In an adult with chronic neuropathic or musculoskeletal pain and no contraindications (e.g., uncontrolled glaucoma, severe hepatic impairment, recent MAO‑inhibitor use, uncontrolled hypertension), what is the recommended SNRI (duloxetine) dosing regimen and what alternative agents can be used if duloxetine is not tolerated or ineffective?

SNRI for Chronic Pain

Duloxetine 60 mg once daily is the first-line SNRI for chronic neuropathic and musculoskeletal pain, started at 30 mg daily for one week to minimize nausea, then increased to the target dose of 60 mg daily. 1, 2

First-Line SNRI Selection

Duloxetine is the preferred SNRI because it has the strongest evidence base among SNRIs for chronic pain conditions and demonstrates superior safety compared to tricyclic antidepressants. 1, 2

Specific Indications with Strong Evidence:

• Diabetic peripheral neuropathy: Duloxetine shows consistent efficacy with sustained effectiveness for up to one year. 1, 2, 3
• Fibromyalgia: FDA-approved with small to moderate improvements in pain, function, and quality of life. 2, 4
• Chronic low back pain: Supported by moderate-quality evidence from the American College of Physicians. 2, 4
• Osteoarthritis: Recommended for multiple joint involvement or inadequate response to topical NSAIDs. 2

Duloxetine Dosing Protocol

Starting Regimen:

• Begin with 30 mg once daily for 1 week to reduce the most common adverse effect of nausea. 1, 3
• Increase to 60 mg once daily after the first week, which is the target therapeutic dose. 1, 2, 3

Dose Adjustments:

• 60 mg once daily is as effective as 60 mg twice daily, so single daily dosing is preferred for simplicity. 1, 3
• Maximum dose is 120 mg daily (given as single dose or divided), though doses above 60 mg are not more efficacious and cause more side effects. 2, 5
• Allow 4-6 weeks at therapeutic dose to assess efficacy, including 2 weeks at the highest tolerated dose. 1

Special Population Considerations:

• Older adults: Start at lower doses and titrate more slowly due to increased risk of adverse events. 1, 2
• Renal impairment: Duloxetine is contraindicated with creatinine clearance <30 mL/min. 2, 6
• Hepatic impairment: Avoid duloxetine in patients with hepatic disease. 5, 6

Alternative SNRIs When Duloxetine Fails or Is Not Tolerated

Second-Line: Venlafaxine

• Venlafaxine is the first alternative SNRI after duloxetine failure, with high-quality evidence for painful diabetic neuropathy and painful polyneuropathies. 1, 2, 7
• Dosing: Requires 2-4 weeks to titrate to efficacious dose of 150-225 mg/day in divided doses (available in short- and long-acting preparations). 1
• Note: Venlafaxine has NOT shown efficacy in postherpetic neuralgia. 1

Third-Line: Desvenlafaxine or Milnacipran

• Desvenlafaxine: Listed as second-line alternative after venlafaxine, started at 50 mg once daily. 2, 7
• Milnacipran: FDA-approved specifically for fibromyalgia, with less robust evidence for other pain conditions. 1, 2

Monitoring Requirements

Cardiovascular Monitoring:

• Monitor blood pressure and pulse regularly, as SNRIs can cause sustained hypertension and increased pulse. 7, 6
• Consider baseline ECG for patients over 40 years due to potential cardiac conduction abnormalities, though duloxetine typically does not produce clinically important ECG changes. 1, 7, 3

Efficacy Assessment:

• Reassess pain and quality of life frequently after reaching therapeutic dose. 1
• Target: ≥50% pain reduction or average pain ≤3/10 with tolerable adverse effects. 1
• If <30% pain reduction at target dose after adequate trial, switch to alternative first-line medication (calcium channel α2-δ ligands like gabapentin/pregabalin, or secondary amine TCAs like nortriptyline/desipramine). 1

Combination Therapy Strategy

If partial pain relief (average pain ≥4/10) after adequate duloxetine trial, add one of the following first-line medications rather than switching: 1

• Gabapentin or pregabalin (calcium channel α2-δ ligands)
• Topical lidocaine for localized peripheral neuropathic pain
• Secondary amine TCA (nortriptyline or desipramine)

Addition of pregabalin or gabapentin may be beneficial for patients not responding adequately to duloxetine 60 mg daily, rather than increasing duloxetine above 60 mg. 5

Advantages Over Other Medication Classes

Compared to Tricyclic Antidepressants:

• SNRIs avoid anticholinergic side effects, orthostatic hypotension, sedation, and cardiac conduction problems that are particularly concerning in older adults. 1, 2
• No need for aminotransferase monitoring with duloxetine, unlike some TCAs. 1

Compared to SSRIs:

• SNRIs demonstrate more consistent benefits than SSRIs for persistent pain due to dual serotonin-norepinephrine effects. 2, 7
• SSRIs like fluoxetine lack comparable evidence of analgesic efficacy. 1

Compared to Opioids:

• SNRIs are strongly preferred over opioids for chronic pain due to opioid risks of addiction, overdose, and death. 2
• Opioids show insufficient evidence for long-term benefits in chronic pain. 2

Mechanism of Action

SNRIs provide analgesia through dual inhibition of serotonin and norepinephrine reuptake, enhancing descending inhibitory pain pathways in the central nervous system. 2, 8

Patients Most Likely to Benefit

Patients with co-occurring chronic pain and depression are especially likely to benefit from SNRI therapy, as depression exacerbates physical pain symptoms. 2, 4

Discontinuation Protocol

Taper dose gradually over at least 2 weeks rather than stopping abruptly to reduce risk of discontinuation syndrome (manifesting as adrenergic hyperactivity). 1, 7

Common Pitfalls to Avoid

• Do not increase duloxetine above 60 mg daily without first trying combination therapy, as higher doses are not more efficacious and cause more side effects. 5
• Do not use duloxetine in severe renal impairment (CrCl <30 mL/min) or hepatic disease. 2, 5, 6
• Do not skip the initial 30 mg week, as this significantly reduces nausea, the most common reason for discontinuation. 1, 3, 6
• Do not expect immediate results—allow adequate trial period of 4-6 weeks at therapeutic dose before declaring treatment failure. 1, 7