Off-label indications for antidepressants in primary care
To the Editor:
The article by Wong and colleagues entitled "Off-label indications for antidepressants in primary care: descriptive study of prescriptions from an indication based electronic prescribing system" reports the prevalence of off-label prescribing of antidepressants in primary care settings. Not surprisingly, the study found that for certain antidepressants the rates of off-label use were very high, which primarily refers to tricyclics and trazodone. Some of the conclusions are charitable: "When evidence to support efficacy is lacking, physicians should exercise caution, prescribe conservatively, and inform patients of this information via a shared decision making process"). Others are less so: "This ideal, however, is challenging to achieve because physicians face time constraints, the drug market and scientific literature are vast and ever-evolving, and many physicians find it challenging to critically appraise and interpret the results of epidemiological studies." The conclusion is that e-prescribing decision support tools involving warnings to physicians and information for the public will solve what has apparently been identified as a problem.
Appropriate prescribing in the article was defined as being either on-label (i.e., approved by regulatory authorities) or “off-label with strong evidence.” The authors used the following definition of "strong evidence" of effectiveness, derived from the DRUGDEX compendium (Thomson Micromedex): "we classified off-label prescriptions as having strong evidence for the prescribed drug if evidence showed that the drug was effective or favoured efficacy for the indication, the drug was recommended for all or most patients with the indication, and at least one randomised clinical trial was included among the studies used to evaluate the drug’s efficacy for the indication." This is an excessively restrictive definition of a proper use for a drug.
The article identifies two main indications for off-label prescribing that do not meet the “strong evidence” straw man definition: tricyclics for pain and trazodone for sleep. Trazodone and tricyclics are used widely for these indications and have some clinical trial support.1-3 The relative lack of larger scale clinical trials is related to the fact that these medications have been generic for many years and that larger scale drug trials are typically supported by pharmaceutical companies. An "on-label and off-label plus strong evidence" standard of practice would likely lead to undesirable shifts in prescribing. Given the limited medication options for sleep, eliminating trazodone would result in a move to the "z-drugs" (zolpidem, zaleplon, and eszopiclone) or, possibly, benzodiazepines (e.g., temazepam or triazolam) for insomnia. Although these medications are on-label, they are associated with a much higher potential for abuse and dependence than trazodone. A second shift would be from tricyclics to narcotic medications, which clearly would be a negative outcome. A balanced view of data is captured well by a Cochrane Database review in regard to the use of amitriptyline for neuropathic pain: “The fact that there is no supportive unbiased evidence for a beneficial effect is disappointing, but has to be balanced against decades of successful treatment in many people with neuropathic pain.”3
The question boils down to the tension between optimal and sufficient evidence for the use of a medication for an unapproved indication. The limited clinical trials data supporting the use of trazodone for sleep or tricyclics for pain has to be balanced against prior experience and the undesirability of alternatives. I am in full agreement with the sentiment expressed by the authors that “(t)hese findings highlight an urgent need to produce more evidence on the risks and benefits of off-label antidepressant use.” In the meantime, off-label uses of these medicines are appropriate.
1. Bossini L, Coluccia A, Casolaro I, et al. Off-Label Trazodone Prescription: Evidence, Benefits and Risks. Curr Pharm Des 2015;21(23):3343-3351.
2. Rico-Villademoros F, Slim M, Calandre EP. Amitriptyline for the treatment of fibromyalgia: a comprehensive review. Expert Rev Neurother 2015;15(10):1123-1150.
3. Moore RA, Derry S, Aldington D, et al. Amitriptyline for neuropathic pain and fibromyalgia in adults. Cochrane database of systematic reviews (Online) 2012;12:Cd008242. doi: 10.1002/14651858.CD008242.pub2
Competing interests: All authors have completed the ICMJE uniform disclosure form at and declare: no support from any organisation for the submitted work; and the following financial relationships with any organisations that might have an interest in the submitted work in the previous three years: Consulting: Acadia Pharmaceuticals, Allergan, Cerecor, Inc., Clintara, LLC, Janssen Pharmaceutica, Medtronic, Inc., Lundbeck A/S, MSI Methylation Sciences, Inc., Nestle’ Health, Pfizer, Inc., Takeda Pharmaceuticals; Grant support: Acadia Pharmaceuticals, Alkermes, Inc., Allergan, Assurex Health, Avanir Pharmaceuticals, Cerecor, Inc., Genomind, Janssen Pharmaceutica, Naurex Inc., Nestle’ Health, Novartis Inc., Otsuka Pharmaceuticals, Takeda Pharmaceuticals.
Competing interests: The author has completed the ICMJE uniform disclosure form and declares: no support from any organisation for the submitted work; and the following financial relationships with any organisations that might have an interest in the submitted work in the previous three years: Consulting: Acadia Pharmaceuticals, Allergan, Cerecor, Inc., Clintara, LLC, Janssen Pharmaceutica, Medtronic, Inc., Lundbeck A/S, MSI Methylation Sciences, Inc., Nestle’ Health, Pfizer, Inc., Takeda Pharmaceuticals; Grant support: Acadia Pharmaceuticals, Alkermes, Inc., Allergan, Assurex Health, Avanir Pharmaceuticals, Cerecor, Inc., Genomind, Janssen Pharmaceutica, Naurex Inc., Nestle’ Health, Novartis Inc., Otsuka Pharmaceuticals, Takeda Pharmaceuticals