Pain in diabetic polyneuropathy

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

[1], [2], [3], [4], [5], [6], [7], [8], [9]

Epidemiology

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

[10], [11], [12], [13], [14], [15]

Pathogenesis

Pathogenetic mechanisms of the development of diabetic polyneuropathy are complex and multifactorial. Hyperglycemia caused by diabetes mellitus causes such metabolic disturbances as intracellular accumulation of sorbitol, excessive glycation of proteins, oxidative stress, which significantly disrupt the structure and functions of neurons. Endothelial cells are also damaged, which leads to microvascular dysfunction. Developing as a result of hypoxia and ischemia, even more activates the processes of oxidative stress and nerve damage. An important pathogenetic mechanism for the development of diabetic polyneuropathy is also considered a deficiency of neurotrophic factors.

With regard to the mechanisms of the development of pain in diabetic polyneuropathy, the main factor is the damage to the fine sensory fibers that provide pain sensitivity. Important mechanisms are the mechanisms of peripheral and central sensitization, the generation of pulses from ectopic foci of the affected nerves, excessive expression of sodium channels, etc.

[16], [17], [18], [19]

Symptoms of the pain in diabetic polyneuropathy

Pain syndrome in diabetic polyneuropathy is characterized by a combination of positive and negative sensory phenomena. Typical complaints - a feeling of tingling and numbness in the feet and legs, intensifying at night. At the same time, patients may experience sharp, shooting, throbbing and burning pains. In some patients, allodynia and hyperesthesia are noted. All of the above disorders are attributed to positive sensory symptoms of neuropathic pain. Negative symptoms include pain and temperature hypoesthesia, which in the initial stages of the disease are moderately expressed and localized in the distal parts of the legs, but progressively spreads proximally and can occur on the hands. Tendon reflexes, as a rule, are reduced, and muscle weakness is limited to the muscles of the foot.

Less often, pain can occur with diabetic asymmetric neuropathy, caused by the vasculitic process in the epineurium. This form usually develops in elderly people with mild diabetes mellitus (often even undiagnosed). Pain occurs in the lower back or in the region of the hip joint and spreads down the leg on one side. In this case, note the weakness and weight loss of the muscles of the hip, pelvis on the same side. Recovery is usually good, but not always complete.

Diabetic thoraco-lumbar radiculopathy is characterized by pain in combination with cutaneous hyperesthesia and hypesthesia 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 and, as a rule, tends to slow recovery of functions.

With a marked increase in the concentration of glucose in the blood (ketoacidosis), acute pain neuropathy can develop, manifested by severe burning pain and a decrease in body weight. Very pronounced allodynia and hyperalgesia, and sensory and motor deficits are minimal.

Treatment of the pain in diabetic polyneuropathy

Treatment for diabetic polyneuropathy involves 2 areas - reducing the severity of pain syndrome (symptomatic therapy) and restoring the function of the affected nerves (pathogenetic therapy). In the latter case, thiectic acid, benfotiamine, nerve growth factors, aldose reductase inhibitors, protein kinase C inhibitors, etc. Are used. Pathogenetic therapy is of paramount importance and predetermines the prediction, but at the same time it is usually not accompanied by a rapid clinical improvement (long repeated courses are needed ) and has little effect on the pain syndrome, which is very often the leading factor that reduces the quality of life of patients. Therefore, patients with pain syndrome in parallel carry out symptomatic therapy aimed at stopping neuropathic pain.

For the relief of neuropathic pain in diabetic polyneuropathy, various non-drug methods (surgical decompression of the peroneal nerve, laser therapy, acupuncture, magnetotherapy, biological feedback, percutaneous electroneurostimulation) are used, but their effectiveness is still unproven, so the basis of treatment is drug therapy - antidepressants, anticonvulsants, opioids and local anesthetics. It should be especially emphasized that simple analgesics and NSAIDs with neuropathic pain are not effective.

• Of antidepressants, amitriptyline is most effective (25-150 mg / day). Treatment is recommended to start with a low dose (10 mg / day), which is gradually increased. At the same time, in addition to blocking the re-uptake of norepinephrine and serotonin, amitriptyline (and other tricyclic antidepressants) blocks postsynaptic m-cholinergic receptors, as well as alpha1-adrenoreceptors and histamine-wide receptors, which causes a number of undesirable effects (dry mouth, sinus tachycardia, constipation, retention of urine, confusion, memory impairment, drowsiness, orthostatic hypotension, dizziness). Tricyclic antidepressants should be used with caution in patients with cardiac pathology, glaucoma, retention of urine, or autonomic disorders. In elderly patients, they can cause imbalance and cognitive disorders. 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 efficacy. In recent years, the effectiveness of other classes of antidepressants, such as venlafaxine and duloxetine, has been proven.
• The effectiveness of 1st 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. With painful form of diabetic polyneuropathy, carbamazepine is effective in 63-70% of cases, but often undesirable side effects (dizziness, diplopia, diarrhea, cognitive disorders) often occur. A number of studies have shown a positive effect when using phenytoin and valproic acid. The experience with diabetic polyneuropathy of anticonvulsants of the second generation as a whole is very limited. Data on the efficacy of topiramate, oxcarbazepine, lamotrigine are few and contradictory. Reliable results were obtained with respect to gabapentin and pregabalin. The efficacy of pregabalin in the treatment of neuropathic pain in adults is demonstrated in 9 controlled clinical trials (duration of admission - up to 13 weeks). The mechanism of action of gabapentin and pregabalin is based on binding to a ₂ sigma subunit of the potential of the dependent calcium channels of peripheral sensory neurons. This leads to a decrease in calcium entry into the neuron, resulting in reduced ectopic activity and release of the main mediators of pain (glutamate, norepinephrine and substance P). Both drugs have good tolerability. The most common side effects are dizziness (21.1%) and drowsiness (16.1%). Based on conducted randomized clinical trials, practical recommendations for the use of these drugs in the treatment of neuropathic pain syndromes are suggested. Gabapentin should be prescribed at a dose of 300 mg / day and gradually increase it to 1800 mg / day (if necessary - up to 3600 mg / day). Pregabalin unlike gabapentin has a linear pharmacokinetics, its starting dose is 150 mg / day, if necessary, the dose after 1 week can be increased to 300 mg / day. The maximum dose is 600 mg / day.
• Possibilities for using opioids are limited due to the risk of developing dangerous complications, as well as mental and physical dependence. That is why they have not found wide application in the treatment of painful diabetic polyneuropathy. In 2 randomized controlled trials, the efficacy of tramadol (400 mg / day) was proven, the drug significantly reduced pain and increased social and physical activity. Tramadol has low affinity for opioid mu receptors and is also an inhibitor of reuptake of serotonin and norepinephrine. According to many researchers, the likelihood of abuse of tramadol 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 (the maximum dose is 100 mg 4 times a day, for elderly patients - 300 mg / day).
• Clinical data on the use of local anesthetics (patch with lidocaine) in neuropathic diabetic pain are limited to open-label studies. It should be borne in mind that local application of anesthetics can reduce pain only at the place of application, that is, their use is advisable in patients with a small area of pain. Obviously, for more precise recommendations on the use of local anesthetics, additional controlled studies are needed. Capsaicin is a local anesthetic obtained from pods of red hot pepper or chili peppers. It is believed that the mechanism of the action of capsaicin is based on the depletion of the stocks of substance P in the endings of peripheral sensory nerves. In one study, local application of capsaicin (within 8 weeks) allowed to reduce the severity of pain by 40%. It should be noted that with the first application of capsaicin, pain is often intensified. The most common side effects are redness, burning sensation and tingling at the place of capsaicin application. In general, taking into account the criteria of evidence-based medicine as first-line drugs for the treatment of pain in diabetic polyneuropathy, gabapentin or pregabalin can be recommended. For drugs of the second line, antidepressants (duloxetine, amitriptyline) and tramadol can be included. Practical experience shows that in some cases rational polypharmacy is appropriate. In this regard, the combination of an anticonvulsant (gabapentin or pregabalin), an antidepressant (duloxetine, venlafaxine or amitriptyline) and tramadol is the most acceptable.

Prevention

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

[20], [21], [22], [23],