Hydrocodone and Acetaminophen

Article Author:
Manuchehr Habibi

Article Editor:
Peggy Kim

Editors In Chief:
Jon Parham
Jon Sivoravong

Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi

3/13/2019 6:21:37 PM


Hydrocodone is one of the most common pain medications prescribed by clinicians and one of the most abused by the patients. It is a relatively potent drug for moderate-to-severe pain control in postoperative patients, trauma and cancer patients.[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 it has been hypothesized to be 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 lead to inhibition of antibody and cellular immune responses, natural killer cell activity, cytokine expression, and phagocytic activity. As a result, opioids have been implicated in 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, decreased energy level which is a result of 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 who have severe respiratory depression, acute or significant bronchial asthma, gastrointestinal obstruction, and anaphylactic reaction due to components of the formula.


Pain relief and adverse events should undergo frequent assessment. 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 hence 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 ingestion of another acetaminophen-containing product. Furthermore, large doses may cause difficulty with breathing. In case of overdose, activated charcoal should be utilized prior to N-acetylcysteine (NAC). For patients presenting 4 hours or more, serum acetaminophen 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, naloxone or nalmefene, are specific antidotes to 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 Allergan, Inc emphasizes in bold letters the importance of warning patients of abuse, misuse, and addiction of hydrocodone and acetaminophen tablet, 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 a 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 IV)

There are also formulary management tools that are used to address both opioid overprescribing and overdose. One of them is 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 had lower rates of use disorder and overdose.[6] (Level IV)

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 to achieve this goal.

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Hydrocodone and Acetaminophen - Questions

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A 35-year-old male with a history of chronic back pain, currently on pain medication, presents to the emergency department with a 24-hour history of fever. He has not taken any medications besides his usually daily prescriptions. Vital signs are temperature 102.0 F, heart rate 101 bpm, respiratory rate 20/minute, and blood pressure 100/80 mmHg. He appears fatigued and diaphoretic. Which of the following will lead to a risk of liver toxicity if given with the medication indicated for his fever?

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In which drug classification is hydrocodone-acetaminophen correctly placed?

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A 45-year-old female, who is currently undergoing treatment for pancreatic cancer, is brought to the ED with a one-hour history of vomiting, nausea, and frequent stools. She has also been sweating profusely and yawning. Vitals are BP: 140/90, Pulse: 120, RR: 22, T: 100 F, and O2 saturation 95%. On exam, she is mildly irritable but responds to questions appropriately. Her pupils are dilated. What is the next step in the management of this patient's symptoms?

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Hydrocodone and Acetaminophen - References


Vardy J,Agar M, Nonopioid drugs in the treatment of cancer pain. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014 Jun 1;     [PubMed]
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;     [PubMed]
Sarhill N,Walsh D,Nelson KA, Hydromorphone: pharmacology and clinical applications in cancer patients. Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer. 2001 Mar;     [PubMed]
Smith HS, The metabolism of opioid agents and the clinical impact of their active metabolites. The Clinical journal of pain. 2011 Nov-Dec;     [PubMed]
Dreyer TR,Michalski T,Williams BC, Patient Outcomes in a Medicaid Managed Care Lock-In Program. Journal of managed care     [PubMed]
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. The American journal of managed care. 2017 May 1;     [PubMed]


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