Third-Line Treatment for Neuropathic Pain

Pharmacological Options

Morphine and oxycodone have demonstrated efficacy in randomized controlled trials for neuropathic pain, with analgesia at least as great as TCAs and gabapentin 1
Start with the smallest effective dose and combine short-acting with long-acting formulations 2
For adults without prior opioid exposure, typical starting doses are morphine 20-40 mg orally or oxycodone 20 mg orally 3
Morphine has 3 times the potency parenterally compared to oral administration 3
The risk of hypogonadism, immunologic changes, cognitive impairment, respiratory depression, and opioid misuse or abuse is associated with opioid use 1, 2
Constipation is a chronic problem requiring prophylactic bowel regimen 1
All patients develop physical dependence, requiring gradual tapering when discontinuing 1
For patients living with HIV specifically, opioids may cause pronociception through upregulation of chemokine receptors 2

A combination regimen of morphine and gabapentin should be considered for possible additive effects and lower individual doses required when combined 2
Patients with failed back surgery syndrome may benefit from spinal cord stimulation when medications are ineffective 4

Ensure adequate trials of first-line agents (gabapentinoids, SNRIs, TCAs) alone and in combination for at least 2-4 weeks at therapeutic doses 4
Verify second-line options have been attempted, including tramadol and combination therapy 4
Consider referral to pain specialist or multidisciplinary pain center before initiating third-line treatments 4
If opioids are chosen, use time-limited trials with careful monitoring for efficacy and adverse effects 2

Certain conditions, such as lumbosacral radiculopathy, HIV-associated neuropathy, and chemotherapy-induced peripheral neuropathy, may be relatively refractory to all first and second-line medications 4
Low-dose naltrexone (1.5-4.5 mg) has shown some efficacy in treatment-resistant neuropathic pain conditions, though this represents emerging evidence 4

Do not use opioids as first or second-line treatment for chronic neuropathic pain due to morbidity and mortality risks 2
Avoid premature escalation to third-line treatments without adequate trials of combination first-line therapies 4
Do not continue ineffective opioid therapy—if substantial benefit is not achieved, taper and discontinue 1
Never abruptly discontinue opioids due to physical dependence; always taper gradually 1
Screen for substance abuse history before initiating opioid therapy, as this increases risk 1