One year before the CDC guidelines on opioid prescribing were issued in March, the FDA had issued guidance to the pharmaceutical industry to develop safer opioid analgesics, with particular emphasis on developing opioid formulations to deter abuse.
The guidance declared, “FDA considers the development of these products a high public health priority.”
Jeremy Adler, MS, PA-C, Senior Pain Management PA, Pacific Pain Medicine Consultants, Encinitas, CA told attendees at the Painweek 2016 conference that the FDA guidance was issued to stem the illegal diversion of prescribable opioids from medical use to supplies for abuse that is contributing to the increasing number of deaths from opioid overdoses.
“Those abusing opioids may do so through a variety of mechanisms, including taking excessive doses, altering formulations, and changing the route of delivery,” Adler explained.
Although the extended-release (ER) oral opioid dosage forms had originally been developed as safer alternatives to immediate-release (IR) formulations for maintaining constant analgesia, Adler described diversion of the drugs away from pain patients to drug abusers who will chew, crush, cut, grate, grind, or mix them with solvents to defeat the ER mechanism and then swallow, inhale, or inject their new IR narcotic creation.
Adler likened the response of the pharmaceutical industry in developing abuse-deterrent formulations (ADF) to reduce deaths from opioid abuse, to the automobile industry’s response to increased auto-related injuries and deaths by developing such structural components as safety glass, air bags, and ABS brakes.
New opioid delivery forms have been developed with physical and chemical barriers that, for example, resist dissolution into solvents or form gels that cannot then be injected. Abuse potential is reduced in another opioid product Adler described that becomes aversive if manipulated—if ground and snorted it is particularly irritating to the nasal mucosa.
Another deterrent strategy described by Adler is to combine the opioid ingredient with an opioid receptor antagonist to interfere with, reduce, or defeat the product’s potential for euphoric effect. In some products the opioid receptor antagonist is sequestered and released if the dosage form is manipulated.
Table. Opioid products with ADF in label, FDA approval dates
|OxyContin||oxycodone ER||ADF 2010|
|Targiniq||oxycodone ER + naloxone||7/2014|
|Embeda||morphine + naltrexone||new label 10/2014|
|Hysingla ER||hydrocodone ER||10/2015|
“We can also change the delivery system,” Adler said. Examples of abuse deterrent opioid release designs include sustained-release depot injectable formulations and subcutaneous implants.
In addition, Adler noted, new opioid molecular entities and prodrugs are being developed that target a reduction in abuse liability as well as improved analgesia and tolerability. One example, described at another Painweek 2016 presentation, is a peripherally acting kappa-opioid receptor agonist now entering phase III clinical trials which may provide an alternative to the dependency-producing µ-opioid receptor analgesics for some pain conditions.
Testing Deterrence in Abusers
To attain FDA approval as an ADF and the corresponding section 9.2 in approved labeling, manufacturers must complete studies of the deterrence mechanism, and the findings must be accepted by the agency.
“The studies must have a meaningful impact on overall abuse of the product,” Adler said.
Laboratory-based in vitro manipulation and extraction studies (category 1 testing for ADF), and in vivo pharmacokinetic studies (category 2) rule out that the manipulated dosage form yields abuse levels of drug. Adler explained that pharmacokinetic study participants are exposed to the pharmaceutically pure drug in amounts that have been detected from manipulation, without the excipients that they would otherwise encounter if using the altered dosage form.
Clinical studies (category 3) are conducted to determine whether recreational drug users derive any positive effects from the manipulated product. The clinical abuse potential study participants are typically recruited through advertisement for recreational users of the drug class, with screening and exclusion of those who are drug dependent.
“The studies are blinded,” Adler explained, “and the subjects are selected in the pre-qualification phase for being able to differentiate between placebo and active opioid.”
Assessments compare the effect of the manipulated product to placebo, and typically to an active control authorized by the FDA for the study protocol such as pentazocine (Talwin). The participants report their subjective drug effects on visual analogue scales, indicating such measures as “liking drug,” “good effect,” “bad effect,” and “likelihood would take drug again.”
Adler noted that the section 9.2 of the approved labeling will describe the specific routes of abuse that the product has been developed to deter. He expects that labeling to be revised as new data are available, and looks forward to the postmarket studies (category 4) that have not yet been conducted but for which FDA guidance has been issued.
“When these [ADF-approved] products are promoted by industry, they have to promote them based on the labeling,” Adler said, “and the labeling indicates that abuse is still possible. Every single one of these products still recognizes that abuse is possible.”
Adler hopes, however, that postmarketing studies will answer a pressing question: “Does the ADF result in meaningful reductions in abuse, misuse, and related adverse clinical outcomes, including addiction, overdose, and death?”