Healthy ageing: Early management of chronic inflammation & peripheral neuropathy in primary care

Ageing is characterized by systemic chronic inflammation, which is accompanied by age-related conditions (eg, type 2 diabetes mellitus [T2DM] and osteoarthritis [OA]) and complications (eg, peripheral neuropathy [PN]). This article summarizes insights from an industry-sponsored symposium on healthy ageing coordinated by the Hong Kong College of Family Physicians, which focused on the role of primary care physicians in management of chronic inflammatory conditions, and in early diagnosis and treatment of PN.

By 2050, the proportion of the world's population >60 years of age is projected to nearly double to 22 percent from 12 percent in 2015. If increased lifespan is dominated by decline in physical and mental capacities, there would be negative implications for older individuals and society. Responsive primary healthcare service and accessible high-quality long-term care can improve older individuals’ quality of life (QoL). [https://www.who.int/news-room/factsheets/detail/ageing-and-health]

Consequences of chronic inflammation
Ageing and sedentary lifestyles are associated with development of low-grade systemic chronic inflammation, which contributes to the development of chronic diseases such as T2DM, OA, sarcopenia, cardiovascular disease (CVD) and Alzheimer’s disease. “These chronic inflammatory diseases account for three out of five deaths worldwide,” said Dr Fei Chan, Specialist in Geriatric Medicine in Hong Kong. [Ageing Res Rev 2020;57:101000; Nat Med 2019;25:1822-1832; https://www.ncbi.nlm.nih.gov/books/NBK493173]

For example, low-grade inflammation contributes to OA development by increasing levels of proinflammatory cytokines in joints. Subsequently, inflammatory cytokines are released from affected joints into the circulation, leading to amplification of systemic low-grade inflammation, which damages tissues and organs over time. (Figure) [Osteoarthritis Cartilage 2013;21:16-21]

Management of chronic inflammation
“While standardized testing for chronic inflammation is currently unavailable, symptoms and comorbidities such as joint pain, diabetes and CVD often indicate chronic inflammation,” said Chan. “Blood testing of erythrocyte sedimentation rate [ESR] and high-sensitivity C-reactive protein level can be biomarkers for assessing the level of chronic inflammation. [https://www.ncbi.nlm.nih.gov/books/NBK493173]

Although corticosteroids or NSAIDs are commonly used to treat inflammatory pain, guidelines recommend using them at the lowest effective doses for short periods in patients with early arthritis due to their potential side effects. [Ann Rheum Dis 2017;76:948-959]

“In my clinical practice, after approximately 1 week of treatment with NSAIDs, patients may take omega-3 fatty acid [FA]–based supplements to further reduce inflammation for better pain control,” suggested Chan.

Omega-3 FAs are polyunsaturated FAs serving as precursors to specialized proresolving mediators, such as resolvins and protectins, which are involved in resolution of inflammation. In preclinical studies in chondrocytes, omega-3 FAs reduced expression of inflammatory and oxidative stress markers, as well as proteinases involved in cartilage degradation. [Pharmacol Ther 2014;141:272-282; Joint Bone Spine 2019;86:451-458]

A randomized controlled trial (RCT) showed that combined supplementation with omega-3 FAs and glucosamine provided incremental clinical benefits in moderate-to-severe OA compared with glucosamine alone. In this study (n=164; mean age, 62.3 years), significantly more patients receiving omega-3 FAs 200 mg plus glucosamine sulfate 500 mg achieved ≥80 percent reduction in Western Ontario and McMaster Universities Arthritis Index pain score at 26 weeks (55 percent vs 39 percent; p=0.044) vs patients receiving glucosamine sulfate 500 mg alone. [Adv Ther 2009;26:858-871]

Omega-3 FA–based supplementation is also associated with a reduction in NSAID use. In an RCT in 81 OA patients aged 40–80 years with regular use of NSAIDs, defined daily dose of NSAIDs decreased significantly after 3 months of omega-3 FA–based supplementation vs placebo (p=0.02). The mean dose reduction in the omega-3 FA group was equivalent to diclofenac 67 mg/day or celecoxib 134 mg/day. [Arthritis Res Ther 2009;11:R192]

“[Based on these findings,] omega-3 FA–based supplementation is a reasonable option for OA patients,” Chan suggested. “It should be noted that patients on anticoagulants such as warfarin may have a slightly increased tendency for bleeding with high-dose omega-3 FAs.”[Am J Cardiol 2006;98:39i-49i]

PN in T2DM and prediabetes
T2DM and its complications substantially contribute to the global burden of mortality and disability. For example, PN is a common complication of T2DM and prediabetes, with a prevalence of 28–49 percent in patients with T2DM and 13–50 percent in individuals with impaired glucose tolerance. [Nat Rev Endocrinol 2018;14:88-98; Diabetes Care 2008;31:464-469; Diabetes Care 2015;38:793-800]

As PN progresses, patients may experience impaired balance and dizziness, resulting in an increased risk of falls. PN is also a risk factor for diabetic foot ulceration. With diabetic foot syndrome, patients may require complex treatment or even amputation.  [Am Fam Physician 2010;82:361-368; Diabetes Care 2004;27:1458-1486]

Early diagnosis of PN: Why and how?
“If not diagnosed and treated in early stages, PN usually progresses into neuropathic pain, which can lead to comorbidities [eg, depression, sleep disorders] that significantly impact patients’ QoL,” said Dr Chi-Nam Lee, Specialist in Neurology in Hong Kong.

“PN diagnosis usually begins with determining the time of symptom onset and progression,” he advised.

Chronic PN symptoms (>12 weeks) can be considered diabetes-related or hereditary. Subacute PN symptoms (4–12 weeks) are associated with a wide range of conditions, including diabetes, vitamin B deficiency, inflammation, alcohol use, and use of certain medications (eg, chemotherapy). Acute-onset PN (<4 weeks) could be due to immunological or infective cause or exposure to toxin. (Table) [JAAPA 2020;33:9-15; J Diabetes Investig 2020;11:1097-1103]

Patients’ medical history may reveal potential PN causes, such as metabolic syndromes and autoimmune diseases. PN signs and symptoms, including numbness, tingling, allodynia, weakness and atrophy, should also be assessed. (Table) 

“Distal sensorimotor polyneuropathy [DSPN] is the most common PN subtype typically caused by diabetes. DSPN patients often experience a stocking-glove pattern of sensory symptoms [eg, numbness, neuropathic pain, allodynia] that evolve in a length-dependent manner,” said Lee. [Diabetes Care 2004;27:1458-1486]

“Neurologic examination is part of PN diagnostic work-up and includes assessments of sensory, reflex and somatosensory function. Sensory examination is useful for detection of affected nerve fibres. Pinprick sensation test can determine small fibre neuropathy, while vibration sense perception test can identify large fibre neuropathy,” Lee said. “Electrodiagnostic studies may help establish PN pathophysiology and differentiate neuromuscular disorders, but these studies are not useful for identifying causes of PN.” (Table)

“While PN diagnosis mainly depends on clinical presentation and neurologic examination, we may consider ESR and HbA_1c blood tests, with or without an oral glucose tolerance test. If necessary, we may perform other tests, such as serum and urine electrophoresis and HIV test,” Lee suggested. (Table) [JAAPA 2020;33:9-15; J Diabetes Investig 2020;11:1097-1103]

Management of DSPN
Optimal diabetes treatment with intensive glycaemic control is a cornerstone of DSPN management. [Diabetes Res Clin Pract 2022;186:109063] However, approximately 19–22 percent of metformin-treated patients develop borderline (200–300 pg/mL) or low (<200 pg/mL) levels of vitamin B₁₂. [Medicine (Baltimore) 2019;98:e17918; J Clin Endocrinol Metab 2016;101:1754-1761]

“In patients treated with metformin, vitamin B₁₂ levels should be regularly measured,” pointed out Lee. [Diabetes Care 2023;46(Suppl 1):S41-S48; Endocr Pract 2020;26:107-139] “In case of vitamin B₁₂ deficiency, dietary supplementation of B vitamins can be considered.” [Diabetes Res Clin Pract 2022;186:109063]

B vitamins (ie, vitamins B₁, B₆ and B₁₂) help maintain neuronal viability and support nerve regeneration. [Biomed Res Int 2021;2021:9968228] Supplementation with B vitamins has been shown to improve PN symptoms and QoL. In a prospective, single-arm, observational study in 411 patients (mean age, 50.9 years; diabetes, 25.3 percent) with mild-to-moderate PN, fixed-dose, once-daily supplementation of B vitamins (vitamin B₁, 100 mg; vitamin B₆, 100 mg; B₁₂, 5,000 mcg) demonstrated a significant reduction in overall Total Symptom Score (TSS; ie, stabbing pain, burning pain, paraesthesia, and numbness) (mean TSS change, 1.090; p<0.0001) at 2 weeks vs baseline, with further reduction shown at 12 weeks (mean TSS change, 3.431). After 12 weeks of B vitamins supplementation, patients reported significant reductions in numbness, burning, tingling and pain (p<0.0001 for each), with an improvement in QoL. [Asian J Med Sci 2018;9:32-40]

Overall, supplementation with B vitamins was well tolerated. During the study period, three of the 411 patients (0.7 percent) experienced ≥1 treatment-related adverse event (dyspepsia, nausea, diabetic foot; n=1 each).

“DSPN management also includes pathogenetic pharmacotherapy and neuropathic pain therapy. Although therapeutic agents are generally effective, potential side effects should be carefully considered,” Lee added. [Diabetes Res Clin Pract 2022;186:109063]

Summary
Chronic inflammation is associated with chronic diseases, including T2DM and OA. Nutraceuticals, such as omega-3 FA–based supplementation, help alleviate OA-related pain and reduce NSAID use.

Early PN diagnosis is essential to identify and treat underlying causes (eg, T2DM and vitamin B deficiency). Supplementation of B vitamins can improve PN-associated symptoms and patients’ QoL.