Acetaminophen + Opioid (Codeine/Hydrocodone/Oxycodone/Tramadol)Rx

Trade Names
Acetaminophen + codeine: Capital and Codeine, Tylenol with Codeine No.3 , Tylenol with Codeine No.4
Acetaminophen + hydrocodone:  Lortab, Lorcet, Lorcet Plus, Vicodin, Vicodin ES, Xodol
Acetaminophen + oxycodone: Percocet, Roxicet, Roxilox, Tylox
Acetaminophen + tramadol: Ultracet

Drug Class: Analgesic/antipyretic with opioid analgesic

Preparations (In 2014 the FDA  phased out all combination tablets that contain >325 mg acetaminophen) 

Acetaminophen + codeine
Tablet: Acetaminophen with codeine #2: 15 mg codeine/300 mg acetaminophen; #3, 30/300 mg; #4, 60/300 mg
Capsules: Acetaminophen with codeine #2: 15 mg codeine/325 mg acetaminophen; #3, 30/325 mg; #4, 60/325 mg
Suspension: Acetaminophen with codeine: 12 mg codeine/120 mg acetaminophen per 5 mL.
Acetaminophen + hydrocodone
Tablet: Lortab 2.5/325 (2.5 mg hydrocodone/325 mg acetaminophen);  Lortab 5/325; Lortab 7.5/325; Lorcet 5/325; Lorcet Plus 7.5/325; Vicodin 5/300; Vicodin ES 7.5/300
Acetaminophen + oxycodone
Tablet:  Percocet – oxycodone 2.5 mg/acetaminophen 325 mg, 5/325 mg, 7.5/325 mg, 10/325 mg
Acetaminophen + tramadol: Ultracet (37.5 mg tramadol and 325 mg acetaminophen)

Dose
Do not exceed acetaminophen 4 g/day from all sources (some experts recommend that the maximum daily acetaminophen dose should be 3 g/day).
The dose of narcotic is selected and titrated according to the severity of the pain and how opioid tolerant the patient is.

Acetaminophen + codeine: Adult dose, one to two tablets containing acetaminophen 300 mg + codeine 15 or 30 mg q 4–6 h p.r.n. with total daily dose not to exceed 8 tablets
Acetaminophen + hydrocodone: Adult dose, one to two tablets containing 325 acetaminophen + 5 to 10 mg hydrocodone q 4–6 h p.r.n. with total daily dose not to exceed 8 tablets
Acetaminophen + oxycodone: Adult dose, one to two tablets containing 325 acetaminophen + 5 to 10 mg oxycodone q 6 h p.r.n. with total daily dose not to exceed 8 tablets
Acetaminophen + tramadol: Adult dose, one to two tablets q 4-6 h p.r.n. (not to exceed 8 tablets per day or 5 days of treatment)

Indications: Pain unresponsive to nonopioid regimens. Most studies show little benefit over nonopioid regimens in chronic musculoskeletal pain.

Mechanism of Action: Acetaminophen (uncertain) inhibits central prostaglandin synthesis. Opioids bind to opioid receptors in CNS and modify pain perception.

Contraindications: Hypersensitivity reactions; opioid or prescription drug abuse

Precautions: Concomitant alcohol use, liver disease and fasting may increase the risk of acetaminophen hepatotoxicity. Avoid or use lower doses with caution in liver disease (usually <2 g/day). Avoid concomitant alcohol. May cause severe hepatotoxicity in overdose. Patient must avoid self-medication with OTC preparations that may also contain acetaminophen. Risk of psychological and physical narcotic dependence should limit use. Avoid dose escalation. Limit dose and duration of therapy if possible. One physician should prescribe all opioids for a particular patient.

Pregnancy Risk: C/D  (neonatal abstinence syndrome)

Adverse Effects: Acetaminophen rarely causes allergy, Stevens-Johnson syndrome, rash, or agranulocytosis. Hepatotoxicity is rare at therapeutic doses. Overdose (usually >8 g/day) causes delayed (48–72 hours) and potentially fatal hepatotoxicity. Controversial evidence links chronic use of acetaminophen to increased risk of renal impairment.

Opioid toxicity (common): GI intolerance, constipation, and dependence are seen with chronic use. Less common are allergy, confusion, dizziness, nervousness, insomnia, and respiratory depression (see individual opioids).

Drug Interactions
Alcohol: Increases risk of hepatotoxicity
Warfarin: Acetaminophen (>2 g/day) may increase the anticoagulant effect
CNS depressants: Effects may be potentiated by opioids

Patient Instructions: Do not exceed prescribed dose. Do not take additional OTC or prescription medications that contain acetaminophen. Do not drink alcohol. May cause drowsiness and constipation. Contains a narcotic and is addictive. Only take for pain. Keep away from children.

Comment: Opioid/narcotic medications are seldom required in the treatment of inflammatory joint disease (i.e., RA, gout). In such conditions, control of inflammation usually controls the associated pain.

Clinical Pharmacology: Acetaminophen oral absorption is rapid and complete. It is 95% metabolized in the liver (mainly conjugation). In overdose, a hepatotoxic metabolite accumulates.

Codeine is methylmorphine, and 10% is metabolized to morphine by cytochrome P450 (CYP) 2D6. Approximately 7% of people have an inactive CYP2D6 enzyme and have little or no analgesic response to codeine. Codeine undergoes hepatic metabolism and renal excretion. Duration of action is 4–6 hours.

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