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WHO Guidelines for the Pharmacological and Radiotherapeutic Management of Cancer Pain in Adults and Adolescents. Geneva: World Health Organization; 2018.

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WHO Guidelines for the Pharmacological and Radiotherapeutic Management of Cancer Pain in Adults and Adolescents.

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6Recommendations for the Pharmacological and Radiotherapeutic Management of Cancer Pain in Adults and Adolescents

The following pages present the recommendations and underlying rationale of the expert GDG.

For ease of reference, the recommendations included in these guidelines refer to classes of medicines outlined in Table 2.

Table 3 presents the cost of some essential pain medicines in countries of different income levels, while Annex 6 contains the pharmacological principles of cancer pain management.

Table 2. Groups and classes of medicines for cancer pain management and specific examples.

Table 2

Groups and classes of medicines for cancer pain management and specific examples.

Table 3. Cost to hospitals in 2015 of selected essential medicines for pain management in US dollars in countries of various income levels.

Table 3

Cost to hospitals in 2015 of selected essential medicines for pain management in US dollars in countries of various income levels.

6.1. Initiation of Pain Relief

This section presents the recommendations, supporting evidence and rationale for the key clinical questions to determine the optimal medicines to use when initiating analgesia in patients with cancer pain (see Annex 4 for details of the questions). During the scoping meeting, the GDG determined that there was uncertainty as to whether initiation of analgesia should include non-steroidal anti-inflammatory drugs (NSAIDs), paracetamol or opioids, either alone or in combination. The intention was to conduct a NMA to allow for direct and indirect comparisons, but too few trials were eligible and an NMA was not possible.

Recommendation

In adults (including older persons) and adolescents with pain related to cancer, 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. (Strong recommendation; low-quality evidence)

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 (2830). 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.

Summary of the evidence

Evidence was derived from pair-wise comparisons from five trials, although none clearly distinguished between patients at pain management initiation and those on maintenance treatment. Inclusion was based on the fact that all five trials included people with cancer pain who were naïve to strong opioids (or were beginning opioid treatment). The studies evaluated buprenorphine, fentanyl, morphine, and oxycodone with a single trial comparing weak opioid + NSAID to NSAIDs.

Two of the five trials compared classes of medicine to evaluate relief of pain, providing very low strength of evidence that strong opioids relieve pain more frequently than weak opioids (RR = 1.80; 95% CI 1.42, 2.29), and favouring combination weak opioids + NSAID to relieve pain more frequently than NSAIDs alone (RR = 1.36; 95% CI 0.98, 1.87) (31,32). One of the trials also evaluated the degree of pain relief, providing very low strength of evidence to favour strong opioids over weak opioids, suggesting no difference (estimated net difference = −3.3; 95% CI -87, 60 on a scale of 0 to 100 [worst] (31).

Three eligible randomized controlled trials (RCTs) evaluated outcomes other than pain relief among persons with cancer who were initiating pain management (3335). These three trials together provided moderate strength of evidence of similar rates of confusion with either morphine or oxycodone (RR = 0.85; 95% CI 0.50, 1.44), nominally favouring morphine. One trial compared all four opioids, providing low strength of evidence of similar rates of confusion with all four medicines (36–47%) (35). No studies reported specifically on quality of life. No trial listed or reported on respiratory depression among the study participants.

Rationale

The RCT evidence on the selection of one particular type of analgesic over others for pain relief was of low quality, but the GDG noted that this uncertainty was related to selection of analgesic and not to uncertainty about whether to use analgesics or not to obtain pain relief. Moderate quality evidence for adverse effects indicated that there was little difference between analgesics. The GDG observed that, although patients valued the pain relief delivered by analgesia, they may have concerns about initiating opioids in particular and that values and preference related to type of analgesia were likely to vary across countries, cultures, clinicians, families and patients. With respect to opioid administration, the GDG noted that acceptability to health-care workers and feasibility of provision were likely to be highly variable regionally, although there was agreement that health-care workers aimed to relieve the pain experienced by their patients and would value greater analgesic options. The GDG also bore in mind the risk of unintended consequences. The GDG noted that balanced regulations on strong opioid medicines, which balance the necessity of their availability to patients who need them with the necessity of tackling their misuse, are possible. Recommendations on how to achieve this balance are presented in other WHO documents (27).

The GDG observed that a recommendation to provide greater access to analgesia at initiation of pain management may be resource-intensive and changes may be required to the regulatory environment in some countries to facilitate this. However, given that the majority of the global population currently does not have access to adequate analgesia, with this inequity likely to increase with the expanding burden of cancer in low- and middle-income countries, the GDG determined to make a strong recommendation in favour of provision of a selection of analgesics for pain management initiation despite the low quality of evidence.

6.2. Maintenance of Pain Relief

This section presents the recommendations, supporting evidence and rationale for each of five key clinical questions related to maintaining pain relief following initiating effective relief of pain in patients with cancer pain.

The questions were: 1) Which is the most effective opioid for maintaining pain relief? 2) Which is the most effective opioid for treating breakthrough pain? 3) What is the evidence for the practice of opioid rotation or opioid switching as compared with continuing use of one opioid? 4) What is the evidence for the benefit of administering modified-release morphine regularly as compared with immediate-release morphine on a 4-hourly or on an “as required” basis? 5) Is there benefit for using the subcutaneous, transdermal or transmucosal routes as compared with the intramuscular and intravenous routes when the oral route for opioids is inappropriate? See Annex 4 for a list of detailed questions.

6.2.1. Choice of Opioid

Recommendation

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. (Strong recommendation; low-quality evidence)

Remarks

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.

Considerations

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.

Summary of the evidence

Thirty-eight eligible RCTs evaluated outcomes of interest among people with cancer who were being managed for their cancer pain (3673). However, few trials clearly distinguished between patients at pain management initiation and those on maintenance treatment, and classification was dependent on the reviewers’ judgement.

Direct and indirect evidence from 13 trials included in the NMA provided high-quality evidence that a combination of strong opioid and NSAID reduces pain (measured on a continuous scale) better than alternative analgesics (see Annex 7 NMA League Table 1 and League Table 2) (51,52,61,74,6573). Direct and indirect evidence from six trials reporting on pain relief as a dichotomous response provided low quality evidence that there may be no differences between analgesics for relief of pain (41,63,64,70,75,76).

Direct evidence for outcomes other than pain relief was obtained from 26 trials comparing different analgesic treatments (3649,5162). The trials evaluated 14 classes of analgesics with 12 studies conducted in older persons.

Direct evidence from five trials evaluated duration of maintenance of pain reduction. There is low strength of evidence of no significant differences between the interventions (codeine, codeine + ibuprofen, diclofenac, morphine extended release every 12 hours, ketorolac, morphine CR, and morphine immediate-release). Four trials evaluated speed of pain relief, providing low strength of evidence of no significant difference between codeine, codeine + ibuprofen, diclofenac, ketorolac, morphine slow-release, morphine immediate-release, and oxycodone slow-release. The studies evaluated different outcomes which ranged from minutes to days.

One trial found no significant difference in quality of life, as measured by the EORTC QTQ-C30, between celecoxib and placebo (very low strength of evidence). There was a difference of 2 on a scale of 0 to 100 [best], but no further data were reported.

Seventeen trials reported on sedation, using various definitions within studies, including sedation, somnolence, drowsiness and tiredness. There was no difference between fentanyl and slow-release morphine for sedation (RR = 0.88; 95% CI 0.52, 1.48). One of the trials explicitly discussed respiratory depression (in fact “respiratory failure”) as an adverse event, with a single occurrence reported among 62 persons taking tapentadol, but none with morphine slow-release. The studies did not report data to allow for evaluation of subgroup differences.

Overall, the evidence indicates that a combination of high-potency opioid combined with an NSAID is better than alternative analgesics for maintenance of pain relief, with no evidence of inconsistency in the data. However, the choice of opioid analgesic may make little or no difference in speed of pain relief, duration of maintenance of pain reduction, or functional outcomes.

Rationale

The evidence does not indicate that there is an obviously-best opioid for maintenance of pain relief. The systematic review reveals some differences between the medicines with regard to adverse effects, which may influence patient and clinical preference. The GDG acknowledged that many differences between opioid medicines are often overstated. The GDG believed that there was minor variability in the patient values and preferences for one opioid over another although individual responses to adverse effects may influence patient choice. The GDG agreed that provision of all analgesic options was likely to be acceptable to key stakeholders such as clinicians and policy-makers but recognized that, for choice of initiation analgesia, there is likely to be variability in the acceptability of opioids in many settings worldwide. The GDG also bore in mind the risk of unintended consequences with diversion being a concern. However, the GDG noted that balanced regulations of these strong analgesics, which balance the necessity of their availability to patients who need them for pain management with the necessity of tackling their misuse, are possible. Recommendations on how to achieve this balance are presented in other WHO documents (27).

The GDG recognized that, while increasing the availability of opioids would require an increase in resources including additional training for health-care workers, good pain control leads to an improvement in patient functional status and appropriate palliative care may be cost effective. The cost of medicines would be an important factor in decisions to make certain medicines available. In low-resource settings, cheaper medicines are preferred as the clinical differences between those and the more expensive medicines are small. Provision of opioids should also improve equity globally with regard to these medicines. For these reasons, the GDG determined that the recommendation would be strong.

6.2.2. Treatment of Breakthrough Pain

Breakthrough pain in cancer refers to a transitory flare of pain in the setting of chronic pain managed with pain medicines around the clock (77).

Best Practice statement

Breakthrough pain should be treated with a rescue medicine, which should be an opioid such as morphine in its immediate-release formulation.

Considerations

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 recommendation 6.2.4, it should be an immediate-release opioid, not a slow-release opioid.

Summary of the evidence

A single small RCT (n = 68) compared analgesics specifically for management of breakthrough pain in an older population with multiple cancer types (42). The trial provided low strength of evidence that the choice between sustained-release and immediate-release morphine may make no difference to prevent breakthrough pain or to reduce pain. The trial did not report on pain relief speed, pain relief maintenance, quality of life, functional outcomes or respiratory depression. The trial provided very low strength of evidence regarding differences between sustained-release and immediate-release morphine to avoid confusion. In the crossover study, two patients developed confusion while taking immediate-release morphine, but the confusion was not attributed to the opioids.

Rationale

The GDG agreed that they could not justify making a recommendation on the basis of only one eligible low-quality RCT that looked at too few of the options that were clinically available. The GDG also noted a high degree of uncertainty regarding patient values and preferences, acceptability and feasibility. However, the GDG highlighted that the cost of certain formulations, such as transmucosal fentanyl, was likely to be prohibitively expensive for some low- and middle-income settings, and that cheaper medicines such as immediate-release oral morphine should be made available as a priority if they are not already available. Given the urgent need for guidance to manage breakthrough pain for both patients and clinicians, the GDG decided to make a best practice statement that breakthrough pain should always be relieved with rescue medicine based on clinical experience and patient need.

This best practice statement was congruent with the recommendation on choice of immediate-release or slow-release morphine (see Section 6.2.4) and was therefore incorporated into the recommendation and does not appear as a standalone Best Practice statement.

6.2.3. 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 (78,79).

No recommendation

In the absence of evidence, WHO makes no recommendation for or against the practice of opioid switching or rotation.

Considerations

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, wherever possible, encourage eligible patients to enrol into such trials.

Summary of the evidence

No RCTs were identified that evaluated switching or rotating opioids in patients with cancer pain.

6.2.4. Choosing between Immediate-Release Morphine and Slow-Release Morphine

Recommendation

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. (Strong recommendation; moderate-quality evidence)

Remarks

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.

Considerations

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.

Summary of the evidence

Ten eligible RCTs compared modified-release morphine (morphine SR) versus immediate-release morphine (37,42,49,8087). Participants had a variety of cancer types in almost all trials. Study participants generally had moderate or severe pain (or the level of pain severity was not explicitly described). The trials evaluated a variety of formulations of morphine slow-release (MS Contin®, Oramorph SR®, Skenan®, MST Continus®, Kapanol® or defined formulations). One trial used ketobemidone for breakthrough pain; the others used morphine immediate-release. All studies (at least implicitly) prescribed the morphine immediate-release to be taken according to a fixed schedule.

There is moderate strength of evidence of no difference in pain relief between slow-release and immediate-release morphine. Pooled data from four trials (n = 222) reporting on pain relief showed no difference between Drug A and Drug B (RR = 0.99; 95% CI 0.95, 1.03). A meta-analysis of four other trials found similar pain scores among participants measured on a continuous scale.

One small trial provided low strength of evidence of no difference in pain relief speed (time to achieving stable pain control, difference between arms −0.4 days; 95% CI −1.1, 0.3). The same trial showed very low strength of evidence of no difference for quality of life, with a difference between arms of 9 points (on a transformed scale of 1 to 100 [best]) with 95% CI -6 to 24). No eligible studies evaluated pain reduction maintenance or functional outcomes. Two studies provided low-quality evidence of no difference between immediate-release and slow-release morphine in sedation scores. Only two trials explicitly reported on respiratory depression as a potential adverse event. They provided low strength of evidence, finding no events in a small overall sample of patients (n = 126). None of the RCTs evaluated subgroups of interest.

Rationale

The choice of slow-release and immediate-release morphine probably makes little or no difference to pain relief and may make no difference to pain relief speed, maintenance of pain relief and sedation. Respiratory distress events may be rare with both formulations. The GDG agreed that there was no clear benefit of one formulation over another. The GDG observed that some patients may prefer slow-release morphine because of the lower pill burden, more sustained analgesia and less waking at night, and that there was likely to be major variability among patients with regard to the choice of formulation. In other patients there may be stigma against certain formulations. Slow-release morphine is typically more expensive than immediate-release morphine. It was not clear which formulation was more cost effective and the GDG noted that the variability in resource requirements was likely to be minor. The GDG remarked that today patients in many countries might have access to only slow-release morphine and that this is inadequate to maintain treatment of breakthrough pain. In other settings, patients may have access to immediate-release morphine, but only in the injectable form which is not appropriate to the outpatient setting. Given that provision of both formulations was highly likely to be acceptable to health-care workers and feasible to implement, the GDG made a strong recommendation with the proviso that the priority medicine is immediate-release oral morphine, with other formulations as acceptable additional options.

6.2.5. 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 (18). Consequently, other routes of opioid administration are often needed.

Best Practice statement

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.

Summary of the evidence

A single small crossover trial compared non-invasive routes versus injected routes for opioids in 20 adults with multiple types of cancer who were selected for the trial because of substantial side-effects related to oral or rectal opioids (88). There was very low strength of evidence to suggest a difference in degree of pain relief between subcutaneous and intravenous hydromorphone (difference = 3.0; 95% CI -15, 21 on a 0 to 100 [worst] scale). The trial did not report on critical or important adverse events. The trial found that sedation, measured by visual analogue scale, improved in both arms with opioid treatment.

Rationale

The GDG could not make a new recommendation on the basis of the very low quality and limited amount of evidence. However, there was consensus that oral or transdermal routes are preferred. When it is possible to administer medicines via either the oral route or the transdermal route, the GDG agreed that the subcutaneous route is preferred over intramuscular injection, as this route is less painful for the patient. A Best Practice statement was therefore formulated.

6.3. Cessation of Opioid Use

If the cause of cancer pain is effectively addressed by anti-cancer treatment (e.g. surgery or chemotherapy), it follows that the use of opioids is no longer necessary and an opportunity exists to decrease or stop opioid use. The GDG developed a clinical question regarding the optimal tapering regimens of interventions to effectively and safely cease use of opioids specifically in patients who have received opioids for cancer pain (see Annex 4 for detailed questions).

Best Practice statement

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.

Summary of the evidence

No eligible studies were found that address this question.

Rationale

The GDG could not make a new recommendation in the absence of evidence. The GDG chose to provide a table outlining a general guide to opioid cessation (see Annex 6) and to make a Best Practice Statement regarding opioid cessation when a patient has developed physical dependence on opioids.

After an abrupt reduction in pain (such as after a nerve block or neuro-ablative procedure), clinicians may consider reducing the dose of opioid until it can be stopped. Following radiotherapy or other anti-cancer treatments, pain relief may be much slower and take days to weeks. If the pain-relieving procedure has been successful, clinicians may consider slowly reducing the dose of opioid, titrated against the patient’s response, until it can be stopped completely if the pain does not recur. Close and regular assessment is needed. If pain recurs, clinicians should take care to suspend dose reduction temporarily and/or to increase the dosage again if necessary until adequate pain relief is achieved.

Efficacy data are available from clinical trials of opioid cessation in persons with opioid dependence undergoing managed withdrawal (89,90). However, it is not clear whether patients with cancer pain will respond to the evidence-based regimens in the same way as persons without cancer and whether optional substitution therapy is desirable in this group of patients. This uncertainty notwithstanding, practitioners looking after patients with cancer may wish to consult and liaise with a specialist in substance use disorders to develop and implement an individualized opioid cessation plan for patients who no longer require opioid analgesia.

6.4. 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 underutilized. 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) (17).

6.4.1. 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 (84,91).

Recommendation

In adults (including older persons) and adolescents, with pain related to cancer, adjuvant steroids should be given to achieve pain control when indicated. (Strong recommendation; moderate-quality evidence)

Remarks

  • 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.

Considerations

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.

Summary of the evidence

Seven eligible trials compared steroids to placebo (see Annex 3, Evidence Profile 5.1) in patients with a variety of cancers (9298). The studies evaluated methylprednisolone (four trials), dexamethasone (two trials) and prednisolone (one trial).

Five trials provided moderate strength of evidence that pain relief was greater in patients taking steroids than in those taking placebo. The summary net difference in pain scores between arms was −9.9 (on a 0 to 100 [worst] scale), 95% CI −16.0 to −3.8, favouring steroids. Over half the weight for this summary estimate came from the only trial that found a statistically significant finding, which also reported the greatest reduction in pain scores with steroids and was published in 1985.

None of the trials reported pain relief speed or duration of pain relief maintenance. Three studies provided very low strength of evidence that patients taking steroids had improved quality of life compared with placebo with a summary net difference (on a 0 to 100 [best] scale) of 12.6 (95% CI 6.2, 19.0). One small trial provided very low strength of evidence regarding gastrointestinal bleeds, being the only study to report this adverse event explicitly. No gastrointestinal bleeds occurred among 31 patients in this crossover study. Two small studies reported on psychiatric adverse events: one trial provided very low strength of evidence regarding depression, with very imprecise estimates of no difference (RR = 1.00; 95% CI 0.06, 15.2), while the other trial provided very low strength of evidence regarding both anxiety and “psychic change” (undefined) in favour of steroids (both RR = 0.59; 95% CI 0.11, 3.20). No study reported on delirium or psychosis.

No trials compared the effects of different steroids against other steroids.

Rationale

Moderate quality of evidence indicates that steroids probably improve pain relief and may improve quality of life but it is uncertain whether, in this population, steroids increase risks of gastrointestinal bleeds or psychiatric adverse events. The GDG remarked that patients – especially young patients – are sometimes reluctant to take the medicines because of their known common side-effects. Older patients are also sometimes reluctant on account of diabetes and other comorbidities. The GDG deemed this option acceptable to clinicians, who frequently appreciate the speed of onset of steroids’ beneficial effects. The resource requirements are small and the option is feasible. The GDG did not believe the therapy would have much impact on equity. The GDG noted that, while some side-effects and adverse events from steroids can be serious, the balance of effects is in favour of their use when indicated; the GDG therefore made a strong recommendation. However, the GDG observed that the absence of evidence comparing different steroids did not support a recommendation in favour of any single specific steroid over another.

6.4.2. 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 (TCAs) and selective serotonin norepinephrine reuptake inhibitors (SNRIs), are commonly used as adjuvant medicines to treat neuropathic pain.

No recommendation

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

Considerations

In the absence of high-quality evidence specific to treating tumour-related neuropathic pain, the GDG noted the efficacy data from antidepressant use in non-cancer neuropathic syndromes and suggested that practitioners may wish to consider an individual trial of therapy with an antidepressant for patients with cancer-related neuropathic pain that is not relieved adequately by a combination of an opioid and either paracetamol or NSAIDs, or both. Care should be taken to evaluate the effectiveness after adequate titration, and treatment should be stopped if not beneficial. Ideally, eligible patients should be enrolled in a clinical trial to establish efficacy in cancer pain and practitioners are encouraged to seek out such trials and facilitate enrolment of eligible patients.

Summary of the evidence

One eligible trial compared amitriptyline to placebo in 60 people with severe neuropathic cancer pain (cancer types and ages not reported) (99). There was low quality of evidence that amitriptyline is more effective than placebo in reducing pain in people with cancer-related neuropathic pain; the net difference in Visual Analogue Scale score (transformed 0 to 100 [worst] scale) was −4.7 (95% CI −9.2, −0.2). The trial did not report data on complete pain relief, pain relief speed, pain reduction maintenance, quality of life, functional outcomes or adverse events.

No eligible trials were found that compared different antidepressants to others.

Rationale

While decades of clinical practice have shown antidepressants to be effective in neuropathic pain syndromes (100), the GDG did not feel sufficiently confident that the evidence indicates their effectiveness in tumour-related neuropathic pain. The GDG therefore opted to make no recommendation because of lack of evidence. The group also noted that some patients might have strong aversions to the use of antidepressants due to stigma and that possible anticholinergic side-effects, such as dry mouth, constipation or sedation, may be an additional burden.

No eligible trials were found that compared different antidepressants with each other. The GDG could not make a recommendation for one antidepressant in preference to others because of the absence of evidence.

6.4.3. Anticonvulsants

Cancer-related neuropathic pain is common and can be caused either by the disease or by cancer treatment. 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 (see Fallon, 2013 (100) for review), including gabapentin, pregabalin, carbamazepine and valproate.

Recommendation

WHO makes no recommendation for or against the use of anti-epileptics/anticonvulsants for the treatment of cancer-related neuropathic pain.

Considerations

In the absence of clear evidence in favour of anti-epileptics, the GDG 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, wherever possible, should encourage eligible patients to enrol into such trials.

Summary of the evidence

The results of the systematic review were not presented. The evidence retrieved for the systematic review for this question was discounted following a revelation of fraud. While gabapentin has been widely prescribed, in 2017 it was rejected for inclusion in the WHO Model list of essential medicines on account of fraudulent evidence (101104).

Rationale

The fraudulent data called into question the systematic review data for this question, resulting in no recommendation being made. The fraudulent data are specific to gabapentin but the review analyses included gabapentin and other anti-epileptics and the GDG felt that a new review would be necessary prior to further evaluation, interpretation and decision-making regarding anti-epileptics in general. This will require assessment in future updates of the guidelines.

6.5. 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 localized cancer (17). The Clinical practice guidelines on management of cancer pain of the European Society of Medical Oncology recommend radiotherapy (105). 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.

6.5.1. 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 (SREs) and reduce bone pain and analgesic requirements (106,107). Examples include clodronate, ibandronate, pamidronate, risendronate, etidronate and zoledronate.

Recommendation

In adults (including older persons) and adolescents with bone metastases, a bisphosphonate should be used to prevent and treat bone pain. (Strong recommendation; moderate-quality evidence)

Considerations

Clinicians should take into account the variable adverse renal effects of bisphosphonates before prescribing.

Summary of the evidence

Bisphosphonates compared to placebo

Forty eligible trials compared bisphosphonates to placebo (108147).

Most trial participants had either breast or prostate cancer. Thirteen studies evaluated clodronate, nine zolendronate, five each ibandronate and pamidronate, and one each etidronate and risendronate. Studies were not explicit about what other drugs (including for pain relief) patients were on, but an informed assumption was made that the bisphosphonates were used as adjuvant therapies to treat or to prevent bone pain from metastases.

There is moderate strength of evidence of greater pain relief with use of bisphosphonates compared with placebo among patients with painful bone metastases. Seven trials evaluated categorical pain relief; however, four evaluated improvements in pain (e.g. reductions of at least 2 points on a 5-point pain scale) (116,126,136,144) and three evaluated complete pain relief (113,123,134). Although favouring use of bisphosphonates, no statistically significant differences in complete relief of pain (RR = 1.61; 95% CI 0.89, 2.93) or pain improvement (RR = 1.24; 95% CI 0.90, 1.71) were found. Fourteen trials evaluated pain on continuous scales (which were each converted to a 100-point scale, with 100 equivalent to worst pain) (110,112,114116,124,125,128,131,132,135,138,140,146). The studies, overall, indicated statistically significant improvement in pain, with an overall net difference of −11.8 (95% CI −17.6, −6.1).

No study evaluated speed of pain relief. A single trial provided low strength of evidence suggesting no significant difference in duration of pain relief between risendronate and placebo in people with prostate cancer.

Five studies provide varying strength of evidence that bisphosphonates do not affect quality of life compared with placebo (111,112,116,119,132). The studies evaluated clodro-nate (three studies), ibandronate (one study) and zolendronate (one study). The five studies provided very low strength of evidence of no significant difference in changes in quality-of-life scores measured on a variety of scales (summary net difference on a 0 to 100 [best] scale = 8; 95% CI -6, 22). One study provided moderate strength of evidence of reduced and delayed deterioration in quality of life with clodronate (RR = 0.81; 95% CI 0.67, 0.99 and HR = 0.71; 95% CI 0.56, 0.92) (111).

Twenty-five trials evaluated the various SREs (108,109,112,117122,124,127,129,130,132,133, 135,137,138,141143,145148). Overall, the trials provided moderate strength of evidence that bisphosphonates reduce the risk of SREs. The six studies that reported hazard ratios for time to first SRE (any) in comparisons of zolendronate (four studies) or ibandronate (two studies) found a statistically significant benefit of bisphosphonates over placebo (HR = 0.71; 95% CI 0.61, 0.84) (109,117,119,133,137,146). Eighteen trials found a reduction in risk of any SRE, yielding a summary RR = 0.81 (95% CI 0.76, 0.86) (108,109,117122,124,127,133,135,137139,145147). Four trials explicitly reported on the risk of osteonecrosis of the jaw (109,125,132,142). Across the studies, there were no occurrences of this adverse event with either bisphosphonates (n = 460) or placebo (n = 450).

Choice of bisphosphonates

Seven eligible studies compared different bisphosphonates in patients with various cancers with bone metastases – mostly breast, prostate and non-small cell lung cancer (148154). The evidence is relatively sparse, with only seven studies evaluating four bisphosphonates (clodronate, ibandronate, pamidronate and zoledronate). Study participants were generally older, with study mean ages ranging from 53 to 73 years of age.

With only two or three studies evaluating pain control, there is low strength of evidence of no differences in relief of pain or mean changes in pain scores across the different bisphosphonates. From one study, pain relief on ibandronate (6%) was less common than on other bisphosphonates (15–26% in one or two studies for each medicine). Changes in pain (as a continuous measure from 0 to 100 [worst]) were similar for each of the four bisphosphonates (−3.3 to −5.0).

Two studies provided very low strength of evidence regarding duration of pain relief. One study found no difference in average duration of pain relief in patients with a variety of cancers (about half of them lung cancer) between ibandronate (5.5 months) and pamidronate (5.2 months) (151). One study reported that in patients with prostate cancer those taking clodronate had longer duration of pain relief (13 months) than those taking zolendronate (9 months, P = 0.03) (152).

Six studies provided very low strength of evidence regarding SREs. Broadly similar percentages of people had any SRE across bisphosphonates (18–26%, with no data on pamidronate). Within studies, fracture rates were mostly similar between bisphosphonates, except in one study of people with breast cancer in which 16% of those taking clodronate had fractures compared with 7% taking pamidronate (P = 0.03). Three studies found no significant differences in rates of spinal cord compression across bisphosphonates. Two studies found no significant differences in rates of bone radiotherapy across bisphosphonates and three studies found no significant differences in rates of bone surgery across bisphosphonates.

Three studies reported on rates of hypercalcaemia across bisphosphonates. Two of these found no differences in the incidence of hypercalcaemia between ibandronate (10.7%) and zolendronate (9.3%), and between clodronate (2.9%) and zolendronate (1.4%) respectively. The third trial reported that the hypercalcaemia rate in the zolendronate group (28%) was lower compared with ibandronate (45%) (RR = 0.64; 95% CI 0.39, 1.03) and compared with pamidronate (50%) (RR = 0.57; 95% CI 0.35, 0.91).

Three studies reported rare rates of osteonecrosis of the jaw for clodronate (1.5%), ibandronate (0.7%), and zolendronate (1.2%), providing low strength of evidence. No studies reported on quality of life.

Rationale

The GDG agreed that the balance of effect fell strongly in favour of prescribing bisphosphonates to appropriate populations when compared with placebo. Osteonecrosis of the mandible, considered a serious adverse event, was deemed sufficiently rare (no cases were observed in the eligible trials; n = 910) that the expected benefits outweighed the risks of harm. Clinicians might differ in their preferences for the use of certain bisphosphonates, since there is evidence of differences in renal adverse effects and therefore the degree to which renal pathologies are be contraindications (155).

The GDG believed that most patients would prefer bisphosphonates over placebo. However, the GDG recognized that bisphosphonates are also expensive, and often prohibitively so. The use of bisphosphonates in populations of older women with osteoporosis and in breast cancer patients with bone metastases has been deemed cost saving or cost effective (depending on population) in a number of high-income countries (156158). It remains to be seen whether these savings would apply to lower-income settings.

Most of the RCTs were conducted with intermittent intravenous administration. Consideration was given to the issue that administration of the bisphosphonates should be intravenous, but this was not deemed to be a sufficiently significant barrier to administration that the strength of the recommendation should be attenuated. The GDG therefore made a strong recommendation in favour of bisphosphonates.

The GDG did not think patients would have major reasons to prefer one bisphospho-nate over another and considered that there would be only minor variability.

When these considerations are combined, the GDG felt that equity could be affected in either direction. Taking into account the inconclusive evidence and other considerations, the GDG agreed that it could not make a recommendation for one bisphosphonate over another.

6.5.2. Monoclonal Antibodies

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

No recommendation

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

Summary of the evidence

Monoclonals compared to placebo

A single small trial compared monoclonals to placebo (see Annex 3, Evidence Profile 5.2.3). The study evaluated tanezumab in 59 adults with prostate cancer, breast cancer, renal cell carcinoma or multiple myeloma with painful bone metastases (ages 32 to 77 years; mean age 56 years) (159). The trial provided very low strength of evidence of no difference in average or worst pain between groups (between-group differences −2.6 [95% CI −11.8, 6.6] and −0.1 [95% CI −9.3, 9.1] respectively), and in the percentage of people who achieved pain relief (by at least 50%) (RR = 1.38; 95% CI 0.55, 3.49). The trial did not report on speed of pain relief, duration of pain relief maintenance, quality of life or functional outcomes. The trial provided very low strength of evidence regarding SREs, reporting only that 1 of 29 (3.4%) patients in the tanezumab arm had a femur fracture but, implicitly, none of the 30 people on placebo had a fracture (although one had undefined metastatic disease progression). No study reported on osteonecrosis of the jaw.

Choice of monoclonals

No eligible trials were found comparing specific monoclonal antibodies with other monoclonal antibodies for preventing and treating bone pain.

Rationale

The GDG could not make a recommendation for or against monoclonal antibodies compared with placebo on the basis of one eligible trial.

The GDG also made no recommendation for or against the use of particular monoclonal antibodies in preference to other monoclonal antibodies to prevent and treat bone pain.

6.5.3. Comparison of Bisphosphonates or Monoclonal Antibodies

No recommendation

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

Summary of the evidence

Nine eligible trials compared monoclonal antibodies and bisphosphonates (159168). All evaluated the monoclonal denosumab and six evaluated zolendronate. Pamidronate and a variety of bisphosphonates (based on local practice) were also evaluated. Studies included patients with metastatic bone lesions, mostly from breast or prostate cancer, but also non-small cell lung cancer, multiple myeloma and other cancers. Three trials with identical protocols (163165) except for cancer inclusion criteria were separately conducted and reported and were also combined and reported in a summary article (168). Patient ages varied widely across studies. Studies were not explicit about what other medicines (including those for pain relief) patients were taking, but an informed assumption was made that the monoclonals and bisphosphonates were used as adjuvant therapies to treat or to prevent bone pain from metastases.

A single large trial of people with either breast cancer or multiple myeloma compared denosumab and zoledronate and provided low strength of evidence for no difference in pain relief (RR = 0.89; 95% CI 0.67, 1.10) and in time until pain relief (speed) (HR = 1.02; 95% CI 0.91, 1.15), and very low strength of evidence for no difference in quality of life (RR = 1.08; 95% CI 0.95, 1.23) (174). No trial evaluated pain reduction maintenance.

Across six trials, there was high-quality evidence that rates of any SRE (RR = 0.86; 95% CI 0.81, 0.91) and fracture (RR = 0.88; 95% CI 0.78, 0.96), bone radiation therapy (RR = 0.80; 95% CI 0.73, 0.88) and hypercalcaemia (RR = 0.58; 95% CI 0.34, 0.81) were statistically significantly more common among those treated with bisphosphonates. Two trials provided low strength of evidence for functional outcomes. Three trials provide high strength of evidence that the risk of osteonecrosis of the jaw is higher with denosumab than with bisphosphponates, with a summary RR = 1.40 (95% CI 0.92, 2.13).

Rationale

The systematic review of evidence suggests that monoclonals reduce the risk of SREs and may improve functional outcomes more than bisphosphonates do, but that they increase the risk of osteonecrosis of the jaw. The choice of monoclonals or bisphosphonates may make little or no difference to bone pain or time to pain relief. Monoclonal antibody regimens involve a lower medicine-administration burden than bisphosphonates do, which patients would prefer, but monoclonals have a significantly higher cost. Osteonecrosis of the jaw (which is higher with monoclonal antibodies) is an outcome sufficiently adverse that the GDG believed it could affect patient preferences, but its expected disutility to patients must be weighed against the expected disutility of SREs which is higher with bisphosphonates.

Although there are relative benefits to the use of denosumab compared with bisphosphonates, the relative cost of denosumab is disproportionate to those benefits. The GDG agreed it they could not recommend one medicine category over the other on these grounds.

6.5.4. 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 (169).

Recommendation

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. (Strong recommendation; high-quality evidence)

Remarks

This recommendation applies to people who already have painful metastases; it is not a recommendation concerning preventive radiotherapy.

Considerations

Use of low-fractionated (single-dose) radiotherapy probably has beneficial effects on treatment coverage, waiting times and financial savings.

Summary of the evidence

Twenty-three eligible RCTs compared low-fractionated to high-fractionated radiotherapy (See Annex 3, Evidence Profile 6.1) (170193). Almost all used a single fractionation of 8 Gy in the low fractionation arms (two older studies used single fractionations of either 10 Gy or a range from 8 to 15 Gy; one study arm which used 5 Gy was omitted). High-fractionated radiotherapy ranged from 20 to 30 Gy, mostly given over 5–10 fractions. These trials included patients with a variety of cancer types, with breast, prostate and lung cancers included in most trials. Among trials that reported participant ages, study participants were mostly older adults; the mean age ranged from 48 to 72 years, with the youngest participant being 16 years of age.

There is high-quality evidence that the different fractionation schedules were similarly effective in terms of producing pain relief and improvement. Under both schedules 25% or 26% of participants achieved complete pain relief (RR = 0.97; 95% CI 0.89, 1.06) and 69% or 71% of participants achieved either complete or partial pain relief (RR = 0.97; 95% CI 0.93, 0.998). Pain relief was infrequently reported on a continuous scale. Three trials provided low-quality evidence of no difference between fractionation schedules. The trials could not be quantitatively combined but all reported statistically nonsignificant differences.

Three studies reported on pain relief speed (i.e. time to complete response), providing moderate strength of no difference between radiotherapy schedules; however, all studies reported outcomes vaguely, either as survival curves showing nonsignificant differences or reporting that pain relief was achieved in two weeks in both study arms. Nine studies reported on the duration of pain relief (pain reduction maintenance), providing moderate quality evidence of no difference between radiotherapy schedules.

Most studies reported no significant difference between radiotherapy schedules without providing data; one trial reported HR = 0.91 (95% CI 0.46, 1.82).

There is high-quality evidence that pathological fractures at the treatment (index) site are more common with low-fractionated than high-fractionated radiotherapy. Across studies, about 3–4% of patients had a pathological fracture at the index site (RR = 1.48; 95% CI 1.08, 2.03). There is high-quality evidence that spinal cord compression (among those treated for spinal metastases) are more common with low-fractionated (2.2%) than high-fractionated radiotherapy (1.4%), although the difference was not statistically significant. Across studies, the RR = 1.45 (95% CI 0.89, 2.37).

Rationale

The GDG agreed that there was no difference in benefit between low-fractionated (single-dose) or high-fractionated (multiple-dose) radiotherapy with respect to the critical outcomes of bone pain relief, speed or duration of pain relief. The GDG recognized that there was high-quality evidence that the important outcome of risk of fracture at the treatment site was greater in those receiving low-fractionated radio-therapy compared to high-fractionated (multiple-dose) radiotherapy.

The GDG observed that there was likely to be minor variabiity among patient values and preferences with regard to low-fractionated therapy with fewer trips to receive treatment being an advantage. Similarly, there was likely to be minor variability in acceptability among health-care workers for providing single-dose radiotherapy. Low-fractionated radiotherapy – where a patient receives a larger single dose (e.g. an 8 Gy fraction) in a single clinic visit – is less expensive in terms of both time and money than a longer schedule in which a patient receives smaller individual doses but an overall greater amount of radiotherapy over several visits (e.g. 20–30 Gy given over 5–10 fractions) (194). Therefore, the GDG established that the negligible clinical differences between the schedules with respect to pain, coupled with the large cost and equity benefits of single-fraction radiotherapy, favoured single-dose over multiple-dose radiotherapy where indicated despite the increase in fracture risk. If more patients were to be given single-dose therapy in settings where there is a shortage of radiation equipment and staff, the same resources could be used for greater coverage, as well as reducing patients’ costs, such as those for travel, making the single-dose option the most feasible. For these reasons and the high quality of evidence, the recommendation was strong.

6.5.5. Radioisotopes for Bone Pain

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

No recommendation

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

Summary of the evidence

Three RCTs compared radioisotopes to a control arm that did not use radioisotopes (119,195,196). All three trials were conducted in men with prostate cancer. The studies evaluated Strontium-89 (two trials) and Samarium-153 (one trial). Trial participants were mostly older adults with a mean age ranging from 69 to 71 years. A single very small trial of 24 participants provided very low quality of evidence of better bone pain relief with radioisotope treatment (RR = 21; 1.37, 322) and a net difference in bone pain on VAS of -38 points (95% CI -47, -29) (low quality of evidence). No trial reported pain relief speed or pain reduction maintenance.

Two trials provided high quality of evidence that SREs were less common after radio-isotope treatment than placebo (RR = 0.86; 95% CI 0.77, 0.95) and that SREs were delayed among those who had received radioisotopes compared with placebo (HR = 0.73; 95% CI 0.62, 0.86). The two trials provided low quality of evidence of similar risk of fracture (RR = 1.05; 95% CI 0.53, 2.08) and spinal cord compression (RR = 0.82; 95% CI 0.39, 1.71). One trial provided moderate quality of evidence of fewer episodes of bone pain (reported as an adverse event) with radiotherapy (RR = 0.81; 95% CI 0.71, 0.91). Another study provided very low quality of evidence of no signifi-cant differences in improvements in quality of life (RR = 0.97; 95% CI 0.68, 1.24).

Rationale

The GDG noted that, in patients with prostate cancer, use of radioisotopes reduces and delays SREs, probably improves quality of life, and may provide greater bone pain relief. However, the GDG decided not to make a recommendation for or against the use of radioisotopes because of their prohibitive cost and the lack of generalizbility of the current evidence, which was drawn only from men with prostate cancer.

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