TABLE OF CONTENTS Page

1. INTRODUCTION 6

1.2 Reference 6

2 BACKGROUND 7

2.1 Definition of pain 7

2.2 What is suffering? 7

2.3 Nociception and innervation 7

2.4 Neuropathic pain 8

2.5 Innervation of the urogenital system 9

2.6 Pain evaluation and measurement 10

2.6.1 Pain evaluation 10

2.6.2 Assessing pain intensity and quality of life (QoL) 10

2.7 References 11

3 CANCER PAIN MANAGEMENT (GENERAL) 13

3.1 Classification of cancer pain 13

3.1.1 References 13

3.2 General principles of cancer pain management 14

3.3 Non-pharmacological therapies 15

3.3.1 Surgery 15

3.3.1.1 References 15

3.3.2 Radionuclides 15

3.3.2.1 Clinical background 15

3.3.2.2 Radiopharmaceuticals: physical characteristics 16

3.3.2.3 Indications and contraindications 16

3.3.2.4 Contraindications 17

3.3.2.5 References 17

3.3.3 Radiotherapy for metastatic bone pain 19

3.3.3.1 Clinical background 19

3.3.3.2 Mechanism of pain relief by radiotherapy 19

3.3.3.3 Imaging 19

3.3.3.4 Radiotherapy scheme 19

3.3.3.5 Spinal cord compression 20

3.3.3.6 Pathological fractures 20

3.3.3.7 Side-effects 21

3.3.3.8 References 21

3.3.4 Physical/psychological therapy 24

3.3.4.1 Physical therapies 24

3.3.4.2 Psychological therapies 24

3.4 Pharmacotherapy 25

3.4.1 Antibiotics 25

3.4.2 Chemotherapy 25

3.4.3 References 25

3.4.4 Bisphosphonates 25

3.4.4.1 Mechanisms of action 25

3.4.4.2 Effects and side-effects 26

3.4.4.3 References 26

3.4.5 Systemic analgesic pharmacotherapy - the ‘analgesic ladder’ 27

3.4.5.1 Non-opioid analgesics 27

3.4.5.2 Opioid analgesics 28

3.4.5.2.1 Opioid administration 28

3.4.5.2.2 Adverse effects and their management 30

3.4.5.2.3 Adjuvant analgesics 32

3.4.5.2.4 References 32

3.4.5.3 Treatment of neuropathic pain 35

3.4.5.3.1 Antidepressants 35

3.4.5.3.2 Anticonvulsant medication 35

3.4.5.3.3 Topical analgesics 36

3.4.5.3.4 NMDA receptor antagonists 36

3.4.5.3.5 Other drug treatments 37

3.4.5.3.6 Summary: treatment of neuropathic pain 37

3.4.5.4 Invasive analgesic techniques 38

3.4.5.4.1 Peripheral nerve catheterisation in the management of cancer pain 38

3.4.5.4.2 Neurolytic blocks to control visceral cancer pain 38

3.4.5.4.3 Epidural and intrathecal opioid application 38

3.4.5.4.4 Chemical rhizotomy 38

3.4.5.4.5 Cordotomy 39

3.4.5.5 References 39

3.5 Quality of life 42

3.5.1 Conclusions 42

3.5.2 References 42

4 PAIN MANAGEMENT IN UROLOGICAL CANCERS 43

4.1 Pain management in prostate cancer patients 43

4.1.1 Clinical presentation 43

4.1.2 Pain due to local impairment 43

4.1.2.1 Invasion of soft tissue or a hollow viscus 43

4.1.2.2 Bladder outlet obstruction 43

4.1.2.3 Ureteric obstruction 43

4.1.2.4 Lymphoedema 43

4.1.2.5 Ileus 43

4.1.3 Pain due to metastases 43

4.1.3.1 Bone metastases 43

4.1.3.1.1 Hormone therapy 44

4.1.3.1.2 Side-effects 44

4.1.3.1.3 Efficacy 45

4.1.3.1.4 Problems 45

4.1.3.1.5 Radiotherapy 45

4.1.3.1.6 Orthopaedic surgery 45

4.1.3.1.7 Radioisotopes 45

4.1.3.1.8 Bisphosphonates 46

4.1.3.1.9 Calcitonin 46

4.1.3.1.10 Chemotherapy 46

4.1.4 Systemic analgesic pharmacotherapy (the ‘analgesic ladder’) 47

4.1.5 Spinal cord compression 48

4.1.6 Hepatic invasion 48

4.1.7 Pain due to cancer treatment 48

4.1.7.1 Acute pain associated with hormonal therapy 48

4.1.7.2 Chronic pain associated with hormonal therapy

4.1.8 Conclusions 48

4.1.9 Recommendations at a glance (stage M1) 49

4.1.10 References 49

4.2 Pain management in transitional cell carcinoma patients 52

4.2.1 Clinical presentation 52

4.2.2 Origin of tumour-related pain 52

4.2.3 Pain due to local impairment 53

4.2.4 Pain due to metastases 53

4.2.5 References 53

4.3 Pain management in renal cell carcinoma patients 54

4.3.1 Clinical presentation 54

4.3.2 Pain due to local impairment 54

4.3.3 Pain due to metastases 55

4.3.4 References 56

4.4 Pain management in patients with adrenal carcinoma 56

4.4.1 Malignant phaeochromocytoma 57

4.4.2 Treatment of pain 57

4.4.2.1 Adrenocortical carcinomas 57

4.4.2.2 Treatment of the pain depending on its origin 57

4.4.3 References 57

4.5 Pain management in penile cancer patients 58

4.5.1 Clinical presentation 58

4.5.2 Pain due to local impairment 59

4.5.3 Lymphoedema 59

4.5.4 Pain due to metastases 59

4.5.5 Conclusions 59

4.5.6 References 59

4.6 Pain management in testicular cancer patients 59

4.6.1 Clinical presentation 59

4.6.2 Pain due to local impairment 59

4.6.3 Pain due to metastases 59

4.6.4 References 60

4.7. Recommendations at a glance 60

5 POST-OPERATIVE PAIN MANAGEMENT 61

5.1 Background 61

5.2 The importance of effective post-operative pain management 61

5.2.1 The aims of effective post-operative pain management 62

5.3 Pre- and post-operative pain management methods 62

5.3.1 Pre-operative patient preparation 62

5.3.2 Pain assessment 62

5.3.3 Pre-emptive analgesia 63

5.3.4 Systemic analgesic techniques 63

5.3.4.1 Non-steroidal anti-inflammatory drugs (NSAIDs) 63

5.3.4.2 Paracetamol 64

5.3.4.3 Metamizole (dipyrone) 64

5.3.4.4 Opioids 65

5.3.4.5 Patient-controlled analgesia 65

5.3.4.6 Fentanyl 65

5.3.4.7 Opioid equi-analgesic doses 66

5.3.5 Regional analgesic techniques 66

5.3.5.1 Local anaesthetic agents 66

5.3.5.2 Epidural analgesia 66

5.3.5.3 Patient-controlled epidural analgesia (PCEA) 66

5.3.5.4 Neural blocks 67

5.3.5.5 Wound infiltration 67

5.3.5.6 Continuous wound instillation 67

5.3.6 Multi-modal analgesia 67

5.3.7 Special populations 67

5.3.7.1 Ambulatory surgical patients 67

5.3.7.2 Geriatric patients 68

5.3.7.3 Obese patients 68

5.3.7.4 Other groups 68

5.3.8 Post-operative pain management teams 68

5.4 Specific pain treatment after different urological operations 69

5.4.1 Extracorporeal shock wave lithotripsy (ESWL) 69

5.4.2 Endoscopic procedures 70

5.4.2.1 Transurethral procedures 70

5.4.2.2 Percutaneous endoscopic procedures 70

5.4.2.3 Laparoscopic procedures 71

5.4.3 Open surgery 71

5.4.3.1 Minor operations of the scrotum/penis and the inguinal approach 71

5.4.3.2 Transvaginal surgery 72

5.4.3.3 Perineal open surgery 72

5.4.3.4 Transperitoneal laparotomy 73

5.4.3.5 Suprapubic/retropubic extraperitoneal laparotomy 74

5.4.3.6 Retroperitoneal approach – flank incision – thoracoabdominal approach 74

5.5 Dosage and method of delivery of some important analgesics 75

5.5.1 NSAIDs 75

5.5.2 NSAIDs with antipyretic effect 75

5.5.3 Selective COX-2 inhibitor 75

5.5.4. Opioids 75

5.6 Peri-operative pain management in children 76

5.6.1 Pre-operative problems 76

5.6.2 Post-operative analgesia 76

5.7 References 77

6. Non-traumatic acute flank pain 82

6.1 Background 82

6.2 Initial diagnostic approach 83

6.2.1 Symptomatology 83

6.2.2 Laboratory evaluation 83

6.2.3 Diagnostic imaging 83

6.2.3.1 Ultrasonography 83

6.2.3.2 Intravenous urography (IVU) 84

6.2.3.3 Unenhanced helical CT (UHCT) 84

6.3 Initial emergency treatment 86

6.3.1 Systemic analgesia 86

6.3.2 Local analgesia 86

6.3.3 Supportive therapy 86

6.3.4 Upper urinary tract decompression 86

6.4 Aetiological treatment 87

6.4.1 Urolithiasis 87

6.4.2 Infectious conditions 87

6.4.3 Other conditions 87

6.4.3.1 Uretero-pelvic junction obstruction 87

6.4.3.2 Papillary necrosis 87

6.4.3.3 Renal infarction 87

6.4.3.4 Renal vein thrombosis 87

6.4.3.5 Intra- or peri-renal bleeding 87

6.4.3.6 Testicular cord torsion 87

6.5 References 87

7. ABBREVIATIONS USED IN THE TEXT 91

1. INTRODUCTION

The European Association of Urology (EAU) Guidelines Group for Pain Management have prepared this guidelines document to assist medical professionals in appraising the evidence-based management of pain in urological practice. These guidelines include general advice on pain assessment, with a focus on treatment strategies relating to common medical conditions and painful procedures. No attempts have been made to exhaustingly cover the topic of pain.

The multidisciplinary panel of experts responsible for this document includes three urologists, two radiotherapists and two anaesthesiologists.

The recommendations provided in the current guidelines are based on a systemic literature search using Medline, the Cochrane Central Register of Controlled Trials, and reference lists in publications and review articles. Where possible a level of evidence (LE) and/or grade of recommendation (GR) have been assigned (1). Recommendations are graded in order to provide transparency between the underlying evidence and the recommendation given (Tables 1 and 2).

It has to be emphasised that the current guidelines contain information for the treatment of an individual patient according to a standardised general approach.

Publication history information:

The Pain Management Guidelines were first published in 2003, with a partial update in 2007, followed

by a full text update in 2009. The current 2010 print includes two new topics, Section 5.6 “Peri-operative pain management in children” and Chapter 6 “Non-traumatic flank pain”. The quick reference guide has been completely reworked.

All texts can be viewed and downloaded for personal use at the society website:

http://www.uroweb.org/professional-resources/guidelines/.

Table 1: Level of evidence

Modified from Sackett et al. (1).

Table 2: Grade of recommendation

Modified from Sackett et al. (1).

1.2 Reference

1. Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2001). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998.

http://www.cebm.net/index.aspx?o=1025 [accessed March 2010].

2. BACKGROUND

2.1 Definition of pain

Pain is the most common symptom of any illness. The physician’s therapeutic task is twofold:

• to discover and treat the cause of the pain

• to treat the pain itself, irrespective of whether the underlying cause is treatable, in order to provide relief from it and reduce the suffering caused by it.

The International Association for the Study of Pain (IASP) has proposed the following working definition: pain is ‘an unpleasant sensory and emotional experience associated with either actual or potential tissue damage, or described in terms of such damage’ (1).

The alerting function of pain evokes protective responses (reflex motor withdrawal and behavioural responses), and is intended to keep tissue damage to a minimum. The capacity to experience pain has a protective role. If tissue damage (cellular breakdown with liberation of biochemical substances) is unavoidable, a cascade of changes occurs in the peripheral and central nervous system responsible for the perception of pain (2). A distinction can be made between adaptive and maladaptive pain (3).

Acute pain – usually occurring in response to an identifiable noxious event with stimulation of the nociceptive system (from the periphery through the spinal cord, brain stem, and thalamus to the cerebral cortex where the sensation is perceived) – has a time-limited course during which treatment, if necessary, is aimed at correcting the underlying pathological process. Acute pain is useful or adaptive because it is a vital physiological sensation that alerts a person to something harmful in the environment that should be avoided. Additionally, if tissue injury occurs (following a noxious stimulus), adaptive pain induces a (reversible) state of localised hypersensitivity (stimuli that would normally not cause pain now cause pain) in and around the injured area, resulting in an avoidance of the damaged part. This adaptive, inflammatory pain tries to aid in repair after tissue damage, promoting healing.

In contrast, maladaptive (pathological) pain offers no biological advantage because it is uncoupled from a noxious stimulus or tissue healing. Maladaptive pain is an expression of an inappropriate plasticity or modifiability of the nervous system, and is usually persistent or recurrent. Maladaptive pain may occur in response to damage to the nervous system (peripheral nerve, dorsal root ganglion, dorsal root, central nervous system), and is known as neuropathic pain. Essentially, maladaptive (neuropathic) pain is pain as a disease (3-5).

2.2 What is suffering?

Pain is a complex experience entailing physiological, sensory, affective, cognitive and behavioural components. An individual’s perception of the intensity of pain relates to the interactions of physical, psychological, cultural and spiritual factors (6). Although the control of pain is central to any effort to relieve suffering, and pain and suffering are closely identified, they are nevertheless distinct.

To define suffering, a psychosocial perspective has been adapted in which suffering is best viewed as a subjective phenomenon that can be influenced by biological, psychological, and social processes. Patients can experience severe pain without suffering (e.g. during childbirth), and suffering can include physical pain, but it is by no means limited to it. Patient distress also results from factors other than pain that add to suffering, such as anxiety, depression, nightmares, change in body perception, and changes in professional and social function.

The differences between pain and suffering are most pronounced in cancer pain patients. Cancer is one of the medical conditions patients fear most: patients and their families are not only convinced that it is the beginning of the end and the patients will certainly die, but they also expect that the patients will die in horrible, excruciating pain (7, 8). Addressing these psychosocial sources as well as the medical sources should be the primary goal of a pain clinic, and can be achieved through a multidisciplinary approach (6).

2.3 Nociception and innervation

Structure of the peripheral neural apparatus

Sensory information from the skin is transmitted to the central nervous system (dorsal horn of the spinal cord) via three different types of primary sensory neurones: A?-, A?-, and C-fibres.

These primary afferent neurones are responsible for transducing mechanical, chemical and thermal information into electrical activity. Although all three classes can transmit non-nociceptive information, under physiological circumstances only C-fibres (dull pain) and A?-fibres (sharp pain) are capable of transmitting nociceptive information from the periphery to the dorsal horn of the spinal cord. Thus, under normal circumstances, A?-fibres are responsive only to non-noxious mechanical stimuli, including touch, vibration and pressure (9-12).

Nociceptive information for the viscera reaches the central nervous system along the sympathetic chains and pelvic parasympathetic chain. However, the density of visceral afferents is low compared with the skin, which can explain the poor localisation of noxious stimuli in the viscera (responsible for the diffuse nature of visceral pain) (13).

The role of the dorsal horn

The nociceptors terminate in a highly ordered way in the dorsal horn of the spinal cord, with the thinly myelinated A? fibres ending in laminae I and V, and the unmyelinated C-fibres ending in lamina II. These high threshold sensory fibres activate a large number of second order interneurones and projection neurones in the spinal cord. The activity generated by nociceptor input is transferred, after complex active processing in the dorsal horn, directly, or via brain stem relay nuclei, to the thalamus and then on to the cortex, where the sensation of pain is generated. Following integration in the dorsal horn, the pain signal is conducted through ascending pathways to the thalamus which, in interaction with limbic circuits, plays a crucial role in the reception and processing of nociceptive information en route to the cortex (12, 14).

Brain areas involved in nociception and pain

Nociceptive messages become more and more difficult to follow as they travel further along the central nervous system (CNS). Numerous brain areas are involved in the various components of pain, which include:

• a sensory-discriminative component that refers to the capacity to analyse location, intensity and duration of the nociceptive stimulus

• an affective component that gives rise to the unpleasant character of painful perception

• a cognitive and evaluative component, which is involved in the phenomena of anticipation, attention, suggestion and past experiences.

Although several circuits responsible for the sensory-discriminative and affective-cognitive components of pain can be distinguished, the global experience of pain, involves complex interactive neural networks of cerebral structures and multiple thalamocorticolimbic pathways (12, 14, 15).

2.4 Neuropathic pain

Definition of neuropathic pain

Neuropathic pain is defined by the IASP as ‘pain initiated or caused by a primary lesion or dysfunction of the nervous system’ (2). This trauma to neural tissue produces abnormalities of neural function that are perceived by the patient as the symptoms and signs of neuropathic pain.

On examination, both negative and positive sensory symptoms may be present. Positive signs include pain, paraesthesia, dysaesthesia, hyperalgesia and allodynia. Negative signs involve sensory deficits (hypoaesthesia and hypoalgesia), weakness, and reflex changes. Clinically, patients may complain of spontaneous ongoing pain (stimulus-independent pain) that is burning, with intermittent shooting or electric shock-like (lancinating) sensations, and/or have pain hypersensitivity evoked in response to stimuli (stimulus-evoked pain) such as hyperalgesia and allodynia (16, 17).

Mechanisms of neuropathic pain

Studies in animal models describe a number of peripheral and central pathophysiological processes after nerve injury that would be the basis of the underlying neuropathic pain mechanism. A change in function, chemistry, and the structure of neurones (neural plasticity) leads to the production of the altered sensitivity characteristics of neuropathic pain. Peripheral sensitisation acts on the nociceptors, and central sensitisation takes place at various levels ranging from the dorsal horn to the brain. In addition, abnormal interactions between the sympathetic and sensory pathways contribute to mechanisms mediating neuropathic pain (14, 18).

Summary of peripheral processes involved in neuropathic pain

The peripheral processes involved in neuropathic pain are:

• nociceptor sensitisation

• alteration in ion channel expression

• neuronal hyperexcitability with ectopic and spontaneous discharge (alteration in the expression of sodium channels and overactive calcium channels)

• sprouting of collateral fibres from intact and damaged sensory axons into denervated areas

• non-synaptic ‘ephatic’ interactions between neurones

• phenotypic switch of A?-fibres (substance-P and calcitonin gene-related peptide release)

• sprouting of sympathetic fibres into the primary afferent fibres and the dorsal root ganglia (sympathetic-induced pain).

Summary of central processes involved in neuropathic pain

The central processes involved in neuropathic pain are:

• N-methyl-D-aspartate receptor activation

• wind up: progressive increase in excitability during the course of the stimulus

• translation-dependent central sensitisation:

- hyperalgesia

- secondary hyperalgesia

- allodynia

• activated microglia release proinflammatory cytokines and growth factors that further activate these cells, creating a positive feedback circuit and inducing pathological pain

• transcription-dependent central sensitisation may induce permanent phenotypic/morphological changes

• sprouting of A-fibres in lamina II

• loss of spinal inhibitory control (gamma-aminobutyric acid, glycine)

• cholecystokinin increase dampens µ-opioid inhibitory mechanisms.

2.5 Innervation of the urogenital system

The differences between the mechanisms of nociception in the skin and viscera are emphasised by studies of the response properties of visceral afferents from the urinary tract (19-21).

Ureter

The only sensation that can be evoked from the ureter is pain, whereas other organs such as the bladder can give rise to several sensations ranging from mild fullness to pain.

Ureteric afferents were thinly myelinated or unmyelinated, and responded to direct probing of a limited area of tissue. Two populations of afferents were distinguished by Cervero and Jänig (22). The first responded to contractions of the ureter and could also be excited by low levels of distension (average threshold 8 mmHg). They appeared to encode levels of distension throughout and beyond the physiological range. The second group did not respond to peristaltic contractions of the ureter, but they could be excited by distension with a wide range of thresholds. When ureters were perfused intraluminally, higher pressure thresholds were seen, although some at least still appeared to respond to distension to only 10 mmHg (22).

Systemic administration of morphine, a ?-opiate receptor agonist, produces a dose-dependent decrease of pain caused by ureteric distension (23).

Urinary bladder

Two distinct groups of afferent fibres capable of signalling noxious stimuli have been identified in the urinary bladder. Most visceral afferents from the urinary bladder are unmyelinated fibres, although a population of myelinated A-fibres is also present (19). The majority of visceral primary afferents from the bladder, urethra, and reproductive and other pelvic organs encode for both noxious and non-noxious stimuli (19-21).

Graded distension of the healthy urinary bladder in humans initially gives rise to a sensation of fullness and eventually pain as volume increases and intravesical pressure exceeds about 25-35 mmHg (24-27). In the inflamed bladder, the sensations during bladder emptying become unpleasant and painful. Nearly all afferents are small, myelinated or unmyelinated, and travel with sympathetic (hypogastric) or parasympathetic (pelvic) nerves. Some exhibit a low level of ongoing discharge when the bladder is empty. Distension excited mainly thin myelinated afferents, with pressure thresholds corresponding to the values where humans report the first sensation of fullness. Nearly all units were activated by the intraluminal pressures reached during normal, non-painful micturition. The activation of a numerically significant population of initially unresponsive afferents indicates that peripheral afferent mechanisms encoding pain from pelvic viscera are highly malleable, and are strongly affected by the state of the tissue. These peripheral changes are obviously likely to be important for signalling pain and discomfort in inflammatory conditions.

Male reproductive organs

The sensory innervation of the testes (dog model) shows that more than 95% of the fibres of the superior spermatic nerve are unmyelinated, with the great majority having polymodal properties (i.e. responding to mechanical, chemical and thermal stimuli) (28). Myelinated and unmyelinated afferents fibres form a homogeneous group with polymodal receptors in testis and/or epididymis. Prostaglandins did not excite but sensitised the afferents to other stimuli (29).

2.6 Pain evaluation and measurement

2.6.1 Pain evaluation

Health professionals should ask about pain, and the patient’s self-report should be the primary source of assessment. Clinicians should assess pain with easily administered rating scales, and should document the efficacy of pain relief at regular intervals after starting or changing treatment.

Systematic evaluation of pain involves the following steps.

• Evaluate its severity.

• Take a detailed history of the pain, including an assessment of its intensity and character.

• Evaluate the psychological state of the patient, including an assessment of mood and coping responses.

• Perform a physical examination, emphasising the neurological examination.

• Perform an appropriate diagnostic work-up to determine the cause of the pain, which may include tumour markers.

• Perform radiological studies, scans, etc.

• Re-evaluate therapy.

The initial evaluation of pain should include a description of the pain using the PQRST characteristics:

P Palliative or provocative factors: ‘What makes it less intense?’

Q Quality: ‘What is it like?’

R Radiation: ‘Does it spread anywhere else?’

S Severity: ‘How severe is it?’

T Temporal factors: ‘Is it there all the time, or does it come and go?’

Pain in patients with cancer is a complex phenomenon consisting of many different aspects. Not all pains will be of malignant origin. For example, cancer patients might have pain from arthritis or cervical spondylosis. They will often have more than one pain problem, and each pain must be individually assessed and evaluated. Some pains may be due to muscular spasm rather than the cancer itself. A key principle is constantly to re-evaluate pain and the effect and side-effects of analgesic therapy.

Pain in cancer patients could be caused by the cancer itself (e.g. tumour pressure on nerve plexus or tumour infiltration), or could be due to secondary muscular spasm. In addition, pain could be secondary to cancer treatments, e.g. radiation-induced brachial plexopathy, or might have no relation to the cancer, e.g. arthritis. In general, cancer pain consists of two broad diagnostic types: nociceptive and neuropathic pain.

When evaluating pain, it is useful to try to determine whether the pain is one of these types or a mixture of the two. Nociceptive pain includes bone pain and soft tissue pain. Typically it is described as a dull, aching pain. This type of pain will be largely sensitive to non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. Neuropathic pain is pain as a result of damage to the peripheral or central nervous system. It is usually described as a burning or sharp, shooting pain. Neuropathic pain is usually not particularly responsive to NSAIDs or opioids. Adjuvant analgesics such as anti-depressants and anti-convulsants should be used in the first instance.

2.6.2 Assessing pain intensity and quality of life (QoL)

There are several ratings scales available to assess pain. There are single-item ratings of pain intensity and pain relief such as the visual analogue scale (unidimensional) or the verbal rating scale, and multiple-item assessments (multidimensional) that measure not only pain intensity but also additional dimensions of the pain experience, including emotional, affective, cognitive and social items (quality of life questionnaires).

Rating pain using a visual analogue scale (VAS, Figure 1) or collection of VAS scales (such as the brief pain inventory) is an essential part of pain assessment. It allows some form of comparison to be made, and facilitates assessment of the efficacy of treatment. The ease of use (and ease of analysis) of the VAS has resulted in its widespread adoption for the measurement of pain intensity in clinical studies. In addition, the VAS score for pain intensity has consistently demonstrated sensitivity to changes in pain levels associated with treatment, especially in acute pain states.

Although the VAS appears to be an attractive method to evaluate pain intensity and changes in pain, there are, however, several limitations for this measurement tool for assessing chronic pain. In chronic pain syndromes, the VAS has shown significant weakness in sensitivity owing to large variability between subjects, probably because of emotional, affective, and cognitive responses to pain together with behavioural and cultural biases, items that are not measured by a unidimensional tool. In addition, increased age and a greater amount of opioid consumption have been shown to be associated with a higher failure rate with the VAS score for measurement of pain intensity.

Figure 1: Visual analogue scale

0 —————————————————————————————————————————- 10

Visual analogue scale

Describe your pain on a scale of 0 to 10

No Mild Moderate Severe Worst

pain possible

pain

0 1 2 3 4 5 6 7 8 9 10

| | | | | | | | | | |

To study the effects of both physical and non-physical influences on patient well-being, an instrument must assess more dimensions than the intensity of pain or other physical symptoms. Several validated questionnaires to assess various quality of life dimensions are available, including the Medical Outcomes Short-Form Health Survey Questionnaire 36 (SF-36), and the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) (30-34).

2.7 References

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3. Woolf CJ. Pain: moving from symptom control toward mechanism-specific pharmacologic management. Ann Intern Med 2004 Mar;140(6):441-51.

http://www.ncbi.nlm.nih.gov/pubmed/15023710

4. Scholtz J, Woolf CJ. Can we conquer pain? Nat Neurosci 2002 Nov;5 Suppl:1062-7.

http://www.ncbi.nlm.nih.gov/pubmed/12403987

5. Wiertelak EP, Smith KP, Furness L, Mooney-Heiberger K, Mayr T, Maier SF, Watkins LR. Acute and conditioned hyperalgesic responses to illness. Pain 1994 Feb;56(2):227-34.

http://www.ncbi.nlm.nih.gov/pubmed/8008412

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http://www.ncbi.nlm.nih.gov/pubmed/9520239

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http://www.ncbi.nlm.nih.gov/pubmed/10335806

8. Cassel EJ. The nature of suffering. N Eng J Med 1982 Mar;306(11):639-45.

http://www.ncbi.nlm.nih.gov/pubmed/7057823

9. Belemonte C, Cervero F. Neurobiology of Nociceptors. Oxford: Oxford University Press, 1996.

10. Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature 2001 Sep;413(6852):203-10.

http://www.ncbi.nlm.nih.gov/pubmed/11557989

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http://www.ncbi.nlm.nih.gov/pubmed/9013357

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http://www.ncbi.nlm.nih.gov/pubmed/15246335

13. Westlund KN. Visceral nociception. Curr Rev Pain 2000;4(6):478-87.

http://www.ncbi.nlm.nih.gov/pubmed/11060594

14. Millan MJ. The induction of pain: an integrative review. Prog Neurobiol 1999 Jan;57(1):1-164.

http://www.ncbi.nlm.nih.gov/pubmed/9987804

15. Apkarian AV, Bushnell MC, Treede RD, Zubieta JK. Human brain mechanisms of pain perception and regulation in health and disease. Eur J Pain 2005 Aug;9(4):463-84.

http://www.ncbi.nlm.nih.gov/pubmed/15979027

16. Chong MS, Bajwa ZH. Diagnosis and treatment of neuropathic pain. J Pain Symptom Manage 2003 May;25(5 Suppl):S4-S11.

http://www.ncbi.nlm.nih.gov/pubmed/12694987

17. Rasmussen PV, Sindrup SH, Jensen TS, Bach FW. Symptoms and signs in patients with suspected neuropathic pain. Pain 2004 Jul;110(1-2):461-9.

http://www.ncbi.nlm.nih.gov/pubmed/15275799

18. Besson JM. The neurobiology of pain. Lancet 1999 May;353(9164):1610-15.

http://www.ncbi.nlm.nih.gov/pubmed/10334274

19. Häbler HJ, Jänig W, Koltzenburg M. Activation of unmyelinated afferent fibres by mechanical stimuli and inflammation of the urinary bladder in the cat. J Physiol 1990 Jun;425:545-62.

http://www.ncbi.nlm.nih.gov/pubmed/2213588

20. Bahns E, Ernsberger U, Jänig W, Nelke A. Functional characteristics of lumbar visceral afferent fibres from the urinary bladder and the urethra in the cat. Pflügers Arch 1986 Nov;407(5):510-18.

http://www.ncbi.nlm.nih.gov/pubmed/3786110

21. Bahns E, Halsband U, Jänig W. Responses of sacral visceral afferent fibres from the lower urinary tract, colon, and anus to mechanical stimulation. Pflügers Arch 1987 Oct;410(3):296-303.

http://www.ncbi.nlm.nih.gov/pubmed/3684516

22. Cervero F, Jänig W. Visceral nociceptors: A new world order?. Trends Neurosci. 1992 Oct;15(10):
374-8.

http://www.ncbi.nlm.nih.gov/pubmed/1279857

23. Roza C, Laird JM. Pressor responses to distension of the ureter in anaesthetised rats: characterisation of a model of acute visceral pain.

Neurosci Lett 1995 Sep 22;198(1):9-12.

24. Roberts WJ, Elardo SM. Sympathetic activation of A-delta nociceptors. Somatosens Res 1985;3(1):
33-44.

http://www.ncbi.nlm.nih.gov/pubmed/2999942

25. Seltzer Z, Devor M. Ephaptic transmission in chronically damaged peripheral nerves. Neurology 1979 Jul;29(7):1061-4.

http://www.ncbi.nlm.nih.gov/pubmed/224343

26. Kruger L, Perl ER, Sedivec MJ. Fine structure of myelinated mechanical nociceptor endings in cat hairy skin. J Comp Neurol 1981 May;198(1):137-54.

http://www.ncbi.nlm.nih.gov/pubmed/7229137

27. Treede R-D, Meyer RA, Raja SN, Campbell JN. Peripheral and central mechanisms of cutaneous hyperalgesia. Prog Neurobiol 1992;38(4):397-421.

http://www.ncbi.nlm.nih.gov/pubmed/1574584

28. Kumazawa T. Sensory innervation of reproductive organs. Prog Brain Res 1986;67:115-31.

http://www.ncbi.nlm.nih.gov/pubmed/3823468

29. Meyer RA, Campbell JN, Raja SN. Peripheral neural mechanisms of nociception In: Wall PD, Melzack R (eds). Textbook of Pain. 3rd ed. Edinburgh: Churchill Livingston, 1994, pp. 13-44.

30. Jensen MP. The validity and reliability of pain measures in adults with cancer. J Pain 2003 Feb;4(1):
2-21.

http://www.ncbi.nlm.nih.gov/pubmed/14622723

31. Rosier EM, Iadarola MJ, Coghill RC. Reproducibility of pain measurement and pain perception. Pain 2002 Jul;98(1-2):205-16.

http://www.ncbi.nlm.nih.gov/pubmed/12098633

32. Fosnocht DE, Chapman CR, Swanson ER, Donaldson GW. Correlation of change in visual analog scale with pain relief in the ED. Am J Emerg Med 2005 Jan;23(1):55-9.

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33. Graham B. Generic health instruments, visual analog scales, and the measurement of clinical phenomena. J Rheumatol 1999 May;26(5):1022-3.

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34. Scott DL, Garrood T. Quality of life measures: use and abuse. Ballieres Best Pract Research Clinical Rheumatol 2000 Dec;14(4):663-87.

http://www.ncbi.nlm.nih.gov/pubmed/11092795

3. CANCER PAIN MANAGEMENT (GENERAL)

3.1 Classification of cancer pain

Figure 2 shows the classification of cancer pain.

Figure 2: Classification of cancer pain

Bone

Nociceptive Soft tissue

Viscus (e.g. bowel, bladder)

Pain

Neuropathic Nerve compression

Nerve infiltration

Urogenital neoplasms frequently metastasise to bone (e.g. spine, pelvis, skull), and such bone metastases are associated with pathological fractures, hypercalcaemia and neurological deficits, leading to substantial impairment of quality of life. The release of algogenic substances in the tissue, microfractures and periosteal tension are the main mechanism for pain sensation (1).

Pain caused by bone metastases is nociceptive pain, but can become associated with neuropathic pain if the tumour invades or compresses a nerve, neural plexus or spinal cord. One-third of patients with tumour-related pain are affected by neuropathic pain components (2). Nociceptive pain is well localised. Initially it occurs on physical movement, but later might also occur at rest.

Neuropathic pain frequently has a constant ‘burning’ character. The efficacy of opioids may be diminished in neuropathic pain, and hence additional co-analgesics are necessary (3). Patients with severe neuropathic pain are a special challenge. Psychological changes frequently occur and specific therapeutic intervention may be necessary (4).

The WHO recommends a stepwise scheme for the treatment of cancer pain syndromes and for neoplastic bone pain. Bisphosphonates and calcitonin are helpful for stabilising bone metabolism. Epidural and intrathecal opioids are sometimes useful in managing bone pain from metastases. Nerve destruction by intrathecal or epidural phenol is sometimes useful in selected patients with neuropathic pain (5).

3.1.1 References

1. Mercadante S. Malignant bone pain: pathophysiology and treatment. Pain 1997 Jan;69(1-2):1-18.

http://www.ncbi.nlm.nih.gov/pubmed/9060007

2. Grond S, Zech D, Diefenbach C, Radbruch L, Lehmann KA. Assessment of cancer pain: a prospective evaluation of 2266 cancer patients referred to a pain service. Pain 1996 Jan;64(1):107-14.

http://www.ncbi.nlm.nih.gov/pubmed/8867252

3. Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain 1999 Dec;83(3):389-400.

http://www.ncbi.nlm.nih.gov/pubmed/10568846

4. Mercadante S, Portenoy RK. Opioid poorly-responsive cancer pain. Part 3. Clinical strategies to improve opioid responsiveness. J Pain Symptom Manage 2001 Apr;21(4):338-54.

http://www.ncbi.nlm.nih.gov/pubmed/11312049

5. Stevens RA, Stotz A. Neurolytic blocks for management of oncologic pain. Cancer Res Ther Control 1999;9:345-53.

3.2 General principles of cancer pain management

The therapeutic strategy depends on the four goals of care:

1. Prolonging survival

2. Optimising comfort

3. Optimising function

4. Relieving pain (Figure 3).

Figure 3: Tumour pain helix

Pain

Escalation Sleeplessness

Depression Worries

Hopelessness Despair

Isolation

The hierarchy of general treatment principles in Table 3 is intended to offer guidance through the decision-making process.

Table 3: Hierarchy of general treatment principles

The guiding principle of care is the individualisation of therapy. Through a process of repeated evaluations, the selection and administration of therapy is individualised so that a favourable balance between pain relief and adverse effects is achieved and maintained.

The next steps in the hierarchy, especially points 2 to 4, necessitate a continuing risk-to-benefit assessment between therapeutic outcome versus tolerability and willingness to accept adverse effects.

The more invasive the therapy, the more difficult the decisions become. This is particularly true of palliative medicine, since here there are limited prospects of healing and there is also the problem of working against time.

If local therapy is not feasible or cannot be well tolerated, then symptomatic measures are appropriate, although local therapy is to be given preference over systemic treatment. In simple cases, measures such as drainage and stenting can make analgesic medication redundant. Examples include inserting a gastric probe, a ureteral stent, a percutaneous nephrostomy, or a bladder catheter. To cite another example, patients who receive an artificial anus due to recurrent subileus caused by peritoneal carcinomatosis are relieved of their pain immediately.

The indication stands in direct relation to the severity of the disease and the operation, especially if there are no prospects of healing. Cases such as these, however, are sometimes in particular need of the invasive measures described above. This is not only to relieve pain for the rest of the patient’s days, but also to improve the general quality of life, even though invasive operations may also have a negative impact on the patient’s well-being. Examples can include evisceration to prevent cloaca in cervical carcinoma, or implanting a prosthetic hip due to a pathological fracture originating in metastasised bladder or kidney cancer.

A gradual strategy (level of evidence: 4) can be considered when dose escalation of a systemically administered opioid fails to yield a satisfactory result. The steps to follow are as follows.

• Switch to another opioid

• Intervene with an appropriate primary therapy or other non-invasive analgesic approach

• Pursue psychological, rehabilitative and neurostimulatory techniques (e.g. transcutaneous electrical nerve stimulation)

• Use invasive analgesic techniques. This approach should be based on a careful evaluation of the likelihood and duration of the analgesic benefit, the immediate risks, and the morbidity of the procedure (epidural infusion)

• Use neurodestructive procedures (chemical or surgical neurolysis, coeliac plexus blockade)

• Finally, some patients with advanced cancer who have comfort as the overriding goal of care, can elect to be deeply sedated.

As is widely discussed in pain-management literature, the importance of physiotherapy and psychological counselling cannot be emphasised too strongly. For further discussion of these points see the sections above.

In conclusion, pain management can be highly effective, especially when interdisciplinary co-operation occurs: pain can be overcome.

3.3 Non-pharmacological therapies

3.3.1 Surgery

Surgery may have a role in the relief of symptoms caused by specific problems, such as obstruction of a hollow viscus, unstable bony structures and compression of neural tissues or draining of symptomatic ascites (1-3). The potential benefits must be weighed against the risks of surgery, the anticipated length of hospitalisation and convalescence, and the predicted duration of benefit. Radical surgery to excise locally advanced disease in patients with no evidence of metastatic spread may be palliative, and potentially increase the survival of some patients (4) (level of evidence: 2b).

3.3.1.1 References

1. Williams MR. The place of surgery in terminal care. In: Saunders C (ed) The management of terminal disease. London: Edward Arnold, 1984; pp. 148-153.

2. Boraas M. Palliative surgery. Semin Oncol 1985 Dec;12(4):368-74.

http://www.ncbi.nlm.nih.gov/pubmed/2417321

3. Sundaresan N, DiGiacinto GV. Antitumor and antinociceptive approaches to control cancer pain. Med Clin North Am 1987 Mar;71(2):329-48.

http://www.ncbi.nlm.nih.gov/pubmed/2881035

4. Temple WJ, Ketcham AS. Sacral resection for control of pelvic tumours. Am J Surg 1992 Apr;
163(4):370-4.

http://www.ncbi.nlm.nih.gov/pubmed/1373043

3.3.2 Radionuclides

3.3.2.1 Clinical background

Bone metastases are the most frequent source of pain during the evolution of cancers (1).

Approximately 30% of patients with osseous metastases have such a degree of pain that analgesics are required and day-to-day activities are disturbed (1): the pain interferes with patients’ quality of life, causing anxiety, isolation, immobility, depression and sleeplessness.

In single lesions, bone stability and pain reduction can be achieved by external beam radiotherapy (level of evidence: Ib; grade of recommendation: A). About 80-90% of these patients will experience durable pain relief, but many will further develop multiple painful metastases (1)

3.3.2.2 Radiopharmaceuticals: physical characteristics

The main physical characteristics of radiopharmaceuticals are as follows.

• 89Sr (strontium-89 chloride) emits a beta particle with a maximum energy of 1.46 MeV, a mean energy of 0.58 MeV, an average soft-tissue range of 2.4 mm and 0.01% abundant gamma emission with a 0.91 MeV photopeak. The physical half-life is 50.5 days (2, 3).

• 153Sm (samarium-153 lexidronam) emits a beta particle with a maximum energy of 0.81 MeV, a mean energy of 0.23 MeV, an average soft-tissue range of 0.6 mm and 28% abundant 0.103 MeV gamma emission with a 0.103-MeV photo peak. The physical half-life is 1.9 days (4).

• 186Re (renium-186 etidronate) emits a beta particle with a maximum energy of 1.07 MeV, a mean energy of 0.349 MeV, an average soft-tissue range of 1.1 mm and a 9% abundant gamma emission with a 0.137–Mev photopeak. The physical half-life is 3.7 days (5).

• Therapy in this context means the intravenous administration of 89Sr chloride or 153Sm lexidronam (153Sm ethylenediaminetetramethylenephosphonate [EDTMP]).

The most important radiopharmaceuticals are 89Sr (strontium-89 chloride), 153Sm (samarium-153 lexidronam) and, to a lesser extent, 186Re (renium-186 etidronate).

There is no clear difference in treatment response between 89Sr, 153Sm and 186Re (2). However, in view of the half-life of the different isotopes, there is a difference in onset of response, duration of response and toxixity. For 153Sm and 186Re, the onset of response is rapid but duration is shorter (6, 7). Note that 186Re is no longer used in many European countries.

3.3.2.3 Indications and contraindications

89Sr and 153Sm lexidronam are indicated for the treatment of bone pain resulting from skeletal metastases involving more than one site and associated with an osteoblastic response on bone scan but without spinal cord compression (1,8-15) (level of evidence: 2, grade of recommendation: B).

89Sr and 153Sm lexidronam have no place in the management of acute or chronic spinal cord compression or in treating pathological fracture (1,8,11) (level of evidence: 2, grade of recommendation: B).