A Practical Approach to the Treatment of Painful Polyneuropathies

Definitions and Overview

Pain has been defined by the International Association for the Study of Pain (IASP, 2019) as “an aversive sensory and emotional experience typically caused by, or resembling that caused by, actual or potential tissue injury.” Restated, pain can occur even in the absence of an actual tissue injury. All that is required to experience pain is for the affected person to believe that such an injury is imminent or has occurred. The IASP also recently updated its definition of NP as indicative of a direct consequence of diseases that affect the somatosensory system ( ). Many pain management experts further subdivide NP into noninflammatory and inflammatory subtypes. Examples of inflammatory NP include herpes zoster neuritis, cancer pain, and complex regional pain syndrome, whereas noninflammatory pain would include conditions such as trigeminal neuralgia and phantom limb pain. PP cannot be as readily classified because the underlying etiology is not always identified. Even when the underlying cause is identified, pain may occur as a result of both inflammatory and noninflammatory mechanisms (e.g., inflammatory vasculitis with secondary axonal loss from ischemia). This is one of many reasons why the EBM recommendations regarding the treatment of NP in general do not necessarily apply to the treatment of PP.

Varying definitions of chronic pain have existed over the last decade. Acute pain was differentiated from chronic pain by stating that acute pain lasted less than 3 to 6 months ( ). However, this definition has fallen out of favor because of its arbitrary nature and because many patients with acute pain eventually develop chronic pain. For these reasons, the American Pain Society revised this definition by stating, “Acute pain follows injury to the body and generally disappears when the bodily injury heals. It is often, but not always, associated with objective physical signs of autonomic nervous system activity. Chronic pain, in contrast to acute pain, is rarely accompanied by signs of sympathetic nervous system arousal” ( ). Expert opinion has come full circle as most recently the IASP defined chronic pain as pain that persists or recurs for more than 3 months ( ).

proposed a different definition of pain that integrates its duration and perceived physical intensity. They describe NP in terms of a “strength-duration curve” in which pain intensity is reported as severe over a relatively short period, whereas chronic pain tends to be reported as less severe but more persistent. From this perspective, they define acute pain as pain elicited by the injury of bodily tissues and activation of nociceptive transducers at the site of local tissue injury. They also opined that the nociceptive transmission may be altered through central processing and that coexistent autonomic phenomena are often observed. In contrast, chronic pain is usually elicited by an injury but may be augmented by other factors that are not necessarily related to the precipitating cause. remarked, “Chronic pain extends for a long period of time, represents low levels of underlying pathology that does not explain the presence and extent of the pain, or both.” They also wrote that acute pain often responds to treatment, whereas chronic pain is “rarely effectively treated.” concluded that “cure” may be a reasonable goal for acute pain processes, whereas “setting realistic expectations” would be more appropriate in patients with chronic pain. Within the patient-physician relationship, it is important to establish realistic expectations for each person in the relationship with shared decision making. This collaboration helps foster a patient- and family-centered care practice model. Paired with objective function-based goals, therapeutic interventions will be more effective.

The division between acute and chronic pain should not lead to the misconception that one cannot transform into the other. One prospective study from New Zealand reported that acute NP accounted for 1% to 3% of consults on an acute pain service ( ). The same study reported that 78% of patients had persistent pain after 6 months and that 56% still had pain after 1 year. Thus, failure to treat acute NP may lead to chronic NP, implying that early intervention is the best course of action. Therefore, it is recommended that NP be treated as early and comprehensively as possible because a “wait and see” attitude is less likely to be effective than one in which the underlying disorder is treated in short order. advised that moderate to severe pain must be treated quickly and aggressively in an attempt to reduce the probability that a chronic pain syndrome will result. Although early and aggressive intervention in a patient with an acute pain process may not result in a “cure,” it may mitigate the severity of the chronic pain syndrome. Patients with chronic pain syndromes rarely experience complete relief and may require long-term medication management, a course of action that should be viewed as a double-edged sword for reasons that are discussed subsequently.

Nerve Anatomy

A simplified view of the peripheral nerve is to subdivide it into its three main structural components: Schwann cells with the myelin sheath that they produce, the vasa nervorum, and the axons. The axons are further classified as afferent or efferent fibers. The afferent, or sensory, fibers can be further subdivided into large, heavily myelinated fibers (Aβ), thinly myelinated fibers (Aδ), and unmyelinated fibers (C fibers). Most sensory fibers within a sensory nerve are the “small fibers” that are either thinly myelinated or unmyelinated. Further, these small fibers tend to be clustered toward the center of the nerve. The blood vessels to the nerves (vasa nervorum) do not penetrate the nerve itself but stop at the epineurium so that the axons receive their nutrients and eliminate their wastes through diffusion. For this reason, the large, heavily myelinated axons at the edge of the nerve are at less risk from hypoxic-ischemic issues than are the small fibers that tend to be clustered in the center of the nerve. The myelinated fibers have an additional advantage in that the myelin sheath acts as an electrical insulator such that the electrical impulse along these nerve fibers only needs to be boosted by firing an action potential at the nodes of Ranvier. In contrast, the unmyelinated fibers must fire an action potential at every contiguous membrane segment. After an action potential is generated, energy must be expended to reestablish the electrochemical gradient. The net result is that lesser myelinated and unmyelinated sensory axons are much more susceptible to toxic-metabolic pathologic processes than are the more heavily myelinated Aβ fibers. Because these “myelin-deficient” fibers must generate an action potential more frequently than their heavily myelinated counterparts, they are also more prone to ischemic processes. These smaller, less myelinated fibers require more energy per unit length than do the heavily myelinated fibers. Viewed from this perspective, the small fibers serve an important purpose as an early warning system indicative of an underlying ischemic or toxic-metabolic process. The smaller fibers thus serve a similar function to the “check engine” light on a car. Either the engine is fully functional or it is not. When nerve function is suboptimal, the “check engine” light is illuminated, advising the operator that there is a problem. In the same way that an illuminated “check engine” light cannot specify the severity of a problem, the severity of the patient’s NP does not necessarily correlate with the severity of the underlying pathology. The presence of a PP usually indicates dysfunction of the smaller fibers or their central connections, often as a result of an ischemic or toxic-metabolic process. Contrast these disorders with those in which the small fibers are relatively spared, as in acquired demyelinating polyneuropathy. Although pain may be a feature of acquired demyelinating polyneuropathies, this is less common and often indicates collateral damage of small fibers secondary to inflammatory processes. The presence of a PP should initiate an investigation for potentially reversible causes, as suggested in Table 6.1 .

Overview of Peripheral Neuropathic Pain Pathophysiology

The precise mechanisms by which NP occurs are not completely understood. One early hypothesis advanced by was the “gate control theory.” They postulated both large and small fiber input onto a wide dynamic range (WDR) neuron remained quiescent until an imbalance in sensory input developed. This would result in the activation of a previously quiescent nociceptive WDR neuron. The WDR neuron would then engage in central NP transmission. This simplistic hypothesis has flaws because it does not predict what is observed in clinical practice. The activation of a WDR neuron as a result of small and large fiber imbalance predicts that loss of one or the other of these fiber types would result in NP. However, patients with hereditary sensory and autonomic neuropathies do not always experience pain. In fact, many have mutilated limbs because of an absence of small fiber function, the exact opposite of what the gate control theory would predict. Another example would be acquired demyelinating polyneuropathies, such as chronic inflammatory demyelinating polyradiculoneuropathy, wherein there is significant large fiber dysfunction, yet pain is not a common feature of this illness. For these reasons, the gate control hypothesis had to be modified.

No optimum theory can explain all the mechanisms involved in NP, let alone the pain experienced in PP. As a first approximation, one can view this process as one in which there is a real or perceived injury to the sensory nervous system such that various mechanisms are activated. At every level of this process, there will be events that favor nociceptive transmission and those that oppose it. From the periphery to the most rostral regions of the CNS, there will be a wider degree and an ever more complex series of inputs on this process. Even though the current understanding of this process is incomplete, some of these mechanisms have been elucidated, as summarized in Tables 6.2 to 6.4 .

There is also some consensus that pain in polyneuropathy likely results from some change in the previous level of functioning of the sensory afferent pathways. Most NP conditions associated with PP develop after an injury to the PNS. Several potential mechanisms are responsible for peripheral NP, including phenotypic switch of nociceptors, ectopic activity in damaged axons, abnormal firing of dorsal root ganglion (DRG) cells, unmaking of silent nociceptors, collateral sprouting, and invasion of dorsal root ganglia ( ). Each of these potential mechanisms provides a rationale for the use of the medications available for the treatment of pain in polyneuropathy.

Table 6.2 summarizes the various mechanisms by which NP can be generated in the PNS. These include direct pain impulse transduction by the transient receptor potential vanilloid channels and tyrosine kinase A (TrkA) receptors activated by nerve growth factor (NGF). In addition, they may induce previously dormant receptor subtypes that include purine receptors (P2X ₃ , P2X _2/3 ), the proteinase-activated receptor (PAR-2), and the bradykinin receptors B1 and B2 ( ). Ion channels that regulate electrochemical transmission, such as voltage-gated sodium, potassium, and calcium channels, are also involved in the transmission of NP ( ; ; ). In most instances, activation of sodium and calcium channels tends to depolarize the membrane and lead to electrical impulse propagation, whereas activation of potassium channels has the opposite effect. Several available medications modify ion conductance, and a more in-depth discussion of these channels is in order.