• Scottish Intercollegiate Guidelines Network (SIGN). Control of pain in adults with cancer. A national clinical guideline. Edinburgh (Scotland): Scottish Intercollegiate Guidelines Network (SIGN); 2008 Nov. 71 p. (SIGN publication; no. 106). [264 references]

Pain in patients with cancer

Management
Screening
Treatment

Anesthesiology
Family Practice
Internal Medicine
Nursing
Oncology
Pharmacology
Physical Medicine and Rehabilitation
Psychology
Radiology
Surgery

Advanced Practice Nurses
Nurses
Occupational Therapists
Pharmacists
Physical Therapists
Physician Assistants
Physicians
Psychologists/Non-physician Behavioral Health Clinicians

To provide recommendations based on current evidence for best practice in the management of pain in adult patients who have cancer

Note: The guideline includes advice mainly concerning pain secondary to the cancer, but many of the principles outlined are applicable to coexisting painful conditions and pain secondary to treatment of the cancer.

Patients aged 12 and over with pain due to cancer

Note: This guideline excludes the treatment of pain in children under the age of 12.

1. Patient issues
   • Effective communication
   • Multidisciplinary approach to care that includes spiritual, psychological and emotional impact of pain
   • Patient education and support
2. Psychosocial issues
   • Routine screening for psychological distress
   • Cognitive behavior therapy (CBT)
   • Biopsychosocial approach that addresses patient adherence
3. Assessment of pain
   • Clinical history and physical examination
   • Pain assessment tools (e.g., McGill Pain Questionnaire, Brief Pain Inventory, self-assessment and observational pain scales)
4. Principles of pain management
   • World Health Organization (WHO) cancer pain relief program
   • WHO analgesic ladder
5. Treatment with non-opioid drugs
   • Paracetamol and/or non-steroidal anti-inflammatory drugs (NSAIDs)
   • Bisphosphonates
   • Antidepressants
   • Anticonvulsants
   • Other analgesics
6. Treatment with opioid drugs
   • Choice of opioid (e.g., morphine or diamorphine)
   • Administration of opioid (e.g., orally, continuous subcutaneous infusion, transdermal administration)
7. Non-pharmacological treatment
   • Radiotherapy
   • Cementoplasty
   • Anaesthetic interventions
   • Complementary therapies (considered but not recommended)

• Pain control
• Development of further pain
• Functional ability
• Quality of life
• Adverse effects of treatment

Searches of Electronic Databases

Not stated

Weighting According to a Rating Scheme (Scheme Given)

Levels of Evidence

1++: High quality meta-analyses, systematic reviews of randomised controlled trials (RCTs), or RCTs with a very low risk of bias

1+: Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias

1-: Meta-analyses, systematic reviews, or RCTs with a high risk of bias

2++: High quality systematic reviews of case control or cohort studies

High quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal

2+: Well-conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal

2-: Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal

3: Non-analytic studies (e.g., case reports, case series)

4: Expert opinion

Systematic Review with Evidence Tables

Expert Consensus

Grades of Recommendation

Note: The grade of recommendation relates to the strength of the evidence on which the recommendation is based. It does not reflect the clinical importance of the recommendation.

A: At least one meta-analysis, systematic review, or randomized controlled trial (RCT) rated as 1++ and directly applicable to the target population; or

A body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results

B: A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or

Extrapolated evidence from studies rated as 1++ or 1+

C: A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or

Extrapolated evidence from studies rated as 2++

D: Evidence level 3 or 4; or

Extrapolated evidence from studies rated as 2+

Good Practice Points: Recommended best practice based on the clinical experience of the guideline development group

A formal cost analysis was not performed and published cost analyses were not reviewed.

External Peer Review
Internal Peer Review

The national open meeting is the main consultative phase of Scottish Intercollegiate Guidelines Network (SIGN) guideline development, at which the guideline development group presents its draft recommendations for the first time. The national open meeting for this guideline was held on 23 April 2007 and was attended by 203 representatives of all the key specialties relevant to the guideline. The draft guideline was also available on the SIGN website for a limited period at this stage to allow those unable to attend the meeting to contribute to the development of the guideline.

Peer Review

All SIGN guidelines are reviewed in draft form by independent expert referees, who are asked to comment primarily on the comprehensiveness and accuracy of interpretation of the evidence base supporting the recommendations in the guideline. A number of general practitioners (GPs) and other primary care practitioners also provide comments on the guideline from the primary care perspective, concentrating particularly on the clarity of the recommendations and their assessment of the usefulness of the guideline as a working tool for the primary care team. The draft is also sent to a lay reviewer in order to obtain comments from the patient's perspective. The comments received from peer reviewers and others are carefully tabulated and discussed with the chairman and with the guideline development group. Each point must be addressed and any changes to the guideline as a result noted or, if no change is made, the reasons for this recorded.

As a final quality control check prior to publication, the guideline and the summary of peer reviewers' comments are reviewed by the SIGN Editorial Group for that guideline to ensure that each point has been addressed adequately and that any risk of bias in the guideline development process as a whole has been minimised. Each member of the guideline development group is then asked formally to approve the final guideline for publication.

Note from the Scottish Intercollegiate Guidelines Network (SIGN) and National Guideline Clearinghouse (NGC): In addition to these evidence-based recommendations, the guideline development group also identifies points of best clinical practice in the full-text guideline document.

The grades of recommendations (A–D) and levels of evidence (1++, 1+, 1-, 2++, 2+, 2-, 3, 4) are defined at the end of the "Major Recommendations" field.

Psychosocial Issues

Psychological Distress

B - Comprehensive chronic pain assessment should include routine screening for psychological distress.

A - Cognitive behaviour therapy should be considered as part of a comprehensive treatment programme for those with cancer related pain and resulting distress and disability.

Psychological Factors and Adherence to Treatment

D - Patient beliefs concerning pain should be assessed and discussed as part of a comprehensive, biopsychosocial cancer pain assessment.

C - Patients should receive education about the range of pain control interventions available to them.

Assessment of Pain

What is Pain?

For the purposes of this guideline, pain has been defined as "an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage."

A comprehensive assessment of pain should consider the following domains:

• Physical effects/manifestations of pain
• Functional effects (interference with activities of daily living)
• Psychological factors (level of anxiety, cultural influences, fears, effects on interpersonal relationships, factors affecting pain tolerance, (see Table below)
• Spiritual aspects

Table. Factors Affecting Pain Tolerance

Adapted from Twycross R, Lack S. Symptom control in far advanced cancer: pain relief London: Pitman; 1983.

Why Assess Pain?

D - Prior to treatment an accurate assessment should be performed to determine the cause, type and severity of pain, and its effect on the patient.

Who Should Assess Pain?

D - The patient should be the prime assessor of his or her pain.

How Should Pain Be Assessed?

D - Patients with cancer pain should have treatment outcomes monitored regularly using visual analogue scales, numerical rating scales or verbal rating scales.

C - Self assessment pain scales should be used in patients with cognitive impairment, where feasible.

C - Observational pain rating scales should be used in patients who cannot complete a self assessment scale.

Principles of Pain Management

B - Patients should be given information and instruction about pain and pain management and be encouraged to take an active role in their pain management.

World Health Organization (WHO) Cancer Pain Relief Programme

D - The principles of treatment outlined in the WHO cancer pain relief programme should be followed when treating pain in patients with cancer.

Using the WHO Analgesic Ladder

B - A patient's treatment should start at the step of the WHO analgesic ladder appropriate for the severity of the pain.

B - Prescribing of analgesia should always be adjusted as the pain severity alters.

D - Analgesia for continuous pain should be prescribed on a regular basis, not 'as required'.

D - Appropriate analgesia for breakthrough pain must be prescribed.

Treatment with Non-Opioid Drugs

Paracetamol and Non-Steroidal Anti-Inflammatory Drugs

A - Patients at all stages of the WHO analgesic ladder should be prescribed paracetamol and/or a non-steroidal anti-inflammatory drug unless contraindicated.

A - Patients taking non-steroidal anti-inflammatory drugs who are at high risk of gastrointestinal complications should be prescribed either misoprostol 800 mcg/day, standard dose proton pump inhibitors or double dose histamine-2 receptor antagonists as pharmacological prophylaxis.

Bisphosphonates

B - Bisphosphonates should be considered as part of the therapeutic regimen for the treatment of pain in patients with metastatic bone disease.

Antidepressants and Anticonvulsants

A - Patients with neuropathic pain should be given either a tricyclic antidepressant (e.g., amitriptyline or imipramine) or anticonvulsant (e.g., gabapentin, carbamazepine or phenytoin) with careful monitoring of side effects.

Cannabinoids

A - Cannabinoids are not recommended for the treatment of cancer pain.

Treatment with Opioid Drugs

Choice of Opioid

Mild to Moderate Pain (Step 2 of the WHO Ladder)

D - For mild to moderate pain, (score 3-6 out of 10 on a visual analogue scale or a numerical rating scale) weak opioids such as codeine should be given in combination with a non-opioid analgesic.

Moderate to Severe Pain (Step 3 of the WHO Ladder)

D - Oral morphine is recommended as first line therapy to treat severe pain in patients with cancer.

D - Diamorphine is recommended as first line subcutaneous therapy to treat severe pain in patients with cancer.

Breakthrough Pain

D - Patients with moderate or severe breakthrough pain should receive breakthrough analgesia.

D - When using oral morphine for breakthrough pain the dose should be one sixth of the around the clock morphine dose and should be increased appropriately whenever the around the clock dose is increased.

Patients with Renal Impairment

C - In the presence of reduced kidney function all opioids should be used with caution and at reduced doses and/or frequency.

Administration of Opioids

D - Continuous subcutaneous infusion of opioids is simpler to administer and equally as effective as continuous intravenous infusion and should be considered for patients unable to take opioids orally.

D - Advice on stability of commonly used drug combinations for continuous subcutaneous infusion should be available to staff who prepare these infusions.

D - Advice on the use of other combinations should be taken from palliative care specialists.

D - Patients with stable pain on oral morphine should be prescribed a once or twice daily modified release preparation.

D - Patients with stable pain on oral oxycodone should be prescribed a twice daily modified release preparation.

Non-Pharmacological Treatment

Radiotherapy for Relieving Pain in Patients with Bone Metastases

B - All patients with pain from bone metastases which is proving difficult to control by pharmacological means should be referred to a clinical oncologist for consideration of external beam radiotherapy or radioisotope treatment.

Cementoplasty

D - Patients with bone pain from malignant vertebral collapse proving difficult to control by pharmacological means should be referred for consideration of vertebroplasty where this technique is available.

D - Patients with bone pain from pelvic bone metastases proving difficult to control by pharmacological means and reduced mobility should be considered for percutaneous cementoplasty.

Anaesthetic Interventions

B - Interventions such as coeliac plexus block and neuraxial opioids should be considered to improve pain control and quality of life in patients with difficult to control cancer pain.

Definitions:

Levels of Evidence

1++: High quality meta-analyses, systematic reviews of randomised controlled trials (RCTs), or RCTs with a very low risk of bias

1+: Well-conducted meta-analyses, systematic reviews, or RCTs with a low risk of bias

1-: Meta-analyses, systematic reviews, or RCTs with a high risk of bias

2++: High quality systematic reviews of case control or cohort studies

High quality case control or cohort studies with a very low risk of confounding or bias and a high probability that the relationship is causal

2+: Well-conducted case control or cohort studies with a low risk of confounding or bias and a moderate probability that the relationship is causal

2-: Case control or cohort studies with a high risk of confounding or bias and a significant risk that the relationship is not causal

3: Non-analytic studies (e.g., case reports, case series)

4: Expert opinion

Grades of Recommendation

Note: The grade of recommendation relates to the strength of the evidence on which the recommendation is based. It does not reflect the clinical importance of the recommendation.

A: At least one meta-analysis, systematic review, or RCT rated as 1++ and directly applicable to the target population; or

A body of evidence consisting principally of studies rated as 1+, directly applicable to the target population, and demonstrating overall consistency of results

B: A body of evidence including studies rated as 2++, directly applicable to the target population, and demonstrating overall consistency of results; or

Extrapolated evidence from studies rated as 1++ or 1+

C: A body of evidence including studies rated as 2+, directly applicable to the target population and demonstrating overall consistency of results; or

Extrapolated evidence from studies rated as 2++

D: Evidence level 3 or 4; or

Extrapolated evidence from studies rated as 2+

Good Practice Points: Recommended best practice based on the clinical experience of the guideline development group

None provided

The specific type of supporting evidence is explicitly identified in each section of the guideline.

Appropriate management of pain in adult patients who have cancer leading to improvement in functional ability and quality of life

Non-steroidal Anti-inflammatory Drugs (NSAIDs)

• The most common serious adverse effects of NSAIDs are due to ulceration of the gastrointestinal (GI) tract. The following have been shown to increase the risk of upper GI toxicity when NSAIDs are prescribed:
  • Increasing age (>65 years)
  • Previous peptic ulcer disease, particularly if complicated with haemorrhage or perforation
  • Comorbid medical illness
  • Smoking
  • Type of NSAID (e.g., ketoprofen, ketorolac and piroxicam are associated with a high risk of serious gastrointestinal toxicity relative to other NSAIDs)
  • Increasing NSAID dose
  • Use of multiple NSAIDs
  • Combined use of NSAIDs and other drugs which could increase the risk of ulceration or bleeding such as corticosteroids, anticoagulants (e.g., warfarin), selective serotonin-reuptake inhibitors or antiplatelet agents (e.g., aspirin)
  • Existing renal, cardiac or hepatic impairment.
• Cyclooxygenase-2 (COX-2) selective inhibitors (e.g., celecoxib, etoricoxib, lumiracoxib and parecoxib) can cause serious, and sometimes fatal GI reactions. Randomised controlled trials have shown that COX-2 selective inhibitors demonstrate an increased risk of thrombotic cardiovascular adverse reactions, particularly myocardial infarction (MI) and stroke.

Bisphosphonates

Osteonecrosis of the jaw (ONJ) is a complication occurring in patients treated with bisphosphonates, especially the aminobisphosphonates. The most significant predisposing factors were found to be:

• Use of aminobisphosphonates with increasing risk over time of exposure and higher doses
• History of trauma, dental surgery, or dental infection. Sixty percent had some form of dento-alveolar surgery resulting in non-healing of the surgical site and necrosis of the bone.

Opioids

• Use of the WHO analgesic ladder has been shown to be effective in managing pain in about three quarters of patients with cancer. Despite dose titration and appropriate management of predictable side effects, a minority of patients at step 3 of the WHO ladder have inadequate pain relief, persistent unacceptable side effects, or a combination of the two. There is an increasing tendency in clinical practice to switch between opioids but the rationale for this in individual patients is not always clear, appropriate or well documented.
• Individuals with renal impairment are at an increased risk for opioid toxicity. In patients with poor or deteriorating kidney function, the following are of considerable importance to prevent or manage toxicity:
  • Choice of opioid
  • Consideration of dose reduction and/or an increase in the dosage interval
  • Change from modified release to an immediate release oral formulation
  • Frequent clinical monitoring and review

  See the original guideline document for information on toxicity specific to the opioid being considered.

Antidepressants and Anticonvulsants

Some patients experience adverse effects.

All cyclooxygenase-2 (COX-2) selective inhibitors are contraindicated for patients with established ischaemic heart disease, peripheral arterial disease or cerebrovascular disease.

• This guideline is not intended to be construed or to serve as a standard of care. Standards of care are determined on the basis of all clinical data available for an individual case and are subject to change as scientific knowledge and technology advance and patterns of care evolve. Adherence to guideline recommendations will not ensure a successful outcome in every case, nor should they be construed as including all proper methods of care or excluding other acceptable methods of care aimed at the same results. The ultimate judgement must be made by the appropriate healthcare professional(s) responsible for clinical decisions regarding a particular clinical procedure or treatment plan. This judgement should only be arrived at following discussion of the options with the patient, covering the diagnostic and treatment choices available. It is advised, however, that significant departures from the national guideline or any local guidelines derived from it should be fully documented in the patient's case notes at the time the relevant decision is taken.
• The extent of risk for osteonecrosis of the jaw (ONJ) in patients taking oral bisphosphonates has not been determined. There are no data available to suggest that discontinuation of bisphosphonates for patients requiring invasive dental treatment reduces the risk of osteonecrosis of the jaw. The clinical judgement of the treating clinician should guide the management plan based on the individual risks/benefits for the patient.

Implementation of national clinical guidelines is the responsibility of local National Health Service (NHS) Board and is an essential part of clinical governance. Mechanisms should be in place to review care provided against the guideline recommendations. The reasons for any differences should be assessed and addressed where appropriate. Local arrangements may then be made to implement the national guideline in individual hospitals, units and practices.

Key points for audit are included in the original guideline document.

End of Life Care
Living with Illness

Effectiveness
Patient-centeredness

• Scottish Intercollegiate Guidelines Network (SIGN). Control of pain in adults with cancer. A national clinical guideline. Edinburgh (Scotland): Scottish Intercollegiate Guidelines Network (SIGN); 2008 Nov. 71 p. (SIGN publication; no. 106). [264 references]

Not applicable: The guideline was not adapted from another source.

2000 Jun (revised 2008 Nov)

Scottish Intercollegiate Guidelines Network - National Government Agency [Non-U.S.]

Scottish Executive Health Department

Not stated

Guideline Development Group: Professor John Welsh, Professor of Palliative Medicine, (Chair) Beatson Oncology Centre, Glasgow; Dr Esther Murray, Consultant Clinical Psychologist in Psychosocial Oncology, Ayrshire Central Hospital; Dr Lesley Colvin, Consultant Anaesthetist, Western General Hospital, Edinburgh; Ms Marguerite Connolly, District Nursing Sister, NHS Grampian; Dr Paul Cormie, MacMillan Lead General Practitioner (Cancer and Palliative Care), NHS Borders; Dr David Craig, Consultant Clinical Psychologist, Southern General Hospital, Glasgow; Dr John Currie, Consultant Anaesthetist, Royal Hospital for Sick Children, Glasgow; Professor Marie Fallon, St Columba's Hospice Chair of Palliative Medicine, Institute of Genetics and Molecular Medicine, Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh; Dr Graeme Giles, Consultant in Palliative Medicine, Strathcarron Hospice, Denny; Mr Adam Gillespie, Lay Representative, Glasgow; Reverend Tom Gordon, Chaplain, Marie Curie Hospice, Edinburgh; Mr Robin Harbour, Quality and Information Director, SIGN; Dr Derek Jones, Lecturer in Occupational Therapy, Queen Margaret University, Edinburgh; Ms Linda Kerr, Clinical Nurse Specialist in Palliative Care, Ayr Hospital; Ms Alison MacRobbie, Palliative/Community Care Pharmacist, NHS Highland; Ms Jane Mair, Community Cancer Support Nurse, Inverurie; Dr Moray Nairn, Programme Manager, SIGN; Dr Kathleen Sherry, Consultant in Palliative Medicine, The Ayrshire Hospice, Ayr; Ms Janet Trundle, Macmillan Specialist Pharmacist in Palliative Care, NHS Greater Glasgow and Clyde; Ms Gillian Wilson, Lay Representative, Dunbar

All members of the guideline development group made declarations of interest and further details of these are available on request from the Scottish Intercollegiate Guidelines Network (SIGN) Executive.

This summary was completed by ECRI on January 3, 2002. The information was verified by the guideline developer as of February 4, 2002. This summary was updated on May 3, 2005 following the withdrawal of Bextra (valdecoxib) from the market and the release of heightened warnings for Celebrex (celecoxib) and other nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). This summary was updated by ECRI on May 20, 2005, following the U.S. Food and Drug Administration advisory on Aredia (pamidronate disodium) and Zometa (zoledronic acid). This summary was updated by ECRI on June 16, 2005, following the U.S. Food and Drug Administration advisory on COX-2 selective and non-selective non-steroidal anti-inflammatory drugs (NSAIDs). This summary was updated by ECRI Institute on January 29, 2009. The updated information was verified by the guideline developer on February 4, 2009. This summary was updated by ECRI Institute on May 1, 2009 following the U.S. Food and Drug Administration advisory on antiepileptic drugs.