Off-label prescribing (OLP) refers to the practice of using medications for indications outside of those approved by the FDA, or in dosages, dose forms, or patient populations that have not been approved by the FDA.1 OLP is common, occurring in many practice settings and nearly every medical specialty. In a 2006 review, Radley et al2 found OLP accounted for 21% of the overall use of 160 common medications. The frequency of OLP varies between medication classes. Off-label use of anticonvulsants, antidepressants, and antipsychotics tends to be higher than that of other medications.3,4 OLP is often more common in patient populations unlikely to be included in clinical trials due to ethical or logistical difficulties, such as pediatric patients and individuals who are pregnant. The Box summarizes several components that contribute to the prevalence of OLP and explains why this practice is often necessary for treating certain substance-related and addictive disorders.
Several aspects contribute to off-label prescribing (OLP). First, there is little financial incentive for pharmaceutical companies to seek new FDA indications for existing medications. In addition, there are no FDA-approved medications for many disorders included in DSM-5, and treatment of these conditions relies almost exclusively on the practice of OLP. Finally, patients enrolled in clinical trials must often meet stringent exclusion criteria, such as the lack of comorbid substance use disorders. For these reasons, using off-label medications to treat substance-related and addictive disorders is particularly necessary.
Several important medicolegal and ethical considerations surround OLP. The FDA prohibits off-label promotion, in which manufacturers advertise the use of a medication for off-label use.5 However, regulations allow physicians to use their best clinical judgment when prescribing medications for off-label use. When considering off-label use of any medication, physicians should review the most up-to-date research, including clinical trials, case reports, and reviews to safely support their decision-making. OLP should be guided by ethical principles such as autonomy, beneficence, nonmaleficence, and justice. Physicians should obtain informed consent by conducting an appropriate discussion of the risks, benefits, and alternatives of off-label medications. This conversation should be clearly documented, and physicians should provide written material regarding off-label options to patients when available. Finally, physicians should verify their patients’ understanding of this discussion, and allow patients to accept or decline off-label medications without pressure.
This article focuses on current and potential future medications available for OLP to treat patients with alcohol use disorder (AUD), gambling disorder (GD), stimulant use disorder, and cannabis use disorder.
Alcohol use disorder
Ms. X, age 67, has a history of severe AUD, mild renal impairment, and migraines. She presents to the outpatient clinic seeking help to drink less alcohol. Ms. X reports drinking 1 to 2 bottles of wine each day. She was previously treated for AUD but was not helped by naltrexone and did not tolerate disulfiram (abstinence was not her goal and she experienced significant adverse effects). Ms. X says she has a medical history of chronic migraines but denies other medical issues. The treatment team discusses alternative pharmacologic options, including acamprosate and topiramate. After outlining the dosing schedule and risks/benefits with Ms. X, you make the joint decision to start topiramate to reduce alcohol cravings and target her migraine symptoms.
Only 3 medications are FDA-approved for treating AUD: disulfiram, naltrexone (oral and injectable formulations), and acamprosate. Off-label options for AUD treatment include gabapentin, topiramate, and baclofen.
Gabapentin is FDA-approved for treating postherpetic neuralgia and partial seizures in patients age ≥3. The exact mechanism of action is unclear, though its effects are possibly related to its activity as a calcium channel ligand. It also carries a structural resemblance to gamma-aminobutyric acid (GABA), though it lacks activity at GABA receptors.
Several randomized controlled trials (RCTs) evaluating the efficacy of gabapentin for AUD produced promising results. In a comparison of gabapentin vs placebo for AUD, Anton et al6 found gabapentin led to significant increases in the number of participants with total alcohol abstinence and participants who reported reduced drinking. Notably, the effect was most prominent in those with heavy drinking patterns and pretreatment alcohol withdrawal symptoms. A total of 41% of participants with high alcohol withdrawal scores on pretreatment evaluation achieved total abstinence while taking gabapentin, compared to 1% in the placebo group.6 A meta-analysis of gabapentin for AUD by Kranzler et al7 included 7 RCTs and 32 effect measures. It found that although all outcome measures favored gabapentin over placebo, only the percentage of heavy drinking days was significantly different.
Gabapentin is dosed between 300 to 600 mg 3 times per day, but 1 study found that a higher dose (1,800 mg/d) was associated with better outcomes.8 Common adverse effects include sedation, dizziness, peripheral edema, and ataxia.
Continue to: Topiramate