Continuing Education Activity

Hydrocodone is a schedule II semi-synthetic opioid medication used to treat pain. Hydrocodone is also an antitussive indicated for cough in adults. In January 2018, the FDA required safety labeling changes for prescription cough and cold medicines containing hydrocodone or codeine to limit the use of these products to adults 18 years of age and older. This activity outlines the indications, mechanism of action, methods of administration, important adverse effects, contraindications, monitoring, and toxicity of hydrocodone so that providers can direct patient therapy to optimal outcomes.

Objectives:

• Identify the mechanism of action of hydrocodone.
• Outline the approved uses for initiating hydrocodone therapy.
• Summarize the adverse event profile and contraindications to using hydrocodone.
• Explain interprofessional team strategies for improving care coordination and communication to advance hydrocodone therapy and improve outcomes and minimize adverse events and misuse, especially in light of the ongoing opioid crisis.

Indications

Hydrocodone is a schedule II semi-synthetic opioid medication used to treat pain. Immediate-release (IR) hydrocodone is available as a combination product (combined with acetaminophen, ibuprofen, etc.) and is FDA approved for the management of pain severe enough to require an opioid analgesic and for which alternative (non-opioid) treatments are inadequate. Single-entity hydrocodone is only available in extended-release (ER) formulations. It is FDA approved to treat persistent pain severe enough to require 24-hour, long-term opioid treatment, and for which alternative treatments are inadequate. Hydrocodone is also an antitussive and indicated for cough in adults. In January 2018, the FDA required safety labeling changes for prescription cough and cold medicines containing hydrocodone or codeine to limit the use of these products to adults 18 years of age and older.

Mechanism of Action

Hydrocodone is an opioid receptor agonist and produces its analgesic effects by activating mu-opioid receptors.[1] Hydrocodone also activates delta-opioid receptors and kappa-opioid receptors as the plasma drug concentration increases beyond typical starting doses.[2] Opioid receptors are located primarily within the central nervous system but also are in the enteric plexus of the bowel, interstitial cells of Cajal, and immune cells of the gastrointestinal tract.[3] Opioid receptors are G-protein-coupled receptors, and agonist stimulation inhibits the formation of cyclic adenosine monophosphate (cAMP), leading to inhibition of the release of nociceptive neurotransmitters, post-synaptic neuronal hyperpolarization, and reduced neuronal excitability.

Administration

Hydrocodone is pharmaceutically available as an oral medication with formulations, including tablets, capsules, and oral solutions. Tablets and capsules are not to be crushed, chewed, or dissolved, as this can lead to uncontrolled rapid medication delivery and overdose.

Hydrocodone IR combination product dosages typically range from 2.5 mg to 10 mg every 4 to 6 hours as needed. There is no dosage modification necessary for patients with renal or hepatic dysfunction. In hydrocodone formulations combined with acetaminophen, the dosage of acetaminophen should not exceed 4 gm/day.

Hydrocodone ER formulations are available in both tablets and capsules. The initial dose of hydrocodone ER formulations in patients who are not opioid-tolerant or are opioid-naïve is between 10 mg to 20 mg every 12 hours to 24 hours, depending on the product. Patients should receive instruction to discontinue all other opioids when starting on a hydrocodone ER medication unless specifically directed by a physician.

Pharmacokinetics

Hydrocodone is metabolized in the liver primarily via the cytochrome P450 enzymes CYP2D6 and CYP3A4. Hydrocodone converts to its active metabolite, hydromorphone, through O-demethylation catalyzed by the CYP2D6 enzyme. Studies have shown that pain relief correlates with plasma concentrations of hydromorphone rather than hydrocodone.[4] Hydrocodone is also metabolized to an inactive metabolite, norhydrocodone, by CYP3A4.[5] There are genetic polymorphisms in CYP2D6 metabolism in different individuals that can lead to variations in plasma hydrocodone concentrations from a standard dose. Genetic variants in hydrocodone metabolism include ultra-rapid, extensive, and weak metabolizer phenotypes.[6]

Hydrocodone IR and ER reach a maximum serum concentration within 1 hour and 5 to 30 hours, respectively.

The half-life elimination of hydrocodone IR and ER is about 4 hours and 7 to 12 hours, respectively.

The excretion of hydrocodone and its metabolites is via the urine.

Adverse Effects

The most common adverse effects of hydrocodone are constipation and nausea (>10%). Other adverse effects of hydrocodone include:

Respiratory: Respiratory depression, cough, shortness of breath

Cardiovascular: Hypotension, hypertension, peripheral edema

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

Dermatologic: Pruritus, diaphoresis, rash

Gastrointestinal: Vomiting, diarrhea, dyspepsia, gastroenteritis, abdominal pain

Genitourinary: Urinary tract infection, urinary retention associated with prostatic hypertrophy

Otologic: Tinnitus

Contraindications

Contraindications to the use of hydrocodone include:

• Hypersensitivity to hydrocodone or any component of the formulation
• Significant respiratory depression
• Known or suspected GI obstruction, including paralytic ileus
• Bronchial asthma in an unmonitored setting

Pregnancy

The use of hydrocodone is not contraindicated in pregnancy but is listed as a US Boxed Warning since opioids cross the placenta, and prolonged use during pregnancy may cause neonatal withdrawal syndrome. Patients taking hydrocodone should receive counseling of the risks associated with opioid use during pregnancy with documentation of such in the medical record.

Breastfeeding

Maternal hydrocodone use during breastfeeding can cause neonatal drowsiness, depression of the central nervous system, and even death of the newborn. Infants are particularly sensitive to even low dosages of opioids.[7]

Monitoring

The Drug Enforcement Agency (DEA) changed hydrocodone from a schedule III substance to a schedule II substance in October 2014 due to concerns of widespread abuse and misuse.[8] Patients initiating hydrocodone should undergo monitoring for pain relief, constipation, respiratory depression, and other adverse effects. The risk of respiratory depression is highest following the initiation of therapy or after an increase in dose. Patients should also undergo monitoring for signs of abuse, misuse, and addiction. Opioids have a narrow therapeutic index and wide variability in response between patients.

Urine or serum drug testing is recommended before opioid initiation and should merit consideration annually and as needed. Close follow up should be performed soon after treatment initiation with a re-evaluation of the risks and benefits of continued opioid therapy at least every three months.

Drug Interactions

Taking hydrocodone with other central nervous system depressants, such as alcohol, benzodiazepines, barbiturates, or other opioids, can lead to profound sedation and respiratory depression and should be avoided.

Patients taking medications that induce (rifampin, phenytoin, carbamazepine, etc.) or inhibit (cimetidine, fluoxetine, ritonavir, etc.) cytochrome enzymes should be cautioned and monitored carefully, as this can lead to wide variations in hydrocodone plasma concentrations.

When administering hydrocodone in combination with acetaminophen, there is a potential interaction with warfarin that may lead to an elevated international normalized ratio (INR) and bleeding.[9]

Toxicity

Signs and symptoms of hydrocodone toxicity include difficulty breathing, apnea, bradycardia, miosis, clammy skin, cyanosis, hypotension, and loss of consciousness. The antidote for opioid overdose is an opioid antagonist medication, such as naloxone. An opioid antagonist is necessary, in the event of a suspected hydrocodone overdose. Airway management is also a possible indication for severe respiratory depression or apnea secondary to hydrocodone toxicity.

The Federal Drug Administration (FDA) has approved hydrocodone formulations with abuse-deterrent properties. The manufacture of these formulations is to prevent abuse through chewing, injecting, or snorting.[10]

Enhancing Healthcare Team Outcomes

Healthcare professionals must be knowledgeable about the signs, symptoms, and management of hydrocodone toxicity and abuse to ensure good patient outcomes.

In September 2018, to reduce the abuse and misuse of opioid analgesics, including hydrocodone, the FDA mandated the training program Risk Evaluation and Mitigation Strategy (REMS) for all drug company personnel with approved opioid analgesics. This program requires training in the fundamentals of acute and chronic pain management and the risks and safe use of opioids by all healthcare providers, including physicians, nurses, and pharmacists who manage patients with pain. The REMS program aims to promote education about safe opioid prescribing recommendations and to reduce unnecessary exposure to and abuse of opioids.