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Introduction
Hydrocodone was first developed in 1923 but only approved for use in the United States of America in its combined form with acetaminophen in 1998 (LiverTox, 2020)(12). The combination of the two medications was originally intended to prevent recreational use or injection of the drug. However, despite these efforts, hydrocodone misuse continues to be a significant problem.
In 2010, more than 99% of the world’s supply of hydrocodone-acetaminophen was consumed in the United States, and American physicians were responsible for more daily-dose prescriptions per million people than in any other developed nation in the world (New York Times, 2013)(13). This disproportionate consumption highlights its ubiquity, as well as the potential for abuse. Therefore, it is crucial to understand the strengths, limitations and appropriate uses of hydrocodone to help contribute to the continual global conversation about safe pain management.
Hydrocodone combined with acetaminophen, commonly marketed in the United States as Norco™, Lortab™ or Vicodin™, are among the most frequently prescribed opioid medications in outpatient settings(17). Understanding the pharmacology, clinical indications and risk profile of hydrocodone can support exploration of its application in palliative care. For patients with moderate pain, it can be a valuable tool in the management of their pain.
Pharmacology
Hydrocodone is a semi-synthetic opioid that functions as a full agonist at the mu-opioid receptor, producing pain relief (FDA, 2021)(9). It also activates delta and kappa-opioid receptors as the drug concentrations rise in the patient’s system(3). In addition to its analgesic properties, hydrocodone can cause respiratory depression (intentionally used in certain cases to alleviate dyspnea), constipation, sedation, reduced gastric motility and euphoria. Like other opioids, the concurrent use with benzodiazepines can significantly increase the risk of respiratory depression(2). The onset of action is typically within 15 to 30 minutes, with peak plasma concentrations occurring around one hour, and a duration of effect lasting approximately four to six hours(3).
Hydrocodone is metabolized hepatically via cytochrome P450 enzymes, primarily CYP3A4 and CYP2D6, forming norhydrocodone, hydromorphone and dihydrocodeine as active metabolites(15). These metabolites may contribute to both analgesic efficacy and variability in patient response.
Like other opioids, hydrocodone should be used with caution in elderly patients due to altered pharmacokinetics and pharmacodynamics.
Dosages and formulations
Hydrocodone and morphine are dosed on a 1:1 ratio, having a similar onset of action and duration to oral morphine(16). However, this should be considered as a general guideline, as individual patient responses and tolerances can differ.
Norco™ formulations typically contain 5 mg or 10 mg of hydrocodone with 325 mg of acetaminophen, designed for short-term relief of moderate pain (FDA, 2021). These doses are fixed, and therefore clinicians cannot titrate the individual components separately. This inflexibility can limit clinical applications. For immediate release hydrocodone-acetaminophen, the typical dose is 5 or 10 mg taken every 4 to 6 hours as needed, with care to not exceed the administration of acetaminophen beyond the allotted daily dose. Lortab™ is a brand-name formulation available in combinations of hydrocodone 5 mg, 7.5 mg or 10 mg with acetaminophen 325 mg(5). Vicodin™ is another brand-name formulation that is available in combinations of hydrocodone 5 mg, 7.5 mg or 10 mg with acetaminophen 300 mg(4).
Hydrocodone is also available as an extended-release formulation, without a combination medication, marketed under the brand names Zohydro® ER and Hysingla® ER. These medications are typically only recommended for patients who are opioid tolerant, or taking 60 mg of oral morphine equivalents for one week straight (FDA, 2016)(10). However, the lowest formulations can also be used for opioid naïve patients, making these medications a unique option. Zohydro® ER is typically more expensive than Hysingla® ER, and is dosed twice daily, whereas Hysingla® ER is usually prescribed to be taken every 24 hours (Extended-release hydrocodone, 2015)(7). This long-acting form of hydrocodone was first approved for use in the United States in 2013, and it is not intended to be used as a “PRN” or as needed medication (FDA, 2016)(10).
Clinical applications
The World Health Organization (WHO) developed a three-step analgesic ladder to guide the management of cancer-related pain. Since its creation, this analgesic guide has since been widely adapted for other types of chronic and acute pain. Hydrocodone is classified as a Step 2 agent on the ladder and deemed suitable for when non-opioid medications are insufficient (WHO, 2019)(18).
In the United States of America, hydrocodone is widely used in outpatient settings for the management of:
- moderate cancer-related pain
- breakthrough pain in patients on chronic opioids
- chronic pain syndromes in certain palliative populations
- dyspnea(1)
- postoperative pain.
Additionally, hydrocodone can be used in the treatment of nonproductive cough due to its antitussive properties(3).
The fixed-doses formulation of hydrocodone-acetaminophen helps facilitate the ease of administration. This can be particularly valuable in low-resource environments, such as home hospice, where convenience and compliance are of the utmost importance. However, this can also prove to be a considerable limitation as acetaminophen has a maximum recommended daily dose, typically 3000-4000 mg/day (FDA, 2021)(9). In patients requiring considerable amounts of opioids for pain relief, this medication may not be appropriate. For this reason, hydrocodone-acetaminophen is not typically recommended for patients with severe pain, and may do better with a medication that does not have a limiting factor, such as morphine or hydromorphone or fentanyl patch(8).
Safety considerations
As previously discussed, hydrocodone has a similar risk profile to other mu-opioid agonists, and it can cause respiratory depression, sedation, constipation, nausea and dependency(2,17).
 analgesic ladder for pain management.png)
Additionally, the combination with acetaminophen may cause the risks of hepatotoxicity when daily doses exceed 3000-4000 mg, depending on the patient’s medical history. Unintentional overdose can occur due to the frequent incorporation of acetaminophen into over-the-counter and prescription medications(11). Drug interactions with acetaminophen can also contribute to negative outcomes.
In the United States, controlled substances are regulated under the Controlled Substances Act (CSA), which classifies drugs into five schedules (Schedule I-V) based on potential for abuse, accepted medical use and safety profile. Schedule I substances (e.g., heroin, LSD) have a high potential for abuse and no accepted medical use. Schedule II drugs include opioids like hydrocodone, oxycodone, fentanyl, methadone or morphine, which have recognized medical uses but carry an elevated risk of abuse and dependence, and are subject to strict regulations. Schedule III and IV substances (e.g., codeine combinations, buprenorphine, benzodiazepines) have lower abuse potential and more flexible prescribing rules. Schedule V are considered to have the lowest potential for abuse. This framework shapes how opioids are prescribed and monitored in clinical practice across the USA(14).
The ongoing opioid crisis in the United States and worldwide has exposed the risks of overprescribing opioid pain medications. To mitigate these risks, healthcare providers must counsel patients and caregivers on safe use, proper administration, storage, and disposal of opioid medications such as hydrocodone(2,9).
Relevance to European practice
Despite overall popularity in the USA, hydrocodone is not readily available in Europe. European palliative care guidelines, including those from the European Society for Medical Oncology (ESMO)(6), favor codeine, tramadol, or low-dose morphine as second-step agents on the WHO analgesic ladder(8). However, hydrocodone does represent a therapeutic option for those seeking multimodal analgesia when available. Additionally, it is possible that European clinicians could encounter patients who have received hydrocodone with or without acetaminophen abroad or who have relocated from other countries where it is frequently prescribed. These efforts can help support opioid stewardship worldwide.
Conclusions
Hydrocodone remains one of the most frequently prescribed opioid medications for moderate pain in the United States of America. It can be a useful tool due to its rapid onset, ease of administration and fixed-dose formulations. However, its limitations include a ceiling effect when combined with acetaminophen, scarcity in Europe as a pharmaceutical option, and abuse/misuse potential. In an effort towards opioid stewardship, it is crucial that prescribers understand the risks and benefits associated with medication to understand its potential role in clinical settings and to contribute to widespread discussions regarding pain control.
Corresponding author: Demi Wolford E-mail: demiwolford@gmail.com
Conflict of interest: none declared.
Financial support: none declared.
This work is permanently accessible online free of charge and published under the CC-BY licence.
