Neuropathic Pain Frequently Precedes Signs of Diabetic Peripheral Neuropathy

Neuropathic pain (NP) affects many individuals with type 1 diabetes (T1D) even in the absence of clinical signs of diabetic peripheral neuropathy (DPN), according to a report published in Diabetes Care.¹ Often the first symptom of DPN, NP may affect up to 25% to 30% of patients with T1D; is characterized as burning, shooting, electric-like, or lancinating; is usually worse at night; and may be accompanied by exaggerated responses to painful stimuli or pain associated with nonpainful stimuli.

“The features and burden of neuropathic pain in type 1 diabetes are poorly understood,” the authors wrote. They also noted the prevalence of DPN is increasing despite improvements in diabetes clinical care.

This study aimed to evaluate the incidence, prevalence, and risk factors for NP in patients with and without clinical signs of DPN. The investigators used data from the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study, conducted over 26 years.

Diabetic Neuropathy Questionnaire

Image credit: Richelle-stock.adobe.com

Between 1983 and 1989, DCCT randomized patients with T1D into intensive or conventional diabetes therapy groups, evaluating the effects of glycemia on diabetes-related complications. Intensive therapy was shown to markedly reduce complications, including DPN. In 1994, 96% of the surviving DCCT cohort enrolled in the EDIC observational study.

The new study included 1324 participants with data available at EDIC year 1 (1994) and collected annually through year 26 of the study. To meet eligibility conditions, the investigators required Michigan Neuropathy Screening Instrument (MNSI) results. A validated instrument with high sensitivity and specificity for DPN, MNSI includes a symptom questionnaire, structured foot examination, and assessment of ankle reflexes and vibratory sensation.²

Participants were divided into 2 groups: those with clinical evidence of DPN who self-reported NP and had a NMSI examination score above 2 (NP DPN+) and those without clinical signs of DPN who self-reported NP and had a MNSI examination score of 2 or lower (NP DPN–). Participants’ median (IQR) age was 36 (30-41) years, the median duration of diabetes was 13 (10-18) years, and median glycated hemoglobin (HbA_1C) was 7.9% (7.2%-8.9%). Female patients accounted for 48% of participants, and 19% of all participants were smokers.

Over the 26-year follow-up, the cumulative incidence of NP was 57%, regardless of concomitant clinical signs of DPN (36% NP DPN+ vs 46% DPN–), suggesting that NP often precedes clinical signs of DPN. Additionally, the prevalence of NP increased from 9% to 20%, representing an increase from 4% to 11% in the NP DPN+ cohort and from 5% to 9% among patients in the NP DPN– cohort.

Compared with the higher cumulative incidence of first occurrence of NP, the lower prevalence suggests NP maybe episodic, frequently remitting. The investigators noted that 39%, 16%, and 42% of participants reported intermittent, isolated (once during follow-up), and no experience of NP, respectively. Conversely, 3% reported persistent NP each year after the initial report.

The study investigators said the most significant risk factors in the NP DPN+ group, in order of significance, were higher HbA_1C, older age, higher mean pulse rate, and any moderately increased albuminuria. In the NP DPN– cohort, the most significant risk factors were mean HbA_1C, followed by female gender.

Information on medication commonly used to treat NP was available starting in year 13 of the EDIC study. By year 26, 32% (42% NP DPN+ and 20% NP DPN-) of patients with NP reported using prescribed medications.

The analysis revealed that cumulative incidence of the first occurrence of NP was very high (> 50%), even in the absence of clinical signs of DPN. NP remission occurred in many people with T1D, irrespective of the use of medications, and was associated with numerous modifiable and nonmodifiable risk factors. Additionally, findings demonstrated that intensive vs conventional therapy, applied early, prevents the later development of NP in T1D. According to the authors, this finding has not been available in any other cohort.

The study included a sizeable, well-characterized group of individuals with T1D followed for nearly 40 years with a standardized and comprehensive broad collection of risk factors. However, the predominantly non-Hispanic White population limits its generalizability to other populations. Still, the authors believe the findings are clinically meaningful. NP is commonly underestimated, particularly when not accompanied by clinical signs of DPN, they saidmost previously reported data on NP do not reflect contemporary standards in diabetic care.

“Our study shows that neuropathic pain incidence in patients with T1D is high and frequently occurred in the absence of clinical signs of neuropathy”, the authors concluded. “Clinicians should be aware to effectively detect and treat neuropathic pain.”

References

1. Braffett BH, El ghormli L, Albers JW, et al. Neuropathic pain with and without diabetic peripheral neuropathy in type 1 diabetes. Diabetes Care. Published online February 1, 2024. doi:10.2337/dc23-1749
2. Michigan Neuropathy Screening Instrument. Michigan Medicine/University of Michagan. Accessed March 6, 2024. https://medicine.umich.edu/sites/default/files/downloads/MNSI_patient.pdf