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11 Articles in Volume 13, Issue #8
Ask the Expert: Intranasal Ketamine for Migraine Therapy
Assessment and Treatment of Neuropathic Pain
Diabetes & PAD: Diagnosis, Prevention, and Treatment Paradigms
Editor's Memo: Chronic Low Back Pain: Bringing Back A Forgotten Treatment
Evaluation and Treatment of Chemo- or Radiation-Induced Painful Complications
Guide to Implantable Devices for Intrathecal Therapy
Is Buprenorphine a ‘Partial Agonist’? Preclinical and Clinical Evidence
Letters to the Editor: Hormones and Genetic Testing
Pain Management in Kenya: A Team Experience
PROP versus PROMPT: FDA Speaks
Use of Ultrasound in Detection Of Rotator Cuff Tears

Assessment and Treatment of Neuropathic Pain

Assessment of neuropathic pain begins with a thorough neurologic history, addressing the nature and onset of pain symptoms and underlying etiologic factors. Such factors include diabetes, alcohol abuse, vitamin deficiencies, environmental neurotoxins, trauma, structural lesions such as herniated nucleus pulposus or carpal tunnel syndrome, and inheritable causes.

Pain can be categorized into four mechanistic types: nociceptive, inflammatory, functional, and neuropathic.1 Nociceptive pain, a transient response to a noxious stimulus, performs a protective function to prevent tissue injury. Inflammatory pain, in which tissue damage causes both spontaneous pain and hypersensitivity, also has a protective function that may prevent further insults to an area of injury. In contrast, functional pain and neuropathic pain are maladaptive types of pain that are not a response to noxious stimuli or tissue injury. In functional pain, there is hypersensitivity due to abnormal central nervous system processing of normal peripheral sensory input. In neuropathic pain, the etiology is a lesion in the nervous system.

The article will focus on the diagnosis and treatment of neuropathic pain.

What Causes Neuropathic Pain?

Neuropathic pain may involve more than one mechanism of action.2 It may result from abnormal peripheral nerve function or neural processing of impulses due to abnormal neuronal receptor and mediator activity. Sodium channels may have altered expression, accumulation, or distribution. There may be increased expression of mRNA for specific neurotransmitters, such as substance P. Accordingly, no single agent may be efficacious for all neuropathic pain, and a targeted medication or combination of medications may be needed for adequate pain management.3 Spontaneous pain and paresthesias associated with sodium channel activity, for instance, may respond best to sodium channel blockers or anticonvulsants. Increased transmission and reduced inhibition of pain pathways associated with hyperalgesia and allodynia may respond better to tricyclic antidepressants (TCAs) or opioids.

There are numerous targets for the pharmacologic treatment of neuropathic pain. In the peripheral nervous system, voltage-gated sodium channels, such as NaV1.7 and NaV1.8, have been found to be involved in various pain syndromes.4 Other diverse peripheral targets include calcium channels, the TRPV1 receptor, neuropeptide receptors, peripheral alpha-2 adrenoceptors, the TrkA neurotrophin receptor, and the P2X3 ATP receptor. Similarly, multiple targets exist in the central nervous system (CNS), including sodium and calcium channels, opioid receptors, the N-methyl-D-aspartate (NMDA) receptor, alpha-2 adrenoceptors, and serotonin/norepinephrine pathways.

Clinical Assessment of Neuropathic Pain

Assessment of neuropathic pain begins with a thorough neurologic history, addressing the nature and onset of pain symptoms and underlying etiologic factors. Such factors include diabetes, alcohol abuse, vitamin deficiencies, environmental neurotoxins, trauma, structural lesions such as herniated nucleus pulposus or carpal tunnel syndrome, and inheritable causes. The sensory phenomena of neuropathic pain manifest as both spontaneous pain (symptoms) and stimulus-evoked pain (signs). The latter may include positive signs, such as hyperalgesia, allodynia, hyperesthesia, paresthesia (burning, pricking), or dysesthesia. There may also be negative signs, such as hypoalgesia, analgesia, or hypoesthesia.5 Hyperalgesia and allodynia can manifest in response to both mechanical stimuli as well as thermal or chemical stimuli. Neuropathic pain patients suffer from spatial sensory abnormalities, such as dyslocalization, extraterritorial spread, and radiation of pain. They also may suffer from temporal abnormalities of after-sensation or abnormal latency.

Evaluation of neuropathic pain symptoms (ie, spontaneous pain) can be performed using a variety of pain scales, inventories, and questionnaires. It is useful to have patients map the distribution of pain on a diagram of the human body, which can demonstrate characteristic patterns such as the stocking-glove distribution (feet/lower limb and hands/arm) of pain that occurs with a distal sensory polyneuropathy (Figure 1). Based on the identification of key words that might discriminate for neuropathic pain, a variety of screening tools have been developed, such as the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS), the Neuropathic Pain Diagnostic Questionnaire (DN4), the Neuropathic Pain Scale (NPS), Neuropathic Pain Symptom Inventory (NPSI), and Neuropathic Pain Questionnaire (NPQ). These tools are based on verbal pain reports, and have limited to no need for bedside testing.

Physical examination for neuropathic pain includes evaluation of sensation (including provoked pain), motor function, and autonomic changes. Sensory examination helps confirm neuropathic pain and distribution and can uncover sensory deficits to various stimuli, including touch, pinprick, temperature, and vibration.6 Allodynia is assessed to determine if pain is provoked by static or dynamic stimuli, such as by light rub with a fingertip, cotton swab, or paintbrush (dynamic allodynia); or perpendicular pressure (static allodynia). Hyperalgesia is diagnosed if the patient has an exaggerated response to single or multiple pinpricks, or thermal stimuli such as a warm or cold test tube or tuning fork (thermal hyperalgesia). Summation (increasing pain to repeated stimulus) and after-sensation (prolonged perception of a stimulus after it is removed) are common during neuropathic pain. Muscle bulk, tone, and strength, as well as coordination and gait, should be assessed. Autonomic changes in limb temperature, sweating, skin color, or hair and nail growth may accompany neuropathic pain.7

Further diagnostic studies may be helpful in some cases of neuropathic pain.8 Blood tests or imaging studies may identify underlying causes of neuropathic pain or other abnormalities, such as rheumatologic disease or structural lesions. Electromyography (EMG) and nerve conduction velocity (NCV) also may play a role, but these studies are insensitive in acute injury and cannot assess the function of the small-fiber nerves that are involved in most neuropathic pain. These studies do not measure pain directly. Hence, normal EMG/NCV studies do not rule out a diagnosis of neuropathic pain, nor do abnormal results prove that pain is neuropathic.9 Small-fiber nerve function can be assessed by quantitative sensory testing, detecting abnormalities even when EMG and NCV are normal.

Neuropathic Pain Treatment

The management of neuropathic pain encompasses establishing a diagnosis, treating any underlying condition that may be causing the pain, providing symptomatic relief from pain and disability, and preventing recurrence. Neuropathic pain can be diagnosed as a specific entity, for example, as peripheral neuropathy or malignant radiculopathy.10 Treatment targeted to the underlying condition—such as surgical release of an entrapped nerve,11 epidural steroids for lumbar radiculopathy,12 or antivirals for herpes zoster—often is an option.8

When such specific treatment is not available or is not effective, symptomatic treatment should be offered. Treatment for long-standing neuropathic pain rarely eliminates the pain. Consequently, the following clinically meaningful goals should be established:

  • Reducing pain
  • Improving physical functioning
  • Reducing psychological distress
  • Improving overall quality of life

It is important for physicians and patients to have appropriate expectations for the outcome of treatment, knowing that it is unlikely that pain will be completely eliminated but that treatment can improve quality of life.13

In some cases, preventive measures should be addressed. Patients with diabetic neuropathy should seek to maintain tight glycemic control
(HbA1C <6). Patients with acute herpes zoster should receive early antiviral agents to prevent postherpetic neuralgia (PHN).

Treatments for neuropathic pain exist on a spectrum of invasiveness (Figure 2).14 On the low end of invasiveness are psychological and physical treatments, such as relaxation therapy and physical exercise programs. Next are topical medications, including lidocaine, capsaicin, and various custom-compounded topical agents of unknown efficacy. The next step includes oral medications—anticonvulsants, TCAs, opioids, and other agents, such as mexiletine or baclofen. Table 1, lists the agents that are FDA-approved for neuropathic pain. Finally, the most invasive treatments are interventional techniques such as nerve blocks, which are usually administered with local anesthetics and/or steroids. The efficacy of a treatment does not necessarily match its invasiveness, and a behavioral therapy or topical medication could be more effective than an interventional technique in a given patient.10,15 Treatments should be evaluated in terms of three important criteria: efficacy, safety, and tolerability.

The PHN Model

Topical Agents

PHN often is used for clinical studies of neuropathic pain. It is a readily distinguishable condition that manifests or persists after an initial injury (acute herpes zoster) has healed.16 The lack of efficacy of peripheral interventions in most PHN patients points to a predominating central pain generator, implicating central nervous system remodeling. Autopsy data confirms chronic peripheral inflammation, neuronal loss in dorsal root ganglia, and reductions of both axons and myelin in affected nerves. The underlying mechanisms of PHN, which may include lowered activation thresholds, ectopic discharges, enlarged receptive fields, and/or collateral sprouting, may be common to other types of neuropathic pain.17 Hence, as we describe the pathophysiology of neuropathic pain, we will focus on PHN as an inclusive example.

The topical 5% lidocaine patch (Lidoderm) has proven efficacy in the treatment of pain secondary to PHN. Lidocaine inhibits voltage-gated sodium channels. In the initial study that led to FDA approval of the 5% lidocaine patch for PHN, Rowbotham et al found that the patch was associated with a larger reduction in pain scores than vehicle-only (placebo) patch among 35 subjects reporting pain severity on a visual analog scale.18

Another large controlled clinical trial compared lidocaine patches to vehicle patches applied directly to the painful skin of subjects with PHN using an “enriched enrollment” study design.19 Prior to study enrollment, all subjects had been treated successfully with lidocaine patches for at least 1 month. They were enrolled in a randomized, 2-treatment period, crossover study. The primary efficacy variable was “time to exit,” and subjects were allowed to exit either treatment period if their pain relief score decreased by 2 or more categories on a 6-item pain relief scale for two consecutive days. The median time to exit was greater than 14 days for the lidocaine patch, versus 3.8 days for placebo. During the study, 78.1% of subjects preferred the lidocaine patch; only 9.4% preferred the placebo. No difference in side effects was observed between the lidocaine patch and placebo. A 2007 Cochrane Review of topical lidocaine concluded that it conferred greater pain relief than placebo, with a similar incidence of adverse skin reactions.20

The 8% capsaicin patch (Qutenza), which targets the TRPV1 receptor as an agonist, also has proven effective for the treatment of PHN pain. The patch is thought to work through a reduction in TRPV1-expressing epidermal nociceptors, and this has been documented by skin biopsy in a healthy volunteer study.21 Two trials of the 8% capsaicin patch have demonstrated that it resulted in a statistically significant reduction in PHN pain compared to that reported with a low-dose control.22,23 The most common side effects were transient and self-limited erythema, pain, pruritus, and papules associated with the patch, which must remain in place for 60 minutes before being removed. The manufacturer of the capsaicin patch recommends applying topical lidocaine to the entire treatment area prior to applying the patch. This has reduced application site pain, which has been shown to return to baseline levels approximately 2.5 hours after patch application.23 This treatment can be repeated every 3 months, if needed.

Anticonvulsants

Presynaptic voltage-gated calcium channels are another important target of neuropathic pain therapy.24 Gabapentin (Neurontin, Gralise, Horizant) is an anticonvulsant that is FDA-approved for PHN treatment.25 Its efficacy was demonstrated in a large multicenter randomized controlled trial for PHN.26 Another randomized controlled trial showed that it was efficacious in the treatment of painful diabetic neuropathy.27 Gabapentin usually is well tolerated, although dizziness and sedation can occur. Clinical experience has shown that high doses (usually up to 3,600 mg daily, divided tid or qid) often are necessary but well-tolerated.25 Pregabalin (Lyrica) is FDA-approved for PHN and painful diabetic peripheral neuropathy, and has demonstrated efficacy in the treatment of pain due to both conditions.28,29 Due to linear kinetics, pregabalin has more consistent absorption and higher bioavailability than gabapentin. Finally, intrathecal ziconotide (Prialt) is a calcium channel antagonist that is FDA-approved for the treatment of severe chronic pain. Clinical trials of intrathecal ziconatide have proven efficacy for chronic pain.30,31 In contrast, intrathecal gabapentin did not alleviate pain when compared with placebo,32 and is thought to act directly in the brainstem to stimulate descending inhibition.33

Antidepressants

Antidepressants are another commonly enrolled class of medications for neuropathic pain. Onset of analgesia with antidepressants generally occurs before the onset of the antidepressant effect.8 TCAs, which act in part by inhibiting norepinephrine and serotonin reuptake, have been shown in multiple clinical trials to reduce the pain of diabetic neuropathy and PHN.34 Adverse effects with TCAs include anticholinergic effects such as blurred vision, cognitive changes, constipation, sedation, tachycardia, and urinary retention. Among TCAs, desipramine and nortriptyline are associated with the fewest side effects and amitriptyline with the most.35,36 It may be advisable to avoid amitriptyline in the elderly due to its relatively high risk for adverse effects.37 Of the serotonin-norepinephrine reuptake inhibitors (SNRIs), duloxetine (Cymbalta) was shown to decrease diabetic neuropathic pain at a dosage of 60 mg daily, without a significant increase in side effects compared with placebo.38 Duloxetine is unique from other antidepressants in that onset of analgesia is usually within 1 week. Another SNRI, venlafaxine, also has been found to be efficacious for painful diabetic peripheral neuropathy, but has a time of onset of over 4 weeks.39 In contrast, the efficacy of selective serotonin reuptake inhibitors for neuropathic pain is inconsistent at best.40

Opioids

Various studies have demonstrated effectiveness, at least in the short-term, of opioids in neuropathic pain disorders. In PHN, both IV morphine41 and controlled-release oxycodone42 have been shown to reduce pain. Controlled-release oxycodone also reduced pain in a study of painful diabetic neuropathy,43 as did tramadol.44 Oral morphine reduced pain in a study of phantom limb pain.45 However, long-term efficacy is not well established with opioids, and the benefits of their use must be balanced against risks of adverse effects and aberrant behaviors.

Emerging Therapies: What’s Next

Emerging potential therapies for neuropathic pain have unique targets. In small studies, cannabis or synthetic cannabinoids have demonstrated decreases in neuropathic pain when administered orally, sublingually, or inhaled (smoked).46-48 Preclinical and clinical studies also suggest a therapeutic window for cannabis dosing, wherein lower doses may have higher efficacy.49 Another novel agent, NGX426, is an AMPA-kainate antagonist that reduced capsaicin-induced pain in healthy volunteers.50 Small studies also suggest that botulinum toxin (onabotuliumtoxinA, Botox), which is FDA-approved for the treatment of migraine headaches, may have a future role in the treatment of some types of neuropathic pain.51,52

Case Example

A 76-year-old man was referred to a pain specialist for persistent burning pain of the left flank and upper abdomen 3 months after onset of a shingles outbreak in the same area. The pain had impaired his ability to sleep. He also reported severe anxiety regarding the possibility of having a pain exacerbation while away from his home, which has limited his social activities. The shingles was treated with acyclovir and the vesicular rash resolved within 6 weeks. His primary care physician started a trial of gabapentin 300 mg tid, which was tolerated well but with little improvement in pain symptoms. A brief trial of gabapentin at a higher dose of 600 mg tid was stopped due to excessive daytime sleepiness. Physical examination was notable for allodynia and hyperalgesia in a left T9 dermatomal distribution and minimal residual scarring. What therapeutic options are available for this patient?

Diagnosis

The patient’s history and physical exam findings are consistent with the diagnosis of PHN. As noted, gabapentin is an anticonvulsant that is approved for this indication, and it was a reasonable first choice for treatment of this patient’s pain symptoms. Although patients are often able to tolerate higher doses of this drug, this patient was limited by its sedating side-effects.

One option for this patient could be a transition from gabapentin to pregabalin, which is also indicated for PHN and might be better tolerated. Consideration could be given to a trial of a TCA, but its side effect profile might be problematic for this elderly patient. Were a TCA to be used, it would be best to avoid amitriptyline and choose nortriptyline or desipramine, which have fewer side effects.

Alternatively, an SNRI like duloxetine could by trialed instead, and also could improve anxiety symptoms. Better yet may be a trial of topical medications, which typically have fewer side effects. The 5% lidocaine patch would be a good choice and also is FDA-indicated for his diagnosis. An alternative topical treatment could be 8% capsaicin patch, which could be administered every 3 months, if effective.

Finally, the patient’s increased anxiety regarding chronic pain should be directly addressed, and he may benefit from referral to a clinical psychologist.

Last updated on: November 4, 2013
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