James Stevermer, MD, MSPH

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.

PRACTICE CHANGER
Early-morning testosterone tests are necessary only for men younger than 45. Because the natural diurnal variation in testosterone levels tends to diminish with age, it is acceptable to test men ages 45 and older before 2 pm.¹

STRENGTH OF RECOMMENDATION
B: Based on a retrospective cohort study.¹

ILLUSTRATIVE CASE
You are finishing up a visit with a 62-year-old man who has erectile dysfunction (ED), and you want to evaluate for androgen deficiency. It’s already noon. Should you ask him to return for an early-morning visit so you can test his testosterone level?

Increasing public awareness of androgen deficiency has led to more men being tested for testosterone levels. Current Endocrine Society guidelines recommend against routine screening for androgen deficiency in men who do not have symptoms.² However, for men with classic symptoms of androgen deficiency—such as decreased libido, ED, infertility, depression, osteoporosis, loss of secondary sexual characteristics, or reduced muscle bulk or strength—measurement of total testosterone level is recommended.²

Due to the natural diurnal variation in serum testosterone levels, the guidelines recommend collecting the sample in the early morning.² This recommendation is based on small observational studies that included mostly men younger than 45, which found a significant difference in testosterone levels between samples drawn early in the morning and in the afternoon.^3-5

In recent years, several studies have indicated that this variation declines as men age.^4-6 Recently, researchers evaluated the effects of age and time of testing on men’s total testosterone levels.

STUDY SUMMARY
Differences in testosterone levels are significant only in younger men
Welliver et al¹ performed a retrospective review of charts from a Minneapolis Veterans Affairs hospital. They identified 2,569 men seen for ED who had total testosterone levels measured between 7 AM and 2 PM in a 15-year period. Men whose total testosterone levels were outside the normal range (> 1,000 or < 50 ng/dL) or who had total testosterone drawn after 2 PM were excluded.

The authors analyzed the results based on age, creating one group for men younger than 40 and five-year age-groups for all other men. Using scatterplot techniques, they separated each age-group into two subgroups based on draw times—7 AM to 9 AM, or 9 AM to 2 PM—and compared the mean total testosterone level for each age and time.

Participants’ mean age was 63. Younger men (< 45) had the largest variation in serum total testosterone, with a large and significant decrease after 9 AM. Only the two youngest groups (ages < 40 and 40 to 44) showed a large decrease in total testosterone in specimens collected after 9 am, compared to those drawn earlier (mean difference, 207 and 149 ng/dL, respectively). This variation was not observed in patients older than 45. Although there was a statistically significant difference between early and later testosterone levels in men ages 70 to 74, the absolute difference—34 ng/dL (452 vs 418 ng/dL)—was unlikely to be clinically significant.

WHAT’S NEW
For older men, later testing will not affect results
This study confirms previous ­research indicating that the diurnal effect on testosterone levels becomes blunted with increasing age, at least in this group of men with ED. Allowing older men to have their total testosterone levels drawn until 2 PM would allow for greater patient flexibility in draw times, with little change in results.

CAVEATS
Study’s methodology cannot account for several potential confounders
This retrospective study analyzed a single random testosterone measurement from each participant, rather than repeat testosterone levels over the course of a day. However, the study was large (2,569 men) and used mean values, which should at least partially mitigate the effect of having only a single measurement from each participant.

The study measured total testosterone and did not account for potential confounding factors—such as obesity or use of testosterone replacement therapy or androgen deprivation therapy—that could affect sex hormone binding globulin, thus potentially altering total testosterone level. However, the authors estimated that less than 2% of the entire cohort was likely to have unrecognized hormonal manipulation with exogenous gonadotropins.

All of the men in the study were seen for ED, and it is possible that men with ED have more flattening of the diurnal variation than men without ED. However, we are unaware of other data that support this.

Up to 30% of men who have a low early-morning testosterone level may have a normal result when testing is repeated.^2,5 Therefore, for all men who have low testosterone level test results, draw a repeat total testosterone level before 9 am to confirm the diagnosis. Also, this study did not evaluate the course of testosterone levels throughout the later afternoon and evening, and it remains unclear whether levels can be drawn even later in the day.

CHALLENGES TO IMPLEMENTATION
Your lab’s policies might require early-morning draws
There will probably be few barriers to implementing this change, unless local laboratory policies are inflexible regarding the timing of testosterone draws. 

REFERENCES
1. Welliver RC Jr, Wiser HJ, Brannigan RE, et al. Validity of midday total testosterone levels in older men with erectile dysfunction. J Urol. 2014;192:165-169.
2. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:2536-2559.
3. Cooke RR, McIntosh JE, McIntosh RP. Circadian variation in serum free and non-SHBG-bound testosterone in normal men: measurements, and simulation using a mass action model. Clin Endocrinol (Oxf). 1993;39:163-171.
4. Bremner WJ, Vitiello MV, Prinz PN. Loss of circadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab. 1983;56:1278-1281.
5. Brambilla DJ, Matsumoto AM, Araujo AB, et al. The effect of diurnal variation on clinical measurement of serum testosterone and other sex hormone levels in men. J Clin Endocrinol Metab. 2009;94:907-913.
6. Crawford ED, Barqawi AB, O’Donnell C, et al. The association of time of day and serum testosterone concentration in a large screening population. BJU Int. 2007;100:509-513.

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 © 2015. The Family Physicians Inquiries Network. All rights reserved. 

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2015;64(7):418-419. 

PRACTICE CHANGER
Early-morning testosterone tests are necessary only for men younger than 45. Because the natural diurnal variation in testosterone levels tends to diminish with age, it is acceptable to test men ages 45 and older before 2 pm.¹

STRENGTH OF RECOMMENDATION
B: Based on a retrospective cohort study.¹

ILLUSTRATIVE CASE
You are finishing up a visit with a 62-year-old man who has erectile dysfunction (ED), and you want to evaluate for androgen deficiency. It’s already noon. Should you ask him to return for an early-morning visit so you can test his testosterone level?

Increasing public awareness of androgen deficiency has led to more men being tested for testosterone levels. Current Endocrine Society guidelines recommend against routine screening for androgen deficiency in men who do not have symptoms.² However, for men with classic symptoms of androgen deficiency—such as decreased libido, ED, infertility, depression, osteoporosis, loss of secondary sexual characteristics, or reduced muscle bulk or strength—measurement of total testosterone level is recommended.²

Due to the natural diurnal variation in serum testosterone levels, the guidelines recommend collecting the sample in the early morning.² This recommendation is based on small observational studies that included mostly men younger than 45, which found a significant difference in testosterone levels between samples drawn early in the morning and in the afternoon.^3-5

In recent years, several studies have indicated that this variation declines as men age.^4-6 Recently, researchers evaluated the effects of age and time of testing on men’s total testosterone levels.

STUDY SUMMARY
Differences in testosterone levels are significant only in younger men
Welliver et al¹ performed a retrospective review of charts from a Minneapolis Veterans Affairs hospital. They identified 2,569 men seen for ED who had total testosterone levels measured between 7 AM and 2 PM in a 15-year period. Men whose total testosterone levels were outside the normal range (> 1,000 or < 50 ng/dL) or who had total testosterone drawn after 2 PM were excluded.

The authors analyzed the results based on age, creating one group for men younger than 40 and five-year age-groups for all other men. Using scatterplot techniques, they separated each age-group into two subgroups based on draw times—7 AM to 9 AM, or 9 AM to 2 PM—and compared the mean total testosterone level for each age and time.

Participants’ mean age was 63. Younger men (< 45) had the largest variation in serum total testosterone, with a large and significant decrease after 9 AM. Only the two youngest groups (ages < 40 and 40 to 44) showed a large decrease in total testosterone in specimens collected after 9 am, compared to those drawn earlier (mean difference, 207 and 149 ng/dL, respectively). This variation was not observed in patients older than 45. Although there was a statistically significant difference between early and later testosterone levels in men ages 70 to 74, the absolute difference—34 ng/dL (452 vs 418 ng/dL)—was unlikely to be clinically significant.

WHAT’S NEW
For older men, later testing will not affect results
This study confirms previous ­research indicating that the diurnal effect on testosterone levels becomes blunted with increasing age, at least in this group of men with ED. Allowing older men to have their total testosterone levels drawn until 2 PM would allow for greater patient flexibility in draw times, with little change in results.

CAVEATS
Study’s methodology cannot account for several potential confounders
This retrospective study analyzed a single random testosterone measurement from each participant, rather than repeat testosterone levels over the course of a day. However, the study was large (2,569 men) and used mean values, which should at least partially mitigate the effect of having only a single measurement from each participant.

The study measured total testosterone and did not account for potential confounding factors—such as obesity or use of testosterone replacement therapy or androgen deprivation therapy—that could affect sex hormone binding globulin, thus potentially altering total testosterone level. However, the authors estimated that less than 2% of the entire cohort was likely to have unrecognized hormonal manipulation with exogenous gonadotropins.

All of the men in the study were seen for ED, and it is possible that men with ED have more flattening of the diurnal variation than men without ED. However, we are unaware of other data that support this.

Up to 30% of men who have a low early-morning testosterone level may have a normal result when testing is repeated.^2,5 Therefore, for all men who have low testosterone level test results, draw a repeat total testosterone level before 9 am to confirm the diagnosis. Also, this study did not evaluate the course of testosterone levels throughout the later afternoon and evening, and it remains unclear whether levels can be drawn even later in the day.

CHALLENGES TO IMPLEMENTATION
Your lab’s policies might require early-morning draws
There will probably be few barriers to implementing this change, unless local laboratory policies are inflexible regarding the timing of testosterone draws. 

REFERENCES
1. Welliver RC Jr, Wiser HJ, Brannigan RE, et al. Validity of midday total testosterone levels in older men with erectile dysfunction. J Urol. 2014;192:165-169.
2. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:2536-2559.
3. Cooke RR, McIntosh JE, McIntosh RP. Circadian variation in serum free and non-SHBG-bound testosterone in normal men: measurements, and simulation using a mass action model. Clin Endocrinol (Oxf). 1993;39:163-171.
4. Bremner WJ, Vitiello MV, Prinz PN. Loss of circadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab. 1983;56:1278-1281.
5. Brambilla DJ, Matsumoto AM, Araujo AB, et al. The effect of diurnal variation on clinical measurement of serum testosterone and other sex hormone levels in men. J Clin Endocrinol Metab. 2009;94:907-913.
6. Crawford ED, Barqawi AB, O’Donnell C, et al. The association of time of day and serum testosterone concentration in a large screening population. BJU Int. 2007;100:509-513.

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 © 2015. The Family Physicians Inquiries Network. All rights reserved. 

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2015;64(7):418-419. 

PRACTICE CHANGER
Early-morning testosterone tests are necessary only for men younger than 45. Because the natural diurnal variation in testosterone levels tends to diminish with age, it is acceptable to test men ages 45 and older before 2 pm.¹

STRENGTH OF RECOMMENDATION
B: Based on a retrospective cohort study.¹

ILLUSTRATIVE CASE
You are finishing up a visit with a 62-year-old man who has erectile dysfunction (ED), and you want to evaluate for androgen deficiency. It’s already noon. Should you ask him to return for an early-morning visit so you can test his testosterone level?

Increasing public awareness of androgen deficiency has led to more men being tested for testosterone levels. Current Endocrine Society guidelines recommend against routine screening for androgen deficiency in men who do not have symptoms.² However, for men with classic symptoms of androgen deficiency—such as decreased libido, ED, infertility, depression, osteoporosis, loss of secondary sexual characteristics, or reduced muscle bulk or strength—measurement of total testosterone level is recommended.²

Due to the natural diurnal variation in serum testosterone levels, the guidelines recommend collecting the sample in the early morning.² This recommendation is based on small observational studies that included mostly men younger than 45, which found a significant difference in testosterone levels between samples drawn early in the morning and in the afternoon.^3-5

In recent years, several studies have indicated that this variation declines as men age.^4-6 Recently, researchers evaluated the effects of age and time of testing on men’s total testosterone levels.

STUDY SUMMARY
Differences in testosterone levels are significant only in younger men
Welliver et al¹ performed a retrospective review of charts from a Minneapolis Veterans Affairs hospital. They identified 2,569 men seen for ED who had total testosterone levels measured between 7 AM and 2 PM in a 15-year period. Men whose total testosterone levels were outside the normal range (> 1,000 or < 50 ng/dL) or who had total testosterone drawn after 2 PM were excluded.

The authors analyzed the results based on age, creating one group for men younger than 40 and five-year age-groups for all other men. Using scatterplot techniques, they separated each age-group into two subgroups based on draw times—7 AM to 9 AM, or 9 AM to 2 PM—and compared the mean total testosterone level for each age and time.

Participants’ mean age was 63. Younger men (< 45) had the largest variation in serum total testosterone, with a large and significant decrease after 9 AM. Only the two youngest groups (ages < 40 and 40 to 44) showed a large decrease in total testosterone in specimens collected after 9 am, compared to those drawn earlier (mean difference, 207 and 149 ng/dL, respectively). This variation was not observed in patients older than 45. Although there was a statistically significant difference between early and later testosterone levels in men ages 70 to 74, the absolute difference—34 ng/dL (452 vs 418 ng/dL)—was unlikely to be clinically significant.

WHAT’S NEW
For older men, later testing will not affect results
This study confirms previous ­research indicating that the diurnal effect on testosterone levels becomes blunted with increasing age, at least in this group of men with ED. Allowing older men to have their total testosterone levels drawn until 2 PM would allow for greater patient flexibility in draw times, with little change in results.

CAVEATS
Study’s methodology cannot account for several potential confounders
This retrospective study analyzed a single random testosterone measurement from each participant, rather than repeat testosterone levels over the course of a day. However, the study was large (2,569 men) and used mean values, which should at least partially mitigate the effect of having only a single measurement from each participant.

The study measured total testosterone and did not account for potential confounding factors—such as obesity or use of testosterone replacement therapy or androgen deprivation therapy—that could affect sex hormone binding globulin, thus potentially altering total testosterone level. However, the authors estimated that less than 2% of the entire cohort was likely to have unrecognized hormonal manipulation with exogenous gonadotropins.

All of the men in the study were seen for ED, and it is possible that men with ED have more flattening of the diurnal variation than men without ED. However, we are unaware of other data that support this.

Up to 30% of men who have a low early-morning testosterone level may have a normal result when testing is repeated.^2,5 Therefore, for all men who have low testosterone level test results, draw a repeat total testosterone level before 9 am to confirm the diagnosis. Also, this study did not evaluate the course of testosterone levels throughout the later afternoon and evening, and it remains unclear whether levels can be drawn even later in the day.

CHALLENGES TO IMPLEMENTATION
Your lab’s policies might require early-morning draws
There will probably be few barriers to implementing this change, unless local laboratory policies are inflexible regarding the timing of testosterone draws. 

REFERENCES
1. Welliver RC Jr, Wiser HJ, Brannigan RE, et al. Validity of midday total testosterone levels in older men with erectile dysfunction. J Urol. 2014;192:165-169.
2. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95:2536-2559.
3. Cooke RR, McIntosh JE, McIntosh RP. Circadian variation in serum free and non-SHBG-bound testosterone in normal men: measurements, and simulation using a mass action model. Clin Endocrinol (Oxf). 1993;39:163-171.
4. Bremner WJ, Vitiello MV, Prinz PN. Loss of circadian rhythmicity in blood testosterone levels with aging in normal men. J Clin Endocrinol Metab. 1983;56:1278-1281.
5. Brambilla DJ, Matsumoto AM, Araujo AB, et al. The effect of diurnal variation on clinical measurement of serum testosterone and other sex hormone levels in men. J Clin Endocrinol Metab. 2009;94:907-913.
6. Crawford ED, Barqawi AB, O’Donnell C, et al. The association of time of day and serum testosterone concentration in a large screening population. BJU Int. 2007;100:509-513.

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 © 2015. The Family Physicians Inquiries Network. All rights reserved. 

Reprinted with permission from the Family Physicians Inquiries Network and The Journal of Family Practice. 2015;64(7):418-419. 

Illustrative case

It’s noon, you are finishing up a visit with a 62-year-old man with erectile dysfunction (ED), and you want to evaluate for androgen deficiency. Should you ask him to return for an early-morning visit so you can test his testosterone level?

Increasing public awareness of androgen deficiency has led to more men being tested for testosterone levels. Current Endocrine Society guidelines recommend against routine screening for androgen deficiency in men who do not have symptoms.² However, for men with classic symptoms of androgen deficiency—such as decreased libido, ED, infertility, depression, osteoporosis, loss of secondary sexual characteristics, or reduced muscle bulk or strength—measurement of total testosterone level is recommended.²

Due to the natural diurnal variation in serum testosterone levels, the guidelines recommend collecting the sample in the early morning.² This recommendation is based on small observational studies that included men mostly younger than 45 years of age that found a significant difference in testosterone levels between samples drawn early in the morning and in the afternoon.^3-5

In recent years, several studies have indicated that this variation declines as men age.^4-6 Recently, researchers evaluated the effects of age and time of testing on men’s total testosterone levels.

STUDY SUMMARY: Differences in testosterone levels are significant only in younger men

Welliver et al¹ performed a retrospective chart review of 2569 men seen at a Minneapolis Veterans Affairs hospital for ED who had total testosterone levels measured between 7 am and 2 pm over a 15-year period. Men whose total testosterone levels were outside the normal range (>1000 or <50 ng/dL) or who had total testosterone drawn after 2 pm were excluded. The authors analyzed the results based on age, creating one group for men ages <40 years and 5-year age groups for all other men. Using scatterplot techniques, they separated each age group into 2 subgroups based on draw times—7 am to 9 am, or 9 am to 2 pm—and compared the mean total testosterone level for each age and time.

The participants’ mean age was 63 years. Younger men (<45 years) had the largest variation in serum total testosterone, with a large and significant decrease after 9 am. Only the youngest 2 groups (ages <40 and 40-44 years) showed a large decrease in total testosterone in specimens collected after 9 am compared to those drawn between 7 am and 9 am (mean difference 207 and 149 ng/dL, respectively). This variation was not observed in patients over age 45. Although there was a statistically significant difference between early and later testosterone levels in men ages 70 to 74 years, the absolute difference—34 ng/dL (452 vs 418 ng/dL)—was unlikely to be clinically significant.

WHAT'S NEW: For older men, later testing will not affect results

This study confirms previous research showing that the diurnal effect on testosterone levels becomes blunted with increasing age, at least in this group of men with ED. Allowing older men to have total testosterone levels drawn until 2 pm would allow for greater patient flexibility in draw times with little change in results.

CAVEATS: Study's methodology cannot account for several potential confounders

This retrospective study analyzed only a single random testosterone level measurement from each participant, rather than repeat testosterone levels over the course of a day. However, the study was large (2569 men) and it used mean values, which should at least partially mitigate the effect of having only a single level from each participant.

Only the youngest 2 groups (ages <40 and 40-44 years) showed a large decrease in total testosterone in specimens collected after 9 am compared to those drawn between 7 am and 9 am.

The study measured total testosterone and did not account for potential confounding factors—such as obesity or use of testosterone replacement therapy or androgen deprivation therapy—that could affect sexhormone binding globulin, thus potentially altering total testosterone level. However, the authors estimated that less than 2% of the entire cohort were likely to have unrecognized hormonal manipulation with exogenous gonadotropins.

All of the men in the study were seen for ED, and it could be that men with ED have more flattening of the diurnal variation than men without ED; however, we are unaware of other data that support this.

Up to 30% of men who have an early-morning testosterone level that is low may have a normal result when testing is repeated.^2,5 Therefore, for all men who have low testosterone level test results, draw a repeat total testosterone level before 9 am to confirm the diagnosis. Also, this study did not evaluate the course of testosterone levels throughout the later afternoon and evening, and it remains unclear whether levels can be drawn even later in the day.

CHALLENGES TO IMPLEMENTATION: Your lab's policies might require early-morning draws

There will probably be few barriers to implementing this change, unless local laboratory policies are inflexible regarding the timing of testosterone draws.

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

It’s noon, you are finishing up a visit with a 62-year-old man with erectile dysfunction (ED), and you want to evaluate for androgen deficiency. Should you ask him to return for an early-morning visit so you can test his testosterone level?

Increasing public awareness of androgen deficiency has led to more men being tested for testosterone levels. Current Endocrine Society guidelines recommend against routine screening for androgen deficiency in men who do not have symptoms.² However, for men with classic symptoms of androgen deficiency—such as decreased libido, ED, infertility, depression, osteoporosis, loss of secondary sexual characteristics, or reduced muscle bulk or strength—measurement of total testosterone level is recommended.²

Due to the natural diurnal variation in serum testosterone levels, the guidelines recommend collecting the sample in the early morning.² This recommendation is based on small observational studies that included men mostly younger than 45 years of age that found a significant difference in testosterone levels between samples drawn early in the morning and in the afternoon.^3-5

In recent years, several studies have indicated that this variation declines as men age.^4-6 Recently, researchers evaluated the effects of age and time of testing on men’s total testosterone levels.

STUDY SUMMARY: Differences in testosterone levels are significant only in younger men

Welliver et al¹ performed a retrospective chart review of 2569 men seen at a Minneapolis Veterans Affairs hospital for ED who had total testosterone levels measured between 7 am and 2 pm over a 15-year period. Men whose total testosterone levels were outside the normal range (>1000 or <50 ng/dL) or who had total testosterone drawn after 2 pm were excluded. The authors analyzed the results based on age, creating one group for men ages <40 years and 5-year age groups for all other men. Using scatterplot techniques, they separated each age group into 2 subgroups based on draw times—7 am to 9 am, or 9 am to 2 pm—and compared the mean total testosterone level for each age and time.

The participants’ mean age was 63 years. Younger men (<45 years) had the largest variation in serum total testosterone, with a large and significant decrease after 9 am. Only the youngest 2 groups (ages <40 and 40-44 years) showed a large decrease in total testosterone in specimens collected after 9 am compared to those drawn between 7 am and 9 am (mean difference 207 and 149 ng/dL, respectively). This variation was not observed in patients over age 45. Although there was a statistically significant difference between early and later testosterone levels in men ages 70 to 74 years, the absolute difference—34 ng/dL (452 vs 418 ng/dL)—was unlikely to be clinically significant.

WHAT'S NEW: For older men, later testing will not affect results

This study confirms previous research showing that the diurnal effect on testosterone levels becomes blunted with increasing age, at least in this group of men with ED. Allowing older men to have total testosterone levels drawn until 2 pm would allow for greater patient flexibility in draw times with little change in results.

CAVEATS: Study's methodology cannot account for several potential confounders

This retrospective study analyzed only a single random testosterone level measurement from each participant, rather than repeat testosterone levels over the course of a day. However, the study was large (2569 men) and it used mean values, which should at least partially mitigate the effect of having only a single level from each participant.

Only the youngest 2 groups (ages <40 and 40-44 years) showed a large decrease in total testosterone in specimens collected after 9 am compared to those drawn between 7 am and 9 am.

The study measured total testosterone and did not account for potential confounding factors—such as obesity or use of testosterone replacement therapy or androgen deprivation therapy—that could affect sexhormone binding globulin, thus potentially altering total testosterone level. However, the authors estimated that less than 2% of the entire cohort were likely to have unrecognized hormonal manipulation with exogenous gonadotropins.

All of the men in the study were seen for ED, and it could be that men with ED have more flattening of the diurnal variation than men without ED; however, we are unaware of other data that support this.

Up to 30% of men who have an early-morning testosterone level that is low may have a normal result when testing is repeated.^2,5 Therefore, for all men who have low testosterone level test results, draw a repeat total testosterone level before 9 am to confirm the diagnosis. Also, this study did not evaluate the course of testosterone levels throughout the later afternoon and evening, and it remains unclear whether levels can be drawn even later in the day.

CHALLENGES TO IMPLEMENTATION: Your lab's policies might require early-morning draws

There will probably be few barriers to implementing this change, unless local laboratory policies are inflexible regarding the timing of testosterone draws.

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

It’s noon, you are finishing up a visit with a 62-year-old man with erectile dysfunction (ED), and you want to evaluate for androgen deficiency. Should you ask him to return for an early-morning visit so you can test his testosterone level?

Increasing public awareness of androgen deficiency has led to more men being tested for testosterone levels. Current Endocrine Society guidelines recommend against routine screening for androgen deficiency in men who do not have symptoms.² However, for men with classic symptoms of androgen deficiency—such as decreased libido, ED, infertility, depression, osteoporosis, loss of secondary sexual characteristics, or reduced muscle bulk or strength—measurement of total testosterone level is recommended.²

Due to the natural diurnal variation in serum testosterone levels, the guidelines recommend collecting the sample in the early morning.² This recommendation is based on small observational studies that included men mostly younger than 45 years of age that found a significant difference in testosterone levels between samples drawn early in the morning and in the afternoon.^3-5

In recent years, several studies have indicated that this variation declines as men age.^4-6 Recently, researchers evaluated the effects of age and time of testing on men’s total testosterone levels.

STUDY SUMMARY: Differences in testosterone levels are significant only in younger men

Welliver et al¹ performed a retrospective chart review of 2569 men seen at a Minneapolis Veterans Affairs hospital for ED who had total testosterone levels measured between 7 am and 2 pm over a 15-year period. Men whose total testosterone levels were outside the normal range (>1000 or <50 ng/dL) or who had total testosterone drawn after 2 pm were excluded. The authors analyzed the results based on age, creating one group for men ages <40 years and 5-year age groups for all other men. Using scatterplot techniques, they separated each age group into 2 subgroups based on draw times—7 am to 9 am, or 9 am to 2 pm—and compared the mean total testosterone level for each age and time.

The participants’ mean age was 63 years. Younger men (<45 years) had the largest variation in serum total testosterone, with a large and significant decrease after 9 am. Only the youngest 2 groups (ages <40 and 40-44 years) showed a large decrease in total testosterone in specimens collected after 9 am compared to those drawn between 7 am and 9 am (mean difference 207 and 149 ng/dL, respectively). This variation was not observed in patients over age 45. Although there was a statistically significant difference between early and later testosterone levels in men ages 70 to 74 years, the absolute difference—34 ng/dL (452 vs 418 ng/dL)—was unlikely to be clinically significant.

WHAT'S NEW: For older men, later testing will not affect results

This study confirms previous research showing that the diurnal effect on testosterone levels becomes blunted with increasing age, at least in this group of men with ED. Allowing older men to have total testosterone levels drawn until 2 pm would allow for greater patient flexibility in draw times with little change in results.

CAVEATS: Study's methodology cannot account for several potential confounders

This retrospective study analyzed only a single random testosterone level measurement from each participant, rather than repeat testosterone levels over the course of a day. However, the study was large (2569 men) and it used mean values, which should at least partially mitigate the effect of having only a single level from each participant.

Only the youngest 2 groups (ages <40 and 40-44 years) showed a large decrease in total testosterone in specimens collected after 9 am compared to those drawn between 7 am and 9 am.

The study measured total testosterone and did not account for potential confounding factors—such as obesity or use of testosterone replacement therapy or androgen deprivation therapy—that could affect sexhormone binding globulin, thus potentially altering total testosterone level. However, the authors estimated that less than 2% of the entire cohort were likely to have unrecognized hormonal manipulation with exogenous gonadotropins.

All of the men in the study were seen for ED, and it could be that men with ED have more flattening of the diurnal variation than men without ED; however, we are unaware of other data that support this.

Up to 30% of men who have an early-morning testosterone level that is low may have a normal result when testing is repeated.^2,5 Therefore, for all men who have low testosterone level test results, draw a repeat total testosterone level before 9 am to confirm the diagnosis. Also, this study did not evaluate the course of testosterone levels throughout the later afternoon and evening, and it remains unclear whether levels can be drawn even later in the day.

CHALLENGES TO IMPLEMENTATION: Your lab's policies might require early-morning draws

There will probably be few barriers to implementing this change, unless local laboratory policies are inflexible regarding the timing of testosterone draws.

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.