clinical practice guidelines

Annals of Oncology 22 (Supplement 6): vi69vi77, 2011 doi:10.1093/annonc/mdr390

Management of cancer pain: ESMO Clinical Practice Guidelines

C. I. Ripamonti1, E. Bandieri2 & F. Roila3 On behalf of the ESMO Guidelines Working Group*
1 3

Supportive Care in Cancer Unit, IRCCS Foundation, National Cancer Institute of Milano, Milan; 2Palliative Care Unit, Azienda Usl Modena (CeVEAS), Modena; Department of Medical Oncology, S. Maria Hospital, Terni, Italy

incidence of pain
According to the World Health Organization (WHO), the incidence of cancer was 12 667 470 new cases in 2008 and, based on projections, it will be >15 million in 2020 [1]. Consistent with this, a systematic review of the literature, which investigated the prevalence of pain in different disease stages and types of cancer during the period 19662005[2], showed no difference in pain prevalence between patients during anticancer treatment and those in an advanced or terminal phase of the disease. In particular, pain prevalence was 64% in patients with metastatic, advanced or terminal phases of the disease, 59% in patients on anticancer treatment and 33% in patients after curative treatment. Moreover, in the systematic review of the literature carried out by Deandrea et al. [3] on studies published from 1994 to 2007, nearly half of the cancer patients were undertreated, with a high variability across study designs and clinical settings. Recent studies conducted both in Italy and in Europe [4, 5] conrmed these data, showing that pain was present in all phases of cancer disease (early and metastatic) and was not adequately treated in a signicant percentage of patients, ranging from 56 to 82.3%. In particular, Apolone et al. [6] evaluated prospectively the adequacy of analgesic care of cancer patients by means of the Pain Management Index (PMI) in 1802 valid cases of in- and outpatients with advanced/metastatic solid tumor enrolled in 110 centers specically devoted to cancer and/or pain management (oncology/pain/palliative centers or hospices). The study showed that patients were still classied as potentially undertreated in 25.3% of the cases (range 9.855.3%). In contrast to the percentage of incidence of pain reported in hematological patients (5% with leukemia and 38% with lymphoma) in the past literature [7], a signicant
*Correspondence to ESMO Guidelines Working Group, ESMO Head Ofce, Via L. Taddei 4, CH-6962 Viganello-Lugano, Switzerland; E-mail: clinicalguidelines@esmo.org Approved by the ESMO Guidelines Working Group: December 2004, last update February 2011. This publication supersedes the previously published versionAnn Oncol 2010; 21 (Suppl 5): v257v260. Conict of interest: Dr Roila has reported that he has been a member of the speakers bureau for Janssen Cilag on cancer pain treatment. Dr Ripamonti and Dr Bandieri have reported no conicts of interest.

proportion of patients with lymphoma and leukemia may suffer from pain not only in the last months of life (83%) [4] but also at the time of diagnosis and during active therapies [8]. Based on these facts it is evident that millions of cancer patients still suffer from cancer-related pain. recommendation. The assessment and management of pain in cancer patients is of paramount importance in all stages of the disease; however, pain is still not adequately treated (expert and panel consensus).

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assessment of patients with pain

According to the literature, most patients with advanced cancer have at least two types of cancer-related pain which derive from a variety of etiologies [9, 10]. Sixty-nine per cent of patients rate their worst pain at a level that impaired their ability to function [11]. Table 1 shows the guidelines for a correct and complete assessment of the patient with pain. The proper and regular self-reporting assessment of pain with the help of validated assessment tools is the rst step for an effective and individualized treatment. The most frequently used standardized scales [12] are reported in Figure 1 and are: visual analog scales (VAS), a verbal rating scale (VRS) and a numerical rating scale (NRS). recommendation. The intensity of pain and the treatment outcomes should be regularly assessed using (i) a visual analog scales (VAS), (ii) a verbal rating scale (VRS) or (iii) a numerical rating scale (NRS) [V, D]. Older age and the presence of limited communicative skills or of cognitive impairment such as during the last days of life makes the self-reporting of pain more difcult, although there is no evidence of clinical reductions in pain-related suffering. When cognitive decits are severe, observation of pain-related behaviors and discomfort (i.e. facial expression, body movements, verbalization or vocalizations, changes in interpersonal interactions, changes in routine activity) is an alternative strategy for assessing the presence of pain (not its intensity) [1316]. Different observational scales are available in the literature [15], but none of them is validated in different languages.

The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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clinical practice guidelines

Table 1. Guidelines for a correct assessment of the patient with pain
d

Annals of Oncology

principles of pain management

Inform the patients about the possible onset of pain at any stage of the disease both during and after diagnostic interventions, in addition to as a consequence of cancer or anticancer treatments, and involve them in pain management. They have to be encouraged to communicate with the physician and/or the nurse about their suffering, the efcacy of therapy and any side effects, and not to consider the analgesic opioids as a therapeutic approach for dying patients [18], thus contributing to reduce opioidophobia. The patients involvement in pain management improves communication and has a benecial effect on patients pain experience [19].

1. Assess and re-assess the pain d Causes, onset, type, site, duration, intensity, relief and temporal patterns of the pain d Presence of the trigger factors and the signs and symptoms associated with the pain d Use of analgesics and their efcacy and tolerability 2. Assess and re-assess the patient d The clinical situation by means of a complete/specic physical examination and the specic radiological and/or biochemical investigations d The presence of interference of pain with the patients daily activities, work, social life, sleep patterns, appetite, sexual functioning and mood d The impact of the disease and the therapy on the physical, psychological and social conditions d The presence of a caregiver, the psychological status, the degree of awareness of the disease, anxiety and depression and suicidal ideation, his/ her social environment, quality of life, spiritual concerns/needs d The presence and intensity of signs, physical and/or emotional symptoms associated with cancer pain syndromes d The functional status d The presence of opiophobia 3. Assess and re-assess your ability to inform and to communicate with the patient and the family d Take time to spend with the patient and the family to understand their needs

recommendation Patients should be informed about pain and pain management and be encouraged to take an active role in their pain management [II, B]. d Prevent the onset of pain by means of the by the clock administration, taking into account the half-life, bioavailability and duration of action of the different drugs. recommendation Analgesic for chronic pain should be prescribed on a regular basis and not on as required schedule [V, D]. d Prescribe a therapy which is simple to be administered and easy to be managed by the patient himself and his family, especially when the patient is cared for at home. The oral route appears to be the most suitable to meet this requirement, and, if well tolerated, it must be considered as the preferred route of administration [2024]. recommendation The oral route of administration of the analgesic drugs should be advocated as the rst choice [IV, C]. d Assess and treat the breakthrough pain (BTP) which is dened as a transitory exacerbation of pain that occurs in addition to an otherwise medically controlled stable pain [25, 26]. It is of sudden onset, occurs for short periods of time and is usually severe. The incidence of BTP has been estimated to be high (2080% depending on the setting) in various surveys [26, 27]. The differences reported are probably due to the different clinical settings analyzed and the different denitions of BTP used.

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Figure 1. Validated and most frequently used pain assessment tools.

recommendation. Observation of pain-related behaviors and discomfort is indicated in patients with cognitive impairment to assess the presence of pain (expert and panel consensus). Psychosocial distress has to be assessed because it is strongly associated with cancer pain [17]. In fact psychosocial distress may amplify the perception of pain-related distress and, similarly, inadequately controlled pain may cause substantial psychological distress. recommendation. The assessment of all components of suffering such as psychosocial distress should be considered and evaluated [II, B].

recommendation Rescue dose of medications (as required) other than the regular basal therapy must be prescribed for breakthrough pain episodes [V, D]. d Tailor the dosage, the type and the route of drugs administered according to each patients needs. The type and the dose of the analgesic drugs is inuenced by the intensity of pain (Table 2) and have to be promptly adjusted to reach a balance between pain relief and side effects. The rescue doses taken by the patients are an appropriate measure of the daily titration of the regular doses [25, 26]. An alternative route for opioid administration should be considered when oral

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clinical practice guidelines

Score on NRSa Analgesics of choice

Table 2. Categorization of pain and appropriate analgesia WHO analgesic ladder step 1 (mild pain) 2 (mild to moderate pain)

<3 out of 10 Paracetamol or NSAIDs 3-6 out of 10 Weak opioids 6 paracetomal or NSAIDs 3 (moderate to severe pain) >6 out of 10 Strong opioids 6 paracetamol NSAIDs

Score on NRS according to references 24, 29, 30. NRS, numerical rating scale; NSAIDs, non-inammatory drugs; WHO, World Health Organization.

recommendation Paracetamol and/or a non-steroidal anti-inammatory drug are effective for treating mild pain [I, A]. Paracetamol and NSAIDS are universally accepted as part of the treatment of cancer pain at any stage of the WHO analgesic ladder. The long-term use of NSAIDs or a cyclo-oxygenase-2 (COX-2) selective inhibitor has to be carefully monitored and reviewed periodically [36] because they can provoke severe toxicity such as: gastrointestinal bleeding, platelet dysfunction and renal failure. COX-2 selective inhibitors may increase the risk of thrombotic cardiovascular adverse reactions [37] and do no protect from renal failure. Not all of the described drugs are available in all countries. recommendation Paracetamol and/or a non-steroidal anti-inammatory drug are effective for treating all intensities of pain, at least in the short term and unless contraindicated [I, A].

administration is not possible because of severe vomiting, bowel obstruction, severe dysphagia or severe confusion, as well as in the presence of poor pain control, which requires rapid dose escalation, and/or in the presence of oral opioid-related adverse effects.

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pain management
In 1986, the WHO proposed a strategy for cancer pain treatment based on a sequential three-step analgesic ladder from nonopioids to weak opioids to strong opioids according to pain intensity [28]. Twenty years after the rst edition [20], the WHO cancer pain relief program remains the referral point for pain management. According to WHO guidelines, opioid analgesics are the mainstay of analgesic therapy and are classied according to their ability to control pain from mild to mildmoderate to moderatesevere intensity. Such pain intensity may be scored on an NRS as reported in Table 2 [24, 29, 30]. However, the intensity of pain is frequently reported as mild, moderate and severe and scored on an NRS respectively as 4, from 5 to 6, and 7 [31]. Opioid analgesics may be combined with non-opioid drugs such as paracetamol or with non-steroidal anti-inammatory drugs (NSAIDs) and with adjuvant drugs. [32, 33].

treatment of mildmoderate pain

Traditionally [20], patients with mildmoderate pain have been treated with a combination product containing acetaminophen, aspirin or NSAID plus a weak immediate-release opioid such as codeine, dihydrocodeine, tramadol or propoxyphene (Table 4). The use of drugs of the second step of the WHO ladder has several controversial aspects. The rst criticism concerns the absence of a denitive proof of efcacy of weak opioids: in a meta-analysis of data reported from clinical RCTs [38] no signicant difference was found in the effectiveness between non-opioid analgesics alone, and the combination of these with weak opioids. The available studies do not even demonstrate a clear difference in the effectiveness of the drugs between the rst and the second step [39]. Uncontrolled studies also show that the effectiveness of the second step of the WHO ladder has a time limit of 3040 days for most patients and that the shift to the third step is mainly due to insufcient analgesia achieved, rather than to adverse effects [40]. A further limitation in the use of weak opioids is represented by the ceiling effect, for which more than a certain threshold of dose cannot increase the effectiveness of the drug but only inuence the appearance of side effects. Many authors have proposed the abolition of the second step of the WHO analgesic ladder, in favor of the early use of morphine at low doses. The few studies on this specic topic [4143], though suggestive, have reported inconclusive results due both to the low number and representativeness of the patients sample studied and to the relatively low statistical power. An RCT is urgently needed to address the relevant issue of the role of WHO step II.

recommendation The analgesic treatment should start with drugs indicated by the WHO analgesic ladder appropriate for the severity of pain [II, B]. Pain should already be managed during the diagnostic evaluation. Most cancer patients can attain satisfactory relief of pain through an approach that incorporates primary antitumor treatments, systemic analgesic therapy and other non-invasive techniques such as psychological or rehabilitative interventions. treatment of mild pain For the treatment of mild pain non-opioid analgesics such as acetaminophen/paracetamol or an NSAID are widely used (Table 3). NSAIDs are superior to placebo in relieving cancer pain in single dose studies. There is no evidence to support superior safety or efcacy of one NSAID over any other [34]. In a randomized clinical trial (RCT) carried out in a small sample of cancer patients on a strong opioid regimen, paracetamol improved pain and well-being [35]. However, these results have not been conrmed by other studies.

recommendation For mild to moderate pain, weak opioids such as codeine, tramadol and dihydrocodeine should be given in combination with non-opioid analgesics [III, C]. As an alternative to weak opioids, consider low doses of strong opiods in combination with non-opioid analgesics [III, C].

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Table 3. Selected non-opioid analgesics for mild pain (WHO step I) Substance Acetaminophen (paracetamol) Acetylsalycic acid Ibuprofen Widely available forms and strengths Tablets, suppositories 5001000 mg Tablets 5001000 mg Tablets 200400600 mg; tablets 800 mg modied release; topical gels Tablets 2575 mg; tablets 100150200 mg modied release Tablets 255075 mg; tablets 100 mg modied release Capsules 250500 mg Tablets 250375500 mg Time to onset (min) 1530 1530 1530; 120+ Caution Hepatotoxicity GI toxicity, allergy, platelet inhibition GI and renal toxicity

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Maximal daily dose 4 1000 mg 3 1000 mg 4 600 mg; 3 800 mg modied release 4 75 mg; 2 200 mg 4 50 mg; 2 100 mg 4 500 mg 2 500 mg

Ketoprofen

30+

GI and renal toxicity

Diclofenac

30120

GI and renal toxicity

Mefenamic acid Naproxen

30+ 30+

GI and renal toxicity GI and renal toxicity

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GI, gastrointestinal; WHO, World Health Organization.

Table 4. Comparison of selected opioids for mild to moderate pain (WHO step II) Substance Widely available forms and strengths Modied-release tablets 6090120 mg Tablet 153060 mg Drops 100 mg/ml; capsules 50 mg Modied-release tablets 100150200 mg Relative effectiveness compared with oral morphine 0.17 Duration of effectiveness (h) 12 46 24 12 Maximal daily dose Starting dose without pretreatment 60120 mg 1560 mg 50100 mg 50100 mg

Dihydrocodeine Codeine Tramadol

240 mg 360 mg 400 mg 400 mg

0.10.2 0.10.2

WHO, World Health Organization.

treatment of moderatesevere pain

Strong opioids (Table 5) are the mainstay of analgesic therapy in treating moderatesevere cancer-related pain, In some countries, pain relief is hampered by a lack of availability or barriers to accessibility to opioid analgesics [44]. Morphine, methadone, oxycodone, hydromorphone, fentanyl, alfentanyl, buprenorphine, heroin, levorphanol and oxymorphone are the most widely used strong opioids in Europe [33, 45]. In the last years in some countries, the consumption of oxycontin and the use of patches of fentanyl and buprenorphine has been increasing [46]. However, there is no evidence from high quality comparative studies that other opioids are superior to morphine in terms of efcacy and tolerability. In many countries, since 1977, oral morphine has been used in Hospices and Palliative Care Units as the drug of choice for the management of chronic cancer pain of moderate to severe intensity because it provides effective pain relief, is widely tolerated, is simple to be administered and is cheap. Moreover, morphine is the only opioid analgesic considered in the WHO essential drug list for adults and children with pain [47].

recommendation The opioid of rst choice for moderate to severe cancer pain is oral morphine [IV, D]. Although the oral route of administration is advocated, the patients presenting with severe pain who needs urgent relief should be treated and titrated with parenteral opioids, usually administered by the subcutaneous (s.c.) or intravenous (i.v.) route. If given parenterally, the equivalent dose is one-third of that of the oral medication. The relative potency ratio of oral to parenteral (s.c. or i.v.) morphine (not subject to rst-pass metabolism) [48, 49] might vary according to the circumstances in which morphine is used and among individual patients. When converting from oral to parenteral morphine, the dose should be divided by three to get a roughly equianalgesic effect, but upward or downward adjustment of the dose may then be required [50]. recommendation The average relative potency ratio of oral to intravenous morphine is between 1:2 and 1:3 [II, A].

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Route Relative effectiveness compared with oral morphinea 1 3 1.52 7.5 + 4c 75 100 + 4c 4812e 1 3 Maximal daily dose Starting dose without pretreatment 2040 mg 510 mg 20 mg 8 mg 12 lg/hd 0.4 mg 0.30.6 mg 17.535lg/h 10 mg 5 mg 5 mg

Table 5. Comparison of selected opioids for moderate to severe pain (WHO step III) Substance

Morphine sulfate Morphine Oxycodone Hydromorphone Fentanyl transdermal Buprenorphine Buprenorphine Buprenorphine transdermal Methadone Nicomorphine Nicomorphine
a

Oral i.v. Oral Oral TTS Oral i.v. TTS Oral Oral i.v.

No upper No upper No upper No upper No upper 4 mg 3 mg 140 lg/h No upper 20 mg 20 mg

limitb limitb limitb limitb limitb

limitb

The relative effectiveness varies considerably in the published literature and among individual patients. Switching to another opiod should therefore be done cautiously with a dose reduction of the newly prescribed opioid. b The maximal dose depends on tachyphylaxis. c Calculated with conversion from mg/day to lg/h. d Not usually used as rst opioid (the 12 lg/h dose corresponds to about 30 mg of oral morphine sulfate daily). e Factor 4 for daily morphine doses <90 mg, factor 8 for doses 90300 mg, and 12 for >300 mg. WHO, World Health Organization; i.v. intravenous.

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The average relative potency ratio of oral to subcutaneous morphine is between 1:2 and 1:3 [IV, C]. Only a few selected patients (12%) with cancer pain, refractory to all conventional strategies and/or dose-limiting analgesic-related side effects, require spinal analgesia [51]. Based on the ndings of Myers, Smith and Kalso [5254] and the documented bias of the investigation of Smith et al. [55], it is evident that the role of intraspinal opioids has not been established, and well-designed, independently funded clinical trials are required. Hydromorphone or oxycodone, in both immediate-release and modied-release formulations for oral administration, are effective alternatives to oral morphine. Transdermal fentanyl and transdermal buprenorphine are best reserved for patients whose opioid requirements are stable. They are usually the treatment of choice for patients who are unable to swallow, patients with poor tolerance of morphine and patients with poor compliance. Although not recommended in the NCCN Clinical Practice Guidelines in Oncology for Adult Cancer Pain [21] because it is a partial agonist, buprenorphine has a role in the analgesic therapy of patients with renal impairment and undergoing hemodialysis treatment [56, 57] where no drug reduction is necessary, buprenorphine being mainly converted in the liver to norbuprenorphine (a metabolite 40 times less potent than the parent compound). Methadone is a valid alternative but, because of marked interindividual differences in its plasma half-life and duration of action, it is still considered as a drug which should be initiated by physicians with experience and expertise in its use. Strong opioids may be combined with ongoing use of a non-opioid analgesic (step 1).

Buprenorphine is the safest opioid of choice in patients with chronic kidney disease stages 4 or 5 (estimated glomerular ltration rate <30 ml/min) [IV, C]. Opioid switching is a practice used to improve pain relief and/or drug tolerability. Although there is no high quality evidence to support this practice, a switch to an alternative opioid is to be considered in clinical practice [58]. This approach requires familiarity with equianalgesic doses of the different opioids [33].

scheduling and titration

Opioid doses should be titrated to take effect as rapidly as possible. Titration is a process for which the dose of the opioid is speedily modied to obtain the tailored dose which provides adequate relief of pain with an acceptable degree of side effects. Normal release morphine has a short half-life and is indicated during the titration phase and for treating BTP episodes. I.v. titration is indicated in patients with severe pain (Table 6) [59]. All patients should receive round-the-clock dosing with provision of a breakthrough dose to manage transient exacerbations of pain. The breakthrough dose is usually equivalent to 1015% of the total daily dose. If more than four breakthrough doses per day are necessary, the baseline opioid treatment with a slow-release formulation has to be adapted. Opioids with a rapid onset and short duration are preferred for breakthrough doses. After the titration period slow-release opioids are indicated.

recommendation In the presence of renal impairment all opioids should be used with caution and at reduced doses and frequency [IV, C].

recommendation Individual titration of dosages by means of normal release morphine administered every 4 h plus rescue doses (up to hourly) for BTP are recommended in clinical practice [IV, C]. The regular dose of slow-release opioids can then be adjusted to take into account the total amount of rescue morphine [IV, C].

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Table 6. Intravenous titration (dose nding) with morphine for severe cancer pain (Harris et al. [59]). Study design and patient population RCT. 62 strong opioid-nave inpatients pain intensity NRS 5 Patients were randomized to receive i.v. morphine (n = 31) or oral IR morphine (n = 31) Initial morphine dosage and route i.v. group: 1.5 mg bolus every 10 min until pain relief (or adverse effects). Oral group: IR morphine 5 mg every 4 h in opioid-naive patients. 10 mg in patients on weak opioids. Rescue dose: the same dose every 1 h max. Subsequent dosage and route i.v. group: Oral IR morphine 4 hourly, on the basis of the previous i.v. requirements. i.v.: p.o. conversion 1:1. Rescue dose: the same dose every 1 h max. Oral group: follow the same scheme Results

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% of patients achieving satisfactory pain relief: d after 1 h: i.v. group, 84%; oral group, 25% (P <0.001) d after 12 h: i.v. group 97%; oral group 76% (P <0.001) d after 24 h: i.v. group and oral group similar. i.v. group: median morphine dosage (i.v.) to achieve pain relief: 4.5 mg (range 1.534.5). In the same group, mean morphine dosage (p.o.) after stabilization: 8.3 (range 2.530) mg. Oral group: median morphine dosage to achieve pain relief: 7.2 (2.515) mg. No signicant adverse events

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IR, immediate release, i.v., intravenous; NRS, numerical rating scale; p.o., per os; RCT, randomized controlled trial.

management of opioid side effects

Many patients develop adverse effects such as constipation, nausea, vomiting, urinary retention, pruritus and central nervous system (CNS) toxicity (drowsiness, cognitive impairment, confusion, hallucinations, myoclonic jerks andrarelyopioid-induced hyperalgesia/allodynia). In some cases a reduction in opioid dose may alleviate refractory side effects. This may be achieved by using a co-analgesic or an alternative approach such as a nerve block or radiotherapy. Other strategies include the continued use of antiemetics for nausea, laxatives for constipation, major tranquillizers for confusion, and psychostimulants for drowsiness. However, since some of the side effects may be caused by accumulation of toxic metabolites, switching to another opioid agonist and/or another route may allow titration to adequate analgesia without the same disabling effects. This is especially true for symptoms of CNS toxicity such as opioid-induced hyperalgesia/allodynia and myoclonic jerks [60]. Naloxone is a short-acting opioid antagonist for i.v. use able to revert symptoms of accidental severe opioid overdose.

showed complete pain relief at 1 month in 27% of the patients, and at least 50% relief in an additional 42% of the patients at any time in the trials included. The radioisotope treatment has also been investigated in a systematic review [62]: the results showed only weak evidence of a small benecial effect on pain control in the short and medium term (16 months), with no modication of the analgesics used. A few RCTs, involving small numbers, have shown that radioisotopes can relieve bone pain in patients with breast cancer [63] and lung cancer [64], while inconsistent results were produced in patients with hormone-refractory prostate cancer [65].

recommendation All patients with pain from bone metastases which is proving difcult to be controlled by pharmacological therapy should be evaluated by a clinical oncologist for consideration of external beam radiotherapy or radioisotope treatment [II, B].

bisphosphonates and bone pain

Bisphosphonates (BPs) form part of the standard therapy for hypocalcemia and the prevention of skeletal-related events in some cancers. There is sufcient evidence supporting the analgesic efcacy of BPs in patients with bone pain due to bone metastases [66]. However, the prescription of BPs should not be considered as an alternative to analgesic treatment and their administration should be started after preventive dental

radiotherapy
Radiotherapy has specic and critical efcacy in providing pain relief caused by bone metastases. Radiotherapy also has a role in tumors compressing nerve structures and cerebral metastases. A systematic review [61] on the use of radiotherapy for bone pain

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Widely available forms and strengths (mg) Tablets 2550 Tablets 1075 Tablets 1025 Tablets 20 Tablets 3060 Tablets 200400 Tablets 200300400800 Tablets 255075100150 200300 mg Drops, tablets, vials Drops, tablets, suppositories, vials Activity Antidepressive Antidepressive Antidepressive Antidepressive Antidepressive Antiepileptic Antiepileptic Antiepileptic Neuroleptic Neuroleptic Sedation +++ (+) + + + + ++ + + + Range of daily doses (mg) 50200 50200 50225 2080 60120 4001600 9003600 150600 320 25200

Table 7. Selected adjuvant drugs for neuropathic pain Substance Amitryptiline Clomipramine Nortriptyline Fluoxetine Duloxetine Carbamazepine Gabapentin Pregabalin Haloperidol Chlorpromazine

Usually the lowest doses of antidepressants and neuroleptics are sufcient as an adjunct to opioids unless severe depression or major psychosis has to be treated with higher doses as appropriate.

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measures [67, 68]. After the rst i.v. infusions of BPs the pain can appear or its intensity increase, and the use of analgesics such as paracetamol or a basal analgesic dose increase is necessary.

recommendation Bisphosphonates should be considered as part of the therapeutic regimen for the treatment of patients with/without pain due to metastatic bone disease [II, B]. Preventive dental measures are necessary before starting bisphosphonate administration [III, A].

antidepressant drugs or anticonvulsants (Table 7). The efcacy and tolerability of the therapy have to be monitored over time. Steroids should be considered in the case of nerve compression. There is evidence in adults that i.v. lidocaine and its oral analog mexiletine are more effective than placebo in decreasing neuropathic pain and can relieve pain in selected patients [73].

recommendation Patients with neuropathic pain should be given either a tricyclic antidepressant or a anticonvulsant and subjected to side effects monitoring [I, A].

treatment of resistant and neuropathic pain

Some patients, whose pain remains inadequately relieved, may benet from invasive anesthetic or neurosurgical treatments. Limited evidence supports the use of subanesthetic doses of ketamine, an N-methyl-D-aspartate (NMDA) antagonist, in intractable pain. Neuropathic pain, either caused by tumor inltration or due to paraneoplastic or treatment-induced polyneuropathy, may not be adequately controlled by opioids alone. Long-lasting and neuropathic pain may cause psychological problems that should be specically addressed. Few studies have been identied which were carried out directly on patients with cancer pain. Evidence from studies in patients without cancer has been reviewed as the pathological mechanism of neuropathic pain involved is believed to be the same. There is evidence from systematic reviews [69, 70] that both tricyclic antidepressants and anticonvulsant drugs are effective in the management of neuropathic pain [69, 71, 72] even if the number needed to treat (NNT) for these drugs is between 3 and 5. Two specic systematic reviews have been identied on the role of anticonvulsant drugs in neuropathic pain, one dealing with gabapentin in the management of pain [71] and the other dealing with various different anticonvulsants [72]. In cancer patients with neuropathic pain, non-opioid and opioid analgesics may be combined with tricyclic

refractory pain at the end of life

Recent data suggest that 5370% of patients with cancer-related pain require an alternative route for opioid administration, months and hours before death [74, 75]. On some occasions, as patients are nearing death, pain is perceived to be refractory. In deciding that a pain is refractory, the clinician must perceive that the further application of standard interventions is either: (i) incapable of providing adequate relief; (ii) associated with excessive and intolerable acute or chronic morbidity; or (iii) unlikely to provide relief, so that other interventional approaches may be necessary to control pain. In this situation, sedation may be the only therapeutic option capable of providing adequate relief. The justication of sedation in this setting is that it is an appropriate and proportionate goal. However, before administering sedative drugs, all the possible causes of suffering must be carefully assessed and evaluated by means of a multidisciplinary specialistic approach which also includes a psychiatric, psychologist and pastoral care personnel. Commonly used agents include opioids, neuroleptics, benzodiazepines, barbiturates and propofol. Irrespective of the agent or agents selected. administration initially requires dose titration to achieve adequate relief, followed subsequently by provision of ongoing therapy to ensure maintenance of the effect. A continuous assessment of the suffering of the patient should be performed during the sedation process.

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note
Levels of evidence [IV] and grades of recommendation [AD] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justied standard clinical practice by the expert authors and the ESMO faculty.

Annals of Oncology

literature
1. Frankish H. 15 million new cancer cases per year by 2020, says WHO. Lancet 2003; 361: 1278. 2. Van den Beuken-van Everdingen MHJ, De Rijke JM, Kessels AG et al. Prevalence of pain in patients with cancer: a systematic review of the past 40 years. Ann Oncol 2007; 18: 14371449. 3. Deandrea S, Montanari M, Moja L et al. Prevalence of undertreatment in cancer pain. A review of published literature. Ann Oncol 2008; 19: 19851991. 4. Costantini M, Ripamonti C, Beccaro M et al. Prevalence, distress, management and relief of pain during the last three months of cancer patients life. Results of an Italian mortality follow-back survey. Ann Oncol 2009; 20: 729735. 5. Breivik H, Cherny N, Collett F et al. Cancer-related pain: a pan European survey of prevalence, treatment, and patient attitudes. Ann Oncol 2009; 20: 14201433. 6. Apolone G, Corli O, Caraceni A et al. Pattern and quality of care of cancer pain management. Results from the Cancer Pain Outcome Research Study Group. Br J Cancer 2009; 100: 15661574. 7. Foley KM. The treatment of cancer pain. N Engl J Med 1985; 313: 8494. 8. Morselli M, Bandieri E, Zanin R et al. Pain and emotional distress in leukaemia patients at diagnosis. Leuk Res 2009; 34: e67e68. 9. Higginson IJ, Murtagh F. Cancer pain epidemiology. In: Bruera E, Portenoy RK (eds). Cancer Pain. Assessment and Management. Vol. 3. Cambridge: Cambridge University Press, 2010; 3752. 10. Portenoy RK, Koh M. Cancer pain syndromes. In: Bruera E, Portenoy RK (eds). Cancer Pain. Assessment and Management, Vol. 4. Cambridge: Cambridge University Press, 2010; 5388. 11. Larue F, Colleau SM, Brasseur L, Cleeland CS. Multicentre study of cancer pain and its treatment in France. BMJ 1995; 310: 10341037. 12. Caraceni A, Cherny N, Fainsinger R et al. The Steering Committee of the EAPC Research Network. Pain measurement tools and methods in clinical research in palliative care: recommendations of an expert working group of the European Association of Palliative Care. J Pain Symptom Manage 2002; 23: 239255. 13. Kaasalainen S. Pain assessment in older adults with dementia using behavioural observation methods in clinical practice. J Gerontol Nurs 2007; 33: 610. 14. Gordon DB, Dahl JL, Miaskowski C et al. American Pain Society recommendations for improving the quality of acute and cancer pain management: American Pain Society Quality of Care Task Force. Arch Intern Med 2005; 165: 15741580. 15. Van Herk R, van Dijk M, Baar FPM, Tibboel D, de Wit R. Observational scales for pain assessment in older adults with cognitive impairments or communication difculties. Nurs Res 2007; 56: 3443. 16. American Geriatrics Society Panel on Persistent Pain in Older Persons. The management of persistent pain in older persons. J Am Geriatr Soc 2002; 50: S205S224. 17. Zaza C, Baine N. Cancer pain and psychosocial factors: a critical review of the literature. J Pain Symptom Manage 2002; 24: 526542. 18. Reid CM, Gooberman Hill R, Hanks GW. Opioid analgesics for cancer pain: symptom control for the living or comfort for the dying? A qualitative study to investigate the factors inuencing the decision to accept morphine for pain caused by cancer. Ann Oncol 2008; 19: 4448. 19. De WitR, van Dam F, Zandbelt L et al. A pain education program for chronic cancer pain patients: follow-up results from a randomized controlled trial. Pain 1997; 73: 5569. 20. World Health Organization. Cancer Pain Relief, 2nd edn. Geneva: World Health Organization, 1996.

21. National Comprehensive Cancer Network. (NCCN) Clinical Practice Guideline in Oncology. Adult Cancer Pain V.I. 2009. 22. Hanks GW, De Conno F, Ripamonti C et al. Morphine in cancer pain: modes of administration. BMJ 1996; 312: 823826. 23. Hanks GW, De Conno F, Cherny N et al. the Expert Working Group of the Research Network of the European Association for Palliative Care. Morphine and alternative opioids in cancer pain. Br J Cancer 2001; 84: 587593. 24. Scottish Intercollegiate Guidelines Network. Control of Pain in Adults with Cancer. A National Clinical Guideline. SIGN-Scottish Intercollegiate Guidelines Network. November 2008. 25. Portenoy RK, Hagen NA. Breakthrough pain: denition, prevalence, and characteristics. Pain 1990; 41: 273281. 26. Mercadante S, Radbruch L, Caraceni A et al. Episodic (breakthrough) pain. Consensus Conference of an expert working group of the European Association for Palliative Care. Cancer 2002; 94: 832839. 27. Bruera E, MacMillian K, Kuehn N et al. Circadian distribution of extra doses of narcotic analgesics in patients with cancer pain: a preliminary report. Pain 1992; 49: 311314. 28. World Health Organization. Cancer Pain Relief. Geneva: World Health Organization, 1986. 29. Wallenstein S, Heidrich Gr, Kaiko R, Houde R. Clinical evaluation of mild analgesics: the measurement of clinical pain. Br J Clin Pharmacol 1980; 10 (Suppl 2): 319s327s. 30. Littman G, Walker B, Schneider B. Reassessment of verbal and visual analog ratings in analgesic studies. Clin Pharmacol Ther 1985; 38: 1623. 31. Serlin RC, Mendoza TR, Nakamura Y, Edwards KR, Cleeland CS. When is cancer pain mild, moderate or severe? Grading pain severity by its interference with function. Pain 1995; 61: 277284. 32. Lussier D, Portenoy RK. Adjuvant analgesic drugs. In: Bruera E, Higginson IJ, Ripamonti C, von Gunten C (eds). Textbook of palliative medicine. London: Edward Arnold Publishers, 2006; 402414. 33. Ripamonti C, Bandieri E. Cancer pain. Crit Rev Oncol Hematol 2009; 70: 145149. 34. McNicol E, Strassels S, Gouds L, Lau J, Carr D. NSAIDs or paracetamol, alone or combined with opioids, for cancer pain (Cochrane Review). Cochrane Database Syst Rev 2009; 1: CD005180. 35. Stockler M, Vardy J, Pillai A, Warr D. Acetominophen (paracetamol) improves pain and well-being in people with advanced cancer already receiving a strong opioid regimen: a randomized, double-blind, placebo-controlled cross-over trial. J Clin Oncol 2004; 22: 33893394. 36. Joint Formulary Committee. British National Formulary. 55th edn. London: British Medical Association and Royal Pharmaceutical Society of Great Britain, 2007. 37. European Medicines Agency. Public statement: European Medicines Agency announces regulatory action on COX-2 inhibitors (EMEA/62838/2005). Available from http://www.emea.europa.eu/pdfs/human/press/pr/6275705 en.pdf. 38. Eisenberg E, Berkey C, Carr DB, Mosteller F, Chalmers C. Efcacy and safety of nonsteroidal antinammatory drugs for cancer pain: a meta-analysis. J Clin Oncol 1994; 12: 27562765. 39. Agency for Healthcare Research and Quality. Evidence Report/Technology Assessment: Number 35 2001. 40. Ventafridda V, Tamburini M, Caraceni A, De Conno F, Naldi F. A validation study of the WHO method for cancer pain relief. Cancer 1987; 59: 850856. 41. Marinangeli F, Ciccozzi A, Leonardis M et al. Use of strong opioids in advanced cancer pain: a randomized trial. J Pain Symptom Manage 2004; 27: 409416. 42. Maltoni M, Scarpi E, Modonesi C et al. A validation study of the WHO analgesic ladder: a two-step vs three-step strategy. Support Care Cancer 2005; 13: 888894. 43. Mercadante S, Porzio G, Ferrera P et al. Low morphine doses in opioid-naive cancer patients with pain. J Pain Symptom Manage 2006; 31: 242247. 44. Cherny NI, Baselga J, De Conno F, Radrbruch L. Formulary availability and regulatory barriers to accessibility of opioids for cancer pain in Europe: a report from the ESMO/EAPC Opioid policy initiative. Ann Oncol 2010; 21: 615626.

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Annals of Oncology

clinical practice guidelines

61. McQuay HJ, Collins S, Carroll D et al. Radiotherapy for the palliation of painful bone metastases. Cochrane Database Syst Rev 2008; 2: CD001793. 62. Roque M, Martinez-Zapata M, Alonso-Coello P et al. Radioisotopes for metastatic bone pain (Cochrane Review). Cochrane Database Syst Rev 2006. 63. Sciuto R, Festa A, Pasqualoni R et al. Metastatic bone pain palliation with 89-Sr and 186-Re-HeDP in breast cancer patients. Breast Canc Res Treat 2001; 66: 101109. 64. Leondi AH, Souvatzoglou MA, Rapti AS et al. Palliative treatment of painful disseminated bone metastases with 186Rhenium-HeDP in patients with lung cancer. J Nucl Med 2004; 48: 211219. 65. Han SH, de Klerk JM, Tan S et al. The PLACORHeN study: a double-blind, placebo-controlled, randomized radionuclide study with (186)Re-etidronate in hormone-resistant prostate cancer patients with painful bone metastases. Placebo Controlled Rhenium Study. J Nucl Med 2002; 43: 11501156. 66. Wog R, Wiffen PJ. Bisphosphonates for relief of pain secondary to bone metastases. Cochrane Syst Rev 2002; 2: CD002068. 67. Ripamonti C, Maniezzo M, Campa T et al. Decreased occurrence of osteonecrosis of the jaws (ONJs) after implementation of dental preventive measure in solid tumours treated with bisphosphonates. The experience of the National Cancer Institute of Milan, Italy. Ann Oncol 2009; 20: 137145. 68. Dimopoulos MA, Kastritis E, Bamia C et al. Reduction of osteonecrosis of the jaw (ONJ) after implementation of preventive measures in patients with multiple myeloma treated with zoledronic acid. Ann Oncol 2009; 20: 117120. 69. Tan P, Barry S, Reken S et al. Pharmacological management of neuropathic pain in non-specialist settings: summary of NICE guidance. BMJ 2010; 340: c1079. 70. Saarto T, Wiffen P. Antidepressants for neuropathic pain (Cochrane Review). Cochrane Syst Rev 2007; 2: CD002068. 71. Wiffen P, Mcquay H, Edwards J, Moore R. Gabapentin for acute and chronic pain (Cochrane Review). Cochrane Syst Rev 2005; 3: CD005452. 72. Wiffen P, Collins S, Mcquay H, Carroll D, Jadad A, Moore A. Anticonvulsant drugs for acute and chronic pain (Cochrane Review). Cochrane Syst Rev 2005; 3: CD001133. 73. Challapalli V, Tremont-Lukats IW, McNicol ED, Lau J, Carr DB. Systemic administration of local anesthetic agents to relieve neuropathic pain. Cochrane Syst Rev 2005; 3: CD003345. 74. Bruera E, MacMillan K, Hanson J. Palliative care in a cancer center: results in 1984 versus 1987. J Pain Symptom Manage 1990; 5: 15. 75. Cherny NJ, Chang V, Frager G et al. Opioid pharmacotherapy in the management of cancer pain: a survey of strategies used by pain physicians for the selection of analgesic drugs and routes of administration. Cancer 1995; 76: 12831293.

45. Ripamonti C, Bareggi C. Pharmacology of opioid analgesia: clinical principles. In: Bruera E, Portenoy RK (eds). Cancer Pain. Assessment and Management, Vol. 11. Cambridge: Cambridge University Press; 2010, 195229. 46. Bandieri E, Chirarolanza A, Luppi M, Magrini N, Marata AM, Ripamonti C. Prescription of opioids in Italy: everything but the morphine. Ann Oncol 2009; 20: 961962. 47. World Health Organization. Model List of Essential Drugs (EDL). Geneva: World Health Organization, 2007. 48. Hanks GW, Hoskin PJ, Aherne GW, Turner P, Poulain P. Explanation for potency of oral morphine on repeated dosage? Lancet 1987; ii: 723725. 49. Kaiko RF. The therapeutic equivalence of IM and PO administration of morphine1:3 or 1:6. J Palliat Care 1988; 4: 6466. 50. Kalso E, Vainio A. Morphine and oxycodone hydrochloride in the management of cancer pain. Clin Pharmacol Ther 1990; 47: 639664. 51. Zech DFJ, Grond S, Lynch J et al. Validation of the World Health Organization guidelines for cancer pain relief: a 10-year prospective study. Pain 1995; 63: 6576. 52. Myers J, Chan V, Jarvis V, Walker-Dilks C. Intraspinal techniques for pain. management in cancer patients: a systematic review. Support Care Cancer 2010; 18: 137149. 53. Smith TJ, Staats PS, Deer T et al. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol 2002; 20: 40404049. 54. Kalso E, Heiskanen T, Rantio M, Rosenberg PH, Vainio A. Epidural and subcutaneous morphine in the management of cancer pain: a double-blind cross-over study. Pain 1996; 67: 443449. 55. Ripamonti C, Brunelli C. Randomized clinical trial of an implantable drug delivery system compared with comprehensive medical management for refractory cancer pain: impact on pain, drug-related toxicity, and survival. J Clin Oncol 2003; 21: 28012802. 56. Boger RH. Renal impairment: a challenge for opioid treatment? The role of buprenorphine. Palliat Med 2006; 20: s17s23. 57. Mercadante S, Arcuri E. Opioids and renal function. J Pain 2004; 5: 219. 58. Mercadante S, Bruera E. Opioid switching: a systematic and critical review. Cancer Treat Rev 2006; 32: 304315. 59. Harris JT, Suresh Kumar K, Rajagopal MR. Intravenous morphine for rapid control of severe cancer pain. Palliat Med 2003; 17: 248256. 60. Cherny N, Ripamonti C, Pereira J et al. Strategies to manage the adverse effects of oral morphine. An evidence-based report. J Clin Oncol 2001; 19: 25422554.

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