The Mechanism and Inflammatory Markers Involved in the Potential Use of N-acetylcysteine in Chronic Pain Management

Abstract

N-acetylcysteine (NAC) has established use as an antidote for acetaminophen overdose and treatment for pulmonary conditions and nephropathy. It plays a role in regulating oxidative stress and interacting with various cytokines including IL-1β, TNFα, IL-8, IL-6, IL-10, and NF-κB p65. The overexpression of reactive oxygen species (ROS) is believed to contribute to chronic pain states by inducing inflammation and accelerating disease progression, favoring pain persistence in neuropathic and musculoskeletal pain conditions. Through a comprehensive review, we aim to explore the mechanisms and inflammatory pathways through which NAC may manage neuropathic and musculoskeletal pain. Evidence suggests NAC can attenuate neuropathic and musculoskeletal pain through mechanisms such as inhibiting matrix metalloproteinases (MMPs), reducing reactive oxygen species (ROS), and enhancing glutamate transport. Additionally, NAC may synergize with opioids and other pain medications, potentially reducing opioid consumption and enhancing overall pain management. Further research is needed to fully elucidate its therapeutic potential and optimize its use in pain management. As an adjuvant therapy, NAC shows potential for chronic pain management, offering significant benefits for public health.

Keywords: NAC; ROS; chronic pain; metalloproteinases; musculoskeletal pain; neuropathic pain; opioids.

Figure 1

NAC’s role in regulating oxidative stress and reducing ROS, inflammation, and pain. Through the indirect and direct pathways shown sequentially, NAC at the end of the pathways decrease ROS/oxidative stress to decrease inflammation and pain as a result.

Figure 2

Pain pathway and NAC inhibiting the activation of NF-κB to slow the progression of inflammation and pain. In its inactive state, NF-κB is bound in the cytoplasm to inhibitors of κB (IκBα). Activation by pro-inflammatory cytokines, such as interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα), epidermal growth factors, or CFA-stimulating TLR-2 and TLR-4 leads to IκBα phosphorylation (P symbol ) and its subsequent destruction [14]. This activation of NF-κB (plus sign) through an inflammation state ultimately triggers the transcription of κB-associated inflammatory genes involved in pain indirectly and directly, such as TNFα, IL-1β, and cyclooxygenase-2 (COX-2) (in nucleus in the figure) [14]. NAC inhibits (minus sign) NF-kB activation, thereby suppressing the production of cytokines such as TNFα, IL-1β, IL-8, and IL-6 which are key in the inflammation pathway and progression of chronic pain.

Figure 3

NAC inhibiting peripheral sensitization by ultimately decreasing glutamate release. Through the cysteine transporters, NAC enters the astrocyte, which increases the cystine/glutamate antiport, leading to the intracellular increase of cystine and extracellular release of glutamate. The release of glutamate from astrocytes activates the mGlu2/3 receptor, which inhibits cAMP. This ultimately inhibits the synaptic release of glutamate and reduction of pain.

Figure 4

NAC inhibiting mature IL-1β to reduce neuropathic pain. MMP-2 and MMP-9 cleave IL-1β to generate neuropathic pain, which NAC has shown to inhibit in some studies mentioned above. This ultimately decreases neuropathic pain.