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, significant 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.

• Hydrocodone is FDA approved for managing severe pain to require an opioid analgesic and for which alternative (non-opioid) treatments are inadequate.[1]
• Hydrocodone is also an antitussive and is indicated for nonproductive 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.[2]

Mechanism of Action

• Hydrocodone is an opioid receptor agonist and produces analgesic effects by activating mu-opioid receptors. Hydrocodone also activates delta-opioid receptors and kappa-opioid receptors as the plasma drug concentration increases beyond typical starting doses.[3][4] 
• Opioid receptors are located primarily within the central nervous system and are in the enteric plexus of the bowel, interstitial cells of Cajal, and immune cells of the gastrointestinal tract. Opioid receptors are G-protein-coupled receptors, and agonist stimulation inhibits cyclic adenosine monophosphate (cAMP) formation, leading to inhibition of nociceptive neurotransmitters' release post-synaptic neuronal hyperpolarization and reduced neuronal excitability.[5][6][7]
• Cough is a protective reflex evoked by airway stimulation. Coughs mediated by mechanical stimulation cough receptors are attenuated by narcotic antitussives primarily at the nucleus tractus solitarius(NTS) level via repression of glutamatergic transmission. Modulation of mu and kappa-opioid receptors possibly contributes to the antitussive activity of opioids. Opioids depress the cough reflex by directly affecting a cough center in the medulla and cause respiratory depression at higher doses.[8][9]

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.

Immediate-release (IR) hydrocodone is available as a combination product (combined with acetaminophen, ibuprofen, etc.). Hydrocodone IR combination product dosages typically range from 2.5 mg to 10 mg every 4 to 6 hours as needed. Clinicians should initiate hydrocodone therapy with 50% of the initial dose in patients with severe hepatic impairment. Similarly, initiate hydrocodone therapy with 50% of the initial dose in end-stage renal disease(ESRD) patients. In hydrocodone formulations combined with acetaminophen, the dosage of acetaminophen should not exceed 4 gm/day.[10][11]

Hydrocodone ER formulations are available in both tablets and capsules. Single-entity hydrocodone is only available in extended-release (ER) formulations. Depending on the product, 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. 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. Hydrocodone is also metabolized to an inactive metabolite, norhydrocodone, by CYP3A4.[12]
• 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.[13]
• There are genetic polymorphisms in CYP2D6 metabolism in different individuals, leading to variations in plasma hydrocodone concentrations from a standard dose. Genetic variants in hydrocodone metabolism include ultra-rapid, extensive, and weak metabolizer phenotypes.[14][15]

Adverse Effects

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

• Respiratory: severe respiratory depression, shortness of breath, respiratory tract infection[10][16] 
• Cardiovascular: hypotension, bradycardia, peripheral edema[17]
• Neurologic: Headache, chills, anxiety, sedation, insomnia, dizziness, drowsiness, fatigue[1]
• Dermatologic: Pruritus, diaphoresis, rash[18]
• Gastrointestinal: Vomiting, dyspepsia, gastroenteritis, abdominal pain[19]
• Genitourinary: Urinary tract infection, urinary retention associated with prostatic hypertrophy[20]
• Otic: Tinnitus, sensorineural hearing loss (SNHL)[21]

Contraindications

• Hypersensitivity to hydrocodone or any component of the formulation
• Bronchial asthma in an unmonitored setting
• Known or suspected gastrointestinal obstruction, including paralytic ileus[22]
• Significant respiratory depression[10]

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 opioid withdrawal syndrome(NOWS). Patients taking hydrocodone should receive counseling on the risks associated with opioid use during pregnancy with such documentation in the medical record.[23]

Breastfeeding

• Maternal hydrocodone use during breastfeeding can cause neonatal drowsiness, depression of the central nervous system, and even death of the newborn. Infants are susceptible to even low dosages of opioids. Contact the clinician immediately if the infant exhibits signs of increased drowsiness (more than usual), difficulty breastfeeding, and breathing difficulties.[24]

Monitoring

Legal Considerations

• The Drug Enforcement Agency(DEA) changed hydrocodone from a schedule III substance to a schedule II substance in October 2014 due to widespread abuse and misuse concerns.

Medical Assessment

• Clinicians should monitor the patients 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.[25] 
• Urine or serum drug testing is recommended before opioid initiation and should merit consideration annually and as needed. In addition, 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.
• Clinicians can use the Opioid Risk Tool (ORT) to identify aberrant behaviors in high-risk patients.[26]  

Drug Interactions

• Taking hydrocodone with central nervous system depressants like alcohol, benzodiazepines, barbiturates, or other opioids, can lead to profound sedation and respiratory depression; hence must be avoided.[27] 
• Medications that induce (rifampin, phenytoin, carbamazepine, etc.) or inhibit (cimetidine, fluoxetine, ritonavir, etc.) cytochrome enzymes should be monitored carefully; this can lead to wide variations in hydrocodone plasma concentrations.[28] 
• Hydrocodone in combination with acetaminophen has a potential drug interaction with warfarin that may lead to an elevated international normalized ratio (INR) and bleeding.[29]

Toxicity

• Signs and symptoms of hydrocodone toxicity are apnea, difficulties in breathing, bradycardia, miosis, clammy skin, cyanosis, hypotension, and loss of consciousness.
• The antidote for overdose is an opioid antagonist medication. Hence, the clinician should administer intravenous naloxone for hydrocodone overdose.
• Indication for Airway management is severe respiratory depression or apnea secondary to hydrocodone toxicity.
• Patients who have taken extended-release preparations need prolonged monitoring even after the reversal, as delayed absorption of hydrocodone is possible.
• Emergency department physicians should refer patients for psychiatric evaluation once the patient is stable.
• It is noteworthy to mention that FDA has approved hydrocodone formulations with abuse-deterrent properties. The manufacture of these formulations is to prevent abuse through chewing, injecting, or snorting.[30]

Enhancing Healthcare Team Outcomes

• Healthcare professionals should comprehend the appropriate indications, adverse drug reactions, and toxicity management to ensure excellent patient outcomes related to hydrocodone therapy.
• 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 necessitates 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 reduce unnecessary exposure to and misuse of opioids.[31]
• Ideally, clinicians should prescribe hydrocodone for appropriate indication considering risks and benefits associated with therapy. Moreover, monitor at each visits the requirement of hydrocodone and aberrant behavior. Whenever prescribing hydrocodone for cough, the clinician should rule out GERD and other disorders.[32]
• The prescription drug monitoring program (PDMP) is an electronic database that tracks controlled substance prescriptions. Clinicians should check in the database before prescribing hydrocodone to prevent multiple refills. It is important to note that data regarding methadone from opiate treatment programs are not available in the PDMP.[33]
• The pharmacist should counsel the patient for the adverse drug reactions associated with hydrocodone therapy and ensure proper dosing considering hepatic and renal function. In case of any doubt, such as early refills, the pharmacist should verify with the prescriber. Likewise, nurses should monitor the pain levels at each visit, the effectiveness of treatment, and watch for signs of adverse events or misuse.
• In case of an overdose of hydrocodone, triage nurses should admit the patient and inform the emergency department physician. The clinician should order the drug levels in urine and evaluate arterial blood gas analysis. Monitor the patient for respiratory depression. Consult the pharmacist about the use of activated charcoal and naloxone. Consult with the intensivist for intensive care unit (ICU) care in severe respiratory depression and paralytic ileus. Once the patient is stable, refer to a psychiatrist and mental health counselor if the overdose is deliberate.[34] 
• The clinician should refer the patient for detoxification if the patient is diagnosed with opioid use disorder. Consequent referral for medication-assisted treatment(MAT) and psychosocial treatment is required to prevent relapse.[35]
• Multiple healthcare providers, including clinicians(MDs, DOs, NPs, PAs), specialists, pharmacists, mental health counselors, and other healthcare professionals, are involved in patient care. Hence it is necessary to work collaboratively to achieve optimal outcomes. An interprofessional team approach would maximize efficacy and minimize adverse drug reactions associated with hydrocodone therapy, improving patient outcomes. [Level 5]