1 - Pain - Management - LR PDF

Guidelines on
Pain
Management &
Palliative Care
A. Paez Borda (chair), F. Charnay-Sonnek, V. Fonteyne,
E.G. Papaioannou
European Association of Urology 2013
Table of Contents
1.

Page
INTRODUCTION
1.1
The Guideline
1.2
Methodology
1.3
Publication history
1.4
Acknowledgements
1.5
Level of evidence and grade of guideline recommendations*
1.6
References
2.
BACKGROUND

2.1
Definition of pain

2.2
Pain evaluation and measurement

2.2.1 Pain evaluation

2.2.2 Assessing pain intensity and quality of life (QoL)

2.3
References
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3.
CANCER PAIN MANAGEMENT (GENERAL)

3.1
Classification of cancer pain

3.2
General principles of cancer pain management

3.3
Non-pharmacological therapies

3.3.1 Surgery

3.3.2 Radionuclides

3.3.2.1 Clinical background

3.3.2.2 Radiopharmaceuticals

3.3.3 Radiotherapy for metastatic bone pain


3.3.3.2 Radiotherapy scheme

3.3.3.3 Spinal cord compression

3.3.3.4 Pathological fractures

3.3.3.5 Side effects

3.3.4 Psychological and adjunctive therapy

3.3.4.1 Psychological therapies

3.3.4.2 Adjunctive therapy

3.4
Pharmacotherapy

3.4.1 Chemotherapy

3.4.2 Bisphosphonates

3.4.2.1 Mechanisms of action

3.4.2.2 Effects and side effects

3.4.3 Denosumab

3.4.4 Systemic analgesic pharmacotherapy - the analgesic ladder

3.4.4.1 Non-opioid analgesics

3.4.4.2 Opioid analgesics

3.4.5 Treatment of neuropathic pain

3.4.5.1 Antidepressants

3.4.5.2 Anticonvulsant medication

3.4.5.3 Local analgesics

3.4.5.4 NMDA receptor antagonists

3.4.5.5 Other drug treatments

3.4.5.6 Invasive analgesic techniques

3.4.6 Breakthrough cancer pain

3.5
Quality of life (QoL)

3.6
Conclusions

3.7
References
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4.
PAIN MANAGEMENT IN UROLOGICAL CANCERS

4.1
Pain management in prostate cancer patients

4.1.1 Clinical presentation

4.1.2 Pain due to local impairment

4.1.2.1 Invasion of soft tissue or a hollow viscus
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PAIN MANAGEMENT & PALLIATIVE CARE - UPDATE MARCH 2013

4.1.2.2 Bladder outlet obstruction

4.1.2.3 Ureteric obstruction

4.1.2.4 Lymphoedema

4.1.2.5 Ileus

4.1.3 Pain due to metastases

4.1.3.1 Bone metastases

4.1.3.2 Hormone therapy

4.1.3.3 Radiotherapy

4.1.3.4 Orthopaedic surgery

4.1.3.5 Radioisotopes

4.1.3.6 Bisphosphonates

4.1.3.7 Denosumab

4.1.3.8 Calcitonin

4.1.3.9 Chemotherapy

4.1.3.10 Systemic analgesic pharmacotherapy (the analgesic ladder)

4.1.4 Spinal cord compression

4.1.5 Hepatic invasion

4.1.6 Pain due to cancer treatment

4.1.6.1 Acute pain associated with hormonal therapy

4.1.6.2 Chronic pain associated with hormonal therapy

4.1.7 Recommendations at a glance (stage M1) (60-65)

4.2
Pain management in transitional cell carcinoma patients


4.2.2 Origin of tumour-related pain

4.2.2.1 Bladder TCC

4.2.2.2 Upper urinary tract TCC


4.2.3.1 Bladder TCC



4.2.5 Conclusion for symptomatic locally advanced or metastatic urothelial cancer

4.3.
Pain management in renal cell carcinoma patients




4.4
Pain management in patients with adrenal carcinoma

4.4.1 Malignant phaeochromocytoma

4.4.2
Treatment of pain

4.4.2.1 Adrenocortical carcinomas

4.4.2.2 Treatment of the pain depending on its origin

4.5
Pain management in penile cancer patients



4.5.3 Lymphoedema


4.5.5 Conclusions

4.6
Pain management in testicular cancer patients




4.7
Recommendations at a glance

4.8
References
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5.
POSTOPERATIVE PAIN MANAGEMENT

5.1
Background

5.2
Importance of effective postoperative pain management

5.2.1 Aims of effective postoperative pain management

5.3
Pre- and postoperative pain management methods

5.3.1 Preoperative patient preparation

5.3.2 Pain assessment
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5.3.3 Pre-emptive analgesia

5.3.4 Systemic analgesic techniques

5.3.4.1 Non-steroidal anti-inflammatory drugs

5.3.4.2 Paracetamol

5.3.4.3 Metamizole (dipyrone)

5.3.4.4 Opioids

5.3.4.5 Patient-controlled analgesia

5.3.4.6 Adjuncts to postoperative analgesia

5.3.5 Regional analgesic techniques

5.3.5.1 Local anaesthetic agents

5.3.5.2 Epidural analgesia

5.3.5.3 Patient-controlled epidural analgesia

5.3.5.4 Neural blocks

5.3.5.5 Wound infiltration

5.3.5.6 Continuous wound instillation

5.3.6 Multimodal analgesia

5.3.7 Special populations

5.3.7.1 Ambulatory surgical patients

5.3.7.2 Geriatric patients

5.3.7.3 Obese patients

5.3.7.4 Drug- or alcohol-dependent patients

5.3.7.5 Other groups

5.3.8 Postoperative pain management teams

5.4
Specific pain treatment after different urological operations

5.4.1 Extracorporeal shock wave lithotripsy

5.4.2 Endoscopic procedures

5.4.2.1 Transurethral procedures

5.4.2.2 Percutaneous endoscopic procedures

5.4.2.3 Laparoscopic procedures

5.4.3
Open surgery

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

5.4.3.2 Transvaginal surgery

5.4.3.3 Perineal open surgery

5.4.3.4 Transperitoneal laparotomy

5.4.3.5 Suprapubic/retropubic extraperitoneal laparotomy

5.4.3.6 Retroperitoneal approach - flank incision - thoracoabdominal approach

5.5
Dosage and method of delivery of some important analgesics

5.5.1 NSAIDs

5.5.2 Opioids

5.6
Perioperative pain management in children

5.6.1 Perioperative problems

5.6.2 Postoperative analgesia

5.7
References
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6.
NON-TRAUMATIC ACUTE FLANK PAIN

6.1
Background

6.2
Initial diagnostic approach

6.2.1 Symptomatology

6.2.2 Laboratory evaluation

6.2.3 Diagnostic imaging

6.2.3.1 Ultrasonography

6.2.3.2 Intravenous urography

6.2.3.3 Unenhanced helical CT

6.3
Initial emergency treatment

6.3.1 Systemic analgesia

6.3.2 Local analgesia

6.3.3 Supportive therapy

6.3.4 Upper urinary tract decompression

6.4
Aetiological treatment

6.4.1 Urolithiasis
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6.4.2 Infectious conditions

6.4.3 Other conditions

6.4.3.1 Ureteropelvic junction obstruction

6.4.3.2 Papillary necrosis

6.4.3.3 Renal infarction

6.4.3.4 Renal vein thrombosis

6.4.3.5 Intra- or perirenal bleeding

6.4.3.6 Testicular cord torsion

6.5
References
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7.
PALLIATIVE CARE

7.1
Background

7.2
Definition and aim of palliative care

7.3
General principles

7.3.1 Communication

7.3.2 Patient-centred treatment

7.3.3 Cultural and spiritual approach

7.3.4 Multidisciplinary approach

7.3.5 Can anyone provide palliative care? Health care staff and advanced
urological diseases

7.4
Treatment of physical symptoms

7.4.1 Pain

7.4.2 Dyspnoea and respiratory symptoms

7.4.3 Cancer anorexia-cachexia syndrome

7.4.4 Vomiting

7.4.5 Other symptoms

7.4.5.1 Fatigue

7.4.5.2 Restlessness

7.4.5.3 Agitated delirium

7.4.5.4 Constipation

7.4.5.5 Anxiety

7.5
Terminal care

7.5.1 When and how to withdraw specific treatment

7.5.2 Parenteral hydration: should it be discontinued in the terminal phases?

7.5.3 Palliative sedation

7.6
Treatment of psychological aspects

7.6.1 Fear

7.6.2 Depression

7.6.3 Family care

7.6.4 Communication of bad news

7.7
References
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ABBREVIATIONS USED IN THE TEXT
1. INTRODUCTION
1.1
The Guideline
The new European Association of Urology (EAU) Guidelines expert panel for Pain Management and Palliative
Care have prepared this guidelines document to assist medical professionals in appraising the evidence-based
management of pain and palliation in urological practice. These guidelines include general advice on pain
assessment and palliation, with a focus on treatment strategies relating to common medical conditions and
painful procedures.
The multidisciplinary panel of experts responsible for this document include a urologist, a radiotherapistoncologist, an anaesthesiologist and a nurse specialised in palliative care.
1.2
Methodology
The recommendations provided in the current guidelines are based on systematic literature search using
Embase/Medline and the Cochrane Central Register of Controlled Trials.
It has to be emphasised that these guidelines contain information for the treatment of an individual patient
according to a standardised general approach.
1.3
Publication history
The Pain Management Guidelines were first published in 2003, with a partial update in 2007, followed by a
full text update in 2009. In 2010 two new topics were added, Section 5.6 Perioperative pain management in
children and Chapter 6 Non-traumatic acute flank pain. The quick reference guide was completely reworked.
In the 2011 print all chapters were abridged.
The current 2013 edition contains partial updates based on the available literature. Section 3.5 on Palliative
Care was moved and expanded to a new Chapter 7, which deals with the subject of Palliative Care.
A quick reference document presenting the main findings of the former Pain Management guidelines is also
available. All texts can be viewed and downloaded for personal use at the EAU website:
http://www.uroweb.org/guidelines/online-guidelines/
1.4 Acknowledgements
The Expert Panel would like to express its gratitude to Dr. Juan Guerra Martnez (JGM), medical oncologist
at the University Hospital of Fuenlabrada, Spain, for his guidance on palliation matters. His assistance and
expertise proved most valuable.
1.5 Level of evidence and grade of guideline recommendations*

References used in the text have been assessed according to their level of scientific evidence (Table 1) and
guideline recommendations have been graded (Table 2) according to the Oxford Centre for Evidence-based
Medicine Levels of Evidence (1). The aim of grading recommendations is to provide transparency between the
underlying evidence and the recommendation given.
Table 1: Level of evidence (LE)*
LE
1a
1b
2a
2b
3
4
Type of evidence
Evidence obtained from meta-analysis of randomised trials
Evidence obtained from at least one randomised trial
Evidence obtained from one well-designed controlled study without randomisation
Evidence obtained from at least one other type of well-designed quasi-experimental study
Evidence obtained from well-designed non-experimental studies, such as comparative studies,
correlation studies and case reports
Evidence obtained from expert committee reports or opinions or clinical experience of respected
authorities
*Modified from Sackett et al. (1).

It should be noted that when recommendations are graded, the link between the level of evidence and grade
of recommendation is not directly linear. Availability of randomised controlled trials (RCTs) may not necessarily
translate into a grade A recommendation where there are methodological limitations or disparity in published
results.
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Alternatively, absence of high level evidence does not necessarily preclude a grade A recommendation, if there
is overwhelming clinical experience and consensus. In addition, there may be exceptional situations where
corroborating studies cannot be performed, perhaps for ethical or other reasons and in this case unequivocal
recommendations are considered helpful for the reader. The quality of the underlying scientific evidence although a very important factor - has to be balanced against benefits and burdens, values and preferences
and cost when a grade is assigned (2-4).
The EAU Guidelines Office does not perform cost assessments, nor can it address local/national preferences
in a systematic fashion. However, whenever these data are available, the expert panels will include the
information.
Table 2: Grade of recommendation (GR)*
GR
A
B
C
Nature of recommendations
Based on clinical studies of good quality and consistency addressing the specific recommendations
and including at least one randomised trial
Based on well-conducted clinical studies, but without randomised clinical trials
Made despite the absence of directly applicable clinical studies of good quality
*Modified from Sackett et al. (1).
1.6
References
1.
Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2009). Produced by Bob
Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since
November 1998. Updated by Jeremy Howick March 2009.
http://www.cebm.net/index.aspx?o=1025 (Access date February 2013)
Atkins D, Best D, Briss PA, et al; GRADE Working Group. Grading quality of evidence and strength of
recommendations. BMJ 2004 Jun 19;328(7454):1490.
http://www.ncbi.nlm.nih.gov/pubmed/15205295
Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence
and strength of recommendations. BMJ 2008;336(7650):924-6.
Guyatt GH, Oxman AD, Kunz R, et al; GRADE Working Group. Going from evidence to
recommendations. BMJ 2008 May 10;336(7652):1049-51.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2376019/?tool=pubmed
2.
3.
4.
2. BACKGROUND
2.1
Definition of pain
Pain is the most common symptom of any illness, and is defined by the International Association for the Study
of Pain (IASP) as 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, and is intended to keep tissue damage to a
minimum. The capacity to experience pain has a protective role. If tissue damage is unavoidable, a cascade of
changes occurs in the peripheral and central nervous system (CNS) responsible for the perception of pain (2).
Acute pain has a time-limited course during which treatment, if necessary, is aimed at correcting the underlying
pathological process. In contrast, maladaptive (pathological) pain offers no biological advantage because it
is uncoupled from a noxious stimulus or tissue healing, and is usually persistent or recurrent. It may occur in
response to damage to the nervous system. It is known as neuropathic pain, and is pain as a disease
(3-5).
2.2
Pain evaluation and measurement
2.2.1 Pain evaluation

Health professionals should ask about pain, and the patients 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 OPQRSTUV characteristics:
O
Onset: When did it start? How long does it last? How often does it occur?
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?
U
Understanding/Impact on you

-
What do you believe is causing this symptom?

-
How is this symptom affecting you and/or your family?
V
Values

-
What is your goal for this symptom?

- What is your comfort goal or acceptable level for this symptom (on a scale of 0 - 10 with 0
being none and 10 being the worst possible)?

- Are there any other views or feelings about this symptom that are important to you or your
family?
Pain in patients with cancer is a complex phenomenon. Not all pain is of malignant origin. Patients often have
more than one pain problem, and each must be individually assessed and evaluated. A key principle is to
constantly re-evaluate pain and the effects and side effects of analgesic therapy.
Pain in cancer patients could be caused by the cancer itself, be due to secondary muscular spasm, be
secondary to cancer treatments, or 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 results from damage to the peripheral or CNS. 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 anticonvulsants should be used in the first instance.
2.2.2 Assessing pain intensity and quality of life (QoL)
There are several rating scales available to assess pain. Rating pain using a visual analogue scale (VAS) or
collection of VAS scales (such as the brief pain inventory) is an essential part of pain assessment. Its
ease of use and analysis has resulted in its widespread adoption. It is, however, limited for the assessment of
chronic pain.
Figure 1: Pain assessment scales

0 - 10

Visual analogue scale
Describe your pain on a scale of 0 to 10

No
Mild
Moderate
Severe

pain

3
|
4
|
5
|
6
|
7
|
2
|
1
|
0
|
Worst
possible
pain
8
|
9
|
10
|
Other common ways of pain assessment are numerical scales (NRS rating 1-10, Faces- Wong Baker scale,
mostly used in children and verbal scales (rating from absence to severe pain) (Figure 1). To study the effects
of both physical and non-physical influences on patient wellbeing, an instrument must assess more dimensions
than the intensity of pain or other physical symptoms. Several validated questionnaires to assess various QoL
dimensions are available, including the Medical Outcomes Short-Form Health Survey Questionnaire 36 (SF36), and the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire
(EORTC QLQ-C30) (6-10).
For cognitively impaired and elderly patients Doloplus-2 offers pain assessment by rating somatic,
psychomotor and psychosocial behaviour. The tool consists of 10 items with four behavioural descriptions
representing increasing severity of pain from 0 to 3. Individual item scores are summed to arrive at a total score
ranging from 0 to 30 points. Five points is the threshold indicating pain (11).
2.3
References
1.
Merskey H, Bogduk N (eds). Classification of chronic pain: descriptions of chronic pain syndromes
and definitions of pain terms. Seattle: IASP Press,1994.
Jacobson L, Mariano AJ. General considerations of chronic pain. In: Loeser JD, ed. Bonicas
Management of Pain. Philadelphia: Lippincott Williams & Wilkins, 2001, pp. 241-254.
Scholtz J, Woolf CJ. Can we conquer pain? Nat Neurosci 2002 Nov;5 Suppl:1062-7.
Wiertelak EP, Smith KP, Furness L, et al. Acute and conditioned hyperalgesic responses to illness.
Pain 1994 Feb;56(2):227-34.
Woolf CJ. Pain: moving from symptom control toward mechanism-specific pharmacologic
management. Ann Intern Med 2004 Mar;140(6):441-51.
Fosnocht DE, Chapman CR, Swanson ER, et al. Correlation of change in visual analog scale with pain
relief in the ED. Am J Emerg Med 2005 Jan;23(1):55-9.
Graham B. Generic health instruments, visual analog scales, and the measurement of clinical
phenomena. J Rheumatol 1999 May;26(5):1022-3.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Jensen MP. The validity and reliability of pain measures in adults with cancer. J Pain 2003 Feb;4(1):
2-21.
Rosier EM, Iadarola MJ, Coghill RC. Reproducibility of pain measurement and pain perception. Pain
2002 Jul;98(1-2):205-16.
Scott DL, Garrood T. Quality of life measures: use and abuse. Ballieres Best Pract Research Clinical
Rheumatol 2000 Dec;14(4):663-87.
Lefebvre-Chapiro, S. The DOLOPLUS 2 scale - evaluating pain in the elderly. European Journal of
Palliative Care, 2001. 8(5): p. 191.
http://www.haywardpublishing.co.uk/_year_search_review.aspx?JID=4&Year=2001&Edition=233
3. CANCER PAIN MANAGEMENT (GENERAL)

3.1
Classification of cancer pain
Cancer pain is classified as mild (1-3), moderate (4-6) and severe (7-10) (1).
The physical causes of pain are either nociceptive or neuropathic. In cancer patients, nociceptive pain tends to
be caused by invasion of the bone, soft tissues or viscera (e.g. bowel, bladder), and neuropathic pain by nerve
compression or infiltration.
Urogenital neoplasms frequently metastasise to bone (e.g., spine, pelvis, and skull). Bone metastases are
associated with pathological fractures, hypercalcaemia and neurological deficits, leading to substantial
impairment of QoL. The release of algogenic substances in the tissue, microfractures and periosteal tension are
the main mechanism for pain sensation (2).

Pain caused by bone metastasis is nociceptive, but can become neuropathic 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 (3). 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, making co-analgesia necessary (4). Patients with severe neuropathic pain are a special
challenge. Psychological changes frequently occur, and specific therapeutic intervention may be necessary (5).
The World Health Organization (WHO) recommends a stepwise scheme for the treatment of cancer pain
syndromes and neoplastic bone pain. Bisphosphonates and calcitonin are helpful for stabilising bone
metabolism. Epidural and intrathecal opioids are sometimes useful in managing metastatic bone pain. Selected
patients with neuropathic pain sometimes benefit from nerve destruction by intrathecal or epidural phenol (6).
3.2 General principles of cancer pain management

The four goals of care are:

prolonging survival;

optimising comfort;

optimising function;

relieving pain.
Pain leads to a vicious cycle of sleeplessness, worry, despair, isolation, hopelessness, depression, and
escalation of pain. The following hierarchy of general treatment principles is useful in guiding the selection of
pain management choices.
1.
Individualised treatment for each patient.
2.
Causal therapy to be preferred over symptomatic therapy.
3.
Local therapy to be preferred over systemic therapy.
4.
Systemic therapy with increasing invasiveness (the WHO ladder).
5.
Conformance with palliative guidelines.
6.
Both psychological counselling and physical therapy from the very beginning.
The fundamental principle is the individualisation of therapy. Repeated evaluations allow the selection and
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administration of therapy to be individualised in order to achieve and maintain a favourable balance between
pain relief and adverse effects.
The next steps in the hierarchy, especially points 2-4, 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 with palliative medicine, where the
prospects of healing are limited and there is 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 preferred over systemic treatment. In simple cases, measures such as drainage
and stenting can make analgesic medication redundant, e.g., gastric probe, ureteral stent, percutaneous
nephrostomy, and bladder catheter. Patients with recurrent subileus caused by peritoneal carcinomatosis are
immediately relieved of their pain when they are given an artificial anus.
The indication is in direct relation to the severity of the disease and the operation, especially if the aim is
palliative, although such cases sometimes require invasive measures, not only to relieve pain in the terminal
phase, but also to improve QoL, although surgery can have a negative impact on patients wellbeing.
Examples 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.
When dose escalation of a systemically administered opioid proves unsatisfactory, the following gradual
strategy can be considered:

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 (TENS).

Use invasive analgesic techniques after 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).

Some patients with advanced cancer and treatment refractory symptoms where comfort is the
overriding goal can elect to be deeply sedated (see chapter 7, section 7.5.3 Palliative sedation).
The importance of physiotherapy and psychological counselling cannot be emphasised too strongly.
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 (7-9).
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 (10-13).
Recommendation
Palliation is not equivalent to minimal invasion. Consider aggressive surgery under certain
circumstances.
LE
2b
GR
B
3.3.2 Radionuclides
For patients presenting with multiple painful bone metastases, both - and -emitting, radionuclides can be
used to obtain pain relief.
3.3.2.2 Radiopharmaceuticals
-Emitting isotopes
The most important -emitting radiopharmaceuticals are: strontium-89 chloride (89Sr) and samarium-153
lexidronam (153Sm ethylenediaminetetramethylenephosphonate [EDTMP]) They are indicated for the treatment
of bone pain resulting from skeletal metastases with an osteoblastic response on bone scan but without spinal
cord compression (14-22) (LE: 2) or pathological fracture (14,17,23) (LE: 2).

These radiopharmaceuticals are delivered intravenously. The patient can pose a radiation
exposure risk for 2-4 days after 153Sm, and 7-10 days after 89Sr (17,19-21,23-30) (LE: 2). Information about
11
radioprotection should be provided. If the pain responds to the initial treatment, administration of 153Sm can be
repeated at intervals of 8-12 weeks in the presence of recurrent pain (14,30,31) (LE: 2).The response rate for
second and subsequent treatments may be lower than for the first (14,18,23,30) (LE: 2).
Side effects:
About 10% of patients experience a temporary increase in bone pain (pain flare) (32-35), generally 2-4 days
after 153Sm, and 1-2 weeks after 89Sr (acute side effect) (17,18). Pain flare is associated with a good clinical
response (LE: 2) (32-35), and sometimes requires a transient increase in analgesia. Pain reduction is unlikely to
occur within the first week, and can occur as late as 1 month after injection. Late side effects include temporary
myelosuppression (platelets and white blood cells). Recovery occurs 4-6 weeks later, depending on bone
marrow reserve. There is generally no significant effect on haemoglobin.
Recommendations
Radiopharmaceuticals are an option for patients with multifocal pain bone metastases when
other treatments such as radiotherapy, hormone therapy or bisphosphonates have failed.
-Emitting radiopharmaceutical are contraindicated within 4 weeks of myelotoxic
chemotherapy (except for cisplatin), or within 12 weeks of hemi-body radiotherapy.
-Emitting radiopharmaceuticals are mainly excreted in urine so precautions must be taken
with urine or blood spills for the first 10 days after treatment.
-Emitting radiopharmaceuticals provide an overall survival benefit in patients with CRPC and
bone metastases.
LE
2b
GR
B
1b
CRPC = castration-resistant prostate cancer

Absolute contraindications:

During or within 4 weeks of myelotoxic chemotherapy (all compounds except cisplatin), or within 12
weeks of hemi-body external radiotherapy in order to avoid severe haematopoietic toxicity.

Known hypersensitivity to EDTMP or similar phosphonate compounds for 153Sm (14).

Glomerular filtration rate (GFR) < 30 mL/min (14,31).

Pregnancy; continued breastfeeding (31).
Relative contraindications:

In acute or chronic severe renal failure (GFR 30-60 mL/min), the dose administered should be
adapted.

With a single painful lesion: external limited field radiotherapy should be performed (36,37).
Caution must be used in the following circumstances:

Urinary incontinence: special recommendations apply, including catheterisation before administration
of the radionuclide (32).

White blood cell count of < 2500/L (31).

Platelets < 80,000/L (31).

Haemoglobin < 90 g/L (31).
-Emitting isotopes: radium-223
-Particle therapy represents a new concept that has also been successful in prolonging survival in phase
III clinical trials (38). Unlike -emitting radiopharmaceuticals, -pharmaceuticals, such as 223Ra, deliver an
intense and highly localised radiation dose to bone surfaces (39). 223Ra thus has potentially better efficacy and
tolerability when compared to -emitters.
In clinical trials, treatment is administered by iv injection once monthly for 4 or 6 months (40-42). No imaging
dose or premedication are required. No radiation protection procedures are required.
Pain response was seen in up to 71% of the patients with a dose response observed 2 weeks after
administration (43). 223Ra has a favourable safety profile with little or no myelotoxic effect (44,45).
A recently completed phase III study has proven that 223Ra provides an overall survival benefit in patients with
CRPC and bone metastases (38). 223Ra is expected to receive approval by various regulatory agencies in the
near future.
12
3.3.3 Radiotherapy for metastatic bone pain

Radiotherapy alleviates metastatic bone pain in approximately 70% of patients, with complete pain relief at the
treated site in up to 40% of patients (46-48) (LE: 1a). The onset of pain relief varies from a few days to 4 weeks
(48) (LE: 2b). The median duration of pain relief reported by most studies is 3-6 months (48) (LE: 1a).
3.3.3.2 Radiotherapy scheme
Single-fraction radiotherapy is as effective as multifraction radiotherapy in relieving metastatic bone pain (4753) (LE: 1a). However, the rates of retreatment and pathological fractures are significantly higher after singlefraction radiotherapy (47,48,54) (LE: 1a).
Single-fraction radiotherapy remains the treatment of choice for alleviating bone pain because of its greater
convenience for patients (LE: 1a), faster patient turnover for the radiotherapy unit (55) and lower costs (53,56)
(LE: 3). The recommended dose is 8 Gy (48-53,57,58) (LE: 1a). Pain relief can be achieved with lower doses (1)
(LE: 1b). These lower doses should be borne in mind if a third retreatment is necessary, or if there is concern
about radiation tolerance (48) (LE: 2b).
In cases of oligometastases (< 5), a case can be made for aggressive therapy, such as radiosurgery or highdose radiotherapy, to improve survival (LE: 3).
3.3.3.3 Spinal cord compression
Metastatic epidural spinal cord compression (MSCC) is a common, severe complication of malignancy.
The most common symptom is back pain (83-95%), and weakness is present in 35-75%. When spinal cord
compression is suspected, magnetic resonance imaging (MRI) is currently the gold standard for detection and
therapeutic management (59-63) (LE: 2b), with sensitivity of 93% (64) (LE: 3) and specificity of 96% (64) (LE: 3).
The level of neurological function at the start of treatment determines the functional outcome (65).
Corticosteroids reduce oedema and may have an oncolytic effect on certain tumours. However, the extent of
the benefit and the optimal dosage are unclear. High-dose corticosteroids carry a significant risk of adverse
effects. One RCT of patients with MSCC showed significantly better functional outcome when radiotherapy
was combined with dexamethasone (66) (LE: 1b).
Radiotherapy is generally the treatment of choice. A multifraction regimen (10 3 Gy) is preferable in these
patients because it allows for a higher dose and thus greater reduction in tumour size. For patients whose
chances of survival are estimated to be poor, a short course of radiotherapy is advised (67) (LE: 1b).
Several uncontrolled surgical trials (59,61,63) and one meta-analysis (60) have indicated that direct
decompressive surgery is superior to radiotherapy alone with regard to regaining ambulatory and sphincter
function, and obtaining pain relief (LE: 1a). However, the decision to pursue surgery must be tempered by
awareness of the attendant significant morbidity and mortality risks. Careful patient selection is of utmost
importance; the criteria are shown in Table 3 (LE: 3).
Table 3: Criteria for selecting patients for primary therapy for spinal cord compression
Absolute criteria
Operability
Duration of paraplegia
Life expectancy
Radiosensitivity
Relative criteria
Diagnosis of primary tumour
Bone fragments with compression
Number of foci of compression
Surgery
Medically operable
< 48 h
> 3 months
Radiotherapy
Medically inoperable
> 48 h
< 3 months
Highly sensitive
Unknown
Present
1 focus
Known
Absent
> 1 foci
A randomised prospective trial has demonstrated that patients treated with a combination of surgery followed
by radiotherapy can remain ambulatory longer, and those who are not ambulatory at presentation have a better
chance of regaining ambulatory function than those treated with radiotherapy alone (62) (LE: 1b).
13
3.3.3.4 Pathological fractures

In patients with impending pathological fractures (e.g., femoral lesion with an axial cortical involvement > 30
mm), a prophylactic orthopaedic procedure should be considered (64).
3.3.3.5 Side effects
Side effects are related to the total dose, fractionation size, and the localisation of the metastases. Acute grade
2-4 toxicity is more frequent after multifraction radiotherapy regimens. The incidence of late toxicity is low (54).
The side effects are mostly transient, lasting a few days and include:
1. Pain flare (within 24 h and due to oedema). Patients should be counselled accordingly and given
breakthrough opioids. Patients receiving single-fraction radiotherapy may be at higher risk than those
receiving multifraction radiotherapy (68). A small phase II study has shown that 8 mg dexamethasone
is effective for prophylaxis of radiotherapy-induced pain flare after palliative radiotherapy for bone
metastases (69) (LE: 3).
2. Symptoms depending on the treatment field and location: nausea (especially with larger fields),
vomiting, diarrhoea, irritation of the throat and oesophagus.
3.3.4 Psychological and adjunctive therapy
3.3.4.1 Psychological therapies
The perception of pain and the suffering it causes derive from a combination of physical, emotional, spiritual,
and social constructs. Psychological assessment and support are an integral and beneficial part of treating
pain in cancer patients (70-72).

There is evidence that highly emotional cancer patients, as detected through their own narratives,
experience less pain than their less emotional counterparts (73). Cultural differences also play a role in pain
perception (74).

Depression is the most prevalent psychiatric diagnosis in patients with cancer. Although there is no
proof that psychotherapy is useful in non-cancer patients with depression, patients with incurable cancer can
benefit from this type of treatment (75). In this setting, structured psychotherapy seems to be more effective
than antidepressant medication (76). Interestingly, effective psychological management results in a reduction in
depressive complaints, inflammatory markers, pain, and fatigue in cancer patients (77).
Cognitive behavioural therapy (CBT), such as relaxation and distraction, can provide pain relief (78-80). As
expected, protocols tailored to individual patient characteristics can result in higher satisfaction in terms of pain
relief, mood improvement and general well-being. The possibility of delivering CBT by home visits, telephone,
or through the internet seems promising (81-83). Virtual consultation and automated symptom monitoring for
cancer patients with depression can exceed all expectations (84). It has also been suggested that CBT may be
particularly helpful for younger cancer patients (85).
More recently, the effects of dignity therapy on distress and end-of-life experience have been formally tested.
Dignity therapy is based on a formal written narrative of the patients life. Its benefits in terms of end-oflife experiences might support its clinical application (86). Families can be dysfunctional (e.g., emotionally
and organisationally) during palliative care and bereavement. Family-focused grief therapy based on
communication, cohesiveness, conflict resolution, and shared grief is effective in protecting family members
against the drama of disease and death (87). Other psychological interventions that aim to minimise caregiver
emotional distress have not been effective (88). Overall, educational programmes that aim to maximise family
and patient satisfaction with pain treatment seem promising (89).
The impact of early detection of psychological distress may improve health outcomes (90). There is also a real
need for screening the patients desire for psychological support, as well as patient distress. This may include
psychological interventions according to the patients needs and desires (91). Different tools are available to
better assess patients needs, such as Palliative Care Needs Assessment Guidelines and Needs Assessment
Tool (92) and the short form of the Supportive Care Needs Survey (SCNS-SF34) (93).
Recommendation
Always offer psychological support to cancer patients and their loved ones.
LE
1a
GR
A
3.3.4.2 Adjunctive therapy

A number of therapeutic strategies have been proposed as non-pharmacological adjunctives to medical and
surgical procedures. To date, there is no conclusive evidence on the effect of reflexology and massage therapy
(94-96). Nevertheless, certain manipulations (e.g., sciatic nerve press) seem to be effective for immediate pain
relief in many oncological conditions (97). The notion that acupuncture may be effective for cancer patients is
14
not supported by the currently available data (98,99). However, modest although significant improvements in
depression and pain scales have been confirmed by well-conducted studies on acupuncture (100).
Evidence from robust studies is still lacking on the effect of traditional Chinese medicine and complementary
alternative medicine (101,102). The effect of cupping therapy - an ancient form of medicine in which suction is
created on the skin - on pain needs to be more rigorously tested (103).
Physical exercise (short walks) can positively affect the pain experience of prostate cancer (PCa) patients (104).
Similarly, moderate exercise positively affects cancer-related sleep disturbance (105). TENS might mitigate
hyperalgesia in cancer patients. Unfortunately, reliable studies in this field are lacking (106).
Listening to music slightly reduces distress, pain intensity and opioid requirements in cancer patients (107,108).
Music relaxation videos seem to positively affect pain severity, opioid consumption, and anxiety level in
patients treated for some gynaecological tumours (109). It is likely that patients harbouring urological tumours
could also benefit.
Strong evidence on the real potential of cannabis derivatives is lacking (110).
Evidence exists of the strong relationship between pain, anxiety and depression, and health-related QoL
in cancer patients (111,112). Sexual dysfunction is a potential long-term complication of cancer treatment.
Following treatment for PCa, transurethral alprostadil and vacuum constriction devices reduce sexual
dysfunction, although negative effects are common. Vaginal lubricating creams are also effective, as are
PDE5 inhibitors (PDE5Is) for sexual dysfunction secondary to prostate cancer treatment (113). Psychological
interventions focused on sexual dysfunction following cancer can be considered as moderately effective (114).
Recommendations
Moderate exercise can be an adjuvant and should be suggested in the treatment of cancer
pain.
Acupuncture and traditional Chinese medicine have not been proven effective in the treatment
of cancer pain.
3.4
LE
1a
GR
A
1a
Pharmacotherapy
The successful treatment of cancer pain depends on the clinicians ability to assess the presenting problems,
identify and evaluate pain syndromes, and formulate a plan for comprehensive continuing care. This requires
familiarity with a range of therapeutic options and responsiveness to the changing needs of the patient. The
treatment of pain must be part of the broader therapeutic agenda, in which tumour control, symptom palliation
(physical and psychological), and functional rehabilitation are addressed concurrently.
3.4.1 Chemotherapy
A successful effect on pain is generally related to tumour response. There is a strong clinical impression that
tumour shrinkage is generally associated with relief of pain, although there are some reports of analgesic
benefit even in the absence of significant tumour shrinkage (115) (LE: 1a).
3.4.2 Bisphosphonates
3.4.2.1 Mechanisms of action

Inhibition of bone resorption: beginning 24-48 h after administration. Target cells are the osteoclasts.
There are three different mechanisms of inhibition of bone resorption corresponding to the three
generations of bisphosphonates. There are four distinct effects on osteoclasts:

-
reduction of osteoclastic activity

-
inhibition of osteoclast adhesion

-
decrease in number of osteoclasts

-
induction of osteoclast apoptosis.

Inhibition of crystallisation and mineralisation: clinically not relevant.

Promotion of osteoblastic bone formation and production of osteoclast resorption inhibitor.

Anti-angiogenic effect and effect on tumour cells.
3.4.2.2 Effects and side effects
The main effects are:

decrease of the risk of skeleton-related events (116) (LE: 1b);

pain relief in 60-85% of patients (116-118) (LE: 1b).
15
The main side effects are:

flu-like symptoms (20-40%), bone pain, fever, fatigue, arthralgia and myalgia (all < 10%);

hypocalcaemia (rapid infusion in older patients with vitamin D deficiency);

acute renal failure (rapid infusion); always check renal function (GFR);

osteonecrosis of the jaw bones (only after iv therapy);

gastrointestinal symptoms can occur after oral administration (2-10%).
Recommendations
Dehydration must be recognised and treated before administration.
When using zoledronate, reduce the dose in the event of impaired renal function (119).
Avoid simultaneous administration of aminoglycosides (120).
Perform clinical examination of the patients mouth and jaws; avoid oral/dental surgery during
administration of iv bisphosphonates (121-125).
LE
2
2
GR
B
B
B
B
3.4.3 Denosumab
Histological findings and analysis of bone turnover markers support the view that bone metastases from PCa
are characterised by an excess osteoclastic activity inducing bone destruction. This results in an increased
risk of skeletal-related events (SREs), such as pathologic fractures, spinal cord compression, pain requiring
radiotherapy or surgery, and hypercalcemia. The receptor activator of nuclear factor-kB ligand (RANKL),
mediates the formation, function, and survival of osteoclasts. Tumour cells induce osteoclast activation, which
then mediates bone resorption and releases growth factors, resulting in a cycle of bone destruction and tumour
proliferation.

Denosumab is a fully human monoclonal antibody that specifically binds and neutralises RANKL,
inhibiting osteoclastogenesis and decreasing osteoclast-mediated bone destruction (126). Improvement in
bone-metastases-free-survival (4.3 months) and increased time to first bone metastasis (3.7 months) has been
reported with denosumab in a phase III randomised placebo controlled trial (127).
Another recently published phase III study, randomised men with CRPC and no previous exposure to iv
bisphosphonate between 120 mg subcutaneous denosumab plus iv placebo, or 4 mg iv zoledronic acid
plus subcutaneous placebo, every 4 weeks until the primary analysis cut-off date. Denosumab significantly
delayed the time to first onstudy skeletal-related event by 18% compared to zoledronic acid, with a betweengroup difference of 3-6 months (128). Occurrences of adverse events and serious adverse events were similar
between groups. More events of hypocalcaemia occurred in the denosumab group (121 [13%]) than in the
zoledronic acid group (55 (6%); p<0.0001). Osteonecrosis of the jaw was infrequent in both groups. The
authors concluded that denosumab was better than zoledronic acid for prevention of skeletal-related events,
and potentially represents a novel treatment option in men with bone metastases from CRPC (128).
A large randomised study (1432 patients) showed that denosumab significantly increased bone-metastasis-free
survival by a median of 4.3 months compared to placebo (median 29.5 (95% CI 25.4-33.3) vs 25.2 (22.2-29.5)
months; hazard ratio (HR) 0.85, 95% CI 0.73-098, P=0.028). Denosumab also significantly delayed time to first
bone metastasis (33.2 (95% CI 29.5-38.0) vs 29.5 (22.4-33.1) months; HR 0.84, 95% CI 0.71-0.98, P=0.032).
Overall survival did not differ between groups (denosumab, 43.9 (95% CI 40.1-not estimable) months vs
placebo, 44.8 (40.1-not estimable) months; HR 1.01, 95% CI 0.85-1.20, P=091). Rates of adverse events and
serious adverse events were similar in both groups (127).
Recommendation
Denosumab use increases bone-metastasis-free survival and delays time to first bone
metastasis in prostate cancer patients.
LE
1b
GR
A
3.4.4 Systemic analgesic pharmacotherapy - the analgesic ladder

Analgesic pharmacotherapy is the mainstay of cancer pain management (129-131). Although concurrent use of
other interventions is valuable in many patients, and essential in some, analgesic drugs are needed in almost
every case. Based on clinical convention, analgesic drugs can be separated into three groups:

Non-opioid analgesics.

Opioid analgesics.

Adjuvant analgesics.
Emphasising that pain intensity should be the prime consideration, the WHO has proposed a three-step
approach to analgesic selection for cancer pain (129,131) (LE: 1a). Known as the analgesic adder, when
16
combined with appropriate dosing guidelines it can provide adequate relief in 70-90% of patients (132,133).

Step 1: non-opioid analgesic Patients with mild to moderate cancer-related pain should be treated
with a non-opioid analgesic.

Step 2: non-opioid analgesic + weak opioid Patients who present with moderate to severe pain or
who fail to achieve adequate relief after a trial of a non-opioid analgesia should be treated with a weak
opioid (e.g. codeine or tramadol), typically by using a combination product containing a non-opioid
(e.g. aspirin or paracetamol) and an opioid (e.g. codeine, tramadol or propoxyphene).

Step 3: non-opioid analgesic + strong opioid Patients who present with severe pain or who fail to
achieve adequate relief with step 2 drugs, should receive a strong opioid (e.g. morphine, fentanyl,
oxycodone, methadon, buprenorphine, or hydromorphone).
3.4.4.1 Non-opioid analgesics

Non-opioid analgesics are paracetamol, metamizole (dipyrone) and non-steroidal anti-inflammatory
drugs (NSAIDs).

Can be useful alone for mild to moderate pain (step 1 of the analgesic ladder).

May be combined with opioids.

Have a ceiling effect of analgesic efficacy.

No tolerance or physical dependence.

Inhibit the enzyme cyclo-oxygenase and block the synthesis of prostaglandins.

Involvement of central mechanisms is also likely in paracetamol analgesia (134).

Potential adverse effects: bleeding diathesis due to inhibition of platelet aggregation,
gastroduodenopathy (including peptic ulcer disease) and renal impairment are the most common;
less common adverse effects include confusion, precipitation of cardiac failure and exacerbation
of hypertension. Particular caution must be used in elderly patients and those with blood-clotting
disorders, predisposition to peptic ulceration, impaired renal function and concurrent corticosteroid
therapy (135).

Non-acetylated salicylates (choline magnesium trisalicylate and salsalate) are preferred in patients
who have a predilection to bleeding; these drugs have less effect on platelet aggregation and no effect
on bleeding time at the usual clinical doses.

Paracetamol rarely produces gastrointestinal toxicity, but, if this occurs, with no adverse effect on
platelet function. Hepatic toxicity is possible, however, and patients with chronic alcoholism and liver disease
can develop severe hepatotoxicity at the usual therapeutic doses (136).
3.4.4.2 Opioid analgesics
Cancer pain of moderate or severe intensity should generally be treated with a systemically administered opioid
analgesic (137). Classification is based on interaction with the various receptor subtypes:

Agonist: most commonly used in clinical pain management, no ceiling effect.

Agonist-antagonist (pentazocine, nalbuphine and butorphanol): ceiling effect for analgesia.
By convention, the relative potency of each of the commonly used opioids is based on a comparison with 10
mg parenteral morphine. Equianalgesic dose information provides guidelines for dose selection when the
drug or route of administration is changed (138).

A trial of systemic opioid therapy should be administered to all cancer patients with moderate or
severe pain (138-141). Patients who present with severe pain should be treated with a strong opioid from the
outset. Patients with moderate pain are commonly treated with a combination drug containing paracetamol or
aspirin plus codeine, tramadol, or propoxyphene, the dose of which can be increased until the maximum dose
of the non-opioid co-analgesia is attained (e.g. 4000 mg paracetamol).
Factors to consider when selecting an opioid include:

pain intensity

patient age

response to previous trials of opioid therapy

co-existing disease

influence of underlying illness, characteristics of the opioid and concurrent medications.
Routes of administration
Opioids should be administered by the least invasive and safest route that can provide adequate analgesia. In
a survey of patients with advanced cancer, more than half required two or more routes of administration prior
to death, and almost a quarter required three or more.
17
Non-invasive routes

Oral routes are the preferred approach in routine practice. Alternative routes are necessary for
patients who have impaired swallowing, gastrointestinal dysfunction, require a very rapid onset of
analgesia, or cannot tolerate the oral route.

Rectal suppositories containing oxycodone, hydromorphone, oxycodone and morphine in
combination are available, and controlled-release morphine tablets can also be administered per
rectum. The potency of rectally administered opioids is believed to approximate to oral dosing (142).

Transdermal routes: fentanyl and buprenorphine have been demonstrated to be effective in
postoperative and cancer pain (143). There is some interindividual variability in fentanyl bioavailability
by this route, which, combined with large differences in elimination pharmacokinetics, necessitates
dose titration in most cases (144). The efficacy of transdermal fentanyl is equal to morphine. The
incidence of side effects such as sedation and constipation are lower than for morphine (145,146)
(LE:1b).

- Transdermal patches able to deliver 12, 25, 50, 75 and 100 mg/h are available. Multiple
patches can be used simultaneously for patients who require higher doses. Current
limitations of the transdermal delivery system include costs, and the need for an alternative
short-acting opioid for breakthrough pain.

- Recently, buprenorphine has become available for transdermal administration. A high
affinity partial -opioid agonist, it is in clinical use for the treatment of acute and chronic
pain (147). Its analgesic effect is comparable with that of other opioids, and it shows no
relevant analgesic ceiling effect throughout the therapeutic dose range (148). Unlike full
-opioid agonists, buprenorphines physiological and subjective effects, including respiratory
depression and euphoria, reach a plateau at higher doses. This ceiling may limit the abuse
potential, and might result in a wider safety margin (149).

Sublingual absorption of any opioid is potentially clinically beneficial, but bioavailability is very poor
with drugs that are not highly lipophilic, so the chances of an adequate response are low (150).
Sublingual buprenorphine, a relatively lipophilic partial agonist, can provide adequate relief for mild
to moderate cancer pain. Overall, this route has limited value due to the lack of formulations, poor
absorption of most drugs, and the inability to deliver high doses or prevent swallowing of the dose. An
oral transmucosal formulation of fentanyl (incorporated into a sugar base) is useful for the rapid relief
of breakthrough pain (151,152). Fentanyl delivered by this means is more effective than oral morphine
at relieving pain (LE: 2).
Recommendations
Transdermal fentanyl is equally effective to morphine. The incidence of side effects is lower
than for morphine.
Oral transmucosal administration of fentanyl should be used to provide rapid relief of
breakthrough pain. The starting dose is 400 g, or 200 g in the elderly and those with a
history of opioid sensitivity or underlying pulmonary disease.
LE
1b
GR
A
2a
Invasive routes
For patients undergoing a trial of systemic drug administration, a parenteral route must be considered when the
oral route is not available. Repeated parenteral bolus injections, which can be administered iv, intramuscularly
(im) or subcutaneously (sc), may be useful in some patients, but are often compromised by the occurrence of
prominent bolus effects (toxicity at peak concentration and/or pain breakthrough at the trough). Repeated im
injections are common, but are painful and offer no pharmacokinetic benefit; their use is not recommended
(153).

Intravenous bolus administration provides the most rapid onset and shortest duration of action. Time
to peak effect correlates with the lipid solubility of the opioid, and ranges from 2-5 min for methadone,
to 10-15 min for morphine ((154). This approach is appropriate in two settings:

- To provide parenteral opioids, usually transiently, to patients who already have venous
access and are unable to tolerate oral opioids.

- To treat very severe pain, for which iv doses can be repeated at an interval as brief as that
determined by the time to peak effect until adequate relief is achieved.

Continuous parenteral infusions is mainly used in patients who are unable to swallow, absorb
opioids or otherwise tolerate the oral route, but is also employed in patients whose high opioid
requirement renders oral treatment impractical (155). Long-term infusions can be administered iv or
sc.

- Ambulatory patients can easily receive a continuous sc infusion using a 27-gauge butterfly
18
needle, which can be left in place for up to a week. A recent study demonstrated that the
bioavailability of hydromorphone by this route is 78% (156), and clinical experience suggests
that dosing can be identical to that for continuous iv infusion. A range of pumps is available
to provide patient-controlled rescue doses (supplemental doses offered on an as-needed
basis to treat pain that breaks through the regular schedule) as an adjunct to continuous
basal infusion.
- Opioids suitable for continuous sc infusion must be soluble, well absorbed and non-irritant.
Extensive experience has been reported with hydromorphone, oxycodone and morphine
(157). Methadone appears to be relatively irritating and is not preferred (158). To maintain the
comfort of an infusion site, the sc infusion rate should not exceed 5 mL/h.
- The infraclavicular and anterior chest sites provide the greatest freedom of movement for
patients, but other sites can be used. A single infusion site can usually be maintained for 5-7
days.
Opioid switching
A systematic search was developed to include studies after 2004, with cancer patients switching between
strong opioids and reporting pain control and adverse effects, usually from morphine or oxycodone to
methadone. The search reviewed 288 papers, among which, only 11 (280 patients) met the inclusion criteria.
Pain intensity was significantly reduced in the majority of studies, and there were fewer serious adverse effects
(159).
Changing the route of administration
Switching between oral and parenteral routes should be guided by knowledge of relative potency to avoid
subsequent over- or underdosing. In calculating the equi-analgesic dose, the potencies of the iv, sc and im
routes are considered equivalent. Perform changes slowly in steps, e.g. gradually reducing the parenteral dose
and increasing the oral dose over a 2-3 day period (LE: 3).
Dosing

round-the-clock dosing. Patients with continuous or frequent pain generally benefit from
A
scheduled around-the-clock dosing, which provides continuous relief by preventing recurrence of
the pain. This approach should be used only in patients with no previous opioid exposure. Patients
should also be provided with a rescue dose. This combination offers gradual, safe and rational dose
escalation that is applicable to all routes of opioid administration.

Controlled-release drug formulations. These preparations of oral opioids can lessen the
inconvenience of around-the-clock administration of drugs with a short duration of action. Numerous
studies have demonstrated the safety and efficacy of these preparations in cancer patients with pain
(160,161).

As-needed (prn) dosing. This strategy is beneficial if rapid dose escalation is necessary or when
beginning therapy with opioids with a long half-life (e.g., methadone or levorphanol). As-needed
dosing may also be appropriate for patients who have rapidly decreasing analgesic requirements, or
intermittent pains separated by pain-free intervals.

Patient-controlled analgesia (PCA). This is a technique of parenteral drug administration in which
the patient controls an infusion device that delivers a bolus of analgesic drug on demand according
to parameters set by the physician. Long-term PCA in cancer patients is most commonly sc using
an ambulatory infusion device. PCA is usually added to a basal infusion rate and acts, in effect, as a
rescue dose.
Adverse effects and their management

Tolerance. There is great variation in the opioid dose required to manage pain (400-2000 mg im
morphine per 24 h) (162). The induction of true analgesic tolerance that could compromise the utility of
treatment can only be said to occur if a patient manifests the need for increasing opioid doses in the
absence of other factors (e.g., progressive disease) that would be capable of explaining the increase
in pain. Extensive clinical experience suggests that most patients who require dose escalation to
manage increasing pain do have demonstrable disease progression (163). This suggests that true
pharmacological tolerance to the analgesic effects of opioids is not a common clinical problem, and
has two important implications:

- Concern about tolerance should not impede the use of opioids early in the course of the
disease.

- Worsening pain in patients receiving a stable dose of opioids should not be attributed to
tolerance, but be assessed as evidence of disease progression or, less commonly, increasing
psychological distress.
19
dverse drug interactions. There is potential for cumulative side effects and serious toxicity to arise
A
from combinations of drugs. The sedative effect of an opioid may add to that of other centrally acting
drugs, such as anxiolytics, neuroleptics and antidepressants. Likewise, constipation produced by
opioids is probably worsened by anticholinergic drugs.
Respiratory depression. This is the most serious adverse effect of opioid therapy, which can impair
all phases of respiratory activity (rate, minute volume and tidal exchange). Clinically significant
respiratory depression is always accompanied by other signs of central nervous system depression,
including sedation and mental clouding. Repeated administration of opioid drugs appears to produce
a rapid tolerance to their respiratory depressant effects, however, so these drugs can be used in the
management of chronic cancer pain without significant risk of respiratory depression. When this does
occur in patients on chronic opioid therapy, administration of the specific opioid antagonist naloxone
usually improves ventilation.
Sedation. Tolerance to this effect usually develops within a period of days to weeks. Patients
should be warned about it, to reduce anxiety and discourage activities that could be dangerous if
sedation occurs (e.g., driving). Some patients have a persistent problem with sedation, particularly
if other sedating drugs are also being taken or if there is comorbidity such as dementia, metabolic
encephalopathy, or brain metastases.
Confusion and delirium. Confusion is a greatly feared effect of opioid drugs, and mild cognitive
impairment is common (164). However, similar to sedation, pure opioid-induced encephalopathy
appears to be transient in most patients, persisting from days to 1-2 weeks. Although persistent
confusion attributable to opioids alone does occur, it is usually related to the combined effect of the
opioid and other factors, including electrolyte disorders, neoplastic involvement of the central nervous
system, sepsis, vital organ failure and hypoxaemia (165). A stepwise approach to management often
culminates in a trial of a neuroleptic drug. Haloperidol in low doses (0.5-1.0 mg orally or 0.25-0.5 mg
iv or im) is most commonly recommended because of its efficacy and low incidence of cardiovascular
and anticholinergic effects.
Constipation. This is the most common adverse effect of chronic opioid therapy (166-168), and
laxative medication should be prescribed prophylactically. Combination therapy is frequently used,
particularly co-administration of a softening agent (e.g. docusate) and a cathartic (e.g., senna,
bisocodyl or phenolphthalein). The doses should be increased as necessary, and an osmotic laxative
(e.g. magnesium sulphate) should be added if required. Chronic lactulose therapy is an alternative that
some patients prefer, and the occasional patient is managed with intermittent colonic lavage using an
oral bowel preparation.
Nausea and vomiting. Opioids may produce nausea and vomiting via both central and peripheral
mechanisms. These drugs stimulate the medullary chemoreceptor trigger zone, increase vestibular
sensitivity, and affect the gastrointestinal tract (increased gastric antral tone, diminished motility,
delayed gastric emptying). The incidence of nausea and vomiting in ambulatory patients is estimated
to be 10-40% and 15-40%, respectively (169), with the effects greatest at the start of therapy.
Metoclopramide is the most reasonable initial treatment. Tolerance typically develops within weeks.
Routine prophylactic administration of an anti-emetic is not necessary. Serotonin antagonists (e.g.,
ondansetron) are not likely to be effective with opioid-induced symptoms as they do not eliminate
apomorphine-induced vomiting and motion sickness, which appear to be appropriate models for
opioid effects. Clinical trials are needed to confirm this.
Addiction and dependence. Confusion about physical dependence and addiction augments the
fear of opioids and contributes substantially to the undertreatment of pain (170). Patients with chronic
cancer pain have a so-called therapeutic dependence on their analgesic pharmacotherapy, which may
or may not be associated with the development of physical dependence, but is seldom associated
with addiction. The medical use of opioids is rarely associated with the development of addiction
(171). There are no prospective studies in patients with chronic cancer pain, but extensive clinical
experience affirms the low risk of addiction in this population (LE: 3). Healthcare providers, patients
and families often require vigorous and repeated reassurance that the risk of addiction is small.
Recommendation
Inform the patient that the use of morphine has a small risk of addiction.
LE
3
GR
A
Adjuvant analgesics
Defined as a drug that has a primary indication other than pain but is analgesic in some conditions,. These
drugs may be combined with primary analgesics on any of the three steps of the analgesic ladder to improve
the outcome for patients who cannot otherwise attain an acceptable balance between relief and side effects. In
20
the management of cancer pain, adjuvant analgesics are conventionally categorised as follows.

Corticosteroids. Widely used as adjuvant analgesics (172,173), this group has been demonstrated
to have analgesic effects, to improve QoL significantly (174), and to have beneficial effects on
appetite, nausea, mood and malaise in patients with cancer (175). The mechanism of analgesia may
involve anti-oedemic and anti-inflammatory effects, plus a direct influence on the electrical activity in
damaged nerves. (i.e., reduction of neuropathic pain). Patients with advanced cancer who experience
pain and other symptoms may respond favourably to a relatively small dose of corticosteroids (e.g.
dexamethasone 1-2 mg twice daily) (LE: 2a).

Benzodiazepines. These drugs have a small analgesic effect (176), and must be balanced by the
potential for side effects, including sedation and confusion. Benzodiazepines are generally used only if
another indication exists, such as anxiety or insomnia (LE: 2b).
Recommendation
Dexamethasone 1-2 mg twice daily can be a valuable adjuvant in the treatment of pain in
advanced cancer.
LE
2a
GR
B
3.4.5 Treatment of neuropathic pain

Numerous options are available for relieving neuropathic pain, including opioids, which give patients significant
pain reduction with greater satisfaction than antidepressants (177,178). However, the potential complications
of opioids mean that they are not always a satisfactory option (179). Beside opioids, effective therapies for
managing neuropathic pain include antidepressants, anticonvulsants, topical treatments (lidocaine patch,
capsaicin), N-methyl-D-aspartate (NMDA) receptor antagonists, baclofen, local anaesthetics, and clonidine
(180,181).
3.4.5.1 Antidepressants
There is clear evidence for the effectiveness of antidepressants in the treatment of neuropathic pain (180).
Antidepressants which work primarily via interaction with pathways running through the spinal cord from
serotoninergic and noradrenergic structures in the brain stem and mid-brain.
Tricyclic antidepressants (TCAs) such as amitriptyline, nortriptyline (metabolite of amitriptyline), imipramine, and
desipramine (metabolite of imipramine) are often the first drugs selected to alleviate neuropathic pain (182,183)
(LE: 1a). The mechanism of action is predominantly by blocking the reuptake of norepinephrine and serotonin
(dual acting), together with a blockade of neuronal membrane ion channels (reducing neuronal influx of Ca2+ or
Na+), and interaction with adenosine and NMDA receptors. However, treatment with these analgesics may be
compromised (and outweighed) by their side effects. TCAs must be used cautiously in patients with a history
of cardiovascular disorders, glaucoma, and urine retention. In addition, combination therapy with monoamineoxidase inhibitors could result in the development of serotonin syndrome.
Duloxetine enhances both serotonin and norepinephrine function in descending modulatory pathways.
It has weak affinity for the dopamine transporter and insignificant affinity for several neurotransmitters,
including muscarinic, histamine, glutamate, and gamma-aminobutyric acid (GABA) receptors. Duloxetine has
demonstrated a significant pain-relieving effect with a generally favourable side-effect profile in painful diabetic
neuropathy (182) (LE: 1b).
Selective serotonin reuptake inhibitors (SSRIs) - sertraline, paroxetine, fluoxetine and citalopram - selectively
inhibit the reuptake of serotonin. These antidepressants have a more favourable side effect profile than TCAs,
but their effectiveness in neuropathic pain is disputed in the literature (second-line pharmacological treatment).
Recommendations
Offer amitriptyline and nortriptyline as a first line treatment for neuropathic pain, with
nortriptyline associated with fewer side effects.
TCAs must be used cautiously in patients with a history of cardiovascular disorders, glaucoma,
and urine retention.
Duloxetine is first-line treatment for neuropathic pain due to diabetic polyneuropathy.
Duloxetine may be tried as an analgesic in other neuropathic pain syndromes.
LE
1b
GR
A
1b
2a
3
A
C
3.4.5.2 Anticonvulsant medication

The rationale for the use of anticonvulsant drugs in treating neuropathic pain is the reduction of neuronal
hyperexcitability, one of the key processes in the development and maintenance of neuropathic pain (184).
21
Different anticonvulsants have demonstrated pain relief by a blockade of neuronal membrane ion channels
(reducing neuronal influx of Ca2+ or Na+), and effects on neurotransmitters (enhancement of GABA, inhibition of
glutamate release) and/or neuromodulation systems (blocking the NMDA receptor) (185,186). Carbamazepine
and phenytoin were initially used for the treatment of trigeminus neuralgia. Although both drugs reduce
neuropathic pain, their attendant side effects and complicated pharmacokinetic profile limit their use.
Despite the introduction of newer anticonvulsants with better side effect profiles, carbamazepine remains the
drug of choice for treating trigeminus neuralgia (187) (LE: 1a). However, oxcarbazepine (10-keto analogue of
carbamazepine), a new anticonvulsant with a similar mechanism of action to that of carbamazepine but with a
better side effect profile, may replace carbamazepine for this purpose (188).
Gabapentin and pregabalin are first-line treatments for neuropathic pain (reducing elements of central
sensitisation), especially in post-zoster neuralgia and diabetic polyneuropathy (189-191) (LE: 1a). The
combination of gabapentin with opioids seems to display synergistic effects in relieving neuropathic pain
(192,193). Gabapentin has a favourable safety profile with minimal concern for drug interactions and no
interference with hepatic enzymes. However, renal failure results in higher gabapentin concentrations and a
longer elimination half-life, making dose adjustments necessary. Pregabalin (3-isobutyl GABA) is a structural
analogue of gabapentin, but shows greater analgesic activity in rodent models of neuropathic pain than did
gabapentin (194). Recent studies confirm the effectiveness of pregabalin in peripheral (including post-herpetic
neuralgia and diabetic polyneuropathy) and central neuropathic pain (195).
Recommendation
Offer gabapentin and pregabalin as first-line treatment for neuropathic pain, especially if
tricyclic antidepressants are contraindicated.
LE
1b
GR
A
3.4.5.3 Local analgesics

Neuropathic pain syndromes are typically associated with touch-evoked allodynia and hyperalgesia that impair
patients QoL. As well as treatment with anticonvulsants and antidepressants, a topical drug can be effective
in treating ongoing pain and allodynia, supporting the idea that peripheral actions are of key importance in the
initiation and maintenance of neuropathic pain.

Local treatments for neuropathic pain include the 5% lidocaine patch, and capsaicin. The 5%
lidocaine patch, a targeted peripheral analgesic, is effective in the treatment of post-herpetic neuralgia and a
variety of other focal peripheral neuropathies (196,197) (first-line pharmacological treatment; LE: 1b). Once a
day, up to three patches are applied to the painful skin, covering as much of the affected area as possible.
Capsaicin causes pain due to release of substance P from the nociceptive terminals, initiating nociceptive
firing. An analgesic response follows because prolonged exposure to capsaicin desensitises the nociceptive
terminals and elevates the pain threshold. Capsaicin (third-line pharmacological treatment) reduces pain in
a variety of neuropathic pain conditions (including post-herpetic neuralgia, diabetic neuropathy and painful
polyneuropathy). It is applied in a 0.075% concentration (198) (LE: 3).
Recommendations
Topical lidocaine 5% should be used as an adjuvant in patients suffering from post-herpetic
neuralgia.
Transdermal capsaicin may be used as an adjuvant in patients with neuropathic pain.
LE
1b
GR
A
3.4.5.4 NMDA receptor antagonists

Within the dorsal horn, ionotropic glutamate receptors (NMDA, 2-amino-3-(3-hydroxyl-5-methyl-4Isoxazole) propionate (AMPA), and kainate) and metabotropic glutamate receptors are all involved in
neuropathic pain (170,199). However, the actions of excitatory amino acids (glutamate) on the NMDA receptor
is considered a pivotal event in the phenomenon of wind-up and neuronal hyperexcitability (enhancement
and prolongation of sensory transmission) that eventually leads to allodynia, and primary and secondary
hyperalgesia.
Subanaesthetic doses of ketamine, and its active enantiomer S(+)-ketamine, given parenterally, neuraxially,
nasally, transdermally or orally, alleviate pain postoperatively and in a variety of neuropathic pain syndromes,
including central pain (200) (LE: 2b). However, ketamine may result in unwanted changes in mood, conscious
perception, and intellectual performance, as well as psychomimetic side effects (including visual and auditory
hallucinations, dissociation and nightmares), limiting its use for neuropathic pain (199). It must therefore be
22
UPDATE FEBRUARY 2012
reserved as a third-line option when other standard analgesic treatments are exhausted (201,202).
The primary role of low-dose systemic ketamine (bolus 0.25 mg/kg followed by continuous administration
at 0.1-0.4 mg/kg/h) is as an antihyperalgesic, antiallodynic, or tolerance-protective compound in patients
with severe acute pain, chronic or neuropathic pain, opioid tolerance, or those at risk for developing chronic
postsurgical pain (following laparotomy, thoractomy, breast surgery, and nephrectomy) (203,204). In the
acute setting ketamine is effective as a rescue analgesic (0.25 mg/kg, iv) for acute pain that is not, or poorly,
responsive to opioids (205).
Despite improved and prolonged analgesia following caudal administration of ketamine in paediatric
anaesthesia, there remains a controversy in the preclinical (animal) and clinical literature as to the safety and
justifiability of this compound for neuraxial administration. In a case report, as well as in an animal study,
severe histological abnormalities indicating neurotoxicity were observed following neuraxial administration of
ketamine (206,207).
Recommendation
Ketamine is effective as an analgesic in neuropathic pain, but may be responsible for severe
life-threatening side effects and should be reserved for specialised pain clinics and as a last
resort (third-line treatment).
LE
2b
GR
B
3.4.5.5 Other drug treatments

Baclofen, a muscle relaxant, is analgesic due to its agonistic effect on the inhibitory GABAB receptors. Baclofen
is efficacious in patients with trigeminal neuralgia, but not in those with other neuropathic pain conditions
(208). However, this analgesic also has antispasticity properties and may induce analgesia by relieving muscle
spasms, a frequent accompaniment of acute neuropathic pain. Baclofen can be considered a second-line
agent for trigeminus neuralgia, or a third-line agent in neuropathic pain syndromes (LE: 3).
Clonidine, an 2-adrenoreceptor agonist, is available as a patch for transdermal administration and has
been used in neuropathic pain states. When used locally, it seems to enhance the release of endogenous
encephalin-like substances, but its use in the treatment of neuropathic pain is focused on intrathecal or
epidural administration in combination with opioids and/or local anaesthetics. This delivery improves pain
control because of a possible supra-additive effect during neuropathic pain treatment (209) (LE: 2b).
Summary: treatment of neuropathic pain

First-line agent:

-
nortirptyline, pregabalin, gabapentin

-
duloxetine (first-line treatment in diabetic polyneuropathy only)

-
lidocaine 5% patch (first-line treatment in post-herpetic neuralgia only).

Second-line agent:

-
opioids/tramadol (first-line treatment in patients with neuropathic cancer pain only).

Third-line agent:

-
baclofen

-
transdermal capsaicin 0.075%

-
ketamine (an anaesthetic).
3.4.5.6 Invasive analgesic techniques
Studies suggest that 10-30% of patients with cancer pain do not achieve a satisfactory balance between
relief and side effects using systemic pharmacotherapy alone without unacceptable drug toxicity (132,133).
Anaesthetic and neurosurgical techniques may reduce the need for systemically administered opioids, while
achieving relief.
Peripheral nerve catheterisation in the management of cancer pain
Tumour infiltration or compression of a peripheral nerve or plexus can result in severe neuropathic pain
resistant to pharmacological treatment. In these patients invasive analgesic techniques may be emphasised
(210,211).
Recommendation
Reversible regional anaesthetic techniques must be considered for the management of neuropathic
pain.
GCP = good clinical practice
GR
GCP
23
Neurolytic blocks to control visceral cancer pain

Visceral cancer pain is mainly treated with NSAIDs and opioids, but neurolytic blockade can be used to
optimise palliative treatment for cancer in the viscera.

Different neurolytic blockades have been described (212,213). A coeliac plexus block is indicated to
treat pain secondary to malignancies of the retroperitoneum or upper abdomen (distal part of the stomach,
pancreas, liver, gall bladder) (214) (LE: 1b). A superior hypogastric plexus block has proven utility for pelvic pain
(rectum, vaginal fundus, bladder, prostate, testes, seminal vesicles, uterus and ovaries) due to a neoplasm that
is refractory to pharmacological treatment (215-217) (LE: 3).
Neuraxial administration of opioids
The delivery of low-dose opioids near the sites of action in the spinal cord may decrease supraspinally
mediated adverse effects. Compared with neuroablative therapies, spinal opioids have the advantage of
preserving sensation, strength and sympathetic function (218,219). Contraindications include bleeding
diathesis, profound leukopenia and sepsis. A temporary trial of spinal opioid therapy should be performed to
assess the potential benefits of this approach before implantation of a permanent catheter.
The addition of a low concentration of a local anaesthetic, such as 0.125-0.25% (levo)bupivacaine, to an
epidural/intrathecal opioid increases the analgesic effect without increasing toxicity (220,221). The potential
morbidity of these procedures requires well-trained clinicians and long-term monitoring (LE: 2).
Recommendation
Continuous intrathecal or epidural administration of morphine may be considered in patients with
inadequate pain relief despite escalating doses with sequential strong opioids, or the development of
side effects (nausea, vomiting, constipation, drowsiness, sedation) limiting further dose increase.
GR
B
3.4.6 Breakthrough cancer pain

Breakthrough cancer pain (BTCP) is a common and debilitating problem (222). It has been defined as an
increase in pain intensity in patients on regularly administered analgesia. Due to their slow onset of action,
oral opioids are not considered to be an efficient treatment for BTCP. Transmucosal, buccal, sublingual
and intranasal fentanyl preparations have shown adequate rapid analgesia. Evidence suggests that oral
transmucosal fentanyl citrate is effective for BTCP, giving more rapid relief than morphine (223).
All the studies performed have shown that these drugs should be administered to opioid-tolerant patients
receiving at least 60 mg/day morphine or its equivalent (224). Proper assessment and classification of BTCP
could improve care and support of patients with this syndrome (225) (LE: 1a).
24
Figure 2: Cancer pain treatment in urology

Pain in patient with urological cancer
Pain assessment using OPQRSTUV (section 2.6) and physical assessment (pain area, pain type, pertinent history, risks of
addiction, associated symptoms-nausea, vomiting, constipation, dyspnoea, tingling, urinary retention)
Mild pain (score 1-3)
Moderate pain (score 4-6)
P
aracetamol
NSAIDs at the lowest
effective dose (need
for periodical pain
assessment)
Consider gastric
protection in long term
NSAIDs use
Weak opioids (codeine
or tramadol) at low
doses in combination
with non-opioids
Opioid nave
patient
Patient under opiod

treatment
Patient under
opiod treatment
Patient under
opiod treatment
Morphine 5 mg x 6
Per os and 2.5-5
mg every h pm for
breakthrough pain.
For elderly or
debilitated consider
starting dos of 2.5
mg x 6
Increase the regular

and breakthrough
doses by 25%
Titrate dose every
24h
Perform frequent
assessments and
opioid titration until
pain is controlled
If pain persists
refer to severe pain
management
Increase the
regular and
breakthrough
doses by 25%
Titrate dose
every 24h
In persistent
pain consider
opioid
switching
Consult
palliative care
specialists
Increase the
regular and
breakthrough
doses by 25%
Titrate dose
every 24h
In persistent
pain consider
opioid
switching
Consult
palliative care
specialists
Hydromorphone 1
mg x 6 per os with
0.5-1 mg every
h pm. For elderly
and debilitated 0.5
mg x 6
In case of inadequate
pain control
Severe pain (score 7-10)
Oxycocone 2.5mg
x 6 per os with
2.5 mg pm for
breakthrough pain
Severe pain crisis
Consult a palliative care specialist
iv access present
Opioid-nave patient
Morphine 5-10 mg
every 10 min until
pain is relieved
No iv access present
Patient on opioids
Opioid-nave patient
Patient on opioids
Give the usual per

os morphine dose
iv every 10 min until
pain is relieved
Morphine 5-10 mg sc
every 20-30 min until
pain is relieved
Give the usual per

os morphine dose sc
every 2-30 min until
pain is relieved
Titrate dose by 25% every 1-2 doses until pain is relieved
3.5
Quality of life (QoL)
Patients facing advanced stages of PCa frequently experience total pain, a mix of physical, psychological,
spiritual and social suffering (226). Information about the illness and the process of care has proven to reduce
distress (227,228). Treatment should include both psychological and somatic symptoms (226).
Physical activities adapted to the patients condition are beneficial in the treatment of fatigue (229-231). Family
caregivers and support groups are crucial components of the patient support system. Members of PCa selfhelp groups provide each other with various types of assistance, usually non-professional and non-material,
for a particular shared, usually burdensome, characteristic (228). Help may involve provision and evaluation
of relevant information, relating personal experiences, listening to, and accepting the experiences of others,
providing sympathetic understanding, and establishing social networks. A supportive self-help group may also
inform the public or engage in advocacy. All efforts should be aimed at improvement of QoL (228).
25
3.6
Conclusions
The goal of analgesic therapy in cancer patients is to optimise analgesia with the minimum of side effects.
Current techniques can provide adequate relief for the large majority of patients. Most will need ongoing
analgesic therapy, and requirements often change as the disease progresses. Patients with refractory pain
should have access to specialists in pain management or palliative medicine who can provide an integrated
multidisciplinary approach.
3.7
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4. PAIN MANAGEMENT IN UROLOGICAL

CANCERS
The prevalence of cancer pain approaches 25% for newly diagnosed cases (1) and > 75% for advanced
disease (2,3). This evidence will substantiate the next update on pain management in urological cancers.
4.1
Pain management in prostate cancer patients
For a complementary approach please refer to the EAU Guidelines on Prostate Cancer (4).
Pain in both early and advanced PCa can be caused directly by the cancer (77%), be related to the treatment
(19%), or be unrelated to either (3%) (5). Management must focus on symptomatic patients with locally
advanced disease or metastases.

The overall incidence of chronic pain in PCa patients is about 30-50%, but as patients enter the
terminal phase this rises to 90% (6). Pain may be directly attributable to tumour infiltration of and growth in
three main areas: bone, nerve or a hollow viscus.
4.1.2.1 Invasion of soft tissue or a hollow viscus
Pain caused by invasion of a hollow viscus is treated with surgery or minimally invasive procedures (e.g.,
catheter, stent or nephrostomy tube).
38
4.1.2.2 Bladder outlet obstruction

Continuous growth of the prostate can lead to an outlet obstruction. Lower urinary tract symptoms (LUTS) can
occur, especially stranguria and an inability to void. Acute pain requires prompt relief. The best method is to
insert a suprapubic catheter and treat the tumour according to the stage (4). If the outlet obstruction persists,
palliative transurethral resection of the prostate (TURP) is an option if no curative therapy can be offered.
4.1.2.3 Ureteric obstruction
Ureteric obstruction is most frequently caused by tumour compression or infiltration within the true pelvis
(7-10). Less commonly, obstruction can be more proximal, associated with retroperitoneal metastases. In most
cases, obstruction is primarily asymmetrical. Untreated progressive ureteric obstruction results in bilateral
hydronephrosis and subsequent renal failure. It is good practice to drain symptomatic hydronephrosis at once,
and to drain only one kidney (the less dilated and better appearing kidney or the one with the better function,
if known) in asymptomatic patients. A nephrostomy tube is superior to a double-J stent for drainage because
the subsequent routine endoscopic replacement of the stent could be increasingly difficult in a continuously
growing prostate gland, and a nephrostomy tube can be changed without anaesthesia. Anterograde ureteral
stenting through the nephrostomy site can also be attempted when the patient desires an internal diversion.
4.1.2.4 Lymphoedema
Patients with a huge prostate mass and/or lymph node metastases in the pelvis frequently get lymphoedema of
the legs. Physiatric techniques such as wraps, pressure stockings and pneumatic pumps can improve function
and relieve pain and heaviness.
4.1.2.5 Ileus
Local obstruction of the rectum is a common occurrence in advanced PCa, and can lead to abdominal pain
caused by obstructive ileus. Rarely, peritoneal involvement can also result in ileus. Surgery and/or rectal
stenting must be performed for mechanical obstruction. Paralytic ileus due to tumour infiltration of a nerve
plexus or secondary to analgesics may require laxatives for opioid-induced constipation to improve motility
and reduce pain.
4.1.3.1 Bone metastases

Bone metastases are the most common cause of chronic pain in patients with PCa (11,12) as a result
of:

- endosteal or periosteal nociceptor activation (mechanical distortion or release of chemical
mediators);

-
tumour growth into adjacent soft tissues or nerves;

-
other complex mechanisms (12).

Widespread bony metastases frequently cause multifocal pain. Patients with multiple bony metastases
typically report pain in only a few sites.

More than 25% of patients with bony metastases are pain free (13).

The factors that convert a painless lesion into a painful one are unknown.
The choice of treatment will depend on the site, histology and stage of the tumour, and on the patients
physical and emotional condition. Although tumour-cell specific therapies are being developed, most
commonly used techniques damage normal tissues, with consequent side effects. The pros and cons of the
therapeutic options should be considered in each case; those with fewest side effects being administered first.
The treatment options are:

hormone therapy

radiotherapy

orthopaedic surgery

radioisotopes

bisphosphonates

denosumab

calcitonin

chemotherapy

systemic analgesic pharmacotherapy (the analgesic ladder).
Other pain management tools such as nerve blocks are rarely used.
39
4.1.3.2 Hormone therapy

Huggins and Hodges (14) first noted the effect of exogenous oestrogen administration on prostatic
carcinoma. A variety of additive or ablative hormone manipulations have been employed, including
oestrogen, anti-androgen (cyproterone, flutamide), oestrogen-mustine complex (estramustine), progestogens,
aminoglutethimide, gonadotrophin-releasing hormone (GnRH) analogues, orchidectomy, adrenalectomy
and hypophysectomy. Corticosteroids are also used for the palliation of pain, particularly pain due to bone
deposits.
For more information on hormone therapy, refer to EAU Guidelines on Prostate Cancer (4). Hormone therapy is
generally much better tolerated than chemotherapy. It can cause a temporary exacerbation of pain (pain flare),
which is generally predictive of a subsequent response (15). In a collected series of protocols, pain relief has
been estimated at 35% (16) to 70% (17). This difference may have been due to patient selection and problems
with pain measurement. Well-differentiated prostatic carcinoma is more likely to respond to hormones than are
poorly differentiated tumours. Manipulations that include replacement corticosteroid therapy or have additional
corticoid effects seem to give higher response rates. Corticosteroids are also used for the palliation of pain,
particularly in bone metastases.
To date, most patients with adenocarcinoma of the prostate present with early-stage tumours and undergo
treatment with curative intent. In cases of disease progression and symptoms, hormone therapy is indicated,
with patients remaining asymptomatic for several years.
4.1.3.3 Radiotherapy

The role of radiotherapy in the management of pain due to bone metastases is unquestionable (18).

Radiotherapy techniques vary widely, from a large dose given as a single treatment to as many as 20
smaller treatments given over 4 weeks.

The biological effect of the radiation depends not only on the total dose delivered, but also on the
number of separate treatments and the total time over which the irradiation therapy is administered.

Palliative doses are smaller than maximum tolerance doses.

It should be noted that radiological evidence of a deposit may considerably underestimate the extent
of disease.
In metastatic adenocarcinoma of the prostate, radiotherapy is associated with palliation of pain from bony
metastases and improved QoL. Radiation therapy is effective at treating painful sites, and might also be
effective at reducing the propensity for adjuvantly treated disease to become symptomatic in most patients
(19). New organ limited approaches as the stereotactic ablative radiation therapy (SABR) of vertebral
metastases can result in excellent local control (20). This effect does not appear to be significantly influenced
by dose-time relationships or histology. The proportion of patients achieving complete pain relief approaches
(70%) (21) (Section 3.3.3).
4.1.3.4 Orthopaedic surgery
If more than 50% of the thickness of the cortex of a long bone is eroded by metastasis, prophylactic fixation
rather than radiotherapy alone should be considered. Internal fixation should be followed by postoperative
radiotherapy because there is a real danger of continued tumour growth and further structural weakness
(22,23). Radiotherapy should not be withheld for fear of inhibiting bone healing and regrowth. There is
good evidence that palliative doses of radiotherapy are associated with recalcification (24). The sequential
combination of radiofrequency and cementoplasty seems promising for the treatment of painful osseous
metastases (25).
4.1.3.5 Radioisotopes
Widespread axial skeletal involvement in PCa has been successfully treated with systemically administered
bone-seeking radioisotopes (see also Section 3.3.2). Commonly used radionuclides are 89Sr chloride and
153Sm-EDTMP. The addition of 89Sr as a single injection of 10.8 mCi (399.6 MBq) is an effective adjuvant
therapy to local field radiotherapy, reducing disease progression, the requirement for further radiotherapy and
analgesic support (26), and improving QoL.
Some evidence suggests that radioisotopes could give complete relief from pain over 1-6 months, with no
increase in analgesia, although adverse effects, specifically leukocytopenia and thrombocytopenia, have been
reported (26). -Particle therapy represents a new concept that has been successful in prolonging survival in
phase III clinical trials (27). Unlike -emitting radiopharmaceuticals, -pharmaceuticals, such as 223Ra, deliver
an intense and highly localised radiation dose to bone surfaces (28). 223Ra thus has potentially better efficacy
and tolerability when compared with -emitters.
40
4.1.3.6 Bisphosphonates
Bisphosphonates can be part of the supportive care for patients with bone metastases and pain (29).
Improvement in pain control has been demonstrated (29). They should be considered for the treatment of
refractory bone pain in metastatic PCa (30). Zoledronic acid (4 mg intravenously over 15 min every 3-4 weeks)
decreased the frequency of skeleton-related events, delayed the time to the first occurrence, and reduced pain
(31). Studies are needed to determine the optimal timing, schedule and duration of treatment in men with bone
metastases.
4.1.3.7 Denosumab
Denosumab reduces the risk of skeletal events in men with castration-resistant bone-metastatic PCa (32).
4.1.3.8 Calcitonin
Current evidence does not support the use of calcitonin to control pain arising from bone metastases (33).
4.1.3.9 Chemotherapy
In about 80% of men with metastatic PCa, primary androgen ablation leads to symptomatic improvement. The
disease eventually becomes refractory to hormone treatment. Systemic chemotherapy should be reserved for
this patient group. Recent data have shown encouraging signs in overall survival, palliation of symptoms and
improvements in QoL (34), particularly with docetaxel.
Trials using single-agent chemotherapy in advanced disease have shown poor results, but newer studies
confirmed that multiagent chemotherapies are more effective. Other studies have confirmed the symptomatic
effect of mitoxantrone plus low-dose prednisone, but none found improved survival.

A PSA-response rate and a reduction of pain were also reported with other combined chemotherapies
(Table 4). Individualised therapy was necessary as side effects were common and no regimen showed a
survival benefit.
A major proportion of the morbidity and mortality related to chemotherapy can be traced to the burden of
bone metastases (35). Any effective hormone therapy or chemotherapy is generally suited to relieve metastatic
pain, or to limit, at least. Over the last decade, several new agents for metastatic castration-resistant prostate
cancer (mCRPC) targeting different mechanisms of progression have been applied successfully: docetaxel,
cabazitaxel, sipuleucel-T, denosumab, and abiraterone acetate, among others (36). Docetaxel is the standard
first-line chemotherapeutic agent (37).

Despite a net survival benefit, the prognosis remains poor. Second-line therapeutic options are
limited. Results from recently completed trials show a statistically and clinically significant improvement in
pain relief and overall survival with cabazitaxel compared with mitoxantrone. Cabazitaxel has been shown to
be well tolerated and has been approved as second-line chemotherapy for mCRPC (37,38). Also, a significant
reduction of tumor associated pain and a survival advantage of 4.6 months compared to placebo following
docetaxel-based chemotherapy has already been shown for abiraterone (phase III study) (38) (LE: 1b)
Cabozantinib is a potent inhibitor of tyrosine kinase c-Met and vascular endothelial growth factor receptor
(VEGFR2) and seems to reduce pain and opioid consumption in patients with mCRPC (39). Denosumab is a
human monoclonal anti-RANKL antibody but it does not reduce pain severity in patients with mCRPC (40).
Although most of these regimens are associated with side effects such as fatigue, mild myelosuppression
and gastrointestinal irritation, they are generally well tolerated by most patients (41). Pain management by
chemotherapy could be effective, although it is much more cost-intensive than the administration of opioids,
and the survival advantage is limited.
4.1.3.10 Systemic analgesic pharmacotherapy (the analgesic ladder)
If the treatments described above provide insufficient pain relief, systemic analgesic pharmacotherapy should
be administered. In most cases, the drug selection scheme proposed by the WHO, the analgesic ladder, is
recommended. Short-term studies have shown that NSAIDs alone are effective in managing cancer pain, with
side effects similar to those with placebo. In about 50% of studies, increasing the dose of NSAIDs increased
efficacy but not the incidence of side effects.
No large clinical difference has been demonstrated between combining an NSAID with an opioid vs either
medication alone (42). Tramadol extended-release tablets and dihydrocodeine extended-release tablets were
effective for the management of chronic tumour pain associated with PCa with bone metastasis on step 2
of the WHO ladder, with tramadol giving slightly better pain management and fewer side effects, particularly
constipation (43).
41
The treatment of constipation in palliative care is based on experimental evidence, and uncertainty persists
about its optimum management in this group of patients (44).

Oral morphine is an effective analgesic for cancer pain, with qualitative evidence showing that it
compares well with other opioids. Morphine is the gold standard for moderate to severe cancer-related pain.
Alternatives such as hydromorphone are available, but no clinically significant difference has been shown
compared to other strong opioids such as morphine (45).

Patients with inadequate pain control and intolerable opioid related toxicity/adverse effects may have
to switch to an alternative opioid for symptomatic relief, although the evidence to support opioid switching is
largely anecdotal, observational or from uncontrolled studies (46).
4.1.4 Spinal cord compression
Spinal cord compression can occur due to the collapse of a vertebral body or to pressure from an extradural
tumour within the spinal canal. Prodromal pain is a feature in 96% of these patients. The overall incidence
in PCa patients is less than 10% (47). Thoracic cord compression is the most common area (70%), and the
incidence of multiple extradural sites can be as high as 18% (48).

Definitive treatment with surgery (anterior decompression with spinal stabilisation) or radiotherapy
should be considered. The symptom of local back pain sometimes disappears, despite an increase in motor
deficits, because of the evolving sensory component of the paraplegia.
Corticosteroids (typically dexamethasone 16 mg daily) are of only temporary use in cord oedema. There is
evidence that decompressive surgery benefits ambulant patients with poor prognostic factors for radiotherapy,
and non-ambulant patients with a single area of compression, paraplegia of < 48 h duration,
non-radiosensitive tumours and predicted survival of > 3 months. There is a significant risk of serious adverse
effects from high-dose corticosteroids (49).
4.1.5 Hepatic invasion
Hepatic invasion by secondary tumour is a common cause of severe hypochondrial pain, often radiating to
the back and shoulder blade. The mechanism may be the stretching of nerve endings in the liver capsule,
diaphragmatic irritation, or haemorrhage into a necrotic area of tumour. Liver pain can often be controlled by
conventional titration of appropriate analgesics or with corticosteroids.

Whole-liver palliative radiotherapy can also be useful in carefully selected patients with refractory pain,
giving far fewer side effects than the alternatives of intra-arterial chemotherapy or hepatic artery embolisation.
Hepatic irradiation can improve abdominal pain with little toxicity in more than half of patients (50). Doses
should not exceed 30 Gy in 15 daily fractions or its equivalent if radiation hepatitis is to be avoided.
4.1.6 Pain due to cancer treatment
4.1.6.1 Acute pain associated with hormonal therapy
Luteinising hormone-releasing hormone (LHRH) tumour flare in PCa
Initiation of LHRH therapy for PCa produces a transient symptom flare in 5-25% of patients (51,52),
presumably caused by an initial stimulation of LH release before suppression is achieved (53,54). The
syndrome typically presents as an exacerbation of bone pain or urinary retention. Spinal cord compression and
sudden death have also been reported (52). Symptom flare is usually observed within the first week of therapy,
and lasts 1-3 weeks. Co-administration of an androgen antagonist at the start of LHRH agonist therapy can
prevent this (55).
4.1.6.2 Chronic pain associated with hormonal therapy
Gynaecomastia
Chronic gynaecomastia and breast tenderness are common complications of anti-androgen therapies for PCa,
the incidence varying between drugs. Frequently associated with diethylstilboestrol (56), it is less common with
flutamide and cyproterone (57-59), and uncommon in patients receiving LHRH agonist therapy (7). In elderly
patients, it must be distinguished from primary breast cancer or secondary cancer in the breast (7).
42
4.1.7
Recommendations at a glance (stage M1) (60-65)
ANTICANCER TREATMENT
Recommendation
Hormonal therapy (orchiectomy, LHRH analogues, diethylstilboestrol equivalent)
Total androgen blockade: flare prevention, second-line
Intermittent androgen suppression experimental
Monotherapy with anti-androgen is an option
First-line treatment controls disease for 12-18 months, second-line individualised
Supportive care
Low-dose glucocorticoids
Chemotherapy
Mitoxantrone plus prednisolone
Estramustine + vinblastine or etoposide or paclitaxel
PAIN MANAGEMENT
Recommendation
Pain assessment (localisation, type, severity, overall distress)
Pain due to painful or unstable bony metastases (single lesions)
External beam irradiation
Pain due to painful bony metastases (widespread)
Radioisotopes (89Sr or 153Sm-EDTMP)
Pain due to painful metastases (many spots)
Bisphosphonates
Denosumab
Systemic pain management
WHO analgesic ladder step 1: NSAID or paracetamol
Opioid administration
Dose titration
Access to breakthrough analgesia
Tricyclic antidepressant and/or anticonvulsant in case of neuropathic pain
4.2
LE
1a
2b
3
2
1b
GR
A
B
B
B
A
1b
1b
2b
B
B
LE
GR
B
1b
1b
1b
A
A
1a
2
1b
1a
B
A
A
Pain management in transitional cell carcinoma patients

From the perspective of pain, there are no differences between transitional cell carcinoma (TCC) and other
histotypes of urothelial malignant tumour. In bladder carcinoma, pain can be present at an early stage as a
burning pain (dysuria), together with irritative symptoms (urgency and frequency), or late in advanced disease
due to obstruction of the upper urinary tract, or local invasion of neighbouring tissues causing pelvic or
metastatic organ invasion. In upper urinary tract TCC, pain is an initial symptom in 18-30% of cases (66,67).
4.2.2 Origin of tumour-related pain
4.2.2.1 Bladder TCC
The main causes of tumour-related pain in bladder TCC are:

obstruction of the upper urinary tract due to growth of bladder tumour close to the ureteral orifices;

Invasion of the surrounding areas by a locally advanced tumour (pelvic wall, nerve roots, other organs
such as bowel, or rectum);

bone metastases;

soft tissue metastases (seldom painful).
The main causes of tumour-related pain in the upper urinary tract TCC are:

obstruction of the upper urinary tract (presenting symptom in around 30% of cases);

acute obstruction due to blood clots;

invasion of the surrounding areas by a locally advanced tumour (posterior abdominal wall, nerve roots,
paraspinous muscles, other organs such as bowel, spleen, or liver);

bone metastases;

43

4.2.3.1 Bladder TCC
Obstruction of the ureteral orifices by tumour infiltration may lead to hydronephrosis and consecutive flank pain
due to ureteral distension (visceral pain). Transurethral resection of the tumour may be effective in eliminating
ureteral obstruction, but in palliative situations, hydronephrosis is mainly treated by temporary or permanent
ureteral stenting or percutaneous/open nephrostomy, similar to the treatment of obstruction caused by PCa
(68).

In locally advanced disease, symptoms are comparable with those caused by T4 PCa. Infiltration
of the contiguous soft tissue and neighbouring organs can cause acute burning pain by infiltration of the
pelvic nerves (neuropathic pain), sometimes associated with paraesthesia irradiating to the lower limb, or
motor deficit. If the tumour invades adjacent organs (small bowel or rectum), there can be obstruction, and
visceral pain due to distension of hollow organs. Growing bladder tumour can cause complete bladder outlet
obstruction, with hypogastric abdominal pain from bladder distension. Obstruction of the lymphatic vessels
by lymphadenopathy can cause lymphoedema of the lower limbs with pain due to distension of muscle fascia
(somatic pain) (68).
In infiltrating and advanced bladder cancer, radical or debulking cystectomy and urinary diversion have a
positive impact on pain, by removing the neoplastic mass invading the surrounding tissues (EAU
Guidelines on Muscle Invasive Bladder Cancer, Chapter 8.1). Extended operations, including excision of
involved bowel, are sometimes indicated. Palliative surgery may be necessary in occlusive intestinal syndromes
(69). In a small retrospective study of patients with tumour infiltration of the rectum by locally recurrent PCa,
total exenteration resulted in significant pain reduction in all patients, and 79% were completely pain free (70).
In a mixed group of cancer patients (colorectal, urinary or gynaecological) with different symptoms such as
bleeding, fistula, or pelvic pain or obstruction, palliative pelvic exenteration improved QoL in 88% (71).
First-line chemotherapy strategies that are mainly based on platinum-containing regimens have some effect in
12-75% of patients with advanced disease (EAU Guidelines on Muscle Invasive Bladder Cancer
Guidelines, Chapter 12). It probably relieves pain by decreasing the neoplastic mass in respondent patients
(72-76) (LE: 1a), but pain control was one of the study end points in only one small study (77).

In a phase III trial, vinflunine, as new second line chemotherapy agent, proved to be very effective
in disease control with 76%, but pain control was not an end point. Quality of life stayed unchanged during
chemotherapy despite drug toxicity (78).
Radiotherapy can be effective in controlling pelvic pain and other symptoms such as frequency and haematuria
due to local disease progression. In a large randomised study with 500 participants, two radiotherapy
schedules (35 Gy in 10 fractions and 21 Gy in three fractions) were compared for symptomatic improvement of
bladder-related symptoms. Sixty-eight percent of the participants achieved symptomatic improvement, 71%
with 35 Gy radiotherapy and 64% with 21Gy. Acute bowel toxicity was noticed in one third of the patients.
There was no significant difference between the two study arms (79) (LE 1a). Some smaller studies have shown
comparable results with respect to improvement of QoL by local radiotherapy (80,81).
Transitional cell carcinoma of the upper urinary tract often presents with microscopic or gross haematuria (7080%), but flank pain also occurs in 20-40% of patients due to obstruction or lumbar mass (EAU Guidelines
on Upper Urinary Tract Urothelial Cell Carcinomas, Chapter 3.4). A multi-institutional study with 654 patients
has shown that local symptoms do not confer worse prognosis compared to patients with incidentally
detected upper urinary tract TCC (82). Locally advanced primary tumours are usually managed by radical
nephroureterectomy. Extended operations including excision of involved bowel, spleen or abdominal wall
muscle are sometimes indicated.
With regard to chemotherapy, the same considerations are valid for upper urinary tract TCC as for bladder TCC
(compare with EAU Guidelines on Upper Urinary Tract Urothelial Cell Carcinomas, Chapter 3.7.2). The standard
chemotherapy regimens that moderately extend survival are MVAC (methotrexate, vinblastin,
adriamycin, cisplatin) and gemcitabine/cisplatin as first-line drugs, as in bladder cancer (83). In a phase II study
of 151 patients with locally advanced or metastatic urothelial cancer, 45 patients (29%) with upper urinary
tract carcinoma were included, and vinflunine as second-line chemotherapy demonstrated moderate activity in
these patients (84)
Haematogenous metastases to the bone are often found in advanced bladder or upper urinary tract TCC. No
44
data are available in the literature concerning the specific effect of chemotherapy on bone metastases alone.
Radiotherapy has a palliative analgesic role in bone metastases (Chapter 3.3.3) and pain reduction > 50%
can be achieved in 50% of patients (85) (LE: 1b). All the data concerning radiotherapy or radionuclide therapy
of bone metastases have been taken from series including different carcinomas such as prostate, breast or
kidney cancer. There are no specific trials studying the effect of radiotherapy on painful bone metastases in
bladder cancer. Single-fraction radiotherapy is as effective as multifraction radiotherapy in relieving metastatic
bone pain (21,86) (LE: 1a). However, the rates of retreatment and pathological fractures are higher after single
fraction radiotherapy (21,86) (LE: 1a).
Radioisotope treatment (Chapter 3.3.2) or hemi-body irradiation can be used in patients with multiple bone
metastases (85). There are no specific studies of radioisotope therapy for bone metastasis in TCC. Orthopaedic
surgery can stabilise pathological fractures, as for those from PCa (Section 3.3.3.4 Pathological fractures)
Recommendations
In locally advanced bladder cancer, palliative cystectomy or exenteration might be an option
for symptom relief.
Use radiotherapy to reduce pain and symptoms of locally advanced bladder cancer.
Use radiotherapy to reduce pain due to bone metastases.
LE
3
GR
B
1a
1b
B
A
4.2.5

Conclusion for symptomatic locally advanced or metastatic urothelial cancer

Chemotherapy in urothelial cell carcinoma is effective in terms of disease control (LE 1b).
There is a correlation between pain control and quality of life (LE 2a).
4.3.
Pain management in renal cell carcinoma patients

Renal cell carcinoma (RCC) is not painful unless the tumour invades adjacent areas or obstructs urine outflow
due to haemorrhage and blood clot formation. Some 20-30% of patients present with metastases, and 30%
of patients, primarily presenting with a localised kidney tumour, develop them during follow-up. Renal cell
carcinoma metastasises mainly to lung, bone, brain, liver and ipsilateral or contralateral adrenergic glands.
Such patients have a maximal 2-year survival rate of 20%. Overall, 50-60% of patients may need treatment for
the symptoms of metastatic disease, mainly pain.
The main origins of tumour-related pain are:

invasion of the surrounding areas by a locally advanced tumour (posterior abdominal wall, nerve roots,
paraspinous muscles, other organs such as bowel, spleen, liver);

obstruction of the upper urinary tract due to haemorrhage and subsequent formation of blood clots;

bone metastases;

Patients with invasion of surrounding areas (e.g. the posterior abdominal wall, nerve roots, paraspinous
muscles, other organs such as bowel, spleen, liver) by a locally advanced primary tumour without metastases
usually present with pain. Surgical management is the only effective option for this type of tumour.

Extended operations that include excision of involved bowel, spleen or abdominal wall muscle are
sometimes indicated.
Adjuvant immunotherapy or radiotherapy is without proven benefit with regard to recurrence. Even in cases
of metastatic disease, palliative nephrectomy is indicated for the control of severe symptoms such as
haemorrhage, pain or paraneoplastic syndromes (GCP). The frequency with which each of these symptoms
is controlled, however, is unclear and there are no data in the literature comparing efficacy of nephrectomy in
palliative situations with other therapies such as angioinfarction of the tumour.

Standard pre-operative (30 Gy) or postoperative radiotherapy offers no survival benefit, and its role in
delaying local progression is questionable (87).

Low dose radiotherapy of soft tissue has no proven benefit for pain or tumour control. However, there
are emerging data indicating that a complete palliative response is more likely when higher biologically effective
doses of irradiation are delivered, especially to patients with a relatively high performance status (88).
In metastatic disease, the EORTC Genitourinary Group study 30947 demonstrated a significant increase in
45
survival with palliative nephrectomy plus immunotherapy compared with immunotherapy (interferon-) alone
(median survival of 17 compared with 7 months) (89) (LE: 2b). There is no special effect on pain relief from
immunotherapy.
Recommendations
GR
Obstruction of the upper urinary tract due to haemorrhage and subsequent formation of blood clots is GCP
effectively treated by radical nephrectomy in non-metastatic tumour.
If the patient is physically fit for surgery, this should be done to increase the QoL, e.g., palliative
GCP
nephrectomy in cases of metastatic tumour.
GCP = good clinical practice
There are no data in the literature about the efficacy of other therapies such as angioinfarction of the tumour
with regard to haemorrhage and pain relief in palliative situations. WHO guidelines recommend analgesic
therapy and/or palliative drainage of the urinary tract if patients are not fit for major surgery.
Patients with bone metastases have a significantly better life expectancy (30 months) than those with visceral
metastases (11.6 months) (90).

Surgery is indicated for solitary bone metastases that can be resected completely, intractable bone
pain, and impending or demonstrable pathological fracture. In bone metastases with extensive soft tissue
involvement and severe pain, amputation of a limb is sometimes required to maintain quality of life. Surgery
for bone metastases achieves a significant decrease in pain in 89-91% of patients (91-93) (LE:3). Additionally,
surgery prevents pathological fractures and spinal compression, and there is a significant impact on survival.
Preoperative embolisation of bone metastases or embolisation alone achieves good pain relief in
hypervascular bone metastases (94,95) (LE: 3).
High-dose radiotherapy for palliation of painful bony metastases has been shown to be effective in 50-75%
of all renal cancer patients (96-98) (LE: 3), and in 67% with general bone metastases (99) (LE: 2b). There is
no impact on survival. Small studies of radionuclide therapy (e.g., 89Sr) have shown good pain relief in bony
metastases from RCC (100) (LE: 3). Also, some minimally invasive attempts to control bone metastases seem
promising (101).
Bone metastases show poor response to immunotherapy, and there is no proven benefit in pain relief.
Hormonal therapy and chemotherapy are even less effective, and have no room in pain control.

Immunotherapy alone achieved an overall response in 15-27% of patients (102). Immunotherapy in
combination with chemotherapy (interleukin-2 + interferon- + 5-fluorouracil) is the most effective therapy,
achieving partial tumour response in up to 46% of patients and complete response in a maximum of 15%,
although these rates are mainly for lung/lymph node metastases (103).
Pain due to soft tissue metastases probably behaves analogous to tumour response, but there are no data on
immunotherapy for pain control. Hormonal therapy has no proven benefit for survival or pain relief.

New inhibitors of the VEGF/VEGFR and mammalian target of rapamycin (mTOR) pathways (sorafenib,
sunitinib, temsirolimus, bevacizumab, everolimus and pazopanib) are changing the second-line therapy to
advanced renal cancer. Nevertheless, it is not clear yet what the ideal therapeutic schedule could be (104).
Renal cell carcinoma tends to spread to the brain. Radiosurgery seems to be an effective treatment modality
for patients with brain metastases from RCC, and early significant tumour volume reduction after radiosurgery
seems to result in long-term survival in RCC patients with brain metastases (105). Further randomised trials
comparing whole brain radiation therapy (WBRT) alone versus WBRT plus stereotactic radiosurgery in treating
patients with radioresistant brain metastases are needed.
4.4
Pain management in patients with adrenal carcinoma
Adrenal carcinoma is a rare disease and has a poor prognosis. Non-functional adrenal lesions of more than 5
cm in diameter should be removed because there is a high probability of malignancy (106).
4.4.1 Malignant phaeochromocytoma
Phaeochromocytomas result from phaeochromocytes, which are the predominant cells of the adrenal medulla
and are also found in the paraganglia near the aorta and in lesser numbers in the ganglia of the sympathetic
nervous system (107). When correctly diagnosed and treated, the disease is curable, unless there are
metastases.
46
Computed tomography (CT) and MRI have the highest sensitivity in detecting the tumour, achieving 94-100%.
A 131I-metaiodobenzylguanidine (131I-MIBG) scan is positive in approximately 87% of cases (108).
Chemotherapy with cyclophosphamide, vincristine and dacarbazine has little effect on metastases (109)
(LE: 2b), but therapeutic doses of 131I-MIBG (33 GBq = 900 mCi) may produce some results (110,111)
(LE: 2b). The hormone response rate is 50%. There are no data on pain relief with 131I-MIBG in metastatic
phaeochromocytoma, but a response rate that is at least the same as for hormone levels should be expected.
Malignant phaeochromocytomas are considered radioresistant, although there are some cases in which
radiation therapy induced partial remission (112) (LE: 3). There is no information about the efficacy of radiation
concerning pain relief in cases of bone or soft tissue metastases.
4.4.2

Treatment of pain
oft tissue and/or bone pain due to metastases are best treated by therapeutic doses of 131I-MIBG,
S
if the phaeochromocytoma takes up this radionuclide (113) (LE: 2b). There is no literature concerning
chemotherapy or radiotherapy and pain relief in metastatic phaeochromocytoma.
Treat the pain symptomatically following the recommendations made in Section 3.4.
4.4.2.1 Adrenocortical carcinomas

Carcinoma of the adrenal cortex is highly malignant, with local and haematogenous metastasis, and 5-year
survival rates of 25-43% for all treatments. Patients with distant metastases have a mean survival of only 4
months (114). An autopsy study showed metastasis to lung (60%), liver (50%), lymph nodes (48%), bone (24%)
and pleura/heart (10%) (115). These tumours often extend directly into adjacent structures, especially the
kidney.
Chemotherapy is of low efficacy. The most effective drug is mitotane, an adrenolytic. The tumour-response rate
is 25-35% (114,116) (LE: 2a). It remains to be proven whether chemotherapy prolongs survival. Radiotherapy
has not been useful except for palliation and pain management (117) (LE: 2b).
4.4.2.2 Treatment of the pain depending on its origin

Abdominal symptoms are typical on first presentation of the tumour. The treatment is surgical
removal of the primary tumour, with attempts to remove the entire lesion even if resection of adjacent
structures is necessary, as well as resection of local lymph nodes.

Soft tissue and/or bone metastases causing local symptoms can be treated by radiotherapy (113,117).
There are no data on chemotherapy or radiotherapy for pain relief in metastatic adrenocortical
carcinomas.

Treat the pain symptomatically following the recommendations given in Section 3.4.
4.5
Pain management in penile cancer patients

Penile cancer is rare in Europe, with an annual incidence of 0.3-1.0 new cases per 100,000 men (118). It mostly
affects men between the ages of 50 and 70 years, with only 19% of cases in those aged < 40 years and 7% in
those < 30 years (119). The penile lesion itself usually alerts the patient to the presence of a penile cancer but
there is often a delay in seeking medical attention.
Lymph node involvement is a critical component of treatment planning and prognosis. Up to 60% of the
patients at the time of presentation have palpable inguinal lymphadenopathy, and up to 85% of men will be
found to have metastatic disease (120). Pain can occur in both early and advanced penile cancer. In the early
stages, acute pain is expressed mainly by voiding dysfunction (infravesical obstruction) due to invasion of the
corpus spongiosum. In advanced disease, pain is also caused by enlarged inguinal or pelvic node metastases
and lymphoedema of the scrotum and lower limbs. Azotemia can develop secondary to nodal obstruction
of the ureters. Hypercalcemia was reported in 17-21% of patients in two series (121). This was attributed
to the parathyroid-hormone-like substances secreted by bulky metastases that stimulate osteoclastic bone
resorption.
Soft tissue and hollow-viscus invasion
Bladder outlet and ureteric obstruction is managed in the same manner as that described in Section 4.1.2.2.
47
4.5.3 Lymphoedema
Patients with a huge inguinal tumour mass, or scarred inguinal tissue after lymph node dissection, often show
lymphoedema of the lower limbs. This is more frequent in cases involving both inguinal and iliac nodes.
Lymphoedema is treated with physiatric techniques (wraps, pressure stockings or pneumatic pumps), which
can both improve function, and relieve pain and heaviness. Orthotics can immobilise and support painful or
weakened structures, and assistive devices can benefit patients with pain on weight-bearing or ambulation.
Pain management begins with antitumour treatment; usually surgery that includes partial/total penectomy, and
inguinal and pelvic lymphadenectomy, depending on the clinical stage of the disease. Advanced penile cancer
has a poor prognosis and must be approached with a multimodal treatment regimen that includes neoadjuvant
chemotherapy, radiotherapy, followed by surgical resection (122).
The chemotherapy regimen that is so far most effective and well tolerated is paclitaxel, ifosfamide and cisplatin
(TIP), although large randomised trials are lacking (123). The role of radiotherapy is mainly palliative because
its use after chemotherapy might decrease the pain from fixed inguinal nodes, bone metastases, spinal
cord compression and paraplegia (124). Treatment of hypercalcemia consists of administration of iv saline
for volume expansion, furosemide to promote diuresis and bisphosphonates to prevent osteoclastic bone
resorption. When tumour erosion into femoral vessels is suspected, emergency intervention with endoluminal
vascular stents or transobturator bypass graft should be undertaken (125,126).
4.5.5 Conclusions
Pain management related to advanced penile carcinoma should include a multimodality regimen that consists
of cisplatin-based chemotherapy, radiotherapy and surgical resection. The goals of palliative care should
be: alleviation of pain using systemic analgesic pharmacotherapy (WHO Ladder) if multimodality therapy is
unsuccessful, wound care, treatment of hypercalcemia and tumour erosion of the large groin vessels.
4.6
Pain management in testicular cancer patients

Testicular cancer generally affects men in the third or fourth decade of life. It is mainly diagnosed causally as an
intrascrotal mass. Approximately 20% of patients present with scrotal or inguinal pain, which disappears after
orchiectomy. Only 11% of patients complain of back or flank pain at first presentation (127). Primary advanced
tumour with pain due to bone metastases is very rare, maximally 3% at first presentation. It should be treated
causally by primary chemotherapy and adjuvant analgesics.
Orchiectomy is an effective treatment for local pain due to scrotal masses.
4.6.3

48
Pain due to metastases

Back or flank pain due to retroperitoneal lymphadenopathy slowly disappears as chemotherapy
causes the mass to decrease (128) (LE: 2b). Temporary analgesia is advisable (see Section 3.4.4).
Retroperitoneal lymph node metastases can also cause obstruction of the ureter, leading to a
symptomatic hydronephrosis with back or flank pain and perhaps additional fever. The therapy of
choice is the immediate treatment of the hydronephrosis by ureteral stenting or the insertion of a
percutaneous nephrostomy.
Bone pain due to bony metastases is very rare and occurs mainly in patients with primary advanced
disease and relapse after chemotherapy (129,130). Treatment with chemotherapy or second-line
chemotherapy may be possible (128). There is no literature on radiotherapy in cases of relapse and
limitation of further chemotherapy.
Back pain and neurological symptoms due to spinal cord compression by vertebral metastases may
require urgent surgery (131) (LE: 3).
4.7
Recommendations at a glance
Table 4: Efficacy of the therapeutic options in pain relief (expert opinion)

Origin of pain/therapeutic options
RCC
TCC
PCa
Penile Adrenergic Testicular

cancer cancer
cancer
Surgery
+++
Radiation
++
++
+++
Radionuclide
+++
++
Chemotherapy
Immunotherapy
Hormone therapy
++
Analgesics
+++
+++
+++
+++
+++
+++
Surgery
+++
+++
Radiation
++
++
Chemotherapy
++
++
+++
Immunotherapy
Hormone therapy
++
Analgesics
+++
+++
+++
+++
+++
+++
+++
+++
++
++
Bone metastases
Soft tissue infiltration
Nerve compression/nerve infiltration

Surgery
Radiation
++
Chemotherapy
++
+++
Immunotherapy
Hormone therapy
++
Analgesics
+++
+++
+++
+++
+++
+++
? = no conclusive data on pain control; - = no pain control; + = low pain control;
++ = moderate pain control; +++ = good pain control.
! Although studies are lacking, patients presenting with bone metastases or soft tissue metastases should not
be refused for radiotherapy as an antalgic effect can be expected.
4.8
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5. POSTOPERATIVE PAIN MANAGEMENT

5.1 Background
Postoperative pain is inevitable in surgical patients, and is associated with tissue damage, the presence of
drains and tubes, or postoperative complications, or a combination of these (1,2).

Approximately 70% of surgical patients experience a certain degree (moderate, severe or extreme)
of postoperative pain (3,4) (LE: 1a). This is usually underestimated and undertreated (1,4), leading to increased
morbidity and mortality, mostly due to respiratory and thromboembolic complications, increased hospital stay,
impaired QoL, and development of chronic pain (1,4-7) (LE: 1a).
5.2
Importance of effective postoperative pain management
The physiological consequences of postoperative pain are shown in Table 5. All of these can delay or impair
postoperative recovery and increase the economic cost of surgery (longer hospitalisation) (8,9) (LE: 3).
Inadequate postoperative pain control may also lead to development of chronic pain (6,10) (LE: 2b).
Table 5: Physiological consequences of postoperative pain
Condition
Stress response to surgery
Respiratory complications
Cardiovascular complications
56
Consequences
Tissue trauma results in release of mediators
of inflammation and stress hormones
Activation of this stress response leads to:
- retention of water and sodium
- increase in metabolic rate
Shallow breathing
Cough suppression
Lobular collapse
Retention of pulmonary secretions
Infections
Hypertension
Tachycardia
Increased myocardial work,
- myocardial ischaemia
- angina
- infarction
Ref.
(11)
LE
2a
(12)
2b
(13)
2b
Thromboembolic complications
Gastrointestinal complications
Musculoskeletal complications
Psychological complications
5.2.1

Reduced mobility due to inadequate pain

management can lead to thromboembolic
episodes
Gastric stasis
Paralytic ileus mostly after open urological
operations
Prolonged confinement to bed:
- reduced mobility
- muscle atrophy
Perioperative pain may provoke fear and
anxiety, which can lead to:
- anger
- resentment
- hostility to medical and nursing personnel
- insomnia
(14)
2a
(15)
2b
(9)
(8,9)
Aims of effective postoperative pain management

To improve patient comfort and satisfaction.
To facilitate recovery and functional ability.
To reduce morbidity.
To promote rapid discharge from hospital (1,2,4) (LE: 1a).
5.3
Pre- and postoperative pain management methods
5.3.1

Preoperative patient preparation

Patient evaluation.
Adjustment or continuation of medication to avoid abstinence syndrome.
Premedication as part of multimodal analgesia.
Behavioural-cognitive interventions for patients and families to alleviate anxiety and fear of
postoperative pain reduce postoperative analgesic requirements and result in better pain management
(1) (LE: 1a).
Recommendation
Preoperative assessment and preparation of patients allow more effective pain management.
LE
1a
GR
A
5.3.2 Pain assessment

Careful pain assessment by the surgeon or the acute pain team before and after treatment can lead to more
efficient pain control, and diminished morbidity and mortality (1,3) (LE: 2a). In the post-anaesthesia care unit,
pain should be evaluated, treated and re-evaluated initially every 15 min and then every 1-2 h. After discharge
to the surgical ward, pain should be assessed every 4-8 h before and after treatment (16,17).

Various rating scales have been described to measure postoperative pain, but their major
disadvantage is that they are all subjective, making their results difficult to evaluate, especially in patients with
communication
difficulties (16).
Recommendation
Adequate postoperative pain assessment can lead to more effective pain control and fewer
complications.
LE
2a
GR
B
5.3.3 Pre-emptive analgesia

Pre-emptive or preventive analgesia is defined as the administration of analgesia before surgical incision to
prevent central sensitisation from incision or inflammatory injury, to achieve optimal postoperative pain control
(18). The results of clinical trials on its efficacy are controversial (18,19) (LE: 2b).
5.3.4 Systemic analgesic techniques
5.3.4.1 Non-steroidal anti-inflammatory drugs
NSAIDs act by inhibiting cyclo-oxygenase (COX) and the subsequent production of prostaglandins. The main
advantages of NSAIDs are that they do not produce respiratory depression or sedation, and seem to decrease
the need for opioids (20). However, their analgesic effect is not strong enough for the management of severe
postoperative pain (21). For NSAID dosage and administration, see Table 12, section 5.5.
57
Intravenous administration of NSAIDs should start 30-60 min before the estimated end of surgery, and
oral administration should start as soon as possible. Intramuscular administration of analgesic drugs for
postoperative pain control is generally avoided because of variability of serum drug concentrations (22).
Their main adverse effects are (21):

gastric irritation, ulcer formation, bleeding;

renal impairment;

bronchospasm, deterioration of asthma;

platelet dysfunction, inhibition of thromboxane A2;

perioperative bleeding;

inhibition of bone healing and osteogenesis.
COX-2 selective inhibitors are associated with fewer gastrointestinal complications and better bone healing.
In addition, they cause minimal platelet inhibition compared with non-selective COX inhibitors (23). However,
COX-2 inhibitors are contraindicated for long-term use in patients with cardiovascular problems (24). The use
of COX-2 inhibitors is approved only for short-term postoperative pain therapy.
Recommendations
NSAIDs are often effective after minor or moderate surgery.
NSAIDs often decrease the need for opioids.
Avoid long-term use of COX inhibitors in patients with atherosclerotic cardiovascular disease.
LE
2a
1b
2a
GR
B
B
B
5.3.4.2 Paracetamol
Paracetamol (acetaminophen) is a relatively safe and effective antipyretic and analgesic for mild to moderate
postoperative pain. In cases of severe postoperative pain, co-administration of paracetamol with strong opioids
seems to reduce the consumption of opioids (25) (LE: 2). Its exact mode of action is unclear, although it may
act by centrally inhibiting COX production (26).
Dosage and routes of administration

1 g four times daily (orally, iv or rectally). Dose should be reduced to 1 g three times daily in patients
with hepatic impairment.

iv administration of paracetamol should start 30 min before the end of surgery, and oral administration
as soon as possible.
Adverse effects
No significant adverse effects have been observed in patients receiving paracetamol for acute postoperative
pain. Caution should be taken when it is administered to patients with chronic alcoholism or hepatic failure. A
dose > 6 g/day can cause acute renal failure.
Combinations of paracetamol with opioids
Paracetamol in combination with an opioid provides adequate postoperative analgesia for mild to moderate
pain without the adverse effects of strong opioids. For dosage and administration of paracetamol/opioid
combinations, see Table 11, Section 5.5.
Recommendations
The use of paracetamol is recommended for postoperative pain management because it
reduces consumption of opioids.
Administer paracetamol as a single therapy to alleviate mild postoperative pain without major
adverse effects.
LE
1b
GR
B
2a
5.3.4.3 Metamizole (dipyrone)

Metamizole is an effective antipyretic and analgesic drug used for mild to moderate postoperative pain and
renal colic. Its use is prohibited in the USA and some European countries because of single reported cases of
neutropenia and agranulocytosis. Elsewhere, it is considered to be a useful analgesic and antipyretic drug for
moderate pain. Long-term use of metamizole is best avoided (27,28) (LE: 2b).
Dosage and route of administration
The dose is 500-1000 mg qds (orally, iv or rectally).
58
Adverse effects
Apart from single sporadic cases of neutropenia and agranulocytosis, metamizole can cause minor side
effects such as nausea, mild hypotension, and allergic reactions. Allergic reactions and the rare complication
of agranulocytosis have been described only after direct iv administration, therefore, iv metamizole should be
administered as a drip (1 g in 100 mL normal saline).
5.3.4.4 Opioids
Opioids are the first-line treatment for severe acute postoperative pain. Correct dose titration can minimise
their unwanted effects (29). Opioid dosage and administration can be found in Tables 12 and 13, section 5.5.
5.3.4.5 Patient-controlled analgesia
Systemic administration of opioids may follow the as needed schedule or around-the-clock dosing. The
most effective mode is PCA (30,31) (LE: 1a) (Table 6).
Table 6: Typical PCA dosing schedule
Drug (concentration)
Morphine (1 mg/mL)
Fentanyl (0.01 mg/mL)
Pethidine (10 mg/mL)
Bolus size
0.5-2.5 mg
10-20 g
5-25 mg
Lockout interval (min)

5-10
5-10
5-10
Continuous infusion
0.01-0.03 mg/kg/h
0.5-0.1 g/kg/h
-
Recommendation
The use of intravenous patient controlled analgesia is recommended because it provides
superior postoperative analgesia, improving patient satisfaction and decreasing risk of
respiratory complications.
LE
1b
GR
A
Opioids adverse effects are:

respiratory depression, apnoea;

sedation;

nausea, vomiting;

pruritus;

constipation;

hypotension.
5.3.4.6 Adjuncts to postoperative analgesia
Adjuncts to postoperative analgesia in low doses, such as ketamine, 2 agonists (clonidine or
dexmedetomidine), or gabapentinoids (gabapentin or pregabalin), in appropriate doses and monitored care
are beneficial in improving analgesic efficacy and reducing opioid-related side effects, with good safety and
tolerability (32,33).

Low-dose ketamine is defined as a bolus dose < 2 mg/kg when given im or < 1 mg/kg when
administered via the iv or epidural route. For continuous iv administration, low-dose ketamine is defined
as a rate of < 20 g/kg/min (34). Its use is contraindicated in patients with coronary disease, uncontrolled
hypertension, congestive heart failure and arterial aneurysms. There are insufficient data to confirm the
neurotoxicity of ketamine, even though some animal studies have shown some degree of neurodegeneration
after continuous use (35) (LE: 2b).

Clonidine when given preoperatively, or epidurally postoperatively (1 g/kg) can reduce opioid
requirements (36).

More clinical evidence on dexmedetomidine is necessary to confirm its definite role in acute
postoperative pain control (37).

In 17 studies up to 2007, patients received a single preoperative dose of 300-1200 mg gabapentin,
30 min-2 h before surgery in the remaining studies, the drug was administered at a dose of 1200-1800 mg/day
at 1-24 h before the procedure and continued for 10 days. Gabapentin, used before as well as after surgery,
decreases pain severity and the need for analgesic supplementation (38).

Perioperative pregabalin (300 mg/day) reduces opioid consumption and opioid-related adverse effects
after surgery, however postoperative pain intensity is not reduced by pregabalin (39).
Single-injection caudal blocks with clonidine or ketamine are beneficial in paediatric patients (40).
59
Recommendations
Administer adjuncts in appropriate doses and monitored care to improve analgesic efficacy
and reduce opioid-related side effects.
Administer clonidine preoperatively or epidurally postoperatively to reduce opioid
requirements.
Gabapentin can be administered before as well as after surgery to decrease pain severity and
need for analgesic supplementation.
LE
1a
GR
A
1a
1a
5.3.5 Regional analgesic techniques

5.3.5.1 Local anaesthetic agents
The most commonly used local anaesthetics are:

bupivacaine;

I-bupivacaine;

ropivacaine.
Bupivacaine is considered to be cardiotoxic in high doses. I-Bupivacaine and ropivacaine appear to be safer,
but the degree of motor blockage they provide is not as good as that of bupivacaine. Ropivacaine has the
longest duration of action.
5.3.5.2 Epidural analgesia
Epidural analgesia provides excellent postoperative pain relief for extended periods after major surgery, and
reduces postoperative complications and consumption of opioids (1,2) (LE: 1a) (Table 7).
Table 7: Typical epidural dosing schemes*
Drug
Morphine
Fentanyl
Sufentanil
Pethidine
Bupivacaine 0.125% or ropivacaine
0.2% + fentanyl 2 g/mL
Single dose
1-5 mg
50-100 g
10-50 g
10-30 mg
10-15 mL
Continuous infusion
0.1-1 mg/h
25-100 g/h
10-20 g/h
10-60 mg/h
2-6 mL/h
*l-bupivacaine doses are equivalent to those of bupivacaine.

5.3.5.3 Patient-controlled epidural analgesia
Patient-controlled epidural analgesia (PCEA) has become very common because it allows individualisation of
dosage, decreased drug use, and greater patient satisfaction. It also seems to provide better analgesia than
intravenous PCA (41,42) (LE: 1a) (Table 8).
Table 8: Typical PCEA dosing schemes
Drug
Morphine
Fentanyl
Pethidine
Bupivacaine 0.125% + fentanyl 4 g/mL
Ropivacaine 0.2% +
fentanyl 5 g/mL
Demand dose
100-200 g
10-15 g
30 mg
2 mL
2 mL
Lockout interval (min)

10-15
6
30
10
20
Recommendation on epidural analgesia

Epidural analgesia, especially PCEA, provides superior postoperative analgesia, reducing
complications and improving patient satisfaction, and is therefore preferable to systemic
techniques (41).
Continuous rate
300-600 g/h
80-120 g/h
4 mL/h
5 mL/h
LE
A
GR
1b
5.3.5.4 Neural blocks

Local anaesthetic blocks (intermittent and continuous) can be used after urological surgical operations to
supplement postoperative analgesia (43) (LE: 2a) (Table 9).
60
Table 9: Examples of neural blocks

Procedure
Iliohypogastric or ilioinguinal nerve infiltration after
hernia repair
Intercostal nerve infiltration
Continuous intrapleural infusion
Drug/dosage
10-20 mL bupivacaine or 0.25-0.5% ropivacaine
5-10 mL bupivacaine or 0.25-0.5% ropivacaine
10 mL/h bupivacaine or 0.1-0.2% ropivacaine
5.3.5.5 Wound infiltration

Intraoperative wound infiltration with local anaesthetic (usually 10-20 mL ropivacaine or 0.25-0.5% bupivacaine)
can provide some postoperative analgesia and may reduce the requirement for systemic analgesia (44) (LE:
2b).
5.3.5.6 Continuous wound instillation
Continuous postoperative wound instillation of a local anaesthetic via a multi-hole catheter placed
intraoperatively by the surgeon has been shown to provide satisfactory analgesia for moderate to severe
postoperative pain, reducing consumption of systemic analgesics (45-47) (LE: 2b).
5.3.6 Multimodal analgesia
The concept of multimodal (balanced) analgesia is that combining different doses and routes of administration
of analgesics improves the effectiveness of pain relief after surgery and reduces the maximal dosage and
adverse effects (48) (LE: 2b). It seems to be more effective when different drugs are administered via different
routes than when different drugs are administered via a single route (1) (LE: 2b).
Recommendation
Multimodal pain management should be used whenever possible because it helps to increase
efficacy while minimising adverse effects.
LE
2b
GR
B
5.3.7 Special populations

5.3.7.1 Ambulatory surgical patients
A multimodal analgesic plan uses a combination of NSAIDs or paracetamol plus local anaesthetics used as
peripheral nerve blocks, tissue infiltration, or wound instillation so as to avoid the use of opioids, which can
prolong hospital stay ([49,50], LE: 2a; [51], LE: 2b).
Recommendations
For postoperative pain control in outpatients, multimodal analgesia with a combination of
NSAIDs or paracetamol plus local anaesthetics should be used.
If possible, avoid opioids.
LE
2b
GR
B
5.3.7.2 Geriatric patients

Pain perception appears to be reduced in geriatric patients, and requirement for analgesia generally decreases
with increasing age (52,53). Geriatric patients can also suffer from emotional and cognitive impairment such as
depression and dementia, which could affect adequate pain management (54). Postoperative delirium in elderly
patients is a common complication and is often multifactorial. It may be associated with administration of
pethidine (55). Multimodal postoperative analgesia may be the pain management technique of choice in elderly
patients, as the drug doses required are lower. However, it is important to be vigilant for adverse reactions,
because they tend to increase in number in the geriatric population (56) (LE: 2b). Epidural analgesia might
diminish the risk of postoperative delirium and respiratory complications in elderly patients (57) (LE: 2b).
Recommendation
LE
Multimodal and epidural analgesia are preferable for postoperative pain management in elderly 2b
patients because these techniques are associated with fewer complications.
GR
B
5.3.7.3 Obese patients

Obese patients appear to be at higher risk for certain postoperative complications, including respiratory,
cardiovascular and thromboembolic episodes, and wound infections (58,59). Administration of opioids to obese
patients is associated with sudden respiratory arrest, therefore, a combination of NSAIDs or paracetamol with
an epidural local anaesthetic might be the safest analgesic solution (60,61) (LE: 2b).
61

If absolutely necessary, opioids should be used with caution under careful titration to avoid
depression of the respiratory drive (61). Oxygen therapy should also be applied postoperatively to increase
oxygen saturation (62).
Recommendations
LE
Postoperative use of opioids should be avoided in obese patients unless absolutely necessary. 2b
An epidural local anaesthetic in combination with NSAIDs or paracetamol is preferable.
2b
GR
B
B
5.3.7.4 Drug- or alcohol-dependent patients

It has been proved that regional anaesthesia and analgesia are preferable to opioids in drug addicts. Moreover,
clonidine is beneficial in those with withdrawal syndrome due to opioid or alcohol abstinence and postoperative
delirium tremens (63) (LE:1a).
5.3.7.5 Other groups
Critically ill or cognitively impaired patients present special difficulties. Regional or multimodal analgesia might
be more effective in such patients because drug doses are reduced and behavioural interventions and patientcontrolled methods are unsuitable (LE: 3).
5.3.8 Postoperative pain management teams
The importance of efficient postoperative pain management has led to the development of acute
postoperative pain management teams, which generally consist of nursing and pharmacy personnel led by
an anaesthesiologist. They have been shown to improve pain relief, decrease analgesic side effects, improve
patient satisfaction, and decrease overall costs and morbidity rates (64-66) (LE: 2b). Improved pain control can
lead to shorter hospitalisation and fewer unscheduled readmissions after day surgery (67) (LE: 3).
5.4 Specific pain treatment after different urological operations

5.4.1 Extracorporeal shock wave lithotripsy
Extracorporeal shock wave lithotripsy (SWL) is a minimally invasive treatment, during and after which 33-59%
of patients do not need any analgesia (68-70) (LE: 2b). Post-treatment pain is unlikely to be severe and oral
analgesics are usually sufficient.
Analgesic plan

Preoperative assessment (see Section 5.3.2).

Intraoperatively: experience exists for alfentanil (0.5-1.0 mg/70 kg iv), given on demand during SWL.
NSAIDs or midazolam given 30-45 min before treatment reduces the need for opioids during the procedure
(LE: 2b). With diclofenac premedication (100 mg rectally), only 18% of patients needed pethidine during
lithotripsy (71). After premedication with 5 mg midazolam orally, 70% of patients were completely free of pain
during treatment, and if buprenorphine was added, this proportion rose to 87% (72). After premedication with
midazolam (2 mg iv, 5 min before treatment), diclofenac or tramadol was safe and effective, with fewer side
effects than fentanyl (73) (LE: 1b). Other effective regimes for intraoperative pain treatment are fentanyl (1 g/kg
iv [74]), sufentanil or remifentanil. These drugs are usually given by the anaesthesiologist because of the risk of
respiratory depression, which was significantly lower (20% vs 53%) after the procedure if remifentanil was used
instead of sufentanil (75,76) (LE: 1b).

ostoperative: NSAIDs, metamizole, paracetamol, codeine and paracetamol combination or tramadol

P
can all be used on an as needed or time-contingent basis. If pain is more severe or persistent,
examination is generally necessary to exclude hydronephrosis or renal haematoma.
Recommendations
Analgesics should be given on demand during and after SWL because not all patients need
pain relief.
Premedication with NSAIDs or midazolam often decreases the need for opioids during the
procedure.
iv opioids and sedation can be used in combination during SWL; dosage is limited by
respiratory depression.
Post-SWL, analgesics with a spasmolytic effect are preferable.
LE
3
GR
B
2b
SWL = extracorporeal shock wave lithotripsy.
62
5.4.2 Endoscopic procedures

5.4.2.1 Transurethral procedures
Transurethral operations are usually performed under spinal anaesthesia (epidural or subarachnoid block) with
the patient awake or mildly sedated, and usually with analgesia for 4-6 h after surgery. Pain is generally caused
by the indwelling catheter or the double-J (ureteral stent following ureterorenoscopy), which mimics overactive
bladder syndrome. Drugs with an antimuscarinic effect have been proven to be useful in addition to the opioids
(77) (LE: 1b).
Analgesic plan

Preoperative assessment: see Section 5.3.

Intraoperative: spinal (intrathecal or epidural) anaesthesia provides intraoperative analgesia and last
for 4-6 h postoperatively.

Postoperative: after 4-6 h, mild oral analgesics such as NSAIDs or paracetamol codeine, or stronger
opioids; also orally. In the case of bladder discomfort from the indwelling catheter, metamizole (orally
or iv), pethidine (iv) or piritramide (iv) is also effective. Antimuscarinic drugs such as oxybutynin (5 mg
orally three times daily) are useful and reduce the need for opioids (77) (LE: 1b).
Recommendations
Postoperative analgesics with spasmolytic effect or mild opioids are preferable.
Antimuscarinic drugs could be helpful in reducing discomfort resulting from the indwelling
catheter.
Antimuscarinic drugs may reduce the need for opioids.
LE
3
3
GR
C
B
5.4.2.2 Percutaneous endoscopic procedures

The analgesic plan is nearly the same as that for transurethral procedures. Local anaesthetic (e.g., 10 mL 0.5%
bupivacaine) can be infiltrated locally into the skin incision. General anaesthesia is required for the procedure
because of the uncomfortable decubitus (prone position) and the prolonged duration of the operation.
5.4.2.3 Laparoscopic procedures
These procedures are performed under general anaesthesia, therefore, patients cannot take oral medication for
at least 4-6 h postoperatively, so parenteral analgesia should be used. Then, oral or systemic analgesia can be
given, depending on bowel motility.

A particular problem after laparoscopic cholecystectomy is the development of shoulder pain as
a result of diaphragmatic irritation following pneumoperitoneum. This seems to be dependent on the intraabdominal pressure used during the procedure, because reduced CO2 insufflation reduces postoperative
shoulder pain (78-80) (LE: 1b). The same could apply for some transabdominal urological laparoscopic
interventions.
Analgesic plan

Preoperative assessment: Section 5.3.

Intraoperative: iv opioids NSAIDs, paracetamol or metamizole administered by an anaesthesiologist.
The infiltration of local anaesthetic into the port incisions reduces pain after laparoscopy (81).

Postoperative: administration of systemic opioids iv (im or sc), is very effective in the immediate
postoperative period. NSAIDs (e.g., paracetamol and/or metamizole) and incisional local anaesthetics
(multimodal concept) can be given to reduce the need for opioids (81,82).
Recommendations
Low intra-abdominal pressure and good desufflation at the end of the procedure reduces
postoperative pain.
NSAIDs are often sufficient for postoperative pain control.
NSAIDs decrease the need for opioids.
LE
1b
GR
A
2a
1b
B
B
5.4.3
Open surgery
5.4.3.1 Minor operations of the scrotum/penis and the inguinal approach
These two types of operations are relatively minor and nearly all patients can take oral analgesics afterwards.
The operation is often performed as an ambulatory procedure under local anaesthesia, or with the aid of an
ilioinguinal or iliohypogastric nerve block.
63
Recommendations
For postoperative pain control, multimodal analgesia with a combination of NSAIDs or
paracetamol plus local anaesthetics should be used.
If possible, avoid opioids for outpatients.
LE
3
GR
B
LE
2A
1b
GR
B
B
5.4.3.2 Transvaginal surgery

General, local or regional anaesthesia can be used for these operations.
Recommendations
NSAIDs are often sufficiently effective after minor or moderate surgery.
NSAIDs decrease the need for opioids.
5.4.3.3 Perineal open surgery

Analgesic plan

Preoperative assessment: Section 5.3.

Intraoperative: general anaesthesia is usually used, particularly for perineal radical prostatectomy,
because of the uncomfortable exaggerated lithotomy position. Sometimes an intrathecal catheter
(epidural) can be sited for intra- and postoperative pain control.

Postoperative: continuous epidural infusion of a combination of opioids and local anaesthetic or PCA
is usually used. When systemic opioids are required, it is advisable to use them in combination with
NSAIDs so as to reduce their dose and side effects. When the patient is able to take oral analgesics,
metamizole or paracetamol codeine can be used.
5.4.3.4 Transperitoneal laparotomy
Analgesic plan


Intraoperative: general anaesthetic and regional technique; sometimes an intrapleural catheter can be
sited.

Postoperative: continuous epidural infusion of a combination of opioids and local anaesthetic. Once
the patient is able to take oral analgesics (depending on bowel motility) metamizole, paracetamol
codeine or tramadol can be used. Multimodal concepts (combining NSAIDs with opioids, fast-track
strategies, keeping abdominal and urinary drainage as short as possible) are useful in reducing the
need for analgesia (48).
Recommendations
LE
The most effective method for systemic administration of opioids is PCA (see Section 5.3.4.5), 1b
which improves patient satisfaction and decreases the risk of respiratory complications.
1b
complications and improving patient satisfaction, and is preferable to systemic techniques (see
Sections 5.3.5.2 and 5.3.5.3).
PCA = patient-controlled analgesia; PCEA = patient-controlled epidural analgesia.
GR
A
A
5.4.3.5 Suprapubic/retropubic extraperitoneal laparotomy

Postoperatively, it is possible to use the oral route for analgesia earlier than after a transperitoneal procedure.
Oral opioids, metamizole and/or paracetamol NSAIDs can be used.
Analgesic plan


Intraoperative: general anaesthetic and regional technique.

Postoperative: continuous epidural infusion of a combination of opioids and local anaesthetic. Once
the patient is able to take oral analgesics metamizole, paracetamol codeine, NSAIDs can be used.
5.4.3.6 Retroperitoneal approach - flank incision - thoracoabdominal approach
Analgesic plan


Intraoperative: general anaesthetic and regional technique; sometimes an intrapleural catheter can be
inserted.

Postoperative: continuous epidural infusion of a combination of opioids and local anaesthetic
gives significantly better pain control compared with iv analgesics (83,84). If epidural analgesia is
64
not possible or refused, PCA should be provided. Once the patient is able to take oral analgesics
(depending on bowel motility) paracetamol codeine or metamizole can be associated (to reduce the
need for opioids) or used alone.
Recommendation
complications and improving patient satisfaction and is therefore preferable to systemic
techniques (see Sections 5.3.5.2 and 5.3.5.3).
LE
1b
GR
A
PCEA = patient-controlled epidural analgesia.
5.5
Dosage and method of delivery of some important analgesics
5.5.1
NSAIDs
Table 10: Dosage and delivery of NSAIDs

Drug
Conventional NSAIDs
(non-selective COX inhibitors)
Ketorolac
Ibuprofen
Ketoprofen
Diclofenac
COX-2 selective inhibitors

Meloxicam
Lornoxicam
Celecoxib
Parecoxib
Etoricoxib
Daily dose
Route of administration
10-30 mg four times daily

400 mg three times daily
50 mg four times daily
75 mg twice daily
50 mg three times daily
100 mg twice daily
Orally or iv
Orally
Orally or iv
Orally or iv
Orally or iv
Rectally
15 mg once per day

4-8 mg twice daily
200 mg once per day
40 mg once or twice daily
90-120 mg once daily
Orally
Orally or iv
Orally
iv form only
Orally
Table 11: Dosage and delivery of paracetamol, metamizole and its combinations with opioids
Drug
Paracetamol
Paracetamol
Metamizole
Metamizole
Method of administration
Orally
iv
Orally
iv
Single dose (mg)

500-1000
1000
500-1000
1000-2500
Maximal dose (mg/day)

4000 (50 mg/kg)
4000 (50 mg/kg)
4000
5000
Paracetamol
Paracetamol 1 g
Paracetamol 600-650 mg
Paracetamol 500 mg
Paracetamol 300 mg
Paracetamol 650 mg
Paracetamol 600-650 mg
Paracetamol 325 mg
Opioid
Codeine 60 mg
Codeine 60 mg
Codeine 30 mg
Codeine 30 mg
Dextropropoxyphene 65 mg
Tramadol 75-100 mg
Oxycodone 5 mg
Times per day

Four
Four
Four
Four
Four
Four
Four
Orally or rectally
Orally or rectally
Orally or rectally
Orally or rectally
Orally
Orally
Orally
5.5.2
Opioids
65
Table 12: Dose and delivery of opioids

Drug
Method of administration
Tramadol
Tramadol
Dihydrocodeine
Piritramid
Pethidine
Pethidine
Pethidine
Pethidine
Morphine*
Morphine*
Morphine*
Morphine*
Morphine*
10-15 min lockout
Orally
iv
Orally
sc/im
Orally
Rectally
sc/im
iv
Orally
Rectally
sc/im
iv
Iv (PCA)
No maximal dose
Common single
dose (mg)
50
50-100
60-120
15-30
25-150
100
25-150
25-100
Starting with 10
Starting with 10
Starting with 5
Starting with 2
0.5-2.5 mg bolus
Maximal dose (mg)

400-600
400-600
240
120
500
500
500
500
No maximal dose
No maximal dose
No maximal dose
No maximal dose
*Strong opioids have no real upper dose limit (except buprenorphine). The dose must be titrated in correlation
with pain relief and depending on the individual strength of unwanted effects such as respiratory depression
(Section 5.3.4.4).
*A simple way of calculating the daily dose of morphine for adults (20-75 years) is: 100 - patients age =
morphine per day in mg.
Table 13: Common equi-analgesic doses for parenteral and oral administration of opioids*
Drug
Morphine
Fentanyl
Pethidine
Oxycodone
Dextropropoxyphene
Tramadol
Codeine
Parenteral (mg)
10
0.1
75
15
37.5
130
Oral (mg)
30
300
20-30
50
150
200
*All listed opioid doses are equivalent to parenteral morphine 10 mg. The intrathecal opioid dose is 1/100, and
the epidural dose 1/10 of the dose required systemically.
5.6
Perioperative pain management in children
5.6.1 Perioperative problems

The main preoperative problems in children are fear of surgery, anxiety about separation from their parents,
and the pain of procedures such as venipuncture. Contrary to the popular belief, the presence of parents
during anaesthesia induction does not alleviate childrens anxiety (85) (LE: 1a). The preoperative use of oral
morphine sulphate, 0.1 mg/kg, can help to prevent crying in children and thereby reduce oxygen consumption
and pulmonary vasoconstriction (Table 16). The prior application of EMLA (2.5% lidocaine and 2.5% prilocaine)
cream helps to reduce the pain of venipuncture (86) (LE: 1a). Atropine, 0.01-0.02 mg/kg iv, im, orally or rectally,
prevents bradycardia during anaesthesia induction.
Table 14: Premedication drugs in children
Drug
Ketamine
Midazolam
Dexmedetomidine
Clonidine
Pentobarbital
Chloral hydrate
Methohexital
66
Dosing
6 mg/kg
0.5 mg/kg
4 g/kg
4 g/kg
4-6 mg/kg
50-100 mg/kg
25-30 mg/kg
Oral, intranasal, im
Oral, intranasal, rectally
Oral, intranasal
Oral
im
Oral
Rectally
Category
NMDA antagonist
Benzodiazepine
2-receptor agonist
2-receptor agonist
Barbiturate
Barbiturate
Barbiturate
Recommendation
Apply EMLA locally to alleviate venipuncture pain in children.
LE
1b
GR
A
5.6.2 Postoperative analgesia

Postoperatively, paracetamol, NSAIDs, opioids and their combinations are used according to the severity of the
surgical procedure (Table 15).
Table 15: Dosage of analgesics in children for postoperative analgesia
Drug
Dose
Paracetamol
10-15 mg/kg every 4 h

6-8 mg/kg every 8-12 h
0.5-1 mg/kg every 3-4 h
0.1 mg/kg every 2-4 h
Infusion: 0.03 mg/kg/h 0.3
mg/kg every 3-4 h
0.1-0.2 mg/kg every 3-4 h
0.04-0.08 mg/kg every
3-4 h
1 mg/kg every 4-6 h
2-3 mg/kg every 3-4 h
Oral, rectally
Ibuprofen
Naproxen
Codeine
Morphine
Oxycodone
Hydromorphone
Tramadol
Pethidine
Oral, iv, rectally

Oral, iv, rectally
Oral
Oral, iv, sc
Severity of surgical
procedure
Minor
Minor
Minor, medium
Minor, medium
Minor, medium
Medium, major
Oral
Oral
Medium
Medium
iv
iv
Medium, major
Medium, major
The postoperative use of COX-2 inhibitors in children is still controversial. PCA can be used safely in children
older than 6 years. Nurse-controlled analgesia is effective in infants and children unable to use PCA (87).

Locoregional techniques such as wound infiltration, nerve blocks, and caudal and epidural analgesia
are also successful (88,89). The most commonly drugs used are bupivacaine and ropivacaine (Table 16). Higher
volumes of lower drug concentrations appear to be more effective than lower volumes of higher concentrations
(90) (LE: 1a). The addition of opioids, ketamine or clonidine increases the duration of pain relief and reduces
the need for rescue analgesia, thus providing more effective pain relief than local anaesthesia alone in caudal
analgesia (91-93) (LE: 1a).
Table 16: Epidural dose of local anaesthesia
Drug
Bolus 0-12 months Bolus > 1 year
Bupivacaine
Ropivacaine
2 mg/kg
2.5 mg/kg
2.5 mg/kg
3.5 mg/kg
Infusion for 0-12

months
0.2 mg/kg/h
0.3 mg/kg/h
Infusion > 1year

0.4 mg/kg/h
0.6 mg/kg/h
67
Figure 3: Postoperative pain management

Acute postoperative pain
Exclude medical/surgical emergency
Refer to appropriate level of treatment
Exclude medical/surgical emergency
No pain
Pain level reassessment

and evaluation every
4-6 hrs unless patient
expresses discomfort
Mild (VAS score 1-3)
Moderate (VAS score 4-6)
Severe (VAS score 7-10)
(SWL, transurethral, percutaneous

endoscopic, transvaginal
procedures)
(Laparoscopic, minor operations

of the scrotum/penis and the
inguinal approach)
(Open surgery - perineal,

transperitoneal, suprapubic,
retropubic extraperitoneal
laparotomy, retroperitoneal
approach, flank incision,
thoracoabdominal approach)
P
aracetamol 500mg-1g x 4
iv and/or NSAIDs (diclofenac
50mg x3 iv, ketorolac 10-30
mg x 4 iv, lornoxicam 4-8mg
x 2 iv, parecoxib 40mg x 2
iv) and/or metamizole 5001000mg x 4 iv or paracetamol
500-1000mg plus codeine
30-60mg x 4 orally.
P
iv) and/or metamizole 5001000mg x 4 iv or paracetamol
500-1000mg plus codeine
30-60mg x 4 orally.
Pethidine 50-100mg x 6 iv or
tramadol 50-100 mg x 6 iv or
morphine 5mg starting dose
x 4-6 times per day sc/im or
2mg starting dose x 6 iv.
P
iv) and/or metamizole 5001000mg x 4 iv
PCA with morphine iv (0.52.5mg bolus, 10-15 min
lockout)
PCEA with morphine 100200g demand dose, lockout
interval 10-15 min and
continuous rate 300-600g/h
ropivacaine 0.2% 2ml
demand dose, and continuous
rate 5ml/h or bupivacaine
0.125% 2ml demand dose and
continuous rate 4ml/h.
In case of persistent pain

pethidine 50-100mg iv or
tramadol 50-100 mg iv prn.
In case of persistent pain add or

increase morphine dose by 2mg
bolus in 1 hr increments
In case of persistent pain extra

morphine 2-5 mg iv or morphine
1-5mg 10-15ml bupivacaine
0.125% or ropivacaine
0,2% bolus epidurally in 1 hr
increments.
5.7
References
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6. NON-TRAUMATIC ACUTE FLANK PAIN

6.1 Background
Acute flank pain is a frequently occurring and complex medical problem. Ureterolithiasis is the most common
non-traumatic cause. However, half of all renal colics are not caused by urolithiasis (1-3) (Table 17).
Table 17: Main urological and non-urological causes of flank pain
Urological causes
Renal or ureteral stones
Urinary tract infection (pyelonephritis, pyonephrosis, renal abscess)
Uretero-pelvic junction obstruction
Renal vascular disorders (renal infarction, renal vein thrombosis)
Papillary necrosis
Intra- or peri-renal bleeding
Testicular cord torsion
6.2
Non-urological causes
Aortic aneurysm
Gallbladder disorder
Gastrointestinal disorders
Pancreatic disease
Gynaecological disorders
Musculoskeletal disease
Initial diagnostic approach
6.2.1 Symptomatology
History and physical examination, including body temperature, can be very helpful in the differential diagnosis
73
of acute flank pain (4).

Acute renal colic is indicated by pain of short duration (< 12 h), nausea, vomiting, loin tenderness and
haematuria (erythrocytes > 10,000/mm3) (4).

Because the signs and symptoms can be very similar, acute uncomplicated pyelonephritis should be
immediately differentiated from complicated renal colic:

- Concomitant fever (> 38C) makes imaging obligatory (5). A radiological evaluation of the
upper urinary tract should be offered to every patient presenting with flank pain and fever to
rule out urinary tract obstruction irrespective of the accompanying symptoms, duration of the
episode and urine macroscopic or microscopic findings.

- Imaging is also imperative in patients with acute flank pain and a solitary kidney (5) (LE: 4).

Acute flank pain in patients with an increased risk for thromboembolic events should raise the
suspicion of renal infarction (6).

Careful abdominal examination can reveal an abdominal aortic aneurysm (misdiagnosed in 30% of
patients).

Renal vein thrombosis (RVT) may often present with symptoms of acute flank pain, proteinuria,
haematuria, hypotension and renal insufficiency.

Obstruction of the ureteropelvic junction can result in acute flank or abdominal pain after a high fluid
volume intake, especially in paediatric patients.

Renal papillary necrosis is not uncommon in the course of systemic diseases such as diabetes
mellitus or analgesic nephropathy; the passage of sloughed papillae down the ureter may cause flank
pain and haematuria.

Testicular torsion should always be excluded in children with acute abdominal/flank pain.

Torsion of the appendix testis can also result in abdominal pain or radiate to the flank.

Spontaneous bleeding either within the kidney or to the retroperitoneum can be caused by kidney
tumours (including angiomyolipomas), bleeding disorders or anticoagulation; acute flank pain is
sometimes the presenting symptom.
Recommendation
Febrile patients (> 38C) with acute flank pain and/or with a solitary kidney need urgent
imaging.
LE
4
GR
B*
*Recommendation based on expert opinion.

6.2.2 Laboratory evaluation
All patients with acute flank pain require a urine test (red and white cells, bacteria or urine nitrite), blood cell
count, and serum creatinine measurement. In addition, febrile patients with flank pain require C-reactive protein
and urine culture. Pyelonephritis obstructive uropathy should be suspected when the white blood count
exceeds 15,000/mm3.
6.2.3 Diagnostic imaging
6.2.3.1 Ultrasonography
Unenhanced helical computed tomography has high sensitivity and specificity for the evaluation of acute
flank pain (7,8) (LE: 1a). Unenhanced helical computed tomography (UHCT) is superior because it detects
ureteral stones with a sensitivity and specificity of 94-100%, regardless of stone size, location and chemical
composition, and identifies extraurinary causes of flank pain in about one-third of all patients presenting with it.
In addition, it does not need contrast agent, and is a time-saving technique (8,9) (LE: 1a).
6.2.3.2 Intravenous urography
The use of US in the management of acute flank pain has been increasing. If the findings of pelvic and/
or ureteral dilatation, stone visualisation and the absence of ureteral ejaculation are combined, sensitivity
to ureteral dilatation can be 96% (7,10,11) (LE: 2a). Together with a plain abdominal radiograph, US can be
accepted when computed tomography (CT) is not available (7,12-16) (LE: 1b).The disadvantages of US include
inability to differentiate dilatation from true obstruction and the need for highly specialised personnel (12).
Sensitivity varies from 58 to 96% in untrained staff in emergency rooms (14), but evidence suggests that, with
even short training, non-specialists can be highly effective at excluding disorders such as abdominal aortic
aneurysm, free abdominal fluids, gallstones and obstructive uropathy (14) (LE: 2b). US is the diagnostic imaging
modality of choice during pregnancy.
6.2.3.3 Unenhanced helical CT
Intravenous urography (IVU) reliably provides information on the anatomy of the urinary collecting system
(ureteral and renal pelvic dilatation) in 80-90% of cases and can identify ureteral calculi in 40-60% of cases.
74
Direct identification of ureteral calculi can be achieved in 40-60% of cases, whereas indirect signs (e.g. ureteral
and renal pelvic dilatation) allow detection in 80-90% of cases. Drawback is that IVU results can be hampered
by poor quality related to suboptimal bowel preparation, toxicity of contrast agents, allergic and anaphylactic
reactions, and by significant radiation exposure. In emergency cases, IVU should be avoided due to the risk of
fornix rupture.

Unenhanced helical CT or IVU should be considered in patients initially evaluated by other means who
are still febrile after 72 h of treatment to rule out further complicating factors (renal, perinephric or prostatic
abscesses) (8,9).

Table 18 shows comparative results of UHCT US and IVU in assessing acute flank pain and suspicion
of ureterolithiasis (17-19). Figure 4 summarises the diagnostic approach to non-traumatic acute flank pain.
75
Figure 4: Diagnostic approach to non-traumatic acute flank pain
Acute flank pain

History, physical examination, temperature, urinalysis pain treatment
If not conclusive
Ultrasonography and/or unenhanced CT scan
Normal + normal
urinalysis
Non-urological
flank pain
Abnormal
Normal +
abnormal
urinalysis
(leucocyturia,
haematuria
or bacteriuria)
Genitourinary
abnormality
Refer patient
Further
investigation and
appropriate treatment
Refer patient
No hydronephrosis
No stone
Non-genitourinary
abnormality
Hydronephrosis
Stone
No stone
Stone
Ureteral obstruction
Check for:
renal infarct
renal abscess
renal vein
thrombosis
tumour
cyst
haematoma
urinoma
extrarenal mass
No UTI
Stone
management
UTI
Treat
infection
Check for:
ureteral tumour
papillary necrosis
upj obstruction
retroperitoneal
fibrosis
No UTI
Management to
relieve pain or
obstruction
UTI
Urinary
drainage
and infection
treatment
Stone
management
CT = computed tomography; UTI = urinary tract infection.
76
Recommendations
LE
Unenhanced helical computed tomography is the diagnostic imaging modality with the highest 1a
sensitivity and specificity for evaluation of non-traumatic acute flank pain.
Ultrasound can be an alternative to unenhanced helical computed tomography in the initial
1b
approach to non-traumatic acute flank pain.
GR
A
A
Table 18: Comparative results of UHCT, US and IVU in assessment of acute flank pain and suspected
ureterolithiasis (12)
Imaging modality
UHCT
Abdominal radiograph + US versus UHCT
Low-dose UHCT versus IVU
6.3
Performance
Sensitivity 100%, specificity 96%, accuracy 98%
UHCT: sensitivity and specificity of 100%
US: sensitivity 100%, specificity 90%
UHCT: sensitivity 97%, specificity 96%
Low-dose UHCT is superior to IVU
Ref. no.
17
18
19
Initial emergency treatment
6.3.1 Systemic analgesia

Pain relief is usually the first, most urgent, therapeutic step (20,21):

Intravenous NSAIDs are very effective in most cases, e.g., a bolus of diclofenac sodium, 75 mg (20)
(LE: 1a); a slow iv injection of ketorolac, 30 mg, four times daily, is equivalent to diclofenac in the
treatment of renal colic (22).

Tests have shown a single dose of dipyrone to be less effective than diclofenac, 75 mg (23) (LE: 1a),
but a slow iv infusion of dipyrone, 1 or 2 g, is just as effective as diclofenac (24).

In cases of unresponsiveness to diclofenac (25) (LE: 1b), or contraindication of NSAIDs (24) (LE: 1b), iv
papaverine hydrochloride (120 mg) is a safe and effective alternative.

Large-scale studies have shown that NSAIDs and opioids are both effective analgesics, but vomiting
is more prevalent with opioids (particularly pethidine) (20).

The combination of iv morphine + ketorolac seems superior to either drug alone, and appears to be
associated with a decrease in the need for rescue doses of analgesia (26).

Antimuscarinics are often used in acute renal colic; there is no evidence that hyoscine butylbromide
reduces opioid requirements in this condition (26) (LE: 1b).
The origin of the pain should be immediately clarified in febrile patients and those with a solitary kidney.
Recommendation
In patients presenting with acute flank pain NSAIDs such as diclofenac (75 mg bolus) and
dipyrone (1-2 g slow iv injection) are the drugs of first choice.
LE
1a
GR
A
6.3.2 Local analgesia

A number of manipulations have been tested in the field of acute renal colic.

Local warming of the abdomen and lower back region seems to decrease pain in patients with acute
renal colic (27) (LE: 1a).

Trigger-point injection of lidocaine can provide effective pain relief in 50% of patients with renal
colic; it is significantly better than iv butylscopolamine bromide + sulpyrine (28) (LE: 1a). There are no
comparative studies with NSAIDs.
6.3.3 Supportive therapy
Patients with acute flank pain often present with moderate to severe dehydration. Fever, vomiting and anorexia
produce serious discomfort and should be treated from the outset. If possible, iv fluids should be generous
(60 mL/h normal saline and 60 mL/h 5% glucose solution), but maintenance iv fluids (20 mL/h normal saline)
can be as effective as forced hydration with regard to pain perception and analgesic use (29) (LE: 1b). No clear
evidence supports using diuretics to treat acute ureteral colic (30). Metoclopramide chloride (0.5 mg/kg/24 h
in three divided doses) can be effective in controlling nausea and vomiting irrespective of aetiology (infectious,
obstructive, oncological).
77
6.3.4 Upper urinary tract decompression

If pain relief cannot be achieved using medical therapy and there are signs of infection and impaired renal
function, upper urinary tract drainage should be undertaken. The main indications for stenting for urgent relief
of obstruction include (31):

urine infection with urinary tract obstruction;

urosepsis;

intractable pain and/or vomiting;

obstruction of a solitary or transplanted kidney;

bilateral obstructing stones;

ureteral calculus obstruction in pregnancy.
Catheter-derived symptoms such as flank pain, pain during voiding, frequency, nocturia and urgency can be
effectively treated with terazosin and tamsulosin (32-34).
New technological advances such as the antireflux JJ ureteral stents seem to minimise catheter-related pain
(35,36) (LE: 1b).
6.4 Aetiological treatment

6.4.1 Urolithiasis
Treatment of urolithiasis is discussed in the EAU Guidelines on Urolithiasis (37).
6.4.2 Infectious conditions
Infectious uncomplicated conditions (i.e. acute pyelonephritis in otherwise healthy individuals) should be
treated with appropriate antibiotics and analgesics according to the EAU Guidelines on Urological Infections
(38).

The first-line treatment of mild cases should be an oral fluoroquinolone (twice daily for 7 days) in
areas with low rates of fluoroquinolone-resistant Escherichia coli. In areas with raised resistance rates, or in
pregnancy, lactation or adolescence, a second- or third-generation oral cephalosporin is recommended. Pain
can usually be controlled with oral NSAIDs (diclofenac 75 mg, three times daily, or dipyrone 500 mg three times
daily) except in pregnant or lactating women.
6.4.3 Other conditions
6.4.3.1 Ureteropelvic junction obstruction
Ureteropelvic junction obstruction can result in intermittent flank or abdominal pain. Symptoms may worsen
during brisk diuresis (after consumption of caffeine or alcohol). Dismembered or non-dismembered pyeloplasty
is standard. A ureteral stent can help to relieve pain in very symptomatic patients prior to definitive surgery.
Outcomes are excellent, with resolution of the obstruction in 90-95% of cases, including newborns (39).
6.4.3.2 Papillary necrosis
Papillary necrosis commonly presents as painless macroscopic haematuria, but can be complicated by ureteral
obstruction. As well as symptomatic treatment, treatment should be given for the underlying cause of papillary
necrosis, such as interstitial nephritis, acute pyelonephritis, diabetes mellitus, analgesic abuse or sickle cell
disease. Ureteral obstruction due to sloughed papillae can be successfully treated with ureteroscopy or
temporary ureteral stenting (40).
6.4.3.3 Renal infarction
There is no specific treatment for acute renal infarction, but the underlying disease (atrial fibrillation, left
ventricular thrombus or a hypercoagulable state) may require anticoagulation with iv heparin followed by
warfarin to prevent future events (41).
6.4.3.4 Renal vein thrombosis
Renal vein thrombosis is often clinically silent, but can present with acute flank pain. Systemic anticoagulation
with heparin to prevent further propagation of thrombus or other thromboembolic phenomena (42) is standard,
but the successful use of fibrinolytic agents in selected patients without clinical contraindications has been
reported (43). Thrombectomy or nephrectomy is reserved for cases refractory to medical therapy.
6.4.3.5 Intra- or perirenal bleeding
Acute spontaneous intra- or perirenal bleeding often results in acute flank pain. Spontaneous renal
haemorrhage (Wunderlichs syndrome), is an unusual and life-threatening cause of acute abdomen.
Nephrectomy is usually the only therapeutic alternative (44,45).
78
6.4.3.6 Testicular cord torsion

Testicular cord torsion can produce lower abdomen and flank pain; it should be treated surgically at once.
6.5
References
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Levine JA, Neitlich J, Verga M, et al. Ureteral calculi in patients with flank pain: correlation of plain
radiography with unenhanced helical CT. Radiology 1997Jul;204(1):27-31.
Eskelinen M, Ikonen J, Lipponen P. Usefulness of history-taking, physical examination and diagnostic
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(Article in Spanish)
7. PALLIATIVE CARE
7.1 Background
The inevitable progression of certain diseases frequently results in unbearable suffering. When cure is no
longer possible, palliation and compassion are mandatory. In the following section the reader will find a
straightforward approach to the treatment of many psychological and physical symptoms. Unfortunately, the
level of evidence for the proposed interventions is poor. Nevertheless, a well-structured map should be applied
to provide the most effective and compassionate care for patients and their loved ones. Also, healthcare
providers deserve particular care because the extent of professional anxiety and frustration can be significant
in this clinical scenario.
7.2
Definition and aim of palliative care
According to the WHO definition (1), palliative care 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. The goal of palliative care is to obtain the highest QoL for
patients and their loved ones.
Palliative care:

provides relief from pain and other distressing symptoms;

affirms life and regards dying as a normal process;

intends neither to hasten nor postpone death;

integrates the psychological and spiritual aspects of patient care;

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

offers a support system to help the family cope during the patients illness and in their own
bereavement;

uses a team approach to address the needs of patients and their families, including bereavement
counselling, if indicated;
81
enhances QoL, and may also positively influence the course of illness;
is applicable early in the course of illness, in conjunction with other therapies that are intended to
prolong life, such as chemotherapy or radiotherapy, and includes investigations needed to understand
and manage better distressing clinical complications (1).
The readiness of patients to accept palliative care and a vision of palliative care shared by the patient and all
caregivers involved are potentially important elements in this definition (2).
7.3 General principles

The panel assumes that the ethics of disease palliation are beyond doubt. Hence, a discussion on ethical
principles is omitted from this document. Legislation on palliative and end-of-life care across Europe is
variable. This panel considered it pointless to address that particular topic in depth. The panel also decided
not to address physician-assisted suicide. Details about this and euthanasia can be found elsewhere (3,4). The
current document focuses on interventions that can be applied in institutions. Home palliation is not addressed
because few patients require this type of care are in the urological setting.
Palliation involves:

communication;

placing the patient at the centre of treatment;

cultural and spiritual approaches;

multidisciplinary approach.
7.3.1 Communication
Communication is one of the cornerstones in palliative care. Good communication skills are relevant not only
in the relationship between caregivers and patient and families, but also with all professionals inside and
outside the hospital. Specific communication skills allow a better assessment of patients needs and improve
patient wellbeing and adherence to treatment. Communication skills include making eye contact with the
patients, asking open-ended questions, responding to a patients emotions, and showing empathy (5). Figure 5
illustrates the principles for communicating with patients about major topics in palliative care.
82
Figure 5: Protocols for communicating with patients about major topics in palliative care
Establishing goals
of medical care
Communicating
bad news
Withdrawing
treatment
Create the right setting: plan what to say, allow adequate time, and determine who else should be present at the meeting
Establish what the patient knows:

clarify the situation and context in
which the discussion about goals is
occurring
Establish what the patient knows:

clarify what the patient can
comprehend; reschedule the talk if
necessary
Establish and review the goals of

care
Explore what the patient is hoping

to accomplish: help distinguish
between realistic and unrealistic
goals
Establish how much the patient

wants to know: recognise and
support preferences; people handle
information in different ways
Establish the context of the

current discussion: discuss what
has changed to precipitate the
discussion
Suggest realistic goals: explore

how goals can be achieved
and work through unrealistic
expectations
Share the information: avoid

jargon, pause frequently, check for
understanding, use silence; do not
minimise the information
Discuss specific treatment in the

context of the goals of care: talk
about whether the treatment will
meet the goals of care
Discuss alternatives to the

proposed treatment: talk about
what will happen if the patient
decides not to have the treatment
Respond empathetically to feelings: be prepared for strong emotions and allow time for response, listen, encourage
description of feelings, allow silence
Make a plan and follow through:

discuss which treatments will be
undertaken to meet the goals,
establish a concrete plan for followup, review and revise the plan
periodically as needed
Follow up: plan for next steps,

discuss potential sources of
support, share contact information,
assess the patients safety and
support, repeat news at future
visits
Plan for the end of the treatment:

document a plan for withdrawal of
treatment and give it to the patient,
the patients family, and members
of the health care team
Adapted from the Education on Palliative and End-of-life Care Project.

Curriculum Emanuel LL, von Gunten CF, Ferris FD, eds. The Education in Palliative and End-of-life Care (EPEC)
Curriculum: The EPEC Project, 1999, 2003.
Communication skills are important at every stage of the disease. Terminal patients deserve specific
information about their condition. This kind of information increases the quality of terminal care (6,7). Several
guidelines have been established to help physicians and nurses improve their communication skills (5,8).

Moreover, it seems important to tailor information to the needs of the individual patient. Difficult
discussions should be personalised to the individual patient. These can vary dramatically both in the area of
disclosure of bad news about prognosis and end-of-life decision making. This also requires proper advanced
care planning at an early stage in the management of patients with terminal cancer (9).

Communication is also part of the relationship between partners, when one member of the couple has
a chronic illness such as cancer. When communication between the couple fails, it is more difficult to address
the patients needs. The Couples Illness Communication Scale (CICS) is a simple tool for the clinical setting
and can provide a springboard for addressing difficulties with illness-related communication between couples.
It can be an aid for decision making in couple counselling. Relationship intimacy and how patients and partners
communicate to achieve this intimacy is important for the psychological adjustment of early-stage PCa
survivors and their partners (10,11).

Many initiatives provide patient guidance and education, from assessment to diagnosis and treatment
planning. For example, at the Prostate Cancer Assessment Clinic, Ottawa Hospital, Canada, a nurse-led
initiative has shown that effective communication between physicians, nurses, patients and families, and the
interdisciplinary team and community partners is the key to improving the experience of PCa patients (12).
83
7.3.2 Patient-centred treatment

Patient-centred treatment is another aspect of palliative care. There is evidence about the benefit of involving
the patient in making any decisions. The patient must be at the heart of every decision and be provided with
greater choice and control (13).
7.3.3 Cultural and spiritual approach
The profound influence of personal circumstances on patients experiences of illness, expectations of medical
interventions, communication styles, and ways of coping should be considered, because it can lead to
misunderstanding, conflict, anger, resentment, and lower quality of care (14).

Spirituality is also an important aspect that should be taken into account. Cancer patients do not
expect spiritual solutions from oncology team members, but they wish to feel comfortable enough to raise
spiritual issues and not be met with fear, judgmental attitudes, or dismissive comments. Spirituality can be a
major resource for both patients and physicians, yet it can never be imposed but only shared (15).

In addition, it may be of interest to assess spiritual outcomes in palliative care. Nine tools have been
identified in a review that has been validated in cross-cultural palliative care populations, and subject to
appraisal of their psychometric properties, they may be suitable for cross-cultural research (16).
7.3.4 Multidisciplinary approach
One of the main principles of palliative care is a multidisciplinary approach. All professions are concerned and
the treatment decision (either palliation or terminal disease management) should be taken on a multidisciplinary
basis (physicians, nurses, social workers, dieticians and psychologists). This is not always easy but it is
effective (17). Multidisciplinary care is based on strong collaboration between acute, hospice and home care. It
has been shown that the problems of many palliative cancer patients would be more appropriately addressed
by advanced home care instead of acute hospital care (18).
7.3.5 Can anyone provide palliative care? Health care staff and advanced urological diseases
Palliative care is practised everywhere and not only in palliative care units or hospices. For various reasons,
people tend to delay facing questions associated with the end of life, and fear of the unknown often creates
an environment of avoidance and an atmosphere of taboo (19). Healthcare professionals who are not used to
working in palliative care often feel helpless. Often, there is a lack of communication with, and active listening
to, patients and their families. This is not well received by patients who need communication with doctors and
nurses (20).

Healthcare professionals caring for patients with advanced cancer are often exposed to burnout
syndrome. It is important to detect signs of this condition at an early stage in order to prevent it from
progressing (21,22). The tool mostly used is the Maslach Burnout Inventory (23).

The way that services are managed influences the occupational wellbeing of healthcare professionals.
Also, services organised around an effective social support system enhance the quality of work life among
caregivers, influencing their perceived stress and their coping strategies. Quality of life of the caregivers affects
the quality of care (24).

Irrespective of the reasons for embarking on palliative care, once it has been decided upon, the
professionals involved should commit themselves to respect the agreed interventions and implement them
in every clinical situation. Clear policies on place of care (hospital, hospice or home), urinary diversions, and
resuscitation are needed. Before assuming professional responsibility for terminal care, practices for parenteral
hydration and antibiotic use should be clarified.
7.4
Treatment of physical symptoms
7.4.1 Pain
All the details concerning pain treatment have been previously addressed in Chapters 3 and 4.
7.4.2 Dyspnoea and respiratory symptoms
Breathlessness is common and very disturbing for patients with many types of advanced cancer. In this setting,
the use of morphine and other opioids is not supported by research studies. Breathing training, walking, chest
wall vibration, and electrical muscle stimulation, are effective non-pharmacological measures for relieving
breathlessness (25).

When compared with placebo, benzodiazepines can cause more adverse effects (such as
drowsiness), but fewer adverse effects are expected when compared to morphine. Despite the lack of evidence
from well-conducted RCTs, benzodiazepines can be considered when opioids and non-pharmacological
support measures fail to control breathlessness (26). Oxygen provides no symptomatic relief of dyspnoea
compared with room air (27) (LE:1b).

Noisy breathing (death rattles) occurs in most people who are dying. The cause of death rattle
84
remains unclear but is presumed to be due to air passing over upper airways secretions. It can be treated
physically or pharmacologically. Although distressing for some professionals and most families, there is no
evidence to suggest that any pharmacological (anticholinergic drugs) or non-pharmacological intervention is
superior to placebo. Nevertheless, atropine 0.5 mg, hyoscine butylbromide 20 mg, and scopolamine 0.25 mg
(subcutaneous, followed by continuous administration) can be moderately effective for treatment of death
rattles (28,29).
Recommendation
Benzodiazepines can be considered when opioids and non-pharmacological measures fail to
control breathlessness.
LE
1a
GR
A
7.4.3 Cancer anorexia-cachexia syndrome

Cancer anorexia-cachexia syndrome (CACS) is frequent in patients with advanced cancer. Nutritional
support in this setting seems to be ineffective (30) (LE: 1b), as does drug therapy. In a few selected cases,
dexamethasone (4 mg/day) or progesterone analogues (megestrol acetate, 480-800 mg/day) can be
considered, because it is thought that they have a significant effect on appetite and weight gain. A patientdoctor shared decision seems necessary before opting for treatment, considering that no gain in survival or
QoL can be expected (31,32). The effect of orally administered cannabis extract (CE) on appetite and QoL in
patients with CACS has been rigorously tested. Although CE is well tolerated, its effect on appetite did not
clearly differ from that with placebo (33).

More recently, a phase II RCT has shown that thalidomide (50 mg/day, orally, for 2 weeks) is effective
against cancer-related anorexia (34).
7.4.4 Vomiting
Chronic nausea occurs in most patients with advanced cancer, and in many cases, it is refractory to
metoclopramide. In this setting, dexamethasone does not seem superior to placebo (32).

Droperidol is an antipsychotic drug that has been used as an antiemetic in the management of
postoperative and chemotherapy-induced nausea and vomiting. Unfortunately, there is insufficient evidence to
advise its use in the management of nausea and vomiting in palliative care (35).

Patients with a high incidence of emesis - usually post-chemotherapy - should receive a serotonin
5-hydroxytryptamine (5-HT3) receptor antagonist (ondansetron, tropisetron, granisetron, dolasetron or
palosetron), dexamethasone, and a neurokinin 1 receptor antagonist such as aprepitant or forsaprepitant.
Preferential use of palonosetron is recommended for moderate emetic risk regimens, combined with
dexamethasone. Patients undergoing high emetic risk radiotherapy should receive a 5-HT3 receptor antagonist
before each fraction and for 24 h after treatment, and may receive a 5-day course of dexamethasone during
fractions 1 to 5 (36).

Electroacupuncture is beneficial for chemotherapy-induced acute vomiting, but studies combining
electroacupuncture with state-of-the-art antiemetics, and in patients with refractory symptoms, are needed
to determine clinical relevance. Self-administered acupressure appears to be protective against acute nausea
and can readily be taught to patients, although this has not been subjected to placebo-controlled studies. Noninvasive electrostimulation appears unlikely to have a clinically relevant impact when patients are given stateof-the-art antiemetic drug therapy (37).
Recommendations
Dexamethasone is not effective in metoclopramide-refractory nausea.
Patients with a high risk of vomiting are effectively treated with a combination of
dexamethasone and 5-HT3 and neurokinin 1 receptor antagonists.
In patients with moderate risk of vomiting, palonosetron combined with dexamethasone is
recommended.
Patients receiving radiotherapy and experiencing emesis can be effectively treated with
combined 5-HT3 receptor antagonist and dexamethasone.
LE
1b
1a
GR
A
A
1a
1a
7.4.5 Other symptoms

7.4.5.1 Fatigue
Asthenia is an overwhelming, persistent feeling of tiredness in which normal activity becomes an effort.
Cancer-related fatigue (CRF) can be a significant problem with a serious impact on QoL. There are several
tools to measure fatigue such as the Brief Fatigue Inventory (BFI), Numeric Rating Scale (NRS), and Revised
Piper Fatigue Scale (PFS). The BFI includes nine items that measure the severity and impact of fatigue. It has
adequate reliability with an established validity (38). The NRS has only one item: fatigue intensity. It is easy and
85
quick to use but less reliable (38). The Revised PFS has 22 items plus five additional open-ended items that
measure four dimensions of subjective fatigue: behaviour/severity, affective meaning (mental aspect of fatigue),
sensory, cognition/mood. It is an adequate and reliable measuring tool with established validity (39).

Trials of erythropoietin and darbopoetin (for anaemic patients) and psychostimulants have provided
evidence for improvement in CRF. There are no data to support the use of paroxetine or progestational steroids
for treatment of CRF. The amphetamine methylphenidate (standard treatment for attention deficit hyperactivity
disorder) has been proposed for treatment of asthenia in patients with advanced cancer (40). There is evidence
suggesting reduction in fatigue and depression when compared with placebo. Its effect on fatigue seems
dose-dependent and sustained over time. Standard oral doses are 10-40 mg/day (41). Data from a phase III
RCT suggest that modafinil - another psychostimulant - can be effective for the treatment of anorexia and
depression in patients with advanced cancer (42) .

Exercise is an effective intervention for patients with CRF (43). Like exercise, psychoeducational
activity is a promising therapy for ameliorating CRF (44).
7.4.5.2 Restlessness
Most patients in the final stages of their lives experience restlessness. Although neuroleptics have been
widely used in this setting, there is insufficient evidence to suggest that a single drug or class of medication is
appropriate for terminal restlessness (45).
Recommendation
Neuroleptics cannot be recommended for treatment of terminal restlessness.
LE
3
GR
C
7.4.5.3 Agitated delirium

There is limited high quality evidence on the role of drug therapy for delirium in terminal patients. Although
benzodiazepines have been widely used, it has not been possible to assess the effectiveness of treatment
options (46,47). However, haloperidol (5-10 mg, intravenous) remains a useful drug for the treatment of many
forms of delirium (48).
7.4.5.4 Constipation
Chronic constipation can be a serious problem for cancer patients taking opioids. Oral lactulose seems more
effective than polyethylene glycol (49). Nevertheless, evidence on laxatives for management of constipation
remains limited due to insufficient RCTs (49).

Interestingly, subcutaneous methylnaltrexone seems effective in inducing laxation in patients with
opioid-induced constipation when standard laxatives fail (50,51). Its safety, however, has to be proven in
properly organised RCTs. No clear recommendations as to the use of a particular laxative can be made
(LE: 1a).
7.4.5.5 Anxiety
Anxiety is a common symptom in patients near the end of life. A myriad of drugs has been used to calm
anxiety in terminally ill patients (including anxiolytics, antidepressants, antipsychotics, benzodiazepines,
butyrophenones, phenothiazines and thienobenzodiazepines). There is currently insufficient evidence on the
role of this type of drug in patients with terminal illness, and it is therefore not possible to draw any conclusions
about the effectiveness of pharmacotherapy in this setting (52).
7.5
Terminal care
For medical practitioners who are trained to save lives, the end of life represents a completely different
professional scenario in which personal skills give way to multidisciplinary, compassionate intervention.
Relieving suffering requires well-trained teams and clearly established goals. It seems clear that early
identification of patients needing palliative care can effectively improve QoL (53).

Recognition of intolerable refractory symptoms, standardised monitoring of disease progress, and
availability of terminal care pathways are crucial for supporting patients and families with terminal disease.

In addition to the above-mentioned interventions, palliative sedation is one of the alternatives to
keep in mind when dealing with terminally ill patients. Patients experiencing refractory symptoms (e.g., pain,
vomiting, delirium and dyspnoea) can be considered for palliative sedation. It consists of the deliberate
administration of drugs in minimum doses and combinations required not only to reduce the consciousness
of the patients but also to achieve adequate alleviation of one or more refractory symptoms, and with the prior
consent given by the patient explicitly, or implicitly, or delegated (54). The aim of palliative sedation is never
to hasten death and there is evidence that it does not jeopardise survival (55,56). Figure 6 is an aid for the
recognition of refractory symptoms.
86
Figure 6: Algorithm for treatment decisions for refractory symptoms
Is the symptom treatable?
Yes
No
Can treatment be given without
unacceptable side effects?
The symptom is refractory

No
Yes
Will the treatment take effect

quickly enough?
The symptom is not refractory

Yes
Source: Royal Dutch Medical Association (KNMG). Guideline for Palliative Sedation. Utrecht, 2009.
Although physicians are responsible for the objective evaluation of symptoms, fully competent patients have
the right to prompt interventions or to refuse any kind of treatment. When the patient is mentally incapable, the
nearest relative can make decisions. For certain complicated cases, physicians might seek the help of their
ethics committee or ask for a legal consultation. Nevertheless, it should always be kept in mind that doubt
should not be expressed in front of a suffering patient.

The ethics of palliative treatment at the end of life seem beyond question. Nevertheless, a few
countries in Europe (Netherlands, Belgium and Switzerland) and some of the United States (Oregon and
Washington) have clear regulations on the right to terminal sedation. Cultural and ethnic differences in the
approach to the end of life are also prominent (57-64), thus making the approach to the final stages of life not
always equitable.
7.5.1 When and how to withdraw specific treatment
With every single intervention, the ethical principles of beneficence, non-maleficence, autonomy and justice
should be considered. Relieving suffering - rather than sustaining life at any cost - might be sensible in patients
with advanced disease. Patients (or relatives when they are incompetent) have the right to ask for treatment
cessation at any time. It will always be taken into account that proxies are supposed to interpret the patients
wishes and not their own. Artificial ventilation, haemodialysis, parenteral nutrition, blood transfusion and
chemotherapy can all be stopped at the patients request (65).
Recommendation
The patient (or relatives if incompetent) should be able to decide on every single intervention.
LE
4
GR
A*

7.5.2 Parenteral hydration: should it be discontinued in the terminal phases?
There is an interesting controversy about forced hydration in terminally ill patients. At present, good quality
studies on this topic are lacking, making recommendations for practice pointless (66).

There is scientific evidence to show that artificial hydration provides no clear benefit in relation to
normalising renal function and electrolyte levels compared with non-hydrated patients (67). Nevertheless, it
seems that parenteral hydration can improve many of the symptoms experienced by terminally ill, dehydrated
cancer patients (68).

The decision should be taken on an individual basis, but it is suggested that patients who cease
drinking are close to death and will gain little from artificial hydration (3).
87
7.5.3 Palliative sedation

Considering the lack of randomised trials on palliative sedation, the panel decided to stick to the principles of
the Royal Dutch Medical Association (KNMG) in this respect (3).

As mentioned earlier, palliative sedation is the deliberate lowering of the level of consciousness in
the last stages of life. As such, it can only be considered in the context of a palliative care plan. The object
of palliative sedation is to relieve suffering, and lowering consciousness is the means to that end. Palliative
sedation never aims to hasten death. Deciding whether the indications for palliative sedation are met is always
a medical task, but not necessarily a matter for specialised physicians. The untreatable nature of the symptoms
must be demonstrated beyond reasonable doubt. Besides the presence of medical indications in the form
of one or more refractory symptoms, another precondition is the expectation that death will ensue in the
reasonably near future that is, within 1-2 weeks (3,69).

It is generally agreed that physicians and nurses should be present the moment palliative sedation
begins (69). Subcutaneous administration is the preferred route and midazolam the drug of choice (1,70). Table
19 provides a suggestion for palliative sedation (3).
Table 19: T
hree steps approach to palliative sedation. In the hospital setting, Phase 3 can follow
Phase 1 (1)
Phase 1
Drug
Midazolam
Bolus
Start with 10 mg s.c. If
necessary, 5 mg every 2
h s.c.
Phase 2
Levomepromazine
25 mg sc/iv, possibly 50
mg after 2 h
Phase 3
Propofol
20-50 mg iv
Continuous administration
Initial dose 1.5-2.5 mg/h sc/iv. If the desired
effect is not achieved, increase the dose
by 50% after a minimum of 4 h, always
in combination with a bolus of 5 mg sc. If
risk factors are present (age > 60 years,
weight < 60 kg, severe kidney or liver
dysfunction, very low serum albumin, and/
or co-medication that could exacerbate the
effect of sedation):
- lower initial dose (0.5-1.5 mg/h), and
- lengthen interval (6-8 h) before increasing
maintenance dose. In the case of doses
>20 mg/h, see Phase 2.
0.5-8 mg/h sc/iv in combination with
midazolam. After 3 days, halve the dose to
prevent drug accumulation. If the desired
effect is not achieved, stop administering
midazolam and levomepromazine; see
Phase 3.
20 mg/h iv, increase by 10 mg/h every15
min. Administration under supervision of an
anaesthesiologist is advisable. In hospital,
this may be considered for Phase 2.
Source: Royal Dutch Medical Association (KNMG). Guideline for Palliative Sedation. Utrecht, 2009.
7.6
Treatment of psychological aspects
7.6.1 Fear
While improvements in screening, prevention and treatment are encouraging, cancer is still related to very
intensive treatment, and finally to death in many patients. It may cause deep fear and depression. The role of
the healthcare giver is important in this process (71). Measuring distress should be a major part of assessing
patient emotional disturbance. Different tools are available such as the Hospital Anxiety and Depression
Scale and the Distress Thermometer. Successful implementation of a screening procedure depends on its
acceptability to patients and clinicians, as well as the clinicians perception of the added value. Distress is
often related to the physical complications of cancer and its treatment, therefore, the approach should include
psychological and physical well-being (72).
Recommendation
Distress must be recognised, measured, treated and monitored at all stages of the disease.
88
LE
2b
GR
A
7.6.2 Depression
There is a strong correlation between physical disease and depression but there is no evidence that depression
may cause cancer. Depression is associated with adverse outcomes such as increased pain, disability and
poor prognosis (73).

The effectiveness of pharmacological agents for anxiety has not yet been proved. Nevertheless, both
psychosocial and pharmacological interventions have been shown to be efcacious in treating depression in
cancer patients (74,75).

One study has shown that prescription prevalence among cancer patients in the last year of
life is almost four times higher than in the general population. One out of 10 patients is prescribed with
antidepressants so close to death that the clinical effects can be questioned (76).

Moreover, behavioural therapy, counselling, psychotherapy, education/information, relaxation and
social support alleviate depression and anxiety (77). Centralised telecare management coupled with automated
symptom monitoring can improve pain and depression outcomes in cancer patients receiving care in
geographically dispersed urban and rural oncology practices (78).

Screening for depression in terminally ill patients can optimise their physical comfort at the end of life
and provide them with the opportunity to confront and prepare for death (79).
Recommendation
Efforts should be made to detect hidden depression.
LE
2b
GR
B*
7.6.3 Family care

Family and relatives have an important role to play in the care of patients with advanced disease and they
should be involved in decision-making about where the patient should be cared for (e.g., home or hospice).
Nevertheless, the patients views should always be kept in mind. In addition, the family is emotionally affected
by the disease, and their emotional distress may influence the patients mood. It is important to screen for
depressive symptoms and predictors of depression among family caregivers, especially in the dying process
and after death (80).

Patients and families need to be prepared for death. The process can then take place under good,
serene conditions (81,82). Otherwise, it can lead to dysfunctional family dynamics that can be disturbing to the
staff members in their efforts to provide optimal palliative care, and to the patient (81). Family-focused grief
therapy based on communication, cohesiveness, conflict resolution, and shared grief is effective in protecting
family members against the drama of disease and death (83).
Table 20: Arresdal Hospice principles of management of intrafamilial conicts (81)
Maintain the palliative perspective
Maintain flexibility
Maintain neutrality
Avoid splitting
Avoid demonising
Consider the possibility and implementation of palliative management

perspective strategies in certain subtypes of family dysfunction and to
extend beyond this (if favourable circumstances allow), incorporate a
more long-term outlook for future rehabilitation of the surviving relatives.
Take into account the strengths, psychological resources, level of
intellect and emotional state of conflicting family members before
deciding whether to use interpretive or supportive techniques. Be
prepared to reflect over strategies that have not been optimal, and
modify as necessary.
Current information for all staff members involved through monoor multidisciplinary meetings is essential. It is important to handle
conicting family dynamics in an open, transparent and professional
way, not to be unexpectedly absorbed as an active part of the conflict,
and to avoid covert behaviour. The principle of neutrality applies to this
strategy in that involvement in long-term prior conflicts is to be avoided.
Avoid, or at least identify and understand splitting between members of
staff by recognizing that dysfunctional families with conflicting dynamics
may display completely opposing attitudes within short periods of time,
which can be challenging to staff. In the worst case scenarios, relatives
in conflict may project their issues onto others as a way to control
fragmented or distressed parts of themselves.
Encourage and enable staff to share awkward, challenging and/or
negative feelings brought on by sudden or inadvertent involvement in
conicting family dynamics.
89
Set necessary limits
Intervention
Limits need to be identified and maintained consistently if behaviour of

a family member threatens the integrity or safety of the patient, other
relatives, staff or the palliative-therapeutic relationship.
Encourage staff members to maintain the professional/personal
balance through multidisciplinary discussions, counselling and prompt
debrieng.
7.6.4 Communication of bad news

Informing patients of bad news about malignancies is a difcult task; bad prognosis for some cancers and
severe symptoms and treatment side effects make it painful for health professionals. It may be easier not to
inform the patient. Nevertheless, disclosure will emphasise uncertainty and anxiety. In addition, patients have
the right to be informed and the right to choose non-disclosure (84). Specific, patient-targeted information
increases the quality of terminal care (7).

Patients families often experience anticipatory grief when learning of a diagnosis of advanced or
terminal cancer. Anticipatory grief can be a response to threats of loss of ability to function independently,
loss of identity, and changes in role definition, which underlie fear of death. When an oncologist delivers bad
news, the patient and family members often hear the same discussion through different filters, which can lead
to conflict and dysfunction. It is then important to provide a supportive and safe environment, and to help
the patients reframe hope realistically so that they may have the opportunity for personal growth as well as
reconciliation of primary relationships toward the end of life (85).

In such situations, good communication skills are needed. There are methods to help health care
professionals deliver information about bad news, such as using sociograms and psychodrama (86).
7.7
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95
8. ABBREVIATIONS USED IN THE TEXT

This list is not comprehensive for the most common abbreviations.
AMPA
ATC
CBT
CNS
COX
CRPC
CT
EDTMP
EORTC
GABA
GFR
GCP
IASP
im
iv
IVU
131J-MIBG
mCRPC
MRI
MSCC
NMDA
NRS
NSAIDs
PACU
PCa
PCA
PCEA
prn
PRPE
QoL
RCC
RLND
RVT
sc
153Sm
89Sr
SRI
SPECT
SWL
TCA
TCC
TENS
TURB
TURP
UHCT
VAS
VRS
WHO
-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate
around-the-clock
cognitive behavioural therapy
central nervous system
cyclo-oxygenase
castration-resistant prostate cancer
computed tomography
ethylenediaminetetramethylenephosphonate
European Organisation for Research and Treatment of Cancer
gamma-aminobutyric acid
glomerular filtration rate
good clinical practice
International Association for the Study of Pain
intramuscular
intravenous
intravenous urography
131J-metaiodobenzylguanidine
metastatic castration-resistant prostate cancer
magnetic resonance imaging
metastatic epidural spinal cord compression
N-methyl-D-aspartate
numerical rating scale
non-steroidal anti-inflammatory drugs
post-anaesthesia care unit
prostate cancer
patient-controlled analgesia
patient-controlled epidural analgesia
as needed
perineal radical prostatectomy
quality of life
renal cell carcinoma
retroperitoneal lymph node dissection
renal vein thrombosis
subcutaneous
samarium-153
strontium-89
selective serotonin reuptake inhibitors
single photon emission computed tomography
extracorporeal shock wave lithotripsy
tricyclic antidepressants
transitional cell carcinoma
transcutaneous electrical nerve stimulation
transurethral resection of bladder tumour
transurethral resection of prostate
unenhanced helical CT
visual analogue scale
verbal rating scale
World Health Organization
Conflict of interest
All members of the General Pain and Palliative Care Guidelines expert panel have provided disclosure
statements on all relationships that they have and that might be perceived to be a potential source of conflict
of interest. This information is publically accessible through the European Association of Urology website. This
guidelines document was developed with the financial support of the European Association of Urology. No
external sources of funding and support have been involved. The EAU is a non-profit organisation and funding
is limited to administrative assistance and travel and meeting expenses. No honoraria or other reimbursements
have been provided.
96

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Guidelines on

European Association of Urology 2013

PAIN MANAGEMENT & PALLIATIVE CARE - UPDATE MARCH 2013

PAIN MANAGEMENT & PALLIATIVE CARE - UPDATE MARCH 2013

PAIN MANAGEMENT & PALLIATIVE CARE - UPDATE MARCH 2013

ABBREVIATIONS USED IN THE TEXT

PAIN MANAGEMENT & PALLIATIVE CARE - UPDATE MARCH 2013

1.5 Level of evidence and grade of guideline recommendations*

*Modified from Sackett et al. (1).

PAIN MANAGEMENT & PALLIATIVE CARE - UPDATE MARCH 2013

*Modified from Sackett et al. (1).

Pain evaluation and measurement

2.2.1 Pain evaluation

PAIN MANAGEMENT & PALLIATIVE CARE - UPDATE MARCH 2013

efficacy of pain relief at regular intervals after starting or changing treatment.

PAIN MANAGEMENT & PALLIATIVE CARE - UPDATE MARCH 2013

Figure 1: Pain assessment scales

PAIN MANAGEMENT & PALLIATIVE CARE - UPDATE MARCH 2013

3. CANCER PAIN MANAGEMENT (GENERAL)

Classification of cancer pain

3.2 General principles of cancer pain management

PAIN MANAGEMENT & PALLIATIVE CARE - UPDATE MARCH 2013

3.3 Non-pharmacological therapies

PAIN MANAGEMENT & PALLIATIVE CARE - UPDATE MARCH 2013

CRPC = castration-resistant prostate cancer

PAIN MANAGEMENT & PALLIATIVE CARE - UPDATE MARCH 2013

3.3.3 Radiotherapy for metastatic bone pain

PAIN MANAGEMENT & PALLIATIVE CARE - UPDATE MARCH 2013

3.3.3.4 Pathological fractures

3.3.4.2 Adjunctive therapy

PAIN MANAGEMENT & PALLIATIVE CARE - UPDATE MARCH 2013

PAIN MANAGEMENT & PALLIATIVE CARE - UPDATE MARCH 2013

The main side effects are:

3.4.4 Systemic analgesic pharmacotherapy - the analgesic ladder

PAIN MANAGEMENT & PALLIATIVE CARE - UPDATE MARCH 2013

PAIN MANAGEMENT & PALLIATIVE CARE - UPDATE MARCH 2013

PAIN MANAGEMENT & PALLIATIVE CARE - UPDATE MARCH 2013

PAIN MANAGEMENT & PALLIATIVE CARE - UPDATE MARCH 2013

3.4.5 Treatment of neuropathic pain

3.4.5.2 Anticonvulsant medication

PAIN MANAGEMENT & PALLIATIVE CARE - UPDATE MARCH 2013

3.4.5.3 Local analgesics

3.4.5.4 NMDA receptor antagonists

UPDATE FEBRUARY 2012

3.4.5.5 Other drug treatments

UPDATE FEBRUARY 2012

Neurolytic blocks to control visceral cancer pain

3.4.6 Breakthrough cancer pain

UPDATE FEBRUARY 2012

Figure 2: Cancer pain treatment in urology

Mild pain (score 1-3)

Moderate pain (score 4-6)

Patient under opiod

Increase the regular

Severe pain (score 7-10)

Severe pain crisis

Consult a palliative care specialist

Give the usual per

Give the usual per

Increase the regular