Pain Management in Palliative Care: What Is Significant?

*Boris Hait*

*"Divinum est sedare dolorem" Galen of Pergamon (129 – 199 A.D.)*

#### **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.

**Keywords:** advanced ill patients, multidimensional approach to pain assessment, total pain, chronification of pain, mechanisms-centred pain therapy, opioid therapy, nociceptive pain, neuropathic pain, mixed pain, WHO scheme on pain management, opioid receptor

#### **1. Introduction**

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:


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


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:


**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**).

#### **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].

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:


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.

**Figure 4.** *Chaos of emotions of the grieving [4].*

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].

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:


**Figure 5.** *Seven sorrows [6].*

*Pain Management in Palliative Care: What Is Significant? DOI: http://dx.doi.org/10.5772/intechopen.112325*

**Figure 6.** *Total pain [7, 8].*

	- 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;

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:


#### **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:

	- 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**).

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**).

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


**Figure 7.**

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

#### **Figure 8.**

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


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].

*Pain Management in Palliative Care: What Is Significant? DOI: http://dx.doi.org/10.5772/intechopen.112325*

**Figure 9.** *Pathophysiology of pain in bone metastases. Source: Self-created.*

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:


#### **Figure 10.**

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

Interpersonal stress profile:

• Lack of social support.

Adaptive copers/minimisers:


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**).

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

*Pain Management in Palliative Care: What Is Significant? DOI: http://dx.doi.org/10.5772/intechopen.112325*

**Figure 11.** *Development of central sensitisation [20].*

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**).

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:


#### **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:

*Pain Management in Palliative Care: What Is Significant? DOI: http://dx.doi.org/10.5772/intechopen.112325*


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


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]:

	- 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.
	- **Tilidine**:
		- a. Preferred in case of renal insufficiency;
		- b. Tilidine is a prodrug that is probably activated by cytochrome isoenzyme (CYP) 3A4 to nortilidine;

## ◦ **Codeine**:


## ◦ **Dihydrocodeine (DHC)** [35]:

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

	- 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.

## ◦ **Tramadol:**


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

## ◦ **Morphine**:

	- 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.

## ◦ **Oxycodone**:


## ◦ **Hydromorphone:**


## ◦ **Fentanyl:**


## ◦ **Buprenorphine**:



## ◦ **Methadone**:


## ◦ **Tapentadol:**


#### **Figure 14.**

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

tapentadol-O-glucuronide as the main metabolite and N-desmethyl tapentadol, are inactive;

	- 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.

#### **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:

	- 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.

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:


and morphine analogues, such as:


as co-medication together with:



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-HT2A 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 pain management of PCPs, transdermal therapeutic systems (TTS) bear particular significance:

	- 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.
	- 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];


#### **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).

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: [75–77].

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

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

	- a. Nociceptive;
	- b. Neuropathic;
	- c. Mixed-pain.
	- 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].


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:


The traditional recommendations of the "WHO Analgesic Ladder" with regard to PRN medication—**1***=***<sup>10</sup>** to **<sup>1</sup>***=***<sup>6</sup>** 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:

	- The phenomenon of EoD failure is primarily due to individual differences in the pharmacokinetics of opioids, among others:
		- a. Genetic polymorphisms of opioid receptors;
		- b. 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.
	- 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.

#### **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 difficultto-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):

a. 50–150 mg;

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

## ◦ **Doxepin** (TCA):


## ◦ **Duloxetine** (SNRI):

a. 30–60 mg;

b. ID: 1 30 mg;

## ◦ **Venlafaxine** (SNRI):

a. 75–150 mg;

b. ID: 1 75 mg;

## ◦ **Mirtazapine** (NaSSA):

a. 15–30 mg;

b. 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:

	- 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:

	- Opioids in increasing dosage, converted to up to 1000 mg morphine equivalents per day (in in opioid rotation technique) [84, 85]
	- Co-analgesics:
		- a. Anticonvulsants, antidepressants;
		- b. Dexamethasone;
		- c. Bisphosphonates;
		- d. Non-opioid analgesics.
	- No adequate pain relief!
	- 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**).

Risk factors for the occurrence of OIH constitute:



**Figure 17.**

*Pain therapy decision-making depending on PCP life expectancy.*


Adding to that, PCPs commonly exhibit several factors potentiating the abovementioned risks, such as:


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].

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

**Figure 18.** *Schematic depiction of OIH. Source: Self-created.*

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].


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]:


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

	- No prefabricated therapeutic schemes at hand!
	- 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**).

#### **Figure 19.**

*Antinociceptive and antihyperalgesic effects [91].*

	- Peripheral;
	- Epidural;
	- Intrathecal.
		- a. 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.

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 nonpharmacological 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]:


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].


*Pain Management in Palliative Care: What Is Significant? DOI: http://dx.doi.org/10.5772/intechopen.112325*


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].

	- 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**).

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 [106–108].

Intrathecal analgesia has the following advantages: [109].



**Figure 20.** *Neuroaugmentative measures in paint therapy [99, 105].*

	- 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:

	- Morphine;
	- Hydromorphone;
	- Fentanyl;
	- Sufentanil;
	- Buprenorphine;
	- Ropivacaine;
	- Bupivacaine;
	- Lidocaine;
	- Ziconotide, blockage of N-type Ca2+ channels;
	- Clonidine, agonist at the <sup>α</sup><sup>2</sup> 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:

*Pain Management in Palliative Care: What Is Significant? DOI: http://dx.doi.org/10.5772/intechopen.112325*

	- Starting at 0.5 mL/h
	- Gradual increase, up to 1.5 mL/h

The following considerations are crucial for the practical implementation:

	- 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:


Case study 2:

	- 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.
	- Opioids:
		- a. Initially, hydromorphone. Gradual dosage increase up to 2 64 mg;
		- b. 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;
		- c. 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:
		- a. Pregabalin, up to 300 mg per days;
		- b. Amitriptyline, up to 100 mg per day;
		- c. Dexamethasone, up to 24 mg per day.

◦ Non-opioid analgesics:

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

b. Metamizole 4–5 mg/d;

	- 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, CTguided 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.

#### **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].

#### **Figure 21.**

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

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:

	- Physiotherapy;
	- Stimulation methods (e.g., transcutaneous electrical nerve stimulation, TENS);
	- Massages;
	- Lymphatic drainage;
	- Positioning therapy;
	- Occupational therapy;

*Pain Management in Palliative Care: What Is Significant? DOI: http://dx.doi.org/10.5772/intechopen.112325*

	- Psychotherapeutically oriented conversations;
	- Learning pain coping strategies
	- Relaxation techniques;
	- Stress management skills, biofeedback;
	- 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:


#### **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:


*Pain Management in Palliative Care: What Is Significant? DOI: http://dx.doi.org/10.5772/intechopen.112325*


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**).

#### **Acknowledgements**

Translation: Robert Jonathan Hait.

#### **Author details**

Boris Hait Centre for Palliative Care, Christliches Klinikum Unna-Mitte, Unna, Germany

\*Address all correspondence to: b.hait@gmx.de

© 2023 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 9**
