Treatment of acute cancer pain

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

Treatment of acute pain in cancer deserves special attention, and this is due to many factors. Currently, in most cases of malignant neoplasms, combined or complex treatment methods are used, since more than half of the patients admitted to oncological institutions have a locally advanced process, with the tumor extending beyond the primary focus, affecting regional lymph nodes or tumor ingrowth into surrounding organs and tissues.

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

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

Literature data indicate that even in the initial forms of the tumor process, oncological patients are characterized by disorders of hemocoagulation, hemorheology, antioxidant protection, immunological indices, not to mention more widespread processes. That is why, according to leading experts, it is necessary to use gentle, pathogenetically substantiated approaches to the choice of pain relief methods and components for the treatment of OBS in oncological patients. Such tactics are especially relevant in widespread tumor processes due to the high probability of relapse of the disease or further progression of the process after some time and, thus, the need for subsequent pain therapy using opiates.

Principles of treatment of acute pain syndrome in oncosurgery

Any operation represents aggression of varying degrees of severity for the patient's body. The higher the degree of this aggression, the greater and, possibly, earlier protection the patient needs. Surgical interventions in oncology differ from operations performed in non-oncological clinics by their high traumaticity and reflexogenicity. Even with small tumor lesions, surgical treatment involves not only the removal of the tumor itself, but also wide lymph node dissection and, accordingly, denervation.

That is why acute pain in an oncological patient should hardly be considered only within the framework of one of its varieties (visceral, somatic, neuropathic, etc.). It is necessary to talk about acute pain of mixed genesis with the predominance of one or another component and use a multimodal approach to the treatment of this syndrome. It is also impossible to ignore the fact that, already upon admission to an oncological institution, before the diagnosis is established, the patient experiences psychological stress, which can lead to serious consequences.

Experimental studies have confirmed that stress conditions accelerate tumor growth. It is during this period (which can be called the first stage of antinociceptive protection) that the patient needs timely pharmacological protection to avoid the development of severe sleep disorders and depressions, which lead to neuroendocrine disorders and, in fact, are "harbingers" of subsequent acute pain in cancer. Behavioral reactions during this period are individual, vary in severity and direction, they are determined by the type of higher nervous activity, life experience, will, upbringing and other factors, but most patients are dominated by fear of the upcoming operation, its outcome, and pain, which can also lead to the development of neuroendocrine stress.

All this is reflected in the definition of the concept of pain given by the International Association for the Study of Pain, according to which pain is not only an unpleasant sensation, but also an emotional experience, combined with existing or possible (which is no less important) tissue damage, or described in terms of such damage. Therefore, it is believed that it is during this period (after referral to an oncology clinic and the entire diagnostic period) that patients need individual pharmacological protection.

Medicines for Acute Cancer Pain Relief

Good results are given by sedatives based on herbal raw materials, such as valerian, motherwort and other various herbal mixtures, which include such components. Some patients need to be prescribed so-called daytime tranquilizers (medazepam, lisopam, etc.), since they are required to have a fairly fast and concentrated reaction during some clinical and instrumental studies. To correct sleep disorders during examination of oncological patients, it is preferable to prescribe non-benzodiadepine tranquilizers from the imidazopyridine group (zolpidem), which belong to the group of partial agonists of the benzodiazepine receptor complex. Due to the fact that they selectively bind to the ω1-subtype of receptors, they have practically no well-known adverse effects characteristic of benzodiazepine receptor agonist drugs. Imidazopyridine drugs do not disrupt the sleep structure, but if there are already existing sleep structure disorders, they help restore normal ratios of sleep phases and stages. These drugs do not cause postsomnic disorders (lethargy, drowsiness, depressed mood, etc.) after morning awakening and thus do not affect the full daytime wakefulness of patients.

An equally important stage is direct pre-anesthetic preparation (premedication), since the effectiveness of postoperative pain syndrome therapy (the second stage of antinociceptive protection) largely depends on its pathogenetic focus. Prevention of nociceptive stimulation (i.e. preventive or preemptive effect on the main links in the pathogenesis of acute pain in cancer) and the development of pain syndrome is much simpler and requires less medication than fighting severe pain that has already developed.

In 1996, at the World Congress on Pain in Vancouver, the method of preemptive analgesia was recognized as a promising direction in the pathogenetic therapy of pain syndromes; it is widely used in the most progressive clinics at present. For these purposes, in addition to benzodiazepine drugs for premedication (30-40 minutes before surgery), peripheral analgesics are prescribed (for example, ketoprofen, paracetamol, diclofenac), although some of them (ketoprofen) also have a central mechanism of antinociceptive action. As a drug for preventive (preemptive) analgesia, a narcotic analgesic of mixed action and medium potency - tramadol deserves attention. Its prescription is most relevant before short-term surgical interventions, which allows reducing the consumption of the main components of general anesthesia and providing full postoperative pain relief.

The next, third stage of protecting the patient's body is the early postoperative period (up to 3 days after surgery) and its most important component is the immediate post-anesthesia period (2-4 hours after surgery), since it is during these hours that the protective effect of anesthesia ceases and nociceptive impulses increase with incomplete restoration of the body's main functions. It is believed that with ineffective analgesia during the first day of the postoperative period, there is a high probability of developing chronic pain syndrome (CPS) in patients, dooming the patient to prolonged suffering (up to 3-6 months). According to leading experts in the field of pain relief, CPS, which occurs as a result of inadequate therapy for acute pain in cancer, is based on plastic changes in the central nervous system. The choice of drugs for pain relief at this stage largely depends on the type of anesthesia used, the components of anesthesia, as well as the volume, trauma and anatomical area affected by the operation. At the current level of development of anesthesiology and resuscitation, it is considered optimal to adhere to a multimodal approach to postoperative pain relief, which implies an impact on different links of nociceptive impulses. However, representatives of various foreign and domestic schools somewhat differ in their views on the issues of treating acute pain in cancer.

As before, opioid analgesics play an important role in the treatment of postoperative pain syndrome - both pure μ-opioid receptor agonists (morphine, trimeperidine, omnopon, sufentanil, fentanyl, etc.) and opiate receptor agonist-antagonists (buprenorphine, butorphanol, nalbuphine, dezocin, tramadol, etc.).

The options for using narcotic analgesics may vary, but they are most often combined with other drugs. The route of administration of opioid analgesics depends on the area of the surgical intervention, its volume, the availability of certain forms of drugs, and the priorities of the clinic.

Intramuscular and intravenous administration (bolus or using infusion pumps), oral, in the form of buccal and sublingual tablets, transdermal, epidural (bolus or infusion) are used. Good results have been obtained from the epidural use of modern local anesthetics (ropivacaine) and their combination with narcotic analgesics (morphine, trimeperidine, etc.) or adrenopositive drugs.

Non-steroidal anti-inflammatory drugs (cyclooxygenase inhibitors) and some other peripheral analgesics are of great importance in postoperative pain relief. Some NSAIDs are approved not only for intramuscular but also for intravenous administration (ketoprofen, lornoxicam, etc.). There are various tablet forms and suppositories, which is extremely important to consider when conducting pain therapy in different categories of patients.

Among the drugs with antinociceptive activity, the adrenopositive drug clonidine, which affects the processes of transmission and modulation, deserves some interest. Clonidine stimulates α1 (segmental level) and α2 (CNS) adrenoreceptors, i.e. it has peripheral and central mechanisms of action. There are emulated and tablet forms of the drug. Intramuscular, intravenous and epidural administration of the drug is used to treat acute pain in cancer.

A significant role in antinociceptive protection is given to polyvalent protease inhibitors (aprotinin, etc.), which, by forming enzyme-inhibitory complexes, inactivate proteases (trypsin, chymotrypsin, kallikrein, etc.) of blood plasma and cellular elements of tissues, i.e., they have a protective effect directly at the site of pain exposure. The drug is administered intravenously (bolus or infusion).

In recent years, antagonists of excitatory acids (tizanidine - tablet forms, ketamine - intravenous infusions) and anticonvulsants - gabapentin (neurontin), pregabalin (lyrica), which interact with (α2-delta-protein) voltage-dependent calcium channels and, thus, exhibit an analgesic effect, have been actively used for postoperative pain relief. The mechanism of action of these drugs, apparently, has not been fully studied, however, the first good results have been obtained in the treatment of OBS with a neuropathic component.

Having studied in detail the works of leading specialists in the field of OBS therapy, one can, for example, present some possible combinations of drugs for drawing up postoperative pain relief schemes. Additionally, it is probably not necessary to dwell on the need for preoperative (examination period) pharmacological protection and the appointment of pathogenetically justified premedication, since this issue has been discussed in sufficient detail above. The routes of administration of drugs for postoperative analgesia may vary depending on the area of the operation (intramuscularly, intravenously, epidurally, orally, etc.). When prescribing certain schemes, it should be taken into account that the reaction to pain is strictly individual and variable in different patients; if necessary, additions can be made to any of the schemes prescribed to the patient.

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

Low-trauma surgeries include, for example, resection of the mammary or thyroid gland, removal of soft tissue tumors, etc., while moderate-trauma surgeries include resection of the lung, stomach or colon, and other surgeries comparable in terms of trauma.

Highly traumatic operations include gastrectomy and pneumonectomy with extended lymphadenectomy, abdominoperineal extirpation of the rectum, one-stage resection and esophageal plastic surgery.

Cytoreductive surgeries for extensive tumor lesions and surgical interventions for the removal of huge (for example, retroperitoneal) tumors, including the removal of large tumors of soft tissues and bone structures with simultaneous replacement of the resulting defect with a revascularized autograft, are particularly traumatic. This conditional division is intended to emphasize once again that the more aggressive the surgical treatment, the more powerful antinociceptive protection patients need.

Below are some possible combinations of drugs for creating postoperative pain relief schemes. It is clear that it is not possible to list all possible scheme options, so we provide only some examples.

Possible drug combinations for postoperative analgesia regimens

Preparations	Traumatic nature of the operation
	small	average	high
Peripheral analgesic (ketoprofen, paracetamol)	+	+	+
Tramadol	+	±
Butorphanol		±
Buprenorphine	-	±	+
Aprotinin	-	+	+
Gabapentin	P/P	P/P	P/P
Ropivacaine	-	±	+
Benzodiazepine	+	+	+
Ketamine	P/P	P/P	P/P

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

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

• to provide a more comfortable condition for patients,
• achieve complete analgesia in the postoperative period,
• significantly reduce the consumption of drugs, including opiates,
• reduce the development of side effects,
• significantly reduce the likelihood of developing chronic heart disease,
• to carry out earlier activation of patients,
• prevent many postoperative complications.

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