Amitriptyline’s anticholinergic adverse drug reactions–A systematic multiple-indication review and meta-analysis

Abstract

Background Half the US population uses drugs with anticholinergic properties. Their potential harms may outweigh their benefits. Amitriptyline is among the most frequently prescribed anticholinergic medicinal products, is used for multiple indications, and rated as strongly anticholinergic. Our objective was to explore and quantify (anticholinergic) adverse drug reactions (ADRs) in patients taking amitriptyline vs. placebo in randomized controlled trials (RCTs) involving adults and healthy individuals. Methods We searched electronic databases from their inception until 09/2022, and clinical trial registries from their inception until 09/2022. We also performed manual reference searches. Two independent reviewers selected RCTs with ≥100 participants of ≥18 years, that compared amitriptyline (taken orally) versus placebo for all indications. No language restrictions were applied. One reviewer extracted study data, ADRs, and assessed study quality, which two others verified. The primary outcome was frequency of anticholinergic ADRs as a binary outcome (absolute number of patients with/without anticholinergic ADRs) in amitriptyline vs. placebo groups. Results Twenty-three RCTs (mean dosage 5mg to 300mg amitriptyline/day) and 4217 patients (mean age 40.3 years) were included. The most frequently reported anticholinergic ADRs were dry mouth, drowsiness, somnolence, sedation, fatigue, constitutional, and unspecific anticholinergic ADRs. Random-effects meta-analyses showed anticholinergic ADRs had a higher odd’s ratio for amitriptyline versus placebo (OR = 7.41; [95% CI, 4.54 to 12.12]). Non-anticholinergic ADRs were as frequent for amitriptyline as placebo. Meta-regression analysis showed anticholinergic ADRs were not dose-dependent. Discussion The large OR in our analysis shows that ADRs indicative of anticholinergic activities can be attributed to amitriptyline. The low average age of participants in our study may limit the generalizability of the frequency of anticholinergic ADRs in older patients. A lack of dose-dependency may reflect limited reporting of the daily dosage when the ADRs occurred. The exclusion of small studies (<100 participants) decreased heterogeneity between studies, but may also have reduced our ability to detect rare events. Future studies should focus on older people, as they are more susceptible to anticholinergic ADRs. Registration PROSPERO: CRD42020111970.

Durable effects of acupuncture for tension-type headache: A systematic review and meta-analysis

“…As regarding pharmacological preventive treatment for TTH, the tricyclic antidepressant amitriptyline is considered as first-line option, followed by mirtazapine and venlafaxine as second and third options [ 2 ]. However, the effects of these prophylactic drugs may be limited and treatment may be complicated by side effects including dizziness, somnolence, weight gain, and gastrointestinal disorders [ 2 , 14 , [35] , [36] , [37] , [38] ]. Evidence of high quality showed that acupuncture was comparable to amitriptyline in number of patients needed to treat for a patient to have a beneficial outcome (number needed to treat [NNT], 11 vs 12) with a higher number of patients needed to treat for a patient to have an adverse event (number needed to harm [NNH], acupuncture vs amitriptyline, 20 vs 2 [1.6 to 2.6]) [ 14 , 19 , 39 ].…”

Amitriptyline inhibits bronchoconstriction and directly promotes dilatation of the airways

“…As anti-muscarinic medication, systemically administered amitriptyline led to typical anticholinergic side effects, such as cconstipation, dry mouth, dry eyes, urinary retention and so on (e.g. [ 35 ]). These effects paved the way for new, more selective and highly compatible antidepressants, like SSRIs and SNRIs.…”

Common Oral Conditions

“…Another 2018 systematic review of patients older than 60 years reported that urological medications had an association with dry mouth (OR for oxybutynin, 18.9 [95% CI, 8.4 to 42.2]; OR for darifenacin, 7.4 [95% CI, 2.9 to 19.2]; OR for fesoterodine, 6.9 [95% CI, 3.6 to 13.4]; OR for solifenacin, 5.3 [95% CI, 2.0 to 14.5]; OR for tolterodine, 4.8 [95% CI, 3.3 to 7.2]; and OR for mirabegron, 1.2 [95% CI, 0.5 to 2.9]), followed by antidepressants (OR, 4.7 [95% CI, 2.7 to 8.3]), and psycholeptics (OR, 2.6 [95% CI, 1.8 to 4.0]) . In particular, a 2023 systematic review and meta-analysis of 9 RCTs (2499 patients) of amitriptyline used for depression, pain, or functional dyspepsia (dose ranges, 5 mg to 300 mg) vs placebo reported that dry mouth was more frequent in patients taking amitriptyline (risk difference, 52.1%; OR, 11.10 [95% CI, 6.5 to 19.1]) . Other medications or conditions that are associated with increased risk of salivary gland hypofunction include immune checkpoints inhibitors (CTLA-4, PD-1, and PD-L1 inhibitors), radiation therapy for head and neck cancers, dehydration, oral chronic graft-vs-host-disease, and Sjögren disease …”

“…8 In particular, a 2023 systematic review and meta-analysis of 9 RCTs (2499 patients) of amitriptyline used for depression, pain, or functional dyspepsia (dose ranges, 5 mg to 300 mg) vs placebo reported that dry mouth was more frequent in patients taking amitriptyline (risk difference, 52.1%; OR, 11.10 [95% CI, 6.5 to 19.1]). 9 Other medications or conditions that are Dry mouth is a common condition that can result from certain medications (anticholinergics, antihypertensives, antihistamines, antipsychotics, sedatives, immune checkpoint inhibitors, and antidepressants), radiation therapy for head and neck cancers, aging, and autoimmune diseases such as Sjögren disease. Dry mouth can lead to increased risk of dental caries, oral infections, and difficulty in speaking and swallowing.…”