Treating Painful Diabetic Peripheral Neuropathy: An Update MATTHEW J. SNYDER, DO, and LAWRENCE M. GIBBS, MD, Saint Louis University Family Medicine Residency, Belleville, Illinois TAMMY J. LINDSAY, MD, Saint Louis University Family Medicine Residency, St. Louis, Missouri Painful diabetic peripheral neuropathy occurs in approximately 25% of patients with diabetes mellitus who are treated in the office setting and significantly affects quality of life. It typically causes burning pain, paresthesias, and numbness in a stocking-glove pattern that progresses proximally from the feet and hands. Clinicians should carefully consider the patient’s goals and functional status and potential adverse effects of medication when choosing a treat- ment for painful diabetic peripheral neuropathy. Pregabalin and duloxetine are the only medications approved by the U.S. Food and Drug Administration for treating this disorder. Based on current practice guidelines, these medica- tions, with gabapentin and amitriptyline, should be considered for the initial treatment. Second-line therapy includes opioid-like medications (tramadol and tapentadol), venlafaxine, desvenlafaxine, and topical agents (lidocaine patches and capsaicin cream). Isosorbide dinitrate spray and transcutaneous electrical nerve stimulation may provide relief in some patients and can be considered at any point during therapy. Opioids and selective serotonin reuptake inhibitors are optional third-line medications. Acupuncture, traditional Chinese medicine, alpha lipoic acid, acetyl-L-carnitine, primrose oil, and electromagnetic field application lackhigh-quality evidence to support their use. (Am Fam Physi- cian. 2016;94(3):227-234. Copyright © 2016 American Academy of Family Physicians.) CME This clinical content ainful diabetic peripheral neuropa- glucose control in patients with type 1 dia- conforms to AAFP criteria thy (DPN) occurs in approximately betes significantly reduced the risk of devel- for continuing medical education (CME). See 30% of patients with diabetes melli- oping DPN (risk difference = 1.84%; 95% CME Quiz Questions on tus who are hospitalized and in 25% confidence interval [CI], –1.11 to –2.56). page 208. Pof patients with diabetes who are treated in A similar analysis of four RCTs in patients 1 Author disclosure: No rel- the office setting. It develops as a late mani- with type 2 diabetes, however, did not show evant financial affiliations. festation of uncontrolled or long-standing a statistically significant reduction in the ▲ 1 4 Patient information: diabetes. As many as 12% of patients with rate of DPN with enhanced glucose control. A handout on this topic, painful DPN do not report symptoms, and Cardiovascular risk factors, including age, written by the authors of 39% of patients with the disorder do not tobacco use, hypertension, obesity, dyslipid- this article, is available receive any treatment.2 emia, and peripheral artery disease, are also at http://www.aafp.org/ afp/2016/0801/p227-s1. Distal symmetric polyneuropathy, which is associated with an increased risk of painful html. characterized by burning pain, paresthesias, DPN.1 and numbness that follows a stocking-glove Pharmacologic and nonpharmacologic pattern and progresses proximally, occurs interventions are available for the treat- in approximately 26% of patients with DPN. ment of painful DPN. However, there are Less than 20% of patients with diabetes expe- few high-quality, head-to-head clinical tri- rience dynamic mechanical allodynia (pain als comparing these therapeutic approaches, in response to stroking lightly), thermal and because the available studies use varying hyperalgesia (increased sensitivity to pain by methodologies, it is difficult to know which thermal stimuli), or pain attacks. treatment strategy may be most effective. Poorly controlled blood glucose lev- els, especially greater variation in glucose Pharmacologic Treatment Options levels, contribute to the occurrence and Only two medications, pregabalin (Lyr- severity of painful DPN.3 A 2012 Cochrane ica) and duloxetine (Cymbalta), have been review of two randomized controlled tri- approved by the U.S. Food and Drug Admin- als (RCTs; n = 1,228) found that enhanced istration (FDA) for the treatment of DPN. AugustDownloaded 1, 2016 from ◆ the Volume American 94, Family Number Physician 3 website at www.aafp.org/afp.www.aafp.org/afp Copyright © 2016 American Academy of FamilyAmerican Physicians. Family For the Physician private, noncom 227- mercial use of one individual user of the website. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests. Diabetic Peripheral Neuropathy Management of Painful Diabetic Peripheral Neuropathy Initial evaluation Guidelines from national organizations such Rule out other causes of neuropathy* as the American Academy of Neurology, Establish treatment goals Optimize glycemic control however, recommend the use of a broader range of medications. Clinicians should consider the patient’s First-line therapy age, health-related quality-of-life goals, Anticonvulsants Antidepressants (TCAs and SNRIs) physical function, and comorbidities, as well Pregabalin† (Lyrica) Amitriptyline‡ as the possible adverse effects of medication Gabapentin (Neurontin) Duloxetine (Cymbalta) use, in the management of pharmacologic therapy. Additionally, medication dosages and the duration of therapy should be regu- Second-line therapy lated and titrated based on regular patient SNRIs§ Opioid-like drugs Topical treatments feedback regarding pain relief, improved Venlafaxine Tramadol|| Lidocaine 5% patch function, and adverse effects.1 or or or Figure 1 presents a treatment algorithm Desvenlafaxine (Pristiq) Tapentadol ER Capsaisin 0.075% cream (Nucynta ER) for painful DPN based on available evi- dence.1-3,5-8 Selected medications and their dosages, costs, and numbers needed to treat Third-line therapy (NNTs) are presented in Table 1.1,7,9-14 Table 2 SSRIs Opioids¶ lists common adverse effects of medications Citalopram (Celexa) Oxycodone controlled 3,12,13,15 used to treat painful DPN. Common or release 16 drug interactions are described in Table 3. Paroxetine (Paxil) or ANTICONVULSANTS Escitalopram (Lexapro) Anticonvulsants, including topiramate (Topamax), valproate (Depacon), oxcar- May consider adding at any time: bazepine (Trileptal), lamotrigine (Lamic- Isosorbide dinitrate spray (30 mg applied to the bottom of feet before bedtime) tal), and lacosamide (Vimpat), as well as the Transcutaneous electrical nerve stimulation newer calcium channel alpha-2-delta ligand class anticonvulsants (gabapentin [Neuron- ER = extended release; SNRI = serotonin-norepinephrine reuptake inhibitor; SSRI = selective serotonin reuptake inhibitor; TCA = tricyclic antidepressant. tin] and pregabalin), have been studied for *—Other causes of neuropathy include malignancy, alcohol use, human immunodefi- the treatment of painful DPN. Based on a ciency virus infection, isoniazid use, and chemotherapy. recent meta-analysis, both the American †—Pregabalin should be used cautiously in patients with heart failure and in persons con- Academy of Neurology and Toronto guide- comitantly using thiazolidinediones, because cases of decompensated heart failure with pregabalin use have been reported.1 In addition, renal insufficiency (creatinine clearance lines recommend pregabalin as the first-line ≤ 30 mL per minute per 1.73 m2 [0.50 mL per second per m2]) requires dose adjustment.3 medication for painful DPN, with gabapen- ‡—Amitriptyline is the only TCA with good evidence of benefit for treating diabetic tin as the first-line alternative.3 neuropathy. TCAs should also be used cautiously and should generally be avoided in older adults because of adverse anticholinergic effects.3,6 TCAs are contraindicated Pregabalin provides consistent pain relief in patients with cardiovascular disease (including unstable angina, recent myocardial based on a dose-dependent response com- infarction, heart failure, and abnormal cardiac conduction) and glaucoma.3 Twelve- pared with placebo. A meta-analysis of seven lead electrocardiography should be performed in all patients older than 40 years to RCTs (n = 1,596) comparing pregabalin with assess for QT prolongation because TCAs may increase the risk of torsades de pointes. §—May consider combination therapy with pregabalin and gabapentin 2,5; however, placebo showed that dosages of 300 mg daily clinicians should be cautious to avoid serotonin syndrome. and 600 mg daily (or divided twice daily) ||—Tramadol lowers the seizure threshold and should be avoided in patients with resulted in greater than 50% pain reduction in epilepsy or in those at risk of seizures.7 ¶—Opioids should be used with caution because long-term use is associated with 39% and 47% of patients, respectively, vs. 22% numerous adverse effects and increased morbidity and mortality. If opioids are used, with placebo. Onset of action occurred at five oxycodone is commonly prescribed, but alternatives include methadone, levorphanol, days with 300 mg and at four days with 600 mg. and morphine. Dosing at 150 mg daily was ineffective.1-3 Common adverse reactions to pregabalin Figure 1. Algorithm for the management of painful diabetic periph- (Table 2 3,12,13,15) produced discontinuation eral neuropathy. rates of 9.8% (300 mg) and 14.6% (600 mg).1 Information from references 1 through 3, and 5 through 8. 228 American Family Physician www.aafp.org/afp Volume 94, Number 3 ◆ August 1, 2016 Diabetic Peripheral Neuropathy