Management of cancer pain in adult patients: ESMO Clinical Practice Guidelines

Pain is common in cancer patients, particularly in the advanced stage of disease when the prevalence is estimated to be more than 70% [1.Portenoy R.K. Treatment of cancer pain.Lancet. 2011; 377: 2236-2247Abstract Full Text Full Text PDF PubMed Scopus (308) Google Scholar], contributing to poor physical and emotional well-being. The most comprehensive systematic review indicates pain prevalence ranging from 33% in patients after curative treatment, to 59% in patients on anticancer treatment and to 64% in patients with metastatic, advanced or terminal disease [2.van den Beuken-van Everdingen M.H. 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 (1160) Google Scholar]. Pain has a high prevalence earlier in disease 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 (159) Google Scholar]. Increased survival with either life-prolonging treatment or curative treatment results in increased numbers of patients experiencing persistent pain due to treatment or disease, or a combination of both [4.Glare P.A. Pamela S. Davies P.S. et al.Pain in cancer survivors.J Clin Oncol. 2014; 32: 1739-1747Crossref PubMed Scopus (149) Google Scholar]. Approximately 5%–10% of cancer survivors have chronic severe pain that interferes significantly with functioning [5.Brown M.D.R. Juan D. Ramirez J.D. Paul Farquhar-Smith P. Pain in cancer survivors.Br J Pain. 2014; 8: 139-153Crossref PubMed Scopus (49) Google Scholar]. Despite guidelines and the availability of opioids (the mainstay of moderate to severe cancer pain management), undertreatment is common. European studies [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 (511) Google Scholar] confirmed these data from the United States, showing that different types of pain or pain syndromes were present in all stages of cancer (Table 1) and were not adequately treated in a significant percentage of patients, ranging from 56% to 82.3%.Table 1Non-tumour-related causes of pain in cancer patientsAcute procedural painIatrogenic pain causesComorbidity-related painPain in cancer survivorsAdjuvant setting–Diagnostic 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–Thoracentesis–Surgery–Chemotherapy–Hormonal therapy–Targeted therapy–Osteonecrosis of the jaw–RT–Steroids (pain due to skin lesions, peripheral neuropathy, mucositis, aseptic femoral head necrosis, infections)–Cardiovascular–Pulmonary–Diabetic neuropathy–Vasomotor headache–Fibromyalgia–May be worsened by anticancer treatments and/or cancer-related pain–Postherpetic neuralgia–Acute thrombosis pain–Follow-up procedures–Persisting postsurgical pain–Persisting anticancer drug-related pain–Persisting RT-related pain–Postherpetic neuralgiaNeo-adjuvant setting– As adjuvant setting plus diagnostic and prognostic tissue biopsy– As adjuvant setting without surgery-related pain– As adjuvant setting– As adjuvant settingLocally advanced setting– As adjuvant setting plus pleurodesis, tumour embolisation, suprapubic catheterisation and nephrostomy insertion– As adjuvant setting plus cryosurgery, thermal ablation, TACE, spinal/epidural injection and opioid hyperalgesia– As adjuvant setting– As adjuvant settingMetastatic setting– As locally advanced setting plus liver, lung or soft tissue diagnostic biopsies, wound care and movement procedural pain– As neo-adjuvant setting– As adjuvant setting– As adjuvant setting plus synergistic pain effects between iatrogenic and disease-related causes in long-term cancer survivorsRT, radiotherapy; TACE, transarterial chemoembolisation. Open table in a new tab RT, radiotherapy; TACE, transarterial chemoembolisation. According to a systematic review published in 2014 [7.Greco M.T. Roberto A. Corli O. et al.Quality of cancer pain management: an update of a systematic review of undertreatment of patients with cancer.J Clin Oncol. 2014; 32: 4149-4154Crossref PubMed Scopus (234) Google Scholar] using the Pain Management Index (PMI) [8.Cleeland C.S. Gonin R. Hatfield A.K. et al.Pain and its treatment in outpatients with metastatic cancer.N Engl J Med. 1994; 330: 592-596Crossref PubMed Scopus (1666) Google Scholar], approximately one-third of patients do not receive appropriate analgesia proportional to their pain intensity (PI). High prevalence has also been documented in haematology patients at diagnosis, during therapy and in the last month of life [9.Bandieri E. Sichetti D. Luppi M. et al.Is pain in patients with haematological malignancies under-recognised? The results from Italian ECAD-O survey.Leuk Res. 2010; 34: e334-e335Crossref PubMed Scopus (0) Google Scholar]. These data reinforce the recommendation that patients with advanced or metastatic cancer require management within an integrated system for palliative care [7.Greco M.T. Roberto A. Corli O. et al.Quality of cancer pain management: an update of a systematic review of undertreatment of patients with cancer.J Clin Oncol. 2014; 32: 4149-4154Crossref PubMed Scopus (234) Google Scholar]. Cancer-related pain may be presented as a major issue of healthcare systems worldwide: ∼14.1 million new cancer cases and 8.2 million deaths occurred worldwide in 2012, based on GLOBOCAN estimates [10.Torre L.A. Bray F. Siegel R.L. et al.Global cancer statistics, 2012.CA Cancer J Clin. 2015; 65: 87-108Crossref PubMed Scopus (20769) Google Scholar] and incidence will be > 15 million in 2020, based on projections [11.Frankish H. 15 million new cancer cases per year by 2020, says WHO.Lancet. 2003; 361: 1278.Abstract Full Text Full Text PDF PubMed Google Scholar]. Initial and ongoing assessment of pain should be an integral part of cancer care and indicates when additional comprehensive assessment is needed (Table 2). The regular self-reporting of PI with the help of validated assessment tools is the first step towards effective and individualised treatment. The most frequently used standardised scales [12.Caraceni A. Cherny N. Fainsinger R. et al.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: 239-255Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar] are reported in Figure 1 and are the visual analogue scale (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 BTcPs, pain syndrome, inferred pathophysiology, pain at rest and/or moving Presence of trigger factors and signs and symptoms associated with the pain Presence of relieving factors Use of analgesics and their efficacy and tolerability 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 NP 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 Interference of pain with the patient’s daily activities, work, social life, sleep patterns, appetite, sexual functioning, mood, well-being and coping Impact of the pain, the disease and the therapy on the physical, psychological and social conditions Presence of a caregiver, psychological status, degree of awareness of the disease, anxiety and depression and suicidal ideation, his/her social environment, QoL, 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 opiophobia 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 Spend time with the patient and the family to understand their needsBTcP, breakthrough cancer pain; NP, neuropathic pain; QoL, quality of life. Open table in a new tab BTcP, breakthrough cancer pain; NP, neuropathic pain; QoL, quality of life. Assessment of the pain descriptors improves the choice of therapy. Pain can be:(i)Nociceptive: caused by ongoing tissue damage, either somatic (such as bone pain) or visceral (such as gut or hepatic pain); or(ii)Neuropathic: caused by damage or dysfunction in the nervous system, such as in brachial plexopathy or in spinal cord compression by tumour [13.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 (48) Google Scholar]. Most patients with advanced cancer have at least two types of cancer-related pain, resulting from a variety of pathophysiology [14.Portenoy R.K. Koh M. Cancer pain syndromes.in: Bruera E. Portenoy R.K. Cancer Pain. Assessment and Management. 4. Cambridge University Press, Cambridge2010: 53-88Google Scholar]. Initial assessment of cancer-related pain for all patients should include:(i)Ask a key screening question, which is not paraphrased and is used consistently. That question should be: ‘What has been your worst pain in the last 24 hours on a scale of 0–10?’, where 0 is no pain and 10 is the worst imaginable [15.Fallon M. Walker J. Colvin L. et al.Pain management in cancer center inpatients: a cluster randomized trial to evaluate a systematic integrated approach-the Edinburgh pain assessment and management tool.J Clin Oncol. 2018; 36: 1284-1290Crossref PubMed Google Scholar].(ii)Monitor if the pain is < 3.(iii)Move to a more detailed assessment if the worst pain is ≥ 3 or if the patient is distressed by pain (as per Table 2). This should also include average pain and pain ‘right now’.(iv)Administer appropriate analgesic and reassess both pain and analgesic side effects.(v)Review analgesic regimen if side effects to prescribed analgesics are present and/or pain persists. Recommendation:•The intensity of pain and the treatment outcomes should be assessed regularly and consistently using the VAS or NRS using the question: ‘What has been your worst pain in the last 24 hours?’ [V, D]. In elderly patients, limited communicative skills and/or cognitive impairment make 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 behaviours and discomfort (e.g. facial expression, body movements, verbalisation or vocalisations, changes in interpersonal interactions, changes in routine activity) is an alternative strategy for assessing the presence of pain (but not its intensity) [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 (67) Google Scholar]. Observational scales are available [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 (67) Google Scholar]; however, none is validated in different languages. Sensitivity to a light touch can signal neuropathic pain (NP). A detailed appraisal of the literature pertaining to pain assessment in patients with cognitive impairment is outside the scope of this guideline but, given the global challenge and projected increase in dementia, this will become increasingly important [17.Lichtner V. Dowding D. Esterhuizen P. et al.Pain assessment for people with dementia: a systematic review of systematic reviews of pain assessment tools.BMC Geriatr. 2014; 14: 138.Crossref PubMed Google Scholar]. Assessment and management of pain in children are not considered in this manuscript, but guidelines have been developed by the World Health Organization (WHO) [18.World Health Organization. WHO Guidelines on the Pharmacological Treatment of Persisting Pain in Children with Medical Illnesses, 2012. www.who.int/medicines/areas/quality_safety/guide_perspainchild/en/ (11 April 2018, date last accessed).Google Scholar]. Recommendation:•Observation of pain-related behaviours and discomfort is indicated in patients with cognitive impairment to assess the presence of pain [V, C]. Psychosocial distress is strongly associated with cancer pain and should be assessed [19.Syrjala K.L. Jensen M.P. Mendoza M.E. et al.Psychological and behavioural approaches to cancer pain management.J Clin Oncol. 2014; 32: 1703-1711Crossref PubMed Scopus (0) Google Scholar]. Psychological distress may amplify pain and similarly, inadequately controlled pain may cause psychological distress [20.Tracey I. Neuroimaging mechanisms in pain: from discovery to translation.Pain. 2017; 158: S115-S122Crossref PubMed Google Scholar]. Recommendation:•The assessment of all components of suffering, such as psychosocial distress, should be considered and evaluated [II, B]. Patients must be informed about possible onset of pain at any stage of the disease, both during/after diagnostic interventions and as a consequence of cancer and/or anticancer treatments. Patients should be empowered and encouraged to communicate with the physician and/or the nurse about their suffering, the efficacy of therapy and side effects. Patient education should include information on the appropriate use of opioids; this should be set in context with other analgesic and non-pharmacological approaches [21.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 (99) Google Scholar]. Patient involvement in pain management improves both communication and pain relief through enhancing both patient understanding and physician assessment and prescribing [22.Bennett M.I. Bagnall A.M. José Closs S. How effective are patient-based educational interventions in the management of cancer pain? Systematic review and meta-analysis.Pain. 2009; 143: 192-199Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar, 23.Sheinfeld Gorin S. Krebs P. Badr H. et al.Meta-analysis of psychosocial interventions to reduce pain in patients with cancer.J Clin Oncol. 2012; 30: 539-547Crossref PubMed Scopus (154) Google Scholar]. It is important to prescribe a therapy that can be managed simply by patients and families themselves. The oral route, if well tolerated, should be considered as the preferred route of administration [24.World Health Organization Cancer Pain Relief.2. World Health Organization, Geneva1996Google Scholar, 25.Hanks G.W. De Conno F. Ripamonti C. et al.Morphine in cancer pain: modes of administration.BMJ. 1996; 312: 823-826Crossref PubMed Google Scholar]. Breakthrough cancer pain (BTcP), defined as ‘a transitory flare of pain that occurs on a background of relatively well-controlled baseline pain’, requires careful assessment and appropriate management. Typical BTcP episodes are of moderate to severe intensity, rapid in onset (minutes) and of relatively short duration (median 30 minutes) [26.Portenoy R.K. Hagen N.A. Breakthrough pain: definition, prevalence, and characteristics.Pain. 1990; 41: 273-281Abstract Full Text PDF PubMed Scopus (778) Google Scholar]. Recommendations:•Patients should be informed about pain and pain management and should be encouraged to take an active role in their pain management [II, B].•The onset of pain should be prevented by means of around-the-clock (ATC) administration, taking into account the half-life, bioavailability and duration of action of different drugs [II, B].•Analgesics for chronic pain should be prescribed on a regular basis and not on an ‘as required’ schedule [V, D].•The oral route of administration of analgesic drugs should be advocated as the first choice [IV, C]. The type and dose of analgesic drugs are influenced by the PI and must be promptly adjusted to reach a balance between optimal pain relief and minimum side effects. Rescue doses [as-needed (prn) doses] should be prescribed proactively for the relief of BTcP pain and to overcome end-of-dose failure. Rescue medication used for end-of-dose failure should help with calculating the daily titration of regular doses. The oral route is preferred except when oral intake is not possible because of severe vomiting, bowel obstruction, severe dysphagia or severe confusion, and in the case of poor pain control which requires rapid dose escalation and/or in the presence of oral opioid-related adverse effects. The WHO proposes a strategy (currently under review) for cancer pain treatment based on a sequential three-step analgesic ladder, from non-opioids to weak opioids to strong opioids, according to PI [24.World Health Organization Cancer Pain Relief.2. World Health Organization, Geneva1996Google Scholar]. The WHO ladder recommends non-opioid analgesics as possible options at all steps; however, this is of greater relevance for the first two steps of the WHO ladder. In practical terms, this means paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) (step 1). Opioid analgesics are the mainstay of analgesic therapy and are classified according to ability to control pain from mild to moderate (step 2) to moderate to severe intensity (step 3) [24.World Health Organization Cancer Pain Relief.2. World Health Organization, Geneva1996Google Scholar, 25.Hanks G.W. De Conno F. Ripamonti C. et al.Morphine in cancer pain: modes of administration.BMJ. 1996; 312: 823-826Crossref PubMed Google Scholar, 26.Portenoy R.K. Hagen N.A. Breakthrough pain: definition, prevalence, and characteristics.Pain. 1990; 41: 273-281Abstract Full Text PDF PubMed Scopus (778) Google Scholar]. However, some authors have suggested eliminating the second step of the analgesic ladder, with weak opioids being replaced with low doses of oral morphine [27.Bandieri E. Romero M. Ripamonti C. et al.Randomized trial of low-dose morphine versus weak opioids in moderate cancer pain.J Clin Oncol. 2016; 34: 436-442Crossref PubMed Scopus (69) Google Scholar, 28.Fallon M. Do We Need Step 2 of the WHO Pain Ladder—An EAPC Research Network Study. EAPC Abstract Book. EAPC, Madrid2017Google Scholar]. Analgesic drugs are only one part of cancer pain management, and an integrated approach to cancer pain management should be adopted; this should incorporate:(i)primary antitumour treatments;(ii)interventional analgesic therapy and(iii)a variety of non-invasive techniques such as psychological and rehabilitative interventions [29.Paice J.A. Ferrell B. The management of cancer pain.CA Cancer J Clin. 2011; 61: 157-182Crossref PubMed Scopus (150) Google Scholar]. Paracetamol and NSAIDs are universally accepted as part of the treatment of cancer pain at any stage of the WHO analgesic ladder. Several relevant systematic reviews are available regarding the efficacy of paracetamol and NSAIDs for cancer pain management, either when used alone or in combination with opioids. Paracetamol is the mainstay of the first two steps of the WHO analgesic ladder in many countries. However, a Cochrane systematic review highlights the lack of knowledge about the effectiveness of paracetamol for cancer pain [30.Wiffen P.J. Derry S. Moore R.A. et al.Oral paracetamol (acetaminophen) for cancer pain.Cochrane Database Syst Rev. 2017; 7: CD012637PubMed Google Scholar]. In 2017, Cochrane identified 11 studies of oral NSAIDs in adults with cancer pain [31.Derry S. Wiffen P.J. Moore R. et al.Oral nonsteroidal anti-inflammatory drugs (NSAIDs) for cancer pain in adults.Cochrane Database Syst Rev. 2017; 12: CD012638Google Scholar]. These included 949 participants; however, no studies examined the effects of NSAIDs together with an opioid (such as morphine), although this is how they are often used. All studies were compromised by small numbers. With any NSAID, moderate or severe cancer pain was reduced to no worse than mild pain in 26%–51% of patients, after 1 or 2 weeks in 4 of the 11 studies. Based on this 2017 Cochrane review, there is no conclusive evidence to support or refute the use of NSAIDs alone or in combination with opioids for the treatment of mild cancer pain. (There is limited evidence that some people with moderate or severe cancer pain can obtain substantial levels of benefit within 1 or 2 weeks.) It is important to monitor and reassess the long-term use of NSAIDs or cyclo-oxygenase-2 (COX-2) selective inhibitors [32.British National Formulary. BNF 75 March–September 2018, 75th edition. London: British Medical Association and Royal Pharmaceutical Society of Great Britain 2018.Google Scholar] because of their significant toxicity (e.g. gastrointestinal bleeding, platelet dysfunction and renal failure). COX-2 selective inhibitors may increase the risk of thrombotic cardiovascular adverse reactions [33.European Medicines Agency. Public statement: European Medicines Agency Announces Regulatory Action on COX-2 Inhibitors (EMEA/62838/2005). www.ema.europa.eu/docs/en_GB/document_library/Public_statement/2009/11/WC500014818.pdf (11 April 2018, date last accessed).Google Scholar] and do not reduce the risk of renal failure. Dipyrone is another non-opioid analgesia that a recent systematic review concluded could be used for the treatment of cancer pain, alone or in combination with opioids [34.Gaertner J. Stamer U.M. Remi C. et al.Metamizole/dipyrone for the relief of cancer pain: a systematic review and evidence-based recommendations for clinical practice.Palliat Med. 2017; 31: 26-34Crossref PubMed Scopus (22) Google Scholar]. Recommendations:•Analgesic treatment should start with drugs indicated by the WHO analgesic ladder appropriate for the severity of pain [II, B].•There is no significant evidence to support or refute the use of paracetamol alone or in combination with opioids for mild to moderate pain [I, C].•There is no significant evidence to support or refute the use of NSAIDs alone or in combination with opioids for mild to moderate pain [I, C]. There are few options to treat mild to moderate cancer pain before moving to strong opioids such as morphine. Tramadol, dihydrocodeine and codeine are the widely available options. There is widespread use of tramadol in palliative care, even though the data on its use are limited and adverse effects can be severe [27.Bandieri E. Romero M. Ripamonti C. et al.Randomized trial of low-dose morphine versus weak opioids in moderate cancer pain.J Clin Oncol. 2016; 34: 436-442Crossref PubMed Scopus (69) Google Scholar, 35.Wiffen P.J. Derry S. Moore R.A. Tramadol with or without paracetamol (acetaminophen) for cancer pain.Cochrane Database Syst Rev. 2017; 5: CD012508.PubMed Google Scholar, 36.World Health Organization. WHO Model List of Essential Medicines: 20th WHO Essential Medicines List (EML), March 2017. www.who.int/medicines/publications/essentialmedicines/en/ (11 April 2018, date last accessed).Google Scholar]. Tramadol has a potential role on step 2 of the analgesic ladder, particularly if other step 2 drugs are not tolerated, but adequate studies comparing tramadol with other step 2 drugs (e.g. codeine or dihydrocodeine) are missing. Tramadol can have significant side effects, such as dizziness, nausea, vomiting and constipation [37.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 (36) Google Scholar]. Tramadol affects serotonin metabolism or availability, potentially leading to serotonin toxicity, particularly in the elderly, and can lower seizure thresholds. Tramadol has a much-reduced analgesic effect in cytochrome P450 2D6 (CYP2D6) poor metabolisers. Dihydrocodeine is also a substrate for CYP2D6; its partial metabolism is limited in poor metabolisers and is blocked by CYP2D6 inhibitors. However, there is no evidence that such inhibition reduces its analgesic effect. Codeine has no or little analgesic effect until metabolised to morphine, mainly via CYP2D6. In poor metabolisers, it is therefore essentially ineffective, while in ultrarapid metabolisers, it is potentially toxic. 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. A meta-analysis of data from randomised controlled trials (RCTs) showed no significant difference between the effectiveness of non-opioid analgesics alone and non-opioids in combination with weak opioids [38.Eisenberg E. Berkey C. Carr D.B. et al.Efficacy and safety of nonsteroidal antiinflammatory drugs for cancer pain: a meta-analysis.J Clin Oncol. 1994; 12: 2756-2765Crossref PubMed Google Scholar]. The available studies do not demonstrate a clear difference in the effectiveness of the drugs between the first and the second step [39.Management of cancer pain evidence report technology assessment: number 35–management of cancer pain summary.J Pain Palliat Care Pharmacother. 2002; 16: 91-102Google Scholar]. A 2014 Cochrane review of weak opioids in cancer pain including 15 studies with 721 participants, although providing newer data, was not able to help formulate recommendations [40.Straube C. Derry S. Jackson K.C. et al.Codeine, alone and with paracetamol (acetaminophen), for cancer pain.Cochrane Database Syst Rev. 2014; 9: CD006601Google Scholar]. The available evidence indicates that codeine is more effective against cancer pain in adults than placebo, but with increased risk of nausea, vomiting and constipation [41.Larkin P.J. Cherny N.I. La Carpia D. et al.Diagnosis, assessment and management of constipation in advanced cancer: ESMO Clinical Practice Guidelines.Annal Oncol. 2018; 29: iv94-iv108Google Scholar]. Work is evolving in the exploration of the place of step 2 in the WHO three-step ladder. Historical work with uncontrolled studies showed 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, and ‘ceiling effect’ with weak opioids, rather than to adverse effects [42.Ventafridda V. Tamburini M. Caraceni A. et al.A validation study of the WHO method for cancer pain relief.Cancer. 1987; 59: 850-856Crossref PubMed Scopus (584) Google Scholar]. Given the lack of data on effectiveness of tramadol, dihydrocodeine and codeine on cancer pain, many authors have proposed the abolition of the second step of the WHO analgesic ladder, in favour of the early use of morphine at low doses, which is not in the current WHO guideline. The evidence base is evolving, with one study in favour of a low-dose morphine approach already reported and results from another RCT expected shortly [27.Bandieri E. Romero M. Ripamonti C. et al.Randomized trial of low-dose morphine versus weak opioids in moderate cancer pain.J Clin Oncol. 2016; 34: 436-442Crossref PubMed Scopus (69) Google Scholar, 28.Fallon M. Do We Need Step 2 of the WHO Pain Ladder—An EAPC Research Network Study. EAPC Abstract Book. EAPC, Madrid2017Google Scholar]. Recommendations:•For mild to moderate pain, weak opioids such as tramadol, dihydrocodeine and codeine can be given in combination with non-opioid analgesics [III, C].•As an alternative to weak opioids, low doses of strong opioids could be an option, although this recommendation is not currently part of WHO guidance [II, C].•There is no evidence of increase in adverse effects from the use of low-dose strong opioids instead of the standard step 2 approach with weak opioids [II, C]. Strong opioids are the mainstay of analgesic therapy in treating moderate to severe cancer-related pain. Although a variety of strong opioids exist and there is no superiority of one over another, morphine is the most widely available and prescribed. In spite of the global agreement that access to opioids is essential, both access to and use of opioids remains poor in many countries. Various factors contribute to poor access and use, which is still problematic in Eastern and South Eastern Europe [43.Manjiani D. Paul D.B. Kunnumpurath S. et al.Availability and utilization of opioids for pain management: global issues.Ochsner J. 2014; 14: 208-215PubMed Google Scholar, 44.Duthey B. Scholten W. Adequacy of opioid analgesic consumption at country, global, and regional levels in 2010, its relationship with development level, and changes compared with 2006.J Pain Symptom Manage. 2014; 47: 283-297Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 45.Berterame S. Erthal J. Thomas J. et al.Use of and barriers to access to opioid anal