Hydrocodone and Acetaminophen

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.


  • 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.


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.[1] The combination of hydrocodone with acetaminophen is much more efficacious 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, but the hypothesis has been that it is the result of activation of descending serotonergic inhibitory pathways in the CNS. Antipyretic effects occur via inhibition of the hypothalamic heat-regulating center.


Hydrocodone and acetaminophen combination is available in a tablet form taken via the oral route. 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.

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]


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.


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 therefore has a potential for abuse, misuse, and use disorder. It is vital to monitor patients for the signs of addiction, abuse, and misuse. 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:

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


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 case of overdose, activated charcoal should be the first attempted intervention before N-acetylcysteine (NAC). For patients presenting 4 hours or more, 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 as there is a high risk of precipitating acute opioid withdrawal in an individual physically dependent on opioids.

Enhancing Healthcare Team Outcomes

It is not a surprise that, without proper barriers and monitoring for detrimental effects of hydrocodone and acetaminophen intoxication, morbidity and mortality of using opioid analgesia can be quite substantial. The drug information sheet from one manufacturer emphasizes in bold letters the importance of warning patients of abuse, misuse, and addiction of hydrocodone and acetaminophen tablets, 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. In addition to the largest system-level intervention, the Prescription Drug Monitoring Program, one of the studies investigated a Medicaid managed care lock-in program requiring that patients receive all scripts from a single prescriber. Although over 55% dropped from the program, the proportion of stable patients, i.e., patients who exclusively filled from one prescriber, increased from 31% to 78% at 36 months.[5] [Level 4]

There are also formulary management tools used to address both opioid overprescribing and overdose. One of them is a prior authorization requirement place 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.[6] [Level 4]

All in all, the battle to reduce the opioid prescription crisis and rates of overdose continues. However, 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]

Article Details

Article Author

Manuchehr Habibi

Article Editor:

Peggy Kim


4/26/2021 7:51:12 AM



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