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

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 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]

Review Questions

• Access free multiple choice questions on this topic.

• Comment on this article.

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]

3.

Sarhill N, Walsh D, Nelson KA. Hydromorphone: pharmacology and clinical applications in cancer patients. Support Care Cancer. 2001 Mar;9(2):84-96. [PubMed: 11305075]

4.

Smith HS. The metabolism of opioid agents and the clinical impact of their active metabolites. Clin J Pain. 2011 Nov-Dec;27(9):824-38. [PubMed: 21677572]

5.

Jóźwiak-Bebenista M, Nowak JZ. Paracetamol: mechanism of action, applications and safety concern. Acta Pol Pharm. 2014 Jan-Feb;71(1):11-23. [PubMed: 24779190]

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.

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

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 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]

Review Questions

• Access free multiple choice questions on this topic.

• Comment on this article.

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]

3.

Sarhill N, Walsh D, Nelson KA. Hydromorphone: pharmacology and clinical applications in cancer patients. Support Care Cancer. 2001 Mar;9(2):84-96. [PubMed: 11305075]

4.

Smith HS. The metabolism of opioid agents and the clinical impact of their active metabolites. Clin J Pain. 2011 Nov-Dec;27(9):824-38. [PubMed: 21677572]

5.

Jóźwiak-Bebenista M, Nowak JZ. Paracetamol: mechanism of action, applications and safety concern. Acta Pol Pharm. 2014 Jan-Feb;71(1):11-23. [PubMed: 24779190]

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]

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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]

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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]

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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.

Norco 5/325 (Hydrocodone Bitartrate & Acetaminophen): Uses, Dosage, Side Effects, Interactions, Warning

Product description

What is Norco 5/325 and how is it used?

Norco 5/325 (hydrocodone acetaminophen and bitartrate) is an opioid analgesic and antitussive (cough suppressant) combined with an antipyretic and analgesic and is used to treat moderate to fairly severe pain. Norco 5/325 is available as a generic .

What are the side effects of Norco 5/325?

Common side effects of Norco 5/325 include:

• lightheadedness,
• nausea,
• vomiting,
• constipation,
• upset stomach,
• headache dizziness or drowsiness,
• restlessness,
• Headache,
• mood changes,
• blurred vision,
• ringing in the ears, or
• dry mouth.

DESCRIPTION

NORCO (hydrocodone bitartrate and acetaminophen) is supplied as tablets for oral use.

Hydrocodone bitartrate is an opioid analgesic and antitussive and occurs as fine white crystals or crystalline powder. It is affected by light. The chemical name is 4,5α-epoxy-3-methoxy-17-methylmorphinan-6-one tartrate (1:1) hydrate (2:5). It has the following structural formula:

Acetaminophen, a 4-hydroxyacetanide, slightly bitter, white, odorless crystalline powder, is a non-opiate, non-salicylate analgesic and antipyretic. Has the following structural formula:

Oral NORCO is available in the following dosages:

Hydrocodone

Acetaminophen Bitartrate

NORCO 7.5 / 325 7.5 mg 325 mg
NORCO 10/325 10 mg 325 mg

In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, crospovidone, magnesium stearate, microcrystalline cellulose, povidone, pregelatinized starch and stearic acid; 7.5mg/325mg tablets include FD&C Yellow #6 Aluminum Lake, 10mg/325mg tablets include D&C Yellow #10 Aluminum Lake. Meets USP 1 dissolution test.

Indications and dosage

INDICATIONS

NORCO is indicated for the relief of moderate to moderately severe pain.

DOSAGE AND ADMINISTRATION

Dosage should be adjusted according to the degree of pain and the response of the patient. However, it should be borne in mind that tolerance to hydrocodone may develop with continued use and that the frequency of adverse effects is dose dependent.

The usual adult dose is one tablet every four to six hours as needed for pain relief. The total daily dosage should not exceed 6 tablets.

HOW SUPPLIED

NORCO 7.5 / 325 Available as capsules of light orange tablets, split in half on one side and embossed with “NORCO 729” on the other side. Each tablet contains 7.5 mg hydrocodone bitartrate and 325 mg acetaminophen. They are supplied as follows:

Bottles of 30
Bottles of 100 pcs.
500 bottles

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NORCO 10/325 Available as yellow capsule-shaped tablets, halved on one side and embossed with “NORCO 539” on the other side. Each tablet contains 10 mg hydrocodone bitartrate and 325 mg acetaminophen. They are supplied as follows:

Bottles of 100 pcs.
Bottles of 500

Store at 20°-25°C (68°-77°F). [See Room Temperature Controlled USP .]

Dispense in a tight, light-resistant container with a child-proof lid.

Watson Pharma, Inc., a subsidiary of Watson, Pharmaceuticals, Inc., Corona, CA 92880, USA, 14716. Revised: July 2007 Cardinal Health, Zanesville, OH 43701.

Side effects and drug interactions

SIDE EFFECTS

The most common adverse reactions are dizziness, sedation, nausea and vomiting. These effects appear to be more pronounced in outpatients than in general patients, and some of these adverse reactions may be alleviated by lying down.

Other adverse reactions include:

Central nervous system: Drowsiness, clouding of consciousness, lethargy, impaired mental and physical performance, anxiety, fear, dysphoria, mental dependence, mood changes.

Gastrointestinal: Prolonged administration of NORCO may cause constipation.

Genitourinary system: Spasm of the ureter, spasm of the vesical sphincter and urinary retention have been reported with opiates.

Respiratory depression: Hydrocodone bitartrate may cause dose-dependent respiratory depression by acting directly on the respiratory centers of the brainstem (see OVERDOSE ).

Special Senses: Hearing impairment or irreversible loss has been reported predominantly in patients with chronic overdose.

Dermatological: Skin rash, pruritus.

The following adverse events can be considered as potential effects of paracetamol: allergic reactions, rash, thrombocytopenia, agranulocytosis. Possible effects of high dosages are listed in the OVERDOSE section.

Drug abuse and dependence

Controlled substance

NORCO is classified as a Schedule III controlled substance.

Abuse and dependence

Mental dependence, physical dependence and tolerance may develop with repeated drug use; therefore, this product should be prescribed and administered with caution. However, psychic dependence is unlikely to develop with short-term use of NORCO for the treatment of pain.

Physical dependence, a condition that requires continued drug use to prevent withdrawal, only becomes clinically significant after several weeks of continuous drug use, although some mild degree of physical dependence may develop after a few days of use. drug therapy. Tolerability, in which higher and higher doses are required to obtain the same degree of pain relief, first manifests itself in a reduction in the duration of the analgesic effect, and then in a decrease in the intensity of pain relief. The rate of development of tolerance in different patients is different.

DRUG INTERACTIONS

Patients receiving other narcotics, antihistamines, antipsychotics, sedatives, or other CNS depressants (including alcohol) concomitantly with NORCO may exhibit additive CNS depression. If combination therapy is contemplated, the dose of one or both agents should be reduced.

The use of MAO inhibitors or tricyclic antidepressants with hydrocodone preparations may increase the effect of the antidepressant or hydrocodone.

Interactions with drugs / laboratory tests

Acetaminophen may give false positive results for 5-hydroxyindoleacetic acid in urine.

Warnings

WARNINGS

Respiratory depression

At high doses or in sensitive patients, hydrocodone may cause dose-dependent respiratory depression by acting directly on the respiratory center of the brainstem. Hydrocodone also affects the center that controls the respiratory rhythm and can cause irregular and periodic breathing.

Head trauma and increased intracranial pressure

The respiratory depressant effects of drugs and their ability to increase cerebrospinal fluid pressure may be markedly exaggerated in the presence of head trauma, other intracranial lesions, or a pre-existing increase in intracranial pressure. In addition, drugs cause adverse reactions that may obscure the clinical course of patients with head injuries.

Acute diseases of the abdominal cavity

Drug administration may obscure the diagnosis or clinical course of patients with acute abdominal conditions.

Precautions

PRECAUTIONS

General

Special Risk Patients

As with any narcotic analgesic, NORCO should be used with caution in elderly or debilitated patients and in patients with severe hepatic or renal impairment, hypothyroidism , illness Addison, prostatic hypertrophy or urethral stricture. The usual precautions should be observed and the possibility of respiratory depression should be kept in mind.

Cough reflex

Hydrocodone suppresses the cough reflex; As with all drugs, caution should be exercised when using NORCO in the postoperative period and in patients with pulmonary disease.

Laboratory tests

In patients with severe liver or kidney disease, the effect of therapy should be monitored by serial tests of liver and/or kidney function.

Carcinogenesis, Mutagenesis, Impairment of Fertility

Adequate studies have not been conducted in animals to determine whether hydrocodone or acetaminophen has the potential to cause carcinogenesis, mutagenesis or impairment of fertility.

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Pregnancy

Teratogenic effects

Pregnancy category C

There are no adequate and well-controlled studies in pregnant women. NORCO should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Non-teratogenic effects

Infants born to mothers who regularly took opioids prior to birth will be physically dependent. Withdrawal signs include irritability and excessive crying, tremors, hyperactive reflexes, rapid breathing, rapid stools, sneezing, yawning, vomiting, and fever. The severity of the syndrome does not always correlate with the duration of maternal opioid use or dose. There is no consensus on how best to deal with withdrawal symptoms.

Handling and Delivery

As with all drugs, administration of this product to the mother shortly before delivery may result in some degree of respiratory depression in the neonate, especially at higher doses.

Nursing mothers

Acetaminophen is excreted in breast milk in small amounts, but the significance of its effects on infants is unknown. It is not known if hydrocodone is excreted in breast milk. Since many drugs are excreted in breast milk and because of the potential for serious adverse reactions in nursing infants to hydrocodone and acetaminophen, a decision should be made whether to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric use

Safety and efficacy in pediatric patients have not been established.

Geriatric Use

Clinical studies of hydrocodone bitartrate 5 mg and acetaminophen 500 mg did not include sufficient numbers of subjects aged 65 years and over to determine if they respond differently than younger subjects. Other reported clinical experience has found no difference in response between older and younger patients. In general, dose selection for the elderly patient should be cautious, usually starting at the lower end of the dosing range, reflecting a greater incidence of decreased hepatic, renal, or cardiac function, as well as concomitant disease or other drug therapy.

Hydrocodone and the main metabolites of acetaminophen are known to be primarily excreted by the kidneys. Thus, the risk of toxic reactions may be higher in patients with impaired renal function due to accumulation of the parent compound and/or metabolites in plasma. Because older patients are more likely to have decreased renal function, care should be taken in dose selection and it may be beneficial to monitor renal function.

Hydrocodone may cause confusion and excessive sedation in the elderly; Elderly patients should generally be initiated on low doses of hydrocodone bitartrate and acetaminophen tablets and monitored closely.

Overdose and contraindications

OVERDOSAGE

Acute overdose may cause toxic effects of hydrocodone or acetaminophen.

Signs and symptoms

Hydrocodone

Severe hydrocodone overdose is characterized by respiratory depression (decreased respiratory rate and/or tidal volume, Cheyne-Stokes respiration, cyanosis), severe drowsiness progressing to stupor or coma, skeletal muscle flaccidity, cold and clammy skin, and sometimes bradycardia, etc. hypotension. In severe overdose, sleep apnea, circulatory failure, cardiac arrest and death can occur.

Acetaminophen

Paracetamol overdose: Dose-dependent, potentially fatal liver necrosis is the most serious side effect. Renal tubular necrosis, hypoglycemic coma, and thrombocytopenia may also occur.

Early symptoms of a potentially hepatotoxic overdose may include nausea, vomiting, sweating and general malaise. Clinical and laboratory evidence of liver toxicity may not appear until 48-72 hours after ingestion.

In adults, liver toxicity has rarely been reported with acute overdoses of less than 10 grams or fatalities with doses of less than 15 grams.

Care

A single or multiple overdose of hydrocodone and acetaminophen is a potentially lethal overdose of polydrug addiction, so consultation with your local poison control center is recommended.

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Immediate treatment includes support for cardiorespiratory function and measures to reduce drug absorption. Vomiting should be induced mechanically or with ipecac syrup if the patient is alert (adequate pharyngeal and laryngeal reflexes). Activated charcoal by mouth (1 g/kg) should be taken after a gastric emptying. The first dose should be accompanied by appropriate laxatives. If repeated doses are used, the laxative may be added with other doses as needed. Hypotension is usually hypovolemic and must be fluid-responsive. Vasopressors and other supportive measures should be used as directed. A cuffed endotracheal tube should be inserted prior to gastric lavage in an unconscious patient and, if necessary, to provide assisted breathing.

Particular attention should be paid to maintaining adequate ventilation. In severe cases of intoxication, peritoneal dialysis or, preferably, hemodialysis may be considered. If hypoprothrombinemia occurs due to an overdose of acetaminophen, vitamin K should be given intravenously.

Naloxone, a drug antagonist, may reverse respiratory depression and coma associated with opioid overdose. Naloxone hydrochloride 0.4 mg to 2 mg is administered parenterally. Because the duration of action of hydrocodone may exceed that of naloxone, the patient should be monitored closely and repeated doses of the antagonist administered as needed to maintain adequate respiration.

The narcotic antagonist should not be used in the absence of clinically significant respiratory or cardiovascular depression.

If the dose of acetaminophen could exceed 140 mg/kg, acetylcysteine ​​should be administered as soon as possible. Serum levels of paracetamol should be determined, as levels four or more hours after ingestion help predict paracetamol toxicity. Do not wait for acetaminophen test results before starting treatment. First you need to get liver enzymes, and then repeat them every 24 hours.

Methemoglobinemia greater than 30% should be treated with methylene blue by slow intravenous administration.

The adult toxic dose of paracetamol is 10 g.

CONTRAINDICATIONS

NORCO should not be used in patients with a history of hypersensitivity to hydrocodone or acetaminophen.

Patients with hypersensitivity to other opioids may show cross-sensitivity to hydrocodone.

Clinical pharmacology

CLINICAL PHARMACOLOGY

Hydrocodone is a semi-synthetic narcotic analgesic and antitussive with many actions qualitatively similar to those of codeine. Most of them affect the central nervous system and smooth muscles. The exact mechanism of action of hydrocodone and other opiates is unknown, although it is thought to be related to the existence of opiate receptors in the central nervous system. In addition to pain relief, drugs can cause drowsiness, mood changes, and clouding of the mind.

The analgesic action of paracetamol is associated with peripheral effects, but the specific mechanism has not yet been determined. The antipyretic effect is transmitted through the hypothalamic heat regulation centers. Acetaminophen inhibits prostaglandin synthetase. Therapeutic doses of paracetamol have little effect on the cardiovascular or respiratory systems; however, toxic doses can cause circulatory failure and shallow breathing.

Pharmacokinetics.

The behavior of the individual components is described below.

Hydrocodone

After oral administration of 10 mg hydrocodone to five adult males, the mean peak concentration was 23. 6 ± 5.2 ng/mL. Peak serum levels were reached at 1.3 ± 0.3 hours and the half-life was 3.8 ± 0.3 hours. Hydrocodone exhibits a complex metabolic pattern including O-demethylation, N-demethylation, and 6-ketoreduction to the corresponding 6-α- and 6-β-hydroxy metabolites. See OVERDOSE for toxicity information.

Acetaminophen

Acetaminophen is rapidly absorbed from the gastrointestinal tract and distributed to most body tissues. The plasma half-life ranges from 1.25 to 3 hours, but may increase with liver damage and after overdose. Excretion of paracetamol occurs mainly due to metabolism (conjugation) in the liver and subsequent excretion of metabolites by the kidneys. Approximately 85% of an oral dose is excreted in the urine within 24 hours of ingestion, primarily as the glucuronide conjugate with small amounts of other conjugates and unchanged drug. see OVERDOSE for toxicity information.

Medication Guide

PATIENT INFORMATION

Hydrocodone, like all drugs, may impair the mental and/or physical abilities required to perform potentially hazardous tasks such as driving a car or operating machinery; patients should be warned accordingly.

Alcohol and other CNS depressants may cause additional CNS depression when taken with this combination product and should be avoided.

Hydrocodone may be habit-forming. Patients should only take the drug for as long as it is prescribed, in the prescribed amounts, and no more frequently than prescribed.

Take the drug only for as long as it is prescribed, in the prescribed amounts and no more often than prescribed.

In the Nizhne-Svirsky reserve, a badger was filmed clean – July 24, 2023

Society0030 Photo: Nizhne-Svirsky State Reserve

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In the Nizhne-Svirsky Reserve, a badger was photographed neatly. In the photographs, the animal “cleanses its skin”, sitting not far from its hole. The footage with the badger was published by the state reserve on Monday, July 24, in its group on VKontakte.

Photo: Nizhne-Svirsky State Reserve

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Recently, a video trap in the Nizhne-Svirsky Reserve filmed how wolves messed up in front of the lens.

Photo: Nizhne-Svirsky State Reserve

Photo: Nizhne-Svirsky State Reserve

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