Cochrane for Clinicians
Putting Evidence into Practice
Opioids for Management of Breakthrough Pain in Cancer Patients
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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
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searching of medical journals and references from key textbooks was undertaken, and drug companies were contacted for unpublished data.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 original reviews, but the summaries should not
be regarded as an official product of the Cochrane Collaboration; minor editing
changes have been made to the text (http://www.cochrane.org).
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.
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., at potterm@fcm.ucsf.edu. Reprints are not available from the author.
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
Cochrane Briefs
Patching for Corneal Abrasions?
Clinical Question
Is patching an effective treatment for simple corneal abrasions?
Evidence-Based Answer
Patching is not beneficial for the treatment of simple corneal abrasions as measured by time to healing, complete healing rates at 24 to 48 hours, or pain.
Practice Pointers
Corneal abrasions are superficial defects of the corneal epithelium that most commonly result from mechanical injuries to the cornea. Experts have long recommended patching (occlusion of the affected eye) for the treatment of simple abrasions; however, recent studies have questioned this traditional guidance.1
Eleven prospective randomized or quasi-randomized controlled trials were identified that studied the effectiveness of patching as measured by corneal healing in children and adults with corneal abrasion. All trials had two treatment groups with participants randomized to wear a patch for 24 hours or no patch; both treatment groups received variable dosing regimens of topical medications, including topical antibiotics, steroids, and cycloplegic eye drops.
Five trials measured the number of participants with complete healing (defined by no fluorescein staining) on each day of follow-up; two trials measured mean time to healing; and six trials measured percentage of healing or abrasion dimension sizes at each day of follow-up. Secondary outcomes measured in the trials included pain scores, analgesia use, treatment compliance, and ability to complete activities of daily living. Three trials mentioned short-term adverse events, and four trials reported long-term complications and follow-up two to seven months after the corneal abrasion. Overall, the studies were rated as being of poor quality because of uncertain adequacy of randomization, lack of intention-to-treat analyses, and high drop-out rates.
Meta-analysis of seven trials reporting complete healing rates on the first day of follow-up showed that more participants in the no-patch group had complete healing (risk ratio = 0.89; 95% confidence interval, 0.79 to 0.99). When the two quasi-randomized trials were excluded from the pooled analysis, the difference in complete healing rates between the groups was nonsignificant. Pooled analysis of studies reporting complete healing rates at day 2 and day 3 of follow-up showed no significant difference between the patch and no-patch groups. Analysis of six studies showed no significant difference between the patch and no-patch groups in the mean number of days to healing.
The nine trials measuring pain had conflicting results: two studies found less pain in the no-patch group, three studies found less pain in the patch group, and four studies found no significant difference. No differences were found in analgesia use, activities of daily living measures, patient compliance, presence of symptoms (e.g., photophobia, tearing, foreign-body sensation, blurred vision), use of mydriatic drops, or complications.
Adverse effects of patching include a loss of binocular vision while the patch is in place, which renders activities requiring depth perception (e.g., walking, driving) challenging. One study involving children showed that those in the patch group had significantly greater difficulty walking than those in the no-patch group.
This review addresses abrasions of less than 0.02 square inches (10 mm2); treatment of larger abrasions has not been adequately addressed.
Source: Turner A, et al. Patching for corneal abrasion. Cochrane Database Syst Rev 2006;(2):CD004764.
REFERENCE
1. Wilson SA, Last A. Management of corneal abrasions. Am Fam Physician 2004;70:123-8.
Beta-Blocker Use in Patients with COPD
Clinical Question
Are beta blockers safe in patients with chronic obstructive pulmonary disease (COPD)?
Evidence-Based Answer
In 20 studies of cardioselective beta blockers in patients with COPD, participants had no adverse pulmonary or respiratory effects. Because of their salutary cardiovascular effects, cardioselective beta blockers should not be withheld from patients with COPD.
Practice Pointers
Beta blockers reduce mortality in patients with ischemic heart disease, heart failure, acute coronary syndrome, myocardial infarction, or hypertension.1,2 However, COPD often is cited as a contraindication to beta-blocker therapy.3,4 Concern about inciting acute bronchospasm with these agents often leads physicians to avoid using them in patients with COPD and life-threatening coronary artery disease.
In 2001, a systematic review reported that cardioselective beta blockers did not have any deleterious effects in patients with reversible airway disease.5 In 2005, the same researchers focused on patients with COPD because these patients are more likely than those with asthma to have underlying ischemic heart disease and therefore may benefit from beta-blockade.
The researchers found 20 trials evaluating the use of beta blockers in patients with COPD: 11 studies with a total of 131 patients evaluating single-dose treatment, and nine studies with a total of 147 patients evaluating treatment of a longer duration. Most of these studies were small, with averages of 12 and 16 patients in the single- and continued-treatment groups, respectively. Trials were included in the analysis if: (1) forced expiratory volume in 1 second (FEV1) was reported at rest; (2) the trials were randomized, controlled, and single- or double-blinded; and (3) participants met the American Thoracic Society definition of COPD or demonstrated a baseline FEV1 of less than 80 percent. The authors evaluated only cardioselective beta1 blockers (e.g., atenolol [Tenormin], metoprolol [Toprol], bisoprolol [Zebeta], acebutolol [Sectral]) because these were most often used in clinical practice.
There was no reduction in FEV1 or increase in respiratory symptoms in patients with COPD given cardioselective beta blockers in single or continued treatment. Four trials also demonstrated no adverse effects in the FEV1 treatment response to beta2 agonists in those patients given beta blockers.
This meta-analysis was limited by small study size, inclusion of only published literature, possible publication bias, and nondelineated randomization in many of the studies. In addition, 80 percent of the patients were men. However, in light of their proven mortality prevention, the benefit of cardioselective beta blockers in patients with COPD who present with an acute coronary syndrome seems to outweigh the perceived risks.
Source: Salpeter S, et al. Cardioselective beta-blockers for chronic obstructive pulmonary disease. Cochrane Database Syst Rev 2005;(4):CD003566.
REFERENCES
1. Sleight P. Beta blockade early in acute myocardial infarction. Am J Cardiol 1987;60:6A-10A.
2. Freemantle N, Cleland J, Young P, Mason J, Harrison J. Beta blockade after myocardial infarction: systematic review and meta regression analysis. BMJ 1999;318:1730-7.
3. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure [Published correction appears in Arch Intern Med 1998;158:573]. Arch Intern Med 1997;157:2413-46.
4. American Heart Association. ACLS Provider Manual. Dallas, Tex.: American Heart Association, 2001:135.
5. Salpeter S, Ormiston T, Salpeter E. Cardioselective beta-blocker use in patients with reversible airway disease. Cochrane Database Syst Rev 2001;(2):CD002992.
This clinical content conforms to
AAFP criteria for evidence-based continuing
medical education (EB CME). See Clinical Quiz on page 1833.
The series coordinator for AFP is Clarissa Kripke, M.D., Department of Family and Community Medicine, University of California, San Francisco.
A collection of Cochrane for Clinicians published in AFP is available at http://www.aafp.org/afp/cochrane.
| Copyright © 2006 by the American
Academy of Family Physicians. |
