Diabetic Peripheral Neuropathy: Painful, Personal, Preventable

This complex condition can be managed with improved glucose control and pharmacologic therapy.

Diabetic peripheral neuropathy (DPN) is neurologically complex and gradually debilitating—and it is surprisingly common.^1,2 At this time, statisticians estimate that approximately half of patients with diabetes will develop neuropathy during their lifetime.³ Its most common presentation is distal symmetrical polyneuropathy (DSP), with its stocking-and-glove pattern of numbness, pain, tingling, or weakness.

DPN can present in other ways. These include small-fiber predominant neuropathy, radiculoplexopathy, and autonomic neuropathy, and other more rare presentations.⁴ Because the vast majority of patients have DSP, most clinicians use the terms DSP and DPN interchangeably. This article follows that convention.

Clinical Manifestations

DPN’s symptoms are symmetrical, occurring in both hands and feet. Patients are more likely to report sensory symptoms (“my socks feel bunched up” or “my shoes seem to fit poorly”) than motor restrictions. It’s also common for patients to report paradoxical symptoms: concurrent numbness and heightened sensitivity. These paradoxical symptoms occur in the form of allodynia (painful sensations out of proportion to the stimuli) and hyperalgesia (increased sensitivity to painful stimuli). Disabling neuropathic pain occurs in up to 20% of the diabetic population, and increases to 40% to 60% in patients with documented DPN.^4-6

Patients usually describe this pain as burning, electric, or stabbing. As the DPN progresses, patients may have balance problems, making DPN patients 2 to 3 times more likely to fall than others.⁷ DPN also increases ulceration and lower-extremity amputation risk.⁸ All of these complications decrease quality of life, especially in patients who have pain.²

Pathophysiology

Researchers have identified several factors that seem to cause or contribute to DPN. Most likely, the proposed mechanisms are linked in a fashion that perpetuates a downward spiral of oxidative stress, inflammation, and dysfunctional cells. The following factors cause or contribute to DPN.

Hyperglycemia. Experts consider hyperglycemia episodes a causative dynamic, suspecting that prolonged hyperglycemia can lead to cellular damage. First, excess glycolysis can overload mitochondrial electron transport chains, thereby causing reactive oxygen species to form.⁹ Changes in 2 metabolic pathways (the polyol and hexosamine pathways) can increase cellular osmolarity and lead to oxidative stress.^10,11 Generation of advanced glycation end products tends to impair cellular function, especially of those that need proteins, and start inflammatory signaling cascades and long-term inflammatory responses.^12-14

Dyslipidemia. Particularly in patients with type 2 diabetes, dyslipidemia is common and linked to DPN.^15,16 Elevated lipids increase inflammatory cytokine release from adipocytes and macrophages.¹⁷ Extra lipids can also bind to extracellular receptors and lead to oxidative stress, and oxidized cholesterol can cause neuronal cell death.^10,17-19

Impaired insulin signaling. Insulin promotes neuronal growth and survival, and when insulin levels fall, mitochondrial dysfunction and oxidative stress occur and DPN may follow.^20-23

Metabolic syndrome. Metabolic syndrome includes dyslipidemia and insulin resistance. Its third component, visceral adiposity, increases systemic plasma free fatty acid concentrations, promoting adipokine secretion and creating pro-inflammatory states.²⁴

Clinical Management

Improved glucose control and pain management are the only options available to patients with DPN at this time. Most clinicians emphasize glucose control in patients with diabetes. Fewer than half of patients who have DPN are treated for pain, however,⁴ so clinicians need to ask proactively about possible pain. No evidence supports one treatment approach over another, but the patient’s comorbidities, concurrent medications, and ability to afford specific agents will guide treatment.

Glucose Control

Glucose control is a modifiable risk factor for DPN,^25-40 and patients with good to excellent glucose control for 5 years experience a 60% to 70% reduction in the incidence of neuropathy compared with those who poorly manage their diabetes.^30,41 Tight glucose control reduces neuropathy in patients with type 1 diabetes better than it does in patients with type 2 diabetes.^31-39,41,42 This is probably due to differences in the duration of neuropathic changes before diabetes onset or diagnosis—type 2 diabetes generally presents after years of obesity and metabolic syndrome.

The consequences of repeated metabolic insult, including oxidative stress, inflammation, and cellular damage, are hard to stop or reverse. Good glucose control alone is an insufficient intervention for people who have type 2 diabetes— they usually respond less robustly than those with type 1 diabetes.

Pain Management

Pain management can substantially improve DPN sufferers’ quality of life. The 2006 and 2010 guidelines from the European Federation of Neurological Societies Task Force and the 2011 guidelines from the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation both address DPN. Guideline authors advise using several classes of drugs—rational polypharmacy. The guidelines disagree in some areas. Several reviews have recommended treatment algorithms for DNP on the basis of drug efficacy and safety.

Because DPN is difficult to treat and has much interpatient variability, prescribers may find that some patients may not respond to or tolerate agents with good evidence to support their use, but do respond to other agents.^43,44 Most prescribers consider gabapentin, pregabalin, tricyclic antidepressants (TCAs), venlafaxine, and duloxetine as first-line treatments. They also tend to titrate the first-line drug to a maximum tolerated dose before switching to a different drug or combination therapy.

Anticonvulsants

Guidelines tend to recommend using anticonvulsants to treat DPN. Four drugs are generally recommended:

• Pregabalin at doses of 300 to 600 mg daily^45-48
• Gabapentin at doses of 900 to 3600 mg daily⁴⁹
• Lamotrigine at doses of 400 mg daily,⁵⁰ although the evidence supporting its use is inconsistent
• Sodium at doses of 500 to 1200 mg daily, again with inconsistent evidence

Antidepressants

Two class I meta-analyses support using TCAs in general for neuropathic pain.^51,52 Although amitriptyline (25-100 mg daily) has been studied in DPN,^53-55 other TCAs could be expected to work as well. Similarly, serotonin-norepinephrine reuptake inhibitors such as venlafaxine 75 mg to 225 mg daily and duloxetine 60 to 120 mg daily have been studied in DPN. The evidence here, too, is inconsistent, but some patients respond well.^56-58

Opioids

When DPN becomes chronic and painful and other drugs fail to bring relief, opioid therapy may be considered. Controlled-release oxycodone, tramadol,or morphine are options.^59-64 Several other drugs have been tried for DPN (Table), and again, the patient’s suitability for and response to these drugs depends on many factors.

Conclusion

Only 1 of the 2 clinical management strategies for DPN—better glucose control— is disease modifying. Pain management is not. As researchers continue to search for modifiable risk factors for DPN, pharmacists need to work better with their patients with diabetes. Encouraging better glucose control is essential, not just to prevent DPN but also to prevent other serious consequences of poor glucose control including retinopathy, cardiovascular disease, and impaired renal function.

Pharmacists should also keep in mind that many patients with DPN have untreated pain and so should ask about pain and refer patients for treatment.

Ms. Wick is a visiting professor at the University of Connecticut School of Pharmacy and a freelance writer from Virginia.

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