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Pain is a protective mechanism that occurs when tissues are being damaged, with the intent to cause the individual to react and remove the painful stimulus.1 Pain is one of the top reasons patients seek care from a physician and is one of the most common ailments treated by physiatrists. For back pain alone, the total cost in the United States ranges from $100-$200 billion annually, with the direct costs estimated at $46.8 billion per year.2 In order to properly treat patients with pain, it is essential that the physician understand the mechanisms responsible for pain.

Sensory receptors:

  1. Mechanoreceptors
  2. Thermoreceptors
  3. Electromagnetic receptors
  4. Chemoreceptors
  5. Nociceptors

Nociceptors are pain receptors:

  1. Free nerve endings in skin and other tissues
  2. Elicit pain by
    1. Mechanical pain stimuli
    2. Thermal pain stimuli
    3. Chemical pain stimuli
      1. Prostaglandins and substance P enhance the sensitivity of nociceptors without direct excitation
      2. Bradykinin, serotonin, histamine, potassium ions, acids, acetylcholine and proteolytic enzymes directly excite chemically induced pain fibers1

When trauma or injury occurs to the cell membrane, phospholipase A2 is released, which converts the phospholipid bilayer membrane of the cell into arachidonic acid. Arachadonic acid is then converted to leukotrienes by lipoocygenase and prostaglandins by cyclooxygenase. 3

A painful stimulus is sensed by the peripheral nociceptor, first by Aδ fibers – fast pain fibers – and about a second later by C fibers- slow pain fibers.

Aδ fibers

  1. Small in diameter (though larger than C fibers)
  2. Myelinated
  3. Fast conducting: 6-30m/sec
  4. Stimulated by mechanical or thermal pain stimuli
  5. Conduct sharp, localized pain
  6. Abundant in the cutaneous tissues and relatively deficient in deep structures
  7. Transmitter: glutamate

C Fibers

  1. Smallest diameter of the nerve fiber types
  2. Unmyelinated
  3. Slow conducting: 0.5-2m/sec
  4. Transmit dull, diffuse pain
  5. Transmitter: substance P.1
Pain Signal Pathway

Afferent nerve fiber

Dorsal horn cells in the spinal cord

Synapse on the ipsilateral side

Ascend the contralateral side of the cord (primarily via the lateral spinothalamic tract, with some fibers traveling in ventrolateral spinoreticulothalamic tract)

Synapse in the thalamus with neurons projecting to the cerebral cortex – the somatosensory area I and II in the parietal lobe, cingulate gyrus, mediofrontal cortex, insular cortex and cerebellum.1,3


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”4

Acute Pain

Acute pain refers to pain provoked by a specific disease or injury, serves a useful biologic purpose and lasts less than 3 to 6 months duration.5 Acute pain is categorized as nociceptive, neuropathic or inflammatory.

Nociceptive pain

  1. Normal response to noxious insult or injury of tissues
  2. Somatic: musculoskeletal (joint pain, myofascial pain)
  3. Cutaneous
  4. Visceral: from the hollow organs and smooth muscle. 6

Neuropathic pain

  1. Initiated or caused by a primary lesion or disease in the somatosensory nervous system.
  2. After tissue or nerve damage, proinflammatory cytokines and chemokines are upregulated in spinal cord glial cells, which plays an important role in the establishment and maintenance of neuropathic pain.7
  3. Includes diabetic neuropathy, postherpetic neuralgia, spinal cord injury pain, phantom limb (post-amputation) pain, and post-stroke central pain. 6

Inflammatory pain

  1. A result of activation and sensitization of the nociceptive pain pathway by a variety of mediators released at a site of tissue inflammation.
  2. The key mediators are:
    1. proinflammatory cytokines [interleukin (IL)-1-alpha, IL-1-beta, IL-6 and tumor necrosis factor (TNF)-alpha]
    2. chemokines
    3. reactive oxygen species
    4. vasoactive amines
    5. lipids
    6. adenosine triphosphate (ATP)
    7. acids
    8. other factors released by infiltrating leukocytes, vascular endothelial cells, or tissue resident mast cells. 6

Chronic pain

Chronic pain is pain that persists beyond the course of an acute disease, or after tissue healing is complete, and typically greater than 3 to 6 months. 5

Chronic pain has two components – the sensation of pain and the reaction or suffering aspect of pain; thus, both aspects must be considered when treating chronic pain. Psychological implications in chronic pain include a person’s subjective tolerance threshold for pain, as well as secondary gains and reward mechanisms. 3

The sensation of chronic pain is typically subcategorized as either neuropathic pain, inflammatory pain or cancer pain.

Neuropathic PainInflammatory PainCancer Pain
Following nerve injuryFollowing tissue injuryDirect effect of tumor
Glial activationSpinothalamic tractEffect of Chemotherapy
Mediators include proinflammatory cytokines and chemokinesMediators include proinflammatory cytokines and chemokinesEffect of Radiation


The placebo effect is defined as any improvement of symptoms or signs following a physically inert intervention.8

The placebo effect is a complex psychobiological phenomenon resulting from various mechanisms depending on the disease, system and therapeutic intervention. 9 The magnitude of the placebo effect may differ between clinical trials and clinical practice: there may be a change in behavior as a result of being studied (the Hawthorne effect) or if the subject expects a positive outcome the placebo effect is potentially intensified (the Halo effect).9

The extent a patient experiences the placebo effect is partially dependent on psychological and personality traits. People with dispositional optimism, behavioral drive and reward responsiveness are more likely to respond to placebo analgesia – likely through increased activation of endogenous opioids.9

Placebo and pharmacologic treatments yield similar neuronal changes in pain, depression and motor disorders (Parkinson’s disease). All placebos are partially effective by engaging the Reward System in the brain (the major mesolimbic and lesser mesocortical pathways). The Reward System is a dopaminergic pathways that runs from the ventral tegmental area via the medial forebrain bundle to the nucleus accumbens. Dopamine release is common throughout all placebo effects, while other neurotransmitters involved in the reward pathway operate on a disease specific model (i.e.: serotonin in depression, opiates/endorphins in pain).10

Functional and molecular neuroimaging, such as Positron Emission Tomography (PET) and functional magnetic resonance imagining (fMRI) of the brain have visualized similar neurobiological manifestations of placebo and active therapy. 9,10 PET shows comparable changes in regional cerebral blood flow, regional cerebral glucose metabolism, mu receptor availability, and synaptic availability of dopamine between placebo and active therapy, while fMRI measures similar blood oxygen level-dependent changes in studies on pain, acupuncture, placebo analgesia, placebo anxiolysis, and emotional processing. Both fMRI and PET show increased dopamine release in the mesolimbic system if expecting active treatment (expectancy-induced reward).10


Chronic pain is hallmarked by an expression of neural plasticity in the peripheral and central nervous systems.11 Though many details of the exact mechanisms of the conversion from acute to chronic pain remain unknown, several neuronal mechanisms have been implicated, as well as changes in gene and gene product expression at the transcriptional, translational and post-translational levels.11,12 Glial cells provide supports to neurons and maintain homeostasis in the peripheral and central nervous systems. A malfunction in the glial cells, a “gliopathy” has been indicated in the failure of acute pain to resolve, and thus become chronic.11


Undertreating of both acute and chronic pain remains a prevalent issue in pain management. As further research into the neurotrasmitters, proinflammatory mediators and neural mechanisms involved in pain continue to evolve, there is hope that this information will translate into improvements in pain medications. Current pharmacotherapy cannot specifically target glial cells separate from neurons, but as further research evolves, perhaps so will our treatment options. 11 Or perhaps future treatments will be able to target epigenetic factors, like non-coding RNAs implicated in the mechanism for gene regulation in the dorsal root ganglia.12


  1. Guyton, Arthur C., and John E. Hall. “Somatic Sensations: II. Pain, Headache, and Thermal Sensations.” Textbook of Medical Physiology. Philadelphia, PA: Elsevier Saunders, 2011. 583-587. Print.
  2. Ma VY, Chan L, Carruthers KJ. Incidence, Prevalence, Costs, and Impact on Disability of Common Conditions Requiring Rehabilitation in the United States: Stroke, Spinal Cord Injury, Traumatic Brain Injury, Multiple Sclerosis, Osteoarthritis, Rheumatoid Arthritis, Limb Loss, and Back Pain. Archives of Physical Medicine and Rehabilitation. 2014;95(5):986-995.
  3. Fields, HL and Levine, JD: Pain mechanisms and management. West J Med. 1984 Sept;141(3): 347-357.
  4. Bonica JJ. The need of a taxonomy. Pain. 1979;6(3):247–252.
  5. Grichnik KP, Ferrante FM. The difference between acute and chronic pain. Mt Sinai J Med. 1991 May;58(3):217-20.
  6. Ganong, William R. Review of Medical Physiology. New York, NY: McGraw-Hill Medical, 2005. Print
  7. Lu Y, Jiang B, Cao D,  Zhang Z, Zhang X, Ji R,  Gao Y.  TRAF6 upregulation in spinal astrocytes maintains neuropathic pain by integrating TNF-α and IL-1β signaling. Pain. 2014 Dec;155(12):2618-2629.
  8. Tavel ME. The placebo effect: the good, the bad, and the ugly. Am J Med. 2014 Jun;127(6):484-488.
  9. Murray D, Stoessl AJ. Mechanisms and therapeutic implications of the placebo effect in neurological and psychiatric conditions. Pharmacol Ther. 2013 Dec;140(3):306-318.
  10. Faria V, Fredrikson M, Furmark T. Imaging the placebo response: A neurofunctional review. Eur Neuropsychoparm. 2008 July; 18(7). 473-485
  11. Ji RR, Berta T, Nedergaard M. Glia and pain: is chronic pain a gliopathy?. Pain. 2013 Dec; 154 Suppl 1:S10-28.
  12. Lutz BM, Bekker A, Tao YX. Noncoding RNAs: new players in chronic pain. Anesthesiology. 2014 Aug; 121(2):409-17.

Author Disclosure

Stephanie E. Rand, MD
Nothing to Disclose