Report from the Front

Recent Actions by the FDA to Protect Children

By Rae Brown, MD, FAAP
Chair, FDA Advisory Committee on Anesthetics and Analgesic Drug Products

In the past few months the FDA has taken actions that should be expected to protect children and are in line with requests from the SPA, the SPPM, and the Section on Anesthesiology and Pain Medicine of the American Academy of Pediatrics. Restrictions on codeine reflect discussions ongoing since December 2015. Similar restrictions on tramadol were also announced to the consternation of some pediatric clinicians. The reasons behind this decision will be elucidate later in this manuscript. The Agency continues to press forward with plans to liberalize the availability of naloxone, a pharmaceutical that has been demonstrated to be life saving in the face of increasingly potent illicit opioids. I would like to touch briefly on each of these topics, but first l feel compelled to comment on abuse deterrent formulations of opioids – what we know and what we don’t know, as this is an area of considerable confusion among many of my colleagues.

Abuse Deterrent Formulations
Abuse deterrent formulations (ADFs) are opioids that have been manufactured with various technologies that would be expected to reduce the risk that substance abusers will alter the compound for purposes of intravenous injection or inhalation. ADFs are not less addictive than the parent compound. Patients that become addicted through the oral intake of progressively larger quantities of oxycodone would be expected to similarly become tolerant and then addicted to the ADF formulation. ADFs do nothing to prevent the most common form of prescription drug abuse: oral intake. The use and misuse of opioids follows a pattern that usually begins with the oral intake of progressively larger quantities of the drug. The ADF compound can be ingested in large quantities if available to the patient. As patients develop tolerance, they may look to obtaining faster or increased effects of the drug, by inhalation or injection. Most of the deaths associated with opioid abuse follow injection, and the purpose of the ADF formulation is to decrease the likelihood of this progression.

Remember: ADFs don’t prevent oral opioid abuse nor do they have any effect on the development of addiction!

Fate of Codeine
In December 2015, an Advisory Committee meeting involving elements of the pediatric and anesthesiology community met for two days to discuss codeine use as an analgesic or antitussive agent in infants and children. Collectively, pediatricians and anesthesiologists had been lobbying the Agency for some years to restrict the sale of codeine in the United States. The FDAs data has revealed 16 deaths associated with the ingestion of codeine by children, or breast-feeding mothers with many more episodes of documented near misses, and the need for an analgesic compound that afforded such genetic variability in its metabolism did not seem reasonable. In addition, many from the pediatric community question its use as a cough suppressant, citing studies that demonstrate a lack of efficacy, especially in infants.

This large group advised the Agency that codeine should be significantly restricted, especially in infants and the mothers of breast-feeding infants. Many on the panel opined that codeine would continue to be used in children unless it was taken off of the market altogether. Also, more than 25 states allow for the sale of combination compounds containing codeine over the counter. These formulations have low concentrations of codeine, but are listed in the “Orange Book” of drugs thought to be generally safe and effective. To restrict prescription codeine without acting on the non-prescription compound seemed problematic.

Eighteen months after this meeting, and with continued pressure from the AAP, the Agency restricted the use of codeine and tramadol in children under the age of 12.  These actions were taken in addition to the boxed warning to codeine’s label that has been in place since 2013.

But why tramadol?
Tramadol is approved in the U.S. for the treatment of pain in adults; but not children. The pathways that affect the breakdown of codeine in the body are similar with tramadol. Both utilize cytochrome CYP2D6 and population studies suggest that tramadol has fast, slow, and no genetic variants yielding high, intermediate, and no presence of the breakdown product – morphine for codeine, and O-desmethyltramadol for tramadol. The unexpected high levels of active metabolites place children, and especially infants, at risk for respiratory compromise. The Agency identified twelve cases of severe respiratory disturbance in its data set. Policy makers feared that an unintended result of further restrictions on codeine would have the unintended consequence of inviting clinicians to switch to tramadol, with resulting adverse breathing issues and deaths.

Clinicians have not accepted the policy relating to tramadol with the support seen with codeine. Many worry that there are very few oral analgesic agents that provide moderate analgesia without the side effect profile of NSAIDS. Some are concerned that prescribing oral hydrocodone or oxycodone sends an unintended message and increases the risk of opioid abuse.  This issue is still evolving and there are no easy solutions.

Naloxone continues to be a hot topic in Washington. With the import of much more potent opioids, such as carfentanil, first responders are finding that many intranasal doses (10-15) may be required to treat apnea in suspected users. Communities around the country are beginning to train community volunteers to carry naloxone for use if necessary. We are still discussing the possibility of an over the counter form.

Perhaps, some consideration should be given by pain physicians whose patients require opioids to co– prescribing naloxone or making kits available for parents to take home.

As always I and the SPPM leadership welcome input, ideas and suggestions to improve pain management and increase safety.