You are seeing a 39-year-old man on a return visit after biopsies confirmed the diagnosis of a squamous cell carcinoma of the left floor of the mouth and ventral tongue with clinically positive nodes in the left upper neck. PET scan revealed no distant metastases. You discuss the various treatment modalities with the patient today, including induction chemo-radiation therapy, and for reasons of his own importance, the patient selects primary wide local excision of the tumor, left neck dissection, and reconstruction with a microvascular free flap. As your discussion turns to perioperative care, the patient acknowledges that he was a former narcotics addict and continues to attend Narcotics Anonymous meetings for maintenance of abstinence. He is very adamant about not taking opioids after the surgery and refuses to reconsider chemotherapy and radiation therapy. However, he does state that he has done some research on alternative pain medications and believes that the drug gabapentin would be a good choice for him postoperatively. You review in your mind the FDA indications for gabapentin and realize that prescribing the drug for routine postoperative pain would be “off label,” and that you have no experience in using it in this manner.
How would you handle this case? Read below for the discussion.
Off-label drug prescribing (OLDP) is a complex and evolving issue in medicine. A physician considering prescribing a certain medication that is not on the FDA-approved indications list must contemplate three aspects of that decision—legal/regulatory, clinical evidence, and ethics. Currently in the US, OLDP is legal and relatively common in medical practice. A number of reasons exist for this legality, including the fact that physicians have been granted broad discretion in extending indications for prescribing a drug that, in their clinical judgment, has a positive benefit/risk ratio. Indeed, just because a drug is “approved” for certain specific conditions does not mean that it might not be helpful for a given patient with a similar or related condition. FDA approval reflects a decision that is made on evidence from clinical research trials submitted to the agency by a pharmaceutical company to treat a limited number of conditions. Because clinical trials are very expensive, not all “possible conditions” that might be targets for this drug will be included in these trials. Thus, there is post-approval latitude for physicians to consider additional conditions that might be improved through treatment with the drug.
While it is not clear just what is the incidence of OLDP in the U.S., it may be as high as 20% for many drugs. Once the FDA approves a drug for use in certain disorders, it can legally be prescribed for other disorders as long as due diligence and good clinical judgment are applied. It is not uncommon for off-label treatments to become standards of care over time as the benefits and safety profiles are increasingly known.
Informed consent for off-label drug prescribing should be considered on a similar level as informed consent for a surgical procedure, especially if the evidence base is sparse and the risks rather high.
The second element of OLDP for physician decision is evaluating both the evidence for the on-label medication use and the available evidence for its off-label use. The on-label evidence will usually be quite extensive, based on clinical trials evidence submitted to the FDA and subsequently published in the drug information. Additionally, information often is reported in the medical literature as clinicians record and report their clinical outcomes with the drugs. FDA approval of drugs for indicated disorders does not mean that they are completely safe and innocuous, as is well known to clinicians.
Simply put, FDA approval indicates that a drug has met certain testing standards and has shown a predominance of benefit over risk. Likewise, a physician has an obligation to search for the evidence base of any drug that she is contemplating prescribing to a patient for an off-label indication. The evidence may range from sparse to plentiful, from anecdotal small-case studies to larger systematic reviews and meta-analyses. The burden of proof for benefit over risk for a given patient does, of course, eventually rest with the physician. Medical societies may give clinical guidance to physicians on OLDP in specificity, or may simply encourage general best effort attempts to use discretion and judgment.
The physician should be aware of the evidence base, if any, for OLDP and contemplate how that information would pertain to her specific patient with a certain disorder. The on-label warnings, drug interactions, and adverse reactions known for a certain drug will clearly be the same for off-label use—there is not much variance—so these must be considered in light of each patient’s medical condition. OLDP to patients in a group not originally included in the clinical trials (i.e., children, pregnant women, elderly) is considered to be potentially riskier, and such risk should be taken seriously. Adverse reactions that occur in a patient while taking a drug prescribed for an off-label condition should be reported to the FDA in the same manner as for on-label indications (800-FDA-1088).
The third element in the decision-making process for an OLDP is the ethical considerations, which can be significant and multiple. While patient autonomy (self-determination) is often considered the primary ethical principle from the patient’s viewpoint, for the physician who is considering an off-label drug use it is a proper balance of the dyad of beneficence and non-maleficence. In the author’s perspective, OLDP requires an enhanced level of due diligence over that required for on-label prescribing because of the potential quality of the evidence base and the implications for patient safety. The patient and physician may be more assured for an off-label use when the patient’s condition is more closely related to the on-label indications than if there is little similarity. Physicians have an ethical duty to obtain as much information as feasible about off-label use before obtaining informed consent from the patient to prescribe the drug.
Additionally, it is most appropriate for the physician to have clinical experience with on-label prescribing of the drug before considering off-label indications, including its use in patients with co-morbidities similar to the patient’s.
After the physician has performed due diligence on the evidence base, she has a duty to obtain informed consent from the patient. There are differing opinions in the profession regarding the extent of disclosure the physician is required to provide with OLDP, varying from no duty to inform of the off-label status, to a complete disclosure of that fact. This author believes that full disclosure of off-label status is the best approach, as well as providing what information is available on benefits, risks, adverse reactions, and alternatives to this drug.
In a few cases, there may be no alternatives, or the risk/benefit ratio may be equivocal, and the patient should be so informed. Depending on the severity of risks and adverse reactions in the face of the patient’s medical conditions, the physician may wish to defer prescribing the drug until the patient has had sufficient time for consideration. Alternatively, if the patient has brought the possibility of using the drug to the physician, usually after Internet searches, the physician may request time to perform her own due diligence.
Informed consent for OLDP should be considered on a similar level as informed consent for a surgical procedure, especially if the evidence base is sparse and the risks rather high. Knowledge of the patient’s cognitive capacity for decision making, along with the physician’s experience, is often key to the content and approach for OLDP informed consent. Patients who do not have the capacity to provide informed consent should likely not be considered for OLDP unless the designated surrogate can understand and provide considered consent.
In this clinical scenario, the patient brings a concern to the surgeon regarding his desire to avoid postoperative opioids, if possible, due to his history of substance abuse—a very thoughtful request. In the midst of an opioid “crisis,” physicians are encouraged to expand their armamentarium of analgesics, and gabapentin is one of the current options. However, gabapentin has recently been identified as a new and potential substance abuse drug in the U.S. It is a federal non-controlled drug, although several states are now reclassifying it as a scheduled drug.
Gabapentin abuse seems to be more common in patients with a history of substance abuse, or current substance abuse, which should be a consideration in this particular patient’s case. While it is true that pain after surgery is akin to neurogenic pain, and perhaps gabapentin may be increasingly used for this indication, the risks for this patient may outweigh its benefits. Additional adverse reactions and side effects include the potential for addiction itself, suicidal ideations, and daytime somnolence.
It would be a reasonable clinical judgment to seek consultation on this patient’s postoperative pain care from a specialist in pain management, as well as to seek additional knowledge about the patient from his primary care physician.
A team approach to pain management is an ethical approach, with all due consideration of the patient’s total best interests.
Dr. Holt is professor emeritus in the department of otolaryngology–head and neck surgery at the University of Texas Health Science Center in San Antonio.