Cochrane for Clinicians

Putting Evidence into Practice

Opioids for Management of Breakthrough Pain in Cancer Patients


Am Fam Physician. 2006 Dec 1;74(11):1855-1857.

Clinical Scenario

A 74-year-old man uses long-acting opioids for chest wall pain associated with lung cancer. He experiences breakthrough pain in the evenings and would like advice about the best way to treat it.

Clinical Question

What evidence is there for the use of rapid-acting opioids in the management of breakthrough cancer pain?

Evidence-Based Answer

Oral transmucosal fentanyl citrate (OTFC [Actiq]), a rapid-acting opioid, has been shown to be an effective treatment for breakthrough cancer pain. Other opioids, including immediate-release oral morphine (MSIR), also may be effective; however, evidence comparing these agents with OTFC is lacking.1

Practice Pointers

Cancer pain comes in many forms and often is undertreated.2 When the pain fails to respond to acetaminophen or nonsteroidal anti-inflammatory drugs, or otherwise becomes intractable, opioids often are recommended.3 Usually, short-acting opioids are used as needed. When the pain persists throughout the day, short-acting opioids are replaced with longer-acting opioids two or three times daily to provide 24-hour relief.

Even after daily opioid dosing has been established, physicians may be called upon to treat worsening pain. In some patients, worsening pain control is a sign of worsening disease and may warrant a thorough reevaluation of the underlying causes. Opioid tolerance is another possible reason for increased medication requirements. However, increased pain (e.g., constipation and abdominal pain) also can be an adverse effect of opioids, and physicians must be careful not to misinterpret these symptoms.

In contrast, breakthrough pain usually is episodic and self-limited. It often recurs at certain times of the day or in response to particular triggers. When breakthrough pain occurs as a result of end-of-dose failure it can be prevented by increasing the frequency of opioid dosing—for example, administering sustained-release morphine every eight hours instead of every 12.4 In situations where breakthrough pain is more difficult to manage, patients often are given rapid-acting opioids such as OTFC or immediate-release morphine to take as needed in addition to their regular doses of longer-acting opioids.

The Cochrane reviewers assessed the evidence for the benefit of additional doses of shorter-acting opioids for breakthrough pain in patients who take long-acting opioids for chronic cancer pain. They found only a few well-designed studies, all of which involved the use of OTFC, an opioid with extremely rapid onset of pain relief that is taken in the form of orally dissolving lozenges.

Only one study compared the effectiveness of OTFC with another opioid.5 This double-blind crossover study involved 134 patients who already managed their breakthrough pain with immediate-release morphine, which has a slightly slower onset of action than OTFC. During the intervention, patients tended to have more effective relief of breakthrough pain and a more rapid onset of relief with OTFC than with immediate-release morphine. Sixty-four of the 93 patients who completed the study said they would like to continue using OTFC for their breakthrough pain. These results suggest that select cancer patients might prefer OTFC over immediate-release morphine.

Cochrane Abstract

Background: Breakthrough pain is a transient increase in pain intensity over background pain. It is a common and distinct component of cancer pain that can have a negative impact on the patient’s and caregivers’ quality of life. Breakthrough pain usually is related to background pain; typically it is of rapid onset, severe in intensity, and self-limiting, with an average duration of 30 minutes. One approach to managing breakthrough pain is using supplemental analgesia (also known as rescue medication) at a dose proportional to the total around-the-clock opioid dosage.

Objectives:This review explores and assesses the evidence for the use of opioids in the management of breakthrough pain in patients with cancer.1

Search Strategy: MEDLINE (1966 to 2005), EMBASE (1980 to 2005), CancerLit (1993 to 2005), CINAHL (1982 to 2005), and Cochrane databases were searched. Hand searching of medical journals and references from key textbooks was undertaken, and drug companies were contacted for unpublished data. There were no language restrictions. Date of most recent search: January 2005.

Selection Criteria: Randomized controlled trials of opioids used as rescue medication against active or placebo comparator in patients with cancer pain were included. Outcome measures sought were reduction in pain intensity measured by an appropriate scale, adverse effects, attrition, patient satisfaction, and quality of life.

Data Collection and Analysis: Eligible studies were selected and examined independently by the two reviewers. Full text was retrieved if any uncertainty about eligibility remained. Non-English texts were screened. Quality assessment and data extraction were conducted using standardized data forms. Drug and placebo dose, titration, route, and formulation were compared, and details of all outcome measures (if available) were recorded.

Primary Results: Four studies (393 participants) met the inclusion criteria. All were concerned with the use of oral transmucosal fentanyl citrate (OTFC [Actiq]) in the management of breakthrough pain. Two studies examined the titration of OTFC, one study compared OTFC with normal-release morphine (MSIR), and one study compared OTFC with placebo.

OTFC was shown to be an effective treatment for breakthrough pain. In comparisons with placebo or morphine, participants gave lower pain intensity scores and higher pain relief scores for OTFC at all time points. Global assessment scores also favored OTFC.

Reviewers’ Conclusions: There is evidence that OTFC is an effective treatment in the management of breakthrough pain. The randomized trial literature for the management of breakthrough pain is small, and no trials were found for other opioids. Given the importance of this subject, more trials need to be undertaken.

These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the originalreviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minorediting changes have been made to the text (

A secondary objective of the review was to find evidence supporting the expert opinion of the European Association of Palliative Care (EAPC) that short-acting opioids for breakthrough cancer pain should be given in proportion to the amount of long-acting opioid being taken by the patient.6 In the four studies reviewed, the optimal safe and effective dose of short-acting opioid varied greatly from patient to patient. Thus, contrary to the EAPC’s recommendations, the reviewers conclude that the optimal dose of opioids for breakthrough cancer pain is best determined through trial and error.

Rapid-acting oral opioids can cause a variety of adverse effects, including respiratory arrest in patients who have not previously used opioids. Although short-acting opioids with a less immediate onset of action (e.g., oxycodone [Roxicodone], codeine) have not been well studied as treatments for breakthrough cancer pain, clinical experience suggests that they are less likely than rapid-acting opioids to cause respiratory suppression when used for episodic pain in patients with no previous opioid use or a relatively low background exposure to long-acting opioids. However, the evidence in this Cochrane review indicates that OTFC, a rapid-acting opioid, is reasonably safe and effective for the treatment of breakthrough cancer pain in patients already taking long-acting opioids for cancer pain. In most studies, the rapid-acting opioids were introduced at low dosages and titrated upward gradually to reduce the risk of adverse effects.

Address correspondence to Michael B. Potter, M.D., Reprints are not available from the author.


show all references

1. Zeppetella G, Ribeiro MD. Opioids for the management of breakthrough (episodic) pain in cancer patients. Cochrane Database Syst Rev. 2006;(1):CD004311....

2. Bernabei R, Gambassi G, Lapane K, Landi F, Gatsonis C, Dunlop R, et al. Management of pain in elderly patients with cancer. SAGE Study Group. Systematic Assessment of Geriatric Drug Use via Epidemiology [Published correction appears in JAMA 1999;281:136]. JAMA. 1998;279:1877–82.

3. Carr DB, Goudas LC, Balk EM, Bloch R, Ioannidis JP, Lau J. Evidence report on the treatment of pain in cancer patients. J Natl Cancer Inst Monogr. 2004;32:23–31.

4. Ventafridda V, Saita L, Barletta L, Sbanotto A, De Conno F. Clinical observations on controlled-release morphine in cancer pain. J Pain Symptom Manage. 1989;4:124–9.

5. Coluzzi PH, Schwartzberg L, Conroy JD, Charapata S, Gay M, Busch MA, et al. Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain. 2001;91:123–30.

6. Hanks GW, Conno F, Cherny N, Hanna M, Kalso E, McQuay HJ, et al., for the Expert Working Group of the Research Network of the European Association for Palliative Care. Morphine and alternative opioids in cancer pain: the EAPC recommendations. Br J Cancer. 2001;84:587–93.

The Cochrane Abstract is a summary of a review from the Cochrane Library. It is accompanied by an interpretation that will help clinicians put evidence into practice. Michael B. Potter, M.D., presents a clinical scenario and question based on the Cochrane Abstract, followed by an evidence-based answer and a critique of the review. The practice recommendations in this activity are available at

The series coordinator for AFP is Clarissa Kripke, M.D., Department of Family and Community Medicine, University of California, San Francisco.



Copyright © 2006 by the American Academy of Family Physicians.
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