains unknown.[17]
Metabolites: Hydromorphone, the major active metabolite, has a 10-33-fold higher binding affinity for the mu-opioid receptor than hydrocodone. It may be up to >100-fold higher in some patients.[18]
Paracetamol
Mechanism of action: Paracetamol acts to inhibit COX enzyme, which is responsible for prostaglandin synthesis.[6]Prostaglandins increase the perception of pain. Inhibition of prostaglandin production helps to alleviate pain.[19]
Absorption/distribution: The half-life of oral paracetamol is 1.25 to 3 hours and peak level is reached by 10–60 minutes after ingestion.[20]
Metabolism/excretion: Paracetamol is metabolized primarily in the liver via glucuronidation and sulfation to mostly non-toxic metabolites and some highly reactive metabolites, which is inactivated by glutathione.[20] 85% of the oral dose is excreted via the kidneys.[2] At high doses, the supply of glutathione cannot meet its demand, thus resulting in the accumulation of highly reactive compounds leading to liver damage.[20]
Society and culture
Legal status
In June 2009, a US Food and Drug Administration (FDA) advisory panel voted by a narrow margin to advise the FDA to remove Vicodin and another opioid, Percocet, from the market because of "a high likelihood of overdose from prescription narcotics and acetaminophen products".[21] The panel also cited concerns of liver damage from their paracetamol component, which is also the main ingredient in commonly used nonprescription drugs such as Tylenol.[21] Each year, paracetamol overdose is linked to about 400 deaths and 42,000 hospitalizations.[22]
In January 2011, the FDA asked manufacturers of prescription combination products that contain paracetamol to limit the amount of paracetamol to no more than 325 mg in each tablet or capsule within three years.[23][24][25][26] The FDA also required manufacturers on all paracetamol-containing products to issue a black box warning indicating the potential risk for severe liver injury and a warning highlighting potential for allergic reactions.[23][24][26]
In August 2014, the Drug Enforcement Administration (DEA) announced that all hydrocodone combination products (HCPs) would be rescheduled from schedule III to schedule II of the Controlled Substances Act (CSA), effective in October 2014.[11] In 2010, more than 16,000 deaths were attributed to abuse of opioid drugs.[11] Even though there are legitimate medical uses for hydrocodone combination products, data suggest that a significant number of individuals misuse them.[11]
Gregory House, the main protagonist of House, constantly carries Vicodin with him and often takes it to relieve his leg pain, something that plays a major role throughout the series.[30][31]
Brand names
Brand names include Adol, Hycet, Lortab, Lorcet, Norco, and Vicodin among others.[32]
^Singla A, Sloan P (2013). "Pharmacokinetic evaluation of hydrocodone/acetaminophen for pain management". Journal of Opioid Management. 9 (1): 71–80. doi:10.5055/jom.2013.0149. PMID23709306.
^Cone EJ, Darwin WD, Gorodetzky CW, Tan T (1 August 1978). "Comparative metabolism of hydrocodone in man, rat, guinea pig, rabbit, and dog". Drug Metabolism and Disposition. 6 (4): 488–93. PMID28931.
^ abKaye AD (2015). Essentials of Pharmacology for Anesthesia, Pain Medicine, and Critical Care. Springer. pp. 134–13. ISBN9781461489481.
^Hydrocodone and acetaminophen (paracetamol): Drug information (Version 390.0 ed.). Lexicomp. 2024.
^Golan DE (2008). Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy. Lippincott Williams & Wilkins. pp. 275–276. ISBN978-0-7817-8355-2.
^ abcSinatra RS (2011). The Essence of Analgesia and Analgesics. Cambridge University Press. p. 256. ISBN978-0-521-14450-6.
