Hydrocodone/paracetamol explained

Hydrocodone/paracetamol (also known as hydrocodone/acetaminophen) is the combination of the pain medications hydrocodone and paracetamol (acetaminophen). It is used to treat moderate to severe pain.^[1] It is taken by mouth. Recreational use is common in the United States.^{[2] [3]}

Common side effects include dizziness, sleepiness, constipation, and vomiting.^[1] Serious side effects include addiction, decreased rate of breathing, low blood pressure, severe allergic reactions, and liver failure. Use during pregnancy may harm the fetus. Use with alcohol is not recommended.^[1] Hydrocodone works by binding to the mu-opioid receptor. How paracetamol works is unclear but may involve blocking the creation of prostaglandins.^[4]

Hydrocodone/paracetamol was approved for medical use in the United States in 1982. In the United States, it is a schedule II controlled substance. In 2021, it was the twentieth most commonly prescribed medication in the United States, with more than 26million prescriptions.^{[5] [6]} It is not available in the United Kingdom,^[7] though the combination codeine/paracetamol (co-codamol) is.^[8] It is sold under the brand names Vicodin and Norco among others.

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. Hydrocodone/paracetamol comes in oral solution and tablet formulations; however strength of each component may vary. 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.^[9]

Recreational

Hydrocodone diversion and recreational use has escalated due to its opioid effects.^[10] 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).^[11]

Pregnancy and breastfeeding

Prolonged use of hydrocodone/paracetamol during pregnancy can result in neonatal opioid withdrawal syndrome. Hydrocodone/paracetamol passes into breast milk and may harm the baby.

Kidney and liver impairment

Use with caution due to possible risk of toxicity.

Side effects

Most common

• Lightheadedness
• Dizziness
• Euphoria
• Sedation
• Nausea and vomiting
• Headaches

Less common

• Central nervous system: drowsiness, confusion, lethargy, anxiety, fear, unease, dependence, mood changes, impairment of mental and physical performance
• Gastrointestinal system: constipation
• Genitourinary system: inability to urinate, bladder spasms
• Respiratory depression: decreased rate and effort of breathing
• Hearing impairment, permanent hearing loss
• Dermatological: rash, itching

Black box warning

"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."

In the US, the label for hydrocodone/paracetamol contains a black box warning about addiction, abuse, and misuse.

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.

Paracetamol: Liver and kidney failure, low blood sugar coma may occur.

Interactions

Hydrocodone may demonstrate an enhanced respiratory depressant effect when combined with other sedatives such as other opioids, benzodiazepines, nonbenzodiazepine sedatives, psychotropics, and anticonvulsants.^[12]

Concurrent use of paracetamol with alcohol products may increase the risk of acute liver failure.

Monitoring

Laboratory function tests should be used to monitor therapy in people with severe liver or renal disease.

Pharmacology

Hydrocodone

• Mechanism of action: Hydrocodone acts primarily as an agonist at the mu-opioid receptors, but is also a weak agonist against the delta opioid and kappa opioid receptors.^[13]
• Absorption/distribution: The oral formulation can be absorbed from the gastrointestinal tract and remain 20–50% bound to plasma proteins.^[13] The onset of analgesia is about 20 to 30 minutes with duration of 4 to 8 hours and t_1/2 of 3 to 4 hours.^[13] Maximum serum levels are achieved at 1.3 hours.^[14]
• Metabolism/excretion: It is metabolized to norhydrocodone by cytochrome P450 3A4 and to hydromorphone, also biologically active, by cytochrome P450 2D6.^{[15] [16]} 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.^[16]
• 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.^[17]

Paracetamol

• Mechanism of action: Paracetamol acts to inhibit COX enzyme, which is responsible for prostaglandin synthesis.^[4] Prostaglandins increase the perception of pain. Inhibition of prostaglandin production helps to alleviate pain.^[18]
• 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.^[19]
• 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.^[19] 85% of the oral dose is excreted via the kidneys. At high doses, the supply of glutathione cannot meet its demand, thus results in the accumulation of highly reactive compounds leading to liver damage.^[19]

Society and culture

Legal status

On 30 June 2009, a U.S. 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". 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.^[20] Each year, paracetamol overdose is linked to about 400 deaths and 42,000 hospitalizations.^[21]

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.^{[22] [23] [24] [25]} 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.^{[22] [23] [25]}

On 22 August 2014, the Drug Enforcement Administration (DEA) announced that all hydrocodone combination products (HCPs) will be rescheduled from Schedule III to Schedule II of the Controlled Substances Act (CSA), effective on 6 October 2014. In 2010, more than 16,000 deaths were attributed to abuse of opioid drugs. Even though there are legitimate medical uses for HCPs, data suggest that a significant number of individuals misuse them.

Popular culture

Actor Matthew Perry struggled with his addiction to Vicodin for many years after a jet ski accident in 1997.^[26]

In May 2017, professional golfer Tiger Woods was arrested by the police for driving under the influence. Woods said that this was due to four prescription drugs that he was taking for a back operation, one of which was Vicodin.^{[27] [28]}

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.^{[29] [30]}

Brand names

Brand names include Adol, Hycet, Lortab, Lorcet, Norco, and Vicodin among others.^[31]

External links

• Vicodin U.S. Federal Regulations

Notes and References

1. Book: Mancano M, Gallagher J . Frequently Prescribed Medications . 2010 . Jones & Bartlett Learning . 9780763781170 . 7 .
2. Book: Parrillo VN . Encyclopedia of Social Problems . 2008 . SAGE . 9781412941655 . 262 .
3. Singla A, Sloan P . Pharmacokinetic evaluation of hydrocodone/acetaminophen for pain management . Journal of Opioid Management . 9 . 1 . 71–80 . 2013 . 23709306 . 10.5055/jom.2013.0149 .
4. Graham GG, Scott KF . Mechanism of action of paracetamol . American Journal of Therapeutics . 12 . 1 . 46–55 . 1 February 2005 . 15662292 . 10.1097/00045391-200501000-00008 . 38261222 .
5. Web site: The Top 300 of 2021 . ClinCalc . 14 January 2024 . 15 January 2024 . https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx . live .
6. Web site: Acetaminophen; Hydrocodone - Drug Usage Statistics . ClinCalc. 14 January 2024.
7. News: Atkins L . Know what a Vike is? . 23 December 2018 . The Guardian . 16 August 2001.
8. Web site: Co-codamol 30/500 Tablets - Summary of Product Characteristics (SmPC) - (eMC) . www.medicines.org.uk . 7 August 2019.
9. Web site: Schedules of Controlled Substances: Rescheduling of Hydrocodone Combination Products From Schedule III to Schedule II . Federal Register . 22 August 2014 . 23 November 2022.
10. Web site: Norco Addiction . The Fix. 4 November 2015. 21 January 2015.
11. Web site: Hydrocodone (Trade Names: Vicodin, Lortab, Lorcet-HD, Hycodan, Vicoprofen) . April 2013 . . 21 May 2013 . 18 April 2013 . https://web.archive.org/web/20130418010504/http://www.deadiversion.usdoj.gov/drug_chem_info/hydrocodone.pdf . live .
12. Becker DE . Adverse drug interactions . Anesthesia Progress . 58 . 1 . 31–41 . 1 January 2011 . 21410363 . 3265267 . 10.2344/0003-3006-58.1.31 .
13. Vallejo R, Barkin RL, Wang VC . Pharmacology of opioids in the treatment of chronic pain syndromes . Pain Physician . 14 . 4 . E343-60 . 1 August 2011 . 10.36076/ppj.2011/14/E343 . 21785485 . free .
14. Web site: October 18, 2013 . Labeling-Package Insert: Hydrocodone/acetaminophen 7.5 mg/325 mg . January 22, 2024 . Drugs@FDA: FDA-Approved Drugs . Chartwell.
15. Cone EJ, Darwin WD, Gorodetzky CW, Tan T . Comparative metabolism of hydrocodone in man, rat, guinea pig, rabbit, and dog . Drug Metabolism and Disposition . 6 . 4 . 488–93 . 1 August 1978 . 28931 .
16. Book: Essentials of Pharmacology for Anesthesia, Pain Medicine, and Critical Care . Kaye AD . Springer . 2015 . 9781461489481 . 134–13.
17. Book: Hydrocodone and acetaminophen (paracetamol): Drug information . Lexicomp® . 2024 . Version 390.0.
18. Book: Principles of Pharmacology: The Pathophysiologic Basis of Drug Therapy . Golan DE . Lippincott Williams & Wilkins . 2008 . 978-0-7817-8355-2 . 275–276.
19. Book: The Essence of Analgesia and Analgesics . Sinatra RS . Cambridge University Press . 2011 . 978-0-521-14450-6 . 256.
20. Web site: FDA advisers vote to take Vicodin, Percocet off market . CNN.
21. News: F.D.A. Plans New Limits on Prescription Painkillers. The New York Times. 13 January 2011. 4 November 2015. 0362-4331. Harris G .
22. FDA limits acetaminophen in prescription combination products; requires liver toxicity warnings . 13 January 2011 . U.S. Food and Drug Administration . 13 January 2011 .
23. Web site: FDA Drug Safety Communication: Prescription Acetaminophen Products to be Limited to 325 mg Per Dosage Unit; Boxed Warning Will Highlight Potential for Severe Liver Failure . 13 January 2011 . U.S. Food and Drug Administration (FDA) . 13 January 2011 .
24. News: FDA orders lowering pain reliever in Vicodin . Perrone M . Associated Press . 13 January 2011 . . 13 January 2011 .
25. News: F.D.A. Plans New Limits on Prescription Painkillers . Harris G . . 13 January 2011 . 13 January 2011 .
26. News: Diver . Tony . 29 October 2023 . 'No one would be surprised if I died': How Matthew Perry opened up about his addiction . en-GB . The Telegraph . 17 December 2023 . 0307-1235.
27. News: Police release dashcam footage of Tiger Woods' DUI arrest. 1 June 2017. Associated press. Guardian. 1 June 2017.
28. News: Murray E . Tiger Woods says medication, not alcohol led to Florida DUI arrest. 1 June 2017. The Guardian. 29 May 2017.
29. Pilot. Pilot (House). House, M.D.. 16 November 2004. 1. 1.
30. Twenty Vicodin. Twenty Vicodin. House, M.D.. 3 October 2011. 8. 1.
31. Web site: Adol (Hydrocodone-Acetaminoph) Oral: Uses, Side Effects, Interactions, Pictures, Warnings & Dosing – WebMD. WebMD. 26 July 2017.