Differential neural blockade has been used to obtain diagnostic information for ill-defined pain conditions that elude specific diagnoses. The technique, although deemed controversial by some,¹ can have the potential to aid pain physicians with a more objective assessment of a patient’s pain and in doing so aid in developing a better approach to treatment.^2,³ The International Association for the Study of Pain defines pain as an “unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage.”⁴ One aspect of pain is nociception, which entails a complex series of electrochemical events that entail transduction of nociceptive stimuli from receptive nerve endings, transmission of impulses, modulation, and translation of subjective sensory and emotional experiences of pain.⁵ Other factors either unrelated or reinforced by this processes contribute to the pain experience. Thus, one of the greatest challenges that face many pain physicians today is identifying the relative contributions of psychosocial, cognitive, visceral, and somatic contributions involved in a patient’s perception of pain. The rationale for performing diagnostic differential neural blocks (DDNBs) is based on the selective blockade of specific neurological pathways and/or modalities while sparing others. In doing so, DDNBs have the potential to do the following⁶: (1) help to determine whether a patient has predominantly a physical or psychological component contributing to the experience of pain, (2) aid in assessing whether pain is mediated via sympathetic or somatic fibers, (3) identify potential response to placebo, and (4) predict a patient’s likelihood for success from interventions such as surgery or neurolysis.

The approach to DDNB is varied and may have evolved over the years. The “classic approach,” as described in 1964 by McCollum and Stephen,⁷ proposes varying concentrations of local anesthetic to be injected intrathecally. This approach mainly relies on the relative susceptibilities of the different types of nerve fibers to create a concentration-dependent response differential that enables the selective blockade of specific neuronal pathways while sparing others. The “modified approach” was introduced as a more time-efficient and practical alternative to its classic counterpart.^3,^8,⁹ Subsequently, clinicians used the “epidural approach” in the hopes of minimizing post–lumbar puncture cephalgia associated with spinal injections.² Other approaches that have also been introduced include the “anatomical approach” and the “opioid approach.” The “anatomical approach” relies on the sequential blockade of specific nerve fibers based on its anatomical locations as opposed to differential susceptibility to varying concentrations of local anesthetic.³ The “opioid approach,” introduced in 1985, suggests the use of epidural opioid in lieu of local anesthetics to eliminate a potential source of bias (i.e., cues of numbness and warmth that the local anesthetic may give to patients undergoing the test).⁶ The latter two approaches do not necessarily provide better diagnostic value than the classic or modified approaches. On the contrary, critics have pointed out that they may be less effective in differentiating specific pain pathways as will be discussed further below.^1,¹⁰^–¹²

Whatever the approach, a DDNB’s utility should lie in its ability to potentially identify a specific neural pathway or pain syndrome for which a diagnosis has not yet been clearly established, especially when an extensive medical workup fails to identify a cause for the pain.

Historical Perspective

The concept of differential nerve blockade is largely based on the early studies of Gasser and Erlanger in 1929.^13,¹⁴ These two American scientists who studied the effects of cocaine on canine peripheral nerves suggested that small-diameter nerve fibers were more susceptible to the blocking actions of local anesthetics compared with larger nerve fibers because the former possess greater surface to volume ratio, thus rendering the axoplasm more readily infiltrated by local anesthetics.¹⁴ This early model of differential neural blockade has come to be known as the “size principle” and has also served as an explanation for the differential loss of function observed clinically during spinal and epidural anesthesia.^15,¹⁶ These findings subsequently led to the use of differential spinal blocks as a diagnostic tool for pain.^7,¹³ However, neurophysiological evidence has since disproven Gasser and Erlanger’s concept of nerve conduction, and over time, their “size principle” has also been challenged.¹⁷^–¹⁹ In 1989, Fink²⁰ proposed the “length principle” as an alternative explanation. This principle suggests that for nerve fiber conduction to be blocked, three consecutive nodes of Ranvier must be exposed to the local anesthetic.²¹ The “length principle” has been considered an extension rather than a renunciation of the original “size principle” because axonal diameter does correlate with internodal distance.²² The thicker the diameter of an axon, the further the internodal distance and the less amount of nodes likely exposed to a given amount of local anesthetic. However, the “size principle,” which has influenced most of the work on differential blocks, could be misleading because given a sufficient length of nerve, there is no apparent difference in the concentration of local anesthetics required for a conduction nerve block in all fibers.²³ To proponents of DDNBs, Fink’s “length principle” provides a valid explanation that links stepwise loss of function observed clinically with neuraxial anesthesia to the concept of differential nerve fiber susceptibility and thus justifies, to a certain extent, its use as a diagnostic tool for pain.³

Classification of Five Types of Pain

DDNBs, as classically described, involve injecting saline and then local anesthetic in gradually increasing strengths into the spinal space.⁷ The goal is to delineate the underlying pain mechanism that could fall under one of five types:

Placebo-Responsive Pain

Pain is considered to be placebo responsive if relief occurs after the injection of saline. It has been shown that up to 35% of patients with true organic pain actually respond to placebo; however, this is short lived and self-limiting.²⁴ If pain relief after placebo persists for an extended period of time, an underlying psychogenic pain mechanism may be considered.

Sympathetic Pain

Pain mediated by sympathetic fibers is inferred if the patient experiences relief after sympathetic fibers are blocked with sympatholytic concentrations of anesthetic, which are thought to be lower anesthetic concentrations sufficient enough to block sympathetic preganglionic B fibers while sparing other fiber types.^25,²⁶ Pain relief should occur concomitantly with signs of sympathetic blockade such as temperature changes and sympathogalvanic response (SGR; the activation of sweat glands by postganglionic sympathetic fibers) but without signs of sensory block.

Somatic Pain

Somatic pain is considered if the patient experiences relief only after a higher concentration of anesthetic is injected and cutaneous sensation to pinprick or temperature is abolished. This type of pain is subserved by Aδ fibers, C fibers, or both.

Visceral Pain

Visceral pain is pain originating from internal organs. Stimuli required to elicit pain in visceral organs vary between structures (e.g., the myocardium is sensitive to ischemia but not to mechanical stimulation). The quality of visceral pain is often different from somatic pain. Although somatic pain is initially sharp followed by localized burning or throbbing, visceral pain tends to be poorly localized, presenting as dull, aching sensations. Although this type of pain is conducted by Aδ and C fibers, the ratio of Aδ to C fibers is 1 : 10 in viscera as opposed to 1 : 2 in cutaneous afferents.²⁷ Furthermore, visceral nociceptive fibers have extensive overlap among their receptive fields.^28,²⁹

Central Pain

If the patient does not gain any relief from any of the injections despite achieving surgical levels of anesthesia of nerves that cover the target organ, then a central mechanism or pain generator should be suspected. Central pain can be attributed to one of four possible causes, including central lesions, true psychogenic pain, malingering, or encephalization.² Central lesions involve damage to or dysfunction of the central nervous system (CNS) above the level of the differential nerve block. Examples include poststroke thalamic pain and multiple sclerosis. Pain with psychogenic features refers to physical pain perpetuated by an underlying psychological disorder such as depression or anxiety. Encephalization is a poorly understood phenomenon that has been proposed to explain central pain³ whereby chronic, severe pain of peripheral origin becomes self-sustaining at a central level and remains persistent despite removal of the original peripheral triggering mechanism. Malingering is the deliberate feigning or exaggeration of pain or illness in anticipation of some benefit such as financial compensation or avoidance of responsibility. There are no valid clinical methods for its assessment and thus can be difficult to prove or disprove.³⁰

Classification of Nerve Fibers

Gasser and Erlanger ¹⁴ earlier developed the classification system for peripheral nerve fibers mainly based on axonal diameter, conduction velocity (in meters per second), and myelination. This system is still in use today and basically categorizes nerve fibers into three types: A, B, and C.

A Fibers

A fibers are myelinated fibers and are further classified into four subtypes. A-α fibers, the largest, are about 15 to 20 micrometers in diameter and subserve large motor function and proprioception; A-β fibers are about 8 to 15 µm in diameter, subserving small motor movements, touch, and pressure sensations; A-γ fibers are 4 to 8 µm in diameter and subserve muscle tone and reflex; and A-δ fibers are 3 to 4 µm in diameter, are thinly myelinated, and are responsible for the transmission of temperature and sharp pain.

B Fibers

B fibers are also myelinated and have a diameter of about 3 to 4 µm. These fibers subserve the preganglionic autonomic system.

C Fibers

C fibers are unmyelinated and are only about 1 to 2 µm in diameter. They transmit dull pain and temperature.

Fiber diameter is a function of how heavily myelinated the axons are. Larger A fibers are heavily myelinated and have greater conduction velocities measured as the distance an action potential travels through an axon over time in meters per second. On the other hand, C fibers are unmyelinated and small in size and have the slowest conduction velocity.^31,³² Properties of nociceptive compared with non-nociceptive somatic afferent neurons include a longer action potential duration and a slower maximum rate of fiber firing. These properties appear to be graded according to the conduction velocity group with the slowest fibers having the longest action potential and least rate of fiber firing (C > Aδ > A-α/β).³³

The Role of Local Anesthetics

Local anesthetics block the propagation of nerve impulses such as those for pain by inhibiting the formation and propagation of action potentials. Several mechanisms have been proposed, but most evidence suggest that the sodium channel is the key target.³⁴ By diffusing through the axonal membrane, local anesthetics bind to the cytoplasmic side of a sodium channel, thereby inhibiting conformational changes that would have otherwise resulted in the channel’s opening for sodium influx and activation. Local anesthetics do not only block inward sodium channels but also the outward potassium channels, which might be an important effect because potassium channels are responsible for repolarization and maintenance of resting membrane potential, which affects excitability.^35,³⁶ Clinical onset depends on the rate of diffusion through the neuronal membrane. Thus, amide-based local anesthetics such as bupivacaine that happen to be more lipophilic are thought to produce nerve blockade more readily than the less lipid soluble ester-based local anesthetics such as procaine. Lipophilicity allows the anesthetic to penetrate a nerve fiber more readily and exert its effect before being removed into the circulation. In theory, a less lipophilic local anesthetic would be the more ideal agent for DDNBs because they produce blockade of smaller fibers (e.g., C fibers) more readily but are then removed by the circulation before they can penetrate the diffusion barriers of larger fibers. As such, greater concentrations of ester-based anesthetics would be needed to create blockade of larger fibers and the differential is more easily established. In vivo studies, however, have found that regardless of type of local anesthetic, a differential in susceptibility exists based on fiber type with A-α fibers consistently less sensitive to local anesthetic, regardless of type, versus the smaller C or A-δ fibers.³⁷ The order of susceptibility to blockade by local anesthetic is as follows: (most susceptible to least susceptible) B < C < A-δ < A-γ < A-β < A-α.^2,^3,^20,³⁸

Proposed Mechanisms of Differential Neural Blockade

DDNBs are based on the premise that a given concentration of local anesthetic can selectively block a specific nerve fiber type while sparing others.¹ The mechanism of this differential effect is not clearly understood.^20,³⁹ Several explanations have been offered.

Bathed Length Principle

For local anesthetics to effectively block a nerve fiber, at least three nodes of Ranvier need to be bathed in the anesthetic because conduction can leap two consecutive blocked nodes but not three.⁴⁰ Fink’s “bathed length principle” suggests that a functional relationship between local anesthetic susceptibility and fiber length (and therefore size) exists.²⁰ That is, smaller diameter fibers are more easily blocked than larger diameter fibers, which tend to have greater internodal distance and thus tend to require more anesthetic for three consecutive nodes to be bathed. After the three-node requirement is met, there is a minimum concentration of local anesthetic required for each fiber type to have all of its sodium channels occupied before conduction can be blocked. This is known as the minimum blocking concentration (Cm). Smaller fibers are thought to have smaller Cms than larger fibers, enabling different types of fibers to respond to different concentrations of anesthetic.^19,⁴¹

Sodium Channel Packing

Sodium channel density at the nodes of Ranvier are thought to be increased as fiber size increases.⁴² This increased distribution of sodium channels on larger fibers is referred to as “sodium channel packing” and has been proposed as one possible mechanism that explains why larger fibers require a higher Cm than do smaller fibers.³

Decremental Conduction

Given an impulse conducting along an axon, there is thought to be a cumulative decrease in the currents excited with successive nodes of Ranvier.²⁰ For local anesthetic concentrations below the Cm, not enough sodium channels within a node are blocked such that at each node, the action potential undergoes a progressive reduction in amplitude and conduction until succeeding nodes are rendered vulnerable to even suboptimal doses of anesthetic. This phenomenon, referred to as “decremental conduction,” has mainly been demonstrated in myelinated axons.^20,⁴³ Thus, for anesthetic concentrations below the Cm, impulse blockade is more likely to occur in fibers in which a greater number of nodes are exposed. Larger fibers are therefore less vulnerable because even if conduction is decrementally slowed, not enough nodes are exposed to the lower anesthetic dose, enabling the impulse to again resume full conduction speed after the conducting membrane is again reached.

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