Understanding Pain Mechanisms: The Basis of Clinical Decision Making for Pain Modulation


Two Forms of Hyperesthesia

  • Allodynia: a painful response to a normally nonpainful stimulus

  • Hyperalgesia: a heightened painful response to a painful stimulus

The Anterolateral Pain Pathway System Includes the Following Tracts

  • Spinothalamic

  • Spinoreticular

  • Spinomesencephalic and spinoparabrachial

  • Spinohypothalamic

The sensations of pain and temperature are subsets of somatic sensation and are carried from the periphery through small myelinated and unmyelinated nerve endings called nociceptors. Acute nociceptive pain is triggered by noxious stimuli, such as a pinprick and excessive heat, by inflammation, or by damage to peripheral nerves. This type of pain is perceived after electrophysiologic transmission along peripheral nerves into the spinal cord, and from there to the cerebral cortex along specific pain pathways. In contrast, neuropathic pain can occur in the absence of a stimulus and is characterized by reduced pain thresholds so that normally non-noxious stimuli elicit the sensation of pain. Furthermore, an unpleasant affective and emotional experience may be associated with pain, which, once again, may or may not be associated with actual tissue damage. If pain was only a function of nociception, in the strict anatomic and physiologic sense, then when the painful stimulus is removed, the perception of pain should be eliminated. However, surgical procedures designed to transect the nociceptive transmission pathways in patients with severe neuropathic pain have met with limited success and have not brought consistent or permanent pain control. Thus, pain is more than just the transmission of sensations from nociceptors that have been stimulated by noxious stimuli.

Pain serves as a warning signal to alert an individual of potential harm so that an appropriate response can result. That response may be a withdrawal mechanism to prevent or minimize injury, or the response may be to seek medical help if the injury warrants such attention. The behavior that an individual demonstrates in response to painful stimuli is an adapted behavior that involves learning and memory. Not all individuals respond the same way to nociceptive input because the perception of pain is subjective. As a result, pain can be difficult to evaluate and treat. To aid with this evaluation and treatment of pain, this chapter is designed to review current pain terminology and mechanisms of pain in both the peripheral nervous system (PNS) and central nervous system (CNS) to enhance the understanding of the role that clinicians play in pain management. In addition, this knowledge will allow the clinician to determine the level within the nociceptive pathways at which specific interventions are most effective in modulating pain.

Pain Terminology

Current Pain Terminology

The International Association for the Study of Pain (IASP) has developed a classification system for pain that includes definitions of pain terms and descriptions of pain syndromes. Terminology used to define pain has undergone alterations and additions through the past decades. Two new terms have been added by the IASP—neuropathic pain and peripheral neuropathic pain. Also, the terms sympathetically maintained pain and sympathetically independent pain have been used ( Table 113-1 , online). These latter two types of pain are associated with complex regional pain syndromes, types I and II. These two syndromes were formerly called reflex sympathetic dystrophy and causalgia ; some authors still use these older terms.

Table 113-1

Pain Terminology

Pain Term Description
Abnormal pain Includes allodynia, hyperalgesia, neuropathic pain, and inflammatory pain in addition to chronic pain
Acute pain Pain of rapid or sudden onset; described as being sharp and localized
Allodynia Perception of pain produced by stimuli that are not normally painful, such as stroking of skin, light pinch, or movement of joint
Analgesia The absence of pain in response to stimulation that would normally be painful
Central sensitization Remodeling of circuitry in the dorsal horns and at supraspinal sites
Chronic pain Pain of long duration with a slower, gradual onset; described as dull, diffuse, and poorly localized
Hyperalgesia A heightened response to noxious (painful) stimuli
Hypoalgesia Diminished pain in response to a normally painful stimulus
Inflammatory pain Result of tissue injury or inflammatory disease
Mirror allodynia Heightened sensitivity to nonpainful stimuli in the limb contralateral to the site of nerve injury
Neuropathic pain Persistent, intense burning or electric-like pain resulting from direct injury, disease, or lesion to peripheral nerves or central neurons
Peripheral sensitization Primary afferents and postsynaptic neurons in the spinal cord sensitized to innocuous stimuli
Radicular pain Deep, radiating pain due to nerve root irritation, e.g., sciatica
Recurrent pain Recurring or episodic; pain that accompanies a reinjury, or it may be a painful episode associated with a disease process such as rheumatoid arthritis
Sympathetic pain Originating from the sympathetic nervous system: complex regional pain syndrome: type I (causalgia) and type II (reflex sympathetic dystrophy)

For more details, see references .

Pain can be defined in a temporal manner: acute, chronic, and recurrent. There are also several abnormal pain states, including allodynia, hyperalgesia, neuropathic pain, and inflammatory pain. The absence of pain, called analgesia , is the absence of pain in response to a stimulation that would normally be painful.

Deep Versus Superficial Pain

Pain originating in the skin is termed superficial pain . This type of pain typically follows a dermatomal pattern or the skin regions innervated by a cutaneous nerve. In contrast, deep pain is more difficult to evaluate using dermatomal maps because it arises from muscles, joints, and blood vessels as well as from compressed or inflamed neurons innervating musculoskeletal tissues. For example, radicular pain involving nerve root irritation is a type of deep pain. The use of myotomal and sclerotomal charts is more appropriate than dermatomal charts for diagnosing deep pain symptoms.

Distinctions Between Acute, Chronic, and Recurrent Pain

Acute pain is defined as pain of rapid or sudden onset (see Table 113-1 , online). Acute pain serves as a strong warning of tissue injury and signals the individual to withdraw from potential harm or to seek medical care. This type of pain is usually described as being sharp and localized. Unless there is pre-existing maladaptive pain, the individual’s response to pain is appropriate in relation to the scope and degree of the stimulus. Therapeutic intervention for acute pain strives to reduce the source of the pain (e.g., reduction of a fracture) and to reduce discomfort through the use of pharmacologic agents and modalities. In their model for the treatment of the patient with low back pain, DeRosa and Porterfield describe acute pain as a close association between the noxious stimuli, tissue damage, and nociception. This definition can be carried over to other patient populations, including the patient with hand and/or upper extremity pain. They support the use of modalities for the patient with acute pain.

Chronic pain is considered pain of long duration with a slower, gradual onset relative to acute pain. Chronic pain is usually described as dull, diffuse, and poorly localized (see Table 113-1 , online). Often, the true cause of this type of pain is unknown or not fully understood. The patient with chronic pain may have sustained a previous injury that generated acute pain. However, on examination, evidence of a previous injury is no longer visible, suggesting that sufficient time has passed for healing to occur. Examples of chronic pain include chronic neck pain and chronic lower back pain. Chronic root compression is one likely inducer of these two conditions. There may also be injuries and subsequent inflammation in surrounding muscles, facet joints, and ligaments contributing to this pain, which further sensitizes (sensitization is discussed later in this chapter) the nociceptors in these tissues contributing to dysfunction and pain. Chronic pain is often associated with abnormal pain states such as allodynia (pain caused by normally nonpainful stimulus) or hyperalgesia (increased response to a painful stimulus). The behaviors associated with chronic pain may appear to be inconsistent, inappropriate, or exaggerated because of the lack of success in pain relief. The patient often becomes frustrated, angry, and depressed. The prognosis of chronic pain is unpredictable because treatment may be directed at anatomic or physiologic abnormalities that have not been clearly identified as the source of the painful stimuli.

Recurrent pain has been characterized as pain that recurs or is episodic (see Table 113-1 , online). Predisposing factors related to recurrent pain include poor physical condition, poor body mechanics, previous injury, and disease processes. It may be pain that accompanies a reinjury, or it may be a painful episode associated with a disease process such as rheumatoid arthritis. Reinjury may be defined as an exacerbation of a previous condition. The individual’s behavioral response to recurrent pain is usually appropriate. This type of pain may be best treated by limited use of modalities and an emphasis on behavior modification techniques, patient education, and general conditioning.

Abnormal Pain States

Abnormal pain states include mechanical allodynia, hyperalgesia, hypoalgesia, neuropathic pain, and inflammatory pain, in addition to chronic pain described previously (see Table 113-1 , online). Allodynia (also known as mechanical allodynia or mechanical hypersensitivity ) and hyperalgesia are distinguishable states of hypersensitivity that have been described as the perceptual counterparts of peripheral or central sensitization (discussed subsequently). Mechanical allodynia is the perception of pain produced by stimuli that do not normally provoke pain, such as stroking of skin, touch, light pinch, or movement of joints. Allodynia occurs after sensitization of the skin/tissue, for example, after sunburn, inflammation, or trauma. The mechanisms of molecular signaling that lead to sensitization of the afferents are described later in this chapter. It is important to note that with allodynia, the initiating stimulus does not normally produce a painful response and is also called a non-noxious stimulus.

Animal models of nerve injury have studied the incidence of mirror allodynia , which is limb allodynia or hypersensitivity contralateral to injury. A study by Li and colleagues revealed that 20% of animals with unilateral nerve injury developed mirror allodynia in the contralateral limb. The inducing type of nerve injury was varied and included axotomy, complete nerve ligation, and partial nerve ligation. Whiplash injuries also result in bilateral limb allodynia, perhaps caused by an injury to cervical nerve roots located in close proximity to the CNS. This last study also found that glial activation occurs in the spinal cord after spinal root injury and that this activation is temporally linked to the presence of bilateral allodynia. This topic is discussed further with central sensitization.

Hyperalgesia is a heightened response to noxious (painful) stimuli. Hyperalgesia is generated and maintained in the periphery through chemical mediators that cause peripheral sensitization. However, with both allodynia and hyperalgesia, there may be remodeling of circuitry within the dorsal horns and in supraspinal sites that contributes to the increased pain (i.e., central sensitization, to be discussed further later). There are various forms of hyperalgesia such as heat, cold, and chemical hyperalgesia. When hyperalgesia occurs locally at the site of damage and proximal tissue it is referred to as primary hyperalgesia , whereas pain spreading beyond the injury site is secondary hyperalgesia . In general, primary hyperalgesia is a consequence of peripheral sensitization, whereas secondary hyperalgesia is due to central sensitization mechanisms in the spinal cord. Inducing causes of hyperalgesia include nerve compression but also muscle injury/inflammation and inflammatory mediators released by tumors, to name a few.

Thus, both allodynia and hyperalgesia are types of hyperesthesia , which is an increased sensitivity to stimulation. The more specific terms should be used for clarity because the allodynia occurs after a normally nonpainful stimulus and hyperalgesia occurs after a normally painful stimulus, but has a greater response than normal. There are also states of reduced sensitivity to a stimulus. Hypoalgesia is a diminished response to a stimulus that normally produces pain.

Neuropathic pain is a maladaptive type of pain resulting from direct injury, disease, or lesion to peripheral nerves or central neurons (see Table 113-1 , online). Neuropathic pain may present with, but is not limited to, a variety of neuropathies (e.g., traumatic injury or compression of one or more nerves), neuritis (inflammation of a nerve or nerves), infections, tumor, stroke, epilepsy, and neurodegenerative disorders. This type of pain is defined as a persistent, intense burning or electric sensation. Examples of peripheral neuropathic pain in the upper quarter include cervical radicular pain and pain associated with peripheral nerve entrapment, such as carpal tunnel syndrome.

Neuritis is a special case of neuropathy occurring as a consequence of inflammatory processes affecting a nerve ending, its axon, or the surrounding tissues. This inflammatory state can be the result of immune-mediated inflammation without disruption of the axon, inflammation in the peripheral target tissue that inflames the axon terminal, or inflammation within an intact axon caused by localized inflammation in the axon or surrounding tissues. The result of each is often hypersensitivity of the skin or deep tissues that are innervated by the involved nerve(s). Interestingly, peripheral nerve recovery after a crush injury is also hindered by the presence of chronic inflammation in the target tissues. Thus, the control of inflammation through the use of ice or pharmaceutical agents should be considered in the treatment of patients with neuritis.

Neuropathic pain can also be divided into sympathetically maintained pain (SMP) and sympathetically independent pain (SIP). The primary source of SMP is thought to be the sympathetic nervous system. Nerve transection often produces this type of pain, which is typically characterized as spontaneous pain, sustained burning pain, tactile allodynia, and cold allodynia. Sprouting of sympathetic fibers that interact with cut or crushed axons is hypothesized to be the cause of this type of pain. Sympathetic pain often has a vasomotor dysfunction, with measurable changes in infrared thermography, specifically, decreased skin temperature in the cutaneous distribution of the involved nerve. Both types of complex regional pain syndrome, type I (causalgia) and type II (reflex sympathetic dystrophy), are linked to this source of pain mediation. SMP can be reversed temporarily with chemical sympathetic blocks (i.e., using phentolamine to block alpha-adrenoceptors or guanethidine to prevent the release of norepinephrine), although surgical sympathectomy appears to be more reliable. Please see Chapter 115 , Chapter 116 for a more detailed discussion on the management of complex regional pain syndrome.

In summary, it is important to note that all of these types of pain are often seen in combination with one another, although they may be experienced alone as well.

Physiologic Basis of Pain: Peripheral Mechanisms


Nociception is the neural response to noxious insults that result in actual tissue damage. This response is mediated by specialized sensory receptors called nociceptors. Sensations elicited by the activation of these nociceptors include prickling, burning, stinging, soreness, and aching. The various types and roles of these nociceptors are discussed in more detail.

Tissue damage is one stimulus that specifically activates the nociceptors located in skin, muscle, joints, and viscera. Nociceptors are specialized sensory organs that, compared with other sensory end-organs, are the least differentiated and exist mostly as bare nerve endings. The three main classes of nociceptors (mechanical, thermal, and polymodal) are widely distributed in skin and deeper tissues and often work in unison. Nociceptors have varied thresholds and sensitivities to external and internal stimuli with which they are able to adapt or maladapt to their microenvironment. For example, the term sleeping or silent nociceptors has been used to describe high-threshold nociceptors that are not normally responsive to noninjurious stimuli but do respond during inflammation.

Types of Nociceptors

Cutaneous sensory neurons are quite diverse physiologically, anatomically, and molecularly. They can be divided into two main groups: nociceptors, which respond to noxious stimuli or to stimuli that will become noxious if prolonged, and low-threshold mechanical receptors that respond to tactile stimuli. Nociceptors can be divided into subgroups by myelination properties (myelinated or not, the latter called free nerve endings), stimulation modality (mechanical, chemical, thermal, or polymodal), or axon diameter (type II or IV) ( Table 113-2 ). There is similar heterogeneity in visceral and musculoskeletal mechanical receptors and nociceptors. Because nociceptor axons carry the axon potential from the periphery into the spinal cord, nociceptors are also afferent neurons (as opposed to efferent neurons whose axons carry the axon potential from the spinal cord to targets in the periphery and are termed motor neurons ).

Table 113-2

Types of Nociceptors

Type Respond to Stimuli Mechanical Threshold, Median (Range), m/sec Conduction Velocity, Mean (Range), m/sec Response
A-HTMR (myelinated) Mechanical, high-intensity mechanical: noxious skin pinch, penetration and probing by sharp object, squeezing 5.4 (0.16–9.2) 6.9 ± 6.17 (3.5–31) Sharp, pricking sensation
C-HTMR (unmyelinated) Mechanical, high-intensity mechanical: noxious skin pinch, penetration and probing by sharp object, squeezing 9.20 (5.3–9.2) 1.0 ± 0.20 (0.5–1.9) Sharp, pricking sensation
C-nociceptor (unmyelinated) Thermal, extreme heat (>45°C) and extreme cold (<5°C) 0.31 (0.16–1.26) 0.7 ± 0.04 (0.2–1.5) Painful cold as burning or aching; freezing pain as stinging
C-polymodal (unmyelinated) Polymodal, firm stroking, chemical, heat (38°–60°C), and cold (10°–21°C) stimuli 0.31 (0.16–1.26) 0.7 ± 0.04 (0.2–1.5) Burning, dull, aching, long lasting

Nociceptor properties are from Boada and Woodbury. HTMR, high-threshold mechanoreceptors.

Mechanical nociceptors are stimulated by intensive pressure, such as a noxious skin pinch, probing the skin with sharp objects, and squeezing. The mechanical nociceptor is activated only when the amount of force is sufficient to cause tissue damage. Mechanical nociceptors are myelinated nociceptors that are also classified as A-nociceptors or A-HTMR (myelinated high-threshold mechanoreceptor). These same nociceptors are also known as Aδ-nociceptors, although some are also Aβ based on their axonal diameters and conduction velocities. These nerves are moderate to small in diameter (1–5 mm and thus type IV afferents), thinly to moderately myelinated, and have a broad range of conduction velocities from slow to moderately fast (see Table 113-2 ). In fact, several A-HTMR nociceptors are as fast as other types of cutaneous mechanoreceptors. The fastest A-HTMR are most likely Aβ-nociceptors, but most A-HTMR are Aδ-nociceptors, which have smaller diameter axons and are therefore slower. The type of pain typically perceived after activation of A-HTMR is a sharp, pricking sensation. Their firing rate increases with stimulus destructiveness. Although many think of nociceptors only as the smaller, unmyelinated C-fibers that are discussed later, these larger and faster mechanical nociceptors are the sensory neurons underlying “first pain” and therefore evolved to provide protection of the skin. Some A-nociceptors are also thermal nociceptors and respond to noxious thermal stimuli. This applies to both extreme heat (respond at more than 45°C) and extreme cold (respond at less than 5°C). These nociceptors respond in a graduated way to temperature changes, with the highest firing rates occurring with temperatures that produce actual tissue damage. Many of the C-nociceptors are also thermal receptors (see C-polymodal nociceptors).

C-nociceptors can be divided into two main groups: those that respond to mechanical stimulation but not to thermal stimuli (C-HTMR [unmyelinated high-threshold mechanoreceptor]) and those that respond to thermal as well as other noxious stimuli (C-polymodal), as shown in Table 113-2 . However, mechanically insensitive cutaneous nociceptors have also been identified that respond only to heat and are thus called thermal receptors (see Table 113-2 ). The C-HTMR nociceptors are high-threshold afferents with slow conduction velocities (see Table 113-2 ) that respond to intensive pressure, such as a noxious skin pinch, probing the skin with sharp objects, and squeezing. In contrast, the mechanically insensitive thermal nociceptors respond to heat greater than 45°C and express a nonselective ligand-gated cation called the transient receptor potential vanilloid 1 channel receptor or TRPV1. In humans, specific TRPV1 antagonists or other drugs acting on this receptor could potentially be used to treat neuropathic pain associated with multiple sclerosis, chemotherapy, amputation, and osteoarthritis.

Polymodal nociceptors are C-nociceptors that are unmyelinated and respond to several types of stimuli. They are activated by firm stroking of the skin, chemical stimuli, and high temperatures (38°–60°C) or cold temperatures (10°–21°C). The pain associated with activation of the C-fibers is burning, dull, aching, and long-lasting in nature. This subset of C-nociceptors is also called group IV afferents because they have unmyelinated, very small diameter axons (<1 mm) that conduct very slowly (see Table 113-2 ). C-fibers are extremely prevalent in number and make up 80% of the total fibers in cutaneous nerves.

In addition to locations in the somatic regions of the body, C-nociceptors also are located within joints, muscles, and viscera. As a component of visceral nerves, C-nociceptors are thought to transmit unpleasant sensations associated with distention of the bowel and bladder, chemical secretions, and inflammation of the visceral structures.

Another method of categorizing nociceptors includes division of the C-nociceptors into peptide or IB4 nociceptor subsets. The peptide subdivision expresses a variety of peptides, including substance P (SP). The peptide nociceptors terminate in lamina I and the outer portion of lamina II of the dorsal horns of the spinal cord. The IB4 subset is so named because they bind the IB4 lectin. The IB4 subdivision expresses fewer peptides than the other, expresses fluoride-resistant acid phosphatase, and terminates in the inner portion of lamina II. Receptor differences between these two subsets lead to differential responsiveness to chemical mediators released and contribute to varied levels of pain modulation at the site of injury.

Projection of Nociceptors into Spinal Cord

Because nociceptors are sensory neurons, they, like other peripheral sensory neurons, are pseudounipolar in shape, with two axons branching from a main axon of the cell body. The cell body is located in the dorsal root ganglia or sensory cranial nerve ganglia, similar to other types of sensory neurons. There is then a peripherally projecting axon that carries impulses from the nociceptor terminal located in the skin, joints, or viscera. This peripheral axon transmits nociceptor information from the peripheral site centrally to the spinal cord. A centrally projecting axon projects into the spinal cord where it terminates in the dorsal horn and releases excitatory neurotransmitters, such as glutamate and SP, onto second-order projection neurons and interneurons. However, first, these centrally projecting nociceptive axons ascend or descend for several spinal segments in a small pathway called Lissauer’s tract (located in the posterolateral sulcus at the tip of the dorsal horn) before terminating in the dorsal horn gray matter. Both the C-nociceptor and the A-nociceptor axons synapse in the lamina of the dorsal horn. Most of the nociceptive fibers terminate in laminae I, II, and V. Note that lamina II is most commonly referred to as the substantia gelatinosa . However, some of these axons also extend deeper to terminate in laminae III, IV, VII, or VIII. The A-nociceptor fibers terminate primarily in laminae I, II, and V, laminae containing many wide dynamic range (WDR) neurons (see the following discussion). In contrast, most C-nociceptors terminate primarily in lamina II, which contains both excitatory and inhibitory interneurons that respond to both noxious and non-noxious stimuli ( Fig. 113-1 ). Interestingly, laminae VII and VIII also receive bilateral input from polymodal nociceptors and project to neurons of the brainstem reticular formation (bilaterally); therefore, these latter laminae contribute to diffuse pain sensations.

Apr 21, 2019 | Posted by in PHYSICAL MEDICINE & REHABILITATION | Comments Off on Understanding Pain Mechanisms: The Basis of Clinical Decision Making for Pain Modulation
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