Continuing Education Activity

Hydrocodone is one of the most common pain medications prescribed by clinicians and one of the most abused by patients. It is a relatively potent drug for moderate-to-severe pain control in postoperative patients, patients with trauma, or patients with cancer. The combination of hydrocodone with acetaminophen is much more efficacious in several randomized studies without any significant changes in adverse effects. Moreover, hydrocodone/acetaminophen has common use as an antitussive agent. This activity outlines the indications, mechanism of action, methods of administration, significant adverse effects, contraindications, monitoring, and toxicity of hydrocodone/acetaminophen so that providers can direct patient therapy to optimal outcomes.

Objectives:

• Identify the mechanism of action of hydrocodone/acetaminophen.

• Outline the approved uses for initiating hydrocodone/acetaminophen therapy.

• Summarize the adverse event profile and contraindications to using hydrocodone/acetaminophen.

• Explain interprofessional team strategies for improving care coordination and communication to advance hydrocodone/acetaminophen therapy, improve outcomes, and minimize adverse events and misuse, especially in light of the ongoing opioid crisis.

Indications

Hydrocodone is one of the most common pain medications prescribed by clinicians and one of the most abused by patients. It is a relatively potent drug for moderate-to-severe pain control in postoperative patients, patients with trauma, and patients with cancer. The combination of hydrocodone with acetaminophen is much more efficacious than placebo in several randomized studies without any significant changes in adverse effects.[1] Moreover, hydrocodone/acetaminophen has common use as an antitussive agent.[2]

Mechanism of Action

Hydrocodone is a full opioid agonist that interacts with the mu-receptors and, to a lesser extent, with delta receptors in the body.[3] Activated mu-opioid receptors lead to the inhibition of nociceptive pain reflexes and induce profound analgesia without affecting other sensory modalities, such as touch. Additionally, activated opioid receptors inhibit neurotransmitter release, including substance P.[3] Hydrocodone reaches maximum serum concentrations within 1 hour with an elimination half-life of 4 to 6 hours.[4] Hydrocodone has to be metabolized by cytochrome P450-dependent oxidative metabolism and glucuronides. CYP3A4 generates hydrocodone metabolites norhydrocodone, and CYP2D6 generates hydromorphone.[3]

Acetaminophen's mechanism of action of analgesia is not fully understood. The hypothesis has been that it results from COX inhibition and activation of descending serotonergic inhibitory pathways in the CNS. Antipyretic effects occur via inhibition of the hypothalamic heat-regulating center. Acetaminophen is readily absorbed from the gastrointestinal tract. Plasma protein binding of acetaminophen is about 10 to 25%. The plasma half-life ranges from 1 to 3 hours; however, it may increase due to liver damage following overdose. Approximately 85% of the drug is eliminated in the urine within 24 hours of administration.[5]

Administration

Hydrocodone and acetaminophen combination is available as an oral tablet and oral solution formulation.

• Hydrocodone bitartrate 5 mg / acetaminophen 300 mg 
• Hydrocodone bitartrate 5 mg / acetaminophen 325 mg
• Hydrocodone bitartrate 7.5 mg / acetaminophen 300 mg
• Hydrocodone bitartrate 7.5 mg / acetaminophen 325 mg
• Hydrocodone bitartrate 10 mg / acetaminophen 300 mg
• Hydrocodone bitartrate 10 mg / acetaminophen 325 mg
• Hydrocodone bitartrate 7.5 mg / acetaminophen 325 mg per 15 mL oral solution

 Dosing Regimen for Pain Management

• The lowest dose necessary for adequate analgesia is recommended and should be titrated individually for each patient, considering the severity of pain, response, and prior analgesic experience.
• For initial oral tablet therapy, the usual adult dose of hydrocodone and acetaminophen ( 5 mg / 300 mg) is one or two tablets every four to six hours as needed for pain. The total daily dosage should not be more than eight tablets.
• For initial oral solution therapy, the usual adult dose of solution ( 7.5mg / 325mg per 15 mL) is one tablespoonful (15 mL) every 4 to 6 hours as needed for pain. The total daily dosage for adults should not be more than six tablespoonfuls.
• For the conversion from other opioids to hydrocodone and acetaminophen therapy, it is recommended to underestimate the dose of hydrocodone bitartrate and acetaminophen on 24 hours basis for managing an adverse reaction due to the risk of overdose. The relative bioavailability information is unknown for conversion from extended-release hydrocodone to hydrocodone and acetaminophen therapy. Close monitoring for signs of excessive sedation and respiratory depression is recommended. The dose should be titrated on an individual basis. Continuous reevaluation of the dose of hydrocodone and acetaminophen is needed to maintain adequate pain control, minimize adverse effects, and monitor the development of addiction, abuse, or misuse.
• For patients who may have a physical dependence on opioids, abrupt discontinuation of hydrocodone and acetaminophen therapy may result in severe withdrawal symptoms, uncontrolled pain, and suicidal tendencies. 

 Specific Patients Population 

• Patient with Hepatic Impairment: There is no dose adjustment guidance in the manufacturer label for patients with hepatic impairment. However, initiating therapy with the lowest dose with continuous monitoring is recommended in these patients. 
• Patient with Renal Impairment: There is no dose adjustment guidance in the manufacturer label for patients with renal impairment. However, 26% of hydrocodone and 85% of acetaminophen are eliminated in the urine, so the drug should be used with caution.
• Pregnant Women: It is considered a pregnancy category C medicine. There is a US box warning related to pregnancy. During pregnancy, prolonged use of hydrocodone and acetaminophen can result in neonatal opioid withdrawal syndrome, which may be life-threatening if not recognized early and treated accordingly.
• Breastfeeding Women: Hydrocodone and Acetaminophen are present in breast milk. The decision to continue or discontinue breastfeeding during therapy should be based on the risk of infant exposure versus the benefits of breastfeeding and treatment to the mother.[6][7]
• Pediatric Patients: The dose of hydrocodone for pediatric patients is titrated based on the desired analgesic effect. While considering acetaminophen dose, it is recommended to consider the maximum daily dose of acetaminophen from all other sources like OTC, other prescription, or combination products. The maximum daily dose should not exceed 2000 mg for acetaminophen to minimize hepatotoxicity maximum. Based on the information provided in the hydrocodone and acetaminophen oral solution label, dosing should be calculated as 0.27 mL/kg child weight (equivalent to 0.135 mg/kg hydrocodone and 5.85 mg/kg dose of acetaminophen) whenever possible.
• Geriatric Patients: For safety and efficacy, it is recommended to start the initial dose at the lower end of the dosing range in geriatric patients and monitor patients closely.

Adverse Effects

Opioid-induced constipation, dizziness, nausea, vomiting, drowsiness, and respiratory depression are common adverse reactions of hydrocodone-acetaminophen medication. There have been reports of progressive sensorineural hearing loss with chronic hydrocodone/acetaminophen use that is not responsive to high-dose steroids but responsive to cochlear implantation.[2]

As with all opioids, tolerance leading to ever-increasing doses of opioids to maintain the same level of pain control and physical dependence is the most common side effect. Moreover, acute and chronic opioid administration can inhibit antibody and cellular immune responses, natural killer cell activity, cytokine expression, and phagocytic activity. As a result, there are implications of opioids, pointing to an increased incidence of infections in subjects with heroin use disorder.

Opioid users also suffer from endocrine changes in the body, including but not limited to sexual dysfunction, depression, and decreased energy levels, resulting from hypogonadotropic hypogonadism. Also, opioid-induced hyperalgesia is a recently recognized phenomenon after patients experience increasing pain despite increasing doses of opioids.[2]

Other Adverse Reactions

• Central Nervous System: Lethargy, mental clouding, impairment of the physical and mental performance, fear, anxiety, dysphoria, mood changes, dependence
• Genitourinary System: Ureteral spasm, urinary retention, spasm of vesical sphincters reported with opiates
• Dermatological: Pruritus and skin rash

Contraindications

Contraindications to hydrocodone/acetaminophen include patients with severe respiratory depression, acute or significant bronchial asthma, gastrointestinal obstruction, and anaphylactic reactions due to components of the formula.

As per the manufacturer's label, several drugs interact with hydrocodone/acetaminophen, and caution should be used when they are coadministered.[8][9]

• CYP3A4 and CYP2D6 Inhibitors: The coadministration of hydrocodone and acetaminophen with CYP3A4 inhibitors (erythromycin, ketoconazole, and ritonavir) may lead to an increase in the plasma concentration of the hydrocodone and this may result in increased or prolonged opioid effects. These effects may be more pronounced when CYP3A4 and CYP2D6 inhibitors are coadministered with hydrocodone and acetaminophen.
• CYP3A4 Inducers: The coadministration of hydrocodone and acetaminophen with CYP3A4  inducers (rifampin, carbamazepine, and phenytoin) may lead to a decrease in the plasma concentration of hydrocodone, and this may result in decreased efficacy.
• Benzodiazepines or Other CNS Depressants: The coadministration of hydrocodone and acetaminophen with benzodiazepines or other CNS depressants, due to its additive pharmacologic effect, may lead to an increase in the risk of hypotension, respiratory depression, severe sedation, coma, and death.
• Serotonergic Drugs: The coadministration of hydrocodone and acetaminophen with other drugs that affect the serotonergic neurotransmitter system (selective serotonin reuptake inhibitors, serotonin and norepinephrine reuptake inhibitors, tricyclic antidepressants, triptans, 5-HT3 receptor antagonists) or with drugs that affect the serotonin neurotransmitter system (mirtazapine, trazodone, tramadol cyclobenzaprine, metaxalone, monoamine oxidase inhibitors) may result in serotonin syndrome. 
• Mixed Agonist/Antagonist and Partial Agonist Opioid Analgesics: The coadministration of hydrocodone and acetaminophen with other opioid analgesics (butorphanol, nalbuphine, pentazocine) may lead to reducing the analgesic effect of opioids and/or precipitate withdrawal symptoms.
• Muscle Relaxants: The coadministration of hydrocodone and acetaminophen with muscle relaxants may enhance the neuromuscular blocking action and induce a higher degree of respiratory depression.
• Diuretics: The coadministration of hydrocodone and acetaminophen with other diuretics may reduce the efficacy of diuretics due to the induction of antidiuretic hormone.
• Anticholinergic Drugs: The coadministration of hydrocodone and acetaminophen with anticholinergic drugs may increase the risk of urinary retention and/or severe constipation.

Monitoring

Pain relief and adverse events should undergo frequent assessments. The dosing should start low and slow and titrated up as necessary to obtain adequate analgesia while having minimal side effects.

Hydrocodone is a DEA Schedule II controlled substance, and it has a potential for abuse, misuse, and use disorder. Consequently, it is vital to monitor patients for addiction, abuse, and misuse signs. In addition, patients with a prior history of drug addiction or mental illness have a higher risk of addiction.

For toxicity monitoring, obtain serial liver function tests in patients with severe hepatic disease. Also, monitor serial renal function in elderly patients and patients with severe renal disease.

The clinicians should monitor the following physical findings for signs of toxicity.

• Signs of confusion and over-sedation in the elderly
• Addiction, abuse, or misuse behaviors and conditions during treatment
• Signs of respiratory depression, especially within 24 to 72 hours of treatment initiation and after dose increases
• Signs and symptoms of respiratory depression and sedation in patients susceptible to the intracranial effects of carbon dioxide retention
• Severe hypotension at the start of treatment and dose modification
• In patients with a history of seizure disorders, monitor for worsened seizure control

Toxicity

Acetaminophen has been associated with fatal hepatic necrosis if taken at doses of more than 4 g per day, especially with the ingestion of another acetaminophen-containing product. Furthermore, large doses may cause difficulty with breathing. In overdose, activated charcoal should be the first attempted intervention before N-acetylcysteine (NAC). The serum acetaminophen level should be obtained promptly for patients presenting for 4 hours or later.

Hydrocodone intake may lead to life-threatening respiratory depression, especially if taken together with benzodiazepines or other CNS depressants. In case of overdose, the first step is to protect the airways and place the patient on invasive ventilation assistance, if needed. The opioid antagonists, nalmefene or naloxone, are specific antidotes for respiratory depression. Opioid antagonists should be avoided in the absence of clinically significant respiratory or circulatory depression. In addition, there is a high risk of precipitating acute opioid withdrawal in an individual who is physically dependent on opioids.

Enhancing Healthcare Team Outcomes

It is not surprising that, without proper barriers and monitoring for the detrimental effects of hydrocodone and acetaminophen intoxication, the morbidity and mortality of using opioid analgesia can be quite substantial. The drug information sheet from the manufacturer emphasizes in bold letters the importance of warning patients of misuse of and addiction to hydrocodone and acetaminophen, which can lead to overdose and death. Multiple efforts point toward reducing prescription abuse and misuse.

The mitigation of opioid overdose and misuse risk starts from the system-level intervention by clinicians and nurses prescribing narcotics. In addition, the Prescription Drug Monitoring Program and Medicaid managed care lock-in program require that patients receive all scripts from a single prescriber. Although over 55% dropped from the program, the proportion of stable patients, ie, patients exclusively filled from one prescriber, increased from 31% to 78% at 36 months.[10] [Level 4]

Pharmacists should use formulary management tools to address both opioid overprescribing and overdose. One is a prior authorization requirement placed by the insurance companies to verify the medication is necessary. Cochran et al. conducted a retrospective cohort study evaluating the effects of prior authorization on the rate of abuse and overdose of patients enrolled in the Pennsylvania Medicaid program from 2010 to 2012. The study demonstrated that plans with prior authorization requirements had lower rates of use disorder and overdose.[11] [Level 4]

All in all, there is a battle to reduce the opioid prescription crisis, and still, rates of overdose continue. Numerous interventions show some promise in mitigating this problem, and it truly takes an interprofessional team, including clinicians, mid-level practitioners, nurses, and pharmacists, to achieve this goal. [Level 5]