Off-Label Uses of Prescription Drugs in Pain Management

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1995 Angarola RT, Joranson DE. Off-label uses of prescription drugs in pain management. APS Bulletin 1995 5(1): 14-15.

Off-Label Uses of Prescription Drugs in Pain Management

Robert T. Angarola, Esq.; David E. Joranson, MSSW

Department editors' note: The off-label use of prescription drugs is a topic of great interest in the field of pain management. Literally thousands of medications are appropriately used by physicians for therapeutic purposes, including pain treatment, even though the U.S. Food and Drug Administration (FDA) has not specifically approved them for a particular use. Recently, the FDA has been questioning the use of drugs for indications not contained in the FDA-approved labeling. An exchange of correspondence with the FDA is provided here for the benefit of readers of APS Bulletin.

The following is the text of a letter written by several members of the American Pain Society to David A. Kessler, Commissioner of Food and Drugs, U.S. Food and Drug Administration, dated April 13, 1994:

We are aware of current FDA concerns about the off-label use of FDA-approved drugs by physicians. This is to request clarification of FDA's position on this issue. Is there any plan to change the current policy that recognizes a physician's ability to prescribe for off-label indications? If so, what would be the procedure for development of a different policy?

Off-label use of drugs to manage pain and other symptoms is common, is essential to effective medical management of patients with pain, and is supported by clinical experience, published literature, case law, and FDA policy statements. These off-label uses of FDA-approved drugs include

antidepressants for insomnia and pain;
opioid analgesics for pediatric pain;
anticonvulsants for a variety of pain problems;
corticosteroids for cancer pain;
antiarrythmics for neuropathic pain;
beta-blockers for migraine prophylaxis;
certain NSAIDs for nonarthritic pain;
amphetamines for opioid-induced sedation;
clonazepam for anxiety.

We look forward to your reply.

David E. Joranson, MSSW
Associate Director for Policy Studies
Pain Research Group
University of Wisconsin Medical School
Madison, WI

J. David Haddox, DDS MD
Director of Center for Pain Medicine
Crawford Long Hospital
Atlanta, GA

June L. Dahl, PhD
Professor of Pharmacology
University of Wisconsin Medical School
Madison, WI

Daniel B. Carr, MD
Director of Anesthesia Pain Clinic
New England Medical Center
Boston, MA

Kathleen M. Foley, MD
Chief of Pain Service
Memorial Sloan-Kettering Cancer Center
New York, NY

The FDA reply

The reply from Stuart L. Nightingale, MD, of the FDA, dated September 28, 1994, is reprinted below:

Dr. Kessler asked that I respond to your letter seeking clarification of FDA's position regarding the off-label use of FDA-approved drugs by physicians. As articulated in the enclosed materials, the agency has long recognized physicians' use of drugs outside the approved labeling within the context of the practice of medicine. See the April 1982 FDA Drug Bulletin at pages 4-5.

The agency also recognizes, however, that off-label use may at times pose problems. Labeling cannot provide full guidance on matters such as dosing, adverse effects, need for special monitoring, etc. for off-label uses. Consequently, we have used a variety of mechanisms over the past several years to encourage sponsors to expand the approved indications for their products to include off-label use where persuasive scientific evidence exists or can be developed to support new uses.

A copy of an April 27, 1993, letter that I sent to a number of professional and scientific organizations asking their assistance in an effort to identify those unlabeled uses which are most extensive, of potential therapeutic significance and which might be supported or partially supported by published or unpublished well-controlled studies is enclosed. I have included the letter from you and your colleagues in the file of responses.

Some observations by my staff regarding your list of drugs and "off-label" uses are also enclosed....

Stuart L. Nightingale, MD
Associate Commissioner Health Affairs

Enclosure from the FDA staff

The FDA staff comments on the list of drugs and uses in the letter by Joranson and colleagues were as follows:

Current labeling and a proposed FDA requirement for a subsection of labeling regarding "pediatric use" already address some of the uses that are mentioned. The following paragraphs are numbered to correspond to uses listed in the letter:

[1] The labeling for Sinequan (doxepin HCl), a tricyclic antidepressant, states, "The target symptoms of psychoneurosis that respond well to Sinequan include anxiety, tension, depression, somatic symptoms and concerns, sleep disturbances, guilt, lack of energy, fear, apprehension and worry." (emphasis supplied by the FDA)
[2] In the Federal Register for October 16, 1992, the FDA published a proposed rule, "Specific Requirements on Content and Format of Labeling for Human Prescription Drugs; Proposed Revision of 'Pediatric Use' Subsection in the Labeling." Pediatric indications and labeling statements about use of a drug in children must be supported by adequate scientific data. The proposed rule would expand on the current approach by explicitly recognizing alternatives for establishing substantial evidence of drug effectiveness in children when the drug has been approved for an indication based on adequate and well-controlled studies in adults.
[3] Tegretol (carbamazepine) was approved for use in trigeminal neuralgia before it was approved as an anticonvulsant. The labeling states, "Tegretol is indicated in the treatment of the pain associated with true trigeminal neuralgia. Beneficial results have also been reported in glossopharyngeal neuralgia." The labeling warns of an association with aplastic anemia and agranulocytosis and goes on to say, "This drug is not a simple analgesic and should not be used for the relief of trivial aches or pains."
[6] The labeling for Inderal (propranolol hydrochloride), a beta-blocker, states, "Inderal is indicated for the prophylaxis of common migraine headache."
[7] Among other NSAIDs, Motrin (ibuprofen), Naprosyn (naproxen), Anaprox (naproxen sodium), Meclomen (meclofenamate sodium), Ponstel (mefanamic acid), Nalfon (fenoprofen calcium), and Toradol (ketorolac tromethamine) are approved for the treatment of pain including nonarthritic pain.
[9] Hoffmann-LaRoche, Inc., the manufacturer of Klonopin (clonazepam), also markets four other benzodiazepine drugs, Valium (diazepam), Librium (chlordiazepoxide HCl), Dalmane (flurazepam hydrochloride), and Versed (midazolam HCl). Two of these, Valium and Librium, are approved for the treatment of anxiety. Dalmane is marketed as an hypnotic. Versed is labeled for perioperative use. It is a common practice for a company to differentiate several similar drugs by studying each for a separate indication. Other benzo- diazepines already labeled for anxiety include Ativan (lorazepam), Serax (oxazepam), Tranxene (clorazepate dipotassium), and Xanax (alprazolam).

Further resources

The FDA recommended further resources on off-label uses of prescription drugs as follows. They are available from David Joranson.

Correspondence from Stuart L. Nightingale, MD (Associate Commissioner for Health Affairs) to Ms. Susan Ulrich (Executive Director of the American College of Clinical Pharmacology), April 27, 1993.
Department of Health and Human Services. (1982). FDA Drug Bulletin, 12(1). Washington DC: U.S. Government Printing Office.
Food and Drug Administration. (1992). Specific Requirements on Content and Format of Labeling for Human Prescription Drugs; Proposed Revision of "Pediatric Use" Subsection in the Labeling. Federal Register, 57(201), 47423-47427.
Food and Drug Administration. (1992, October 27). Proposed Pediatric Regulations. Talk Paper No. T92-48. Rockville, MD: Author.
Nightingale, MD, Stuart L. Unlabeled Uses of Approved Drugs. Drug Information Journal, 26, 141-147.

David Joranson is associate director for policy studies with the Pain Research Group at the University of Wisconsin Medical School in Madison, WI. Robert Angarola is a director of the U.S. Cancer Pain Relief Committee and a partner in the law firm of Hyman, Phelps & McNamara, PC, in Washington, DC.