Pain Management in Palliative Care: What Is Significant?

Abstract

In pain management of advanced ill patients, various factors appear to be of significance: multidimensional approach and realisation of pain as a complex perception (Total Pain). Existential fear and an exceptional role of pain as a leading symptom in palliative patients ought to be mentioned—chronification of pain progresses rapidly, oftentimes with less preconditions. In advanced ill patients, even the slightest pain stimulus may result in a sensation of total pain. We discuss mechanisms-centred pain therapy (opioid therapy in particular), depending on the pain character—nociceptive, inflammatory, neuropathic, dysfunctional, mixed pain—as a challenge in palliative care: -contemporary understanding of the significance and role of WHO pain management—genetically determined polymorphism of (opioid) receptors and enzyme systems—problems of plasma protein binding and interactions of analgetic drugs—differences in the elimination of various opioid drugs—active metabolites of opioids, peculiarities of the onset, duration and regulation of action—asymmetric pain distribution, breakthrough pain, end-of-dose failure, opioid-induced hyperalgesia—practical considerations on preferred choice of analgetics in patients with different comorbidities and of advanced age.

1. Introduction

“Divinum est sedare dolorem” Galen of Pergamon (129 – 199 A.D.)

In a British study, doctors and nurses were asked only one simple question: How often do you look your patients directly in the eye during a conversation? Most of the answers were anything but satisfactory. Nevertheless, our experiences clearly testify that adequate and dignified care of an advanced ill person is only possible under the precondition of a proper physician-patient relationship – when we meet our patients at eye level (Figure 1).

Figure 1.

Meeting at eye level. Courtesy of Centre for Palliative Care, Unna, Germany. 2002.

Especially when treating palliative care patients (PCP), it becomes obvious how important it is to perceive the patient holistically in his or her uniqueness, with all of his or her particularities, concerns and values. Pain in particular, as an extremely complex phenomenon, can only be understood on the condition that we include all dimensions of the person we are facing. Only then can we truly strive for success in pain therapy.

With the expression of our respect and our understanding towards the person who entrusts us with so much he or she holds dear, the construction of our relationship with the patient begins. Without this relationship, the process of treatment cannot take place. This is the fundamental aspect of the palliative attitude.

The specifics of pain management in palliative care patients will be discussed in the chapter at hand.

2. Palliative care and advanced illness patients

The World Health Organisation (WHO) defines [1] palliative care (PC) as follows:

“PC is an approach that improves the quality of life of patients and their families facing the problem associated with life-threatening illness, through the prevention and relief of suffering by means of early identification and impeccable assessment and treatment of pain and other problems, physical, psychosocial, and spiritual.

Palliative Care:

• Provides relief from pain and other distressing symptoms;

• Affirms life and regards dying as a normal process;

• Intends neither to hasten or postpone death;

• Integrates the psychological and spiritual aspects of patient care;

• Offers a support system to help patients live as actively as possible until death;

• Offers a support system to help the family cope during the patient’s illness and in their own bereavement;

• Uses a team approach to address the needs of patients and their families, including bereavement counselling, if indicated;

• Will enhance quality of life and may also positively influence the course of illness;

• Is applicable early in the course of illness, in conjunction with other therapies that are intended to prolong life, such as chemotherapy or radiation therapy, and includes those investigations needed to better understand and manage distressing clinical complications”.

Taking into account the WHO’s definition of palliative care, the basics and main principles of PC can be inferred:

• Treating with a “high-person, low-technology” approach. The patients’ needs are given priority, and the patient takes an active role in the mutual decision-making process himself (cf. concept of shared decision-making);

• Interdisciplinary approach (involving different occupational groups, including volunteers);

• Continuity of care (inpatient—day-care—outpatient), ensuring adequate care for patients at home as well;

• Excellent symptom control with the aim of alleviating symptoms;

• PC offers are not limited to the last days and weeks of life. For the benefit of the patient, many principles of palliative care can be applied in the early stages of disease, alongside an effective causal treatment directed at the underlying disease;

• Commitment to the care for loved ones (“the Significant Others”). Supporting the bereaved even after the patient’s death.

Thus, the scope of palliative care extends to various settings, clinical pictures and can be applied in different stages of an incurable disease. In this context, the definition of a palliative care patient is important.

We define a patient as a palliative care patient if at least the following conditions are met:

• The patient has an incurable disease;

• He suffers from a high symptom burden, which may include somatic, psychosocial and various other problems;

• The patient has consented to palliative care (Figure 2).

Figure 2.

When do we offer palliative care services? [2].

There are various criteria serving as indicators for the initiation of palliative care. However, Boyd et al. refer to the so-called “surprise question,” a question that helps us to identify the right moment to admit the patient to the palliative care setting. The question is: Would I, as a caregiver, be surprised for the patient to die within 6 to 12 months? If this is not the case, then the time has come to provide my patient with palliative care. Nevertheless, the practitioner can only answer such a question with certainty if he (1) has known the patient long enough and (2) is adequately familiar with patient’s situation, that is, by being intensively involved in caring for the patient. Caregiver and patient have to be close to each other.

The foundations of PC were laid down by the grande dame of palliative care and the hospice movement, Dame Cicely Saunders (Figure 3).

Figure 3.

Dame Cicely Saunders. Courtesy of Centre for Palliative Care, Unna, Germany. 2001.

3. The concept of “total pain”

“The death of a loved one is an extreme experience of death and radically demands grief. At the same time, however, this experience is also a challenge to self-realisation in the face of change. Grief in particular can trigger a piece of self-realisation” [3].

Grief entails a kaleidoscope of feelings, a chaos of emotions (see Figure 4) [5].

Figure 4.

Chaos of emotions of the grieving [4].

However, grief affects not only the relatives but primarily the patients who are confronted with a fatal diagnosis. The process of dealing with grief usually begins at the time when the patient learns about his or her diagnosis. In this context, we are talking about anticipatory grief.

This means that the advanced ill is constantly in a state of existential threat and stress. Consequences and expected reactions of this state include:

• Severe psychological stress (approx. 70% of those affected are afraid of pain);

• Previous living habits, circumstances and goals can be questioned extensively;

• Solutions are necessary but not included in a person’s previous coping repertoire;

• Confronting death and dying is often associated with existential fear;

• Existential fear cannot be reduced or eliminated, but dealing with it must rather be learned;

• The gradual processing of the diagnosis begins;

• The illness is accompanied by new perceptions that can contribute to further uncertainty.

The person affected comes to terms with his or her life identity and takes stock.

It is beyond question that all these factors strongly influence the processing of pain and ultimately decide the picture of pain that develops within the patient. Thus, in addition to the physical, psychological and emotional factors, the patient’s social environment and spiritual aspects also play a major role. This is especially true for chronic pain.

Since pain is a very subjective perception of signals emanating from different dimensions of the universe called human being, we can only understand it if we develop a broader view.

No less a figure than Cicely Saunders recognised this and contributed substantially to the understanding of the multidimensionality of chronic pain, coining the term “Total Pain”. Cicely Saunders always stood for simplicity in explaining the phenomena and for a solution-oriented approach. The grande dame of palliative care implemented the ancient, empirical perception of pain and suffering (see “Altar of the Seven Sorrows”, Figure 5) in her model of “Total Pain” (see Figure 6). This notion serves as the basis for the concept of “Total Care” which guides us, as caregivers, in our actions today [9].

Figure 5.

Seven sorrows [6].

Figure 6.

Total pain [7, 8].

With the help of this model, the necessity of a multi-professional approach to the treatment and care of patients with chronic pain becomes apparent.

Particularly in palliative care patients, who live under constant existential anxiety and are confronted with major problems in all dimensions of human existence, we often observe that pain chronification develops much faster, triggered by the mechanisms mentioned above.

This is particularly true for very old patients and those suffering from dementia. In advanced age, pain chronifies much more frequently. Also, any pain can directly be perceived as “total pain” by a patient with significant cognitive impairment or disturbance of consciousness [10].

Pain in PCPs bears, among others, the following characteristics:

• It is one of the most common symptoms;

• Often described as the most distressing of all symptoms;

• Hence, the special status of pain within the realm of PCP symptoms:

  • the advanced illness patient associates pain with the underlying disease;

  • is linked to the progression of the disease;

  • tumour pain in particular occupies a particular psychological dimension;

• Pain influences other symptoms;

• Paint itself is influenced by other symptoms.

Thus, a vicious circle forms that carries a considerable negative impact on the quality of the patient’s life [11]. Interrupting this vicious circle is one of the primary tasks in pain therapy for PCPs [12].

PCPs commonly exhibit several symptoms at the same time. On average, up to ten symptoms can be found in a palliative care patient that significantly impacts the quality of life. In addition to the symptoms that our patient report on a regular basis, such as pain, weakness, dyspnoea, nausea, vomiting, constipation, xerostomia, oedema, restlessness and sleep disturbances, our patients are also burdened by symptoms that occur less often and could therefore be more easily overlooked when the patient’s clinical status is evaluated. These include pruritus, dysgeusia, dysphagia and singultus [13]. Thus, it is crucial for the caregiving team to utilise a checklist for the assessment of symptoms so that precise questions can be asked, examined and documented in detail. Adequate pain therapy takes into account the patient’s entire symptom burden and the perception of all human dimensions.

In the treatment and support of the multimorbid advanced ill, establishing a working relationship with the patient and his or her relatives (“the Significant Others”) is of utmost importance. Thus, our first questions towards the patient ought to be: “Who are you? What kind of person are you? What is important to you as a human being?” The discussion of therapy goals and planning further measures have to be performed alongside the patient on the basis of shared decision-making. Thus, the groundwork for establishing a successful therapeutic plan is laid by understanding the values, wishes, necessities and concerns of the person affected. This attitude is fundamental to palliative care. Only in grasping the situation holistically can we achieve meeting the patient at eye level.

In order to build a working relationship with the patient, proper communication is vital. An indispensable prerequisite for this is our ability to self-reflect. In doing so, one has to ask oneself a handful of critical questions, for example: “How do I, as a practitioner, affect my patient? And how does the patient affect me?” Here, the team is a substantial resource of support. Because dignified, professional care at eye level can only succeed in a multi-professional team.

By adopting this attitude, we can live up to the PCP’s expectations and demands vis-à-vis his or her caregivers, notably:

• Having enough time for the patient;

• Being fair and holding a frank conversation;

• Being confident in our actions;

• Being flexible;

• Being able to make decisions together.

4. Pain assessment as a basis for decision-making in therapy

‘No treatment of pain until the pain is well evaluated’ – this motto is the key to successful pain therapy.

What does proper pain assessment mean? Cicely Saunders has been associated with having stated that the failure to assess pain is a critical barrier to good pain management.

Given the complexity and high subjectivity of experiencing pain, it is of utmost importance to let the patient talk freely about his sensations, to grant him enough space in order to describe the pain in as much detail as possible by himself. Thus, “patient self report“is the best tool for pain assessment. Therefore, the patient should lead an active role in the management of his own pain.

There are additional preconditions for an ideal evaluation, diagnosis and continued monitoring of pain:

• Optimal pain evaluation and treatment can only be achieved within a team;

• Relatives of the patient should also be involved in pain evaluation. The perception of the patient’s caregivers not only is able to reveal further details of pain analysis but also often shows important accompanying factors that can influence the entire experience of pain and the associated impairment;

• Each location of pain should be evaluated independently and separately;

• Reassessment should take place

  • At regular intervals;

  • After the initiation of therapy;

  • Whenever the intensity of pain escalates;

  • Whenever new localisations of pain occur.

Ideally, when evaluating pain, there should be a balance between self-observation and observation by others. In doing so, the patient should be allocated adequate space for his or her own pain assessment.

Pain assessment encompasses, on the one hand, the evaluation of all parameters of pain (see Figure 7). On the other hand, the precise analysis of the quality of pain is of particular importance for the preparation of an extended pain diagnosis as well (Figure 8).

Figure 7.

Crucial parameters of pain evaluation. Source: Self-created.

Figure 8.

Categorising pain based on pathophysiology (quality of pain). Source: Self-created.

PCPs often exhibit a “mixed pain” syndrome with components of both nociceptive and neuropathic pain [9]. This effect can be seen, that is, in the pathophysiological pain cascade of bone metastases (see Figure 9).

Figure 9.

Pathophysiology of pain in bone metastases. Source: Self-created.

Furthermore, neuropathic pain in palliative therapy may also arise under the influence of specific mechanisms. Among those are:

• Tumour compression of nerves;

• Surgical resection of the tumour with iatrogenic impairment of nerval structures;

• Radiotherapy;

• Chemotherapy.

Among others, changes in mitochondrial function can facilitate the development of neuropathia [14, 15] as well as numerous cytostatic agents, for instance, Paclitaxel and Vincristine [16].

The results of the pain analysis should be presented in a clear, simple and understandable manner with the help of suitable measuring instruments. Thus, transparency for the entire caregiving team is achieved and may serve as a basis for therapeutic action. The not purely physical mechanisms of pain development, which are rarely considered in classical pain evaluation forms, should be taken into particular account. In that way, the pain assessment is able to live up to the complexity and subjectivity of pain in patients with advanced chronic diseases.

For a proper cognitive-emotional diagnosis, tools such as the patient’s self-esteem, self-efficacy, coping strategies as well as personal disease processing models, for example, externalisation, internalisation and catastrophising [17] may be taken into account.

For example, in Turk and Rudy’s classification of patients with chronic pain (1988), the following is elaborated: [18].

Dysfunctional profile:

• High intensity of pain;

• High degree of interference between pain and activities;

• Low level of perceived control;

• High affective impairment;

• Low level of activity.

Interpersonal stress profile:

• Lack of social support.

Adaptive copers/minimisers:

• Low pain intensity;

• Low affective impairment;

• High level of perceived control;

• High activity profile.

After having conducted a proper pain analysis, classifying the patient’s pain symptoms properly and adequately appears to bear tremendous significance for the success of pain therapy. Adding to that, understanding the mechanisms of peripheral and central sensitisation is indispensable for a differentiated targeted pain therapy (see Figures 10 and 11).

Figure 10.

Mechanisms of peripheral sensitisation: Nociceptive, inflammatory pain [19].

Figure 11.

Development of central sensitisation [20].

First, the noxious stimulation of afferent C fibres triggers the release of inflammatory neuropeptides such as Substance P, Calcitonin Gene-Related Peptide (CGRP) and Neurokinin A (NK A). The process of neurogenic inflammation is initiated. If the release of inflammatory mediators continues, pain chronification occurs. Adding to that, the ongoing neurogenic inflammation causes an awakening of dormant neurons leading to an increased emission of nociceptive stimuli. This pathophysiological cascade results in enhanced perception of pain—peripheral sensitisation emerges [21, 22].

In the case of central sensitisation (see Figure 11), chronic emission of nociceptive stimuli leads to an overactivity of the nociceptive system, which in turn can eventually result in a loss of function of the antinociceptive system. Thus, pain signals can be transmitted with less inhibition and the chronification of pain is further amplified. Furthermore, chronic pain also leads to morphological changes in the central nervous system [23].

In the advanced ill, the processes of pain chronification often arise quicker and with fewer preconditions. Even a small pain stimulus is able to trigger the image of “total pain”.

5. Mechanisms-oriented pain therapy

A differentiated pain therapy can only succeed by taking into account the underlying mechanisms of pain. Accordingly, a proper pain analysis, including the precise description of pain characteristics (nociceptive, inflammatory, neuropathic, dysfunctional, mixed-pain), is a challenge within palliative care and a vital part of pain management.

Among other things, this statement is based on understanding the various main action sites for different analgesics (see Figure 12).

Figure 12.

Sites of action of analgesics.

The fact that, on the one hand, different anatomical structures are activated at different levels during the development of different types of pain and, on the other hand, different analgesic substances exert their effect at different sites of action explains the importance of a targeted and varied approach in pain therapy. The principles of drug selection for pain therapy in chronic pain, in which different analgesic agents are combined, can be seen in Figure 12. Thus, in nociceptive pain, both non-steroidal analgesics and opioids can be used, separately or in combination, since both substance classes exert their effect at peripheral nociceptors. At the same time, a combination of different analgesic classes allows the use of each substance’s lowest dose. Particularly in geriatric patients or PCPs, it is vital to ensure that the dose of each individual analgesic substance is as low as reasonably achievable [10].

With regard to opioids, the research results of the last decades have revealed tremendous interindividual differences in opioid effectiveness [24]. This also applies to the side effects. In addition to pharmacokinetic factors, the genetic variability of opioid receptors due to numerous alternative splicing variants is discussed as a possible cause [25]. This variability can explain, among other things, different reactions to various opioids as well as deviating dose requirements and manifestations of side effects in patients [26].

For example, about one-eighth of the Caucasian population (10 to 14% of all patients) carrying the 118A > G single-nucleotide polymorphism in the MOR gene OPRM1 may require increased doses of opioids in order to achieve a similar analgetic effect in comparison to non-carriers [25, 27].

When treating PCPs, this practically means that special caution and flexibility is required in situations when:

• Consistent dose increases of an opioid do not lead to the desired analgesic effect;

• Severe and unusual side effects occur under opioid therapy;

• Signs of overdosing manifest even under low opioid doses.

6. Basics of pain management in PCPs

In general, adequate pain management in patients with cancer or other advanced chronic disease can be achieved through the following approaches:

• Primary (causal) measures;

• Systemic analgesic therapy;

• Drug-free measures, including psychological interventions, rehabilitative therapy, etc.

If adequate pain relief cannot be attained, other options should be discussed, including:

• Invasive pain therapy measures, such as blockades, catheter procedures;

• Palliative sedation therapy if symptoms are refractory in an end-of-life situation [28].

Causal measures must not be undervalued in the treatment of PCPs. For example, palliative radiotherapy of spinal metastases may help in achieving significant pain relief. However, as the chronic disease progresses, the patient’s symptom burden increases and his general condition deteriorates. Thus, the options for causal therapy diminish and symptomatic pain therapy (systemic and also regional invasive measures) becomes more and more important.

As is known, the recommendations for the differentiated use of analgesic medication in patients with chronic pain are presented in the “WHO Analgesic Ladder” [29]. What practical significance does this scheme bear today, about 40 years after its first publication? And which aspects in patients with advanced illness and at the end of life do we have to pay particular attention to?

Are we meant to always adhere to the “WHO Analgesic Ladder”? Here are a few considerations along the way [30]:

• Particularly in the setting of palliative care, non-physical factors as well as all parameters evaluated in the assessment of pain play an important role in the decision-making process of prescribing pain medication. In contrast, the classical “WHO Analgesic Ladder”, notably, takes into consideration only one single parameter-pain intensity, namely. Thus, the WHO scheme merely functions as an orientation guide!

• In the case of severe pain right at the onset of treating PCPs, not uncommonly, two stages of the WHO schemes are skipped, since:

  • 70% of all tumour patients end up needing level III drugs [31];

  • Strong stage III opioids can now also be dosed in very small quantities and thus carry less side effects.

• Significance of level II analgesics [32]:

  • Tilidine:

    1. Preferred in case of renal insufficiency;

    2. Tilidine is a prodrug that is probably activated by cytochrome isoenzyme (CYP) 3A4 to nortilidine;

    3. In two successive phase I reactions (sequential metabolism), the analgesically active metabolite nortilidine is formed first, which is further degraded to the pharmacologically ineffective bisnortilidine. Both reaction steps are catalysed by CYP3A4;

    4. Therefore, the AUC values (area under the blood-plasma-concentration vs. time curve) are of particular importance when considering the efficacy of this opioid. In one study, the combination of tilidine and the strong CYP3A4 inhibitor ritonavir led to altered pharmacokinetic parameters such as increased AUC values of nortilidine [33];

    5. With regard to PCPs, on the one hand, a significant change in pharmacokinetics can lead to large variations of the AUC curve and thus to significant interindividual differences in the effectiveness of tilidine. But on the other hand, according to one study, adverse drug effects caused by this were of a merely moderate and transient nature due to the further degradation into the pharmacologically ineffective bisnortilidine [33];

    6. The elimination of nortilidine is hardly changed in terminal renal failure, which means that a dose adjustment is not necessary. Thus, a reduction of the dose of tilidine in patients with severely impaired kidney function appears not to be required. Tilidine and its metabolites cannot be removed from the body by dialysis [34];

    7. Neither Tilidine has serotonergic properties, nor does it lower the seizure threshold, a fact that renders it a favourable drug in advanced illness patients.

  • Codeine:

    1. Its use in PCPs is evaluated as critical;

    2. Codeine is a prodrug and is only converted to active morphine by CYP2D6 through O-demethylation;

    3. Thus, the substance is subject to high individual variations depending on the metabolisation activity of the CYP2D6 enzymatic system;

    4. That is, patients who are “CYP2D6 ultrarapid metabolisers” will produce much higher amounts of morphine derived from codeine in a shorter period of time, whereas “CYP2D6 poor metabolisers” may hardly activate any codeine at all [35];

    5. In renal insufficiency, morphine-6-glucuronide and morphine-3-glucuronide accumulate as active metabolites of morphine, which can lead to a rapid overdosing [36, 37].

  • Dihydrocodeine (DHC) [35]:

    1. A semi-synthetic derivative of codeine with a low bioavailability when administered orally (approx. 20%). This is due to poor gastrointestinal absorption;

    2. Metabolised in the liver by CYP2D6 to an active metabolite, dihydromorphine, and by CY3A4 to a secondary primary metabolite, nordihydrocodeine;

    3. The CYP2D6-catalysed metabolite dihydromorphine (DHM) has a 100-fold higher affinity for μ-opioid receptors than DHC but contributes only marginally to the analgesic effect of DHC, meaning:

       1. clinical response independent of the patient’s individual CYP2D6 metabolising phenotype;

       2. Thus, with regard to the analgesic effect of DHC, clinically relevant interactions with CYP2D6 inhibiting substances are scarcely to be expected [38];

       3. Among others, this is due to the fact that the parent substance DHC, in contrast to codeine, already unfolds an analgesic effect before entering biotransformation.

    4. Nevertheless, drugs that either are degraded by or induce the CYP2D6 enzyme can significantly influence the plasma level of DHM and lead to severe side effects [35].

  • Tramadol:

    1. It is a prodrug: via CYP2D6, the active metabolite O-desmethyltramadol is formed;

    2. Limited analgesic effect of tramadol expected in patients with poor metaboliser (PM) or intermediate metaboliser (IM) status;

    3. Comedication with CYP2D6 inhibiting drugs reduces the formation of O-desmethyltramadol;

    4. Belongs to the group of so-called dual opioids. This substance blocks the neuronal reuptake of serotonin and has the potential to induce serotonin syndrome when administered alone or in combination with other serotonergic drugs;

    5. Notably, comedication of tramadol and selective serotonin reuptake inhibitors (SSRI) fluoxetine and paroxetine bears a serious risk. These SSRIs are potent inhibitors of CYP2D6, leading to a decreased formation of active analgesic tramadol metabolites when co-administered. This may result in failure of effective pain management, prompting the caregiver to increase the dose of tramadol while in doing so, as a consequence, increasing the likelihood of developing serotonin syndrome;

    6. Particularly in advanced illness patients, this grave risk increases if elevated levels of the substances mentioned above are to be expected, for instance, in the case of deteriorating renal function.

• Potent opioids—what substance to select for the use in advanced illness patients [32]?

  • Morphine:

    1. Morphine is hepatically degraded by glucuronidation to morphine-3-glucuronide and morphine-6-glucuronide. Morphine-6-glucuronide is the pharmacologically active metabolite binding to the μ-opioid receptor (MOR) and is eliminated renally;

    2. One of the advantages of morphine in advanced illness patients is the possibility of using this substance, which has been known for almost 200 years, in all possible forms of administration:

       1. oral as tablets or drops;

       2. rectal;

       3. parenteral: subcutaneous, intravenous, epidural, intrathecal and also local application in the form of morphine-gel 0.1 or 0.2%, in order to also use the effect on MOR in the skin, for example, in treating exulcerating wounds.

    3. In the context of renal insufficiency, morphine-6-glucuronide accumulates in the plasma with not only an increased analgesic effect but also a consequential risk of overdosing, leading to sedation and respiratory depression;

    4. Morphine-3-glucuronide can also accumulate amid kidney impairment and bears a possible neuroexcitatory effect [39];

    5. In patients with a glomerular filtration rate (GFR) <30 mL/min, the dose of morphine should therefore be reduced or, preferably, avoided entirely [37, 40].

  • Oxycodone:

    1. Oxycodone is degraded by CYP3A4 to the inactive metabolite noroxycodone and metabolised by CYP2D6 to the active metabolite oxymorphone;

    2. CYP3A4 inhibitors, such as ciprofloxacin, clarithromycin, levomepromazine or ketoconazole, increase the plasma concentration of oxycodone and oxymorphone and thus enhance the analgesic effect and potentiate side effects. A daily intake of ca. 300 mL or more of grapefruit juice, also a known CYP3A4 inhibitor, can also become pharmacologically relevant;

    3. CYP2D6 inhibitors, including many substances such as celecoxib, dimenhydrinate, duloxetine, fluoxetine, levomepromazine, melperone and methadone, do not lead to clinically significant interactions with oxycodone;

    4. In uraemic patients, the elimination of oxycodone is significantly reduced [41];

    5. However, the half-life is significantly prolonged in patients on an individual basis, especially in advanced illness patients;

    6. Oxycodone and its metabolites are dialysable. Thus, oxycodone should be administered after dialysis;

    7. The same applies to the combination preparation of oxycodone/naloxone. Notably, liver insufficiency should be particularly taken into account in this case as well because naloxone, a potent MOR antagonist, is hepatically metabolised. Due to the naloxone not being adequately degraded amid liver insufficiency, its plasma level rises and it effectively binds to spinal MORs, partially cancelling out the analgesic effect of oxycodone;

    8. Particularly in advanced illness patients, liver insufficiency among others has to be expected. We therefore consider the dosage of more than 40–50 mg of naloxone per day as critical for PCPs;

    9. Furthermore, oxycodone has a non-negligible affinity to the ϰ-receptor (KOR).

  • Hydromorphone:

    1. Hydromorphone is absorbed in the gastrointestinal tract and is subject to presystemic elimination. The active substance has an oral bioavailability of about 32%. Hydromorphone is metabolised in the liver and eliminated renally predominantly in the form of conjugated hydromorphone, dihydroisomorphine and dihydromorphine [42];

    2. The metabolisation leads to the formation of analgesically inactive substances that are known to be associated with various toxic side effects, for example, enhanced neuroexcitation [43, 44];

    3. Haemodialysis reduces plasma concentration by about ½. This can result in failed symptom control regarding pain, eventually inducing withdrawal symptoms;

    4. Nevertheless, hydromorphone is preferred by many caregivers as a substance that can be administered in renal insufficiency.

  • Fentanyl:

    • Is a highly lipophilic molecule and thus bears significant plasma protein binding properties; [45]

    • As fentanyl binds to plasma proteins such as albumin and alpha-1-acid glycoprotein, hypoalbuminaemia (for example, due to cachexia or liver failure) may influence fentanyl pharmacokinetics [46, 47].

    • Fentanyl is predominantly hepatically metabolised via CYP3A4 mediated N-dealkylation, resulting in the formation of inactive metabolites such as, among others, norfentanyl [48] (see Figure 13);

    • Approximately 10% of the intact molecule as well as all inactive metabolites are excreted renally. Although this notion is widely accepted among scholars, a recent study has outlined that the hepatic N-dealkylation process may not be as important as formerly assumed. There may be various, yet unknown, metabolic processes involved for a significant part of fentanyl degradation;

    • As fentanyl is mainly metabolised in the liver, the substance is suitable for use in patients with renal insufficiency [50, 51].

  • Buprenorphine:

    1. Binds with high affinity to MORs and, in doing so, acts as a partial agonist;

    2. At the KOR, it bears partial agonistic and very effective antagonistic properties;

    3. Is a highly lipophilic substance;

    4. Carries only a moderate risk of respiratory depression at dosage increase compared to other opioids;

    5. Due to idle receptor kinetics, elimination progresses slower;

    6. With an exceptionally high first-pass effect, the oral bioavailability is very low (approx. 6%). Therefore, oral administration appears not to be viable. Sublingual administration, however, results in a higher bioavailability, especially when administered in a liquid form [52];

    7. CYP3A4 and CYP3A5 catalyse the formation of the active metabolite norbuprenorphine. However, its pharmacological efficacy is significantly lower compared to the initial substance. Buprenorphine itself inhibits CYP3A4;

    8. Buprenorphine and norbuprenorphine are glucuronidated in the liver and excreted mainly via bile and faeces. Only 10 to 30% of the substance is excreted via the kidneys [53]. Therefore, the use of buprenorphine in patients with renal insufficiency is rational and applicable;

    9. Due to the antagonistic effect on the KOR, a sedative effect is not expected to a significant extent. Thus, the patient’s vigilance remains mostly unhampered by the medication, allowing the patient to be more active throughout the day. This phenomenon justifies the preferred use of buprenorphine in geriatric patients as well as in those with advanced illness, oftentimes being cachectic and therefore plagued by constant fatigue;

    10. In addition, some authors point towards an antidepressant effect in patients with non-psychotic unipolar depression [54, 55]. Particularly, a PCP can benefit from this twice. This advantage is of substantial clinical significance given that some studies indicate that the antidepressant effect of buprenorphine takes maximum effect after a relatively short time (a few days), in contrast to conventional antidepressants (a few weeks).

  • Methadone:

    1. Is an opioid with dual effect as it binds at the MOR and partly also at the δ-opioid receptor (DOR), as an agonist, as well as at the NMDA receptor as an antagonist. Thus, methadone can be expected to be effective in both nociceptive and neuropathic pain, that is, in mixed-pain syndrome;

    2. Is a racemate (R- and S- enantiomer);

    3. Is a substrate of the CYP3A4 isoenzyme and is degraded into a few inactive metabolites. The interactions in biotransformation can lead, among others, to QT interval prolongation. Furthermore, MAO inhibitors should not be co-medicated with methadone because of the risk of a severe drop in blood pressure;

    4. Adding to that, co-administering serotonergic agents can trigger serotonin syndrome [44, 56];

    5. It has high oral bioavailability [57];

    6. Renal and hepatic insufficiency does not have a significant effect on methadone clearance;

    7. The relative equianalgesic ratio of oral morphine to oral methadone is estimated at 4:1 to 12:1 [58]. Due to the higher analgesic potency, changing opioid substances to methadone must be performed cautiously and gradually by titration;

    8. Enhanced lipid solubility of methadone leads to a high volume of distribution: Topical forms of application are also conceivable. The fraction of plasma protein binding of the substance is 60–90%, almost twice as high as morphine’s plasma protein binding property. These two qualities contribute to a relatively long plasma half-life and, consequently, to the risk of accumulation. Adding to that, plasma half-life of methadone is subject to extensive interindividual variations;

    9. Therefore, in PCPs, we consider the use of methadone to be questionable as the plasma albumin levels in these patients are oftentimes significantly lowered—particularly in advanced stages of the disease. Due to this fact, it is particularly difficult to foresee and estimate the expected clinical effect in relation to the administered dose. The limited predictability bears the danger of rapid overdosing;

    10. Among the potential side effects, neurotoxicity and myoclonia ought to be mentioned as these symptoms occur more frequently in PCPs when using methadone [43, 44].

  • Tapentadol:

    1. Like tramadol, tapentadol belongs to the group of opioids with a dual action mechanism, whereby analgesia is achieved, on the one hand, by agonising the MOR and, on the other hand, by an inhibition of noradrenaline reuptake;

    2. Compared to other opioids, tapentadol has a better side effect profile which makes it a preferred choice in PCPs [59, 60, 61, 62];

    3. The dual action mechanism allows the substance to be used not only for chronic nociceptive pain but also for neuropathic pain;

    4. Due to the first-pass effect, tapentadol has an oral bioavailability of slightly more than 30%;

    5. Tapentadol is absorbed pretty quickly and, to a large extent, glucuronidated in the liver. Only about 20% of the substance remains bound to plasma proteins. The metabolites of tapentadol, including tapentadol-O-glucuronide as the main metabolite and N-desmethyl tapentadol, are inactive;

    6. Tapentadol itself has no influence on the activity of the CYP system, which significantly reduces the risk of pharmacological interactions. This is seen as a crucial advantage especially when being confronted with polypharmacy, a common sight in PCPs;

    7. When comparing two dual action mechanism opioids—tapentadol and tramadol—the former is predominantly favoured:

       1. Tapentadol bears a higher analgesic effectiveness;

       2. The side effect profile of tapentadol is more beneficial;

       3. The potential for pharmacological interactions is lower with tapentadol;

       4. In contrast to tramadol, intraindividual genetic variations appear to hardly play a role with tapentadol, which facilitates the dosing and controllability of the substance and makes its use safer and its effects more predictable in PCPs.

• For recommendations of converting dosages of different opioids, see Figure 14 [64].

Figure 13.

Fentanyl metabolism and elimination [49].

Figure 14.

Opioid conversion for morphine equivalent doses: “Cross of Sittl-Grießinger” [63].

7. What needs to be considered for differentiated opioid therapy in its practical implementation?

• Given the peculiarities of the various opioids at hand for the treatment of patients, numerous factors have to be taken into account before administering pain medication:

• Consideration of genetic polymorphisms of the opioid receptors, especially of the MOR;

• Intraindividual polymorphisms of the cytochrome isoenzyme system, which determines differences in the effect, degradation or metabolisation of opioid substances;

• The processes of opioid elimination and associated mechanisms of effect prolongation or toxic accumulation of the substances are influenced by various factors, including [40, 65, 66]:

  • Renal function;

  • Liver function;

  • Water solubility or lipophilicity of the substances;

  • Metabolites, possibly leading to increased plasma levels of active substances and to subsequent overdosing.

• In pain management for PCPs, pharmacological interactions often pose a challenge for the caregiver due to the even narrower therapeutic range of many substances and the high proportion of elderly patients with multiple concomitant diseases [67].

As an example, the serotonin syndrome, a feared possible outcome of medication interactions, should be mentioned (see Figure 15), especially when applying phenylpiperidine opioids, such as:

• Methadone;

• Fentanyl;

• Pethidine;

• Tramadol;

and morphine analogues, such as:

• Oxycodone;

• Codeine;

as co-medication together with:

• MAO inhibitors (rasagiline, moclobemide);

• SSNI, SNRI (venlafaxine, mirtazapine);

• Tricyclic antidepressants;

• St. John’s wort extract;

• Setrons (5-HT₃-receptor antagonists);

• Triptans;

• Levodopa.

Figure 15.

Signs of serotonin syndrome.

Since the patient exhibits many serotonin-dependent effects—clinical symptoms that are, in itself, rather unspecific and generic—the clinical picture can often be overlooked, diagnosing is impeded and thus may ultimately lead to the death of the patient [68]. The neuroexcitatory triad of changes in consciousness, neuromuscular hyperactivity (such as tremor, hyperreflexia, myoclonia, rigidity) and autonomic instability is crucial in making the diagnosis, whereby—most notably—mydriasis and an increase in body temperature are indicative of the suspected pathology. Treating serotonin syndrome consists of the discontinuation of serotonergic pharmaceuticals and a symptomatic, if necessary, intensive medical therapy, as well as of using serotonin antagonists, such as cyproheptadine. Alternatively, atypical neuroleptics with antagonistic activity against the 5-hydroxytryptamine receptor 2A (5-HT_2A receptor), that is, olanzapine 10 mg sublingually, may be applied [69].

Side effects within the scope of differentiated opioid therapy often occur as a result of pharmacokinetic interactions, leading to changes in the concentration-time profiles of the simultaneously administered drugs. As a result, the effects on the body of at least one substance involved are altered.

In our practical work, we advocate opioid monotherapy, evading combinations of different opioid analgesics at the same time, if possible. Depending on the PCP’s individual pain pattern and course of disease, we do not always succeed in adhering to this principle as we ought to combine two or even more different opioids when prescribing pro re nata medication (rescue substances).

Nowadays, morphine continues to retain its position as a drug of choice for differentiated opioid therapy, but:

• In the case of renal insufficiency, tilidine, buprenorphine, fentanyl or hydromorphone should be preferred [70];

• In the case of liver insufficiency, substances being predominately metabolised in the liver are to be avoided, if possible, or at least administered with a reduced dose, that is, buprenorphine.

In pain management of PCPs, transdermal therapeutic systems (TTS) bear particular significance:

• A main principle of palliative care states that oral opioid administration is preferred as long and as much as possible, in cooperation with the conscious and informed patient;

• Indication of TTS: limited to cases of dysphagia of various origins, otherwise only as alternative medication if other oral opioids have failed in alleviating the symptoms properly;

• However, the use of TTS can improve the quality of life or patient compliance, especially in advanced illness patients [63];

• The caregiver has to exercise caution regarding the application of TTS in the following circumstances:

  • Cachexia, which is a frequent concomitant feature in PCPs. This applies in particular to the fentanyl matrix patch [71]. Given the relatively high fat solubility of fentanyl, substance diffusion through the skin depends on the sufficient amount of fat tissue. It may also be difficult for the patch to stick firmly to the skin for the required three-day period in a cachectic patient. Thus, it is not uncommon for the patch to come off earlier;

  • Unstable pain syndrome (e.g., asymmetric pain curve);

  • Short life expectancy, as patients in an end-of-life (EoL) situation often show unstable pain curves. Yet flexibility in dosage is crucially important, most notably in opioid-naïve patients in an EoL situation. This can predominantly be achieved by using short-acting opioids. Consequently, when using TTS in opioid-naïve patients in the advanced phase of disease, adverse drug effects are more likely to occur as a result of changing absorption depending on the patient’s skin condition and fluctuating body temperature. Hence, we can more frequently expect confusion, respiratory depression, nausea, vomiting, constipation and other side effects.

• Buprenorphine TTS:

  • Due to its high lipophilicity, this substance—like the fentanyl TTS [72]—needs enough fatty tissue in order to exhibit a stable and consistent effect when applied as TTS. However, the adhesive matrix of this specific TTS generates more stable diffusion values and, due to the rear polyethylene cover sheeting, this TTS is less sensitive to, that is, mechanical and thermic interference [73];

  • Can be applied in at low dosage, starting at 5 μg/h;

  • Buprenorphine carries a relatively low risk for pharmacological interactions. Therefore, its use is of particular advantage in PCPs or patients of advanced age due to the frequent presence of numerous concomitant diseases and hence polypharmacy;

  • Local allergic skin reactions appear to occur at a higher incidence when using transdermal buprenorphine in comparison with fentanyl patches.

8. Approach to the management of fluctuating pain dynamics: Asymmetrical pain, breakthrough pain, end-of-dose failure

In the course of the day, patients can experience a varying distribution of pain intensity. In order to register these intricacies as a caregiver in order to conduct proper targeted pain management, a detailed, extensive and standardised pain assessment is indispensable.

Given a consistent distribution of pain (see Figure 16, curve 1), it is comparably easy to alleviate the symptoms. Here, the aim is to achieve a consistent plasma level of the analgesic substance and hence pharmacologically “capturing” the consistent burden of pain symptoms. Unfortunately, when dealing with chronic persistent pain conditions in PCPs, this “simplest” form of pain distribution is hardly seen. Much more frequently, advanced illness patients report a varying, fluctuating intensity of pain over the course of the day (see Figure 16, curves 2 and 3).

Figure 16.

Dynamic distribution of pain intensity over the course of the day. Source: Self-created.

A curve depicting an asymmetrical distribution of pain may correspondingly require an asymmetrical distribution of analgesic substances in the patient’s blood plasma. For example, in the case of predominantly evening and nocturnal chronic pain, one third of the total daily dose is to be administered in the early and late morning, while two thirds are allocated to an afternoon and evening administration. Pain management results have to be closely and critically monitored and evaluated.

Apart from a varying intensity of the patient’s baseline pain perception, pain management is additionally complicated by intermittent additional pain peaks known as breakthrough pain (BTP) [74]. BTP is comparably more common in PCPs.

Successful relief of breakthrough pain episodes depends on several factors, including: [75, 76, 77].

• Detailed and close analysis of breakthrough pain, for instance:

  • Predictability of BTP;

  • Initial development (relatively slow and building up vs. rapid, lightning-like onset);

  • Duration of BTP episode;

  • Frequency of episodes over the course of the day;

  • Quality of BTP episodes:

    1. Nociceptive;

    2. Neuropathic;

    3. Mixed-pain.

• Usually, an adjustment to the baseline retard opioid medication is necessary [78].

• Crucially, a close dialogue within the interdisciplinary caregiving team has to be assured, that is, via:

  • Regular joint ward rounds at the patient’s bedside (doctors/nurses);

  • Interdisciplinary meetings;

  • Standardised documentation within the team;

  • Raising the nursing staff’s awareness to the topic of BTP;

  • Ensuring the patient’s quick and unproblematic access to pro re nata (PRN) medication, that is, fast-acting analgesics;

  • Providing adequate training focussing on BTP to all professional groups involved.

The data available for patients with tumour disease points to the vital importance of addressing this topic thoroughly: [77].

• Prevalence of 40–80% of all tumour patients;

• Frequency of 1 to 6 episodes per day on average;

• Ca. 60% of patients suffer from 2 to 4 attacks per day;

• Poor predictability (only 25–30%);

• Short duration of <30 min in 75% of patients;

• High pain intensity at Numerical Rating Scale (NRS) 7–10;

• Mostly a mixed pain syndrome. Thus, BTP is commonly more difficult to treat.

As to our experience, ideal pain management, especially for BTP, can only be achieved within a well-functioning interdisciplinary team of caregivers. For example, in the case of a patient with osseous metastatic disease of prostate carcinoma, it is essential for the nursing staff to be briefed on the type of pain episodes, including the possibility of predictable BTP during movements or exercise. This empowers the caregivers to accordingly administer a PRN medication 20–30 minutes prior to, that is, morning care which constitutes a common reason for predictable pain episodes.

Retard formulation opioid analgesics are usually not applicable for disrupting BTP episodes. Here, fast-acting opioids and rapid onset opioids (ROO) are on hand. The decision, which of these substances to use, also depends on the results of the pain assessment. In the case of a BTP pain episode building up relatively slowly and longer lasting, the additional usage of fast-acting opioids is indicated [79]. In contrast, amid lightning-like pain peaks that could be described, that is, as an “electric shock”, usually lasting only a short time period, the use of ROOs is preferred.

ROO formulations are distinguishable by the administration form of its analgesic substance, fentanyl:

• Transmucosal;

• Buccal pill;

• Buccal film;

• Sublingual;

• Nasal spray.

The traditional recommendations of the “WHO Analgesic Ladder” with regard to PRN medication—$\raisebox{1ex}{$\mathbf{1}$}\!\left/ \!\raisebox{-1ex}{$\mathbf{10}$}\right.$ to $\raisebox{1ex}{$\mathbf{1}$}\!\left/ \!\raisebox{-1ex}{$\mathbf{6}$}\right.$ of the equivalent daily total dose of morphine at single administration—are substantially subject to individual variations and are only partially applicable, especially in advanced illness patients. Here, caution is especially required in patients whose daily dose, converted to morphine, exceeds 100 mg in total.

With regard to the dosage of ROOs, the following rule applies: Firstly, administer 100 μg of fentanyl sublingually, buccally or nasally. If the analgesic effect is insufficient, apply an additional equal dose after ca. 15 to 20 minutes. If there is a noticeable improvement in analgesia, administer 200 μg of fentanyl directly during the next episode of pain.

When facing a lack of therapeutic success with regard to BTP, consider the following pitfalls:

• Dosage too low of baseline therapy with slow-release, retard opioids;

• Dosage too low of PRN medication;

• Time intervals too long between dose administrations of baseline therapy (“end-of-dose failure”, EoD). EoD “failure refers to medication wearing off before the next regular analgesic dose is due […]” [80], leading to increasing pain perception in between dose applications.

  • The phenomenon of EoD failure is primarily due to individual differences in the pharmacokinetics of opioids, among others:

    1. Genetic polymorphisms of opioid receptors;

    2. Polymorphisms of hepatic enzyme systems given presence of several gene variants with different properties:

       1. rapid metabolisers;

       2. intermediate metabolisers;

       3. extensive metabolisers and

       4. poor metabolisers.

  • EoD failure is a not uncommonly seen trait of TTS, for example, with fentanyl patches.

• BTP episode of very short duration and very high intensity;

  • Conventional PRN medication is often administered in such cases, that is, fast-acting formulations of morphine, hydromorphone or oxycodone. These preparations only take effect after at least 20 to 30 minutes. Therefore, ROOs should be preferably considered;

  • The medication should be positioned within the patient’s reach. No time should be wasted;

  • The nursing staff should be sensitised to the fact that the patient has to receive the medication immediately when pain is expressed.

• Delayed intake of PRN medication;

• Usage of slow-release retard formulations as PRN (“rescue medication”).

9. Co-analgesics and topical application

In palliative care, classical co-analgesics are prescribed as well, but the usage frequency of these drugs is higher. This is due to the increased prevalence of difficult-to-treat neuropathic and atypical pain in advanced illness patients, especially in those with tumour pain. These pain syndromes cannot only be caused by the underlying tumorous disease but also occur as a consequence of treatment [81]. With regard to neuropathic pain, the fraction of pain caused by cancer treatment appears to be higher than the fraction of pain as a result of the disease itself [81].

It can further be inferred that neuropathic cancer pain leads to significantly greater impairment of the patient’s daily life and quality of life and, consequently, to a higher need for analgesics than nociceptive cancer pain [82].

Here, too, evaluating pain quality plays a key role. In the treatment of neuropathic pain, a number of antidepressants and anticonvulsants are mainly recommended.

Antidepressants are mainly used for sympatalgia (e.g., for permanent burning pain accompanied by allodynia and tingling paraesthesia), while anticonvulsants like the calcium channel blockers pregabalin and gabapentin as well as the sodium channel blocker carbamazepine are primarily used for neuralgic pain.

• Recommended daily doses of common antidepressants in pain management:

  • Amitriptyline (TCA):

    1. 50–150 mg;

    2. Initial dosage (ID): 1 x 10 mg;

  • Doxepin (TCA):

    1. 25–150 mg;

    2. ID: 1 × 25 mg;

  • Duloxetine (SNRI):

    1. 30–60 mg;

    2. ID: 1 × 30 mg;

  • Venlafaxine (SNRI):

    1. 75–150 mg;

    2. ID: 1 × 75 mg;

  • Mirtazapine (NaSSA):

    1. 15–30 mg;

    2. ID: 1 × 7.5 mg.

In our experience, the usage of moderate doses of both antidepressants and anticonvulsants is recommended in PCPs. We rarely prescribe higher doses than 150 mg pregabalin or 300 mg gabapentin to minimise adverse drug effects.

Furthermore, analgesics are locally applied as well. On the one hand, topical formulations of morphine are used in exulcerating wounds, for instance, extensive ENT tumours, mammary carcinoma or decubital ulcers, applied as a 0.1% or 0.2% gel. On the other hand, the local anaesthetic lidocaine—approved for use in postherpetic neuralgia—can be applied as a 5% patch to many other local pain syndromes of neuropathic origin, too, according to our experience. A lidocaine patch is applied for 12 hours a day. It can be cut if necessary and thus adapted to the affected areas. The maximum daily dose is three patches.

In palliative care, the usage of capsaicin patches (i.e., 8% topical formulation) is rather limited due to its unpleasant irritating effect on the skin, especially at initial application.

Among all co-analgesics, ketamine comes to the fore as treatment in PCPs. The substance is often considered as ultima ratio for neuropathic pain control. As a highly lipophilic substance, this non-competitive N-methyl-D-aspartate (NMDA) receptor inhibitor leads to substantial analgesia in tumour-associated neuropathic pain as well as in ischaemic pain and in local pain syndromes when administered in subnarcotic doses. The substance can be applied variously: intravenous (0.5–1.5 mg/kg BW), subcutaneous, intramuscular, oral and topical [83]. Among others, a blockade of NMDA receptors is associated with reversal of opioid tolerance. Ketamine is metabolised via CYP3A4; interactions are hardly described. Ketamine is rightly classified by the WHO as an “essential drug for the management of refractory pain”.

According to our experience, S-ketamine should be applied orally as follows:

• In combination with apple juice for the improvement of gustatory perception;

• Gradual titration over the course of several days, that is:

  • From day 1 on: 3 × 5 mg

  • From day 3 on: 3 × 10 mg

  • From day 5 on: 3 × 15 mg

  • From day 7 on: 3 × 25 mg

  • From day 10 on: 3 × 50 mg

Case study 1:

• Female patient, 57 y.;

• Diagnosis: metastasised cervix cancer, encircling the entire pelvic area and lower abdomen;

• Severe pain, NRS 8–10: nociceptive and neuropathic (mixed-pain) in the entire lower abdomen/small pelvis;

• Initial treatment:

  • Opioids in increasing dosage, converted to up to 1000 mg morphine equivalents per day (in in opioid rotation technique) [84, 85]

  • Co-analgesics:

    1. Anticonvulsants, antidepressants;

    2. Dexamethasone;

    3. Bisphosphonates;

    4. Non-opioid analgesics.

  • No adequate pain relief!

• Thus, application of S-ketamine:

  • Orally, gradually titrated;

  • Starting at 3 × 5 mg/d to 4 × 250 mg/d (after 12 days);

  • Hereunder, satisfying analgesia with reduced pain intensity of NRS 2–3.

10. Problem area: opioid-induced hyperalgesia

When advanced illness patients receive opioid therapy, they de facto find themselves set in a field of tension between pain, analgesia, development of tolerance toward analgesics and opioid-induced hyperalgesia [86].

The phenomenon of opioid-induced hyperalgesia (OIH) is currently being described with increasing frequency [87, 88]. Among other things, it is associated with the fact that in the last two decades, more and more patients have been receiving permanent opioid treatment. Nowadays, many patients not suffering from a tumour disease as well as patients of advanced age and those living with dementia are also prescribed various opioid substances for the treatment of chronic pain and dyspnoea.

OIH describes a clinical situation when patients on long-term opioid therapy suddenly, or amid dose increase, begin to experience an uptick in pain intensity. This state is characterised by a hypersensitisation towards nociceptive stimuli, resulting in exacerbating pain in intensity and quality, exceeding the expected analgesic effect of dose increase (see Figure 17).

Figure 17.

Pain therapy decision-making depending on PCP life expectancy.

Risk factors for the occurrence of OIH constitute:

• Prolonged use of opioids;

• High doses of opioid analgesics;

• Frequent rotation of opioid classes;

• Frequent combinations of two or more different opioid substances;

• Abrupt discontinuation of opioids (“withdrawal syndrome”), especially if the last opioid substance has been taken for a long time;

• Administration of opioid antagonists amid long-term opioid therapy.

Adding to that, PCPs commonly exhibit several factors potentiating the above-mentioned risks, such as:

• Atypical pain patterns, more frequently;

• Higher prevalence of neuropathic pain or mixed-pain syndromes [81];

• Often “total pain” syndrome (Figure 18).

Figure 18.

Schematic depiction of OIH. Source: Self-created.

OIH is a well-known complication of opioid therapy [89]. The underlying mechanisms are not yet fully understood. Ultimately, imbalance of pronociceptive and antinociceptive systems seems to play a major role [90, 91]. According to the opponent-process theory, equilibrium is achieved by balancing the two opposing processes, pronociceptive and antinociceptive. A shift in balance by influencing one of the sides in particular can result in either opioid-induced analgesia or OIH.

Repeated opioid exposure leads to increasing activation of the pronociceptive systems and thus to a decrease in the analgesic effect of opioids. At the same time, an increase in the sensitivity of the nociceptors is observed as well as an activation of pain-modulating and pain-inhibiting systems alike. Thus, this is a pronociceptive process that is related to the processes of tolerance development to opioid substances but differs distinctly from opioid tolerance [92]. Via the process of OIH, opioids may enhance the sensibility towards nociceptive stimuli.

The following systems and mechanisms are pivotal to the development of OIH: [92].

• Central glutaminergic system;

• Spinal dynorphins may increase the levels of excitatory neuropeptides, enhancing the response to nociceptive stimuli;

• Activation of descending antinociceptive spinal pathways;

• Genetic mechanisms;

• Reuptake reduction of neuropeptides and amplification of the nociceptive response;

  • Possibly, morphine-3-glucuronide is involved in this process.

Changes in the activity of NMDA receptors are also associated with hypersensitivity of nociceptive structures. In 2009, Silverman described several factors linking the NMDA receptor to developing OIH: [86].

• NMDA receptors are found to be activated in OIH [93];

• Activation and inhibition of the glutamate transport system results in varying levels of glutamate available as a ligand for NMDA receptors;

• Long-term opioid therapy can lead to NMDA receptor-induced apoptotic cell death of spinal neurons in the dorsal horn;

• “Cross talk” between neural mechanisms of pain and tolerance may be at work.

Amid inhibition of the NMDA receptor, the development of OIH and opioid tolerance can be effectively prevented [86].

Unfortunately, the first possible signs of OIH are often overlooked in clinical routine. In addition, differentiating between OIH and opioid tolerance is de facto challenging. What can assist us in correctly diagnosing OIH in time? Telltale signs may include the following [86]:

• Unexplained increase in pain amid ongoing opioid therapy;

• Occurrence of diffuse allodynia unrelated to the original pain;

• Increase in pain intensity while increasing opioid dosage;

• Limited, short-termed pain relief after dose increase;

• Changes in pain intensity dynamics.

Therapeutic strategies are limited and not always lead to success. We have to consider the importance of the following:

• Supporting the patient intensively in an interdisciplinary caregiving team;

• Continuous monitoring and repeated pain assessment;

• High individual freedom in therapeutic decisions, made by a qualified team;

  • No prefabricated therapeutic schemes at hand!

• Careful reduction of the total opioid dose;

• Rotating opioids, choosing substances with higher antihyperalgesic properties:

  • Different opioids possess varying degrees of hyper- or antihyperalgesic qualities [90];

  • That is, fentanyl, sufentanil and alfentanil hold relatively high hyperalgesic qualities and are therefore considered to bear a significant risk for developing OIH;

  • Buprenorphine appears to have the highest antihyperalgesic activity among the most commonly used opioid substances. In particular, sublingual administration of buprenorphine seems to be an attractive option [86];

  • L-polamidone and methadone, as dual action mechanism opioids, can also be employed for opioid rotation [94] due to their antagonistic effect on the NMDA receptor;

  • In general, combining opioids with varying receptor selectivity is conceivable, thereby suppressing sensitisation processes and optimising pain therapy (Figure 19).

• COX inhibitors and, questionably, paracetamol reduce spinal release of excitatory neurotransmitters, which activate the pronociceptive and anti-opioid systems and thus show a synergistic effect together with NMDA receptor antagonists;

• NMDA antagonist ketamine is an excellent antihyperalgesic substance [83];

• α2-agonists, such as clonidine, moxonidine and methyldopa, may be beneficial [87];

• Tricyclic antidepressants (TCA) are said to play a role in treating OHI by inhibiting the release of acetylcholine;

• Memantine as a non-competitive antagonist of the NMDA receptor is applicable;

• Nitric oxide (NO) is assumed to have an effect on NMDA receptors as well [95];

• Interventional regional pain therapy procedures, including blockades (i.e., sympathetic blockade), catheter procedures:

  • Peripheral;

  • Epidural;

  • Intrathecal.

    1. When applying non-opioid analgesics intrathecally, a rapid and substantial reduction of opioid dosage is possible, and thus, an attenuation of hyperalgesic mechanisms is feasible.

• Ziconotide intrathecally. The preparation, first obtained from the venom of the Conus magus snail, is a highly potent non-opioid analgesic substance [96]. However, ziconotide can only be administered intrathecally and has an unfavourable side effect profile. Both factors justify the reluctant usage in palliative care and must therefore be considered merely as ultima ratio [97].

Figure 19.

Antinociceptive and antihyperalgesic effects [91].

Our clinical observations have revealed that while opioid treatment remains a valid, effective and often the main therapeutic option in treating patients with chronic pain, we cannot consider it to be a panacea. Particularly in patients at advanced stages of disease, significant comorbidities and a high symptom burden, it is not uncommon for adverse drug effects, opioid tolerance or addiction to develop. Problems related to OIH have been capturing more and more attention in recent years as well. This prompts us to provide far-sighted, patient-centred support to our patients. Handling the prescribed medication is a very sensitive and decisive issue, especially given that polypharmacy is a common sight in PCPs. Furthermore, it is indispensable for the caregiving team to reflect extensively together with the patient and his relatives (the “Significant Others”) on the aspired and realistic extent of therapeutic success. In doing so, talking frankly about possible side effects, complications and obstacles along the way as well is vital. This process of joint reflection shapes the therapeutic strategy and ultimately entitles us to make a mutual decision amid informed consent.

When facing a PCP in pain, there are myriads of various pharmacological and non-pharmacological treatment options, pathophysiological mechanisms and phenomena, obstacles and problem areas to consider along the way in order to establish effective pain management. We as caregivers have to broaden our horizon and not treat targeted pain therapy merely as a set of pharmaceuticals. “Differentiated pain therapy” requires a whole new philosophy in dealing with advanced illness patients [98].

11. Invasive pain therapy: a feasible option in palliative care?

Until the 1970s, invasive or neurodestructive methods dominated pain therapy for incurable (especially tumour) diseases. Invasive methods were used in ca. 85% of all tumour patients, whereas currently the share of invasive pain therapy measures is approx. 2–3% [99]. Given the advances in systemic pharmacotherapy, the proportion of non-invasive pharmacological management of patients with cancer-related pain has increased drastically. In 90 to 95% of cases, adequate pain control can be achieved via non-invasive pain therapy [100]. Nevertheless, 5–10% of patients continue to suffer from severe pain, even amid escalating combined systemic analgesic treatment [101].

In these situations, invasive pain management is one of the options to consider.

However, deciding on the use of aggressive pain management procedures in palliative care is often not straightforward. One of the most important principles of symptom control in PCPs is to alleviate discomfort without causing additional harm or adding new distress to the patient. Thus, in the decision-making process, it is imperative that we take into account the PCP’s stage of the incurable disease and, accordingly, whether the invasive measures being considered are still appropriate.

Therefore, we see the option of invasive pain management in palliative care as an additive therapy rather than a substitute for pharmacological treatment. However, once the decision is made to go forward with invasive measures, the aim is twofold [102, 103]:

• Improving the analgesic effect of the preceding therapy;

• Dose reduction of conventional opioids and mitigation of side effects.

Close monitoring of the opioid dose after the application of invasive procedures is a top priority in order to avoid respiratory depression, especially in advanced phases of the disease.

Possible indications for invasive pain management in palliative care include: [104].

• Therapy-refractory pain, after having applied all feasible options according to the “WHO Analgesic Ladder”;

• Unbearable side effects of conventional systemic pain therapy;

• Oral route of drug administration inapplicable;

• Tumour pain with a distinct neuropathic pain component, for example, plexopathy;

• Therapy-resistant, persistent and relapsing breakthrough pain whose intensity is significantly higher than the baseline pain.

The invasive procedures at hand may be categorised as either neuroablative and neurodestructive, causing irreversible damage to neural structures, or neuromodulative and neuroaugmentative, having a reversible influence on defined neural structures or systems.

Neurodestructive methods include: [99].

• Surgical sectioning or partial destruction of the nerve, for instance, using percutaneous catheter-assisted thermal lesion;

• Neurolytic methods utilising:

  • Alcohol 96%;

  • Phenol;

  • Glucose 40%.

Neuroaugmentative procedures modulate neuronal ionic currents or chemical information transmissions at the receptor or neuron of the spinal cord [99]. This also includes spinal (epidural or intrathecal) drug application and spinal cord stimulation (see Figure 20).

Figure 20.

Neuroaugmentative measures in paint therapy [99, 105].

Reversible interruptions of stimuli with the help of local anaesthetics, such as peripheral nerve blocks and percutaneous intrathecal or peridural blocks, are an effective option for pain management in palliative care. However, invasive neuroablative methods, such as invasive neurolysis (i.e., percutaneous neurolysis of the celiac ganglion or plexus hypogastricus), percutaneous or open chordotomy as well as percutaneous rhizotomy, are hardly used in contemporary palliative care anymore [106, 107, 108].

Intrathecal analgesia has the following advantages: [109].

• Immediate effect of the substances at spinal receptors;

• Bypassing the hepatic first-pass metabolism;

• Highest analgesic efficiency with relatively low toxicity in comparison with other administration forms;

• Neuroaugmentative measure with temporary effect, not neurodestructive;

• Intrathecally applied; analgesics bear a potency at least 100 times higher than orally and 10 times higher than epidurally applied; therefore:

  • Lower doses and volumes required for comparable analgesic effect;

  • Resulting in a more direct, local and targeted pain therapy;

  • While observing relatively little craniocaudal spread and hence evaluating the risk of serious respiratory or cardiovascular adverse drug effects as low and reasonable.

Among others, the following substances can be applied intrathecally:

• Opioids, blockage of opiate receptors in the substantia gelatinosa of the spinal cord:

  • Morphine;

  • Hydromorphone;

  • Fentanyl;

  • Sufentanil;

  • Buprenorphine;

• Local anaesthetics, blockage of Na⁺ channels at Aδ and C fibres:

  • Ropivacaine;

  • Bupivacaine;

  • Lidocaine;

• And other non-opioid substances:

  • Ziconotide, blockage of N-type Ca²⁺ channels;

  • Clonidine, agonist at the α₂ receptor in the spinal cord;

  • Ketamine, blockage of NMDA receptors in the spinal cord.

For intrathecal or epidural use via continuous application, local anaesthetics can be combined with opioids, that is:

• Bupivacaine 0.2% + Hydromorphone 0.02 mg/mL

  • Starting at 0.5 mL/h

  • Gradual increase, up to 1.5 mL/h

The following considerations are crucial for the practical implementation:

• The tip of the spinal catheter should be placed in the middle of the dermatome level of the required blockage area;

• The positioning of the catheter is vital, and therefore, it has to be X-ray-controlled;

• Substance spread within the spinal cord is limited to a few centimetres around the catheter tip, whereby differences arise depending on the substance’s hydro- and lipophilicity:

  • Fentanyl, highly lipophilic: spread is oftentimes limited to area encompassing two vertebrae from the catheter tip

  • Morphine, highly hydrophilic: diffused spread and thus an effect similar to a systemic effect.

With regard to decisions on therapy options in palliative care, the selection criteria depend on the PCP’s current situation and estimated prognostic life expectancy, which, among other things, can answer the question of the appropriateness of the measures being considered (see Figure 17) [110, 111].

If the patient has a short life expectancy and a high symptom burden, the decision would be made in favour of an epidural rather than a spinal catheter, with an external pump for drug application. If the patient has a longer life expectancy and is in an adequately good general state, an intrathecal (spinal) catheter may be justified, including the placement of an internal pump with subcutaneous catheter tunnelling.

Most usefully, the pumps should be operated in PCA (Patient Controlled Analgesia) mode. The following advantages apply to this procedure:

• Continuous administration allows for a constant level of analgesic substance to attained;

• Combinations of different drugs are possible as well;

• Bolus administration is feasible as PRN (or rescue) medication for breakthrough pain;

• Maximum amounts can be individually defined, facilitating good controllability and preventing overdosing;

• The patient remains mobile and flexible.

Case study 2:

• Female patient, 49 y.;

• Diagnosis: extensively cervically metastasised mammary carcinoma. Metastases are palpable subcutaneously, that is, at the interscalene triangle, non-exulcerating;

• Tumorous lesions encircling the right brachial plexus, resulting in plexopathy;

• Severe pain of neuropathic origin: peripheral, neuralgic and sympathalgic pain affecting the total upper right limb:

  • Shooting, “lightning strike”-like pain extending all the way down into the hand;

  • Burning pain attacks of the hand, up to NRS 10;

  • Tingling paraesthesia, numbness affecting the hand;

  • Allodynia;

  • Vegetative phenomena: thermal dysaesthesia, local diaphoresis;

  • Partial mono-palsy of the right arm and hand.

• Initial treatment:

  • Opioids:

    1. Initially, hydromorphone. Gradual dosage increase up to 2 × 64 mg;

    2. In addition: fentanyl patch. Gradual dosage increase up to 125 μg/h. Initially, changing patches every 72 h. Later, suspecting “end of dose failure”, change at every 48 h;

    3. PRN medication:

       1. Hydromorphone acute 2.6 mg, max. 6× per day;

       2. Hydromorphone 2 mg s.c., max. 6× per day;

       3. Fentanyl sublingually (ROO), 100 to 400 μg, amid extreme pain spikes.

  • Co-analgesics, among others:

    1. Pregabalin, up to 300 mg per days;

    2. Amitriptyline, up to 100 mg per day;

    3. Dexamethasone, up to 24 mg per day.

  • Non-opioid analgesics:

    1. Parecoxib 40 mg i.v., 1/d for 10 days;

    2. Metamizole 4–5 mg/d;

  • Palliative radiotherapy of the region primarily affected.

• Only marginal mitigation of symptom burden (pain intensity fluctuating between NRS 5–10), no adequate pain relief!

• Notably, the burning pain attacks of the hand are perceived as unbearable and are not noticeably affected by the therapy. Due to the allodynia, the patient achieves temporary limited pain relief by submerging her hand into boiling water.

• Given the failure of the preceding pharmacological and radiotherapeutic pain management to sufficiently alleviate the PCP’s symptom burden, a decision has been made to establish a peripheral blockage of the right brachial plexus:

  • Initially, a diagnostical interscalene blockage utilising 20 mL of ropivacaine 0.75% has been performed, resulting in almost complete anaesthesia of the upper limb and painlessness;

  • Given the difficulty of establishing a continuous blockage due to extensive subcutaneous metastases, the permanent measure via the interscalene triangle has been realised amid CT guidance;

  • Successful blockage via the infraclavicular region. Retrograde, CT-guided advance of the catheter tip towards the brachial plexus. Subsequently, 5-cm tunnelling of the catheter to reduce the risk of infection and catheter dislocation;

  • Initiation of PCA analgesia via an external pump, utilising ropivacaine 0.375% and buprenorphine 0.4 mg/d.

• Substantial pain relief! Currently, pain intensity amounts to NRS 3 and rare BTP episodes with reduced intensity of NRS 4. Subsequently, the opioid dosage could be reduced to less than 50 mg/d of morphine (converted), up to 2 × 4 mg of hydromorphone.

• Permanent (> 3 months) satisfactory symptom control (see Figure 21)!

Figure 21.

PCP with infraclavicular catheter amid tumour lesions encircling the brachial plexus. Courtesy of Centre for Palliative Care, Unna, Germany. 2004.

12. Non-pharmaceutical aspects of pain management in palliative care

Preventive medicine and palliative care hold clinically relevant overlaps and are both classic, yet so far underdeveloped, cross-sectional areas of health care [112].

Due the common presence of severe comorbidities, a poor general state and a lower resilience and endurance of the advanced ill, non-drug options of pain therapy are, unfortunately, frequently set aside. However, these methods can be an effective addition to drug treatment [113]. “Physiotherapy within the realms of palliative care is an exceptional means of preserving and improving quality of life and independence” [114].

Various methods can be considered as valid additive measures in pain therapy, [112, 115] including:

• General physical methods, that is:

  • Physiotherapy;

  • Stimulation methods (e.g., transcutaneous electrical nerve stimulation, TENS);

  • Massages;

  • Lymphatic drainage;

  • Positioning therapy;

  • Occupational therapy;

  • Treatments with warmth and coldness;

  • Vibrations and stimulation;

  • Kinesiology tapes;

• Psychotherapeutic interventions, that is:

  • Psychotherapeutically oriented conversations;

  • Learning pain coping strategies

  • Relaxation techniques;

  • Stress management skills, biofeedback;

• Complementary measures, including:

  • Homoeopathy;

  • Aromatherapy;

  • Acupuncture;

  • Yoga, Qi-Gong;

  • Reiki therapy;

  • Rhythmic embrocation after Wegman and Hauschka;

  • Singing bowl massage;

  • Phytotherapy;

  • Music therapy;

  • Art therapy.

The significance and potential of rehabilitative measures in palliative care is substantial:

• It opens up the possibility of directing the patient’s sight away from the illness and his frailty itself towards the proper use of the PCP’s remaining resources. This in some cases new perspective aids in strengthening salutogenesis, a more positive attitude and resilience in general.

• In employing additional non-pharmaceutical approaches, the advanced ill feels his needs and sorrows being taken seriously. He feels understood, and even the slightest progress in addressing his symptom burden adds to his positivity. This may foster hope.

13. To ensure that pain management works well

What is the decisive factor for a good outcome of our efforts to ensure adequate pain management in palliative care?

Caring for an advanced illness patient constitutes a multidisciplinary challenge. Thus, when working together in a caregiving team of various professions, it is crucial to reflect on one’s own actions and on those of the whole team with a critical look.

I asked my colleagues, especially the palliative care nurses: “What do you expect from us, the doctors, in the joint care of an advanced illness person in pain?”

The answers turned out to be telling:

• Openness and willingness to engage in interdisciplinary exchange and hence to share a preparedness to change perspectives;

• Focus on the patient’s needs and sorrows;

• Flexibility and creativity in everyday work;

• Ensuring a continuity of patient care: asking questions on one’s own initiative regularly, performing continuous pain and symptom control;

• When establishing a treatment regime for pain management, always include PRN or rescue medication;

• A close exchange of information between team members in the event of changes in therapy is indispensable;

• Enabling the nursing staff, especially at outpatient care services, to make independent decisions on the administration of PRN medication within clearly communicated boundaries to ensure flexible, timely and goal-driven patient care. In order to do so, the colleagues have to be informed on, authorised for and entrusted with the application of the rescue medication and its limitations;

• Demanding and promoting additional training of nursing colleagues within the topics of palliative care and symptom control in particular.

The message for us doctors is to keep in mind seemingly simple notions—and to implement them into our work. And we will be rewarded for it. Because the greatest gift for us is our patients’ satisfaction, their calm glance full of joy, hope and peace (Figure 22).

Figure 22.

When pain management succeeds. Courtesy of Centre for Palliative Care, Unna, Germany. 2006.

Acknowledgments

Translation: Robert Jonathan Hait.