Description of the condition
Diabetic polyneuropathy (DPN) is one of the most common chronic complications of diabetes mellitus (DM), affecting 50% of all individuals with diabetes (Tesfaye 2010). An internationally accepted definition of DPN for clinical practice is “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes" (Boulton 2005).
DPN is frequently asymptomatic but it may be clinically evident through a set of positive and negative symptoms. The positive symptoms are often painful and the negative are abnormalities associated with lack of sensation or, less commonly, with weakness. Chronic neuropathic pain, depression, balance disorders, foot ulcerations, Charcot arthropathy, osteomyelitis, and amputations are some examples of complications associated with progressively advanced stages of DPN (Callaghan 2012). In DPN, pain is typically distal, symmetrical, and worsens at night. The patient usually describes the sensation as tingling, a deep ache, sharp shooting or burning. On examination it is common to find hyperalgesia (abnormal sensitivity to painful stimuli) and allodynia (heightened sensitivity to non-noxious stimuli).
The combination of neuropathic symptoms, signs, and abnormal electrical diagnostic studies provides researchers with the most accurate diagnosis of polyneuropathy (England 2005; Tesfaye 2010). However, in clinical practice, the diagnosis of DPN can be made after a careful clinical examination with at least two neurological tests. For example, the combination of temperature and vibratory tests (on neurological examination) provides 87% sensitivity in detecting DPN (Boulton 2005). The most important differential diagnoses in the assessment of DPN include spinal stenosis, hypothyroidism, vitamin B12 and thiamine deficiency, and other nutritional polyneuropathies such as alcohol-related neuropathy. Furthermore, polyneuropathy may be associated with uraemia, cancer, peripheral arterial disease, hepatitis, neurotoxic drugs, and toxins. Additionally, rarer possibilities are human immunodeficiency disease, vasculitis, connective tissue diseases, amyloidosis, and inherited neuropathies, such as Charcot-Marie-Tooth disease.
Neuropathic pain is frequently encountered in diabetics with and without diagnosed neuropathy, but its prevalence is difficult to ascertain, as definitions vary enormously among studies. It is thought that between 16% and 24% of people with DPN may experience chronic neuropathic pain (Boulton, 2010). In clinical trials, the severity of pain is evaluated through pain scales (visual analogue scale (VAS) and 11-point Likert scale) and outcomes must be evaluated through validated instruments (for example, Brief Pain Inventory, McGill Pain Questionnaire, and Neuro-Qol) (Cruccu 2004). The usual criteria for including a patient in such trials are the presence of DPN associated with neuropathic pain lasting for six months or longer, and a mean weekly pain on a zero to 10 VAS of between four and 10. The usual reasons to exclude a patient from a painful DPN trial are proximal neuropathies, pain of central origin, non-neuropathic pain, and pain that is not DPN-related.
A long period of non-controlled hyperglycaemia, metabolic imbalances, such as oxidative stress, increased polyol flux, accumulation of advanced glycation end-products, and dyslipidaemia (increase in low density lipoprotein (LDL) and triglycerides) are the main factors associated with DPN development. However, total hyperglycaemic exposure seems to be the most important factor associated with DPN (Tesfaye 2010). The elucidation of metabolic disruptions related to hyperglycaemia remains the foremost target for research, with the aim of reversing or minimising these homeostatic imbalances and eventually reducing complications and negative impact on quality of life.
Apart from tight blood glucose control, no treatments have shown any capacity to arrest DPN progression. In addition, the pharmacological treatment of painful DPN remains a challenge for physicians and the ability of the individual to tolerate treatment remains a major consideration in any treatment decision (Ziegler 2009). A multifaceted treatment approach to chronic neuropathic pain in DPN is reasonable, but results have been modest so far. Currently, there are many treatments for painful DPN, but quite a few have adverse effects that limit their utility (Bril 2011), and few papers have studied the effects of treatment on function and quality of life.
Description of the intervention
Acetyl-L-carnitine (ALC) is an ester of L-carnitine, which is a naturally occurring amino acid. ALC is produced in the kidneys, central nervous system (CNS) and liver via the action of ALC-transferase and is stored in skeletal muscle. ALC plays an essential role in the transfer of long-chain fatty acids into the mitochondria for β-oxidation (Sima 2007). ALC supports cell metabolism when there is hypoxia, for example during reduced circulation, or due to genetic metabolic defects. ALC binds organic acids and fragmented free fatty acids in order to expel them from the cell, and to prevent the harmful effects that fatty acid fragments can have on cell and on tissue structures.
In addition, ALC is able to reduce tumour necrosis factor alpha (TNFα) concentration and has an antioxidant effect on mitochondrial DNA, whilst stimulating mitochondrial DNA synthesis. Therefore, ALC not only assists in the transportation of long-chain fatty acids through the inner mitochondrial membrane for β-oxidation, but also helps energy availability and prevents toxic accumulation of long-chain fatty acids (Williamson 1992).
Administration of ALC can be oral, intravenous (IV) or intramuscular (IM). Oral doses range from 1.5 g to 3.0 g by day, in divided doses. IV and IM doses range from 1.0 g to 2.0 g daily.
How the intervention might work
Recent clinical trials, usually in groups of patients with an advanced stage of DPN, have shown disappointing outcomes from experimental treatments based on vitamin supplementation, aldose reductase inhibitors and protein kinase C inhibitors. In these studies, each different drug has targeted a single underlying pathogenetic factor. By contrast, substitution of ALC in DPN targets several mechanisms and could be a more advantageous therapy (Sima 2007).
In experimental as well as human diabetic neuropathy, ALC is depleted in peripheral nerves (Scarpini 1996). Replenishment of ALC enhances regional blood flow, increases myo-inositol and free carnitine levels, and reduces malonyl dialdehyde (that is, reduces lipid peroxidation). Another mechanism to explain the effects of ALC in DPN could be via diabetic dyslipidaemia, as oral L-carnitine supplementation in people with diabetes significantly reduces plasma lipoprotein A levels by as much as 20.9% after six months (Derosa 2003). On the other hand, one theoretical role of ALC in peripheral neuropathy is the reduction of pain. ALC may abate the overexcitability of Aδ and C fibres in the dorsal root ganglion and regulate their connections with interneurons in the spinal medulla (Chiechio 2006).
Why it is important to do this review
Polyneuropathy is a frequent, heterogeneous, polymorphic and devastating complication of diabetes mellitus (Rolim 2009) because of the debilitating symptoms it causes and the associated higher risk of other complications, in particular those involving the cardiovascular system and the foot. The World Health Organization (WHO) estimates that "someone somewhere in the world loses a limb due to DM every 30 seconds" (Boulton 2005) .
Currently, it is estimated that there are 366 million adults with diabetes in the world (Vidal-Casariego 2013). Of these, approximately half have some phenotype of neuropathy and 16% to 24% have chronic painful DPN. Of those with chronic painful DPN, up to 39% have never received any kind of treatment for their pain (Daousi 2004). There is therefore an enormous worldwide burden of disease, and an unmet need for prevention and treatment of the diabetes, the neuropathy and the resultant painful symptoms.
Recently, at least four systematic reviews and meta-analyses have been published about ALC or L-carnitine and its effects on different conditions: type 2 diabetes mellitus (Vidal-Casariego 2013), secondary prevention of cardiovascular disease (DiNicolantonio 2013), hepatic encephalopathy (Jiang 2013), and end-stage renal failure under haemodialysis (Chen 2014), with positive results in all except renal failure. ALC has also shown promise as a therapeutic agent for DPN in small numbers of studies but the published data have not been considered as a whole and subjected to meta-analysis. This review will systematically evaluate the evidence on the effectiveness and safety of ALC for this highly prevalent condition.