Neuropathic pain affects 7% to 10% of the general population; however, the prevalence is likely underestimated due to limitations of current epidemiologic research.1-3 Many patients with neuropathic pain also experience anxiety, depression, insomnia, disability, and reduced quality of life.4,5 Unfortunately, management remains suboptimal because traditional drugs provide only modest pain relief.6 Neuropathic pain remains difficult to treat, challenging providers across multiple disciplines. Management strategies address neuropathic pain as a broad entity without regard for a specific cause. Ongoing research aims to individualize management of neuropathic pain by predicting treatment responses in individual pain phenotypes.
According to the International Association for the Study of Pain (IASP), neuropathic pain is the direct result of a lesion or disease of the central or peripheral somatosensory nervous system (Figure 1).7 In contrast, nociceptive pain is caused by actual or impending tissue damage outside of the somatosensory nervous system. Patients may present with mixed pain syndromes (coexisting neuropathic and nociceptive pain), which further complicate diagnosis and treatment. Additionally, some neurologic disorders indirectly cause painful complications (such as spasticity and rigidity) that require different treatment regimens outside the realm of neuropathic pain management.8 This article focuses on managing patients with neuropathic pain, although some of the treatment approaches also may be beneficial for patients with mixed pain.
PERIPHERAL VS. CENTRAL
Peripheral neuropathic pain is more commonly encountered in the primary care setting than central neuropathic pain. This type of neuropathic pain may develop as a result of mononeuropathy (carpal tunnel syndrome or sciatica), polyneuropathy (diabetes), varicella zoster virus (postherpetic neuralgia), trauma, surgically induced nerve injury, Guillain-Barré syndrome, chemotherapy, or radiculopathy.
Central neuropathic pain is associated with spinal cord injury, multiple sclerosis, stroke, tumor compression, amputation (phantom limb pain), and complex regional pain syndrome type II. Note that complex regional pain syndrome type I does not meet the IASP definition of neuropathic pain because patients have no identifiable nerve damage.6
Some neuropathic pain conditions, such as spinal cord injury or phantom limb pain, may be underrepresented because much of the current research on neuropathic pain focuses on painful diabetic peripheral neuropathy and postherpetic neuralgia.
HISTORY AND PHYSICAL EXAMINATION
Patients with neuropathic pain may have positive and/or negative signs and symptoms (Table 1). Positive signs and symptoms reflect nervous system hyperactivity; negative signs and symptoms reflect loss of nervous system function. The presence of both positive and negative signs and symptoms is highly suggestive of an underlying neuropathic pain condition. This is a nonspecific finding, however, as patients with nociceptive pain may experience both positive and negative symptoms.5
Positive signs and symptoms include burning, shooting, stabbing, coldness, tightness, paresthesias, or electric shock-like sensations. The pain may be characterized as continuous or intermittent, and spontaneous or evoked.4
Negative signs and symptoms are nonpainful and are often discovered during physical examination.5 Findings may include muscle weakness; loss of deep tendon reflexes; absent or impaired sensation to light, touch, pinprick, vibration, and temperature.4,5
Establishing the patient's pain distribution is perhaps the most important part of clinical evaluation. Neuropathic pain is localized to a peripheral nerve region or to neuroanatomical correlates of the central nervous system, such as dermatomes, myotomes, and afferent spinal pathways, raising suspicion for an underlying lesion or disease of the somatosensory nervous system.8
History and physical examination remain the gold standard of the neuropathic pain diagnosis. Despite screening tools such as the Douleur Neuropathique en 4, Leeds Assessment of Neuropathic Symptoms and Signs, and PainDETECT, no consensus exists on which tool is superior. They all miss 10% to 20% of patients who are later diagnosed with neuropathic pain syndromes.9,10 Keeping these limitations in mind, primary care providers may use the tools along with clinical judgment to help establish a diagnosis of neuropathic pain. As mentioned above, the combination of negative and positive signs and symptoms is highly suggestive of a neuropathic pain syndrome, especially when localized to a neuroanatomic region of the body.
In 2008, Treede and colleagues proposed a grading system that incorporates a focused approach to clinical evaluation with additional diagnostic testing to determine the likelihood of neuropathic pain.8 Useful diagnostic tests may include plain radiographs, CT, MRI, electromyography (EMG), somatosensory-evoked potentials, laser-evoked potentials, skin biopsy, or reflex responses.8 An underlying cause should be identified when possible. In the primary care setting, this may involve laboratory testing, radiographs, CT, MRI, and referral to a specialist service.
No concrete evidence demonstrates the effectiveness of nonpharmacologic interventions such as exercise, biofeedback, cognitive behavioral therapy (CBT), transcutaneous electrical nerve stimulation (TENS), and repetitive transcranial magnetic stimulation (rTMS) in treating neuropathic pain.11 Potential benefits of treatment may outweigh the risks; providers may consider one or more of these therapies in addition to traditional pharmacologic management.
Pharmacologic management focuses on neuropathic pain as a broad clinical entity, and regardless of cause, similar treatment strategies often are used.11,12 An exception is trigeminal neuralgia. Multiple research studies analyze the condition as a separate entity because of its distinct treatment approach.
Guidelines and consensus statements for the pharmacologic management of neuropathic pain have been published by the IASP's special interest group on neuropathic pain, the Canadian Pain Society, the European Federation of Neurological Societies, and the United Kingdom's National Institute for Health and Clinical Excellence (NICE). These statements apply to neuropathic pain in general and do not take underlying causes into account. Disease-specific recommendations are provided only for painful diabetic peripheral neuropathy. The findings from these reports are summarized below.
First-line treatment options include tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors (SNRIs), gabapentin, and pregabalin (Table 2).6,12,13 When deciding which medication to prescribe first, consider patient preferences, lifestyles, risk factors, comorbidities, insurance coverage, and the patient's financial situation.
Tricyclic antidepressants, especially amitriptyline, have historically been used as first-line treatment for neuropathic pain, despite a lack of high-quality evidence demonstrating their efficacy.6,12-15 According to a NICE meta-analysis, patients taking tricyclic antidepressants were more likely to report at least 30% pain relief.12 For patients who achieve adequate pain relief with amitriptyline but are unable to tolerate the adverse reactions, consider switching to nortriptyline or imipramine. Anticholinergic adverse reactions to tricyclic antidepressants are common, and include sedation, dry mouth and constipation. When tricyclic antidepressants are taken at bedtime, their sedating properties may be used strategically for treating neuropathic pain and associated insomnia.
SNRIs include duloxetine and venlafaxine. Both drugs, especially duloxetine, are recommended as first-line treatment for painful diabetic peripheral neuropathy.6,12,13,15 They also may be used as first-line treatments for neuropathic pain from other causes.6,12,13,15 NICE reports that patients taking duloxetine were more likely to report at least 30% pain relief from all causes.12 Duloxetine also significantly reduced pain intensity in a study of patients with chemotherapy-induced painful peripheral neuropathy.13 In general, duloxetine is preferred over venlafaxine due to its greater evidence of efficacy.6,12
Pregabalin is strongly recommended for first-line treatment of neuropathic pain by each of the organizations mentioned above. This drug has dose-dependent effects and is given twice daily.6,15 According to NICE, patients taking pregabalin were more likely to report at least 30% pain reduction.12 Efficacy for pain relief has been established in patients with postherpetic neuralgia and chronic pain resulting from spinal cord injury.13,15 Common adverse reactions to pregabalin include dizziness, somnolence, and weight gain.
Gabapentin is an anticonvulsant that may be used to treat neuropathic pain and may be dosed several times a day. NICE reports that patients taking gabapentin were more likely to report at least 50% pain relief.12 Unfortunately, there is less consensus on when gabapentin should be prescribed. The IASP Special Interest Group on Neuropathic Pain and the Canadian Pain Society endorse first-line use of gabapentin for patients with neuropathic pain, regardless of underlying cause.6,13 However, the European Federation of Neurological Sciences recommends first-line use of gabapentin only for painful diabetic peripheral neuropathy, postherpetic neuralgia, and central pain.15 Common adverse reactions to gabapentin include dizziness, somnolence, and fatigue.
Second-line treatment options include tramadol, lidocaine patches, and high-concentration capsaicin patches.11 Consider using tramadol before opioids such as morphine and oxycodone because it generally has a less significant effect on cognition and a decreased risk of misuse and abuse.6 Lidocaine patches and high-concentration capsaicin patches lack high-quality evidence of efficacy but have more favorable safety profiles and usually are well tolerated.11-13 Topical lidocaine may be a prudent treatment option for older adults who may not be able to tolerate the adverse reactions to more aggressive pharmacologic treatments. Special training is encouraged for healthcare providers interested in prescribing and/or administering high-concentrate capsaicin patches. The long-term effects of these patches have not been thoroughly investigated.11
Cannabinoids and opioids for neuropathic pain are controversial. Finnerup and colleagues recommend opioids as third-line treatment due to concerns for potential abuse, diversion, misuse, and overdose.6 Opioids may be used most appropriately on a short-term basis, perhaps for acute pain control during titration of other agents. Cannabinoids also remain controversial. They are available in several routes of administration, including oral and intramucosal, and may play a role in treating central neuropathic pain, though additional research is needed.13 In many states, legislation continues to limit the free prescription of cannabinoids. Similar to opioids, cannabinoids raise concerns for abuse, misuse, and psychosis, especially in patients with a premorbid psychiatric history.
Research to date fails to show significant efficacy of one drug over another for specific neuropathic pain conditions, with the exception of duloxetine for painful diabetic peripheral neuropathy and carbamazepine for trigeminal neuralgia.11-13 Promising research suggests that patients with certain sensory phenotypes may be more likely to respond to specific medications (for example, patients with pinprick hyperalgesia had a positive response to pregabalin), but this is still under investigation.16
Neuropathic pain is an important clinical issue that often is accompanied by anxiety, depression, sleep disturbance, functional impairment, and reduced quality of life. Due to the refractory nature of neuropathic pain, clinicians should consider using pharmacologic and nonpharmacologic intervention in patient management. A multidisciplinary approach that involves the patient and includes the primary care provider, pain specialist, physical and occupational therapists, psychologist, neurologist, and/or physiatrist is recommended.
1. Torrance N, Smith BH, Bennett MI, Lee AJ. The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain
2. Bouhassira D, Lantéri-Minet M, Attal N, et al Prevalence of chronic pain with neuropathic characteristics in the general population. Pain
3. van Hecke O, Austin SK, Khan RA, et al Neuropathic pain
in the general population: a systematic review of epidemiological studies. Pain
4. Gilron I, Baron R, Jensen T. Neuropathic pain
: principles of diagnosis and treatment. Mayo Clin Proc
5. Magrinelli F, Zanette G, Tamburin S. Neuropathic pain
: diagnosis and treatment. Pract Neurol
6. Finnerup NB, Attal N, Haroutounian S, et al Pharmacotherapy for neuropathic pain
in adults: a systematic review and meta-analysis. Lancet Neurol
7. International Association for the Study of Pain. Taxonomy. http://www.iasp-pain.org
/Taxonomy#Neuropathicpain. Accessed November 21, 2016.
8. Treede RD, Jensen TS, Campbell JN, et al Neuropathic pain
: redefinition and a grading system for clinical and research purposes. Neurology
9. Baron R, Binder A, Wasner G. Neuropathic pain
: diagnosis, pathophysiological mechanisms, and treatment. Lancet Neurol
10. Haanpää M, Attal N, Backonja M, et al NeuPSIG guidelines on neuropathic pain
11. Dworkin RH, O'Connor AB, Kent J, et al Interventional management of neuropathic pain
: NeuPSIG recommendations. Pain
12. Centre for Clinical Practice at NICE (UK). Neuropathic Pain: The Pharmacological Management of Neuropathic Pain in Adults in Non-Specialist Settings
. London: National Institute for Health and Clinical Excellence (UK); 2010.
13. Moulin D, Boulanger A, Clark AJ, et al Pharmacological management of chronic neuropathic pain
: revised consensus statement from the Canadian Pain Society. Pain Res Manag
14. Moore RA, Derry S, Aldington D, et al Amitriptyline for neuropathic pain
in adults. Cochrane Database Syst Rev
15. Attal N, Cruccu G, Baron R, et al EFNS guidelines on the pharmacological treatment of neuropathic pain
: 2010 revision. Eur J Neurol
16. Simpson DM, Schifitto G, Clifford DB, et al Pregabalin for painful HIV neuropathy: a randomized, double-blind, placebo-controlled trial. Neurology