Diabetes mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia due to impaired insulin secretion, insulin action, or both. The global burden of diabetes is substantial, with approximately 422 million people affected worldwide, and diabetes-related complications causing an estimated 1.5 million deaths annually, as reported by the World Health Organization (WHO).1 The global prevalence of diabetes is projected to rise to 578 million by 2030, highlighting the growing public health challenge posed by this condition.2 DM is primarily classified into two major types: type 1 diabetes mellitus (T1DM), characterized by autoimmune-mediated destruction of pancreatic β-cells, and type 2 diabetes mellitus (T2DM), associated with insulin resistance and relative insulin deficiency. Despite differences in pathophysiology, chronic hyperglycemia remains a central feature in both types, contributing to long-term complications. Current therapeutic strategies for managing DM include lifestyle modifications (e.g., dietary changes, exercise), pharmacological interventions to improve glycemic control, and insulin therapy in patients with T1DM or advanced T2DM.3

Diabetes-related complications are broadly categorized into microvascular and macrovascular complications. Microvascular complications include diabetic retinopathy, nephropathy, and neuropathy, which result from damage to small blood vessels. Macrovascular complications, on the other hand, involve atherosclerotic damage to large arteries, increasing the risk of cardiovascular disease, stroke, and peripheral vascular disease.4 Among these complications, diabetic neuropathy (DN) is a significant cause of morbidity, affecting approximately 30 % of diabetic patients, with up to 50 % developing neuropathy over the course of their disease.5 DN primarily manifests as distal symmetric polyneuropathy (DSP), which is characterized by symmetric sensory and motor deficits, often presenting as numbness, tingling, burning pain, and weakness in the distal extremities in a stocking-and-glove pattern.6

The pathogenesis of DSP involves complex metabolic and vascular mechanisms, including oxidative stress, advanced glycation end product (AGE) accumulation, activation of the polyol pathway, mitochondrial dysfunction, and inflammatory responses. Hyperglycemia-induced oxidative stress increases the production of mitochondrial reactive oxygen species (ROS), which in turn disrupts endothelial function and impairs neuronal activity. Other contributing factors include impaired calcium homeostasis, low-grade inflammation, and altered lipid metabolism, which collectively exacerbate neuronal damage and dysfunction.7 The diagnosis of diabetic neuropathy is primarily clinical, based on the presence of symptoms and signs of peripheral nerve dysfunction, along with the exclusion of other potential causes of neuropathy. The American Diabetes Association (ADA) recommends comprehensive neurological examinations, including sensory and autonomic function tests, to confirm the diagnosis.8,9 The Michigan Neuropathy Screening Instrument (MNSI) and the Douleur Neuropathique 4 (DN-4) questionnaire are widely used for screening and diagnosing diabetic neuropathy with high sensitivity and specificity.10,11

Current pharmacological treatments for diabetic neuropathy primarily focus on pain management rather than disease modification.12 First-line pharmacological agents include gabapentinoids (e.g., pregabalin, gabapentin), serotonin-norepinephrine reuptake inhibitors (SNRIs) (e.g., duloxetine), and tricyclic antidepressants (e.g., amitriptyline).13, 14, 15, 16, 17 These agents provide symptomatic relief but are often associated with significant systemic side effects, which may limit patient compliance and long-term use.18

In recent years, interest in medicinal plants with analgesic, anti-inflammatory, and antioxidant properties has increased as potential adjunct therapies for managing diabetic neuropathy.18, 19, 20 Chamomile (Matricaria chamomilla), one of the most widely used medicinal plants, has demonstrated pharmacological properties that may be beneficial in treating neuropathic pain.21, 22, 23 Chamomile contains bioactive compounds, including flavonoids (e.g., apigenin, luteolin, quercetin), terpenoids (e.g., chamazulene, α-bisabolol), and coumarins,24, 25, 26 which exhibit antioxidant, anti-inflammatory, and analgesic effects.27, 28, 29, 30, 31, 32, 33, 34, 35 Apigenin and chamazulene inhibit prostaglandin E2 synthesis and suppress leukotriene B4 activity, thereby reducing inflammation and pain sensitivity. α-Bisabolol and borneol, major components of chamomile oil, have demonstrated analgesic effects in preclinical models of neuropathic and inflammatory pain.36, 37, 38 These bioactive molecules act through several interconnected mechanisms, including downregulation of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6), inhibition of reactive oxygen species (ROS) production, and modulation of nociceptive signaling pathways via suppression of prostaglandins and leukotrienes. Collectively, these pathways contribute to neuroprotection, decreased oxidative stress, and reduction of peripheral sensitization, which may ultimately result in alleviation of neuropathic pain.39, 40, 41, 42 A visual summary of these molecular mechanisms is presented in Fig. 1, illustrating the potential therapeutic actions of chamomile oil in diabetic neuropathy.

Several clinical studies have explored the potential benefits of chamomile in neuropathic pain management. A study conducted in Turkey in 2017 demonstrated that aromatherapy massage with chamomile, lavender, rosemary, and rose geranium oils significantly reduced neuropathic pain in diabetic patients after four weeks of treatment.43 Similarly, a randomized clinical trial conducted by Heydari et al. (2016) showed that topical application of Citrullus colocynthis (bitter apple) extract, which shares some pharmacological properties with chamomile, resulted in a significant reduction in pain scores and improvement in nerve function among diabetic neuropathy patients.44 In a 2015 study conducted in Fasa, topical application of chamomile oil for four weeks resulted in significant improvements in pain relief and functional performance among patients with carpal tunnel syndrome, further supporting the analgesic potential of chamomile in peripheral nerve disorders.37

Given the established anti-inflammatory, analgesic, and antioxidant properties of chamomile, its potential in treating diabetic neuropathy warrants further investigation. The widespread availability and favorable safety profile of chamomile make it a promising candidate for adjunctive therapy in diabetic neuropathy management. This study aims to evaluate the efficacy of topical chamomile oil in reducing neuropathic pain and improving nerve function among patients with diabetic neuropathy, using validated clinical tools such as the Neurothesiometer index, Michigan questionnaire, and DN-4 questionnaire. The findings from this study could provide valuable insights into the role of chamomile as a complementary therapy in diabetic neuropathy and inform future clinical practice guidelines.