Almost half of people diagnosed with diabetes mellitus (DM) develop diabetic neuropathy, a condition significantly impacting the quality of daily life. Such patients are estimated to require surgery at least twice as often as nondiabetic patients and are predestined to undergo several procedures under regional anesthesia.

Among several types of diabetic neuropathy, painful diabetic neuropathy (PDN) is one of the most common complications, affecting approximately 30-40% of the diabetic population. The most common presentation of diabetic peripheral neuropathy (DPN) is a distal symmetrical polyneuropathy with numbness in the distal extremities, like a stocking distribution. Common PDN symptoms manifest tingling, burning, sharp, shooting, and lancinating pain typically in feet, and as the disease progresses, it can include the entire legs and upper extremities. Such PDN symptoms often worsen at night, causing sleep disturbances, and may be accompanied by allodynia. Moreover, loss of sensation in patients with DPN can lead to unattended wounds that, combined with peripheral vascular disease and impaired wound healing, may lead to infection and, ultimately, amputation. The pathophysiologic mechanisms underlying DPN are complicated; DM leads to several pathological changes in neuronal, immune, and vascular cells that can lead to structural and functional alterations of the nervous system (e.g., inflammation, oxidative stress, and mitochondrial dysfunction), which results in DPN.

In an operating room, DM may change how nerves respond to nerve blocks or neuraxial techniques during regional anesthesia. In practice for chronic pain management, PDN significantly lowers the quality of daily life accompanied by insomnia, which needs aggressive pain control using medication and interventional procedures. Therefore, here, we aim to discuss 1) what we should understand for optimal regional anesthesia in DPN and 2) which interventional procedures (invasive and noninvasive pain procedures) are available to manage PDN.

Regional Anesthesia in Diabetic Peripheral Neuropathy: Perspective of Anesthesiologists in an Operating Room

The development of DPN impacts the performance of regional anesthesia. Like other neuropathic pain conditions, such as postherpetic neuralgia, diabetic neuropathic nerves are more difficult to stimulate. The threshold of nerve stimulation has been markedly increased in DPN, and double guidance (usually ultrasonography and nerve stimulation) is safer while advancing needles. Notably, there is high inter-patient variability in stimulation threshold in such patients, and the precise value cannot be predicted accurately from detailed neurological testing (i.e., nerve conduction velocity).

According to the postulated pathophysiologic mechanisms, it is suspected that neuropathic nerves would be more sensitive to local anesthetics; therefore, lower doses of local anesthetics would be necessary for patients with DPN. Although the onset time of nerve blocks is not significantly different between diabetics and nondiabetics, DPN increases block duration. Theoretically, the decrease in nerve blood flow (deficient microcirculation) would lead to a prolonged washout phase, which was supported by Sertoz et al., that the regression time of motor block and sensory block during sciatic nerve block was significantly longer in the group with the higher HbA1C. The reasons for the prolonged block duration have yet to be clarified. However, both pharmacodynamic (more sensitive sodium currents) and pharmacokinetics (prolonged residence time of local anesthetics around the nerve due to decreased nerve blood flow) mechanisms have been suggested.

Regarding complications of nerve blocks in DPN, DM increases the risk of infection, mainly when catheters are used. Besides, a recent study by Lee CS et al. described that complicated DM increased the prevalence of deep spinal infection after epidural injections (in outpatient pain practice) three times more (odds ratio = 3.18; 95% CI = 1.30~6.7). However, despite evidence that diabetic nerves seem more sensitive to local anesthetics, there are no clinical data to suggest regional anesthesia should be withheld from patients in whom a good indication exists.

Painful diabetic peripheral neuropathy: Perspective of pain physicians

The most common DPN is distal symmetric polyneuropathy, with the characteristic of a glove- and stocking-like presentation of distal sensory or motor function loss. Because PDN is associated with increased mortality and morbidity, early recognition and preventive measures are essential. Nevertheless, diagnosing DPN or PDN is challenging, particularly in patients with early and mild neuropathy, and there is no established gold standard. Furthermore, there is no established DPN treatment other than improved glycemic control; only symptomatic management is available for PDN. However, thanks to health-conscious living, almost one-third of patients with PDN derive sufficient pain relief with existing pharmacotherapies. These include antidepressants (tricyclic acid, serotonin-norepinephrine reuptake inhibitor), anticonvulsants (calcium-channel blocker, sodium channel blocker), and others (sarpogrelate). A more detailed and distinct symptom profile from patients with PDN may help identify patients more responsive to one treatment versus another. In addition to pharmacological, physical, cognitive, or educational management for PDN, large randomized clinical trials are still lacking in identifying the most effective minimally invasive interventions. Transcutaneous electrical nerve stimulation, oriental acupuncture, pain scrambler therapy, sympathetic ganglion block, and botulinum toxin injections have been investigated as alternative therapeutic outcomes for PDN. In addition, spinal cord stimulation (SCS) has been suggested as a treatment option for patients with refractory PDN. According to a recent meta-analysis, more patients receiving SCS achieved at least a 50% reduction in pain intensity and improved health-related quality of life (using EQ-5D utility score) compared with the best medical therapy. Such findings demonstrate that SCS is an effective therapeutic adjunct to the best medical therapy in reducing pain intensity and improving health-related quality of life in patients with PDN.

References

1. Ten Hoope W, Looije M, Lirk P. Regional anesthesia in diabetic peripheral neuropathy. Curr Opin Anaesthesiol. 2017.

2. Calcutt NA. Diabetic neuropathy and neuropathic pain: a (con)fusion of pathogenic mechanisms? Pain 2020 Sep;161(Suppl 1):S65-S86.

3. Sertoz N, Deniz MN, Ayanoglu HO. Relationship between glycosylated hemoglobin level and sciatic nerve block performance in diabetic patients. Foot Ankle Int 2013;45:85-90.

4. Lee CS, Park YJ, Moon JY, Kim YC. Deep spinal infection after outpatient epidural injections for pain: A retrospective sample cohort study using a claims database in South Korea. Anesthesiology 2021;134:925-36.

5. Duarte RV, Nevitt S, Maden M, Meier K, Taylor RS, Eldabe S, de Vos CC. Spinal cord stimulation for the management of painful diabetic neuropathy: a systematic review and meta-analysis of individual patient and aggregate data. Pain 2021 Nov 1;162(11):2635-2643.