WHO Guideline for the Pharmacological and Radiotherapeutic Management of Cancer Pain in Adults and Adolescents in Secondary Care

This specialist Guidelines summary provides overarching principles of effective health systems and best clinical practice, with evidence-based guidance on initiating and managing cancer pain in adolescents and adults, including older persons.

This summary covers medical and radiotherapeutic management of cancer pain. Anaesthetic, psychological, social, spiritual, physiotherapeutic, and surgical modes of cancer pain management are integral to comprehensive cancer pain management, and are discussed, but are outside the scope of the guideline.

The recommendations are organised into three areas:

• analgesia of cancer pain—choice of analgesic when initiating pain relief and choice of opioid for maintenance of pain relief, including optimisation of rescue medication, route of administration, and opioid rotation and cessation
• adjuvant medicines for cancer pain—including steroids, antidepressants, and anticonvulsants
• management of pain related to bone metastases—including use of bisphosphonates and radiotherapy.

This summary is intended for use in a secondary care setting by oncologists.

For the complete set of recommendations, please refer to the full guideline. 

Reflect on your learning and download our Reflection Record.

Cancer Pain Management—Guiding Principles

The Goal of Optimum Management of Pain is to Reduce Pain to Levels Which Allow an Acceptable Quality of Life

• Although as much as possible should be done clinically to relieve a patient's pain from cancer, it may not be possible to eliminate pain completely in all patients. The goal of pain management, therefore, is to reduce pain to a level that allows for a quality of life that is acceptable to the patient. The benefit of pain relief must be balanced against the risk of adverse effects and overdose that may result in respiratory depression
• A diagnosis of 'refractory pain' should not be made too early as, apparently, 'refractory pain' may simply be due to a lack of access to state-of-the-art pain treatment. Invasive interventions for pain, such as nerve blocks, may be unnecessary when pain management guidelines are followed.

Global Assessment of the Person Should Guide Treatment, Recognising That Individuals Experience and Express Pain Differently

• The first step in cancer pain management should always be assessment of the patient. The assessment should be as comprehensive as possible consistent with the patient's comfort, and should include a detailed history, physical examination, assessment of psychological circumstances, and an assessment of pain severity using an appropriate pain measurement tool and indicated diagnostic procedures
• Early identification of patients with potential cancer pain should be performed proactively in all care settings, and especially in primary care. Assessment and reassessment at regular intervals are key to ensuring that treatment is appropriate and safe, as well as minimising and addressing side effects over the course of a patient's care plan.

Please refer to the full guideline for further information on the following assessment scales for specific populations:

• Brief Pain Inventory
• Critical Care Pain Observation Tool
• Pain Assessment In Advanced Dementia
• Integrated Palliative Outcomes Scale.

Safety of Patients, Carers, Healthcare Providers, Communities and Society Must be Assured

• Provision of analgesia for cancer pain management can carry risks to the safety of patients, their families and society more broadly. Consequently, proper and effective stewardship of opioid analgesics in the cancer treatment setting is essential to ensure the safety of patients and to reduce the risk of diversion of medicine into society. The safety of healthcare providers may also be at risk if they are coerced into diversionary activities, threatened for access to medicines, or at risk of abuse themselves
• Patient assessment should pay close attention to patients' psychological history, their patterns of opioid consumption, and any history of substance use, to identify risk factors for improper use and signs of substance use disorders that should influence clinical decision making
• The presence of opioids in households presents a risk of misuse or unintentional overdose by children, adolescents, and other household members. Safe, secure storage of opioid analgesics should be optimised at household level, and provision made for the safe disposal or return of unused opioid medicines to a pharmacy at the end of life or when no longer needed.

A Pain Management Plan Includes Pharmacological Treatments and May Include Psychosocial and Spiritual Care

• Pain is an outcome of a person's biological, psychological, social, cultural, and spiritual circumstances. Therefore, although pharmacological interventions are the mainstay of cancer pain management, psychosocial care is also an essential component of a comprehensive care plan. Healthcare teams should include this aspect of care when devising patient care plans, enabling supportive and culturally appropriate counselling for patients and their families. Care plans should allow for spiritual counselling appropriate to the beliefs of the patient and family
• Cancer patients may experience depression, fear, and anxiety. Very anxious or depressed patients should receive appropriate therapy for their psychological needs, which may be pharmacological or otherwise, in addition to an analgesic. If the psychological as well as physiological aspects of pain are not treated, the pain may remain intractable.

Administration of Analgesic Medicine Should Be Given 'by Mouth', 'by the Clock', 'for the Individual', and with 'Attention to Detail'

By mouth:

• whenever possible, analgesics should be given by mouth

By the clock:

• doses of analgesic should be given at the appropriate fixed intervals of time. The dose should be increased gradually until the patient is comfortable. The next dose should be given before the effect of the previous dose has worn off

For the individual:

• management of an individual patient's pain requires careful global assessment, as described above, plus differential diagnosis of the type of pain (for example, nociceptive somatic pain, or nociceptive visceral pain or neuropathic pain), the site of origin of the pain and a decision about optimum treatment. The correct dose is the dose that relieves the patient's pain to a level acceptable to the patient
• previous World Health Organization (WHO) guidance included a pain management ladder (Algorithm 1) which has been widely used in the cancer care community. However, a pain management ladder is only a general guide to pain management
• with respect to opioids, patients' responses may vary by patient and by medicine. At times, adverse effects or patient choice may preclude escalation. It is therefore useful if multiple opioid medicines are accessible since each has slightly different properties. It is essential that oral immediate-release and injectable morphine is always accessible.

Algorithm 1: The Three-step Analgesic Ladder

With Attention to Detail:

• the first and last doses of the day should be linked to the patient's waking time and bedtime. Ideally, the patient's analgesic medicine regimen should be written out in full for patients and their families to work from, and should include the names of the medicines, reasons for use, dosage, and dosing intervals. Patients should be warned about possible adverse effects of each of the medicines they are being given.

Cancer Pain Management Should Be Integrated as Part of Cancer Care

• Cancer pain management should be integrated into cancer treatment plans throughout the care continuum, including when a patient's disease is not terminal, as necessary. Treatment should begin by giving the patient an understandable explanation of the causes of the pain. Anti-cancer treatment and pharmacotherapy for cancer pain relief should be given concurrently if the patient is in pain.

Medicines for Cancer Pain Management

The recommendations included in this summary refer to classes of medicines outlined in Table 1.

Table 1: Groups and Classes of Medicines for Cancer Pain Management and Specific Examples

Initiation of Pain Relief

Recommendation

• In adults (including older persons) and adolescents with pain related to cancer, non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol, and opioids generally should be used at the stage of initiation of pain management, either alone or in combination, depending on clinical assessment and pain severity, in order to achieve rapid, effective, and safe pain control.

Remarks

• Patients should be started on a type and strength of analgesic appropriate to their type and severity of pain
• Mild analgesics (paracetamol, NSAIDs) should not be given alone for initiation of management of moderate or severe pain. Patients may be started on a combination of paracetamol and/or NSAIDs with an opioid, such as oral morphine, if indicated by pain severity as measured on a validated numeric or visual analogue pain rating scale.

Considerations

• Paracetamol, NSAIDs, morphine, and other opioids have been regarded as mainstays of cancer pain treatment for decades and remain so today. Paracetamol, ibuprofen, and several opioids are included in the WHO Model list of essential medicines for pain and palliative care. Since there is known clinical variation in patients' responses to specific analgesic medicines, a range of opioid analgesics should ideally be accessible to adult, adolescent, and older patients with cancer pain
• Co-formulations of combined opioid and non-opioid analgesics are discouraged because of the loss of ability to titrate each analgesic independently, and the risk of exposure to high, potentially toxic doses of the non-opioid analgesics such as paracetamol or ibuprofen.

Maintenance of Pain Relief

Choice of Opioid

• In adults (including older persons) and adolescents with pain related to cancer, any opioid may be considered for maintenance of pain relief, depending on clinical assessment and pain severity, in order to sustain effective and safe pain control
  • the correct dose of opioid is the dose that relieves the patient's pain to an acceptable level. Patient responses to opioid medicines vary by patient and vary by medicine
  • the choice of analgesic medicine, dosage, and timing should be guided by the specific pharmacokinetics of each opioid medicine, the contraindications, and the adverse effects in different patients; the dose or medicine that successfully relieves pain for one patient will not necessarily do so for others. Therefore, while it is imperative that oral immediate-release and injectable morphine are accessible to everyone, it may be optimal if a range of opioid medicines is accessible to patients, since the medicine that is most appropriate for one patient will not necessarily be appropriate for another.

Treatment of Breakthrough Pain

• Breakthrough pain should be treated with a rescue medicine, which should be an opioid such as morphine in its immediate-release formulation
  • the regularity of administration should be appropriate to the medicine. In addition to regular administration, patients should have access to a rescue medicine. A rescue dose that is 50–100% of the regular 4-hourly dose may be considered. In the absence of evidence, the choice of specific medicine may depend on affordability and ease of administration. As in the recommendation in Choosing Between Immediate-release Morphine and Slow-release Morphine (below), it should be an immediate-release opioid, not a slow-release opioid.

Switching or Rotating Opioid Medicines

Patients receiving increasing doses of an opioid for inadequately controlled cancer pain may develop adverse effects before achieving an acceptable level of analgesia. It has been proposed that opioid switching might improve the balance between analgesia and adverse effects.

• In the absence of evidence, the WHO makes no recommendation for or against the practice of opioid switching or rotation
  • in the absence of any evidence, practitioners may wish to consider an individual trial of therapy and to switch to another opioid for those patients who do not achieve adequate analgesia or have side effects that are severe, unmanageable, or both
  • ideally, clinicians should identify active clinical trials testing the efficacy of opioid rotation in patients with cancer pain and, whenever possible, encourage eligible patients to enrol into such trials.

Choosing Between Immediate- and Slow-release Morphine

• Regularly-dosed immediate-release oral morphine, or regularly-dosed slow-release morphine, should be used to maintain effective and safe pain relief. With either formulation, immediate-release oral morphine should be used as rescue medicine
• Immediate-release oral morphine must be available and accessible to all patients who need it. The availability of slow-release morphine is optional as an addition to, but not instead of, the availability of immediate-release oral morphine
  • patients sometimes place high value on the availability of both formulations; therefore, having both options available is preferred if resources allow. If a health system must choose between one formulation or the other, immediate-release oral morphine should be chosen as it can be used as both maintenance and rescue medicine, whereas slow-release morphine cannot be used for rescue.

Route of Administration of Opioids

Oral administration of opioids is usually preferable, whenever possible, to avoid the discomfort, inconvenience, and expense of parenteral administration. However, cancer patients often become unable to take oral medicines at some point in the course of their illness because of, for example, dysphagia, bowel obstruction, or vomiting. Consequently, other routes of opioid administration are often needed.

• When oral or transdermal routes are not possible, the subcutaneous route is preferred over intramuscular injection as the subcutaneous route is less painful for the patient.

Cessation of Opioid Use

If the cause of cancer pain is effectively addressed by anti-cancer treatment (for example, surgery or chemotherapy), it follows that the use of opioids is no longer necessary and an opportunity exists to decrease or stop opioid use.

• If patients have developed physical dependence on opioids over the course of the management of their pain, opioid dosages should be decreased gradually to avoid withdrawal symptoms.

Adjuvant Medicines for Cancer Pain Management

Adjuvant analgesics used in conjunction with opioids have been found to be beneficial in the management of many cancer pain syndromes; however, they are currently underutilised. Adjuvant medicines may be necessary to enhance pain relief–such as corticosteroids in nerve compression–or to treat concomitant psychological disturbances such as insomnia, anxiety, and depression (sedatives and antidepressants).

Steroids

Steroids are among the most commonly used adjuvant medicines for management of cancer pain of several types: metastatic bone pain, neuropathic pain, and visceral pain.

• In adults (including older persons) and adolescents, with pain related to cancer, adjuvant steroids should be given to achieve pain control when indicated
  • in general, steroids should be prescribed for as short a period as possible
  • optimum dosing of steroids for cancer pain depends on many clinical factors, including location and type of pain, presence of or risk for infection, stage of illness, presence of diabetes mellitus, and the goals of care, among others
  • when treating cancer pain or complications caused at least in part by oedema surrounding a tumour, steroids with the least mineralocorticoid effect are preferable
• Appropriate doses of steroids differ depending on the indication and medicine. Following an initiation dose, the dose should be reduced over time and the optimal maintenance dose should be determined by the analgesic requirement of the patient
• Care should be taken with regard to patient selection for the prescription of steroids because some patients may have contraindications.

Antidepressants

Cancer-related neuropathic pain is common and can be caused either by the disease or by cancer treatment. Two classes of antidepressants, tricyclic antidepressants and selective serotonin norepinephrine reuptake inhibitors, are commonly used as adjuvant medicines to treat neuropathic pain.

• The WHO makes no recommendation for or against the use of antidepressants to treat cancer-related neuropathic pain.

Anticonvulsants

• Anticonvulsants are commonly used as adjuvant medicines to treat neuropathic pain. Certain anti-epileptics have been reported to be effective for treatment of neuropathic pain, including gabapentin, pregabalin, carbamazepine, and valproate
• The WHO makes no recommendation for or against the use of antiepileptics/anticonvulsants for the treatment of cancer-related neuropathic pain
  • in the absence of clear evidence in favour of anti-epileptics, the guideline development group suggested that practitioners may wish to consider an individual trial of therapy and prescribe an anti-epileptic for those patients who do not achieve adequate analgesia or have side effects that are severe, unmanageable, or both
  • ideally, clinicians should identify active clinical trials testing the efficacy of anticonvulsants in patients with cancer pain and, whenever possible, should encourage eligible patients to enrol into such trials.

Management of Bone Pain

• Some cancer pains are best treated with a combination of drug and non-drug measures. For instance, radiation therapy, if available, should be considered in patients with metastatic bone pain, or pressure pain from localised cancer. The Clinical practice guidelines on management of cancer pain of the European Society of Medical Oncology recommend radiotherapy. All patients with pain from bone metastases which is proving difficult to control by pharmacological therapy should be evaluated by a clinical oncologist for consideration of external beam radiotherapy or radioisotope treatment.

Bisphosphonates

Bisphosphonates inhibit osteoclast activity, and their use in cancer patients prevents the increased bone resorption common in metastatic bone disease. Thus, they can reduce complications or skeletal-related events, and reduce bone pain and analgesic requirements. Examples include clodronate, ibandronate, pamidronate, risendronate, etidronate, and zoledronate

• In adults (including older persons) and adolescents with bone metastases, a bisphosphonate should be used to prevent and treat bone pain
  • clinicians should take into account the variable adverse renal effects of bisphosphonates before prescribing.

Monoclonal Antibodies

Monoclonal antibodies to various targets, including osteoclasts and nerve growth factor, have been studied for management of bone pain due to cancer.

• The WHO makes no recommendation for or against the use of monoclonal antibodies to prevent and treat bone pain.

Comparison of Bisphosphonates or Monoclonal Antibodies

• The WHO makes no recommendation for or against the comparative advantage of monoclonal antibodies over bisphosphonates to prevent and treat bone pain.

Single-fraction Radiotherapy Compared with High-fractionated Radiotherapy

Radiotherapy is used to reduce analgesic requirements, improve quality of life, and maintain or improve skeletal function by mitigating the risk of pathological fractures and spinal cord compression. Palliative radiotherapy is indicated for bone pain after the appearance of a new painful site and after insufficient beneficial effect from an initial radiotherapy treatment.

• In adults (including older persons) and adolescents with pain related to bone metastases, single-dose fractionated radiotherapy should be used when radiotherapy is indicated and available.

Radioisotopes for Bone Pain

Radioisotopes are sometimes administered for diffuse bone pain that cannot be treated with radiotherapy.

• The WHO makes no recommendation for or againstthe use of radioisotopes for achieving pain control in adults and adolescents with pain related to bone metastases.