What are the indications, recommended dosing, and contraindications for nortriptyline in an adult with moderate to severe depression and neuropathic pain?

Nortriptyline for Depression and Neuropathic Pain

Nortriptyline is a first-line treatment for neuropathic pain with established efficacy (NNT 3.6), but should be started at low doses (10-25 mg at bedtime) and titrated slowly to 75-150 mg/day, with mandatory ECG screening for patients over 40 years before initiation. 1, 2

Indications

Neuropathic Pain (Primary Indication)

• Nortriptyline is recommended as first-line therapy for multiple neuropathic pain conditions including diabetic peripheral neuropathy, postherpetic neuralgia, and chronic low back pain with radicular features 1, 2, 3
• For diabetic neuropathy specifically, the NNT is 1.3, indicating exceptional efficacy 1
• Important limitation: Nortriptyline is NOT effective for HIV-associated neuropathy or chemotherapy-induced peripheral neuropathy, where trials have shown no benefit 1, 4
• Lumbosacral radiculopathy is notably more refractory to nortriptyline compared to other neuropathic pain conditions 4

Depression (Secondary Indication)

• Nortriptyline is effective for moderate to severe depression, though this is not its primary modern indication 1
• The analgesic effects occur independently of antidepressant effects and are established in non-depressed patients 1

Recommended Dosing

Starting Dose and Titration

• Start with 10-25 mg at bedtime to minimize anticholinergic side effects 1, 2
• Increase by 25 mg every 3-7 days as tolerated 2
• Target therapeutic dose: 75-150 mg/day for both neuropathic pain and depression 1, 5, 2
• Pain relief often occurs at lower doses than required for depression 5

Special Population Adjustments

• Elderly patients (≥65 years): Start at 10 mg/day and use substantially lower maintenance doses (30-50 mg/day in divided doses) due to higher plasma concentrations of active metabolites 5, 2
• Patients with cardiac disease: Limit doses to less than 100 mg/day when possible 2, 4

Critical Safety Threshold

• Doses exceeding 100 mg/day carry increased risk of sudden cardiac death, particularly in patients with cardiovascular disease or elderly patients 5

Time to Efficacy Assessment

• Allow at least 2-4 weeks at therapeutic dose before declaring treatment failure 2, 4
• Some patients may show significant benefit within the first week, but full assessment requires longer duration 6

Contraindications and Precautions

Absolute Contraindications

• Recent myocardial infarction 4
• Cardiac arrhythmias or heart block 4
• Prolonged QTc syndrome 5

Mandatory Pre-Treatment Screening

• ECG screening is required for all patients over 40 years before starting therapy 2, 4
• This identifies patients with undiagnosed conduction abnormalities who are at higher risk

Relative Contraindications and Cautions

• Cardiovascular disease of any type requires extreme caution and consideration of alternative treatments 5, 2
• Elderly patients are at higher risk for falls due to orthostatic hypotension 1
• Patients with urinary retention, narrow-angle glaucoma, or severe constipation due to anticholinergic effects 1, 2

Common Adverse Effects

Anticholinergic Effects (Most Common)

• Dry mouth, constipation, urinary retention, blurred vision - occur in approximately 1 in 6 patients (NNH 4.6-6) 1, 2, 7
• These effects can be reduced by starting with low doses at bedtime and slow titration 1
• Nortriptyline has fewer anticholinergic effects than amitriptyline, making it the preferred secondary amine TCA 1, 5, 4

Cardiovascular Effects

• Orthostatic hypotension is the most significant cardiovascular concern in otherwise healthy individuals 1, 6
• QTc prolongation can occur, necessitating ECG monitoring 5
• Major adverse effects leading to withdrawal occur in approximately 1 in 28 patients 7

Clinical Algorithm for Treatment Failure

If Partial Response (25-50% pain reduction)

• Add a medication from a different class (gabapentin 1800-3600 mg/day or pregabalin 300-600 mg/day) rather than increasing nortriptyline dose beyond 150 mg/day 1, 2, 4
• Combination therapy targets different neurotransmitter systems and may provide superior relief 4

If No Response After Adequate Trial

• Switch to an alternative first-line agent such as duloxetine (60-120 mg/day) or pregabalin (300-600 mg/day) 2, 4
• Duloxetine offers advantages of fewer anticholinergic effects and no ECG monitoring requirement 4

If Multiple First-Line Agents Fail

• Consider tramadol (50-400 mg/day) as second-line therapy 1, 4
• Refer to pain specialist or multidisciplinary pain center for refractory cases 4

Important Clinical Pearls

• Nortriptyline is pharmacologically redundant with amitriptyline since it is amitriptyline's active metabolite - never combine these medications 5
• Once-daily dosing at bedtime provides convenience and may help with sleep disturbance 1
• Therapeutic drug monitoring can be useful when approaching maximum doses to ensure adequate levels 5
• The analgesic effect is independent of mood improvement, so lack of depression does not predict treatment failure 1
• Nortriptyline has comparable efficacy to amitriptyline and gabapentin but with a superior tolerability profile compared to amitriptyline 5, 3