Pain Pathophysiology and Management

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12 Pain Pathophysiology and Management

John Markman

Clinical Vignette

A 53-year-old woman with type 2 diabetes mellitus presented with burning pain in both feet. This was persistent throughout the day, and began to make it rather uncomfortable to stand or walk for any prolonged period of time. This was particularly worse at night, often preventing her from getting to sleep. Eventually this pain became so intense that this middle-aged lady had to stop working as a hair stylist, despite being the sole wage earner for her family. She had been noncompliant with her diabetic monitoring and her various medications as evidenced by wide fluctuations in her serum glucose. Her neurologic examination demonstrated a stocking hypoesthesia in both feet with loss of her Achilles muscle stretch reflexes. She also has an asymptomatic plantar ulcer under her right great toe.

Comment: This very common clinical scenario illustrates the toll that chronic pain can have on an otherwise healthy individual, as well as the potential social and economic repercussions of untreated chronic pain.

Neuropathic Pain Syndromes

Neuropathic pain encompasses an array of chronic debilitating nerve injury syndromes that specifically have an adverse impact on the quality of life. To capture the diversity of etiologies, the International Association for the Study of Pain has defined neuropathic pain rather broadly as a “pain initiated or caused by a primary lesion or dysfunction in the nervous system.” These syndromes originate at every level of the neuraxis and include diabetic polyneuropathy, HIV neuropathy, postsurgical pain, postherpetic neuralgia (PHN), trigeminal neuralgia, complex regional pain syndrome (CRPS), spinal cord injury pain, poststroke pain, multiple sclerosis, and phantom limb pain.

Neuropathic pain may be subdivided into two broad neuroanatomic subgroups based on the localization of nerve injury. Central nervous system syndromes result from pathology of the brain and spinal cord such as that associated with a demyelinating plaque in multiple sclerosis or stroke. Peripheral neuropathic pain syndromes are the far more common group and include processes such as reactivation of the varicella-zoster virus giving rise to PHN and painful diabetic polyneuropathy.

Pathophysiology

The understanding of the relationship between the clinical features of neuropathic pain and underlying molecular mechanisms in humans remains in its infancy. Following nerve injury, neuronal remodeling occurs, with microscopic structural changes in the neuronal membrane and individual membrane bound ion channels. Animal models suggest that neuronal remodeling alters the membrane electrical properties, resulting in a state of hyperexcitability wherein thresholds are lowered, action potentials are propagated more easily, and the duration of nerve impulses is prolonged. These aberrant action potentials are reproduced at multiple anatomic levels: from the primary sensory neuron, to the sensory ganglia, and neurons within the dorsal horn of the spinal cord (Fig. 12-1). Such a pattern of aberrant nerve discharges may account for the positive symptoms of neuropathic pain. The cognizant perception of painful symptoms is based on the neural pathways commencing in the periphery at the primary sensory nerve ending, transmitted through the dorsal root ganglia, the spinal cord, up to the thalamus and finally the somatosensory parietal cerebral cortex (Fig. 12-2). During the passage of nerve potentials along this pathway, a number of opportunities are available at the various synapses for modulation of the impulses per se and thus the eventual perception of the original stimulus.

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Figure 12-1 Mechanisms of Neuropathic Pain.

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Figure 12-2 Pain Pathway.

When chronic pain syndromes develop, there is evidence to support the conjecture that different ion channels are involved in both remodeling and ectopic neuronal signaling. The variability in symptomatology as well as the response to pharmacologic treatment may depend on the specific type of channel involved. An example of this correlation is the expression of the acid- and heat-sensitive capsaicin/vanilloid receptor (TRPV1) in nociceptive C-fibers. Inflammation and focal tissue acidity following nerve injury may activate this receptor, enhancing exaggerated pain responses. On the other hand, continuous activation of this receptor may desensitize these fibers and account for the analgesic efficacy of capsaicin.

In addition, an alteration of central nervous system signal transduction also occurs in some patients suffering from neuropathic pain. Following nerve injury, retrograde transport of growth factors from the distal neuron to the cell body is impaired or lost. Disruption of intercellular signaling cascades causes structural changes in second- and third-order neurons, altering the expression of neuromodulators such as brain-derived natriuretic factor and substance P in nociceptive A-fibers. Simultaneously, ectopic activity and injury discharge may cause preferential death of inhibitory interneurons located in the superficial laminae of the dorsal horn. These changes ultimately lead to decreased inhibition of pain signaling within the spinal cord. In addition to changes in inhibitory pathway signaling, the preferential loss of C-fiber neurons as observed in animal models may lead to remodeling of synaptic architecture. Following denervation, A-fiber neurons from deep laminar loci sprout new afferents to form functional synapses in portions of the spinal column formerly occupied by C-fiber termini. This expansion of neuronal receptive fields may play a key role in the zones of hyperalgesia adjacent to the territory of primary nerve injury.

Diagnosis and Clinical Manifestations

The diagnosis of neuropathic pain syndromes requires a thorough exam and careful consideration of a patient’s medical history. Neuropathic pain symptoms are distinct from nonneuropathic (nociceptive) pain. The following criteria have been proposed to define and differentiate neuropathic pain from nociceptive pain:

1. Pain and sensory symptoms that persist beyond the healing period.
2. Presence of neurologic sensory signs manifesting as negative and positive sensory phenomena.
3. Presence of other neurologic signs, including motor, manifesting as negative and positive motor phenomena, or autonomic signs.

Using this schema, there are four forms of pain that are characterized by positive sensory phenomena:

dysesthesia (unpleasant abnormal sensation),
paresthesia (abnormal sensation),
hyperalgesia (exaggerated response to painful stimulus), and
allodynia (pain caused by nonnoxious stimulus).

In contrast, negative phenomena refer to loss of sensation. Differences in quality and spatial characteristics of pain symptoms may also be used to distinguish neuropathic pain from nonneuropathic pain, with symptoms of stimulus-evoked pain, shooting pain, electric shock, burning, and cold significantly more common in patients with neuropathic pain. Neuropathic pain also tends to be perceived as a superficial sensation, whereas other forms of pain are felt in deeper tissues, muscles, and joints. Motor as well as other nonsensory neurologic symptoms may also occur in neuropathic pain syndromes. These include weakness, spasticity, tremor, ataxia, apraxia, spasticity, hypotonia, muscle spasms, and muscle tenderness. The concordance of these nonsensory symptoms with positive and negative phenomena is strongly suggestive of the presence of a neuropathic pain syndrome.

The quality, intensity, and duration of symptoms should always be carefully assessed in any chronic pain patient, and the characteristics and distribution of aberrant sensory phenomena can be used to guide the focused neurologic examination. Standard neurologic physical exam tools such as cotton wisps, tuning forks, and warm and cold objects may be used to evaluate evoked pain and, when coupled with a thorough neurologic examination, may help to localize the lesion. In the presence of confirmatory history and laboratory data, positive and negative phenomena (evoked or spontaneous) occurring in the territory of a localized lesion confirms the clinical diagnosis.

In addition to the history and physical examination, ancillary studies may aid in diagnosis. These are very important for confirming or excluding the presence of underlying etiologies for neuropathic pain. Magnetic resonance imaging is used to assess the integrity of central neuroanatomic structures involved in pain signaling pathways. These include the spinal cord, brainstem, thalamus, and cortices (see Fig. 12-1). Peripheral sources for the pain can sometimes be defined by electromyography and nerve conduction studies. The latter particularly assess the function of large myelinated nerve fibers. Nonneurologic tests such as oral glucose tolerance, Tzanck prep (a rapid test previously performed to diagnose infections caused by herpes viruses) and enzyme-linked immunosorbent assay. This can be used to confirm or exclude the presence of a number of underlying diseases that may lead to sequelae of neuropathic pain. Psychiatric evaluation is also useful in evaluating possible somatization disorders in patients with multisystem complaints that may date back into early developmental stages.

Treatment

Gauging the efficacy of treatment protocols represents a significant challenge in the treatment of neuropathic pain. Severity of pain is typically assessed at the time of exam, as well as over short time intervals, and subjectively graded by the patient on the 0–10 numeric rating scale, with a score of 0 representing “no pain” and a score of 10 representing “worst possible pain.” Research suggests that clinically important pain relief is achieved with a 30% reduction in score on this scale, corresponding to a categoric rating of “moderate relief” or “much improved.” In addition, counseling patients and families about reasonable expectations for symptom improvement is crucial. Patients must understand that partial reduction in pain intensity is the norm with pharmacotherapy. Furthermore, successful treatment will require a program of adaptive coping by the patient per se. A comprehensive approach that calls on close monitoring of side effects of medications used to treat neuropathic pain is essential, as many of these drugs have significant adverse events, especially when used in older patients.

Multitiered Approach to Pain Management

The International Association for the Study of Pain has developed a multitier approach to managing neuropathic pain. This is centered around patient communication and a number of available pharmacotherapeutic agents. The first step in this system involves a thorough clinical evaluation and discussion of a patient’s underlying disease state as outlined above. The second step in the multitiered approach to managing NP is the prescription of a “first-line” pharmaceutical agent. Following prescription, the third step in treatment is reevaluation of the patient’s pain intensity and its response to therapy. Therapy is continued if the patient’s response has been complete. In contrast, if the patient has not responded to this medication, or the side effect profile is unacceptable, another first-line therapy needs to be initiated. Finally, if the patient reports a partial response, the initial therapy is continued and another first- or second-line medication is combined with this. If acceptable symptom resolution does not occur with this approach, then the physician needs to consider introducing a third-line pharmaceutical agent.

First-Line Prescription Agents

These include topical lidocaine, calcium channel α2-δ ligands (gabapentin, pregabalin), tricyclic antidepressants (TCAs) and serotonin norepinephrine reuptake inhibitors.

Putative calcium channel ligands such as gabapentin inhibit presynaptic calcium channel α2-δ subunits activity in the superficial laminae of the dorsal horn of the spinal cord. Their exact site of action within the central nervous system as antiepileptic agents and for their other benefits remains unclear.

Tricyclic antidepressants historically are thought to modulate pain signaling by affecting both serotonergic and noradrenergic reuptake in descending inhibitory supraspinal pathways (Fig. 12-3). Desipramine and nortriptyline are preferred for neuropathic pain because of their favorable side-effect profiles relative to amitriptyline. Although their anticholinergic side effects demand careful consideration when these are used in patients with comorbidities, TCAs will relieve pain in PHN, postmastectomy pain syndrome, and painful diabetic neuropathy (PDN) and nondiabetic peripheral neuropathy. These agents should be tried alone initially, and then may be used in combination to pursue symptomatic improvement if necessary, provided that the clinician carefully monitors their interactions and side effects.

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Figure 12-3 Serotonin Synapses of Pain Pathways.

Lidocaine

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