The wide range of etiologies underlying neuropathic pain render this modality
a particularly challenging condition to manage. In addition, most available
treatment options have limited efficacy. As the population ages, and as
both the incidence of diabetes and the survival rates after chemotherapy
treatment increase, the number of patients with neuropathic pain is expected
to rise, according to a recent
Nature Reviews article.1
"Pain is complex, and even if you identify a medication that has an
effect on a specific aspect of the pain pathway, the ascending or descending
pathway, it is an extremely complex condition," said Vernon Williams,
MD, a neurologist and director of the Kerlan-Jobe Center for Sports Neurology
and Pain Medicine at Kerlan-Jobe Orthopaedic Clinic in Los Angeles, California,
in an interview with
Clinical Pain Advisor.
"It is not just
sensory; there's an emotional and cultural aspect," he explained. This
is true for nociceptive pain as well, he said, but it is particularly
true for neuropathic pain because it tends to cause much worse quality
of life than nociceptive pain does, and it is an unfamiliar kind of pain
that people can have difficulty understanding.
Preventing Neuropathic Pain
The challenge of treating neuropathic pain makes prevention a particularly
high priority. Genetic etiologies cannot be prevented; however, preventing
shingles, which often causes
postherpetic neuralgia, with herpes zoster vaccination is critical to the prevention of neuropathic pain.
In addition, providers can work with patients to manage conditions or treatments
known to increase the risk for neuropathic pain, such as diabetes, chemotherapy, and
perioperative interventions, to reduce the likelihood of postsurgical pain.
Screening and Diagnosing Neuropathic Pain
In cases in which prevention fails or is not an option, 3 diagnostic classifications
exist for neuropathic pain: possible, probable, and definite.2 A "possible"
diagnosis applies when the patient's history suggests a neurological
lesion or disease or an account of one's pain consistent with biological
plausibility, but such categorization requires further testing. A "probable"
diagnosis, determined on the basis of clinical examination of sensory
signs with bedside and/or quantitative sensory testing, indicates a need
to start treatment. Only those patients who have undergone an objective
diagnostic test (eg, skin biopsy,
neurophysiological assessment) that indicates either a lesion or dysfunction of the somatosensory nervous
system would receive a "definite" diagnosis.
Validated screening tools for neuropathic pain, which can suggest a probable
diagnosis requiring treatment initiative, include the following: Leeds
Assessment of Neuropathic Symptoms and Signs, Douleur Neuropathique 4
questions, Neuropathic Pain Questionnaire, painDETECT, ID Pain, and Neuropathic
Pain Symptom Inventory. Each of these tools relies on varying requirements
in assessing specific symptoms or descriptors of pain, clinical exam items,
affect or location of pain, provoking factors of pain, and/or temporal aspects.
"From a practical standpoint, the things most commonly done have to
do with the patient history and physical examination," Dr Williams
said. "If the character and distribution of the pain by patient history
is consistent with neuropathic pain, that is often sufficient." Pain
descriptions that include burning, electric, or radiating pain are common,
as are presence of allodynia or hyperpathia. Bedside assessment of sensory
symptoms might involve observing the response to pressure, vibration,
pinpricks, cold, heat, or light touch (to assess allodynia).
Several objective tests for nerve damage are of varying utility:
- Quantitative sensory tests, using standardized mechanical and thermal stimuli,
provide reliable information about loss and gain of function of different
afferent nerve fibers classes and can be useful in identifying different
- Laser-evoked potentials most reliably assess integrity of Aδ and
C fibers, whereas nerve conduction studies, trigeminal reflexes, or somatosensory-evoked
potentials assess Aβ function.4
- Skin biopsy is highly sensitive for identifying small-fiber neuropathies,
but evidence linking neuropathic pain to skin biopsy findings is limited.5
- Corneal confocal microscopy is noninvasive, but costly, and not widely
available; in addition, evidence linking neuropathic pain with corneal
abnormalities is scarce, and nonneuropathic eye conditions may affect
Treatment Options and Pain Management
The 3 broad categories of pain management include medications, interventional
therapies, and physical or psychosocial therapies. Generally speaking,
a single medication will usually be inadequate to treat such a complex
and intense condition, and typical analgesics such as acetaminophen, nonsteroidal
anti-inflammatory drugs, or weak opioids are nearly always ineffective.
"There is going to be some kind of rational polypharmacy instead of
a single bullet," Dr Williams said. "The combination of medications
and interventional treatments can be very effective with neuropathic pain."
The only drug classes with solid evidence of effectiveness are tricyclic
antidepressants, such as amitriptyline and serotonin-noradrenaline reuptake
inhibitors like duloxetine, which are considered first-line treatments.
The antiepileptics pregabalin and gabapentin are also first-line, but
best for peripheral neuropathic pain, although more recent research has
produced negative results. Combining either of these antiepileptics with
a tricyclic antidepressant can be more tolerable and effective than monotherapy,
particularly for diabetic neuropathic pain.
Second-line treatments include lidocaine 5% patches (modest effect),
capsaicin 8% patches (lacks long-term safety data), and tramadol (primarily for peripheral
neuropathic pain), which work in some patients, but often modestly, and
with low success rates.
BotulinumtoxinA as a third-line treatment has proven particularly beneficial
for peripheral neuropathic pain and neuropathic pain resulting from diabetes,
herpes, and trigeminal neuralgia. Opioids such as oxycodone and morphine
are also considered third-line treatment for neuropathic pain, but are
less effective and more prone to misuse, overdose, morbidity, death, and
Patients who do not show adequate response to medications may try interventional
treatments such as nerve blocks, modulation of specific neural structures,
or surgical procedures for targeted drug delivery, but risks for infection
or other adverse effects are possible.
Neurostimulation to interfere with pain signals at different processing
stages consist of cryoablation or the application of electrical, radiofrequency,
or magnetic energy to pain pathways. Nerve blocks and steroid injections
offer short-term relief (typically lasting a few months), and do not reduce
the likelihood of later surgical intervention.
Spinal cord stimulation is ideal for patients not responding to other treatments,
as it was shown to be relatively safe, reversible, cost-effective, and
long-lasting (with results lasting a minimum of 24 months in several studies),
particularly if burst- and high-frequency stimulation is used vs monophonic
square-wave pulse. Although less evidence supports neurostimulation of
afferent fibers outside the spinal cord as a viable option, this intervention
has also shown relief for several neuropathic pain conditions, including
occipital and postherpetic neuralgia.7
Epidural motor cortex stimulation, repetitive transcranial magnetic stimulation,
and transcranial direct current stimulation comprise the 3 types of epidural
or transcranial cortical neurostimulation.8 An estimated 60% to 65% of
patients experience at least a 40% reduction in pain intensity from epidural
motor cortex stimulation, which requires surgery to place the electrodes.
Meanwhile, repetitive transcranial magnetic stimulation and transcranial
direct current stimulation are noninvasive and use magnetic coils or electrodes
placed on the scalp to ease central, peripheral, and facial neuropathic
pain for a minimum of 2 weeks. However, repetitive transcranial magnetic
stimulation is contraindicated for those with aneurysm clips, deep brain
electrodes, cardiac pacemakers, cochlear implants, or a history of epilepsy.
A more controversial approach is that of deep brain stimulation: whereas
this intervention was found to be effective for some patients, it is associated
with serious risks, including seizure during the procedure, lead fractures,
and wound infections.8
Intrathecal therapy to deliver morphine or
ziconotide to specific nerves using an implanted, refillable pump is considered a
last resort option.9 Dizziness, nausea, confusion, memory impairment,
uncontrolled eye movements, and an increase in serum creatine kinase are
the most common adverse events, but more serious morbidities and death
are also associated with this treatment.
Of all psychological interventions, cognitive behavioral therapy is the
only one supported by evidence; however, effect size is modest and varies
"People with chronic pain are not passive; they actively attempt to
change the causes of pain and change their own behaviour in response to
pain," wrote review author, Luana Colloca, MD, PhD, an associate
professor of anesthesiology at the University of Maryland School of Nursing,
and colleagues. "However, for many patients, such change without
therapeutic help is unachievable, and repeated misdirected attempts to
solve the problem of pain drive them further into a cycle of pain, depression
and disability." Further, it is not currently possible to reliably
determine patients who will benefit most from psychological treatments
or those most at risk for pain that is exceptionally difficult to manage.
Cognitive behavioral therapy would need to be part of an interdisciplinary
approach, Dr Williams said, just as would biofeedback, acupuncture, mindfulness
meditation, or other nonpharmacological approaches if any of those offer
a patient some additional relief.
Looking Ahead: Phenotyping and Personalized Medicine
Although emerging, the practice of identifying specific phenotypes to better
determine course of treatment is promising for a future of personalized
medicine. For example, evidence suggests that patients displaying mechanical
allodynia, but with intact nociceptive function, will be more likely to
respond to systemic and topical sodium channel blockers, botulinum toxin
A, and clonidine gel. "It would not be surprising if phenotyping
has a great part to play in demonstrating the efficacy of psychological
interventions as it does for medications," the authors wrote.
Phenotype identification could also rely on genetic identifiers or certain
combinations of symptoms or subjective descriptions of pain. For example,
the voltage-gated sodium channel, Nav1.7, is established as an important
pharmacological target, and identification of genetic mutations affecting
this protein may inform treatment decisions.11
Dr Williams told
Clinical Pain Advisor that the field is headed in the direction of using genetics, phenotype
identification, and personalized medicine, but it is still in the early stages.
"It's an approach that makes sense and that we're all endeavoring
to get to, and sometimes we can do that, but we're still defining
what those characteristics are," Dr Williams said. The neuropathic
pain categories that present the biggest challenges for genetics-based
stratification are acquired ones, such as neuropathic pain resulting from
diabetes, stroke, cancer, trauma, shingles, or anything else that's
polygenic or specific to an acquired disease. But eventually overcoming
these challenges to offer personalized approaches to pain management will
pay off in multiple ways.
"It's good medicine, it tends to be less costly, and people tend
to have higher satisfaction, as opposed to starting treatment in a stepwise
fashion," Dr Williams added. "Trial-and-error has dominated
our approach for quite some time, but we're starting to be able to
move out of that and have a more specific approach that's stratified
and hopefully gives us a higher hit rate in terms of success sooner than
that trial-and-error and stepwise approach."