Neuropathic Pain Complexity Requires Thoughtful Approach and Combination of Interventions
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.
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 phenotypes.3
- 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 the results.6
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 diversion.
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 across patients.10
"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."
Anthony H. Dickenson has received speaking or consulting fees from Seqirus, Grünenthal, Allergan, and Mundipharma.
Didier Bouhassira has consulted for Grünenthal, Pfizer, and Indivior.
David L. Bennett has consulted for Abide, Eli Lilly, Mundipharma, Pfizer, and Teva.
David Yarnitsky has received a lecture honorarium from Pfizer and holds equity in BrainsGate, and Theranica.
Roy Freeman has served on the advisory boards for Abide, Astellas, Biogen, Glenmark, Hydra, Novartis, and Pfizer.
Andrea Truini has received research funding, lecture honoraria, and speaking or consulting fees from Mundipharma, Pfizer, Grünenthal, and Angelini Pharma.
Nadine Attal has received advisory board or speakers honoraria from Astellas, Teva, Mundipharma, Johnson and Johnson, Novartis, and Sanofi Pasteur MSD.
Nanna B. Finnerup has received advisory board honoraria from Teva Pharmaceuticals, Novartis, and Grünenthal, and research funding from EUROPAIN Investigational Medicines Initiative.
Eija Kalso has served on the advisory boards of Orion Pharma and Grünenthal and received lecture honoraria from Orion Pharma and AstraZeneca.
Robert H. Dworkin has received compensation for research activities from Abide, Aptinyx, Astellas, Boston Scientific, Centrexion, Dong-A, Eli Lilly, Glenmark, Hope, Hydra, Immune, Novartis, NsGene, Olatec, Phosphagenics, Quark, Reckitt Benckiser, Relmada, Semnur, Syntrix, Teva, Trevena, and Vertex.
Srinivasa N. Raja has received research funding from Medtronic Inc and advisory board honoraria from Allergan, Daiichi Sankyo, Grünenthal USA Inc, and Lexicon Pharmaceuticals.
Christopher Eccleston and Taylor Ludman reported no relevant financial relationships.
- Colloca L, Ludman T, Bouhassira D, et al. Neuropathic pain. Nat Rev Dis Primers. 2017;3:17002. doi: 10.1038/nrdp.2017.2
- Finnerup NB, Haroutounian S, Kamerman P, et al. Neuropathic pain: an updated grading system for research and clinical practice. Pain. 2016;157:1599-1606.
- Backonja MM, Attal N, Baron R, et al. Value of quantitative sensory testing in neurological and pain disorders: NeuPSIG consensus. Pain. 2013;154:1807-1819.
- Valeriani M, Pazzaglia C, Cruccu G, Truini A. Clinical usefulness of laser evoked potentials. Neurophysiol Clin. 2012;42(5):345-353.
- Truini A, Biasiotta A, Di Stefano G, et al. Does the epidermal nerve fibre density measured by skin biopsy in patients with peripheral neuropathies correlate with neuropathic pain? Pain. 2014;155:828-832.
- Papanas N, Ziegler D. Corneal confocal microscopy: recent progress in the evaluation of diabetic neuropathy. J Diabetes Investig. 2015;6(4):381-389.
- Mekhail NA, Mathews M, Nageeb F, Guirguis M, Mekhail MN, Cheng J. Retrospective review of 707 cases of spinal cord stimulation: indications and complications. Pain Pract. 2011;11(2):148-153.
- Moore NZ, Lempka SF, Machado A. Central neuromodulation for refractory pain. Neurosurg Clin N Am. 2014;25(1):77-83.
- Pope JE, Deer TR, Bruel BM, Falowski S. Clinical uses of intrathecal therapy and its placement in the pain care algorithm. Pain Pract. 2016;1092-1106.
- Otis JD, Sanderson K, Hardway C, Pincus M, Tun C, Soumekh S. A randomized controlled pilot study of a cognitive-behavioral therapy approach for painful diabetic peripheral neuropathy. J Pain. 2013;14(5):475-482.
- Cregg R, Cox JJ, Bennett DL, Wood JN, Werdehausen R. Mexiletine as a treatment for primary erythromelalgia: normalization of biophysical properties of mutant L858F NaV 1.7 sodium channels. Br J Pharmacol. 2014;171(19):4455-4463.