A Review of Pharmacologic Treatment Options for Painful Diabetic Neuropathy

Diabetic peripheral neuropathy (DPN) is a complication of diabetes mellitus that can be associated with significant pain and reduced quality of life. Diabetic neuropathy is a heterogeneous group of disorders, of which DPN is the most common type. The involvement of small fibers in DPN is associated with pain and burning or tingling sensation, whereas large fiber involvement is characterized by numbness and loss of protective sensation, which can increase risk for foot ulcers.¹ DPN is defined as the presence of signs or symptoms of nerve dysfunction in patients with diabetes, after exclusion of nondiabetic causes of neuropathy.² Pharmacologic agents are often required for treatment of DPN, with pregabalin and duloxetine being the most commonly recommended therapeutic options.²

Previous studies have reported that up to one-half of patients with DPN may be symptomatic.² The prevalence of painful diabetic neuropathy ranges from 15% to 30% in patients with diabetes mellitus.^1-3 Painful DPN predominantly affects the feet and legs and has a significant negative effect on quality of life, mobility, and mood. However, many patients never receive treatment for this complication.^3,4

According to the American Diabetes Association guidelines for medical care in diabetes, assessment for DPN, including a careful history and assessment of temperature or pinprick sensation and vibration sensation, should be completed in all patients with diabetes starting at the time of diagnosis of type 2 diabetes and 5 years after the diagnosis of type 1 diabetes, with regular monitoring thereafter.¹

There is a well-recognized triad of chronic pain, anxiety/depression, and sleep interference in painful DPN, which impairs activities of daily living.⁵ Although good glycemic control may prevent or delay development and/or progression of neuropathy, no studies have found compelling evidence that glycemic control or lifestyle management are clearly effective for neuropathic pain.² The recommended management in these cases usually involves pharmacologic treatment.

A systematic review⁶ that assessed the effect of pharmacologic treatments for DPN on pain and quality of life reported that there was a substantial body of evidence on the effectiveness of 3 drugs approved by the US Food and Drug Administration (FDA) for the treatment of pain in DPN: duloxetine, pregabalin, and tapentadol. Furthermore, additional non-FDA-approved agents were found to have a potential benefit in these cases, including oxacarbazepine, venlafaxine, tricyclic antidepressants, tramadol, and botolinum toxin.⁶

Pregabalin

Pregabalin, a calcium channel α2-δ subunit ligand that is structurally related to gabapentin, was approved for the management of neuropathic pain in 2004 and is considered a first-line treatment for painful DPN.⁵ Pregabalin reduces neuropathic pain within 1 week of initiating therapy by inhibiting release of neurotransmitters such as glutamate and reducing hyperexcitability at the spinal cord.⁵  

Starting doses range from 75 to 150 mg/d with relatively quick up-titration over several weeks to maximal tolerated doses (600 mg/d).^5,7 It is important to escalate pregabalin to an effective and tolerable dose.

Overall, pregabalin is well tolerated and its relatively common adverse effects include dizziness, somnolence, peripheral edema, headache, and weight gain.⁸ While the risk for addiction and drug dependency with pregabalin is low, there are data pointing to a significant increase in the number of deaths linked to this agent from 2012 to 2016 in England and Wales.⁵ In the United States, pregabalin is a Schedule V controlled substance under the Controlled Substances Act of 1970.

Multiple randomized controlled trials and systematic reviews have supported the efficacy of pregabalin for painful DPN.⁵ In addition to pain relief, pregabalin was found to improve all other components of the triad that leads to impaired function in patients with painful DPN, including improvement in sleep interference, mood disturbance, and anxiety.⁵

Duloxetine

Duloxetine, a selective norepinephrine and serotonin reuptake inhibitor, has been found to be effective and safe for painful DPN.⁹ A 2014 Cochrane review concluded that there is an adequate amount of moderate-quality evidence to conclude that daily doses of 60 and 120 mg are efficacious for pain reduction in painful DPN.¹⁰ Common adverse effects include nausea, dizziness, constipation, and dyspepsia.¹¹

Tapentadol

Tapentadol, a centrally acting opioid analgesic, was approved by the FDA for painful DPN based on previous studies supporting its beneficial properties.^1,12 However, a 2015 systematic review and meta-analysis revealed inconclusive evidence supporting the effectiveness of the agent in reducing neuropathic pain.¹² In light of these findings, along with the risk for addiction, it is not usually a recommended first- or second-line option.¹

Comparison of Medications

Several studies have compared pregabalin with other medications for painful DPN. In head-to-head studies, the efficacy of pregabalin and amitriptyline was similar, with a greater proportion of adverse events associated with the latter.¹³ In a similar fashion, duloxetine and pregabalin were not statistically different in pain relief.⁹ However, although pregabalin was associated with improved sleep continuity, duloxetine increased wake and reduced total sleep time.⁹ The combination of several therapeutic agents to treat painful DPN was not shown to be superior to monotherapy.⁵

Conclusion and Future Directions

The management of patients with painful DPN requires the use of agents proven to be effective, such as pregabalin, that also may aid in improving sleep and mood.

With regard to potential therapeutic agents, there are several possible novel therapies for painful DPN.⁵ Mirogabalin, which has a higher affinity for the α2-δ1 subunit, was found to be an effective agent for pain reduction in patients with DPN. Furthermore, there are numerous ongoing trials assessing the efficacy of agents directed at voltage-gated sodium channels, which may serve as an important therapeutic target.⁵

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References

1. American Diabetes Association. Standards of medical care in diabetes — 2020. Diabetes Care. 2020;43(suppl 1).

2. Pop-Busui R, Boulton AJM, Feldman EL, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care. 2017;40:136-154.

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9. Boyle J, Eriksson MEV, Gribble L, et al. Randomized, placebo-controlled comparison of amitriptyline, duloxetine, and pregabalin in patients with chronic diabetic peripheral neuropathic pain. Diabetes Care. 2012;35(12):2451-2458.

10. Lunn MPT, Hughes RAC, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev. 2014;1:CD007115.

11. Griebler ML, Morey-Vargas OL, Brito JP, et al. Pharmacologic interventions for painful diabetic neuropathy: an umbrella systematic review and comparative effectiveness network meta-analysis. Ann Intern Med. 2014;161:639-649.

12. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: systematic review, meta-analysis and updated NeuPSIG recommendations. Lancet Neurol. 2015;14(2):162-173.

13. Bansal D, Bhansali A, Hota D, Chakrabarti A, Dutta P. Amitriptyline vs. pregabalin in painful diabetic neuropathy: a randomized double blind clinical trial. Diabet Med. 2009;26(10):1019-1026.