Kevin Frazer, MD

PRACTICE CHANGER
Consider treating patients with acute low back pain with naproxen only, as adding cyclobenzaprine or oxycodone/acetaminophen to scheduled naproxen increases adverse effects and does not improve functional assessment at seven days or three months.

Strength of Recommendation
B: Based on a high-quality, randomized controlled trial (RCT).¹

A 46-year-old man presents to the emergency department (ED) with low back pain (LBP) after helping a friend move a couch three days ago. He denies any direct trauma to his back and describes the pain as a “spasm” in his lumbar spinal region with no radicular symptoms. The pain worsens with prolonged standing and position changes. He has tried acetaminophen with no benefit. You diagnose a lumbar muscular strain. What medications should you prescribe to help relieve his LBP and improve his overall function?

Acute LBP prompts nearly 2.7 million ED visits in the United States each year.² It leads to persistent subjective impairment and con­tinued analgesic use at seven days (impairment, 70%; analgesic use, 69%) and three months (48% and 46%, respectively) after ED discharge.³ Systematic reviews show that monotherapy with NSAIDs or muscle relaxants is more effective than placebo for pain relief.^4,5 A secondary analysis of patients (N = 715) from a prospective cohort study showed worse functioning at six months in those who were prescribed opiates for LBP than in those who were not.⁶

Monotherapy or combination therapy for LBP?
Because medications used for LBP have different mechanisms of action, clinicians frequently combine them in an attempt to improve symptoms and function.² Current evidence on combination therapy shows mixed results. A large RCT (N = 867) showed that the combination of cyclobenzaprine and ibuprofen led to lower subjective pain intensity, but it did not result in self-reported pain improvement, compared to cyclobenz­a­prine alone. However, a small RCT (N = 40) demonstrated im­­proved LBP and spasm with naprozen plus cyclobenzaprine, compared to naproxen alone.^7,8

This study sought to determine the benefit of treating acute LBP with cyclobenzaprine or oxycodone/acetaminophen in combination with an NSAID, compared to treatment with an NSAID alone.

Continue for the study summary >>

STUDY SUMMARY
Adding second pain reliever provided no significant benefit
This double-blinded RCT enrolled 323 adults presenting to an ED with two weeks or less of nontraumatic, nonradicular LBP.¹ Subjects had a score of > 5 on the Roland-Morris Disability Questionnaire (RMDQ), which measures functional impairment due to LBP (range, 0-24). Patients were excluded if they had radicular pain radiating below the gluteal folds, direct trauma to the back within the previous month, pain lasting > 2 wk, a recent history of multiple LBP episodes per month, or a history of opioid use.

All subjects received 10 days’ worth of naproxen (500 mg bid). They were then randomized to receive either oxycodone/acetaminophen (5 mg/325 mg), cyclobenzaprine (5 mg), or placebo, with instructions to take one to two tablets as needed every eight hours for 10 days. All patients also received a 10-minute educational session emphasizing the role of nonpharmacologic interventions.

The primary outcome was change in the RMDQ between ED discharge and a phone call seven days later; a 5-point improvement in the RMDQ was considered clinically significant. Secondary outcomes included subjective description of worst pain, frequency of LBP, frequency of analgesic use, satisfaction with treatment, median number of days to return to work and usual activities, need for follow-up health care visits, and opioid use. Investigators also asked about any adverse effects.

At seven days, reported RMDQ scores had improved by 9.8 points in patients taking naproxen plus placebo, 10.1 points in those receiving naproxen plus cyclobenzaprine, and 11.1 points in those using naproxen plus oxycodone/acetaminophen. There were no statistically significant between-group differences for placebo vs cyclobenzaprine or oxycodone/acetaminophen (0.3 points and 1.3 points, respectively) or cyclobenzaprine vs oxycodone/acetaminophen (0.9 points).

Secondary outcomes. At seven days, there was no significant difference between study groups in subjective pain assessment, frequency of LBP, or use of as-needed medications in the prior 24 hours. There was also no difference in the median number of days to return to work or need for follow-up health care visits.

Among patients who took more than one dose of the study medication, those who took oxycodone/acetaminophen were more likely to describe their worst pain in the last 24 hours as mild/none, compared to patients taking placebo (number needed to treat, 6). About 72% of all subjects reported that they would choose the same treatment option again, with no difference between groups. At three months, there was no difference between groups in subjective pain assessment, frequency of LBP, use of as-needed medications, or opioid use during the previous 72 hours.

Adverse effects, including drowsiness, dizziness, stomach ir­ritation, and nausea or vomiting, were more common in the oxy­codone/acetaminophen and the cyclobenzaprine treatment groups, with a number needed to harm of 5.3 and 7.8, respectively.

Continue for what's new >>

WHAT’S NEW
Second med adds nothing
This RCT found that adding cyclobenzaprine or oxycodone/aceta­minophen to naproxen for the treatment of nontraumatic, nonradicular acute LBP did not significantly improve functional assessment at seven days or three months after the initial ED visit. But it did increase adverse effects.

CAVEATS
Specific subset studied
This study was performed in a single urban ED and included a very specific subset of LBP patients, which limits the generalizability of the results. However, patients often present to primary care with similar LBP complaints, and the results of the study should reasonably apply to other settings.

The findings may not generalize to all NSAIDs, but there is no evidence to suggest that other NSAIDs would behave differently when combined with cyclobenzaprine or oxycodone/acetaminophen. In this analysis, only about one-third of patients used the as-needed medication more than once daily; another third used it intermittently or never.

CHALLENGES TO IMPLEMENTATION
Patients may expect more
Patients expect to receive prescriptions, and clinicians are inclined to write them if they believe doing so will help their patients. The evidence, however, does not demonstrate a benefit to these prescription-only medications for LBP.

REFERENCES
1. Friedman BW, Dym AA, Davitt M, et al. Naproxen with cyclobenzaprine, oxycodone/acetaminophen, or placebo for treating acute low back pain: a randomized clinical trial. JAMA. 2015;314:1572-1580.
2. Friedman BW, Chilstrom M, Bijur PE, et al. Diagnostic testing and treatment of low back pain in United States emergency departments: a national perspective. Spine (Phila Pa 1976). 2010;35:E1406-E1411.
3. Friedman BW, O’Mahony S, Mulvey L, et al. One-week and 3-month outcomes after an emergency department visit for undifferentiated musculoskeletal low back pain. Ann Emerg Med. 2012;59:128-133.
4. Roelofs PD, Deyo RA, Koes BW, et al. Nonsteroidal anti-inflammatory drugs for low back pain: an updated Cochrane review. Spine (Phila Pa 1976). 2008;33:1766-1774.
5. van Tulder MW, Touray T, Furlan AD, et al. Muscle relaxants for nonspecific low back pain: a systematic review within the framework of the Cochrane collaboration. Spine (Phila Pa 1976). 2003;28:1978-1992.
6. Ashworth J, Green DJ, Dunn KM, et al. Opioid use among low back pain patients in primary care: is opioid prescription associated with disability at 6-month follow-up? Pain. 2013; 154:1038-1044.
7. Childers MK, Borenstein D, Brown RL, et al. Low-dose cyclobenzaprine versus combination therapy with ibuprofen for acute neck or back pain with muscle spasm: a randomized trial. Curr Med Res Opin. 2005;21:1485-1493.
8. Borenstein DG, Lacks S, Wiesel SW. Cyclobenzaprine and naproxen versus naproxen alone in the treatment of acute low back pain and muscle spasm. Clin Ther. 1990;12:125-131.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(6):404-406.

PRACTICE CHANGER
Consider treating patients with acute low back pain with naproxen only, as adding cyclobenzaprine or oxycodone/acetaminophen to scheduled naproxen increases adverse effects and does not improve functional assessment at seven days or three months.

Strength of Recommendation
B: Based on a high-quality, randomized controlled trial (RCT).¹

A 46-year-old man presents to the emergency department (ED) with low back pain (LBP) after helping a friend move a couch three days ago. He denies any direct trauma to his back and describes the pain as a “spasm” in his lumbar spinal region with no radicular symptoms. The pain worsens with prolonged standing and position changes. He has tried acetaminophen with no benefit. You diagnose a lumbar muscular strain. What medications should you prescribe to help relieve his LBP and improve his overall function?

Acute LBP prompts nearly 2.7 million ED visits in the United States each year.² It leads to persistent subjective impairment and con­tinued analgesic use at seven days (impairment, 70%; analgesic use, 69%) and three months (48% and 46%, respectively) after ED discharge.³ Systematic reviews show that monotherapy with NSAIDs or muscle relaxants is more effective than placebo for pain relief.^4,5 A secondary analysis of patients (N = 715) from a prospective cohort study showed worse functioning at six months in those who were prescribed opiates for LBP than in those who were not.⁶

Monotherapy or combination therapy for LBP?
Because medications used for LBP have different mechanisms of action, clinicians frequently combine them in an attempt to improve symptoms and function.² Current evidence on combination therapy shows mixed results. A large RCT (N = 867) showed that the combination of cyclobenzaprine and ibuprofen led to lower subjective pain intensity, but it did not result in self-reported pain improvement, compared to cyclobenz­a­prine alone. However, a small RCT (N = 40) demonstrated im­­proved LBP and spasm with naprozen plus cyclobenzaprine, compared to naproxen alone.^7,8

This study sought to determine the benefit of treating acute LBP with cyclobenzaprine or oxycodone/acetaminophen in combination with an NSAID, compared to treatment with an NSAID alone.

Continue for the study summary >>

STUDY SUMMARY
Adding second pain reliever provided no significant benefit
This double-blinded RCT enrolled 323 adults presenting to an ED with two weeks or less of nontraumatic, nonradicular LBP.¹ Subjects had a score of > 5 on the Roland-Morris Disability Questionnaire (RMDQ), which measures functional impairment due to LBP (range, 0-24). Patients were excluded if they had radicular pain radiating below the gluteal folds, direct trauma to the back within the previous month, pain lasting > 2 wk, a recent history of multiple LBP episodes per month, or a history of opioid use.

All subjects received 10 days’ worth of naproxen (500 mg bid). They were then randomized to receive either oxycodone/acetaminophen (5 mg/325 mg), cyclobenzaprine (5 mg), or placebo, with instructions to take one to two tablets as needed every eight hours for 10 days. All patients also received a 10-minute educational session emphasizing the role of nonpharmacologic interventions.

The primary outcome was change in the RMDQ between ED discharge and a phone call seven days later; a 5-point improvement in the RMDQ was considered clinically significant. Secondary outcomes included subjective description of worst pain, frequency of LBP, frequency of analgesic use, satisfaction with treatment, median number of days to return to work and usual activities, need for follow-up health care visits, and opioid use. Investigators also asked about any adverse effects.

At seven days, reported RMDQ scores had improved by 9.8 points in patients taking naproxen plus placebo, 10.1 points in those receiving naproxen plus cyclobenzaprine, and 11.1 points in those using naproxen plus oxycodone/acetaminophen. There were no statistically significant between-group differences for placebo vs cyclobenzaprine or oxycodone/acetaminophen (0.3 points and 1.3 points, respectively) or cyclobenzaprine vs oxycodone/acetaminophen (0.9 points).

Secondary outcomes. At seven days, there was no significant difference between study groups in subjective pain assessment, frequency of LBP, or use of as-needed medications in the prior 24 hours. There was also no difference in the median number of days to return to work or need for follow-up health care visits.

Among patients who took more than one dose of the study medication, those who took oxycodone/acetaminophen were more likely to describe their worst pain in the last 24 hours as mild/none, compared to patients taking placebo (number needed to treat, 6). About 72% of all subjects reported that they would choose the same treatment option again, with no difference between groups. At three months, there was no difference between groups in subjective pain assessment, frequency of LBP, use of as-needed medications, or opioid use during the previous 72 hours.

Adverse effects, including drowsiness, dizziness, stomach ir­ritation, and nausea or vomiting, were more common in the oxy­codone/acetaminophen and the cyclobenzaprine treatment groups, with a number needed to harm of 5.3 and 7.8, respectively.

Continue for what's new >>

WHAT’S NEW
Second med adds nothing
This RCT found that adding cyclobenzaprine or oxycodone/aceta­minophen to naproxen for the treatment of nontraumatic, nonradicular acute LBP did not significantly improve functional assessment at seven days or three months after the initial ED visit. But it did increase adverse effects.

CAVEATS
Specific subset studied
This study was performed in a single urban ED and included a very specific subset of LBP patients, which limits the generalizability of the results. However, patients often present to primary care with similar LBP complaints, and the results of the study should reasonably apply to other settings.

The findings may not generalize to all NSAIDs, but there is no evidence to suggest that other NSAIDs would behave differently when combined with cyclobenzaprine or oxycodone/acetaminophen. In this analysis, only about one-third of patients used the as-needed medication more than once daily; another third used it intermittently or never.

CHALLENGES TO IMPLEMENTATION
Patients may expect more
Patients expect to receive prescriptions, and clinicians are inclined to write them if they believe doing so will help their patients. The evidence, however, does not demonstrate a benefit to these prescription-only medications for LBP.

REFERENCES
1. Friedman BW, Dym AA, Davitt M, et al. Naproxen with cyclobenzaprine, oxycodone/acetaminophen, or placebo for treating acute low back pain: a randomized clinical trial. JAMA. 2015;314:1572-1580.
2. Friedman BW, Chilstrom M, Bijur PE, et al. Diagnostic testing and treatment of low back pain in United States emergency departments: a national perspective. Spine (Phila Pa 1976). 2010;35:E1406-E1411.
3. Friedman BW, O’Mahony S, Mulvey L, et al. One-week and 3-month outcomes after an emergency department visit for undifferentiated musculoskeletal low back pain. Ann Emerg Med. 2012;59:128-133.
4. Roelofs PD, Deyo RA, Koes BW, et al. Nonsteroidal anti-inflammatory drugs for low back pain: an updated Cochrane review. Spine (Phila Pa 1976). 2008;33:1766-1774.
5. van Tulder MW, Touray T, Furlan AD, et al. Muscle relaxants for nonspecific low back pain: a systematic review within the framework of the Cochrane collaboration. Spine (Phila Pa 1976). 2003;28:1978-1992.
6. Ashworth J, Green DJ, Dunn KM, et al. Opioid use among low back pain patients in primary care: is opioid prescription associated with disability at 6-month follow-up? Pain. 2013; 154:1038-1044.
7. Childers MK, Borenstein D, Brown RL, et al. Low-dose cyclobenzaprine versus combination therapy with ibuprofen for acute neck or back pain with muscle spasm: a randomized trial. Curr Med Res Opin. 2005;21:1485-1493.
8. Borenstein DG, Lacks S, Wiesel SW. Cyclobenzaprine and naproxen versus naproxen alone in the treatment of acute low back pain and muscle spasm. Clin Ther. 1990;12:125-131.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(6):404-406.

PRACTICE CHANGER
Consider treating patients with acute low back pain with naproxen only, as adding cyclobenzaprine or oxycodone/acetaminophen to scheduled naproxen increases adverse effects and does not improve functional assessment at seven days or three months.

Strength of Recommendation
B: Based on a high-quality, randomized controlled trial (RCT).¹

A 46-year-old man presents to the emergency department (ED) with low back pain (LBP) after helping a friend move a couch three days ago. He denies any direct trauma to his back and describes the pain as a “spasm” in his lumbar spinal region with no radicular symptoms. The pain worsens with prolonged standing and position changes. He has tried acetaminophen with no benefit. You diagnose a lumbar muscular strain. What medications should you prescribe to help relieve his LBP and improve his overall function?

Acute LBP prompts nearly 2.7 million ED visits in the United States each year.² It leads to persistent subjective impairment and con­tinued analgesic use at seven days (impairment, 70%; analgesic use, 69%) and three months (48% and 46%, respectively) after ED discharge.³ Systematic reviews show that monotherapy with NSAIDs or muscle relaxants is more effective than placebo for pain relief.^4,5 A secondary analysis of patients (N = 715) from a prospective cohort study showed worse functioning at six months in those who were prescribed opiates for LBP than in those who were not.⁶

Monotherapy or combination therapy for LBP?
Because medications used for LBP have different mechanisms of action, clinicians frequently combine them in an attempt to improve symptoms and function.² Current evidence on combination therapy shows mixed results. A large RCT (N = 867) showed that the combination of cyclobenzaprine and ibuprofen led to lower subjective pain intensity, but it did not result in self-reported pain improvement, compared to cyclobenz­a­prine alone. However, a small RCT (N = 40) demonstrated im­­proved LBP and spasm with naprozen plus cyclobenzaprine, compared to naproxen alone.^7,8

This study sought to determine the benefit of treating acute LBP with cyclobenzaprine or oxycodone/acetaminophen in combination with an NSAID, compared to treatment with an NSAID alone.

Continue for the study summary >>

STUDY SUMMARY
Adding second pain reliever provided no significant benefit
This double-blinded RCT enrolled 323 adults presenting to an ED with two weeks or less of nontraumatic, nonradicular LBP.¹ Subjects had a score of > 5 on the Roland-Morris Disability Questionnaire (RMDQ), which measures functional impairment due to LBP (range, 0-24). Patients were excluded if they had radicular pain radiating below the gluteal folds, direct trauma to the back within the previous month, pain lasting > 2 wk, a recent history of multiple LBP episodes per month, or a history of opioid use.

All subjects received 10 days’ worth of naproxen (500 mg bid). They were then randomized to receive either oxycodone/acetaminophen (5 mg/325 mg), cyclobenzaprine (5 mg), or placebo, with instructions to take one to two tablets as needed every eight hours for 10 days. All patients also received a 10-minute educational session emphasizing the role of nonpharmacologic interventions.

The primary outcome was change in the RMDQ between ED discharge and a phone call seven days later; a 5-point improvement in the RMDQ was considered clinically significant. Secondary outcomes included subjective description of worst pain, frequency of LBP, frequency of analgesic use, satisfaction with treatment, median number of days to return to work and usual activities, need for follow-up health care visits, and opioid use. Investigators also asked about any adverse effects.

At seven days, reported RMDQ scores had improved by 9.8 points in patients taking naproxen plus placebo, 10.1 points in those receiving naproxen plus cyclobenzaprine, and 11.1 points in those using naproxen plus oxycodone/acetaminophen. There were no statistically significant between-group differences for placebo vs cyclobenzaprine or oxycodone/acetaminophen (0.3 points and 1.3 points, respectively) or cyclobenzaprine vs oxycodone/acetaminophen (0.9 points).

Secondary outcomes. At seven days, there was no significant difference between study groups in subjective pain assessment, frequency of LBP, or use of as-needed medications in the prior 24 hours. There was also no difference in the median number of days to return to work or need for follow-up health care visits.

Among patients who took more than one dose of the study medication, those who took oxycodone/acetaminophen were more likely to describe their worst pain in the last 24 hours as mild/none, compared to patients taking placebo (number needed to treat, 6). About 72% of all subjects reported that they would choose the same treatment option again, with no difference between groups. At three months, there was no difference between groups in subjective pain assessment, frequency of LBP, use of as-needed medications, or opioid use during the previous 72 hours.

Adverse effects, including drowsiness, dizziness, stomach ir­ritation, and nausea or vomiting, were more common in the oxy­codone/acetaminophen and the cyclobenzaprine treatment groups, with a number needed to harm of 5.3 and 7.8, respectively.

Continue for what's new >>

WHAT’S NEW
Second med adds nothing
This RCT found that adding cyclobenzaprine or oxycodone/aceta­minophen to naproxen for the treatment of nontraumatic, nonradicular acute LBP did not significantly improve functional assessment at seven days or three months after the initial ED visit. But it did increase adverse effects.

CAVEATS
Specific subset studied
This study was performed in a single urban ED and included a very specific subset of LBP patients, which limits the generalizability of the results. However, patients often present to primary care with similar LBP complaints, and the results of the study should reasonably apply to other settings.

The findings may not generalize to all NSAIDs, but there is no evidence to suggest that other NSAIDs would behave differently when combined with cyclobenzaprine or oxycodone/acetaminophen. In this analysis, only about one-third of patients used the as-needed medication more than once daily; another third used it intermittently or never.

CHALLENGES TO IMPLEMENTATION
Patients may expect more
Patients expect to receive prescriptions, and clinicians are inclined to write them if they believe doing so will help their patients. The evidence, however, does not demonstrate a benefit to these prescription-only medications for LBP.

REFERENCES
1. Friedman BW, Dym AA, Davitt M, et al. Naproxen with cyclobenzaprine, oxycodone/acetaminophen, or placebo for treating acute low back pain: a randomized clinical trial. JAMA. 2015;314:1572-1580.
2. Friedman BW, Chilstrom M, Bijur PE, et al. Diagnostic testing and treatment of low back pain in United States emergency departments: a national perspective. Spine (Phila Pa 1976). 2010;35:E1406-E1411.
3. Friedman BW, O’Mahony S, Mulvey L, et al. One-week and 3-month outcomes after an emergency department visit for undifferentiated musculoskeletal low back pain. Ann Emerg Med. 2012;59:128-133.
4. Roelofs PD, Deyo RA, Koes BW, et al. Nonsteroidal anti-inflammatory drugs for low back pain: an updated Cochrane review. Spine (Phila Pa 1976). 2008;33:1766-1774.
5. van Tulder MW, Touray T, Furlan AD, et al. Muscle relaxants for nonspecific low back pain: a systematic review within the framework of the Cochrane collaboration. Spine (Phila Pa 1976). 2003;28:1978-1992.
6. Ashworth J, Green DJ, Dunn KM, et al. Opioid use among low back pain patients in primary care: is opioid prescription associated with disability at 6-month follow-up? Pain. 2013; 154:1038-1044.
7. Childers MK, Borenstein D, Brown RL, et al. Low-dose cyclobenzaprine versus combination therapy with ibuprofen for acute neck or back pain with muscle spasm: a randomized trial. Curr Med Res Opin. 2005;21:1485-1493.
8. Borenstein DG, Lacks S, Wiesel SW. Cyclobenzaprine and naproxen versus naproxen alone in the treatment of acute low back pain and muscle spasm. Clin Ther. 1990;12:125-131.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Copyright © 2016. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2016;65(6):404-406.

Illustrative Case

A 46-year-old man presents to the emergency department (ED) with low back pain (LBP) after helping a friend move a couch 3 days earlier. He denies any direct trauma to his back and describes the pain as a spasm in his lumbar spinal region with no radicular symptoms. The pain worsens with prolonged standing and any position changes. He has tried acetaminophen with no benefit. You diagnose a lumbar muscular strain. What medications should you prescribe to help relieve his LBP and improve his overall function?

Acute LBP prompts close to 2.7 million ED visits annually in the United States.² It leads to persistent subjective impairment and continued analgesic usage at 7 days (impairment 70%, analgesic use 69%) and at 3 months (48% and 46%, respectively) after ED discharge.³ Systematic reviews show that monotherapy with nonsteroidal anti-inflammatory drugs (NSAIDs) or muscle relaxers is better than placebo for relieving pain.^4,5 A secondary analysis of patients (N=715) from a prospective cohort study showed that patients prescribed opiates for LBP had worse functioning at 6 months than those not prescribed opiates.⁶

Monotherapy or combination therapy for LBP? That is the question

Because medications used for LBP have different mechanisms of action, clinicians frequently combine them in an attempt to improve symptoms and function.² Current evidence evaluating combination therapy demonstrates mixed results. A large RCT (N=867) showed that the combination of cyclobenzaprine and ibuprofen led to lower subjective pain intensity, but did not result in self-reported pain improvement (based on answers to the Patient Global Impression of Change and the Oswestry Disability Index) than cyclobenzaprine alone. However, a small RCT (N=40) combining naproxen with cyclobenzaprine demonstrated improved LBP and spasm compared to naproxen alone.^7,8

This study sought to determine the benefit of treating acute LBP with cyclobenzaprine or oxycodone/acetaminophen in combination with an NSAID compared to treatment with an NSAID alone.

Study Summary

Adding second pain reliever to the NSAID provided no significant benefit

This double-blinded RCT enrolled 323 adult patients presenting to an ED with ≤2 weeks of nontraumatic, nonradicular LBP, which was defined as pain between the lower border of the scapulae and the upper gluteal folds.¹ Participants had a score of >5 on the Roland-Morris Disability Questionnaire (RMDQ), which measures functional impairment due to LBP (range: 0-24). Patients were excluded if they had radicular pain radiating below the gluteal folds, direct trauma to the back within the previous month, pain duration >2 weeks, or a recent history of >1 LBP episode per month. Patients with current or past chronic opioid use were also excluded.

All participants received 10 days’ worth of naproxen (500 mg twice daily). They were then randomized to receive either: oxycodone 5 mg/acetaminophen 325 mg; cyclobenzaprine 5 mg; or placebo, with instructions to take one to 2 tablets prn every 8 hours for 10 days. They were told that if one tablet afforded sufficient relief, there was no need to take the second one, but if the first tablet did not provide relief within 30 minutes, they should take the second one. All patients also received a 10-minute educational session emphasizing the role of exercise, stretching, physical/massage therapy, and other non-pharmacologic interventions.

The primary outcome was change in the RMDQ between ED discharge and a phone call 7 days later, with a 5-point improvement in the RMDQ considered clinically significant. Secondary outcomes at 7 days and 3 months after ED discharge included subjective description of worst pain, frequency of LBP pain, frequency of analgesic use, satisfaction with treatment, median number of days to return to work and usual activities, need for follow-up health care visits, and opioid use. Investigators also asked about any adverse effects at 7 days and 3 months.

At 7 days, patients randomized to naproxen plus placebo improved on reported RMDQ scores by a mean of 9.8 points, naproxen plus cyclobenzaprine by 10.1 points, and naproxen plus oxycodone/acetaminophen by 11.1 points. Between group differences in mean RMDQ changes showed no statistically significant differences with placebo vs cyclobenzaprine (0.3 points; P=.77), placebo vs oxycodone/acetaminophen (1.3 points; P=.28), and cyclobenzaprine vs oxycodone/acetaminophen (0.9 points; P=.45).

Secondary outcomes. At 7 days, there was no significant difference between study groups in subjective pain assessment, frequency of LBP, or use of as-needed medications in the prior 24 hours. There was also no difference in the median number of days to return to work or need for follow-up health care visits. In patients who took more than one dose of the study medication, those who took oxycodone/acetaminophen were more likely to describe their worst pain in the last 24 hours as mild/none when compared to those taking placebo (number needed to treat [NNT]=6). About 72% of all subjects reported that they would choose the same treatment option again, with no difference between groups. At 3 months, no difference existed between groups in subjective pain assessment, frequency of LBP, use of as-needed medications, or opioid use during the previous 72 hours.

Adverse effects, including drowsiness, dizziness, stomach irritation, and nausea or vomiting, were more common in the oxycodone/acetaminophen and cyclobenzaprine treatment groups with a number needed to harm (NNH) of 5.3 and 7.8, respectively.

At 7 days, there was no significant difference between study groups in subjective pain assessment, frequency of low back pain, or use of as-needed medications in the previous 24 hours.

What’s New

A second pain reliever adds nothing—except adverse effects

This RCT found that adding cyclobenzaprine or oxycodone/acetaminophen to naproxen for the treatment of nontraumatic, nonradicular acute LBP did not significantly improve functional assessment based on RMDQ scores or pain measures at 7 days or 3 months after the initial ED visit. It did, however, increase adverse effects.

Caveats

Researchers studied a specific subset of patients

This study was performed in a single-site urban ED and included a very specific subset of LBP patients, which limits the generalizability of the results. However, patients often present to their primary care physician with similar LBP complaints, and the results of the study should reasonably apply to other settings.

The findings may not generalize to all NSAIDs, but there is no evidence to suggest that other NSAIDs would behave differently when combined with cyclobenzaprine or oxycodone/acetaminophen. In this intention-to-treat analysis, only about one-third of patients used the as-needed medication more than once daily; about another third of patients used the as-needed medication intermittently or never.

Challenges to Implementation

Patients may expect more than an NSAID for their back pain

Patients expect to receive prescriptions, and physicians are inclined to write them if they believe they will help their patients. The evidence, however, does not show a benefit to these prescription-only medications for low back pain.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative Case

A 46-year-old man presents to the emergency department (ED) with low back pain (LBP) after helping a friend move a couch 3 days earlier. He denies any direct trauma to his back and describes the pain as a spasm in his lumbar spinal region with no radicular symptoms. The pain worsens with prolonged standing and any position changes. He has tried acetaminophen with no benefit. You diagnose a lumbar muscular strain. What medications should you prescribe to help relieve his LBP and improve his overall function?

Acute LBP prompts close to 2.7 million ED visits annually in the United States.² It leads to persistent subjective impairment and continued analgesic usage at 7 days (impairment 70%, analgesic use 69%) and at 3 months (48% and 46%, respectively) after ED discharge.³ Systematic reviews show that monotherapy with nonsteroidal anti-inflammatory drugs (NSAIDs) or muscle relaxers is better than placebo for relieving pain.^4,5 A secondary analysis of patients (N=715) from a prospective cohort study showed that patients prescribed opiates for LBP had worse functioning at 6 months than those not prescribed opiates.⁶

Monotherapy or combination therapy for LBP? That is the question

Because medications used for LBP have different mechanisms of action, clinicians frequently combine them in an attempt to improve symptoms and function.² Current evidence evaluating combination therapy demonstrates mixed results. A large RCT (N=867) showed that the combination of cyclobenzaprine and ibuprofen led to lower subjective pain intensity, but did not result in self-reported pain improvement (based on answers to the Patient Global Impression of Change and the Oswestry Disability Index) than cyclobenzaprine alone. However, a small RCT (N=40) combining naproxen with cyclobenzaprine demonstrated improved LBP and spasm compared to naproxen alone.^7,8

This study sought to determine the benefit of treating acute LBP with cyclobenzaprine or oxycodone/acetaminophen in combination with an NSAID compared to treatment with an NSAID alone.

Study Summary

Adding second pain reliever to the NSAID provided no significant benefit

This double-blinded RCT enrolled 323 adult patients presenting to an ED with ≤2 weeks of nontraumatic, nonradicular LBP, which was defined as pain between the lower border of the scapulae and the upper gluteal folds.¹ Participants had a score of >5 on the Roland-Morris Disability Questionnaire (RMDQ), which measures functional impairment due to LBP (range: 0-24). Patients were excluded if they had radicular pain radiating below the gluteal folds, direct trauma to the back within the previous month, pain duration >2 weeks, or a recent history of >1 LBP episode per month. Patients with current or past chronic opioid use were also excluded.

All participants received 10 days’ worth of naproxen (500 mg twice daily). They were then randomized to receive either: oxycodone 5 mg/acetaminophen 325 mg; cyclobenzaprine 5 mg; or placebo, with instructions to take one to 2 tablets prn every 8 hours for 10 days. They were told that if one tablet afforded sufficient relief, there was no need to take the second one, but if the first tablet did not provide relief within 30 minutes, they should take the second one. All patients also received a 10-minute educational session emphasizing the role of exercise, stretching, physical/massage therapy, and other non-pharmacologic interventions.

The primary outcome was change in the RMDQ between ED discharge and a phone call 7 days later, with a 5-point improvement in the RMDQ considered clinically significant. Secondary outcomes at 7 days and 3 months after ED discharge included subjective description of worst pain, frequency of LBP pain, frequency of analgesic use, satisfaction with treatment, median number of days to return to work and usual activities, need for follow-up health care visits, and opioid use. Investigators also asked about any adverse effects at 7 days and 3 months.

At 7 days, patients randomized to naproxen plus placebo improved on reported RMDQ scores by a mean of 9.8 points, naproxen plus cyclobenzaprine by 10.1 points, and naproxen plus oxycodone/acetaminophen by 11.1 points. Between group differences in mean RMDQ changes showed no statistically significant differences with placebo vs cyclobenzaprine (0.3 points; P=.77), placebo vs oxycodone/acetaminophen (1.3 points; P=.28), and cyclobenzaprine vs oxycodone/acetaminophen (0.9 points; P=.45).

Secondary outcomes. At 7 days, there was no significant difference between study groups in subjective pain assessment, frequency of LBP, or use of as-needed medications in the prior 24 hours. There was also no difference in the median number of days to return to work or need for follow-up health care visits. In patients who took more than one dose of the study medication, those who took oxycodone/acetaminophen were more likely to describe their worst pain in the last 24 hours as mild/none when compared to those taking placebo (number needed to treat [NNT]=6). About 72% of all subjects reported that they would choose the same treatment option again, with no difference between groups. At 3 months, no difference existed between groups in subjective pain assessment, frequency of LBP, use of as-needed medications, or opioid use during the previous 72 hours.

Adverse effects, including drowsiness, dizziness, stomach irritation, and nausea or vomiting, were more common in the oxycodone/acetaminophen and cyclobenzaprine treatment groups with a number needed to harm (NNH) of 5.3 and 7.8, respectively.

At 7 days, there was no significant difference between study groups in subjective pain assessment, frequency of low back pain, or use of as-needed medications in the previous 24 hours.

What’s New

A second pain reliever adds nothing—except adverse effects

This RCT found that adding cyclobenzaprine or oxycodone/acetaminophen to naproxen for the treatment of nontraumatic, nonradicular acute LBP did not significantly improve functional assessment based on RMDQ scores or pain measures at 7 days or 3 months after the initial ED visit. It did, however, increase adverse effects.

Caveats

Researchers studied a specific subset of patients

This study was performed in a single-site urban ED and included a very specific subset of LBP patients, which limits the generalizability of the results. However, patients often present to their primary care physician with similar LBP complaints, and the results of the study should reasonably apply to other settings.

The findings may not generalize to all NSAIDs, but there is no evidence to suggest that other NSAIDs would behave differently when combined with cyclobenzaprine or oxycodone/acetaminophen. In this intention-to-treat analysis, only about one-third of patients used the as-needed medication more than once daily; about another third of patients used the as-needed medication intermittently or never.

Challenges to Implementation

Patients may expect more than an NSAID for their back pain

Patients expect to receive prescriptions, and physicians are inclined to write them if they believe they will help their patients. The evidence, however, does not show a benefit to these prescription-only medications for low back pain.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

Illustrative Case

A 46-year-old man presents to the emergency department (ED) with low back pain (LBP) after helping a friend move a couch 3 days earlier. He denies any direct trauma to his back and describes the pain as a spasm in his lumbar spinal region with no radicular symptoms. The pain worsens with prolonged standing and any position changes. He has tried acetaminophen with no benefit. You diagnose a lumbar muscular strain. What medications should you prescribe to help relieve his LBP and improve his overall function?

Acute LBP prompts close to 2.7 million ED visits annually in the United States.² It leads to persistent subjective impairment and continued analgesic usage at 7 days (impairment 70%, analgesic use 69%) and at 3 months (48% and 46%, respectively) after ED discharge.³ Systematic reviews show that monotherapy with nonsteroidal anti-inflammatory drugs (NSAIDs) or muscle relaxers is better than placebo for relieving pain.^4,5 A secondary analysis of patients (N=715) from a prospective cohort study showed that patients prescribed opiates for LBP had worse functioning at 6 months than those not prescribed opiates.⁶

Monotherapy or combination therapy for LBP? That is the question

Because medications used for LBP have different mechanisms of action, clinicians frequently combine them in an attempt to improve symptoms and function.² Current evidence evaluating combination therapy demonstrates mixed results. A large RCT (N=867) showed that the combination of cyclobenzaprine and ibuprofen led to lower subjective pain intensity, but did not result in self-reported pain improvement (based on answers to the Patient Global Impression of Change and the Oswestry Disability Index) than cyclobenzaprine alone. However, a small RCT (N=40) combining naproxen with cyclobenzaprine demonstrated improved LBP and spasm compared to naproxen alone.^7,8

This study sought to determine the benefit of treating acute LBP with cyclobenzaprine or oxycodone/acetaminophen in combination with an NSAID compared to treatment with an NSAID alone.

Study Summary

Adding second pain reliever to the NSAID provided no significant benefit

This double-blinded RCT enrolled 323 adult patients presenting to an ED with ≤2 weeks of nontraumatic, nonradicular LBP, which was defined as pain between the lower border of the scapulae and the upper gluteal folds.¹ Participants had a score of >5 on the Roland-Morris Disability Questionnaire (RMDQ), which measures functional impairment due to LBP (range: 0-24). Patients were excluded if they had radicular pain radiating below the gluteal folds, direct trauma to the back within the previous month, pain duration >2 weeks, or a recent history of >1 LBP episode per month. Patients with current or past chronic opioid use were also excluded.

All participants received 10 days’ worth of naproxen (500 mg twice daily). They were then randomized to receive either: oxycodone 5 mg/acetaminophen 325 mg; cyclobenzaprine 5 mg; or placebo, with instructions to take one to 2 tablets prn every 8 hours for 10 days. They were told that if one tablet afforded sufficient relief, there was no need to take the second one, but if the first tablet did not provide relief within 30 minutes, they should take the second one. All patients also received a 10-minute educational session emphasizing the role of exercise, stretching, physical/massage therapy, and other non-pharmacologic interventions.

The primary outcome was change in the RMDQ between ED discharge and a phone call 7 days later, with a 5-point improvement in the RMDQ considered clinically significant. Secondary outcomes at 7 days and 3 months after ED discharge included subjective description of worst pain, frequency of LBP pain, frequency of analgesic use, satisfaction with treatment, median number of days to return to work and usual activities, need for follow-up health care visits, and opioid use. Investigators also asked about any adverse effects at 7 days and 3 months.

At 7 days, patients randomized to naproxen plus placebo improved on reported RMDQ scores by a mean of 9.8 points, naproxen plus cyclobenzaprine by 10.1 points, and naproxen plus oxycodone/acetaminophen by 11.1 points. Between group differences in mean RMDQ changes showed no statistically significant differences with placebo vs cyclobenzaprine (0.3 points; P=.77), placebo vs oxycodone/acetaminophen (1.3 points; P=.28), and cyclobenzaprine vs oxycodone/acetaminophen (0.9 points; P=.45).

Secondary outcomes. At 7 days, there was no significant difference between study groups in subjective pain assessment, frequency of LBP, or use of as-needed medications in the prior 24 hours. There was also no difference in the median number of days to return to work or need for follow-up health care visits. In patients who took more than one dose of the study medication, those who took oxycodone/acetaminophen were more likely to describe their worst pain in the last 24 hours as mild/none when compared to those taking placebo (number needed to treat [NNT]=6). About 72% of all subjects reported that they would choose the same treatment option again, with no difference between groups. At 3 months, no difference existed between groups in subjective pain assessment, frequency of LBP, use of as-needed medications, or opioid use during the previous 72 hours.

Adverse effects, including drowsiness, dizziness, stomach irritation, and nausea or vomiting, were more common in the oxycodone/acetaminophen and cyclobenzaprine treatment groups with a number needed to harm (NNH) of 5.3 and 7.8, respectively.

At 7 days, there was no significant difference between study groups in subjective pain assessment, frequency of low back pain, or use of as-needed medications in the previous 24 hours.

What’s New

A second pain reliever adds nothing—except adverse effects

This RCT found that adding cyclobenzaprine or oxycodone/acetaminophen to naproxen for the treatment of nontraumatic, nonradicular acute LBP did not significantly improve functional assessment based on RMDQ scores or pain measures at 7 days or 3 months after the initial ED visit. It did, however, increase adverse effects.

Caveats

Researchers studied a specific subset of patients

This study was performed in a single-site urban ED and included a very specific subset of LBP patients, which limits the generalizability of the results. However, patients often present to their primary care physician with similar LBP complaints, and the results of the study should reasonably apply to other settings.

The findings may not generalize to all NSAIDs, but there is no evidence to suggest that other NSAIDs would behave differently when combined with cyclobenzaprine or oxycodone/acetaminophen. In this intention-to-treat analysis, only about one-third of patients used the as-needed medication more than once daily; about another third of patients used the as-needed medication intermittently or never.

Challenges to Implementation

Patients may expect more than an NSAID for their back pain

Patients expect to receive prescriptions, and physicians are inclined to write them if they believe they will help their patients. The evidence, however, does not show a benefit to these prescription-only medications for low back pain.

ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.

ILLUSTRATED CASE

An 82-year-old patient presents to the emergency department with several episodes of melena over the past week and one episode of hematemesis this morning. He denies any shortness of breath, dizziness, lightheadedness, or fatigue. He is tachycardic but normotensive. Lab results note a hemoglobin level of 8.3 g/dL. Should you order a transfusion of red blood cells?

Acute upper gastrointestinal bleeding (UGIB) commonly requires hospital admission, with approximately 61 cases per 100,000 population in the United States in 2009.² Gastroduodenal peptic ulcer disease accounts for the majority of these cases.³ Although trends indicate an overall decrease in cases requiring hospitalization, UGIB remains a condition associated with a mortality rate of 2.5% and inpatient costs of $2 billion annually.^2,3

Studies have been inconclusive—until now
An RCT published in 1999 showed a restrictive transfusion strategy (hemoglobin threshold of 7 g/dL) to be at least as effective as—and possibly superior to—a liberal strategy (threshold of 10 g/dL) in critically ill patients.⁴ In 2010, an RCT demonstrated that a liberal transfusion strategy (also defined as a transfusion threshold of 10 g/dL) did not reduce the rates of death or in-hospital morbidity in elderly patients after hip surgery.⁵ A recent Cochrane review of transfusion strategies for UGIB included only 3 small studies (N=93), so its authors could not draw any firm conclusions.⁶ The results of a new RCT, detailed below, are more conclusive.

STUDY SUMMARY: Restrictive transfusion policy lowers mortality risk

Villanueva et al conducted a nonblinded RCT comparing outcomes in patients admitted to the hospital with moderate-risk acute UGIB transfused on a liberal vs a restrictive strategy.¹ The restrictive group used a transfusion hemoglobin threshold of 7 g/dL and a posttransfusion target of 7 to 9 g/dL; the liberal group used a threshold of 9 g/dL, with a posttransfusion target of 9 to 11 g/dL. Patients received one unit of red blood cells at a time until their hemoglobin was above the predetermined threshold.

Patients were excluded if they declined blood transfusion; had massive exsanguinating bleeding, acute coronary syndrome, symptomatic peripheral vasculopathy, stroke, lower GI bleeding, or a transient ischemic attack; had received a transfusion within the previous 90 days; or had a recent history of surgery or trauma. Patients at low risk of rebleeding (as defined by the Rockall risk scoring system) were also excluded. Randomization was stratified by the presence or absence of cirrhosis of the liver.

Participants (N=921) had confirmed hematemesis and/or melena on admission. All underwent emergency gastroscopy within 6 hours of admission, with subsequent interventions based on endoscopic findings. In addition to established hemoglobin levels, patients received a transfusion anytime they developed signs or symptoms related to anemia, massive bleeding, or the need for surgery. Staff monitored hemoglobin levels every 8 hours during the first 48 hours, then daily thereafter.

Both groups had similar baseline characteristics, including hemoglobin on admission and source of bleeding. The authors used intention-to-treat analysis to identify the primary outcome: death from any cause at 45 days. Secondary outcomes were further bleeding and in-hospital complications.

During hospitalization, 49% of patients in the restrictive group and 86% of those in the liberal group received a blood transfusion (P<.001). Thirty-two patients (17 from the restrictive group and 15 from the liberal group) withdrew from the study, leaving 889 patients for overall analysis.

At 45 days, overall mortality from any cause was 5% in the restrictive group and 9% in the liberal group (P=.02; number needed to treat [NNT]=25). Sub-group analysis revealed a lower risk of death in patients with cirrhosis and Child-Pugh class A or B disease assigned to the restrictive transfusion group vs the liberal group. The results showed a trend toward a lower risk of death in patients with bleeding from varices or peptic ulcers for the restrictive group, as well.

In addition, the restrictive transfusion group had a significantly lower rate of adverse events (40% vs 48% for the liberal transfusion group; P=.02, NNT=13), with a significant reduction in transfusion reactions (3% vs 9%; P=.001, NNT=17) and cardiac complications (11% vs 16%; P=.04, NNT=20). The restrictive group had a lower rate of further bleeding (10% vs 16% for the liberal transfusion group; P=.01, NNT=17), as well.

WHAT'S NEW: Many reasons to limit transfusions for acute upper GI bleed

This RCT provides evidence that patients with acute UGIB have improved survival rates and fewer adverse events when a restrictive transfusion strategy is used. In addition to improving patient outcomes, a restrictive strategy will likely reduce costs and overall use of blood products. Thus, the study, along with other recent evaluations, adds evidence to support more restrictive transfusion thresholds.

The AABB (formerly named the American Association of Blood Banks) recently
released guidelines calling for restrictive transfusion thresholds (7-8 g/dL) in stable hospitalized patients.⁷ In 2012, the American College of Gastroenterology published a practice guideline with a recommended target hemoglobin level of ≥7 g/dL in the management of patients who have ulcer bleeding but no signs of intravascular depletion or comorbidities such as coronary artery disease.⁸

CAVEATS: Results might differ when endoscopy is delayed

The patients in the study detailed here underwent emergency gastroscopy within 6 hours of admission, and both groups received the same therapies based on endoscopic findings. It remains unclear whether the benefits of a restrictive transfusion strategy would persist in patients who do not undergo endoscopy within that timeframe. And, because the reported baseline characteristics of the patients did not include the prevalence of cardiac disease, caution should be exercised before extrapolating these results to patients with underlying (active or historical) cardiac disease.

CHALLENGES TO IMPLEMENTATION: Changing long-held policies may be difficult

Although RCTs as well as clinical guidelines suggest that restrictive transfusion policies are safe and effective, changing long-held clinical practices is never easy.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATED CASE

An 82-year-old patient presents to the emergency department with several episodes of melena over the past week and one episode of hematemesis this morning. He denies any shortness of breath, dizziness, lightheadedness, or fatigue. He is tachycardic but normotensive. Lab results note a hemoglobin level of 8.3 g/dL. Should you order a transfusion of red blood cells?

Acute upper gastrointestinal bleeding (UGIB) commonly requires hospital admission, with approximately 61 cases per 100,000 population in the United States in 2009.² Gastroduodenal peptic ulcer disease accounts for the majority of these cases.³ Although trends indicate an overall decrease in cases requiring hospitalization, UGIB remains a condition associated with a mortality rate of 2.5% and inpatient costs of $2 billion annually.^2,3

Studies have been inconclusive—until now
An RCT published in 1999 showed a restrictive transfusion strategy (hemoglobin threshold of 7 g/dL) to be at least as effective as—and possibly superior to—a liberal strategy (threshold of 10 g/dL) in critically ill patients.⁴ In 2010, an RCT demonstrated that a liberal transfusion strategy (also defined as a transfusion threshold of 10 g/dL) did not reduce the rates of death or in-hospital morbidity in elderly patients after hip surgery.⁵ A recent Cochrane review of transfusion strategies for UGIB included only 3 small studies (N=93), so its authors could not draw any firm conclusions.⁶ The results of a new RCT, detailed below, are more conclusive.

STUDY SUMMARY: Restrictive transfusion policy lowers mortality risk

Villanueva et al conducted a nonblinded RCT comparing outcomes in patients admitted to the hospital with moderate-risk acute UGIB transfused on a liberal vs a restrictive strategy.¹ The restrictive group used a transfusion hemoglobin threshold of 7 g/dL and a posttransfusion target of 7 to 9 g/dL; the liberal group used a threshold of 9 g/dL, with a posttransfusion target of 9 to 11 g/dL. Patients received one unit of red blood cells at a time until their hemoglobin was above the predetermined threshold.

Patients were excluded if they declined blood transfusion; had massive exsanguinating bleeding, acute coronary syndrome, symptomatic peripheral vasculopathy, stroke, lower GI bleeding, or a transient ischemic attack; had received a transfusion within the previous 90 days; or had a recent history of surgery or trauma. Patients at low risk of rebleeding (as defined by the Rockall risk scoring system) were also excluded. Randomization was stratified by the presence or absence of cirrhosis of the liver.

Participants (N=921) had confirmed hematemesis and/or melena on admission. All underwent emergency gastroscopy within 6 hours of admission, with subsequent interventions based on endoscopic findings. In addition to established hemoglobin levels, patients received a transfusion anytime they developed signs or symptoms related to anemia, massive bleeding, or the need for surgery. Staff monitored hemoglobin levels every 8 hours during the first 48 hours, then daily thereafter.

Both groups had similar baseline characteristics, including hemoglobin on admission and source of bleeding. The authors used intention-to-treat analysis to identify the primary outcome: death from any cause at 45 days. Secondary outcomes were further bleeding and in-hospital complications.

During hospitalization, 49% of patients in the restrictive group and 86% of those in the liberal group received a blood transfusion (P<.001). Thirty-two patients (17 from the restrictive group and 15 from the liberal group) withdrew from the study, leaving 889 patients for overall analysis.

At 45 days, overall mortality from any cause was 5% in the restrictive group and 9% in the liberal group (P=.02; number needed to treat [NNT]=25). Sub-group analysis revealed a lower risk of death in patients with cirrhosis and Child-Pugh class A or B disease assigned to the restrictive transfusion group vs the liberal group. The results showed a trend toward a lower risk of death in patients with bleeding from varices or peptic ulcers for the restrictive group, as well.

In addition, the restrictive transfusion group had a significantly lower rate of adverse events (40% vs 48% for the liberal transfusion group; P=.02, NNT=13), with a significant reduction in transfusion reactions (3% vs 9%; P=.001, NNT=17) and cardiac complications (11% vs 16%; P=.04, NNT=20). The restrictive group had a lower rate of further bleeding (10% vs 16% for the liberal transfusion group; P=.01, NNT=17), as well.

WHAT'S NEW: Many reasons to limit transfusions for acute upper GI bleed

This RCT provides evidence that patients with acute UGIB have improved survival rates and fewer adverse events when a restrictive transfusion strategy is used. In addition to improving patient outcomes, a restrictive strategy will likely reduce costs and overall use of blood products. Thus, the study, along with other recent evaluations, adds evidence to support more restrictive transfusion thresholds.

The AABB (formerly named the American Association of Blood Banks) recently
released guidelines calling for restrictive transfusion thresholds (7-8 g/dL) in stable hospitalized patients.⁷ In 2012, the American College of Gastroenterology published a practice guideline with a recommended target hemoglobin level of ≥7 g/dL in the management of patients who have ulcer bleeding but no signs of intravascular depletion or comorbidities such as coronary artery disease.⁸

CAVEATS: Results might differ when endoscopy is delayed

The patients in the study detailed here underwent emergency gastroscopy within 6 hours of admission, and both groups received the same therapies based on endoscopic findings. It remains unclear whether the benefits of a restrictive transfusion strategy would persist in patients who do not undergo endoscopy within that timeframe. And, because the reported baseline characteristics of the patients did not include the prevalence of cardiac disease, caution should be exercised before extrapolating these results to patients with underlying (active or historical) cardiac disease.

CHALLENGES TO IMPLEMENTATION: Changing long-held policies may be difficult

Although RCTs as well as clinical guidelines suggest that restrictive transfusion policies are safe and effective, changing long-held clinical practices is never easy.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

ILLUSTRATED CASE

An 82-year-old patient presents to the emergency department with several episodes of melena over the past week and one episode of hematemesis this morning. He denies any shortness of breath, dizziness, lightheadedness, or fatigue. He is tachycardic but normotensive. Lab results note a hemoglobin level of 8.3 g/dL. Should you order a transfusion of red blood cells?

Acute upper gastrointestinal bleeding (UGIB) commonly requires hospital admission, with approximately 61 cases per 100,000 population in the United States in 2009.² Gastroduodenal peptic ulcer disease accounts for the majority of these cases.³ Although trends indicate an overall decrease in cases requiring hospitalization, UGIB remains a condition associated with a mortality rate of 2.5% and inpatient costs of $2 billion annually.^2,3

Studies have been inconclusive—until now
An RCT published in 1999 showed a restrictive transfusion strategy (hemoglobin threshold of 7 g/dL) to be at least as effective as—and possibly superior to—a liberal strategy (threshold of 10 g/dL) in critically ill patients.⁴ In 2010, an RCT demonstrated that a liberal transfusion strategy (also defined as a transfusion threshold of 10 g/dL) did not reduce the rates of death or in-hospital morbidity in elderly patients after hip surgery.⁵ A recent Cochrane review of transfusion strategies for UGIB included only 3 small studies (N=93), so its authors could not draw any firm conclusions.⁶ The results of a new RCT, detailed below, are more conclusive.

STUDY SUMMARY: Restrictive transfusion policy lowers mortality risk

Villanueva et al conducted a nonblinded RCT comparing outcomes in patients admitted to the hospital with moderate-risk acute UGIB transfused on a liberal vs a restrictive strategy.¹ The restrictive group used a transfusion hemoglobin threshold of 7 g/dL and a posttransfusion target of 7 to 9 g/dL; the liberal group used a threshold of 9 g/dL, with a posttransfusion target of 9 to 11 g/dL. Patients received one unit of red blood cells at a time until their hemoglobin was above the predetermined threshold.

Patients were excluded if they declined blood transfusion; had massive exsanguinating bleeding, acute coronary syndrome, symptomatic peripheral vasculopathy, stroke, lower GI bleeding, or a transient ischemic attack; had received a transfusion within the previous 90 days; or had a recent history of surgery or trauma. Patients at low risk of rebleeding (as defined by the Rockall risk scoring system) were also excluded. Randomization was stratified by the presence or absence of cirrhosis of the liver.

Participants (N=921) had confirmed hematemesis and/or melena on admission. All underwent emergency gastroscopy within 6 hours of admission, with subsequent interventions based on endoscopic findings. In addition to established hemoglobin levels, patients received a transfusion anytime they developed signs or symptoms related to anemia, massive bleeding, or the need for surgery. Staff monitored hemoglobin levels every 8 hours during the first 48 hours, then daily thereafter.

Both groups had similar baseline characteristics, including hemoglobin on admission and source of bleeding. The authors used intention-to-treat analysis to identify the primary outcome: death from any cause at 45 days. Secondary outcomes were further bleeding and in-hospital complications.

During hospitalization, 49% of patients in the restrictive group and 86% of those in the liberal group received a blood transfusion (P<.001). Thirty-two patients (17 from the restrictive group and 15 from the liberal group) withdrew from the study, leaving 889 patients for overall analysis.

At 45 days, overall mortality from any cause was 5% in the restrictive group and 9% in the liberal group (P=.02; number needed to treat [NNT]=25). Sub-group analysis revealed a lower risk of death in patients with cirrhosis and Child-Pugh class A or B disease assigned to the restrictive transfusion group vs the liberal group. The results showed a trend toward a lower risk of death in patients with bleeding from varices or peptic ulcers for the restrictive group, as well.

In addition, the restrictive transfusion group had a significantly lower rate of adverse events (40% vs 48% for the liberal transfusion group; P=.02, NNT=13), with a significant reduction in transfusion reactions (3% vs 9%; P=.001, NNT=17) and cardiac complications (11% vs 16%; P=.04, NNT=20). The restrictive group had a lower rate of further bleeding (10% vs 16% for the liberal transfusion group; P=.01, NNT=17), as well.

WHAT'S NEW: Many reasons to limit transfusions for acute upper GI bleed

This RCT provides evidence that patients with acute UGIB have improved survival rates and fewer adverse events when a restrictive transfusion strategy is used. In addition to improving patient outcomes, a restrictive strategy will likely reduce costs and overall use of blood products. Thus, the study, along with other recent evaluations, adds evidence to support more restrictive transfusion thresholds.

The AABB (formerly named the American Association of Blood Banks) recently
released guidelines calling for restrictive transfusion thresholds (7-8 g/dL) in stable hospitalized patients.⁷ In 2012, the American College of Gastroenterology published a practice guideline with a recommended target hemoglobin level of ≥7 g/dL in the management of patients who have ulcer bleeding but no signs of intravascular depletion or comorbidities such as coronary artery disease.⁸

CAVEATS: Results might differ when endoscopy is delayed

The patients in the study detailed here underwent emergency gastroscopy within 6 hours of admission, and both groups received the same therapies based on endoscopic findings. It remains unclear whether the benefits of a restrictive transfusion strategy would persist in patients who do not undergo endoscopy within that timeframe. And, because the reported baseline characteristics of the patients did not include the prevalence of cardiac disease, caution should be exercised before extrapolating these results to patients with underlying (active or historical) cardiac disease.

CHALLENGES TO IMPLEMENTATION: Changing long-held policies may be difficult

Although RCTs as well as clinical guidelines suggest that restrictive transfusion policies are safe and effective, changing long-held clinical practices is never easy.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.