Acetaminophen; Codeine
Capital® and Codeine
Capital® with Codeine
Phenco-Care™
TY-PAP with Codeine
Tylagesic™
Tylenol® with Codeine
Vopac™
Classification:
» Analgesics
Analgesics
» Opiate Agonists
NOTE: Acetaminophen; codeine is a schedule C-III controlled substance.
NOTE: This monograph discusses the use of acetaminophen-codeine combination products for management of mild to moderate pain. Clinicians may wish to consult the individual monographs for more information about the specific mechanism of action and pharmacokinetics of each agent.
Description: Acetaminophen and codeine are used together to treat moderate to severe pain due to cancer, dental procedures, headache, back pain, and arthralgias and myalgias. Acetaminophen is a non-salicylate analgesic with similar analgesic potency as NSAIDs, and codeine is an oral semisynthetic opiate agonist derived from the opioid alkaloid, thebaine. The combination of acetaminophen and codeine produces additive analgesia as compared to the same doses of either agent alone. Combinations containing higher doses of one or both components give progressively increasing analgesia. However, dosage escalation of this combination is limited by the maximum dose and “ceiling effect” of acetaminophen. The combination of acetaminophen and opioid analgesics may achieve a “dose-sparing” effect such that lower doses of the both agents produce pain relief with fewer side effects. The acetaminophen-codeine combination is available as tablets and liquid dosage forms.
Mechanism of Action: Acetaminophen-codeine combination produced analgesia through two different mechanisms of action leading to a synergistic analgesic affect.  Acetaminophen; Codeine Tablet (Tab 300;60 mg;mg)
- Codeine: Codeine is a weak µ-opiate receptor agonist and the majority of its analgesic affect is due to metabolism to morphine. Opiate analgesia is mediated through changes in the perception of pain at the spinal cord and higher levels in the CNS. Opiate analgesics also alter the emotional response to pain. The stimulatory effects of opioids are the result of ‘disinhibition’ as the release of inhibitory neurotransmitters such as GABA and acetylcholine is blocked. The antitussive effect of codeine is due to direct action of codeine in the cough center of the medulla.
- Acetaminophen: Acetaminophen acts primarily in the CNS and increases the pain threshold by inhibiting cyclooxygenase, an enzyme involved in prostaglandin (PG) synthesis. Acetaminophen inhibits both isoforms of central cyclooxygenase, COX-1 and COX-2. Acetaminophen weakly inhibits PG synthesis in peripheral tissues, which is the reason for its lack of clinical useful peripheral anti-inflammatory effects. The antipyretic activity of acetaminophen is exerted by blocking the effects of endogenous pyrogen on the hypothalamic heat-regulating center by inhibiting PG synthesis.
Pharmacokinetics: Acetaminophen-codeine is administered orally. The onset of analgesia is within 30 minutes with peak analgesic effects in about 90 minutes. The duration of analgesia is 3 - 4 hours. Both acetaminophen and codeine are metabolized in the liver via cytochrome P450 (CYP) isoenzymes and excreted through the kidney. Administration of other drugs which affect these isoenzymes may affect the efficacy and incidence of adverse reactions from the acetaminophen-codeine combination.
- Codeine: The metabolism of codeine is primarily by glucuronidation with a minor amount of codeine metabolized to morphine via O-demethylation. The metabolism to morphine is mediated by CYP 2D6. Codeine and its active metabolite morphine have decreased clearance in the presence of renal impairment. Liver dysfunction may lessen analgesia due to decreased metabolism of codeine to morphine.
- Acetaminophen: Acetaminophen primarily undergoes glucuronidation and sulfate conjugation; however, a small percentage of the dose is metabolized via CYP 2E1 and 1A2 to a hepatotoxic metabolite. Depletion of glucuronide and sulfate stores due to chronic ethanol use or acute acetaminophen overdose may increase oxidative metabolism of acetaminophen leading to hepatotoxicity. Decreases in liver function may lead to acetaminophen-induced hepatotoxicity and decrease in renal function may lead to decreased excretion of and acetaminophen metabolites.
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References
. Beaver WT. Aspirin and acetaminophen as constituents of analgesic combinations. Arch Intern Med 1981;141:293 - 300.
[ Revised 8/17/2007 4:02:00 PM ]
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