On 2016 Jul 13, Jenna Wong commented:

None

On 2016 Jul 16, David Keller commented:

Doxepin - an antidepressant with strong scientific evidence supporting its off-label use for insomnia

Wong wrote: "Regarding the off-label use of antidepressants for insomnia, we disagree with Keller that it is supported by strong scientific evidence".

To demonstrate that Wong is incorrect, I cite doxepin, an antidepressant with strong evidence supporting its off-label use for insomnia at the 10 mg dose approved only for depression. Both of the references cited by Wong to contradict me were published in 2005, 5 years before the FDA approval of doxepin for insomnia. In 2010, the FDA approved doxepin for insomnia at the doses of 3 mg and 6 mg, which can be given sequentially if needed. Physicians continue to prescribe cheap generic doxepin 10 mg to treat insomnia (off-label at 10 mg), based on the strong scientific evidence supporting its FDA-approved insomnia doses of 3 mg and 6 mg. Doxepin 10 mg is the lowest dose approved for use as a cheap generic antidepressant, and I daresay that the vast majority of prescriptions for that dose are written off-label for insomnia, which has the benefit of saving the patient substantial money on the high cost of the doses branded for insomnia.

On 2016 Jul 13, Jenna Wong commented:

We thank Keller for his comment. We agree that the level of supporting scientific evidence is the most important aspect to consider when determining the appropriateness of off-label drug use. In our article, we state that our findings “highlight the need to evaluate the evidence supporting off-label antidepressant use,” which neither assumes that all off-label antidepressant use is inappropriate, nor assumes that all off-label indications require official regulatory approval. In cases where off-label use lacks scientific evidence, our position is that physicians should exercise caution and carefully consider the potential risk-benefit ratio when prescribing antidepressants for off-label indications. However, to assess risk-benefit, physicians must have easy access to sources of knowledge that evaluate and summarize the existing scientific evidence.

Regarding the off-label use of antidepressants for insomnia, we disagree with Keller that it is supported by strong scientific evidence. In fact, the article [1] that he cites to support this claim states that “[the] NIH State of Science Conference on insomnia treatments reviewed the status of antidepressants reporting minimal scientific evidence supporting their use,” and that “[of] particular concern in using antidepressants for insomnia are a number of unique potential side effects”. Other review articles have also made similar conclusions [2].

References:

[1] Asnis GM, Thomas M, Henderson MA. Pharmacotherapy Treatment Options for Insomnia: A Primer for Clinicians. Int J Mol Sci. 2015;17(1).

[2] WB M. A review of the evidence for the efficacy and safety of trazodone in insomnia. J Clin Psychiatry. 2005;66(4):469-476.

On 2016 Jun 29, David Keller commented:

In Defense of Off-Label Prescribing of Antidepressants

Wong and colleagues report that, in their study, 29.4% of all antidepressant prescriptions were written "for non-depressive indications, including unapproved (off-label) indications that have not been evaluated by regulatory agencies" [1]. The authors imply that patients treated for unapproved indications with antidepressants would benefit if these off-label treatments were evaluated by regulatory agencies. However, the small profit margins of generic medications make the cost of regulatory approval for every beneficial indication prohibitively expensive.

Recently, a study by Eguale and colleagues demonstrated that off-label use of prescription drugs is associated with increased adverse drug events only when such use lacks strong scientific evidence [2]. Wong and colleagues found that the two most common off-label indications for antidepressants were insomnia and pain [1], both of which are supported by strong scientific evidence [3], [4]. Less common off-label indications, such as migraine, also have strong scientific support [5].

The findings of Eguale and colleagues demonstrate that patient safety does not require specific regulatory approval for every off-label indication, and that it is not necessary to spend the large sums of money which would be required to obtain FDA approval for every off-label indication. [6]

References

1: Wong J, Motulsky A, Eguale T, Buckeridge DL, Abrahamowicz M, Tamblyn R. Treatment Indications for Antidepressants Prescribed in Primary Care in Quebec, Canada, 2006-2015. JAMA.2016;315(20):2230-2232. doi:10.1001/jama.2016.3445.

2: Eguale T, Buckeridge DL, Verma A, Winslade NE, Benedetti A, Hanley JA, Tamblyn R . Association of Off-label Drug Use and Adverse Drug Events in an Adult Population. JAMA Intern Med. 2016 Jan 1;176(1):5563. doi:10.1001/jamainternmed.2015.6058. PubMed PMID: 26523731.

3: Asnis GM, Thomas M, Henderson MA. Pharmacotherapy Treatment Options for Insomnia: A Primer for Clinicians. Int J Mol Sci. 2015 Dec 30;17(1). pii: E50. doi: 10.3390/ijms17010050. PubMed PMID: 26729104; PubMed Central PMCID:PMC4730295.

4: Janakiraman R, Hamilton L, Wan A. Unravelling the efficacy of antidepressants as analgesics. Aust Fam Physician. 2016 Mar;45(3):113-7. PubMed PMID: 27052046.

5: Jackson JL, et al. A Comparative Effectiveness Meta-Analysis of Drugs for the Prophylaxis of Migraine Headache. PLoS One. 2015 Jul 14;10(7):e0130733. doi:10.1371/journal.pone.0130733. eCollection 2015. PubMed PMID: 26172390; PubMed Central PMCID: PMC4501738.

6: Keller DL. In Defense of Off-label Prescribing. JAMA Intern Med. 2016 Jun 1;176(6):861. doi: 10.1001/jamainternmed.2016.1403. PubMed PMID: 27273485.

On 2016 Jun 29, David Keller commented:

In Defense of Off-Label Prescribing of Antidepressants

Wong and colleagues report that, in their study, 29.4% of all antidepressant prescriptions were written "for non-depressive indications, including unapproved (off-label) indications that have not been evaluated by regulatory agencies" [1]. The authors imply that patients treated for unapproved indications with antidepressants would benefit if these off-label treatments were evaluated by regulatory agencies. However, the small profit margins of generic medications make the cost of regulatory approval for every beneficial indication prohibitively expensive.

Recently, a study by Eguale and colleagues demonstrated that off-label use of prescription drugs is associated with increased adverse drug events only when such use lacks strong scientific evidence [2]. Wong and colleagues found that the two most common off-label indications for antidepressants were insomnia and pain [1], both of which are supported by strong scientific evidence [3], [4]. Less common off-label indications, such as migraine, also have strong scientific support [5].

The findings of Eguale and colleagues demonstrate that patient safety does not require specific regulatory approval for every off-label indication, and that it is not necessary to spend the large sums of money which would be required to obtain FDA approval for every off-label indication. [6]

References

1: Wong J, Motulsky A, Eguale T, Buckeridge DL, Abrahamowicz M, Tamblyn R. Treatment Indications for Antidepressants Prescribed in Primary Care in Quebec, Canada, 2006-2015. JAMA.2016;315(20):2230-2232. doi:10.1001/jama.2016.3445.

2: Eguale T, Buckeridge DL, Verma A, Winslade NE, Benedetti A, Hanley JA, Tamblyn R . Association of Off-label Drug Use and Adverse Drug Events in an Adult Population. JAMA Intern Med. 2016 Jan 1;176(1):5563. doi:10.1001/jamainternmed.2015.6058. PubMed PMID: 26523731.

3: Asnis GM, Thomas M, Henderson MA. Pharmacotherapy Treatment Options for Insomnia: A Primer for Clinicians. Int J Mol Sci. 2015 Dec 30;17(1). pii: E50. doi: 10.3390/ijms17010050. PubMed PMID: 26729104; PubMed Central PMCID:PMC4730295.

4: Janakiraman R, Hamilton L, Wan A. Unravelling the efficacy of antidepressants as analgesics. Aust Fam Physician. 2016 Mar;45(3):113-7. PubMed PMID: 27052046.

5: Jackson JL, et al. A Comparative Effectiveness Meta-Analysis of Drugs for the Prophylaxis of Migraine Headache. PLoS One. 2015 Jul 14;10(7):e0130733. doi:10.1371/journal.pone.0130733. eCollection 2015. PubMed PMID: 26172390; PubMed Central PMCID: PMC4501738.

6: Keller DL. In Defense of Off-label Prescribing. JAMA Intern Med. 2016 Jun 1;176(6):861. doi: 10.1001/jamainternmed.2016.1403. PubMed PMID: 27273485.

On 2016 Jul 13, Jenna Wong commented:

None