Management of cancer pain: ESMO Clinical Recommendations

Over 80% of cancer patients with advanced metastatic disease suffer pain caused mostly by direct tumor infiltration, and half of pain in cancer patients may be attributed to the effects of surgery, radiotherapy or chemotherapy.

Abstract

Over 80% of cancer patients with advanced metastatic disease suffer pain caused mostly by direct tumor infiltration. Pain undermines quality of life considerably and is a clinically important indicator of tumor progression. Cancer pain may be acute or chronic and should be addressed accordingly. Approximately 20% of pain in cancer patients may be attributed to the effects of surgery, radiotherapy or chemotherapy. All patients should be evaluated for the presence of pain at every visit. Pain severity is best assessed by patient self-report and may be aided by visual analogue scales (VAS), numerical rated scales (NRS) and/or verbal rated scales (VRS). The extent of diagnostic investigation must be appropriate to the patient's general status and the goals of care. Pain should already be managed during the diagnostic evaluation. Most cancer patients can attain satisfactory relief of pain through an approach that incorporates primary anti-tumor treatments, systemic analgesic therapy and other non-invasive techniques such as psychological or rehabilitative interventions. Step-wise escalation of analgesic therapy should usually follow the 'pain ladder' as described by the World Health Organization (WHO). Mild pain (NRS: 1–4) is treated with non-opioid analgesics such as acetaminophen/paracetamol or a non-steroidal anti-inflammatory drug (NSAID) (Table 1). When NSAIDs are used over a prolonged period gastric protection is recommended. Caution and vigilance is required when using potentially nephrotoxic NSAIDs and when using these medications in patients at risk of bleeding.Table 1Selected non-opioid analgesics (WHO step I)SubstanceWidely available forms and strengthsTime to onset (min)CautionMaximal daily dose (mg)Acetaminophen (paracetamol)Tablets, suppositories 500–1000 mg15–30Hepatotoxicity4–6 × 1000Acetylsalycic acidTablets 500–1000 mg15–30GI toxicity, allergy, platelet inhibition3 × 1000IbuprofenTablets 200–400–600 mg; tablets 800 mg modified release; topical gels15–30 + 120GI and renal toxicity4 × 600; 3 × 800 modified releaseKetoprofenTablets 25–75 mg; tablets 100–150–200 mg modified release+ 30GI and renal toxicity4 × 75; 2 × 200DiclofenacTablets 25–50–75 mg; tablets 100 mg modified release30–120GI and renal toxicity4 × 50; 2 × 100Mefenamic acidCapsules 250–500 mg+ 30GI and renal toxicity4 × 500NaproxenTablets 250–375–500 mg+ 30GI and renal toxicity2 × 500GI, gastrointestinal; WHO, World Health Organization. Open table in a new tab GI, gastrointestinal; WHO, World Health Organization. Traditionally, patients with moderate pain (NRS: 5–7) have been treated with a combination product containing acetaminophen, aspirin or an NSAID plus a weak immediate release opioid such as codeine, dihydrocodeine, tramadol or propoxyphene or a strong opioid at low doses such as morphine or oxycodone (Table 2). The doses of these combination products can be increased until their maximum dose is attained (e.g. 4000 mg of acetaminophen and 240 mg of codeine). Recent years have witnessed the proliferation of new opioid formulations that may improve the convenience of drug administration for patients with moderate pain. These include controlled release formulations of codeine, dihydrocodeine, tramadol, morphine and oxycodone in dosages appropriate for moderate pain. Additional options include low-dose formulations of transdermal fentanyl and of transdermal buprenorphine.Table 2Comparison of selected opioids for mild to moderate pain (WHO level II)SubstanceWidely available forms and strengthsRelative effectiveness compared with oral morphineDuration of effectiveness (h)Maximal daily dose (mg)Starting dose without pretreatment (mg)DihydrocodeineModified release tablets 60–90–120 mg0.171224060–120TramadolDrops 100 mg/ml, capsules 50 mg0.1–0.22–440050–100Modified release tablets 100–150–200 mg0.1–0.21240050–100WHO, World Health Organization. Open table in a new tab WHO, World Health Organization. Morphine is most commonly used in severe pain (NRS: 8–10). Oral administration is the preferred route. If given parenterally, the equivalent dose is one-third of the oral medication. Hydromorphone or oxycodone, in both immediate release and modified 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 to morphine and patients with poor compliance. Earlier worries regarding an inferior equipotency ratio of buprenorphine to oral morphine or of a ceiling effect and partial antagonistic effects of buprenorphine as compared with fentanyl have not been substantiated by newer publications. Methadone is a valid alternative but may be more complicated to use because of marked inter-individual differences in its plasma half-life and duration of action. Methadone use 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). Patients presenting with severe pain that needs urgent relief should be treated with parenteral opioids, usually administered by the s.c. or i.v. route. Intramuscular injections are painful and have no pharmacokinetic advantage. Opioid doses should be titrated to take effect as rapidly as possible. All patients should receive around the clock dosing with provision of a 'breakthrough dose' to manage transient exacerbations of pain. The 'breakthrough dose' is usually equivalent to +10–15% 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. 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 and—rarely—opioid-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 like opioid-induced hyperalgesia/allodynia and myoclonic jerks. This approach requires familiarity with equianalgesic doses of the different opioids (Table 3).Table 3Comparison of selected opioids for moderate to severe pain (WHO step III: may be combined with step I medication)Substance routeRelative effectiveness compared with oral morphineaThe relative effectiveness varies considerably in published literature and between individual patients. Switching to another opiod should therefore be done cautiously with a dose reduction of the newly prescribed opioid.Maximal daily doseStarting dose without pretreatmentMorphine sulfate oral1no upper limitbThe maximal dose depends on tachyphylaxis.20–40 mgMorphine parenteral3no upper limitbThe maximal dose depends on tachyphylaxis.5–10 mgOxycodone oral1.5–2no upper limitbThe maximal dose depends on tachyphylaxis.20 mgHydromorphone oral7.5no upper limitbThe maximal dose depends on tachyphylaxis.8 mgFentanyl transdermal+4cCalculated with conversion from mg/day to μg/h.no upper limitbThe maximal dose depends on tachyphylaxis.12 μg/hdNot usually used as first opioid (the 12 μg/h dose corresponds to 30–60 mg of oral morphine sulfate daily).Buprenorphine oral754 mg0.4 mgBuprenorphine intravenous1003 mg0.3–0.6 mgBuprenorphine transdermal+4cCalculated with conversion from mg/day to μg/h.140 μg/h17.5–35 μg/hMethadone oral4–8–12eFactor 4 for daily morphine doses 300 mg.no upper limitbThe maximal dose depends on tachyphylaxis.10 mgNicomorphine oral120 mg5 mgNicomorphine i.v.320 mg5 mgWHO, World Health Organization.a The relative effectiveness varies considerably in published literature and between 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 μg/h.d Not usually used as first opioid (the 12 μg/h dose corresponds to 30–60 mg of oral morphine sulfate daily).e Factor 4 for daily morphine doses 300 mg. Open table in a new tab WHO, World Health Organization. Naloxone is a short-acting opioid antagonist for i.v. use able to revert symptoms of accidental severe opioid overdose. Radiotherapy has specific and critical efficacy in the relief of pain caused by bone metastases, tumors compressing neural structures and cerebral metastases. It is essential for managing radicular pain. Surgery may have a specific and critical efficacy in the relief of pain caused by impending or evident fractures. Surgery or other interventional approaches may be necessary to control pain caused by obstruction of hollow organs. Some patients, whose pain remains inadequately relieved, may benefit 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 caused either by tumor infiltration 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 specifically addressed. Non-opioid and opioid analgesics may be combined with antidepressive or neuroleptic psychoactive drugs or anti-epileptic drugs in the case of neuropathic pain (Table 4). Steroids should be considered in case of nerve compression. There is sufficient evidence for use of bisphosphonates for refractory bone pain but not for general use as first-line therapy of bone pain.Table 4Selected co-analgesics for neuropathic painSubstanceWidely available forms and strengthsActivitySedationRange of daily doses (mg)AmitryptilineTablets 25–50 mgAntidepressive+++50–200ClomipramineTablets 10–75 mgAntidepressive(+)50–200NortriptylineTablets 10–25 mgAntidepressive+50–225FluoxetineTablets 20 mgAntidepressive+20–80HaloperidolDrops, tablets, vialsNeuroleptic+3–20ChlorpromazineDrops, tablets, suppositories, vialsNeuroleptic++25–200CarbamazepineTablets 200–400 mgAntiepileptic+400–1600GabapentinTablets 200–300–400–800 mgAntiepileptic+900–3600PregabalinTablets 25–50–75–100–150–200–300 mgAntiepileptic+150–600 Open table in a new tab 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 are either: (i) incapable of providing adequate relief, (ii) associated with excessive and intolerable acute or chronic morbidity or (iii) unlikely to provide relief within a tolerable time frame. In this situation, sedation may be the only therapeutic option capable of providing adequate relief. The justification of sedation in this setting is that it is goal appropriate and proportionate. 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 effect. Levels of evidence [I–V] and grades of recommendation [A–D] as used by the American Society of Clinical Oncology are given in square brackets. Statements without grading were considered justified standard clinical practice by the expert authors and the ESMO faculty.