Pharmacists are in a unique position to assess patients' risks and then qualify them for specific opioids.
With the new extended-release (ER) oxycodone that meets all 3 FDA requirements for abuse-deterrent labeling, and even more novel products on the way, pharmacists are in a unique position to assess patients’ risks and then qualify them for specific opioids.
Considering the new CDC guidelines for opioid prescribing for chronic pain, there’s a lot at stake for prescribers, pharmacists, and patients alike. This article will take us from abuse-deterrent formulations (ADFs), to product-specific attributes, to the burgeoning role of pharmacists as providers.
ER vs. IR
ER opioid formulations are attractive options for drug abusers because they contain relatively large doses intended to be released over an extended period of time. However, manipulation by chewing, crushing, or dissolving can release the drug more rapidly, a phenomenon known as “dose dumping.”1
Immediate-release (IR) opioids are associated with wider fluctuations in serum levels. The peaks are linked to an increased risk for dose-related complications, including sedation and respiratory depression, while the troughs are associated with recurrence variation in pain control and increased risk for pseudoaddiction and hyperalgesia.2,3 In comparison, ER formulations provide steady levels over time and less fluctuation.
Unfortunately, when ER formulations are manipulated, they can lose their timed-release profile and behave similarly to IR formulations by releasing the drug rapidly.
As a result of increased awareness of toxicities and deaths due to manipulation of ER formulations, there has been a parallel surge of IR prescriptions and decline in ER prescriptions. For instance, prescriptions for ER oxycodone declined from 7.3 million in 2010 to 4.7 million in 2014, while prescriptions for IR oxycodone increased from 10.4 million to 15.8 million in the same period.4
In response to the growing opioid abuse epidemic, the FDA released an action plan that includes expanding access to ADFs and issuing guidance for studies that should be conducted to evaluate ADFs.
Three types of premarketing studies are required for ADFs5:
1. Laboratory-based in vitro manipulation and extraction studies evaluating the ease that an ADF can be mechanically or chemically compromised or defeated.
2. Pharmacokinetic studies comparing the pharmacokinetic profile of the manipulated, in vivo formulation to the intact formulation.
3. Clinical abuse potential studies evaluating the impact of an ADF in conjunction with the likelihood of abuse by assessing the subjective effects of the formulation on likeability, euphoria, and other drug abuse-related effects.
There are currently 6 FDA-approved ADFs, all of which are ER opioids: reformulated OxyContin, Embeda, MorphaBond, Targiniq ER, Hysingla ER, and Xtampza ER. There are others that are arguably ADFs but don’t meet FDA specifications for such labeling.
Xtampza ER is the most recently approved ADF, and it’s formulated using DETERx technology. This technology combines fatty acids and waxes with the active drug, which is then incorporated into microspheres designed to resist physical and chemical manipulations when the particle size is reduced by chewing, crushing, breaking, or dissolving.6
Studies were conducted to evaluate the effect of chemical and physical manipulations on the rate of drug release for Xtampza and OxyContin.7,8 Xtampza had a 3- to 6-fold decrease in drug release between tampered and intact product compared with OxyContin. Intranasal administration had a 30% lower peak exposure than oral Xtampza and a 50% lower peak exposure than IR oxycodone.
It’s important to note the maximum daily dose (MDD) of Xtampza is 288 mg (equivalent to 320 mg oxycodone), which was assigned because the excipient wasn’t studied in doses above the cut-off listed in the insert, and the MDD wasn’t determined based on the oxycodone content.6,9,10
Following manipulation, the crushed contents of Xtampza ER capsules have proven to be bioequivalent to intact Xtampza following oral administration. Additionally, there was no alcohol-induced dose dumping demonstrated, as co-ingestion with 20% and 40% alcohol didn’t result in higher exposure.10
Hysingla ER tablet has similar physiochemical properties to the reformulated OxyContin, causing difficulty when attempting to crush, break, or dissolve those products. They also form a viscous hydrogel when subjected to an aqueous environment, further deterring injection.11
Embeda capsule contains pellets of morphine sulfate surrounding an inner core of naltrexone that is non-digestible when administered intact.12 If crushed or chewed, however, the naltrexone within the pellet is released along with morphine to block its effect. King Pharmaceuticals voluntarily withdrew Embeda from the market in 2011 for not meeting a pre-specified stability requirement, but Embeda was brought back in 2014.13,14
Targiniq ER tablet contains co-formulated naloxone and oxycodone. When taken appropriately, naloxone isn’t absorbed through the gastrointestinal tract.15 Targiniq loses ER characteristics when chewed or crushed, resulting in a rapid release of oxycodone and naloxone. For intranasal and intravenous administration, the associated increase in plasma concentrations of naloxone occupies the mu-receptor, thereby inhibiting oxycodone. Following oral administration, however, the naloxone doesn’t reach adequate levels to completely inhibit the mu-receptor, resulting in unopposed exposure to high levels of oxycodone and increased risk for overdose.
Accidental Misuse Among Patients with Dysphagia
There have been instances where ER formulations were unexpectedly crushed without the intention for abuse, such as in elderly patients who may crush their medication for ease of ingestion. Approximately 6 million US patients have difficulty swallowing, so this becomes a serious issue with the increase in the older adult population and the rising prevalence of chronic pain.16
The only ER opioids specially formulated to account for swallowing difficulties are Embeda, Xtampza, Kadian, and Avinza. The latter 2 aren’t considered ADFs since accidental chewing on the pellets could result in toxic exposure to morphine. Meanwhile, chewing Embeda pellets will result in rapid release of the sequestered naltrexone, precipitating opioid withdrawal.
As for Xtampza, each microsphere has its own ER profile, and manipulation studies demonstrated no difference in ER profiles between manipulated and intact Xtampza. In fact, Xtampza has been evaluated in chronic pain with dysphagia and is the only ER opioid that doesn’t carry the black box warning “do not crush, chew, or dissolve.”17
Balancing Opioids Risks and Benefits
Considering the misuse of manipulated ER dosage forms, it’s incumbent on pharmacists to understand the real differences among opioids, paying specific attention to ER formulations and ADFs. Most ER products aren’t abuse deterrent and can be crushed for snorting or injecting. From a practical perspective, it seems safer and more reasonable to select an ER over an IR formulation because, when taken as prescribed, the ER formulation results in lower peaks and fewer dosing intervals. Therefore, you could make the argument that, when taken as prescribed, ER opioids are safer than their IR counterparts.
Although pharmacists and prescribers need to exercise extreme caution with opioid therapy, this is an area ripe for pharmacist collaboration with prescribing clinicians. Such alliance ranges from risk stratification in terms of opioid abuse or misuse, to qualifying patients for in-home naloxone as outlined here, to further educating clinicians on new updates and guidelines, advocating for legitimate patients, and making recommendations for specific opioids based on individual patients.
The recently released CDC guidelines have had an unnerving effect on prescribers nationwide, resulting in diminished access to pain therapy, specifically opioids. Several primary care physicians voiced their concerns, including one clinician who stated in a recent Medscape post, “I see a huge chill on opiate prescribing followed by a massive increase in heroin deaths.”
While most of the CDC’s recommendations seem like common sense on the surface, it appears that many legitimate opioid users are being lumped together and scrutinized, resulting in decreased accessibility to a prescribing clinician even after receiving and appropriately taking opioids for decades. There’s no doubt we should take a closer look at the legitimacy of opioid prescribing as an ongoing process for each patient, but if prescribers cut patients off from their legitimate pain medications based on an irrational fear of liability, it could ultimately result in negative consequences equal to or worse than overprescribing.
The CDC guidelines are without a doubt evidence-based, but the evidence and corresponding conclusive statements are based on unmatched sample sizes and isolated populations, which have resulted in great criticism by key opinion leaders as being inappropriate and falling short on science and logic. Most studies cited within the guidelines noted “serious limitations” or “very serious limitations” in regards to evaluating opioid abuse or addiction,18-31 overdose,32-34 dose titration,35-40 function,41-43 all-cause mortality,44, 45 and risk assessment strategies.46-49
Expanding the Pharmacist’s Role
One particular author who participated in pharmaceutical care as a clinician within inpatient and outpatient care, ambulatory care, and academia in the Northeast and then in the Rocky Mountain Region observed vast differences in the role and acceptance of clinical pharmacists by providers. In Utah, for instance, there seems to be fewer barriers for pharmacists to be accepted as therapeutics experts. By allowing physicians to focus on diagnostics, pharmacists practice collaborative drug therapy management to manage chronic conditions in high-risk patients. Although such alignments exist in the northeast, it seems more commonplace from the Midwest to the Pacific Coast.
Regularly scheduled ambulatory care practice meetings focus on high-risk patients that involve pharmacy, care management, social work, a medical assistant, and a primary care physician (PCP). This allows each health care professional to best contribute to patients’ care needs based on their individual expertise. PCPs welcome input from each area of the care team. Routinely, PCPs use a “warm handoff” approach to introduce patients to the pharmacist while the patients are already in the clinic to see their provider in order to facilitate a relationship between the patient and the clinical pharmacist.
This practice model is also commonplace nationwide within federal institutions such as the Department of Veterans Affairs, Department of Defense, and Public Health Service. Meanwhile, a pharmacist in Congress is advocating for expanded pharmacist utilization on a national level.
Looking at the bigger picture, pharmacists, physicians and all health care professionals should be focusing on the individual patient. Pharmacists can offer exceptional expertise in selecting the best therapies for patients and also help prescribers with the best rational polypharmacy to treat pain prior to starting opioids or to synergize the effect of opioids with nonopioids, so that the lowest possible effective dose is used for each drug. Each particular opioid should be selected based on the individual needs of the patient, rather than a population of patients that happens to have pain with a simple endgame of reducing the opioid dose.
Federal agencies should start working together to look at the larger picture by recognizing pharmacists as providers in order to improve justification for the presence of clinicians from a business model perspective. The CDC should work more closely with the FDA and Congress to better understand what pharmacists are trained to do as a profession: minimize medication risk, improve quality of life, maximize therapeutic benefit, and save lives. Opioid therapeutics is a perfect practice model for pharmacists’ expertise.
This article was collaboratively written with Hannah R. Fudin, PharmD, and Mena Raouf, PharmD.
Dr. Fudin received her PharmD from Albany College of Pharmacy and Health Sciences and completed 2 residency programs: a PGY1 pharmacy practice residency at Virtua and PGY2 ambulatory care residency at Rhode Island Hospital. She is currently employed at the University of Utah College of Pharmacy as an assistant clinical professor of pharmacotherapy.Dr. Raouf received his PharmD from Albany College of Pharmacy and Health Sciences. He will be pursuing PGY1 pharmacy practice residency at the VA Tennessee Valley Healthcare System.
This article is the sole work of the authors and stated opinions/assertions do not reflect the opinion of employers or employee affiliates. It was not prepared as part of the author(s) duty as federal employees.
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