Hydrocodone/APAP: Drug Whys
By Mike McEvoy
Generic name: Hydrocodone/APAP (multiple manufacturers)
Common U.S. brand names: Lortab (UCB Pharma), Vicodin (Abbott Laboratories)
Popularity: First most commonly prescribed drug between 2002-2007 (U.S.)
Class: Analgesic combination, narcotic
Treatment Uses — Relief of moderate to moderately-severe pain. Has been used as an antitussive (cough suppressant: an effect of the hydrocodone component) and is as effective and possibly a more potent antitussive than codeine. Hydrocodone is a centrally acting analgesic used to provide additive pain relief when non-narcotic analgesics are ineffective. Acetaminophen (abbreviated APAP) is a peripherally acting analgesic agent found in many combination products and also available by itself.
APAP is also an antipyretic (fever lowering) agent. This combination product emphasizes a commonly overlooked principal in pain management. While narcotics may offer greater analgesia than non-narcotic agents, combinations of the two nearly always produce better pain control than either agent alone. In EMS systems without access to narcotics, protocols often call for administration of acetaminophen or other non-narcotic analgesic agents to patients with pain. While non-narcotic agents are unlikely to be effective in severe pain, they will always provide additional effectiveness for narcotics given later during the course of patient care. Every algorithm for pain management emphasizes continuation of non-narcotic agents when escalating to stronger (usually narcotic) drugs. Dose strengths of hydrocodone/APAP start with the number of milligrams of hydrocodone and follow with the acetaminophen dose. The most commonly prescribed strength of hydrocodone/APAP is 7.5/500.
Dosing and Administration — For moderate to moderately-severe pain in adults, initial oral dosing is one 7.5/500 tablet of hydrocodone/APAP every four to six hours as needed, not to exceed eight tablets in any 24-hour period. Alternatively, one or two 5/500 tablets can be given every four to six hours as needed, also not to exceed eight tablets over 24 hours. Dose adjustment is based on pain severity and patient response. The limiting factor is the APAP — healthy adults should not ingest more than 4 grams (4,000 milligrams) of acetaminophen per day.
Although not commonly prescribed, there is a liquid preparation of hydrocodone/APAP available in a standard strength of 7.5 milligrams of hydrocodone and 500 milligrams of APAP in each 15 milliliters of elixir. Pediatric dosing using the elixir for children between 2 and 13 years old is 0.27 milliliters per kilogram (weight) given orally every four to six hours as needed up to a maximum of six doses per day. This equates to 0.135 milligrams per kilogram of hydrocodone and 9 milligrams per kilogram of acetaminophen. Children 14 years of age and older can be given an adult equivalent dose of 15 milliliters orally every four to six hours, up to six doses per day. The 15 milliliter dose provides 7.5 milligrams of hydrocodone and 500 milligrams of APAP. It is very important to measure liquid doses exactly. Household teaspoons and tablespoons are not adequate measuring devices. To deliver exact dosages, use a calibrated measuring cup or syringe. There are no published dosing data for children under 2 years old. Similar dosing is recommended for adults and children when used as an antitussive.
Taking hydrocodone/APAP with food decreases the absorption rate of the acetaminophen component although this effect appears most significant when taken with food high in carbohydrates. Many patients find it necessary to take hydrocodone/APAP with food or milk to minimize gastric irritation. For rapid relief of pain, taking on an empty stomach or with food low in carbohydrates would provide fastest absorption.
There are strong suggestions in medical literature that patients with liver dysfunction (hepatic insufficiency) and patients who consume three or more alcoholic drinks per day should lower daily use of acetaminophen. How much less they should take is unclear, although most studies demonstrate harm in the form of liver damage and increased risk of gastrointestinal bleeding to this patient population at daily doses above 2 grams (2,000 milligrams). Therefore wise practitioners limit APAP to 2 grams daily for patients who consume three or more alcoholic drinks per day or have hepatic insufficiency. One of the most startling and compelling studies of APAP dangers came from the Acute Liver Failure Study Group in 2005. Researchers reported APAP poisoning is now the most common cause of acute liver failure requiring liver transplant in the United States. The majority are unintentional poisonings and the drug most often implicated is — you guessed it — hydrocodone/APAP.
Dosage adjustments are not specifically recommended in older patients although caution is warranted in older or debilitated patients because to the central nervous system depressant effects of hydrocodone.
Overdoses of hydrocodone/APAP are potentially lethal polydrug overdoses. Activated charcoal is particularly effective at binding acetaminophen. Hemodialysis is helpful in removing the drug from the body. Consultation with a poison control center should be used to guide patient management. Nalaxone can reverse the respiratory depression and coma associated with narcotic (hydrocodone) overdose. If the acetaminophen dose exceeds 200 milligrams per kilogram or 7 grams total of APAP (whichever is lower), acetylcysteine should be administered promptly. Serum acetaminophen levels obtained four or more hours following ingestion help to predict toxicity, but should not delay initiation of treatment. Clinical and laboratory evidence of liver toxicity may not become apparent until 48 to 72 hours post-ingestion. Of note, significant liver damage is rarely reported with acute overdoses under 10 grams, and fatalities rarely seen with less than 15 grams in healthy adult patients. Significantly smaller overdoses have killed patients with preexisting liver dysfunction.
Pharmacology/Pharmacokinetics/Stability — After oral administration of hydrocodone/APAP, peak concentrations are reached in the bloodstream at 1.3 hours and remain active for 3.8 hours. The liver metabolizes nearly all each hydrocodone/APAP dose, and about 85 percent of the broken down drug components appear in the urine within 24 hours of an oral dose. Small quantities of acetaminophen are excreted in breast milk. however acetaminophen is considered compatible with breastfeeding by the American Academy of Pediatrics. Hydrocodone passage into breastmilk is theoretically expected based on molecular weight. While risks to a nursing infant cannot be ruled out, they are likely small with occasional use by a nursing mother at recommended doses. Monitoring the infant for sedation, changes in feeding patterns, or gastrointestinal symptoms associated with centrally acting narcotic use are recommended. Oddly, and despite being the most commonly prescribed medication in the United States, the exact mechanisms of action for both APAP and hydrocodone remain unknown. APAP is thought to lower fever by acting on the hypothalamic heat regulating center and exert analgesic effects by inhibiting prostaglandin synthesis. Hydrocodone has an action similar to codeine which mostly involves activation of opiate receptors in the central nervous system and smooth muscle.
Hydrocodone/APAP tablets vary considerably in appearance and strengths between manufacturers. They should be stored at room temperature between 59-86 F and protected from light and moisture using a tight, light-resistant container.
Cautions and Warnings — Like any narcotic, physical and psychological dependence can occur with long term use. Particular caution should be directed at keeping this medication away from small children. Hydrocodone/APAP should be used with caution in patients with preexisting kidney or liver disease; kidney and liver function should be monitored regularly. The sedative properties of hydrocodone/APAP make it inadvisable for patients taking this medication to drive or operate heavy machinery. Although uncommon at therapeutic doses, hydrocodone does produce dose-related respiratory depression.
Important Side Effects and Interactions — The most common side effects of hydrocodone/APAP are constipation, nausea and vomiting. Skin rash and itching are also reported, as is urinary retention in males. Lightheadedness and sedation occur in some patients. Patients should be observed for respiratory depression induced by the hydrocodone component of this drug. Confusion and hallucinations have occasionally been reported. Rarely, serious liver and/or kidney damage have occurred in patients taking hydrocodone/APAP, most often in those with preexisting renal or hepatic disease.
Seventy-one drugs are reported to interact with hydrocodone/APAP. Of these, the most significant involve other drugs also known to be liver or kidney toxic. Combinations of these drugs with hydrocodone/APAP are inadvisable. Additionally, drugs with central nervous system depressant effects may produce profound sedation and/or additive respiratory depression when combined with hydrocodone/APAP. These include barbiturates, benzodiazepines, muscle relaxants, and alcohol (ethanol). While the evidence is weak at best, at least three studies have suggested that hydrocodone/APAP may increase plasma concentrations of oral contraceptives (OC’s) while simultaneously decreasing plasma levels of APAP. There have been no significant reports of food-drug interactions with hydrocodone/APAP.
Average Costs — U.S.
5/500 tablet and 7.5/500 tablet (generic)
Patient cost: $ 0.25 and 0.26 each*
Large Hospital cost: $0.04 and 0.05 each
*(Wal Mart® and Target don’t include this med in their $4/month programs)
1. MICROMEDEX® Healthcare Series: Thomson Micromedex, Greenwood Village, Colorado (accessed April, 2008).
2. Albany Medical Center Pharmacy, Albany, New York.
3. Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, et al. Acetaminophen-Induced Acute Liver Failure: Results of a United States Multicenter, Prospective Study. Hepatology. 2005;42 (6):1364-1372.