Chronic pain syndrome (CPS) in adult patients in need of palliative medical care: clinical guidelines

List of Abbreviations

VAS – visual analog scale

HIV – human immunodeficiency virus

VC – medical commission

WHO – World Health Organization

EAPC – European Association for Palliative Care

GI – gastrointestinal tract

ZNO – malignant neoplasms

PPI – proton pump inhibitors

CT – computed tomography

MRI – magnetic resonance imaging

NP – neuropathic pain

НОШ – Numerical Rating Scale

NSAIDs – non-steroidal anti-inflammatory and antirheumatic drugs (M01A)

PS – psychotropic substances

PMC – palliative medical care

PET/CT – positron emission tomography / computed tomography

GFR – glomerular filtration rate

AIDS – acquired immunodeficiency syndrome

TDS – transdermal delivery system

LCE – level of confidence of evidence

US – ultrasound examination

GRS – grade of recommendation strength

CCF – chronic cancer pain syndrome

CNS – central nervous system

GRADE – Grading of Recommendations Assessment, Development and Evaluation

IASP – International Association for the Study of Pain

Terms and Definitions

Adequate pain control – sustained analgesia in which the intensity of chronic (persistent) background pain during the day is less than 40 mm on the VAS or less than 4 points on the 0-10 NRS, or estimated in another equivalent of tolerable pain / complete analgesia, and is not accompanied by intolerable adverse events.

Adjuvant analgesics – drugs whose primary indication is not pain relief, but which in certain situations help reduce pain. These include, in particular, certain antiepileptic drugs, antidepressants, glucocorticoids, and centrally acting muscle relaxants.

ATC – Anatomical Therapeutic Chemical classification system for medicinal products.

Pain – an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or resembling such an experience.

End-of-dose failure pain – pain that occurs at the end of the dosing interval when the concentration of the analgesic in the blood drops below the minimum therapeutic (analgesic) level.

Pain intensity - the primary component characteristic of the severity of pain experienced and described by the patient (see the definition of pain severity).

Short-acting dosage forms – a term used interchangeably with terms such as "immediate-release" and "conventional-release" dosage forms.

Neuropathic pain – pain caused by a lesion or disease of the somatosensory nervous system (central or peripheral divisions). Neuropathic pain may persist even without ongoing stimulation.

Non-opioid analgesic – an analgesic whose pain-relieving effect is mediated by a central mechanism not involving the activation of opioid receptors. These include analgesic-antipyretics (N02B other analgesics and antipyretics) – central cyclooxygenase inhibitors paracetamol** (N02BE anilides) and metamizole sodium (N02BB pyrazolones), including in combinations not containing codeine. For the purposes of these guidelines, the central analgesic nefopam (N02BG other analgesics and antipyretics), which has a different mechanism of action, is considered separately.

Non-steroidal anti-inflammatory drug (NSAID) – a medicinal product possessing rapid analgesic and anti-inflammatory effects mediated by the inhibition of central and peripheral cyclooxygenases (M01A non-steroidal anti-inflammatory and antirheumatic drugs, excluding symptomatic slow-acting drugs for osteoarthritis - SYSADOA, formerly known as "chondroprotectants").

Nociceptive pain – pain arising from tissue damage and resulting from the activation of nociceptors.

Nociplastic (dysfunctional) pain - pain that arises from altered nociception despite no clear evidence of actual or threatened tissue damage causing the activation of nociceptors or evidence of disease or lesion of the somatosensory system causing neuropathic pain.

Opioid-naive patient – a patient who does not meet the criteria for opioid tolerance regarding the dose and duration of opioid use.

Opioid-tolerant patient – a patient receiving at least 60 mg/day of oral morphine or an equianalgesic dose of another opioid (30 mg/day of oral oxycodone [including in combination with naloxone], 25 mcg/h of transdermal fentanyl) for 1 week or longer.

Acute pain - a sensory response with the subsequent engagement of emotional-motivational, autonomic, and other factors upon a breach of body integrity. Under normal conditions, pain is a biologically driven signaling phenomenon and disappears when the causes of damage are eliminated.

Persistent pain - a term used to denote prolonged, constant pain associated with a somatic disease, severe infections, malignancies, etc.

Tolerance – a decrease in sensitivity to a pharmacological agent following repeated administration, requiring a dose increase to achieve the previous effect.

Extended-release dosage forms – a term used interchangeably with terms such as "sustained-release", "controlled-release", as well as "retard preparations".

Breakthrough pain – an episode of severe pain occurring on a background of persistent pain adequately controlled by regular (stable) opioid therapy.

Strong opioid (opioid analgesic) – an analgesic whose pain-relieving effect is associated with agonist activity at opioid receptors for which the drug has a high affinity, determining its high analgesic potential for relieving moderate and severe pain. Strong opioids registered in the Russian Federation include all opioid analgesics of the N02A group, except for tramadol (including in combination with paracetamol).

Withdrawal syndrome – a complex of unpleasant symptoms occurring upon the abrupt cessation or dose reduction of a medicinal product (psychoactive substance) after repeated, usually prolonged and/or high-dose use of the given product (substance). It can be induced by the administration of an antagonist drug. It is a criterion for established physical dependence on the drug (substance).

Weak opioid (opioid analgesic) – an analgesic whose pain-relieving effect is associated with agonist activity at opioid receptors for which the drug has a low affinity, determining its analgesic potential for relieving moderate pain. Weak opioids registered in the Russian Federation include tramadol (N02AX02), including tramadol in combination with paracetamol (N02AJ13), as well as low-dose codeine in combination products (N02BE71).

Opioid rotation – the clinical practice of substituting one opioid analgesic for another due to dose-limiting adverse reactions and/ schak or insufficient analgesic efficacy, or other reasons preventing the continued use of the previous drug in a patient.

Spontaneous pain – a type of breakthrough pain occurring without apparent causes (an identifiable trigger). As a rule, it has a more gradual onset and a longer duration compared to provoked breakthrough pain.

Provoked (incident) pain is pain caused by a medical procedure or the patient's voluntary action (walking, swallowing, etc.)—predictable pain; or by an involuntary action (coughing, tenesmus, etc.)—unpredictable pain. It may be a variant of breakthrough pain if it meets the criteria for the latter.

Pain severity is a complex characteristic that includes pain intensity, as well as the severity of pain-related distress and functional impairment.

Chronic pain is pain that develops as a result of prolonged noxious stimulation—beyond the normal healing period (3 months). Cerebral systems, with the involvement of integrative nonspecific (monoaminergic) systems of the central nervous system, play a dominant role in the development of chronic pain.

1. Brief information on the disease or condition

1.1 Definition of the disease or condition

Pain is not only a symptom of most diseases, but also a complex psychophysiological phenomenon involving emotion regulation and generation mechanisms, motor, humoral, and hemodynamic manifestations that shape the pain syndrome. In 2020, the International Association for the Study of Pain (IASP) defined pain as follows: "An unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage" [1]. Chronic pain is defined as pain that persists longer than the time normal healing would take, or in other words (including cases where there are no clear signs of actual tissue damage) persists / recurs for three months or more [55]. However, according to modern concepts, chronic pain has important differences from acute (signaling) pain beyond just duration.

1.2 Etiology and pathogenesis of the disease or condition (group of diseases or conditions)

Chronic pain syndrome is effectively an independent disease. It serves no protective function and has no biological purpose. On the contrary, chronic pain leads to maladaptation, abnormal perception of painful and non-painful impulses, and is accompanied by various central nervous system dysfunctions. The clinical presentation depends on the localization of the lesion, the patient's constitution, psychological state, and individual pain threshold, as well as prior pain experience [2, 3].

The primary cause of chronic pain syndrome is long-standing, constant pain that causes an imbalance in the peripheral and central nervous systems. In this case, neuronal receptors and fibers undergo continuous activation, leading to increasing stimulation of the central nervous system (spinal cord and brain) by noxious stimuli. One of the main causes of chronic pain is the emergence of hyperreactive neuron clusters at various levels of the central nervous system. Their pathological activity is caused by the breakdown of neuronal inhibition mechanisms, hyperexcitability of neurons, and the activation of inactive synapses, which unite these neurons into a single focus of excitation with self-sustaining ectopic activity. This activity leads to functional, structural, and adaptive (neuroplastic) changes in the brain and spinal cord, causing the pain to persist even after its cause has been eliminated [4, 5].

Pain caused by a malignant tumor process has its own specific features. Tumor cells grow rapidly, compressing adjacent healthy tissues that are sensitive to mechanical stimuli (visceral pain), or invading or compressing peripheral and central nervous system structures (e.g., neuropathic pain). During development and growth, the tumor releases specific algogens: endothelin, prostaglandins, and tumor necrosis factor-alpha (TNF-α), which excite or increase the susceptibility of peripheral receptors and nerve fibers to sensory stimuli. Tumors also release hydrogen ions (H+), leading to local acidosis accompanied by a similar effect. Proteolytic enzymes produced by tumor cells continuously excite and destabilize sensory sympathetic innervation, leading to neuropathic pain. Pain caused by tumor metastases results from direct tumor damage to C-affbrents of sensory neurons innervating the bone marrow, as well as from an imbalance between osteoclast and osteoblast activity. Bones lose strength and are subject to osteolysis, pathological fractures, and microfractures, making mechanical periosteal deformation the primary source of pain [6].

Nociceptive somatic pain occurs as a result of tissue damage or exposure to a noxious agent, including a tumor, with subsequent activation of pain receptors (nociceptors) in the bones, skin, subcutaneous tissue, muscles, soft tissues, etc. This pain is well localized, can be intermittent or constant, and has various descriptive characteristics: dull or sharp, pressing, throbbing, jerking, drilling, gnawing, bursting, etc. [7].

Nociceptive visceral pain occurs upon damage to sympathetically innervated organs (such as involvement of the pancreas, stomach and intestinal walls, or stretching of the liver capsule, etc.). This pain is poorly localized and has a diffuse character (dull with exacerbations, squeezing, cramping, pulling, debilitating, etc.) [7].

Neuropathic pain is the result of damage to the nervous system at the peripheral or central level, or a pathological process in the somatosensory system. It often accompanies severe nociceptive pain syndromes, but sometimes occurs as an independent type of pain, for example, after surgery, during chemotherapy, as a result of nerve compression by a tumor, viral nerve damage, or in severe forms of diabetes [6, 7].

Neuropathic pain is easy to recognize:

• the patient describes their pain as unusual: burning, shooting, “like an electric shock,” or other strange sensations;

• an area of skin near the pain localization may be either numb or excessively sensitive, to the extent that even a light touch of fabric is painful [7, 8, 9].

Nociplastic (dysfunctional) pain is pain that occurs in the absence of nociceptor activation and visible organic damage, including within the nervous system. The main difference between the dysfunctional type of pain and nociceptive or neuropathic pain is that routine examination fails to identify the cause of the pain or organic diseases that could explain its origin. Typical examples of such pain include fibromyalgia, tension headache, and psychogenic pain (somatoform pain disorder) [10].

1.3 Epidemiology of the Disease or Condition

Chronic / persistent pain can result from the following conditions:

1) chronic diseases (tumor processes, cardiovascular, neurological, endocrine, psychiatric, rheumatoid, etc.);

2) life-threatening diseases (can provoke both acute and chronic pain simultaneously, e.g., malignancies, HIV/AIDS).

Estimates of the prevalence of pain in various diseases are reflected in WHO guidelines [11]:

• Oncological diseases: 35–96%;

• Cardiovascular diseases: 41–77%;

• Renal failure: 47–50%;

• Chronic obstructive pulmonary disease: 34–77%;

• HIV/AIDS: 63–80%;

• Liver cirrhosis: 67%;

• Multiple sclerosis: 43%;

• Parkinson's disease: 82%;

• Alzheimer's disease and other dementias: 47%;

• Rheumatoid arthritis: 89%;

• Diabetes mellitus: 64%;

• Multidrug-resistant tuberculosis: 90%.

Cancer patients account for about 1/3 of all adult palliative care patients [56]. At the same time, pain is one of the main distressing symptoms of malignant neoplasms (MN). Despite the remarkable progress made in tumor diagnosis and therapy, WHO expert projections indicate that cancer morbidity and mortality will increase in the near future, leading to a rising number of patients with tumor-related pain syndromes.

In Russia, approximately 4 million patients (3,973,295 people in 2020) are registered with a confirmed diagnosis of malignant neoplasms, of whom about 300 thousand die annually and more than 560 thousand new cases are detected [57]. In the early stages of the tumor process, 35–50% of patients complain of pain; as malignant neoplasms progress, this number increases to 75%, and in the terminal stage to 95–100%. Thus, the number of cancer patients in need of analgesic therapy significantly exceeds the number of deaths from malignant neoplasms and in our country alone exceeds 430 thousand patients [7].

1.4 Features of Coding the Disease or Condition

Pain, not elsewhere classified (R52):

R52.1 – constant intractable pain;

R52.2 – Other chronic pain.

Pain is a manifestation or symptom of a disease or condition, therefore, when drawing up medical documentation, the ICD-10 code corresponding to the underlying disease is used, which can be supplemented with codes indicating the existence of pain in the patient. This is important in the differential diagnosis of complex cases when the cause of pain cannot be established immediately.

Palliative care (Z51.5).

According to the Decree of the Government of the Russian Federation No. 1180-r dated May 16, 2022, “On the list of diseases or conditions (groups of diseases or conditions) for which the use of a medicinal product is permitted in accordance with the indicators (characteristics) of the medicinal product not specified in the instructions for its use”, off-label prescribing of medicinal products is permitted when providing palliative care (Z51.5).

1.5 Classification of the disease or condition

The most frequently used pain classifications:

● By pathophysiological mechanism: nociceptive – somatic (superficial/deep) or visceral; neuropathic – peripheral or central; nociplastic (dysfunctional).

● By temporal factor: acute or chronic, however, such a division is conventional and is not necessary for making a decision on the treatment strategy, since the symptoms and causes of these two types may overlap, and pathophysiological factors may not depend on duration. It is acceptable to use the term “persistent” pain. Breakthrough pain is singled out separately.

● By etiology: cancer or non-cancer pain (has no significant impact on the therapy tactics in advanced, incurable, and progressive diseases).

● By anatomical localization: for example, headache, back pain, myofascial, rheumatic, skeletal, neurological, vascular; however, classification by localization/function does not always take into account the mechanism of pain and does not offer strategies for pain treatment [12].

1.6 Clinical presentation of the disease or condition

Chronic pain syndrome causes a number of pathological reactions: release of catecholamines, resulting in: mydriasis, tachycardia, arterial hypertension, tachypnea, increases skeletal muscle tone and causes convulsive activity. Over time, all these autonomic reactions lead to body maladaptation: they disrupt night sleep, drastically reduce appetite, cause depression and psychosomatic disorders, contribute to the development of malnutrition and, consequently, systemic inflammatory response syndrome. All these factors cause suppression of immune function, imbalance of neuro-endocrine-immune interactions, which exacerbate the progression of the underlying pathological process causing the pain. Long-standing pain is one of the most powerful unpleasant sensations in humans, reducing the quality of life up to suicidal consequences.

2. Diagnostics, medical indications and contraindications for diagnostic methods

The criteria for diagnosing chronic pain syndrome in an adult patient in need of palliative medical care should be considered:

• the presence of the patient's complaints of pain;

• the score on pain assessment scales indicating the presence of pain;

• the duration of pain for the majority of days for at least 3 months;

• the presence of pain-related significant emotional distress and/or impairment in functional activity (daily, social, occupational).

2.1 Complaints and Anamnesis

Any perception of pain is subjective, therefore there is no method for its objective measurement. Taking a history of chronic pain syndrome should include the following important points (see Appendix A3. Sample form of the questionnaire for initial pain assessment):

1) number and localization of pain foci;

2) duration of the preceding pain history;

3) effectiveness of previous pain therapy;

4) applied analgesics;

5) impact of pain on physical activity;

6) impact of pain on the duration of night sleep;

7) impact of pain on the ability to eat and other factors.

2.2 Physical Examination

Comments: pain must be evaluated regularly. The goal of pain assessment is to understand what the patient is experiencing and to identify factors influencing it (exacerbating and relieving). Subjective methods of pain assessment using scales are routinely used: this is done by the patient themselves, or by a doctor, nurse, or in the absence of contact with the patient, by the caregiver. In the evaluation process, the type of pain (nociceptive, neuropathic, nociplastic (dysfunctional), mixed), its intensity (mild, moderate, severe), and duration (acute or chronic) are identified; localization is established, and treatment efficacy is determined. For any type of pain, it is necessary to understand the cause and treat it, if possible.

Pain assessment is carried out by a physician or nurse at each visit and examination of the patient separately during movement and at rest, which must be recorded in the medical documentation (see Appendix A3. Sample form of the pain assessment diary).

Pain intensity is assessed using various scales, the most frequently used of which are: the numerical rating scale (NRS, synonym: numerical rating scale), which has a digital grading corresponding to scores from 0 to 10, and the visual analog scale (VAS), which is a 10 cm uncalibrated segment reflecting pain intensity in millimeters from 0 to 100 mm (Fig. 1, see Appendix G1. Visual Analog Scale, Appendix G2. Numerical Rating Scale (Numerical Rating Scale and Appendix G3. Wong-Baker FACES Scale). The patient is invited to rate their perception of pain over the past 24 hours on the scale (from minimal to excruciating), which allows expressing the assessment quantitatively in millimeters on the VAS or in scores on the NRS [14].

By comparing the obtained data with the clinical picture and the results of instrumental examination methods, the degree of pain intensity is determined according to the following grading [14, 58]:

o no pain: 0–4 mm on VAS or 0 scores on NRS;

o mild pain: 5–44 mm on VAS or 1–3 scores on NRS;

o moderate pain: 45–74 mm on VAS or 4–6 scores on NRS;

o severe pain: 75–100 mm on VAS or 7–10 scores on NRS.

A decrease in pain intensity on the NRS by 2 scores or 30% is considered clinically significant, changes of more than 3 scores on the NRS or 50% on the VAS are considered substantial; treatment results are interpreted depending on the nature of the pain syndrome, but usually a change of more than 20 mm is considered substantial [58].

Pain assessment in individuals with cognitive impairment is based on principles similar to pain assessment in children. The basis is behavioral reactions and the ability to distract or comfort, with the severity of manifestations assessed dynamically. A holistic approach to relieving a number of symptoms that may be interrelated or expressed in various forms (for example, when pain manifests as agitation) is extremely vital. In this regard, all changes in the patient's behavior should be regarded as a possible manifestation of pain in the presence of confusion:

To determine the cause of discomfort (e.g., pain, feeling cold) in severe cognitive impairment, the opinion of multiple caregivers must be taken into account.

For screening and monitoring the condition of patients with moderate and severe cognitive impairment, various pain assessment tools for patients with cognitive impairment have been described in the literature, but to date they have not undergone linguistic adaptation and validation in the Russian Federation.

Additionally, such components of pain as psychological and physical suffering (burdensome symptoms capable of intensifying the sensation of pain) and psychosocial disorders should be taken into account and assessed [15, 16].

Visual Analog Scale

Numerical Rating Scale

Wong-Baker FACES Scale

Figure 1 – Scales for pain intensity assessment

To detect neuropathic pain, a screening questionnaire should be used (see Appendix G4. DN4 Neuropathic Pain Diagnostic Questionnaire [59, 60] intended for physicians of non-neurological specialties. The questionnaire makes it possible to detect the presence of neuropathic pain with a certainty of more than 80%. The presence of neuropathic pain in a patient is highly probable if the DN4 score is ≥4.

Palliative patients often present with two types of pain simultaneously: neuropathic and nociceptive (mixed type of pain).

2.3 Laboratory Diagnostics

Laboratory tests do not provide significant diagnostic information regarding the intensity, localization, and type of pain syndrome.

2.4 Instrumental Diagnostics

Comments. Instrumental diagnostic methods, such as radiography, ultrasound examination (ultrasound), magnetic resonance imaging (MRI), computed tomography (CT), positron emission tomography combined with computed tomography (PET-CT), etc., are auxiliary. They allow determining the nature, localization, and severity of the pathological process that serves as the source of pain [62,63,64]. These methods are irrelevant in choosing pain management tactics, as palliative care aims to improve the quality of life in patients with incurable diseases where treatment options for the underlying condition are exhausted.

The purpose of examining a patient with any pain syndrome is to clarify the nature of the pain and to identify the disease causing the pain.

It is important to identify multiple sources, both primary and additional if present, as well as to clarify the localization of pain sensations [62,63,64].

For any acute or chronic pain, it is necessary to assess its qualitative and quantitative characteristics: intensity, the patient's description of pain and sensory sensations, as well as how unpleasant and unbearable the pain is.

In addition, factors that increase or decrease pain should be clarified, and the duration of the pain syndrome, fluctuations in pain, and sensory disturbances over time should be assessed.

During the examination, it is also necessary to assess the presence of pain behavior signs, pain "catastrophizing", comorbid pain, or emotional-affective disorders existing independently or caused by pain, sleep disturbances, and the degree of social maladaptation [65,66,67].

It must be remembered that minor destruction can cause severe pain and, conversely, a widespread pathological process may occur without pain.

2.5 Other Procedures

Not required.

3. Treatment, including drug and non-drug therapies, diet therapy, and pain management

3.1 Conservative therapy

The principles of cancer pain management were first proclaimed by the WHO in 1986 [68]. Subsequently, they extended to the management of non-cancer pain and thus can be used to provide palliative care to patients requiring analgesia, regardless of the cause of the pain syndrome. However, the management algorithm itself in the form of the "3-step analgesic ladder" (Fig. 2) in the third revision of the WHO guidelines from 2018 is proposed to be considered largely as an educational tool [69]. Even earlier, in 2012, the EAPC Research Network scientifically evaluated the WHO guidelines regarding opioid use based on modern evidence-based medicine methods using the GRADE system and published its recommendations, where certain provisions of cancer pain pharmacotherapy were revised and clarified [15, 16]. In particular, emphasis was placed on the fact that a patient with severe pain syndrome may immediately require strong opioid analgesics (group N02A, excluding tramadol**, including combinations), and in this case, it is not required to sequentially move from the first step of the "ladder" to the third.

Thus, the choice of chronic pain therapy should be determined by the intensity and pathogenetic characteristics of the pain. Opioid therapy remains the main method of pain treatment in the provision of palliative care to cancer and non-cancer patients.

Figure 2 – World Health Organization "Analgesic ladder" [68].

3.1.1 General principles of chronic pain therapy in the provision of palliative medical care

Comments: Analgesic therapy should be initiated with an analgesic whose potency and dose correspond to the intensity of pain assessed by the patient using a validated VAS or NRS. Thus, weak analgesics (paracetamol**, NSAIDs) should not be prescribed as sole therapy to a patient suffering from moderate to severe pain. Considering the intensity of the pain, such a patient may initially require the prescription of an opioid (e.g., oral morphine**) or a combination of an opioid with paracetamol** / NSAIDs. Based on available randomized trials involving opioid-naive patients, it is impossible to determine the preferred type of analgesic for initial therapy [69]. At the same time, the frequency of side effects between weak and strong analgesics differs insignificantly (although they differ in nature).

Comments: The correct opioid dose is considered to be the dose that ensures a reduction in the patient's pain to an acceptable level (pain intensity less than 40% on the VAS or less than 4 points on the NRS). Response to opioid medications may vary among different patients and depends on both patient characteristics and the drug used. An opioid effective in one patient may not produce a sufficient effect in another patient at the same dose. Tolerability of drugs varies similarly. The choice of opioid, its dosage, and administration schedule should be based on the pharmacokinetic parameters of the specific drug, taking into account contraindications and side effects, as well as the patient's condition and comorbidities.

Comments: medicinal products should be administered in the most effective, convenient, and at the same time least painful way. The EAPC Research Network recommends the oral route of administration as the preferred option if oral analgesics can be used [15]. The transdermal route of administration is possible in cases of moderate to severe continuous and prolonged pain (e.g., in GI tumors), taking into account the clinical picture of the disease and patient preferences. Among parenteral routes of administration, the subcutaneous route is the primary one, and intravenous administration is used when rapid pain control is needed. The intramuscular route is not used for continuous analgesia. Spinal (epidural and intrathecal) administration of opioids (in particular, morphine** and #fentanyl**) [150, 151] and/or anesthetics (bupivacaine**) [152] is used in some patients with intense pain, poor response to routine systemic opioid therapy, or due to poorly tolerated adverse reactions from high opioid doses. The spinal route of opioid administration falls under the category of off-label use, but in a number of refractory pain cases, it allows achieving a successful result [153, 154]. Opioid doses for intrathecal administration are lower than for oral and epidural administration, on average by 300 times and 24 times, respectively [70]. In particular, intrathecal administration of morphine** is most often limited to a dose of 1–4 mg, and #fentanyl** (at Z51.1) – from 5 to 25 mcg [155].

Comments: analgesics should be prescribed regularly according to a schedule, without waiting for pain to worsen, taking into account the duration of the drug's action and the patient's individual characteristics.

Comments: analgesic doses are selected starting from high doses of weak drugs to low doses of strong analgesics in accordance with pain intensity. The transition to a stronger analgesic is determined by worsening pain, poor response to the applied analgesic therapy, and adverse drug reactions in a specific patient. At the same time, a patient with severe pain syndrome may initially require a strong opioid, the use of which should begin with small doses, achieving the minimum effective dosage for the specific patient through dose titration.

Comments: effective analgesia is achieved by selecting an analgesic and its adequate dose (dose titration) that provides pain relief until the next dose. There is no single dose and combination of drugs that is universal for everyone. In addition, previously effective doses and/or drugs in the same patient at a certain point may become ineffective due to the progression of the underlying disease, impaired absorption, development of tolerance (when using opioids), and other reasons, which is the basis for reviewing and correcting the analgesia regimen.

Comments: it is necessary to regularly evaluate the effectiveness of therapy and manage emerging side effects. It is recommended that the patient keep a daily individual diary (see Appendix A3. Sample pain assessment diary).

3.1.2 Mild pain therapy

Pain intensity is assessed by the patient as mild, ranging from 5 to 44 mm on the VAS or 1-3 points on the NRS.

Comments: mild pain may respond to therapy with non-opioid analgesics paracetamol** and metamizole sodium, as well as NSAIDs. Available data do not allow identifying the most effective drug from the group of non-opioid analgesics / NSAIDs. Various NSAIDs, paracetamol**, and metamizole sodium have been studied in cancer patients with moderate to severe pain syndrome and have demonstrated approximately similar activity, with the exception of paracetamol**. At the same time, convincing evidence for or against the use of non-opioid analgesics / NSAIDs for the treatment of mild pain, including in patients with progressive non-cancer conditions, has not yet been obtained. Metamizole sodium and ketorolac** cannot be considered as primary agents for the treatment of chronic pain, since the continuous course of therapy with these drugs is limited to five days (and ketorolac** injections to only two days) according to their instructions for use.

The efficacy of the centrally acting non-opioid analgesic nefopam, available only as a solution for infusion and intramuscular injection, has been evaluated in patients with chronic pain syndrome only in isolated studies. Apparently, its intrinsic analgesic activity in the recommended daily dose range is of no clinical significance; nevertheless, a trend towards a reduced need for opioids (opioid-sparing effect) has been noted with its use [75]. In addition, according to the instructions for use, nefopam is indicated for acute pain syndrome.

The use of non-opioid analgesics/NSAIDs is accompanied, if necessary, by adjuvant and symptomatic therapy: antiepileptics, antidepressants, antispasmodics (A03A and A03B), centrally acting muscle relaxants, anxiolytics, hypnotics and sedatives (including benzodiazepine-like agents), glucocorticosteroids, bisphosphonates (M05BA, bisphosphonates), and other drugs [23] (see Appendix A3. Adjuvant analgesics and symptomatic therapy agents). The purpose of using such drugs is to increase the effectiveness of analgesic therapy, taking into account the specifics of the patient's pain pathogenesis, while avoiding escalation of the dose of the main analgesic or switching to a stronger drug, especially an unjustified one. In particular, antidepressants and antiepileptic drugs are recommended as first-line therapy for neuropathic pain [60, 94] (see section 3.1.9). Anxiolytics are necessary to relieve agitation associated with pain syndrome; sedatives and hypnotics are used to treat sleep disorders, including sleep initiation disorders associated with pain syndrome [148, 149]. Antispasmodics (A03A and A03B) potentiate the effect of analgesics in spastic pain and colic; centrally acting muscle relaxants are used to treat painful skeletal muscle spasms (cramps); glucocorticoids are effective in nerve and spinal cord compression, as well as in cases of pronounced peritumoral edema in progressive malignant neoplasms [113, 147]. Bisphosphonates are recommended to reduce pain associated with bone metastases if standard therapies have been exhausted [156].

Comments: class-specific adverse reactions of NSAIDs include: hepatotoxicity, nephrotoxicity, as well as cardiovascular risks (in the form of arterial hypertension destabilization, decompensation of chronic heart failure, and arterial thrombosis) and gastrointestinal risks (NSAID-associated dyspepsia, gastropathy, and enteropathy complicated by GI perforation and bleeding, among others). The risk of gastrointestinal and cardiovascular adverse reactions varies among different NSAIDs. The use of selective COX-2 inhibitors (M01AH coxibs) compared to non-selective NSAIDs is associated with a lower risk of gastrointestinal damage; the most gastrotoxic NSAIDs include indomethacin, naproxen, and ketorolac** [78]. The lowest risk of cardiovascular events among NSAIDs (except for acetylsalicylic acid**) in several meta-analyses has been shown only for naproxen, but all NSAIDs are equally capable of worsening the course of chronic heart failure [79, 80]. Thus, when choosing an NSAID, risk factors for adverse reactions in a particular patient should be taken into account (see Appendix A3. Risk factors for complications associated with NSAID use (for the general population) and prescribing recommendations. At the same time, one must bear in mind the likelihood of an increased risk of typical NSAID complications in palliative care patients suffering from anorexia, cachexia, protein deficiency, who have undergone courses of chemotherapy and/or radiotherapy, etc., since the body's reparative capabilities in such patients are significantly reduced [76]. When choosing an NSAID, one can be guided by the drug that was effective and well tolerated by the patient in the past. Nevertheless, for safety reasons, any NSAID should be used for the shortest possible course at the lowest effective dose. It is advisable to use proton pump inhibitors to prevent upper GI damage—which, however, do not reduce and, according to some data, even increase the risk of small intestine mucosal injury (NSAID-associated enteropathy) [81, 82, 83]—or H2-histamine receptor blockers. For some patients, opioids may represent a safer and more effective alternative to NSAIDs [76].

3.1.3 Moderate pain therapy

Pain intensity is assessed by the patient as moderate, ranging from 45 mm to 74 mm on the VAS or 4-6 points on the NRS, or if adequate control is not achieved by regular intake of paracetamol, NSAIDs, and adjuvant analgesics. The list of opioids for moderate chronic pain therapy is presented in Table 1.

Table 1 – Opioids for moderate pain therapy in palliative medical care in the Russian Federation

1 #Buprenorphine + Naloxone is used for Z51.5 [7, 171, 174, 179].

Non-opioid analgesics / NSAIDs, antiepileptic drugs, antidepressants, anxiolytics, hypnotics and sedatives (including benzodiazepine-like drugs), systemic antihistamines, glucocorticoids, antispasmodics (A03A and A03B), muscle relaxants, bisphosphonates (M05BA, bisphosphonates), etc. may additionally be used as adjuvant analgesics (see section 3.1.2 above). Additionally, it is advisable to prescribe therapy to reduce the side effects of the drugs used: proton pump inhibitors, laxatives, antiemetics, H2-histamine receptor blockers, etc. (see Appendix A3. Adjuvant analgesics and agents for symptomatic therapy).

Comments: regular use of the weak opioid tramadol** ensures effective analgesia without pronounced adverse side effects throughout the day. For the treatment of moderate pain, tramadol is used in a daily dose of up to 400 mg (in individuals over 75 years of age — up to 300 mg/day) [51] (Table 1).

Comments: The EAPC has introduced changes to the list of step 2 drugs on the "analgesic ladder", where it is recommended to use low doses of strong opioids as an alternative alongside weak opioids (Fig. 1). Taking into account the drugs registered in Russia, it is possible to use: preparations of morphine**, naloxone + oxycodone**, tapentadol**, fentanyl** in the form of a transdermal therapeutic system (TTS).

Comments: The Russian drug propionylphenylethoxyethylpiperidine is a synthetic opioid agonist, comparable in potency to trimeperidine. It is well absorbed through the oral mucosa and is used in the form of sublingual (buccal) tablets (Table 1).

Comments: for patients who for objective reasons cannot be prescribed oral forms of prolonged-release opioids (except for patients with severe cachexia, sweating, hyperthermia, or skin lesions), both drugs are an effective non-invasive means of transporting opioids into the systemic circulation.

Comments: parenteral administration of morphine** for moderate pain is carried out in fractional doses of 3–5 mg 2–4 times a day, up to a total of 10 mg/day; prolonged subcutaneous or intravenous infusion can be used [53]. Taking into account the invasive forms of strong opioids registered in the Russian Federation, it is possible to use a combination drug containing Codeine + Morphine + Noscapine + Papaverine + Thebaine, in the form of a solution for subcutaneous administration, taking into account individual tolerance to the components. Trimeperidine** in tablets and parenteral solution is not recommended for chronic pain therapy due to the risk of neurotoxic effects from the accumulating metabolite normeperidine, especially in debilitated patients.

3.1.4 Severe pain therapy

Pain intensity is assessed by the patient as severe, ranging from 75 mm to 100 mm on the VAS or 7–10 points on the NRS, or if adequate control is not achieved by regular intake of weak opioids or low doses of strong opioids (Table 1) combined with adjuvant analgesics.

Table 2 – Opioid analgesics in non-invasive dosage forms for the treatment of severe pain in the provision of palliative medical care in the Russian Federation

1#Buprenorphine + naloxone is used for Z51.5 [7, 171, 174, 179];

2The maximum dose of tapentadol in film-coated tablets is 700 mg on the first day, and 600 mg per day on subsequent days.

Comments: strong opioids registered in the Russian Federation for the treatment of chronic pain syndrome include morphine**, naloxone + oxycodone**, fentanyl**, buprenorphine**, tapentadol**, and propionylphenylethoxyethylpiperidine** (see Appendix A3. List of registered opioid preparations in injectable dosage forms, List of registered opioid preparations in non-invasive dosage forms, Brief characteristics of opioid preparations in non-invasive dosage forms). Prolonged-release forms of strong opioids are: morphine** in capsules and tablets, the combination drug naloxone + oxycodone** in tablets, tapentadol** in tablets, fentanyl** TTS (Table 2).

In patients without swallowing disorders and without moderate to severe renal and hepatic impairment, taking into account their preferences, strong pain therapy is initiated with oral tablet formulations (morphine**, naloxone + oxycodone**, tapentadol**) [15, 50] (see Appendix A3. Determination of the degree of hepatic impairment and Determination of the degree of renal impairment). In patients with swallowing disorders, oral morphine solution can be used, as well as the contents of prolonged-release morphine capsules, where morphine is presented in the form of sustained-release microgranules, including administration via a nasogastric tube or gastrostomy. If oral forms are impossible for objective reasons, including patient refusal of oral medication, nausea or vomiting, intolerance to morphine or naloxone + oxycodone** or tapentadol** preparations, therapy is initiated with fentanyl** TTS. Available data indicate no significant differences in analgesic efficacy between orally administered strong opioids—morphine** and the naloxone + oxycodone** preparation—allowing only partially substantiated recommendations for the use of either of these two drugs as the drug of choice.

Comments: transdermal opioids are indicated for patients with severe persistent pain and swallowing disorders when transmucosal (buccal or sublingual) administration is impossible; for example, in mucositis, ulcerative or tumor lesions of the oral mucosa.

Transdermal opioids are the treatment of choice in patients with preserved swallowing function if severe pain is constant/persistent. According to an analysis of randomized trials, no significant differences in efficacy were found between transdermal and oral opioids, but the former showed superiority regarding the risk of constipation and patient preference. This indicates that in some cases, transdermal opioids are convenient and effective analgesics in opioid-naive patients [15]. Exceptions include patients with severe cachexia, hyperhidrosis, compromised skin integrity, and high fever. In these situations, the appropriateness of using transdermal opioids must be assessed, and the efficacy and safety of the drug should be monitored more carefully; a dose reduction may be required.

Comments: morphine** is metabolized in the liver to form active metabolites that are excreted primarily by the kidneys (85%) and in the bile (10%). Due to these elimination characteristics, the dose of morphine** should be reduced in patients with impaired intestinal transit (constipation), and severe renal and hepatic impairment. Fentanyl**, unlike morphine**, has inactive metabolites, making it the preferred drug of choice for patients with moderate to severe renal and hepatic impairment. Tapentadol** is contraindicated in patients with severe renal or severe hepatic impairment. (see Appendix A3. Determination of the degree of hepatic impairment and Determination of the degree of renal impairment).

Comments: available data provide clearly justified recommendations that the subcutaneous route is a simple and effective alternative method in patients unable to take opioids orally or transdermally. Intravenous infusions are used when subcutaneous administration is contraindicated (in severe peripheral edema, blood clotting disorders, peripheral circulation disorders, and the need to administer large volumes and high doses of the drug) and when rapid pain relief is required. In some cases, continuous patient-controlled analgesia is used for subcutaneous and intravenous opioid infusions. When switching from oral morphine** to subcutaneous and intravenous administration, it should be taken into account that the relative analgesic potency is the same for both routes of administration and ranges from 3:1 to 2:1 (non-invasive: invasive).

Comments: trimeperidine** undergoes biotransformation to form a neurotoxic N-demethylated metabolite, normeperidine, which stimulates the central nervous system (tremor, muscle twitching, hyperreflexia, and seizures may occur). The metabolite has a long half-life (15–20 hours), which can lead to a cumulative effect, especially common in cancer patients—a risk highlighted by WHO, EAPC, and IASP, which recommend limiting trimeperidine** therapy to 3–5 days. Due to the short duration of the intramuscularly administered dose of trimeperidine** (an average of 4 hours), the main indication for its use is acute pain (severe and moderate intensity): postoperative pain, trauma, burns, and pain syndromes in internal medicine (unstable angina, myocardial infarction, etc.). The efficacy of trimeperidine** decreases by 2–3 times when administered enterally; therefore, trimeperidine** tablets have not found widespread use in the treatment of acute pain either.

3.1.5 Strong opioid dose titration

Comments: immediate-release dosage forms of strong opioids should be used for dose titration. For these purposes, morphine** in the form of film-coated tablets of 5 and 10 mg, oral solution, or (if non-invasive forms cannot be used) subcutaneous or intravenous injection solution is used. The analgesic effect of oral immediate-release morphine** formulations begins 30 minutes after administration and lasts about 4–6 hours. After the first dose of the drug, the duration of its action should be determined, and as soon as the pain recurs, the next dose of morphine** should be given and continued on the same principle (as the effect of the previous dose wears off). For elderly and/or cachectic patients, it is recommended to start oral morphine** therapy with a dose of 2.5–5 mg. After 24 hours, the required dosing frequency of oral morphine** for the next 24 hours should be calculated, and a "round-the-clock" therapy schedule should be prescribed to the patient. The maximum efficacy of the prescribed dose of oral morphine** should be evaluated 60–90 minutes after administration. If the effect is unsatisfactory (pain persists), an additional dose of morphine** should be prescribed in addition to the main regimen without changing the scheduled time of the next dose. The final effective daily dose of morphine** is estimated by simply summing up all doses used during the day. If the selected daily dose adequately controls pain for 2–3 days, the patient can be switched to prolonged-release morphine** formulations (tablets or capsules) or other strong opioids at an equivalent dose, selecting the appropriate single dose of the drug taking into account its dosing frequency. If the short-acting morphine** dose is insufficient, its gradual increase should be continued each time by no more than 30–50% of the daily dose until full pain control is achieved or difficult-to-control adverse reactions appear [28, 52]. In the latter case, the issue of changing the treatment should be considered (discontinuing morphine** and using another opioid, or reducing the morphine** dose and adding other drugs, using non-pharmacological methods, etc.).

Dose titration of a strong opioid in patients who cannot swallow can be performed by parenteral administration of morphine** (from 2.5 to 5 mg), taking into account the patient's age and condition severity.

Renal impairment can lead to the accumulation of active morphine** metabolites; therefore, its administration should be avoided in this condition, and other opioids should be used (e.g., buprenorphine** or fentanyl**). However, in individual cases, in the presence of mild or moderate renal impairment, morphine** preparations may be used in lower doses, increasing the intervals between doses (up to 6–8 hours), or applying subsequent doses only as needed [52].

To titrate the dose of tapentadol**, its immediate-release dosage form can be used – 50 mg film-coated tablets every 4–6 hours; moreover, in the absence of an effect, the second dose of the drug can be taken 1 hour after the initial dose.

To titrate the dose of the naloxone + oxycodone** preparation, prolonged-release tablets at a dosage of 5 mg/2.5 mg every 12 hours are used; this regimen may be difficult in case of increased pain during the dosing interval, which will require the use of a fast-acting strong opioid (e.g., morphine**) to relieve it.

3.1.6 Opioid rotation

Comments: when switching opioids, safety regarding overdose must be ensured. Risks associated with drug rotation are manageable if the equivalent dose table is used (see Appendix A3. Table of Equianalgesic Opioid Dose Conversion) and consideration is given to the bioavailability of dosage forms, drug-drug interactions, history of opioid use, presence of hepatic and renal impairment, patient age, and other factors (see Appendix A3. Determination of the Severity of Hepatic Impairment. Additionally, for safety reasons, it is recommended to reduce the calculated equianalgesic dose of the new opioid by 25–50% upon initial administration. Exception: dose reduction may not be required when rotating to fentanyl** transdermal patch (TDS) and tapentadol** (in the latter case, if dose reduction is necessary, it is recommended to decrease it by no more than 30%).

Drugs that act as partial or full opioid receptor antagonists, such as buprenorphine**, should be used with caution against the background of other opioids due to the potential acute onset of withdrawal syndrome and unpredictable side effects.

Comments: changing the opioid and/or its route of administration should be done only when there is an insufficient analgesic effect at high doses of the drug and/or upon the development of intolerable adverse reactions.

3.1.7 Breakthrough pain therapy

Comments: research data allow for a strong recommendation in favor of prescribing additional opioids in immediate-release dosage forms for severe pain attacks occurring against the background of relatively well-controlled background pain using opioid therapy. These may include oral and transmucosal opioid formulations, as well as injections when no other alternative is available.

Studies have shown that the rescue dose of an opioid for treating breakthrough pain is individualized and must be determined by titration [39].

Timely treatment of breakthrough pain with short-acting medications contributes to better pain control and reduces unjustified escalation of long-acting opioid doses [13, 15, 21, 27, 38].

If a patient requires 4 or more doses of an opioid per day to relieve breakthrough pain, a review of the daily base opioid dose towards an increase is required.

Comments: The pharmacokinetics of oral opioids, specifically morphine (onset of analgesia in 20–30 min, peak effect in 60–90 min, and duration of action 3–6 h), least reflect the temporal characteristics of most breakthrough pain episodes, resulting in an insufficient and/or delayed effect and accompanied by additional adverse events [70]. Such drugs are suitable for patients with predictable breakthrough pain episodes or episodes with a slow onset. The dose of oral opioid for pain prevention/relief is equivalent to 1/6 (10–15%) of the total daily dose of the base opioid used for regular persistent pain therapy [28].

Comments: Transmucosal fentanyl formulations, otherwise known as rapid-onset opioids, produce an effect within 1–5 minutes of administration; they are indicated for the treatment of breakthrough cancer pain only in opioid-tolerant patients. In the Russian Federation, a metered nasal fentanyl spray is registered but currently unavailable for use. Propionylphenylethoxyethylpiperidine** buccal tablets are essentially a transmucosal formulation. However, compared to fentanyl preparations (the most lipophilic opioid with the highest analgesic potency), the effect of propionylphenylethoxyethylpiperidine** develops more slowly and is inferior in potency.

Opioid medications for treating breakthrough pain against the background of therapy for background persistent pain with prolonged-release forms of strong opioids (fentanyl** TDS, morphine**, naloxone+oxycodone**, tapentadol** tablets or capsules):

A. Treatment of predictable pain and pain with a slow onset:

1) morphine** film-coated tablets or oral morphine solution (dose equivalent to 1/6 of the total daily dose of the base opioid);

2) propionylphenylethoxyethylpiperidine** buccal tablets (approximate dose from 10 mg to 20–40 mg buccally or sublingually);

3) tapentadol** film-coated tablets (dose equivalent to 1/6 of the total daily dose of prolonged-release tapentadol**, or 50 mg);

B. Treatment of unpredictable pain and pain with a rapid onset:

1) morphine** (or a combination drug containing Codeine + Morphine + Noscapine + Papaverine + Thebaine) in the form of an injection solution; preferred route of administration is subcutaneous or intravenous (dose equivalent to 1/6 of the total daily dose of the base opioid, taking into account the parenteral administration of morphine**);

2) fentanyl** injection solution (approximate dose 0.05–0.1 mg intravenously; dose equivalent to 1/6 of the total daily dose of the base opioid) – in an inpatient setting only;

Example of morphine** dose calculation for breakthrough pain treatment.

If the patient is receiving prolonged-release oral morphine** at a dose of 60 mg twice daily, the total daily dose of the drug is 120 mg.

The calculated dose of morphine** film-coated tablets or oral morphine solution will be 20 mg (120 mg ÷ 6).

The calculated dose of morphine** injection solution will be 7 mg (oral morphine** dose of 20 mg divided by 3 [20 mg ÷ 3]).

Thus, to relieve an episode of breakthrough pain, this patient will need to take 2 tablets of morphine** 10 mg each, or the contents of 2 ampoules of oral morphine** solution 2 mg/mL – 5 mL, or an injection of morphine** at a dose of 7 mg.

If the patient has to use morphine** for "breakthrough pain" therapy more than 4 times a day, the dose of prolonged-release morphine** (base therapy) should be increased.

3.1.8 Management of opioid therapy complications

Comments: all patients taking opioid analgesics are at risk of developing constipation [43]. The incidence of constipation reaches 90%. Opioids inhibit longitudinal intestinal peristalsis while simultaneously causing spastic increases in smooth muscle contractions. Bowel evacuation can be facilitated by prescribing osmotic laxatives that reduce intestinal water absorption (lactulose**, macrogol**, etc.), contact laxatives (sennosides A and B**, bisacodyl**, sodium picosulfate), and stool softeners (liquid paraffin (vaseline oil), glycerol in the form of rectal suppositories). Laxatives will be effective only with adequate oral fluid intake. Laxatives should be taken throughout the entire period of opioid therapy, as tolerance to this opioid side effect does not develop. Their dose gradually increases with continuous use; it is recommended to switch laxatives, combine them, or periodically cleanse the bowel using an enema [23, 47].

Comments: the onset of nausea and vomiting with opioid use occurs at the beginning of therapy as a temporary side effect; intestinal atonia and paresis may also be the cause. Therefore, when initially prescribing opioids, especially tramadol, it is necessary to prescribe metoclopramide. The duration of antiemetic prescription during opioid therapy usually does not exceed 2 weeks, since tolerance to the emetic effect of opioids develops by this time. If nausea persists, it is necessary to prescribe or adjust the dosage of antiemetics, and if there is no positive effect, switch the opioid [54].

Comments: drowsiness is a depressed level of consciousness characterized by a constant desire to sleep and difficulty maintaining wakefulness. The degree of sedative effect in patients taking opioids can range from a mild desire to sleep and fatigue to severe drowsiness and coma, and may also be accompanied by other CNS side effects such as hallucinations, cognitive impairment, agitation, myoclonus, respiratory depression, and delirium. Patients should be informed about the possibility of developing drowsiness or reduced concentration at the beginning of treatment with strong opioids or when increasing the dosage, and that this phenomenon resolves over time. Patients should be warned that impaired concentration may affect their ability to drive vehicles and perform other tasks requiring focused attention.

3.1.9 Neuropathic pain therapy

The main method of treating neuropathic pain in palliative care patients is pharmacotherapy, which is carried out using a whole range of medicinal products (see Appendix A3. Adjuvant Analgesics and Agents for Symptomatic Therapy). Their efficacy and safety in the treatment of neuropathic pain has been confirmed by numerous foreign meta-analyses and systematic reviews [60, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103]. The basic guideline for the treatment of neuropathic pain in Russia is the clinical guidelines for the diagnosis and treatment of neuropathic pain by the Russian Association for the Study of Pain [60].

• Additionally, other adjuvant agents are used in the treatment of neuropathic pain in Z51.5, specifically #clonidine, #clonazepam [164-170].

For clonidine: Recommendation Grade A (Level of Evidence – 1).

For clonazepam: Recommendation Grade C (Level of Evidence – 4).

Comments: gabapentinoids (N03AX other antiepileptic drugs) gabapentin (N03AX12) and pregabalin** (N03AX16) act similarly to the inhibitory neurotransmitter GABA (gamma-aminobutyric acid). The action of the drugs is directed at different levels of neuronal transmission: they promote an increase in the synthesis and release of GABA, while inhibiting the synthesis and transport of glutamate, one of the main factors in the sensitization of pain structures and hyperalgesia, and also suppress Ca++ currents, stabilizing the postsynaptic membrane. An important positive quality of both drugs for use in palliative patients is that gabapentin and pregabalin** do not undergo hepatic metabolism and do not induce or inhibit hepatic microsomal enzymes. Gabapentin is excreted unchanged via renal clearance with a half-life of 5-7 hours. The elimination of gabapentin from the systemic circulation is directly proportional to creatinine clearance and, consequently, is reduced in elderly individuals and patients with renal impairment. About 80% of the administered dose of gabapentin is found unchanged in the urine, and 20% in the feces. Unlike gabapentin, pregabalin** has linear pharmacokinetics, which ensures predictability of changes in plasma drug concentration with dose increases or decreases. Pregabalin** is absorbed into the blood faster and has a higher bioavailability (90%) compared to gabapentin (60-80%) [104].

The most characteristic side effects of gabapentinoids: drowsiness, dizziness, weakness, ataxia, fatigue. These phenomena are not life-threatening, but require caution when titrating the dose in debilitated patients and patients receiving opioids.

Carbamazepine**—an older-generation antiepileptic drug—was for a long time the first-line drug in the treatment of neuropathic pain. Its therapeutic effect in neuropathic pain caused by hyperexcitation of the nervous system's pain structures is associated with the inhibition of pain impulse conduction in peripheral nerves due to the modulation of voltage-gated Na+ channels and inhibition of Ca++ currents, as well as an increase in the concentration of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) in the CNS. The use of carbamazepine in palliative patients is limited by its serious side effects: the risk of leukopenia and thrombocytopenia, interstitial nephritis, as well as cardiotoxicity, hepatotoxicity, and endocrine disorders. Carbamazepine** has proven efficacy only in trigeminal and glossopharyngeal neuralgia [89, 90].

Non-selective monoamine reuptake inhibitors (amitriptyline**) have an analgesic mechanism mediated by the inhibition of serotonin and norepinephrine reuptake in neuronal synapses, as well as the restoration of descending antinociceptive neuronal pathways. TCAs are widely used in patients with neuropathic pain caused by various etiologies: diabetic or chemotherapy-induced polyneuropathy, herpetic and trigeminal neuralgia, phantom pain, and neuropathic pain in cancer patients [60, 89, 92].

At the same time, it should be borne in mind that amitriptyline** undergoes biotransformation in the liver to form active metabolites, which are excreted slowly by the kidneys; the excretory function of the kidneys is frequently impaired in palliative care patients. Adverse drug reactions are associated with M-cholinergic receptor blockade: dry mouth, urinary retention, decreased intestinal peristalsis, and increased sweating, which impairs patients' quality of life. It should be considered that amitriptyline** is cardiotoxic and contraindicated in glaucoma, prostatic hyperplasia, pyloric stenosis, etc.; therefore, the dose of amitriptyline** in palliative care patients generally does not exceed 50 mg per day.

Selective serotonin and norepinephrine reuptake inhibitors (N06AX other antidepressants), duloxetine and #venlafaxine, have a mechanism of action similar to non-selective monoamine reuptake inhibitors, but unlike the latter, they lack significant affinity for histamine, muscarinic, and alpha-adrenergic receptors, which ensures better tolerability. Duloxetine and #venlafaxine have been most extensively studied regarding their effect on neuropathic pain. Duloxetine has been studied in painful diabetic polyneuropathy, central post-stroke pain, and neuropathic pain due to spinal cord injury, while #venlafaxine (in Z51.5) has been studied only in the treatment of diabetic polyneuropathy and peripheral neuropathy [60,89,93,94]. In the Russian Federation, duloxetine is approved for the treatment of painful diabetic polyneuropathy, whereas #venlafaxine is approved only for the treatment of depression. Duloxetine is used in single doses of 30–60 mg, with a total daily dose of 60–120 mg. Characteristics: use with caution in patients with cardiac pathology, angina pectoris, glaucoma, and renal impairment. Elimination: undergoes hepatic metabolism to form inactive metabolites, which are excreted by the kidneys. Precautions: nausea, vomiting, dizziness, asthenia, insomnia, hyperexcitability, increased blood pressure, and skin flushing are possible during the first few days of administration. #Venlafaxine is used for the treatment of neuropathic pain (in Z51.5) at a single dose of 37.5–70 mg, with the daily dose reaching 70–225 mg [60,89,93,94]. Characteristics: use with caution in patients with cardiac pathology, angina pectoris, glaucoma, and renal impairment. Elimination: undergoes hepatic metabolism to form active metabolites, which are excreted by the kidneys (87%). Administration may cause dizziness, asthenia, weakness, insomnia, nervous hyperexcitability, increased blood pressure, and skin flushing.

Second-line drugs — opioids — were discussed in previous sections of the clinical guidelines. Certain studies have shown that the opioid tapentadol possesses intrinsic antineuropathic activity due to a mechanism of action mediated not only by opioid receptor stimulation, but also by the inhibition of noradrenaline reuptake in neuronal structures [96,97].

Third-line drugs. The local anesthetic lidocaine in the form of a 5% medicated plaster is prescribed for localized neuropathies predominantly characterized by painful cutaneous sensory disorders (areas of allodynia, hyperalgesia, pathological pruritus, etc.). Dose: 1 to 3 plasters applied for 12 hours followed by a 12-hour break. Characteristics: non-toxic, has no drug interactions since lidocaine does not enter the systemic circulation. In the Russian Federation, it is approved for the treatment of postherpetic neuralgia. A number of studies have also demonstrated the efficacy of topical application of 5% lidocaine using the same regimen for painful diabetic polyneuropathy [89,100,105] and vertebrogenic pain [160–163]. Precautions: the plaster should not be applied to damaged skin surfaces.

According to a number of studies, #botulinum toxin type A has demonstrated efficacy when administered via repeated subcutaneous injections (at 12-week intervals) at a dose of 50–200 IU for diabetic, postherpetic, and trigeminal neuralgias [89, 103]. In Russia, the drug is not approved for the treatment of neuropathic pain under any of the underlying diseases/conditions causing it. Its use for peripheral neuropathic pain is permissible under Z51.5 if clinical experience is available.

Additional adjuvant agents that may be considered if first-line drugs fail to treat neuropathic pain in patients receiving palliative care (Z51.5) include #clonidine and #clonazepam. #Clonidine may be effective in peripheral neuropathic pain [164–167]. As an adjuvant, #clonidine is administered intrathecally and perineurally at doses of 50–150 mcg in combination with local anesthetics, or orally at 0.15 mg up to 3 times a day. #Clonidine stimulates central alpha2-adrenoreceptors, thereby reducing the tone of the vasomotor center in the medulla oblongata (hypotensive effect), and presynaptic alpha2-adrenoreceptors, thereby decreasing the release of catecholamines from sympathetic terminals and mitigating the sympathetic component of pain (neuropathic and visceral). The risk of sedation, hypotension, and orthostatic reactions must be taken into account. #Clonazepam may be effective in neuropathic cancer pain and phantom limb pain [168–170]. #Clonazepam dose titration begins at 0.5 mg orally (preferably at bedtime due to the sedative effect), followed by daily increases of 0.5 mg based on tolerability, up to a total average daily dose of 2–4 mg. The action of #clonazepam as an adjuvant analgesic is related to GABA-mediated inhibition of ectopic activity in damaged peripheral nerves [170].

3.1.10 Pain management in the final hours of life

It should be noted that the provision of palliative care to a patient in the final weeks and days of life has certain specific features [40, 46].

Comments: for various reasons, in some patients immediately prior to death, pain becomes "refractory" and resistant to effective treatment.

Comments: in such cases, further application of standard approaches is exhausted and does not contribute to adequate pain relief for the remainder of the life [33, 43, 45].

Comments: if it is necessary to reduce the opioid dose, it should be decreased by no more than 50% within 24 hours to avoid breakthrough pain, to prevent withdrawal syndrome, and to avoid causing suffering to the patient.

Comments: the development of certain distressing symptoms and conditions can increase the level of pain in patients in severe condition and/or with impaired consciousness. These include pressure ulcers, vomiting, edema syndrome, constipation, urinary retention, agitation episodes, etc.

Comments: the issue of sedation is discussed with the patient and/or their legal representative and decided upon at a medical board meeting. In some clinical cases, medical sedation is the only method capable of providing adequate pain relief and alleviating the patient's suffering. Antipsychotics (neuroleptics), benzodiazepine derivatives, and, in case of their ineffectiveness and available application experience, barbiturates and #propofol** (for Z51.5) are most frequently used. #Propofol** (for Z51.5) is used as a continuous intravenous infusion at an initial dose of 0.16 mg/kg/h combined with a continuous intravenous or subcutaneous infusion of midazolam at 0.08 mg/kg/h; subsequently, doses are adjusted based on the patient's individual response and usually range from 0.16 to 1.3 mg/kg/h for propofol and from 0.08 to 0.5 mg/kg/h for midazolam [172, 173]. Regardless of the drug (or drugs) used, its prescription primarily requires determining the dose that ensures adequate pain relief, followed by the continuation of therapy to consolidate the effect.

3.2 Non-drug treatment

Along with pharmacological methods of pain management, it is necessary to fully utilize other types of therapy for pain and correction of the patient's quality of life.

Physical activity. Activity and mobility (stimulation, change of activity, improvement of blood supply) have a positive effect on the body's ability to independently suppress pain [123]. In addition, the elasticity increases and the functional capabilities of tissues expand, in particular, muscle tissues or intervertebral discs.

Relaxation. Relaxation techniques are extremely important for easing tense muscles and reducing overall physical tension. Reading, listening to music, meeting with friends, meditation, dancing, and walking are examples of effective ways to relax. Special relaxation techniques, such as progressive muscle relaxation or autogenic training, are also effective [124].

Psychotherapy. Psychological pain therapy involves utilizing one's resources more effectively than before to cope with pain. Therapy explores strategies for pain reduction. In addition, therapy includes training in how to change behaviors and thought patterns that contribute to the development of pain. Psychotherapy helps ensure that pain takes up less and less space in the patient's daily life , while other, more important areas of life come to the forefront [47, 54]. The combination of physical activity, psychotherapeutic, and pharmacological treatment is called "multimodal therapy" and is typically used within an interdisciplinary approach [125,126].

4. Medical Rehabilitation and Sanatorium-Resort Treatment

In addition to the aforementioned pain therapy methods, all patients and their loved ones should be provided with psychological assistance and support. Properly structured communication with patients significantly improves the patient's psychological status, neutralizes anxiety, reduces fears, and helps decrease pain intensity [17, 18].

5. Prevention and Dispensary Observation

Not applicable.

6. Organization of Medical Care

The organization of chronic pain treatment is carried out in accordance with current regulatory legal acts establishing the procedure for prescribing medications and documenting treatment appointments in the patient's medical records and on prescription forms.

As part of the provision of primary palliative pre-medical and medical care, the treatment of chronic pain syndrome, including the prescription of medicinal products containing narcotic drugs and psychotropic substances from Lists II and III of the Schedule, is carried out by feldshers—provided they are assigned the functions of a treating physician—and other medical workers with secondary medical education from feldsher health posts, feldsher-midwife stations, medical outpatient clinics, and other medical organizations (or their structural subdivisions) providing primary pre-medical health care, as well as by general practitioners, district general practitioners, family physicians, and specialists from medical organizations providing primary health care or primary specialized health care [127].

The treatment of chronic pain syndrome within the framework of specialized palliative medical care, including the prescription of medicinal products containing narcotic drugs and psychotropic substances from Lists II and III of the Schedule, is carried out by specialist physicians holding the position of palliative care physician, other specialist physicians, and medical workers with secondary vocational education from adult palliative care offices, adult mobile palliative care teams, adult palliative care departments, adult hospices, adult nursing care departments, adult nursing homes (hospitals), adult palliative day care centers, and adult respiratory centers [127].

When providing primary pre-medical and medical palliative care and specialized palliative medical care in outpatient settings, the prescription of medicinal products—including those containing narcotic drugs and psychotropic substances from Lists II and III of the Schedule—is carried out independently by a medical worker based on the severity and nature of the patient's disease. Information about the prescribed medication (name of the medication, dosage, route of administration and application, dosing regimen, duration of treatment, and justification for the prescription) is entered by the medical worker into the patient's medical records. The medical worker issues the prescription for medications, including those containing narcotic drugs and psychotropic substances from Lists II and III of the Schedule, on a paper prescription form bearing their signature and/or, with the consent of the patient or their legal representative, on a prescription form in the form of an electronic document using the medical worker's enhanced qualified electronic signature [128].

The prescription of medications by decision of a medical commission when providing primary pre-medical and medical palliative care and specialized palliative medical care in outpatient settings is performed in cases of the initial prescription to a patient of medicinal products containing narcotic drugs and psychotropic substances from Lists II and III of the Schedule (if the head of the medical organization decides that it is necessary to coordinate the prescription of such medications with the medical commission) [128].

For patients with chronic pain syndrome of any genesis, repeated prescriptions of medicinal products containing narcotic drugs and psychotropic substances from Lists II and III of the Schedule are performed independently by the medical worker [128].

The quantity of prescribed medications included in the list of drugs subject to subject-quantitative accounting, when providing palliative care to patients, may be increased in accordance with clinical guidelines by no more than 2 times compared to the amount of narcotic drugs or psychotropic substances that can be prescribed on a single prescription form [128].

In cases where it is necessary to issue a prescription for a narcotic (psychotropic) medicinal product at home as part of the provision of palliative care, prior endorsement of the prescription with the stamp of the medical organization, the seal of the medical organization, or the structural subdivision of the medical organization reading "For prescriptions" is permitted; this is applied by a person authorized by the head of the medical organization, indicating their surname, first name, patronymic (if applicable), and affixing their personal signature. The fact that a prescription was issued at home may be additionally confirmed by photo and/or video materials [128].

When providing emergency medical care, medicinal products—including those containing narcotic drugs and psychotropic substances from Lists II and III of the Schedule—are prescribed by a medical worker of an emergency medical team or a medical worker of a medical organization if a patient recognized as needing palliative care presents with pain syndrome that cannot be relieved by available analgesics [129].

When providing palliative medical care to a patient in inpatient settings, the prescription of medicinal products, including those containing narcotic drugs and psychotropic substances from Lists II and III of the Schedule, is performed by a medical worker individually, without issuing a formal prescription form [128].

Coordination of the prescription of medications with the head of the department, the responsible on-duty physician, or another person authorized by an order of the chief physician of the medical organization, as well as with a clinical pharmacologist (if available), is necessary in cases of prescribing medications—including those containing narcotic drugs and psychotropic substances from Lists II and III of the Schedule—that are not included in the list of vital and essential drugs.

In such cases, the prescription of medications is recorded in the patient's medical records and certified by the signature of the medical worker and the head of the department (responsible on-duty physician or other authorized person) [128].

By decision of the medical commission, patients receiving inpatient palliative care are prescribed medications not included in the list of vital and essential drugs in cases of substitution due to individual intolerance or for life-saving indications.

The decision of the medical commission is recorded in the patient's medical records and the medical commission logbook [128].

A medical worker of a medical organization (or its structural subdivision) located in a rural locality carries out the prescription of medications, including those containing narcotic drugs and psychotropic substances from Lists II and III of the Schedule, independently [128].

Upon discharging a patient from a medical organization that provided them with inpatient palliative medical care, by decision of the head of the medical organization, the patient is prescribed medications—with a prescription issued in the form of an electronic document and/or on paper (except for prescriptions for medicinal products to be dispensed free of charge or at a discount)—or such medications are dispensed to the patient (or their legal representative) simultaneously with the discharge summary from the medical history. This includes medications containing narcotic drugs and psychotropic substances from lists II and III of the Schedule, and potent medicinal products, for a treatment duration of up to 5 days [127].

It is necessary to exercise systematic control over compliance with the rules for following the algorithms for the diagnosis and treatment of chronic pain syndrome (CPS), as well as the algorithms and requirements for maintaining medical documentation. Individuals authorized by an order of the head of the medical organization must conduct a monthly selective review and analysis of at least 10 inpatient (outpatient) medical records of patients with CPS, followed by drawing up a final conclusion on the audit of the evaluated cases.

When indicated, patients with CPS are hospitalized in structural units of medical organizations that provide specialized inpatient palliative medical care.

Indications for hospitalization of patients with CPS in an adult palliative care department are:

- severe pain syndrome that is refractory to outpatient treatment, including at home or in inpatient social service institutions;

- selection of an analgesic therapy regimen for continued treatment at home.

Indications for hospitalization of patients with CPS in an adult hospice are:

- severe pain syndrome in the terminal stage of the disease, predominantly in patients with oncological diseases, refractory to outpatient treatment, including at home or in inpatient social service institutions;

- the need to select a therapy regimen for continued treatment at home [127].

Indications for discharge of patients with CPS from an adult palliative care department and adult hospice are:

- achievement of adequate analgesia;

- selection of an optimal analgesic therapy regimen in terms of efficacy and tolerability.

7. Additional Information

No information available

Criteria for Evaluating the Quality of Medical Care

References

Appendix A1. Working Group Composition

1. Abuzarova Guzel Rafailovna – Doctor of Medical Sciences, Head of the Center for Palliative Care for Cancer Patients at the P.A. Herzen Moscow Oncology Research Institute – branch of the National Medical Research Radiological Centre of the Russian Ministry of Health

2. Arutyunov Grigory Pavlovich – Professor, Corresponding Member of the RAS, Chief freelance specialist therapist of the Moscow Healthcare Department, Head of the Department of Propaedeutics of Internal Diseases and Radiation Diagnostics at the Pirogov Russian National Research Medical University of the Russian Ministry of Health, Honored Doctor of the Russian Federation, member of the Presidium of the Russian Scientific Medical Society of Internal Medicine.

3. Danilov Alexey Borisovich – Professor, Doctor of Medical Sciences, Head of the Department of Nervous Diseases at the I.M. Sechenov First Moscow State Medical University, Institute of Interdisciplinary Medicine.

4. Danilov Andrey Borisovich – Professor, Doctor of Medical Sciences at the Department of Nervous Diseases of the I.M. Sechenov First Moscow State Medical University, Doctor of Medical Sciences, Professor of the Department of Nervous Diseases at the Institute of Professional Education of the I.M. Sechenov First Moscow State Medical University, Institute of Interdisciplinary Medicine.

5. Kunyaeva Tatyana Aleksandrovna – Candidate of Medical Sciences, Associate Professor at the Department of Outpatient Therapy with a Course of Public Health and Healthcare Organization at the N.P. Ogarev National Research Mordovia State University, Chief Freelance Specialist in Therapy for the Volga Federal District, Chief Freelance Specialist Therapist-Pulmonologist of the Ministry of Health of the Republic of Mordovia, Deputy Chief Medical Officer of the Mordovia Republican Central Clinical Hospital.

6. Molchanov Igor Vladimirovich - Professor, Doctor of Medical Sciences, Head of the Department of Anesthesiology and Intensive Care at the Russian Medical Academy of Continuous Professional Education, Chief Freelance Anesthesiologist-Intensivist of the Russian Ministry of Health.

7. Nevzorova Diana Vladimirovna – Candidate of Medical Sciences, Director of the Federal Scientific and Practical Center for Palliative Medical Care, Associate Professor at the Department of Medical and Social Expertise, Emergency and Outpatient Therapy of the I.M. Sechenov First Moscow State Medical University, Chief Freelance Specialist in Palliative Care of the Ministry of Health of the Russian Federation, Chairman of the Board of the Association of Professional Participants in Hospice Care.

8. Protsenko Denis Nikolaevich - Candidate of Medical Sciences, Chief Freelance Specialist in Anesthesiology and Intensive Care, Chief Medical Officer of City Clinical Hospital No. 40 of the Moscow Healthcare Department, Head of the Department of Anesthesiology and Intensive Care at the Pirogov Russian National Research Medical University of the Russian Ministry of Health.

9. Pchelintsev Mikhail Vladimirovich – Candidate of Medical Sciences, Associate Professor at the Department of Pharmacology and Evidence-Based Medicine of the Pavlov First Saint Petersburg State Medical University.

10. Sidorov Aleksandr Vyacheslavovich – Head of the Department of Pharmacognosy and Pharmaceutical Technology at the Yaroslavl State Medical University of the Russian Ministry of Health, Chief Researcher at the Federal Scientific and Practical Center for Palliative Medical Care at the I.M. Sechenov First Moscow State Medical University of the Russian Ministry of Health (Sechenov University), Doctor of Medical Sciences, Associate Professor.

Expert Panel:

1. Vlasov Vasily Viktorovich – Doctor of Medical Sciences, Professor at the Department of Healthcare Management and Economics of the Department of Politics and Management, Faculty of Social Sciences, National Research University Higher School of Economics, member of the Expert Committee on Medical Research of the WHO Regional Office for Europe, member of the RAS Commission on Combating Pseudoscience and Falsification of Scientific Research, RAS Expert, member of the Public Council under the Russian Ministry of Health, Vice President of the Association of Specialists in Evidence-Based Medicine.

2. Zvartau Edwin Eduardovich – Doctor of Medical Sciences, Professor, Director of the A.V. Valdman Institute of Pharmacology, Head of the Department of Pharmacology at the Pavlov First Saint Petersburg State Medical University.

Appendix A2. Methodology for Developing Clinical Guidelines

The clinical guidelines set forth the rules of pharmacotherapy for chronic pain syndrome in cancer patients and patients with non-cancer palliative conditions, taking into account the specifics of the list of opioids registered in Russia. In accordance with the recommendations of the World Health Organization, as well as European recommendations on palliative medicine, the primary method for controlling chronic pain syndrome is pharmacotherapy based on non-invasive forms of opioids. It is used on an outpatient basis and in a hospital setting regardless of the stage of the disease. Full pain control must be carried out at all stages of patient treatment, including the provision of palliative medical care.

When preparing the clinical guidelines, a modern rating assessment of the strength of evidence using the GRADE system was used. The evidence base for the recommendations consisted of publications included in the Cochrane Library, EMBASE and MEDLINE databases, as well as the results of studies conducted in Russia. The search depth was 15 years. Expert consensus was used in formulating the recommendations. The text of the recommendations provides levels of certainty of evidence (1–5) separately for diagnostic methods (Table A2-1) and methods of prevention, treatment, and medical rehabilitation (Table A2-2), as well as grades of recommendation (A, B, C) (Table A2-3), in accordance with the Order of the Ministry of Health of the Russian Federation No. 103n dated February 28, 2019 "On approval of the procedure and timelines for the development of clinical guidelines, their revision, standard template of clinical guidelines, and requirements for their structure, composition, and scientific validity of the information included in clinical guidelines" [106].

Target audience of these clinical guidelines.

1. healthcare organizers,

2. specialist physicians,

3. general practitioners,

4. palliative care physicians,

5. nursing staff (nurses and feldshers),

6. students of medical universities and colleges,

7. faculty members of medical universities and colleges,

8. residents, interns,

9. postgraduate students (postgraduate education).

Table A2-1. Scale for assessing levels of certainty of evidence (LCE) for diagnostic methods (diagnostic interventions) [106].

Table A2-2. Scale for assessing levels of certainty of evidence (LCE) for methods of prevention, treatment, and medical rehabilitation, including those based on the use of natural therapeutic factors (preventive, therapeutic, and rehabilitative interventions) [106].

Table A2-3. Levels of Evidence Grading Scale for prevention, diagnostic, treatment, and medical rehabilitation methods, including those based on natural therapeutic factors (prophylactic, diagnostic, therapeutic, and rehabilitation interventions) [106].

Procedure for updating clinical guidelines: once every 3 years.

Clinical guidelines will be updated to incorporate all emerging important recommendations in the management of chronic pain. The scheduled update period is 3 years after their approval. Given the scarcity of studies, especially domestic ones, in the field of chronic pain management in palliative care patients, as well as the current lack of availability of certain required opioids in various formulations, updating the guidelines through a revision of parts of them or the entire document may be carried out in a shorter (earlier) timeframe if new significant evidence is published.

Appendix A3. Reference Materials

These clinical guidelines have been developed taking into account the following regulatory and legal documents:

1. Federal Law No. 323-FZ dated November 21, 2011 "On the Fundamentals of Health Protection in the Russian Federation".

2. Federal Law of the Russian Federation No. 3-FZ dated January 8, 1998 "On Narcotic Drugs and Psychotropic Substances".

3. Federal Law No. 501-FZ dated December 31, 2014 "On Amendments to the Federal Law 'On Narcotic Drugs and Psychotropic Substances'".

4. Order of the Ministry of Health of the Russian Federation and the Ministry of Labor and Social Protection of the Russian Federation No. 345n/372n dated May 31, 2019, "On Approval of the Regulations on the Organization of Palliative Medical Care, Including the Procedure for Interaction Between Medical Organizations, Social Welfare Organizations, and Public Associations and Other Non-Profit Organizations Operating in Health Protection".

5. Order of the Ministry of Health of the Russian Federation No. 4n dated January 14, 2019, "On Approval of the Procedure for Prescribing Medicinal Products, Prescription Form Templates for Medicinal Products, the Procedure for Issuing These Forms, Their Accounting and Storage" (as amended).

6. Federal Law No. 61-FZ dated April 12, 2010, "On Circulation of Medicinal Products".

7. Order of the Government of the Russian Federation No. 2406-r dated October 12, 2019, "On Approval of the List of Vital and Essential Drugs for Medical Use".

8. Order of the Government of the Russian Federation No. 1180-r dated May 16, 2022, "On the List of Diseases or Conditions (Groups of Diseases or Conditions) for Which the Use of a Medicinal Product is Permitted in Accordance with Indicators (Characteristics) of the Medicinal Product Not Specified in Its Instructions for Use".

9. Fallon M., Giusti R., Aielli F., Hoskin P., Rolke R., Sharma M., Ripamonti C. I. on behalf of the ESMO Guidelines Committee. Management of cancer pain in adult patients: ESMO Clinical Practice Guidelines. Annals of Oncology. 2018; 29 (Supplement 4): iv166–iv191.

10. Use of Opioid Analgesics in the Treatment of Cancer Pain: Evidence-based Recommendations from the EAPC. - Lancet Oncol 2012; 13: e58–e68.

11. National Institute for Health and Clinical Effectiveness (NICE). Guide to the Methods of Technology Appraisal [reference N0515] (2004). Opioid medications in palliative therapy: http://www.dft.gov.uk/dvla/medical/ataglance.aspx.

12. NCCN Clinical Practice Guidelines in Oncology. Palliative Care. Version 1.2020.

13. NCCN Clinical Practice Guidelines in Oncology. Adult Cancer Pain. Version 2.2021.

14. WHO guidelines for the pharmacological and radiotherapeutic management of cancer pain in adults and adolescents. Geneva: World Health Organization; 2018. – 140 P.

15. The list of essential medicines used in palliative care can be obtained on the website of the International Association for Hospice and Palliative Care: www.hospicecare.com/resources/emedicine.

16. A Guide to the Use of Drugs and Alternative Remedies in Palliative Care: www.palliativedrugs.com

17. World Health Organization. Palliative care [online]: https://www.who.int/health-topics/palliative-care

Sample questionnaire form for initial pain assessment

Sample pain assessment diary form

Risk factors for NSAID-related complications (for the general population) and therapy prescription recommendations [76, 107, 108]

Notes: 1myocardial infarction, acute coronary syndrome, coronary and other arterial revascularization, acute cerebrovascular accident / transient ischemic attack, clinically overt coronary artery disease, aortic aneurysm, peripheral artery disease, chronic heart failure; 2with target organ damage or other risk factors; 3total cholesterol ≥8 mmol/L, or LDL >6 mmol/L, or BP ≥180/100 mm Hg.

Abbreviations: BP – blood pressure; GI – gastrointestinal tract; CAD – coronary artery disease; DM – diabetes mellitus; CVS – cardiovascular system; CKD – chronic kidney disease.

Adjuvant analgesics and symptomatic therapy agents

Notes: 1medications recommended in accordance with indicators (characteristics) not specified in their instructions for use (off-label) are used only with Z51.5;

2zoledronic acid medications are used for the treatment of metastatic bone pain off-label when other methods of pharmacotherapy and/or radiotherapy are exhausted. The dosing regimen indicated in the table is based on the results of clinical studies [157-159]. In general, the appropriateness of bisphosphonate therapy in patients with pain syndrome due to metastatic bone lesions, based on the benefit-risk ratio, is confirmed by data from a Cochrane systematic review [156].

List of registered opioid medications in injectable dosage forms

List of registered opioid medications in non-invasive dosage forms

Notes: * the medication is intended for the treatment of acute pain

Brief characteristics of opioid medications in non-invasive dosage forms

Morphine**

The classic and most frequently used opioid in palliative practice. By mechanism of action, it is a non-selective opioid receptor agonist with a predominant effect on µ-receptors and to a lesser extent on κ-receptors. It exhibits diverse central and peripheral effects, among which the analgesic and antitussive effects, as well as the reduction and suppression of the respiratory center activity, are of greatest clinical significance. The latter accounts for the use of morphine** in low doses (1-5 mg orally) to relieve refractory dyspnea (off-label use) [113]. Among adverse events, nausea, constipation, and sedation are most common; orthostatic reactions are possible. Due to its spasmogenic action and the ability to release histamine from mast cells, morphine** is contraindicated in bronchopulmonary obstructive diseases.

In patients with swallowing disorders, the use of morphine** in the form of an oral solution can be considered, which may be administered via a nasogastric tube, gastrostomy, or in small portions orally (taking into account the bitter taste of morphine**).

Morphine** is metabolized in the liver via glucuronidation to form the practically inactive morphine-3-glucuronide and the active morphine-6-glucuronide, which possesses neurotoxic properties. Excretion of morphine** and its metabolites is carried out 90% by the kidneys and 10% by the intestines.

In patients with hepatic or renal impairment, it is recommended to reduce the dose of morphine** or choose another medication (the drug of choice is fentanyl**).

Analgesic potency of oral morphine** compared to morphine** administered subcutaneously and intravenously is 1/2-1/3. It is intended for the treatment of severe pain not relieved by other, weaker analgesics, including cases of intolerance to the latter. In doses up to 30 mg/day orally, it can be used for the treatment of moderate pain as an alternative to tramadol**.

Single (starting) dose: 5-10 mg for opioid-naive patients.

Maximum daily dose: none for opioid-tolerant patients.

Dosage forms: film-coated tablets, 5 mg and 10 mg; oral solution 2 mg, 6 mg or 20 mg / 1 ml in 5 ml ampoules; prolonged-release capsules 10, 30, 60, 100 mg; prolonged-release film-coated tablets, 10 mg, 30 mg, 60 mg, 100 mg.

Prescription form: 107/u-NP.

Fentanyl**

Fentanyl** is a synthetic opioid acting predominantly on µ-opioid receptors in the central nervous system and peripheral tissues. It differs by having the highest lipophilicity among opioid medications and possesses the highest analgesic potency. Fentanyl** is characterized by the typical effects of natural opioids, but histamine reactions occur significantly less frequently. Despite fairly complete absorption in the gastrointestinal tract, fentanyl** undergoes a pronounced first-pass effect in the liver (presystemic elimination), and therefore it is used only parenterally: transdermally (for the treatment of chronic pain), transmucosally (for breakthrough cancer pain relief), and by injection (in a hospital setting only).

Fentanyl** transdermal patch (TTS) is a rather convenient dosage form for the treatment of chronic pain. The pharmacokinetic features of the transdermal form must be taken into account. Upon the first application of the patch, the analgesic effect develops slowly, within 24 hours, as the therapeutic concentration of fentanyl** in the blood is reached. Therefore, during the first day, the patient may require additional analgesia. It is most appropriate to use transdermal fentanyl** in patients with a titrated (stable) opioid dose, performing rotation according to the principles outlined in the text of these guidelines (see section 3.1.6). Steady-state concentration of fentanyl** is usually reached by the end of the second 72-hour patch application, when conclusions can be drawn about the adequacy of the dose or the need for its correction (this is also true for assessing the effect after increasing the patch dosage). A fentanyl** depot is formed in the subcutaneous adipose tissue, which maintains a stable concentration of the substance in the blood and allows analgesia to be maintained during replacement. If the analgesic effect decreases after the very first patch application, it is permissible to replace the patch after 48 hours with a patch of the same dosage, followed by a dose increase if necessary only after 72 hours.

Transdermal fentanyl** less frequently causes constipation, nausea, and vomiting. It is convenient in patients with swallowing disorders. However, in patients with cachexia, fever, or excessive sweating, the application of the patch may be difficult, and in the first two cases requires a review of the medication dose.

The metabolism of fentanyl** in the liver is carried out via microsomal oxidation (mainly CYP3A4) to inactive metabolites. Excretion of fentanyl is carried out mainly by the kidneys: 75% as metabolites and less than 10% in unchanged form. About 9% of fentanyl is excreted in the feces, mainly as metabolites.

Fentanyl** is the opioid of choice in patients with moderate to severe renal and hepatic impairment.

Analgesic potency of parenterally administered fentanyl** (IV, transdermally, transmucosally) compared to oral morphine** is 100-300 (higher). At a dosage of 12.5 mcg/h, it can be used for the treatment of moderate pain as an alternative to tramadol**.

Single (starting) dose: 12.5 mcg/h for opioid-naive patients.

Maximum daily dose: none for opioid-tolerant patients.

Dosage forms: transdermal therapeutic system (TTS) patch 12.5 mcg/h, 25 mcg/h, 50 mcg/h, 75 mcg/h, 100 mcg/h; metered-dose nasal spray 50 mcg/dose, 100 mcg/dose, 200 mcg/dose (currently this dosage form is not available for use).

Prescription form: 148-1/у-88 (for transdermal patch).

Naloxone + oxycodone**

The medicinal product is a combination of a prolonged-release agonist (oxycodone) and an antagonist (naloxone) of κ-, µ-, and δ-opioid receptors in the central nervous system and peripheral tissues. The analgesic effect is provided by oxycodone, which has a high bioavailability of approximately 87% when administered orally. Conversely, only 3% of naloxone reaches the systemic circulation upon oral administration due to a pronounced first-pass hepatic effect (presystemic elimination). Therefore, a clinically significant systemic effect of naloxone after oral administration is unlikely. At the same time, by competing with oxycodone for opioid receptors in the intestine, naloxone reduces the severity of constipation—a typical side effect of opioid therapy. In addition, due to the impossibility of separating naloxone, the risk of diversion of the drug into illicit channels for the purpose of intentional use for parenteral (intravenous or intranasal) administration after crushing the tablet is reduced. When rotating from high doses of "pure" opioid agonists to the oxycodone + naloxone** combination, signs of withdrawal syndrome and/or increased pain may occur.

Oxycodone and naloxone are metabolized in the liver via microsomal oxidation (CYP3A4, CYP2D6) and glucuronidation. The oxidation of oxycodone produces an active metabolite, oxymorphone, which does not make a significant contribution to the overall effect of the drug. The elimination of oxycodone, naloxone, and their metabolites is carried out mainly by the kidneys.

In patients with renal impairment and mild hepatic impairment, the drug should be used with caution. In moderate and severe hepatic impairment, the drug is contraindicated due to a significant increase in the systemic exposure of oxycodone and, especially, naloxone.

Analgesic potency of oral oxycodone compared to oral morphine is 1.5–2 (higher). It is intended for the treatment of pain requiring opioid therapy. At a daily dose of up to 10 mg naloxone + 20 mg oxycodone, it can be used to treat moderate pain as an alternative to tramadol.

Single (starting) dose: 5 mg naloxone + 10 mg oxycodone for opioid-naive patients.

Maximum daily dose: 80 mg naloxone + 160 mg oxycodone (due to the presence of naloxone in the drug composition).

Dosage forms: prolonged-release film-coated tablets, 2.5 mg + 5 mg, 5 mg + 10 mg, 10 mg + 20 mg, 20 mg + 40 mg.

Prescription form: 148-1/у-88.

#Buprenorphine + naloxone

Another example of an agonist combined with an opioid receptor antagonist. However, unlike the "pure" opioid agonist oxycodone, buprenorphine exhibits the properties of a partial µ-opioid receptor agonist and κ-opioid receptor antagonist. These properties result in a lower risk of typical opioid adverse events (constipation, respiratory depression, sedation) and a low abuse potential of buprenorphine. Due to the presence of naloxone in the composition, the drug is protected against parenteral abuse. However, buprenorphine is characterized by cardiovascular adverse events such as increased blood pressure and tachycardia.

The metabolism of buprenorphine is carried out in the liver via microsomal oxidation (CYP3A4). Active metabolites are excreted by the kidneys (30%) and liver (70%).

Co-administration of the drug with "pure" agonists is hazardous regarding the development of withdrawal syndrome and breakthrough pain!

Buprenorphine is among the opioids of choice in patients with hepatic and renal impairment. However, one must keep in mind a substantial increase in plasma naloxone concentration in patients with moderate and severe hepatic impairment, which may nullify the analgesic effect of buprenorphine.

The main limitation for the use of the drug is the indication for acute pain therapy according to the package leaflet of the medicinal product registered in the Russian Federation.

Analgesic potency of sublingual buprenorphine compared to oral morphine** is 75 (higher). It is intended for the treatment of moderate to severe acute pain (in Z51.5).

Single (starting) dose: 1–2 tablets.

Maximum daily dose: 8 tablets (1.6 mg + 1.6 mg).

Dosage forms: sublingual tablets 0.2 mg + 0.2 mg.

Prescription form: 148-1/у-88.

Tramadol**

A drug with a mixed (bimodal) opioid and non-opioid mechanism of action, possessing prodrug properties. In medicinal products, tramadol** exists as a racemic mixture of two stereoisomers—enantiomers of (±)-tramadol, which have different mechanisms of action. The parent molecule (+)-tramadol and, to a greater extent, its active metabolite O-desmethyltramadol (M1) act as opioid receptors agonists with a predominant effect on µ-type receptors. The affinity of the M1 metabolite for µ-opioid receptors is approximately 300 times higher than that of the parent molecule [114]. In addition, (±)-tramadol inhibits the neuronal reuptake of serotonin, and (-)-tramadol additionally inhibits the reuptake of noradrenaline. The effect on the monoaminergic system enhances the activity of descending antinociceptive pathways and, along with the excitation of opioid receptors, helps reduce the transmission of pain impulses in the central nervous system.

Similar to other opioids, tramadol** has an antitussive effect. It has a lower abuse (addictive) potential, suppresses the respiratory center less, and causes constipation less frequently compared to other opioids [114].

Upon oral administration of immediate-release dosage forms (conventional tablets, capsules), the maximum concentration of tramadol** in the blood is reached in approximately 2 hours. Despite almost complete (about 90%) absorption, it undergoes a first-pass hepatic effect (presystemic elimination), resulting in a bioavailability of about 68%, which increases with repeated administration. The half-life ($t_{1/2}$) is 5–6 hours (for the M1 metabolite—about 8 hours). Tramadol** and its metabolites, including active ones, are excreted by the kidneys (90%) and feces (10%).

The metabolism of tramadol** is mediated by the cytochrome P450 (CYP450) system, predominantly by the CYP2D6 isoform, the activity of which is subject to variability due to genetic polymorphisms. This determines the variable response of patients regarding the efficacy and tolerability of the drug and, consequently, the rate of dose titration and its magnitude. Potential drug interactions with CYP modulators must be taken into account. Tramadol intake** is associated with the risk of serotonin syndrome, especially when using high doses and when co-administered with other opioids or serotonergic agents—antidepressants (SSRIs, SNRIs, tricyclics, MAO inhibitors), antimigraine agents (5-HT1 receptor agonists), antiemetics (5-HT3 receptor antagonists). Symptoms of serotonin syndrome include: confusion, agitation, hyperthermia, sweating, ataxia, tremor, hyperreflexia, tachycardia, arterial hypertension, myoclonus, diarrhea.

In patients with hepatic or renal impairment, it is recommended to reduce the dose of tramadol** or increase the dosing intervals.

Analgesic potency of tramadol** compared to oral morphine**: 1/10–1/6. It is intended for the treatment of moderate-intensity pain, including cases of inefficacy/intolerance of non-opioid analgesics/NSAIDs.

Single (starting) dose: from 50 mg to 200 mg depending on pain intensity.

Maximum daily dose: 400 mg (in patients over 75 years of age – 300 mg/day).

Dosage forms: capsules 50 mg; tablets 50 and 100 mg; prolonged-release film-coated tablets 100 mg; rectal suppositories 100 mg (this dosage form is currently unavailable for use). A fixed combination of tramadol 37.5 mg with paracetamol 325 mg in tablets is available: the efficacy of 2 tablets of this combination is comparable to 100 mg of tramadol with fewer side effects; the maximum daily dose is 8 tablets.

Prescription form: 148-1/у-88.

Tapentadol**

Like tramadol**, it is a drug with a mixed opioid and non-opioid mechanism of action, but has several advantageous differences from its prototype. Tapentadol** is a 'pure' μ-opioid receptor agonist; the non-opioid component of its mechanism of action is mediated by inhibition of monoamine reuptake, predominantly norepinephrine. Thus, compared with tramadol**, tapentadol therapy is theoretically associated with a lower risk of serotonin syndrome and drug interactions with serotonergic agents. In addition, clinically important differences of tapentadol** from tramadol** include higher analgesic potency and the possibility of using tapentadol for the treatment of severe pain; intrinsic activity of the molecule and cytochrome-independent metabolism to inactive metabolites. The effect on the monoaminergic system complements the opioid effect of tapentadol** in neuropathic pain of cancer and non-cancer origin [115,116,117].

In patients with severe hepatic or renal insufficiency, the use of tapentadol** is contraindicated; in moderate hepatic insufficiency, caution is necessary and the starting daily dose should be reduced by 50%.

Analgesic potency of tapentadol compared to oral morphine: 0.3–0.4. Indicated for the management of moderate to severe pain requiring opioid therapy. Extended-release tablets are indicated for chronic pain management, while immediate-release tablets are used for acute pain. A total daily dose of 100 mg can be used for moderate pain management as an alternative to tramadol.

Single (starting) dose: 50 mg.

Maximum daily dose: 500 mg (extended-release tablets) and 600 mg (immediate-release tablets).

Dosage forms: extended-release film-coated tablets, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg; film-coated tablets, 50 mg, 75 mg, 100 mg.

Prescription form: 148-1/у-88.

Propionylphenylethoxyethylpiperidine**

Synthetic agonist predominantly of μ-opioid receptors. Well absorbed through the oral mucosa, used as sublingual (buccal) tablets. Has pronounced antispasmodic, vasodilating, and moderate antitussive effects.

Orthostatic hypotension is possible during the first days of administration. It has a rapid onset of action (within 5-10 min), making it more suitable for breakthrough pain relief. The use of the drug as the primary analgesic, especially at high doses for a prolonged period, should be avoided due to its high addiction potential. It is not used in stomatitis, gingivitis, and other diseases of the oral mucosa.

Metabolized via glucuronidation in the liver to inactive metabolites excreted predominantly by the kidneys.

Contraindicated in patients with hepatic or renal impairment.

Analgesic potency of propionylphenylethoxyethylpiperidine** compared to oral morphine**: 0.9. Indicated for the treatment of moderate to severe pain requiring opioid therapy.

Single (starting) dose: 10-20 mg in opioid-naive patients.

Maximum daily dose: 250 mg.

Dosage forms: buccal tablets 20 mg.

Prescription form: 107/u-NP.

Drugs for the treatment of nausea and vomiting associated with opioid use

Metoclopramide** is a first-line antiemetic agent that helps reduce nausea, stimulates upper gastrointestinal motility (prokinetic effect), and increases lower esophageal sphincter tone (classified under ATC group A03FA: gastrointestinal motility stimulants). Single dose: 20 mg; daily dose: 60 mg (for all administration routes). Frequency of administration: 1–3 times daily. Special considerations: concurrent use with neuroleptics (especially phenothiazines and butyrophenone derivatives) increases the risk of extrapyramidal reactions; concurrent use with oral morphine accelerates intestinal absorption of morphine and enhances its sedative effect. If the effect is insufficient, its action can be potentiated by prescribing dexamethasone twice daily (morning and lunch). It may cause ECG QT interval prolongation and cardiac arrhythmias, including torsades de pointes.

Domperidone – an alternative to metoclopramide (from the same A03FA group). Administered as 10-20 mg orally or sublingually with each meal and at bedtime. Also indicated for gastroparesis. May cause ECG QT interval prolongation and cardiac arrhythmias, including torsades de pointes; contraindicated in severe electrolyte disturbances and heart failure.

Haloperidol** – an effective antipsychotic drug (neuroleptic) with potent central antiemetic action. Prescribed at 0.3–0.5 mg 2–3 times a day (1.5–3 mg/day). Haloperidol**, when combined with an opioid, tranquilizer, or hypnotic, may enhance the central nervous system depressant effects of these drugs. Haloperidol**, possessing central adrenolytic properties, may contribute to the development of arterial hypotension, especially in hypovolemic patients. It prolongs the ECG QT interval, particularly against the background of hypokalemia or the use of other drugs that increase QT interval duration. However, when administered in low doses, side effects are extremely rare. Contraindicated in clinically significant heart diseases (including recent acute myocardial infarction, decompensated heart failure, arrhythmias, and second- or third-degree heart block).

Chlorpromazine** – an antipsychotic drug, an alternative to haloperidol**, but less effective. Single doses: 12.5–25 mg 3 times a day.

The most potent modern antiemetics used in oncology are ondansetron** preparations, which have the ability to block 5-HT3 serotonin receptors responsible for the emetic reflex (A04AA serotonin 5-HT3 receptor antagonists). The need for these drugs in opioid therapy is rare; they are used according to special regimens, primarily for the treatment of nausea and vomiting associated with the toxic effects of chemotherapy. Most frequently, they are used parenterally due to the severity of the patient's vomiting at doses of 8 mg intravenously or intramuscularly over 30 seconds, or via intravenous infusion of up to 16 mg in 50–100 ml of 0.9% sodium chloride solution or 5% glucose solution for injection over 15 minutes (#subcutaneous injections, including continuous subcutaneous infusion of 16 mg/24 hours).

In intractable and profuse vomiting, in addition to antiemetic therapy, it is necessary to additionally prescribe medications that suppress gastrointestinal secretion, for example, an M-anticholinergic – a semi-synthetic quaternary belladonna alkaloid hyoscine butylbromide in a daily dose of up to 100 mg orally, rectally, or via injection.

Most antiemetic drugs, primarily antipsychotics (neuroleptics), can cause extrapyramidal disorders (especially in young patients, with prolonged use and maximum doses) and require correction with trihexyphenidyl. In addition, when using all of the above drugs, it is necessary to consider the risk of ECG QT interval prolongation and cardiac arrhythmias, including ventricular torsades de pointes.

Equianalgesic opioid conversion table

Analgesic potential is calculated relative to oral morphine, whose analgesic effect is taken as 1 [69, 76, 109-112].

1doses of combination drugs are given for the opioid component (buprenorphine, oxycodone)

Comments:

● to determine the equipotential dose of oral morphine, MULTIPLY the opioid dose from the 1st column by the analgesic potential;

● to determine the equipotential dose of the opioid from the 1st column, DIVIDE the oral morphine dose by the analgesic potential;

● for a safe switch from one opioid analgesic to another, the calculated equipotential dose of the new drug for the first administration should be reduced by 30-50%, and then, in the absence of severe adverse effects, gradually increased to the required level.

Assessment of the severity of hepatic impairment

1. Assessment using the Model of End-stage Liver Disease MELD 2016 modification incorporating sodium concentration (MELD-Na) [118].

Originally used to determine liver transplantation priority in patients older than 12 years. It is used to assess the severity of liver failure and patient prognosis in specific clinical situations associated with liver pathology. MELD can be applied to any patient with end-stage liver disease regardless of the etiology of cirrhosis.

MELD(i) = 0.957 × ln(creatinine) + 0.378 × ln(bilirubin) + 1.120 × ln(INR) + 0.643

Round the obtained value to the nearest tenth and multiply by 10.

If MELD(i) > 11, perform an additional calculation:

MELD = MELD(i) + 1,32 × (137 – Na) – [0,033 × MELD(i) × (137 – Na)]

ln - natural logarithm; INR - international normalized ratio.

Units of measurement: creatinine and bilirubin in mg/dL; sodium in mmol/L

(conversion: creatinine in mg/dL × 88.4 = µmol/L; bilirubin in mg/dL × 17.104 = µmol/L).

If the value of creatinine, bilirubin, or INR is less than 1.0, use 1.0 in the formula.

If the creatinine concentration is > 4.0 mg/dL or the patient has undergone 2 or more hemodialysis sessions or continuous venovenous hemodialysis within the past week, use a creatinine value of 4.0 in the formula.

If Na < 125 mmol/L, use 125 in the formula; if Na > 137 mmol/L, use 137 in the formula.

Maximum MELD value = 40

A poor prognosis is associated with a MELD value > 18.

The higher the MELD value, the more severe the liver disease course

MELD score and 3-month mortality:

● 40 and above – 71.3% mortality (severe liver failure)

● 30–39 – 52.6% mortality (severe liver failure)

● 20–29 – 19.6% mortality (moderately severe liver failure)

● 10–19 – 6.0% mortality (moderately severe liver failure)

● <9 – 1.9% mortality (mild liver failure)

Exceptions: the following diseases/conditions are automatically assigned a MELD index value of 22 (or 28 in the case of hyperoxaluria), with the value increasing by 10% every 3 months from the time of diagnosis:

- Hepatocellular carcinoma;

- Hepatorpulmonary syndrome with PaO2 < 60 mmHg;

- Portopulmonary hypertension with a mean pulmonary artery pressure > 25 mmHg at rest;

- Hepatic artery thrombosis;

- Familial amyloid polyneuropathy;

- Primary hyperoxaluria with signs of alanine-glyoxylate aminotransferase deficiency;

- Cystic fibrosis with FEV1 < 40%;

- Intraductal cholangiocarcinoma.

Free online MELD-Na calculators using laboratory units commonly used in Russia:

https://medicalc.ru/meld;

https://mdcalc.ru/meld/calc.php

2. Assessment according to the Child-Turcotte-Pugh classification [119].

Used to assess the severity of liver cirrhosis and 1-year survival prognosis.

Interpretation of results:

5–6 points: class A (well-compensated liver function); 1-year survival – 100%;

7–9 points: class B (marked liver function impairment); 1-year survival – 80%;

10–15 points: class C (decompensation of disease and liver function); 1-year survival – 45%.

Free online Child-Turcotte-Pugh calculators:

https://medicalc.ru/childpew;

https://medsoftpro.ru/kalkulyatory/child-pugh.html;

https://mdcalc.ru/ctp/calc.php

Determination of the degree of renal impairment

1. Severity of chronic kidney disease according to S.I. Ryabov and B.B. Bondarenko [120].

2. Classification of chronic kidney disease (CKD) according to Kidney Disease: Improving Global Outcomes (KDIGO) [121].

3. Stages of acute kidney injury according to KDIGO criteria [122].

Appendix B. Physician Action Algorithms

General diagnostic and treatment algorithm for a patient with chronic pain

Step 3 pain management ladder

Appendix C. Patient Information

1. What are opioid analgesics (strong opioids)?

Strong opioids are morphine and morphine-like painkillers (weak opioids, in turn, are tramadol and similar analgesics). They block pain signals in the spinal cord and brain. Other strong opioids are usually prescribed for people who cannot tolerate morphine, as well as those who have difficulty swallowing tablets.

2. Why have you been prescribed a strong opioid?

In most cases, if you have been prescribed a strong opioid, it is because other painkillers are not relieving your pain. You may have previously taken paracetamol or other anti-inflammatory drugs (e.g., ibuprofen, diclofenac) or weak opioids (tramadol). These do not always provide sufficient pain relief, even if you combine one with another (or all three). If you have very severe pain, your doctor may prescribe strong opioids right away.

3. You have been prescribed morphine. Does this mean you are dying?

In cancer treatment, opioids can be used at several stages. If you are prescribed morphine, it does not mean you are close to death. Some cancer patients take strong opioids for months or even years, while others do not need them at all.

Strong opioids provide more freedom: patients sleep better and feel less pain when moving. Appetite may return, not just for food, but for life in general.

4. Do opioid analgesics (strong opioids) completely eliminate

pain?

Usually yes, but sometimes they cannot completely relieve pain, especially certain types of it: bone pain, neuralgia, or pain caused by pressure ulcers. In such cases, additional drug therapy may be needed. For example, to treat cancer-related bone pain, anti-inflammatory drugs are often required along with strong painkillers. And certain types of pain, such as tension headaches, migraines, muscle spasms, and cramps, are not treated with opioids at all. Your doctor will certainly recommend suitable treatment for you.

5. Why do some patients need a higher dose of strong opioids than others?

There may be many reasons for this, including:

• differences in pain severity;

• differences in how your body responds to pain;

• the cause of the pain (opioids do not relieve different types of pain equally well);

• differences in the body's sensitivity to strong opioids;

• the use of other painkillers and non-pharmacological treatments;

• differences in the severity of adverse reactions.

6. Isn't it better to postpone opioid analgesics (strong opioids) until the pain becomes unbearable?

You may be concerned that your body will get used to morphine and that, if this happens, there will be nothing left to relieve the pain. If pain returns while you are taking morphine (or another strong opioid), your doctor or nurse will increase the dose to relieve the pain (if necessary, this can be done several times).

7. Will I have to keep increasing the dose to control my pain?

Not necessarily. Many people remain on low or moderate doses throughout their illness. Sometimes it is possible to reduce the dose or stop taking opioids altogether (for example, after radiotherapy for affected bones). But this should always be done under medical supervision.

8. How long do I need to take strong opioids? Does the effect wear off over time?

You can take opioids for the rest of your life, whether that is months or years. Usually, the effect does not wear off. If you need to increase the dose, it is typically because your disease is causing more pain, not because the effect of the opioids is weakening.

9. Will I become addicted to taking opioids?

If you mean, 'Will I become dependent on this substance and be unable to stop even when I no longer need it for pain relief?', the answer is definitely NO.

Addiction (psychological) is very rare when strong opioids are taken for pain relief, and you do not need to worry about this. On the other hand, if you have previously abused substances similar to morphine (e.g., heroin), you may experience difficulties when reducing your opioid dose.

If you no longer need to take opioids, it is best to gradually reduce the dose under medical supervision. This is because people who have taken strong opioids for several months and then suddenly stop will develop withdrawal symptoms, manifested by general malaise and diarrhea. However, the dose required to prevent withdrawal symptoms is much lower than the dose needed for pain relief.

10. Is it possible to stop taking opioid analgesics (strong opioids)?

Yes, it is possible. If your pain is under control and you have been on a stable dose of strong opioids for some time, your doctor may suggest lowering the dose if you experience side effects. However, suddenly stopping long-term use of strong opioids is ill-advised, because the pain may return and you may develop withdrawal symptoms. Therefore, it is best to reduce the dose of strong painkillers gradually under the supervision of your doctor.

In addition, you can reduce the dose or stop taking strong opioids if you have undergone other pain treatments, for example:

• following radiotherapy (often used for bone pain), the opioid dose may be gradually tapered off over several weeks;

• following a nerve block (a special injection to numb a painful nerve), the opioid dose can be halved immediately and reduced further over the following days.

11. How soon will the pain go away?

This depends on your body's individual characteristics, but usually people notice some improvement right away. If you have several different types of pain, are depressed, or experience anxiety, achieving maximum effect may take three to four weeks.

Pain management has three main goals:

• ensure a good night's sleep and comfortable well-being during the day;

• completely relieve pain during the day at rest;

• relieve pain when walking and performing other activities.

The third level of pain relief is not always achieved with medications alone.

Sometimes it is necessary to limit certain activities if they continue to cause pain.

12. What happens if potent opioids do not relieve the pain?

You can try several other options. It is often necessary to take an anti-inflammatory painkiller along with an opioid to achieve sufficient pain relief. For neuralgia, hormonal drugs (cortisone) and other medications are frequently prescribed.

Pain treatment also includes:

• psychological support for you and your family;

• relaxation therapy, massage, and acupuncture;

• radiotherapy (especially for bone pain and neuralgia);

• sometimes: injections to "turn off" nerves (nerve blocks).

In some cases, activities that exacerbate pain should be limited.

13. Will potent opioids cause constipation?

For most people, this is the most unpleasant side effect of treatment with potent opioids. As a rule, the doctor prescribes a laxative when you start opioid therapy.

Remember that:

• the laxative dosage varies for different people;

• the attending physician may adjust the dose several times until the optimal one is found;

• the laxative dose prescribed by your doctor is very likely to be higher than for those not taking opioids;

• since opioids cause persistent constipation, be prepared to take a laxative two to three times a day;

• the goal is to have soft stools every two to three days (more frequent is great luck);

• if you feel that the laxative is not working, consult your doctor as soon as possible;

• if there is no stool for three days, use a suppository laxative (inserted into the rectum) or talk to a nurse about an enema (solution injected into the rectum) to help empty your bowels.

Along with taking laxatives, you can drink prune juice in the mornings and generally drink more fluids throughout the day. Simply adding fiber to your diet will not help with opioid-induced constipation.

14. Will I need to take an antiemetic?

If you vomit after taking an opioid, the drug will not have time to be absorbed into the bloodstream. In this case, the pain will not subside, and you may lose faith in the drug's efficacy. To prevent this, some doctors prescribe antiemetics along with potent opioids. Others prescribe them only to those who truly need them.

You need to take an antiemetic if you are currently experiencing nausea and had vomiting when taking weak opioids (e.g., tramadol) or had vomiting when taking potent opioids in the past.

You do not need an antiemetic if you are not currently nauseous, or if you have previously taken codeine or morphine (or any other opioid) without experiencing nausea.

15. What should I do if you suffer from dry mouth while taking opioids?

Opioids can cause dry mouth. The main cause of dryness is often another medication that can be replaced (or its dosage reduced). If the dryness is caused by the opioid, you need to regularly moisten your mouth by sipping ice water or sparkling mineral water. To stimulate saliva flow, try chewing sugar-free, low-tack chewing gum or sucking on ice cubes.

16. Can taking potent opioids cause increased sweating?

Yes, it certainly can. Sweating can be severe and is often more noticeable at night. Try lowering the room temperature and wearing cotton clothing. Keep a change of nightwear close by in case you sweat heavily. Sometimes paracetamol or other anti-inflammatory painkillers help. If sweating bothers you significantly, discuss it with your doctor.

17. Does tobacco smoking affect the required opioid dose?

Smoking has no relation to the effect of opioids. They work the same way for both smokers and nonsmokers, so there is no difference in dosage.

It is always preferable to quit smoking, but when a person is in severe pain, it is not the right time.

18. Should a patient continue taking potent opioids when they are in an unconscious state?

If the patient suddenly loses consciousness, call their doctor or an ambulance; they will advise you on what to do next.

If the patient is unconscious and the attending physician or nurse says they will die in a few days or even hours, it is important to continue opioid therapy. With patches, this is easiest—just keep applying them.

If the patient was taking medications orally, it is necessary to switch to injections or another non-oral formulation. However, since many patients become increasingly lethargic before falling unconscious, the medication can be replaced in time to avoid an emergency.

The primary reason to continue treatment with potent opioids is that even unconscious patients feel pain and become restless. Additionally, if they have been taking potent opioids for many weeks and suddenly stop, withdrawal symptoms may develop: anxiety, sweating, diarrhea, and fecal incontinence.

Appendix G. Assessment Scales, Questionnaires, and Other Evaluation Tools

Appendix G1. Visual Analog Scale

Russian name: visual analog scale (VAS).

Original name: Visual Analog Scale.

Source: A. Williamson, B. Hoggart: Pain: a review of three commonly used pain rating scales. Journal of Clinical Nursing. 14:798-804 2005.

Pain: A guide for students and physicians: textbook / edited by Academician of the Russian Academy of Medical Sciences N.N. Yakhno. – Moscow: MEDpress-inform, 2010. – 304 p.

Type: scale.

Purpose: assessment of pain intensity.

Explanation: The VAS is a 10 cm (100 mm) line on which the patient is asked to make a mark corresponding to the intensity of pain experienced at the moment (or over a certain period, e.g., the last week); the patient chooses between "no pain" and "worst pain imaginable". The distance in centimeters between the beginning of the scale ("no pain") and the patient's mark is then measured with a centimeter ruler, and centimeters are converted into points (1 cm = 10 mm = 1 point).

Key (interpretation):

Up to 4 points – mild pain;

4–7 points – moderate pain;

More than 7 points – severe pain.

Notes: in addition to medical personnel, legal representatives/caregivers may use this scale after receiving instructions from a healthcare professional.

Appendix G2. Numerical Rating Scale (NRS)

Russian name: Numeric Rating Scale (NRS), synonym: numerical rating scale.

Original name: Numeric Rating Scale.

Source: A. Williamson, B. Hoggart: Pain: a review of three commonly used pain rating scales. Journal of Clinical Nursing. 14:798-804 2005.

Pain: A guide for students and physicians: textbook / edited by Academician of the Russian Academy of Medical Sciences N.N. Yakhno. – Moscow: MEDpress-inform, 2010. – 304 p.

Type: scale.

Purpose: assessment of pain intensity.

Explanation: The scale is a horizontal line, 10 cm long, with numbers from 0 to 10 placed on it, where 0 is "no pain" and 10 is "worst imaginable pain". The patient is asked to choose a number from 0 to 10 corresponding to the severity of their pain sensations.

Content (template):

Key (interpretation):

Up to 4 points – mild pain;

4–7 points – moderate pain;

More than 7 points – severe pain.

Notes: in addition to medical personnel, legal representatives/caregivers may use this scale after receiving instructions from a healthcare professional.

Appendix G3. Wong-Baker FACES Pain Rating Scale

Russian name: Wong-Baker FACES Pain Rating Scale.

Original name: Wong-Baker FACES® Pain Rating Scale.

Source (official developers' website, validation publication):

Donna Lee Wong, Connie Morain Baker. Comparison of the assessment scale. Pediatric Nursing. Pain in children.Jan-Feb 1988. Vol.14. №1.

Aleksandrovich Yu.S., Gordeev V.I. Assessment and prognostic scales in critical care medicine - 3rd ed., revised and enlarged - St. Petersburg: ELBI-SPb, 2015 - 320 p.

Type: scale.

Purpose: general assessment of pain intensity.

Content (template):

Key (interpretation): The Wong-Baker FACES Pain Rating Scale is designed to assess the condition of adult patients and children older than 3 years. The scale consists of 6 faces, ranging from smiling (no pain) to crying (pain as bad as it can be). The specialist assessing pain must explain to the patient in simple terms that they need to choose which of the presented faces describes their pain level.

Notes: in addition to medical personnel, legal representatives/caregivers may use this scale after receiving instructions from a healthcare professional.

Appendix G4. DN4 Neuropathic Pain Diagnostic Questionnaire

Russian title: Neuropathic Pain Diagnostic Questionnaire.

Original title: Neuropathic pain diagnostic questionnaire, DN4.

Source (official developer website, validation publication): Bouhassira D., Attal N., Fermanian J. et al. Development and validation of the neuropathic pain symptom

inventory. Pain 2004; 108: 248-57.

Type: questionnaire.

Intended for: physicians of non-neurological specialties.

Content (template):

Please complete this questionnaire by checking one answer for each item in the 4 questions below.

Interpretation: if the total score is ≥4, the patient has a high probability of neuropathic pain.

Notes: the questionnaire allows the detection of neuropathic pain with a certainty of more than 80%.