Introduction

Management of pain related to urological pathologies is an important aspect of urological care. Depending on the site and cause of the pain, a number of options are available to the treating physician. Guiding principle is to balance benefits of treatment against side effects.

This document summarises the findings of the expert panel regarding the management of prostate cancer–related pain. While the urologist will be the main treating physician for most of the patient’s clinical course, in many cases—and certainly if treatment extends over a longer period of time—involvement of a number of specialists from other disciplines constitutes a standard approach, irrespective of the healthcare setting.

Evidence acquisition

An international multidisciplinary group of urologists, radio-oncologists and anaesthesiologists have assessed the data based on a structured literature search of MedLine, Embase and the Cochrane Library, covering a time frame of 2000 through 2010. A level of evidence (LE) and grade of recommendation (GR) have been assigned based on a system modified from the Oxford Centre for Evidence-Based Medicine [1].

This article presents a section of the European Association Urology (EAU) Guidelines on General Pain Management which are available in different formats through the EAU Central Office and the association website (http://www.uroweb.org/guidelines/on-line.guidelines/).

Pain evaluation and measurement

Pain can occur in both the early and advanced stages of prostate cancer. It could be caused directly by the cancer (77%), be related to the cancer treatment (19%) or be unrelated to either (3%) [2]. The overall incidence of chronic pain in prostate cancer patients is about 30–50%, but rises to 90% as patients enter the terminal phase of their illness [3]. Pain may be directly attributable to tumour growth in three main areas, i.e. tumour infiltration of bone, nerve or a hollow viscus.

Several rating scales are available to assess pain, including:

  • the visual analogue scale (VAS) (unidimensional) (Fig. 1)

    Fig. 1
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    Visual analogue scale (VAS)

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  • the verbal rating scale (VRS) (unidimensional)

  • multiple-item assessments (multidimensional), which measure not only pain intensity but also additional dimensions of the pain experience, such as the emotional, affective, cognitive and social items, e.g. quality-of-life questionnaires, including the McGill Pain questionnaire, the Medical Outcomes Short-Form Health Survey Questionnaire 36 (SF-36) and the European Organisation for Research and Treatment of Cancer Quality of Life Core Questionnaire (EORTC QLQ-C30) [4–6].

Ease of use of the VAS and VRS has resulted in widespread adoption of these scales to measure pain intensity. In chronic pain syndromes, however, both of these measurement scales have shown significant weakness in sensitivity which is attributed to the fact that these are unidimensional tools. Variability between subjects due to, for instance, different emotional, affective and cognitive responses to pain which may also be linked to cultural difference are not measured by the VAS or VRS. To study the effects of both physical and non-physical influences on patient well-being, an instrument must assess more dimensions than the intensity of pain or other physical symptoms. Instruments that assess these aspects during disease or treatment are health-related QoL questionnaires such as the McGill pain questionnaire, the SF36 and the EORTC QLQ-C30 [4–6].

Urogenital neoplasms frequently metastasise to bone. Pathological fractures, hypercalcaemia and neurological deficits lead to the substantial impairment of QoL. The release of algogenic substances in the tissue, microfractures and periosteal tension are the main mechanisms for pain sensation [7].

In patients with cancer pain (Fig. 2), the pathophysiological mechanism is nociceptive in 65–68% of cases, neuropathic in 8–9% or a combination of both nociceptive and neuropathic pain in 23–27% of cases [8, 9]. Neuropathic pain is defined by the International Association for the Study of Pain as ‘pain arising as a direct consequence of a lesion affecting the somatosensory system’ [10]. It is characterised by positive (allodynia, hyperalgesia) and negative symptoms (muscle weakness, loss of reflexes). Positive symptoms are due to an abnormal excitability of the nervous system, while negative symptoms are due to a loss of sensation resulting from loss of axons or neurons [11].

Fig. 2
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Classification and origin of cancer pain

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General principles of cancer pain management

The four main goals of pain management and palliative care are: prolonging survival, optimising comfort, optimising function and relieving pain. Table 1 provides a hierarchy of treatment principles through which these goals can be achieved.

Table 1 Hierarchy of general treatment principles (panel consensus)
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Pain due to local impairment

Surgery

While there is a certain reluctance to apply surgical principles in cancer palliation, surgery offers a good chance for symptom improvement when medication therapies are no longer possible. Radical surgery to excise locally advanced disease in patients without evidence of metastatic spread may help prevent painful local problems [12] (LE: 4).

Recurrent bladder outlet obstruction can be extremely disturbing and should be treated endoscopically when hormonal deprivation fails.

Ureteral obstruction can result in pain in prostate cancer patients. Irrespective of QoL issues, percutaneous nephrostomy drainage and retrograde stenting can be acceptable options for untreatable pain. Similarly, unilateral or bilateral ureteral re-implantation can be considered in this setting [13] (LE: 4). Minimally invasive interventions, such as vertebroplasty and kyphoplasty, are options in certain painful vertebral fractures [14].

Table 2 summarises specific pain management in prostate cancer patients suffering from pain due to local impairment [15, 16].

Table 2 Specific pain management in case of local impairment
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Androgen deprivation

A variety of additive or ablative hormone manipulations have been used (Table 3), including oestrogen, anti-androgen (bicalutamide, flutamide, cyproterone), oestrogen-mustine complex (estramustine) and gonadotropin-releasing hormone (GnRH) analogues. Hormone therapy can cause a ‘flare’ or temporary exacerbation of pain, which is generally a predictor of subsequent response.

Table 3 Hormone therapy
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Cyproterone acetate provides fewer side effects than oestrogens and has a lower incidence of cardiovascular complications [17] (LE: 1a).

Pain due to metastases

Bone metastases are the commonest cause of chronic pain in prostate cancer, and multifocal pain is frequent. More than 25% of patients with bone metastases are pain-free. Patients with multiple bone metastases typically report pain in only a few sites. Treatment options are hormone therapy (see Table 3), radiotherapy, radionuclides, orthopaedic surgery, bisphosphonates, corticosteroids, chemotherapy and systemic analgesic pharmacotherapy (‘analgesic ladder’).

Radiotherapy

The role of radiotherapy in the palliation of symptomatic bone metastases is well established [18], with complete or partial pain relief obtained in 20–50% and in 50–80% of patients, respectively. The onset of pain relief varies from a few days to 4 weeks. Single-fraction radiotherapy, with a recommended dose of 8 Gy, is as effective as multifraction radiotherapy in relieving metastatic bone pain [19, 20] (LE: 1a).

Metastatic epidural spinal cord compression is a severe complication that affects almost 5–10% of patients with cancer (there are no data exclusively on prostate cancer). Functional outcome is determined by neurological function. A delay in treatment is the most common cause of an unfavourable outcome. High-dose corticosteroids—although ‘a must’ in every guidance approaching cord compression—carries a significant risk of serious adverse effect [21]. Direct decompressive surgery is superior to radiotherapy alone, with regard to regaining ambulatory function, pain relief and recovering sphincter function [22] (LE: 1a). Radiotherapy is recommended as the primary treatment for patients who do not fulfil the recommendations for surgery listed in Table 4. In general, multifraction radiotherapy is preferable [21].

Table 4 Criteria for selecting patients for primary therapy for spinal cord compression
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Ambulatory function is superior in patients treated with surgery followed by radiotherapy, compared to radiotherapy alone. For impending pathological fractures, a prophylactic orthopaedic procedure should be considered.

Radionuclides

The most important radiopharmaceuticals are strontium-89 chloride and samarium-153 lexidronam. Both radiopharmaceuticals emit predominantly beta particles, which are responsible for the therapeutic response in 60–80% of patients [23].

Radiopharmaceuticals are indicated for treating bone pain, resulting from skeletal metastases involving >1 site and associated with an osteoblastic response on bone scan, but without spinal cord compression [24] (LE: 2, GR: B). Pain reduction occurs after the first week. Analgesics should be continued until pain improves.

There is a risk of temporary pain flare in 10% of the patients [25, 26]. The most important late side effect is temporary myelosuppression [23, 24] (LE: 2). Radiation exposure to the public is possible [4] (LE: 2).

Radiopharmaceuticals should not be administered if the glomerular filtration rate is <30 mL/min [27]. Because of the myelosuppression, white blood cell count >3,500/μL and platelets >100,000/μL are desirable [23, 26].

Bisphosphonates

Bisphosphonates are pyrophosphate analogues that act through five mechanisms:

  • Inhibition of bone resorption (24–48 h after administration) due to reduction of osteoclastic activity;

  • Inhibition of osteoclast adhesion;

  • Decrease in number of osteoclasts and induction of osteoclast apoptosis;

  • Inhibition of crystallisation and mineralisation;

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

Anti-angiogenic effect and effect on tumour cells

The main effects of bisphosphonates are a decrease in the risk of skeleton-related events and adequate pain alleviation in 60–85% [28] (LE: 1a). Their side effects are ‘flu-like’ symptoms (20–40%), bone pain, fever, fatigue, arthralgia and myalgia (all <10%), hypocalcaemia, acute renal failure and osteonecrosis of the jaw bones. Dental status has to be evaluated prior to administration. Zoledronic acid, a nitrogen-containing third-generation bisphosphonate, is the most effective bisphosphonate in the treatment of metastatic bone disease [29] (GR: A). Other bisphosphonates, including pamidronate and clodronate, seem to be less effective in this setting [30].

Corticosteroids

Corticosteroids are also used for the palliation of pain, particularly due to bone deposits. 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) [31] (LE: 1b).

Chemotherapy

The possibility of successful pain relief is usually related to the likelihood of tumour response. There is a strong clinical impression that tumour shrinkage is generally associated with pain relief, though there are some reports of analgesia, even in the absence of significant tumour shrinkage. Chemotherapy is much more cost-intensive than the administration of opioids and has a limited survival advantage. However, recent data from randomised studies in patients with metastatic prostate cancer after chemotherapy, particularly those using docetaxel, have provided encouraging improvements in overall survival, palliation of symptoms and improvements in QoL. Docetaxel compared to mitoxantrone provided a better response to pain and improvement in QoL (31–35% vs. 22%) [32] (LE:1a).

Systemic analgesic pharmacotherapy

Analgesic drugs used in prostate cancer pain management are separated into three groups:

  • non-opioid analgesics

  • opioid analgesics

  • adjuvant analgesics—drugs with other primary indications that can be effective analgesics in specific circumstances.

The Cancer Unit of the WHO proposed a useful approach to drug selection for cancer pain, which has become known as the ‘analgesic ladder’ (Fig. 3) [33]. With appropriate dosing, this approach provides adequate relief in 70–90% of patients [34].

Fig. 3
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The World Health Organization’s ‘analgesic ladder’

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In incurable oncologic patients with quick progression of the disease and reduced life expectancy, recent data, however, suggest a direct move from step 1 to step 3 (excluding step 2) resulting in superior pain relief and increased patient satisfaction [35].

The introduction of a fourth step in the WHO analgesic ladder (including interventional treatment such as intrathecal administration of analgesics, peripheral nerve catheterisation and neurolytic blockades) has been proposed in patients with intractable cancer pain who failed to response adequately to pharmacological treatment [36, 37].

Non-opioid analgesics

Non-opioid analgesics can be useful alone for mild-to-moderate pain (Step 1 of the analgesic ladder), or combined with opioids (Steps 2 and 3). The use of NSAIDs has not been established for cancer pain treatment, even though there is some evidence that ibuprofen is effective for cancer pain [38].

The adverse effects of NSAIDs are gastric irritation, ulcer formation, bleeding, renal impairment, bronchospasm, asthma deterioration, platelet dysfunction and inhibition of osteogenesis.

The use of cyclo-oxygenase 2 (COX-2) selective inhibitors is not established for cancer pain, even though their use is associated with fewer gastrointestinal complications and minimal platelet inhibition compared with non-selective COX inhibitors. This is because their long-term use has been associated with cardiovascular problems [39].

Paracetamol (acetaminophen) is used for mild-to-moderate cancer pain. In cases of moderate-to-severe post-operative pain, the co-administration of paracetamol with strong opioids appears to reduce opioid consumption [40] (LE: 1a). The exact mode of action of paracetamol is unclear, but probably involves the central inhibition of COX production. The dose (500 mg to 1 g 3–4 times daily (orally or rectally) should be reduced in patients with hepatic impairment or chronic alcoholism as exceeding the dose can cause acute hepatic failure. A dose greater than 6 g in 24 h can cause acute renal failure.

Opioids

Opioids are the choice for moderate-to-severe cancer pain (Table 5). The key principle for their safe and effective use is to titrate the dose against pain relief and to minimise unwanted effects. Factors to consider for opioid selection are: age, pain intensity, prior opioid therapy and co-existing disease. Opioids should be given by the least invasive and safest route that is capable of providing adequate analgesia. Their main adverse effects are respiratory depression, apnoea, sedation, confusion, delirium, nausea, vomiting, pruritus, constipation, hypotension, addiction, dependence and tolerance.

Table 5 Opioids: drugs, dosage and administration
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Weak opioids, such as codeine and tramadol, along with tricyclic antidepressants (TCAs) and NSAIDs produce a variable response in different population groups, due to genetic polymorphism of cytochrome P450 enzymes, and careful dose titration is therefore necessary [41]. Oral administration is the preferred route in routine practice. The potency of opioids administered rectally is believed to approximate oral dosing [42]. The transdermal system for fentanyl and buprenorphine administration has been demonstrated to be effective in cancer pain [43]. The incidence of side effects, such as sedation and constipation, is lower compared with morphine [43, 44].

An oral transmucosal (sublingual) formulation of fentanyl, which incorporates the drug into a sugar base, is useful for providing rapid relief of breakthrough pain and appears to be more effective than oral morphine [45]. There are many different opioids combinations with paracetamol for oral or rectal administration.

Opioids in patients with continuous or frequent pain can be administered using an ‘around-the-clock’ dosing schedule, with a so-called ‘rescue dose’ as needed. The ‘as needed’ dosing scheme may be appropriate for patients, who have rapidly decreasing analgesic requirements or intermittent pain separated by pain-free intervals. They can also be administered as controlled release preparations.

Patient-controlled analgesia (PCA) is a technique that can be used in postoperative patients and may also be used to manage acute pain in end-stage cancer patients. It consists of parenteral (intravenous or epidural) drug administration, in which the patient controls an infusion device that delivers a bolus of analgesic drug ‘on demand’. In most cases, PCA is added to a basal infusion rate and acts essentially as a rescue dose. Opioids are also provided in controlled release preparations, which can lessen the inconvenience associated with the short duration of action.

Adjuvant analgesics

Adjuvant analgesics may be combined with primary analgesics in 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 the management of cancer pain, the following groups are distinguished:

  • corticosteroids (see above)

  • antidepressants

  • benzodiazepines

  • anticonvulsants.

  • S(+)-ketamine.

Antidepressants

tricyclic antidepressants (TCAs) are often the first drugs selected and have a particular role in the treatment of neuropathic pain [46]. They act by blocking the reuptake of norepinephrine and serotonin. Tricyclic antidepressants must be used cautiously in patients with a history of cardiovascular disorders, glaucoma and urine retention. Although TCAs are first-line treatment in patients with neuropathic (non-cancer) pain, there are few data evaluating its analgesic effect in patients with neuropathic cancer pain. Based on the available literature (in non-cancer neuropathic pain), it is assumed that these analgesics also have an analgesic effect in patients with neuropathic pain due to cancer (LE: 4, GR: C).

Selective serotonin reuptake inhibitors (SSRIs), such as sertraline, paroxetine, fluoxetine and citalopram, selectively inhibit the reuptake of serotonin and have a more favourable side effect profile than TCAs. However, their analgesic effect is questionable in neuropathic (cancer) pain [46].

Benzodiazepines

these drugs are known to relieve patients’ anxiety, insomnia and phobia. Their analgesic effect is associated with conditions of high anxiety, muscle spasm and deafferentation [47].

Anticonvulsants

lamotrigine, carbamazepine, diphantoine, pregabaline and gabapentine are effective in the treatment of neuropathic pain. However, studies are only available for gabapentine in neuropathic cancer pain, and gabapentine is therefore recommended as first-line treatment in the management of neuropathic cancer pain ([48] (LE: 2, GR: A).

S(+)-ketamine

oral or intravenous administration of S(+)-ketamine may be effective in patients with severe neuropathic cancer pain, despite treatment with anticonvulsants and/or antidepressants (LE: 4, GR: C). It can have severe side effects (including hallucinations, dissociation and nightmares), which limit its usefulness and widespread use in neuropathic cancer pain. For this reason, S(+)-ketamine should only be considered as a third-line option, for use when standard analgesic treatments are exhausted [49].

Invasive analgesic techniques

In patients with cancer pain that fails to respond to systemic analgesics, interventional procedures can be considered.

Effective relief of neuropathic pain due to malignant infiltration of the lumbar plexus has been achieved with local anaesthetic agents administered through a psoas sheet catheter. A continuous sacral root nerve block has been used to treat severe neuropathic cancer pain due to infiltration of a sacral nerve [50, 51].

For progressive tumour invasion (involvement of the whole sacral plexus), it may be more appropriate to control pain using intrathecal morphine, given alone or in combination with local anaesthetic agents. The aim is to induce pain relief by placing a small dose of an opioid close to opioid receptors located at the dorsal horn of the spinal cord. This also means that the total dose of opioids administered can be reduced, leading to less opioid-induced side effects. It may be beneficial to add a low dose of a local anaesthetic agent (usually bupivacaine), particularly in patients with neuropathic pain. Intrathecally administered local anaesthetic agents can result in sensory and motor impairment. The potential for other complications, such as meningitis, should also be taken into account [52, 53].

Finally, the sympathetic nervous system has been implicated in the maintenance of cancer pain syndromes. In patients with intractable pelvic pain due to genitourinary neoplastic disease, a superior hypogastric block may result in pain control [54].

Table 6 presents recommendations for pain control in metastasised prostate cancer.

Table 6 Recommendations for pain control in metastasised prostate cancer
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Palliative care/physical-psychological support/quality of life

Palliative care is defined by the WHO as an approach that improves the QoL 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. It includes pain management, as well as functional, psychosocial and spiritual support [14]. Palliative care may take place at any stage of the disease, alone, or in combination with active curative treatment.

Medical, psychological, physical, social, hospice and pastoral interdisciplinary services can be helpful at the end of a patient’s life [15]. Patients in an advanced stage of prostate cancer often experience ‘total pain’, which is a mixture of physical, psychological, spiritual and social suffering [55]. Information about the illness and the process of care has been proven to reduce distress [56, 57] and treatment should include both psychological and somatic symptoms [55].

Moderate exercise seems to provide a certain benefit in the treatment of fatigue [58, 59] (LE: 1a). Family caregivers and support groups are crucial components of the patient’s support system [15]. Members of prostate cancer self-help groups provide each other with various types of help, usually non-professional and non-material, for a particular, shared, usually burdensome, feature [57]. The help may take the form of providing and evaluating relevant information, relating personal experiences, listening to and accepting others’ experiences, providing sympathetic understanding and establishing social networks. A supporting self-help group may also work to inform the public or engage in advocacy. All efforts are aimed at improving a patient’s QoL [56].

Summary

This text presents a summary of only one section of the EAU Guidelines on Pain Management. More detailed information on this topic, as well as additional information on the management of pain in urological practice, can be found in the full text version. These guidelines are available on the EAU Web site (http://www.uroweb.org/guidelines/online-guidelines/).