Managing Diabetic Peripheral Neuropathy of the Feet

Diabetic neuropathy is a common and debilitating complication of diabetes mellitus (DM). Diabetic peripheral neuropathy (DPN), which primarily affects the feet, is a prevalent form of diabetic neuropathy that can affect an individual’s quality of life. DPN is present in approximately 50% of patients with diabetic neuropathy; it can result in conditions such as edema, gangrene, and ulcers if left untreated.1 Approximately 10% of people with diabetes display DPN at initial diagnosis. Within 10 years after diagnosis, the prevalence of DPN among people with diabetes reaches approximately 40% to 50%. Hyperglycemia is a major contributing factor in the development and progression of DPN.2

Painful DPN occurs in 10% to 20% of patients with diabetes and in 40% to 50% of patients with diabetic neuropathy. Affected individuals experience symptoms such as electric or stabbing sensations, paresthesia, hyperesthesia, burning pain, and deep aching pain. These symptoms can contribute to sleep disturbances, anxiety, and depression.3 The prevalence of DM and DPN are shown in Figure 1.1,2



Diabetes significantly increases the risk of requiring lower extremity amputation, with foot ulcers being the main precursor to amputation.4 Between 2010 and 2019, nearly 70% of all amputations in the United States were performed on people with diabetes.5 DPN of the feet can severely reduce mobility and functional ability, with substantial effects on daily activities and independence. Studies have shown that DPN is strongly related to the risk for falls, with some people 20 times more likely to fall compared with individuals of the same age who do not have diabetes.6

Patient Eligibility for Therapeutic Regimens and Indications for Treatment

Effective management of DPN of the feet begins with the identification of patients who may benefit from US Food and Drug Administration (FDA)-approved therapies. Patient complaints of numbness and/or pain in the feet may suggest the presence of DPN, especially if such features demonstrate a symmetrical distribution and are initially noticed in the toes.2 Therefore, clinicians should regularly monitor these symptoms in patients with diabetes to ensure early neuropathy detection and timely intervention. Diagnostic assessments for DPN include examination of clinical symptoms and signs, which has low sensitivity and high variability; quantitative sensory testing using a biothesiometer, thermoaesthesiometer, or neurosensory analyzer; and corneal confocal microscopy.1

Selection of Prescription Nonopioid DPN Pharmacotherapy

DPN management requires a tailored approach that considers each patient’s needs and symptoms.

The American Academy of Neurology (AAN) issued an updated guideline on oral and topical treatments for painful diabetic neuropathy in December 2021, which was also endorsed by the American Association of Neuromuscular and Electrodiagnostic Medicine. This guideline recommends that clinicians assess the effects of DPN on physical function and assess whether a person has a comorbid mood or sleep disorder when formulating a DPN treatment plan, as treatment of concurrent mood and sleep disorders may reduce pain.7

Clinicians should assess patient preferences for effective oral, topical, nontraditional, and nonpharmacologic interventions for DPN. When systemic therapy is appropriate, the guideline recommends treatment with tricyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs), gabapentinoids, and sodium channel blockers to reduce DPN-associated pain. For patients preferring nonsystemic or nonpharmacologic interventions, clinicians can consider topical therapies, such as capsaicin and glyceryl trinitrate, and can discuss nonpharmacologic interventions that may include cognitive behavioral therapy and lifestyle modifications.7

Prescription pharmacotherapies that have received FDA approval specifically for DPN-related pain are discussed below.

Capsaicin 8% Topical System

Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is an agonist of transient receptor potential vanilloid 1 (TRPV1), a receptor involved in pain transmission. Capsaicin is the active ingredient found in various species of chili peppers; it exerts pharmacologic effects on type C nociception nerve fibers, which are involved in the conduction of slow neuropathic pain.8 Repeated exposure to topically administered capsaicin results in desensitization to painful stimuli.9

Over-the-counter formulations of capsaicin have been shown to decrease pain associated with DPN; however, these formulations may require multiple applications each day to provide sustained pain relief.10 A higher concentration capsaicin formulation delivered via a patented matrix technology has been approved to rapidly deliver 8% capsaicin for the treatment of painful DPN of the feet in adults.11 This prescription-only capsaicin 8% topical system provides sustained relief of DPN foot pain after a single treatment for up to 12 weeks vs placebo. This topical delivery system allows for a reduced application frequency in comparison to low-dose capsaicin formulations.12

The recommended dosage of the capsaicin 8% topical system is a single, 30-minute application on the feet, with a maximum of 4 topical systems per treatment. Application of this system should only be performed by a physician or other qualified healthcare professional, with at least 3 months between treatments. The efficacy of the capsaicin 8% topical system was studied in a 12-week, double-blind, randomized, placebo-controlled, multicenter trial, which showed a 30% reduction in pain associated with DPN by week 12 among patients in the treatment group, compared with a 22% reduction among patients in the placebo group.11


Benefits of the capsaicin 8% topical system
Flip
The capsaicin 8% topical system can benefit patients by providing targeted pain relief that specifically addresses neuropathic pain symptoms associated with DPN; its localized application minimizes systemic side effects.

Pregabalin

Pregabalin is indicated for the treatment of neuropathic pain associated with DPN, which it achieves by binding to alpha2-delta sites in central nervous tissues, thereby reducing the release of neurotransmitters involved in pain transmission. Pregabalin may also mediate pain through interactions with descending noradrenergic and serotonergic pathways that originate in the brainstem and modulate pain transmission in the spinal cord. The recommended dosage of pregabalin for the treatment of DPN is 165 to 330 mg once daily, in the form of extended-release tablets that should be swallowed whole after an evening meal. In a 19-week randomized withdrawal study comparing various doses of pregabalin with placebo, pregabalin treatment produced statistically significant improvements in mean pain score. Among patients receiving pregabalin, 79.8% achieved at least 30% improvement and 73.6% achieved at least 50% improvement; among patients in the placebo group, 64.9% achieved at least 30% improvement and 54.6% achieved at least 50% improvement.13 Although this randomized study involved patients with postherpetic neuralgia, it was sufficient to support FDA approval for the treatment of DPN.

Duloxetine

Duloxetine, an SNRI, is indicated for the treatment of neuropathic pain associated with DPN in adults. The mechanism of action by which duloxetine reduces pain associated with DPN is unclear, but it is believed to involve the potentiation of serotonergic and noradrenergic activity in the central nervous system. The recommended dosage of duloxetine for the treatment of DPN is 60 mg once daily, in the form of delayed-release tablets that should be swallowed whole. The efficacy of duloxetine was assessed in two 12-week, randomized, double-blind, placebo-controlled, fixed-dose trials involving adult patients who had at least 6 months of pain associated with DPN. Among 791 patients enrolled, 75% completed the trials. The results showed that duloxetine treatment produced a statistically significant improvement in mean pain score from baseline and increased the proportion of patients with at least 50% reduction in pain. Some patients experienced pain relief as early as week 1, and this improvement persisted throughout the trial. Duloxetine carries a boxed warning for suicidal thoughts and behaviors in children, adolescents, and young adults; patients receiving duloxetine should be monitored for the emergence or worsening of suicidal thoughts and behaviors.14 Table 1 provides an overview of nonopioid prescription pharmacotherapies that have received FDA approval specifically for pain associated with DPN.11,13,14



TCAs

TCAs, such as amitriptyline and nortriptyline, are effective therapies for pain associated with DPN and have been used as first-line treatment. This class of medication works by inhibiting presynaptic reuptake of serotonin and noradrenaline, but the N-methyl-D-aspartate (NMDA) receptor and ion channel blockade may also contribute to pain relief.15 However, TCAs may have limited utility because they display more adverse effects compared with newer agents. The numerous potential side effects of TCAs, especially in medically compromised and older patients, include cardiac arrhythmias, myocardial infarction, orthostatic hypotension, and glaucoma. In 1 study from 1999 to 2001 that analyzed a large US healthcare claims database to understand prescribing patterns for TCAs among older patients with DPN, 47.9% of patients prescribed a TCA for DPN had evidence of potentially inappropriate use related to comorbidities or concurrent intake of contraindicated medications.16 This finding highlights the need for greater attention to medication safety and prescribing practices concerning the use of TCAs in the treatment of DPN and related health conditions among older people.

Medication Management in Specific Populations

Effective medication management requires close monitoring of treatment efficacy and safety, as well as careful consideration of the specific populations who are receiving these drugs. It is particularly important to use a tailored approach when treating older adults, people with comorbidities, and patients taking multiple medications. Older adults often experience age-related physiological changes that can influence drug pharmacokinetics and pharmacodynamics. Because renal function tends to decline with age, there may be a need to adjust the dosage of medications that are primarily excreted through the kidneys. For example, there is evidence that pregabalin, often used to treat neuropathic pain and seizures, requires dose modification based on renal function in older adults.13,17 Moreover, older people tend to experience increased interindividual variability because of age-related impairments in many regulatory processes that enable functional integration between cells and organs. Therefore, caution should be exercised when prescribing therapies to these individuals.18 For instance, duloxetine, commonly used for the management of depression and anxiety disorders, is extensively metabolized in the liver; its use should be avoided in people with hepatic impairment.14 In such cases, alternative therapies should be considered.

References

1. Kumsa HT, Abdisa LG, Tolessa LT, et al. Early detection and treatment device for diabetic foot neuropathy. Ir J Med Sci. 2023;192(1):143-148. doi:10.1007/s11845-022-02958-3

2. Callaghan BC, Little AA, Feldman EL, Hughes RAC. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev. 2012;(6):CD007543. doi:10.1002/14651858.CD007543.pub2

3. van Nooten F, Treur M, Pantiri K, Stoker M, Charokopou M. Capsaicin 8% patch versus oral neuropathic pain medications for the treatment of painful diabetic peripheral neuropathy: a systematic literature review and network meta-analysis. Clin Ther. 2017;39(4):787-803.e18. doi:10.1016/j.clinthera.2017.02.010

4. Boyko EJ, Zelnick LR, Braffett BH, et al. Risk of foot ulcer and lower-extremity amputation among participants in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications study. Diabetes Care. 2022;45(2):357-364. doi:10.2337/dc21-1816

5. Walicka M, Raczyńska M, Marcinkowska K, et al. Amputations of lower limb in subjects with diabetes mellitus: reasons and 30-day mortality. J Diabetes Res. 2021;2021:8866126. doi:10.1155/2021/8866126

6. Reeves ND, Orlando G, Brown SJ. Sensory-motor mechanisms increasing falls risk in diabetic peripheral neuropathy. Medicina (Kaunas). 2021;57(5):457. doi:10.3390/medicina57050457

7. Price R, Smith D, Franklin G, et al. Oral and topical treatment of painful diabetic polyneuropathy: Practice Guideline update summary: report of the AAN guideline subcommittee. Neurology. 2022;98(1):31-43. doi:10.1212/WNL.0000000000013038

8. Basith S, Cui M, Hong S, Choi S. Harnessing the therapeutic potential of capsaicin and its analogues in pain and other diseases. Molecules. 2016;21(8):966. doi:10.3390/molecules21080966

9. Anand P, Bley K. Topical capsaicin for pain management: therapeutic potential and mechanisms of action of the new high-concentration capsaicin 8% patch. Br J Anaesth. 2011;107(4):490-502. doi:10.1093/bja/aer260

10. Goodwin B, Chiplunkar M, Salerno R, et al. Topical capsaicin for the management of painful diabetic neuropathy: a narrative systematic review. Pain Manag. 2023;13(5):309-316. doi:10.2217/pmt-2023-0006

11. Qutenza®. Prescribing information. Averitas Pharma, Inc; 2023. Accessed August 6, 2023. https://www.qutenza.com/pdfs/Qutenza_Prescribing_Information.pdf

12. Simpson DM, Robinson-Papp J, Van J, et al. Capsaicin 8% patch in painful diabetic peripheral neuropathy: a randomized, double-blind, placebo-controlled study. J Pain. 2017;18(1):42-53. doi:10.1016/j.jpain.2016.09.008

13. Lyrica®. Prescribing information. Pfizer, Inc; 2017. Accessed August 15, 2023. www.accessdata.fda.gov/drugsatfda_docs/label/2017/209501s000lbl.pdf

14. Cymbalta®. Prescribing information. Eli Lilly and Company; 2021. Accessed August 15, 2023. https://pi.lilly.com/us/cymbalta-pi.pdf

15. Sindrup SH, Otto M, Finnerup NB, Jensen TS. Antidepressants in the treatment of neuropathic pain. Basic Clin Pharmacol Toxicol. 2005;96(6):399-409. doi:10.1111/j.1742-7843.2005.pto_96696601.x

16. Berger A, Dukes E, Edelsberg J, Stacey B, Oster G. Use of tricyclic antidepressants in older patients with diabetic peripheral neuropathy. Clin J Pain. 2007;23(3):251-258. doi:10.1097/AJP.0b013e31802f67dd

17. Derry S, Bell RF, Straube S, Wiffen PJ, Aldington D, Moore RA. Pregabalin for neuropathic pain in adults. Cochrane Database Syst Rev. 2019;(1):CD007076. doi:10.1002/14651858.CD007076.pub3

18. Mangoni AA, Jackson SH. Age-related changes in pharmacokinetics and pharmacodynamics: basic principles and practical applications. Br J Clin Pharmacol. 2004;57(1):6-14. doi:10.1046/j.1365-2125.2003.02007.x

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Reviewed September 2023