Author(s): Sagar S. Parikh, MD, Elisa Chiu, DO, Roy Taborda, MD
Originally published: September 11, 2015 Last updated: December 15, 2020
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Overview and Description

According to the International Association for the Study of Pain (IASP), pain is defined as an unpleasant sensory and emotional experience associated with or resembling actual or potential tissue damage. Pain is one of the top reasons patients seek care from a physician and is one of the most common ailments treated by physiatrists. Back pain alone accounts for the single leading cause of disability worldwide13. In order to effectively treat patients with pain conditions, it is essential to learn the mechanisms responsible for pain.

Pain and Nociception

Pain and Nociception are two distinct phenomena.  While Nociception is a physiologic process by which stimuli that are associated with tissue damage activate neural pathways, Pain is an individualized conscious experience.  One can say that nociception is objective in its character, while pain perception is very much subjective.  In some cases, pain can even occur in the absence of nociception.

Nociception is the peripheral and central nervous system processing of information received by nociceptors. Nociceptors are free nerve endings in the skin and other tissues that detect potentially damaging stimuli through mechanical, thermal, or chemical stimulation. Following tissue injury, a variety of chemicals are released and exude their effect on primary nociceptors.  Substances like bradykinin, serotonin, histamine, prostaglandins, and leukotrienes act as inflammatory mediators at the site of injury and either directly activate or indirectly excite nociceptors2.  Once the noxious stimuli is received via a nociceptor, it’s transduced into electrical signals, where they are transmitted along a first-order afferent neuron to the spinal cord dorsal horn where it then synapses with a second-order neuron.  Glutamate and Aspartate are the two excitatory neurotransmitters found at these synapses and are released by both presynaptic neurons and some adjacent glial cells.  Two main types of second-order neurons are Nociceptive-specific (NS) neurons and Wide Dynamic Range (WDR) neurons both located in the dorsal horn.  WDR neurons are labeled as such because they are known to receive signals from both A-beta fibers as well as the nociceptive A-delta and C fibers. From there it crosses midline to the contralateral side and travels up the spinal cord via the lateral spinothalamic tract and, to a lesser degree, the spinoreticular tract. These tracts eventually project to the thalamus and other brainstem structures.  From there they project to various cortical sites such as the somatosensory cortex, insula, anterior cingulate cortex, or the prefrontal cortex2.  From these cortical structures, descending modulatory signals project downward and modulate the signal at the level of the dorsal root ganglion, spinal cord, and supraspinal structures. GABA and glycine are key inhibitory neurotransmitters found at the supraspinal and spinal levels.  The net effect of this pain pathway (transduction at the nociceptor, transmission to the CNS, and modulation at various levels) produces an individual’s perception of pain and their overall pain experience.

Peripheral Sensitization

Peripheral sensitization is a direct consequence of primary nociceptors becoming exposed to inflammatory mediators (ex. bradykinin, serotonin, histamine, prostaglandins, cytokines, and leukotrienes) during tissue injury which then reduces the nociceptor threshold for activation and thus increases the reactivity and responsiveness of that nociceptor.  The results is an amplification of pain signaling occurring at the peripheral site of tissue injury26.

Central Sensitization

Central Sensitization represents an alteration in the central nervous system somatosensory process.  It represents not only pain hypersensitivity or hyperalgesia (a phenomenon that can also be seen in peripheral sensitization) with the lowering of nociceptor pain threshold, but also allodynia, a phenomenon where non-nociceptive neural pathways (such as A-beta fibers) begin triggering central pain pathways. Pain generation and pain pathway stimulation can occur even after tissue healing in the setting of central sensitization26.

Pain Fibers

Pain and Temperature stimuli are sensed by two types of peripheral sensory fibers, Aδ and C fibers. Of the two, Aδ fibers are larger and more myelinated, and thus conduct faster than C fibers, which are unmyelinated. Aδ fibers tend to be clustered in separated small areas, helping localize the stimulus, whereas C fibers are more numerous and broadly distributed. In contrast, A-beta fibers transmit touch sensation, are much larger in diameter, and due to their high-myelination transmit information at a faster rate than A-delta and C fibers (Table 1).

Table 1

Sensory FiberVelocitySensation
A-beta35-90 m/sec (myelinated)Touch
Aδ6-30 m/sec (thinly myelinated)Sharp, localized pain, temperature
C0.5-2 m/sec (unmyelinated)Dull, diffuse, burning pain, temperature

Relevance to Clinical Practice

Multidisciplinary approaches to pain treatment are of utmost importance, and treatment strategies are tailored based on the location and type of pain a patient is experiencing.  According to IASP, pain can be categorized as either: nociceptive, neuropathic, inflammatory, or nociplastic. It can also be characterized based on its duration, as acute and chronic pain.  These concepts are important as our treatment strategies as physiatrists or pain specialists will be directly influenced by these qualifiers.  For example, Acute pain tends to be directly related to a specific mechanism of injury and thus is easier to conceptualize, identify, and treat.  Chronic pain on the other hand typically involves and added dimension of suffering and emotional/cognitive overlay and must be handled by a more multidimensional approach.   Along this same vein, a healthcare provider would treat painful peripheral neuropathy differently than pure nociceptive pain, so the definitions are worth reviewing.

Nociceptive pain

  • Normal response to noxious insult or injury of tissues caused by activation of a nociceptive afferent nerve fiber (A-δ or C fibers).
  • These nociceptors are free nerve endings that terminate just below the skin, in tendons, joints, and in body organs
    • Somatic: pain transmitted along sensory fibers and is usually discrete and localized.
    • Visceral: pain carried by sympathetic fibers and is usually diffuse in nature or not well localized. Typically from the hollow organs and smooth muscle6.

Neuropathic pain

  • Initiated or caused by a primary lesion or disease in the somatosensory nervous system (peripheral or central nervous system) which can lead to loss of function, spontaneous “burning” pain, hypersensitivity, or allodynia.
  • After 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 pain7.
  • Includes but is not limited to diabetic or other peripheral neuropathy, postherpetic neuralgia, spinal cord injury pain, phantom limb (post-amputation) pain, and post-stroke central pain6.

Inflammatory pain

  • Pain caused by the activation of the immune response or inflammatory cascade that occurs after tissue injury or infection23. 
  • Increase in pain hypersensitivity and general sensory threshold.
  • Mediators of inflammatory pain include but are not limited to:
    • Prostaglandins, bradykinin, histamine, serotonin, Proinflammatory cytokines [interleukin (IL)-1-alpha, IL-1-beta, IL-6 and tumor necrosis factor (TNF)-alpha], adenosine triphosphate (ATP), Chemokines, Reactive oxygen species, Substance P, and Nerve Growth Factor.

Nociplastic pain (aka Centralized Pain)

Pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of peripheral nociceptors or evidence for disease or lesion of the somatosensory system causing the pain2.

Acute Pain

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

Chronic pain

Chronic pain is pain that persists beyond the course of an acute disease, or after tissue healing is presumed to have occurred, and typically lasts greater than 3-6 months5.  It is associated with significant emotional distress or functional disability that cannot be accounted for by another chronic pain condition22. Chronic pain has two components – the sensation of pain and the reaction or suffering that the patient is experiencing. Both aspects must be considered when treating patients in chronic pain and a multimodal and multidisciplinary approach is needed.  It is this additional undertone of suffering that makes treating chronic pain complex and challenging.  Psychological implications in chronic pain include a person’s subjective perception and tolerance threshold for pain, as well as secondary gains and reward mechanisms3.

Pain convergence/referred pain

Pain convergence is caused by the merging of afferent information of the visceral organs and those of somatic origin on the same spinal cord segment. This causes hyperreactivity of the dorsal horn neurons which is interpreted as coming from the same dermatome25. A good example is pain incurred during cardiac ischemia. Pain generated from cardiac tissue injury is also experienced down the left shoulder, neck, and arm because of multiple primary sensory neurons converging on a single central ascending tract. As a result, pain is perceived to come from both somatic and visceral sources.

Placebo

Placebo is defined as a beneficial effect produced by a placebo drug or treatment, which cannot be attributed to the properties of the placebo itself and must therefore be due to the patient’s belief in that treatment. The placebo effect is the reduction in pain perceived that cannot be attributed to medication or intervention alone. This effect is a powerful and complex psychological and neurobiological phenomenon that modulates one’s perception of pain. The magnitude of the placebo effect is highly variable and can be influenced by a multitude of factors. Verbal suggestions can play a large role in the placebo effect. For example, if patients are told a drug can significantly reduce their pain, they may experience a larger placebo effect than if they were told the drug may or may not be effective. Similarly, the placebo effect can have a meaningful impact on the overall management of pain even when in the presence of already strong analgesia.The “open/hidden” drug paradigm suggests that simply becoming aware of treatment enhances the overall analgesic effect and, as a result, requires less actual medication17.

Prior positive experience with an active agent has also been shown to have a larger placebo analgesic effect after placebo administration15. The extent a patient experiences the placebo effect is also 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 opioids9. Interestingly, one study demonstrated that higher treatment price led to an increase in placebo analgesia18.

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 pathway 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 imaging (fMRI) of the brain have visualized similar neurobiological manifestations of placebo and active therapy9,10. For example, functional neuroimaging reveals an important connection between the initiation of placebo analgesia in the dorsolateral prefrontal cortex and reduction in pain reported through the anterior cingulate cortex and periaqueductal gray area. Additionally, spinal inhibition can be significant under placebo via the ipsilateral dorsal horn. Together, these findings reveal placebo analgesia can alter the pain experience via inhibition of nociceptive activity.17

PET scans show 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.

Clinical application of the placebo effect is controversial and does not mean placebos should be prescribed in substitution of pain medication. Instead, this powerful effect can enhance the effectiveness of analgesic therapy by amplifying the inherent placebo component. Utilizing verbal instructions, positive cues and associations, prior positive experiences, and other social context, pain modulation can be maximized for more effective analgesia16.

Emerging Issues

Ethics of Placebo Use:

Despite several studies supporting excellent outcomes because of placebo analgesia it also poses an ethical dilemma for several medical practitioners. The physician-patient relationship risks suffering by the deceptive use of placebo as a form of treatment. However, a more ethically tenable justification for placebo use was recently demonstrated. Open-label conditions, for example, provide patients with the knowledge they are taking placebo and despite lack of traditional treatment, it has been demonstrated to yield significant clinical improvement in a variety of disorders and thus negating the need for deception16.

Chronic Pain Treatment and Therapeutics:

Chronic pain is hallmarked by an expression of neural plasticity in the peripheral and central nervous systems11. 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 levels11,12. Glial cells provide support 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 chronic11. New drug therapies are being researched to help control the alteration in activity of these glial cells and may show promise as an effective treatment strategy12.  In the interim, chronic pain should continue to be treated in a multidisciplinary fashion.

Gaps in Knowledge/ Evidence Base

According to the CDC, chronic pain affects more than 50 million adults in the United States. With the opioid epidemic rising each year, there has been an increasing effort to better diagnose and treat pain. Understanding and utilizing both pain and placebo physiology and mechanisms of action can help clinicians provide multi-faceted and creative effective analgesic treatment.

Today the treatment of pain is not limited to pain specialists, physiatrist, or even only physicians.  Multiple types of healthcare practitioners treat pain, however the knowledge base for pain understanding, diagnosis, and treatment is not standard across these different providers.  Because of this, there is a possibility of misdiagnosing or undertreating pain, and this remains to be a prevalent issue in pain management. Improper understanding and medication practices fueled the opioid epidemic and as the prescription of opioids increased in frequency over the past decade, the overall level of pain relief did not adjust in an equal manner.  This highlights the need for better knowledge and practice patterns.  As further research into the neurotransmitters, proinflammatory mediators and neural mechanisms involved in pain continue to evolve, there is hope that this information will translate into improvements in pain medications and therapies.

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Original Version of the Topic

Stephanie E. Rand, MD. Pain and placebo physiology. 9/11/2015

Author Disclosure

Sagar S. Parikh, MD
Nothing to Disclose

Elisa Chiu, DO
Nothing to Disclose

Roy Taborda, MD
Nothing to Disclose