Diabetes mellitus

Diabetes mellitus is a syndrome characterised by chronic hyperglycaemia resulting from relative insulin insufficiency or resistance or both. According to recent data compiled by the WHO, diabetes affects more than 150 million people worldwide. Five to ten per cent have type 1 (formerly known as insulin‐dependent) and 90% to 95% have type 2 (non‐insulin‐dependent) diabetes mellitus. It is likely that the incidence of type 2 diabetes will rise as a consequence of lifestyle patterns conducive to obesity (Creager 2003). Both forms cause increased morbidity and mortality due to macrovascular disease and microvascular damage. Diabetic neuropathy is one of the main complications of the microvascular insult (Gale 2002).

Diabetic neuropathy

Historically, it was only after Marchal de Calvi's observations of 1864 that neuropathy was accepted as a consequence rather than a cause of diabetes. Diabetes can affect the peripheral (both proximal and distal), cranial and autonomic nerves. Distal peripheral neuropathy, the commonest presentation, produces a symmetrical pattern of pain, loss of sensation and weakness in the limbs, starting distally and progressing proximally. Proximal neuropathies cause pain in the thighs, hips or buttocks and lead to weakness in the lower limbs. Cranial neuropathy, which is less common, affects mainly the oculomotor nerve, although other cranial nerves are also at risk. Autonomic neuropathy involves damage to the nerves fibres carrying the parasympathetic and sympathetic nerve fibres involved in digestion, bowel, bladder control, sexual function and blood pressure regulation.

The international consensus meeting for the outpatient management of neuropathy agreed upon defining diabetic peripheral neuropathy (DPN) as 'the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes' (Soliman 2002). Diabetic peripheral neuropathy is associated with increased mortality relative to its severity (Forsblom 1998), with complications such as foot ulcers, and with impaired quality of life (Benbow 1998). Diabetic peripheral neuropathy is a major health problem from which approximately 50% of diabetic patients worldwide suffer (Sugimoto 2000). A prospective study in Europe of 4,400 patients found the prevalence of DPN to be 7.5% in diabetics at diagnosis; after 25 years, this number rose to 45% (Pirart 1995). Specifically in the UK, a study of 6,487 diabetic patients by the WHO suggests the prevalence of DPN to be around 29% (Wild 2001). These figures highlight the great need to find an effective treatment for this condition.

Management of diabetic neuropathy

The DCCT research group study (DCCT 1993) showed that rigorous control of blood glucose levels reduces the risk of developing neuropathy in diabetic subjects. However, this study did not study the effects of near‐normoglycaemia on existing symptomatic DPN, and thus this question remains open (Ziegler 1999). It seems unlikely that patients with established peripheral nerve loss could achieve improvement through glycaemic control, and it has yet to be proven that meticulous control of blood glucose can arrest the progression of symptomatic neuropathy (Pfeifer 1995). In addition, achievement of near‐normal blood glucose concentration is neither easy nor without risk. In the largest study of its kind, the severity and frequency of hypoglycemic episodes were approximately three times higher in patients receiving intensive glycaemic control therapy than in patients on conventional regimens (DCCT 1993). A lifetime of recurrent hypoglycaemia may result in progressive cognitive and intellectual deterioration due to the cumulative effects of small, subclinical insults to the brain.

Various experimental agents have been suggested to slow the progression of DPN. Of these, aldose reductase inhibitors have been most extensively studied. However, a meta‐analysis of randomised, controlled trials of aldose reductase inhibitors indicates that any benefit of treatment has not been conclusively demonstrated (Nicolucci 1996). In short, it has yet to be proven if any form of intervention can favourably influence the progression of symptomatic neuropathy (Pfeifer 1995).

As there are currently no therapies that can reverse the neuropathological processes of DPN, management relies mainly on the pharmacological treatment of overt symptoms, the most common of which is pain. Treatment for pain may start with a tricyclic antidepressant or, if the side‐effects of these drugs are a consideration, as in the elderly, other agents may be tried (Marchettini 2004). Meta‐analyses of randomised controlled trials of tricyclic antidepressants (Collins 2000), anticonvulsants (Collins 2000), capsaicin (Mason 2004) and tramadol (Duhmke 2004) have shown that these treatments are significantly superior to placebo in alleviating the pain of DPN. However, these established treatments often fail to provide adequate pain relief, which has lead to a search for alternative analgesics.

Pathophysiology of diabetic neuropathy

Four main hypotheses have been put forward to explain how hyperglycaemia leads to neuropathy (Brownlee 2001; Feldman 2003; Fernyhough 2003). The first of these suggests that DPN is a result of changes in gene expression and protein function that are induced by excess intracellular glucose being shunted into the hexosamine pathway. The second hypothesis states that hyperglycaemia increases levels of the second messenger diacylglycerol, which activates protein kinase C. Increased levels of these intracellular messengers lead to vascular occlusion and other effects contributing to nerve insult. The third hypothesis suggests that diabetic blood vessels suffer from increased intracellular Advanced Glycation of End Products (AGE). AGE arises from auto‐oxidation of glucose to glyoxal and decomposition and fragmentation of other glucose products, and impairs cell‐to‐cell adhesion and intercellular interactions. Finally, a number of recent studies have shown that in diabetes there is a depletion of reducing agents, such as NAD(P)H (Oates 2002; Tomlinson 1992), due to increased aldose reductase activity and excessive production of reactive oxygen species through the polyol pathway. According to all four hypotheses, disruption of the respective pathway occurs as a direct or indirect consequence of hyperglycaemia‐induced superoxide overproduction by the mitochondrial electron transport chain. In the diabetic state, unchecked superoxide accumulation and the subsequent pathway abnormalities result in impaired neural function and loss of neurotrophic support and, in the long‐term, apoptosis of neurons and Schwann cells. Hence, inhibition of superoxide accumulation may block both the initiation and progression of nerve injury (Feldman 2003). This observation has prompted the development of novel forms of treatment using antioxidants, such as vitamin E and alpha‐lipoic acid (ALA).

Alpha‐lipoic acid

Alpha‐lipoic acid (ALA), otherwise known as 6,8‐thioctic acid, was discovered in 1937 by Snell and colleagues (Snell 1937) who found that certain bacteria needed a compound from potato extract for growth. Alpha‐lipoic acid is a low molecular weight (Mr 170) antioxidant, like ascorbic acid (vitamin C) and tocopherol (vitamin E) (Morikawa 2001), and is a potent lipophilic free radical scavenger. ALA has also been found to be synthesized by animals, where it is covalently bound to the amino group of lysine residues and functions as a cofactor of mitochondrial enzymes by catalyzing oxidative decarboxylation of pyruvate, ketoglutarate, and branched‐chain keto acids. Although the biosynthetic pathway of ALA is not well understood, ALA seems to be synthesized in mitochondria from octanoic acid and a sulphur source (Packer 2001). Recent work has shown evidence of mitochondrial dysfunction in diabetic neuropathy (Fernyhough 2003), which raises questions about the endogenous levels of ALA in those with DPN.

Alpha‐lipoic acid in diabetic neuropathy

In animal studies, ALA has been shown to prevent or even reverse hyperglycaemia induced nerve dysfunction (van Dam 2002) by reducing free radical medicated oxidative stress. It has also been demonstrated that ALA improves nerve blood flow and peripheral nerve fibre conduction, and increases endoneurial glucose uptake and energy metabolism in experimental diabetic peripheral neuropathy (Low 1997; Nagamatsu 1995). Other studies have even shown that ALA in Type 2 diabetic patients can, over several weeks, improve insulin sensitivity (Jacob 1996). These studies form the rationale behind clinical trials of ALA in human DPN.

The first of the double‐blind studies on ALA in DPN was performed by Sachse and colleagues in 1980 (Ziegler 1999). It failed to demonstrate any difference between drug and placebo treatment in subjective symptoms, nerve conduction velocity and vibration perception threshold. However, as other trials were conducted, double‐ or single‐blind or open, with varying doses and methods of administration, improvements were reported. Nevertheless, due to differences in the sample sizes, choice of doses used and assessment tools, it was hard to state if ALA is effective (Ziegler 1999).

A meta‐analysis of four randomised placebo‐controlled trials (comprising 1,258 patients) using ALA infusions of 600 mg intravenously per day for 3 weeks in diabetic patients with positive symptoms of peripheral neuropathy has recently been published (Ziegler 2004) and has suggested that such treatment produces clinically significant improvements in both neuropathic symptoms and deficits. However, the authors did not consider all known trials of ALA. Indeed, no systematic review of ALA in DPN is known. This review aims to fill that gap and then to maintain an up‐to‐date record.

A number of composite measures for assessing the severity of DPN are available. One of these is the Total Symptom Score (TSS). The TSS quantifies the presence, severity (mild, moderate or severe), and frequency (infrequently, frequent or constant) of asleep‐numbness, burning, lancinating pain and prickling on a range of 0 (no symptoms) to 14.64 (all symptoms severe and almost continuously present). The TSS was developed because diabetic peripheral neuropathy is primarily a sensory disorder, and because it is more often the occurrence of positive phenomena, as opposed to sensory loss, which concerns patients. In addition, the measurement of TSS is of relevance to healthcare purchasers as painful neuropathy is amongst the commonest reasons for referral to tertiary neuromuscular practice. The TSS has been used in clinical trials, primarily those of ALA, although there are no validation studies known to the authors as yet.