Original Authors

Robert W. Hurley, MD, PhD 
Chief, Division of Pain Medicine
Associate Professor
Department of Anesthesiology, Neurology, Psychiatry, Orthopedics and Rehabilitation

Nataliya Yakovleva, MD
Resident Physician
Department of Anesthesiology

University of Florida
Gainesville, FL

Revised December 9, 2014, by

Robert W. Hurley, MD, PhD
Professor and Vice-Chair

William Ross, MD
Pain Medicine Fellow

Department of Anesthesiology
Medical College of Wisconsin
Milwaukee, WI

Introduction

Diabetic peripheral neuropathies (DPNs) are the most common types of neuropathies worldwide. There has been significant progress in the understanding of the clinical aspects of these conditions; however, many questions remain unanswered or difficult to answer in terms of causation, risk factors and genetic susceptibility, effective treatments and restoration of nerve functions, and pain management. The major problem in studying DPNs is the lack of a suitable animal model that addresses acute and chronic events leading to DPN. Unfortunately and despite numerous drug trials, other than strict glycemic control, which is often difficult to maintain, there are no other treatments to slow the progression or delay the development of DPN.

Pathophysiology

Hyperexcitability of and aberrant spontaneous impulse generation by damaged first-order sensory neurons and their peripheral axons are well-established processes that strongly contribute to pain associated with DPN. Central neuropathic mechanisms can also contribute to pain experienced with diabetes. Some studies have demonstrated that thalamic dysfunction occurs in patients with diabetes mellitus and that in experimental models of this disease, neurons in the ventral posterolateral thalamus can become hyperexcitable, firing at abnormally high frequencies and generating aberrant spontaneous activity.^[1]

One potential therapeutic option with limited clinical acceptance is the cannabinoids, for which cannabinoid receptors (CB) are expressed on neurons and microgli.^[2] The Department of Clinical Neurosciences and the Hotchkiss Brain Institute at the University of Calgary in Alberta, Canada, studied the accumulation and activation of spinal and thalamic microglia in streptozotocin (STZ)-diabetic CD1 mice and the impact of cannabinoid receptor agonism/antagonism during the development of a chronic neuropathic pain state. They provided either intranasal or intraperitoneal cannabinoid agonists/antagonists at multiple doses both at the initiation of diabetes and after establishment of its related neuropathic pain state. Cannabinoids had antinociceptive effects in this model of diabetes in rodents.^[2]

These studies^[2] showed that tactile allodynia and thermal hypersensitivity were observed over eight months in diabetic mice without intervention. Microglial density increases were seen in the dorsal spinal cord and in thalamic nuclei and were accompanied by elevation of phosphorylated p38 MAPK, a marker of microglial activation. When initiated coincidentally with diabetes, moderate-to-high doses of intranasal cannabidiol (cannaboid receptor 2 agonist) and intraperitoneal cannabidiol attenuated the development of a neuropathic pain state, even after their discontinuation and without modification of the diabetic state. Cannabidiol was also associated with restriction in elevation of microglial density in the dorsal spinal cord and elevation in phosphorylated p38 MAPK. When initiated in an established DPN pain state, both CB1 and CB2 agonists demonstrated an antinociceptive effect until their discontinuation. There were no pronociceptive effects demonstrated for either CB1 or CB2 antagonists. The prevention of microglial accumulation and activation in the dorsal spinal cord was associated with limited development of a neuropathic pain state. Cannabinoids demonstrated antinociceptive effects in this mouse model of DPN.

Interventions such as these may also benefit humans with DPN, and their early introduction may also modify the development of the neuropathic pain state.^[3]

Symptoms

DPN is one of the most debilitating complications of diabetes. DPN is a major cause of foot ulceration and lower limb amputation. Early diagnosis and management are key factors in reducing morbidity and mortality. Current techniques for clinical assessment of DPN are relatively insensitive for detecting early disease or involve invasive procedures such as skin biopsies. There is a need for less painful, noninvasive, and safe evaluation methods. Eye-care professionals already play an important role in the management of diabetic retinopathy but recent studies have indicated that the eye may also be an important site for the diagnosis and monitoring of neuropathy. Corneal nerve morphology is a promising marker of DPN occurring elsewhere in the body. New evidence suggests that retinal anatomical markers and a range of functional visual indicators could similarly provide useful information regarding neural damage in diabetes, although this line of research is less well established.^[4] It’s a new era in medicine supporting a potential diagnostic role for retinal structure and visual functional markers in the diagnosis and monitoring of DPNs.

Charcot neuro-osteoarthropathy (CNO) is one of the more devastating complications affecting diabetic patients with peripheral and/or autonomic neuropathy. The acute phase of the disease is often misdiagnosed and can rapidly lead to deformity and amputation. The rapid progression toward foot deformation calls for early detection and intervention. Classical neurotraumatic and neurotrophic theories fail to explain all of the features of the condition, although recent advances that have clarified the mechanisms underlying the pathophysiology may make up for this lack. New data have emerged on the central role of the RANK/RANK-ligand (RANK-L)/osteoprotegerin (OPG) system in the pathogenesis of osteopenia.^[5] Now we recognized that the acute phase of CNO can be triggered by any factor leading to local inflammation of the foot, especially in predisposed patients. As the cornerstone of treatment remains any method that avoids weight-bearing on the foot, the primary importance of the RANK/RANK-L/OPG signaling pathway is that it opens up the field to new treatment strategies for the future.

Diagnosis

An early diagnosis of peripheral neuropathy in diabetic patients is useful to slow down the progress of this complication. Nerve conduction tests are the gold standard for this diagnosis but they are challenging for the patients. Many studies examined whether it is possible to assess the presence of DPN at an early stage by static posturography tests.^[6] Patients with DPN demonstrate a shift from physiological ankle control to hip postural control as monitored by specific posturography analysis.

Treatment Options

Anticonvulsants

Anticonvulsant agents, such as carbamazepine, valproic acid, and gabapentin have traditionally been used for the treatment of neuropathic pain due to their membrane stabilizing capabilities. Several systematic reviews indicate that anticonvulsants are effective for the treatment of pain from DPN. Valproic acid has been shown to decrease the VAS pain score by >2.5 points compared to controls and produce a modest improvement in nerve conduction of motor efferents.^[7] One systematic review examined 7 randomized controlled trials (4 placebo-controlled, 3 active control) examining the analgesic efficacy of gabapentin for neuropathic pain. The authors noted that the combined number needed to treat (NNT) for gabapentin versus placebo in the treatment of pain from DPN was 2.9 [95% CI, 2.2-4.3] with 64% of patients improved on gabapentin versus 28% on placebo. The analgesic efficacy of gabapentin may be enhanced when combined with an opioid such as morphine or sustained-release oxycodone and is highly effective when combined with nortriptyline.^[8] Pregabalin, an anticonvulsant with the same mechanism of action as gabapentin but improved bioavailability, has also been shown to be effective for the treatment of pain from DPN in a number of studies and has been FDA approved for neuropathic pain in the United States.^[9-13]  Newer formulations of gabapentin have also been evaluated for their efficacy in treating DPN pain. In a randomized controlled trial (RCT), encarbil, a transported prodrug form of gabapentin, failed to demonstrate efficacy compared to placebo at doses of 3,600 mg daily.^[14] In a double-blind, placebo-controlled RCT of the gastroretentive gabapentin drug gralise, 35% of patients had a 50% reduction of pain compared to 8% of the placebo group at a daily dose of 3,000 mg.^[15]

Topiramate has been shown to improve DPN pain scores and induce nerve regeneration while also possessing the benefit of causing weight loss and improving lipid profile; however, in an RCT, 39.5% of subjects discontinued use due to the side effect profile.^[16-17]

Lacosamide has demonstrated a modest decrease in DPN pain compared to placebo but its side effect profile limited is use.^[18]

There is limited data for the use of carbamazepine, oxycarbazepine, or lamotrigine.^[19] Evidence for AEDs for DPN pain demonstrates that if a single AED fails, patients may still respond to a different AED or a combination of 2 or more.^[20]

Antidepressants

Like anticonvulsant agents, antidepressant agents (specifically the tricyclic antidepressant agents [TCAs] or selective serotonin and norepinephrine inhibitors [SSNRIs]) have been used for the treatment of neuropathic pain. There have been several systematic reviews examining the analgesic efficacy of TCAs for the treatment of pain from DPN.^[19,21] These systematic reviews indicate that TCAs are extremely effective at relieving DPN pain with an NNT of 1.3 from 5 randomized trials and an NNT of 3.4 from a review of 16 RCTs. It appears that amitriptyline and imipramine are more efficacious in treating DPN pain because of their balanced inhibition of NE and 5HT when compared to more NE-specific compounds such as nortriptyline and desipramine.^[22] In a systematic review of 3 RCTs comparing duloxetine, a SSNRI, to placebo, duloxetine was found to be effective for the treatment of DPN pain.^[23] The NNT was 5.2 for 60 mg administered once a day and a number needed to harm of 8.8. There appears to be little difference in the overall incidence of minor adverse reaction between antidepressants and anticonvulsants, and the difference in analgesic efficacy between the two classes of agents is minimal. The other major class of antidepressant agents, the selective serotonin reuptake inhibitors (SSRIs), is not effective in relieving pain from DPN. The NNT for 50% pain relief by SSRIs in peripheral neuropathy is 6.8 (3.9-27).^[19] Venlafaxine ER was demonstrated superior to placebo for DPN pain and, when combined with gabapentin, was shown to improve pain, mood, and quality of life; however, cardiovascular adverse events limit the use of venlafaxine in DM.^[24]

Local Anesthetics

Although intravenous lidocaine has been used to treat DPN pain, the duration of analgesia and the need for repeated infusions makes this modality of local anesthetic administration impractical. Mexiletine, an oral analogue of lidocaine, has been used for the treatment of DPN pain with limited success.^[25] One of the limiting factors for the use of mexiletine is the presence of dose-dependent side effects, which limit its overall analgesic efficacy. Lidocaine can also be administered transdermally as a 5% lidocaine patch.^[26] A multicenter RCT did demonstrate that it was as effective as pregabalin in reducing DPN pain over a four-week period and was free of side effects.^[19]

NMDA Receptor Antagonists

Because the N-Methyl-D-aspartate (NMDA) receptor plays a central role in nociceptive processing and chronic pain, it would be reasonable to expect that NMDA receptor antagonists may attenuate neuropathic pain. There are only a few clinically available forms of NMDA receptor antagonists, with dextromethorphan being one of the most commonly available. There are only a few studies examining the analgesic efficacy of NMDA receptor antagonists for DPN pain, and, as such, it is difficult to draw any definitive conclusions regarding the analgesic efficacy of this class of drugs for this indication.^[27] Dextromethorphan may provide pain relief in some subjects (reduction of pain intensity by 24%-33%) and may provide greater analgesia with higher doses.^[28]

Opioids and Tramadol

Although opioids have traditionally been viewed as ineffective for the treatment of neuropathic pain, opioids are now recognized as an important and effective analgesic option for the treatment of neuropathic pain. The few studies examining the analgesic efficacy of opioids in DPN suggest that opioids will provide effective analgesia for patients with DPN with an NNT of 2.6 (for at least 50% pain relief).^[29] Two RCTs have confirmed efficacy of sustained-release oxycodone for DPN pain.^[29-30] Tramadol, a drug that provides analgesia primarily via inhibition of noradrenergic and serotonergic mechanisms, also may provide effective analgesia for diabetic neuropathy. In a six-week RCT, it was shown to be better than placebo for DPN, and a follow-up study demonstrated pain relief could last up to six months.^[31-32] Similarly, tapentadol also has been demonstrated to be superior to placebo for moderate to severe DPN pain in two RCTs.^[33]

Other

Because the pathophysiology of DPN is different from that for other types of neuropathic pain, different treatment options are available for the treatment of DPN that may not be effective for other neuropathic pain states. Because oxidative stress may play an important role in the pathogenic mechanisms of diabetic neuropathy, use of antioxidants such as alpha-lipoic acid may have some beneficial effect for the treatment of DPN. A meta-analysis of alpha-lipoic acid for diabetic neuropathy (4 trials) demonstrated that administration of alpha-lipoic acid may significantly decrease pain, burning, and numbness from diabetic neuropathy.^[34] By interfering with the polyol pathway, which plays a key role in the pathogenesis of the microvascular complications of DPN, aldose reductase inhibitors have been used for the treatment of DPN; however, a meta-analysis of available trials did not indicate any benefit with regard to pain control. The administration of ranirestat, an aldose reductase inhibitor, was not found to produce any reduction in the sensory deficits associated with DPN.^[35] The intradermal administration of botulinum toxin A to affected painful areas has been shown to have resulted in a greater than 2-point (out of 10) reduction in pain scores compared to control groups.^[36] However, this did not result in any changes in the patient’s function or quality of life.

Many non-traditional therapies have been used to treat DPN with case-study or case-series level of evidence; however some treatment modalities have been exposed to rigorous randomized controlled trials. Pulsed electromagnetic fields directed to the areas of pain were found to be of no benefit for patients with DPN pain.^[37]

Capsaicin 0.075% has demonstrated pain reduction and improved quality of life in an eight-week treatment study.^[38]

Topical clonidine 0.1% gel in a double blind, placebo-controlled RCT demonstrated efficacy in reducing foot pain scores by 2.6 points when compared to a 1.4 point reduction by placebo group; however, it was only demonstrated efficacious in patients with residual cutaneous sensation.^[39]

Combined Therapy

The response rates to monotherapy for DPN pain are only around 50%. Combination pharmacotherapy can be used in instances where less than adequate response is obtained by monotherapy or when side effects limit further dose up-titration of a single agent. A study demonstrated that the combination of nortriptyline with gabapentin at maximum tolerated doses was more effective than either monotherapy.^[40] Effective analgesic combinations include antidepressants with AEDs or either class with opioids or tramadol.^[33]

Table 1. Dosing Recommendations for Diabetic Peripheral Neuropathy Pain

Acknowledgment: Thank you to Dr. Nataliya Yakovleva for her efforts on the first version of this web article.

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