Can nortriptyline be used to treat fibromyalgia?

Nortriptyline for Fibromyalgia Treatment

Direct Answer

Nortriptyline can be used to treat fibromyalgia, but amitriptyline is the preferred tricyclic antidepressant with stronger evidence and guideline support. 1

Evidence for Tricyclic Antidepressants in Fibromyalgia

Amitriptyline as the Gold Standard TCA

• Amitriptyline at 10-75 mg/day is recommended as a first-line pharmacological option with Level Ia, Grade A evidence for pain reduction and improved function in fibromyalgia. 1

• The number needed to treat (NNT) for 50% pain relief with amitriptyline is 4.1, meaning approximately one in four patients achieves substantial benefit. 2

• Amitriptyline produces a moderate analgesic effect (standardized mean difference = -0.40) and modest improvements in sleep problems (SMD = 0.47) and fatigue (SMD = 0.48). 1

• Compared with placebo, amitriptyline reduces sleep disturbances (SMD -0.97), fatigue (SMD -0.64), and improves quality of life (SMD -0.80). 3

Nortriptyline-Specific Evidence

• Nortriptyline has been directly studied in fibromyalgia in at least one double-blind, randomized, controlled trial comparing it to amitriptyline and placebo. 4

• In this Brazilian study of 118 fibromyalgia patients, nortriptyline 25 mg at bedtime for 8 weeks showed improvement rates of 26.7% on the Fibromyalgia Impact Questionnaire (FIQ), 19.5% on number of tender points, and 72.2% on patient global improvement—though these did not reach statistical significance compared to placebo. 4

• Amitriptyline outperformed nortriptyline in the same study, with 36.5% improvement on FIQ and 86.5% on global improvement (p ≤ 0.03 versus placebo). 4

• Nortriptyline had a higher side effect profile (31 adverse events) compared to amitriptyline (16 adverse events) in this trial. 4

Clinical Positioning of Nortriptyline

When to Consider Nortriptyline

• Nortriptyline may be considered as an alternative tricyclic when amitriptyline is poorly tolerated due to anticholinergic effects (dry mouth, constipation, urinary retention, morning sedation), though it still carries anticholinergic burden. 2

• Nortriptyline is a secondary amine tricyclic with theoretically fewer anticholinergic effects than the tertiary amine amitriptyline, though clinical evidence in fibromyalgia does not consistently support superior tolerability. 4

Preferred Alternatives to Both TCAs

• Duloxetine 60 mg once daily is the preferred first-line agent according to multiple guidelines, with FDA approval for fibromyalgia and superior tolerability compared to tricyclics. 1, 5

• Duloxetine should not be increased above 60 mg/day because doses of 120 mg provide no additional pain relief but increase adverse events. 1

• Pregabalin 300-450 mg/day is another FDA-approved first-line option with Level Ia, Grade A evidence, producing 38% greater likelihood of achieving ≥30% pain reduction versus placebo (RR 1.38,95% CI 1.25-1.51). 1

• Milnacipran 100-200 mg/day is a third FDA-approved SNRI option with similar efficacy to duloxetine. 1

Treatment Algorithm Incorporating Nortriptyline

Step 1: First-Line Pharmacotherapy

• Begin with duloxetine 60 mg daily OR pregabalin 300-450 mg/day as the initial pharmacologic choice, tailoring selection to individual factors (comorbid depression favors duloxetine; prominent sleep disturbance may favor pregabalin). 1

Step 2: If First-Line Agents Fail or Are Contraindicated

• Consider amitriptyline 10-50 mg at bedtime as the preferred tricyclic, starting at 10 mg and increasing by 10 mg weekly to target 25-50 mg nightly. 1, 2

• Amitriptyline is particularly beneficial for patients with prominent sleep disturbances due to its sedating properties. 1

Step 3: Nortriptyline as a Second-Line TCA

• If amitriptyline causes intolerable anticholinergic side effects but a tricyclic is still desired, switch to nortriptyline 25 mg at bedtime, recognizing that evidence for nortriptyline is weaker than for amitriptyline. 4

• Use the same gradual titration approach as with amitriptyline, monitoring for anticholinergic effects and morning sedation. 2

Step 4: Combination or Alternative Strategies

• If partial response (30-50% pain reduction) occurs with duloxetine or pregabalin, consider adding amitriptyline rather than switching, though this increases risk of drug interactions. 1

• Tramadol is recommended only when first-line medications are ineffective, with Level Ib, Grade A evidence but opioid-related risks requiring careful monitoring. 1

Critical Pitfalls to Avoid

• Never use nortriptyline as a first-line agent when amitriptyline, duloxetine, or pregabalin are available and tolerated, as these have stronger evidence. 1, 4

• Avoid tricyclics in older adults (≥65 years) due to anticholinergic effects including orthostatic hypotension, falls risk, cognitive impairment, and urinary retention. 1

• Do not prescribe corticosteroids or strong opioids for fibromyalgia under any circumstances, as they lack efficacy and cause significant harm. 1, 2

• Therapeutic effects of tricyclics typically emerge over 3-7 weeks; do not abandon treatment prematurely. 2

• Never discontinue tricyclics abruptly—taper gradually over 2-4 weeks to prevent withdrawal symptoms. 2

Evidence Quality Summary

• The evidence for nortriptyline in fibromyalgia is third-tier at best, derived from a single adequately powered randomized trial showing numerical but not statistically significant benefit over placebo. 4

• In contrast, amitriptyline has Level Ia, Grade A evidence from multiple guidelines including the European League Against Rheumatism, though even this evidence is considered modest by Cochrane review standards. 1, 6

• The most robust evidence supports duloxetine and pregabalin as first-line agents, both with FDA approval and Level Ia, Grade A guideline recommendations. 1, 5