Low-dose amitriptyline: A potential therapeutic option for chronic pain in older people

Abstract

The use of antidepressants in older adults with chronic pain is controversial. We found Dr. Narayan et al.'s article, titled ‘Efficacy and Safety of Antidepressants for Pain in Older Adults: A Systematic Review and Meta-Analysis’, on the use of antidepressants in older people with chronic pain to be highly engaging.¹ They conducted a systematic review and meta-analysis on the efficacy and safety of antidepressants for chronic pain in older people. Due to various limitations, they concluded that the benefits and harms of antidepressant medicines for most types of chronic pain, especially knee OA, are unclear.

BMS, a common type of chronic orofacial pain affecting mainly postmenopausal women, has uncertain pathophysiology.

We previously reported that low doses of amitriptyline are effective in managing pain in older people with BMS.² Furthermore, even in patients over 80 years old, amitriptyline demonstrates efficacy when used in low doses with careful administration.³

Regarding common side effects, managing these side effects in elderly patients will be effective through regular visits and examination.^{2, 3} Hence, it is crucial to monitor for anticholinergic side effects such as drowsiness, dry mouth and constipation, as well as potential falls due to dizziness and any changes in cognitive function in clinical assessment.

A therapeutic window exists for the dosages of amitriptyline that are effective in managing chronic pain, indicating that its efficacy is not dose-dependent.⁴ In contrast to the doses used in psychiatry for depression (typically 100 mg/day or more), amitriptyline is effective at doses of 5–20 mg/day in the treatment of BMS. The use of amitriptyline at this dosage is considerably lower than the doses employed in the RCTs included in the authors' study, suggesting a reduced risk of side effects and withdrawal symptoms.

The challenges of administering antidepressants to older people with chronic pain are not only limited to concerns about side effects but also encompass issues related to their overall efficacy in this population. Serotonin's role in pain modulation is complex, as it can either exacerbate or alleviate pain depending on the receptor subtype activated. This bidirectional effect is attributed to the distinct pathways involved in serotonin-mediated pain processing, with some receptors promoting analgesia and others enhancing nociception.⁵ Additionally, the elevation of serotonin levels might disrupt the delicate equilibrium with dopamine, thus hindering pain inhibition via the reward pathway. Therefore, increasing serotonin levels alone may exacerbate pain rather than produce therapeutic benefits.

Moreover, chronic pain modulation involves not only serotonin but also other monoamines, such as dopamine and noradrenaline. Consequently, antidepressants that modulate serotonergic, noradrenergic or dopaminergic pathways may exhibit therapeutic potential in managing chronic pain.⁵ This is also reflected in the study by Narayan et al., which demonstrated the efficacy of duloxetine, a dual serotonin and noradrenaline reuptake inhibitor, albeit with a modest effect size. Amitriptyline, which similarly targets both serotonin and noradrenaline, and to some dopamine transporters, may offer superior efficacy compared to other antidepressants. However, as previously mentioned, its therapeutic effect does not appear to be dose-dependent, suggesting that there may be an optimal therapeutic window at lower doses. Although not specifically in older people, other reports have also demonstrated the effectiveness of low-dose amitriptyline (5–25 mg/day) in managing conditions such as lower back pain, chronic neck pain and chest pain.^6-8

Given the above, it is conceivable that low doses of certain antidepressants, such as amitriptyline, may be effective and safe for patients with other types of chronic pain. Research on the use of antidepressants for chronic pain in older people is still limited; therefore, as the authors have pointed out, there is a need for more prospective studies and numerous real-world investigations. In conclusion, careful clinical management and the accumulation of treatment data are essential for the effective treatment of chronic pain in older people using antidepressants.

Takayuki Suga: Writing—original draft. Trang Thi Huyen Tu: Writing—review and editing. Motoko Watanabe: Writing—review and editing. Takahiko Nagamine: Writing—supervision, review and editing. Akira Toyofuku: Conceptualization; funding acquisition; supervision; writing—review and editing.

There are no conflicts of interest to declare.