Table of contents

Abstract 80

Introduction 80

Clinical assessment of pain 81

Components of pain pathophysiology 81

General principles of cancer pain management 82

Pharmacological treatment 82

Non-opioid analgesics 83

Opioid analgesics 84

Supportive agents and adjuvant analgesics 90

Non-pharmacological pain management 91

Physiotherapy 92

Acupuncture 92

Physical exercise 92

Psychological support 92

Interventional methods of pain management 93

Conclusions 97

Article Information and Declarations 97

References 98

These guidelines contain evidence-based principles of diagnostic and therapeutic procedures, prepared taking into account the value of scientific evidence and categories of recommendations. The rules of conduct should always be interpreted in the context of the individual clinical situation. Recommendations do not always correspond to the current rules of reimbursement in Poland. In case of doubt, current reimbursement possibilities of individual procedures should be determined. Strength of recommendations and quality of scientific evidence:

I A — Strong recommendation, high-quality evidence

I B — Strong recommendation, moderate-quality evidence

I C — Strong recommendation, low-quality evidence

II A — Weak recommendation, high-quality evidence

II B — Weak recommendation, moderate-quality evidence

II C — Weak recommendation, low-quality evidence

ABSTRACT

In order to elaborate diagnostic and therapeutic recommendations regarding the management of cancer patients with pain, a narrative review of the literature in PubMed and Cochrane database was conducted for the period of 2000–2022. An Expert Group of three scientific associations: Polish Association of Palliative Care, Polish Association for the Study of Pain, and Polish Association of Clinical Oncology was appointed, which made a literature review and formulated guidelines with strength of recommendations and quality of evidence.

To achieve optimal effect of pain treatment cancer patients require complex clinical assessment of pain with detailed recognition of pathophysiology, intensity and time frame (baseline and breakthrough — episodic) of pain. Pain evaluation should encompass other symptoms, comorbidities, disturbances in psychological, social, and spiritual dimensions, which may induce patients’ suffering and total pain appearance. An important role plays anticancer local and systemic treatment, which may induce or exacerbate pain induced by cancer or comorbidities.

A standard approach in patients with chronic pain in the course of cancer and other diseases is based on World Health Organization (WHO) analgesic ladder algorithm, which is supplemented with non-pharmacological management. It is recommended an individual approach in pain treatment depending on clinical situation of a concrete patient. Efforts should be made to effectively manage other symptoms, which accompany cancer. An introduction of specific treatment taking into account given pathophysiology, time frame and intensity of pain increase effectiveness and significantly shorten time necessary to achieve effective analgesia, and moreover contribute to decrease intensity and frequency of adverse effects of analgesics used.

Keywords: cancer, clinical assessment, pain, pharmacotherapy, treatment

Oncol Clin Pract 2024; 20, 2: 79–99

Introduction

Pain is one of the most common symptoms in cancer patients. Ensuring the most effective pain management, which is an inalienable right of every patient and, at the same time, the basic duty of every doctor and nurse, allows for maintaining the highest possible quality of life (QoL) for patients and caregivers. According to the International Association for the Study of Pain (IASP), pain is an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage [1]. The following important characteristics of pain have been distinguished:

Pain can be differentiated according to its duration (acute vs. chronic), pathophysiology (receptor, neuropathic, mixed, nociplastic), and place of sensation (localized vs. generalized) [2]. Untreated or ineffectively treated pain is a factor that interferes with proper functioning of the body; pain contributes to the occurrence or intensification of shock symptoms, lowers immunity, and is a factor that significantly reduces patients’ quality of life (QoL), which makes effective anti-cancer treatment difficult or impossible and increases the cost of therapy many times over [3]. Ineffective therapy or lack of pain management can lead to emotional and psychotic disorders as well as depression.

Pain should be considered and treated in the context of a specific clinical situation, taking into account patients’ general condition, other symptoms, comorbidities, and anticancer treatment, as well as in the context of non-medical aspects: psychological, social, and spiritual problems of patients and caregivers. The prevalence of pain is estimated at 40–50% of patients undergoing anticancer treatment and 60–70% of patients in an advanced cancer stage [4].

Clinical assessment of pain

Pain is a subjective phenomenon, which is related to individual sensitivity to pain stimuli as well as the multidimensional impact of pain on the physical, mental, social, and spiritual domains. The mental state of patients and their personalities play an important role in the perception of pain [5]. In addition, a significant practical problem is the lack of objective measures of pain; hence its clinical assessment is most often based on the patient’s subjective report, and in the absence of self-assessment, on the assessment made by the caregivers and medical staff.

A simple tool for individual assessment of pain intensity is a visual analog scale (VAS), on which the patient indicates the point corresponding to the perceived intensity of pain on a 10-cm continuous line (from no pain to the strongest pain). In clinical practice, the standard tool for assessing pain intensity is the numerical rating scale (NRS), in which the degree of pain severity is defined by the patient with an appropriate number in the range from 0 (no pain) to 10 (the strongest pain). Sometimes a descriptive Likert verbal scale is used to assess pain intensity (no pain, mild pain, moderate pain, severe pain, very severe pain). In children, people who do not know a language, the illiterate, and in patients with cognitive and dyslexic deficits, behavioral pictorial scales are used. Pain intensity should be assessed both before starting treatment and regularly monitored during treatment. A slightly more detailed assessment of pain is provided by the tools adapted to Polish conditions: Memorial Pain Assessment Card (MPAC) and Brief Pain Inventory — Short Form (BPI–SF). The MPAC tool consists of three numerical scales in which the patient assesses pain intensity, pain relief, and general mood and pain intensity is also assessed according to a verbal scale. There is also a section completed by the doctor or nurse, which includes the pathophysiology, location, type of pain (background and breakthrough), and treatment. On the other hand, the BPI–SF contains numerical rating scales for describing pain intensity and pain relief in the last 24 hours, as well as the impact of pain on patients’ daily activities during the same period.

Patients with the neuropathic component of pain have various sensory symptoms that may coexist in various combinations. Therefore, clinical examination of patients should include assessment of sensitivity to touch, pricking, pressure, low and high temperature, and vibration, as well as time summation. In recent years, several scales (screening tools) based on verbal description of pain, with or without elements of a clinical examination, have been developed, and they significantly facilitate diagnosis of neuropathic pain and implementation of appropriate treatment. The Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale consists of five questions about pain and two items of the clinical examination; specificity of the scale is 85%, sensitivity is 80%, and if the number of points is > 12/24, the pain is predominantly neuropathic. Another much simpler Douleur Neuropathique 4 Questions (DN4) scale contains seven symptom questions and three clinical examination items. Specificity of the scale is 83%, and sensitivity is 90%. If the number of “yes” answers is > 4/10, the pain is mainly neuropathic [6].

To assess the nociplastic component, the Central Sensitization Inventory (CSI) questionnaire with 25 questions is used, which has also been translated and adapted to Polish. A score > 40/100 indicates involvement of central sensitization and the nociplastic component of pain [7].

In clinical practice, a useful tool for pain assessment by patients and caregivers can be a diary for regular observation and monitoring of pain treatment, as well as a patient guide on how to manage pain in cancer patients. Both the diary and the guide are available online [8].

Components of pain pathophysiology

The pathophysiology of pain involves two main mechanisms. The first is associated with mechanical and/or chemical activation of pain receptors (nociceptors) and causes nociceptive pain with or without an inflammatory component (somatic, visceral). The second mechanism — independent of the activation of pain receptors — is caused by damage to the somatosensory nervous system and is classified as neuropathic pain. Neuropathic pain is characterized by hyperalgesia (increased sensitivity to pain stimuli) and allodynia (pain caused by stimuli that normally do not cause pain). Neuropathic pain is often described by patients as burning, stinging, pricking with a tingling sensation, or tearing, often accompanied by sensory disturbances such as hyperesthesia or hypoesthesia or sensations similar to the passage of electric current. It should be emphasized that neuropathic pain is more difficult to treat than nociceptive pain, which is characterized by significantly greater effectiveness of non-opioid and opioid analgesics. It is worth noting that somatic bone pain in cancer patients also shows the characteristics of neuropathic pain; hence it is classified as pain with a neuropathic component. Nociplastic pain is pain that results from changes in the central processes of nociceptive control. It occurs in the absence of clear evidence of actual or impending tissue damage that causes activation of peripheral nociceptors or evidence of disease or damage to the somatosensory system that causes pain [9]. Nociplastic pain is the most difficult to recognize and treat, which may contribute to the ineffectiveness of pain management. In cancer patients, the pathophysiology of pain is usually mixed, with receptor, neuropathic, and nociplastic mechanisms contributing in varying degrees to clinical manifestation.

According to the period of occurrence, pain experienced by patients can be divided into constant, i.e., background (baseline) pain and breakthrough pain, also referred to as episodic pain [10]. Background pain occurs for more than 12 hours a day, while breakthrough pain is defined as an attack of strong and usually short-term pain, with rapidly increasing intensity, despite effectively treated background pain. The time to the maximum intensity of breakthrough pain is usually a few minutes, and the median duration is about 30 minutes, although a pain episode can last from several tens of seconds to several hours. In more recent publications, episodic pain is also diagnosed in patients with ineffectively treated background pain when opioids are not administered or in the absence of background pain. Breakthrough pain can occur without a specific cause (spontaneous, idiopathic pain), or can also be triggered by a specific factor (incidental pain). Breakthrough pain does not include end-of-dose pain, which occurs before the administration of the next dose of a regularly used analgesic and requires correction of background pain treatment [11].

Incidental pain can be divided into independent of the patient’s will (involuntary) or dependent on the patient’s will (voluntary), i.e., caused by the predictable and voluntary activity of patients or care activities (procedural pain). The strategy for the treatment of spontaneous and incidental involuntary pain consists of administration of analgesics with a rapid onset of analgesic action at the onset of pain to ensure effective analgesia in the shortest possible time. The most used for this purpose are fast-acting fentanyl products, applied by the transmucosal route (nasal, buccal, or sublingual). However, in the case of pain caused by predictable and voluntary activity of patients or care activities (procedural pain), the occurrence of pain should be prevented by applying an additional dose of an analgesic in advance, which will effectively prevent or significantly reduce the intensity of incidental pain. For this purpose, immediate-release opioids can be administered orally or parenterally (subcutaneously, usually at home, or intravenously, usually in stationary or outpatient settings) [12].

General principles of cancer pain management

Whenever possible, treatment of chronic pain should target the underlying condition to achieve permanent relief and prevent other complications. If the cause cannot be identified or eliminated, symptomatic treatment should be used, taking into account the clinical manifestation, especially the pathophysiology, intensity, and time pattern of pain.

Pharmacological treatment

Pharmacotherapy and non-pharmacological methods are used in the management of cancer pain (II A).

In the treatment of background (constant) pain, pharmacotherapy should be conducted continuously to maintain a constant therapeutic blood concentration of drugs, and analgesics should be administered at regular intervals in line with their pharmacokinetic profile, the most convenient route for the patient, with a preference for oral administration. However, if the patient prefers a different route of administration, when oral treatment is not possible, when the patient is taking other drugs that change the bioavailability of analgesics, or when side effects are difficult to treat, analgesics are administered by other routes (transdermal, subcutaneous, intravenous, intrathecal, or topical). It is advisable to use drugs with a long duration of action (oral route with controlled release) and, if necessary (breakthrough pain), drugs with a rapid onset and short duration of analgesic effect (immediate-release oral formulations), which is adequate to the characteristics of breakthrough pain. Frequent breakthrough pain (more than 3 episodes a day) is an indication to consider adjusting the treatment of background pain. An effectiveness of pain therapy should be monitored, and side effects of analgesic therapy should be prevented and treated accordingly.

The use of analgesics is based on the analgesic ladder algorithm developed by the World Health Organization (WHO), according to which analgesics can be divided into three groups [13]. Step I included non-opioid analgesics: non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol, and metamizole. The next group consists of opioids from step II of the WHO analgesic ladder (“weak” opioids): tramadol, codeine, and dihydrocodeine. At step II of the WHO analgesic ladder, low doses of “strong” opioids may also be used: oxycodone or morphine (at a dose of 20 mg and 30 mg/day, respectively, administered orally). The next group consists of opioids from step III of the WHO analgesic ladder (“strong” opioids): morphine, oxycodone, oxycodone/naloxone, fentanyl, buprenorphine, tapentadol, methadone, and hydromorphone (currently unavailable in Poland). Treatment is based on the individual selection of an analgesic adequate to the intensity and pathophysiology of the patient’s pain.

Treatment begins with step I drugs (usually with pain intensity corresponds to NRS 1–3). In patients with moderate pain (NRS 4–6), treatment begins with step II or low doses of step III opioids. There is no ceiling effect during treatment with “strong” opioids observed during treatment with step I and II analgesics, which allows the majority of patients to expect a better analgesic effect after increasing the dose of the drug. When using opioid drugs, steps II and III of the WHO analgesic ladder, concomitant administration of non-opioid analgesics may be considered (different mechanism of analgesic effect). However, step II and III opioids should not be combined. At each step of the WHO analgesic ladder, it is advisable to consider the use of supportive agents, which include analgesic adjuvants (co-analgesics) that increase the effect of analgesics and drugs that reduce or prevent their side effects. At each treatment step, there may be indications for the administration of supportive drugs, which include a group of co-analgesics (adjuvant analgesics), increasing the analgesic effects of pain medications in some types of pain (mainly in neuropathic, bone pain and visceral colicky pain) or due to their mechanism of analgesic action in specific types of pain (neuropathic pain, nociplastic pain) and drugs to prevent or alleviate the side effects of opioids (laxatives and antiemetics).

Non-opioid analgesics

They are used alone in mild pain (NRS 1–3) and as supportive agents in pain with moderate (NRS 4–6) and severe (NRS 7–10) intensity, together with opioids.

Non-steroidal anti-inflammatory drugs (NSAIDs) block prostaglandin synthesis by inhibiting cyclooxygenase (COX) activity and, to a lesser extent, expression of the induced isoform of nitric oxide synthase. They also have non-cyclooxygenase mechanisms of analgesic action; therefore, their choice should be individualized (Tab. 1). Since NSAIDs, except nabumetone, are weak acids and can damage the gastroduodenal mucosa, concomitant use of a proton pump inhibitor (PPI) is recommended in patients at risk. The decision to add a PPI should be individualized, and these drugs should be administered in patients with a clinically significant risk of gastropathy. The use of omeprazole is not recommended due to numerous pharmacokinetic interactions, including with analgesics, and due to the possible side effect on mitochondrial function, which is important in cancer patients. The adverse effect of NSAIDs on the liver is most often manifested by an asymptomatic increase in aminotransferase activity. In particular, administration of diclofenac should be avoided in patients at risk of drug-induced hepatopathy. The adverse effect of NSAIDs on the kidneys may, in turn, lead to peripheral edema and sometimes to acute renal failure. The risk of nephropathy is particularly increased in patients taking concomitant medications that inhibit the activity of the renin-angiotensin-aldosterone system, loop diuretics, and spironolactone. An increased risk of nephropathy may occur with concomitant administration of NSAIDs and paracetamol due to the inhibition of plasma renin activity by paracetamol, and this is of particular importance in dehydrated patients. There is a variable risk of cardiovascular complications associated with the use of NSAIDs; therefore, in this particular group of patients, the choice of NSAIDs should be individualized in relation to the expected analgesic efficacy and side effect profile. In the case of a clinically significant risk of NSAID-induced adverse effects, especially in the elderly, it is worth choosing drugs with a short peripheral half-life.

Special care should be taken in elderly patients receiving chronic NSAID treatment due to the increased risk of adverse reactions, especially worsening heart failure and renal insufficiency. Rectal administration of NSAIDs is not recommended due to the long latency period of the analgesic effect, and the incidence of side effects is not reduced compared to the oral route. Two systemic NSAIDs should not be administered concomitantly, as this does not increase analgesic efficacy but significantly increases the risk of gastrointestinal mucosa damage and other side effects, but systemic and topical NSAIDs may be combined. NSAIDs are highly effective in the treatment of bone pain, with an inflammatory and receptor component, but are ineffective in neuropathic and nociplastic pain.

Paracetamol has analgesic and antipyretic effects but does not cause peripheral anti-inflammatory effects. At therapeutic doses, NSAIDs class side effects from the gastrointestinal tract and kidneys do not appear; however, paracetamol inhibits plasma renin activity and, especially in dehydrated patients, has a potentially nephrotoxic effect. The clinical effect after administration of paracetamol occurs after 15–30 minutes, depending on the pharmaceutical form of the drug. When using paracetamol in the correct dosage (maximum daily dose 4 g/day), no serious side effects are usually observed, except for allergic skin reactions. At higher doses or with long-term use, side effects may occur, especially in the liver. Paracetamol is contraindicated in patients with liver failure, as well as in patients taking concomitant drugs that are CYP3A4 inducers, e.g., dexamethasone or carbamazepine. When using paracetamol for a long time, special care should be taken in malnourished patients, those abusing alcohol, and using barbiturates and oral anticoagulants. Paracetamol does not cause bronchospasm in people with bronchial asthma. The combination of NSAIDs and paracetamol has a synergistic analgesic and antipyretic effect [14]. Due to its pharmacokinetic and pharmacodynamic profile, paracetamol should not be used in inflammatory pain and visceral pain.

Metamizole is a non-opioid analgesic from step I of the WHO analgesic ladder, devoid of anti-inflammatory effect. The mechanism of the analgesic action is mainly COX2 inhibition in the central nervous system (CNS) and, to a lesser extent, COX1 inhibition and possibly activation of the opioidergic system. This agent has a spasmolytic effect resulting from the central inhibition of adenosine reuptake, which is important in the treatment of acute colic pain and visceral pain. The maximum daily dose of metamizole is 5 g. In cancer patients, the drug is most often used in the treatment of breakthrough, colic and visceral pain. Metamizole should not be administered regularly for more than 7 days due to an increased risk of side effects, especially from the hematopoietic system.

Opioid analgesics

Opioids play a key role in the treatment of moderate to severe cancer pain by affecting three types of opioid receptors: μ, k and d, currently referred to as MOR, KOR, and DOR, respectively, and the nociceptin receptor NOR. Opioid receptors are located in numerous structures of the central and peripheral nervous system. The effects of opioids depend on many factors, including an affinity for opioid receptors, effects on the serotonergic, adrenergic, and N-methyl-D-aspartic (NMDA) receptors, as well as on physicochemical properties and pharmacokinetic characteristics. In the treatment of breakthrough pain, the dose of short-acting (immediate-release) opioids administered via an oral route is usually 10–20% of the total daily dose of regularly administered opioids. When using fentanyl with a rapid onset of analgesia via the transmucosal route, the principle of titration from the lowest available dose of a given product always applies. The above rule also applies to the replacement of one fentanyl product with another (also administered by the same route, e.g., intranasally), as well as to significant changes in the treatment of background pain (significant change in the dose of the background opioid or rotation of opioids).

Step II opioid analgesics of the WHO analgesic ladder (“weak” opioids)

Step II opioids of the WHO analgesic ladder are most often used in patients with moderate pain (NRS 4–6) [15]. Exceeding the recommended maximum doses usually does not cause an additional analgesic effect but may intensify side effects (“ceiling effect”). Tramadol, codeine, and dihydrocodeine are available in Poland (Tab. 2).

Tramadol is the most commonly used step II opioid of the WHO analgesic ladder, with an analgesic effect several times weaker than that of morphine (II A). Tramadol exhibits a dual mechanism of analgesic action: in addition to acting on opioid (predominantly μ) receptors in the CNS, it activates the descending antinociceptive system by inhibiting the reuptake of norepinephrine and serotonin. Tramadol is metabolized in the liver by cytochrome P–450, and then approximately 90% (after oral administration) is excreted via the kidneys, with approximately 10% excreted in feces. The analgesic effect of tramadol depends on the activity of the CYP2D6 enzyme. It catalyzes the conversion of the parent compound to O-desmethyltramadol (M1), which has a significant analgesic effect by activating μ-opioid receptors. In the Caucasian population, 7–10% of people do not metabolize of tramadol to M1 (poor metabolizers), then the analgesic effect may be much weaker, while 1–2% excessively metabolize tramadol to M1 (ultrarapid metabolizers). This results in a higher risk of side effects, including nausea and vomiting, sedation, and respiratory depression.

The most commonly observed side effects associated with the use of tramadol are nausea and hyperhidrosis, especially at the beginning of treatment. The advantage of tramadol is a lower impact on the motility of the gastrointestinal tract and a weak constipation-inducing effect, as well as a lower risk of causing respiratory depression compared to other opioids. Tramadol is available in many formulations, including a controlled release form. Tablets, oral drops (40 drops = 100 mg), and ampoules are used, which can be administered subcutaneously and intravenously. The drug should be used in doses up to 400 mg/day, administered in the immediate-release formulations every 4–6 hours, or in prolonged-acting forms every 12 hours. In breakthrough pain during treatment with tramadol as a background drug, immediate-release preparations of tramadol are used. Tramadol is available as a fixed-dose combination (FDC) with paracetamol and dexketoprofen, which accelerates the onset of action of the drug and causes a synergistic analgesic effect.

Due to the prolonged half-life of tramadol and its being an active metabolite in patients with renal failure, it is recommended to reduce its dose and to extend the intervals between subsequent doses or to switch to another opioid. Extending the dosing intervals and reducing the dose is also recommended in patients with hepatic impairment. In patients with a history of epilepsy, tramadol is not recommended due to an increased risk of seizures, and in patients without a history of epilepsy, the drug does not increase the risk of seizures. Due to an increase in the concentration of porphyrins, tramadol raises the risk of attacks in patients with acute porphyria. Tramadol should not be administered together with antidepressants that inhibit the reuptake of serotonin, as well as serotonin and norepinephrine, and tricyclic antidepressants, as it may lead to symptoms of serotonin syndrome. The use of tramadol with CYP3A4 inducers (mainly carbamazepine or dexamethasone) is contraindicated because an increased amount of N-desmethyltramadol is synthesized, which has no analgesic effect but has a proconvulsant effect. In the case of concomitant use of CYP2D6 inhibitors with tramadol, the risk of nausea and vomiting increases significantly, and the simultaneous administration of tramadol and carbamazepine worsens its analgesic effect.

Codeine is an agonist of the μ-opioid receptor, with an analgesic effect approximately 10 times lower than that of morphine. Codeine is a prodrug with an analgesic effect dependent on the conversion to morphine determined by the activity of CYP2D6, as well as other metabolites (mainly codeine-6-glucuronide). Due to its strong antitussive properties, it is considered the drug of choice in patients with moderate pain and cough. A common side effect of codeine is constipation. Codeine is only administered orally in the form of immediate-release tablets or solution. The analgesic effect occurs after 15–30 minutes and lasts for 4–6 hours (T1/2 3–4 hours). The maximum daily dose of codeine is 240 mg. Codeine is also available in FDC with paracetamol, paracetamol and caffeine, acetylsalicylic acid and ibuprofen. Due to its pharmacokinetic profile and genetically variable metabolism, codeine is not recommended for the treatment of pain.

Dihydrocodeine (DHC) is a derivative of codeine. The analgesic potency of DHC is approximately 5 times weaker than that of morphine administered via an oral route. The drug is metabolized mainly to DHC-6-glucuronide and dihydromorphine, and side effects are usually less severe compared to codeine. Unlike codeine and tramadol, the analgesic effects of DHC do not depend on CYP2D6 activity. Dihydrocodeine is only available as controlled-release tablets to be taken every 12 hours. The maximum daily dose of DHC is 240 mg. DHC is recommended in patients with moderate pain, often accompanied by cough and shortness of breath.

A common feature of tramadol and codeine metabolism is the dependence of the analgesic effect and side effects on the genetically determined CYP2D6 activity, as well as renal excretion (the latter also applies to DHC), while the analgesia and side effects of DHC do not depend on CYP2D6 activity. At step II of the WHO analgesic ladder, low doses of “strong” (morphine up to 30 mg, oxycodone up to 20 mg per day orally) can be used instead of “weak” opioids [16].

Step III opioid analgesics of the WHO analgesic ladder (“strong” opioids)

Opioids without the ceiling effect from step III of the WHO analgesic ladder are recommended for the treatment of severe and very severe pain (NRS 7–10) [17]. Morphine, oxycodone, oxycodone/naloxone, fentanyl, buprenorphine, tapentadol, and methadone are available in Poland, and hydromorphone is not available yet [18]. According to the European Association for Palliative Care (EAPC) guidelines, morphine, oxycodone, and hydromorphone are the first-choice opioids in the treatment of moderate to severe cancer pain (I A) [13]. In the treatment of chronic pain, the use of pethidine and pentazocine is contraindicated due to the toxic effects of their metabolites.

Morphine is the standard opioid recommended by the WHO and the European Society for Medical Oncology (ESMO). The strength of the analgesic effect of other opioids is compared to morphine (I A). It is a pure agonist of opioid (predominantly μ) receptors. The main metabolites are morphine-3-glucuronide and morphine-6-glucuronide, and, like the parent compound, they are excreted by the kidneys. Morphine is a hydrophilic opioid of choice in the treatment of pain and in patients with dyspnea [19]. Concomitant use of morphine and benzodiazepines, and other CNS depressants increases the risk of sedation, hypotonia, and respiratory depression. Constipation may be a significant problem during treatment with morphine [20]. Many drugs taken concomitantly with morphine, including drugs with anticholinergic effects (e.g., pridinol and tizanidine) and serotonin receptor antagonists, also increase defecation disorders.

In the treatment of pain, morphine is used orally with immediate- and controlled-release formulations or parenterally (subcutaneously, intravenously), rarely intrathecally and topically. The equivalent oral dose is approximately 3-fold higher than the parenteral dose due to limited absorption from the gastrointestinal tract and significant hepatic first-pass effect. Treatment usually starts with low single doses (tablets, less often water solution with immediate release), usually 5 mg (patients not previously treated with “weak” opioids) or 10 mg (patients previously treated with “weak” opioids), administered every 4–6 hours. In the case of starting morphine treatment with controlled-release tablets in patients previously untreated with “weak” opioids, a single dose of morphine of 10 mg every 12 hours is most often used (20 mg daily), while treatment of patients previously receiving “weak” opioids usually starts with a single dose of 20 or 30 mg every 12 hours (daily dose is 40 mg and 60 mg, respectively). Sometimes administration of controlled-release morphine is recommended every 8 hours. The initial doses given in patients with renal impairment, severe cachexia, and the elderly are usually half as low. In these groups of patients, due to reduced elimination of morphine metabolites, close monitoring is required, and sometimes also prolongation of the intervals between subsequent administrations of the drug, change of administration route to parenteral, or switch (rotation) to another opioid. Moderate liver damage does not significantly affect the metabolism of the drug.

Morphine product, dose, and administration route are determined individually, using the principle of gradually increasing doses until a satisfactory analgesic effect with side effects acceptable to the patient is obtained (titration). During the treatment of background pain with controlled-release morphine, immediate-release morphine products are used in the treatment of breakthrough pain, usually in a dose equal to approximately 10–20% of the daily dose. During the treatment of background pain with immediate-release morphine, the dose administered in the treatment of breakthrough pain is usually equal to a single dose administered every 4–6 hours [21]. In patients in whom morphine is regularly used subcutaneously or intravenously, the rescue dose is most often administered by the same route and is usually equal to a single dose.

Oxycodone is a semi-synthetic μ and k receptor agonist (I A). Unchanged oxycodone and its metabolites are mainly excreted via the kidneys, which requires careful use of the drug in cases of impaired renal function [22]. Oxycodone is administered orally or parenterally (subcutaneously or intravenously) [23]. The morphine-to-oxycodone equivalent dose ratio is 1.5–2:1 for the oral route. When switching from parenteral to oral oxycodone administration, a 3:4 ratio is applied, i.e., the oral dose is slightly higher than the parenteral dose. Controlled-release oxycodone tablets are given every 12 hours. During oxycodone treatment, oxycodone or immediate-release morphine or transmucosal fentanyl products can be used as the primary treatment for breakthrough pain.

Oxycodone/naloxone is a 2:1 combination of oxycodone and naloxone in one controlled-release tablet (I B). In clinical trials, the product was shown to be effective in the treatment of chronic cancer pain and pain in the course of non-cancerous diseases while improving or preventing opioid-induced constipation [24]. The recommended daily dose cannot exceed 160 mg/80 mg and should be achieved gradually by titration [25]. Contraindications to the use of oxycodone/naloxone are typical of opioids; however, hepatic, renal, and portal circulation disorders, allergy to the product’s ingredients, and diarrhea are also important.

Fentanyl is a pure μ-opioid receptor agonist. Its analgesic strength compared to morphine is approximately 100:1. The significant lipophilicity of the drug is used in transdermal and transmucosal therapy. Fentanyl is metabolized in the liver by CYP3A4 to the inactive norfentanyl and then excreted by the kidneys mostly (90%) as inactive metabolites. It is well tolerated by patients with moderate hepatic and renal insufficiency. The use of transdermal and intravenous fentanyl is quite safe in advanced chronic kidney disease (grades 4–5) with a glomerular filtration rate below 30 mL/min. Compared to morphine, fentanyl has a less pronounced sedative effect, releases histamine to a small extent, and less frequently causes constipation [26].

For the treatment of pain, fentanyl is administered by the transdermal, transmucosal, and parenteral routes. Transdermal patches are applied every 72 hours, with the analgesic effect about 12 hours after applying the first patch, and full analgesic effectiveness is achieved after 2–5 changes of patches (II B). Particular care should be taken in patients with fever due to the increased rate of absorption and release of the drug and, consequently, the increased risk of side effects.

In the treatment of breakthrough pain during therapy with transdermal fentanyl and other opioids, intranasal formulations, or buccal/sublingual fentanyl tablets with a rapid onset of analgesic effect can be used (Tab. 3) [27]. The general principle of use of transmucosal fentanyl products is dose titration, which also applies when changing the type of fentanyl formulation (e.g., from intranasal to buccal or vice versa or between different intranasal products) and after switching from using other traditional opioids for breakthrough pain (e.g., short-acting morphine or oxycodone). According to SPC rapid-onset fentanyl products can only be recommended to cancer patients who are using opioids to treat their background pain (daily dose of oral morphine of 60 mg or equivalent dose of morphine administered by other routes or an equivalent dose of other opioids, used for at least 7 days). During therapy with transdermal fentanyl, oral immediate-release morphine or morphine administered by other routes (subcutaneous, intravenous) may also be used for breakthrough pain management. The choice of transmucosal administration route of fentanyl for the treatment of breakthrough pain should be based on clinical assessment of pain exacerbation characteristics, condition of the nasal and oral mucosa, and the patient’s preferences. Fentanyl has a serotonergic effect, which is worth remembering, especially in polytherapy.

Buprenorphine is a partial agonist of μ-opioid and nociceptin receptors and an antagonist of the k-opioid receptor. The potency of buprenorphine is approximately 75 times greater than that of morphine. In the analgesic therapeutic dose range, buprenorphine acts as a pure μ-opioid agonist and shows no ceiling effect. Drug metabolites are excreted in 70–80% by the digestive tract and a small amount by the kidneys. Buprenorphine is a safe opioid in patients with chronic renal failure and in dialysis patients. It is rapidly absorbed through the oral mucosa and is used in the form of sublingual tablets administered every 6–8 hours as it is poorly absorbed from gastrointestinal tract. Due to its high lipophilicity, the drug is administered transdermally as patches applied to the skin every 72–96 hours (II B). The analgesic effect of the first buprenorphine patch occurs after about 12 hours [28]. Oral or subcutaneous morphine or fentanyl fast-acting products are most commonly used for the treatment of breakthrough pain during background therapy with transdermal buprenorphine [29]. Buprenorphine patches are the only “strong” opioid available on Rp prescriptions.

Tapentadol is a representative of a new group of opioid analgesics with a complex mechanism of action: agonistic effect on opioid receptors, predominantly μ, and inhibition of norepinephrine reuptake in the CNS (I B). Due to the complex mechanism of analgesia, tapentadol has an analgesic effect typical of opioids and antidepressants from the group of norepinephrine reuptake inhibitors [30]. In addition to effective analgesia, including in patients with neuropathic pain, tapentadol is characterized by good treatment tolerance. Compared to other opioids, it is associated with limited side effects related to the influence on opioid receptors (particularly important in terms of the adverse impact on the gastrointestinal tract), low risk of interactions with other drugs (metabolism outside the cytochrome P–450 enzyme system), and lower potential for addiction [31].

Methadone is a synthetic μ and k opioid receptor agonist, NMDA receptor antagonist that increases monoamine levels (I A). The analgesic potency, compared to oral morphine, is 4–12-fold higher. Methadone causes less severe constipation, nausea, and vomiting and it can be safely used in chronic renal failure and dialysis patients. Due to the complex pharmacokinetics, significant risk of drug interactions, and prolongation of the QT interval, it is recommended that methadone treatment should be conducted by a physician experienced in pain management. The drug is used orally in the form of syrup (concentration 1 mg/1 mL), administered every 12 hours at a single initial dose of 2.5–5 mg. It is recommended not to exceed the initial daily dose of 10 mg in patients who have not previously been treated with other strong opioids. In patients who fail to achieve an adequate analgesic effect or experience severe side effects during treatment with other opioids, it is suggested to consider switching to methadone [32]. Methadone is used not only in the treatment of chronic pain but also in the treatment of opioid addiction and withdrawal syndromes.

Side effects of opioid analgesics

An individual system of opioid receptors in each person may be the cause of a different analgesic effect of opioids and different profiles and severity of side effects [33]. The most commonly observed side effects of opioids include constipation and other post-opioid gastrointestinal disorders. From the beginning of treatment with opioids, it is usually necessary to use prophylactic osmotic laxatives orally: macrogol or, less frequently, lactulose (due to it having more side effects) alone or in combination with irritants: senna derivatives, bisacodyl, and sometimes rectal irritants, e.g., glycerin suppositories.

The drugs of choice in the treatment of opioid-induced bowel dysfunction (OIBD) are peripherally acting μ-opioid receptor antagonists (PAMORA), such as naldemedine, N-methylnaltrexone, and naloxegol. Nausea and vomiting are less frequently observed side effects of opioids, and metoclopramide, haloperidol, and thiethylperazine are the most commonly used in their treatment. Metoclopramide, due to the inhibition of CYP2D6 activity, should not be administered in patients taking tramadol concomitantly and other drugs with hepatic clearance dependent on cytochrome P450 isoenzyme. Other side effects of opioids include drowsiness, dry mouth, balance disorders, skin itching, excessive sweating, hallucinations, respiratory depression (rare, most often associated with improper opioid dosing), urinary symptoms (urinary retention), myoclonus, and very rarely seizures. In the case of respiratory depression, intravenous naloxone should be administered (1 amp = 400 μg should be diluted in 10 mL of saline and administered 40–80 μg, i.e., 1–2 mL, every 30–60 seconds until opioid overdose symptoms subside).

In the case of opioid side effects, four strategies are commonly used: reducing the dose of systemically administered opioids, symptomatic treatment adequate to complication pathophysiology, changing the route of opioid administration, and rotation (switching) of opioids. The concept of opioid rotation means changing the currently used opioid analgesic to another opioid. Opioid replacement enables the elimination of metabolites, which may be important in patients treated with morphine who suffer from deterioration of renal function or dehydration. Similarly, in the case of analgesic inefficacy during treatment with one opioid, a switch to another opioid should be made. Due to incomplete cross-tolerance, care should be taken when converting the corresponding doses of different opioids, and lower converters should be used than those resulting from tables of equivalent doses of opioids, whose usefulness in clinical practice is limited. In each case, the patient requires determination of additional dose — single and daily — and close monitoring during titration to achieve an effective dose. In most patients, switching to opioids improves the effectiveness of pain management and reduces side effect intensity. Occasionally, two-step III opioids are administered simultaneously (e.g., morphine or oxycodone with fentanyl or buprenorphine), which is based on slightly different binding to receptor subtypes and differences in physicochemical properties of different opioids. There are no guidelines in this regard due to the small number of clinical trials conducted so far.

Supportive agents and adjuvant analgesics

Supportive agents are recommended at every step of the WHO analgesic ladder and include adjuvant analgesics (co-analgesics) that relieve pain or enhance the analgesic effect of other analgesics as well as drugs that prevent or treat side effects of opioids (laxatives, antiemetics). While analgesics are selected according to the intensity of pain, in the selection of adjuvant analgesics, attention is paid mainly to the specific pathophysiology of pain. Adjuvant analgesics are particularly useful in the treatment of pain with neuropathic, nociplastic, and bone components (Tab. 4) [34]. Antiepileptic drugs are most commonly used — mainly gabapentinoids (gabapentin, pregabalin, mirogabalin), less often older drugs: valproic acid, clonazepam, carbamazepine (I A). In addition, antidepressants, norepinephrine and serotonin reuptake inhibitors (venlafaxine in a daily dose of 150–225 mg, duloxetine, milnacipran), some of selected selective serotonin reuptake inhibitors (SSRIs) — vortioxetine and tricyclics (amitriptyline) are frequently used (I A). Other classes of medications used to treat neuropathic pain include topical medications (lignocaine and capsaicin) (II C) and systemic NMDA blockers (ketamine and dextromethorphan) (II B). In bone pain, NSAIDs (II A), bisphosphonates, and denosumab are most often used; moreover, due to the frequent component of neuropathic pain, antiepileptic drugs (usually pregabalin and gabapentin) are sometimes considered [35]. In the treatment of neuropathic pain caused by nerve compression and bone pain, glucocorticoids are used, especially in the case of involvement of the respiratory system and the coexistence of dyspnea, liver tumors, and brain metastases [36]. Due to the pharmacokinetic-pharmacodynamic profile, dexamethasone is particularly indicated. Attention should be paid to observing the rules of careful dosing (titration) of adjuvant analgesics, especially in combination with opioids, which allows for avoiding or at least significantly reducing the risk of side effects.

Non-pharmacological pain management

In some cancer patients, severe pain is not always effectively relieved by pharmacological treatment alone. In these patients, non-pharmacological methods are used, including anticancer treatment (systemic and local: radiotherapy and surgery), interventional methods, physiotherapy, acupuncture, physical exercise, and psychological support [37]. Radiation therapy is effective in bone pain, which in 60–80% of patients causes a significant reduction or complete resolution of pain, and the analgesic effect often lasts for many months. In some patients different procedures are used, including orthopedic operations, surgical immobilization (stabilization), vertebroplasty (in the case of pathological fractures of vertebral bodies), blocks of musculoskeletal system structures, nerve plexuses and peripheral nerves, neurodestructive procedures (neurolysis, cryolesia, thermolesion) within the nervous system and the administration of analgesics and/or adjuvant analgesics by intrathecal route (subarachnoid or extradural). Due to the complex etiology of pain and occurrence of total pain, many patients require psychological, social, and spiritual support.

Physiotherapy

Physiotherapy should be considered at every stage of cancer pain management as an element of multimodal therapy. In some patients, especially the elderly, the type of physiotherapy should be adapted to their physical capacity and capabilities [38]. Most often, indications for the use of physiotherapy include:

Techniques used to treat myofascial pain in cancer patients include:

Therapeutic techniques used in patients with bone pain and the role of the physiotherapist include:

Transcutaneous electrical nerve stimulation is a cheap and easily accessible method, which can also be performed at home, and side effects are rare (allergic skin reactions, skin burns, edema, pain intensifying). Contraindications to the use of TENS include pacemakers, epilepsy, and mental illness. TENS may be a useful option in the treatment of cancer pain, especially resistant to standard treatment and significantly reducing quality of life. It also has an analgesic effect on musculoskeletal and neuropathic pain [39]. Concerns regarding the safety and effect of TENS on cancer relate to the possible increased local blood supply to tissues due to electrical stimulation. However, the increased blood supply is due to muscle contraction; therefore, electrical stimulation below the motor threshold should not increase blood flow in a given body area.

Acupuncture

Acupuncture can be used to treat cancer pain, especially caused by tumors and surgery; analgesic effects are also possible in other pain syndromes that are difficult to treat, such as neuropathy after chemotherapy and joint pain induced by hormone therapy [40]. Clinical use of acupuncture in cancer patients may improve the effectiveness of standard pharmacotherapy in accordance with WHO recommendations and the quality of life of cancer patients [41].

Acupuncture is recommended by the American College of Chest Physicians for the treatment of pain in patients with lung cancer, especially when standard methods are ineffective or intolerable. Acupuncture is also recommended by the American Society of Clinical Oncology for the treatment of chronic pain in women during and after breast cancer therapy and in cancer survivors. Acupuncture is also recommended for elderly patients due to its effectiveness, low invasiveness, and significant safety [42].

Physical exercise

Many patients believe that rest and stillness can relieve pain. However, cancer patients can safely perform ex- ercises both during and after cancer treatment. These exercises can reduce the intensity of anxiety, depression, and fatigue associated with cancer, as well as improve the quality of life and functioning of patients after anticancer treatment. The lower credibility of this evidence relates to beneficial effects of exercise on sleep quality. The exercise program should be selected individually according to the patient’s preferences and performance status (PS) according to the Eastern Cooperative of Oncology Group (ECOG) scale. According to the recommendations, cancer patients with ECOG PS 0–2 can do moderate aerobic exercise (brisk walking, light cycling, water exercises) three times a week for 30 minutes and muscle strengthening exercises twice a week for 20–30 minutes. For patients with ECOG PS 3–4, programs individually selected by physiotherapists are recommended.

In elderly patients, in particular, moderate physical activity for a total of 150 minutes per week is recommended, but also shorter physical activities, such as slow walking and light housework. According to the WHO recommendations, elderly people with reduced mobility can perform physical activity 3 or more days a week to improve balance and prevent falls. When elderly people cannot perform the recommended physical activity due to their health condition, physical activity adapted to their capabilities is recommended [43].

Psychological support

Psychological methods used in the treatment of pain include meditation, hypnotherapy, relaxation, cognitive-behavioral therapy, biofeedback, visualization, and music therapy [44]. The assumption is to influence various functions of the body through proper brain training. However, there are no studies evaluating the effectiveness of psychological methods in patients suffering from pain. The results of studies conducted in cancer patients indicate that psychological techniques can not only reduce the intensity of pain but also have a positive impact on other quality-of-life components, including reducing anxiety and improving the quality of sleep and mood [45]. In elderly cancer patients, psychoeducation methods are also effective, which include education about pain and its treatment, relaxation, training, and group support.

Interventional methods of pain management

Interventional methods include various techniques, from simple injections into tender points within the muscles to invasive neurodestructive methods and intrathecal implantation of catheters and stimulators (Tab. 5). The development of pharmacotherapy, and especially the introduction of many opioids and adjuvant analgesics, has significantly reduced the importance of interventional methods in recent years, although they are considered in 5–10% of patients. Interventional procedures in cancer patients should be considered at every stage of disease. The main indications for the use of interventional methods are pain that is resistant to pharmacological treatment, with a limited extent and clear localization, e.g., metastasis to the rib, compression of the intercostal nerve, or treatment-resistant side effects of pharmacotherapy [46]. Neurodestructive procedures can also be used in the early stages of the disease, especially neurolysis of the celiac plexus (II B) or the superior hypogastric plexus (II C) before the tumor causes significant anatomical distortions. Interventional methods of treatment should not be regarded as step IV of the WHO analgesic ladder but should be performed early enough when the patient begins to experience pain. This approach allows for a significant reduction in complex pharmacological treatment and/or delay in its initiation. The following minimally invasive intervention methods can be performed in cancer patients:

In selected patients, more invasive interventional procedures can be performed in specialized units, such as:

Patients with multiple pain locations, a complex pain mechanism (central), dynamically intensifying pain, and poor general condition are carefully qualified for interventional methods. The patient’s age is not a contraindication to the use of interventional methods.

The premise for the use of interventional techniques is the possibility of acting directly at the site of pain. An early and sometimes just one block may prevent the development of potential pain syndrome (phantom pain after limb/breast amputation, pain after thoracotomy/mastectomy). Blockades have a special role in pain syndromes, in which the modulating factor is the excessive activity of the sympathetic nervous system. A classic example of pain that may be dependent on the sympathetic nervous system is neuropathic pain, which occurs in 7–10% of the general population and in over 30% of cancer patients. Therefore, blocks are an important element of therapy for this type of pain [47]. Another possibility of using interventional techniques is their application to inject drugs into the immediate surroundings affected by the disease process: into joint and epidural space (opioids and steroids). In cancer patients, the positive effect of continuous epidural (II C) or subarachnoid (II B) blockade is especially related to neuropathic and bone pain, sometimes also inflammatory, by reducing swelling around the spinal cord.

Blockades are also used as an important diagnostic and prognostic method. A positive but short-term effect of a blockade may confirm the indication for neurodestructive surgery. In cancer patients, not only all advantages but also potential adverse effects of therapeutic treatment should be carefully considered. In each case of using interventional techniques, there is a risk of complications and side effects. Permanent damage to the nervous structures, especially the peripheral nerve, may be associated with unpleasant consequences, such as paresthesia, numbness, and motor deficits; therefore, before performing a neurodestructive procedure, patients should be informed about the possibility of side effects and potential complications. It is also necessary to obtain the patient’s informed written consent for the procedure. Performing a neurodestructive procedure may be preceded by a diagnostic and prognostic block with the use of local anesthetics (LAs). This procedure helps to determine the source of pain and its mechanism and also indicates the patient the advantages and disadvantages of future neurolysis/thermolesion. It should be remembered that LAs are always stronger than neurodestructive agents, and the patient is exposed to the same procedure twice. It is always worth thinking carefully about performing a diagnostic block.

Elderly patients may be considered for an invasive procedure if they meet the following criteria:

In cancer patients, one of the most frequently performed invasive procedures is neurolysis within the structures of the sympathetic nervous system:

Neurodestructive procedures can be conducted by physical or chemical factors or surgical incisions (mechanical factors). The physical factors that damage nerve fibers include low (cryolesia) and high temperature (thermolesion) and hypo- and hyperosmotic solutions. Chemical agents that damage nerve fibers include primarily ethyl alcohol and, less often, phenol and glycerol. Nervous tissue, such as the celiac plexus, can also be damaged by ionizing radiation (radioablation of the celiac plexus), which consists of the destruction of the celiac plexus and pancreatic tumor with a safe dose of ionizing radiation. The procedure is used in patients with pancreatic neoplasms, in whom neurolysis of the celiac plexus cannot be performed (due to too large tumor dimensions, especially located within the body and tail of the pancreas, or vascular infiltration). It is one of the most modern interventional techniques used in the treatment of pain in patients with pancreatic cancer. Poland was the first country in Europe where such procedures were performed [48].

The neurodestructive mechanism of a chemical compound with a neurolytic effect includes inducing Wallerian degeneration of nerve fibers, i.e., the disintegration of protein and lipid substances in axons and changes in myelin sheaths. The increase in fluid pressure inside the nerve fiber impairs blood flow in the blood vessels supplying the nerve. Shortly after the destruction of nerve structures, the regeneration process begins, the duration of which depends on the extent of neurodestruction — usually, the nerve fiber regenerates at a rate of about 1 mm/day. The drug is administered near the nerve without affecting its structure.

Ethyl alcohol is the oldest and most commonly used neurolytic agent with low toxicity, used in a concentration of 50–100% (usually about 65%). Alcoholic neurolysis occurs rapidly and lasts for 5–7 months. Factors limiting the use of alcohol include rapid tissue diffusion, which requires the use of large volumes, making it more difficult to obtain a spatially limited neurolytic effect. During alcohol injection, the patient may experience pain, and alcoholic neuritis may occur. Tissue irritation caused by alcohol can be reduced by using a mixture with LAs, the alcohol concentration is then about 65%; it is also beneficial to rinse the needle with 1–2 mL of 0.9% NaCl or lignocaine. Accidental entry of alcohol into the tissues can cause local neuralgia.

In clinical practice, neurodestructive procedures within sympathetic fibers and/or ganglia, neurodestruction of the sensory roots of the spinal cord, and, selectively, mixed nerves are mainly performed [49]. The most commonly performed celiac plexus neurolysis reduces the intensity of pain in 90% of patients with pancreatic cancer, while complete pain relief is reported by up to 60% of patients. Neurolysis allows reducing the dose of systemically administered opioids, but it does not completely replace pharmacological treatment. An alternative to celiac plexus neurolysis may be celiac nerve neurolysis/thermolesion. The most common use of blockades and neurolysis in cancer patients is presented in Tables 4 and 5. Interventional methods of pain treatment may be associated with serious complications; therefore, they should be performed in specialized units after a thorough analysis of indications and contraindications [50].

Conclusions

In order to obtain the optimal effect of analgesic therapy, cancer patients require a comprehensive clinical assessment of pain, with the recognition of the pathophysiology, intensity, time pattern of pain, other symptoms, comorbidities, and disturbances in the psychological, social and spiritual dimension that may contribute to the patient’s suffering and occurrence of total pain. The standard treatment is based on the WHO analgesic ladder algorithm and individualization of pain therapy, depending on the patient’s clinical situation, taking into account non-pharmacological methods. Efforts should also be made to ensure effective treatment of other symptoms associated with cancer. Palliative and supportive care improves the quality of life of cancer patients by increasing overall survival and improving the quality of life for families and caregivers. The basic principles of pain pharmacotherapy in cancer patients include:

Article Information and Declarations

Funding

The article was not funded.

Acknowledgments

None.

Conflict of interest

The authors declare no conflict of interest.

References