The use of duloxetine-a double reuptake inhibitor in the treatment of painful diabetic neuropathy
Diabetic neuropathy, as it is known, is a common complication of diabetes mellitus and is registered in 30% of patients on the basis of the hospital register, in 25% of patients during large-scale population studies. The morbidity rate is 2% per year. The most common type of diabetes is symmetrical distal polyneuropathy (DPN), which accounts for about 80% of all cases of diabetic neuropathy.
The main etiological factors associated with DPN are the duration of the disease, poor glycemic control, age, smoking and dyslipidemia. Pain is the most common disturbing symptom that forces the patient to consult a doctor. Not only diabetic polyneuropathy, but focal and multifocal diabetic neuropathies, such as isolated cranial nerve paralysis or proximal motor neuropathy of the lower extremities, can be accompanied by pain. The frequency of painful diabetic neuropathy according to studies varies from 8 to 26% among diabetic patients, depending on the criteria for assessing the pain syndrome. Distal symmetrical polyneuropathy is combined with autonomous disorders.
The onset of DPN is usually sudden and in the absence of early intervention, the course is chronic and progressive. A decrease or loss of the function of thin nerve fibers leads to a violation of the perception of pain (pain from touching hot and pricking), as well as temperature perception – cold (A -) and heat (C-fibers). With the involvement of Tolstoy (Aa and Aß) of nerve fibers, the speed of conduction along the nerve slows down and sensitivity to touch, pressure and vibration decreases, which in severe cases can lead to sensory ataxia (ataxic gait).
The involvement of sensory fibers in the process causes “positive symptoms”, which include paresthesia, dysesthesia and pain, and can also be accompanied by” negative ” symptoms – a decrease in sensitivity.
Persistent or episodic pain is usually localized in the feet, increases at night and decreases during walking. Patients describe the pain as deep aching, but also as piercing or as a burning sensation in the legs. Pain caused by stimuli that are not usually accompanied by pain – allodynia and hyperalgesia-significant pain caused by stimuli, usually accompanied by mild pain – they may also be present. The pain may at the same time be accompanied by a decrease in sensitivity. Neuropathic pain in diabetes mellitus persists for several years in some patients, causing both physical and emotional suffering, while in others it disappears completely or partially, despite a progressive decrease in the function of thin nerve fibers. Remission of pain is combined with sudden metabolic changes, a short duration of pain, a previous decrease in body weight and less severe forms of loss of sensitive functions.
Chronic pain is a common condition, accompanied by a decrease in the quality of life and is associated with disability, however, a third of patients do not receive any treatment, 40% of patients receive inadequate therapy and only 2% are treated by pain specialists.
Although the pathogenesis of pain has not yet been sufficiently disclosed, it is obvious that chronic neuropathic pain occurs as a result of damage and disruption of adaptation mechanisms in both the peripheral and central nervous systems.
Primary pain receptors (nociceptors) are sensory nerve endings located in various tissues and organs. The transmission and perception of pain is a bilaterally directed process and is carried out through ascending and descending neuronal pathways. After the tissue damage, there is a massive release of inflammatory mediators-histamine, prostaglandins and bradykinin, which activate and sensitize nociceptors. Next, the pain impulse along the primary afferent neurons enters the synapses of the posterior horns of the spinal cord, where the impulse passes into second-order neurons, while it is released into the intersynaptic cleft substance p. According to the second-order neurons of the posterior horns, the pain impulse ascends along the anterolateral spinothalamic tract, affecting synapses in the thalamus, and then enters the somatosensory region of the cerebral cortex for interpretation. In turn, the brain modulates ascending impulses by descending neuronal mechanisms that exercise their control through descending spinothalamic pathways. Among the various modulators and neurotransmitters, serotonin (5-hydroxytryptophan, 5-HT) and norepinephrine (NA) are especially important. Experimental animal studies have demonstrated the participation of the serotonergic and noradrenergic systems in the modulation of pain. The descending pathways are designed to suppress incoming stimuli from the gastrointestinal tract and musculoskeletal systems.
The dysfunction of these pathways is accompanied by increased sensitivity to pain and even painful reactions to normal non-painful stimuli. Thus, an increase in the content of 5-HT and NA is accompanied by an endogenous analgesic effect acting through a descending inhibitory neuronal pathway at the level of the brain and spinal cord.
Diabetic pain neuropathy is the result of both metabolic and microcirculatory disorders in neurons caused by chronic hyperglycemia, which lead to pathological impulses from peripheral nociceptors recognized by the brain as pain. Over time, there is a “central sensitization”, leading to further intensification and chronization of pain. Central sensitization leads to neuronal plasticity and changes in the conduct of pain, which eventually transform into conditions when a small pain stimulus can be recognized as very strong, or the pain can persist even in the absence of any stimuli.Diabetic pain neuropathy is the result of both metabolic and microcirculatory disorders in neurons caused by chronic hyperglycemia, which lead to pathological impulses from peripheral nociceptors recognized by the brain as pain. Over time, a “central sensitization” occurs, leading to further strengthening and chronization of pain. Central sensitization leads to neuronal plasticity and changes in pain conduction, which eventually transform into states where a small pain stimulus can be recognized as very strong, or the pain can persist even in the absence of any stimuli.
Recent studies have shown that diabetes affects all levels of the nervous system – from the peripheral nerve to the brain. Magnetic resonance imaging confirmed the lesion of the type of demyelination at the level of the spinal cord already in the early stages of neuropathy, identical to the consequences observed in spinal cord injury.
A study with magnetic resonance spectroscopy shows the presence of thalamic dysfunction in diabetic sensorimotor polyneuropathy. Thus, diabetes has a much more generalized effect on the nervous system than was previously assumed.
The dysfunction of the noradrenergic and / or serotonergic systems of the brain and spinal cord has common psychopharmacological mechanisms involved in the development of both pain and depression. The use of antidepressants, as shown in animal experiments, can cause the growth of hippocampal neurons and, thus, induce neurogenesis. This property of anti-depression drugs promotes neuroplasticity, and thus helps to influence the main symptoms of depression associated with mood and motivation. Studies show that “double-acting” drugs that affect both the serotonin and noradrenalinergic systems have the most significant effect on both depression and chronic pain.
Treatment of neuropathic pain
Chronic pain associated with diabetic neuropathy, by its prevalence, occupies the second place in the structure of neuropathic pain after back pain. The treatment of pain implies an impact on the pathophysiological mechanisms of its formation. The main goal of this approach is to ensure the analgesic activity of the drug or drug combinations while reducing the number of side effects, which allows improving the patient’s adherence to treatment.
The treatment of pain caused by diabetic damage to the peripheral nervous system is a difficult task. The progression of DPN largely depends on the severity of diabetes and the degree of maintenance of glycemic control over time. In the treatment of pain, various non-medicinal methods of treatment are used (acupuncture, magnetic therapy, percutaneous electrical stimulation, massage, etc.), the effectiveness of which remains unproven. Currently, drug therapy is the most effective in the treatment of neuropathic pain. It should be immediately emphasized that simple analgesics and non-steroidal anti-inflammatory drugs in the treatment of pain in DPN are not recommended because of their ineffectiveness and the high frequency of adverse events with prolonged use (complications from the gastrointestinal tract, liver and blood).
The main groups of drugs for the treatment of neuropathic pain in DPN are: antidepressants, anticonvulsants, opioid analgesics.
Currently, the possibility of pathogenetic treatment of pain neuropathy is being discussed. The results obtained in multicenter placebo-controlled studies on the use of alpha-lipoic (thioctic) acid show the possibility of short-term relief of pain symptoms accompanying mild or moderate neuropathy, which recovers 3-6 months after discontinuation of the drug. Long-term treatment of severe persistent pain requires, as a rule, the appointment of systemic or topical pharmacological agents with analgesic activity in monotherapy or in combination.
Tricyclic antidepressants (TCAS) have long existed as a first-line therapy for the treatment of diabetic neuropathy pain. Amitriptyline, prescribed in gradually increasing doses from 10 to 150 mg per day, provides an analgesic effect regardless of the antidepressant effect in 7-58% of patients, which may not occur immediately, but after 2-3 weeks from the start of treatment.
TCA inhibits the reuptake of serotonin and nor-epinephrine, reduces sympathetic activity, affects the receptors of the central nervous system. The use of TCA is limited by such known intolerable side effects as sedation, visual impairment, dry mouth, orthostatic hypertension and cardiac arrhythmia.
Currently, there is numerous evidence of the effectiveness and validity of treatment with antidepressants for neuropathic pain syndrome. Tricyclic antidepressants inhibit the reuptake of 5-HT and NA, but they have additional effects on muscarinic, histamine and α-adrenergic receptors, thereby
exhibiting side effects that limit their use.
Selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine and citalopram, have no obvious evidence of an analgesic effect, although their effect on pain has been shown in preclinical studies.
Recently, interest has been shown in the so-called “double-acting inhibitors” that simultaneously reduce the reuptake of both serotonin and norepinephrine, which include duloxetine and milnacipram. The results obtained in numerous animal studies in experimental models of chronic pain have convincingly shown that the effect on serotonergic and noradrenergic systems are more effective than just one serotonergic system. At the same time, the perception of pain is inhibited both at the level of the posterior horns of the spinal cord and at the level of supraspinal mechanisms (transmission of central pain).
A particularly effective and sufficiently studied selective and balanced double-acting inhibitor is Duloxetine (Cymbalta), the effect of which is apparently mediated by the effect on α1-adrenergic receptors and 5-HT2-receptors. The effect of duloxetine on neuropathic pain has been studied in animals (rat models). It was shown that in terms of the effect of exposure to 5-HT, it is similar to paroxetine, and in terms of the ability to support the concentration of NA – desipramine. Compared with other double-acting inhibitors (venflaxin and milnacipran), it surpassed them in effectiveness. This effect was dose-dependent, did not cause neurological deficit and had a positive effect on mechanical allodynia. Thus, the potential use of duloxetine in the treatment of persistent neuropathic pain conditions in humans was justified.
The effectiveness of duloxetine for the treatment of pain-related diabetic peripheral neuropathy has been proven in three double-blind, placebo-controlled studies. These studies included 1139 patients with type 1 and type 2 diabetes mellitus and diabetic neuropathy lasting more than 6 months; all of them had a 12-week phase with fixed doses of duloxetine.
In the first study (Goldstein et al 2005), patients received 20 mg, 60 mg once and 60 mg twice a day, as well as a placebo for 12 weeks. The second (Raskin et al. 2006) and third (Wernicke et al.2006 ) studies compared doses of duloxetine 60 and 120 mg per day and placebo also prescribed for 12 weeks. The second and third studies had an extended open phase, in which a comparison of duloxetine and conventional treatment was carried out. The main objective of this phase of the study was to assess the safety and satisfaction of patients with treatment, as well as to assess the quality of life (EQ-5D).
The average age of the patients included in the studies was 60 years, the duration of diabetes was 11.7 years, the duration of neuropathy was 3.9 years (Table 2). All patients had symptoms of pain diabetic neuropathy of a typical symmetrical nature, which lasted at least 6 months. The pain intensity was ≥4 according to the average pain intensity scale for 24 hours (maximum 10). The level of glycated hemoglobin at inclusion was ≤12%, i.e. the patients were mainly in a state of unsatisfactory glycemic control. In order to avoid the indirect effect of duloxetine by affecting the depressive component of pain, patients with symptoms of depression, as well as other mental and somatic diseases that could affect the result of treatment, were excluded from the study. In the course of the study, the primary criteria of effectiveness were evaluated – the scale of the average intensity of pain during 24 hours of Liqueur; secondary the effectiveness criteria included the scale of the most intense pain and the intensity of night pain, a brief description of pain (BPI), a general clinical impression of severity (CGI), the patient’s general impression of improvement (PGIImprovement), a short McGill questionnaire on pain, dynamic allodynia, a short health status questionnaire (SF-36). In all three studies, patients with clinically pronounced episodes of depression were excluded from the study.
The results of the studies showed that the analgesic effect of duloxetine develops quickly – after a week of treatment, both 60 mg and 120 mg of duloxetine. The pain reduction was statistically significant and remained significant. The results of the studies showed that the analgesic effect of duloxetine develops quickly – after a week of treatment, both 60 mg and 120 mg of duloxetine. The pain reduction was statistically significant and remained significant during 12 weeks of treatment. The amount of pain reduction was 65% for 60 mg, 64% for 120 mg in the first study, 63% and 69%, respectively, in the second study and significantly exceeded the level of response to placebo treatment (42%). It was found that changes in the Beck anxiety scale did not affect the result, but the analysis of the Beck depression scale showed a moderate effect on the result of pain assessment. Thus, it was concluded that the direct effect of duloxetine on the daily average pain scale is 88.6%, and the indirect effect reaches 11.4%.
As a result of the studies, as primary: the intensity of pain (average, strongest and weakest), evaluated on a scale The 24-hour intensity and secondary criteria differed significantly compared to placebo. Patients also noted an improvement in their health status in certain domains of the SF-36 scale, as well as quality of life (EQ-5D).
The safety and tolerability of duloxetine was evaluated in three studies, as well as in three continued (52 weeks) open comparative studies. The study was not completed due to side effects of 20% of patients in the placebo group, 20.9% of patients receiving 60 mg, and
25.8% of patients receiving 120 mg of duloxetine. The study of the safety and tolerability of duloxetine (Cymbalta) showed a dose-related dependence of the side effects of the drug, the most typical of which is for a dose of 60 mg per day. there were nausea (22%), dizziness (13%), drowsiness (18%), constipation (11%) and weakness (7%). These side effects were somewhat more often observed when taking 120 mg of duloxetine per day. However, in most patients, the side effects were moderate and mild, regardless of the type of treatment.
When compared with standard therapy in open In 52-week studies (amitriptyline, carbamazepine, gabapentin and venlaflaxine), duloxetine showed sufficient
safety and tolerability. The most frequent (more than 10%) side effects when taking duloxetine were nausea, and with standard therapy – peripheral edema, pain in the extremities, drowsiness and dizziness.
During the studies, minor changes in the level of glycated hemoglobin and lipids were noted, but only the change in high-density lipoproteins was statistically significant for all three studies.
In the continued 52-week phase of the study, the effect of duloxetine on the quality of life was evaluated. According to the domains of bodily pain, physical condition and physical functions, a positive effect of the drug was noted. For the remaining SF-36 domains, the changes were negative, but to a less pronounced extent compared to the changes in the standard treatment groups. According to the quality of life assessment scale, duloxetine significantly exceeded the standard treatment.
The metabolism of duloxetine is carried out in the liver under the influence of the cytochrome-P450 enzyme with the appearance of two active metabolites, its half-life is 12 hours. The drug is excreted mainly through the kidneys (70%). The use of duloxetine in patients with renal insufficiency requires caution. After taking 60 mg the maximum concentration of the drug in plasma and the distribution of the drug are approximately 2 times higher in patients with end-stage renal failure on hemodialysis than in patients with normal renal function. However the half-life is the same in both groups. Pharmacokinetic analysis in the population showed that with a small or moderate degree of renal insufficiency (creatinine clearance 30-80 ml per minute), there is no significant effect on the pharmacokinetics of duloxetine. Cymbalta is not recommended for patients with end-stage renal insufficiency and creatinine clearance of less than 30 ml / min.
The effectiveness of duloxetine, as well as the frequency of side effects in the treatment of diabetic neuropathy, does not differ significantly with increasing age of patients. However, when prescribing the drug to elderly patients requires caution when increasing the dose of the drug. During pregnancy, especially in the third trimester, it is desirable
to reduce the dose as much as possible.
With a sharp withdrawal of the drug, such phenomena as dizziness, nausea, headache, paresthesia may occur. The frequency of these symptoms is low and is about 2%, and therefore a gradual reduction in the dose of the drug is recommended.
Thus, neuropathic pain in diabetes mellitus it has a complex character and is caused, unlike nociceptive pain, by disorders in both the peripheral and central nervous systems. More and more data are accumulating, indicating a whole range of disorders, including changes in the structure and function of the spinal cord, thalamic neuronal dysfunction, and a decrease in the inhibitory effect of descending neuronal pathways. Progress in the study of the pathogenesis of neuropathy opens up new ways to search for drugs that have a direct impact on the pathophysiological mechanisms of pain.
The use of duloxetine (Cymbalta), a balanced selective double serotonin and norepinephrine reuptake inhibitor, in patients with diabetes mellitus, occupies an important place in the complex treatment of diabetic pain neuropathy.