<p>Ameliorative Effects Of N-Acetylcysteine As Adjunct Therapy On Symptoms Of Painful Diabetic Neuropathy</p>

Abstract

PurposePainful diabetic neuropathy (PDN) is a variant of diabetic peripheral neuropathy which is highly prevalent and distressing in diabetic patients. Despite its high burden, the optimal treatment of PDN has remained a clinical challenge. To explain the emergence and maintenance of PDN, increasing attention has been focused on dimensions of inflammation and oxidative toxic stress (OTS). Accordingly, the aim of this study was to investigate the effects of oral N-acetylcysteine (NAC), an agent with known anti-oxidant and anti-inflammatory effects, as an adjunct therapy in patients suffering from PDN.Patients and methods113 eligible patients with type 2 diabetes suffering from PDN were randomly assigned to either the pregabalin + placebo or pregabalin + NAC group for 8 weeks (pregabalin at a dose of 150 mg per day, NAC and matched placebo at doses of 600 mg twice a day). Mean pain score was evaluated at baseline, week 1, 2, 4, 6, and 8 of the study based on the mean 24 hr average pain score, using an 11-point numeric rating scale (NRS). As secondary efficacy measures, mean sleep interference score (SIS) resulting from PDN, responder rates, Patient Global Impression of Change (PGIC), Clinical Global Impression of Change (CGIC), and safety were also assessed. Additionally, serum levels of total antioxidant capacity (TAC), total thiol groups (TTG), catalase activity (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), nitric oxide (NO), and malondialdehyde (MDA) were assessed at baseline and at the end of the study.ResultsNinety patients completed the eight-week course of the study. The decrease in mean pain scores and mean sleep interference score in pregabalin + NAC group was greater in comparison with pregabalin + placebo group (p value<0.001 in both conditions). Moreover, more responders (defined as ≥50% reduction in mean pain score from baseline to end-point) were observed in the pregabalin + NAC group, in comparison with pregabalin + placebo group (72.1% vs 46.8%). More improvement in PGIC and CGIC from baseline to the end of the study was reported in pregabalin + NAC group. Oral NAC had minimal adverse effects and was well tolerated in almost all patients. Furthermore, in respect to OTS biomarkers, adjuvant NAC significantly decreased serum level of MDA and significantly increased serum levels of SOD, GPx, TAC, and TTG.ConclusionThe pattern of results suggests that compared to placebo and over a time period of 8 weeks, adjuvant NAC is more efficacious in improving neuropathic pain associated with diabetic neuropathy than placebo. Ameliorative effects of NAC on OTS biomarkers demonstrated that NAC may alleviate painful symptoms of diabetic neuropathy, at least in part by its antioxidant effects.

The Interplay between Oxidative Stress, Exercise, and Pain in Health and Disease: Potential Role of Autonomic Regulation and Epigenetic Mechanisms

“…Finally, nitric oxide reduces receptor thresholds, resulting in peripheral and central sensitization [ 93 ], and the inhibitory activity of the central nervous system, leading to central sensitization of the dorsal horn neurons [ 94 ]. In line with the above observations, oxidative stress has also been associated to chronic pain and proposed to be a possible contributor to the maintenance of pain symptoms [ 20 , 84 , 95 , 96 ]. While both inflammatory and oxidative processes cover a role in the acute nociceptive phase, it is mainly the production of ROS that seems to account for the maintenance of nociceptive processes in the chronic phase [ 97 ].…”

N-Acetylcysteine: A Review of Clinical Usefulness (an Old Drug with New Tricks)

“…Likewise, animal studies investigating retinopathy [ 69 ] and diabetic nephropathy [ 70 ] show promising results. Recently, a study in humans has shown significant benefit in painful peripheral neuropathy [ 71 ]. Patients with painful neuropathy improved over 8 weeks with the use of NAC (600 mg bid) as adjuvant therapy to pregabalin.…”

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“…Beyond this, recent research has revealed that NAC may also have antinociceptive and analgesic effects; surprisingly enough, favorable effects of NAC supplementation in various types of chronic pain syndromes have been demonstrated in a number of clinical studies 23 . Although the precise mechanism by which NAC exerts its antinociceptive and analgesic effect is not known; it is suggested that it also may be related to its anti‐inflammatory and antioxidant actions 19,38‐41 . Thus, NAC, through its antinociceptive and analgesic activities, may also be able to relieve the pain symptoms associated with CP/CPPS.…”

“…This study also revealed that NAC could significantly decrease the plasma level of pro‐inflammatory biomarkers such as tumour necrosis factor alpha (TNF‐α) that have an essential role in prostate inflammation 18 . Further, emerging data suggest that NAC supplementation may also be helpful in managing several chronic pain conditions, in particular neuropathic pains 18‐20 . So, considering the probable neuropathic nature of pain associated with CP/CPPS, 12,13 NAC treatment may also alleviate pain in patients affected with CP/CPPS.…”