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The Neuropathic Pain: Comparison
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Please note this is a comparison between Version 2 by Conner Chen and Version 1 by Imane Ridouh.

A consensus definition of neuropathic pain is ‘pain resulting from a lesion of the somatosensory system, which results in faulty pain signaling’

  • neuropathic pain
  • chronic pain

1. Neuropathic Pain

Neuropathic pain occurs when your nervous system is damaged or not working properly. You can feel pain at any level of the nervous system—peripheral nerves, spinal cord, and brain. The spinal cord and brain together are called the central nervous system. Peripheral nerves are nerves that run throughout other parts of the body, such as organs, arms, legs, fingers, and toes.

Damaged nerve fibers send false signals to pain centers. Nerve function may change at the site of nerve injury as well as in areas of the central nervous system (central sensitization).

Neuropathy is a dysfunction or change in one or more nerves. Diabetes causes about 30% of neuropathy cases. Determining the source of neuropathic pain is not always easy. There are hundreds of diseases associated with this pain.

2. Background: Definition, Etiology, and Pathogenesis

A consensus definition of neuropathic pain is ‘pain resulting from a lesion of the somatosensory system, which results in faulty pain signaling’ [1]. The somatosensory system includes the peripheral nerves, spinal cord, and the cerebral cortex. Neuropathic pain is associated with many conditions including spinal cord compression, HIV, amputation, fibromyalgia, multiple sclerosis, postherpetic neuralgia, and diabetic neuropathy, and its pathogenesis in each of these states depends on the associated disease process. In the case of diabetic neuropathy, for example, longstanding hyperglycemia induces many metabolic processes including generation of free radicals and deposition of advanced glycation end-products in the microvasculature supplying peripheral nerves. These degradative processes result in direct toxicity and decreased blood flow, leading to nerve fiber degeneration and hyperexcitability of the primary afferent nociceptors [2].
Pain transmission through nociceptive nerve fibers involves many signaling molecules and ion channels, the most well studied of which are briefly mentioned below. Voltage gated sodium channels are involved in neuronal depolarization, and blockage of these channels is the mechanism of action of many first line pain medications. Transient potential receptor channels are expressed on nociceptive nerve fibers, such as C-fibers, and are involved in the development and maintenance of chronic pain. Blockage of voltage gated calcium channels, an alternative conduit involved in neuronal excitability, is the mechanism of action of gabapentin. Glutamate is the main excitatory neurotransmitter released by nociceptive afferent neurons and binds to the N-methyl-D-aspartic acid receptor, which is involved in central sensitization of spinal nociceptive neurons. Conversely, G-Amino Butyric Acid (GABA) is the main inhibitory neurotransmitter, and activation of GABA receptors causes inhibition of signal transmission. Substance P and Calcitonin Gene Related Peptide (CGRP) are neuropeptides released by nociceptive C-fibers and play a role in pain perception as well as signaling in the hypothalamus and amygdala. Finally, opioid receptors are widely distributed through the CNS and periphery. Presynaptically, opioids inhibit neurotransmitter release by reducing Ca2+ influx. Postsynaptically, opioids cause K+ efflux, which hyperpolarizes the cell and decreases the synaptic transmission [3].
Patients experiencing neuropathic pain often have comorbid mood disorders, including depression and anxiety. A 2008 epidemiological study by Gustorff et al. suggests that about 34% of neuropathic pain patients experience feelings of depression, 25% report feelings of anxiety, and 60% report strong or predominant sleep disturbances [4]. Animal models have been used to demonstrate an association between neuropathic pain and depressive behavior with associated changes in the amygdala. Gonclaves et al. found increased signs of depressive-like behavior in rats who had undergone spared nerve injury (SNI), a procedure often used to induce neuropathic pain in animal models. They also noted increase amygdala volume in the SNI rats compared to controls [5]. The amygdala is involved in processing emotional states, and thus may be responsible for the connection between chronic pain and negative emotional states like depression and anxiety. Finally, chronic neuropathic pain causes sleep disruption, but sleep disruption also enhances pain perception and reduces pain tolerance [6].
Taken together, the etiology of neuropathic pain is ultimately multifactorial, as there are well established connections between neuropathic pain, depression, anxiety, and sleep problems.

3. Impact

The prevalence of neuropathic pain in the United States in a 2009 study was estimated to be about 9.8% [7]. Neuropathic pain management is extremely burdensome on our medical system. The economic burden includes both direct costs related to diagnosing and treating the pain and associated complications, as well as indirect costs due to lost wages, lost productivity, need for home care, and leaving the workforce due to disability [8] A 2004 study found a threefold increase in health care costs in patients with peripheral neuropathy compared to matched controls [9]. Schaefer and colleagues quantified the cost of direct and indirect costs of neuropathic pain in US patients and found mean direct costs to payers to be $6016 and mean indirect cost to be $19,000 per patient. These costs varied significantly but were positively correlated with pain severity [10]. They also found high neuropathic pain levels to be associated with significant decrease in quality of life, including increased anxiety and depression, and worsened sleep status [11]. The prevalence and economic burden of neuropathic pain underscore the importance of exploring new and adjunct treatments.

4. Focus on Natural Remedies

The focus in treating neuropathic pain is management of symptoms. Neuropathic pain is seen as a chronic condition, and even reversal of the underlying condition does not always result in resolution of the patient’s symptoms. A multimodal approach to management is often necessitated in such individuals, including both pharmacological and nonpharmacological options. Whereas typical pharmacologic interventions include voltage gated calcium channel blockers, serotonin and norepinephrine reuptake inhibitors, sodium channel inhibitors amongst others, a growing portfolio of non-pharmacological therapies have become increasingly utilized for neuropathic pain in recent years with varying degrees of efficacy. These include massage therapy and acupuncture, TENS units, trigger point injections, and spinal cord stimulators. With increased consumer interest in “natural” alternative options, essential oils, herbal remedies, and dietary supplements have gained significant traction as possible adjunct treatment options. This interest is particularly high in regions of the world with a long history of traditional medicine, including large parts of Asia, Africa, and Latin America [12].

References

  1. Giovannini, S.; Coraci, D.; Brau, F.; Galluzzo, V.; Loreti, C.; Caliandro, P.; Padua, L.; Maccauro, G.; Biscotti, L.; Bernabei, R. Neuropathic Pain in the Elderly. Diagnostics 2021, 11, 613.
  2. Kaur, S.; Pandhi, P.; Dutta, P. Painful diabetic neuropathy: An update. Ann. Neurosci. 2011, 18, 168–175.
  3. Kocot-Kępska, M.; Zajączkowska, R.; Mika, J.; Kopsky, D.; Wordliczek, J.; Dobrogowski, J.; Przeklasa-Muszyńska, A. Topical Treatments and Their Molecular/Cellular Mechanisms in Patients with Peripheral Neuropathic Pain—Narrative Review. Pharmaceutics 2021, 13, 450.
  4. Gustorff, B.; Dorner, T.E.; Likar, R.; Grisold, W.; Lawrence, K.; Schwarz, F.; Rieder, A. Prevalence of self-reported neuropathic pain and impact on quality of life: A prospective representative survey. Acta Anaesthesiol. Scand. 2007, 52, 132–136.
  5. Gonçalves, L.; Silva, R.; Pinto-Ribeiro, F.; Pêgo, J.M.; Bessa, J.M.; Pertovaara, A.; Sousa, N.; Almeida, A. Neuropathic pain is associated with depressive behaviour and induces neuroplasticity in the amygdala of the rat. Exp. Neurol. 2008, 213, 48–56.
  6. Stroemel-Scheder, C.; Kundermann, B.; Lautenbacher, S. The effects of recovery sleep on pain perception: A systematic review. Neurosci. Biobehav. Rev. 2020, 113, 408–425.
  7. Yawn, B.P.; Wollan, P.C.; Weingarten, T.N.; Watson, J.C.; Hooten, W.M.; Melton, L.J. The Prevalence of Neuropathic Pain: Clinical Evaluation Compared with Screening Tools in a Community Population. Pain Med. 2009, 10, 586–593.
  8. McCarberg, B.H.; Billington, R. Consequences of neuropathic pain: Quality-of-life issues and associated costs. Am. J. Manag. Care 2006, 12, S263–S268.
  9. Berger, A.; Dukes, E.M.; Oster, G. Clinical characteristics and economic costs of patients with painful neuropathic disorders. J. Pain 2004, 5, 143–149.
  10. Schaefer, C.; Sadosky, A.; Mann, R.; Daniel, S.; Parsons, B.; Tuchman, M.; Anschel, A.; Stacey, B.R.; Nalamachu, S.; Nieshoff, E. Pain severity and the economic burden of neuropathic pain in the United States: BEAT Neuropathic Pain Observational Study. Clin. Outcomes Res. 2014, 6, 483–496.
  11. Sadosky, A.; Schaefer, C.; Mann, R.; Daniel, S.; Parsons, B.; Bergstrom, F.; Nieshoff, E.; Tuchman, M.; Nalamachu, S.; Anschel, A.; et al. Burden of neuropathic pain on quality of life in the United States: BEAT neuropathic pain observational study. J. Pain 2013, 14, S31.
  12. Forouzanfar, F.; Hosseinzadeh, H. Medicinal herbs in the treatment of neuropathic pain: A review. Iran J. Basic Med. Sci. 2018, 21, 347–358.
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