Hydrocodone/paracetamol

Hydrocodone / Paracetamol

Combination of
Hydrocodone	Opioid analgesic
Paracetamol	Anilide analgesic
Clinical data
AHFS/Drugs.com	entry
Licence data	US FDA:link
Pregnancy cat.	C(US)
Legal status	Schedule III (US)
Routes	Oral
Identifiers
CAS number	330988-71-1 Y
ATC code	?
PubChem	CID 11247932
ChemSpider	9422965 Y
Y(what is this?)  (verify)

Hydrocodone/paracetamol (also known as hydrocodone/acetaminophen) is a combination of two analgesic products hydrocodone and paracetamol (acetaminophen) used to relieve moderate to severe pain.^[1] It is usually found in tablet form, produced and marketed under the trade names Vicodin, Vicodin ES, Vicodin HP, Anexsia, Anolor DH5, Bancap HC, Zydone, Dolacet, Lorcet, Lortab, and Norco, as well as generic brands. Hydrocodone also comes in a combination with ibuprofen, available under the trade name Vicoprofen.

Medical uses

Hydrocodone/paracetamol, like other opioid analgesics, is used to manage pain. It is most commonly prescribed for relief of moderate to moderately severe pain of acute, chronic, or post-operative types.

Formulations

Hydrocodone/paracetamol is made as a mixture of hydrocodone and paracetamol. Paracetamol acts as an analgesic/antipyretic. Hydrocodone is a semi-synthetic opioid analgesic.

Pregnancy

This drug is classified under pregnancy category C. Although not enough research has been done to deem this drug safe for pregnant women, if the positive effects outweigh the possible negatives, then it can be taken. If taken in the time before delivery, it may give rise to respiratory depression in the baby. Mothers using any opioids regularly during pregnancy run the risk of their babies being substance-dependent and, therefore, going through withdrawal symptoms after birth. Withdrawal symptoms include excessive crying, vomiting, irritability, tremors, and fever. Nursing mothers should not use this drug, as paracetamol is transferred through breast milk; it is unknown whether Hydrocodone is.^[2]

Adverse effects

A diagram showing the side effects of Vicodin (hydrocodone/paracetamol)

Side-effects of hydrocodone/paracetamol are most commonly upset stomach, nausea, and altered mental status (e.g., dizziness, light headedness). Other rarer side-effects include allergic reaction, seizures, clammy skin, paranoia, hallucinations, severe weakness, dizziness, hyperventilation, unconsciousness, jaundice (yellowing of eyes or skin), unusual fatigue, bleeding, bruising, stomach pain,^[3] constipation, dry mouth, decreased appetite, muscle twitches, sweating, hot flashes, itching, tinnitus, hearing loss, decreased urination, and altered sex drive. Vicodin also has depressant effects on the central nervous system. However, some of the less mundane effects can be desirable effects that are sought after by some. Those effects include euphoria and drowsiness, as well as slowing of the pulse.

Unlike NSAIDs, paracetamol does not cause ulcers. However, paracetamol can cause liver damage, and, thus, dosages should never exceed 4000 mg a day; this is especially important and will be a smaller number of doses when using mixed drugs like Vicodin. It is imperative that users of this drug follow physician-prescribed dosages. Liver damage can manifest, ranging from abdominal pain to outright liver failure, and can necessitate a liver transplant to avoid death.

Pharmacodynamics

Besides the activity of hydrocodone and acetaminophen on their own, there is observed a factor of analgesia related to the two substances in tandem^{[citation needed]} that is not altogether understood, but this independent synergy has been observed to be related to the inhibition of prostaglandins. The pharmacodynamics of a mixed drug such as Vicodin depends on the kinetics of the drugs that comprise it.

Hydrocodone: Acts at μ-opioid receptors.^[4] Hydrocodone is metabolized to hydromorphone by the activity of cytochrome P450 2D6. Cytochrome 3A4 forms the substrate norhydrocodone. Note that this conversion is only somewhat responsible for the effects of hydrocodone.^[5] Hydrocodone passes through the blood-brain barrier (BBB) because of its modifications. The brain is typically where the analgesic effects are being carried out. Many of the side-effects of this drug are caused by the fact that it so readily crosses the blood-brain barrier. The half-life of hydrocodone is approximately 3.8 hrs.

Paracetamol: The major active metabolites are sulphates and glucuronide conjugates. Its main mode of action is to inhibit the activity of the enzyme cyclooxygenase (COX). COX enzymes are necessary for the production of prostaglandins. Prostaglandins are a form of hormone (although rarely classified as such) that are indicated to be mediators of pain, fever, and inflammation. The half-life of paracetamol may be measured either by salivary or by plasma counts. Both measurements give a varying half-life between 1 and 4 hours.^[6] Peak levels are reached between 40–60 minutes after ingestion. It has been proposed that paracetamol aids in the reduction of pain by increasing serotonergic neurotransmissions.^[7] Paracetamol is a peripherally acting drug, and hence does not cross the BBB as readily as hydrocodone.^{[citation needed]}

Society and culture

Manufacture

The principal constituent of Vicodin, hydrocodone, has the same basic structure as morphine but is metabolized by different enzymes. There are three variations of Vicodin, with different amounts of hydrocodone in each. Hydrocodone, like oxycodone, is an intermediate-strength analgesic that has similar effects as morphine; hydrocodone is approximately twice as potent as morphine by mouth for acute use. The tablets are made with less hydrocodone than paracetamol. The theory of using the mix comes from the idea that these drugs alleviate pain using different mechanisms and also that the adverse side-effects of each separate drug are reduced by using reduced dosages of both drugs in order to get the same analgesic effect.^[8]

Both hydrocodone and acetaminophen are white crystalline powders, which are then manufactured into tablet form. Manufacturers of hydrocodone (generic or otherwise) include Abbott Laboratories (makers of trademark Vicodin), Amerisource Health Services Corp, Cardinal Health, Drx Pharmaceutical Consultants Inc, Eckerd Corp, Hospira Inc, Mallinckrodt Pharm. Quality Care, Pdrx Pharmaceuticals Inc, Physicians Total Care Inc, Rx Papoo s Packaging Inc, and Watson Pharmaceuticals.

On January 13, 2011, FDA announced that it is asking manufacturers of prescription acetaminophen combination products to limit the maximum amount of acetaminophen in these products to 325 mg per tablet, capsule, or other dosage unit. FDA believes that limiting the amount of acetaminophen per tablet, capsule, or other dosage unit in prescription products will reduce the risk of severe liver injury from acetaminophen overdosing, an adverse event that can lead to liver failure, liver transplant, and death.^[9]

Legal status

In the United States, Vicodin production is regulated in part by the Controlled Substances Act of 1970. This guarantees that all manufacturing, importing, possession, and distribution of drugs are to be overseen and regulated by the federal government.

In the U.S. Vicodin is a Schedule III drug. Pure codeine and hydrocodone are Schedule II drugs, but, when compounded with paracetamol or with an NSAID, they can become a Schedule III drug. Schedule III drugs are classified by the U.S. government as having the potential to cause moderate or low physical dependence, or a high psychological dependence if misused.

United States

To qualify for treatment as a Schedule III medication in the United States, hydrocodone must be combined with a non-narcotic ingredient in a recognized therapeutic amount. There are four dosage forms recognized by the U.S. authorities:

• per 100 ml (i.e., a liquid), which must have no more than 300 mg of (dissolved) hydrocodone in addition to the therapeutic amount of a non-narcotic ingredient
• per dosage unit (i.e., a solid, pill or capsule), which must have no more than 15 mg of hydrocodone in addition to the therapeutic amount of a non-narcotic ingredient

Proposed U.S. ban

On June 30, 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 painkiller, Percocet, from the market because of "a high likelihood of overdose from prescription narcotics and acetaminophen products". The panel cited concerns of liver damage from their acetaminophen component, which is also the main ingredient in commonly-used nonprescription drugs such as Tylenol.^[10] Each year, acetaminophen overdose is linked to about 400 deaths and 42,000 hospitalizations.^[11]

The U.S. Food and Drug Administration is asking manufacturers of prescription combination products that contain acetaminophen to limit the amount of acetaminophen to no more than 325 milligrams (mg) in each tablet or capsule.^{[12][13][14][15]} Manufacturers will have three years to limit the amount of acetaminophen in their prescription drug products to 325 mg per dosage unit.^[13][15] The FDA also is requiring manufacturers to update labels of all prescription combination acetaminophen products to warn of the potential risk for severe liver injury.^[12][13][15]

Hydrocodone, the narcotic component of Vicodin, is still available in Canada as a single drug and marketed under the trade name Hycodan in syrup and tablet forms by Bristol-Myers-Squibb.^[16]

Popular media

The popular American television medical drama, House plot centers on the central character's habitual use (and abuse) of Vicodin to manage pain stemming from an infarction in his quadriceps muscle incurred some years earlier.

Vicodin is referenced in multiple songs by rapper Eminem such as "Kill You", "Under the Influence", "Deja Vu", "Old Time's Sake", "Underground", "Going Through Changes", "Oh No", and "Cocaine". He also featured a Vicodin pill on the CD of his debut album The Slim Shady LP. The rapper has admitted to an addiction to the painkiller (along with other substances), the hiatus in rapping that it caused, and the subsequent rehabilitation required to return to his career.^[17]

References

1. ^ Vicodin Information from Drugs.com
2. ^ Vicodin HP Official FDA information, side effects and uses. - Drugs.com
3. ^ Drugs.com (March 24, 2008). "Vicodin". Cerner Multum, Inc.. http://www.drugs.com/vicodin.html. Retrieved 2008-06-09. 
4. ^ Zacny JP, Gutierrez S, Bolbolan SA (June 2005). "Profiling the subjective, psychomotor, and physiological effects of a hydrocodone/acetaminophen product in recreational drug users". Drug Alcohol Depend 78 (3): 243–52. doi:10.1016/j.drugalcdep.2004.11.009. PMID 15893155. 
5. ^ Inhibition of Cytochrome P450 2D6 Metabolism of Hydrocodone to Hydromorphone Does Not Importantly Affect Abuse Liability — JPET
6. ^ Lee, HS; Ti, TY; Lye, WC; Khoo, YM; Tan, CC (January 1996). "Paracetamol and its metabolites in saliva and plasma in chronic dialysis patients". Br J Clin Pharmacol 41 (1): 41–7. doi:10.1111/j.1365-2125.1996.tb00157.x. PMID 8824692. 
7. ^ Garrone, B., Polenzani L., De Santi, S., Moreci, W., and Guglielmotti, A. (2007). "Paracetamol reduces neuropathic pain-like behaviour in rats by potentiating serotonergic neurotransmission". Int J Integ Biol 1 (3): 196–205. ISSN 0973-8363. http://ijib.classicrus.com/IJIB/Arch/2007/1027.pdf. 
8. ^ Beaver WT, McMillan D (October 1980). "Methodological considerations in the evaluation of analgesic combinations: acetaminophen (paracetamol) and hydrocodone in postpartum pain". Br J Clin Pharmacol 10 Suppl 2: 215S–223S. PMC 1430165. PMID 7192153. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=1430165. 
9. ^ Acetaminophen Information, United States Food and Drug Administration
10. ^ FDA Advisers vote to take Vicodin, Percocet off market, CNN
11. ^ Reasons Not to Panic Over a Painkiller, The New York Times
12. ^ ^{a b} "FDA limits acetaminophen in prescription combination products; requires liver toxicity warnings" (Press release). U.S. Food and Drug Administration (FDA). January 13, 2011. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm239894.htm. Retrieved January 13, 2011. 
13. ^ ^{a b c} "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". U.S. Food and Drug Administration (FDA). January 13, 2011. http://www.fda.gov/Drugs/DrugSafety/ucm239821.htm. Retrieved January 13, 2011. 
14. ^ Matthew Perrone (January 13, 2011). "FDA orders lowering pain reliever in Vicodin". The Boston Globe. Associated Press. http://www.boston.com/lifestyle/health/articles/2011/01/13/fda_orders_lowering_pain_reliever_in_vicodin/. Retrieved January 13, 2011. 
15. ^ ^{a b c} Gardiner Harris (January 13, 2011). "F.D.A. Plans New Limits on Prescription Painkillers". The New York Times. http://www.nytimes.com/2011/01/14/health/policy/14fda.html. Retrieved January 13, 2011. 
16. ^ Medscape: Medscape Access
17. ^ Eminem Opens Up About Overcoming Painkiller Addiction, Access Hollywood, May 4, 2009

External links

• Norco information from Drugs.com
• Norco Website
• Vicodin U.S. DEA Drug Schedule
• Vicodin U.S. Federal Regulations
• U.S. National Library of Medicine: Drug Information Portal - Vicodin