Introduction

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:

Classification of Nerve Fibers

Gasser and Erlanger¹⁴ 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.

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.