Pain and Placebo Physiology

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 worldwide.¹ 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 distinct concepts. While nociception is a physiologic process by which stimuli that are associated with tissue damage activate neural pathways, pain is an individualized conscious experience. Nociception can be considered objective, while pain perception is highly subjective. Notably, pain may 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.² Substances like bradykinin, serotonin, histamine, prostaglandins, and leukotrienes act as inflammatory mediators at the site of injury and either directly activate or indirectly excite nociceptors.³ 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.⁴

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 receive signals from both A-beta fibers as well as the nociceptive A-delta and C fibers. These fibers cross the midline and travel up the spinal cord via the lateral spinothalamic tract and, to a lesser degree, the spinoreticular tract. These tracts eventually project to the thalamus, other brainstem structures, and eventually various cortical sites such as the somatosensory cortex, insula, anterior cingulate cortex and the prefrontal cortex.³ From these cortical structures, descending modulatory signals project downward and modulate nociception at the level of the dorsal root ganglion, spinal cord, and supraspinal structures. Gamma-aminobutyric acid (GABA) and glycine are key inhibitory neurotransmitters found at the supraspinal and spinal levels. The combined processes of nociception, transmission to the CNS, and modulation at various levels ultimately shape 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. This results in an amplification of pain signaling occurring at the peripheral site of tissue injury.⁵

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 sensitization.⁵

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 Aδ and C fibers (Table 1).⁶

Table 1

Types of Pain Fibers

Relevance to Clinical Practice

Multidisciplinary approaches are essential in the treatment of pain, with strategies tailored to 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, acute or chronic. These concepts are important as our treatment strategies as physiatrists or pain specialists are directly influenced by them. For example, acute pain tends to be directly related to a specific mechanism of injury and thus is easier to conceptualize, identify, and treat. In contrast, chronic pain typically incorporates elements of suffering, emotional stress, and cognitive factors, necessitating a multidimensional approach.

Table 2

Pain Categories

Acute pain

Acute pain refers to pain provoked by noxious stimuli, such as a specific disease or injury resulting in the release of pro-inflammatory markers leading to the activation of downstream effects.  Acute pain lasts less than 3 months, is marked by acute inflammatory reactants, and typically serves a biologic purpose. The three categorizations of acute pain are nociceptive (from tissue injury), neuropathic (from nerve injury), and inflammatory (from pro-inflammatory acute phase reactants).⁹

Chronic pain

Unlike acute pain that provides survival value in the setting of threatened tissue injury, chronic pain persists beyond the protective indication and does not play a role in healing. Typically lasting longer than 3-6 months, chronic pain is a distressing sensory and emotional process often associated with significant functional disability that cannot be accounted for by another condition.¹² Chronic pain is influenced by a bidirectional dynamic relationship between biological, psychological, and social factors termed the biopsychosocial model.¹³ Psychological implications in chronic pain include a person’s subjective perception and tolerance threshold for pain, as well as secondary gains and reward mechanisms.¹⁴ The complexities of chronic pain require a personalized multimodal, interdisciplinary approach for treatment.

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. Two current theories analyzing the pathological mechanism of referred pain attribute the phenomenon to 1) central sensitization of convergent neurons and 2) peripheral reflexes of dichotomizing afferent fibers.¹⁵ The resulting effect leads to pain arising from pathologies from distant structures that can be associated with secondary effects in the referred areas, such as hyperalgesia and trophic changes.¹⁵ One example is referred 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

The placebo effect, also known as placebo analgesia, 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 medication.¹⁶

Prior positive experience with an active agent has also been shown to have a larger placebo analgesic effect.¹⁷ 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 opioids.¹⁸ Interestingly, one study demonstrated that higher treatment price led to an increase in placebo analgesia.¹⁹ Another study examined the efficacy of the placebo analgesia effect in a virtual reality setting. The study suggested that a virtual placebo was equally as effective as a physical placebo in evaluating for acute pain. This may serve as another non-invasive, non-pharmacological tool in treating pain.²⁰

Factors that Influence Placebo Analgesia

• Verbal suggestions/cues
• Prior knowledge of treatment
• Optimism
• Behavioral drive
• Reward responsiveness
• Prior positive experience with an active agent

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).²¹

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 therapy (Table 3).^18,21 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.¹⁶

Table 3

Functional and Molecular Neuroimaging

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 analgesia.²³

Emerging Issues

Ethics of placebo use

Despite several studies supporting excellent outcomes of placebo analgesia, it also poses an ethical dilemma for medical providers. The physician-patient relationship may be negatively affected by the deceptive use of placebo as a form of treatment. However, a more ethically tenable justification for placebo use was recently demonstrated. For example, open-label conditions provide patients with the knowledge that they are taking placebo. Despite the lack of traditional treatment, it has been demonstrated to yield significant clinical improvement in a variety of disorders and thus, negating the need for deception.²³

Chronic pain treatment and therapeutics

Chronic pain is hallmarked by an expression of neural plasticity in the peripheral and central nervous systems.²⁴ 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.^24,25 Glial cells provide support to neurons and maintain homeostasis in 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.²⁴ 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 strategy. One study investigated the relationship between language and the effect of placebo. They found that the people with chronic back who spoke about their experience, pain, and themselves were most likely have a placebo analgesia versus those patients who were not vocal.²⁶ These studies further contribute to the current guidelines to treat chronic pain in a multidisciplinary fashion as well as guidance towards new innovations in treating chronic pain.

Gaps in Knowledge/Evidence Base

There has been an increasing effort to better diagnose and treat chronic pain. Understanding and utilizing both pain and placebo physiology and mechanisms of action can help clinicians provide multi-faceted, effective analgesic treatment. As further research into neurotransmitters, proinflammatory mediators and neural mechanisms involved in pain continue to evolve, this information may translate into improvements in pain medications and therapies. For example, recent research has investigated the role of NaV1.8 voltage-gated sodium channel in acute post-surgical pain transmission and demonstrated that patients treated with a NaV1.8 sodium channel antagonist after abdominoplasty or bunionectomy had statistically significantly reduced acute pain levels.²⁷ Suzetrigine, a NaV1.8 antagonist, was recently granted FDA approval for the treatment of moderate to severe acute pain, and provides an alternative to traditional opioid analgesics.²⁷

References

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Original Version of the Topic

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

Previous Revision(s) of the Topic

Sagar S. Parikh, MD, Elisa Chiu, DO, Roy Taborda, MD. Pain and Placebo Physiology. 12/14/2020

Author Disclosure

Ellie Ok, DO
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Alyssa Anderson, MD
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Samuel Olson, MD
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Jennifer Tram, MD
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