Most meetings of the FDA’s Anesthetic and Analgesic Drug Products Advisory Committee (AADPAC) are held to review a New Drug Application (NDA), usually for a novel opioid preparation. But, on November 15, the AADPAC discussed the concept and implications of “opioid sparing” as a potential product label claim for a non-opioid type of medication.
Although trends in outpatient opioid prescriptions appear to be heading in an encouraging direction (see figure below), the demonstration that a non-opioid medication could further decrease the overall use of opioids for acute pain has obvious implications for the amount of opioids prescribed and taken by patients who undergo painful surgical procedures. This will also decrease exposure in the community where prescribed opioids may become diverted for recreational use.
In recent years, some across-the-board measures (e.g. state laws that limit the duration of prescribed opioids) have attempted to reduce opioid prescribing, but as the FDA emphasized in their presentation at the meeting, these “one size fits all” strategies will not account for individual patient variation, and may lead to inadequate pain treatment in some patients.
Currently, there are six approved products that contain vague opioid-sparing language in the drug’s package insert, without actually claiming a clinically meaningful reduction in opioid use:
- IV ibuprofen (Caldolor) is an injectable non-steroidal anti-inflammatory drug (NSAID) approved for management of pain or fever;
- Bupivacaine liposome injectable suspension (Exparel) is a local anesthetic with properties that extend its duration of action greater than non-liposomal preparations of bupivacaine; it has been approved for surgical incision infiltration and interscalene brachial plexus nerve block (for upper extremity surgery);
- IV acetaminophen (Ofirmev) is an injectable form of acetaminophen indicated for the treatment of pain or fever;
- Elagolix (Orilissa) is an orally administered gonadotropin-releasing hormone (GnRH) receptor antagonist indicated for the management of moderate to severe pain associated with endometriosis;
- Ketorolac tromethamine nasal spray (Sprix) is an NSAID indicated for the short term (up to 5 days) management of moderate to moderately severe pain; and
- Abiraterone acetate (Zytiga) is an orally administered CYP17 inhibitor indicated for the treatment of prostate cancer.
For each medication listed above, section 14 of the package insert (the section about clinical studies on which the approval was based) describes results of prospective trials that included a decrease in opioid consumption when the drug was administered, but the FDA does not include that particular property of the drug in section 1 (Indications and Usage).
The indications are essentially synonymous with the label claim for which manufacturers can then use for marketing purposes. One can imagine how impactful it would be to have an opioid-sparing claim on a product’s label. (The recent challenges to this rule based on First Amendment rights of truthful speech — see U.S. v. Caronia — are beyond the scope of this current discussion.)
At the November meeting, the FDA asked us to discuss the definition of “opioid sparing” and to discuss the types of study designs that would best demonstrate a reduction in opioid use for an acutely painful condition. After hearing presentations by representatives of the Biotechnology Innovation Organization, and public commentators, we debated the merits of different types of clinical trials, such as those with and without active comparators.
In other words, if a novel drug is seeking “opioid-sparing” label claims, is it sufficient for it to be superior to placebo? Or should it be compared with an active opioid comparator, such as morphine? Most committee members seemed to agree that an active opioid comparator would be essential for such as claim.
More details about discussions of opioid sparing will be posted for public view here, and it will be fascinating to see how the FDA approaches this concept in the future.
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