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11 Articles in Volume 16, Issue #2
Gender and the Pain Experience
Sex and Gender Differences In the Pain Experience
Medical Management of Diabetic Neuropathy
Comorbid Substance Use Disorders: Primer for Pain Management
Marijuana Use Disorder: Common and Often Untreated
Acupuncture: New Approach for Temporomandibular Disorders
Opioid-Maintained Patients Who Require Surgery
Natural Protein Points to New Inflammation Treatment
Lessons from the Murder Conviction of Dr. Hsiu-Ying “Lisa” Tseng
Zohydro vs Hysingla: What is the Difference in These Extended-Release Agents?
Letters to the Editor: Opioid Calculator, Testosterone for SCI

Zohydro vs Hysingla: What is the Difference in These Extended-Release Agents?

Ask the Expert from March 2016

For patients with moderate to severe pain, opioids have been used as a cornerstone of pharmaceutical therapy to help improve pain relief and quality of life.

There are a vast number of opioids and opioid combinations on the market, which differ in mechanisms of action, pharmacokinetic and pharmacodynamic profiles, formulations, and other characteristics that give providers the ability to treat their patients in an individualized fashion.

Hydrocodone is a semi-synthetic opioid agonist that binds to mu receptors with relative selectivity, resulting in typical opioid agonist activity.1 This has historically been commercially formulated as immediate-release (IR) combination products containing acetaminophen (APAP), aspirin (ASA), or ibuprofen for patients with moderate to severe pain; butalbital, aspirin, or acetaminophen with caffeine for headache patients; and various belladonna alkaloids to act as an antitussive.2

In the last few years, 2 hydrocodone extended-release (ER) products have been approved by the U.S. Food and Drug Administration (FDA)—Zohydro and Hysingla.1,3 These products contain only hydrocodone and differ in a variety of ways, both when compared to each other and when matched against other opioids.

Brief Approval History

On October 25, 2013 the FDA approved Zohydro (developed by Zogenix) for the treatment of moderate to severe pain.4 One year later, on November 20, 2014, the FDA approved Hysingla (developed and manufactured by Purdue Pharma), the second single-entity hydrocodone product for the treatment of moderate to severe pain.5

Both drugs were assigned a Schedule II controlled substance status by the U.S. Drug Enforcement Agency (DEA). In August 2014, the DEA rescheduled all short-acting combination hydrocodone products from Schedule III to Schedule II.6

The combination products were originally Schedule III ostensibly because they offered a synergistic effect, decreasing the amount of hydrocodone required to reach therapeutic levels of pain relief and thus created less of a chance that patients would experience euphoric effects from the opioid.7

It was also believed that the adverse effects caused by higher concentrations of the adjuvant medications (APAP, ASA, ibuprofen) would limit the total amount of medication taken at one time, further decreasing the likelihood of misuse or abuse.8

Unfortunately, these beliefs were more theoretical than clinically relevant. Several studies have shown that hydrocodone (both combination and single entity) has a similar abuse liability when compared to various Schedule II opioids, including morphine, oxycodone, and hydromorphone, at equianalgesic doses.9,10

There are a few contradicting studies that suggest oxycodone has the highest abuse liability profile due to higher likability scores and fewer negative effects.9 However, the overwhelming majority of literature supports relative equality in terms of abuse potential between hydrocodone and other opioids.

This realization was part of the reason for the rescheduling that took place in 2014. New York State enacted legislation to change the scheduling in advance of Federal regulation. This resulted in a decrease in prescribed hydrocodone that was congruent to an oxycodone prescription increase—at almost the same rate.11 This trend is illustrated in Figure 1.


Each Zohydro ER hard gelatin capsule contains 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, or 50 mg of hydrocodone intended for every 12 hour dosing.1 Such dosing of Zohydro ER results in similar overall hydrocodone exposure compared to IR hydrocodone products, but its maximal concentrations are lower (Figure 2).1

The prolonged absorption causes peak concentration to occur about 5 hours after dose administration and a total plasma half-life of about 8 hours. This half-life allows for dosing every 12 hours and steady state to be reached approximately 3 days after initiation. It is important to note that these pharmacokinetic properties are independent of the dose of Zohydro ER up to 50 mg.1

The initial approval of Zohydro ER was extremely controversial, as the original formulation did not contain abuse deterrent technology (ADT).12-14 This was met with significant political repercussions among state governments and various professional and patient advocacy organizations, including the Massachusetts state governor who declared a state of emergency and banned prescribing privileges for Zohydro in 2014.13

Many critics of the original Zohydro ER formulation argued that because it was extended-release and had larger amounts of hydrocodone per capsule, it would allow for a greater abuse potential when not taken as prescribed. While these assertions theoretically may be true, the fact is that there are no oral opioids on the market that are 100% abuse proof—people can still take more dosage units than prescribed.15 This among other reasons are why a federal judge eventually overturned the ban in Massachusetts.13

In order to prescribe Zohydro ER, clinicians are required to complete a risk assessment and pain management treatment agreement—a restriction that in essence is good medical practice for any and all prescribed medications, opioid or not.13

In January 2015, Zohydro ER was reformulated to contain BeadTek technology.16 The BeadTek technology of Zohydro ER contains “excipients that form a viscous gel when crushed and dissolved in liquids,” making the hydrocodone difficult to inject.17 It is important to note that this new formulation of Zohydro ER maintains the same pharmacokinetic and efficacy profiles as the older formulations, however studies are ongoing to get FDA-approval for the ADT labeling in the updated package insert.17

Unfortunately, due to the increased financial costs of incorporating ADT, Zogenix eventually sold their product to Pernix in April 2015.18


Hysingla ER was originally approved with ADT. Each Hysingla ER film-coated tablet contains 20 mg, 30 mg, 40 mg, 60 mg, 80 mg, 100 mg, or 120 mg of hydrocodone to be administered once daily.3 Like Zohydro ER, when compared to immediate-release hydrocodone products, Hysingla’s overall exposure is similar, but maximal concentrations are lower (Figure 3). Peak serum concentration occurs at 14 to 16 hours for all doses, and mean terminal half-life ranges from 7 to 9 hours. This half-life allows for dosing every 24 hours and steady state to be reached approximately 3 days after initiation.3

Hysingla’s ADT makes it more difficult to crush, break, or dissolve, but when crushed and placed into a liquid it forms a thick gel, increasing the difficulty of injection.32 In vitro data has shown that this ADT may help deter intranasal and intravenous use, and that it is expected to reduce intranasal and oral abuse when chewed.3 Although there have been no trials to date directly comparing the ability of the 2 formulas of Zohydro and Hysingla to deter abuse or misuse, all opioids have the potential to be abused.

Both Zohydro ER and Hysingla ER are required to provide post-marketing surveillance for FDA approval of the abuse deterrent label. Despite the advantages of extended-release hydrocodone outlined above, various political groups and politicians have met them both with heavy criticism. Both products now contain ADT, which will hopefully deter and discourage abusers so that legitimate pain sufferers may use these agents.

In fact, data collected from the National Addictions Vigilance Intervention and Prevention Program (NAVIPPRO) between February 2014 and June 2015 has shown that out of just over 85,000 substance abuse treatment center assessments, about 22% reported abuse of any prescription opioid (more than 18,000 cases). In this context, only 39 cases (0.05% of all assessments) were related to Zohydro.20

It is important to note that both Zohydro ER and Hysingla ER make up only a small portion (<1%) of the market share of extended-release opioids.21 Therefore, the number of reports of abuse would be expected to be low compared to opioids with larger market share.

Per author communications with Purdue, planned post-marketing studies for Hysingla ER will evaluate misuse and abuse, and their consequences, addiction, overdose, and death in the community. Data from these studies will be submitted to FDA and made available.


From a political perspective, the creation of the ER hydro-codone products triggered much angst among lawmakers, the media, and political activists nationwide. However, expanding our pharmacologic armamentarium provides more options, not only when initiating certain therapies for patients, but also when patients experience adverse or allergic drug reactions, and/or dosing failures.

Patient’s suffering from chronic pain must have access to multiple agent options such as Zohydro ER and Hysingla ER with the caveat that they are carefully selected, prescribed and dispensed by well-intentioned, educated providers and pharmacists, all of whom must look past the negative stigma and rhetoric to best serve their patients.

Last updated on: March 16, 2016
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