Pain

NEUROPATHIC PAIN. Approach and treatment

NEUROPATHIC PAIN. Approach and treatment

Neuropathic pain is defined as pain originating from a lesion or dysfunction of the nervous system (central, peripheral and autonomic).

It is a frequent cause of pain, commonly misdiagnosed and undertreated, and related to changes in emotional state, disability and loss of quality of life of patients.

Unlike pain of nociceptive origin, which is the result of physiological activation of nociceptors, chronic neuropathic pain becomes a disease by modifying the regular pathways of pain transmission.

According to the site of the lesion or dysfunction it can be classified as peripheral, central or autonomic. It has also been classified according to its etiology, signs and symptoms, and mechanisms of possible origin of the pain.

The difficulty and complexity of its classification, as well as the mechanism of action and its treatment, is mainly due to the fact that, in general, the same patient may present more than one symptomatology, mechanism of production and location of the lesion. It is worth mentioning that neuropathic pain can coexist or ride with pain of nociceptive and idiopathic origin, and that, like any chronic disease, it generally affects the patient’s emotional state.

Diagnosis

Initially, both the diagnosis and treatment of this type of pain was made by relating the pain to the concomitant disease that a patient might have. This approach was no longer used because not all patients with a pre-existing disease or condition had pain. For example, the prevalence of painful diabetic neuropathy in a UK study was 16% in patients with that disease. On the other hand, diabetic patients affected by related neuropathic pain may present with different types and characteristics of pain, including allodynia, hyperalgesia, sensory deficit, spontaneous pain, mechanical pain, or different response to cold or heat.

It is equally impossible to predict the course of the painful condition and the degree of physical disability in patients suffering from the same disease. In general, neuropathic pain is rarely cured or disappears and tends to become chronic.

Another approach proposed for its classification, diagnosis and treatment options was based mainly on the mechanism-symptom relationship. Multiple pathophysiological mechanisms have been identified, at least theoretically, that can generate painful symptomatology both in the peripheral and central nervous system. We believe it is necessary and obligatory to know and remember them, therefore, we will mention them:

  • Peripheral sensitization and ectopic impulses generated in primary afferent nociceptive fibers by damage or injury to a peripheral nerve.

Painful sensation is normally generated by the activation, by a stimulus, of the activity of C-fibers (unmyelinated) and Ad-fibers (small myelinated). Sensitization results in an abnormal response (activation of nociceptors) without the presence of a sufficiently painful stimulus, injury or tissue inflammation. As a consequence of this, we can find symptoms related to spontaneous pain such as: allodynia, hyperalgesia, allodynia to temperature increase, hyperalgesia to heat in the affected area.

The generation of ectopic discharges, following peripheral nerve injury or a chronic inflammatory response, has been associated with sensitization in an area remote from the site of injury, particularly adjacent to the dorsal root of the ganglion, and has been associated with increased activation of voltage-dependent sodium channels.

  • Influence of sympathetic activity and catecholamines on sensitization and damage of primary afferent fibers.

Normally, primary afferent nociceptors are not sensitive to catecholamines and their activity is not affected by the sympathetic system. After nerve injury, the natural regeneration of nociceptive C-fibers is done through an adrenoreceptor mechanism. In addition to this peripheral mechanism, it is thought that there is a junction of afferent and sympathetic neurons within the root of the dorsal ganglion. This could explain not only the pain mechanism of sympathetic maintained pain and complex regional pain syndromes, but also an increase in allodynia and hyperalgesia such as that related to temperature changes.

  • Inflammation of a peripheral nerve trunk.

The connective tissue of the perineural sheath of peripheral nerves is innervated by sensory fibers. These small nociceptor fibers can potentially be a source of pain in those pathological conditions with an important inflammatory component (postherpetic neuralgia), which may explain the hyperalgesic component in this type of disease.

  • Central sensitization as a consequence of nociceptor hyperactivity.

Prolonged nociceptor activity over time results in an increased physiological response by the CNS. In addition, a growth of the field of receptive neurons located in the posterior aspect of the medulla is observed. This process is called central sensitization. Neuropeptides such as substance P and excitatory amino acids released by C-terminal fibers act on NMDA receptors contributing to this process.

When the condition of central sensitization occurs, the primary afferent mechanoreceptor fibers (Ab fibers), which normally respond to innocuous tactile stimuli, begin to activate centrally the neurons that respond to painful signals. This phenomenon is a physiological and reversible response.

  • Reorganization of synapses at the central level as a consequence of nociceptor degeneration.

The damage of a peripheral nerve can lead to generate a process of anatomical reorganization at the central level that would lead to produce a state of mechanical allodynia. Lamina II of the dorsal aspect of the medulla normally receives the stimulus of small caliber fibers generating a preferential response to nociceptive stimuli. When the phenomenon of central reorganization occurs, the Ab mechano-receptor fibers, which normally end in the deeper laminae (III and IV), grow and regenerate and then directly contact lamina II producing the above mentioned symptomatology.

  • Disinhibition: Differential loss of afferent fibers Ad

There is evidence that different types of neuropathic pain can be produced by the loss or change of sensations of a particular type of afferent Ad fibers, specifically, those that transmit cold.

Currently this orientation has fallen into disuse because it is difficult to demonstrate the particular mechanism that produces neuropathic pain in each individual. Moreover, one mechanism alone could explain different symptoms, and different symptoms could be explained by different mechanisms.

Neuropathic pain is characterized by spontaneous and provoked pain, by positive symptomatology such as paresthesias and dysesthesias, and by negative signs such as sensory deficit. In addition to this, other symptomatology and clinical signs such as paresis, paralysis, muscle contractures and autonomic signs can be added. It is not possible to determine the etiology of neuropathic pain based on the clinical features of the pain alone.

Therefore: The diagnosis should be made based on a meticulous clinical history (anamnesis, diagnostic orientation test), physical and neurological examination, topographic diagnosis of the lesion (complementary tests) and the etiological diagnosis of the lesion.

Treatment

A correct diagnosis will allow us to tailor treatment for each patient. We believe that the multimodal and multidisciplinary approach is the most appropriate.

Pharmacological treatment:

Generally, analgesic drugs; NSAIDs and opioids, their derivatives and related, do not significantly improve the intensity of pain when the pain is purely neuropathic in origin, so we must use adjuvant drugs from the outset.

First-line antiepileptic drugs , with less adverse effects and more tolerable, such as gabapentin and pregabalin, are the drugs of choice from the beginning. Then, in case of analgesic failure, second-line antiepileptics such as carbamazepine, oxcarbazepine, valproic acid, Lamotrigine, topiramate, clonazepam, phenytoin are chosen.

Antidepressants: Their direct action on pain has been demonstrated. In addition, neuropathic pain, being a chronic condition, is generally associated with a depressive or anxious state, therefore, by improving the emotional portion, the painful pathology will improve. We have a wide variety of these drugs with different compositions and forms of action, among which are: Tricyclics (amitriptyline), serotonin receptor inhibitors (fluoxetine, sertraline, paroxetine, citalopram), duals (duloxetine, venlafaxine) and dopaminergics (bupropion). The failure or adverse effects that any of these drugs may present would not rule out the use of the whole pharmacological group, since most of them act and are compounded differently, so it would be advisable to try the use of another related drug.

Local anesthetics: Lidocaine administered IV or in patch form, mexiletine orally.

Other options to consider.

  • NMDA Receptor Blockers: Ketamine
  • Opiates: Methadone, oxycodone, morphine, codeine, fentanyl. Except for particular conditions, we suggest their use in this order. Special attention should be paid to methadone, which is a multireceptor drug, especially in those related to pain.
  • Corticosteroids: Dexamethasone, prednisolone.
  • Anxiolytics: Benzodiazepines
  • Gaba receptor agonists : Baclofen
  • Alpha-adrenergic agonists: Clonidine
  • Substance P depletors: Capsaicin (desensitization of afferent C-fibers).
  • Action on osteoclastic activity: Calcitonin

Invasive treatment:

  • Nerve blocks: Peripheral and central. Blockages of the autonomic system. IV blocks. Temporary analgesia, which can range from days to months, beyond the duration of the physiological effect of the anesthetic compound, justifies the repeated use of nerve blocks.
  • Infiltrations: articular with local anesthetics, corticoids and hyaluronic acid, pericardial and neuromuscular junction (trigger points) with lidocaine and botulinum toxin.
  • Pulsed radiofrequency
  • Ablative procedures: thermal radiofrequency, use of neurodestructive substances (alcohol, phenol).
  • Neuromodulation of pain: Implantable systems: electrical stimulators of peripheral nerves and spinal cord. Medication infusion pumps.
  • Complementary treatments: TENS, Acupuncture.

References

Haanpaa M, Treede Rolf-Detlef. Diagnosis and Classification of Neuropathic Pain. IASP. Pain clinical updates. Vol.XVIII, issue 7. September 2010.

Baron R. Peripheral Neuropathic Pain: From mechanisms to symptoms. The clinical journal of pain. Vol 16. No.2, Supplement 2000:512-20.

Martinez-Salio et al. Diagnosis and treatment of neuropathic pain. Consensus conference. In: Med Clin (barc). 2009;133(16):629-636.