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10 Articles in Volume 14, Issue #2
How Safe Is Epidural Steroid Injection? Examining Drug-Related Factors
How Important Is Evidence-Based Medicine in Epidural Injection for Low Back Pain?
Current Access to Opioids—Survey of Chronic Pain Patients
Opioid Prescribing Part 2: Appropriate Documentation of Follow-up Visits
Neuropathic Pain: A Literature Review
Translating Chronic Pain Research Into Practice: Chronic Pain and the Brain
Intractable Pain: Time To Understand and Use the Term (Again)
Are Antibiotics a Treatment Option for Low Back Pain?
Genetic Mutations in Cytrochrome P 450 2D6
Light Exercise May Lead To Faster Recovery After Concussion

Neuropathic Pain: A Literature Review

Chronic pain is a common problem in the community and major source of healthcare utilization in the United States. In one study, the reported prevalence of chronic pain in the general population was as high as 46.5%.1 Discussion of chronic pain can be quite complex, but one simplified approach is to classify it into 3 categories: pain from tissue damage (nociceptive pain), pain from somatosensory damage (neuropathic pain), or a mix of the two. The term “neuropathic pain” has come into common use only in the last 25 years and is frequently cited as a common cause of chronic pain.

In this article, I have reviewed 6 papers published recently that provide important information in answering questions that general practitioners may be faced with when seeing patients with neuropathic pain.

Classifying Neuropathic Pain

Clifford Woolf, MD, PhD, is a pioneer in advancing our knowledge of neuropathic pain and its associated conditions. As recently as 5 years ago, the definition of neuropathic pain was pain thought to be resulting from “dysfunction” of the central or peripheral nervous system (PNS). More recently, that definition has changed to a “disease” of the somatosensory nervous system. Dr. Woolf and his colleagues present a good introduction to the causes of neuropathic pain, the mechanisms involved (including genetics), and the effect of treatment.2 Table 1 summarizes key points from the article.

Dr. Woolf and colleagues review exactly why the definition of neuropathic pain has changed: that neuropathic pain is actually an expression of maladaptive plasticity within the nociceptive system and that several changes must occur to create this disease state. Most important to note is that in neuropathic pain, there are many pathophysiological changes in the PNS and the central nervous system (CNS). It is, in fact, a manifestation of maladaptive plasticity of the nervous system, and while the primary disease (and the neural changes secondary to it) is important to understand, it is the cascade of PNS and CNS changes that cause chronic neuropathic pain (Table 2). As the authors note: “the pain associated with acute neural damage usually transitions to chronic neuropathic pain in a minority of patients.”2

 

Genetics Play a Role

There are several risk-conferring genes for the development of neuropathic pain, and while no whole-genome association study has been done for neuropathic pain, candidate gene-association studies have noted preliminarily polymorphisms in catechol-O-methyltransferase (COMT) that modulate nociceptive and dysfunctional pain. This and other genetic polymorphisms may provide clues to the genetics of neuropathic pain.

Effect on Treatment

Currently, treatment of neuropathic pain is based on the underlying disease. It is important to note that the authors discuss how our current treatment regimens need to change. Right now, we merely suppress symptoms, but we need to move toward a more disease-modifying strategy that can prevent the neuronal plasticity as well as reduce the potential risk for developing this disease. Woolf et al suggest that “given the complexity of numerous intertwined genetic, cellular, and molecular components that cause neuropathic pain, clinical classifications need to incorporate multiple aspects of the pain phenotype to guide the identification of underlying mechanisms and helps assess the likelihood of response to treatment.”2

Specific Neuropathic Conditions

While the number of neuropathic conditions are long and numerous, I chose to review 2 specific conditions: complex regional pain syndrome3 and diabetic peripheral neuropathy.4

CRPS

Complex regional pain syndrome (CRPS) has been described in the literature as early as 1864 during the Civil War, when Silas Weir Mitchell and colleagues published their book titled Gunshot Wounds and Other Injuries of the Nerves.5 In it, they describe “long after the trace of the effects of a wound has gone….neuralgic symptoms are apt to linger, and too many carry with them throughout long years this final reminder of the battlefield.”

CRPS was previously called reflex sympathetic dystrophy (RSD) or causalgia (from the greek, kausis meaning “burning,” and algos meaning “pain”). However, not every presentation of the disease presents with a sympathetic component. For this reason, the Special Consensus Group of the International Association for the Study of Pain (IASP) created the term complex regional pain syndrome in 1994 to allow for a more broad inclusion of patients that showed varying levels of the disease process. In 2007, the diagnostic criteria were further revised and are commonly referred to as the “Budapest criteria.”6

While the exact mechanisms are still not fully understood, Marinus et al presents the current understanding of the mechanisms involved.3 The pathophysiology of CRPS is multifactorial. In this review, the authors suggest that the following factors account for most or all of the clinical features in CRPS:

Inflammation (Neurogenic Inflammation)

In-vivo experiments in humans have shown that cytokine signaling is amplified even after minor tissue trauma. This excites nociceptors and can induce long-term peripheral sensitization. It can also increase the release of inflammatory neuropeptides in primary afferent neurons. Substance P and calcitonin-gene-related peptide (CGRP) can be released, causing vasodilation and protein extravasation; the signs this causes are termed neurogenic inflammation.

The authors suggest that post-junction signaling, which is caused by either hampered inactivation of neuropeptides or increased receptor availability, is the most likely mechanism leading to this neurogenic inflammation in CRPS.

Vasomotor Dysfunction

Patients with CRPS often experience vasomotor dysfunction. Typically, this is the pattern: the affected limb is warmer than the unaffected limb early on, but later, it becomes colder than the unaffected limb.

This pattern of temperature change in CRPS has been studied, and the data suggest that in CRPS, there is a unilateral inhibition of cutaneous sympathetic vasoconstrictor neurons. The authors suggest that the initial trauma triggers functional changes in the spinal cord, brainstem, or brain, and these changes lead to thermoregulatory impairment.

It should be noted that not all CRPS patients demonstrate this pattern of temperature change in the affected limb.

Nociceptive Sensitization

The inhibition of cutaneous sympathetic vasoconstrictor neurons may lead to the sensitization of the nociceptors. There may be sympathetic-
afferent coupling, which is the theoretical basis for sympathetically maintained pain. Figure 1 illustrates a patient with lower extremity CRPS.

Maladaptive Neuroplasticity

Hyperalgesic priming may explain why some patients develop chronic pain. This theory suggests that transient insult causes long-term changes in the primary afferent nociceptors, particularly the epsilon isoform of protein kinase C. They are then “primed” to be hyperresponsive to further insults, even mild ones. This aberrant afferent activity can lead to plastic changes in the CNS.

As mentioned, there have been recent changes to meeting the clinical definition of CRPS. Although current research agrees that the pathophysiology of CRPS are multifactorial, all of these components are still unable to fully provide us with a clear understanding of why this phenomenon occurs after an injury, which leaves us to continue the daunting task of piecing together these aspects and finding the missing links. While CRPS is essentially a diagnosis of exclusion, it is important to keep this in our differential armamentarium since early recognition and subsequent intervention has shown better outcomes.

Diabetic Peripheral Neuropathy

While diabetes can injure various peripheral nerves, the most common pattern is distal symmetrical polyneuropathy. With the growing incidence of diabetes in the general population, there is going to be an increasing burden on frontline practitioners to diagnose and treat this condition. Diabetic peripheral neuropathy (DPN) can be quite debilitating, leading to substantial pain and significantly impaired quality of life. It affects patients psychologically and interpersonally and is associated with increasingly high healthcare costs. Callaghan et al review clinical manifestation and current treatment of DPN (Figure 2).4

Hyperglycemia is a key factor in diabetic neuropathy, but other factors contribute an important cause as well. Dyslipidemia, impaired insulin signaling, and metabolic syndrome have all been implicated in either causing or exacerbating DPN. In fact, even in the absence of overt diabetes other aspects of metabolic syndrome could be sufficient to cause neuropathy. As this review acknowledges, there are
2 effective treatments: glucose control and pain management.

Glucose control can decrease the development of and progression of DPN in patients with type 1 diabetes. Its effect in patients with type 2 diabetes, however, is less.

The two main options for pharmacological management for DPN are anticonvulsants and antidepressants. Several treatment algorithms are presented by the authors: all 3 recommend gabapentin, pregabalin, tricyclic antidepressants (TCAs), venlafaxine, and duloxetine as first-line treatments. All algorithms recommend titrating a first-line drug to a maximum tolerated dose before switching to a different drug or combination therapy.

At this time, there are no disease-modifying treatments for diabetic distal symmetrical polyneuropathy. If more research were conducted on modifiable risk factors, it is possible that disease-modifying treatments may be developed. There is evidence suggesting an association between components of metabolic syndrome (including prediabetes) and neuropathy. Studies should be done to better understand this association.

As the authors note, although pain is a common feature, it is often under-reported and undertreated in patients with DPN. This article provides important evidence-based consensus guidelines for frontline practitioners to use medication interventions. While glucose control is the only proven disease-modifying intervention for these patients, its effect on neuropathy is much smaller in patients with type 2 diabetes than those with type 1. Because of this, we have to find further modifiable risk factors, which could provide us with even newer treatments for this disease.

Assessment

The Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain (IASP) published guidelines for assessing neuropathic pain. These guidelines were updated and revised in 2011.7 While this article by Haanpää et al discusses different screening questionnaires for identifying neuropathic pain patients, accurate clinical examination is the basis for neuropathic pain diagnosis. Careful bedside examination includes touch/vibration, cold, warmth, and pain sensibility. The authors suggest tactile sense be assessed by a piece of cotton wool, pinprick sense by a wooden cocktail-stick, thermal sense by warm and cold objects, and vibration sense by a 128-Hz tuning fork (Table 3).

It is important to understand that positive sensory phenomena such as allodynia and hyperalgesia may be common in neuropathic pain states, whereas negative sensory phenomena such as hypoesthesia and hypoalgesia are usually reported in non-neuropathic pain (muscular pain).

Screening Tools

The authors review validated neuropathic pain screening tools—only tools that have been validated for general neuropathic pain (Table 4). The various screening tools have the benefit of being useful to non-specialists and specialists alike. Currently, there is no agreement on diagnosing neuropathic pain, so these screening tools fill a needed role in identifying patients with neuropathic pain.

Clinical Examination

In diagnosing neuropathic pain, the clinical examination is critical, particularly sensory testing. This bedside examination should be guided by the clinician’s tentative diagnosis, and the clinician should remember that patients may struggle to communicate what they feel in regards to these sensory abnormalities. The abnormalities may be unfamiliar and challenging to describe.

Quantitative Sensory Testing

After the beside sensory examination has been performed, more advanced neurophysiological techniques may be used as an adjunct. It can be done to document the sensory profile.

Pain Intensity and Pain Quality

Pain intensity should be assessed with a numeric scale—the Likert scale (0 = no pain; 10 = worst possible pain) or the Visual Analog Scales (VAS). To discriminate between various pain mechanisms in neuropathic pain, the Neuropathic Pain Scale (NPS) or the Neuropathic Pain Symptom Inventory (NPSI) can be used. They have been validated for neuropathic pain, and they can be used to evaluate treatment effect.

Psychological Assessment

Fear of movement can be assessed with the Tampa Scale of Kinesiophobia. The Pain-Coping Inventory or the Pain Catastrophizing Scales can be used for measuring passive coping or catastrophizing. Sleep, mood, functional capacity, and quality of life can be assessed as secondary outcomes in intervention studies. The clinician should follow the recommendations of the IMMPACT group.

Disability Assessment

The Oswestry Disability Index can be used to assess disability in low back pain with a neuropathic component. For patients with painful diabetic neuropathy, the Brief Pain Index (BPI)-DPN is recommended. For other types of neuropathic pain, the Brief Pain Inventory and the Pain Disability Index are recommended.

While the article discusses more sophisticated neurophysiological techniques such as quantitative sensory testing, it stresses that bedside sensory examination can even be more sensitive than these more advanced approaches and should be the preferred first assessment.

Treatment

The last 2 articles come from leaders in the field of pain pharmacology, Drs. O’Connor and Dworkin. The first paper discusses the foundation of pharmacological treatments used in neuropathic conditions,8 while the second delves into an update on the status of newer treatments such as lacosamide, botulinum toxin, and the high-concentration capsaicin patch.9

In addition to assessment tools, the NeuPSIG developed evidence-based guidelines for pharmacologic management of neuropathic pain. Pain physicians have used these guidelines regularly in treating neuropathic pain conditions. In general, treatment for neuropathic pain routinely begins with either antidepressants (TCAs) and/or calcium channel alpha-2-delta ligands (gabapentin or pregabalin). In cases of partial but insufficient pain relief by either of these drugs, combinations are often used. Recent randomized control trials, have demonstrated that the combination of a TCA and an anticonvulsant may be synergistic in effect.10 While opioids have shown greater pain relief than placebo, these guidelines state they should be reserved for those who have failed first-line medications as listed above.

First-line Treatments

Antidepressants with both norephinephrine and serotonin reuptakes inhibition are preferred. Tricyclic antidepressants are useful for treatment several types of neuropathic pain. To help reduce common adverse effects (dry mouth, constipation, etc.), it is recommended to start patients with low dosages administered at bedtime. There should then be a slow titration to higher dosages. Using a secondary amine TCA is another option to reduce these adverse effects.

Gabapentin and pregabalin are calcium channel ά2-δ ligands. At the ά2-δ subunit, they bind to voltage-gated calcium channels, thereby inhibiting neurotransmitter release. Both can cause dose-dependent dizziness and sedation; reduce this by starting at a lower dosage and titrating slowly and cautiously.

In patients with postherpetic neuralgia and allodynia, the 5% lidocaine patch has shown efficacy. This is most appropriate for well-localized neuropathic pain. Table 5 lists FDA-approved treatments for neuropathic pain.

Second-Line Treatment

In certain clinical circumstances, second-line medications may be appropriate for first-line use, including opioid analgesics. There have been several randomized controlled trials (RCTs) of opioids that demonstrate greater pain relief than placebo with various types of neuropathic pain; the pain relief was at least equal to pain relief from TCAs and gabapentin. However, given long-term safety concerns associated with opioids, they should be reserved for patients who failed the first-line medications summarized above, opioids may be considered.

Third-Line Treatment

If patients do not tolerate or do not respond to first-line and second-line medications, the following third-line medications may be considered:

  • certain antidepressant medications
  • certain antiepiletpic medications
  • topical low-concentration capsaicin
  • dextromethorphan
  • memantine
  • mexiletine.

 

Newer Treatment Options

The article by Dworkin et al goes on to further discuss more recent advances in medications, such as the use of botulinum toxin and the capsaicin 8% patch, as well as the new antiepileptic medication lacosamide (Vimpat).9 There has been a recent interest in the use of these 3 medications in treating neuropathic pain. However, more controlled trials are necessary to consistently prove their efficacy in this condition.

Botulinum Toxin

Some preclinical and human studies suggest that botulinum toxin may provide pain relief for patients with neuropathic pain. It has been studied in postherpetic neuralgia (Figure 3, page 48), posttraumatic or postoperative neuropathic pain, diabetic peripheral neuropathy, and mechanical allodynia. Two studies in particular on postherpetic neuralgia showed conflicting results. Both were small studies, but, as the authors write, “the increasing number of negative trials of NP treatments will make it challenging to update guidelines for the pharmacological management of NP.”9

High-concentration Capsaicin Patch

Multiple RCTs using a high-concentration capsaicin patch have been done in patients with postherpetic neuralgia and painful HIV neuropathy. This application was well-tolerated; there were transient increases in pain related to patch application, as well as site reactions. However, this single application was efficacious in pain reduction for patients with PHN or painful HIV neuropathy; it could, therefore, be a worthwhile additional treatment to current pharmacological management.

Lacosamide

This new antiepileptic medication has activity at voltage-gated sodium channels. It has been studied in patients with painful diabetic peripheral neuropathy, but has not been approved for this indication. This may be because there was inadequate efficacy demonstrated in the trials, or it may be because there were safety concerns. Knowing the reason for the lack of approval is necessary before making recommendations on lacosamide’s use.

Selective Serotonin Reuptake Inhibitors

Interestingly, SSRIs have been third-line medications for neuropathic pain. However, there have been 3 positive RCTs in treating painful polyneuropathies, so a re-evaluation of its use in neuropathic pain may be warranted.

Combination Therapies

Several RCTs have been done to examine various combination therapies for neuropathic pain. Before recommendations can be made, additional studies must be done.

 

Last updated on: March 11, 2014
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