Diabetic neuropathy – a growing pain for Australians

Diabetic peripheral neuropathy (DPN) is a frequent complication affecting up to 50% of diabetics. A significant proportion of these patients have disabling pain, which can impede their daily occupational and social activities, and lead to excess consumption of health care services.1,2 Given the alarming rise in prevalence rates for diabetes, painful peripheral neuropathic syndromes can cause significant burdens on the Australian community. This article provides an overview of the scope of diabetes and the risk factors, symptoms, burden and treatment options for painful diabetic neuropathy. Recent clinical trials have identified four classes of medications that are effective in treating pain associated with diabetic neuropathy.3

Background

Diabetes mellitus is a common medical condition in the Australian community. It is estimated that approximately one in four Australians over the age of 25 years has diabetes or its precursor, impaired glucose metabolism (associated with increased risk of heart disease).⁴ In 2000, this equated to approximately 940,000 Australian adults with diabetes. A prevalence study has found that for every known case of diabetes, there was one undiagnosed case, highlighting the current substantial burden of this disease on the Australian population.⁴ Unfortunately, these prevalence figures are increasing at alarming rates across all age groups³ and it is predicted that prevalence rates among people over the age of 15 years will increase to 10.5% by the year 2016.^4,5 An aging population and increased rates of obesity are likely contributing factors.⁵

Among the various macro- and micro-vascular complications of diabetes, neuropathy is a common cause of morbidity and death.⁶ Epidemiological studies have reported a prevalence rate of up to 24% for painful diabetic neuropathy within the diabetic population.⁷ It is more frequent in type 2 diabetes and occurs more commonly with increased duration and severity of disease (particularly poor glycaemic control).^3,7 The pain associated with diabetic neuropathy may be significantly disabling to impede on daily activities as discussed below. Extrapolation of national figures on the prevalence of diabetes across approximately 10,000 GP medical practices in Australia, suggests that each practice will treat an average of 25-30 patients with painful diabetic neuropathy.

Clinical Features

Diabetic neuropathy is a broad term encompassing symmetrical, autonomic and focal neuropathies.⁸ Symmetrical neuropathies refer to sensory and motor deficits such as the classical glove and stocking anaesthesia. Focal neuropathies include conditions such as nerve entrapment syndromes that may be associated with symptoms of pain, muscular weakness or paralysis. Autonomic neuropathy is caused by impairments in the autonomic nervous system, which may cause postural hypotension, gastroparesis, nocturnal diarrhoea, loss of bladder control and erectile dysfunction. Furthermore, a diagnosis of symptomatic autonomic neuropathy also greatly increases a patient’s overall mortality rate.⁸

Distal sensory polyneuropathy (DSPN) is the most common form of neuropathy and the most common cause of pain.³ Patients may exhibit a variety of positive and negative sensory signs and symptoms depending on the modality affected. Typically small nerve fibres are affected first, causing nocturnal symptoms of tingling, burning, prickling, shooting-pain, deep aching, pins and needles, tightness, or cold sensations in the feet.³ As the condition progresses larger fibres are disrupted leading to sensory loss, numbness, tingling, loss of coordination and late motor signs.³ However during consultation, all functional systems should be examined in detail. A new sensitive and specific neuropathic pain diagnostic questionnaire (DN4) may facilitate general practitioners in the diagnosis of these disorders.⁹

Diagnosis of DSPN requires the presence of neuropathy consistent with diabetes mellitus and exclusion of other common causes of neuropathy. Efforts must be made to exclude other potential causes of neuropathy such as metabolic derangements (uremia, hypothyroidism), exposure to toxins (smoking, alcohol and some medication adverse events), infections, inflammatory disease (sarcoidosis), and connective tissue/autoimmune diseases (lupus).³

Burden

Painful diabetic neuropathy creates significant impacts on a patient’s life.^2,7 Often symptoms are worse at night contributing to sleep deprivation and depressive syndromes. Pain has also been shown to interfere with quality of life, general activity, mobility, employment and social activities.^2,7 Research has demonstrated that neuropathy sufferers utilise significant levels of health resources.² In addition, patients experience significant activity and work limitations and thus poor productivity levels.² From the medical perspective, diabetic neuropathy can contribute to the ‘diabetic foot’, which is prone to infection, ulceration and even amputation. Appropriate foot care is necessary to prevent such deformities.³

Risk Factors

The incidence of painful diabetic neuropathy is directly related to glycaemic control and other non-controllable risk factors such as age, genetic risk and duration of diabetes. However, there a variety of potentially modifiable risk factors including raised triglyceride level, body-mass index, smoking, poor diet and hypertension.⁶ In addition, damage to blood vessels and nerve injury are recognised predisposing factors.⁸ Knowledge of these factors can help you identify patients at risk and guide preventative strategies.

Treatment

Management of painful diabetic neuropathy requires a multi-disciplinary approach.³ General methods include patient education regarding risk factors, optimising glycaemic control, encouraging smoking cessation and aggressive treatment of co-morbid hypertension and dyslipidaemia.³ Numerous clinical trials have identified effective pharmacological agents for painful diabetic neuropathy. These include antidepressants, anticonvulsants, opioid analgesics (such as tramadol and oxycodone) and topical local anaesthetics.^3,10,11 Unfortunately the antidepressants (including tricyclics and venlafaxine) and opioids may be associated with significant side effects that limit their use.¹¹ The gabapentinoids such as gabapentin (Neurontin^(R)) and pregabalin (LYRICA^(R)) have proven evidence-based efficacy for the treatment of painful diabetic neuropathy, have a higher number-needed-to-harm and lack serious adverse effects.¹²

The gabapentinoids are now considered first line agents in the treatment of painful diabetic neuropathy.^12,13 The theory behind their efficacy is centred on the reduction of neuronal hyperexcitability.¹⁴

However, pregabalin offers advantages over gabapentin in linear pharmacokinetics, linear dose response, faster onset of pain relief and reduction in sleep disturbance (within the first week of therapy), and providing an effective starting dose, 75mg twice daily.¹⁵

Treatment of diabetic neuropathic pain is a rapidly developing field. Medical professionals are encouraged to consider emerging therapies for diabetes and associated neuropathies in management strategies.

References: 

1. Argoff CE, et al. Diabetic peripheral neuropathic pain: clinical and quality-of-life issues. Mayo Clin Proc. 2006 Apr; 81(4 Suppl): S3-11.
2. Gore M, et al. Burden of illness in painful diabetic peripheral neuropathy: the patients’ perspectives. J Pain. 2006 Dec; 7(12): 892-900.
3. Fink E, Oaklander AL. Diabetic neuropathy, Pain Management Rounds 2005; 2(3): 1-6. Available [online] at URL: http://www.massgeneral.org/neurology/biopsy/Snell_Diabetes_review.pdf
4. Zimmet P. Diabesity in Australia: An affair of the heart. Heart Lung Circ. 2003; 12(Suppl 2): S95-8.
5. Chittleborough CR, et al. The increasing prevalence of diabetes in South Australia: The relationship with population ageing and obesity. Public Health. 2007; 121(2): 92-9.
6. Tesfaye S, et al. Vascular Risk Factors and Diabetic Neuropathy. N Engl J Med 2005; 352(4): 341- 350. Schmader KE. Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy. Clin J Pain 2002; 18(6): 350-4.
7. Quattrini C, Tesfaye S. Understanding the impact of painful diabetic neuropathy. Diabetes Metab Res Rev 2003; 19: S2-S8. 
8. Bouhassira D, et al. Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain. 2005; 114(1-2): 29-36. 
9. Varkonyi T, Kempler P. Diabetic neuropathy: new strategies for treatment Diabetes Obes Metab. 2007; 1463-1326.
10. Chong MS, Hester J. Diabetic painful neuropathy: current and future treatment options Drugs 2007; 67(4): 569-85.
11. SPHERE. Positive management of persistent pain – neuropathic pain treatment algorithm and diagnostic questionnaire. Available [online] at URL: http:/www.spheregp.com.au/index.htm
12. Finnerup NB, et al. Algorithm for neuropathic pain treatment: An evidence based proposal. Pain. 2005; 118: 289-305.
13. Helme R. Drug treatment of neuropathic pain. Australian Prescriber 2006; 29(3): 72-5. Available [online] at URL http://www.australianprescriber.com/upload/pdf/articles/803.pdf
14. LYRICA^(R) Product Information.

Click here to view the DN4 patient questionnaire.