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Neuropathic pain

According to the definition made by the International Association of Pain Studies in 1997, neuropathic pain, is a system whereby the pain is caused by primary lesion or dysfunction.

Although the clinical course may vary according to the area of origin, it begins with a disorder related to pain management in the central and peripheral nervous system and develops as a secondary to this disor. However, in many patients with neuropathic pain, there is no pathological finding in the central nervous system, and neuropathic pain can not be observed in many patients with nervous system pathology.


Neuropathic pain, a chronic type of pain, can last for months or years after the onset of the disease.



Neuropathic pain can be classified as central or peripheral neuropathic pain according to the origin. The autonomic nervous system also affects neuropathic pain. Such neuropathic pain is defined as Complex Regional Pain Syndromes.




In the etiology of peripheral neuropathic pain, peripheral nerve damage plays a role in different causes.


Factors that play a role in this damage:


  • .Focal nerve damage

  • Trauma (crushing, avulsion, incision, stretching)

  • Tumor (neuroma)

  • Infection (postherpetic neuralgia)

  • Ischemia

  • Jamming

  • Damage (hot, cold, electricity, radiation)

  • Generic nerve damage

  • toxins

  • Metabolic effects (Diabetes mellitus)

  • Schwann cell damage

  • Nutritional disorders (Vit B12 deficiency)

  • Multiple sclerosis

  • Guillaine Barre syndrome



The incidence of neuropathic pain in the general population is 1-2%. However, this incidence may be higher in some patient For example, in 8% of stroke patients, central venous pancreatic pain may develop within 1 year, while 10-15% of patients with HIV infection develop neuropathic pain. In patients with multiple sclerosis, moderate-to-severe pain was reported in 22% of cases.


After acute herpes zoster infection, 20% deafferentation pain can develop especially in patients over 60 years of age. This ratio reaches 34% over 80 years old.


In diabetic patients, neuropathic pain is seen in 50%, especially if the disease lasts for more than 25 years.



The pathophysiology of neuropathic pain is not well understood. As a matter of fact, experimental studies related to nontraumatic neuropathic pain are few. However, it is thought that peripheral and central sensitization mainly play a role in the pathogenesis of chronic neuropathic pain.


The inflammatory and growth factors released after a peripheral nerve injury are released.

As a consequence, nociceptive neurotransmitters such as substance P and brain-derived neurotrophic factor (BDNF) are emerging.


Adrenergic, TrpV1, P2X and m opioid receptors associated with these released neurotransmitters and Ad and C fibers affect the sodium and calcium channels. The resulting ectopic discharges are caused by peripheral sensitization. Ab fibers also play a role, especially in the process of mechanical allodynia.


Central sensitization, neuropathic pain persistence and painless stimuli are the causes of posttraumatic pain.

 Factors that play a role in this sensitization in the spinal cord:

• Increased upregulation of N-methyl-D-aspartate (NMDA)

• Calcium ion changes in the cell

• Decrease in inhibitor control


Although the underlying mechanisms are not fully understood, it is thought that C fiber sensitization, partial denervation, ectopic activity, endogenous nerve growth factor (NGF) and damaged and undamaged neurons play a role in pathogenesis in the development of neuropathic pain. A symptom can occur through several mechanisms (peripheral and central sensitization in the allodynia of the touch) and multiple mechanisms in the pathogenesis of a syndrome (postherpetic neuralgia).




Whether or not there is an abnormal feeling in the history should be questioned. Hyperalgesia, dysesthesia, allodynia, hyperpathy, hyperesthesia and persistent burning may be the pain types. It should be known whether infection, metabolic disorders, autoimmune diseases and malignancy are present in the underlying pathology. The severity of pain should be assessed and paroxysmal attacks of pain should be asked. The quality of life, emotional and psychological status of the patient should also be assessed. Sleep disturbances and physical restraints are also parameters to be emphasized in the history. Treatments the patient has already received and their response should be known.



 In patients with neuropathic pain clinically symptoms are manifested by persisting pain. Pain may occasionally show paroxysmal course. The character may be of a flammable or sinking nature or of a flammable nature. Abnormal feelings after stimulation, sleep disturbances, emotional and psychological disturbances, physical restraints and autonomic symptoms may accompany the pain. Pain may not always be localized, but in some patients it may be anatomically symptomatic in the appropriate region.



Abnormal sensation manifests itself as hyperalgesia or allodyni. Hyperalgesia is defined as painful stimulation with increased pain response. It can be classified as mechanical, thermal or chemical hyperalgesia. Whereas allodynia is a pain response given to a painless stimulus. It is classified as dynamic and cold allody



Physical examination:

Determining the boundaries of the affected area of the patient also leads to monitoring during treatment. Examination of the superficial nerve is carried out with cotton, brush sheath, thread, needle penetration and tactile to understand the presence of abnomal sensation. Skin temperature measurement can give insight into the autonomic change. Edema, colour change, sweating disorder, atrophy of the skin and nail changes are important in the evaluation of sympathetic pain. Assessment of tactile and vibration thresholds is an auxiliary parameter in both diagnosis and follow-up.



Advanced examinations:

Quantitative Sensory Test (QST) is an important test in the follow-up of treatment by determining baseline value. Magnetic Resonance Examination (MRI) and electromyography can be performed to determine the location of the nerve lesion.

Positron Emission Tomography (PET) and Functional MRI (fMRI) are promising methods in terms of clarifying the mechanisms of neuropathic pain and directing treatment. 





Postherpetic Neuralgia: 


Post herpetic neuralgia (PHN) develops in about 10% of the herpes zoster cases.

The rate is higher in old people. Diabetes mellitus is a predisposing factor for herpes zoster and increases the likelihood of developing postherpetic neuralgia.If the pain persists for 4-6 weeks after the dermatomal vesicles heal, a PHN diagnosis is made. PHN pain is a persistent, inflammatory, irritating pain and sometimes knife like stabbing. Starting spontaneous or triggered by slight stimulation of the skin. On skin, is usually hyperesthesia and hyperalgesia but rarely analgesia.  Frequent dysesthesia and paresthesia may accompany. PHN can be very prolonged especially in patients over 60 years of age. 


Diabetic Neuropathy:

The most common cause of neuropathic pain is diabetic neurop. Different mechanisms play a role in the development of diabetic neuropathy. It is about the "sorbitol route", which is mostly rinsed and studied. Glucose is converted to sorbitol by the aldose reductase enzyme. Overgrowth of this pathway due to hyperglycemia leads to accumulation of sorbitol in the cell. This accumulation leads to myoinositol and taurine depletion in the cell, which eventually degrades cell metabolism.

The reduction of taurine and myoinositol in the cell has been reported to lead to a decrease in Na + -K + ATPase activity and a decrease in the rate of neurotransmission. The second mechanism is decreased endoneural blood flow and nerve ischemia. Reduced nerve blood flow leads to reduced nerve conduction velocity. Disorders related to neurotrophic factors have been found in findings that may be responsible for diabetic neuropathy. The views on the role of autoimmune mechanisms in the development of diabetic neuropathy have begun to gain importance in recent years. There are many studies showing the presence of microscopic vasculitis in nerve biopsies of patients with diabetic lumbosacral radiculopopathy. These findings have led to the application of immunodomalytic therapies, including intravenous immunoglobulin in the anterior segment, in the treatment of diabetic neuropathy. Diabetic neuropathy is clinically characterized as mononeuropathy or polyneuropathy. It is often seen in the third cranial nerve neuropathy. Ayrıca median ulnar, peroneal, femoral ve lateral kutanöz sinirler de tutulur. Pain is expressed by the patient as throbbing, burning, cramping and pain in distal areas.


Sensory symmetric polyneuropathy is seen in 35% of diabetic patients. In addition, burning pain complaint may be accompanied by drowsiness, paresthesia, and autonomic dysfunction.



Fantom Extreme Pain:

 Phantom extremity pain (FEA) is defined as pain following surgical or traumatic amputation.

Pain may be accompanied by sensory disturbances, paresthesia, dysesthesia, hyperpathy.

Phantom pain may occur in the first week after amputation by 50-75%, or in some cases after a few months or years. It is suggested that the preamputation pain is the root of phantom extremity pain. But this relationship is not clear. Post-amputation factors also play a role in FEA.



The severity of the pain varies from patient to patient. Severe pain usually accompanies paresthesia. It can be continuous and periodical. Pain quality is also very variable. It is described as flammable, cramp-like and acutely painful. Pain is localized to the phantom (not available) distal to the limb (hands and feet). The stump pain usually has a palpable neuroma in the incision area.


Emotional touch and pressure, emotional tension, air change, autonomic and reflex movements, stimulation of other body regions may increase pain. Rest, cold or hot application and prosthetic application can lift the pain from the middle. Phantom pain usually declines gradually and disappears within 1-2 years.



Neuropathic pain management approach to other painful syndromes approach is not established. 

There are differences in etiological factors and mechanisms, as well as differences in the approach to neuropathic pain in different disciplines



Targets in the treatment of neuropathic pain:


• Reduction of pain intensity

• Reduction of painful surface area

• The pain must be a change of character and quality.

Various treatment approaches have been proposed to achieve this goal.



 Transcutaneous Electrical Nerve Stimulation (TENS):

In the treatment of neuropathic pain, TENS is a low-grade treatment modality that may be effective in some cases and has a potential side effect, although there is less evidence than other treatment approaches. Positive results have been reported with high and low frequency warning techniques in neuropathic pain.


Neural Blocks:

The efficacy of neural blocks with local anesthetic or neurolytic agents was not studied in randomized placebo controlled trials. The mechanism of action of such interventions envisages blockage of delivery of painful impulses from the periphery. It is suggested that this blockage reduces pain by reducing neurotransmitter release and sensitization


Some neuropathic pain syndromes in which neural blocks can be applied:

• Postherpetic neuralgia has been reported to reduce pain with recurrent stellar ganglion blockade.

. Neuropathic pain in peripheral vascular ischemic diseases can reduce pain and allodynia with neurolytic lumbar sympathetic block.

• Severe persistent pain can be relieved by ablation of the trigeminal neuralgia ganglion.

• In the case of complex regional pain syndrome, intravenous blotting with guanethidine and ketanserin has been reported to relieve pain. There is an opinion that the pressure applied on the nerve by the turniken used in this method may also contribute to the pain palliation.


Topical treatments:

It is known that capsaicin inhibits substance P release in the Ad and C fibers through TrpV1 receptors. Patients who have been given capsic acid cream first develop a burning pain, and in repeated applications this sensation is almost absent. It has been reported that diabetic neuropathy and postherpetic neuralgia cause partial pain reduction. Lidocaine patches can also contribute to pain palliation, especially in patients with postherpetic neuralgia.



Systemic pharmacological treatment:

Drug therapy is the most common approach currently used in the treatment of neuropathic pain. Agents that can be used:

 • Antidepressants

• Anticonvulsants

• NMDA antagonists

• Opioids

• Cyclooxygenase inhibitors

• Tramadol




Tricyclic antidepressants, selective serotonin reuptake inhibitors (SSRI), serotonin and noradrenalin reuptake inhibitors (SNRI); Inhibition of neurotransmitter uptake and inhibition of desendan inhibitor pathways, and inhibition of sodium channels, thereby reducing ectopic discharges, are implicated in the treatment of neuropathic pain. Placebo-controlled trials with tricyclic antidepressants have shown significant efficacy on neuropathic pain. Amitriptyline, nortriptyline and dothiepinin activities have been reported to be more prominent. It is reported that amitriptillin can be started at a dose of 10 mg and increased up to 50 mg. It can limit the use of sedatives and anticholinergic side effects It has been reported to increase the risk of myocardial infarction especially in cardiac patients for long-term use.


In recent years venlafaxine (SNRI) has been found to be effective in painful diabetic neuropathy.




Classical anticonvulsants:

Older generation anticonvulsants such as carbamazepine and phenytoin have been used frequently in the treatment of neuropathic pain. It has been suggested that the mechanisms of action are modulation of voltage-dependent Na + channels. The effects of carbamazepine have also been shown in trigeminal neuralgia, postherpetic neuralgia, and painful diabetic neuropathy. The effect is limited in other neuropathic pain syndromes.


It is recommended to use in cases of neuronal membrane potential change such as central pain.


 Side effects:


  • central nervous system

  • Fatigue

  • He is stunned

  • Headache

  • Diplopi

  • Unbalance

  • Gastrointestinal system

  • Nausea

  • Vomiting

  • Skin

  • Photosensitivity

  • Hematologic

  • Lökopeni

  • Thrombocytopenia

  • Suppression of bone marrow

  • Hepatic

  • Increase in liver enzymes





Valproic acid:

 Valproic can be used in the treatment of neuropathic pain. Common side effects are nausea, dizziness and tremor. Common side effects are nausea, dizziness and tremor.Teratogenic effect restricts its use in young women.


Gabapentin and pregabalin:

Mechanisms of action differ from other anticonvulsants. They are linked to the a2-d protein in voltage-dependent Ca ++ channels. These subunits play an important role in the formation of allodynia and hyperalgesia of spinal cord and posterior root ganglion. Both agents reduce the release of glutamate, noradrenaline, serotonin, dopamine, substance P and calcitonin in the spinal cord. No effects on release of opioid and gamma amino butyric acid have been shown.




• They become fast absorbers after oral administration

• Easily pass the blood brain barrier

• Metabolisms are negligible

• Most urine is eliminated without change



Reduce secondary hyperalgesia areas in human neuropathic pain models. For this reason, central sensitization may be effective in neuropathic pain types. Although their efficacy has been shown significantly compared to the placebo, treatment response can be obtained in 50% of the patients.

Residual pain may also remain in the response. Side effects are mild and moderate. It can be observed in 6-16% of patients with dizziness, ataxia, fatigue and sleepiness. Despite being preferred due to the mild side effects, their efficacy does not add an additional advantage to classical anticonvulsants



NMDA antagonists:

The effects of ketamine and other NMDA antagonists on neuropathic pain in experimental and clinical studies have been demonstrated. As an adjuvant, ketamine is recommended by the World Health Organization in the treatment of neuropathic pain. Although there is not enough supportive data, it has been observed to be effective in many patients. Side-effect potential is generally a limiting factor in use. The most important side effects are behavioral changes, nightmares, hyperactivity, memory and learning disorders.








Nonsteroidal antiinflammatory agents:

Use in neuropathic pain should be discussed. In some studies, efficacy has been reported in painful diabetic neuropathies. However, there is no postherpetic neuralgia activity. It has been emphasized that the combination of anticonvulsants may have an additive or synergistic effect.




It is accepted that the effect of opioids on neuropathic pain is over m, k and d opioid receptors. The use of opioids in neuropathic pain is controversial. It has been reported that the efficacy is very low in experimental studies. In the clinic, the doses required to achieve effective analgesia were reported to be very high compared to nociceptive and inflammatory pain.




The plant is an effective agent. Its effect is demonstrated by inhibition of opioid receptors and serotonin-noradrenaline uptake. Neuropathic pain was found to be more effective than placebo. Nausea, sedation and constipation are important side effects.


Other agents:

Systemic local anesthetics can be used in the treatment of neuropathic pain by reducing spontaneous nerve activity by acting on Na + channels. Lidocaine and mexiletine are clinically applicable preparations. Non-malignant neuropathic pain was found to be more effective.


A2 agonist agents such as clonidine and a1 agonists such as prazosin and terazosin have also been tried drugs in the treatment of neuropathic pain.



Combination therapy:

It has been shown in experimental studies that the combination of drugs in different groups of neuropathic pain treatment may be further enhanced by additive and synergistic effects. Combination therapy can also significantly reduce side-effect potential by keeping drug doses used low. The recommended combinations are opioid + gabapentin, nonsteroidal antiinflammatory + gabapentin and opioid + clonidine.





Preemptive analgesia promises to prevent the development of stubborn neuropathic pain. In particular, studies showing that the incidence of phantom pain can be reduced by preoperative epidural opioid administration will increase the use of this application.


In addition, preoperative administration of gabapentin reduces the use of secondary hyperalgesia and postoperative morphine in neuropathic pain models.

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