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Chronic and refractory pain: a systematic review of pharmacologic management in oncology.

Brant JM, Keller L, McLeod K, Yeh C, Eaton LH. Chronic and refractory pain: a systematic review of pharmacologic management in oncology. Clin J Oncol Nurs. 2017 Jun 1;21(3):31-53. PubMed External Web Site Policy

View the original guideline documentation External Web Site Policy

This is the current release of the guideline.

This guideline updates a previous version: Aiello-Laws L, Reynolds J, Deizer N, Peterson M, Ameringer S, Bakitas M. Putting evidence into practice: what are the pharmacologic interventions for nociceptive and neuropathic cancer pain in adults. Clin J Oncol Nurs. 2009 Dec;13(6):649-55. [55 references]

This guideline meets NGC's 2013 (revised) inclusion criteria.

UMLS Concepts (what is this?)

SNOMEDCT_US
Abiraterone (699678007), Administration of substance via transdermal route (431224009), Anesthetic (373266007), Anesthetic (5776009), Antidepressant (36236003), Antidepressant (372720008), Buprenorphine (31684002), Buprenorphine (387173000), Cancer pain and symptom management (413742003), Cannabinoid (421921003), Cannabis (22924007), Chronic pain (82423001), Drug therapy (416608005), Duloxetine (407032004), Duloxetine (407033009), Fentanyl (373492002), Fentanyl (40648001), Gabapentin (108402001), Gabapentin (386845007), Intramuscular injection (76601001), Local anesthetic (27548001), Local anesthetic (373477003), Medical oncology (394593009), Methadone (387286002), Methadone (51758009), Naloxone (372890007), Naloxone (89018006), Neoplasm (108369006), Non-steroidal anti-inflammatory agent (16403005), Non-steroidal anti-inflammatory agent (372665008), Oxycodone (414984009), Oxycodone (55452001), Pain (22253000), Pain management (278414003), Radioactive isotope (89457008), Radiopharmaceuticals (349358000), Tapentadol (441757005), Tapentadol (442004000), Topical local anesthetic (386760001), Tramadol (108507005), Tramadol (386858008)
UMD

National Guideline Clearinghouse (NGC) has assessed this guideline's adherence to standards of trustworthiness, derived from the Institute of Medicine's report Clinical Practice Guidelines We Can Trust External Web Site Policy.

NEATS Assessment More about NGC's appraisal Standard of Trustworthiness
No Disclosure of Guideline Funding Source
Good Disclosure and Management of Financial Conflict of Interests
Guideline Development Group Composition
Yes Multidisciplinary Group
Yes Methodologist Involvement
Poor Patient and Public Perspectives
Use of a Systematic Review of Evidence
Very Good Search Strategy
Excellent Study Selection
Excellent Synthesis of Evidence
Evidence Foundations for and Rating Strength of Recommendations
Good Grading the Quality or Strength of Evidence
Very Good Benefits and Harms of Recommendations
Excellent Evidence Summary Supporting Recommendations
Very Good Rating the Strength of Recommendations
Poor Specific and Unambiguous Articulation of Recommendations
Poor External Review
Fair Updating

Major Recommendations

Note from the National Guideline Clearinghouse (NGC): Refer to the original guideline document for full dosages, references, and other essential information about the evidence. The recommendation ratings (Recommended for Practice, Likely To Be Effective, Effectiveness Not Established, Effectiveness Unlikely, Not Recommended for Practice, Expert Opinion) are defined at the end of the "Major Recommendations" field.

See also the NGC summaries of the related Oncology Nursing Society (ONS) guidelines on cancer-related pain:

Chronic Pain

Recommended for Practice

  • Methadone
  • Extended- and sustained-release opioids
  • Transdermal fentanyl
  • Buprenorphine
  • Oxycodone and naloxone
  • Tramadol and tapentadol
  • Anesthetics
  • Bone-modifying agents
  • Gabapentin combinations
  • Nonsteroidal anti-inflammatory drugs

Likely to Be Effective

  • Early opioid use
  • Abiraterone
  • Antidepressants
  • Duloxetine
  • Cannabis/cannabinoids
  • Radiopharmaceuticals

Effectiveness Not Established

  • Once-daily fentanyl patch
  • Low-dose methadone
  • Acetaminophen
  • Caffeine
  • Corticosteroids
  • Flurbiprofen
  • Herbal medicine
  • Topical anesthetic (lidocaine patch)
  • Memantine
  • Omega-3 fatty acids
  • Pregabalin
  • Tanezumab

Effectiveness Unlikely

Calcitonin

Refractory Pain

Recommended for Practice

Intraspinal analgesia

Benefits Balanced with Harms

Ketamine

Effectiveness Not Established

  • Systemic administration of anesthetic agents
  • Intrathecal dexmedetomidine
  • Dimethyl sulfoxide and sodium bicarbonate
  • KRN5500
  • Pregabalin and antidepressant combination
  • Ziconotide
  • Opioid switching or rotation

Definitions

Recommended for Practice

Interventions for which effectiveness has been demonstrated by strong evidence from rigorously designed studies, meta-analysis, or systematic reviews, and for which expectation of harms is small compared to the benefits

Likely To Be Effective

Interventions for which effectiveness has been demonstrated from a single rigorously designed conducted controlled trial, consistent supportive evidence from well-designed controlled trials using small samples, or guidelines developed from evidence and supported by expert opinion

Benefits Balanced With Harm

Interventions for which clinicians and patients should weigh the beneficial and harmful effects according to individual circumstances and priorities

Effectiveness Not Established

Interventions for insufficient or conflicting data or data of inadequate quality currently exist, with no clear indication of harm

Effectiveness Unlikely

Interventions for which lack of effectiveness has been demonstrated by negative evidence from a single rigorously conducted controlled trial, consistent negative evidence from well-designed controlled trials using small samples, or guidelines developed from evidence and supported by expert opinion

Not Recommended for Practice

Interventions for which lack of effectiveness or harmfulness has been demonstrated by strong evidence from rigorously conducted studies, meta-analyses, or systematic reviews, or interventions where the costs, burden, or harm associated with the intervention exceed anticipated benefit

Expert Opinion

Low-risk interventions that are consistent with sound clinical practice, suggested by an expert in a peer reviewed publication, and for which limited evidence exists (an expert is an individual who has published peer reviewed material in the domain of interest.)

For further information, see the "Decision rules for summative evaluation of a body of evidence" document (see the "Availability of Companion Documents" field).

Clinical Algorithm(s)

None provided

Disease/Condition(s)

Cancer-related chronic and refractory pain

Guideline Category

Management

Treatment

Clinical Specialty

Nursing

Oncology

Intended Users

Advanced Practice Nurses

Nurses

Guideline Objective(s)

To synthesize evidence-based pharmacologic interventions for the management of chronic and refractory cancer pain

Target Population

Patients with cancer-related chronic and refractory pain

Interventions and Practices Considered

  1. Methadone
  2. Extended- and sustained-release opioids
  3. Transdermal fentanyl
  4. Buprenorphine
  5. Oxycodone and naloxone
  6. Tramadol and tapentadol
  7. Anesthetics
  8. Bone-modifying agents
  9. Gabapentin combinations
  10. Nonsteroidal anti-inflammatory drugs
  11. Early opioid use
  12. Abiraterone
  13. Antidepressants
  14. Duloxetine
  15. Cannabis/cannabinoids
  16. Radiopharmaceuticals
  17. Intraspinal analgesia

Note:

  • The following was considered for refractory pain but benefits are balanced with harm: ketamine.
  • The following was considered for chronic pain but effectiveness is unlikely: calcitonin.
  • The following were considered but effectiveness is not established: for chronic pain: acetaminophen, corticosteroids, flurbiprofen, herbal medicine, low-dose methadone, memantine, omega 3 fatty acids, once daily fentanyl patch, pregabalin, tanezumab, topical anesthetics (lidocaine patch); for refractory pain: systemic anesthetics, dimethyl sulfoxide and sodium bicarbonate, intrathecal dexmedetomidine, KRN5500, opioid switching or rotation, pregabalin and antidepressant combination, ziconotide.

Major Outcomes Considered

  • Pain intensity/relief
  • Quality of life
  • Side effects of pharmacologic agents

Methods Used to Collect/Select the Evidence

Searches of Electronic Databases

Description of Methods Used to Collect/Select the Evidence

A thorough search of PubMed and CINAHL® from January 1, 2009 to July 31, 2016 was conducted.

The Oncology Nursing Society (ONS) Putting Evidence Into Practice (PEP) program conducted a literature search for pain prior to 2009. Thirty-four articles from the previous search were included in the cancer-related pain guidelines. These articles were subject to the same inclusion and exclusion criteria as the articles for the new search.

Research studies published from January 2005 to June 2016 are included in the review.

Pain Topic Search Strategy

The following strategy was used across all four pain guidelines (see the "Major Recommendations" field).

Databases Used

PubMed

(pain[ti] AND cancer[ti]) OR ((pain[ti] OR pain[majr]) AND neoplasms[majr]) AND (("2009/01/01"[PDAT] : "2016/07/31"[PDAT]) AND "humans"[MeSH Terms] AND English[lang] AND cancer[sb])

CINAHL®

  • (MH "Cancer Pain" OR (TI cancer AND TI pain)) OR ( MM pain AND (cancer OR neoplasms OR oncolog*))
  • Limiters: English language; clinical queries: therapy–high sensitivity, therapy–high specificity, therapy–best balance

Inclusion Criteria

  • Full research report, systematic review, guideline, or meta-analysis
  • Study must report results of measurement of pain, including acute, chronic, breakthrough, or refractory pain.
  • The study examines a pharmacologic or nonpharmacologic intervention aimed at affecting pain.
  • Sample must include patients with cancer.
  • Include pediatric and/or adult studies
  • Studies aimed at treatment of pain (may include other symptoms) rather than treatment of the cancer
  • Sample size of at least 40, or 20 per study group
  • For complex interventions, the description of the intervention must be sufficient to identify the components of that intervention.

Exclusion Criteria

  • Gray literature
  • Descriptive study
  • Studies involving the use of standard short-acting or sustained or extended-release opioids (Only studies involving new formulations or unusual use of these medications will be included.)
  • Studies involving examination of effects of different types of surgical anesthesia
  • Studies involving surgical procedures as the primary intervention

Number of Source Documents

One hundred eighty-four studies were included in the review for pharmacologic management of chronic and refractory cancer pain.

Methods Used to Assess the Quality and Strength of the Evidence

Expert Consensus (Committee)

Weighting According to a Rating Scheme (Scheme Given)

Rating Scheme for the Strength of the Evidence

Panels of advanced practice nurses, staff nurses, and doctorally-prepared nurse researchers reviewed the literature base in the identified outcome areas. Professional health services librarians assisted in the conduct of the literature searches. Based on their analysis, the panels then formulated a judgment about the body of evidence related to the intervention under consideration. Three major components were considered by the panels in classifying the collective evidence into one of six Weight of Evidence categories (see the "Rating Scheme for the Strength of the Recommendations" field):

  • Quality of the data, with more weight assigned to levels of evidence higher in the PRISM categorization (such as randomized trials and meta-analyses)
  • Magnitude of the outcome (e.g., effect size or minimal clinically important difference)
  • Concurrence among the evidence (based on the premise that an investigator has less confidence in findings in which the lines of evidence contradict one another)

Methods Used to Analyze the Evidence

Review of Published Meta-Analyses

Systematic Review with Evidence Tables

Description of the Methods Used to Analyze the Evidence

The Oncology Nursing Society (ONS) information resources supervisor thoroughly searched the literature according to the strategy and search terms shown in the "Description of Methods Used to Collect/Select the Evidence" field. Studies that met inclusion criteria were assigned to pairs of pain Putting Evidence Into Practice (PEP) team members, who reviewed and summarized included articles using a standard form. Each article was reviewed by one pain PEP team member and then peer-reviewed by the second pain PEP team member. The form included information about the purpose of the study and a brief description of the intervention, sample size and characteristics, study design, measurement instruments, conclusions, limitations that show risk of bias and threats to validity in design, and implications for nursing practice.

Methods Used to Formulate the Recommendations

Expert Consensus

Description of Methods Used to Formulate the Recommendations

The Putting Evidence Into Practice (PEP) program is a multifaceted project that involves the coordination of Oncology Nursing Society (ONS) staff as well as volunteer team contributors. PEP topic teams are comprised of volunteer nurse researchers, advanced practice nurses, and staff nurses who have demonstrated experience and interest in a PEP topic. Topic leaders are nurse scientists or advanced practice nurses with demonstrated expertise in the topic through research and/or publications.

PEP team members applied the ONS PEP classification scheme (see the "Rating Scheme for the Recommendations" field) to individual interventions via Web-based meetings occurring about every six months. PEP team members included nurse scientists, advanced practice nurses, and staff nurses. Classification considers all previous as well as new evidence for each intervention. Conferences are facilitated by ONS research staff and classification of individual interventions is determined by team consensus.

Teams categorize interventions based on the ONS PEP weight-of-evidence classification schema. The schema is intended to be used with existing research-based knowledge on health interventions and is based on previous research. PEP teams consider the entire body of evidence rather than a single study for classification, and more weight is given to studies that rank higher in ONS's priority symptom management project categorization. Team members also consider the magnitude of the outcome and the concurrence of the evidence for an intervention prior to assigning a classification. Interventions are classified by team consensus after application of the schema.

Rating Scheme for the Strength of the Recommendations

Recommended for Practice

Interventions for which effectiveness has been demonstrated by strong evidence from rigorously designed studies, meta-analysis, or systematic reviews, and for which expectation of harms is small compared to the benefits

Likely To Be Effective

Interventions for which effectiveness has been demonstrated from a single rigorously designed conducted controlled trial, consistent supportive evidence from well-designed controlled trials using small samples, or guidelines developed from evidence and supported by expert opinion

Benefits Balanced With Harm

Interventions for which clinicians and patients should weigh the beneficial and harmful effects according to individual circumstances and priorities

Effectiveness Not Established

Interventions for insufficient or conflicting data or data of inadequate quality currently exist, with no clear indication of harm

Effectiveness Unlikely

Interventions for which lack of effectiveness has been demonstrated by negative evidence from a single rigorously conducted controlled trial, consistent negative evidence from well-designed controlled trials using small samples, or guidelines developed from evidence and supported by expert opinion

Not Recommended for Practice

Interventions for which lack of effectiveness or harmfulness has been demonstrated by strong evidence from rigorously conducted studies, meta-analyses, or systematic reviews, or interventions where the costs, burden, or harm associated with the intervention exceed anticipated benefit

Expert Opinion

Low-risk interventions that are consistent with sound clinical practice, suggested by an expert in a peer reviewed publication, and for which limited evidence exists (an expert is an individual who has published peer reviewed material in the domain of interest.)

For further information, see the "Decision rules for summative evaluation of a body of evidence" document (see the "Availability of Companion Documents" field).

Cost Analysis

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

Method of Guideline Validation

External Peer Review

Description of Method of Guideline Validation

The article has been reviewed by independent peer reviewers to ensure that it is objective and free from bias.

Type of Evidence Supporting the Recommendations

The type of supporting evidence is identified for each recommendation (see the original guideline document).

Potential Benefits

  • Buprenorphine may be useful in patients with opioid use disorders and in those with neuropathic pain syndromes.
  • Oxycodone and naloxone can be combined to decrease the risk of constipation in patients taking opioids. Two observational studies, four randomized controlled trials (RCTs), and one systematic review of 18 studies reported comparable or better pain control with the oxycodone and naloxone combination. A reduction in laxative use and improved bowel function were also noted.
  • Two descriptive studies with about 300 patients noted a decrease in pain intensity and improved quality of life when controlled-release oxycodone was employed early.
  • One double-blind, placebo-controlled RCT reported that abiraterone in combination with prednisone (Deltasone®, Rayos®, Sterapred®, Prednicot®) resulted in a longer reduction of pain and longer time to skeletal-related events
  • Studies show less constipation in patients using transdermal (TD) fentanyl.
  • An open-label study found that tetrahydrocannabinol (THC) oral spray improved pain severity, sleep, and fatigue.
  • Four observational trials found significant reductions in pain intensity with intraspinal analgesia. One prospective trial with long-term follow-up found that patients had a significant reduction in pain intensity at hospital discharge and for as long as six months, as well as a reduction in systematic opioid intake.

Potential Harms

  • Only experienced clinicians should prescribe methadone because of its long half-life and potential for oversedation. Codeine is widely available worldwide, and evidence supports its use for cancer pain compared to placebo, but nausea, vomiting, and constipation are common side effects. Clinicians should also be aware that about 10% of the population is unable to metabolize codeine in its active form, resulting in ineffective analgesia.
  • Administration of nonsteroidal anti-inflammatory drugs (NSAIDs) should be balanced with risks of toxicity, including renal, gastrointestinal, or cardiac toxicities, as well as thrombocytopenia and bleeding disorders.
  • In studies of radiopharmaceuticals, acute pain flare was the primary toxicity, but bone marrow suppression also occurred.
  • In some trials, tramadol was associated with more nausea, vomiting, and loss of appetite.
  • Significant side effects associated with ketamine include hallucinations, somnolence or drowsiness, feelings of insobriety, nausea, vomiting, hallucinations, and depersonalization or derealization.

Qualifying Statements

The authors take full responsibility for the content of the article. The authors did not receive honoraria for this work. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias.

Description of Implementation Strategy

An implementation strategy was not provided.

Implementation Tools

Resources

Staff Training/Competency Material

For information about availability, see the Availability of Companion Documents and Patient Resources fields below.

IOM Care Need

Getting Better

Living with Illness

IOM Domain

Effectiveness

Patient-centeredness

Bibliographic Source(s)

Brant JM, Keller L, McLeod K, Yeh C, Eaton LH. Chronic and refractory pain: a systematic review of pharmacologic management in oncology. Clin J Oncol Nurs. 2017 Jun 1;21(3):31-53. PubMed External Web Site Policy

Adaptation

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

Date Released

2017 Jun 1

Guideline Developer(s)

Oncology Nursing Society - Professional Association

Source(s) of Funding

Oncology Nursing Society

Guideline Committee

Oncology Nursing Society Putting Evidence Into Practice® (ONS PEP) Expert Panel

Composition of Group That Authored the Guideline

Authors: Jeannine M. Brant, PhD, APRN, AOCN®; FAAN; Lisa Keller, RN, OCN®, MS; Karen McLeod, MSN, RN, OCN®, CNL; Chao Yeh, PhD, RN; Linda H. Eaton, PhD, RN, AOCN®

Financial Disclosures/Conflicts of Interest

All volunteers complete the standardized Oncology Nursing Society (ONS) conflict of interest and confidentiality forms.

The authors take full responsibility for this content and did not receive honoraria or disclose any relevant financial relationships.

Guideline Status

This is the current release of the guideline.

This guideline updates a previous version: Aiello-Laws L, Reynolds J, Deizer N, Peterson M, Ameringer S, Bakitas M. Putting evidence into practice: what are the pharmacologic interventions for nociceptive and neuropathic cancer pain in adults. Clin J Oncol Nurs. 2009 Dec;13(6):649-55. [55 references]

This guideline meets NGC's 2013 (revised) inclusion criteria.

Guideline Availability

Available to subscribers from the Clinical Journal of Oncology Nursing Web site External Web Site Policy.

Availability of Companion Documents

The following are available:

  • Brant JM, Eaton LH, Irwin MM. Cancer-related pain: assessment and management with Putting Evidence Into Practice interventions. Clin J Oncol Nurs. 2017 Jun 1;21(3):4-7. Available to subscribers from the Clinical Journal of Oncology Nursing Web site External Web Site Policy.
  • Chronic pain. [internet]. Pittsburgh (PA): Oncology Nursing Society. 2017 Mar 30. Available from the Oncology Nursing Society (ONS) Web site External Web Site Policy.
  • Refractory/intractable pain. [internet]. Pittsburgh (PA): Oncology Nursing Society. 2017 Mar 30. Available from the ONS Web site External Web Site Policy.
  • Mitchell SA, Friese CR. Decision rules for summative evaluation of a body of evidence. [internet]. Pittsburgh (PA): Oncology Nursing Society. Available from the ONS Web site External Web Site Policy.
  • Johnson LA. Putting Evidence Into Practice: the process for evidence-based research. Clin J Oncol Nurs. 2014 Dec;18(6 Suppl):2-4. Available from the Clinical Journal of Oncology Nursing Web site External Web Site Policy.
  • Putting Evidence Into Practice (PEP) rating system overview. [internet]. Pittsburgh (PA): Oncology Nursing Society. Available from the ONS Web site External Web Site Policy.
  • ONS journal activity 2017: chronic and refractory pain: a systematic review of pharmacologic management in oncology. [internet]. Pittsburgh (PA): Oncology Nursing Society. Available from the ONS Web site External Web Site Policy.

Patient Resources

None available

NGC Status

This NGC summary was completed by ECRI Institute on December 3, 2010. The information was verified by the guideline developer on February 3, 2011. This summary was updated by ECRI Institute on October 28, 2013 following the U.S. Food and Drug Administration advisory on Acetaminophen. The currency of the guideline was reaffirmed by the developer in 2011 and this summary was updated by ECRI Institute on November 8, 2013. This summary was updated by ECRI Institute on September 18, 2015 following the U.S. Food and Drug Administration advisory on non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs). This summary was updated by ECRI Institute on February 5, 2018. The updated information was verified by the guideline developer on February 21, 2018.

This NEATS assessment was completed by ECRI Institute on November 16, 2017. The information was verified by the guideline developer on February 21, 2018.

Copyright Statement

This summary is based on the original guideline, which is copyrighted by the Oncology Nursing Society (ONS).

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