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Dr. Throm is an assistant professor of pharmacy practice at Midwestern University College of Pharmacy-Glendale, Glendale, Arizona.

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Amitriptyline for neuropathic pain in an adult diabetic patient; ketorolac for pain relief during a pediatric sickle-cell crisis; fentanyl (Actiq) lollipops during pregnancy for refractory migraines; fentanyl (Fentora) buccal tablets for headaches; propofol for itching related to epidural morphine—as the pharmacist, would you dispense these medications?^1-5

Each scenario is an example of offlabel prescribing—prescribing a product not FDA approved for that particular indication (indication not included in the package insert).^2,6-10 More than 150 million mentions of off-label uses were reported in the 160 most commonly prescribed medications; one quarter were supported by scientific rigor.⁶ Couple this with the estimated 50 million individuals affected by pain, and it becomes likely that patients may be prescribed an off-label medication for pain.¹¹

Recent articles in the Wall Street Journal paint a jaded, biased picture of the off-label use of opioid analgesics for treating pain.^3,4,12 Because off-label prescribing is common and controversial, pharmacists and other health care professionals should be familiar with the clinical and legal implications of such off-label prescribing.

Why Off-label Use Continues

Off-label prescribing is common for conditions such as cancer, AIDS/HIV, headaches, pain, pediatrics, pregnancy, psychiatric disorders, and rare diseases.^{1,2,5-7,10,12,13} Aggressive treatment, narrow labeling in the FDA-approved package inserts, and lack of clinical trials in select populations contribute to this off-label use.^2,13,14 It has been proposed that off-label use stems from clinical trials in similar diseases or from "learning by doing."^5,7

Off-label Uses for Pain

Nonsteroidal anti-inflammatory drugs (NSAIDs), acetaminophen, and opioid analgesics are commonly used in patients with acute and chronic pain; select patients may benefit from tricyclic antidepressants (TCAs) or epileptics for supplemental pain relief.¹¹ When used at appropriate doses with careful monitoring, these agents are safe and effective.

TCAs and Anticonvulsants

Neuropathic pain may be classified as 3 main types: postherpetic neuralgia (PHN), diabetic peripheral neuropathy (DPN), and trigeminal neuralgia (TN).¹ Antidepressants (amitriptyline), anticonvulsants (gabapentin), opioids (tramadol), and topical treatments (5% lidocaine patch) are commonly used for treating neuropathic pain.¹ The only FDA-approved treatments, however, include the 5% lidocaine patch, gabapentin and pregabalin for PHN, pregabalin and duloxetine for DPN, and carbamazepine for TN.¹

Unlike the TCAs, which commonly cause anticholinergic effects, sedation, orthostatic hypotension/syncope, cardiac arrhythmias, and weight gain, duloxetine (serotonin-norepinephrine reuptake inhibitor) has a more favorable side-effect profile and FDA backing.¹ Amitriptyline, the first-line agent for neuropathic pain, is backed by clinical evidence rather than FDA approval and is considered off label.

Ketorolac
Ketorolac is commonly used for acute, short-term pain relief in adults. Ketorolac may be administered intravenously or orally, but its use is limited to no more than 5 days due to adverse effects (eg, bleeding, renal dysfunction).¹⁵ Although ketorolac is not FDA approved for patients younger than 16 years, it is commonly used in children who have pain secondary to sickle-cell crises.²

Opioid Analgesics
Triptans, select NSAIDs, and select opioid analgesics are FDA-approved agents commonly used for headaches. A study conducted in a specialty headache clinic, however, discovered that, of the 379 prescriptions written in 1 month, approximately half met criteria for off-label use.¹⁰ The 4 most common off-label drugs that accounted for more than half of the off-label prescriptions included antiepileptics (topiramate and lamotrigine), antidepressants (venlafaxine), and botulinum toxin type A.¹⁰

The use of opioid analgesics (Actiq and Fentora) for headache pain has been a hot topic as evidenced by recent articles in the Wall Street Journal.^3,4 The information presented to the public may have been biased and may have instilled fear in the public about pain and addiction, promoting concern that curbing the availability of opioid analgesics may negatively impact the patients who truly require opioids (eg, the nonaddicted pain patients with cancer or other chronic pain conditions).¹²

With the proper assessment and management of both pain and addiction risk by a trained professional, treatment strategies may be tailored to meet individual needs.¹² Although both Actiq and Fentora are FDA approved for cancer patients only, trained providers continue to prescribe these agents off label for pain of noncancer origin.^12,16,17

Propofol
Common adverse drug events for opioid analgesics include constipation, respiratory depression, altered mental status, and itching due to histamine release.¹¹ Typical treatment for itching may include switching to a different opioid, changing administration route, or administering cost-effective antihistamines (eg, diphenhydramine).¹¹ One clinical study found that subhypnotic doses of propofol relieved itching in a patient receiving epidural and intrathecal morphine, however.¹⁸ The use of propofol for this indication is considered off label.

Resources for Off-label Use

Besides completing an evidencebased literature search, common resources on off-label or unapproved uses of medications can be used: (1) American Hospital Formulary Service run by the American Society of Health-System Pharmacists (www.ashp.org/ahfs); (2) United States Pharmacopoeia Drug Information; and (3) Drugdex and Drug Evaluations, both maintained by Micromedex (www.micromedex.com).^5,7-9,19,20 In addition, Facts and Comparisons' Off-Label Drug Facts assists health care professionals in identifying published literature regarding a specific drug use that is not currently FDA approved.⁵

Many reimbursement claims may be denied by private payers, Medicare, or Medicaid if prescribed off label, unless the medication is cited in these references (excluding Facts and Comparisons' Off-Label Drug Facts).^7-9,13,20 Published scientific evidence for drug use also can be used as part of the appeals and exceptions process.⁹ The Physicians' Desk Reference does not contain information on off-label indications.^8,10

Legal Implications of Off-label Use

Although it is legal for physicians to prescribe a medication for an off-label indication, marketing and promotion of off-label indications by drug companies is illegal.^7,8,20 Numerous lawsuits have alleged off-label marketing by drug companies.^20,21 Manufacturers are permitted to disseminate peer-reviewed published studies on the safety and effectiveness of off-label uses that have been or will be studied and submitted for FDA approval.^7,8,20 To make an educated evaluation of an off-label indication, therapeutic letters or academic detailing can help.²¹

There may be health-policy, regulatory, ethical, medicolegal, and economic implications associated with off-label prescribing (Table)⁵; therefore, various factors must be weighed when deciding when to prescribe an off-label drug (eg, clinical data, promotions, reimbursement hurdles).⁷

The following are suggestions to limit malpractice claims due to off-label prescribing: (1) discuss with the patient that the prescribed drug is off label; (2) prescribe with the best intentions to diagnose, treat, and directly benefit the patient; and (3) base the recommendation on expert medical opinion and sound, reputable peerreviewed scientific literature.²²

The pharmacist is the final safety check before a patient uses an off-label indication; it is important to be familiar with off-label prescribing of pain medications to promote patient safety, which includes proper monitoring and individual assessment.

References

1. Jackson KC 2nd. Pharmacotherapy for neuropathic pain. Pain Pract. 2006;6:27-33.
2. Eiland LS, Knight P. Evaluating the off-label use of medications in children. Am J Health Syst Pharm. 2006;63:1062-1065.
3. Carreyrou J. Narcotic ‘lollipop' is big seller despite FDA curbs. The Wall Street Journal. November 3, 2006.
4. Carreyrou J, Goldstein J. Cephalon drug is tied to several deaths. Off-label marketing of cancer painkiller is focus of three probes. The Wall Street Journal. September 14, 2007.
5. Demonaco HJ, Ali A, Hippel E. The major role of clinicians in the discovery of off-label drug therapies. Pharmacotherapy. 2006;26:323-332.
6. Radley DC, Finkelstein SN, Stafford RS. Off-label prescribing among office-based physicians. Arch Intern Med. 2006;166:1021-1026.
7. Hampton T. Experts weigh in on promotion, prescription of off-label drugs. JAMA. 2007;297:683-684.
8. Blum RS. Legal considerations in off-label medication prescribing. Arch Intern Med. 2002;162:1777-1779.
9. Medicare Rights Center. Off-base: the exclusion of off-label prescriptions from Medicare Part D coverage. August 2007. www.medicarerights.org. Accessed November 2, 2007.
10. Loder EW, Biondi DM. Off-label prescribing of drugs in specialty headache practice. Headache. 2004;44:636-641.
11. American Pain Society. Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain. 5th ed. Glenview, IL: American Pain Society; 2003.
12. Passik SD, Kirsh KL. Weighing in on the off-label use of Actiq for noncancer-related pain: a recipe for success or a recipe for disaster? Pain Med. 2007;8:130-133.
13. Eastman P. Reimbursement policies discourage off-label drug use. Oncology Times. 2005;27:8,10.
14. Benjamin DK Jr, Smith PB, Murphy MD, et al. Peer-reviewed publication of clinical trials completed for pediatric exclusivity. JAMA. 2006;296:1266-1273.
15. Toradol package insert. Roche Pharmaceuticals. Nutley, NJ:2002.
16. Actiq package insert. Cephalon Inc. Salt Lake City, UT:2007.
17. Fentora package insert. Cephalon Inc. Salt Lake City, UT:2007.
18. Borgeat A, Wilder-Smith OH, Saiah M, Rifat K. Subhypnotic doses of propofol relieve pruritus induced by epidural and intrathecal morphine. Anesthesiology. 1992;76:510-512.
19. Watson J. Off-label drug use in cancer care. Hematology and Oncology News and Issues. March 2007;18-20. www.HONIonline.com. Accessed November 2, 2007.
20. Watson J. Off-label drug use in cancer care-Part II. Hematology and Oncology News and Issues. April 2007;24-31. www.HONIonline.com. Accessed November 2, 2007.
21. Kondro W. "This is the kind of information we need." CMAJ. 2007;176:430.
22. Riley JB, Basilius PA. Physicians' liability for off-label prescriptions. Hematology and Oncology News and Issues. May/June 2007;24-27,37. www.HONIonline.com. Accessed November 2, 2007.