Pain syndromes are important to understand as a neurologist as 1 in 10 people in the U.S. suffers from chronic pain! Also, this topic is covered on neurology examinations. Here you will review the pathophysiology of pain with appropriate depth for RITE® and board examinations, and become familiar with the most commonly tested pain syndromes.

Authors: Brian Hanrahan MD, Steven Gangloff MD

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Pathophysiology of Pain

  • Pain perception is a function of the peripheral and central nervous system via both excitatory and inhibitory pathways.
  • Glutamate and substance P are the neurotransmitters most involved in promoting pain sensation, while norepinephrine, serotonin, and endogenous opioids like enkephalin inhibit pain sensation.

Ascending pain pathway

  • Noxious stimuli applied to skin → Travels along aδ (fast) and C (slow) nerve fibers within afferent first-order neurons → synapses in substantia gelatinosa within the dorsal horn of spinal cord→ ascends through the tract of Lissauer up 3 spinal levels and decussates to contralateral side → ascends through spinothalamic tract (second-order neuron) → synapses on ventral posterior lateral (VPL) nucleus of thalamus → travels along third-order neurons to the somatosensory cortex.

      • While the somatosensory cortex functions to localize pain, the amygdala, insula, anterior cingulate cortex, prefrontal cortex, and thalamus aid in the perception of pain.

Descending (modulatory/inhibitory) pain pathway

  • Pain perception is modulated and regulated by fibers within the periaqueductal gray, as well as the locus coeruleus.
    • After a pain response is received, fibers from the locus coeruleus descend to transmit norepinephrine back to the dorsal horn to attenuate that pain response.
    • The periaqueductal grey (and rostral ventromedial medulla) contain opioid receptors and use the endogenous opioid enkephalin in the descending pathway to blunt pain response.
      • Enkephalin inhibits GABA and in turn, allows for serotonin levels to increase.
  • Norepinephrine and serotonin function in this descending inhibitory pathway as the main neurotransmitters for pain inhibition.

Small Fiber Neuropathy

  • Presents initially with distal tingling/burning of lower extremities. It can also present with autonomic symptoms.
  • The causes of small fiber neuropathy are diverse, including but not limited to hypothyroidism, rheumatologic diseases, HIV, alcohol abuse, and immunosuppressive medications.
    • The most common cause is diabetes. Improved glycemic control can prevent the progression of neuropathy, but is not effective at controlling pain.

  • Treatment:
    • Gabapentin (Level B evidence):
      • Mechanism of action: Despite its name, it has no effect on GABA receptors. It exerts its anti-nociceptive effects through modulation of presynaptic voltage-gated calcium channels.
      • It is renally excreted unchanged, as it does not undergo hepatic metabolism.
      • It can also be used for thalamic pain syndrome and postherpetic neuralgia.
    • Pregabalin (Level A evidence):
      • Mechanism of action: Modulation of presynaptic voltage-gated calcium channels
      • It may also be used for postherpetic neuralgia, refractory partial seizures, generalized anxiety disorder, and social anxiety disorder.
    • Amitriptyline, duloxetine, venlafaxine, sodium valproate, and capsaicin are other treatment options that have level B evidence in the management of painful diabetic neuropathy.
    • Management of concurrent depression and/or sleep apnea can also help modulate pain perception.

Trigeminal Neuralgia (Tic Douloureux)

  • Presents with stabbing facial pain triggered by touching the face, eating, drinking, or speaking.
  • Most cases of trigeminal neuralgia are felt to be due to compression of the trigeminal nerve by a vascular loop.
  • Imaging is indicated on initial workup to exclude other, though less common, structural causes such as a meningioma, cerebellopontine angle neoplasm, multiple sclerosis, or aneurysm.
  • Treatment: Carbamazepine and oxcarbazepine.
    • Gamma knife radiosurgery is reserved for patients with medically refractory symptoms.

Idiopathic Glossopharyngeal Neuralgia (IGN)

  • Much less common than trigeminal neuralgia, IGN presents with intense paroxysmal pain originating at the tonsillar fossa or ear.
    • Triggers include talking, chewing, and laughing.
  • Syncope can occur with IGN due to activation of the carotid sinus/body sensory fibers of the glossopharyngeal nerve, resulting in bradycardia and hypotension from peripheral arterial vasodilatation.
  • Symptomatic management is the same as trigeminal neuralgia.

Postherpetic Neuralgia

  • Presents with the persistence of burning pain in the same sensory distribution of a past herpes zoster rash. Symptoms must persist more than 3 months after the rash’s resolution.
  • Treatment:
    • Administration of antiviral agents within 72 hours of the onset of herpes zoster can reduce the intensity and duration of acute illness and can prevent postherpetic neuralgia.
    • TCAs, gabapentin, pregabalin, opioids, and topical lidocaine patches.
    • Aspirin cream and capsaicin cream give some mild transient symptom relief as well.

Complex Regional Pain Syndrome Type 1 (CRPS 1)

  • A.K.A. Reflex sympathetic dystrophy (RSD)
  • Caused by tissue damage around a nerve or near its C (slow) and aδ (fast) fibers that innervate surrounding tissue, resulting in progressive pain in the distribution of the affected nerve.
  • Symptoms include pain, swelling, autonomic dysregulation (hyperhidrosis, hyperalgesia), tremor, and dystrophy/atrophy.
  • Treatment:
    • Physical therapy
    • NSAIDs, TCAs, gabapentin/pregabalin, topical lidocaine, or capsaicin cream.

Central Neuropathic Pain

  • A lesion at any level of the central nervous system from the cortex to the spinal dorsal horn can lead to central neuropathic pain.
  • Pain severity, location, and characteristics can be variable.
  • Common causes include stroke and demyelinating disease.
  • Treatment: carbamazepine, TCAs, gabapentin/pregabalin, lamotrigine, and opioids.

Neuralgic Amyotrophy

Parsonage-Turner syndrome

  • A.K.A. Idiopathic neuralgic amyotrophy.

  • Sometimes also called idiopathic brachial plexopathy.

  • Presents with sudden onset severe unilateral shoulder or scapular or upper limb pain (less commonly lumbosacral plexus) that is followed by progressive weakness, muscle atrophy, and numbness.

  • Possible triggers include extreme exercise, surgery, infection, vaccination, or trauma.
  • EMG may show axonal denervation.
  • Symptoms typically improve with time but may be recurrent.

Subacute Sensory Neuronopathy

  • Paraneoplastic, most often associated with small-cell lung cancer and anti-Hu, less commonly anti-CV2.
  • Consists of electric-shock sensations in an extremity, that progress to involve other extremities, face, and trunk.
  • Dorsal root ganglia are inflamed.

Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)

  • Presents with paresthesias, numbness, pain, weakness, atrophy, and possibly temporary paralysis after pressure is applied to nerves. While healthy people can have these symptoms after prolonged nerve compression, patients with HNPP develop symptoms with minimal pressure, and the symptoms last longer.
  • Autosomal dominant mutation in PMP-22 (peripheral myelin protein).

Fibromyalgia

  • Widespread chronic body pain with numerous trigger points that can be accompanied by fatigue and trouble with memory and sleep.
  • The mechanism is not well understood. “Central sensitization,” a problem with CNS pain regulation and processing, may be at play. There are also often components of physical and emotional stressors.
    • The periaqueductal gray is involved in CNS pain regulation and processing and some studies suggest it may be involved in fibromyalgia.
  • Treatment: Education, exercise, cognitive behavioral therapy, pregabalin, SNRIs.

References

  1. Gronseth, G., et al. “Practice Parameter: The Diagnostic Evaluation and Treatment of Trigeminal Neuralgia (an Evidence-Based Review): Report of the Quality Standards Subcommittee of the American Academy of Neurology and the European Federation of Neurological Societies.” Neurology, vol. 71, no. 15, 2008, pp. 1183–1190., doi:10.1212/01.wnl.0000326598.83183.04.
  2. Lacomis, David. “Small-Fiber Neuropathy.” Muscle & Nerve, vol. 26, no. 2, 2002, pp. 173–188., doi:10.1002/mus.10181.
  3. Luu, Mai. “Practice Parameter: Treatment of Postherpetic Neuralgia: an Evidence-Based Report of the Quality Standards Subcommittee of the American Academy of Neurology.” Douleurs : Evaluation – Diagnostic – Traitement, vol. 6, no. 3, 2005, p. 179., doi:10.1016/s1624-5687(05)80258-6.
  4. Teixeira, M. J., et al. “Glossopharyngeal Neuralgia: Neurosurgical Treatment and Differential Diagnosis.” Acta Neurochirurgica, vol. 150, no. 5, Apr. 2008, pp. 471–475., doi:10.1007/s00701-007-1493-6.
  5. Feinberg, J. H., & Radecki, J. (2010). Parsonage-turner syndrome. HSS journal : the musculoskeletal journal of Hospital for Special Surgery, 6(2), 199-205.
  6. Van Alfen N, Hannibal MC, Chance PF, et al. Hereditary Neuralgic Amyotrophy. 2008 Feb 27. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2018.
  7. Clauw D., 2014. Fibromyalgia, A Clinical Review. JAMA. 311(15):1547–1555.
  8. Nahin RL. Estimates of pain prevalence and severity in adults: United States, 2012. Journal of Pain. 2015;16(8):769-780.
  9. Purves D, Augustine GJ, Fitzpatrick D, et al., editors. Neuroscience. 2nd edition. Sunderland (MA): Sinauer Associates; 2001. The Nociceptive Components of the Thalamus and Cortex. Available from: https://www.ncbi.nlm.nih.gov/books/NBK10997/
  10. Bril V, England J, Franklin GM, et al. Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. Neurology 2011;76:1758-1765.

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