Pharmacotherapy of Neuropathic Pain

(Updated February 2022)

The chart below reviews pharmacologic options for neuropathic pain. If monotherapy fails, combo therapy can be tried.1,7,13 Meds that are NOT recommended include carbamazepine (except for trigeminal neuralgia [beyond the scope of this chart]), levetiracetam, and mexiletine.1,7 There are no studies using acetaminophen or nonsteroidal antiinflammatory drugs (NSAIDs).A 30% to 50% decrease in pain on a 10-point pain scale is typical.For other interventions to consider, see footnote d.

--Information in table may differ from product labeling--

Drug/Drug Class

Target Pain

Dosing

Efficacya

Clinical Considerations

Preferred Options

Tricyclic antidepressants (TCAs)c

Diabetic neuropathy, postherpetic neuralgia, peripheral nerve injury, radiculopathy, poststroke pain, spinal cord injury pain, neuropathic pain in MS1,2

Amitriptyline, nortriptyline, desipramine:

  • Initial: 10 to 25 mg daily.7
  • Increase by 10 mg/week.7
  • Target dose: 10 to 150 mg once daily or divided BID.1,7 (Amitriptyline effective dose 25 to 100 mg for diabetic neuropathy [per ADA].18).

In patients ≥65 years of age: do not use >75 mg of amitriptyline, imipramine, or clomipramine.1

NNT ~ 3 to 4 for 50% pain reduction.1

For diabetic neuropathy:

  • NNT ~ 2 to 3 for 50% pain reduction.32
  • Efficacy of amitriptyline unclear.18

May not be effective for HIV neuropathy.2

Gabapentin plus nortriptyline is more effective than either alone for diabetic neuropathy or postherpetic neuralgia [Evidence Level B-1].14

Usually inexpensive.

Most studies used amitriptyline, but nortriptyline and desipramine are better tolerated.1,7,32

Can combine with pregabalin or gabapentin.1,14

Consider for patients with pain-related insomnia.2

Notable side effects: heart block, sudden death at daily doses >100 mg, sedation, constipation, dry mouth, urinary retention, blurred vision, confusion, orthostasis, weight gain.1,2 

Serotonin norepinephrine reuptake inhibitors (SNRIs)c

Diabetic neuropathy, neuropathic pain in MS, chemotherapy-related peripheral neuropathy (duloxetine)1,7

Duloxetine:

  • Initial: 30 mg daily.7 (20 to 30 mg for diabetic neuropathy [per ADA].18)
  • Increase by 30 mg/week.7
  • Target dose: 60 to 120 mg once daily.1 (40 to 60 mg for diabetic neuropathy.31)

Venlafaxine:

  • Initial: 37.5 mg daily.7
  • Increase by 37.5 mg each week.7
  • Target dose 150 to 225 mg once daily (extended-release).(75 to 225 mg for diabetic neuropathy [per ADA].18)

Desvenlafaxine:

  • Initial: 50 to 100 mg/day.40
  • May increase every three days.40
  • Target dose: 200 mg/day.31

NNT ~ 6 to 7 for 50% pain reduction.1

For diabetic neuropathy:

  • NNT ~ 3 to 5 for 50% pain reduction.32
  • Most/best evidence is for duloxetine.31

Duloxetine has the most data.

  • FDA- and Health Canada-approved for diabetic neuropathy.
  • A drug of choice for diabetic neuropathy (per ADA).12

Consider for patients with comorbid depression or anxeity.31 Effective in depressed and nondepressed patients.2

Notable side effects: nausea (duloxetine >venlafaxine), anorexia, constipation, dry mouth, sweating, anxiety, hypertension (venlafaxine >duloxetine), insomnia (venlafaxine >duloxetine),2 dizziness,19 sexual dysfunction (venlafaxine >duloxetine).39

Gabapentin or pregabalin

Diabetic neuropathy, postherpetic neuralgia, peripheral nerve injury, poststroke pain (pregabalin), spinal cord injurypain (pregabalin)1,2

Gabapentin IR:

  • Initial: 100 to 300 mg daily.7
  • Increase by 100 to 300 mg/week.7
  • Target dose 1,200 to 3,600 mg/day (1,800 to 3,600 mg/day for diabetic neuropathy18), divided TID.1
  • Requires dose reduction in kidney impairment.7

Pregabalin

  • start with 25 to 150 mg daily, divided.7
  • Increase weekly by 25 to 150 mg.7
  • Target dose 300 to 600 mg/day, divided BID.
  • Requires dose reduction in kidney impairment.7

For postherpetic neuralgia, NNT ~ 7 to 8 for 50% pain reduction.22,28

For diabetic neuropathy, NNT ~ 5 to 6 for 50% pain reduction.32

Gabapentin plus nortriptyline is more effective than either drug alone for diabetic neuropathy or postherpetic neuralgia [Evidence Level B-1].14

FDA- and Health Canada-approved for postherpetic neuralgia (gabapentin [US], pregabalin), diabetic neuropathy (pregabalin [a drug of choice, per ADA]12), and spinal cord injury (pregabalin).

Pregabalin:18

  • has a more predictable dose response.
  • works faster.
  • has a narrower dosage range.
  • can be titrated faster.

Can combine with an SNRI.1

Consider for patients with anxiety or restless legs syndrome.32,33

Notable side effects: sedation, dizziness, weight gain, edema, blurred vision.1,2 

Adverse effects may be more severe in the elderly.18

Some risk (seems to be dose-dependent) of euphoria, abuse, dependence (pregabalin>gabapentin).3

Anticonvulsants (sodium channel blockers)

Diabetic neuropathy31

Titrateto the following evidence-based effective doses:31

  • Lamotrigine: 200 to 400 mg/day.
  • Oxcarbazepine: 1,400 to 1,800 mg/day.
  • Lacosamide: 400 mg/day.
  • Valproic acid: 1,000 to 1,200 mg/day (20 mg/kg).

Modestly more effective than placebo [Evidence level B-1].17,31,34.37

NNT ~4 to 8 for 50% pain reduction.17,34,37

Consider for patients with seizure disorders.31

Follow label instructions for uptitration.

Rare risk of serious skin reactions and arrhythmias (particularly lamotrigine and lacosamide).35,36

Some experts recommend against use of valproic acid for diabetic neuropathy.2

Topical Options

Lidocaine 5% patch (Rx; US only)

Localized peripheral neuropathic pain (particularly postherpetic neuralgia).1,5 No studies for diabetic neuropathy.19

One to three patches (10 x 14 cm; can cut) to affected area for 12 hours daily.5

Approval based on one single-dose and two two-week studies.5

About half of patients in the two-week clinical trials were taking an oral medication for postherpetic neuralgia.5

NNT ~ 4 for diabetic neuropathy for 50% pain reduction.32

FDA-approved for postherpetic neuralgia.5

May have some benefit.1

Good safety profile.1

Consider first-line in patients in whom side effects of systemic medications are of concern (e.g., elderly).1

Capsaicin patch (Qutenza; US; compassionate release availability [Health Canada])

Localized peripheral neuropathic pain (particularly postherpetic neuralgia, diabetic neuropathy [feet] and HIV neuropathy)1,6,7 

Applied in clinic every three months (one to four patches to affected area for 60 minutes [30 minutes for diabetic neuropathy of the feet]).6

NNT ~ 8 to 11.30

FDA-approved for postherpetic neuralgia and diabetic neuropathy of the feet.6

Concern with long-term use; may damage epidermal nerve fibers.1

Requires pre-application of topical anesthetic and blood pressure monitoring due to transient increase in pain.Local cooling or oral analgesics may be needed post-treatment.6

Capsaicin cream <1%

Localized peripheral neuropathic pain (particularly postherpetic neuralgia)7

Apply up to four times daily.15

Minimal benefit vs placebo.7

Diabetic neuropathy evidence is of low quality.19

NNT ~ 7 for 50% pain reduction.32

Counsel patients that burning sensation at application site is common, decreases over time, and can be soothed with a cool washcloth.41

Counsel patients that consistent and continued use is important for efficacy; it does not work “as needed.”41

Nonpreferred Options

Tramadolc

Diabetic neuropathy, mixed neuropathies7

50 mg BID to QID. Max total daily dose 400 mg.8 Reduce dose in patients with kidney impairment and in the elderly.

NNT ~ 4 to 5 for 50% reduction in pain, based on low-quality data.24

Third-line due to:1,19

  • safety/tolerability concerns.
  • low strength of evidence.

Experts advise against use for diabetic neuropathy.12,31

Preferred over strong opioids.1,7 Less constipation, nausea, and abuse potential than strong opioids.7,18

Can cause confusion in elderly.7,16

Inexpensive.

Consider for acute exacerbations or concomitant non-neuropathic pain.16

Tapentadol

Diabetic neuropathy7

ER:4

  • Initial: 50 mg twice daily.
  • Increase by 50 mg once or twice daily every three days.
  • Max: 250 mg twice daily.

Requires dose reduction in moderate liver impairment.4

Not recommended in severe liver or kidney disease.4

Studies conflicting and of poor quality.1,19

Nucynta ER is FDA-approved for diabetic neuropathy.

Evidence is weaker than with pregabalin or duloxetine.12

Safety concerns (e.g., respiratory depression, misuse), especially long-term.12

Avoid.12,31

Opioids

Postherpetic neuralgia, poststroke pain2

Use a low dose.8

Oxycodone (based on very low-quality evidence):29

  • NNT ~ 5.7 for 30% pain reduction (diabetic neuropathy).
  • NNH ~ 4.3

There is less evidence for other opioids.

Last-line due to concerns about misuse and overdose.1

Experts advise against use for diabetic neuropathy.12,31

Avoid chronic use.16

In polyneuropathy, long-term opioid use is associated with poor functional status, dependence, and overdose.25

Cannabinoids

Neuropathic pain in MS (Sativex, dronabinol), diabetic neuropathy (nabilone; efficacy unclear19)

Dronabinol (Marinol, generics [US]) for central neuropathic pain in MS:10

  • Initial: 2.5 mg daily.
  • Increase by 2.5 mg every other day.
  • Max dose: 5 mg BID.

Nabilone (Cesamet, [generics, Canada]) for diabetic neuropathy:7

  • Initial: 0.25 to 0.5 mg at bedtime.
  • Increase by 0.5 mg weekly.
  • Max dose: 3 mg BID.
  • In US, available only as 1 mg capsules.

NNT ~ 11 for 30% pain reduction, based on moderate quality evidence.23

Smoked cannabis may be effective for HIV neuropathy and other neuropathies.11,27

Misuse and psychiatric and cognitive effects of concern.23 NNH = 10 for psychiatric disorders.23

Notable side effects: dizziness, confusion, sedation.23

Long-term data lacking.23

Sativex (delta-9-tetrahydrocannabinol) buccal spray is Health Canada-approved for neuropathic pain in MS (adjunct).9

  • Can cause positive urine test for cannabinoids.7

Selective serotonin reuptake inhibitors (SSRIs)c

Diabetic neuropathy, polyneuropathy7

Varies.

Poor analgesic effect.Less effective than TCAs or SNRIs.7

Fluoxetine may not be effective.7

Consider citalopram, escitalopram, or paroxetine.7

Natural Products

Alpha-lipoic acid

Diabetic neuropathy

Doses of 600 to 1,800 mg/day have been used in studies. It can take three to five weeks before improvement is noticed.20

Although it might be beneficial, there is not enough high-quality evidence to recommend to most people.20

Alpha-lipoic acid is possibly effective for decreasing sensations of burning, pain, numbness, and prickling of the feet and legs.20

Notable side effects: nausea, vomiting, dizziness, rash, hypoglycemia, hypotension.20

Coenzyme Q10

Diabetic neuropathy

400 mg once daily for 12 weeks.38

Although it might be beneficial, there is not enough high-quality evidence to recommend to most people.38

Well-tolerated.38

Study duration 12 weeks.38

Metanx

Diabetic neuropathy

One capsule twice daily.21

Has shown only minimal improvement in patients with mild neuropathy [Evidence Level B-1].21 

A medical food. Contains the biologically active forms of folic acid, vitamin B6, and vitamin B12.21

The rationale for the product is based on B vitamins’ role in improving microvascular function, reducing oxidative stress, and preventing formation of advanced glycation end products.21 However, routine use of B vitamins for treatment of neuropathy is not recommended unless a deficiency exists or is suspected.26

Cost: $180 per month.b

  1. If a drug is effective for more than one type of peripheral neuropathic pain, efficacy for all other types can generally be assumed.2
  2. Wholesale acquisition cost (US). US medication pricing by Elsevier, accessed June 2021.
  3. Use caution combining serotonergic agents (e.g., TCAs, SNRIs, SSRIs, tramadol).2,7
  4. Other interventions include nerve blocks, spinal cord stimulation, intrathecal meds, and surgery.For diabetic neuropathy, cognitive behavioral therapy, Tai Chi, exercise, or mindfulness can be offered.31 Transcutaneous electrical nerve stimulation is not better than placebo based on low-quality studies.19 Don’t recommend tight glucose control to improve symptoms.12

Abbreviations: ADA = American Diabetes Association; BID = twice daily; ER = extended-release; HIV = human immunodeficiency virus; IR = immediate-release; MS = multiple sclerosis; QID = four times daily; SNRI = serotonin norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant; TID = three times daily.

Levels of Evidence

In accordance with our goal of providing Evidence-Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish.

Level

Definition

Study Quality

A

Good-quality patient-oriented evidence.*

  1. High-quality randomized controlled trial (RCT)
  2. Systematic review (SR)/Meta-analysis of RCTs with consistent findings
  3. All-or-none study

B

Inconsistent or limited-quality patient-oriented evidence.*

  1. Lower-quality RCT
  2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings
  3. Cohort study
  4. Case control study

C

Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening.

*Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life).

[Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56. https://www.aafp.org/afp/2004/0201/p548.pdf.]

References

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  3. Canadian Agency for Drugs and Technologies in Health. Rapid response report: summary with critical appraisal. Abuse and misuse potential of pregabalin: a review of the clinical evidence. April 24, 2012. http://www.dpic.org/sites/default/files/PregabalinAbuse_CADTH_24Apr2012.pdf. (Accessed June 14, 2021).
  4. Prescribing information for Nucynta ER. Collegium Pharmaceutical. Stoughton, MA 02072. March 2021.
  5. Product information for Lidoderm. Endo Pharmaceuticals. Malvern, PA 19355. November 2018.
  6. Product information for Qutenza. Averitas Pharma. Morristown, NJ 07960. March 2021.
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Cite this document as follows: Clinical Resource, Pharmacotherapy of Neuropathic Pain. Pharmacist’s Letter/Prescriber’s Letter. July 2021. [370731]

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