325 5 norco. Hydrocodone and Acetaminophen: Proper Use, Dosage, and Precautions

07.11.202215.07.2023 by alexxlab

What is the proper use of hydrocodone and acetaminophen combination. How to administer hydrocodone and acetaminophen safely. What are the indications and mechanism of action for hydrocodone and acetaminophen. How to dose hydrocodone and acetaminophen for pain management. What are the adverse effects and contraindications of hydrocodone and acetaminophen.

Содержание

Understanding Hydrocodone and Acetaminophen Combination

Hydrocodone and acetaminophen combination is a widely prescribed medication for managing moderate to severe pain. This potent analgesic formulation combines the opioid properties of hydrocodone with the pain-relieving and fever-reducing effects of acetaminophen. Healthcare providers often prescribe this medication for postoperative patients, those with trauma, and individuals suffering from cancer-related pain.

The efficacy of this combination has been demonstrated in several randomized studies, showing superior pain relief compared to placebo without significant increases in adverse effects. Additionally, hydrocodone/acetaminophen finds use as an antitussive agent, helping to suppress cough in certain clinical scenarios.

Key Components of the Combination

Hydrocodone: An opioid analgesic
Acetaminophen: A non-opioid pain reliever and antipyretic

Mechanism of Action: How Hydrocodone and Acetaminophen Work

Understanding the mechanism of action of hydrocodone and acetaminophen is crucial for healthcare providers to optimize patient therapy. Each component of this combination medication works through distinct pathways to provide pain relief.

Hydrocodone’s Mechanism

Hydrocodone functions as a full opioid agonist, primarily interacting with mu-opioid receptors and, to a lesser extent, delta receptors in the body. When activated, these receptors initiate a cascade of events that lead to potent analgesia:

Inhibition of nociceptive pain reflexes
Reduction in the perception of pain without affecting other sensory modalities
Suppression of neurotransmitter release, including substance P

Hydrocodone reaches peak serum concentrations within an hour of administration and has an elimination half-life of 4 to 6 hours. Importantly, it requires metabolism by the CYP2D6 enzyme to convert into its active form, hydromorphone.

Acetaminophen’s Mechanism

While the exact mechanism of acetaminophen’s analgesic action remains not fully elucidated, current hypotheses suggest it works through:

Inhibition of cyclooxygenase (COX) enzymes
Activation of descending serotonergic inhibitory pathways in the central nervous system
Antipyretic effects via inhibition of the hypothalamic heat-regulating center

Acetaminophen is rapidly absorbed from the gastrointestinal tract, with plasma protein binding ranging from 10% to 25%. Its plasma half-life typically spans 1 to 3 hours, though this can be prolonged in cases of liver damage following overdose.

Administration and Dosage Forms of Hydrocodone/Acetaminophen

The hydrocodone and acetaminophen combination is available in various formulations to cater to different patient needs and pain management scenarios. Healthcare providers should be familiar with these options to select the most appropriate form for each patient.

Available Formulations

Oral tablets:
- 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
Oral solution:
- Hydrocodone bitartrate 7.5 mg / acetaminophen 325 mg per 15 mL

The availability of multiple strengths and formulations allows for precise dosing tailored to individual patient needs and pain severity.

Dosing Regimen for Effective Pain Management

Proper dosing of hydrocodone/acetaminophen is critical for achieving optimal pain relief while minimizing the risk of adverse effects. Healthcare providers should adhere to the principle of using the lowest effective dose for the shortest duration necessary.

Initial Dosing for Oral Tablets

For adults starting oral tablet therapy:

Usual dose: One or two tablets of hydrocodone 5 mg / acetaminophen 300 mg every four to six hours as needed for pain
Maximum daily dosage: Not to exceed eight tablets

Initial Dosing for Oral Solution

For adults beginning oral solution therapy:

Usual dose: One tablespoonful (15 mL) of solution containing hydrocodone 7.5 mg / acetaminophen 325 mg every 4 to 6 hours as needed for pain
Maximum daily dosage: Not to exceed six tablespoonfuls

It’s crucial to note that these are general guidelines, and dosing should be individualized based on the patient’s pain severity, response to treatment, and prior analgesic experience.

Dosing Considerations for Opioid-Tolerant Patients

When converting patients from other opioids to hydrocodone/acetaminophen therapy, healthcare providers should exercise caution:

Initially underestimate the 24-hour hydrocodone dose to manage potential adverse reactions
Closely monitor for signs of excessive sedation and respiratory depression
Titrate the dose individually, considering the patient’s response and tolerability

The relative bioavailability for conversion from extended-release hydrocodone to immediate-release hydrocodone/acetaminophen is not well-established, necessitating careful monitoring and adjustment.

Adverse Effects and Safety Considerations

While hydrocodone/acetaminophen can be highly effective for pain management, it’s associated with a range of potential adverse effects. Healthcare providers and patients should be aware of these risks to ensure safe and appropriate use.

Common Adverse Effects

Gastrointestinal disturbances: nausea, vomiting, constipation
Central nervous system effects: dizziness, drowsiness, confusion
Respiratory depression (especially at higher doses or in opioid-naive patients)
Pruritus and sweating
Headache

Serious Adverse Effects

More severe adverse effects, while less common, can occur and require immediate medical attention:

Severe respiratory depression
Liver toxicity (due to acetaminophen, especially in overdose or chronic high-dose use)
Addiction and physical dependence
Serotonin syndrome (when combined with other serotonergic medications)
Adrenal insufficiency with prolonged use

Healthcare providers should educate patients about these potential risks and the importance of adhering to prescribed dosages.

Contraindications and Precautions

Certain conditions and factors contraindicate the use of hydrocodone/acetaminophen or necessitate extra caution. Understanding these contraindications is crucial for safe prescribing practices.

Absolute Contraindications

Known hypersensitivity to hydrocodone, acetaminophen, or any component of the formulation
Significant respiratory depression
Acute or severe bronchial asthma in an unmonitored setting or absence of resuscitative equipment
Known or suspected gastrointestinal obstruction, including paralytic ileus

Relative Contraindications and Precautions

Certain conditions require careful consideration and potential dose adjustments:

Hepatic impairment
Renal impairment
Chronic obstructive pulmonary disease (COPD) or cor pulmonale
History of substance abuse or addiction
Elderly or debilitated patients
Pregnancy and breastfeeding

In these cases, healthcare providers should weigh the potential benefits against the risks and consider alternative pain management strategies when appropriate.

Monitoring and Toxicity Management

Proper monitoring is essential when prescribing hydrocodone/acetaminophen to ensure therapeutic efficacy and minimize the risk of adverse effects and toxicity.

Regular Monitoring Parameters

Pain intensity and functional improvement
Respiratory rate and depth
Signs of sedation
Liver function tests, especially with prolonged use
Signs of physical dependence or addiction

Managing Toxicity

In cases of suspected overdose or toxicity, prompt action is crucial:

Opioid toxicity: Administration of naloxone and supportive care
Acetaminophen toxicity: N-acetylcysteine treatment and liver function monitoring
Respiratory depression: Airway management and ventilatory support if needed

Healthcare providers should have protocols in place for managing potential toxicities and educate patients on signs of overdose to seek immediate medical attention.

Interprofessional Team Strategies for Optimal Use

Effective pain management with hydrocodone/acetaminophen requires a coordinated effort from an interprofessional healthcare team. This approach can improve patient outcomes, minimize adverse events, and reduce the risk of misuse or addiction.

Key Team Members and Roles

Prescribing physicians: Assess pain, determine appropriate dosing, and monitor efficacy
Pharmacists: Review drug interactions, provide patient education on proper use and potential side effects
Nurses: Monitor patient response, assess for adverse effects, and provide ongoing education
Pain specialists: Consult on complex cases or when escalation of pain management is needed
Mental health professionals: Address psychological aspects of pain and screen for substance abuse risk

Strategies for Improved Care Coordination

Implement standardized pain assessment tools across the care team
Establish clear communication channels for reporting patient progress and concerns
Develop and adhere to institutional protocols for opioid prescribing and monitoring
Utilize electronic health records to track prescriptions and flag potential misuse
Conduct regular team meetings to discuss complex cases and update treatment strategies

By employing these interprofessional strategies, healthcare teams can optimize the use of hydrocodone/acetaminophen, improving pain management outcomes while mitigating risks associated with opioid therapy.

Hydrocodone and Acetaminophen – StatPearls

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.

Access free multiple choice questions on this topic.

Indications

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 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 CYP2D6 to its active form, 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 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 taking into account the severity of pain, response, and prior analgesic experience.
For initial oral tablets 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. So 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 tendency.

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 as 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 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 experienced 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 may 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 since 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 the 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 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). For patients presenting for 4 hours or later, the serum acetaminophen level should be obtained promptly.

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 abuse, misuse, and addiction of 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, i.e., 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 of them is a prior authorization requirement placed by the insurance companies to verify that 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]

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References

1.: Vardy J, Agar M. Nonopioid drugs in the treatment of cancer pain. J Clin Oncol. 2014 Jun 01;32(16):1677-90. [PubMed: 24799483]
2.: Benyamin R, Trescot AM, Datta S, Buenaventura R, Adlaka R, Sehgal N, Glaser SE, Vallejo R. Opioid complications and side effects. Pain Physician. 2008 Mar;11(2 Suppl):S105-20. [PubMed: 18443635]
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6.: Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): Sep 19, 2022. Hydrocodone. [PubMed: 30000284]
7.: Drugs and Lactation Database (LactMed®) [Internet]. National Institute of Child Health and Human Development; Bethesda (MD): Mar 21, 2022. Acetaminophen. [PubMed: 30000253]
8.: Monte AA, Heard KJ, Campbell J, Hamamura D, Weinshilboum RM, Vasiliou V. The effect of CYP2D6 drug-drug interactions on hydrocodone effectiveness. Acad Emerg Med. 2014 Aug;21(8):879-85. [PMC free article: PMC4150819] [PubMed: 25156930]
9.: Lee D, Stout P, Egdorf D. Houston Cocktail: Driving under influence of hydrocodone, alprazolam, and carisoprodol. Forensic Sci Int. 2021 Apr 28;323:110819. [PubMed: 33964487]
10.: Dreyer TR, Michalski T, Williams BC. Patient Outcomes in a Medicaid Managed Care Lock-In Program. J Manag Care Spec Pharm. 2015 Nov;21(11):1006-12. [PubMed: 26521112]
11.: Cochran G, Gordon AJ, Gellad WF, Chang CH, Lo-Ciganic WH, Lobo C, Cole E, Frazier W, Zheng P, Kelley D, Donohue JM. Medicaid prior authorization and opioid medication abuse and overdose. Am J Manag Care. 2017 May 01;23(5):e164-e171. [PMC free article: PMC6719534] [PubMed: 28810127]

: Disclosure: Manuchehr Habibi declares no relevant financial relationships with ineligible companies.
: Disclosure: Peggy Kim declares no relevant financial relationships with ineligible companies.