December CE Article

December CPE Article

Management of Diabetes-Related Neuropathic Pain

Author: Lourdes Cross, PharmD, BCACP, CDCES and Long Phan, PharmD; Sullivan University College of Pharmacy and Health Sciences The author declare that there are no financial relationships that could be perceived as real or apparent conflicts of interest. Universal Activity #0143-0000-20-012-H01-P&T 2.5 Contact Hours Expires 12/14/23 Goal: To aid pharmacists and pharmacy technicians in understanding of current recommendations for treatment of pain associated with diabetic peripheral neuropathy and to assist with appropriate use of medications. Learning Objectives: At the conclusion of this Knowledge-based article, the reader should be able to: 1.

Describe the epidemiology of diabetic peripheral neuropathy (DPN)

Discuss pharmacologic recommendations for the management of DPN

Compare and contrast pharmacologic options for the management of DPN

Introduction and gabapentinoid antiepileptic agents. Capsaicin Diabetic peripheral neuropathy (DPN) is a major complication of diabetes, with a reported prevalence of 30% in hospitalized patients and 20% in ambulatory patients.1 As the duration of diabetes increases, so does the risk of developing neuropathy. An estimated 7% to 10% of patients newly diagnosed with diabetes have neuropathy, and this is also an option, but it is generally poorly tolerated. In the United States, the three medications that are FDA-approved are duloxetine, pregabalin, and the capsaicin patch (8%). Comparative efficacy is similar among the first-line medication options. A two- to three-month trial is usually required to assess response to initial therapy. number increases to 50% in patients with longterm diabetes (>25 years duration).2 Patients may describe symptoms as numbness (similar to wear- First-line Pharmacotherapy ing gloves or socks), tingling, burning, aching, or sensitivity to touch. Peripheral neuropathy is one of the most important risk factors for amputations Serotonin-Norepinephrine Reuptake Inhibitors and ulcers in people with diabetes, and it also in- Duloxetine, a serotonin-norepinephrine reuptake creases risk for gait instability and falls. Further- inhibitor (SNRI), is a first-line treatment option for more, it may lead to insomnia, depression, anxiety, painful DPN given its efficacy, safety, and tolerabillimited mobility, and overall reduced quality of life. ity. It is also FDA-approved for use in patients with Established neuropathy is generally not reversible, major depressive disorder, generalized anxiety disso the primary goal of management is to slow pro- order, fibromyalgia, or chronic musculoskeletal gression, prevent complications, and alleviate pain. pain. The recommended initial dose of duloxetine for DPN is 60 mg daily. Lower doses may be considered when tolerability is a concern. In one sysTreatment for Neuropathic Pain temic review which included 2,728 participants, Management of neuropathic pain is an important component of care in patients with DPN. First-line pharmacotherapy options include antidepressants duloxetine 60 mg daily compared to placebo was effective in reducing pain by ≥50% at 12 weeks (risk ratio [RR] 1.73, 95% confidence interval [CI] 1.44-

2.08).3 Doses greater than 60 mg daily are not recommended, because they are no more efficacious and associated with increased side effects.4 Improvement in pain may be seen as early as one week after treatment.5 The SNRIs are generally well tolerated. The most but should be used cautiously due to the risk for daily for a period of 6 weeks each.9 A median pain loxetine which was a significant improvement in pain compared to baseline values (P<0.001). A systematic review found no significant differences among TCAs in analgesic efficacy.10

Because of their side effects, TCAs are generally reVenlafaxine is not as well studied as duloxetine, but served for refractory pain once alternatives have doses between 150 and 225 mg daily have shown been tried first. Potential adverse reactions include some effectiveness for DPN.6 In a randomized, pla- anticholinergic effects (constipation, dry mouth, cebo-controlled study that evaluated venlafaxine blurry vision, urinary retention) and orthostatic hyextended-release (ER), the pain intensity reduction potension. Amitriptyline has a higher incidence of at week 6 was 27% (placebo), 32% (75 mg), and 50% anticholinergic effects compared to desipramine (150-225 mg; P<0.001 vs. placebo). The number and nortriptyline. TCAs should be used with caution needed to treat (NNT) for the 50% pain intensity re- in patients with a history of cardiovascular disease duction with higher dose venlafaxine was 4.5 at (including previous myocardial infarction, stroke, week 6, which is comparable to those of tricyclic tachycardia, or conduction abnormalities). Use antidepressants and gabapentin.7 Similar to dulox- should be limited in older adults due to increased etine, venlafaxine is a good option for patients with risk of sedation, cardiovascular events, and falls asconcomitant depression or anxiety. sociated with dizziness and orthostasis. The TCAs may be helpful when sedation is a desired effect, such as in patients with sleep onset difficulties. common side effects include nausea, dry mouth, decreased appetite, dizziness, drowsiness, fatigue, Gabapentinoid Antiepileptic Agents and headache. In addition, SNRIs can exacerbate Pregabalin is FDA-approved for the management restless legs syndrome. Venlafaxine exhibits more of neuropathic pain associated with DPN. The usual noradrenergic activity with higher doses and has starting dose of pregabalin immediate release for been shown to cause dose-dependent increases in DPN is 75 to 150 mg daily. The immediate-release blood pressure. SNRIs should not be taken with formulation should be given in two to three divided other serotonin or norepinephrine reuptake inhibi- doses and increased based on response and tolerators (including tricyclic antidepressants), but they bility in increments of 75 mg/day every ≥3 days can be combined with pregabalin or gabapentin. based on response and tolerability (maximum 300 to 450 mg daily). Higher doses up to 600 mg daily Tricyclic Antidepressants fit. The pregabalin extended-release formulation Based on the American Diabetes Association position statement for the treatment of diabetic neuropathy, tricyclic antidepressants (TCAs; including amitriptyline, nortriptyline, desipramine) are effective and recommended in the management of DPN should be initiated at 165 mg daily and may be increased to a maximum dose of 330 mg daily. In one systematic review, more patients in the pregabalin group had a ≥50% reduction in pain intensity versus placebo (31% vs 25%; RR 1.3, 95% CI 1.2-1.5).9 cardiovascular adverse effects.6 The starting dose of amitriptyline or nortriptyline is 10 to 25 mg daily and may be gradually titrated up to 100 mg daily. Desipramine should be initiated at 25 mg daily and can be gradually increased to 200 mg daily over a few weeks. Up to 6 to 8 weeks may be needed before reasonable effects are noted by the patient.8 A lower dose is usually required for pain compared to when TCAs are used for depression. Although not FDA-approved for DPN, data also support the use of gabapentin for reducing pain in diabetic neuropathy. In one meta-analysis, 37 studies were included to evaluate the use of oral gabapentin at daily doses of 1200 mg or more in a total of 1,277 patients with DPN.11 Gabapentin was significantly better than placebo in achieving a ≥50% pain intensity reduction (38% vs 21%; RR 1.9, 95% CI 1.52.3). The usual starting doses for gabapentin are 100 In a randomized, cross-over, active-control trial, 58 patients received amitriptyline and duloxetine once gradually titrated to a usual effective dose of 900 to 3600 mg daily in three divided doses. have shown increased risk without additional beneto 300 mg one to three times daily, and it can be score reduction of >50% was achieved in 55% of patients on amitriptyline and 59% of patients on du- Patients who have an unsatisfactory response to |26| Kentucky Pharmacists Association | November/December 2020

treatment with gabapentin may respond to equiva- water and hot weather.16 Severe irritation to the lent doses of pregabalin.12 It is suggested that the eyes, mucous membranes, respiratory tract, or skin analgesic action of pregabalin is 6 times that of may occur due to unintended capsaicin exposure. gabapentin in terms of effectiveness in dosage conversion.13 Therefore, a patient receiving 1,800 mg of gabapentin would require 300 mg of pregabalin to Lidocaine achieve a comparable effect. Lidocaine 5% patches are possibly effective in lessGabapentin and pregabalin have similar side effects profiles, which includes somnolence, dizziness, ataxia, peripheral edema, and weight gain. In addition, both require renal dose adjustments. Pregabalin has a warning for those at risk of addiction or habituation. If discontinuation is desired, gabapentin or pregabalin should be withdrawn gradually. study of lidocaine 5% topical patches, 70% of patients with DPN reported a ≥30% reduction in mean daily pain compared with baseline values.17 Lidocaine patches should not be applied for more than 12 hours in a 24-hour period. Lidocaine patches may be cut without disrupting the integrity of the dosage form. Rapid withdrawal can precipitate seizures, even in patients without a seizure history. Opioids

Other Therapy Second- and third-line medications for pain associated with DPN include topical analgesics and opioids. While opioids are effective, concerns for adverse reactions and addiction limits their widespread use.

Capsaicin applied to painful areas of the feet for 30 minutes (up to 4 patches in a single application) every three months as needed. One systematic review found that the NNT for the high-concentration capsaicin patch is 10.64 (95% CI 7.4-19).15 The patch should only be applied by a health care provider in a wellventilated area. The area should be pretreated with a topical anesthetic such as lidocaine prior to patch application. Capsaicin patches may be cut to match the size and shape of the treatment area. Although capsaicin has been effective in reducing pain in DPN clinical trials, many patients cannot tolerate the adverse effects, including local burning and skin irritation which is exacerbated by warm ening the pain of DPN. In an open-label, 3-week Tapentadol extended-release was approved by the FDA for the treatment of neuropathic pain associated with DPN. However, it is generally not recommended as first- or second-line therapy due to concerns for addiction and safety compared to modest pain reduction.18 Per the American Diabetes Association, the use of any opioids for chronic neuropathy carries the risk of addiction and should be avoided.18

Capsaicin is an option for add-on or monotherapy. Conclusion Capsaicin contains a substance derived from chili peppers that desensitizes afferent sensory nerves.14 Capsaicin 0.075% cream can be gently rubbed into painful areas until thoroughly absorbed up to 4 times daily. Hands should be washed with soap and water immediately after application, unless hands are a part of the painful area. If applying to hands, patients should wait 30 minutes before washing. Neuropathy is one of the leading causes of morbidity in patients with diabetes. The painful symptoms associated with diabetic neuropathy can limit function and decrease quality of life. Treatment for DPN pain includes antidepressants (SNRIs, TCAs), gabapentinoid anticonvulsants, and topical medications. The selection of a medication for DPN should be individualized based on comorbidities, drug inThe high-concentration capsaicin 8% patch can be ences.

teractions, side effects, cost, and patient prefer-

FDAApMedication prove Usual Recommended Comments Dosed for DPN? Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs)

Duloxetine Yes Initial: 60 mg/day Avoid concomitant use with other serotonin or norepinephrine reuptake inhibiMaximum: 60 mg/day tors (including TCAs) Venlafaxine No Initial: 37.5-75 mg/day AE: nausea, dry mouth, decreased appetite, dizziness, drowsiness, fatigue, (extendedMaximum: 225 mg/day headache release)

Tricyclic Antidepressants (TCAs)

Amitripty- No Initial: 10-25 mg/day Avoid concomitant use with other serotonin or norepinephrine reuptake inhibiline Maximum: 150 mg/day tors divided in 1 to 2 doses Avoid use in geriatric population if possible; less-severe anticholinergic and seDesipra- No Initial: 12.5 mg/day dation effects with desipramine and nortriptyline mine Maximum: 250 mg/day AE: anticholinergic effects (e.g., dry mouth, urinary retention), sedation, cardiac divided in 1 to 2 doses arrythmias, orthostatic hypotension Nortripty- No Initial: 12-25 mg/day line Maximum: 100 mg/day

Gabapentinoid Anticonvulsants

Gabapentin No Immediate-release May be used with SNRIs or TCAs Initial: 100-300 mg 1 to 3 times daily Maximum: 1200 mg 3 times daily Extended-release Initial: 300 mg daily Maximum: 3600 mg/ day Requires renal dose adjustment Pregabalin has a warning for those at risk of addiction or habituation AE: somnolence, dizziness, ataxia, lower extremity edema, weight gain

Pregabalin Yes Immediate-release Initial: 75-150 mg/day in 2 to 3 divided doses Maximum: 300 to 450 mg/day Extended-release Initial: 165 mg/day Maximum: 330 mg/day

Other

Capsaicin Yes (patc h) Cream (0.075%) Apply 4 times daily Patch (8%) Apply up to 4 patches to feet for 30 min every 3 months as needed May be used as adjunct to oral medications Wash hands with soap and water immediately after applying (unless hands are part of the treatment area); if applying cream to hands, wait 30 minutes before washing hands AE: localized stinging, burning, itching

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