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Tame the Pain: Pharmacotherapy for Diabetic Neuropathy
Long Phan, PharmD, Walgreens
Lourdes Cross, PharmD, Sullivan University College of Pharmacy and Health Sciences

Diabetic peripheral neuropathy (DPN) is one of the most common complications of diabetes. An estimated 7% to 10% of patients newly diagnosed with type 2 diabetes and up to 50% in patients with long-term diabetes (>25 years duration) have neuropathy.¹ DPN is a leading cause of disability, foot ulceration, and amputations. It also increases the risk for gait instability, falls, anxiety, depression, and sleep disturbances.² The aim of this review is to discuss pharmacotherapy options based on existing guidelines and studies for the treatment of painful DPN. A table of the medications can be found in the file, Management of Diabetic Peripheral Neuropathy, which is located in the ADCES Pharmacy Community of Interest Library.

Treatment for Neuropathic Pain

Although treatment of neuropathic pain does not alter the natural history of neuropathy, it is important to improve the quality of life of patients. First-line options for management of DPN include serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), and gabapentinoid anticonvulsants.^3,4 In the United States, the three FDA-approved medications for DPN are duloxetine, pregabalin, and the capsaicin patch (8%).

First-line Pharmacotherapy

Serotonin-Norepinephrine Reuptake Inhibitors

Duloxetine is an SNRI that is FDA-approved for painful DPN, major depressive disorder, generalized anxiety disorder, fibromyalgia, and chronic musculoskeletal pain. The recommended initial dose of duloxetine for DPN is 60 mg daily.⁴ Lower doses may be considered when tolerability is a concern. Doses greater than 60 mg daily are not recommended, because they are no more efficacious and associated with increased side effects.⁵ Improvement in neuropathic pain may be seen as early as one week after treatment.⁶ Venlafaxine is not as well studied as duloxetine, but doses between 150 and 225 mg daily have shown some effectiveness for DPN.⁴ Similar to duloxetine, venlafaxine is a good option for patients with concomitant depression or anxiety.

The SNRIs are generally well tolerated. The most common side effects include nausea, decreased appetite, drowsiness, and headache. Venlafaxine exhibits more noradrenergic activity with higher doses and has been shown to cause dose-dependent increases in blood pressure. SNRIs should not be taken with other serotonin or norepinephrine reuptake inhibitors (including tricyclic antidepressants), but they can be combined with pregabalin or gabapentin.

Tricyclic Antidepressants

TCAs (including amitriptyline, nortriptyline, desipramine) are effective and recommended in the management of DPN.⁴ Amitriptyline and nortriptyline should be started at a dose of 10 to 25 mg daily and gradually titrated up as needed to a maximum of 100 mg (nortriptyline) or 150 mg (amitriptyline) daily.⁴ Desipramine should be initiated at 12.5 mg daily and can be gradually increased to 250 mg daily over a few weeks. It often takes 6 to 8 weeks to titrate TCAs to effective doses for DPN.⁷ TCAs are generally reserved for refractory neuropathic pain due to side effects, which include constipation, dry mouth, blurry vision, urinary retention, and orthostatic hypotension. Secondary amines (e.g., desipramine, nortriptyline) are better tolerated than tertiary amines (e.g., amitriptyline). TCAs should be used with caution in patients with a history of cardiovascular disease due to the potential for cardiac conduction abnormalities.

Gabapentinoid Anticonvulsants

Pregabalin is FDA-approved for the management of neuropathic pain associated with DPN. The usual starting dose of pregabalin for DPN is 75 to 150 mg daily (immediate-release) or 165 mg daily (extended-release).⁴ It may be gradually increased to achieve maximum benefit at 300 to 600 mg daily (immediate-release) or 330 mg daily (extended-release). Although not FDA-approved for DPN, data also support the use of gabapentin for reducing pain in diabetic neuropathy. The usual starting dose for gabapentin is 100 to 300 mg one to three times daily, and it can be gradually titrated to a usual effective dose of 900 to 3600 mg daily.⁴ Patients who have an unsatisfactory response to treatment with gabapentin may respond to equivalent doses of pregabalin.⁸ It is suggested that the analgesic action of pregabalin is 6 times that of gabapentin in terms of effectiveness in dosage conversion.⁹ Therefore, a patient receiving 1,800 mg of gabapentin would require 300 mg of pregabalin to achieve a comparable effect. Gabapentin and pregabalin have similar side effects profiles, which includes somnolence, dizziness, ataxia, peripheral edema, and weight gain. Gabapentin is also associated with withdrawal-precipitated seizures, so it should be tapered gradually if discontinuation is desired. In patients with chronic kidney disease, the doses of gabapentin and pregabalin need to be adjusted.

Other Therapy

Capsaicin

Capsaicin is an option for add-on or monotherapy. Capsaicin is an alkaloid derived from red chili peppers that desensitizes afferent sensory nerves.¹⁰ Capsaicin 0.075% cream can be gently rubbed into painful areas until thoroughly absorbed up to 4 times daily.³The high-concentration capsaicin 8% patch can be applied to painful areas of the feet for 30 minutes (up to 4 patches in a single application) every three months as needed.¹¹ The patch should only be applied by a health care provider to an area pretreated with a topical anesthetic. Capsaicin patches may be cut to match the size and shape of the treatment area. Side effects include local burning and irritation which is exacerbated by warm water and weather.³

Lidocaine

Lidocaine 5% patches are possibly effective in lessening the pain of DPN. They have low systemic absorption and may be used in combination with other analgesic medications.¹² Lidocaine patches should not be applied for more than 12 hours in a 24-hour period. The patches may be cut without disrupting the integrity of the dosage form.

Opioids

Opioids are not generally recommended as first- or second-line therapy due to concerns for addiction and safety. Tapentadol extended-release was approved by the FDA for the treatment of neuropathic pain associated with DPN. However, a recent systematic review and meta-analysis by the Special Interest Group on Neuropathic Pain within the International Pain Study Association found that evidence supporting the effectiveness of tapentadol for neuropathic pain was inconclusive.¹¹ Per the American Diabetes Association, the use of any opioids for chronic neuropathy should be avoided if possible.¹³

Conclusion

Painful diabetic neuropathy is one of the most common chronic complications of diabetes mellitus. Treatment currently includes SNRIs, TCAs, gabapentinoid anticonvulsants, and topical medications. The selection of therapy should involve consideration of comorbidities, drug interactions, side effects, cost, and patient preferences.


References

1. Bansal V, Kalita J, Misra UK. Diabetic neuropathy. Postgrad Med J. 2006;82(964):95-100.
2. Khdour MR. Treatment of diabetic peripheral neuropathy: a review. J Pharm Pharmacol. 2020;72(7):863-872.
3. Bril V, England J, Franklin GM, et al. Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76(20):1758-1765.
4. Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care. 2017;40(1):136-154.
5. Ormseth MJ, Scholz BA, Boomershine CS. Duloxetine in the management of diabetic peripheral neuropathic pain. Patient Prefer Adherence. 2011;5:343-356.
6. Goldstein DJ, Lu Y, Detke MJ, Lee TC, Iyengar S. Duloxetine vs. placebo in patients with painful diabetic neuropathy. Pain. 2005;116(1-2):109-118.
7. Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain. 2007;132(3):237-251.
8. Stacey BR, Dworkin RH, Murphy K, Sharma U, Emir B, Griesing T. Pregabalin in the treatment of refractory neuropathic pain: results of a 15-month open-label trial. Pain Med. 2008;9(8):1202-1208.
9. Ifuku M, Iseki M, Hidaka I, Morita Y, Komatus S, Inada E. Replacement of gabapentin with pregabalin in postherpetic neuralgia therapy. Pain Med. 2011;12(7):1112-1116.
10. Chong MS, Hester J. Diabetic painful neuropathy: current and future treatment options. Drugs. 2007;67(4):569-585.
11. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162-173.
12. Baron R, Mayoral V, Leijon G, Binder A, Steigerwald I, Serpell M. 5% lidocaine medicated plaster versus pregabalin in post-herpetic neuralgia and diabetic polyneuropathy: an open-label, non-inferiority two-stage RCT study. Curr Med Res Opin. 2009;25(7):1663-1676.
13. 11. Microvascular complications and foot care: standards of medical care in diabetes-2020. Diabetes Care. 2020;43(Suppl 1):S135-S151.