Antidepressants for joint pain. Antidepressants in the treatment of osteochondrosis: why is it needed, how to take it, a review of drugs Pain treatment with antidepressants

14.02.2021

Over the past few decades, an incredible number of clinical studies, differing in their methodological quality, have been conducted to assess the efficacy and safety of antidepressants in the treatment of patients with various types of pain syndromes. The effectiveness of antidepressants against the background of chronic nonspecific and specific pain syndromes, in particular against the background of osteoarthritis and rheumatoid arthritis, fibrositis, fibromyalgia, has been shown (Fishbain D., 2000) (Strumpf M., 2001).

The tricyclic antidepressant amitriptyline, including in low doses, is one of the most prescribed antidepressants (Lockhart P., 2011). Orbai A.M. and Meyerhoff J.O. published a review that retrospectively analyzes the outcomes of treatment of patients with chronic low back pain and lumbar spinal stenosis using low-dose tricyclic antidepressants, including amitriptyline. So, out of 26 patients, 20 showed an improvement in the picture of pain syndrome.

Moreover, the majority of patients noted improvements even when taking amitriptyline or nortriptyline at a dose of 10 mg, which remained at the same level during further treatment. The number of patients with lumbar pain combined with irradiation to the leg, improvement of the symptomatic picture, was significantly higher in comparison with the number of patients with only back pain. Thus, it has been shown that tricyclic antidepressants are an effective therapeutic method for pain control in a population of patients with lumbar spinal stenosis (Orbai A.M., Meyerhoff J.O., 2010).

In a randomized, double-blind, placebo-controlled study of 78 men with chronic low back pain treated with the tricyclic antidepressant nortriptyline at doses of 50-150 ng / ml for 8 weeks, there was a significant decrease in the assessments of the intensity and nature of pain ( Descriptor Differential Scale) and disability ( Impact Profile). Significant differences in assessments of health-related quality of life ( Quality of Well-Being Scale) moods ( Beck Depression Inventory, Spielberger State Anxiety Inventory, Hamilton Anxiety / Depression Rating Scales) and the clinical outcomes of pain syndrome assessed by the researchers (Clinical Global Impression) did not differ significantly between the nortriptyline and placebo groups. Thus, it was confirmed the presence of analgesic activity of nortriptyline in comparison with placebo, and independently of its antidepressant action (Atkinson J.H., Slater M.A., Williams R.A., 1999).

Thus, one psychometric study assessed the potential influence of psychological factors on the response of patients with chronic low back pain receiving treatment with the antidepressant clomipramine. The study involved 30 hospitalized patients with chronic low back pain who received intravenous injections of an antidepressant during the first 10 days of the study and then orally in tablets for 20 days.

Psychological testing was performed using a validated questionnaire Minnesota Multiphasic Personality Inventory. Also on days 0, 4, 10 and 30, tests were used Saint Antoine Questionnaire, YOUR, Schöber "s maneuver and conducted a general examination. So, initially, before initiating therapy, patients had high scores MMPI, which indicated the presence of hypochondria, depression and hysteria. These estimates significantly decreased in 76% of patients (n = 23) by the 30th day of the study.

Of the 13 patients with high scores for hypochondria and hysteria, 5 of these scores significantly decreased during hospitalization and returned to baseline values after returning home. Thus, it has been shown that the response to treatment with clomipramine is better in non-depressive patients. Moreover, hypochondria and hysteria are the best predictors of response to antidepressant treatment. These data can be used to select patients with chronic spinal pain who can demonstrate the maximum response to antidepressant treatment (Fouquet B., 1997).

Another clinical study compared the effects of doxepin and desipramine at doses of 188 mg / day and 173 mg / day, respectively, in 36 volunteers with chronic spinal pain and affective or dysthymic disorders. Treatment with both antidepressants was associated with a significant reduction in depression symptoms (70%). Pain intensity also decreased in both groups (response in 50% of patients). At the same time, the severity of pain decreased more intensively in the doxepin group. The level of β-endorphin in the cerebrospinal fluid did not change during treatment (Ward N., 1984). In another randomized trial, doxepin demonstrated the ability to induce adverse events from the autonomic nervous system (anticholinergic effects) and sedation (Amsterdam J.D., 1982).

Hameroff S.R. et al. published the results of a 6-week, randomized, double-blind clinical study evaluating the efficacy of doxepin in the treatment of chronic back and neck pain in 36 patients. Thus, antidepressant therapy led to a significant improvement in the symptomatic picture of depression ( Hamilton depression scores), severity of pain ( Global Assessment Scale scores), reducing the negative effect of pain on the activity of patients, improving sleep and muscle tension. Some of these positive changes were noted as early as 1 week after the start of admission. The dose of doxepin in the study was 200 mg / day, and the concentration of doxepin and its metabolite nor-doxepin in the blood plasma of the volunteers averaged 80 ng / ml.

Doxepin therapy was not associated with adverse events. There were no significant changes in the concentrations of β-endorphin and / or enkephalin in the cerebrospinal fluid (Hameroff S.R., 1984). Thus, doxepin can be considered as a potential adjuvant analgesic in the treatment of patients with chronic pain associated with depression (Aronoff G.M., Evans W.O., 1982).

Vorobieva O.V. and Akarachkova E.S. presented the results of a clinical observation of 20 patients with chronic dorsalgia who received the antidepressant tianeptine (Coaxil®) at a dose of 12.5 mg 3 times a day. According to the results of psychometric testing, 90% of patients showed signs of depression. Tianeptine therapy for 6 weeks was associated with a reduction in depression, muscle dysfunction, and pain. There was also a positive trend in autonomic dysfunction, sleep disorders and quality of life. Thus, the authors noted that tianeptine is a highly effective and safe method of treating depression against the background of chronic back pain and has a positive effect on pain syndrome (Vorobeva O.V., Akarachkova E.S., 2004).

One open, comparative study conducted in Russia assessed the efficacy and tolerability of the prolonged-release drug venlafaxine (Velaxin) at a dose of 75 mg / day for 8 weeks in the treatment of 48 patients with subacute or chronic pain associated with spondylogenic dorsopathy. The intensity of the analgesic action of the antidepressant was assessed based on the mean scores on the scales YOUR and VPS 34, restrictions on daily activity according to the questionnaire Modified Pain Disability Questionnaire (mPDQ) and also measured scores for anxiety and depression.

For the treatment of pain syndromes, antidepressants have been used, which primarily include the tricyclic antidepressant amitriptyline. Unfortunately, its use for pain syndromes is limited due to side effects. In this regard, the attention of specialists was attracted to new generations of drugs, in particular venlafaxine, which has a more favorable safety profile. This review summarizes the clinical and pathophysiological data regarding the use of this drug for various pain syndromes.

Antidepressant use for chronic pain

Major depressive disorder and generalized anxiety disorder are often associated with chronic pain syndromes. Examples of such syndromes include back pain, headache, gastrointestinal pain, and joint pain. In addition, a number of pain syndromes not associated with depressive and anxiety disorders (diabetic and postherpetic neuralgia, cancer pain, fibromyalgia) pose great difficulties in treatment.

The association between major depressive disorder and generalized anxiety disorder with painful and non-painful physical symptoms has been noted by clinicians for a long time. One international study showed that at the initial examination, 69% of patients with major depressive disorder had only somatic complaints and did not have a single psychopathological symptom. Another study showed that an increase in the number of physical symptoms increases the likelihood of a patient having a depressive or anxiety disorder.

Besides major depressive and generalized anxiety disorder, pain is one of the main complaints in fibromyalgia, irritable bowel syndrome, chronic pelvic pain, migraine, vulvodynia, interstitial cystitis, temporomandibular joint symptom. Some researchers suggest that disorders of the affective spectrum such as major depressive disorder, generalized anxiety disorder, social phobias, fibromyalgia, irritable bowel syndrome, and migraine may have a common genetic predisposition.

The exact causal relationship between chronic pain and depression remains unknown, but the following hypotheses have been put forward: depression precedes the development of chronic pain; depression is the result of chronic pain; episodes of depression occurring before the onset of chronic pain predispose to the development of depressive episodes after the onset of chronic pain; psychological factors such as maladaptive coping strategies contribute to the formation of an interaction between depression and chronic pain; depression and pain have similar characteristics, but are different disorders.

Numerous studies have shown that dual-acting antidepressants (selective serotonin reuptake inhibitors - SSRIs and norepinephrine) used to treat depression may also be effective in treating chronic pain. Dual-acting drugs such as tricyclic antidepressants (amitriptyline, clomipramine) and venlafaxine, or a combination of antidepressants with serotonergic and noradrenergic effects, have been shown to be more effective than antidepressants that act primarily on one neurotransmitter system.

Thus, fluoxetine (due to a preferential increase in serotonin) and desipramine (due to a predominant increase in norepinephrine) cause a faster and better therapeutic effect than monotherapy with desipramine. Another study showed that clomipramine (a dual-acting antidepressant) induces remission of depression in 57-60% of cases compared with the group of patients who took monoaminergic antidepressants - citalopram or paroxetine (remission in only 22-28% of patients). A meta-analysis of 25 double-blind studies revealed a higher efficacy of dual-acting antidepressants (clomipramine and amitriptyline) compared to tricyclic monoaminergic antidepressants (imipramine, desipramine) and selective serotonin inhibitors (fluoxetine, fluvoxamine, paroxramine), citalopramine.

An analysis of 8 clinical studies examining the efficacy of venlafaxine compared with selective serotonin inhibitors (paroxetine, fluoxetine, fluvoxamine) found that the remission rate after 8 weeks of drug intake was significantly higher in the group of patients receiving venlafaxine (45%) compared with those receiving who received selective serotonin reuptake inhibitors (35%) or placebo (25%).

The double effect on serotonin and norepinephrine is more pronounced in the treatment of chronic pain. Both serotonin and norepinephrine are involved in pain control via descending pain pathways. This explains why most researchers are finding the benefit of dual-acting antidepressants for treating chronic pain. The exact mechanism of action by which antidepressants produce analgesic effects remains unknown. However, antidepressants with a dual mechanism of action have a longer lasting analgesic effect than antidepressants, which act on only one of the aminergic systems.

Venlafaxine treatment

The use of tricyclic antidepressants for pain syndromes is limited due to numerous side effects, such as sedation, cognitive impairment, orthostatic hypotension, cardiac arrhythmias, dry mouth, constipation, which is associated with the affinity of tricyclic antidepressants for muscarinic, cholinergic, histamine and a1-adrenergic receptors ...

The drug venlafaxine, like tricyclic antidepressants, inhibits the reuptake of serotonin and norepinephrine, but has a more favorable safety profile, since it has no affinity for muscarinic, cholinergic, histamine and a1-adrenergic receptors. Venlafaxine has been shown to be effective and safe in several animal models, healthy volunteers, and patients with a variety of pain syndromes.

In a study by E. Lang et al. the use of venlafaxine has led to a decrease in the manifestations of hyperalgesia caused by surgical compression of the sciatic nerve. An effect was found both with prophylactic venlafaxine (before surgery) and with venlafaxine after surgery, i.e. after the development of neuropathic damage. In another study, a single dose of venlafaxine had no effect in healthy rats, while an increase in pain threshold was noted in models with chronic sciatic nerve compression. Studies with multiple doses of venlafaxine have been shown to be effective in a group of healthy rats and rats with chronic sciatic nerve compression. These effects were suppressed by a-methyl-p-tyrosine (an inhibitor of norepinephrine synthesis) and parachlorophenylalanine (an inhibitor of serotonin synthesis), but not by naloxone (an opioid antagonist), which indicates a specific mechanism of action of venlafaxine that is not associated with opioid neurotransmitter systems.

In a study on rats with vincristine-induced neuropathy, the integrative supraspinal pain response was assessed - vocalization in response to paw pressure, and the spinal C-fiber nociceptive evoked reflex. The results showed that venlafaxine induces a dose-dependent increase in the vocalization threshold on the paw pressure test and a moderate but dose-dependent suppression of the C-fiber evoked reflex. Hence, both supraspinal and spinal mechanisms may be involved in the antihyperalgesic effect of venlafaxine. In rat models with unilateral mononeuropathy, venlafaxine in combination with tramadol has been shown to increase the pain threshold compared to venlafaxine alone, tramadol alone, or placebo. These facts may indicate that venlafaxine may enhance the antinociceptive effects of opioids.

In another model of studying the effects of venlafaxine, a dose-dependent antinociceptive effect was demonstrated in mice after intraperitoneal administration of the drug. Indirect receptor analysis showed that venlafaxine affected the k-opioid and o-opioid receptor subtypes, as well as a2-adrenergic receptors. This study points to the possible involvement of opioid systems with venlafaxine.

The analgesic effect of venlafaxine in humans was studied in a group of 16 healthy volunteers in a randomized, double-blind, crossover study. Subjects receiving venlafaxine showed significant increases in pain thresholds after single electrical stimulation. During the cold test and the pain pressor test, no significant changes in pain thresholds were obtained.

There have also been numerous studies on the efficacy of venlafaxine in patients with chronic pain syndromes. In addition, a 1-year open-label study was conducted to investigate the efficacy and safety of venlafaxine in 197 patients diagnosed with major depressive disorder with or without pain. Treatment with tricyclic antidepressants as well as SSRIs in these patients was unsuccessful. The severity of depression was assessed using the Hamilton scale, and the intensity of pain was assessed by the visual analogue scale (VAS). The patients took the long-acting form of the drug, venlafaxine-HR. The venlafaxine-XR dose was titrated every 3 days with a median dose of 225 mg once daily. The use of additional antidepressants and opioid-opioid analgesics was not permitted, although cyclooxygenase-2 inhibitors were permitted for short-term pain relief. The following types of pain were observed in patients in the depression + pain group: back pain, postoperative hip pain, osteoarthritis, fibromyalgia, complex regional pain syndrome, regional myofascial pain, carpal tunnel syndrome, migraine, and pain associated with polyneuropathy. After the use of venlafaxine, there was a significant decrease in the number of points on the Hamilton Depression Scale both in patients with depression and in the "depression + pain" group of patients. In addition, the patients in the "depression + pain" group showed a significant decrease in the level of pain according to the VAS. 11 patients were excluded from the study due to side effects such as nausea, anxiety, agitation, sexual dysfunction.

A retrospective analysis of 5 double-blind, placebo-controlled, randomized trials to assess the effect of venlafaxine on various symptoms, including pain, was performed in patients with generalized anxiety disorder without depression. The use of long-acting venlafaxine resulted in a significantly greater reduction in pain in patients with generalized anxiety disorder after 8 weeks and after 6 months of treatment compared with placebo.

Neuropathic pain is associated with damage to the nervous system itself at the central (post-stroke, phantom pain, trigeminal neuralgia) and peripheral levels (diabetic polyneuropathy, postherpetic neuralgia). Unlike nociceptive pain, neuropathic pain is difficult to treat with analgesics (including opioids) and nonsteroidal anti-inflammatory drugs (NSAIDs). The first-line drugs for most neuropathic pain syndromes are tricyclic antidepressants (with the exception of trigeminal neuralgia, in which carbamazepine is the first-line drug). Unfortunately, frequent side effects limit the widespread use of tricyclic antidepressants.

The efficacy of venlafaxine has been studied in painful diabetic neuropathy, polyneuropathy, and neuropathic pain due to breast cancer.

The venlafaxine study for painful diabetic neuropathy randomized 244 patients without depression to receive venlafaxine-XR 75 mg / day (81 patients), 150-225 mg / day (82 patients), or placebo (81 patients) for up to 6 weeks ... Patients included in the study experienced daily pain of moderate or severe intensity (according to VAS) for at least 3 months prior to the study. Patients who received venlafaxine-XR at a dose of 150-225 mg / day demonstrated a significantly more pronounced decrease in pain intensity by 3-6 weeks of treatment compared with placebo and by 5-6 weeks of treatment compared with patients who received 75 mg / day The most pronounced improvement was noted at the 6th week of treatment. This fact indicates that a 6-week course of treatment is required to adequately assess the analgesic efficacy of venlafaxine.

The most common side effect in this study was nausea, which occurred in 5% of patients in the placebo group, 22% in the 75 mg venlafaxine group, and 10% of patients taking venlafaxine 150-225 mg. Withdrawal from the study due to side effects was 4%, 7%, and 10%, respectively, in the placebo group given 75 mg and 150–250 mg venlafaxine.

A randomized, controlled, double-blind, triple-crossover study evaluated the efficacy of venlafaxine, imipramine, and placebo in patients with painful polyneuropathy lasting at least 6 months. The dose of venlafaxine was titrated up to 112.5 mg 2 times a day, imipramine up to 75 mg 2 times a day. Evaluation of the effectiveness was carried out after 4 weeks of treatment. Patients who received venlafaxine showed significant improvement over placebo (p<0,001), достоверных различий в эффективности между группами венлафаксина и имипрамина не было. Частота таких побочных явлений, как сухость во рту и повышенная потливость встречались чаще в группе имипрамина, а усталость чаще встречалась в группе венлафаксина.

In a 10-week, randomized, double-blind, placebo-controlled, crossover study in patients with neuropathic pain after breast cancer treatment, venlafaxine was used at a dose of 75 mg / day. There was a significant reduction in pain intensity in the venlafaxine group compared with placebo on a verbal rating scale.

A number of open studies and reported cases of venlafaxine indicate the effectiveness of this drug for various types of pain. Participation in a prospective, placebo-controlled, double-blind study enrolled 150 patients with migraine with and without aura (duration of the disease from 1 to 4 years). The efficacy of venlafaxine, fluoxetine, sertraline and paroxetine in the prophylactic treatment of migraine was compared. The treatment lasted 3 months or more. A significant number of patients taking venlafaxine reported improvement in their condition compared to placebo and other drugs. Treatment was discontinued early due to nonspecific side effects in 2 patients from the venlafaxine group.

In one of the headache centers, a retrospective analysis of data from 97 patients with chronic headache (chronic tension headache, migraine with and without aura, a combination of migraine and tension headache) with a duration of at least 2 years who received treatment with venlafaxine at a dose 75 mg 2 times a day. A decrease in the number of attacks was noted by 37% of the patients included in the analysis, 45% did not find any changes, and in 18% of patients the number of headache attacks increased.

A retrospective open-label study examining the effect of venlafaxine-XR in the treatment of migraine and chronic tension headache showed a significant reduction in the number of headache attacks per month at the last visit compared with the beginning of treatment in both groups. In the migraine group, the average number of headache attacks per month decreased from 16.1 to 11.1. In the tension headache group, the average number of headache episodes decreased from 24 to 15.2.

N.V. Latysheva and E.G. Filatova investigated the effect of venlafaxine (Pliva, velafax) in chronic daily headache. The study involved 69 patients with chronic daily headache and 30 patients with episodic migraine, as well as 15 control participants. Research has shown that venlafaxine is an effective and safe treatment for headache attacks. Prophylactic treatment with velafax leads to a pronounced clinical relief of the patient's condition, a reduction in the use of analgesics. According to the authors, the positive effect of the drug may be associated with a decrease in the severity of allodynia, which was confirmed by the normalization of the threshold of the painful R3 component of the blink reflex, which reflects the functional state of the stem structures and the spinal nucleus of the trigeminal nerve involved in maintaining central sensitization.

Venlafaxine is also effective in the treatment of fibromyalgia. In a study by M. Dwight et al. in 60% of patients diagnosed with fibromyalgia, concomitant major depressive and generalized anxiety disorders were found. The median dose of venlafaxine was 167 mg / day (ranged from 37.5 to 300 mg / day). The results were assessed on the Hamilton Anxiety and Depression Scale, McGill pain questionnaire and VAS. As a result of the treatment, there was a significant improvement in the studied indicators of effectiveness. The most common side effects were constipation, dry mouth, weakness, insomnia and nausea.

Surgery for breast cancer often results in postoperative neuropathic pain. A randomized, double-blind study was conducted in which 80 women underwent partial or total mastectomy for breast cancer. The authors evaluated the effect of venlafaxine on postmastectomy pain syndrome. Treatment began the night before surgery and continued for 2 weeks after surgery. Patients received 75 mg / day venlafaxine or placebo. The administration of venlafaxine significantly reduced the incidence of postmastectomy pain in the chest (28.7 vs 8.7%; p = 0.002), in the armpit (26.5 vs 10%; p = 0.01) and in the arm (22.5% vs 8.7%; p = 0.002) compared with placebo. There were no significant differences in terms of postoperative analgesia, edema, phantom pain, or sensory changes.

Conclusion

Nociceptive impulse transmission involves the involvement of the ascending afferent somatosensory, spinothalamic pathways that pass through the plate of the posterior dorsal horn of the spinal cord. These nociceptive impulses are modulated through the activation of descending inhibitory pathways originating from the periaqueductal gray matter of the brain. Both serotonin and norepinephrine are involved in downstream inhibitory mechanisms and contribute to changes in neurochemical transmission in the spinal cord. These changes may facilitate the release of substance P, a neurotransmitter that enhances nociceptive transmission, as well as influence the effects of endogenous endorphins. The results of the above studies support the hypothesis that the analgesic effect of antidepressants is a result of the intrinsic analgesic properties of antidepressant molecules, and not the indirect effect of antidepressants on pain through a decrease in depression or general sedation.

Venlafaxine is a serotonin and norepinephrine reuptake inhibitor. Through their mechanisms, the relief of neuropathic pain is provided. Venlafaxine does not bind to muscarinic-cholinergic, histamine and a1-adrenergic receptors, due to which, when administered, it is possible to avoid many undesirable effects that develop with the use of tricyclic antidepressants.

Clinical studies indicate that venlafaxine is a good treatment for patients with chronic pain syndromes associated with major depressive disorder or generalized anxiety disorder. This is important because more than 40% of patients with major depressive disorder have at least one symptom of pain (headache, back pain, joint pain, limb pain, or gastrointestinal pain). The use of venlafaxine can reduce both the level of depression and the severity of pain.

Venlafaxine-XR is indicated for major depressive, generalized anxiety, and social anxiety disorders at doses ranging from 75 to 225 mg / day. For some patients, low doses of venlafaxine may be effective. Treatment can be started at 37.5 mg / day with a gradual increase in dose over 4-7 days to 75 mg / day.

Studies have shown that the analgesic effect of venlafaxine is due to mechanisms not associated with depression. Consequently, venlafaxine has also been shown to be effective in pain syndromes unrelated to depression and anxiety. Although indications for the administration of venlafaxine for chronic pain have not yet been included in the instructions for use, the available data indicate that a dose of 75-225 mg / day is effective for most pain syndromes. Data from randomized, controlled trials have shown that pain relief occurs within 1–2 weeks after starting treatment. However, some patients require 6 weeks of treatment for the analgesic effect of venlafaxine to become evident.

The most common side effect of venlafaxine found in pain management is nausea. Other side effects include agitation, anorexia, constipation, dizziness, dry mouth, headache, insomnia, drowsiness, sexual dysfunction, and vomiting.

There is currently no indication for venlafaxine for the "treatment of chronic pain". Further research is needed to clarify the efficacy, dosing, and safety of venlafaxine in a variety of pain syndromes.

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Willis W.D., Westlund K.N. Neuroanatomy of the pain system and of the pathways that modulate pain. J Clin Neurophysiol 1997; 14: 2-31.
Wyeth Pharmaceuticals. Effexor XR (venlafaxine) package insert Philadelphia, PA, 2003.

Articles

Doctor

J. Levin, E. Demina, L. Dobrovolskaya, A. Ostroumova

ETC. Kamchatnov

Russian medical journal

Kamchatnov P.R., Radysh B.B., Kutenev A.V., Kazakov A.Yu.

Russian medical journal

Mosolov S.N.

Russian medical journal

The ability to experience pain is the most important defense mechanism that ensures the survival, learning and adaptation of living organisms to changing environmental conditions. Pain not only informs about tissue damage, but also triggers reflex and behavioral responses, allowing you to minimize the damaging effect. The definition of the International Association for the Study of Pain is as follows: "Pain is an unpleasant sensory and emotional experience associated with existing or possible tissue damage or described in terms of such damage."

In the case of real tissue damage, acute (epicritical) pain and hypersensitivity (hyperalgesia) develop, which are of a protective nature and normally completely regress after healing, which is biologically justified. In some cases, the pain regresses until the tissue heals (for example, with hematomas, cuts, abrasions), such pains are called transient. Pain that is associated with the activation of pain receptors (nociceptors) after tissue damage and corresponds to the degree of tissue damage and the duration of the action of damaging factors, and then completely regresses after healing, is called nociceptive or acute pain.

In contrast to acute pain, unpleasant sensory sensations may persist or appear after healing, in this case not carrying a protective function, but causing suffering. The appearance of such pain is usually associated with damage to the peripheral or central nervous system, and they are chronic. Chronic pain is considered as pain that has "broken away" from the underlying disease and acquired a "superorganic" character. The International Pain Association defines chronic pain as "pain that continues beyond the normal healing period." There are various approaches to assessing the duration of chronic pain. According to experts from the International Association for the Study of Pain, chronic pain should be discussed in cases where it has existed for at least 3 months. But the main difference between chronic pain and acute pain is not the time factor, but qualitatively different neurophysiological, psychophysiological and clinical relationships.

In the body, two opposite systems exist in parallel and interact - nociceptive (conductive pain) and antinociceptive (suppressive conduction and perception of pain). An imbalance between these two systems towards activation of the nociceptive system or suppression of the activity of the antinociceptive system and leads to the development of chronic pain syndromes.

Painful afferentation is directed to the brain along the spinothalamic, spinoreticular, spinomesencephalic pathways. Inside the spinothalamic tract, the lateral neospinothalamic and medial paleospinothalamic pathways are isolated. The neospinothalamic pathway conducts nerve impulses at a high speed, ends in the ventrolateral nuclear complex of the thalamus, from where, after switching in the neurons of this nucleus, impulses enter the somatosensory cortex. The spinoreticular and spinomesencephalic pathways are projected into the reticular formation, the periaqueductal gray matter, the hypothalamus and into the medial and intralaminar thalamic nuclei, connecting further with the structures of the limbic system and diffusely spreading through the brain.

It is also assumed that painful afferentation can be carried out along other ascending pathways. These pathways are grouped into two systems - the lateral one, which includes the neospinothalamic, posterolateral, spinocervical pathways, and the medial, consisting of the paleospinothalamic, spinoreticular, spinomesencephalic pathways - multisynaptic propriospinal ascending systems. The lateral system provides fast conduction of painful impulses with its clear localization and assessment of the nature and duration of irritation. Conduction through the medial multisynaptic system occurs at a much slower rate, but at the same time there is a wide involvement of various brain structures associated with motivational-affective and vegetative-humoral accompaniment of pain. These two different systems, carrying out painful afferentation, together with the anatomical and functional features of the peripheral part of the nociceptive system, probably underlie the provision of the so-called epicritic and protopathic types of pain. Considering that addiction to the first type of pain is possible, that is, the elimination of pain during repeated pain irritations, and the second (protopathic) component only increases, we can assume their unequal participation in the formation of acute and chronic pain. This is also evidenced by the different inclusion of the emotional-affective and vegetative-somatic components in the formation of general reactions of the body in acute and chronic pain.

The main hypothesis for the occurrence of chronic pain syndrome is considered to be the central modification of the incoming sensory impulse. The theory of central sensory impulse modification suggests the presence of several synapses along the path of sensory stimulus to the cerebral cortex, the most important of which are the posterior horns of the spinal cord, stem structures, the thalamus, and the cortex itself. According to the theory of gate control, at each of the above levels, the impulse is stimulated or inhibited by collateral axons, as well as the ascending or descending pathways of the nociceptive and antinociceptive systems.

The most important neurotransmitters that act at the level of the dorsal horns of the spinal cord are substance P (inducing pain impulse) and endogenous opioids such as methenkephalin (inhibiting pain impulse). An inhibitory effect from the corticospinal tract is also possible due to the neurotransmitter glycine. This may be the basis for the analgesic action of baclofen in neuropathic pain syndrome. At the level of the posterior horns of the spinal cord, the most potent of all known groups of painkillers, narcotic analgesics, act. The effectiveness of narcotic analgesics (similar in structure to endogenous opioids) is highest in the acute stage of pain syndrome development, when the afferent sensory influx has not yet overcome the spinal level of nociceptive impulse transmission. Opiates are ineffective for chronic pain.

At the level of the brain stem, the inhibitory effect is serotonergic and noradrenergic structures. Moderate short-term deficiency of serotonergic structures leads to the development of anxiety and pain; with long-term serotonin deficiency, depression can develop. This explains the pronounced analgesic effect of low doses of antidepressants in chronic pain syndrome, even in the absence of antidepressant action. However, the greater efficacy of tricyclic antidepressants in comparison with serotonin reuptake inhibitors may indicate a greater role of noradrenergic structures in the formation of chronic pain.

The next synaptic level includes the thalamus, the limbic system, and the adjacent subcortical and cortical structures of the brain. This is where the subjective assessment of the pain sensation takes place, which was mentioned above. Neurotransmitters that inhibit the transmission of nociceptive information from subcortical structures to the cortex are poorly understood; it is known that one of them is γ-aminobutyric acid (GABA). It is assumed that it is at this level that anticonvulsants have an analgesic effect.

Chronic pain develops when the last cortical-cortical synaptic level is sensitized by afferent sensory influx. It is believed that this transformation occurs within 6 months, which gives the practitioner a "therapeutic window" for the appointment of specific analgesic therapy.

The main feature of chronic pain syndromes is their high placebo dependence. This is due to a high degree of subjectivity in the perception of pain, depending on gender, age, cultural national traditions, upbringing and, finally, the emotional state. Precisely because of the high placebo dependence, the treatment of chronic pain is an extremely difficult task for practicing doctors, primarily because it requires them to be as attentive to the patient as possible, sincere sympathy, the establishment of trusting relationships and mutual sympathy - in general, everything that is implied under the term "placebo". If all this is impossible for some reason, it is better to immediately refer the patient to another specialist, otherwise, at best, no positive dynamics will be observed against the background of the therapy, and at worst, you may encounter the "nocebo" effect (psychologically determined deterioration of the condition). But the establishment of empathy between the doctor and the patient cannot guarantee the patient's recovery. The main problem with the placebo effect is its short duration - the analgesic effect of the placebo will not last indefinitely and after a few weeks of taking the new drug, the pain will return to its original level, even if the dose is increased. This process is not due to the development of addiction or tolerance to the drug, but to the depletion of the psycho-physiological mechanisms of autoanalgesia that underlie the placebo effect. Thus, the selection of adequate therapy for chronic pain syndromes can take many months: after all, in order to make sure that the drug is selected correctly, it will take several weeks, during which in most cases the placebo effect is depleted.

Chronic pain syndromes are observed in various diseases of the nervous system and can develop through common pathophysiological mechanisms. In addition, one mechanism may be involved in the development of several symptoms, and the same symptom in different patients may be associated with different pathophysiological mechanisms. It should also be noted that the mechanisms underlying a particular symptom may change during the course of the disease. Thus, in patients with chronic pain, it is difficult to determine the mechanisms of pain syndrome development based on the etiological factors that caused the underlying disease, or on the basis of the localization and severity of symptoms. However, without identifying pathophysiological mechanisms, it is impossible to develop an optimal treatment strategy for patients with pain. Such identification, in turn, is based on knowledge of clinical manifestations and analysis of their relationship with various pathophysiological mechanisms that can be influenced by the selection of pathogenetically based therapy.

Based on the described neurophysiological, neurochemical, psychological components of the nociceptive and antinociceptive systems, the main therapeutic approaches to the treatment of chronic pain are formulated as follows.

Qualitative and quantitative assessment of pain. Identification and assessment of accompanying pain sensory, motor, autonomic, somatic and mental disorders.
Early initiation of symptomatic analgesic therapy in order to prevent the development and chronicity of pain.
Clarification of the etiology and localization of the lesion, impact on the source and cause of pain: 1) elimination of the source of pain and restoration of damaged tissues; 2) the effect on the peripheral components of pain - somatic (elimination of inflammation, edema, etc.) and neurochemical stimulants of pain receptors; The most pronounced effect in this case are drugs that affect the synthesis of prostaglandins (non-narcotic analgesics, paracetamol, non-steroidal anti-inflammatory drugs) and provide a decrease in the concentration of substance P in the terminals of the fibers that conduct pain impulses (paprika preparations for external use - capsaicin, capsin, etc.) ...
Impact on the conduct of pain afferentation: inhibition of pain impulses along peripheral nerves and in the dorsal root node (administration of local anesthetics, alcoholic and phenolic denervation, transection of peripheral nerves, gangliectomy); surgical stereotaxic destruction of the corresponding ascending pathways and nuclei of the thalamus, as well as electrical stimulation of the posterior columns and various cerebral structures through chronically implanted electrodes.
Determination of the mechanisms of pain. Impact on the processes occurring in the posterior horns. In addition to applications of capsicum preparations that reduce the concentration of substance P in the posterior horns, a number of other methods of therapy are used:
1. the introduction of opiates systemically or locally (epidural or subdural), which enhances enkephalinergic inhibition of pain impulses;
2. electrical stimulation and other methods of physical stimulation (physiotherapy, acupuncture, percutaneous electroneurostimulation, massage, etc.), causing inhibition of nociceptive neurons of the dorsal horn by activating enkephalinergic neurons;
3. the use of drugs that affect GABAergic structures to reduce the excitability of neurons in the posterior horn (baclofen, sirdalud, gabapentin);
4. the use of anticonvulsants (carbamazepine, diphenin, lamotrigine, valproates and benzodiazepines) that inhibit the conduction of nerve impulses along sensory nerves and have an agonistic effect on the GABAergic receptors of the neurons of the posterior horns and cells of the nucleus of the spinal pathway of the trigeminal nerve. These drugs are especially effective for neuralgia;
5. the use of drugs agonists α 2 -adrenergic receptors - clonidine, etc.;
6. the use of serotonin reuptake blockers, which increase the concentration of this neurotransmitter in the nuclei of the reticular formation of the brain stem, from which descending inhibitory pathways emanate that affect the interneurons of the posterior horn (Prozac, fluoxetine, amitriptyline);
7. the use of a fundamentally new class of drugs - SNEPCO (Selective NEuronal Potassium Channel Opener - selective neuronal potassium channel openers), which affect the sensitization of dorsal horn neurons by stabilizing the resting membrane potential and indirect antagonism of NMDA receptors (flupirtin, catadolone);
8. the use of NMDA receptor antagonists that "erase" pain memory (ketamine, dextromethorphan).
Impact on the perception of pain: the effect on the psychological (and at the same time on the neurochemical) components of pain with the use of psychotropic pharmacological drugs (antidepressants, tranquilizers, neuroleptics); the use of psychotherapeutic methods.
Impact on concomitant disorders: elimination of sympathetic activation in vegetatively supported chronic pain syndromes, for example, in erythromelalgia, complex regional pain syndrome, etc. (sympatholytic drugs, sympathectomy); restoration of the normal pattern of afferentation along the nerve fiber in case of neuropathic pain (metabolic therapy - B vitamins, L-carnitine; vascular therapy - antioxidants, antiplatelet agents, vasoactive drugs; etc.).

The increasingly popular concept of evidence-based medicine calls for the standardization of a clinical approach to chronic pain management based on the results of double-blind, randomized, placebo-controlled trials. However, at present, only a few studies on the effectiveness of drugs for chronic pain syndromes meet the above requirements. The spectrum of the proposed analgesic therapy for chronic pain syndromes has been increasing exponentially in recent years. The new drugs have significantly fewer side effects, however, in terms of the effectiveness of the analgesic effect, they do not exceed the traditionally used tricyclic antidepressants and anticonvulsants, while the cost of treatment with these drugs is much higher. A meta-analysis of literature data shows that the largest number of authors prefer tricyclic antidepressants, followed by dextromethorphan and carbamazepine, tramadol and levodopa, gabapentin and capsaicin proved to be less effective drugs, and, finally, in the last place were selective inhibitors of serotrionin reuptake and natrium reuptake. mexiletine. Great hopes are pinned on the new class of substances SNEPCO, which have shown high efficiency in the treatment of chronic musculoskeletal pain; their therapeutic potential for chronic neuropathic pain syndromes requires clarification.

These methods can be used, depending on the specific clinical situation, separately or, which happens more often with neurogenic pain, in combination. A separate aspect of the problem of pain is the tactics of managing patients. The experience available to date has proven the need for examination and treatment of patients with chronic pain in specialized inpatient or outpatient centers. Due to the wide variety of types and mechanisms of pain, even with a similar underlying disease, there really is a need to participate in their diagnosis and treatment of various specialists - neurologists, anesthesiologists, psychologists, clinical electrophysiologists, physiotherapists, etc. Only an integrated interdisciplinary approach to the study of theoretical and clinical problems of pain can solve the urgent task of our time - ridding people of suffering associated with pain.

A. N. Barinov, Candidate of Medical Sciences
MMA them. I.M.Sechenova, Moscow

8720 0

Amitriptyline (Amitriptyline)

Tablets, dragees, capsules, solution for intravenous and intramuscular administration, solution for intramuscular administration, film-coated tablets

Pharmachologic effect:

Anti-depressant agent (tricyclic antidepressant). It also has some analgesic (central genesis), H2-histamine blocking and antiserotonin effects, helps to eliminate bedwetting and reduces appetite. It has a strong peripheral and central anticholinergic effect due to a high affinity for m-cholinergic receptors; a strong sedative effect associated with an affinity for H1-histamine receptors, and alpha-adrenergic blocking action.

It has the properties of an antiarrhythmic drug of subgroup Ia, like quinidine in therapeutic doses, it slows down ventricular conduction (in case of an overdose, it can cause severe intraventricular blockade).

The mechanism of antidepressant action is associated with an increase in the concentration of norepinephrine in the synapses and / or serotonin in the central nervous system (a decrease in their reabsorption). The accumulation of these neurotransmitters occurs as a result of inhibition of their reuptake by the membranes of presynaptic neurons. With prolonged use, it reduces the functional activity of beta-adrenergic and serotonin receptors in the brain, normalizes adrenergic and serotonergic transmission, restores the balance of these systems, disturbed in depressive conditions.

In anxiety-depressive states, it reduces anxiety, agitation and depressive manifestations.

The mechanism of antiulcer action is due to the ability to block H2-histamine receptors in the parietal cells of the stomach, as well as to have a sedative and m-anticholinergic effect (in case of gastric ulcer and duodenal ulcer, it relieves pain, helps to accelerate ulcer healing).

Efficacy for bedwetting is apparently due to anticholinergic activity, leading to an increase in the ability of the bladder to stretch, direct beta-adrenergic stimulation, the activity of alpha-adrenergic agonists, accompanied by an increase in sphincter tone, and central blockade of serotonin uptake.

The central analgesic effect may be associated with changes in the concentration of monoamines in the central nervous system, especially serotonin, and the effect on the endogenous opioid systems.

The mechanism of action for bulimia nervosa is unclear (may be similar to that for depression). A clear effect of the drug has been shown in patients with bulimia, both without depression, and in its presence, while a decrease in bulimia can be observed without a concomitant weakening of the depression itself.

During general anesthesia, it lowers blood pressure and body temperature. Does not inhibit

MAO. The antidepressant effect develops within 2-3 weeks after the start of use.

Indications for use

Depression (especially with anxiety, agitation and sleep disorders, including in childhood, endogenous, involutional, reactive, neurotic, medicinal, with organic brain damage, alcohol withdrawal), schizophrenic psychoses, mixed emotional disorders, behavioral disorders (activity and attention), nocturnal enuresis (except for patients with bladder hypotension), bulimia nervosa, chronic pain syndrome (chronic pain in cancer patients, migraine, rheumatic diseases, atypical pain in the face, postherpetic neuralgia, post-traumatic neuropathy, diabetic, etc. peripheral neuropathy), headache, migraine (prevention), gastric ulcer and 12 duodenal ulcer.

Venlafaxine (Venlafaxine)

tablets, sustained release capsules, modified release capsules

pharmachologic effect

Antidepressant. Venlafaxine and its main metabolite O-desmethylvenlafaxine are potent inhibitors of serotonin and norepinephrine reuptake and weak dopamine reuptake inhibitors.

It is believed that the mechanism of antidepressant action is associated with the ability of the drug to enhance the transmission of nerve impulses to the central nervous system. In terms of inhibition of serotonin reuptake, venlafaxine is inferior to selective serotonin reuptake inhibitors.

Indications for use

Depression (treatment, relapse prevention).

Duloxetine (Duloxetine)

capsules

pharmachologic effect

Inhibits the reuptake of serotonin and noadrenaline, resulting in increased serotonergic and noradrenergic neurotransmission in the central nervous system. It weakly suppresses the uptake of dopamine, without having a significant affinity for histaminergic, dopaminergic, cholinergic and adrenergic receptors.

Duloxetine has a central mechanism for suppressing pain syndrome, which is primarily manifested by an increase in the threshold of pain sensitivity in pain syndrome of neuropathic etiology.

Indications for use

Depression, diabetic peripheral neuropathy (painful form).

Fluoxetine

tablets

pharmachologic effect

Antidepressant, selective serotonin reuptake inhibitor. Improves mood, reduces tension, anxiety and fear, eliminates dysphoria. Does not cause orthostatic hypotension, sedation, non-cardiotoxic. A persistent clinical effect occurs after 1-2 weeks of treatment

Indications for use

Depression, bulimic neurosis, obsessive-compulsive disorder, premenstrual dysphoria.

R.G. Esin, O.R. Esin, G. D. Akhmadeeva, G.V. Salikhova

According to the data of primary medical care requests, up to 80% of patients suffering from depression present exclusively somatic complaints, for example, headache, abdominal pain, muscle pain in the back, joints, and also in the neck. The question arises why painful somatic manifestations, so common in depression, have not been sufficiently reflected in guidelines for the diagnosis of this disease, although in many cases they may be the only signs of a depressive disorder?

One possible reason for this is that this kind of complaint is usually attributed to a medical condition, especially in therapeutic practice. In the event that complaints are limited to increased fatigue, loss of strength and painful somatic manifestations, and there are no clear affective and autonomic symptoms, many doctors are inclined to the often exhausting search for somatic pathology. In turn, the suspicion of the presence of a depressive or anxiety disorder in a patient usually arises on the condition that his complaints are predominantly psychological or emotional in nature. Another common mistake is that the goal of treating depressed patients is to simply improve their condition rather than achieve remission. Currently, the recommended standard of care for patients with depression is the complete elimination of all symptoms: not only emotional, autonomic, but also painful somatic manifestations of this disease.

Antidepressants are the fastest growing group of psychotropic drugs. It is enough to cite some figures. Thus, over the past 15 years, 11 innovative antidepressants have been registered, including venlafaxine and duloxetine over the past two years.

Currently, at least 10 different classes of antidepressants have been identified, based on the monoamine theory. They are grouped according to their chemical structure - tricyclic antidepressants (amitriptyline, melipramine, clomipramine, etc.), specific or selective mechanism of action - MAO inhibitors (MAOI - phenelzine), reversible MAO type A inhibitors (moclobemide, pirlindole), selective serotonin uptake (fluvoxamine, fluoxetine, paroxetine, sertraline, citalopram, escitalopram), selective norepinephrine reuptake inhibitors (reboxetine), selective serotonin reuptake stimulants (tianeptine), norepinephrine reuptake inhibitors (norepinephrine reuptake inhibitors) (norepinephrine reuptake inhibitors) and dopamine (bupropion), noradrenergic and specific serotonergic (mirtazapine) and serotonin antagonists and reuptake inhibitors (nefazodone).

Numerous studies have shown that dual-acting antidepressants (selective serotonin and norepinephrine reuptake inhibitors) used to treat depression may also be effective in treating chronic pain, dual-acting drugs such as tricyclic antidepressants (amitriptyline, clomipramine) and venlafaxine, or a combination of antidepressants with serotonergic and noradrenergic effects, demonstrated greater effectiveness of treatment compared to antidepressants acting mainly on one neurotransmitter system.

The double effect (serotonergic and noradrenergic) leads to a more pronounced effect in the treatment of chronic pain. Both serotonin and norepinephrine are involved in pain control via descending pain pathways (ANCs). This explains the benefits of dual-acting antidepressants for treating chronic pain. The exact mechanism of action by which antidepressants produce analgesic effects remains unknown. However, antidepressants with a dual mechanism of action have a longer lasting analgesic effect than antidepressants, which act on only one of the monoaminergic systems.

Tricyclic antidepressants (amitriptyline) and norepinephrine and serotonin reuptake inhibitors (venlafaxine, duloxetine) have shown the greatest efficacy in the treatment of patients with chronic pain, and their analgesic effect is not believed to be directly related to their antidepressant properties.

The greatest preference for the treatment of pain syndromes is given to amitriptyline. However, it has a significant number of contraindications. The main mechanism of action of tricyclic antidepressants is to block the reuptake of norepinephrine and serotonin, which increases their amount in the synaptic cleft and enhances the effect on postsynaptic receptors. In addition, amitriptyline is able to block the sodium channels of peripheral nerve fibers and neuronal membranes, which makes it possible to suppress ectopic impulse generation and reduce neuronal excitability. The side effect of tricyclic antidepressants is due to the blockade of beta-adrenergic, antihistamine (HI) and acetylcholine receptors, which significantly limits their use, especially in elderly patients.

They also have unwanted interactions with opioid analgesics, MAO inhibitors, anticoagulants, antiarrhythmics, etc.). It has been shown that amitriptyline is highly effective in acute and chronic neuropathic pain syndromes, as well as chronic back pain, fibromyalgia. The effective dose of a drug for treating pain may be lower than the dose used to treat depression.

Venlafaxine has recently been widely used for the treatment of pain syndromes, both associated with depression and without it. Venlafaxine in small doses inhibits the reuptake of serotonin, and higher doses of norepinephrine. The main analgesic mechanism of venlafaxine is due to its interaction with alpha2- and beta2-adrenergic receptors. modulating the activity of the antinociceptive system (suture nuclei, periaqueductal gray matter, blue spot). To date, convincing data have been accumulated on the high clinical efficacy of venlafaxine in the treatment of a variety of pain syndromes. Clinical studies indicate that venlafaxine is a good treatment for patients with chronic pain syndromes associated with major depressive disorder or generalized anxiety disorder. This is important because more than 40% of patients with major depressive disorder have at least one symptom of pain (headache, back pain, joint pain, limb pain, or gastrointestinal pain). The use of venlafaxine can reduce both the level of depression and the severity of pain. Venlafaxine-XR is indicated for major depressive, generalized anxiety, and social anxiety disorders at doses ranging from 75 to 225 mg / day. For some patients, low doses of venlafaxine may be effective. Treatment can be started at 37.5 mg / day with a gradual increase in dose over 4-7 days to 75 mg / day.

Studies have shown that the analgesic effect of venlafaxine is due to mechanisms not associated with depression.In this regard, venlafaxine was effective in pain syndromes not associated with depression and anxiety. Although indications for the administration of venlafaxine for chronic pain have not yet been included in the instructions for use, the available data indicate that a dose of 75-225 mg / day is effective for most pain syndromes. Data from randomized, controlled trials have shown that pain relief occurs within 1–2 weeks. after starting treatment. Some patients require a 6-week course of treatment for venlafaxine to have a good analgesic effect.