For Medical Practitioners
For Medical Practitioners
Pathophysiology of Pain
The International Association for the Study of Pain (IASP) defines pain as, “an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage”. The nature of pain includes emotional and physical suffering.
Acute pain is usually nociceptive. Nociceptive pain arises from somatosensory pain receptor as a response to potential or actual non-neural tissue damage (pain originating from somatic: joint, muscle, ligament, or visceral organs: appendix, kidney). Nociceptors respond to heat, cold, vibration, stretch stimuli, and chemical substances released from tissues in response to tissue disruption or inflammation.
Chronic pain is a pathological process, when acute pain becomes chronic and persists more than 3 months, continuous or recurrent. Chronic pain may persist in the absence of tissue damage. Permanent structural alterations in specific brain areas are implemented in the development of chronic pain. There is growing evidence for hippocampal involvement in pain pathophysiology, particularly, hippocampal abnormalities after nerve injury-induced pain in mice, as well as reduced hippocampal volume in patients with chronic pain. It is important to decrease the intensity of acute pain and assure sufficient nutrition for the purpose of diminishing or preventing permanent changes in the nervous system that may transform to chronic pain.
More than 1.5 billion people worldwide suffer from chronic pain – the disabling condition affecting quality of life and putting financial burden on the patients and their families.
Pathophysiology of Pain
- Chronic primary pain is an idiopathic pain, that cannot be better explained by another chronic pain condition: fibromyalgia syndrome, irritable bowel syndrome, chronic pelvic pain, chronic regional pain syndrome.
- Chronic cancer pain is caused by the cancer itself and by the cancer treatment (surgical, chemotherapy, radiotherapy, and others).
- Chronic postsurgical and posttraumatic pain develops after a surgical procedure or a tissue injury (trauma or burns), lasting 3 months or more after surgery or tissue trauma. Other causes must be excluded (a pain from pre-existing condition, infection, recurrent malignancy).
- Neuropathic pain is a demonstrable lesion or the disease of the somatosensory nervous system, caused by nerve compression or the abnormal processing of pain signals by the brain and spinal cord. Neuropathic pain can be an increased response to a painful stimulus (hyperalgesia) or a painful response to normally a non-painful stimulus (allodynia).
- Chronic headache and orofacial pain is a headache or orofacial pain that occurs on at least 50% of the days during at least 3 months (temporomandibular disorders, post-traumatic trigeminal neuropathic pain, migraine).
- Chronic visceral pain originates from the internal organs of the head and neck region and the thoracic, abdominal, and pelvic cavities.
- Chronic musculoskeletal pain is a nociceptive pain characterized by persistent inflammation of infectious, autoimmune or metabolic etiology, such as rheumatoid arthritis, and by structural changes affecting bones, joints, tendons, or muscles
Neurochemistry of Pain Pathway
Neurotransmission of Pain
There are three classes of transmitter compounds: excitatory neurotransmitters, inhibitory neurotransmitters, and neuropeptides.
- Neuropeptides: Substance P and neurokinin A serve as excitatory neuropeptides in the somatosensory system. The key inhibitory neuropeptides are the enkephalins and somatostatin.
- Excitatory Neurotransmitters: glutamate and aspartate amino acids. They activate N-methyl-D-aspartate (NMDA) pain receptors. Recent animal study showed NMDA receptors in primary afferent terminals undergo a dramatic increase in their functionality by brain-derived neurotrophic factor (BNDF) during neuropathic pain. This is likely due to potentiation of the synapses between primary afferents and dorsal horn neurons during chronic pain.
- Inhibitory Neurotransmitters: amino acids glycine, gamma-amino-butyric acid (GABA), acetylcholine (Ach), and Serotonin.
Product Description of the Primary Ingredients
PROLEEVA™ consists of a patent-pending proprietary formulation of Choline Bitartrate, Turmeric Root Powder, Devil’s Claw Root Powder, 5-Hydroxytryptophan (from Griffonia Simplicifolia Seed Extract), L-Arginine, gamma-Aminobutyric Acid (GABA), Bromelain Complex, Matcha Green Tea Leaf Powder, Asian Ginseng Root, and Caffeine Anhydrous.
All the ingredients above fall into the classification of Generally Recognized as Safe (GRAS) as defined by the Food and Drug Administration (FDA) (Sections 201(s) and 409 of the Federal Food, Drug, and Cosmetic Act).
Patients with pain disorders may have increased nutritional demand and require certain amino acids in the amount that cannot be obtained from normal diet alone. Complex of amino acids included in PROLEEVA plays crucial role in modulation of pain. In addition, PROLEEVA contains ingredients of herbal supplements with antinociceptive, anti-inflammatory, and antioxidant properties. For centuries, people used herbal medicine for variety of diseases. Nowadays, with support by clinical trials, herbalism is proving to be effective as adjunctive in a treatment of pain, fatigue, and inflammation.
5-Hydroxytryptophan is a metabolic intermediate in biosynthesis of serotonin from tryptophan. Tryptophan, an essential amino acid, is metabolized to serotonin, a neurotransmitter that controls mood and pain. Tryptophan can also be metabolized to kynurenine via tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) in the brain. Kynurenine derivatives contribute to neurotoxicity and, via interaction with glutamate receptors, to pain and depression as well. IDO1 is upregulated in the brain in response to either pain or stress, could account for the link between pain and depression. IDO1 catalyzes the formation of kynurenine from tryptophan, which leaves less tryptophan available for serotonin production. Moreover, proinflammatory cytokines like IL-6 play a role in pain and depression, and some induce IDO1. Human studies demonstrated elevated plasma IL-6 levels in patients with chronic pain and depression. Animal studies report IL-6 boosts IDO1 expression in hippocampus. Therefore, it is important to prevent the interaction between pain and depression in the first place, by normalizing tryptophan metabolic pathway. PROLEEVA complex includes 5-Hydroxytryptophan and the ingredients implicated in down-regulation of proinflammatory cytokines.
Choline Bitartrate is an essential nutrient, which also known as Lecithin, Choline is precursor of neurotransmitter acetylcholine, a major neurotransmitter in central and peripheral nervous system. Acetylcholine is a neurotransmitter at the neuromuscular junction and in the autonomic ganglia. In the brain cholinergic neurotransmission targets neuronal excitability, modifies presynaptic release of neurotransmitters, and coordinates the firing of groups of neurons. Acetylcholine regulates memory and cognition, due to influence on synaptic plasticity. In the spinal cord Acetylcholine modulates pain via its effects on nicotinic or muscarinic receptors, lessens firing of NMDA-pain receptors, potentiates the release of endogenous opiate peptides in the spinal cord, increases pain threshold. There is evidence that Choline supplementation improves exercise performance among individuals with choline deficiency and it has no effects on healthy individuals. Moreover, higher dietary choline intakes are associated with more favorable body composition (lower body fat and higher lean body mass) and lower insulin resistance. L-arginine is a semi-essential amino acid that must be supplied in the diet in some pathological conditions, including, chronic pain, trauma, sepsis, and cancer.
L-Arginine is mainly metabolized intracellularly by nitric oxide synthase (NOS) and arginase. nitric oxide synthases and arginases, which are closely integrated with the control of immune response under physiological and pathological conditions. Nitric oxide is a messenger molecule, playing important role in pain modulation, inflammation, and regulation of apoptosis. NO can be generated by three different isoforms of the enzyme NO synthase (NOS): neuronal nNOS, inducible iNOS, and endothelial eNOS. Neuronal NO synthase (nNOS) implicated in modulating physiological functions such as learning, memory, neurogenesis, central blood pressure, and peripheral vascular tone regulation. Inducible NOS (iNOS), when induced in macrophages, produces large amounts of NO, which represent a major cytotoxic principle of those cells. Once induced by any harmful agent (bacteria, cytokine), iNOS is constantly active. iNOS produces large amounts of NO by immune and non-immune, which represent a major cytotoxic principle of those cells. iNOS is implicated in inflammatory and auto-immune processes. Endothelial NOS impede atherogenesis, fibrous plaque formation. Significant oxidative stress may deplete L-arginine, therefore it converts eNOS from an NO-producing enzyme to an enzyme that generates O2 (NOS uncoupling). Moreover, highly expressed Arginase compete with NOS for substrate. Relative L-Arginine deficiency can be improved by L-Arginine supplement. There are some other antioxidant effects of L-Arginine supplementation. Recent study on animals and humans observe L-arginine prevents the increase in the spinal NO level in diabetic group and delays the development of behavioral and histologic changes of diabetic neuropathy. L-arginine can be useful in diabetic patients to prevent diabetic neuropathy.
Gamma-Aminobutyric Acid (GABA) is an amino acid which works as major inhibitory neurotransmitter in brain and gut. GABA down-regulates activity pain receptors-NMDA and decreases firing of pain neurons, therefore improves neuropathic pain (such as diabetic neuropathy, postherpetic neuralgia, and central neuropathic pain). Currently, there are no sufficient evidence that GABA supplement alone crosses blood-brain barrier to an adequate degree. One study observes increase of blood-brain barrier permeability to GABA concurrently administered with L-Arginine. Some clinical trials indicate GABA supplement may work through the signaling on gut GABA receptors.
Turmeric (Curcuma longa; an Indian spice) has a long history of safe use as food and it has long been used as in anti-inflammatory treatment in traditional Chinese and Ayurvedic medicine. Turmeric root powder contains a yellow-pigmented fraction that mainly consists of curcuminoids. Studies showed antioxidant and anti-inflammatory properties of Turmeric. Curcumin abate inflammation by inhibiting tumor necrosis factor-alpha, Interleukins, Cyclooxygenase 1 (COX-1) and COX-2, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and 5-lipoxygenase (5-LOX). Therefore, Curcumin improves joint function measured by morning stiffness, movements, and pain in patients with arthritis.
Devil’s Claw (Harpagophytum procumbens), an African plant with high medicinal value, exhibits strong anti-inflammatory characteristics, due to direct inhibitory effect on the COX-2 enzyme and Prostaglandin E2 (PGE2). In animal studies H. procumbens extract crosses blood-brain barrier, dose-dependently increases superoxide dismutase, catalase and glutathione peroxidase activities in brain and reduces lipid peroxidation activity. H. procumbens extract exhibits its antioxidant effects by reducing the expression of hyperalgesia and allodynia. Devil’s Claw root powder has been used to treat a wide range of pathological conditions, including pain, arthritis and inflammation.
Bromelain complex is naturally derived mixture of proteolytic enzymes obtained from pineapple (Ananas comosus) and possesses notable anti-inflammatory, fibrinolytic effects, antiedematous, and immunomodulatory effects. Proteolytic enzymes in Bromelain complex downregulate the expression levels of Cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE-2). Bromelain complex is characterised by low toxicity compared to non-steroidal anti-inflammatory drugs, and is suitable for treatment of inflammation. In human studies bromelain demonstrated the reduction of IL-1β, IL-6 and TNF-α secretion when immune cells are already stimulated in the condition of inflammation-induced overproduction of cytokines. All of the above make Bromelain effective in treatment of osteo and rheumatoid arthritis.
Matcha Green Tea Leaf Powder is produced from the plant Camellia sinensis. Matcha is a traditional Chinese and Japanese tea. It contains the highest concentration of amino acid L-theanine than in any other green tea. L-theanine i is a competitive antagonist of glutamate receptors, it binds to NMDA receptors, and acts as antagonist. L-theanine crosses blood-brain barrier and acts as neuroprotector by inhibiting glutamate metabolism and neurotransmission within the central nervous system. Furthermore, L-theanine increases level of dopamine and GABA, and regulates serotonin levels in the brain. L-theanine by itself has anxiolytic properties. Matcha Green Tea Leaf has the highest caffeine content compared with other green teas. Studies showed combination caffeine and green tea increase metabolism and enhance the improvement of fatigue, alertness, and focus. Furthermore, Camellia sinensis plays an effective role in the treatment of osteo and rheumatoid arthritis, due to its antioxidant properties. It modulates levels of antioxidants, and reduces levels of free radicals.
Caffeine Anhydrous is the most popular legal psychoactive substance. It improves fatigue, attention span, alertness, and accuracy of reactions. It increases energy, alertness, wakefulness, the accuracy of reactions, and the ability to concentrate and focus attention and decreases fatigue. Caffeine amplifies dopaminergic transmission via both presynaptic as well as postsynaptic mechanisms. Therefore, supraspinal dopaminergic transmission increases arousal and motivation as well as spontaneous motor activity and prolonged exercise time. Serotonin transmission is enhanced by caffeine at spinal level which causes excitation of alpha motoneuron pool and antinociception. Human studies have revealed an increase in central excitability, endurance, spinal excitability, and self-sustained firing, as well as decreases in force sensation, and muscle pain after oral caffeine administration. Caffeine down-regulates nociception via central blocking of adenosine receptors that influence pain signaling or by blocking of peripheral adenosine receptors on primary afferent nociceptors. Caffeine is gaining a more prominent role in treatment of migraine. It crosses blood-brain barrier, acts as a vasoconstrictor on cranial vessels, and is described as safe and well-tolerated abortive medication for the treatment of acute migraine.
Asian ginseng root (Panax ginseng) has been used in Chinese medicine for thousands of years. Panax ginseng exerts neuroprotective and antioxidant action It lessens neuronal damage by activation of the cytoprotective transcriptional factor Nrf2, which results in decrease in reactive oxygen species. Ginseng is neuroprotective in various chronic neurodegenerative disorders. It promotes neuronal survival, neuronal growth and differentiation. Panax ginseng inhibited neuronal damage and generation of intracellular reactive oxygen species (ROS) induced by excitatory amino acids, such as glutamate and N-methyl-D-aspartate (NMDA). Studies showed Ginseng improves memory and chronic fatigue including cancer related. Moreover, Asian ginger root exert analgesic and anti-inflammatory activities in treatment of autoimmune arthritis, due to its immunomodulatory properties. It is observed, Panax ginseng suppresses the effects of tumor necrosis factor alpha (TNF-a), the major mediator of inflammation.
List of Abbreviations
- Ach – Acetylcholine
- BNDF – Brain-derived neurotrophic factor
- COX – Cyclooxygenase
- EAA – Excitatory amino acid e
- NOS – endothelial nitric oxide synthase
- FDA – Food and Drug Administration
- GABA – Gamma-amino-butyric acid
- GRAS – Generally Recognized as Safe
- IASP – International Association for the Study of Pain
- IL-1β – Interleukin-1 beta
- IL-6 – Interleukin-6
- iNOS – inducible nitric oxide synthase
- IDO1 – Tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase 1 5-LOX – 5-lipoxygenase 5-LOX
- NF-κB – Nuclear factor kappa-light-chain-enhancer of activated B cells
- NMDA – N-methyl-D-aspartate
- NO – Nitric oxide
- NOS – Nitric oxide synthase
- nNOS – Neuronal nitric oxide synthase
- PGE2 – Prostaglandin E2
- ROS – Reactive oxygen species
- TNFα – Tumor necrosis factor alpha
- Picciotto MR1, Higley MJ, Mineur YS. Acetylcholine as a neuromodulator: cholinergic signaling shapes nervous system function and behavior. Neuron. 2012 Oct 4;76(1):116-29. doi: 10.1016/j.neuron.2012.08.036.
- Nazarian A1, Gu G, Gracias NG, Wilkinson K, Hua XY, Vasko MR, Yaksh TL. Spinal N-methyl-D-aspartate receptors and nociception-evoked release of primary afferent substance P. Neuroscience. 2008 Mar 3;152(1):119-27. doi: 10.1016/j.neuroscience.2007.11.037.
- Jurenka JS1. Altern Med Rev. 2009 Jun;14(2):141-53. Anti-inflammatory properties of curcumin, a major constituent of Curcuma longa: a review of preclinical and clinical research. Oltean H1, Robbins C, van Tulder MW, Berman BM, Bombardier C, Gagnier JJ. Herbal medicine for low-back pain. Cochrane Database Syst Rev. 2014 Dec 23;(12):CD004504. doi: 10.1002/14651858.CD004504.pub4.
- Abramson SB1. Nitric oxide in inflammation and pain associated with osteoarthritis. Arthritis Res Ther. 2008;10 Suppl 2:S2. doi: 10.1186/ar2463. Epub 2008 Oct 17.
- Rodriguez PC1, Ochoa AC2, Al-Khami AA3. Arginine Metabolism in Myeloid Cells Shapes Innate and Adaptive Immunity. Front Immunol. 2017 Feb 7;8:93. doi: 10.3389/fimmu.2017.00093. eCollection 2017.
- Treede RD1, Rief W, Barke A, Aziz Q, Bennett MI, Benoliel R, Cohen M, Evers S, Finnerup NB, First MB, Giamberardino MA, Kaasa S, Kosek E, Lavandʼhomme P, Nicholas M, Perrot S, Scholz J, Schug S, Smith BH, Svensson P, Vlaeyen JW, Wang SJ. A classification of chronic pain for ICD-11. Pain. 2015 Jun;156(6):1003-7. doi: 10.1097/j.pain.0000000000000160
- Naber M1, Hommel B1, Colzato LS1.Improved human visuomotor performance and pupil constriction after choline supplementation in a placebo-controlled double-blind study.Sci Rep. 2015 Aug 14;5:13188. doi: 10.1038/srep13188.
- Chen W1, Walwyn W, Ennes HS, Kim H, McRoberts JA, MarvizónNeurosci. BDNF released during neuropathic pain potentiates NMDA receptors in primary afferent terminal. JC.Eur J. 2014 May;39(9):1439-54. doi: 10.1111/ejn.12516. Epub 2014 Mar 11.
- Förstermann U1, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J. 2012 Apr;33(7):829-37, 837a-837d. doi: 10.1093/eurheartj/ehr304. Epub 2011 Sep 1.
- Rastogi V1, Santiago-Moreno J2, Doré S3. Ginseng: a promising neuroprotective strategy in stroke. Front Cell Neurosci. 2015 Jan 20;8:457. doi: 10.3389/fncel.2014.00457. eCollection 2014.
- El-Lithy GM1, El-Bakly WM1, Matboli M2, Abd-Alkhalek HA3, Masoud SI1, Hamza M4. Prophylactic L-arginine and ibuprofen delay the development of tactile allodynia and suppressspinal miR-155 in a rat model of diabetic neuropathy. Transl Res. 2016 Nov;177:85-97.e1. doi: 10.1016/j.trsl.2016.06.005. Epub 2016 Jun 23.
- Kim HG1, Cho JH, Yoo SR, Lee JS, Han JM, Lee NH, Ahn YC, Son CG. Antifatigue effects of Panax ginseng C.A. Meyer: a randomised, double-blind, placebo-controlled trial. PLoS One. 2013 Apr 17;8(4):e61271. doi: 10.1371/journal.pone.0061271. Print 2013.
- Kalmar JM1, Cafarelli E. Caffeine: a valuable tool to study central fatigue in humans? Exerc Sport Sci Rev. 2004 Oct;32(4):143-7.
- Gao X1,2, Wang Y2,3, Randell E2, Pedram P2, Yi Y2, Gulliver W2, Sun G2 .Higher Dietary Choline and Betaine Intakes Are Associated with Better Body Composition in theAdult Population of Newfoundland, Canada. PLoS One. 2016 May 11;11(5):e0155403. doi: 10.1371/journal.pone.0155403. eCollection 2016.
- Tanwar A1, Chawla R2, Ansari MM3, Neha3, Thakur P2, Chakotiya AS2, Goel R2, Ojha H2, Asif M4, Basu M2, Arora R5, Khan HA6. In vivo anti-arthritic efficacy of Camellia sinensis (L.) in collagen induced arthritis model. Biomed Pharmacother. 2017 Mar;87:92-101. doi: 10.1016/j.biopha.2016.12.089. Epub 2016 Dec 31. Clin Nutr. 2016 Dec 18. pii: S0261-5614(16)31345-0. doi: 10.1016/j.clnu.2016.12.004.
- Shyamaladevi N1, Jayakumar AR, Sujatha R, Paul V, Subramanian EH. Evidence that nitric oxide production increases gamma-amino butyric acid permeability of blood-brain barrier. Brain Res Bull. 2002 Jan 15;57(2):231-6.
- Parenti C1, Aricò G2, Chiechio S3, Di Benedetto G4, Parenti R5, Scoto GM6. Involvement of the Heme-Oxygenase Pathway in the Antiallodynic and Antihyperalgesic Activity of Harpagophytum procumbens in Rats. Molecules. 2015 Sep 15;20(9):16758-69. doi: 10.3390/molecules200916758.
- Lee DC1, Lau AS. Effects of Panax ginseng on tumor necrosis factor-α-mediated inflammation: a mini-review. Molecules. 2011 Mar 30;16(4):2802-16. doi: 10.3390/molecules16042802.
- Maurer HR1. Bromelain: biochemistry, pharmacology, and medical use. ell Mol Life Sci. 2001 Aug;58(9):1234-45
- Hashempur MH1, Sadrneshin S2, Mosavat SH3, Ashraf A4. Green tea (Camellia sinensis) for patients with knee osteoarthritis: A randomized open-labelactive-controlled clinical trial. Clin Nutr. 2016 Dec 18. pii: S0261-5614(16)31345-0. doi: 10.1016/j.clnu.2016.12.004. [Epub ahead of print]
- Georgiev MI1, Alipieva K, Orhan IE. Cholinesterases inhibitory and antioxidant activities of Harpagophytum procumbens from in vitro systems. phytother Res. 2012 Feb;26(2):313-6. doi: 10.1002/ptr.3555. Epub 2011 Jul 1.
- Daily JW1, Yang M2, Park S2. Efficacy of Turmeric Extracts and Curcumin for Alleviating the Symptoms of Joint Arthritis: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. 2016 Aug;19(8):717-29. doi: 10.1089/jmf.2016.3705. J Med Food.
- Kim S1, Lee Y, Cho J. Korean red ginseng extract exhibits neuroprotective effects through inhibition of apoptotic cell death. Biol Pharm Bull. 2014;37(6):938-46.
- Egashira N1, Ishigami N, Pu F, Mishima K, Iwasaki K, Orito K, Oishi R, Fujiwara M. Theanine prevents memory impairment induced by repeated cerebral ischemia in rats. Phytother Res. 2008 Jan;22(1):65-8.
- Marks DM1, Shah MJ, Patkar AA, Masand PS, Park GY, Pae CU. Serotonin-norepinephrine reuptake inhibitors for pain control: premise and promise. Curr Neuropharmacol. 2009 Dec;7(4):331-6. doi: 10.2174/157015909790031201.
- Outlaw J1, Wilborn C, Smith A, Urbina S, Hayward S, Foster C, Wells S, Wildman R, Taylor L. Effects of ingestion of a commercially available thermogenic dietary supplement on resting energy expenditure, mood state and cardiovascular measures. J Int Soc Sports Nutr. 2013 Apr 30;10(1):25. doi: 10.1186/1550-2783-10-25.
- Baratloo A1, Rouhipour A2, Forouzanfar MM1, Safari S1, Amiri M3, Negida A4. The Role of Caffeine in Pain Management: A Brief Literature Review. Anesth Pain Med. 2016 Mar 26;6(3):e33193. doi: 10.5812/aapm.33193. eCollection 2016.
- Joel J Gagnier,1,2 Sigrun Chrubasik,3,4 and Eric Manheimer5 Harpgophytum procumbens for osteoarthritis and low back pain: A systematic review. BMC Complement Altern Med. 2004; 4: 13. Published online 2004 Sep 15. doi: 10.1186/1472-6882-4-13
- Nathan PJ1, Lu K, Gray M, Oliver C. The neuropharmacology of L-theanine(N-ethyl-L-glutamine): a possible neuroprotective and cognitive enhancing agent. Herb Pharmacother. 2006;6(2):21-30.
- Vidhya Rathnavelu,1 Noorjahan Banu Alitheen,2 Subramaniam Sohila,3 Samikannu Kanagesan,4 Potential role of bromelain in clinical and therapeutic applications. Biomed Rep. 2016 Sep; 5(3): 283–288. Published online 2016 Jul 18. doi: 10.3892/br.2016.720
- Harima A1, Shimizu H, Takagi H. Analgesic effect of L-arginine in patients with persistent pain. Eur Neuropsychopharmacol. 1991 Dec;1(4):529-33.
- Srinivasa N. Raja MD, Michelle R. Hoot PhD, and Patrick M. Dougherty PhD, Anatomy and physiology of somatosensory and pain processing. “Essentials of Pain Medicine” 3rd edition, Chapter 2, 8-15
- Patrick M. Dougherty PhD, Srinivasa N. Raja MD, and Jessica Boyette-Davis PhD, Neurochemistry of somatosensory and pain processing, “Essentials of Pain Medicine”, 3rd edition, Chapter 2, 8-15
- Editors: Gerald F. Gebhart, Robert F. Schmidt Reference Work 2013. Encyclopedia of Pain.ISBN: 978-3-642-28752-7 (Print) 978-3-642-28753-4 (Online)