Hydrocodone functions as an opioid receptor agonist and activates mu-opioid receptors to produce analgesic effects. In addition, hydrocodone activates delta- and kappa-opioid receptors as the plasma drug concentration increases beyond the starting doses. This activity focuses on single-ingredient hydrocodone for pain relief. This activity outlines the indications, mechanism of action, significant adverse effects, contraindications, monitoring, toxicity, and other critical elements of hydrocodone therapy in the clinical setting. These details are essential for the interprofessional healthcare teams responsible for managing the care of patients with pain and related conditions and sequelae.

Objectives:

• Identify appropriate indications for hydrocodone therapy, distinguishing between its use in severe chronic pain and nonproductive cough in adults.

• Assess patients for pain relief while monitoring both the effectiveness of hydrocodone and any potential adverse effects, signs of misuse, or addiction.

• Select the most appropriate formulation and strength of hydrocodone based on the patient's pain intensity, duration, and individual needs, considering factors such as age, renal or hepatic impairment, and potential drug interactions.

• Collaborate with an interprofessional healthcare team, including physicians, pharmacists, mental health counselors, pain management specialists, and addiction specialists, to optimize patient outcomes and ensure comprehensive care.

Adverse Effects

The most common adverse effects of hydrocodone include frequent constipation and nausea. Additional adverse effects of hydrocodone include the following:

• Respiratory: Severe respiratory depression, shortness of breath, respiratory tract infection 

• Cardiovascular: Hypotension, bradycardia, and peripheral edema 

• Neurologic: Headache, chills, anxiety, sedation, insomnia, dizziness, drowsiness, and fatigue 

• Dermatologic: Pruritus, diaphoresis, and rash

• Gastrointestinal: Vomiting, dyspepsia, gastroenteritis, constipation, and abdominal pain Genitourinary: Urinary tract infection and urinary retention associated with prostatic hypertrophy 

• Otic: Tinnitus and sensorineural hearing loss (SNHL)

• Endocrine: Secondary adrenal insufficiency

Drug-Drug Interactions

• Concurrent use of hydrocodone with central nervous system depressants, such as alcohol, benzodiazepines, barbiturates, or other opioids, can result in profound sedation and respiratory depression; therefore, these combinations must be avoided.

• Medications that induce (eg, rifampin, phenytoin, and carbamazepine) or inhibit (eg, cimetidine, fluoxetine, and ritonavir) cytochrome enzymes should be closely monitored. This can result in significant variations in hydrocodone plasma concentrations.

• The combination of hydrocodone and acetaminophen poses a potential drug interaction with warfarin, causing an elevated international normalized ratio (INR) and an increased risk of bleeding.

• Concurrent use of hydrocodone with CYP3A4 inhibitors or discontinuation of CYP3A4 inducers can result in a fatal overdose of hydrocodone. Consequently, it is crucial to avoid this combination.

Contraindications

Contraindications to hydrocodone use include:

• Hypersensitivity to hydrocodone or any component of the formulation

• Bronchial asthma in an unmonitored setting

• Known or suspected gastrointestinal obstruction, including paralytic ileus [

• Significant respiratory depression 

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• Monitoring

Legal Considerations

Owing to widespread abuse and misuse concerns, the Drug Enforcement Agency (DEA) reclassified hydrocodone combination products from Schedule III to Schedule II drugs in October 2014. A study indicates that this rescheduling is associated with a substantial decrease in hydrocodone overdose rates

Medical Assessment

• Clinicians should vigilantly monitor patients for pain relief, constipation, respiratory depression, and other potential adverse effects. Any adverse effects that arise should be promptly addressed and treated as necessary.

• The highest risk of respiratory depression occurs after initiating therapy or increasing the dose. Consideration should be given to providing a monitored setting for selected high-risk patients starting opioid therapy or undergoing dosage escalation. Patients should also undergo monitoring for signs of abuse, misuse, and addiction. Caution is advised due to opioids' narrow therapeutic index and the substantial variability in response among patients.

• Urine or serum drug testing is recommended before initiating opioid therapy and should be considered annually and as needed. In addition, close follow-up should be conducted shortly after treatment initiation, involving a re-evaluation of the risks and benefits of continued opioid therapy at least every 3 months or sooner for high-risk patients.

• Clinicians can use the Opioid Risk Tool (ORT) to identify aberrant behaviors in high-risk patients.

• Morphine milligram equivalence (MME) should be used for conversion, considering factors such as age, pharmacogenetics, hepatic and renal function, and concurrent use of benzodiazepines. The Centers for Disease Control and Prevention (CDC) advises exercising caution when the daily dosage exceeds 50 MME.

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• Prevention of Medical Errors

Hydrocodone may be mistaken for oxycodone. To prevent prescribing errors, the Institute of Safe Medical Practices (ISMP) recommends using Tallman lettering (oxyCODONE/HYDROcodone).

Toxicity

The signs and symptoms of hydrocodone toxicity include apnea, breathing difficulties, bradycardia, miosis, clammy skin, cyanosis, hypotension, decreased level of consciousness, and loss of consciousness. Overdose-related pulmonary complications include noncardiogenic pulmonary edema and aspiration pneumonitis. Central respiratory depression leading to CO2 retention often results in respiratory acidosis. 

Management of Overdose

The antidote for overdose is an opioid antagonist medication. Clinicians should administer intravenous naloxone for hydrocodone overdose. Naloxone can be administered through intravenous, intramuscular, intranasal, subcutaneous, and endotracheal routes. Patients with low respiratory rates or apnea should receive an initial dose of 0.4 to 2 mg of naloxone. For patients who develop respiratory failure, administration of 2 mg of naloxone is recommended. Naloxone dosing may be repeated every 2 to 3 minutes, depending on the clinical response. If the patient shows signs of opioid withdrawal, the naloxone infusion should be stopped.

Opioid receptors are G-protein-coupled receptors. Agonist stimulation inhibits cAMP formation, inhibiting nociceptive neurotransmitters' release, postsynaptic neuronal hyperpolarization, and reduced neuronal excitability

Naloxone, a highly competitive mu-receptor antagonist, reverses the inhibition of cAMP formation and nociceptive neurotransmitters' release and reverses the postsynaptic neuronal hyperpolarization and reduced neuronal excitability. This reversal extends to clinical signs and symptoms of opioid toxicity, including respiratory depression and decreased level of consciousness.

The indication for airway management is severe respiratory depression or apnea secondary to hydrocodone toxicity. In acute respiratory distress syndrome cases, management involves ensuring adequate oxygenation, utilizing low tidal volume ventilation, and applying high positive end-expiratory pressure (PEEP). Caution is essential to prevent ventilator-induced lung injury.

Patients who have taken ER preparations require prolonged monitoring even after the reversal, as delayed absorption of hydrocodone is possible. Emergency department clinicians should refer stabilized patients to psychiatric evaluation.

The FDA has approved hydrocodone formulations with abuse-deterrent properties. These formulations are designed to deter misuse by preventing chewing, injecting, or snorting.Hydrocodone can cause life-threatening secondary adrenal insufficiency, which requires immediate corticosteroid replacement.[