What are the uses of venlafaxine 100 mg? What is the recommended dosage? What are the potential side effects? Get all the details in this comprehensive guide.

Venlafaxine 100 mg: Uses and Indications

Venlafaxine 100 mg is a prescription medication primarily used to treat major depressive disorder (MDD), generalized anxiety disorder (GAD), social anxiety disorder (SAD), and panic disorder (PD). It belongs to a class of antidepressants called serotonin-norepinephrine reuptake inhibitors (SNRIs), which work by increasing the availability of the neurotransmitters serotonin and norepinephrine in the brain.

Venlafaxine Dosage Guide

Usual Adult Dosage for Depression

For the treatment of major depressive disorder (MDD), the recommended starting dose of immediate-release venlafaxine is 37.5 mg orally twice a day or 25 mg orally three times a day. The maintenance dose is typically 75 to 150 mg orally per day, given in divided doses. The maximum recommended dose is 225 mg per day for moderately depressed outpatients and 375 mg per day for severely depressed inpatients.

For the extended-release formulation, the recommended starting dose is 75 mg orally once a day. The maintenance dose is typically 75 to 225 mg orally once a day, and the maximum recommended dose is 225 mg per day for moderately depressed outpatients and 375 mg per day for severely depressed inpatients.

Usual Adult Dosage for Generalized Anxiety Disorder (GAD)

For the treatment of generalized anxiety disorder (GAD), the recommended starting and maintenance dose of the extended-release formulation is 75 mg orally once a day. The maximum recommended dose is 225 mg per day.

Usual Adult Dosage for Social Anxiety Disorder (SAD)

For the treatment of social anxiety disorder (SAD), the recommended dose of the extended-release formulation is 75 mg orally once a day. There is no evidence that doses greater than 75 mg per day confer additional benefit.

Usual Adult Dosage for Panic Disorder (PD)

For the treatment of panic disorder (PD), the recommended starting dose of the extended-release formulation is 37.5 mg orally once a day for 7 days, followed by 75 mg orally once a day thereafter. The maintenance dose is typically 75 to 225 mg orally once a day, and the maximum recommended dose is 225 mg per day.

Dose Adjustments

Renal Dose Adjustments

For patients with mild to moderate renal dysfunction, the total daily dosage of the immediate-release formulation should be reduced by 25%. For the extended-release formulation, the total daily dose should be reduced by 25% to 50% for those with renal dysfunction (GFR 10 to 70 mL/min), by 50% for those with mild to moderate renal dysfunction (CrCl 30 to 89 mL/min), and by at least 50% for those with severe renal dysfunction (CrCl less than 30 mL/min).

Liver Dose Adjustments

For patients with mild to moderate liver dysfunction, the total daily dosage of the immediate-release formulation should be reduced by 50%. For the extended-release formulation, the total daily dose should be reduced by 50% for those with mild to moderate liver dysfunction (Child-Pugh 5 to 9) and by at least 50% for those with severe liver dysfunction (Child-Pugh 10 to 15) and hepatic cirrhosis.

Dose Adjustments When Switching Formulations

Patients may be switched from the immediate-release to the extended-release formulation by using the nearest equivalent daily dosage (e.g., from 37.5 mg immediate-release orally twice a day to 75 mg extended-release orally once a day).

Treatment Discontinuation

Abrupt discontinuation of venlafaxine should be avoided when possible. Patients should be monitored for adverse events, and treatment should be gradually reduced in 75 mg intervals every week. Providers should consider resuming the previously prescribed dose if patients develop intolerable symptoms following a dose reduction or treatment discontinuation, and subsequent dose reductions may continue at a more gradual rate.

Precautions and Contraindications

Patients should be monitored for the development of serotonin syndrome, which can be a life-threatening condition. Venlafaxine should not be used concurrently with monoamine oxidase inhibitors (MAOIs), and at least 14 days should elapse between discontinuing MAOI therapy and starting venlafaxine treatment. At least 7 days should elapse between stopping venlafaxine treatment and starting an MAOI.

Patients who require urgent treatment with linezolid or intravenous methylene blue during venlafaxine treatment should have the potential benefits weighed against the risks of serotonin syndrome, and venlafaxine should be stopped promptly.

Side Effects of Venlafaxine 100 mg

The most common side effects of venlafaxine 100 mg include nausea, dry mouth, constipation, loss of appetite, sweating, and dizziness. More serious side effects may include increased blood pressure, increased heart rate, and suicidal thoughts or behaviors, especially in younger patients. Patients should be closely monitored for these potential side effects, and healthcare providers should be notified immediately if any concerning symptoms arise.

In conclusion, venlafaxine 100 mg is a widely prescribed medication used to treat a variety of mental health conditions, including depression, anxiety, and panic disorder. It is important for patients to follow the recommended dosage guidelines and to be aware of potential side effects and precautions. Regular communication with healthcare providers is essential to ensure the safe and effective use of this medication.

Venlafaxine Dosage Guide + Max Dose, Adjustments

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Medically reviewed by Drugs.com. Last updated on Nov 12, 2021.

Applies to the following strengths: 25 mg; 50 mg; 75 mg; 100 mg; 37.5 mg; 150 mg; 225 mg; 112.5 mg

Usual Adult Dose for:

• Depression
• Generalized Anxiety Disorder
• Social Anxiety Disorder
• Panic Disorder

Additional dosage information:

• Renal Dose Adjustments
• Liver Dose Adjustments
• Dose Adjustments
• Precautions
• Dialysis
• Other Comments

Usual Adult Dose for Depression

Immediate release:

• Initial dose: 37.5 mg orally twice a day OR 25 mg orally 3 times a day
• Maintenance dose: 75 to 150 mg orally per day, given in divided doses
• Maximum dose:
• Moderately depressed outpatients: 225 mg/day
• Severely depressed inpatients: 375 mg/day

Extended release:

• Initial dose: 75 mg orally once a day
• Maintenance dose: 75 to 225 mg orally once a day
• Maximum dose:
• Moderately depressed outpatients: 225 mg/day
• Severely depressed inpatients: 375 mg/day

Comments:

• The daily dosage of immediate-release formulations may be divided into 2 or 3 doses/day.
• Healthcare providers should consider initial extended release doses of 37.5 mg orally once a day for 4 to 7 days (before increasing the dose to 75 mg/day) in patients who may require additional time to adjust to the drug.
• Doses may be increased in daily increments of up to 75 mg orally at intervals of no less than 4 days.
• Patients should be periodically reassessed for the continued need of maintenance treatment and for the appropriate dose of treatment.
• Use of doses exceeding 225 mg/day is limited.

Use: Treatment of major depressive disorder (MDD)

Usual Adult Dose for Generalized Anxiety Disorder

Extended release:

• Initial dose: 75 mg orally once a day
• Maintenance dose: 75 to 225 mg orally once a day
• Maximum dose: 225 mg/day

Comments:

• Healthcare providers should consider initial extended release doses of 37.5 mg orally once a day for 4 to 7 days (before increasing the dose to 75 mg/day) in patients who may require additional time to adjust to the drug.
• Doses may be increased in daily increments of up to 75 mg orally at intervals of no less than 4 days.

Use: Treatment of generalized anxiety disorder (GAD)

Usual Adult Dose for Social Anxiety Disorder

Extended release: 75 mg orally once a day

Comment: There is no evidence that doses greater than 75 mg/day confer additional benefit.

Uses:

• Treatment of social anxiety disorder (SAD)
• Treatment of social phobia

Usual Adult Dose for Panic Disorder

Extended release:

• Initial dose: 37.5 mg orally once a day for 7 days, then 75 mg orally once a day thereafter
• Maintenance dose: 75 to 225 mg orally once a day
• Maximum dose: 225 mg/day

Comment: Doses may be increased in daily increments of 75 mg orally at intervals of no less than 7 days.

Use: Treatment of Panic Disorder (PD), with or without agoraphobia

Renal Dose Adjustments

Immediate release:

• Mild to moderate renal dysfunction: The total daily dosage should be reduced by 25%.

Extended release:

• Renal dysfunction (glomerular filtration rate [GFR] 10 to 70 mL/min): The total daily dose should be reduced by 25% to 50%.
• Mild to moderate renal dysfunction (CrCl 30 to 89 mL/min): The total daily dose should be reduced by 50%.
• Severe renal dysfunction (CrCl less than 30 mL/min): The total daily dose should be decreased by at least 50%.

Liver Dose Adjustments

Immediate release:

• Mild to moderate liver dysfunction: The total daily dosage should be reduced by 50%.
• Patients with cirrhosis: The dosage should be reduced by at least 50%.

Extended release:

• Mild to moderate liver dysfunction (Child-Pugh 5 to 9): The total daily dose should be reduced by 50%.
• Severe liver dysfunction (Child-Pugh 10 to 15) and hepatic cirrhosis: The total daily dose should be decreased by at least 50%.

Dose Adjustments

Immediate release TO extended release formulations: Patients may be switched to the nearest equivalent daily dosage (e. g., from 37.5 mg [immediate release] orally 2 times a day to 75 mg [extended release] orally once a day)

Treatment Discontinuation:

• Abrupt discontinuation should be avoided when possible.
• Patients should be monitored for adverse events.
• Treatment should be gradually reduced in 75 mg intervals every week.
• Providers should consider resuming the previously prescribed dose in patients who develop intolerable symptoms following a dose reduction or treatment discontinuation; subsequent dose reductions may continue at a more gradual rate.

Switching patients to/from MAOIs:

• Starting treatment with this drug: At least 14 days should elapse between discontinuing MAOI therapy and starting treatment.
• Stopping treatment with this drug: At least 7 days should elapse between stopping treatment and starting an MAOI.

Patients who require urgent treatment with linezolid/IV methylene blue during treatment:

• The potential benefits must outweigh the risks of serotonin syndrome.
• This drug should be stopped promptly before administering linezolid/IV methylene blue.
• Patients should be monitored for serotonin syndrome for 7 days OR 24 hours after the last dose of linezolid/IV methylene blue, whichever comes first.
• Treatment may resume 24 hours after the last dose of linezolid/IV methylene blue.

Precautions

US BOXED WARNINGS:
SUICIDAL THOUGHTS AND BEHAVIORS; SUICIDALITY AND ANTIDEPRESSANT DRUGS:

• Antidepressants increased the risk compared to placebo of suicidality (e.g., suicidal thoughts and behavior) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders.
• These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over age 24; there was a reduction in risk with antidepressant use in patients aged 65 and older.
• Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide.

Recommendations:

• Anyone considering the use of this drug in a child, adolescent, or young adult must balance this risk with the clinical need.
• In patients of all ages who are started on antidepressant therapy, monitor closely for clinical worsening and emergence of suicidality or unusual behavior.
• Advise families and caregivers of the need for close observation and communication with the prescriber.
• This drug is not approved for use in pediatric patients.

CONTRAINDICATIONS:

• Hypersensitivity to the active component, desvenlafaxine, or any of the ingredients
• Starting treatment with this drug in patients already receiving therapy with MAOIs (e.g., linezolid, IV methylene blue)
• The concomitant use of MAOIs or within 7 days of stopping treatment with this drug
• The use of this drug within 14 days of stopping an MAOI

Safety and efficacy have not been established in patients younger than 18 years.

Consult WARNINGS section for additional precautions.

Dialysis

Hemodialysis:

• Immediate release: The total daily dose should be reduced by 50%.
• Extended release: The total daily dose should be reduced by at least 50%.

Peritoneal dialysis: Data not available

Other Comments

Administration advice:

• This drug should be taken with food at the same time each day.
• The capsules should not be divided, crushed, or chewed.

General:

• Patients should have their treatment regularly reviewed to evaluate for the ongoing efficacy of therapy.
• Individual dose adjustments may be necessary.

Monitoring:

• CARDIOVASCULAR: Regular blood pressure monitoring
• NERVOUS SYSTEM: Signs/symptoms of serotonin syndrome
• PSYCHIATRIC: Discontinuation symptoms, and worsening/emergence of suicidal thoughts

Patient advice:

• The prolonged release capsules contain spheroids. The insoluble portion of these is eliminated and may be seen in the feces.
• Inform patients that this drug may impair judgement, thinking, and motor skills, and they should avoid driving or operating machinery if these side effects occur.
• Advise patients to speak to their healthcare provider if they become pregnant, intend to become pregnant, or are breastfeeding.

Frequently asked questions

• SSRI’s vs SNRI’s – What’s the difference between them?
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Venlafaxine Interactions Checker – Drugs.com

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There are 672 drugs known to interact with
venlafaxine, along with
11 disease interactions, and 2 alcohol/food interactions.

Of the total drug interactions,
145 are major, 523 are moderate, and 4 are minor.

Does venlafaxine interact with my other drugs?

Enter other medications to view a detailed report.

• View all 672 medications that may interact with venlafaxine
• View venlafaxine alcohol/food interactions (2)
• View venlafaxine disease interactions (11)

Most frequently checked interactions

View interaction reports for venlafaxine and the medicines listed below.

• Major
• Moderate
• Minor
• Unknown

• Abilify (aripiprazole)
• Adderall (amphetamine / dextroamphetamine)
• Aspir 81 (aspirin)
• Aspirin Low Strength (aspirin)
• Benadryl (diphenhydramine)
• CoQ10 (ubiquinone)
• Crestor (rosuvastatin)
• Cymbalta (duloxetine)
• Eliquis (apixaban)
• Fish Oil (omega-3 polyunsaturated fatty acids)
• Flonase (fluticasone nasal)
• Lipitor (atorvastatin)
• Lyrica (pregabalin)
• Metoprolol Succinate ER (metoprolol)
• Metoprolol Tartrate (metoprolol)
• Nexium (esomeprazole)
• Norco (acetaminophen / hydrocodone)
• ProAir HFA (albuterol)
• Seroquel (quetiapine)
• Singulair (montelukast)
• Symbicort (budesonide / formoterol)
• Synthroid (levothyroxine)
• Tylenol (acetaminophen)
• Vitamin B12 (cyanocobalamin)
• Vitamin C (ascorbic acid)
• Vitamin D2 (ergocalciferol)
• Vitamin D3 (cholecalciferol)
• Vyvanse (lisdexamfetamine)
• Xanax (alprazolam)
• Zyrtec (cetirizine)

Venlafaxine alcohol/food interactions

There are 2 alcohol/food interactions with venlafaxine.

Venlafaxine disease interactions

There are 11 disease interactions with venlafaxine which include:

• depression
• renal disease
• renal/liver disease
• mania
• glaucoma
• hypertension
• hyponatremia
• mania
• seizures
• urinary tract obstruction
• weight loss

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Related treatment guides

• Anxiety and Stress
• Anxiety
• Bipolar Disorder
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Drug Interaction Classification

These classifications are only a guideline. The relevance of a particular drug interaction to a specific individual is difficult to determine. Always consult your healthcare provider before starting or stopping any medication.

Major	Highly clinically significant. Avoid combinations; the risk of the interaction outweighs the benefit.
Moderate	Moderately clinically significant. Usually avoid combinations; use it only under special circumstances.
Minor	Minimally clinically significant. Minimize risk; assess risk and consider an alternative drug, take steps to circumvent the interaction risk and/or institute a monitoring plan.
Unknown	No interaction information available.

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The use of antidepressants as part of a combination therapy for the painful form of diabetic polyneuropathy | Shishkova V.N.

The prevalence of diabetes mellitus (DM) worldwide has reached epidemic levels and continues to rise steadily. According to the World Health Organization, in 2000 there were about 160 million patients with diabetes in the world, WHO epidemiologists predict that by 2025 the number of patients with diabetes will exceed 400 million people, of which 80–90% will be patients with type 2 diabetes [1]. An increase in the prevalence of DM is accompanied by an increase in the frequency of vascular complications, which, in turn, are the cause of blindness, chronic renal failure, coronary heart disease, myocardial infarction, stroke, peripheral polyneuropathy, and severe disorders of the central nervous system (CNS), leading to early disability and high mortality in such patients.

The age of patients at the onset of type 2 diabetes is gradually decreasing, in particular in developing countries, where the maximum detection of diabetes occurs at the age of 45 to 64 years (compared to the group of 65 years and older in developed countries). The increased risk of developing type 2 diabetes in adolescents and children is alarming [2]. The early development of DM, especially in young people, is associated with more frequent early mortality, various complications leading to disability, reduced social activity and poor quality of life.
Studies have shown that at the onset of type 2 diabetes, about 50% of patients already have macro- and microvascular complications. Perhaps this is the result of the fact that metabolic disorders occur much earlier than the first clinical manifestations of DM and lead to irreversible vascular changes by the time of diagnosis.
Diabetic polyneuropathy (DP) is the most common complication of DM. On average, the frequency of neuropathy among patients with diabetes is 25%, with an in-depth neurological examination it increases to 50%, and with the use of electrophysiological research methods, the study of autonomic functions and quantitative assessment of sensitivity – up to 90%. Neuropathy is usually a late complication in patients with type 1 diabetes, but in patients with type 2 diabetes, neuropathy may be diagnosed first [3]. Given the long latent period of type 2 diabetes, a common clinical situation may be the identification of signs of polyneuropathy preceding the appearance of signs of diabetes itself. In many patients, neurological disorders are the first symptoms of the disease, even at the stage of initial disorders of carbohydrate metabolism (impaired glucose tolerance and fasting glycemia), and subsequently, with timely therapeutic and preventive measures, prevent the development of DM. With increasing duration and severity of diabetes, the frequency of diabetic neuropathy steadily increases. Approximately 50% of patients with type 1 diabetes lasting more than 25 years will develop polyneuropathy [4].
DP can be acute and chronic, symmetrical and asymmetric, asymptomatic or painful. Chronic distal symmetric sensory and sensorimotor polyneuropathy are the most common variants of DP. This type of neuropathy, as a rule, reflects the duration and severity of hyperglycemia and depends on the duration of diabetes and the effectiveness of hypoglycemic therapy, but sometimes it is the first manifestation of latent diabetes. Also, this variant of polyneuropathy is often combined with other microvascular complications of diabetes – nephropathy and retinopathy. Hyperglycemia caused by DM causes serious metabolic disorders, such as excessive protein glycation and oxidative stress, which significantly impair the structure and function of neurons [5]. Oxidative stress promotes damage to the endothelial cells that underlie the membrane of endoneurial vessels, leading to microvascular dysfunction. The resulting hypoxia and ischemia further activate the processes of nerve damage. An essential mechanism for the formation of DP is the deficiency of neurotrophic factors, which reduces the ability of the affected nerve to regenerate. Also in the pathogenesis, activation of protein kinase C and blocking the release of nitric oxide, which regulates vascular tone, play a certain role, which contributes to the development of endothelial dysfunction and the progression of microangiopathy. The appearance of pain in DP is due to damage to the thin sensory fibers responsible for pain sensitivity [6].
Polyneuropathy usually begins gradually, sometimes asymmetrically, and slowly progresses, always becoming symmetrical over time. The progressive course can sometimes be interrupted by periods of stabilization or remission of varying duration, usually on the background of improvement. The clinical picture is dominated by sensory disturbances in the form of sensations of pain, numbness, paresthesia in the lower extremities. Parasthesia manifests itself as sensations of cold, tingling, burning, which occur spontaneously or when touched. In 50% of patients with polyneuropathy, pain is its only manifestation [7]. The pain can be burning, cutting, tearing, penetrating, less often – dull. Often it is noted at rest and intensifies at night, disturbing sleep, touching the skin becomes extremely painful. In typical cases, the patient cannot even bear the touch of a woolen blanket, and then sometimes ordinary bed linen.
Pain in DP has a complex genesis. Its appearance is associated with the generation of thin unmyelinated fibers or hyperglycemia. It is known that hyperglycemia can lower the pain threshold and reduce the effect of analgesics, so the normalization of blood glucose levels can lead to a significant reduction in pain. In most patients, the pain tends to spontaneously decrease within a few months, but sometimes it steadily increases. The regression of pain may indicate not only the restoration of functions, but also the further progression of the pathological process.
Pain in DP most often develops in patients with distal symmetric sensorimotor polyneuropathy. Typical complaints are tingling and numbness in the feet and legs, worse at night. At the same time, patients may experience sharp, shooting, throbbing and burning pains. Some patients present with allodynia and hyperesthesia. All of the above disorders are referred to as positive sensory symptoms of neuropathic pain. Negative symptoms are pain and temperature hyperesthesia, which in the initial stages of the disease are presented moderately in the distal sections, but as they progress, they spread proximally, and the upper limbs may gradually be involved in this process. Tendon reflexes are usually reduced, and muscle weakness is limited to the muscles of the foot [8].
Treatment
Since the lack of compensation for SD, i.e. chronic hyperglycemia is the main pathogenetic factor that triggers the processes of damage to nerve fibers, then the main condition for the stabilization and regression of the manifestations of diabetic neuropathy, as well as its prevention, will be the normalization of carbohydrate metabolism. Thus, the basis of the treatment of DP is the optimal control of blood sugar levels and the correction of all metabolic disorders. Other risk factors that may be associated with diabetic neuropathy are hyperlipidemia, hypertension, smoking, alcohol consumption, and being overweight. Although there have been no studies showing a reduction in the risk of developing neuropathy, influencing these reversible factors may prevent other long-term complications of diabetes, such as cardiovascular disease (CVD).
The first step in treating the painful form of DP is glycemic control and correction of other metabolic disorders. In the Diabetes Control and Complications Trial (DCCT), improved glycemic control in patients with type 1 DM, achieved as a result of intensive insulin therapy, not only reduced the level of neuropathy, but also slowed its progression by 57% [9]. It should be noted that a slowdown in the progression, and not a reversal, of neuropathy was achieved. Similar conclusions were made in the UKPDS (UK Prospective Diabetes Study), which included more than 5,000 patients with type 2 diabetes. It was shown that intensive therapy by the end of the 15th year of follow-up resulted in a 40% decrease in the incidence of polyneuropathy compared with the group where the glucose concentration was maintained at a higher level [10].
Pathogen-targeted treatment can slow down, stop, or even reverse the course of neuropathy. A clear correlation has been shown between the level of hyperglycemia and the development and progression of neuropathies, including pain forms [11]. After improvement in glycemic control, there may be a slowdown in the progression, stabilization and partial regression of symptoms with already developed polyneuropathy. On average, manifestations of polyneuropathy begin to decrease after 6 months. after achieving optimal control of hyperglycemia. At the same time, not only subjective sensory symptoms decrease, but also manifestations of autonomic dysfunction, and the speed of impulse conduction along the nerves increases. However, even in patients with long-term excellent glycemic control with a glycosylated hemoglobin (HbA1C) level of less than 8%, the lifetime pain level of DP remains more than 20% [12].
There is no doubt that the stabilization of blood glucose levels can reduce the severity of pain, while sharp fluctuations in the level of glycemia contribute to increased pain. Therefore, therapy should avoid episodes of hypoglycemia, which can exacerbate damage to peripheral nerve fibers.
Pharmacotherapy
Pharmacotherapy of DP is aimed at restoring the affected nerves, preventing new disorders (pathogenetic therapy) and reducing the severity of pain syndrome (symptomatic therapy). In the first case, a-lipoic acid, benfotiamine, nerve growth factors, aldose reductase inhibitors, protein kinase C inhibitors, acetyl-L-carnitine, and vascular therapy are used [13]. This direction of therapy is important and largely determines the prognosis, incl. and pain syndrome. However, this treatment is carried out for long courses and is not always accompanied by obvious clinical improvement. At the same time, even with mild polyneuropathy, severe pain can occur, which is very often the leading factor in reducing the quality of life of patients, leading to sleep disturbances, depression, anxiety, and social exclusion. These pains are the only complaints of the patient. That is why it is important to carry out timely symptomatic therapy aimed at eliminating the pain syndrome, in parallel with pathogenetic therapy.
In chronic pain of any origin, it is necessary to influence primarily the etiological and pathogenetic processes, as well as all kinds of factors that contribute to the development and intensification of pain. Treatment should include a complex of medications, physical and psychotherapeutic methods. It should be remembered that neuropathic pain, unlike nociceptive pain, is difficult to treat with conventional analgesics and non-steroidal anti-inflammatory drugs, so these drugs are not recommended for the treatment of pain in DP. Moreover, their long-term use for patients with diabetes, nephropathy and CVD can be dangerous [6].
The main groups of drugs for the treatment of the painful form of DP are antidepressants, anticonvulsants, opioid analgesics and local anesthetics. The main drugs for the treatment of neuropathic pain are presented in Table 1. The choice of a drug for the treatment of neuropathic pain is carried out taking into account the characteristics of its therapeutic effect and side effects that are present in patients with concomitant diseases, as well as individual tolerance.
Use of antidepressants
for neuropathic pain
Antidepressants are beneficial in the treatment of chronic pain of any origin, but are especially important in the treatment of neuropathic pain. The analgesic effect of antidepressants is not directly related to their antidepressant effect. This is evidenced by the following facts: the analgesic effect is often manifested in much lower doses and usually develops faster than the antidepressant; manifests itself both in patients with depression and in patients without affective disorders.
The therapeutic efficacy of antidepressants prescribed for the relief of neuropathic pain has been demonstrated in a meta-analysis of several placebo-controlled trials. It is assumed that it is associated with an increase in the activity of noradrenergic and, to a lesser extent, serotonergic systems, which have an inhibitory effect on the conduction of pain impulses along nociceptive pathways in the CNS. Monoamine reuptake inhibitors increase the concentration of mediators in the synapses of the antinociceptive system, activate it and suppress pain conduction. Of these, the least selective are tricyclic antidepressants [8], which block the reuptake of norepinephrine and serotonin in presynaptic neurons, which contributes to the activation of descending anti-pain effects and inhibits the passage of pain afferentation. Tricyclic antidepressants amitriptyline and imipramine have the greatest analgesic ability already in the first days of treatment (amitriptyline at a dose of 50-75, 150 mg and above), while the antidepressant effect occurs only after a few weeks or months [14]. Treatment is recommended to start with a low dose (10 mg / day), gradually titrating it. However, in addition to blocking the reuptake of noradrenaline and serotonin, tricyclic antidepressants block postsynaptic muscarinic, cholinergic, α1-adrenergic and histamine receptors to varying degrees. This is accompanied by a number of undesirable effects, such as dry mouth, sinus tachycardia, constipation, urinary retention, confusion, memory impairment, sedation, drowsiness, dizziness, orthostatic hypotension. Also, tricyclic antidepressants can cause imbalance and cognitive impairment in elderly patients, as well as. these drugs are metabolized with the participation of enzymes of the cytochrome P-450 system, they can interact with other drugs that are also metabolized by these enzymes. Thus, despite the effectiveness of relatively low doses of tricyclic antidepressants, the spectrum of their side effects is very wide (dry mouth, nausea, vomiting, increased intraocular pressure, constipation, urinary retention; tachycardia, arrhythmias, orthostatic hypotension due to the adrenergic action of drugs, as well as pronounced sedation and dizziness), which limits their use, especially in the elderly.
Serotonin reuptake inhibitors
Selective serotonin reuptake inhibitors (SSRIs) have a safer and more favorable tolerability profile than tricyclic antidepressants, but only block the reuptake of serotonin, but not norepinephrine. SSRIs are indicated mainly in cases where chronic pain is associated with depression, and the patient does not tolerate tricyclic antidepressants well. Although SSRIs cause fewer side effects, they have a less pronounced analgesic effect, which may be due to the lack of a direct effect on noradrenergic transmission. Studies conducted with a representative of this group – fluoxetine in patients with neuropathic pain in DP, showed only its limited effectiveness, and therefore it is practically not used to treat pain in patients with DP [15].
Nevertheless, it has been shown that another representative of the SSRI group, paroxetine, can also have an independent analgesic effect in several types of neuropathic pain, incl. and in DP, which was confirmed in clinical studies [16]. The starting dose of paroxetine for relief of pain in DP is 20 mg/day, then, if necessary, it is titrated (depending on the severity of symptoms and tolerability of the drug) to 40 mg/day, divided into 2 doses. The average therapeutic daily dose of paroxetine for the correction of pain is 20–40 mg. The polyvalence of the clinical action of paroxetine, as well as its good tolerability, is evidenced by the results of numerous studies [17].
It is also noted that, along with high clinical activity, the drug has a good speed of action. In addition, according to a number of studies, paroxetine helps to reduce platelet aggregation, which prevents thrombosis and has a protective effect on the vascular endothelium, which is an important aspect of therapy in patients with diabetes at high risk of developing CVD [18].
Serotonin reuptake inhibitors
and norepinephrine
For a long time, tricyclic antidepressants, including amitriptyline, imipramine, nortriptyline, and desipramine, have been used as first-line drugs in patients with painful DP, but they often cause severe side effects and are poorly tolerated by many patients. Most representatives of SSRIs, despite better tolerability, do not lead to a more pronounced reduction in pain compared to tricyclic antidepressants and are not used, with rare exceptions (for example, paroxetine in the treatment of the painful form of DP). The development of a new class of antidepressants that inhibit the reuptake of both serotonin and norepinephrine has led to a breakthrough in the treatment of the painful form of DP.
This group of drugs includes venlafaxine (Velafax) and duloxetine. Their effectiveness is based on the activation of descending serotonergic and noradrenergic pathways that suppress pain in the CNS [19]. In a comparative study with treatment for 4 weeks. imipramine, one of the most effective representatives of the group of tricyclic antidepressants, and venlafaxine showed the same effectiveness of these drugs in reducing the severity of pain [20].
Venlafaxine (Velafax) and its active metabolites are strong serotonin and norepinephrine reuptake inhibitors and weak dopamine reuptake inhibitors. Venlafaxine (Velafax) also has a central effect by reducing the perception of pain. The scheme of titration of venlafaxine is as follows: on the 1st week. therapy, the drug is used at a dose of 37.5 mg / day, from the 2nd week. – 75 mg / day, on the 3rd – 150 mg, if necessary – further titration on the 4th week. 225 mg / day, divided into 3 doses. The rapidity of the analgesic effect of venlafaxine (Velafax) is noted by the beginning of the 4th week. taking the drug.
The number of patients who need to be treated with venlafaxine to obtain a reliable effective result – a decrease in the severity of pain by 50% in 4 weeks. therapy, calculated according to the results of many clinical studies and is 5 patients (95% CI 3. 4-14), which is a demonstration of its high efficiency. For an objective assessment of these data, we will give an example of the same indicator for other drugs that are often recommended and currently used in the treatment of the painful form of DP: pregabalin – 4.5, but the duration of therapy is more than 6 weeks. and when using the maximum dosages, gabapentin – 4, but at a dose of 3600 mg / day and the duration of therapy – more than 4 weeks. [21].
An indirect meta-analysis of the effectiveness of the second representative of this class of antidepressants, duloxetine, in comparison with gabapentin and pregabalin also showed that it is comparable in efficacy and safety with these drugs, which have recently been recommended as the most effective for pain manifestations of polyneuropathy [22].
To date, sufficient experience has been accumulated in the effective clinical use of venlafaxine (Velafax) in patients with a painful form of diabetic lesions of the nervous system, in all clinical studies it provided a significant reduction in pain compared with placebo. The most common side effects were nausea, dry mouth, and drowsiness. In addition to reducing the severity of pain during the day, taking the drug also leads to a decrease in night pain and an improvement in the quality of life. The effectiveness of venlafaxine (Velafax) is most related to the direct effects of this drug and does not depend on age, gender, type of diabetes, and duration of diabetic neuropathy [23-26]. In May 2010, a new, prolonged form of Velafax appeared – Velafax MB capsules, which shows better tolerance compared to other forms.
Use of anticonvulsants
for neuropathic pain
Anticonvulsants are most effective for acute and paroxysmal pain. Of particular interest are the data that anticonvulsants, by reducing the impulse activity of axon membranes, not only reduce the severity of sensory symptoms, but also improve the function of the nervous system and reduce the severity of apoptosis [27], which suggests a pathogenetic mechanism of their action in DP. According to controlled studies, anticonvulsants reduce the intensity of pain by at least half in about 50% of patients with neuropathic pain. Of the anticonvulsants, carbamazepine is most often used in clinical practice, especially in the presence of trigeminal and postherpetic neuralgia, as well as for the treatment of pain in the setting of diabetic neuropathy [28]. The frequency of relief of pain in trigeminal neuralgia while taking carbamazepine varies, according to different authors, within 58–90%, and in diabetic neuropathy it reaches 63%, which, along with economic availability, determines the widespread use of the drug in these diseases [29]. The mechanism of its action is probably associated with the blockade of sodium channels.
Carbamazepine is initially prescribed at a dose of 100 mg 2 times a day, and then it is increased to 200 mg 3–4 times a day. The maximum dose is 1200 mg / day. Side effects (dizziness, ataxia, blurred vision, nausea, drowsiness, headache) are less likely with a slow increase in dose. It is preferable to use sustained-release preparations of carbamazepine (for example, carbamazepine retard), which are enough to take 2 times / day. They provide a more stable concentration of the drug during the day, which reduces the likelihood of a side effect.
Thus, for successful treatment of neuropathic pain, which is a manifestation of distal DP, it is necessary to diagnose this complication as early as possible in a patient with DM, taking into account the period of a long latent course of this pathology, and timely initiation of treatment. Undoubtedly, early combination therapy is the most promising in the treatment of the painful form of DP, and the combination of drugs from different groups will be optimal, which can achieve maximum pain reduction with minimal risk of adverse reactions. In this regard, the combination of the following drugs may be most acceptable: the anticonvulsant carbamazepine and an antidepressant (venlafaxine, paroxetine).

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