Treatment of nociceptive back pain

Treatment of nociceptive pain syndrome involves three aspects:

• limitation of nociceptive flow into the central nervous system from the site of injury,
• suppression of the synthesis and secretion of algogens,
• activation of antinociception.

Limitation of nociceptive impulses

From the site of injury, local anesthetics are used, the most popular of which are procaine (novocaine), lidocaine. Their mechanism of action is to block the sodium channels of the neuron membrane and its processes. Without activation of the sodium system, the generation of the action potential and, consequently, the nociceptive impulse is impossible.

To interrupt nociceptive afferentation, methods of blockade of conduction along peripheral nerves and the spinal cord are used. In this manual, we do not pursue the goal of a detailed presentation of the corresponding methods; they are covered in detail in specialized literature on pain relief methods. We will briefly report on the blockade methods used:

• Surface anesthesia
• Infiltration anesthesia
• Regional anesthesia (peripheral nerve block)
• Central blockade

Surface anesthesia aims to block the excitation of nociceptors when the cause of pain is localized superficially in the skin. In general therapeutic or neurological practice, it is possible to use "lemon peel" type infiltration with 0.5 - 0.25% novocaine solution. It is possible to use local anesthetics in the form of ointments and gels.

Infiltration anesthesia is used to introduce anesthetic into the deep layers of the skin and skeletal muscles (eg, myogenic gripper zones). Procaine is the preferred agent.

Regional anesthesia (peripheral nerve block) should be performed by specialists with specialized training. Severe complications of peripheral nerve block include apnea, circulatory depression, and epileptic seizures. For early diagnosis and successful treatment of severe complications, the same standards of basic monitoring as for general anesthesia should be followed. Currently, brachial plexus blocks (supraclavicular and subclavian), intercostal nerve blocks, musculocutaneous nerve blocks, radial, median and ulnar nerve blocks, digital nerve blocks of the upper limb, Birou intravenous regional anesthesia of the upper limb, femoral, obturator, and selasch nerve blocks are used. blockade of nerves in the popliteal fossa, regional anesthesia of the foot, intravenous regional anesthesia of the lower limb according to Bier, blockade of intercostal nerves, cervical plexus, parevertebral thoracic blockade, blockade of the ilioinguinal, iliohypogastric, femoral-genital nerves, infiltration anesthesia of the penis.

Spinal, epidural and caudal anesthesia involve the administration of a local anesthetic in close proximity to the spinal cord, so they are collectively referred to as "central block".

Spinal anesthesia involves injecting a local anesthetic solution into the subarachnoid space of the spinal cord. It is used for operations on the lower extremities, hip joint, perineum, lower abdomen, and lumbar spine. Spinal anesthesia can only be performed in an operating room that is fully equipped for monitoring, general anesthesia, and resuscitation.

Unlike spinal anesthesia, which results in a complete block, epidural anesthesia may provide options from analgesia with a weak motor block to deep anesthesia with a complete motor block, which depends on the selection of the anesthetic, its concentration and dose. Epidural anesthesia is used in various surgical interventions, in the first period of labor, for the treatment of postoperative pain. Epidural anesthesia can only be performed if there is a full supply of equipment and drugs necessary for the treatment of possible complications - from mild arterial hypotension to circulatory arrest.

Caudal anesthesia involves the administration of anesthetic through the sacral hiatus, a midline bone defect in the lowest part of the sacrum that is covered by the dense sacrococcygeal ligament. In 5-10% of people, the sacral hiatus is absent, so caudal anesthesia is not possible for them. Like the epidural space of the lumbar spine, the sacral canal is filled with venous plexus and loose connective tissue.

Suppression of synthesis and secretion of algogens

One of the mechanisms of peripheral sensitization and primary hyperalgesia is the synthesis and secretion of algogens in the lesion site. When tissues are damaged, phospholipase A2 metabolizes phospholipids of cell membranes to arachidonic acid, which in turn is oxidized by the enzyme cyclooxygenase (COX) to cyclic endoperoxides, which are converted by the enzymes prostaglandin isomerase, thromboxane synthetase, and prostacyclin synthetase into prostaglandins, thromboxane A2, and prostacyclins, respectively. Prostaglandins (PG) can both directly stimulate peripheral nociceptors (PGE2, PGI2) and sensitize them (PGE2, PGE1, PGF2a, PGI2). As a result of the increase in the afferent nociceptive flow to the structures of the spinal cord and brain, an NMDA-dependent increase in the concentration of intracellular calcium occurs, causing the activation of phospholipase A2, which stimulates the formation of free arachidonic acid and the synthesis of prostaglandins in neurons, which in turn increases the excitability of the spinal cord nociceptive neurons. COX is inhibited by drugs belonging to the group of nonsteroidal anti-inflammatory drugs (NSAIDs).

Despite the wide variety of nonsteroidal anti-inflammatory drugs, all "standard" drugs of this class of drugs have common positive and negative properties. This is due to the universal molecular mechanism of their pharmacological activity, namely, COX inhibition. There are two COX isoforms: the "structural" enzyme COX-1, which regulates the production of PG, providing physiological activity of cells, and the inducible isoenzyme COX-2, which participates in the synthesis of PG in the inflammation focus. It has been shown that the analgesic effects of NSAIDs are determined by COX-2 inhibition, and side effects (gastrointestinal tract damage, renal dysfunction and platelet aggregation) are determined by COX-1 inhibition. There is data on other mechanisms of the analgesic activity of NSAIDs. These include: central opioid-like antinociceptive action, blockade of NMDA receptors (increased synthesis of kynurenic acid), changes in the conformation of G-protein subunits, suppression of afferent pain signals (neurokinins, glutamate), increased serotonin content, anticonvulsant activity.

Currently, non-selective COX inhibitors that block both isoforms of the enzyme and "selective" COX-2 inhibitors are used in clinical practice. According to the recommendations of the FDA (2005), COX-2 selective NSAIDs are coxibs; COX-2 non-selective non-steroidal anti-inflammatory drugs are Diclofenac, Diflunisal, Etodolac, Fenoprofen, Flurbiprofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Mefenamic Acid, Meloxicam, Nabumetone, Naproxen, Oxaprozin, Lornoxicam, Piroxicam, Salsalate, Sulindac, Tolmetin.

According to the recommendations for the use of non-steroidal anti-inflammatory drugs (2009), selective COX-2 inhibitors include coxibs and some other NSAIDs (meloxicam, nimesulide, nabumetone, etololac).

The "gold standard" among traditional NSAIDs remains sodium diclofenac, which has all the necessary dosage forms - injection, tablets and suppositories. In terms of the "risk-benefit" ratio, diclofenac occupies an intermediate position between coxibs and other traditional NSAIDs.

Despite differences in drug selectivity, the FDA has developed general recommendations for the use of COX inhibitors:

• An increase in cardiovascular complications is recognized as possible with the use of the entire class of NSAIDs (excluding low doses of aspirin)
• It is recommended to add additional warnings about the possibility of developing cardiovascular and gastrointestinal complications to the instructions for all NSAIDs, both selective and traditional, including over-the-counter forms.
• When prescribing all NSAIDs, it is recommended to use the minimum effective dose for the shortest possible period of time.
• All manufacturers of traditional NSAIDs must provide a review and results of clinical studies for subsequent analysis and assessment of cardiovascular risks associated with NSAID use.
• These decisions also apply to over-the-counter forms of NSAIDs.

In 2002, DLSimmons et al. reported the discovery of a third isoform of cyclooxygenase, COX-3, which is expressed predominantly in neurons and is not directly involved in tissue inflammation, but plays a role in pain modulation and the genesis of fever, and a specific inhibitor of COX-3 is acetaminophen.

Acetaminophen has an analgesic effect without a significant local anti-inflammatory component, and is one of the non-opioid analgesics recommended by WHO for the treatment of chronic pain, including cancer pain. As an analgesic, it is somewhat inferior to NSAIDs and methylsulfazole, but can be used in combination with one of them with a better result.

Metamizole sodium has a good analgesic effect comparable to that of NSAIDs, but differs from the latter in its weakly expressed anti-inflammatory effect. In many foreign countries, metamizole is prohibited for clinical use due to possible fatal hematotoxic reactions during long-term therapy (agranulocytosis). However, severe complications, including fatal ones, are also possible when using NSAIDs (NSAID-induced bleeding, renal failure, inaphylactic shock) and paracetamol (liver failure, anaphylaxis). Refusal of clinical use of metamizole at this stage should be considered premature, since it expands the possibilities of non-opioid therapy of acute and chronic pain, especially in cases of contraindications to the use of NSAIDs and paracetamol. Side effects of metamizole may manifest themselves as sclergic reactions of varying severity, suppression of hematopoiesis (agranulocytosis), and impaired renal function (especially in dehydrated patients). Metamizole and NSAIDs should not be prescribed simultaneously due to the risk of combined nephrotoxic effects.

Currently, the classification of non-narcotic analgesics in relation to COX isoforms is as follows

Groups of drugs	Example
Non-selective COX inhibitors	NSAIDs, acetylsalicylic acid in high doses
Selective COX-2 inhibitors	Coxibs, meloxicam, nimesulide, nabumetone, etodolac
Selective inhibitors of NOG-3	Acetaminophen, metamizole
Selective COX-1 inhibitors	Low doses of acetylsalicylic acid (blocks COX-1 dependent aggregation Platelets, but does not have anti-inflammatory and analgesic activity)

Activation of antinociception

A shift in the balance between the activity of the nociceptive and antinociceptive systems towards the latter is possible with pharmaceuticals belonging to different classes, either by inhibiting the secretion of excitatory amino acids (glutamate, aspartate) or by activating the secretion of inhibitory ones (GABA).

_{Agonists of a 2} -adrenoreceptors have found wide application in the therapy of somatogenic pain. One of the most effective and safe drugs of this series is tizanidine. Its analgesic effect is associated with the activation of spinal presynaptic a ₂ -adrenoreceptors, which limits the secretion of excitatory amino acids from the central terminals of nociceptors. An undoubted positive property of tizanidine is the presence of a sedative effect, which is important for the normalization of sleep in patients with acute and chronic pain. In addition, the drug has a gastroprotective effect due to the inhibition of gastric secretion. Recently, a form of tizanidine with slow (modified release) was registered in Russia - Sirdalud MR (Sirdalud MP). The capsule contains 6 mg of tizanidine, which is slowly released over 24 hours. The pharmacokinetics of the drug are more favorable than those of regular sirdalud, as it allows maintaining an optimal concentration of the drug in the blood for a longer time, without high peak concentrations that cause drowsiness.

Thus, for the simultaneous suppression of peripheral and central sensitization, it is advisable to simultaneously prescribe NSAIDs and Tizanidine, which simultaneously neutralizes gastrotoxicity and has a sedative and muscle relaxant effect.

Activation of antinociception is also possible by potentiation of GABA-ergic transmission by benzodiazepines. The presence of two types of benzodiazepine receptors has been established: type 1 receptors predominate in the cerebellum, globus pallidus and cerebral cortex, and type 2 receptors - in the caudate nucleus and putamen. Type 1 receptors participate in the implementation of anxiolytic activity, and type 2 mediates the anticonvulsant effect of benzodiazepines. Benzodiazepine receptors are localized on the postsynaptic membranes of the GABA-ergic systems of the central nervous system. Activation of the GABA receptor by the released neurotransmitter leads to the opening of this channel, an increase in membrane permeability for chlorine and, consequently, to hyperpolarization of the postsynaptic membrane, leading to an increase in the cell's resistance to excitatory signals. Benzodiazepines prolong the lifespan of open ion channels in response to GABA without affecting the number of channels or the movement of chloride ions.

Recently, much attention has been paid to magnesium deficiency in the genesis of neurological disorders. Magnesium ion is a physiological blocker of calcium channels associated with NMDA receptors. Magnesium deficiency is manifested by sensitization of receptors, including nociceptors, which can manifest itself in paresthesia, sensitization of CNS neurons (restless legs syndrome, increased muscle contractility, cramps, musculoskeletal zero). An effective corrector of magnesium deficiency is drugs containing organic magnesium salts, for example, magnesium lactate (Magnelis B6). Organic magnesium salts have high bioavailability with no side effects. Clinical experience indicates the need to correct magnesium deficiency in chronic pain.