Introduction
Hydrocodone is a semi-synthetic opioid analgesic derived from codeine that is widely prescribed for the management of moderate to severe pain. It is typically formulated in combination with non-opioid analgesics such as acetaminophen or ibuprofen to enhance its therapeutic effects. As a Schedule II controlled substance in the United States, hydrocodone carries significant abuse potential and requires careful clinical oversight.
Mechanism of Action
Hydrocodone exerts its analgesic effects primarily through agonist activity at mu-opioid receptors in the central nervous system. This binding inhibits nociceptive neurotransmission in the spinal cord and brain, altering pain perception. Additionally, hydrocodone affects the medullary cough center, providing antitussive properties. Its activity at opioid receptors also produces euphoric effects that contribute to its abuse potential.
Indications
- Management of pain severe enough to require an opioid analgesic
- Alternative treatment for cough in adults (limited to specific formulations)
- FDA-approved for persistent pain that requires around-the-clock treatment (extended-release formulations)
Dosage and Administration
Immediate-release formulations:- Adults: 2.5-10 mg every 4-6 hours as needed for pain
- Maximum daily dose: Typically limited by acetaminophen content (≤4,000 mg/day)
- Opioid-naïve patients: Start with 10 mg every 12 hours
- Titrate gradually based on pain control and tolerability
- Renal impairment: Reduce dose by 25-50% for CrCl <30 mL/min
- Hepatic impairment: Use with caution and consider dose reduction
- Elderly: Start with lower doses due to increased sensitivity
- Pediatrics: Safety and effectiveness not established in patients <18 years
Pharmacokinetics
- Absorption: Well absorbed from GI tract; bioavailability ~50% due to first-pass metabolism
- Distribution: Vd ~4 L/kg; crosses placenta and blood-brain barrier
- Metabolism: Extensive hepatic metabolism via CYP3A4 to hydromorphone (active) and norhydrocodone
- Elimination: Renal excretion (primarily as metabolites); half-life ~4 hours
Contraindications
- Significant respiratory depression
- Acute or severe bronchial asthma
- Known or suspected gastrointestinal obstruction
- Hypersensitivity to hydrocodone or formulation components
- Concurrent use with monoamine oxidase inhibitors (MAOIs) or within 14 days
Warnings and Precautions
Black Box Warnings:- Risk of addiction, abuse, and misuse
- Life-threatening respiratory depression
- Accidental ingestion by children can be fatal
- Neonatal opioid withdrawal syndrome with prolonged use during pregnancy
- Cytochrome P450 3A4 interaction risk
- Risks from concomitant use with benzodiazepines or other CNS depressants
- Increased risk in elderly, cachectic, or debilitated patients
- Head injury and increased intracranial pressure
- Seizure disorders
- Adrenal insufficiency
- Severe hepatic or renal impairment
- Risk of paralytic ileus
Drug Interactions
Major interactions:- CYP3A4 inhibitors (ketoconazole, clarithromycin): ↑ hydrocodone levels
- CYP3A4 inducers (rifampin, carbamazepine): ↓ hydrocodone efficacy
- Benzodiazepines, alcohol, other CNS depressants: ↑ respiratory depression
- Serotonergic drugs: ↑ risk of serotonin syndrome
- Anticholinergic drugs: ↑ risk of urinary retention and constipation
Adverse Effects
Common (≥10%):- Constipation
- Nausea
- Vomiting
- Somnolence
- Dizziness
- Pruritus
- Respiratory depression
- Hypotension
- Adrenal insufficiency
- Androgen deficiency
- Anaphylaxis
- Seizures
- Serotonin syndrome
Monitoring Parameters
- Pain intensity and relief scores
- Respiratory rate and oxygen saturation
- Blood pressure, especially during initiation
- Bowel function and need for laxatives
- Signs of misuse or addiction
- Mental status changes
- Renal and hepatic function in long-term use
- Signs of hypogonadism with chronic use
Patient Education
- Take exactly as prescribed; do not crush or chew extended-release tablets
- Avoid alcohol and other CNS depressants
- Report difficulty breathing or unusual drowsiness immediately
- Manage constipation with increased fluids, fiber, and laxatives if needed
- Do not share medication with others
- Proper storage and disposal to prevent accidental ingestion
- Potential for dependence and withdrawal if stopped abruptly
- Avoid driving or operating machinery until effects are known
- Inform all healthcare providers of hydrocodone use
References
1. FDA Prescribing Information: Hydrocodone Bitartrate 2. Trescot AM, Datta S, Lee M, Hansen H. Opioid pharmacology. Pain Physician. 2008;11(2 Suppl):S133-S153. 3. Benyamin R, Trescot AM, Datta S, et al. Opioid complications and side effects. Pain Physician. 2008;11(2 Suppl):S105-S120. 4. Chou R, Fanciullo GJ, Fine PG, et al. Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain. 2009;10(2):113-130. 5. Webster LR, Cochella S, Dasgupta N, et al. An analysis of the root causes for opioid-related overdose deaths in the United States. Pain Med. 2011;12 Suppl 2:S26-S35. 6. Clinical Pharmacology [Internet]. Tampa (FL): Elsevier. Hydrocodone. Updated 2023. 7. UpToDate: Hydrocodone drug information. Wolters Kluwer Health.