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Neuropathic Pain
Janet Grotticelli, DO, MBA, CHSE
image BASICS
  • Defined as pain caused by a lesion or disease that leads to an abnormal and dysfunctional somatosensory system (1)
  • A complex state that arises from abnormal neural activity secondary to disease, injury, or dysfunction of the peripheral or central nervous system
  • Can exist without ongoing disease
  • Can arise from damage to the nerve pathways at any point from the terminals of the peripheral nociceptors to the cortical neurons in the brain
  • May be triggered by direct nerve injury, infection, metabolic dysfunction, autoimmune disease, neoplasm, drugs, radiation, and neurovascular disorders
  • May reflect abnormal central nervous system activity rather than a manifestation of any underlying pathology itself (i.e., phantom limb pain, complex regional pain syndrome [CRPS])
Data is challenging due to the diversity of related clinical entities.
  • Includes various chronic conditions that together, affect up to 8% of the population (2)
  • Approximately 20% of people with cancer have cancer-related neuropathic pain as a result of either the disease or its treatment (3).
  • The lifetime incidence of herpes zoster (shingles) is ˜25%. Studies in the United States and Netherlands found 2.6% and 10%, respectively, will develop chronic postherpetic neuralgia (3).
  • 33 million people infected with HIV across the world; ˜35% have neuropathic pain (3)
  • Up to 50% of people with diabetes have some form of neuropathy.
  • Positive symptoms due to changes in peripheral nerves, loss of inhibitory mechanisms in CNS, and central sensitization
  • Negative symptoms (sensory deficits) reflecting neural damage
  • Associated with a predisposing factor
  • Risk factors:
    • Demyelinating disorders (multiple sclerosis, Guillain-Barré)
    • Neoplasm (primary/metastatic)
    • Neurovascular (central poststroke syndrome, diabetes, trigeminal neuralgia)
    • Autoimmune disease (Sjögren syndrome, polyarteritis nodosa)
    • Structural disease (herniated disc disease) (4)
  • General risk factors include older age, female gender, physical inactivity, manual occupation
  • There is growing evidence of genetic factors
  • Includes factors that increase the risk of underlying conditions, as well as those that increase the risk of pain when these conditions are present:
    • Diabetes
    • Herpes zoster
    • Trigeminal neuralgia
    • HIV
    • Lyme disease
    • Cancer and chemotherapy
    • Stroke
    • Multiple sclerosis
    • Trauma
    • Surgery
    • Limb amputation
    • Nutritional deficiencies
    • Medications
  • Depression/anxiety
  • Insomnia
  • Drug dependence
The diagnosis is based primarily on history (e.g., underlying disorder and distinct pain qualities) and the findings on physical examination (e.g., pattern of sensory disturbance); however, several tests may sometimes be helpful (2,5)[A].
  • Positive signs/symptoms (2,6)[A]
    • Hypoesthesia (abnormally reduced sensation of a tactile stimulus) to touch or cold
    • Hypoalgesia (abnormally reduced pain sensation to a noxious stimulus)
    • Hyperalgesia: (abnormally increased pain sensation to a noxious stimulus) to pinprick, blunt pressure, heat, or cold
    • Allodynia: (pain sensation to a nonnoxious stimulus) for example, pain evoked by light touch, clothing, bed sheets
  • Motor signs and symptoms: may include hypotonia, tremor, dystonia, ataxia, hypo-/hyperreflexia, or motor neglect. Motor symptoms include weakness, fatigability, decreased range of motion, joint stiffness, and spontaneous muscle spasm (4)[A].
  • Sensory examination
    • Light touch, pinprick, vibration sense, and proprioception may be diminished or absent in the involved nerve territory.
    • Sensory disturbance may aberrantly extend beyond a discrete nerve territory.
  • Skin examination
    • Alterations in temperature, color, sweating, and hair growth suggestive of CRPS
    • Residual dermatomal scars consistent with previous herpes zoster (shingles) infection
    • Characteristic skin changes consistent with diabetes mellitus
  • Nociceptive pain: induced by transmission impulses along peripheral nociceptors usually due to tissue damage
  • Differentiate by clinical signs and symptoms, mechanisms and therapeutic management
For definite diagnosis, the abnormal sensory findings are confirmed to the innervation territory of the lesioned nervous system structure AND diagnostic test(s) confirming a nervous system lesion or disease that could explain neuropathic pain (1)[A].
Initial Tests (lab, imaging)
None specifically for neuropathic pain but can rule in or out a cause of symptoms
  • Neuroimaging based on affected area
  • Blood and cerebrospinal fluid samples
    • Structural tests:
      • Skin biopsy analyses
      • Sural nerve biopsy
      • Structural imaging tests
  • Serum B12
  • 25-hydroxyvitamin D
  • Thyroid-stimulating hormone (TSH)
  • Rapid plasma reagin (RPR) or Venereal Disease Research Laboratory (VDRL) test
  • Fasting glucose, creatinine Lyme serology
Follow-Up Tests & Special Considerations
  • Nerve conduction study (NCS): The standard electrodiagnostic tool for assessing peripheral nerve fiber function (2)[A].
  • Electromyography (2)[A]
  • Evoked potentials (2)[A]
  • Quantitative Sensory Testing (2)[A]
  • Thermography (2)[A]
  • CSF samples (2)[A]
  • Generally resistant to acetaminophen or NSAIDs
  • Learn ways to relax body and mind
  • The efficacy of systemic drug treatments is generally not dependent on the etiology of the underlying disorder (2,7).
  • Combined therapy (polypharmacy) may be more effective.
  • Treatment needs to be individualized
First Line
  • Calcium channel alpha-2-delta ligands
    • Gabapentin (2,8)[A]
      • Dosing: 1,200 to 3,600 mg in three divided doses
      • Precautions: reduce dosages in renal insufficiency
      • Common side effects: sedation, dizziness, peripheral edema, weight gain
    • Pregabalin (2,8)[A]
      • Used for the treatment of PDN, spinal cord injury, PHN, fibromyalgia (3)[A]
      • Dosing: 300 to 600 mg in two doses
      • Precautions: reduce dosages in renal insufficiency
      • Common side effects: sedation, dizziness, peripheral edema, weight gain
  • P.713

  • Tricyclic antidepressants (2,8)[A]
    • Nortriptyline, desipramine, amitriptyline, clomipramine, imipramine
      • Dosing: start at 10 to 25 mg at bedtime, then increase by 10 to 25 mg every 4 to 7 days up to 150 mg/day to efficacy and side effects
      • Precautions: cardiac disease, glaucoma, prostatic adenoma, seizure, tramadol use
      • Geriatric considerations: patients (dose ≤75 mg daily)
      • Common side effects: somnolence, anticholinergic effects, weight gain
  • Serotonin-norepinephrine reuptake inhibitors (SNRIs) (2,8)[A]
    • Duloxetine
      • Dosing: 30 mg once daily/60 mg twice daily. Effective doses 60 to 120 mg daily
      • Precautions: hepatic disorder, tramadol use, hypertension
      • Common side effects: nausea
    • Venlafaxine
      • Dosage: 37.5 mg once or twice daily/225 mg daily. Effective doses 150 to 225 mg daily
      • Precautions: cardiac disease, hypertension; tramadol use
      • Common side effects: nausea, hypertension at high dosages
  • Topical lidocaine (first line for elderly, frail patients only)
    • Lidocaine, 5% plasters (2,8)[A]
      • Dosage: 1 to 3 patches/3 patches for 12 hours to cover the painful area
      • Precautions: none
      • Common side effects: local erythema, itch, rash
    • Carbamazepine (9)[A]
Second Line
  • Topical treatments (2)[A]
    • Lidocaine patches
      • (See “Topical Lidocaine”)
    • Capsaicin high-concentration patches (8%)
      • Dosage: 1 to 4 patches to cover the painful area, repeat every 3 months; 30 minutes application to feet, 60 minutes application to remainder of body; avoid use on face
      • Precautions: caution in progressive neuropathy
      • Common side effects: pain, erythema, itching, rare hypertension (initial increase in pain)
  • Tramadol (2)[A]
    • Dosage: 50 mg once or twice daily/400 mg daily as long-acting drug. Increase by 50 to 100 mg every 3 to 7 days
    • Precautions: history of substance abuse, suicide risk
    • Geriatric considerations: use of antidepressant in elderly patients.
    • Common side effects: nausea, vomiting, constipation, dizziness, somnolence
Third Line
  • Opioids (2)[A]
    • Morphine, oxycodone
      • Dosage: 10 to 15 mg morphine every 4 hours or as needed (equianalgesic doses for other opioids)/up to 300 mg morphine has been used
      • Precautions: history of substance abuse, suicide risk, risk of misuse on long-term use
    • Botulinum toxin type A
      • Dosage: 50 to 300 units subcutaneously to the painful area; repeat every 3 months
      • Precautions: infection of area
      • Common side effects: pain at injection site
Referral to pain clinic if refractory to initial treatment or additional therapies below are warranted.
  • Cannabinoids (dronabinol and nabilone): The appropriateness of medical marijuana for a patient should be comprehensive assessments that revolve around risk-benefit discussion (8,10).
  • Neural stimulation (11)
  • Spinal cord stimulation (SCS): Pain that is continuous and unchanging responds best. The most common indication is failed back surgery syndrome with leg pain. Less common indications are peripheral nerve injury, CRPS, and painful peripheral neuropathy (11).
  • Dorsal root ganglion stimulation to treat challenging pain syndromes that do not respond to conventional SCS (11).
  • Peripheral nerve stimulation (PNS): indications include pain in the distribution of an accessible peripheral nerve. The most common nerves treated are the supraorbital, infraorbital, greater occipital, ulnar, median, suprascapular, intercostal, ilioinguinal, iliohypogastric, genitofemoral, lateral femoral cutaneous, saphenous, sciatic, posterior tibial, superficial peroneal, and sural nerves (11).
  • Intrathecal drug delivery considered invasive and labor intensive, may be used when other conservative therapies fail (11).
  • Transcutaneous electrical nerve stimulation is widely used, evidence is poor in supporting the efficacy (11).
  • Osteopathic manipulative treatment should be offered to all patients. Myofascial trigger point release can be an effective primary technique. Indirect or passive myofascial techniques may be used to address all regions of tissue texture change (12).
  • Hypnosis can reduce pain and anxiety related to the pain.
  • Acupuncture
Nerve destructive procedures haven't shown effectiveness and may cause additional insult/injury (an exception is treatment of terminal cancer) (11).
  • Sympathectomy dorsal root entry zone lesion (dorsal rhizotomy)
  • Lateral cordotomy
  • Trigeminal nerve ganglion ablation (13)[A]
  • Multidisciplinary team
  • Periodic evaluation to rule out other treatable conditions (2)
Patient Monitoring
  • Pain management requires ongoing evaluation, patient education, and reassurance
  • Patient compliance and adequacy of analgesic drug titrations should be continually evaluated and documented.
Chronic course of pain symptoms often requires management with numerous medications and adjunctive therapies.
1. Haanpää M. Clinical Examination of a Patient with Possible Neuropathic Pain. International Association for the Study of Pain, 2014 Refresher Courses: 15th World Congress on Pain.
2. Gilron I, Baron R, Jensen T. Neuropathic pain: principles of diagnosis and treatment. Mayo Clin Proc. 2015;90(4):532-545.
3. van Hecke O, Austin SK, Khan RA, et al. Neuropathic pain in the general population: a systematic review of epidemiological studies. Pain. 2014;155(4):654-662.
4. Finnerup NB, Sindrup SH, Jensen TS. The evidence for pharmacological treatment of neuropathic pain. Pain. 2010;150(3):573-581.
5. Gilron I, Watson CP, Cahill CM, et al. Neuropathic pain: a practical guide for the clinician. CMAJ. 2006;175(3):265-275.
6. Kerstman E, Ahn S, Battu S, et al. Neuropathic pain. Handb Clin Neurol. 2013;110:175-187.
7. Finnerup NB, Attal N, Haroutounian S, et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14(2):162-173.
8. Attal N, Bouhassira D. Pharmacotherapy of neuropathic pain: which drugs, which treatment algorithms? Pain. 2015;156(Suppl 1):S104-S114.
9. Zhou M, Chen N, He L, et al. Oxcarbazepine for neuropathic pain. Cochrane Database Syst Rev. 2013;(3):CD007963.
10. Hill KP. Medical marijuana for treatment of chronic pain and other medical and psychiatric problems: a clinical review. JAMA 2015;313(24):2474-2483.
11. Wallace M. Interventional and Nonpharmacological Therapies for Neuropathic Pain. International Association for the Study of Pain, 2014 Refresher Courses: 15th World Congress on Pain.
12. Galluzzi KE. Managing neuropathic pain. J Am Osteopath Assoc. 2007;107(10)(Suppl 6): ES39-ES48.
13. Straube S, Derry S, Moore RA, et al. Cervico-thoracic or lumbar sympathectomy for neuropathic pain and complex regional pain syndrome. Cochrane Database Syst Rev. 2013;(9):CD002918.
  • M79.2 Neuralgia and neuritis, unspecified
  • E10.40 Type 1 diabetes mellitus with diabetic neuropathy, unsp
  • E11.40 Type 2 diabetes mellitus with diabetic neuropathy, unsp
Clinical Pearls
  • Neuropathic pain is a chronic pain syndrome, affecting between 2% and 8% of people with a major impact on quality of life.
  • The ongoing challenge for clinicians (and patients) is being able to determine which treatment is most likely to work for any one individual.
  • The first line of treatment is pharmacologic and may be more beneficial with additional therapies.
  • Generally resistant to acetaminophen or NSAIDs