Neuropathic Pain – Causes, Symptoms, Diagnosis, Treatment and Ongoing care
- Neuropathic pain is defined as pain in association with primary injury or dysfunction of the nervous system, with or without ongoing tissue damage.
- Divided into 2 groups based on the location of the suspected lesion: central vs peripheral:
- Newer data suggest a possibility that most neuropathic syndromes have a component of both central and peripheral mechanisms.
- An important consideration with a patient with neuropathic pain is the absence of any deficit or injury. Socially, the patient appears “normal,” yet suffers from a chronic painful condition. This can lead to psychosocial distress, as the patient is labeled “drug seeking.”
- May be triggered by numerous insults, including direct nerve injury, infection, metabolic dysfunction, autoimmune disease, neoplasm, drugs, radiation, and neurovascular disorders
- May reflect the pathologic operation of a dysfunctional nervous system rather than a manifestation of any underlying pathology itself (i.e., phantom limb pain, complex regional pain syndrome [CRPS]):
- Patients may paradoxically experience pain and hypersensitivity in an area of denervation.
- System(s) affected: Nervous; Musculoskeletal
Epidemiologic data are limited. It will also be varied, depending on the inclusion criteria: Radiculopathies, peripheral neuropathy, etc.:
- >3 million Americans suffer from painful diabetic neuropathy (PDN).
- 1 million Americans suffer from postherpetic neuralgia (PHN).
Estimated at 1.5% of the population, although recent studies in England, Germany, and France place it around 6–8% of the population.
- Polyneuropathy (diabetes mellitus, alcohol induced, post chemotherapy)
- Trauma (nerve entrapment, post surgical, nerve injury)
- Infection (HIV, herpes zoster)
- Central mechanisms (stroke, MS, spinal cord injury, limb amputation)
- Nutritional deficiencies (B12, folate)
- Medications (AIDS medications DDC and DDI, antibiotics metronidazole and isoniazid, some chemotherapeutics, amiodarone, hydralazine, phenytoin, nitrofurantoin)
- Positive symptoms due to changes in peripheral nerves, loss of inhibitory mechanisms in CNS, and central sensitization
- Negative symptoms likely due to axonal or neuronal loss
- Associated with a predisposing factor
- In addition to possible etiologies listed as risk factors above, others include:
- Demyelinating disorders (multiple sclerosis, Guillain-Barré)
- Neoplasm (primary or metastatic)
- Neurovascular (central post stroke syndrome, trigeminal neuralgia)
- Autoimmune disease (Sjögren syndrome, polyarteritis nodosa)
- Structural disease (herniated disc disease)
Commonly Associated Conditions
- Sleep disturbance
- May have history of nerve trauma; however, absence does not exclude the diagnosis of neuropathic pain
- Clinical manifestation can include both negative and positive sensory symptoms and signs. Motor dysfunction is rare.
- Pain is often described as burning, shocklike, tingling, numbing, or intensely hot or cold.
- Positive signs and symptoms:
- Hyperalgesia: An exaggerated pain response to a noxious stimulus
- Allodynia: The perception of pain due to a non-noxious stimuli; for instance, gentle mechanical pressure, light pinprick, hot or cold stimuli, and vibration cause pain.
- Negative signs and symptoms:
- Reduced sensation to touch, pinprick, temperature, or vibration
- Motor signs and symptoms:
- Signs may include hypotonia, tremor, dystonia, ataxia, hypo-/hyper-reflexia, or motor neglect. Motor symptoms include weakness, fatigability, decreased range of motion, joint stiffness, and spontaneous muscle spasm.
Diagnostic Tests & Interpretation
Initial lab tests
None specifically for neuropathic pain, but tests to rule out other causes should be considered:
- Serum B12
- 25 vitamin D
- RPR or VDRL
- Fasting glucose, creatinine
- Lyme serology
Follow-Up & Special Considerations
Studies may include nerve conduction, electromyography, evoked potentials, quantitative sensory testing, thermography, radiologic imaging
- Used to rule out other causes for pain
- Consider imaging based on affected area. MRI shows greatest anatomical detail for spine.
- PET and SPECT scans, standard MRI, and functional MRI all have been used to map synaptic activity in the thalamus and somatosensory cortex. Initial studies using these imaging techniques have suggested maladaptive reorganization of the thalamus and somatosensory cortex.
- Sympathetic nerve blocks
- Epidural steroids
- Peripheral nerve blocks
- Dorsal column stimulator and peripheral nerve stimulator
- All 1st-line agents are those that have been studied the most. However, the more we understand about chronic opioid therapy, the more we recommend not starting an opioid until other neuropathic agents have failed. In general, moving from 1 anticonvulsant or TCA to the other should be considered the 1st step of action.
- An anticonvulsant that has the broadest evidence for efficacy against neuropathic pain, FDA approved for its treatment (1)[A]
- Evidence supports efficacy in PDN, PHN, phantom limb pain, Guillain-Barré syndrome, acute and chronic pain from spinal cord injury, and CRPS type 1 (2)[A]
- Start 300 mg daily, increase gradually; dosing up to 600 mg t.i.d. is suggested; max dose of 3,600 mg/d in divided doses; adjust dose in renal insufficiency
- Adequate trial of 3–8 weeks of therapy at full dose before considering it a failure
- Interactions: No major drug–drug interactions
- Adverse effects: Dizziness, somnolence, GI symptoms, peripheral edema
- Tricyclic antidepressants:
- This class has the most evidence supporting their role in neuropathic pain (3)[A].
- Dosing: Start at 10–25 mg at bedtime, then titrate up to antidepressant drug levels.
- Secondary amines (nortriptyline, desipramine) are safer than amitriptyline and imipramine.
- Precautions: Small therapeutic-to-toxic window; use caution in prescribing to those with cardiac risk factors, glaucoma, urinary retention; suicide susceptibility
- Should obtain a pretreatment ECG for documentation and monitoring any arrhythmias
- Absolute contraindication with MAOIs
- Interactions: Numerous possible drug–drug interactions (type 1C antiarrhythmics, SSRIs, anticholinergics, sympathomimetics, CNS depressants)
- Adverse effects: QT interval abnormalities, arrhythmias, sedation, dry mouth, constipation, sexual dysfunction, weight gain, postural hypotension
- Tramadol (4)[A]:
- Norepinephrine and serotonin inhibitor with a major metabolite that acts as an opioid (mu receptor) agonist
- Dosage: 250 mg/d divided doses, max 400 mg/d
- Precautions: Avoid in those with seizure history
- Interactions: Increased seizure risk in those taking SSRIs, TCAs, MAOIs, neuroleptics concomitantly; increased risk of serotonergic symptoms if used with SSRIs, MAOIs; adjust dose for renal insufficiency, hepatic disease
- Adverse effects: Dizziness, nausea, constipation, somnolence, orthostatic hypotension
- FDA-approved for treatment of neuropathic pain secondary to PHN and diabetic polyneuropathy. Also approved for fibromyalgia (5)[A].
- Dosage: Start at 75 mg b.i.d., maximum dose 300 mg b.i.d.
- Interactions: No major drug–drug interactions
- Opioids (2)[A]:
- According to World Health Organization, should be used in “ladder” fashion, added to nonopioid agents if they are insufficient. However, this is usually for palliative cancer patients. Chronic opioid therapy can be detrimental to psychosocial environment of the patient.
- Evidence for increased efficacy when used in conjunction with gabapentin
- Controlled-release opioids recommended (controlled release oxycodone, morphine, transdermal fentanyl, methadone)
- Dosage: Start with short-acting analgesic equivalent to oral morphine sulfate 5–15 mg q4h; after 1–2 weeks of treatment, calculate equivalent dose of long-acting agent and use short-acting opioids for breakthrough.
- No clear maximum dosage, but trials do not show benefits at doses higher than 180 mg/d of morphine.
- Precaution: Avoid in those with history of substance abuse, use with caution in the elderly, may cause respiratory depression
- Interactions: Additive effects with CNS depressants, increased risk of serotonin syndrome with serotonergic agents
- Adverse effects: Constipation, sedation, nausea, lightheadedness
- Adjuvant therapies with opioids should be used to treat nausea/vomiting, constipation, sedation, pruritus, etc.
- Some evidence suggests use of other medications:
- Antidepressants: Paroxetine, venlafaxine, duloxetine, bupropion, citalopram (2)
- Duloxetine has comparable efficacy and tolerability to gabapentin and pregabalin in treatment of diabetic peripheral neuropathic pain (6)[A].
- Anticonvulsants: Topiramate, Zonegran, lamotrigine, carbamazepine, oxcarbazepine
- Antiarrhythmics: Mexiletine
- NMDA receptor antagonists: Ketamine, dextromethorphan (5)
- Other agents: Baclofen, clonidine, capsaicin
- Topical lidocaine; 5% lidocaine patch:
- FDA-approved for treatment of PHN but has been used for other focal neuropathic pain syndromes
- Dosage: Up to 3 patches for 12 hours daily
- Interactions: No significant drug–drug interactions
- Adverse effects: Mild skin reactions
- Cochrane Review in 2007 showed insufficient evidence to recommend as 1st line.
Issues for Referral
Referral to pain clinic or neurosurgery is appropriate if refractory to initial treatment.
- Transcutaneous electrical nerve stimulation (TENS) may be helpful; optimal dosing is yet to be established (7)[B].
- Spinal cord stimulation may be effective for chronic pain, especially if back surgery failed (8)[B].
Complementary and Alternative Medicine
See Additional Therapies.
Nerve destructive procedures:
- Should be used with caution as a refractory to treatment different pain can ensue. If nononcolgical nerve damage, most neurolytic procedures are not recommended.
- Sympathetectomy: More studies needed for effectiveness and safety
- Dorsal root entry zone lesion (dorsal rhizotomy)
- Lateral cordotomy
- Trigeminal nerve ganglion ablation
- Multidisciplinary team improves care.
- Opioid contracts to prevent abuses
Random urinalysis for specific prescribed drug and all drugs of abuse for patients receiving opioid therapy
Chronic course of pain symptoms often requires management with numerous medications and adjunctive therapies.
Long-term disability is a possibility. Drug addiction is possible.
1. Wiffen PJ, et al. Gabapentin for acute and chronic pain. Cochrane Database Syst Rev. 2007;4:CD005452.
2. Schmader KE. Epidemiology and impact on quality of life of postherpetic neuralgia and painful diabetic neuropathy. Clin J Pain. 2002;18:350–4.
3. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007;4:CD005454.
4. Hollingshead J, et al. Tramadol for neuropathic pain. Cochrane Database Syst Rev. 2007;2:CD003726.
5. Galluzzi KE. Managing neuropathic pain. J Am Osteopath Assoc. 2007;107:ES39–48.
6. Quilici S, Chancellor J, Lothgren M, et al. Meta-analysis of duloxetine vs. pregabalin and gabapentin in the treatment of diabetic peripheral neuropathic pain. BMC Neurol. 2009;9:6.
7. Carrol D, et al. TENS for chronic pain. Cochrane Database Syst Rev. 2007;4:2007.
8. Mailis-Gagnon A, et al. Spinal cord stimulation for chronic pain. Cochrane Database Syst Rev. 2007;4:CD003783.
Eisenberg E, McNicol E, Carr DB. Opioids for neuropathic pain. Cochrane Database Syst Rev. 2006;3:CD006146.
Kroenke K, Krebs EE, Bair MJ. Pharmacotherapy of chronic pain: a synthesis of recommendations from systematic reviews. Gen Hosp Psychiatry. 2009 May-Jun;31:206–19.
Raja SN, Haythornthwaite JA. Combination therapy for neuropathic pain–which drugs, which combination, which patients? N Engl J Med. 2005;352:1373–5.
Torrance N, Smith BH, Benett MI, Lee AJ. The epidemiology of chronic pain of predominantly neuropathic origin. Results from a general population survey. J Pain. 2006;7(4):281–289.
Wiffen PJ, McQuay HJ, Moore RA. Carbamazepine for acute and chronic pain. Cochrane Database Syst Rev. 2005;CD005451.
- 356.9 Unspecified idiopathic peripheral neuropathy
- 729.2 Neuralgia, neuritis, and radiculitis, unspecified
- 247398009 Neuropathic pain (finding)
- 25416002 peripheral neuralgia (disorder)
- Multidisciplinary approach to pain management is suggested.
- Gabapentin is 1st-line for neuropathic pain. Followed by other antiseizures, TCAs and SNRIs.
- A trial of interventional nerve blockage should be recommended prior to committing to chronic analgesic therapy.
- Opioids are used after 2 or 3 other attempts at treatment, in combination with other 1st-line agents. Opioids are generally considered weak neuropathic agents. Thus, high dosages are required to be effective in dealing with chronic pain. This presents a problem with potential for side effects, misuse, and addiction.