The Use of “Off-Label” Drugs

To the Editor: We would like to respond to a statement contained in Dr. Rowlingson’s editorial (1) concerning the “off-label uses of non-opioid drugs.” We must point out that if it were not for the courageous off-label use of bupivacaine 25 years ago by the National Children’s Hospital Group and our pediatric colleagues in Boston, Toronto, Baltimore, and Seattle, we would not be where we are today with our efforts to provide profound postoperative analgesia to suffering children through the use of caudal, epidural and peripheral nerve blocks. When we began this research there was no Federal Food and Drug Administration (FDA) approval for the use of bupivacaine in infants and children, and it was only through off-label use that this effort was launched. In fact, even now the PDR states: “Until further experience is gained in children younger than 12 years, administration of Sensorcaine (bupivacaine HCl) Injection in this age group is not recommended.”(2). When Broadman administered the first epidural opioid to a 6-year-old boy, the only drug available in the United States was Winthrop® preservative-free meperidine (unpublished data, 1983). The information on how to safely use neuraxialmeperidine was obtained from Lloyd Reddick (personal communication). This axis opioid was administered to a suffering child in an off-label manner but with IRB approval. The opioid provided this boy with several days of profound analgesia, without any adverse side effects. This event may have launched a new era: the use of spinal axis opioid analgesia in pediatric patients. In our opinion, the neuraxial opioid of choice in infants and children today is hydromorphone (3), because, in equianalgesic doses, it appears to have fewer adverse side effects than morphine (i.e., pruritus, nausea, and vomiting). Hydromorphone also has better rostral spread, allowing caudal administration in abdominal cases in young children. The use of this drug is still off-label and will likely remain so, because pharmaceutical manufacturers have no financial incentive to conduct the necessary safety/efficacy research trials to obtain a FDA-approved indication for this generic medication. Perhaps, the most classic case of off-label use of an anesthetic is the millions of times per year that caudal/epidural bupivacaine is safely and effectively used to perform spinal blocks, even though the package warns “NOT FOR SPINAL ANESTHESIA.” This is a prime example that off-label use does not necessarily mean unsafe. This logic is very true in the case of gabapentin, the medication implicated by Dr. Rowlingson in his editorial. If it had not been for the off-label use of gabapentin by the Mellick brothers (4) for reflex sympathetic dystrophy in 1997, we would have lost access to what has become the first-line drug in the management of neuropathies associated with diabetes (5), Acquired Immune Deficiency Syndrome (6), and Guillain-Barre syndrome (7). The most recent use of gabapentin by Dr. Pandey et al. (8,9), in which gabapentin administered by mouth in a single dose on the evening prior to surgery reduced the need for narcotic analgesics by 50% in the postoperative period, provides hope that similar results can be obtained in children undergoing scoliosis surgery and other painful orthopedic procedures. In our experience, the only adverse side effect one observes with gabapentin is somnolence, a potentially beneficial side effect of a premedication. It is almost certain that FDA approval will neither be sought nor obtained for the perioperative use of gabapentin to promote opioid sparing in the postoperative period in adults. Even more remote is the possibility that the necessary research will be done on behalf of children. Unfortunately, off-label use is the only option for pediatric anesthesiologists in their quest to optimally manage acute and chronic pain in infants and children. Lynn M. Broadman, MD Igor Semenov, MD Department of Anesthesiology Pittsburgh Children’s Hospital Pittsburgh, PA [email protected]