Cancers are among the leading causes of morbidity and mortality worldwide, responsible for 18.1 million new cases and 9.6 million deaths in 2018 (1).
Pain is experienced by 55% of patients undergoing anti-cancer treatment and by 66% of patients who have advanced, metastatic or terminal disease (2). There are several physiological mechanisms by which cancer causes pain. Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or is described in terms of such damage (3). Cancer and pain can also cause psychological suffering in the form of anxiety, depression, fear or a sense of hopelessness, and anxiety and depression can in turn exacerbate pain.
The goal of pain management is to relieve pain to a level that allows for an acceptable quality of life. These guidelines focus on pain caused by the direct effect of cancer -such as extension into soft tissues, visceral involvement, bone involvement, nerve compression or injury, raised intracranial pressure, or a combination of these (Table 1).
Other types of pain related to cancer can be due to side-effects of treatment such as those caused by nerve injury during surgery, chemotherapy-induced peripheral neuropathy, muscle spasm, lymphoedema, constipation or pressure ulcers. These types of pain are beyond the scope of these guidelines.
Patients with cancer may require pain relief at all stages of their disease, and not only at the end of life. Better results in terms of symptom management can be achieved when palliative care is introduced early in the course of illness, through a peoplecentred approach concurrently with disease-modifying therapies (4). As a result of early diagnosis and improved cancer treatment, cancer patients are living longer. Nevertheless, in many settings, patients often present with cancer that is so advanced that any disease-modifying treatment may not be effective or feasible. For these patients, the preferred treatment option is palliative care and pain relief when needed.
The mainstay of cancer pain therapy is pharmacological interventions, but radiotherapeutic, anaesthetic, neurosurgical, psychological, physiotherapeutic, spiritual and social interventions all play essential roles in adequate cancer pain management.
Pain relief and palliative care are an imperative of universal health coverage, yet recent estimates state that 25.5 million people died in 2015 with serious health-related suffering (5). Expert opinion and data from country experiences from several lowincome countries, where treatment coverage is often low or non-existent, suggest that approximately 80% of people dying from cancer experience moderate or severe pain lasting on average for 90 days (5). Thus, cancer pain is a major cause of unnecessary suffering.
Everyone has a right to the enjoyment of the highest attainable standard of physical and mental health, and states have an obligation to take steps towards "the creation of conditions which would assure to all medical service and medical attention in the event of sickness" (6). This includes palliative care and access to adequate pain management.
International drug control conventions state that "the medical use of narcotic drugs continues to be indispensable for the relief of pain and suffering and that adequate provision must be made to ensure the availability of narcotic drugs for such purposes" (7). Palliative care and pain relief is an essential health service component of Universal Health Care (8).
Despite being an issue of human rights and states' legal obligations, many people do not receive the pain relief they need. In 2006, it was estimated that 5.5 billion people (83% of the world's population) lived in countries with low or non-existent access to adequate pain management (9). Opioids are essential treatment for moderate to severe cancer pain. Even though oral morphine is on the World Health Organization (WHO) Model list of essential medicines as well as on the list of basic essential noncommunicable disease (NCD) medicines for primary health care (10), in 2015 only 43% of countries reported that it was generally available in primary care facilities in the public health sector (11). There was a strong income gradient for this trend, with 77% of high-income countries reporting the general availability of oral morphine compared with 15% and 13% of low-and lower-middle-income countries respectively (11). Effective guidance is necessary to alleviate this preventable cancer pain pandemic.
While patients in most countries suffer from inadequate or no access to opioid analgesic medicines, an epidemic of opioid overdoses in the United States has been observed in the last two decades (12,13). Inappropriate marketing of prescription opioids by pharmaceutical companies (14) and inappropriate prescription by medical practitioners with little attention to the development of opioid-use disorders and the risk of opioidinduced respiratory depression are postulated to have contributed to the epidemic (15).
Global treatment guidelines for cancer pain -informed by the issues outlined aboveare required to ensure that active pain from cancer can be adequately managed while ensuring patient and nonpatient safety. Country experiences have shown that balancing these goals is possible with appropriate measures and guidance (16).
Former WHO cancer pain guidelines, namely Cancer pain relief (1986) (17), Cancer pain relief with a guide to opioid availability (1996) (18) and Cancer pain relief and palliative care in children (1998) (19) made seminal recommendations that set global standards for cancer pain management. Yet, there are several reasons why an update is required namely:
 The 1986 and 1996 guidelines were developed on the basis of reports of a WHO expert committee. Current WHO guidelines are evidence-based using standardized, quality-assured methods for evidence appraisal and decision-making.
 Clinical practice continues to evolve. The WHO analgesic ladder, introduced in 1986 and disseminated worldwide, remains recognized as a useful educational tool but not as a strict protocol for cancer pain treatment (20). The three-step ladder was proposed in 1986 on the basis of the premise that doctors and health-care professionals should learn how to use a few drugs well. There are now new pain assessments, interventions and new delivery methods that were unavailable in 1996 (21,22,23), and new tools have been developed for pain assessment (Annex 1).
 There is also a need to provide guidance that is suitable for the realities of low-and middle-income countries. This is especially important for instructions on the use of opioid analgesics, as accessibility and knowledge of their use remains poor in many low-and middle-income settings.
 There is an ever-growing epidemiological imperative for new, up-to-date guidelines. Global cancer incidence is rising, populations are ageing, and improvement of clinical practice must meet the challenge. The provision of new guidance on cancer pain management aims to improve global clinical practice and to facilitate the removal of barriers to adequate pain relief for all who need it.

# OBJECTIVES AND TARGET AUDIENCE OF THESE GUIDELINES
The intended audience for these guidelines includes: health-care providers, physicians, nurses, pharmacists, and caregivers, policy and programme managers, public health officials and academics. The objectives of these guidelines are:
- To provide management guidance to health-care providers (i.e. the end-users of these guidelines: physicians, nurses, pharmacists and caregivers) on the adequate relief of pain associated with cancer or its treatment in adults and adolescents.
- To assist policy-makers, programme managers and public health personnel to create and facilitate appropriately balanced policies on opioids and prescribing regulations for effective and safe cancer pain management.
These guidelines constitute a part of WHO's efforts to promote training, improved knowledge and confidence about appropriate pain relief among health-care providers and public health officials. Through the dissemination and use of the guidelines, it is hoped that access to effective and safe pain relief will increase and that millions of adults and adolescents suffering from cancer pain (the people affected by this guideline) will receive the care to which they have a right. If used in the context of palliative care, guidelines for the management of cancer pain in adults and adolescents will contribute to the achievement of Universal Health Coverage.

# SCOPE OF THE GUIDELINES
Pharmacological and radiotherapeutic interventions are the mainstay of cancer pain treatment. These guidelines focus on the medical management of cancer pain and make recommendations on the pharmacological and radiotherapeutic methods of cancer pain management. Anaesthetic, psychological, social, spiritual, physiotherapeutic and surgical modes of cancer pain management are integral to comprehensive cancer pain management and are discussed in this document but are outside the scope of these guidelines.
These guidelines cover the management of cancer pain in adults (including older persons aged 60 years and over) and adolescents (aged 10-19 years) whose cancer pain management is delivered within the health system at any level, from specialized cancer centres to primary care centres in the community and patients' homes. The recommendations apply to the full range of income settings.

# METHODS USED IN THE GUIDELINES
Full methods of the guideline development process, including the systematic review methods, are provided in Annex 2.
In summary, the GDG met on 28-29 July 2016 to outline the scope of the guideline questions and then met again on 20-21 November 2017 to deliberate and determine the recommendations made in response to 13 key clinical questions. The questions included issues such as the optimal choice of medicines for initiating and maintaining cancer pain relief, management of breakthrough pain, use of adjuvant medicines including steroids, anticonvulsants and anti-epileptics for cancer pain relief and optimal management of bone pain. See Annex 4 for the full details of the clinical questions.
Systematic reviews were completed for each question by independent review teams in advance of the meeting and shared with the GDG prior to the meeting. This included a network meta-analysis (NMA) comparing different groups and classes of analgesic medicines for managing cancer pain.
Outcomes were rated by GDG members, according to the importance of each outcome from the perspective of the person living with cancer pain, as "not important" (1-3), "important" (4-6) or "critical" (7)(8)(9). Outcomes rated as critical were included in final GRADE (Grading of Recommendations Assessment, Development and Evaluation) evidence profile tables which were presented to the GDG for determining the balance between benefits and potential harms. The steps undertaken for the retrieval of evidence, assessment and synthesis are summarized in Annex 2.
For making recommendations on interventions, GRADE methodology as defined in the WHO Handbook for guideline development was used to provide a rating of the overall quality of evidence arising from each systematic review (categorized as very low, low, moderate or high).
Values and preferences of the intervention were considered from the perspectives of patients. These perspectives were discussed by the GDG members, all of whom had broad professional experience of the field.
When considering the use of resources, the GDG was presented with the pricing of drugs where this was available and brought their knowledge of medication prices from around the world to the considerations. No formal cost-effectiveness studies were conducted, but the GDG considered the longer-term benefits of each recommendation in terms of possible reductions in hospitalization and morbidity. The GDG proffered observations and their own experiences regarding the acceptability of interventions to health-care workers and the feasibility of implementation of recommended interventions, especially in regions were resources are scarce or absent. Similarly, the effect of provision of an intervention on equity was carefully considered through discussion within the GDG. No formal surveys of patients or health-care providers were conducted.
Based on the agreed quality of the evidence and with consideration given to the values and preferences of patients, the acceptability and feasibility of the intervention within the health-care system, the potential impact on equity and the resource implications, the GDG decided on the direction of the recommendation (either in favour or against an intervention) and whether to make strong or conditional recommendations using a benefit-risk assessment of each intervention. In the absence of any evidence on a particular review question, the GDG chose to make no recommendation.
For several questions where evidence was scant or lacking, the GDG recognized that established practices exist but did not formulate recommendations for or against the practices. For two such questions, best practice statements were formulated instead in view of the potential benefit and lack of any observed harms from current practices. For those questions where harms or lack of effect were less certain, specifically in patients with cancer pain, the GDG advocated that clinicians conduct an individual trial of therapy in their patients and assess the response accordingly. Ideally, and wherever possible, clinicians are encouraged to enrol eligible patients into a clinical trial to establish efficacy and build the evidence base.
Conflicts of interest were managed by requesting all GDG members to complete a WHO Conflicts of Interest (COI) form in advance of the meeting and to declare these before the entire GDG. Relevant declared interests of GDG members are reported in Annex 4. None of the declared interests were considered by WHO to be conflictual. WHO policies on COI were fully applied throughout.

# CANCER PAIN MANAGEMENT -GUIDING PRINCIPLES
The GDG and stakeholders who developed the guidelines determined that all recommendations arising from the meeting would be underpinned by the following overarching principles of effective health systems and best clinical practice:

# THE GOAL OF OPTIMUM MANAGEMENT OF PAIN IS TO REDUCE PAIN TO LEVELS WHICH ALLOW AN ACCEPTABLE QUALITY OF LIFE
While 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, RECOGNIZING 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, 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 (24). Assessment and re-assessment at regular intervals are key to ensuring that treatment is appropriate and safe, as well as minimizing and addressing side-effects over the course of a patient's care plan (25).
Annex 1 provides examples of pain assessment scales for specific populations.

# SAFETY OF PATIENTS, CARERS, HEALTH-CARE 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 health-care 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 optimized 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, while pharmacological interventions are the mainstay of cancer pain management, psychosocial care is also an essential component of a comprehensive care plan. Health-care 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.

# ANALGESICS, INCLUDING OPIOIDS, MUST BE ACCESSIBLE: BOTH AVAILABLE AND AFFORDABLE
Opioid analgesics are essential for the adequate treatment of moderate and severe cancer pain. Yet access and availability are poor in most low-and middle-income 5. CANCER PAIN MANAGEMENT -GUIDING PRINCIPLES countries. Barriers to adequate pain relief include: regulatory and legal barriers, attitude and knowledge barriers, and economic and procurement impediments (26). Addressing all of these barriers will be necessary in a country to increase access to adequate pain relief. In many settings, cancer pain management will be impossible unless policy changes enable access to adequate pain relief medicines. These issues are comprehensively addressed in Ensuring balance in national policies on controlled substances (2011) (27). Clinical and policy guidelines should be complementary in order to increase overall access to controlled pain relief medicines. Annex 5 presents international conventions on the availability of opioid analgesics.

# ADMINISTRATION OF ANALGESIC MEDICINE SHOULD BE GIVEN "BY MOUTH", "BY THE CLOCK", "FOR THE INDIVIDUAL" AND WITH "ATTENTION TO DETAIL"
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 assessment as described in item 2 above, plus differential diagnosis of the type of pain (e.g. 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 WHO guidance included a pain management ladder which has been widely used in the cancer care community (See /). However, a pain management ladder is only a general guide to pain management (Annex 1). 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.

# RECOMMENDATIONS 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.

# 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.
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)
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.
Paracetamol, NSAIDs, morphine, and other opioids have been regarded as mainstays of cancer pain treatment for decades and remain so today (28-30). 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 naive 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  (31).
Three eligible randomized controlled trials (RCTs) evaluated outcomes other than pain relief among persons with cancer who were initiating pain management (33)(34)(35). 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.
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 29 6. RECOMMENDATIONS FOR THE PHARMACOLOGICAL AND RADIOTHERAPEUTIC MANAGEMENT OF CANCER PAIN IN ADULTS AND ADOLESCENTS recommendation in favour of provision of a selection of analgesics for pain management initiation despite the low quality of evidence.

# 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.

# 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. (Strong recommendation; low-quality evidence)
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.

# Summary of the evidence
Thirty-eight eligible RCTs evaluated outcomes of interest among people with cancer who were being managed for their cancer pain. 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,(65)(66)(67)(68)(69)(70)(71)(72)(73). 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 (36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60)(61)(62). 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 but no further data were reported.
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 policymakers 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.

# 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.
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.
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.

# 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).

# RECOMMENDATIONS FOR THE PHARMACOLOGICAL AND RADIOTHERAPEUTIC MANAGEMENT OF CANCER PAIN IN ADULTS AND ADOLESCENTS

# No recommendation
In the absence of evidence, 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, 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.
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 slowrelease morphine cannot be used for rescue. 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 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.
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, 35 6. RECOMMENDATIONS FOR THE PHARMACOLOGICAL AND RADIOTHERAPEUTIC MANAGEMENT OF CANCER PAIN IN ADULTS AND ADOLESCENTS 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.

# 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  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.
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.

# 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.
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.

# 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).
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).
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)
 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.

# 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 (92)(93)(94)(95)(96)(97)(98). 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  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  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.
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.

# No recommendation
WHO makes no recommendation for or against the use of antidepressants to treat cancer-related neuropathic pain.
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  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.
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.
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.
WHO makes no recommendation for or against the use of anti-epileptics/anticonvulsants for the treatment of cancer-related neuropathic pain.
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 (101)(102)(103)(104).
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, 41 6. RECOMMENDATIONS FOR THE PHARMACOLOGICAL AND RADIOTHERAPEUTIC MANAGEMENT OF CANCER PAIN IN ADULTS AND ADOLESCENTS interpretation and decision-making regarding anti-epileptics in general. This will require assessment in future updates of the guidelines.

# 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.
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 (108-147). 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 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 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.
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 (156-158). It remains to be seen whether these savings would apply to lowerincome 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 bisphosphonate 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.

# 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 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.
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.

# 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 (159)(160)(161)(162)(163)(164)(165)(166)(167)(168) 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).
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.
This recommendation applies to people who already have painful metastases; it is not a recommendation concerning preventive radiotherapy.
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) (170 -193). 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).
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 radiotherapy 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.

# 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
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. Differences in trial protocols, differences in the measurement of pain outcomes, and significant heterogeneity among trial participants limited opportunities for pooling results using meta-analysis. It would be helpful for the continuous building of evidence if assessment and measurement of pain are standardized in future cancer pain management trials to allow for statistical data synthesis. For example, a validated scale may be endorsed by country associations and recommended for use in clinical practice and research.
The risk of bias was noted to be high across many trials. Future trials should conform to standard RCT methods and investigators should ensure that methodological quality is not compromised during the conduct of the trial. The CONSORT statement provides a useful template for reporting clinical trials (197).
Clinical trial evidence was absent or very limited for the use of several adjuvant therapies, including choice of corticosteroid, and for anticonvulsants and antidepressants, despite these being part of established practice for cancer pain management. Trial research is urgently needed to address the clinical uncertainty apparent in this area.
Trial data may provide supportive data to recommend the practice or, importantly, indicate if there is no benefit, or indeed harm, thus allowing for amendment of current clinical protocols to reduce unnecessary cost and avoid potential harms. Outcomes should include efficacy, safety and pharmaco-economic outcomes. Comparisons should not only be against placebo but also against analgesics and other medicines.
As in many fields, most trials were conducted in high-income settings. Research on cancer pain management should be prioritized in low-and middle-income countries where cancer is increasing significantly. As outlined in the Lancet Commission Report on Palliative Care and Pain Relief, trial investigators may wish to measure serious health-related suffering as an outcome and evaluate an essential, affordable package of palliative care and pain relief interventions (5). The latter may be best assessed by using an implementation science approach and a pragmatic trial study design. Studies are also required on the optimal route of administration for opioids and on the costeffectiveness thereof.
Research on opioids should take account of the ongoing opioid crisis in North America and evaluate the risk for substance misuse in all trials of opioid use across different settings. Evidence-based protocols for opioid cessation should be evaluated in patients 51 7. RESEARCH AGENDA with cancer pain who no longer require pain management in order to better guide cancer pain clinicians in this area.
A global landscape analysis of the effects of restrictive legislation and regulations (including the negative effects of barriers to adequate access to opioids) will be helpful. Such an analysis may include an evaluation of the reasons why, in some countries (e.g. in Europe), opioids are available but have not resulted in an opioid crisis of the scale observed in North America.
The use of cannabinoids was not included as a PICO question in this guidelines process but is currently being widely investigated for both chronic non-cancer and cancerrelated pain; trials and syntheses of current data on cannabinoids for cancer pain are warranted.

# INTERESTS DECLARED BY PERSONS INVOLVED IN GUIDELINE DEVELOPMENT
For full details of these declared interests and GDG and ERG member characteristics, see Annex 4: Background to the development of the guidelines and details of personnel. Of the invited experts who became GDG members, none declared potential conflicts of interest that were deemed to require specific management in GDG meetings or during the guideline development process.

# FUNDING SOURCES
To comply with WHO policy, no commercial entity funding has been used to produce these guidelines. Only WHO core funds have been used in the production of these guidelines.

# ANNEX 1: EVALUATION OF PAIN
Designing optimum analgesia is one of the most fundamental tasks in health care and depends on the evaluation of a patient's pain -including its causes, severity and effects on the patient. However, as a "sensory and emotional experience" that may or may not be associated with tissue damage, evaluation of pain is not always easy (1). No single assessment technique is universally applicable. The evaluation must be based in part on clinical judgement regarding factors such as the underlying conditions, haemodynamic stability, acuity of the conditions and the pain, and previous and current treatments. It must also take into consideration psychosocial factors such as

# PA IN PE RS IS TI N G O R IN C RE AS IN G P A IN P E R S IS T IN G O R IN C R E A S IN G

# BRIEF PAIN INVENTORY
One of the most commonly used tools for assessing pain in adults and adolescents pain scales is the brief pain inventory or BPI (3). The BPI (Figure A1.2) concisely registers pain location and treatments and also measures pain intensity and the effect of pain on activities of daily life. The inventory has been validated in many languages and with both malignant and non-malignant pain.
Date: _ _ _ _ / _ _ _ _ / _ _ _ _ Time: _ _ _ _ _ _ _ Name: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Last First
STUDY ID #:_ _ _ _ _ _ _ _ _ _ DO NOT WRITE ABOVE THIS LINE HOSPITAL #: _ _ _ _ _ _ _ _ _ _ Date: _ _ _ _/ _ _ _ _ / _ _ _ _ Time: _ _ _ _ _ _ _ _ Name: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Last First

# PAIN ASSESSMENT IN ADVANCED DEMENTIA
The Pain Assessment in Advanced Dementia tool (PAINAID, Figure A1.4) is one of several tools developed to assess pain in patients with advanced dementia (5,6). Others include Doloplus-2 ( 7) and the Pain Assessment Checklist for Seniors with Limited Ability to Communicate-II or PACSLAC-II (8).
- 11 196 citations. Additional manual searches for existing systematic reviews were conducted on the Cochrane website and at /.
Independent duplicate screening of citations resulted in preliminary acceptance of 454 primary articles and 41 existing systematic reviews. After full text assessment, 195 randomized controlled trials (RCTs) were considered eligible for one or more of the PICO questions; of these 129 had been included in 19 existing systematic reviews (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). The original plan was to rely fully on the existing systematic reviews for study descriptions, results data and assessment of study methodological quality (risk of bias). However, accessible data from the existing systematic reviews were generally too incomplete or poorly reported to allow this approach; in addition, the systematic review team found many instances of incorrect data or data that they could not find in the original study articles. Therefore, for the vast majority of primary studies from existing systematic reviews, the review team obtained data from the original publications.

# ASSESSMENT OF STUDY QUALITY AND METHODS OF REVIEW SYNTHESIS
The methodological quality of study was assessed with the Cochrane risk of bias tool. However, when existing systematic reviews provided study-level quality ratings, the systematic review team used those, regardless of the quality assessment method used.
For the evidence profiles, the team conducted two additional steps to allow determination of overall risk of bias, consistent with GRADE methodology, as follows (20):
 First, the overall quality of each RCT was determined.
 If a study had a high risk of bias due to inadequate randomization or allocation concealment methodology, the study was deemed to have very serious limitations.  If randomization and allocation concealment methodologies were low risk of bias (or unclear due to inadequate reporting) but the studies did not mask outcome assessors or they had high attrition rates (or a high percentage of study participants not analysed) or there was evidence of selective outcome reporting or there was an important other potential bias, the study was rated overall as having serious limitations.
 However, if the study had two or more of these limitations, it was deemed to have very serious limitations.
 Otherwise, studies were rated as having no serious limitations.
 Studies could have different overall study quality assessments for different outcomes (e.g. if there was high attrition for only one outcome of interest).
 Second, for each outcome within an evidence profile, the risks of bias of all studies were assessed together.
 If more than half the studies (or the larger, dominant studies) were deemed to have very serious limitations, then the overall evidence base was also deemed to have very serious limitations.
 If this was not the case, but more than half the studies (or the larger, dominant studies) were deemed to have serious (or very serious) limitations, then the overall evidence base was deemed to have serious limitations.
 Otherwise the evidence base was deemed to have no serious limitations.
Study findings were assessed for consistency primarily of direction of effect, with lesser emphasis on magnitude of effect and minimal emphasis on differences in statistical significance. When meta-analysis was conducted, the statistical heterogeneity of treatment effect was assessed with the statistical significance of the heterogeneity and the I-squared statistic. However, if the direction of effect was consistent across studies, the heterogeneity of the actual effect size alone did not yield a determination of inconsistent.
Given the strict eligibility criteria, the generalizability of all eligible trials was deemed to be directly applicable to adults (or adolescents) with cancer pain. Studies of nonapplicable populations were not included. Consequently, assessment of indirectness was based primarily on whether the outcomes being assessed were directly relevant to the outcome of interest. The primary reasons for downgrading based on indirectness related to studies that assessed pain outcomes that were not full (or near-full) pain relief but were only a decrease in pain scores (e.g. by 2 points out of 10). Some that included quality-of-life and functional outcome measures were also downgraded if they were deemed to be inadequate measurement tools. Ideally, these indirect outcomes or measures were not included but, where there was limited direct evidence, the systematic review team included them.
The evidence was downgraded for imprecision based mostly on small sample size (for continuous outcomes) with an arbitrary total sample size (across arms and studies) of 300 as a threshold and, separately, wide confidence intervals in relation to the measure (or scale). However, if a small study provided a precise estimate, the evidence was not downgraded.
Other considerations were noted. The main ones were used where there was only a single study evaluating a given outcome for a given question. The accuracy of a single study's estimate of an effect size requires corroboration before it can be considered to be adequate evidence to make a clinical decision with any confidence. If a study is large (i.e. well-powered), rigorously conducted, and the outcome evaluated as a primary outcome, then the study may provide higher strengths of evidence.
Where feasible, the systematic review team conducted meta-analyses of categorical and continuous data when there were at least two trials with the same comparisons. The systematic review team was liberal in what it allowed for meta-analysis, taking account of the nature of the review questions. The review team ignored cancer types or other differences in study populations and differences in follow-up durations. The team combined sets of interventions, such as all bisphosphonates or all opioids; it also ignored differences in doses, routes, strengths and other related factors. For categorical outcomes the review team mostly ignored differences in outcome definitions (such as pain relief being complete  or great. For categorical outcomes, the team calculated or meta-analysed the risk ratio (RR). The direction of the RR was determined by the outcome being assessed (i.e. for "good" outcomes -e.g. pain relief -higher RR favours the intervention over control; for "bad" outcomes -e.g. skeletal-related events (SREs) -lower RR favours the intervention). Absolute differences were based on meta-analysed risk ratios and meta-analysed control rates.
For continuous measures of pain, quality of life and functional outcomes, the systematic review team first converted the reported measures to uniform scales of 0 to 100. Following standard convention, for pain control 100 = worst pain, and for quality of life and functional outcomes 100 = best status. When necessary, reported scales were reversed to ensure uniform directionality. Other continuous outcomes (e.g. time) were meta-analysed only if comparable units could be used across studies (e.g. studies reporting pain relief in hours were not meta-analysed with studies reporting pain relief in days).
Methods for the network meta-analyses for certain systematic review questions are discussed in Annex 7.

# EVIDENCE TO RECOMMENDATIONS: METHODS

# GROUP PROCESSES USED FOR CONSENSUS AND DISAGREEMENT RESOLUTION
At the scoping meeting, the Guideline Development Group (GDG) agreed that Nandi Siegfried would be co-chair for the development of this guideline, and that Eduardo Bruera would be the other co-chair. The GDG convened to determine the direction, strength and wording of the final recommendations. These were established by consensus. Consensus was defined as a position indicated in the group discussion that was summarized for clarification by a chair; if the co-chairs' clarification was not reopened for discussion by a member of the GDG, this was considered unanimous consensus.
In cases where unanimity could not be reached, a majority (>50%) vote by raising of hands (of GDG members only and excluding observers, World Health Organization (WHO) staff and other non-GDG parties) determined the final GDG decision. The GDG were offered the possibility for minority notes to be taken and reflected in the discussion of the recommendation in the final guideline, but all decisions found adequate consensus to render this offer unnecessary.

# ASSESSMENT OF THE DIRECTION AND QUALITY OF EVIDENCE
The GDG was provided with the full results of the systematic reviews in reports prior to the meeting and the results and the accompanying GRADE assessment of the quality of the evidence was presented at the meeting. The GDG discussed the results and agreed on an overall quality of evidence for each intervention using the following definitions of level of evidence quality in accordance with the GRADE methodology:
We are very confident that the true effect lies close to that of the estimate of the effect.
Moderate We are moderately confident in the effect estimate: the true effect is likely to be close to the estimate of the effect but there is a possibility that it is substantially different.
Our confidence in the effect estimate is limited: the true effect may be substantially different from the estimate of the effect.

# Very low
We have very little confidence in the effect estimate: the true effect is likely to be substantially different from the estimate of effect.

# METHODS FOR ASSESSMENT OF VALUES AND PREFERENCES, ACCEPTABILITY, FEASIBILITY AND EQUITY
Values and preferences were considered from the perspectives of patients, clinicians and policy-makers. These perspectives were outlined and discussed by the GDG members who represented all relevant stakeholder groups in addition to having broad professional experience of the field.
The GDG members offered observations from their own experience regarding the acceptability of interventions to health-care workers and the feasibility of implementing recommended interventions, especially in regions where resources are scarce or absent. Similarly, the effect of provision of an intervention on equity was carefully considered in the GDG discussions.
No formal patient or health-care provider surveys were conducted.

# HOW RESOURCES WERE CONSIDERED
Considerations of resource use relied on the International drug price indicator guide (21), a recent peer-reviewed medication pricing publication (22). If prices could not be found in this source, other medication pricing data websites (goodrx.com (23), drugs. com (24) or pharmacychecker.com ( 25)) were used. GDG members also brought their knowledge of medication prices around the world to these discussions. No formal cost-effectiveness studies were conducted.

# DISCUSSION OF RECOMMENDATION STRENGTH AND EVIDENCE QUALITY
Based on the agreed quality of the evidence and with consideration given to the values and preferences of patients, the acceptability and feasibility of the intervention within the health-care system, the potential impact on equity and the resource implications, the GDG decided on the direction of the recommendation (either in favour of or against an intervention) and whether to make strong or conditional recommendations using a benefit-risk assessment analysis of each intervention. In the absence of any evidence for a certain review question, the GDG chose to make no recommendation.

# For policy-makers
The recommendation can be adopted as policy in most situations.
Policy-making will require substantial debate and involvement of various stakeholders.

# PEER REVIEW
The document underwent peer review and comments were incorporated.

# REVIEW AND PLAN FOR UPDATING THESE GUIDELINES
Guidelines will be assessed biennially by reconvening available members of the original steering group in order to decide whether there have been developments that warrant an update of the guidelines. The first of these biennial reviews will be held in 2019. Conference invitations to discuss and present the guidelines will be accepted when possible.
A publication in a peer-reviewed journal articulating novel developments that emerge from the systematic reviews will be considered.
It is intended that the guidelines should be available in all the official languages of WHO, and NGOs in official relations with WHO will be encouraged to support translation of the guidelines through their activity workplans with WHO. Translation into non-United Nations languages and publication in these languages by third parties will be encouraged.

# DERIVATIVE PRODUCTS
It is hoped that these guidelines will be the first step in a series of clinical guidelines on symptom management in palliative care. The guidelines will also add to the growing compendium on pain management guidance. Owners, co-owners and members of advisory boards of pharmaceutical companies were excluded from the External Review Group (ERG) and GDG membership and from participation in other parts of the development process. Board memberships and directorships of professional bodies were evaluated for their potential to be conflicts of interest, as were the funding sources of the bodies. All GDG members were asked to share their curricula vitae, and a brief biography of all potential members was published publicly on the WHO website from June to September 2016. There was a standing agenda item on "Conflicts of Interests" at the beginning of all Guideline Development Group meetings where declared conflicts of interest were presented before the entire GDG. Relevant declared conflicts of interest of GDG members were reported in the guidelines publication, as was the strategy employed to manage conflicts of interest during the meeting. WHO policies on conflicts of interest were fully applied throughout.

# THE IMPORTANCE OF RELIABLE ESTIMATES
WHO and the INCB are working on a joint guide for estimating requirements for substances under international control. This is a particularly important step in the supply cycle of opioid analgesics as it ensures the uninterrupted supply of these essential medicines. Countries introducing or enlarging the coverage of pain relief services will need to forecast adequately the quantities of opioid analgesics that will be increasingly supplied in the health system.
If an annual estimate proves to be inadequate, the competent national authority can submit supplementary estimates to the INCB at any time during the course of the year. However, the competent national authority will be requested to provide an explanation of the circumstances necessitating additional drug quantities. As far as possible, such supplementary estimates should be used only in the case of unforeseen circumstances and for the introduction of new treatments (11).
The market availability of controlled substances is confined to the estimates submitted to the INCB. Hence, it is crucial for managers and other parties concerned with the procurement of strong opioids to be aware of national estimates for the relevant drugs. The Board publishes changes in the estimates received from governments on a monthly basis on the Internet (www.incb.org), or on a quarterly basis in the form of a hard copy technical report sent to governments, as a guide to exporting countries.

# DOMESTIC MANUFACTURE OF STRONG OPIOID ANALGESICS
After a country has received confirmation of its estimates from the INCB, it may start procedures for manufacturing or importing of opioid analgesics under Schedule I. The Single Convention requires governments to license individuals and enterprises involved in the manufacture of opioid medicines. In order to prevent the diversion of these strong opioids to illicit markets, manufacturers must make resources available for recordkeeping and security procedures, as well as for the provision of secure facilities from the moment the raw materials are acquired until the finished products are distributed.
In addition, governments should assure the quality of the manufactured medicines, such as by enforcing Good Manufacturing Practices and the requirement of a market authorization by the national medicines regulatory authority.

# THE REPORTING SYSTEM FOLLOWING EXPORTATION, IMPORTATION AND CONSUMPTION OF OPIOIDS
The competent national authority in the country must send quarterly reports to the INCB of all imports and exports of opioid analgesics classified under Schedule I. It is also mandatory to make an annual inventory and to report the total amount of opioids manufactured, consumed and held in stock at the central level (e.g. licensed central warehouses, manufacturers' warehouses). The annual inventory does not include medicines stored in retail pharmacies, retail distributors or other health services which, for official purposes, are considered to have been consumed. "Stock" is defined in Article 1 of the Single Convention on Narcotic Drugs, 1961, as amended by the 1972 Protocol.

# DISTRIBUTION OF STRONG OPIOIDS
The Single Convention requires countries to ensure that trade and distribution can be performed only by licensed parties. The competent national authority normally provides trade and distribution licences to private companies, either manufacturers or wholesalers. A manufacturer or wholesaler may distribute the finished products directly to licensed pharmacies or hospitals. Wholesalers must also be licensed by the competent national authority and must comply with rules concerning security and recordkeeping. The Single Convention neither requests countries to provide exclusive rights for the storage, distribution and trade of controlled medicines to one single state agency or private company, nor suggests that opioids be managed within a special or separate medicine distribution system.
However, some countries have separated the storage and distribution of controlled medicines from the distribution system for other medicines. They have also established additional requirements to those mandated by the Single Convention. These may sometimes have a negative impact on the accessibility to strong opioids and may increase distribution costs.

# USUAL REQUIREMENTS FOR PRESCRIBING AND DISPENSING OPIOIDS
The Single Convention requires medical prescriptions to prescribe and dispense controlled medicines to individuals. Legal requirements for prescriptions vary from country to country. However, in accordance with most prescription medicines, a prescription for an opioid analgesic should specify the following:
 the name and business address of the prescribing health professional;
 the name of the patient;
 the date of the prescription;  the preparation to be dispensed (e.g. morphine tablet);
 the dose to be dispensed in milligrams (words and numbers);
 the frequency of dispensing (e.g. daily, twice daily); and
 the signature of the prescribing doctor or health professional.
Requirements for duplicate prescriptions and special prescription forms increase the administrative burden both for health-care workers and drug control authorities. The problem is compounded if forms are not readily available, or if health professionals need to pay for them. The conventions allow for duplicate prescriptions and special prescription forms if countries consider them necessary or desirable. Governments should ensure that this system does not impede the availability and accessibility of controlled medicines. No limit is set on the quantity of medicines or the length of the treatment inscribed in a prescription.

# WORLD HEALTH ASSEMBLY RESOLUTION 67.19 (2014) ON STRENGTHENING OF PALLIATIVE CARE AS A COMPONENT OF COMPREHENSIVE CARE THROUGHOUT THE LIFE COURSE
In 2014, the World Health Assembly ( 14):
 Affirmed that access to palliative care and to essential medicines for medical and scientific purposes, manufactured from controlled substances, including opioid analgesics such as morphine, in line with the three United Nations international drug control conventions, contributes to the realization of the right to the enjoyment of the highest attainable standard of health and well-being;
 Noted that the availability and appropriate use of internationally controlled medicines for medical and scientific purposes, particularly for the relief of pain and suffering, remains insufficient in many countries, and highlighted the need for Member States, with the support of the WHO Secretariat, the United Nations Office on Drugs and Crime and the International Narcotics Control Board (INCB), to ensure that efforts to prevent the diversion of narcotic drugs and psychotropic substances under international control pursuant to the United Nations international drug control conventions do not result in inappropriate regulatory barriers to medical access to such medicines;
Manufacturer's recommendation. Because mean oral bio-availability is 50% (range 3560%), some centres use a conversion ratio of 2:1 rather than 3:1.
Because mean oral bio-availability is 80% (range 40-100%), some centres use 1:1, e.g. methadone 30 mg/24h PO p methadone 30 mg/24h SC/IV.
The same conversion ratios as for morphine PO to fentanyl TD can be used for morphine PO to fentanyl SC/IV.
Volume constraints for a syringe driver may prevent doses >500 mcg/24h being used.
The assumption is that morphine SC/IV is twice as potent as PO.

# IV. OPIOID CESSATION
High-quality evidence for opioid tapering protocols is lacking. Opioid tapering should be individualized depending on the clinical situation. For patients who do not have a substance use disorder, Table A6.5 provides a general strategy for opioid tapering when opioid therapy is no longer indicated (10).