Treatment of acute pain in cancer

Increasing interest in the treatment of acute pain in cancer, which also include postoperative pain syndrome, is noted every year. This is due to new fundamental research in the field of physiology and pharmacology. In the domestic and foreign literature this issue is paid great attention, and the pharmacotherapy of acute pain in cancer, according to leading experts, should be regarded as an independent direction in anesthesiology and resuscitation.

Particular attention deserves the treatment of acute pain in cancer, and this is due to many factors. Currently, in most cases, malignant neoplasms use combined or complex methods of treatment, since more than half of patients entering oncology facilities have a locally advanced process, with the release of the tumor beyond the primary focus, regional lymph node involvement or tumor growth into surrounding organs and fabrics.

All this presupposes the need for preoperative radiotherapy or chemotherapeutic treatment, and in some cases, their combinations. However, it is well known that the above treatment methods can cause such side effects as radiation and toxic reactions, resorptive endotoxicosis, the severity of which depends on the chemotherapy scheme, the irradiation zone and the individual characteristics of the patient's body.

The current level of development of anesthesiology and resuscitation can significantly reduce contraindications to surgical treatment even in patients with a common tumor process and the syndrome of cancer intoxication (with all clinical and laboratory manifestations), previously considered inoperable, despite the presence of pronounced changes in homeostasis and severe concomitant and competing diseases . In recent years, with massive tumor processes, the maximum "cytoreduction" is increasingly performed to remove the bulk of tumor tissue, decompress organs, tissues and main vessels, to create conditions for palliative postoperative radiotherapy or drug therapy and improve the quality of life of patients.

The literature data indicate that even with the initial forms of the tumor process for oncological patients, haemocoagulation, hemorheology, antioxidant protection, immunological indices, not to mention more widespread processes are characteristic. That is why, according to leading experts, it is necessary to use gentle, pathogenetically grounded approaches to the choice of methods of anesthesia and components for treating OPS in cancer patients. Such tactics become particularly relevant in the prevalence of tumor processes due to the high likelihood of recurrence of the disease or the further progression of the process after a while and, thus, the need for subsequent analgesic therapy using opiates.

Principles of treatment of acute pain syndrome in oncosurgery

Any operation represents for the patient's body aggression of one degree or another. The higher the degree of this aggression, the greater and, possibly, the earlier protection is needed by the patient. Operative interventions in oncology differ from those performed in non-oncological clinics, high traumatic and reflexogenic. Even with small tumor lesions, operative treatment implies not only removal of the tumor itself, but also broad lymphodissection, and, accordingly, denervation.

That is why hardly the acute pain in an oncological patient should be considered only within the framework of one of its varieties (visceral, somatic, neuropathic, etc.). It is necessary to speak about the MPS of mixed genesis with the predominance of one or another component and use a multimodal approach to the treatment of this syndrome. We can not discount the fact that, already entering a cancer center, before the diagnosis is established, the patient experiences psychological stress, which can lead to serious consequences.

Experimental studies confirmed that stress states accelerate the growth of tumors. It is during this period (which can be called the first stage of antinociceptive protection) that the patient needs timely pharmacological protection, in order to avoid the development of severe sleep and depression disorders that lead to neuroendocrine disorders and, in fact, "harbingers" of subsequent acute pain in cancer. Behavioral responses in this period are individual, different in degree of intensity and direction, they are caused by the type of higher nervous activity, life experience, will, education and other factors, but most patients are dominated by fear of the forthcoming operation, its outcome, and pain, which can also lead to the development of neuroendocrine stress.

All this is reflected in the definition of the pain concept given by the International Pain Association, by definition, pain is not only an unpleasant sensation, but also an emotional experience associated with the already existing or possible (not less important) tissue damage, or described in terms of such damage. Therefore, it is believed that it is during this period (after referral to the oncology clinic and the entire period of diagnosis) that patients need individual pharmacological protection.

Medications to relieve acute pain in cancer

Good results are given to sedative preparations based on plant raw materials, such as valerian, motherwort and other various plant dues, which include such components. Some patients need the appointment of so-called day tranquilizers (medazepam, lysopam, etc.), because they require a fairly fast and concentrated reaction in the course of some clinical and instrumental studies. For the correction of sleep disorders during the examination, it is preferable to prescribe non-benzodideapine tranquilizers from the group of imidazopyridines (zolpidem) to oncological patients, which are referred to the group of partial agonists of the benzodiazepine receptor complex. Because they selectively bind to the ω1 subtype of the receptors, they do not practically display the well-known undesirable effects characteristic of benzodiazepine receptor agonists. Imidazopyridine preparations do not interfere with the structure of sleep, but with existing disturbances in the structure of sleep, they contribute to the restoration of normal phase relationships and sleep stages. These drugs do not cause post-somnolent disorders (lethargy, drowsiness, depressed mood, etc.) after a morning awakening and thus do not affect full-fledged daytime wakefulness of patients.

No less important stage is immediate prednarkoznaya preparation (premedication), because of its pathogenetic orientation, the effectiveness of therapy of postoperative pain syndrome largely depends (the second stage of antinociceptive protection). Prevention of nociceptive stimulation (those preventive or proactive effects on the main links of the pathogenesis of acute pain in cancer) and the development of pain syndrome are much simpler and require less medical costs than fighting with already developed severe pain.

In 1996, at the World Congress on Pain, Vancouver, the method of preventive analgesia (preemptive analgesia) was recognized as a promising direction in the pathogenetic therapy of pain syndromes, and is widely used in the most progressive clinics at the present time. For these purposes, in addition to benzodiazepine preparations for premedication (30-40 minutes before surgery), peripheral action analgesics (eg, ketoprofen, paracetamol, diclofenac) are prescribed, although some of them (ketoprofen) also have a central mechanism of antinociceptive action. As a preparation for preventive analgesia, a narcotic analgesic of a mixed mechanism of action and an average potency, tramadol, deserves attention. The most urgent is its appointment before short-term surgical interventions, which allows to reduce the consumption of the main components of general anesthesia and provide full-fledged postoperative analgesia.

The next, the third stage of the patient's body protection is the early postoperative period (up to 3 days after the operation) and its most important component is the nearest post-amniotic period (2-4 hours after the operation), because during these hours the protective effect of anesthesia ceases and nociceptive impulsation increases incomplete recovery of the body's basic functions. It is believed that with ineffective analgesia during the first day of the postoperative period, there is a high probability of formation of chronic pain syndrome (CHD) in patients, which condemns the patient to prolonged anguish (up to 3-6 months). At the heart of HBS, which arose as a result of inadequate therapy of acute pain in cancer, according to leading experts in the field of anesthesia, plastic changes of the CNS lie. The choice of drugs for anesthesia at this stage largely depends on the used version of anesthesia, the components of anesthesia, and also on the volume, trauma and anatomical area affected by the operation. At the modern level of the development of anesthesiology and intensive care, it is considered optimal to adhere to the multimodal approach to postoperative analgesia, which implies the impact on the different links of nociceptive impulses. However, representatives of various foreign and national schools differ in their views on the treatment of acute pain in cancer.

As before, for the treatment of postoperative pain syndrome an important role is assigned to opioid analgesics - as pure agonists of μ-opioid receptors (morphine, trimeperidine, omnopon, sufentanil, fentanyl, etc.) and opiate receptor agonist-antagonists (buprenorphine, butorphanol, nalbuphine, dezocine, tramadol, etc.).

Variants of use of narcotic analgesics can be different, but more often they are combined with other drugs. Determination of the route of opioid analgesics depends on the zone of operation, its volume, availability of certain forms of drugs and priorities of the clinic.

Intramuscular and intravenous administration (bolus or using infusomats), oral, in the form of buccal (buccal) and sublingual (sublingual) tablets, transdermal, epidural (bolus or in the form of infusion) are used. Good results were obtained from the epidural application of modern local anesthetics (ropivacaine) and their combination with narcotic analgesics (morphine, trimiperidine, etc.) or adrenoreactive drugs.

Great importance in conducting postoperative analgesia is given to non-steroidal anti-inflammatory drugs (cyclooxygenase inhibitors) and some other peripheral analgesics. Some of the NSAIDs are allowed not only for intramuscular, but also for intravenous administration (ketoprofen, lornoxicam, etc.). There are various tableted forms and candles, which is extremely important when considering pain therapy in different categories of patients.

Among drugs that have antinociceptive activity, a certain adenopositive drug clonidine deserves a certain interest, which affects the processes of transmission and modulation. Clonidine stimulates α1 (segmental level) and α2 (CNS) adrenoceptors, ie, it has peripheral and central mechanisms of action. There are emulsified and tablet forms of the drug. To treat acute pain in cancer use intramuscular, intravenous and epidural administration of the drug.

A significant role in antinociceptive protection is assigned to polyvalent protease inhibitors (aprotinin etc.), which by the formation of enzyme-inhibitory complexes inactivate proteases (trypsin, chymotrypsin, kallikrein, etc.) of blood plasma and cellular tissue elements, i.e. Have a protective effect directly in the place of pain. Enter the drug intravenously (bolus or infusion).

In recent years, antagonists of excitatory acids (tizanidine-tableted forms, ketamine-intravenous infusions) and anticonvulsants-gabapentin (neurontin), pregabalin (lyric), which interact with (α2-delta-protein) voltage-dependent calcium channels and, thus, exhibit an analgesic effect. The mechanism of action of these drugs, apparently, has not been fully studied, but the first good results were obtained in the treatment of OBS with the neuropathic component.

Having studied in detail the work of leading specialists in the field of OBS therapy, it is possible, for example, to present some possible combinations of drugs for the design of postoperative analgesia regimens. In addition, it is not necessary to dwell on the need for a preoperative (study period) pharmacological protection and the appointment of a pathogenetically grounded premedication, since this issue has been discussed in sufficient detail above. The routes of administration of drugs for postoperative analgesia may be different depending on the zone of operation (intramuscular, intravenous, epidural, through the mouth, etc.). When assigning these or other schemes, it should be borne in mind that the reaction to pain is strictly individual and variable in different patients; additions can be made to any of the prescribed schemes if necessary.

Depending on the prevalence (stage), the localization of the oncological process, the volume of the removed or resected tissues, the reflexogenicity of the surgical intervention with a sufficient degree of conventionality, all operations on the level of injury to the tissues of the patient's body can apparently be divided into small, medium and high traumatic operations.

To surgical interventions of minor traumatism can be attributed, for example, resection of the lacteal or thyroid gland, removal of the soft tissue tumor, etc., the average traumaticity - resection of the lung, stomach or large intestine and others comparable in the degree of trauma surgery.

To operations of a high level of traumatic tissue include gastrectomy and pneumonectomy with enlarged lymphadenectomy, abdominal perineal rectum extirpation, one-stage resection and esophageal plastic surgery.

Cytoreductive operations with extensive tumor lesions and surgical interventions for the removal of large (eg, retroperitoneal) tumors, including the removal of large soft tissue tumors and bone structures with a one-step replacement of the formed defect with a revascularized autologous transplant, are particularly traumatic. This conditional division is once again called to emphasize that the more aggressive the surgical treatment, the more powerful antinociceptive protection patients need.

Below are some possible combinations of drugs for the design of postoperative analgesia. It is clear that it is not possible to list all possible variants of schemes, therefore we give only some examples.

Possible combinations of drugs for postoperative analgesia

Preparations	Traumatic surgery
	small	mean	high
An analgetic of peripheral action (ketoprofen, paracetamol)	+	+	+
Tramadol	+	±
Butorphanol		±
Buprenorphine	-	±	+
Aprotinin	-	+	+
Gabapentin	P / p	P / p	P / p
Ropivacaine	-	±	+
Benzodiazepine	+	+	+
Ketamine	P / p	P / p	P / p

Note S / n - according to the indications, if there is a neuropathic component, ± or-or (combinations of some drugs and routes of administration are possible).

According to the publications of recent years, the pathogenetically substantiated choice of drugs and ways of their introduction for postoperative antinociceptive protection of the patient's body (including all stages) allows:

• provide a more comfortable state of patients,
• achieve full-fledged analgesia in the postoperative period,
• significantly reduce the consumption of drugs, including opiates,
• reduce the development of side effects,
• significantly reduce the likelihood of development of CHD,
• to conduct an earlier activation of patients,
• prevent many postoperative complications.

Accumulated by leading scientists and clinicians, experience shows that preventive and multimodal analgesia is a modern promising direction in the treatment of postoperative pain in cancer, providing high-quality analgesia.