Could Neuropathic Pain Be a Consequence of Treatment for Diabetes?

Podiatric physicians are often one of the first health professionals consulted by patients for neuropathic lower extremity pain. It is essential as a health professional to recognize various causes of lower extremity neuropathic pain. Descriptions of treatment-induced diabetic neuropathy (TIDN), previously known as insulin neuritis, first appeared from Caravati in 1933.¹ Caravati described a case in which a patient with diabetes reported numbness, tingling, and shooting pains in the lower extremities that appeared four weeks after initiating insulin therapy. The pain increased despite analgesics but the pain resolved within three days of stopping insulin, which resulted in severe hyperglycemia. Continued attempts at insulin use with this patient resulted in similar pain levels. He called the condition insulin neuritis, and it was considered rare.¹

TIDN often occurs when patients with diabetes mellitus and uncontrolled blood sugar levels start insulin andor antidiabetic treatment that lead to abrupt normalization of blood sugar levels. TIDN is thought to stem from apoptosis of axons induced by sudden glucose deprivation.²

Clinically, the diagnostic criteria for treatment-induced diabetic neuropathy are acute onset of neuropathic pain and autonomic failure symptoms occurring within 8 weeks of documented drop-in HbA1c by more than 2 percent over three months.¹ Examples of autonomic failure symptoms include heart palpitations, lightheadedness, orthostatic hypotension, fatigue, abnormal sweating, vomiting, and supine hypertension.

A 2015 retrospective study published by Gibbons and Freeman in the medical journal Brain described a group of 954 patients with lower extremity neuropathy and autonomic failure symptoms. The authors concluded that TIDN might occur after rapid glycemic control with insulin and patients receiving oral antidiabetics. They also reported that greater than 10 percent of the patients in the study who had a decrease in glycosylated hemoglobin A1c (HbA1c) greater than 2 percent decrease in 3 month period (104954) developed TIND.³

The study performed by Gibbons and Freeman provided evidence that treatment-induced diabetic neuropathy might be more common than we once thought and often underreported or not diagnosed. The authors concluded that a gradual reduction in the HbA1c rate of less than two percentage points over three months decreased the risks of treatment-induced neuropathic pain.³

Moreover, patients diagnosed with TIDN have an increased risk for retinopathy and nephropathy.²

Treatment for TIDN is an antiepileptic or antidepressant medication. Usually, TIDN is reversible, but damage can extend beyond the nerves. In some severe cases of TIDN, hospitalization for pain management might be indicated. Although it is difficult to predict who will develop TIDN, it is essential to consider treatment-induced neuropathic pain as a possible differential diagnosis when treating patients with diabetic neuropathy after a rapid blood glucose reduction.

Dr. Robinson is the Chair of and an Assistant Professor in the Department of Medicine at the Temple University School of Podiatric Medicine. She is a Diplomate of the American Board of Podiatric Medicine.

References

1.Gibbons CH, Freeman R. Treatment-induced diabetic neuropathy: a reversible painful autonomic neuropathy. Ann Neurol. 2010;67(4):534-541. doi:10.1002ana.21952

2. Siddique N, Durcan R, Smyth S, Tun TK, Sreenan S, McDermott JH. Acute diabetic neuropathy following improved glycaemic control: a case series and review. Endocrinol Diabetes Metab Case Rep. 2020;20201:19-0140.

3. Gibbons CH, Freeman R. Treatment-induced neuropathy of diabetes: an acute, iatrogenic complication of diabetes. Brain. 2015;138(Pt 1):43–52