Management of cancer pain: ESMO Clinical Practice Guidelines

Abstract

According to a systematic review of the literature, pain prevalence ranges from 33% in patients after curative treatment to 59% in patients on anticancer treatment and to 64% in patients with metastatic, advanced or terminal phase [1.Van den Beuken-van Everdingen M.H.J. De Rijke J.M. Kessels A.G. et al.Prevalence of pain in patients with cancer: a systematic review of the past 40 years.Ann Oncol. 2007; 18: 1437-1449Abstract Full Text Full Text PDF PubMed Scopus (1297) Google Scholar]. No difference in pain prevalence was found between patients undergoing anticancer treatment and those in an advanced or terminal phase of the disease [1.Van den Beuken-van Everdingen M.H.J. De Rijke J.M. Kessels A.G. et al.Prevalence of pain in patients with cancer: a systematic review of the past 40 years.Ann Oncol. 2007; 18: 1437-1449Abstract Full Text Full Text PDF PubMed Scopus (1297) Google Scholar]. Factors influencing the development of chronic pain in cancer survivors who have completed treatment include peripheral neuropathy due to chemotherapy, radiation-induced brachial plexopathy, chronic pelvic pain secondary to radiation and postsurgical pain [2.Sun V. Borneman T. Piper B. et al.Barriers to pain assessment and management in cancer survivorship.J Cancer Surviv. 2008; 2: 65-71Crossref PubMed Scopus (53) Google Scholar]. Pain has a high prevalence in specific cancer types such as pancreatic (44%) and head and neck cancer (40%) [3.Burton A.W. Fanciullo G.J. Beasley R.D. et al.Chronic pain in cancer survivor: a new frontier.Pain Med. 2007; 8: 189-198Crossref PubMed Scopus (181) Google Scholar]. Moreover, another systematic review of the literature showed that nearly half of cancer patients were under-treated, with a high variability across study designs and clinical settings [4.Deandrea S. Montanari M. Moja L. et al.Prevalence of undertreatment in cancer pain. A review of published literature.Ann Oncol. 2008; 19: 1985-1991Abstract Full Text Full Text PDF PubMed Scopus (654) Google Scholar]. Recent studies conducted both in Italy and pan European [5.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: 729-735Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 6.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: 1420-1433Abstract Full Text Full Text PDF PubMed Scopus (564) Google Scholar] confirmed these data, showing that different types of pain or pain syndromes [7.Higginson I.J. Murtagh F. Bruera E. Portenoy R.K. Cancer pain epidemiology.Cancer Pain. Assessment and Management. 3. Cambridge University Press, 2010: 37-52Google Scholar, 8.Morselli M. Bandieri E. Zanin R. et al.Pain and emotional distress in leukaemia patients at diagnosis.Leuk Res. 2009; 34: e67-e68Crossref PubMed Scopus (27) Google Scholar] were present in all phases of cancer (early and metastatic) (Table 1) and were not adequately treated in a significant percentage of patients, ranging from 56% to 82.3%. In a prospective study [9.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: 1566-1574Crossref PubMed Scopus (140) Google Scholar], the adequacy of analgesic care of cancer patients was assessed by means of the Pain Management Index in 1802 valid cases of in- and outpatients with advanced/metastatic solid tumors enrolled at centers specifically devoted to cancer and/or pain management (oncology/pain/palliative centers or hospices). The study showed that, even in these centers, patients were still classified as potentially under-treated in 9.8%–55.3% of the cases.Table 1Causes of pain, other than cancer related pain, during natural history of cancer patientClinical Setting causes of painAcute Procedural PainIatrogenic Pain due to:Comorbidity-related painPain in cancer survivorsAdjuvant settingDiagnostic intervention Lumbar puncture ± headache Transthoracic needle biopsy Endoscopy ± visceral dilatation Bone marrow aspiration/biopsy, Blood sampling, Central line position, Arterial line, Injections, Medication of skin ulcers Myelography and lumbar puncture ThoracocentesisSurgery, Chemotherapy, Hormonal therapy, Target therapy Osteonecrosis of the jaw Radiation therapy Steroids can cause pain due to:skin lesions, peripheral neuropathy, mucositis aseptic head femoral necrosis, infectionsCardiovascular, Pulmonary Diabetic neuropathy, Vasomotor headache, Fibromyalgia, The comorbidity-related pain may be worsened by anticancer treatments and /or worse cancer-related pain Postherpetic neuralgia Acute thrombosis painFollow up procedures Persisting postsurgical pain Persisting anticancer drug-related pain Persisting radiation therapy-related pain Postherpetic neuralgiaNeoadjuvant settingAs adjuvant setting plus: Diagnostic and prognostic tissue biopsyAs adjuvant setting without surgery-related painAs adjuvant settingAs adjuvant settingLocally advanced settingAs adjuvant setting plus: Pleurodesis, tumor embolization, Suprapubic catheterization, Nephrostomy insertionAs adjuvant setting, plus: Cryosurgery, Radiothermoablation-high intensity focused ultrasound; Transarterial chemoembolization Spinal/epidural injection; Opioid hyperalgesiaAs adjuvant settingAs adjuvant settingMetastatic settingAs locally advanced setting plus: Liver, lung, soft tissue diagnostic biopsies, Wound care, Movement procedural painAs neoadjuvant settingAs adjuvant settingAs adjuvant setting plus: Synergistic pain effects between iatrogenic and disease-related causes in long survivors Open table in a new tab Contrary to the percentage of incidence of pain reported in hematologic patients in past literature, a significant proportion of patients with lymphoma and leukemia may suffer from pain not only in the last months of life (83%) [5.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: 729-735Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar, 10.Portenoy R.K. Koh M. Bruera E. Portenoy R.K. Cancer pain syndromes.Cancer Pain. Assessment and Management. 4. Cambridge University Press, 2010: 53-88Google Scholar], but also at the time of diagnosis and during active treatment [10.Portenoy R.K. Koh M. Bruera E. Portenoy R.K. Cancer pain syndromes.Cancer Pain. Assessment and Management. 4. Cambridge University Press, 2010: 53-88Google Scholar]. Despite published guidelines and educational programs on the assessment and treatment of cancer-related pain, in any stage of oncological disease, unrelieved pain continues to be a substantial worldwide public health concern in patients with either solid or hematological malignancies. Cancer-related pain may be presented as a major issue of healthcare systems worldwide if we consider that the incidence of cancer was 12.667.470 new cases in 2008 and, based on projections, it will be >15 million in 2020 [11.Frankish H. 15 million new cancer cases per year by 2020, says WHO.Lancet. 2003; 361: 1278Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar]. Initial and ongoing assessment of pain and of patients with pain at any disease stage should clarify both the need for additional comprehensive evaluation and a rational plan of care. Table 2 presents the guidelines for the adequate assessment of patients with pain. The proper and regular self-reporting assessment of pain intensity (PI) with the help of validated assessment tools is the first step towards effective and individualized treatment. The most frequently used standardized scales [12.Caraceni A. Cherny N. Fainsinger R. et al.The Steering Committee of the EAPC Research NetworkPain 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: 239-255Abstract Full Text Full Text PDF PubMed Scopus (360) Google Scholar] are reported in Figure 1 and are visual analogue scales (VAS), the verbal rating scale (VRS) and the numerical rating scale (NRS).Table 2Guidelines for the adequate assessment of the patient with pain at any stage of the disease1. Assess and re-assess the pain • causes, onset, type, site, absence/presence of radiating pain, duration, intensity, relief and temporal patterns of the pain, number of breakthrough pains, pain syndrome, inferred pathophysiology, pain at rest and/or moving • presence of the trigger factors and the signs and symptoms associated with the pain • presence of the relieving factors • use of analgesics and their efficacy and tolerability • require the description of the pain quality *aching, throbbing, pressure: often associated with somatic pain in skin, muscle and bone *aching, cramping, gnawing, sharp: often associated with visceral pain in organs or viscera *shooting, sharp, stabbing, tingling, ringing: often associated with neuropathic pain caused by nerve damage2. Assess and re-assess the patient • clinical situation by means of a complete/specific physical examination and the specific radiological and/or biochemical investigations • presence of interference of pain with the patient's daily activities, work, social life, sleep patterns, appetite, sexual functioning, mood, well-being, coping • impact of the pain, the disease and the therapy on the physical, psychological and social conditions • 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, problems in communication, personality disorders • presence and intensity of signs, physical and/or emotional symptoms associated with cancer pain syndromes • presence of comorbidities (i.e. diabetic, renal and/or hepatic failure etc.) • functional status • presence of opioidophobia or misconception related to pain treatment • alcohol and/or substance abuse3. Assess and re-assess your ability to inform and to communicate with the patient and the family • Take time to spend with the patient and the family to understand their needs Open table in a new tab The assessment of the quality of pain improves the choice of the therapy: pain is termed nociceptive when it is caused by ongoing tissue damage, either somatic or visceral or neuropathic, if sustained by damage or dysfunction in the nervous system (Table 1) [2.Sun V. Borneman T. Piper B. et al.Barriers to pain assessment and management in cancer survivorship.J Cancer Surviv. 2008; 2: 65-71Crossref PubMed Scopus (53) Google Scholar]. According to the literature, most patients with advanced cancer have at least two types of cancer-related pain which derives from a variety of etiologies [7.Higginson I.J. Murtagh F. Bruera E. Portenoy R.K. Cancer pain epidemiology.Cancer Pain. Assessment and Management. 3. Cambridge University Press, 2010: 37-52Google Scholar, 10.Portenoy R.K. Koh M. Bruera E. Portenoy R.K. Cancer pain syndromes.Cancer Pain. Assessment and Management. 4. Cambridge University Press, 2010: 53-88Google Scholar]. Sixty-nine percent of patients rate their worst pain at a level that impaired their ability to function [13.Larue F. Colleau S.M. Brasseur L. et al.Multicentre study of cancer pain and its treatment in France.BMJ. 1995; 310: 1034-1037Crossref PubMed Scopus (310) Google Scholar]. The intensity of pain and the treatment outcomes should be regularly assessed using (i) VAS, or (ii) VRS or (iii) the NRS [V, D]. In older age, the presence of limited communicative skills or of cognitive impairment such as during the last days of life makes self-reporting of pain more difficult, although there is no evidence of clinical reduction in pain-related suffering. When cognitive deficits 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 (but not intensity) [14.Kaasalainen S. Pain assessment in older adults with dementhia using behavioural observation methods in clinical practice.J Gerontol Nurs. 2007; 33: 6-10Crossref PubMed Scopus (32) Google Scholar, 15.Gordon D.B. Dahl J.L. 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: 1574-1580Crossref PubMed Scopus (538) Google Scholar, 16.Van Herk R. van Dijk M. Baar F.P.M. et al.Observational scales for pain assessment in older adults with cognitive impairments or communication difficulties.Nurs Res. 2007; 56: 34-43Crossref PubMed Scopus (69) Google Scholar, 17.American Geriatrics Society Panel on Persistent Pain in Older PersonsThe management of persistent pain in older persons.J Am Geriatr Soc. 2002; 50: S205-S224PubMed Google Scholar]. Different observational scales are available in the literature [16.Van Herk R. van Dijk M. Baar F.P.M. et al.Observational scales for pain assessment in older adults with cognitive impairments or communication difficulties.Nurs Res. 2007; 56: 34-43Crossref PubMed Scopus (69) Google Scholar] but none of them is validated in different languages. Assessment and management of pain in children are not considered in this manuscript because WHO guidelines on ‘the pharmacological treatment of persisting pain in children with medical illness’ are available. 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 [18.Zaza C. Baine N. Cancer pain and psychosocial factors: a critical review of the literature.J Pain Symptom Manage. 2002; 24: 526-542Abstract Full Text Full Text PDF PubMed Scopus (270) Google Scholar]. In fact, psychological distress may amplify the perception of pain-related distress and similarly, inadequately controlled pain may cause substantial psychological distress. The assessment of all components of suffering such as psychosocial distress should be considered and evaluated [II, B]. •Inform the patients about the possible onset of pain in any stage of the disease, both during and after diagnostic interventions and as a consequence of cancer or anticancer treatments, and involve them in pain management. Patients must be encouraged to communicate with the physician and/or the nurse about their suffering, the efficacy of therapy and side effects and to not consider analgesic opioids as a therapeutic approach for dying patients [19.Reid C.M. Gooberman Hill R. Hanks G.W. Opioid analgesics for cancer pain: symptom control for the living or comfort for the dying? A qualitative study to investigate the factors influencing the decision to accept morphine for pain caused by cancer.Ann Oncol. 2008; 19: 44-48Abstract Full Text Full Text PDF PubMed Scopus (107) Google Scholar], thus contributing to reduce opioidophobia. Patient involvement in pain management improves communication and has a beneficial effect on patients' pain experience [20.De Wit R. 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: 55-69Abstract Full Text Full Text PDF PubMed Scopus (140) Google Scholar]. Patients should be informed about pain and pain management and be encouraged to take an active role in their pain management [II, B].•Prevent the onset of pain by means of ‘by the clock’ administration, taking into account the half-life, bioavailability and duration of action of different drugs; Analgesic for chronic pain should be prescribed on a regular basis and not on an ‘as required’ schedule [V, D].•Prescribe a therapy which can be administered simply and easily managed by the patients themselves and their families, 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 [21.World Health OrganizationCancer Pain Relief.2nd edition. World Health Organization, Geneva1996Google Scholar, 22.National Comprehensive Cancer Network(NCCN) Clinical Practice Guideline in Oncology..Adult Cancer Pain. 2009; Google Scholar, 23.Hanks G.W. De Conno F. Ripamonti C. et al.Morphine in cancer pain: modes of administration.BMJ. 1996; 312: 823-826Crossref PubMed Scopus (13) Google Scholar, 24.Hanks G.W. De Conno F. Cherny N. et al.of the Expert Working Group of the Research Network of the European Association for Palliative CareMorphine and alternative opioids in cancer pain.Br J Cancer. 2001; 84: 587-593Crossref PubMed Scopus (799) Google Scholar, 25.Scottish Intercollegiate Guidelines NetworkControl of Pain in Adults with Cancer. A National Clinical Guideline Edinburgh, Scotland: SIGN—Scottish Intercollegiate Guidelines Network, 2008Google Scholar, 26.Caraceni A. Hanks G. Kaasa S. et al.Use of opioid analgesics in the treatment of cancer pain: evidence-based recommendations from the EAPC.Lancet Oncol. 2012; 13: 58-68Abstract Full Text Full Text PDF PubMed Scopus (872) Google Scholar]; The oral route of administration of analgesic drugs should be advocated as the first choice [IV, C].•Assess and treat breakthrough pain (BTP) defined as ‘a transitory flare of pain that occurs on a background of relatively well controlled baseline pain’ [27.Portenoy R.K. Hagen N.A. Breakthrough pain: definition, prevalence, and characteristics.Pain. 1990; 41: 273-281Abstract Full Text PDF PubMed Scopus (804) Google Scholar]. Typical BTP episodes are of moderate to severe intensity, rapid in onset (minutes) and relatively short in duration (median 30 min) [27.Portenoy R.K. Hagen N.A. Breakthrough pain: definition, prevalence, and characteristics.Pain. 1990; 41: 273-281Abstract Full Text PDF PubMed Scopus (804) Google Scholar]. Rescue dose of medications (as required or prn) other than the regular basal therapy must be prescribed for BTP episodes [V, D].•Tailor the dosage, the type and the route of drugs administered according to each patient's needs. The type and dose of analgesic drugs are influenced by the intensity of pain and have to be promptly adjusted to reach a balance between pain relief and side effects. The rescue doses (prn) taken by the patients are an appropriate measure of the daily titration of the regular doses. An alternative route for opioid administration should be considered when oral intake 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. In 1986, the World Health Organization (WHO) proposed a strategy for cancer pain treatment based on a sequential three-step analgesic ladder from non opioids to weak opioids to strong opioids according to PI [28.World Health OrganizationCancer Pain Relief. World Health Organization, Geneva1986Google Scholar]. Twenty years after the publication of the first edition [21.World Health OrganizationCancer Pain Relief.2nd edition. World Health Organization, Geneva1996Google Scholar], the WHO cancer pain relief program remains the reference point for pain management. According to WHO guidelines, opioid analgesics are the mainstay of analgesic therapy and are classified according to their ability to control pain from mild to mild–moderate to moderate–severe intensity [25.Scottish Intercollegiate Guidelines NetworkControl of Pain in Adults with Cancer. A National Clinical Guideline Edinburgh, Scotland: SIGN—Scottish Intercollegiate Guidelines Network, 2008Google Scholar, 29.Wallenstein S. Heidrich Gr Kaiko R. Clinical evaluation of mild analgesics: the measurement of clinical pain.Br J Clin Pharmacol. 1980; 10: 319S-327SCrossref PubMed Scopus (109) Google Scholar, 30.Littman G. Walker B. Schneider B. Reassessment of verbal and visual analog ratings in analgesic studies.Clin Pharmacol Therap. 1985; 38: 16-23Crossref PubMed Scopus (146) Google Scholar, 31.Serlin R.C. Mendoza T.R. Nakamura Y. When is cancer pain mild, moderate or severe? Grading pain severity by its interference with function.Pain. 1995; 61: 277-284Abstract Full Text PDF PubMed Scopus (1179) Google Scholar]. Opioid analgesics may be combined with nonopioid drugs such as paracetamol or nonsteroidal anti-inflammatory drugs (NSAIDs) (Algorithm 1) and with adjuvant drugs [32.Lussier D. Portenoy R.K. Bruera E. Higginson I.J. Ripamonti C. von Gunten C. Adjuvant analgesic drugs.Textbook of Palliative Medicine. Edward Arnold Publishers, London2006: 402-414Google Scholar, 33.Paice J.A. Ferrell B. The management of cancer pain.CA Cancer J Clin. 2011; 61: 157-182Crossref PubMed Scopus (160) Google Scholar]. 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 noninvasive techniques such as psychological or rehabilitative interventions. Nonopioid analgesics such as acetaminophen/paracetamol or an NSAID are indicated for the treatment of mild pain. NSAIDs are superior to placebo in controlling cancer pain in single dose studies. Paracetamol and NSAIDS are universally accepted as part of the treatment of cancer pain at any stage of the WHO analgesic scale. There is no evidence to support superior safety or efficacy of one NSAID over any other [34.McNicol E, Strassels S, Gouds L. NSAIDs or paracetamol, alone or combined with opioids, for cancer painCochrane Database of Systematic Reviews 2005, Issue 2. Art. No.: CD005180. 10.1002/14651858.CD005180Google Scholar]. 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.Stockler M. Vardy J. Pillai A. 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: 3389-3394Crossref PubMed Scopus (105) Google Scholar]. A recent systematic review of the literature shows that the addition of an NSAID to WHO Step III opioids can improve analgesia or reduce opioid dose requirement [36.Nabal M. Librada S. Redondo S. et al.The role of paracetamol and nonsteroidal anti-inflammatory drugs in addition to WHO Step III opioids in the control of pain in advanced cancer. A systematic review of the literature.Palliat Med. 2012; 26: 305-312Crossref PubMed Scopus (73) Google Scholar]. It is mandatory to periodically monitor and revise the long-term use of NSAIDs or cyclo-oxygenase-2 (COX-2) selective inhibitors [37.Joint Formulary CommitteeBritish National Formulary.55th edition. British Medical Association and Royal Pharmaceutical Society of Great Britain, London2007Google Scholar] because they can induce severe toxicity such as: gastrointestinal bleeding, platelet dysfunction and renal failure. COX-2 selective inhibitors may increase the risk of thrombotic cardiovascular adverse reactions [38.European Medicines Agency Public statement: European Medicines Agency announces regulatory action on COX-2 inhibitors (EMEA/62838/2005) http://www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2009/11/WC500014818.pdfGoogle Scholar] and do not offer protection from renal failure. Paracetamol and/or a NSAID are effective for treating mild pain [I, A]. Paracetamol and/or a NSAID are effective for treating all intensities of pain, at least in the short term and unless contraindicated [I, A]. In the meta-analysis of Grond et al. [39.Grond S. Radbruch L. Weak opioids. Meta-analysis for the therapy of chronic pain.Der Schmer. 1998; 12: 142-155Crossref PubMed Scopus (9) Google Scholar] on the analgesic efficacy and tolerability of weak opioids versus placebo 10/16 RCTs show the superiority of opioids. However, 14/16 RCTs were single dose studies and no data are available on long- term use. Recently, tramadol at doses of 1 and 1.5 mg/kg every 6 h was compared with placebo in 36 patients with neuropathic pain (NP) [40.Arbaiza D. Vidal O. Tramadol in the treatment of neuropathic cancer pain: a double-blind, placebo-controlled study.Clin Drug Investig. 2007; 27: 75-83Crossref PubMed Scopus (54) Google Scholar]. In the 18 patients on tramadol, significant improvements in pain relief, Karnofsky Performance Status and sleep, as well as much more frequent adverse effects such as nausea, vomiting and constipation were found. In an RCT [41.Rodriguez R.F. Castillo J.M. Castillo M.P. et al.Hydrocodone/acetaminophen and tramadol chloridrate combination tablets for the management of chronic cancer pain: a doubl-blind comparative trial.Clin J Pain. 2008; 24: 1-4Crossref PubMed Scopus (36) Google Scholar], the analgesia and tolerability of two doses of hydrocodone/paracetamol (25 or 50/2500 mg/day) were compared with two doses of tramadol (200 or 400 mg/day) in 118 patients. The PI reduction was evident after the double dose intake, but a significant difference in analgesia was not found. Moreover, the patients treated with tramadol had a significant major incidence of nausea, vomiting, vertigo, anorexia and asthenia. In an RCT, the efficacy and tolerability of oral tramadol versus hydrocodone and versus codeine was compared in 177 patients [42.Rodriguez R.F. Bravo L.E. Castro F. et al.Incidence of weak opioids adverse events in the management of cancer pain: a double-blind comparative trial.J Palliat Med. 2007; 10: 56-60Crossref PubMed Scopus (37) Google Scholar]. No significant difference in analgesic efficacy was found; however the use of tramadol produced a significantly higher percentage of side effects. Traditionally [21.World Health OrganizationCancer Pain Relief.2nd edition. World Health Organization, Geneva1996Google Scholar], patients with mild–moderate 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. The use of drugs of the second step of the WHO ladder has several controversial aspects. The first criticism concerns the absence of a definitive proof of efficacy of weak opioids: in a meta-analysis of data reported from clinical randomized controlled trials [43.Eisenberg E. Berkey C. Carr D.B. et al.Efficacy and safety of nonsteroidal antinflammatory drugs for cancer pain: a meta-analysis.J Clin Oncol. 1994; 12: 2756-2765Crossref PubMed Scopus (214) Google Scholar], no significant difference was found in the effectiveness between nonopioid analgesics alone, and the combination of these with weak opioids. The available studies do not demonstrate a clear difference in the effectiveness of the drugs between the first and the second step [44.Agency for Healthcare Research and QualityEvidence Report/Technology Assessment: Number 35. 2001; Google Scholar]. Uncontrolled studies also show that the effectiveness of the second step of the WHO ladder has a time limit of 30–40 days for most patients and that the shift to the third step is mainly due to insufficient analgesia achieved, rather than to adverse effects [45.Ventafridda V. A validation study of the WHO method for cancer pain relief.Cancer. 1987; 59: 851-856Crossref Scopus (618) Google Scholar]. 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 influence 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 specific topic [46.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: 409-416Abstract Full Text Full Text PDF PubMed Scopus (155) Google Scholar, 47.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: 888-894Crossref PubMed Scopus (104) Google Scholar, 48.Mercadante S. Porzio G. Ferrera P. et al.Low morphine doses in opioid-naive cancer patients with pain.J Pain Symptom Manage. 2006; 31: 242-247Abstract Full Text Full Text PDF PubMed Scopus (71) Google Scholar], though suggestive, have reported inconclusive results due both to the low number and representativeness of the patient sample studied and to the relatively low statistical power. An RCT is strongly needed to address the relevant issue of the role of WHO step II because data supporting the role of the modified two-step analgesic ladder or oral tramadol as an alternative to codeine/paracetamol are insufficient to recommend their routine use in cancer patients with mild to moderate cancer pain [49.Tassinari D. Drudi F. Rosati M. et al.The second step of the analgesic ladder and oral tramadol