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9 Articles in Volume 13, Issue #9
Perioperative Pain Plan: Why is it Needed
A Case for Spinal Cord Stimulation Therapy—Don’t Delay
History of Pain: The Nature of Pain
Safe Usage of Analgesics in Patients with Chronic Liver Disease: A Review of the Literature
PROP Versus PROMPT: FDA Speaks
Editor's Memo: Long-Acting Opioids: More Than a Labeling Issue
Use of Long-term Muscle Relaxants
PAINWeek Highlights: Coping Skills, Insomnia, and Opioid Abuse Deterrence
Letters to The Editor

History of Pain: The Nature of Pain

“From the brain alone arise our pleasures, laughter, and jests, as well as our sorrows, pain, and griefs.”—Hippocrates

Our thinking regarding the nature of pain has shifted over the past four centuries from the linear dualistic concepts of Descartes to the Gate Control Theory of Pain, a more global model that includes affective components of pain.1,2 The evolution of scientific research has helped us appreciate that the pain experience is more complex and highly multifaceted from the subjective to the specific. This article will discuss the nature of pain with some general assumptions based on our current understanding and then move to more specific considerations.

Subjective Nature of Pain

After 30 years of experience working with pain patients, it is obvious to me that the pain experience is subjective by nature. The pain experience can change on a moment’s notice, depending on the external demands imposed on our nervous system. So why is it so difficult to accept the subjective nature of pain?

One explanation is that the nature of science has been based on the empirical search for cause-and-effect relationships and the scientific community is uncomfortable with subjective data. Today’s neuroscientists, for example, search for more specific intracellular mechanisms to explain the pain experience. Professionally, I use subjective impressions to formulate my clinical impressions and treatment plans.

Second, the individual nature of the pain experience is highly variable. As we know, no two patients are the same even though they can be matched on numerous physical, social, and psychological factors. Because the pain experience is so individualized, this raises additional challenges for the physician treating pain patients.

Third, pain is a perceptual experience, which involves multiple integrated systems that act in a coordinated fashion. The pain experience as a perceptual process was mentioned throughout the 19th and 20th centuries, culminating with the work of Livingston, and Melzack and Wall.3,4 When I was a faculty member in the anesthesiology department at Oregon Health & Science University (OHSU), I attempted to impress upon our anesthesia residents that to be effective in working with chronic pain patients you needed to treat the patient’s perception of their pain. Further, it is important to consider that perception has thresholds, which can be explained by modifications in the periphery after injury or inflammation.

Loeser’s Model of Pain

In the August issue of Practical Pain Management, I introduced the Melzack and Casey model of pain that was published in 1968 (Figure 1).5 I still use it today to formulate my clinical impressions and treatment plans. Now, I would like to introduce another more contemporary model of pain by John Loeser (Figure 2).6 In Loeser’s model, nociception is at the center—which is physiological in nature and similar to the sensory component of the Melzack and Casey model. This model is based on overlying circles that are actually linear in nature. It starts with a physiological stimulus (nociceptive) that leads to pain (sensory) and results in suffering (affective). Finally, the outer circle represents pain or antalgic behaviors.


The main difference between the two models is that the Melzack and Casey model is circular in nature and all of the components are interdependent. The Loeser model, by contrast, is linear in nature. Accumulating research suggests that our nervous system is highly integrated, interdependent, and reciprocal in nature.

Definition of Pain

Next, we need to consider how we define pain. There are a number of definitions of pain as represented by various pain organizations. The definition that predominates research is promulgated by the International Association for the Study of Pain (IASP): “An unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”7 IASP also added that pain is a subjective experience. It is associated with our perception of the event and influenced by our past experiences. It is important to note that this definition is not a dualistic, either sensory or emotional experience, but a combination of both, as reflected in the Gate Control Theory of Pain.

Acute vs Chronic

We now need to consider how acute pain is differentiated from chronic pain. In other words, what is a normal response to an event such as trauma or surgery as compared with abnormal persistent pain that continues beyond an expected timeframe. The expected timeframe is a hotly debated topic, but, generally, it is felt that pain persisting longer than 3 to 6 months (outside the expected timeframe of recovery) is considered chronic. There are many in the field, including pain physicians, researchers, and pain psychologists, that feel that the passage of time is somewhat of an arbitrary and artificial benchmark. John J. Bonica, MD, suggested that chronic pain be defined as pain that persists longer than 1 month beyond the normal healing period or that is associated with a pathological process that causes continuous or recurrent pain over months or years.8 According to Serge Marchand, PhD, an expert in pain mechanisms, the distinction between acute and chronic pain is essential, because acute pain plays a protective role and acts as an alarm. Further, acute pain enables us to recognize that there is a problem. Conversely, chronic pain does not play a protective role if it persists long after the triggering event is resolved.9

How Pain Works

As we move toward more specific considerations regarding the nature of pain, some basics about the nervous system should be reviewed. The history of pain provides valuable background on the evolution of thinking regarding the neurophysiology of pain.1,2 As noted, Charles Sherrington (1857-1952) was the first to introduce the term nociception (activity of receptors and nerve fibers caused by potentially harmful stimulation of the body).10 Today, we know that for painful stimulation to reach consciousness, it has to be influenced by mechanisms within the central nervous system (CNS). This influence can increase or decrease the nociceptive stimulus. Further, we need to understand the process of the painful stimulus as it travels from the periphery to the higher centers in the brain.

From nociceptive stimulation to perception, it is now known that a whole series of endogenous mechanisms influence our experience of pain. These excitatory and inhibitory mechanisms may increase or reduce the nociceptive signal that translates into more or less intense pain.9

So how does this process begin? To answer this question we need to introduce the term transduction: the process by which the energy of a stimulus is transformed into an electrical response. How does the energy of a stimulus transfer into an electrical response? According to current thinking, the nociceptor has more than one transduction mechanism that result from direct excitation or through receptor cells. Continuous painful stimulation results in sensitizing the CNS, which contributes to the pain experience.9 There are three categories of pain fibers as described in Table 1.

Pathways of Pain Reception And Transmission

Over the course of my pain practice, many of my patients have experienced radiating pain. It is especially prevalent in patients who present with severe back or neck injuries. This type of pain is quite different from pain generated from the periphery, which implier a different function. Marchand cites a number of characteristics that describe radiating pain. The condition has different transmission speeds and the precise location does not assume the same importance. Further, radiating pain often develops gradually.9 The body reacts instinctively to radiating pain that results in splinting or chronic muscle contraction. We must remember that the body will protect itself when injured by forming a natural splint, which compounds the pain experience by adding another source of pain. Research that started with Henry Head (1861-1948) and has progressed over the past 100 years indicates that radiating pain follows certain zones called dermatones.11 The path radiating pain follows throughout the different zones will pass through different segments in the spinal cord. The transmission of radiating pain is not well understood at this time. Regardless of this dilemma, Marchand stated, “In all cases the subjective localization of the resulting pain is not representative of the site of pathology.”9


There are two important concepts that need to be introduced in order to fully appreciate the pain experience at the neurophysiological level.

First is temporal summation, which results from different speeds between the faster and slower fibers (A-delta and C fibers). According to Marchand, “high frequency repetitive nociceptive afferent stimulation will produce a temporal summation of the nociceptive afferent impulses originating from the slower C fibers. This accumulation of nociceptive activity within the spinal cord is called wind up, which contributes to spinal sensitization.”9 The concept of wind up is important for patients to understand at the clinical level. When I explain wind up to patients I use the example of a light switch to illustrate that pain does not switch on and off, but accumulates or winds up. If the patient understands the concept of wind up, they can use behavioral techniques to neutralize sympathetic reactivity before it builds or winds up.

The next important concept to consider is spinal sensitization, which has received considerable attention over the past few years. Spinal sensitization is defined as “an increase in excitability and spontaneous discharge of the dorsal horn neurons of the spinal cord, an expansion of receptor fields, and an increase in responses evoked by the stimulation of small caliber fibers (hyperalgesia) and large caliber fibers (allodynia).”9

Spatial summation is also important to consider since pain stimuli can cover larger areas on the skin, as in the case of severe burns. When nociceptors are included, it has a multiplying effect on the impulses traveling to the CNS that results in a more intense perception of pain.9 Both of these concepts are relevant to the study of fibromyalgia as a chronic pain condition. Recent research has suggested that fibromyalgia patients may have a deficit in the inhibitory system, which is not found in other pain conditions.12

Periphery to CNS

To continue our understanding of the pain signal, we need to address the transmission from the periphery to the central nervous system (CNS). This is not an easy concept to explain, because of the variety of receptors and overlap of their receptive fields. In addition, the pain signal is influenced by a number of neurochemicals found along the pathways that can stimulate or sensitize the nociceptor.

As the pain signal progresses to the dorsal horns (region of the spinal cord where afferent fibers enter the spinal cord) from the periphery, the fibers are separated into two groups: The large fibers, A-beta, enter on the dorsal medial side; and the smaller fibers, A-delta and C fibers, enter on the ventrolateral position. The grey matter, composed of all bodies and the unmyelinated portions of nerve fibers of the spinal cord, is divided into 10 layers or laminae. The A-delta fibers end in laminae I, afferent fibers coming from the deep tissue end in laminae I and V, and C fibers end in I and II. The larger, A-beta fibers end in laminae III or deeper (Figure 3).9

Dorsal Horns

The workings of the dorsal horn becomes very interesting because different fibers are coming together from different systems that connect with each other. According to Marchand: “The confluence of afferent impulses originating from different systems allows us to better understand the interaction that can exist among systems that seem independent at first. Therefore, muscular pain could be exacerbated by new visceral pain and vice versa.”9 As I explain to my patients, you can experience multiple types of pain, which can act in an additive fashion as the pain experience reaches consciousness.

As we move further along in our understanding of pain, we need to discuss what happens to the pain signal once it enters the CNS. Basically, there are three types of neurons that play a specific role. First, there are projection neurons; neurons with long axons that link it to remote parts of the nervous system, muscles, or glands. Second, there are excitatory interneurons; these are neurons that send the signal from one cell to another and connect signals that are transmitted from the CNS to PNS (peripheral nervous system or efferent neurons). Third, there are inhibitory neurons that prevent activation of the receiving cell.9

We can now appreciate the complexity of the pain signal as it enters the CNS. Try to imagine a 3-wire electrical cord where each wire has a specific function. Within each of the three major groups of neurons, there are specific neurons with specific functions and some with multiple functions. Now add multireceptive or wide-dynamic neurons, which basically gather information provided by primary afferent nociceptors with mechanoreceptors. Wide-dynamic range neurons (WDR) respond in a graduated manner to stimulation.9 According to Le Bars, these neurons include excitatory and inhibitory areas. Modification of these receptive fields can play an active role in certain pain conditions.13 A discussion of these specific functions is beyond the scope of this article.

As the pain signal exits the dorsal horn, the pain pathway becomes more unpredictable based on surgical outcome data. Evidence from ablative procedures that targeted pain-conducting pathways suggests that pain messages travel to the brain by multiple pathways. These findings help explain why sympathetic ablations are not always effective in eliminating pain.

One pathway that is important to our discussion is the spinoreticulothalamic tract. This pathway is composed of axons that travel from the spinal cord to the brainstem reticular formation before establishing their connection with the thalamus. This tract is divided into the lateral and medial tracts and both are responsible for pain transmission and project to the thalamus.9 According to Willis, the spinothalamic tract has the necessary qualities for localization and perception. This is relevant for the sensory discriminative component of pain. Further, the spinoreticular tract projects toward the brain stem, thalamus, and cortex, which plays a major role in the perception or motivational-affect component.14 Both of these components have major implications for the Gate Control Theory of Pain.4

Spinoreticular Tract

The lateral and medial tracts project upward to the thalamus, which basically serves as a relay station for almost all sensory information going to and from the forebrain. Keep in mind that the forebrain or frontal cortex is responsible for complex intellectual functions. Prior to the 19th century, pain was thought to be primarily an old brain or limbic phenomenon. Today, we know that the new brain, or neocortex, is intrinsically involved in the pain experience primarily due to the thalamus acting as a relay station. The thalamus, therefore, becomes a center for the integration of nociceptive information, which subsequently plays an important role in pain modulation.9 Henry Head stated, “pain is a very complex sensory and emotional experience.”11,15 The development of the MRI, fMRI and PET scans has confirmed that the higher centers in the brain play an important role in the perception of pain. We also know these higher cortical centers contribute valuable influences, such as reasoning and higher order intellectual processing in the perception of pain.

In addition, based on recent evidence we now know there are four cerebral centers that play a role in the pain experience. They are the primary and secondary somatosensory cortex, which processes sensory information (touch, temperature and pain) and is connected to the sensory-discriminative components of pain. Both of these centers are located in the parietal lobe. The third is the anterior cingulate cortex, which is located under the temporal lobe. This part of the cortex is part of the old brain or limbic system. Evidence suggests that the anterior cingulate cortex plays an important role in the motivational-affective part of the pain experience. Finally there is the insular cortex, which is located deep within the temporal and frontal lobes. Recent evidence now suggests that this center plays an important role in the affective component of pain.16 Based on the above findings, we can now fully appreciate Henry Head’s comments in the early part of the 20th century. He maintained that the nature of the pain experience is highly complex because of the intricate balance between the sensory and affective components.


The knowledge of the above neurophysiological components now sets the stage for the next step in our journey that began at the periphery and now has arrived at the level of the brain. We now have to consider what happens next to the pain signal, since what goes up, must come down. To begin this discussion, I need to introduce pain modulation that occurs within the body. The Gate Control Theory of Pain influenced our thinking away from linear pain transmission to a model that asserted that the pain signal is modulated once it enters the CNS. Modulation can act either in an excitatory manner, where the pain signal is increased, or in an inhibitory fashion, where the pain signal is decreased or absent. It is important to consider that when inhibition is interrupted, it can result in chronic pain.

A number of neurotransmitters are associated with the inhibition system, including serotonin (5-hydroxytryptamine or 5-HT), which is a monamine neurotransmitter that plays a role in temperature regulation, sensory perception, and sleep. Next is norepinephrine, a neurotransmitter that belongs to the catecholamines. It is produced both in the brain and in the PNS, sympathetic division of the autonomic nervous system, and produces a variety of behavioral effects including pain inhibition. There is gamma-aminobytyric acid (GABA), an amino acid transmitter operating in the brain whose main function is to inhibit neuronal firing.

In addition, we need to discuss the different levels of inhibition that occur within the CNS. According to Marchand, there are spinal mechanisms that can be diffuse or local in nature.9 To further explain spinal modulation, Melzack and Wall hypothesized that selective stimulation of the large caliber afferents (A-beta) pain neurons blocks the smaller pain fibers (A-delta and C fibers).4 Selective stimulation of the afferent non-pain fibers reduces the transmission of pain as it enters the spinal cord, which influences pain only in the dermatone, an area of the skin innervated by sensory fibers from the dorsal root.9

On a clinical level, I have evaluated more than 5,000 chronic pain patients who were being considered for a spinal cord stimulator (SCS). My experience and outcome data on the effectiveness of SCS is mixed, which suggests that our current understanding of selective spinal modulation is far from complete.8,15,17-19

Pain is further modulated in an apparent coordinated fashion, including a number of areas within the brain that involves multiple descending mechanisms. The work of Fields and Basbaum has demonstrated that the rostioventral medulla (toward the front of the lower half of the brainstem) plays an important role in pain modulation.20

Further, specific areas involved in descending inhibition include the periaqueductal gray matter, which is a cluster of neurons located in the pons and nucleus raphe magnus. The pons is the main structure that receives and transmits information from the forebrain to the spinal cord and PNS. Marchand points out that the two regions contain origins of the descending serotonergic and noradrenergic tracts, which contribute to the inhibition of the pain signal.9 It is interesting to note that low concentrations of both serotonin and norepinephrine in the cerebrospinal fluid have been associated with fibromyalgia.21 The above findings reinforce the important usage of antidepressant medicines to improve inhibitory mechanisms.

Higher Centers of CNS

Finally, we need to include the role that the higher centers in the CNS play in pain modulation. Our knowledge has recently improved with the advancement of imaging technology, especially when considering the roles sensory and emotional components play in the higher cortical regions.22 A number of regions in the higher cortex are involved in pain perception, which relate to the sensory-discriminative component of the Gate Control Theory of Pain. The interaction between higher centers and the limbic structures play a role in the motivational-affective component of the theory. Both of these influences contribute to pain modulation.9 I pointed out earlier, the process of pain perception is personal and dependent on the individual’s past experiences, cultural influences, and psychological status, all of which need to be considered when evaluating the patient who presents with chronic pain.


Our knowledge of the pain experience has moved forward from a simple linear, dualistic model to a more global, intricate model that includes the importance of affective or emotional influences. Advances in neurophysiology and neuroanatomy have improved our knowledge with regard to the role modulation plays in the pain experience. Improvements in imaging have provided valuable information that has resulted in improved care for the pain patient.

Last updated on: November 21, 2013
Continue Reading:
History of Pain: The Psychosocial Assessment of Pain
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