Diabetic polyneuropathy pain

Diabetic polyneuropathy is a common complication of diabetes mellitus. The most common variants of peripheral nervous system damage in diabetes mellitus are distal symmetric sensory and sensorimotor polyneuropathy. These same forms of polyneuropathy are most often accompanied by pain syndrome. Diabetic polyneuropathy is the most common cause of neuropathic pain.

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Epidemiology

According to most authors, the frequency of pain syndrome in diabetic polyneuropathy reaches 18-20%.

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Pathogenesis

Pathogenetic mechanisms of diabetic polyneuropathy development are complex and multifactorial. Hyperglycemia caused by diabetes mellitus causes metabolic disorders such as intracellular accumulation of sorbitol, excessive protein glycation, oxidative stress, which significantly disrupt the structure and functions of neurons. Endothelial cells are also damaged, which leads to microvascular dysfunction. The resulting hypoxia and ischemia further activate the processes of oxidative stress and nerve damage. Deficiency of neurotrophic factors is also considered an important pathogenetic mechanism for the development of diabetic polyneuropathy.

As for the mechanisms of pain development in diabetic polyneuropathy, the main factor is considered to be damage to the fine sensory fibers that provide pain sensitivity. Of great importance are the mechanisms of peripheral and central sensitization, generation of impulses from ectopic foci of affected nerves, excessive expression of sodium channels, etc.

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Symptoms diabetic polyneuropathy pain

The pain syndrome in diabetic polyneuropathy is characterized by a combination of positive and negative sensory phenomena. Typical complaints are tingling and numbness in the feet and shins, which intensify at night. At the same time, patients may experience sharp, shooting, pulsating and burning pain. Some patients experience allodynia and hyperesthesia. All of the above disorders are classified as positive sensory symptoms of neuropathic pain. Negative symptoms include pain and temperature hypoesthesia, which are moderately expressed in the initial stages of the disease and are localized in the distal parts of the legs, but as the disease progresses, they spread proximally and may occur in the arms. Tendon reflexes are usually reduced, and muscle weakness is limited to the muscles of the foot.

Less frequently, pain may occur with diabetic asymmetric neuropathy caused by a vasculitic process in the epineurium. This form usually develops in elderly people with mild diabetes mellitus (often even undiagnosed). The pain occurs in the lower back or in the hip area and spreads down the leg on one side. At the same time, weakness and thinning of the thigh and pelvic muscles on the same side are noted. Recovery is usually good, but not always complete.

Diabetic thoracolumbar radiculopathy is characterized by pain combined with cutaneous hyperesthesia and hypoesthesia in the area of innervation of the affected roots. This form of diabetic polyneuropathy often develops in elderly patients with a long history of diabetes mellitus and, as a rule, tends to slow recovery of functions.

With a marked increase in blood glucose concentration (ketoacidosis), acute painful neuropathy may develop, manifested by severe burning pain and weight loss. Allodynia and hyperalgesia are very pronounced, and sensory and motor deficits are minimal.

Treatment diabetic polyneuropathy pain

Treatment for diabetic polyneuropathy involves two directions - reducing the severity of pain syndrome (symptomatic therapy) and restoring the function of the affected nerves (pathogenetic therapy). In the latter case, thioctic acid, benfotiamine, nerve growth factors, aldose reductase inhibitors, protein kinase C inhibitors, etc. are used. Pathogenetic therapy is of the utmost importance and largely determines the prognosis, but at the same time it is usually not accompanied by rapid clinical improvement (long-term repeated courses are necessary) and has little effect on pain syndrome, which is very often the leading factor reducing the quality of life of patients. Therefore, in patients with pain syndrome, symptomatic therapy is carried out in parallel, aimed at relieving neuropathic pain.

To relieve neuropathic pain in diabetic polyneuropathy, various non-drug methods are used (surgical decompression of the peroneal nerve, laser therapy, acupuncture, magnetic therapy, biofeedback, transcutaneous electrical neurostimulation), but their effectiveness remains unproven to date, so the basis of treatment is drug therapy - antidepressants, anticonvulsants, opioids and local anesthetics. It should be especially emphasized that simple analgesics and NSAIDs are not effective for neuropathic pain.

• Of the antidepressants, amitriptyline (25-150 mg/day) is the most effective. It is recommended to start treatment with a low dose (10 mg/day), which is gradually increased. At the same time, in addition to blocking the reuptake of norepinephrine and serotonin, amitriptyline (and other tricyclic antidepressants) blocks postsynaptic m-cholinergic receptors, as well as alpha1-adrenergic receptors and histamine receptors, which causes a number of undesirable effects (dry mouth, sinus tachycardia, constipation, urinary retention, confusion, memory impairment, drowsiness, orthostatic hypotension, dizziness). Tricyclic antidepressants should be used with caution in patients with cardiac pathology, glaucoma, urinary retention or autonomic disorders. In elderly patients, they can cause imbalance and cognitive impairment. Selective serotonin reuptake inhibitors have fewer side effects, but clinical trials conducted on patients with neuropathic pain in diabetic polyneuropathy (fluoxetine, paroxetine) have demonstrated only limited effectiveness. In recent years, other classes of antidepressants, such as venlafaxine and duloxetine, have proven effective.
• The effectiveness of first-generation anticonvulsants in the treatment of neuropathic pain is associated with their ability to block sodium channels and inhibit ectopic activity in presynaptic sensory neurons. In the painful form of diabetic polyneuropathy, carbamazepine is effective in 63-70% of cases, but its use often causes undesirable side effects (dizziness, diplopia, diarrhea, cognitive impairment). A number of studies have noted a positive effect when using phenytoin and valproic acid. Experience with the use of second-generation anticonvulsants in diabetic polyneuropathy is generally very limited. Data on the effectiveness of topiramate, oxcarbazepine, lamotrigine are few and contradictory. Encouraging results have been obtained for gabapentin and pregabalin. The efficacy of pregabalin in the treatment of neuropathic pain in adults has been demonstrated in 9 controlled clinical trials (duration of administration - up to 13 weeks). The mechanism of action of gabapentin and pregabalin is based on binding to the α2 _sigma subunit of potential-dependent calcium channels of peripheral sensory neurons. This leads to a decrease in calcium entry into the neuron, resulting in a decrease in ectopic activity and the release of the main pain mediators (glutamate, norepinephrine and substance P). Both drugs are well tolerated. The most common side effects are dizziness (21.1%) and drowsiness (16.1%). Based on the randomized clinical trials, practical recommendations for the use of these drugs in the treatment of neuropathic pain syndromes are proposed. Gabapentin should be prescribed at a dose of 300 mg / day and gradually increased to 1800 mg / day (if necessary - up to 3600 mg / day). Pregabalin, unlike gabapentin, has linear pharmacokinetics, its starting dose is 150 mg/day, if necessary, the dose can be increased to 300 mg/day after 1 week. The maximum dose is 600 mg/day.
• The use of opioids is limited due to the risk of developing dangerous complications, as well as mental and physical dependence. That is why they are not widely used in the treatment of painful diabetic polyneuropathy. Two randomized controlled trials have proven the effectiveness of tramadol (400 mg/day) - the drug significantly reduced the severity of pain and increased social and physical activity. Tramadol has a low affinity for opioid mu-receptors and is also an inhibitor of serotonin and norepinephrine reuptake. According to many researchers, the likelihood of tramadol abuse is much lower than other opioids. The most common side effects are dizziness, nausea, constipation, drowsiness and orthostatic hypotension. To reduce the risk of side effects and dependence, tramadol should be started with low doses (50 mg 1-2 times a day). If necessary, the dose is increased every 3-7 days (maximum dose - 100 mg 4 times a day, for elderly patients - 300 mg/day).
• Clinical data on the use of local anesthetics (lidocaine patch) for neuropathic diabetic pain are limited to open studies. It should be borne in mind that local application of anesthetics can reduce pain only at the site of application, i.e. their use is advisable in patients with a small area of pain distribution. Obviously, more precise recommendations for the use of local anesthetics require additional controlled studies. Capsaicin is a local anesthetic obtained from the pods of red hot peppers or chili peppers. It is believed that the mechanism of action of capsaicin is based on the depletion of substance P in the endings of peripheral sensory nerves. In one study, local application of capsaicin (for 8 weeks) reduced the severity of pain by 40%. It should be noted that the pain often intensifies when capsaicin is first applied. The most common side effects are redness, burning, and tingling at the site of capsaicin application. In general, taking into account the criteria of evidence-based medicine, gabapentin or pregabalin can be recommended as first-line drugs for the treatment of pain syndrome in diabetic polyneuropathy. Second-line drugs include antidepressants (duloxetine, amitriptyline) and tramadol. Practical experience shows that in some cases rational polypharmacotherapy is advisable. In this regard, the most acceptable is a combination of an anticonvulsant (gabapentin or pregabalin), an antidepressant (duloxetine, venlafaxine or amitriptyline) and tramadol.

Prevention

The main condition for preventing the development of polyneuropathy is considered to be normoglycemia, but it is not possible to achieve it in all cases, therefore the disease, as a rule, has a progressive course.

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