A. Primary Types of Pain

1. Nociceptive Pain
   1. Heat and cold
   2. Acute intense mechanical force: surgery, trauma
   3. Chemical irritants
2. Inflammatory Pain
   1. Direct tissue damage including neurons
   2. Mediated by various chemokines and cytokines
3. Neuropathic Pain
   1. Peripheral nerve lesions - AIDS, diabetes mellitus, trauma recovery
   2. Central nervous system lesions - multiple sclerosis, spinal cord injury, stroke
4. Functional Pain
   1. No clear lesions along pain tracks
   2. Due to abnormal responsiveness or function of nervous system
   3. Includes fibromyalgia, irritable bowel syndrome, some types of non-cardiac chest pain
5. Mixed Types of Pain
   1. Cancer Pain
   2. Visceral Pain

B. Pain Sensation [1,2]

1. Mechanical, chemical, or thermal damage to tissue stimulate nociceptive neurons
2. These nociceptive ("pain sensing") neurons increase their discharge rate
   1. Discharge rate is in proportion to the logarithm of stimulus intensity
   2. High-threshold nociceptors respond only when stimulus intensity exceeds a threshold
3. Tissue Destruction
   1. Activates nociceptive neurons directly
   2. Also activates inflammatory pathways
   3. Inflammation leads to release of many cytokines with nociceptive modifying (as well as inflammatory) activities
   4. Key neural function of inflammatory compounds is to amplify nociceptive signals
   5. Thus, inflammation and pain pathways are linked (see below)
4. Nerve Fibers involved in Sensation
   1. Type A ß - light touch, hair movement (myelinated)
   2. Type A delta1 - mechanical force (myelinated)
   3. Type A delta2 - thermal, mechanical (± myelination)
   4. Type C - polymodal pain fibers (0.5-1.5µm axon diameter)
5. Nociceptive Nerve Fibers
   1. Type C nerve fibers appear to be major carriers of nociceptive signals
   2. Type A delta2 nerve fibers detect heat/cold and other noxious stimuli
   3. These fibers carry nociceptive information from visceral and somatic sites
   4. Under conditions of C fiber damage, A delta2 fibers can transmit pain information [7]
   5. The information is carried to the dorsal horn of the spinal cord
   6. The dorsal horn neurons integrates incoming signals and adapts to them ("memory")
   7. Pain sensation and "memory" are critical elements in neuropathic pain (below)
   8. Dorsal horn neurons form spinal ascending pathways
   9. Ascending pathways then relay nociceptive information to various brain centers
   10. These include thalamic, limbic and cortical structures responsible for affective and sensory-discriminative responses
   11. Larger nerve fibers (Aß and A-alpha) responsible for proprioception, vibratory sensation, muscle-stretch reflexes and muscle strength may also be affected in pain [10]
6. Neurotransmitters Mediating Pain
   1. Substance P (SP)
   2. Neuropeptide Y (NP-Y)
   3. ATP
   4. Neurokinin 1 (NK-1)
   5. Cholecystekinin (endogenous inhibitor of opioid receptors)
   6. Glutamate
   7. Bombesin
   8. Calcitonin Gene Related Peptide (CGRP)
   9. Adenosine
   10. Modulating effects by serotonin
7. Neurotransmitters Inhibiting Pain
   1. Peripheral opiates
   2. Central opiates (endorphins) are main pain blockers
   3. Gamma-aminobutyric acid (GABA)
   4. Glycine
   5. Enkephalins
8. Receptors Associated with Nociceptors
   1. Glutamate (NMDA and AMPA type) receptors
   2. NK-1 receptor
   3. Acetylcholine receptor
   4. Neuropeptide Y receptor
   5. PGE receptor
   6. Adenosine receptor
   7. GABA-A and GABA-B receptors
   8. Somatostatin receptor
   9. Adrenaline (epinephrine, ß-adrenergic) receptor
   10. Opioid receptors (mu, kappa, delta subtypes)
   11. CCK receptor
   12. Serotonin receptor
   13. Bradykinin receptor
   14. Histamine receptor
   15. Bombesin receptor
   16. SP (capsaicin) receptor
   17. Others

C. Neuropathic Pain [3]

1. Neuropathic pain is chronic pain which persists after an acute insult which has resolved
   1. It comprises a group of persistent pain syndromes with no clear etiology
   2. For a specific insult which has resolved, only a small percentage of patients will develop neuropathic pain
   3. Currently there is no way to predict which patients will develop neuropathic pain
   4. Chronic pain is independently related to low self-rated health [11]
2. Classification of Neuropathic Pain
   1. Currently classified on basis of insult which caused the insult to nervous system
   2. It appears that any type of trauma can induce long-term, "memory"-like pain responses
   3. Moreover, ischemic, metabolic, toxic, infectious or other tissue damage can lead to neuropathic patin syndromes
   4. Allodynia - pain evoked by a normally innocuous stimulus
   5. Hyperalgesia - enhanced pain evoked by a noxious stimulous
3. Proposed Pathophysiology [3,4,5]
   1. May be caused by primary lesion in central or peripheral nerves
   2. Spinal neuron hyperexcitation may play a critical role in persistance of pain
   3. Spontaneous activity in C fibers thought to be responsible for burning pain
   4. In addition, C fiber activity may be responsible for spinal neuron hyperexcitation
   5. Stimulus independent activity in large myelinated type A fibers can cause paresthesias
   6. Increased expression of ion channels and receptors that initiate and mediate action potentials
   7. Tetrodotoxin insensitive sodium channels are likely involved in spontaneous activities
   8. Sympathetic nervous system may have some role in a few patients
   9. Reduction in GABA inhibitory neurotransmitters in dorsal horn has also been found
   10. NMDA type glutamate receptors in the CNS also play a key role
   11. Prodynorphin, an opioid neuropeptide, is expressed in spinal interneurons
   12. Prodynorphin stimulates kappa-opioid receptor signalling [8]
   13. Inflammation, driven by initial pain stimulus, can perpetuate neuronal firing
   14. Chemokines and their receptors may play an important role in maintaining neuronal firing [4]
   15. Stress response (hypothalmic-pituitary-adrenal) axis plays some role in pain sensation
4. Symptoms
   1. Persistent or paroxysmal pain independent of a stimulus
   2. Pain may be shooting, lancinating or burning
   3. Stimulus evoked pain may also occur and includes hyperalgesia and allodynia
   4. Hyperalgesia is increased pain response to suprathreshold noxious stimulus
   5. Hyperalgesia is due to abnormal processing of nociceptive input (likely dorsal horn)
   6. Allodynia is sensation of pain elicted by non-noxious stimulus
   7. Allodynia may be caused by action of low threshold Aß fibers at CNS level or by reduction in the threhold of nociceptor terminals in the periphery
5. Common Neuropathic Pain Conditions
   1. Trigeminal Neuralgia
   2. Reflex Sympathetic Dystrophy Syndrome
   3. Post-Phlebitic Syndrome
   4. Phantom-Limb Syndrome
   5. Diabetic neuropathy
6. Current Therapy
   1. Largely inadequate
   2. Carbamazepine and gabapentin have reasonably good efficacy in trigeminal neuralgia
   3. Gabapentin (Neurontin®) has good efficacy in postherpetic neuralgia, diabetic neuropathy
   4. Combined gabapentin + morphine is superior to either for severe neuropathic pain [12]
   5. Opioids - usually necessary to adequately control pain but equivocal short term efficacy [13]
   6. Higher doses of opioids more effective on pain control but not sleep or activity levels compared with lower doses in chronic neuropathic pain [9]
   7. Other antiepileptics, particularly with sodium channel blocking activity
   8. Mexilitine - antiarrhythmic / analgesic with Na channel blocking activity
   9. Alpha adrenergic receptor blockers
   10. Calcium channel blockers have little activity
7. Experimental Therapy
   1. Sodium Channel Blockers - specific for neuronal Na Channels
   2. NMDA Antagonists
   3. Neurokinin 1 Receptor blockers
   4. Neuronal nitric oxide synthase blockers / glycine site antagonists
   5. Protein kinase C gamma inhibitors
   6. Chemokine receptor blockers [4]
   7. Nerve growth factor

D. Visceral Pain [6]

1. Characteristics
   1. Not evoked from all viscera (not from kidney, liver, lung parenchyma)
   2. Not always linked to visceral injury
   3. Diffuse and poorly loclaized
   4. Often referred to other locations
   5. Accompanied with motor and autonomic reflexes (nausea, vomiting, muscle tension)
2. Mechanisms
   1. High threshold receptors and intensity coding receptors contribute to visceral pain
   2. Brief acute pain (such as acute colonic pain) likely triggered by activation of high threshold afferents
   3. Extended forms of noxious stimuli (such as ischemia) result in sensitization of high threshold receptors and stimujlate previously unresponsive silent nociceptors
   4. Once sensitized, these nociceptors will fire early in noxious stimulus process
   5. Organ inflammation (including that related to ischemia) augments these processes
3. Afferent Neurons Innervating Somatic and Visceral Tissues
   1. Two distinct biochemical classes: peptide class (SP and CGRP) and non-peptide class
   2. These neurons are fine caliber unmyelinated (Type C) primary afferents
   3. Most visceral afferent fibers belong to the SP/CGRP class of neurons
   4. SP appears to play an important role in mediating visceral pain
4. Spinal Pathways
   1. Three different pathways appear to carry visceral nociceptive information
   2. Dorsal column
   3. Spino(trigemino)-parabrachioamygdaloid
   4. Spinohypothalamic
5. Repeated noxious stimulation of visceral afferents can induce excitability in the CNS
   1. Changes in both the spinal cord and brain have been found
   2. May play a role in autonomic and motor reflexes commonly found with visceral pain
   3. Hunched posture in appendicitis may be due to these changes
6. Treatment
   1. Current treatment is symptomatic with little specificity for visceral pain pathways
   2. Opiates are the mainstay of therapy for severe visceral pain
   3. However, blocking substance P may be more specific and effective
   4. Serotonin receptors may reduce peripheral neural sensitization
   5. NMDA inhibitors may reduce central neural sensitization

E. Pain And Inflammation [1]

1. Leukocytes and platelets may release locally active neurohormones causing pain
   1. Prostaglandin E
   2. Adenosine
   3. Bradykinin
   4. Histamine
   5. ATP
   6. Opioids
   7. Adenosine
   8. Glutamate
   9. Serotonin
2. Lymphocytes also have opiate receptors which may down regulate inflammation
3. May explain efficacy of glucocorticoids in some pain-related conditions
   1. Inflammatory diseases
   2. Neoplastic diseases

References

1. Woolf CJ. 2004. Ann Intern Med. 140(6):441
2. Loeser JD and Melzack R. 1999. Lancet. 353(9164):1607
3. Woolf CJ and Mannion RJ. 1999. Lancet. 353(9168):1959
4. White FA, Jung H, Miller RJ. 2007. Proc Natl Acad Sci USA. 104(51):20151
5. Gottschalk A, Smith DS, Jobes DR, et al. 1998. JAMA. 279(14):1076
6. Cervero F and Laird JMA. 1999. Lancet. 353(9170):2145
7. Baron R. 2000. Lancet. 356(9232):785
8. Vogt BA. 2002. NEJM. 347(5):362
9. Rowbotham MC, Twilling L, Davies RS, et al. 2003. NEJM. 348(13):1223
10. Mendell JR and Sahenk Z. 2003. NEJM. 348(13):1243
11. Mantyselka PT, Turunen JHO, Ahonen RS, Kumpusalo EA. 2003. JAMA. 290(18):2435
12. Gilron I, Bailey JM, Tu D, et al. 2005. NEJM. 352(13):1324
13. Eisenberg E, McNicol ED, Carr DB. 2005. JAMA. 293(24):3043