John Hickner, MD, MSc

ILLUSTRATIVE CASE

A 34-year-old woman comes to your office and asks to be taken off the paroxetine you prescribed for her 4 months ago. The medication is working well; her depression has been in remission for at least 12 weeks. But she no longer enjoys sex. She used to have a healthy libido and satisfying arousal and orgasm, but since starting the antidepressant, her sexual interest and pleasure have been low.

Although she’s afraid of sinking back into a depression without the medication, she’s willing to take the risk. If she were your patient, what alternatives would you suggest?

Sexual dysfunction affects an estimated 30% to 50% of patients on selective and nonselective SRIs, and some studies report rates as high as 70% to 80%.² Many patients stop taking these antidepressants prematurely, often because of sexual side effects.^3,4

Phosphodiesterase type 5 (PDE-5) inhibitors are well established as an effective treatment for erectile dysfunction,⁵ and randomized controlled trials (RCTs) have shown sildenafil to be effective in treating male SRI-induced sexual impairment.^6,7 For women, there has been no parallel evidence-based treatment.

Limited options, with little support

Typically, women who reported antidepressant-associated sexual disturbances have been offered options for which there was only weak evidence—dose changes or augmentation with another agent, switching to another antidepressant, or taking occasional drug holidays. A 2004 Cochrane review found that there were no RCTs involving dose changes or drug holidays.⁸ Among studies of the efficacy of switching to a different drug, nefazodone was the only agent whose use was supported by a double-blind RCT.⁹ Augmentation trials of a wide range of medications and supplements—including amantadine, bupropion, buspirone, granisetron, mirtazapine, olanzapine, ephedrine, ginkgo biloba, and yohimbine—yielded mixed results. Indeed, the research found that some were no better than placebo.

PDE-5 inhibitors for women? Inconclusive studies to date

Female sexual dysfunction is generally divided into 4 domains: disorders of desire, arousal, orgasm, or pain. Decreased desire and delayed or absent orgasm are the most common sexual side effects of SRI antidepressants in women.¹⁰ Several studies of PDE-5 inhibitors in this patient population have had positive results,^11-15 so there has been good reason to think that they might help this subset of women. However, all the studies were small and nonblinded, and therefore inconclusive—until now.

STUDY SUMMARY: Finally, a well-done RCT provides some answers

Investigators enrolled 98 premenopausal women from 7 US research centers in a double-blind randomized trial. To qualify, participants had to be diagnosed with major depression in remission, be taking a selective or nonselective SRI for >8 weeks, and be on a stable dose for >4 weeks. They also had to meet Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for substance-induced sexual dysfunction lasting >4 weeks, but have no history of sexual impairment independent of antidepressants. Finally, participants had to engage in some form of regular sexual activity—intercourse, oral sex, and masturbation all qualified—at least twice a month, and be willing to continue efforts to have sex at least once a week during the study. Women with other medical, psychiatric, or sexual problems were excluded, as were those who were pregnant, breastfeeding, or able to become pregnant and not using reliable contraception.

Participants were randomized to receive 50 mg of sildenafil (n=49) or a matching placebo tablet (n=49), which they were instructed to take 1 to 2 hours before sexual activity. The dose could be adjusted to 2 tablets (100 mg sildenafil) based on investigator assessment of the patient’s response to the initial dose. Participants and all study personnel were blinded to group assignment.

The primary outcome was change from baseline to end-point in the Clinical Global Impression Scale, a clinician-rated scale based on review of patient symptoms that was adapted to evaluate sexual function. Secondary outcomes were changes in 3 other sexual function scales, the Hamilton Rating Scale for Depression, and measured hormone levels.

Investigators followed the women for 8 weeks, measuring outcomes at 2, 4, and 8 weeks.

Sildenafil is better than placebo

Using an intention-to-treat analysis with the last measurement (2, 4, or 8 weeks) as the end-point, both the treatment and placebo groups experienced improvement in sexual function. The sildenafil group improved more than the placebo group. On the Clinical Global Impression Scale (1 to 7, with higher scores indicating worse sexual function), sildenafil users went from a mean of 4.8 to 2.8, while placebo users went from a mean of 4.7 to 3.6. The difference in mean change from baseline was 0.8 (95% confidence interval [CI] 0.6-1.0; P=.001). Using a more conservative analysis in which participants who did not return for the 8-week follow-up visit were assumed to have returned to baseline, the difference in mean change from baseline was smaller (0.6, 95% CI, 0.3-0.8; P=0.03) but still statistically significant.

Orgasmic function shows significant improvement

The sexual function scales used as secondary outcomes provided more detail about which types of sexual dysfunction benefited from sildenafil. On all 3 scales, orgasmic function significantly favored sildenafil over placebo. In the domains of desire, arousal, and pain disorders, small to moderate improvements were seen in both groups, with no statistically significant differences. One potential confounder—a difference in the course of participants’ underlying depression— was ruled out because depression scale results remained unchanged from baseline to endpoint in both groups.

Baseline levels of cortisone, estradiol, follicle-stimulating hormone, leuteinizing hormone, progesterone, prolactin, sex hormone-binding globulin, testosterone, thyroid-stimulating hormone, and thyroxine, were normal, with no differences between the sildenafil and placebo groups.

WHAT’S NEW: Women have an evidence-based option

Like their male counterparts, we can now offer women whose depression is effectively treated by SRI antidepressants—and who are motivated to stay sexually active despite medication-associated side effects—an effective pharmacotherapeutic treatment.

CAVEATS: Side effects and study funding are worth noting

Side effects. Significantly more participants in the sildenafil group vs the placebo group experienced the following side effects: headache (43% vs 27%), visual disturbance (14% vs 2%), dyspepsia (12% vs 0%), flushing (24% vs 0%), nasal congestion (37% vs 6%), and palpitations (8% vs 2%). Nausea was the only side effect that was more common in the placebo group, reported by only 2% of those in the intervention group but 16% of those on placebo.

No serious adverse events occurred, however, and the medication appears to have been well tolerated overall, despite relatively high rates of side effects. Participants in the intervention group used an average of 5 doses of sildenafil per 2-week interval, the same number as those in the placebo group.

Small treatment effect. The difference in response between sildenafil and placebo was not large: 0.8 points on a 7-point scale. But this difference is likely a clinically meaningful effect to the women with this problem.

Drug company funding. Pfizer, the maker of Viagra, funded this study through an investigator-initiated grant. Some researchers argue that female sexual dysfunction has been defined, or even invented, by drug companies seeking to create new markets for their products.¹⁶ This concern, coupled with the fact that this is the only double-blind randomized trial to show that sildenafil benefits women with antidepressant-associated sexual impairment, raises the question of whether this finding will be replicated in future trials.

We were reassured by the authors’ statement that Pfizer had no role in the study design, implementation, analysis, or manuscript preparation. And we know from clinical practice that women do suffer from SRI-induced sexual side effects, and sometimes stop taking much-needed antidepressants because the medication interferes with their ability to have a satisfying sex life. We believe this study was well done and offers a promising new therapy that deserves consideration. We hope that additional trials will follow and that investigators and journals will not hesitate to publish negative results.

Not for all women with sexual dysfunction

It’s a safe bet that these findings will be used to market sildenafil to women. It is therefore important for physicians and patients to keep in mind that this trial focused on a well-defined subset of women with sexual dysfunction: those on a stable dose of an SRI, with depression in remission, who were otherwise healthy and not pregnant, breastfeeding, or planning pregnancy, and who were motivated to be sexually active. Although this study does support the use of sildenafil for women in this subset, it does not support the use of PDE-5 inhibitors such as sildenafil for all women with sexual difficulties.

CHALLENGES TO IMPLEMENTATION: You have to ask!

Studies have repeatedly found that many women who experience sexual problems do not broach the subject with their doctors.¹⁷ So don’t wait for your female patients to bring it up. Sexual side effects are common enough with SRI antidepressants that all prescribers should mention the possibility in advance. Tell patients to let you know if they develop medication-related sexual dysfunction, and reassure them that there are treatments that can help.

Acknowledgment

The PURLs Surveillance System is 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.

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 34-year-old woman comes to your office and asks to be taken off the paroxetine you prescribed for her 4 months ago. The medication is working well; her depression has been in remission for at least 12 weeks. But she no longer enjoys sex. She used to have a healthy libido and satisfying arousal and orgasm, but since starting the antidepressant, her sexual interest and pleasure have been low.

Although she’s afraid of sinking back into a depression without the medication, she’s willing to take the risk. If she were your patient, what alternatives would you suggest?

Sexual dysfunction affects an estimated 30% to 50% of patients on selective and nonselective SRIs, and some studies report rates as high as 70% to 80%.² Many patients stop taking these antidepressants prematurely, often because of sexual side effects.^3,4

Phosphodiesterase type 5 (PDE-5) inhibitors are well established as an effective treatment for erectile dysfunction,⁵ and randomized controlled trials (RCTs) have shown sildenafil to be effective in treating male SRI-induced sexual impairment.^6,7 For women, there has been no parallel evidence-based treatment.

Limited options, with little support

Typically, women who reported antidepressant-associated sexual disturbances have been offered options for which there was only weak evidence—dose changes or augmentation with another agent, switching to another antidepressant, or taking occasional drug holidays. A 2004 Cochrane review found that there were no RCTs involving dose changes or drug holidays.⁸ Among studies of the efficacy of switching to a different drug, nefazodone was the only agent whose use was supported by a double-blind RCT.⁹ Augmentation trials of a wide range of medications and supplements—including amantadine, bupropion, buspirone, granisetron, mirtazapine, olanzapine, ephedrine, ginkgo biloba, and yohimbine—yielded mixed results. Indeed, the research found that some were no better than placebo.

PDE-5 inhibitors for women? Inconclusive studies to date

Female sexual dysfunction is generally divided into 4 domains: disorders of desire, arousal, orgasm, or pain. Decreased desire and delayed or absent orgasm are the most common sexual side effects of SRI antidepressants in women.¹⁰ Several studies of PDE-5 inhibitors in this patient population have had positive results,^11-15 so there has been good reason to think that they might help this subset of women. However, all the studies were small and nonblinded, and therefore inconclusive—until now.

STUDY SUMMARY: Finally, a well-done RCT provides some answers

Investigators enrolled 98 premenopausal women from 7 US research centers in a double-blind randomized trial. To qualify, participants had to be diagnosed with major depression in remission, be taking a selective or nonselective SRI for >8 weeks, and be on a stable dose for >4 weeks. They also had to meet Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for substance-induced sexual dysfunction lasting >4 weeks, but have no history of sexual impairment independent of antidepressants. Finally, participants had to engage in some form of regular sexual activity—intercourse, oral sex, and masturbation all qualified—at least twice a month, and be willing to continue efforts to have sex at least once a week during the study. Women with other medical, psychiatric, or sexual problems were excluded, as were those who were pregnant, breastfeeding, or able to become pregnant and not using reliable contraception.

Participants were randomized to receive 50 mg of sildenafil (n=49) or a matching placebo tablet (n=49), which they were instructed to take 1 to 2 hours before sexual activity. The dose could be adjusted to 2 tablets (100 mg sildenafil) based on investigator assessment of the patient’s response to the initial dose. Participants and all study personnel were blinded to group assignment.

The primary outcome was change from baseline to end-point in the Clinical Global Impression Scale, a clinician-rated scale based on review of patient symptoms that was adapted to evaluate sexual function. Secondary outcomes were changes in 3 other sexual function scales, the Hamilton Rating Scale for Depression, and measured hormone levels.

Investigators followed the women for 8 weeks, measuring outcomes at 2, 4, and 8 weeks.

Sildenafil is better than placebo

Using an intention-to-treat analysis with the last measurement (2, 4, or 8 weeks) as the end-point, both the treatment and placebo groups experienced improvement in sexual function. The sildenafil group improved more than the placebo group. On the Clinical Global Impression Scale (1 to 7, with higher scores indicating worse sexual function), sildenafil users went from a mean of 4.8 to 2.8, while placebo users went from a mean of 4.7 to 3.6. The difference in mean change from baseline was 0.8 (95% confidence interval [CI] 0.6-1.0; P=.001). Using a more conservative analysis in which participants who did not return for the 8-week follow-up visit were assumed to have returned to baseline, the difference in mean change from baseline was smaller (0.6, 95% CI, 0.3-0.8; P=0.03) but still statistically significant.

Orgasmic function shows significant improvement

The sexual function scales used as secondary outcomes provided more detail about which types of sexual dysfunction benefited from sildenafil. On all 3 scales, orgasmic function significantly favored sildenafil over placebo. In the domains of desire, arousal, and pain disorders, small to moderate improvements were seen in both groups, with no statistically significant differences. One potential confounder—a difference in the course of participants’ underlying depression— was ruled out because depression scale results remained unchanged from baseline to endpoint in both groups.

Baseline levels of cortisone, estradiol, follicle-stimulating hormone, leuteinizing hormone, progesterone, prolactin, sex hormone-binding globulin, testosterone, thyroid-stimulating hormone, and thyroxine, were normal, with no differences between the sildenafil and placebo groups.

WHAT’S NEW: Women have an evidence-based option

Like their male counterparts, we can now offer women whose depression is effectively treated by SRI antidepressants—and who are motivated to stay sexually active despite medication-associated side effects—an effective pharmacotherapeutic treatment.

CAVEATS: Side effects and study funding are worth noting

Side effects. Significantly more participants in the sildenafil group vs the placebo group experienced the following side effects: headache (43% vs 27%), visual disturbance (14% vs 2%), dyspepsia (12% vs 0%), flushing (24% vs 0%), nasal congestion (37% vs 6%), and palpitations (8% vs 2%). Nausea was the only side effect that was more common in the placebo group, reported by only 2% of those in the intervention group but 16% of those on placebo.

No serious adverse events occurred, however, and the medication appears to have been well tolerated overall, despite relatively high rates of side effects. Participants in the intervention group used an average of 5 doses of sildenafil per 2-week interval, the same number as those in the placebo group.

Small treatment effect. The difference in response between sildenafil and placebo was not large: 0.8 points on a 7-point scale. But this difference is likely a clinically meaningful effect to the women with this problem.

Drug company funding. Pfizer, the maker of Viagra, funded this study through an investigator-initiated grant. Some researchers argue that female sexual dysfunction has been defined, or even invented, by drug companies seeking to create new markets for their products.¹⁶ This concern, coupled with the fact that this is the only double-blind randomized trial to show that sildenafil benefits women with antidepressant-associated sexual impairment, raises the question of whether this finding will be replicated in future trials.

We were reassured by the authors’ statement that Pfizer had no role in the study design, implementation, analysis, or manuscript preparation. And we know from clinical practice that women do suffer from SRI-induced sexual side effects, and sometimes stop taking much-needed antidepressants because the medication interferes with their ability to have a satisfying sex life. We believe this study was well done and offers a promising new therapy that deserves consideration. We hope that additional trials will follow and that investigators and journals will not hesitate to publish negative results.

Not for all women with sexual dysfunction

It’s a safe bet that these findings will be used to market sildenafil to women. It is therefore important for physicians and patients to keep in mind that this trial focused on a well-defined subset of women with sexual dysfunction: those on a stable dose of an SRI, with depression in remission, who were otherwise healthy and not pregnant, breastfeeding, or planning pregnancy, and who were motivated to be sexually active. Although this study does support the use of sildenafil for women in this subset, it does not support the use of PDE-5 inhibitors such as sildenafil for all women with sexual difficulties.

CHALLENGES TO IMPLEMENTATION: You have to ask!

Studies have repeatedly found that many women who experience sexual problems do not broach the subject with their doctors.¹⁷ So don’t wait for your female patients to bring it up. Sexual side effects are common enough with SRI antidepressants that all prescribers should mention the possibility in advance. Tell patients to let you know if they develop medication-related sexual dysfunction, and reassure them that there are treatments that can help.

Acknowledgment

The PURLs Surveillance System is 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.

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 34-year-old woman comes to your office and asks to be taken off the paroxetine you prescribed for her 4 months ago. The medication is working well; her depression has been in remission for at least 12 weeks. But she no longer enjoys sex. She used to have a healthy libido and satisfying arousal and orgasm, but since starting the antidepressant, her sexual interest and pleasure have been low.

Although she’s afraid of sinking back into a depression without the medication, she’s willing to take the risk. If she were your patient, what alternatives would you suggest?

Sexual dysfunction affects an estimated 30% to 50% of patients on selective and nonselective SRIs, and some studies report rates as high as 70% to 80%.² Many patients stop taking these antidepressants prematurely, often because of sexual side effects.^3,4

Phosphodiesterase type 5 (PDE-5) inhibitors are well established as an effective treatment for erectile dysfunction,⁵ and randomized controlled trials (RCTs) have shown sildenafil to be effective in treating male SRI-induced sexual impairment.^6,7 For women, there has been no parallel evidence-based treatment.

Limited options, with little support

Typically, women who reported antidepressant-associated sexual disturbances have been offered options for which there was only weak evidence—dose changes or augmentation with another agent, switching to another antidepressant, or taking occasional drug holidays. A 2004 Cochrane review found that there were no RCTs involving dose changes or drug holidays.⁸ Among studies of the efficacy of switching to a different drug, nefazodone was the only agent whose use was supported by a double-blind RCT.⁹ Augmentation trials of a wide range of medications and supplements—including amantadine, bupropion, buspirone, granisetron, mirtazapine, olanzapine, ephedrine, ginkgo biloba, and yohimbine—yielded mixed results. Indeed, the research found that some were no better than placebo.

PDE-5 inhibitors for women? Inconclusive studies to date

Female sexual dysfunction is generally divided into 4 domains: disorders of desire, arousal, orgasm, or pain. Decreased desire and delayed or absent orgasm are the most common sexual side effects of SRI antidepressants in women.¹⁰ Several studies of PDE-5 inhibitors in this patient population have had positive results,^11-15 so there has been good reason to think that they might help this subset of women. However, all the studies were small and nonblinded, and therefore inconclusive—until now.

STUDY SUMMARY: Finally, a well-done RCT provides some answers

Investigators enrolled 98 premenopausal women from 7 US research centers in a double-blind randomized trial. To qualify, participants had to be diagnosed with major depression in remission, be taking a selective or nonselective SRI for >8 weeks, and be on a stable dose for >4 weeks. They also had to meet Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (DSM-IV) criteria for substance-induced sexual dysfunction lasting >4 weeks, but have no history of sexual impairment independent of antidepressants. Finally, participants had to engage in some form of regular sexual activity—intercourse, oral sex, and masturbation all qualified—at least twice a month, and be willing to continue efforts to have sex at least once a week during the study. Women with other medical, psychiatric, or sexual problems were excluded, as were those who were pregnant, breastfeeding, or able to become pregnant and not using reliable contraception.

Participants were randomized to receive 50 mg of sildenafil (n=49) or a matching placebo tablet (n=49), which they were instructed to take 1 to 2 hours before sexual activity. The dose could be adjusted to 2 tablets (100 mg sildenafil) based on investigator assessment of the patient’s response to the initial dose. Participants and all study personnel were blinded to group assignment.

The primary outcome was change from baseline to end-point in the Clinical Global Impression Scale, a clinician-rated scale based on review of patient symptoms that was adapted to evaluate sexual function. Secondary outcomes were changes in 3 other sexual function scales, the Hamilton Rating Scale for Depression, and measured hormone levels.

Investigators followed the women for 8 weeks, measuring outcomes at 2, 4, and 8 weeks.

Sildenafil is better than placebo

Using an intention-to-treat analysis with the last measurement (2, 4, or 8 weeks) as the end-point, both the treatment and placebo groups experienced improvement in sexual function. The sildenafil group improved more than the placebo group. On the Clinical Global Impression Scale (1 to 7, with higher scores indicating worse sexual function), sildenafil users went from a mean of 4.8 to 2.8, while placebo users went from a mean of 4.7 to 3.6. The difference in mean change from baseline was 0.8 (95% confidence interval [CI] 0.6-1.0; P=.001). Using a more conservative analysis in which participants who did not return for the 8-week follow-up visit were assumed to have returned to baseline, the difference in mean change from baseline was smaller (0.6, 95% CI, 0.3-0.8; P=0.03) but still statistically significant.

Orgasmic function shows significant improvement

The sexual function scales used as secondary outcomes provided more detail about which types of sexual dysfunction benefited from sildenafil. On all 3 scales, orgasmic function significantly favored sildenafil over placebo. In the domains of desire, arousal, and pain disorders, small to moderate improvements were seen in both groups, with no statistically significant differences. One potential confounder—a difference in the course of participants’ underlying depression— was ruled out because depression scale results remained unchanged from baseline to endpoint in both groups.

Baseline levels of cortisone, estradiol, follicle-stimulating hormone, leuteinizing hormone, progesterone, prolactin, sex hormone-binding globulin, testosterone, thyroid-stimulating hormone, and thyroxine, were normal, with no differences between the sildenafil and placebo groups.

WHAT’S NEW: Women have an evidence-based option

Like their male counterparts, we can now offer women whose depression is effectively treated by SRI antidepressants—and who are motivated to stay sexually active despite medication-associated side effects—an effective pharmacotherapeutic treatment.

CAVEATS: Side effects and study funding are worth noting

Side effects. Significantly more participants in the sildenafil group vs the placebo group experienced the following side effects: headache (43% vs 27%), visual disturbance (14% vs 2%), dyspepsia (12% vs 0%), flushing (24% vs 0%), nasal congestion (37% vs 6%), and palpitations (8% vs 2%). Nausea was the only side effect that was more common in the placebo group, reported by only 2% of those in the intervention group but 16% of those on placebo.

No serious adverse events occurred, however, and the medication appears to have been well tolerated overall, despite relatively high rates of side effects. Participants in the intervention group used an average of 5 doses of sildenafil per 2-week interval, the same number as those in the placebo group.

Small treatment effect. The difference in response between sildenafil and placebo was not large: 0.8 points on a 7-point scale. But this difference is likely a clinically meaningful effect to the women with this problem.

Drug company funding. Pfizer, the maker of Viagra, funded this study through an investigator-initiated grant. Some researchers argue that female sexual dysfunction has been defined, or even invented, by drug companies seeking to create new markets for their products.¹⁶ This concern, coupled with the fact that this is the only double-blind randomized trial to show that sildenafil benefits women with antidepressant-associated sexual impairment, raises the question of whether this finding will be replicated in future trials.

We were reassured by the authors’ statement that Pfizer had no role in the study design, implementation, analysis, or manuscript preparation. And we know from clinical practice that women do suffer from SRI-induced sexual side effects, and sometimes stop taking much-needed antidepressants because the medication interferes with their ability to have a satisfying sex life. We believe this study was well done and offers a promising new therapy that deserves consideration. We hope that additional trials will follow and that investigators and journals will not hesitate to publish negative results.

Not for all women with sexual dysfunction

It’s a safe bet that these findings will be used to market sildenafil to women. It is therefore important for physicians and patients to keep in mind that this trial focused on a well-defined subset of women with sexual dysfunction: those on a stable dose of an SRI, with depression in remission, who were otherwise healthy and not pregnant, breastfeeding, or planning pregnancy, and who were motivated to be sexually active. Although this study does support the use of sildenafil for women in this subset, it does not support the use of PDE-5 inhibitors such as sildenafil for all women with sexual difficulties.

CHALLENGES TO IMPLEMENTATION: You have to ask!

Studies have repeatedly found that many women who experience sexual problems do not broach the subject with their doctors.¹⁷ So don’t wait for your female patients to bring it up. Sexual side effects are common enough with SRI antidepressants that all prescribers should mention the possibility in advance. Tell patients to let you know if they develop medication-related sexual dysfunction, and reassure them that there are treatments that can help.

Acknowledgment

The PURLs Surveillance System is 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.

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 68-year-old man with a history of ulcer disease and mild renal insufficiency comes to your office complaining of severe pain in his right foot. You note swelling and redness around the base of the big toe and diagnose acute gout. Wishing to avoid nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine because of the patient’s medical history, you wonder what you can safely prescribe for pain relief.

NSAIDs have become the mainstay of treatment for acute gout,^3,4 replacing colchicine—widely used for gout pain relief since the early 19th century.⁵ Colchicine fell out of favor because it routinely causes diarrhea and requires caution in patients with renal insufficiency.⁶ Now, however, there is growing concern about the adverse effects of NSAIDs.

Comorbidities, age, mean fewer options

NSAIDs increase the risk of gastrointestinal (GI) bleeding, especially in the first week of use.⁷ Cyclooxygenase-2 (COX-2) inhibitors, considered as effective as NSAIDs in treating acute gout pain,⁸ are also associated with GI bleeds.⁹ In addition, NSAIDs and COX-2 inhibitors increase cardiovascular risks, prompting the American Heart Association to recommend restricted use of both.¹⁰ NSAIDs’ effect on renal function, fluid retention, and interactions with anticoagulants are additional concerns, because gout patients are generally older and often have comorbid renal and cardiovascular diseases.^3,11-13

In the United States, nearly 70% of patients who develop acute gout seek treatment from primary care physicians.¹² Family physicians need a safe alternative to NSAIDs to relieve the severe pain associated with this condition. Will oral corticosteroids fit the bill?

STUDY SUMMARIES: Oral steroids: A safe and effective alternative

Janssens et al¹ conducted a double-blind, randomized equivalence trial of 118 patients to compare the efficacy of prednisolone and naproxen for the treatment of monoarticular gout, confirmed by crystal analysis of synovial fluid. The study was conducted in the eastern Netherlands at a trial center patients were referred to by their family physicians. Those with major comorbidities, including a history of GI bleed or peptic ulcer, were excluded.

Participants were randomized to receive either prednisolone 35 mg* or naproxen 500 mg twice a day, with look-alike placebo tablets of the alternate drug, for 5 days. Pain, the primary outcome, was scored on a validated visual analog scale from 0 mm (no pain) to 100 mm (worst pain experienced).¹⁵ The reduction in the pain score at 90 hours was similar in both groups. Only a few minor side effects were reported in both groups, and all completely resolved in 3 weeks.

The study by Man et al² was a randomized trial that compared indomethacin with oral prednisolone in 90 patients presenting to an emergency department in Hong Kong. Diagnosis of gout was made by clinical impression. Participants in the indomethacin group also received an intramuscular (IM) injection of diclofenac 75 mg, and those in both groups were monitored for acetaminophen use as a secondary endpoint.

Pain reduction, the primary endpoint, was assessed with a 10-point visual analog score, and was slightly better statistically in the oral steroid group. The study was not designed to evaluate for safety, but the authors noted that patients in the indomethacin group experienced more adverse effects (number needed to harm [NNH] for any adverse event: 3; NNH for serious events: 6).

Short-term steroids have few side effects

In both studies, patients receiving oral steroids experienced no significant side effects. This finding is consistent with other studies that have investigated short-term oral steroid use in the treatment of both rheumatoid arthritis and asthma.^16,17

WHAT’S NEW?: Evidence supports use of steroids for acute gout

In the United States, prednisone is prescribed as treatment for acute gout only about 9% of the time.¹² These 2 studies—the first randomized trials comparing oral steroids with NSAIDs, the usual gout treatment—may lead to greater use of steroids for this painful condition.

Both studies were well designed and conducted in an outpatient (or emergency) setting. Both showed that a short course of oral steroids is as effective as NSAIDs, and without significant side effects.

Previous studies have compared IM steroids with NSAIDs, and IM steroids with IM adrenocorticotropic hormone (ACTH).^18,19 However, these studies were not blinded—just one of their methodological problems.⁴

CAVEATS: Joint aspiration is not the norm

In the Janssens study, participants were diagnosed with gout after monosodium urate crystals were found in joint aspirate.¹ This may not be the usual practice in primary care settings, where a clinical diagnosis of gout is typically made. The authors indicate that the failure to perform joint aspiration will lead to occasional cases of septic arthritis being treated with oral steroids. We recommend joint aspiration or a referral for such a procedure when clinical evidence (eg, fever and leukocytosis) is suggestive of septic arthritis.

Possible impact of acetaminophen

In the study by Man et al, acetaminophen was used by both groups as an adjunct for pain relief, and the amount used was higher (mean 10.3 g vs 6.4 g over 14 days) in the oral steroid group. It is possible that some of the pain relief experienced by those in the steroid group may have been from acetaminophen; however, a difference of 4 g over a 14-day period makes that unlikely. Even if additional acetaminophen is required, the advantages of oral steroids rather than NSAIDs or colchicine for patients with contraindications remain.

Also of note: These trials examined short-term treatment of acute gout. These findings cannot be extrapolated to the treatment of intercurrent gout or chronic gouty arthritis, since long-term steroid use has severe adverse effects.

CHALLENGES TO IMPLEMENTATION: No significant barriers

We found little to prevent physicians from adopting this practice changer. Oral steroids are readily available and inexpensive, and most primary care clinicians regularly prescribe them for other conditions. This practice change recommendation should be readily implemented.

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

* Prednisone is the precursor of prednisolone and is activated in the liver. The activity of both drugs is comparable, and prednisone and prednisolone can be converted milligram to milligram. However, prednisolone may be preferred for patients with severe liver disease.¹⁴ (In the United States, prednisolone is available as a liquid and prednisone as a tablet.)

PURL METHODOLOGY
The PURLs Surveillance System is 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 68-year-old man with a history of ulcer disease and mild renal insufficiency comes to your office complaining of severe pain in his right foot. You note swelling and redness around the base of the big toe and diagnose acute gout. Wishing to avoid nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine because of the patient’s medical history, you wonder what you can safely prescribe for pain relief.

NSAIDs have become the mainstay of treatment for acute gout,^3,4 replacing colchicine—widely used for gout pain relief since the early 19th century.⁵ Colchicine fell out of favor because it routinely causes diarrhea and requires caution in patients with renal insufficiency.⁶ Now, however, there is growing concern about the adverse effects of NSAIDs.

Comorbidities, age, mean fewer options

NSAIDs increase the risk of gastrointestinal (GI) bleeding, especially in the first week of use.⁷ Cyclooxygenase-2 (COX-2) inhibitors, considered as effective as NSAIDs in treating acute gout pain,⁸ are also associated with GI bleeds.⁹ In addition, NSAIDs and COX-2 inhibitors increase cardiovascular risks, prompting the American Heart Association to recommend restricted use of both.¹⁰ NSAIDs’ effect on renal function, fluid retention, and interactions with anticoagulants are additional concerns, because gout patients are generally older and often have comorbid renal and cardiovascular diseases.^3,11-13

In the United States, nearly 70% of patients who develop acute gout seek treatment from primary care physicians.¹² Family physicians need a safe alternative to NSAIDs to relieve the severe pain associated with this condition. Will oral corticosteroids fit the bill?

STUDY SUMMARIES: Oral steroids: A safe and effective alternative

Janssens et al¹ conducted a double-blind, randomized equivalence trial of 118 patients to compare the efficacy of prednisolone and naproxen for the treatment of monoarticular gout, confirmed by crystal analysis of synovial fluid. The study was conducted in the eastern Netherlands at a trial center patients were referred to by their family physicians. Those with major comorbidities, including a history of GI bleed or peptic ulcer, were excluded.

Participants were randomized to receive either prednisolone 35 mg* or naproxen 500 mg twice a day, with look-alike placebo tablets of the alternate drug, for 5 days. Pain, the primary outcome, was scored on a validated visual analog scale from 0 mm (no pain) to 100 mm (worst pain experienced).¹⁵ The reduction in the pain score at 90 hours was similar in both groups. Only a few minor side effects were reported in both groups, and all completely resolved in 3 weeks.

The study by Man et al² was a randomized trial that compared indomethacin with oral prednisolone in 90 patients presenting to an emergency department in Hong Kong. Diagnosis of gout was made by clinical impression. Participants in the indomethacin group also received an intramuscular (IM) injection of diclofenac 75 mg, and those in both groups were monitored for acetaminophen use as a secondary endpoint.

Pain reduction, the primary endpoint, was assessed with a 10-point visual analog score, and was slightly better statistically in the oral steroid group. The study was not designed to evaluate for safety, but the authors noted that patients in the indomethacin group experienced more adverse effects (number needed to harm [NNH] for any adverse event: 3; NNH for serious events: 6).

Short-term steroids have few side effects

In both studies, patients receiving oral steroids experienced no significant side effects. This finding is consistent with other studies that have investigated short-term oral steroid use in the treatment of both rheumatoid arthritis and asthma.^16,17

WHAT’S NEW?: Evidence supports use of steroids for acute gout

In the United States, prednisone is prescribed as treatment for acute gout only about 9% of the time.¹² These 2 studies—the first randomized trials comparing oral steroids with NSAIDs, the usual gout treatment—may lead to greater use of steroids for this painful condition.

Both studies were well designed and conducted in an outpatient (or emergency) setting. Both showed that a short course of oral steroids is as effective as NSAIDs, and without significant side effects.

Previous studies have compared IM steroids with NSAIDs, and IM steroids with IM adrenocorticotropic hormone (ACTH).^18,19 However, these studies were not blinded—just one of their methodological problems.⁴

CAVEATS: Joint aspiration is not the norm

In the Janssens study, participants were diagnosed with gout after monosodium urate crystals were found in joint aspirate.¹ This may not be the usual practice in primary care settings, where a clinical diagnosis of gout is typically made. The authors indicate that the failure to perform joint aspiration will lead to occasional cases of septic arthritis being treated with oral steroids. We recommend joint aspiration or a referral for such a procedure when clinical evidence (eg, fever and leukocytosis) is suggestive of septic arthritis.

Possible impact of acetaminophen

In the study by Man et al, acetaminophen was used by both groups as an adjunct for pain relief, and the amount used was higher (mean 10.3 g vs 6.4 g over 14 days) in the oral steroid group. It is possible that some of the pain relief experienced by those in the steroid group may have been from acetaminophen; however, a difference of 4 g over a 14-day period makes that unlikely. Even if additional acetaminophen is required, the advantages of oral steroids rather than NSAIDs or colchicine for patients with contraindications remain.

Also of note: These trials examined short-term treatment of acute gout. These findings cannot be extrapolated to the treatment of intercurrent gout or chronic gouty arthritis, since long-term steroid use has severe adverse effects.

CHALLENGES TO IMPLEMENTATION: No significant barriers

We found little to prevent physicians from adopting this practice changer. Oral steroids are readily available and inexpensive, and most primary care clinicians regularly prescribe them for other conditions. This practice change recommendation should be readily implemented.

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

* Prednisone is the precursor of prednisolone and is activated in the liver. The activity of both drugs is comparable, and prednisone and prednisolone can be converted milligram to milligram. However, prednisolone may be preferred for patients with severe liver disease.¹⁴ (In the United States, prednisolone is available as a liquid and prednisone as a tablet.)

PURL METHODOLOGY
The PURLs Surveillance System is 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 68-year-old man with a history of ulcer disease and mild renal insufficiency comes to your office complaining of severe pain in his right foot. You note swelling and redness around the base of the big toe and diagnose acute gout. Wishing to avoid nonsteroidal anti-inflammatory drugs (NSAIDs) and colchicine because of the patient’s medical history, you wonder what you can safely prescribe for pain relief.

NSAIDs have become the mainstay of treatment for acute gout,^3,4 replacing colchicine—widely used for gout pain relief since the early 19th century.⁵ Colchicine fell out of favor because it routinely causes diarrhea and requires caution in patients with renal insufficiency.⁶ Now, however, there is growing concern about the adverse effects of NSAIDs.

Comorbidities, age, mean fewer options

NSAIDs increase the risk of gastrointestinal (GI) bleeding, especially in the first week of use.⁷ Cyclooxygenase-2 (COX-2) inhibitors, considered as effective as NSAIDs in treating acute gout pain,⁸ are also associated with GI bleeds.⁹ In addition, NSAIDs and COX-2 inhibitors increase cardiovascular risks, prompting the American Heart Association to recommend restricted use of both.¹⁰ NSAIDs’ effect on renal function, fluid retention, and interactions with anticoagulants are additional concerns, because gout patients are generally older and often have comorbid renal and cardiovascular diseases.^3,11-13

In the United States, nearly 70% of patients who develop acute gout seek treatment from primary care physicians.¹² Family physicians need a safe alternative to NSAIDs to relieve the severe pain associated with this condition. Will oral corticosteroids fit the bill?

STUDY SUMMARIES: Oral steroids: A safe and effective alternative

Janssens et al¹ conducted a double-blind, randomized equivalence trial of 118 patients to compare the efficacy of prednisolone and naproxen for the treatment of monoarticular gout, confirmed by crystal analysis of synovial fluid. The study was conducted in the eastern Netherlands at a trial center patients were referred to by their family physicians. Those with major comorbidities, including a history of GI bleed or peptic ulcer, were excluded.

Participants were randomized to receive either prednisolone 35 mg* or naproxen 500 mg twice a day, with look-alike placebo tablets of the alternate drug, for 5 days. Pain, the primary outcome, was scored on a validated visual analog scale from 0 mm (no pain) to 100 mm (worst pain experienced).¹⁵ The reduction in the pain score at 90 hours was similar in both groups. Only a few minor side effects were reported in both groups, and all completely resolved in 3 weeks.

The study by Man et al² was a randomized trial that compared indomethacin with oral prednisolone in 90 patients presenting to an emergency department in Hong Kong. Diagnosis of gout was made by clinical impression. Participants in the indomethacin group also received an intramuscular (IM) injection of diclofenac 75 mg, and those in both groups were monitored for acetaminophen use as a secondary endpoint.

Pain reduction, the primary endpoint, was assessed with a 10-point visual analog score, and was slightly better statistically in the oral steroid group. The study was not designed to evaluate for safety, but the authors noted that patients in the indomethacin group experienced more adverse effects (number needed to harm [NNH] for any adverse event: 3; NNH for serious events: 6).

Short-term steroids have few side effects

In both studies, patients receiving oral steroids experienced no significant side effects. This finding is consistent with other studies that have investigated short-term oral steroid use in the treatment of both rheumatoid arthritis and asthma.^16,17

WHAT’S NEW?: Evidence supports use of steroids for acute gout

In the United States, prednisone is prescribed as treatment for acute gout only about 9% of the time.¹² These 2 studies—the first randomized trials comparing oral steroids with NSAIDs, the usual gout treatment—may lead to greater use of steroids for this painful condition.

Both studies were well designed and conducted in an outpatient (or emergency) setting. Both showed that a short course of oral steroids is as effective as NSAIDs, and without significant side effects.

Previous studies have compared IM steroids with NSAIDs, and IM steroids with IM adrenocorticotropic hormone (ACTH).^18,19 However, these studies were not blinded—just one of their methodological problems.⁴

CAVEATS: Joint aspiration is not the norm

In the Janssens study, participants were diagnosed with gout after monosodium urate crystals were found in joint aspirate.¹ This may not be the usual practice in primary care settings, where a clinical diagnosis of gout is typically made. The authors indicate that the failure to perform joint aspiration will lead to occasional cases of septic arthritis being treated with oral steroids. We recommend joint aspiration or a referral for such a procedure when clinical evidence (eg, fever and leukocytosis) is suggestive of septic arthritis.

Possible impact of acetaminophen

In the study by Man et al, acetaminophen was used by both groups as an adjunct for pain relief, and the amount used was higher (mean 10.3 g vs 6.4 g over 14 days) in the oral steroid group. It is possible that some of the pain relief experienced by those in the steroid group may have been from acetaminophen; however, a difference of 4 g over a 14-day period makes that unlikely. Even if additional acetaminophen is required, the advantages of oral steroids rather than NSAIDs or colchicine for patients with contraindications remain.

Also of note: These trials examined short-term treatment of acute gout. These findings cannot be extrapolated to the treatment of intercurrent gout or chronic gouty arthritis, since long-term steroid use has severe adverse effects.

CHALLENGES TO IMPLEMENTATION: No significant barriers

We found little to prevent physicians from adopting this practice changer. Oral steroids are readily available and inexpensive, and most primary care clinicians regularly prescribe them for other conditions. This practice change recommendation should be readily implemented.

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

* Prednisone is the precursor of prednisolone and is activated in the liver. The activity of both drugs is comparable, and prednisone and prednisolone can be converted milligram to milligram. However, prednisolone may be preferred for patients with severe liver disease.¹⁴ (In the United States, prednisolone is available as a liquid and prednisone as a tablet.)

PURL METHODOLOGY
The PURLs Surveillance System is 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 23-year-old woman presents to your office with a 1-week history of cough, purulent nasal discharge, and unilateral facial pain. You diagnose acute sinusitis.

Should you prescribe an antibiotic?

No. Yet it’s no wonder that most adults treated for acute sinusitis leave the doctor’s office with a prescription for antibiotics. Until the publication of the meta-analysis by Young and colleagues¹ featured in this PURL, we have lacked A-level evidence from studies conducted in realistic settings—like your practice and ours.

Review of serial data from the National Ambulatory Medical Care Surveys (NAMCS) from 1999 through 2005 does show a slight downward trend in antibiotic prescribing for acute sinusitis: 1999-2002 data showed that 83% of cases of acute sinusitis were treated with an antibiotic.² Data from the 2004 and 2005 NAMCS reveal that family physicians prescribed antibiotics for 80% of patients with acute sinusitis in 2004 and 76% of patients in 2005 (S. Medvedev, unpublished data, NAMCS database, March 2008).

Is this continued high rate of antibiotic prescribing justified?

Do antibiotics improve symptoms and shorten the duration of illness or not?

These questions are important, obviously, not only because of the high rate of prescribing but also because sinusitis is one of the most common diagnoses: approximately 20 million cases annually in the United States, or about 21% of all outpatient antibiotic prescriptions for adults.²

Which patients might benefit from antibiotics?

Common clinical signs and symptoms cannot identify patients with rhinosinusitis for whom treatment is clearly justified, given the cost, adverse events, and bacterial resistance associated with antibiotic use

• Severity of symptoms is important only in that signs suggestive of a serious complication are the sole reason for immediate antibiotic treatment
• Purulent discharge noted in the pharynx on exam was associated with a higher likelihood of benefit from antibiotics, but NNT was 8
• Antibiotics are not justified even if a patient reports having symptoms for longer than 7-10 days

Source: Young et al.¹

A diagnostic dilemma

Before we discuss the evidence that is summarized in the excellent meta-analysis by Young and colleagues,¹ let’s acknowledge that acute sinusitis is undeniably a diagnostic dilemma. Distinguishing bacterial from viral infection is nearly impossible on clinical grounds because the symptoms are so similar. A litany of identical upper respiratory symptoms accompanies both viral and bacterial sinus infections. Purulent nasal secretions, maxillary facial pain (especially with unilateral predominance), maxillary tooth pain (which is uncommon with sinus infection), altered sense of smell, and worsening illness after improvement constitute the short list of signs and symptoms that has some predictive value, but even the presence of all of these is not a terrific predictor of bacterial sinus infection. Plain x-rays have low accuracy in distinguishing viral from bacterial infection. Computed tomography (CT) sinus scans are better but far from perfect, are not readily available in practice, and are expensive.

Sinusitis in the real world

How effective are antibiotics for patients diagnosed not by sinus x-rays or CTs, but by signs and symptoms—as we typically do in daily practice?

A meta-analysis³ of 13 randomized controlled trials (RCTs) found that sinusitis improved without antibiotics, but it included trials in which patients were recruited based on results of imaging studies and cultures, which are not normally used in primary care clinical practice. That study compared antibiotic treatment to placebo for acute uncomplicated sinusitis; 35% of placebo-treated patients were clinically cured by 7 to 12 days and 73% were improved after 7 days. Antibiotic therapy increased cure rates by 15% and improvement rates by 14%, yielding a number needed to treat of 7 to achieve 1 additional positive outcome at 7 days.

STUDY SUMMARY: Meta-analysis of primary care trials

Young and colleagues¹ aggregated and analyzed individual patient-level data from all known placebo-controlled, randomized, antibiotic treatment trials of adults with clinical symptoms of acute sinusitis that were conducted in primary care settings. They excluded trials that used imaging or bacterial culture as part of patient recruitment.

Studies were included that allowed the use of concomitant medication such as nonsteroidal anti-inflammatory drugs, decongestants, or nasal steroids, as long as patients in both groups had access to the same medications. All trials excluded patients with severe symptoms such as high fever, periorbital swelling or erythema, or intense facial pain, important exclusions that we will discuss below.

They identified 10 such studies and completed an intent-to-treat analysis of the 9 double-blind trials for which patient level data were available. Using individual data from 2547 patients, the odds ratio for an overall antibiotic treatment effect was 1.37 (95% confidence interval, 1.13-1.66), with a number needed to treat (NNT) of 15.

This finding means that 15 patients needed to be given an antibiotic for 1 additional patient to be cured at 8 to 15 days after treatment commenced. Using statistical modeling, they determined that 64% of patients treated with placebo were cured at 14 days compared with 70% given an antibiotic. One patient out of 1381 treated with placebo experienced a serious complication, a brain abscess.

Do antibiotics benefit any subgroups?

The investigators also analyzed the prognostic value of specific signs and symptoms to answer the question: Is there any subgroup of patients who might benefit more from antibiotic treatment?

Duration. Patients with a longer duration of symptoms, more severe symptoms, or increased age took longer to cure, but were no more likely to benefit from antibiotic treatment than other patients.

Symptoms, such as a previous common cold, pain on bending, unilateral facial pain, tooth pain, and purulent nasal discharge did not have any prognostic value.

Only one sign—purulent discharge noted in the pharynx on examination—was associated with a higher likelihood of benefit from treatment with antibiotics, but the NNT was still 8 in this group. Patients with symptoms for 7 days or longer were no more likely to respond to antibiotics than those with symptoms for fewer than 7 days.¹

WHAT’S NEW: Realistic evidence from realistic settings

We believe this meta-analysis provides a high level of evidence against routine treatment of sinusitis with antibiotics in primary care practice. Treating 15 patients with an antibiotic to possibly benefit 1 patient 2 weeks after treatment commences does not seem like a good idea when one considers the cost and complications of antibiotic use. Diarrhea and other adverse outcomes are 80% more common among patients with sinusitis who are treated with an antibiotic compared with placebo.³ As noted above, prior meta-analyses of antibiotic treatment for acute sinusitis have been more encouraging than this meta-analysis, with a number needed to treat of 7, but those meta-analyses are clearly overly optimistic for the results one will achieve in primary care practice using clinical signs and symptoms to diagnose acute sinusitis.^3,4 Unlike the Young study, they included trials in specialty clinics with CT scans and sinus puncture and culture used for the diagnostic standard.

Symptoms >1 week are not a reason to prescribe

One very important new finding in this meta-analysis that should change practice is that the duration of illness did not predict a positive response to antibiotics.

Current national recommendations are to use an antibiotic for patients with a duration of illness longer than 1 week, as these patients are presumably more likely to have a bacterial infection.^5-7 However, that recommendation had been based on expert opinion, not on data from clinical trials. A longer duration of symptoms should not be a reason to prescribe an antibiotic for sinusitis symptoms.

How can you help your patient?

What to do, then, for patients with acute sinusitis? Treat the symptoms, which means recommending pain medication for facial pain or headache and saline nasal spray for the nasal discharge, not antibiotics or nasal corticosteroids. Side effects will be fewer and costs will be lower.

• Saline irrigation. A 2007 Cochrane review of 8 chronic and recurrent sinusitis trials showed that nasal saline irrigation is effective for reducing symptoms of chronic and recurrent sinusitis.⁸ Although we do not have high-quality RCT data on saline nasal irrigation for treatment of acute sinusitis, nasal saline irrigation is harmless and inexpensive.
• What about nasal steroids? The evidence is equivocal, and the most recent high-quality RCT of nasal steroids showed no effect.⁹

CAVEATS: Refer seriously ill patients and complicated cases

A very important caveat to our recommendation is that seriously ill patients must be managed differently. Very infrequently a patient develops a serious complication of acute sinusitis such as brain abscess, periorbital cellulitis, or meningitis. Therefore, seriously ill patients with signs and symptoms of acute bacterial sinusitis, such as high fever, periorbital erythema or edema, severe headache, or intense facial pain must be carefully evaluated and treated with great caution and close follow-up. These patients should be referred immediately for consultation with an otolaryngologist.

Of course, mildly ill patients today may become quite ill tomorrow, so always provide advice to patients to return if they are getting worse, a good clinical practice for any condition that is usually benign but occasionally serious.

Patients who have prolonged or recurrent sinusitis symptoms need further evaluation for other diagnoses such as allergies, cystic fibrosis, fungal sinus infection, and other illnesses associated with immune compromise. These complicated patients benefit from consultation with an otolaryngologist who has a specific interest in chronic and recurrent sinusitis, and perhaps consultation from an infectious disease specialist as well.

CHALLENGES TO IMPLEMENTATION: The patient who wants a pill

Some patients may be accustomed to receiving an antibiotic prescription for their “sinus infections” and may resist conservative management. It may be difficult to convince them that antibiotics won’t make a difference when they attribute past resolution of symptoms to antibiotics.

Take enough time to educate your patients on the natural course of illness, the positive benefits of nasal saline, and the reasons not to use unnecessary antibiotics (eg, they are not effective, have potential adverse effects, and can contribute to future antibiotic resistance); this effort will save you time in future visits.¹⁰ A “just in case you don’t get better” prescription to be filled only if the patient is not improving in the next few days is about 50% effective in reducing antibiotic usage for upper respiratory infections.¹¹

Acknowledgement

We acknowledge Sofia Medvedev of the University HealthSystem Consortium (UHC) in Oak Brook, IL for analysis of the National Ambulatory Medical Care Survey data.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 23-year-old woman presents to your office with a 1-week history of cough, purulent nasal discharge, and unilateral facial pain. You diagnose acute sinusitis.

Should you prescribe an antibiotic?

No. Yet it’s no wonder that most adults treated for acute sinusitis leave the doctor’s office with a prescription for antibiotics. Until the publication of the meta-analysis by Young and colleagues¹ featured in this PURL, we have lacked A-level evidence from studies conducted in realistic settings—like your practice and ours.

Review of serial data from the National Ambulatory Medical Care Surveys (NAMCS) from 1999 through 2005 does show a slight downward trend in antibiotic prescribing for acute sinusitis: 1999-2002 data showed that 83% of cases of acute sinusitis were treated with an antibiotic.² Data from the 2004 and 2005 NAMCS reveal that family physicians prescribed antibiotics for 80% of patients with acute sinusitis in 2004 and 76% of patients in 2005 (S. Medvedev, unpublished data, NAMCS database, March 2008).

Is this continued high rate of antibiotic prescribing justified?

Do antibiotics improve symptoms and shorten the duration of illness or not?

These questions are important, obviously, not only because of the high rate of prescribing but also because sinusitis is one of the most common diagnoses: approximately 20 million cases annually in the United States, or about 21% of all outpatient antibiotic prescriptions for adults.²

Which patients might benefit from antibiotics?

Common clinical signs and symptoms cannot identify patients with rhinosinusitis for whom treatment is clearly justified, given the cost, adverse events, and bacterial resistance associated with antibiotic use

• Severity of symptoms is important only in that signs suggestive of a serious complication are the sole reason for immediate antibiotic treatment
• Purulent discharge noted in the pharynx on exam was associated with a higher likelihood of benefit from antibiotics, but NNT was 8
• Antibiotics are not justified even if a patient reports having symptoms for longer than 7-10 days

Source: Young et al.¹

A diagnostic dilemma

Before we discuss the evidence that is summarized in the excellent meta-analysis by Young and colleagues,¹ let’s acknowledge that acute sinusitis is undeniably a diagnostic dilemma. Distinguishing bacterial from viral infection is nearly impossible on clinical grounds because the symptoms are so similar. A litany of identical upper respiratory symptoms accompanies both viral and bacterial sinus infections. Purulent nasal secretions, maxillary facial pain (especially with unilateral predominance), maxillary tooth pain (which is uncommon with sinus infection), altered sense of smell, and worsening illness after improvement constitute the short list of signs and symptoms that has some predictive value, but even the presence of all of these is not a terrific predictor of bacterial sinus infection. Plain x-rays have low accuracy in distinguishing viral from bacterial infection. Computed tomography (CT) sinus scans are better but far from perfect, are not readily available in practice, and are expensive.

Sinusitis in the real world

How effective are antibiotics for patients diagnosed not by sinus x-rays or CTs, but by signs and symptoms—as we typically do in daily practice?

A meta-analysis³ of 13 randomized controlled trials (RCTs) found that sinusitis improved without antibiotics, but it included trials in which patients were recruited based on results of imaging studies and cultures, which are not normally used in primary care clinical practice. That study compared antibiotic treatment to placebo for acute uncomplicated sinusitis; 35% of placebo-treated patients were clinically cured by 7 to 12 days and 73% were improved after 7 days. Antibiotic therapy increased cure rates by 15% and improvement rates by 14%, yielding a number needed to treat of 7 to achieve 1 additional positive outcome at 7 days.

STUDY SUMMARY: Meta-analysis of primary care trials

Young and colleagues¹ aggregated and analyzed individual patient-level data from all known placebo-controlled, randomized, antibiotic treatment trials of adults with clinical symptoms of acute sinusitis that were conducted in primary care settings. They excluded trials that used imaging or bacterial culture as part of patient recruitment.

Studies were included that allowed the use of concomitant medication such as nonsteroidal anti-inflammatory drugs, decongestants, or nasal steroids, as long as patients in both groups had access to the same medications. All trials excluded patients with severe symptoms such as high fever, periorbital swelling or erythema, or intense facial pain, important exclusions that we will discuss below.

They identified 10 such studies and completed an intent-to-treat analysis of the 9 double-blind trials for which patient level data were available. Using individual data from 2547 patients, the odds ratio for an overall antibiotic treatment effect was 1.37 (95% confidence interval, 1.13-1.66), with a number needed to treat (NNT) of 15.

This finding means that 15 patients needed to be given an antibiotic for 1 additional patient to be cured at 8 to 15 days after treatment commenced. Using statistical modeling, they determined that 64% of patients treated with placebo were cured at 14 days compared with 70% given an antibiotic. One patient out of 1381 treated with placebo experienced a serious complication, a brain abscess.

Do antibiotics benefit any subgroups?

The investigators also analyzed the prognostic value of specific signs and symptoms to answer the question: Is there any subgroup of patients who might benefit more from antibiotic treatment?

Duration. Patients with a longer duration of symptoms, more severe symptoms, or increased age took longer to cure, but were no more likely to benefit from antibiotic treatment than other patients.

Symptoms, such as a previous common cold, pain on bending, unilateral facial pain, tooth pain, and purulent nasal discharge did not have any prognostic value.

Only one sign—purulent discharge noted in the pharynx on examination—was associated with a higher likelihood of benefit from treatment with antibiotics, but the NNT was still 8 in this group. Patients with symptoms for 7 days or longer were no more likely to respond to antibiotics than those with symptoms for fewer than 7 days.¹

WHAT’S NEW: Realistic evidence from realistic settings

We believe this meta-analysis provides a high level of evidence against routine treatment of sinusitis with antibiotics in primary care practice. Treating 15 patients with an antibiotic to possibly benefit 1 patient 2 weeks after treatment commences does not seem like a good idea when one considers the cost and complications of antibiotic use. Diarrhea and other adverse outcomes are 80% more common among patients with sinusitis who are treated with an antibiotic compared with placebo.³ As noted above, prior meta-analyses of antibiotic treatment for acute sinusitis have been more encouraging than this meta-analysis, with a number needed to treat of 7, but those meta-analyses are clearly overly optimistic for the results one will achieve in primary care practice using clinical signs and symptoms to diagnose acute sinusitis.^3,4 Unlike the Young study, they included trials in specialty clinics with CT scans and sinus puncture and culture used for the diagnostic standard.

Symptoms >1 week are not a reason to prescribe

One very important new finding in this meta-analysis that should change practice is that the duration of illness did not predict a positive response to antibiotics.

Current national recommendations are to use an antibiotic for patients with a duration of illness longer than 1 week, as these patients are presumably more likely to have a bacterial infection.^5-7 However, that recommendation had been based on expert opinion, not on data from clinical trials. A longer duration of symptoms should not be a reason to prescribe an antibiotic for sinusitis symptoms.

How can you help your patient?

What to do, then, for patients with acute sinusitis? Treat the symptoms, which means recommending pain medication for facial pain or headache and saline nasal spray for the nasal discharge, not antibiotics or nasal corticosteroids. Side effects will be fewer and costs will be lower.

• Saline irrigation. A 2007 Cochrane review of 8 chronic and recurrent sinusitis trials showed that nasal saline irrigation is effective for reducing symptoms of chronic and recurrent sinusitis.⁸ Although we do not have high-quality RCT data on saline nasal irrigation for treatment of acute sinusitis, nasal saline irrigation is harmless and inexpensive.
• What about nasal steroids? The evidence is equivocal, and the most recent high-quality RCT of nasal steroids showed no effect.⁹

CAVEATS: Refer seriously ill patients and complicated cases

A very important caveat to our recommendation is that seriously ill patients must be managed differently. Very infrequently a patient develops a serious complication of acute sinusitis such as brain abscess, periorbital cellulitis, or meningitis. Therefore, seriously ill patients with signs and symptoms of acute bacterial sinusitis, such as high fever, periorbital erythema or edema, severe headache, or intense facial pain must be carefully evaluated and treated with great caution and close follow-up. These patients should be referred immediately for consultation with an otolaryngologist.

Of course, mildly ill patients today may become quite ill tomorrow, so always provide advice to patients to return if they are getting worse, a good clinical practice for any condition that is usually benign but occasionally serious.

Patients who have prolonged or recurrent sinusitis symptoms need further evaluation for other diagnoses such as allergies, cystic fibrosis, fungal sinus infection, and other illnesses associated with immune compromise. These complicated patients benefit from consultation with an otolaryngologist who has a specific interest in chronic and recurrent sinusitis, and perhaps consultation from an infectious disease specialist as well.

CHALLENGES TO IMPLEMENTATION: The patient who wants a pill

Some patients may be accustomed to receiving an antibiotic prescription for their “sinus infections” and may resist conservative management. It may be difficult to convince them that antibiotics won’t make a difference when they attribute past resolution of symptoms to antibiotics.

Take enough time to educate your patients on the natural course of illness, the positive benefits of nasal saline, and the reasons not to use unnecessary antibiotics (eg, they are not effective, have potential adverse effects, and can contribute to future antibiotic resistance); this effort will save you time in future visits.¹⁰ A “just in case you don’t get better” prescription to be filled only if the patient is not improving in the next few days is about 50% effective in reducing antibiotic usage for upper respiratory infections.¹¹

Acknowledgement

We acknowledge Sofia Medvedev of the University HealthSystem Consortium (UHC) in Oak Brook, IL for analysis of the National Ambulatory Medical Care Survey data.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 23-year-old woman presents to your office with a 1-week history of cough, purulent nasal discharge, and unilateral facial pain. You diagnose acute sinusitis.

Should you prescribe an antibiotic?

No. Yet it’s no wonder that most adults treated for acute sinusitis leave the doctor’s office with a prescription for antibiotics. Until the publication of the meta-analysis by Young and colleagues¹ featured in this PURL, we have lacked A-level evidence from studies conducted in realistic settings—like your practice and ours.

Review of serial data from the National Ambulatory Medical Care Surveys (NAMCS) from 1999 through 2005 does show a slight downward trend in antibiotic prescribing for acute sinusitis: 1999-2002 data showed that 83% of cases of acute sinusitis were treated with an antibiotic.² Data from the 2004 and 2005 NAMCS reveal that family physicians prescribed antibiotics for 80% of patients with acute sinusitis in 2004 and 76% of patients in 2005 (S. Medvedev, unpublished data, NAMCS database, March 2008).

Is this continued high rate of antibiotic prescribing justified?

Do antibiotics improve symptoms and shorten the duration of illness or not?

These questions are important, obviously, not only because of the high rate of prescribing but also because sinusitis is one of the most common diagnoses: approximately 20 million cases annually in the United States, or about 21% of all outpatient antibiotic prescriptions for adults.²

Which patients might benefit from antibiotics?

Common clinical signs and symptoms cannot identify patients with rhinosinusitis for whom treatment is clearly justified, given the cost, adverse events, and bacterial resistance associated with antibiotic use

• Severity of symptoms is important only in that signs suggestive of a serious complication are the sole reason for immediate antibiotic treatment
• Purulent discharge noted in the pharynx on exam was associated with a higher likelihood of benefit from antibiotics, but NNT was 8
• Antibiotics are not justified even if a patient reports having symptoms for longer than 7-10 days

Source: Young et al.¹

A diagnostic dilemma

Before we discuss the evidence that is summarized in the excellent meta-analysis by Young and colleagues,¹ let’s acknowledge that acute sinusitis is undeniably a diagnostic dilemma. Distinguishing bacterial from viral infection is nearly impossible on clinical grounds because the symptoms are so similar. A litany of identical upper respiratory symptoms accompanies both viral and bacterial sinus infections. Purulent nasal secretions, maxillary facial pain (especially with unilateral predominance), maxillary tooth pain (which is uncommon with sinus infection), altered sense of smell, and worsening illness after improvement constitute the short list of signs and symptoms that has some predictive value, but even the presence of all of these is not a terrific predictor of bacterial sinus infection. Plain x-rays have low accuracy in distinguishing viral from bacterial infection. Computed tomography (CT) sinus scans are better but far from perfect, are not readily available in practice, and are expensive.

Sinusitis in the real world

How effective are antibiotics for patients diagnosed not by sinus x-rays or CTs, but by signs and symptoms—as we typically do in daily practice?

A meta-analysis³ of 13 randomized controlled trials (RCTs) found that sinusitis improved without antibiotics, but it included trials in which patients were recruited based on results of imaging studies and cultures, which are not normally used in primary care clinical practice. That study compared antibiotic treatment to placebo for acute uncomplicated sinusitis; 35% of placebo-treated patients were clinically cured by 7 to 12 days and 73% were improved after 7 days. Antibiotic therapy increased cure rates by 15% and improvement rates by 14%, yielding a number needed to treat of 7 to achieve 1 additional positive outcome at 7 days.

STUDY SUMMARY: Meta-analysis of primary care trials

Young and colleagues¹ aggregated and analyzed individual patient-level data from all known placebo-controlled, randomized, antibiotic treatment trials of adults with clinical symptoms of acute sinusitis that were conducted in primary care settings. They excluded trials that used imaging or bacterial culture as part of patient recruitment.

Studies were included that allowed the use of concomitant medication such as nonsteroidal anti-inflammatory drugs, decongestants, or nasal steroids, as long as patients in both groups had access to the same medications. All trials excluded patients with severe symptoms such as high fever, periorbital swelling or erythema, or intense facial pain, important exclusions that we will discuss below.

They identified 10 such studies and completed an intent-to-treat analysis of the 9 double-blind trials for which patient level data were available. Using individual data from 2547 patients, the odds ratio for an overall antibiotic treatment effect was 1.37 (95% confidence interval, 1.13-1.66), with a number needed to treat (NNT) of 15.

This finding means that 15 patients needed to be given an antibiotic for 1 additional patient to be cured at 8 to 15 days after treatment commenced. Using statistical modeling, they determined that 64% of patients treated with placebo were cured at 14 days compared with 70% given an antibiotic. One patient out of 1381 treated with placebo experienced a serious complication, a brain abscess.

Do antibiotics benefit any subgroups?

The investigators also analyzed the prognostic value of specific signs and symptoms to answer the question: Is there any subgroup of patients who might benefit more from antibiotic treatment?

Duration. Patients with a longer duration of symptoms, more severe symptoms, or increased age took longer to cure, but were no more likely to benefit from antibiotic treatment than other patients.

Symptoms, such as a previous common cold, pain on bending, unilateral facial pain, tooth pain, and purulent nasal discharge did not have any prognostic value.

Only one sign—purulent discharge noted in the pharynx on examination—was associated with a higher likelihood of benefit from treatment with antibiotics, but the NNT was still 8 in this group. Patients with symptoms for 7 days or longer were no more likely to respond to antibiotics than those with symptoms for fewer than 7 days.¹

WHAT’S NEW: Realistic evidence from realistic settings

We believe this meta-analysis provides a high level of evidence against routine treatment of sinusitis with antibiotics in primary care practice. Treating 15 patients with an antibiotic to possibly benefit 1 patient 2 weeks after treatment commences does not seem like a good idea when one considers the cost and complications of antibiotic use. Diarrhea and other adverse outcomes are 80% more common among patients with sinusitis who are treated with an antibiotic compared with placebo.³ As noted above, prior meta-analyses of antibiotic treatment for acute sinusitis have been more encouraging than this meta-analysis, with a number needed to treat of 7, but those meta-analyses are clearly overly optimistic for the results one will achieve in primary care practice using clinical signs and symptoms to diagnose acute sinusitis.^3,4 Unlike the Young study, they included trials in specialty clinics with CT scans and sinus puncture and culture used for the diagnostic standard.

Symptoms >1 week are not a reason to prescribe

One very important new finding in this meta-analysis that should change practice is that the duration of illness did not predict a positive response to antibiotics.

Current national recommendations are to use an antibiotic for patients with a duration of illness longer than 1 week, as these patients are presumably more likely to have a bacterial infection.^5-7 However, that recommendation had been based on expert opinion, not on data from clinical trials. A longer duration of symptoms should not be a reason to prescribe an antibiotic for sinusitis symptoms.

How can you help your patient?

What to do, then, for patients with acute sinusitis? Treat the symptoms, which means recommending pain medication for facial pain or headache and saline nasal spray for the nasal discharge, not antibiotics or nasal corticosteroids. Side effects will be fewer and costs will be lower.

• Saline irrigation. A 2007 Cochrane review of 8 chronic and recurrent sinusitis trials showed that nasal saline irrigation is effective for reducing symptoms of chronic and recurrent sinusitis.⁸ Although we do not have high-quality RCT data on saline nasal irrigation for treatment of acute sinusitis, nasal saline irrigation is harmless and inexpensive.
• What about nasal steroids? The evidence is equivocal, and the most recent high-quality RCT of nasal steroids showed no effect.⁹

CAVEATS: Refer seriously ill patients and complicated cases

A very important caveat to our recommendation is that seriously ill patients must be managed differently. Very infrequently a patient develops a serious complication of acute sinusitis such as brain abscess, periorbital cellulitis, or meningitis. Therefore, seriously ill patients with signs and symptoms of acute bacterial sinusitis, such as high fever, periorbital erythema or edema, severe headache, or intense facial pain must be carefully evaluated and treated with great caution and close follow-up. These patients should be referred immediately for consultation with an otolaryngologist.

Of course, mildly ill patients today may become quite ill tomorrow, so always provide advice to patients to return if they are getting worse, a good clinical practice for any condition that is usually benign but occasionally serious.

Patients who have prolonged or recurrent sinusitis symptoms need further evaluation for other diagnoses such as allergies, cystic fibrosis, fungal sinus infection, and other illnesses associated with immune compromise. These complicated patients benefit from consultation with an otolaryngologist who has a specific interest in chronic and recurrent sinusitis, and perhaps consultation from an infectious disease specialist as well.

CHALLENGES TO IMPLEMENTATION: The patient who wants a pill

Some patients may be accustomed to receiving an antibiotic prescription for their “sinus infections” and may resist conservative management. It may be difficult to convince them that antibiotics won’t make a difference when they attribute past resolution of symptoms to antibiotics.

Take enough time to educate your patients on the natural course of illness, the positive benefits of nasal saline, and the reasons not to use unnecessary antibiotics (eg, they are not effective, have potential adverse effects, and can contribute to future antibiotic resistance); this effort will save you time in future visits.¹⁰ A “just in case you don’t get better” prescription to be filled only if the patient is not improving in the next few days is about 50% effective in reducing antibiotic usage for upper respiratory infections.¹¹

Acknowledgement

We acknowledge Sofia Medvedev of the University HealthSystem Consortium (UHC) in Oak Brook, IL for analysis of the National Ambulatory Medical Care Survey data.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A mother brings her 3-year-old son to your office first thing in the morning. The boy has fever and right ear pain. You see that the tympanic membrane is dull, red, and bulging. The mother has been up most of the night with her child. She implores you to “do something.” She is exhausted and her son is crying and holding his right ear. You know that antibiotics will not provide immediate pain relief and oral analgesics will take a while to help. What can you offer that will help right away?

Until this study, we’ve had only 1 placebo-controlled trial to guide how we manage a big problem. Big in terms of distress to parents and children, and in sheer numbers—acute otitis media (AOM) is extremely common in children.^2,3

Routine antibiotics: Woeful lack of evidence

Even when antibiotics are indicated, pain relief is minimal and takes several days.^4-8 Despite “a woeful lack of substantial evidence on the question of antibiotic therapy” for AOM, it is the most common reason for the prescription of antibiotics in children.^4,6 A Cochrane review showed that antibiotics have no effect on recurrence of AOM or complications, including hearing impairment.⁵ The same review showed no pain reduction in 24 hours and only 30% pain reduction in 2 to 7 days with antibiotic use.⁵ Antibiotics clearly have a minimal role in providing pain relief for AOM.

Oral analgesics too slow

Oral analgesic use in AOM has been studied and has shown good results. We calculated the number needed to treat (1.0 divided by the absolute risk reduction) for both ibuprofen (number needed to treat [NNT]=5) and acetaminophen (NNT=6) from data in the 1996 trial by Bertin et al.⁹

It is a common practice in the United States to treat AOM with oral analgesics. However, the onset of pain relief with oral medications can be slow and the relief is generally not complete, so oral medications are not immediately helpful to meet the needs of our crying 3-year-old patient and his exhausted mother.

Topical anesthetics

To our knowledge, prior evidence on the efficacy of topical anesthetics is limited to 1 placebo-controlled trial. A randomized trial by Hoberman et al,¹⁰ with 54 subjects, showed a statistically significant 25% reduction in pain with the analgesic drops Auralgan (containing antipyrine, benzocaine, and glycerine) at 30 minutes when compared with olive oil. A 2006 Cochrane review¹¹ did not include the Bolt et al trial¹ described in this PURL, but did include the Hoberman trial¹⁰ and 3 trials that compared a topical anesthetic with naturopathic herbal ear drops for AOM pain, and the review concluded that evidence was insufficient.

Topical anesthetic plus oraI analgesia for earache relief

STUDY SUMMARY: Pain measured by visual analogue, Bieri faces scales

This double-blind, randomized, placebo-controlled trial¹ compared aqueous lidocaine 2% drops with saline drops in the ear, for reducing pain due to AOM in patients 3 to 17 years of age. The trial was conducted at an Australian children’s hospital emergency room. The study evaluated “lignocaine,” the name for lidocaine in Australia.

Emergency physicians instilled 3 drops of either lidocaine or saline into the affected ear in the 2 groups (n=31 in the study group and n=32 in the placebo group). Patients, parents, treating physicians, and staff administering ear drops and assessing pain were blinded to group assignment. Doctors measured pain at baseline and after 30 minutes and patients measured pain at baseline, 10, 20, and 30 minutes after the drops were instilled, using the Bieri faces pain scale and a visual analogue scale.¹²

Lidocaine reduced pain scores by 50% from baseline at 10 and 30 minutes compared with saline. No serious side effects were noted at 30 minutes, although 3 patients in the lidocaine group complained of mild dizziness the next day. The treating physician prescribed paracetamol (equivalent to acetaminophen) for participants in both the lidocaine and the placebo group at their discretion. The proportion given paracetamol was similar in both groups.

WHAT’S NEW: Pain relief is immediate

Family physicians have used topical anethestics for otitis externa for decades. This RCT adds evidence that topical anesthetics are useful for providing immediate pain relief from AOM, as well. The 2004 guidelines from the American Academy of Pediatrics and the American Academy of Family Physicians indicate that management of AOM should include the assessment and treatment of pain.

We think that topical agents such as lidocaine and benzocaine are useful adjuncts to oral analgesics in providing immediate pain relief, especially in the face of evidence showing that antibiotics do not offer significant pain relief.

Previous studies have shown that aqueous lidocaine is ineffective on uninflamed tympanic membrane.¹³ The results of this study are consistent with increased uptake of the drug through the inflamed tympanic membrane.

CAVEATS: Children >3 years studied

This trial included only children older than 3 years, so the results may not apply to younger children and infants.

This essentially was a study of ear pain treatment, which, in our view, does not detract from the clinical usefulness of the findings. Topical anesthetics seem to be useful for ear pain in general.

Concurrent analgesics

Some variability existed in the oral analgesics the children received, as these agents were given at the discretion of the parents and treating physicians. We think that this does not detract from the study findings, as it represents a practical, real-world setting, which is desirable in an effectiveness RCT. Moreover, the extent of pain reduction was over and above that conferred by analgesic administration.

CHALLENGES TO IMPLEMENTATION: Lidocaine is not sold in a dropper

Aqueous lidocaine is not sold in a bottle with a dropper: our search on www.drugstore.com and www.drugs.com did not yield an otic preparation with only aqueous lidocaine. However, 2% injectable lidocaine, which is readily available, can be used with a dropper. Aqueous lidocaine can be compounded at a compounding pharmacy and placed in a bottle with a dropper.

Benzocaine might be a suitable substitute

In preparing this PURL, we learned from several colleagues that they always keep a bottle of benzocaine in their pocket and they apply the drops to the ears of their pediatric patients with AOM when they see them in their offices or in the emergency department.

Benzocaine is available in various brand names (eg, Auralgan, Americaine, A/B otic drops, among others). These are oil suspensions and not an aqueous solution as used in this study, so it would be important not to use these preparations in the presence of a ruptured tympanic membrane because the oil suspension may not be absorbed. The aqueous solution will be absorbed so it can be used even if a ruptured tympanic membrane is suspected.

In most situations rupture of the tympanic membrane gives immediate pain relief. However, in some, the pain persists and it may be difficult to tell if the tympanic membrane has ruptured or the debris and pus is from otitis externa. In those situations, the aqueous lidocaine solution might be preferred.

Should parents give drops at home?

This study does not address home use of these drops. However, benzocaine preparations have been used safely for many years for otitis externa at home, and we cannot think of any reason why drops could not be prescribed for home use in acute otitis media.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A mother brings her 3-year-old son to your office first thing in the morning. The boy has fever and right ear pain. You see that the tympanic membrane is dull, red, and bulging. The mother has been up most of the night with her child. She implores you to “do something.” She is exhausted and her son is crying and holding his right ear. You know that antibiotics will not provide immediate pain relief and oral analgesics will take a while to help. What can you offer that will help right away?

Until this study, we’ve had only 1 placebo-controlled trial to guide how we manage a big problem. Big in terms of distress to parents and children, and in sheer numbers—acute otitis media (AOM) is extremely common in children.^2,3

Routine antibiotics: Woeful lack of evidence

Even when antibiotics are indicated, pain relief is minimal and takes several days.^4-8 Despite “a woeful lack of substantial evidence on the question of antibiotic therapy” for AOM, it is the most common reason for the prescription of antibiotics in children.^4,6 A Cochrane review showed that antibiotics have no effect on recurrence of AOM or complications, including hearing impairment.⁵ The same review showed no pain reduction in 24 hours and only 30% pain reduction in 2 to 7 days with antibiotic use.⁵ Antibiotics clearly have a minimal role in providing pain relief for AOM.

Oral analgesics too slow

Oral analgesic use in AOM has been studied and has shown good results. We calculated the number needed to treat (1.0 divided by the absolute risk reduction) for both ibuprofen (number needed to treat [NNT]=5) and acetaminophen (NNT=6) from data in the 1996 trial by Bertin et al.⁹

It is a common practice in the United States to treat AOM with oral analgesics. However, the onset of pain relief with oral medications can be slow and the relief is generally not complete, so oral medications are not immediately helpful to meet the needs of our crying 3-year-old patient and his exhausted mother.

Topical anesthetics

To our knowledge, prior evidence on the efficacy of topical anesthetics is limited to 1 placebo-controlled trial. A randomized trial by Hoberman et al,¹⁰ with 54 subjects, showed a statistically significant 25% reduction in pain with the analgesic drops Auralgan (containing antipyrine, benzocaine, and glycerine) at 30 minutes when compared with olive oil. A 2006 Cochrane review¹¹ did not include the Bolt et al trial¹ described in this PURL, but did include the Hoberman trial¹⁰ and 3 trials that compared a topical anesthetic with naturopathic herbal ear drops for AOM pain, and the review concluded that evidence was insufficient.

Topical anesthetic plus oraI analgesia for earache relief

STUDY SUMMARY: Pain measured by visual analogue, Bieri faces scales

This double-blind, randomized, placebo-controlled trial¹ compared aqueous lidocaine 2% drops with saline drops in the ear, for reducing pain due to AOM in patients 3 to 17 years of age. The trial was conducted at an Australian children’s hospital emergency room. The study evaluated “lignocaine,” the name for lidocaine in Australia.

Emergency physicians instilled 3 drops of either lidocaine or saline into the affected ear in the 2 groups (n=31 in the study group and n=32 in the placebo group). Patients, parents, treating physicians, and staff administering ear drops and assessing pain were blinded to group assignment. Doctors measured pain at baseline and after 30 minutes and patients measured pain at baseline, 10, 20, and 30 minutes after the drops were instilled, using the Bieri faces pain scale and a visual analogue scale.¹²

Lidocaine reduced pain scores by 50% from baseline at 10 and 30 minutes compared with saline. No serious side effects were noted at 30 minutes, although 3 patients in the lidocaine group complained of mild dizziness the next day. The treating physician prescribed paracetamol (equivalent to acetaminophen) for participants in both the lidocaine and the placebo group at their discretion. The proportion given paracetamol was similar in both groups.

WHAT’S NEW: Pain relief is immediate

Family physicians have used topical anethestics for otitis externa for decades. This RCT adds evidence that topical anesthetics are useful for providing immediate pain relief from AOM, as well. The 2004 guidelines from the American Academy of Pediatrics and the American Academy of Family Physicians indicate that management of AOM should include the assessment and treatment of pain.

We think that topical agents such as lidocaine and benzocaine are useful adjuncts to oral analgesics in providing immediate pain relief, especially in the face of evidence showing that antibiotics do not offer significant pain relief.

Previous studies have shown that aqueous lidocaine is ineffective on uninflamed tympanic membrane.¹³ The results of this study are consistent with increased uptake of the drug through the inflamed tympanic membrane.

CAVEATS: Children >3 years studied

This trial included only children older than 3 years, so the results may not apply to younger children and infants.

This essentially was a study of ear pain treatment, which, in our view, does not detract from the clinical usefulness of the findings. Topical anesthetics seem to be useful for ear pain in general.

Concurrent analgesics

Some variability existed in the oral analgesics the children received, as these agents were given at the discretion of the parents and treating physicians. We think that this does not detract from the study findings, as it represents a practical, real-world setting, which is desirable in an effectiveness RCT. Moreover, the extent of pain reduction was over and above that conferred by analgesic administration.

CHALLENGES TO IMPLEMENTATION: Lidocaine is not sold in a dropper

Aqueous lidocaine is not sold in a bottle with a dropper: our search on www.drugstore.com and www.drugs.com did not yield an otic preparation with only aqueous lidocaine. However, 2% injectable lidocaine, which is readily available, can be used with a dropper. Aqueous lidocaine can be compounded at a compounding pharmacy and placed in a bottle with a dropper.

Benzocaine might be a suitable substitute

In preparing this PURL, we learned from several colleagues that they always keep a bottle of benzocaine in their pocket and they apply the drops to the ears of their pediatric patients with AOM when they see them in their offices or in the emergency department.

Benzocaine is available in various brand names (eg, Auralgan, Americaine, A/B otic drops, among others). These are oil suspensions and not an aqueous solution as used in this study, so it would be important not to use these preparations in the presence of a ruptured tympanic membrane because the oil suspension may not be absorbed. The aqueous solution will be absorbed so it can be used even if a ruptured tympanic membrane is suspected.

In most situations rupture of the tympanic membrane gives immediate pain relief. However, in some, the pain persists and it may be difficult to tell if the tympanic membrane has ruptured or the debris and pus is from otitis externa. In those situations, the aqueous lidocaine solution might be preferred.

Should parents give drops at home?

This study does not address home use of these drops. However, benzocaine preparations have been used safely for many years for otitis externa at home, and we cannot think of any reason why drops could not be prescribed for home use in acute otitis media.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A mother brings her 3-year-old son to your office first thing in the morning. The boy has fever and right ear pain. You see that the tympanic membrane is dull, red, and bulging. The mother has been up most of the night with her child. She implores you to “do something.” She is exhausted and her son is crying and holding his right ear. You know that antibiotics will not provide immediate pain relief and oral analgesics will take a while to help. What can you offer that will help right away?

Until this study, we’ve had only 1 placebo-controlled trial to guide how we manage a big problem. Big in terms of distress to parents and children, and in sheer numbers—acute otitis media (AOM) is extremely common in children.^2,3

Routine antibiotics: Woeful lack of evidence

Even when antibiotics are indicated, pain relief is minimal and takes several days.^4-8 Despite “a woeful lack of substantial evidence on the question of antibiotic therapy” for AOM, it is the most common reason for the prescription of antibiotics in children.^4,6 A Cochrane review showed that antibiotics have no effect on recurrence of AOM or complications, including hearing impairment.⁵ The same review showed no pain reduction in 24 hours and only 30% pain reduction in 2 to 7 days with antibiotic use.⁵ Antibiotics clearly have a minimal role in providing pain relief for AOM.

Oral analgesics too slow

Oral analgesic use in AOM has been studied and has shown good results. We calculated the number needed to treat (1.0 divided by the absolute risk reduction) for both ibuprofen (number needed to treat [NNT]=5) and acetaminophen (NNT=6) from data in the 1996 trial by Bertin et al.⁹

It is a common practice in the United States to treat AOM with oral analgesics. However, the onset of pain relief with oral medications can be slow and the relief is generally not complete, so oral medications are not immediately helpful to meet the needs of our crying 3-year-old patient and his exhausted mother.

Topical anesthetics

To our knowledge, prior evidence on the efficacy of topical anesthetics is limited to 1 placebo-controlled trial. A randomized trial by Hoberman et al,¹⁰ with 54 subjects, showed a statistically significant 25% reduction in pain with the analgesic drops Auralgan (containing antipyrine, benzocaine, and glycerine) at 30 minutes when compared with olive oil. A 2006 Cochrane review¹¹ did not include the Bolt et al trial¹ described in this PURL, but did include the Hoberman trial¹⁰ and 3 trials that compared a topical anesthetic with naturopathic herbal ear drops for AOM pain, and the review concluded that evidence was insufficient.

Topical anesthetic plus oraI analgesia for earache relief

STUDY SUMMARY: Pain measured by visual analogue, Bieri faces scales

This double-blind, randomized, placebo-controlled trial¹ compared aqueous lidocaine 2% drops with saline drops in the ear, for reducing pain due to AOM in patients 3 to 17 years of age. The trial was conducted at an Australian children’s hospital emergency room. The study evaluated “lignocaine,” the name for lidocaine in Australia.

Emergency physicians instilled 3 drops of either lidocaine or saline into the affected ear in the 2 groups (n=31 in the study group and n=32 in the placebo group). Patients, parents, treating physicians, and staff administering ear drops and assessing pain were blinded to group assignment. Doctors measured pain at baseline and after 30 minutes and patients measured pain at baseline, 10, 20, and 30 minutes after the drops were instilled, using the Bieri faces pain scale and a visual analogue scale.¹²

Lidocaine reduced pain scores by 50% from baseline at 10 and 30 minutes compared with saline. No serious side effects were noted at 30 minutes, although 3 patients in the lidocaine group complained of mild dizziness the next day. The treating physician prescribed paracetamol (equivalent to acetaminophen) for participants in both the lidocaine and the placebo group at their discretion. The proportion given paracetamol was similar in both groups.

WHAT’S NEW: Pain relief is immediate

Family physicians have used topical anethestics for otitis externa for decades. This RCT adds evidence that topical anesthetics are useful for providing immediate pain relief from AOM, as well. The 2004 guidelines from the American Academy of Pediatrics and the American Academy of Family Physicians indicate that management of AOM should include the assessment and treatment of pain.

We think that topical agents such as lidocaine and benzocaine are useful adjuncts to oral analgesics in providing immediate pain relief, especially in the face of evidence showing that antibiotics do not offer significant pain relief.

Previous studies have shown that aqueous lidocaine is ineffective on uninflamed tympanic membrane.¹³ The results of this study are consistent with increased uptake of the drug through the inflamed tympanic membrane.

CAVEATS: Children >3 years studied

This trial included only children older than 3 years, so the results may not apply to younger children and infants.

This essentially was a study of ear pain treatment, which, in our view, does not detract from the clinical usefulness of the findings. Topical anesthetics seem to be useful for ear pain in general.

Concurrent analgesics

Some variability existed in the oral analgesics the children received, as these agents were given at the discretion of the parents and treating physicians. We think that this does not detract from the study findings, as it represents a practical, real-world setting, which is desirable in an effectiveness RCT. Moreover, the extent of pain reduction was over and above that conferred by analgesic administration.

CHALLENGES TO IMPLEMENTATION: Lidocaine is not sold in a dropper

Aqueous lidocaine is not sold in a bottle with a dropper: our search on www.drugstore.com and www.drugs.com did not yield an otic preparation with only aqueous lidocaine. However, 2% injectable lidocaine, which is readily available, can be used with a dropper. Aqueous lidocaine can be compounded at a compounding pharmacy and placed in a bottle with a dropper.

Benzocaine might be a suitable substitute

In preparing this PURL, we learned from several colleagues that they always keep a bottle of benzocaine in their pocket and they apply the drops to the ears of their pediatric patients with AOM when they see them in their offices or in the emergency department.

Benzocaine is available in various brand names (eg, Auralgan, Americaine, A/B otic drops, among others). These are oil suspensions and not an aqueous solution as used in this study, so it would be important not to use these preparations in the presence of a ruptured tympanic membrane because the oil suspension may not be absorbed. The aqueous solution will be absorbed so it can be used even if a ruptured tympanic membrane is suspected.

In most situations rupture of the tympanic membrane gives immediate pain relief. However, in some, the pain persists and it may be difficult to tell if the tympanic membrane has ruptured or the debris and pus is from otitis externa. In those situations, the aqueous lidocaine solution might be preferred.

Should parents give drops at home?

This study does not address home use of these drops. However, benzocaine preparations have been used safely for many years for otitis externa at home, and we cannot think of any reason why drops could not be prescribed for home use in acute otitis media.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 39-year-old, otherwise healthy woman presents to your clinic with a sore throat, nasal congestion, and dry cough she’s had since yesterday. She wants an antibiotic, but your evaluation reveals an uncomplicated viral upper respiratory infection—a common cold. You would like to provide her with an alternative treatment, but you are aware of the lack of evidence for clear benefit of zinc lozenges, echinacea, and vitamin C. Is there any other medication that might benefit this patient?

Yes. Pelargonium sidoides, a species of South African geranium used for centuries in Zulu medicine,² shows promise as an herbal remedy for respiratory infections. Two randomized trials show that extracts of P sidoides improve symptoms of acute bronchitis which, like the common cold, is usually caused by a virus.^3-5

There is a plausible biological mechanism of action. In vitro studies show that Pelargonium extract induces the interferon system and up-regulates cytokines important in protecting host cells from viral infection.⁶

BACKGROUND: $17 billion dollar cold

Our patients want more relief from cold symptoms and are clearly willing to pay for it. Americans spend approximately $2.9 billion annually on over-the-counter (OTC) cold preparations and $1.1 billion on unnecessary antibiotics.⁷ The term “common cold” refers to a collection of symptoms, including sore throat, rhinorrhea, nasal congestion, cough, low-grade fever, and malaise, usually self-limited and lasting 10 to 14 days, caused by a number of viruses, most commonly by a rhinovirus.⁸ According to the 2005 National Ambulatory Medical Care Survey, the common cold is the third most common diagnosis in physicians’ offices behind only hypertension and well-infant/child visits.⁹ A 2001 US telephone survey determined that approximately 500 million episodes of non-influenza viral infection occur annually, resulting in direct costs of $17 billion for physician services and medications and approximately 200 million missed days of work.⁷

CLINICAL CONTEXT: Evidence proves most cold remedies don’t work

Although colds are common and result in annoying symptoms and missed work, much of the money spent on remedies is wasted. A truly effective treatment would be valuable to our patients.

Despite brisk sales, evidence for the efficacy of various cold remedies is inconclusive and contradictory. We found 6 Cochrane reviews of cold treatments, including antitussives, antihistamines, decongestants, vitamin C, echinacea, and zinc lozenges. With the exception of pseudoephedrine for nasal symptoms, the evidence that any product improves symptoms or decreases the duration of the cold is not encouraging.

Cough medications. The 2004 Cochrane Review of OTC medications for cough¹⁰ found no consistent evidence that any of them work. Codeine was no more effective than placebo for reducing cough symptoms. Three efficacy studies of dextromethorphan for cough showed either no difference or small but possibly clinically insignificant improvement in cough over placebo. One study of guaifenesin showed benefit over placebo in reducing cough frequency; another one showed no benefit over placebo.

Vitamin C, echinacea. Three Cochrane reviews found no conclusive evidence of benefit over placebo for either vitamin C¹¹ or echinacea¹² in treating the common cold.

Zinc. A new panel has been convened by the Cochrane group to reassess the effectiveness of zinc, but a 1999 Cochrane review¹³ found no benefit for zinc over placebo.

Antihistamines are not effective for relieving cold symptoms.¹⁴

Pseudoephedrine is the only medication with good-quality evidence for effectiveness, but only for reducing nasal symptoms.¹⁵ The authors concluded that patients may be encouraged to continue pseudoephedrine for up to 5 days if found to be effective with the first dose. Nasal congestion and discharge, however, are only 2 of the many irritating symptoms of a cold.

You can be a “REALITY CHECKER”

Bernard Ewigman, MD, MSPH

If you are in full-time clinical practice, a medical director of a practice, or otherwise directly involved in decision-making about adopting new practices, join our team of “reality checkers.”

Just email me at [email protected]

STUDY SUMMARY: Duration and severity of symptoms are reduced

This was a multicenter, prospective, double-blind, placebo-controlled randomized trial to evaluate the effectiveness of a liquid herbal preparation from the roots of Pelargonium sidoides for decreasing the duration and severity of symptoms of the common cold.

Patient characteristics. Patients were recruited from 8 outpatient departments in Ukraine between December 2003 and May 2004. Two hundred and seven (207) patients were eligible. The number of ineligible and excluded patients was not stated. These 207 patients were randomized into 1 of 4 groups:

• 52 received 30 drops 3 times daily vs 51 patients who received placebo
• 52 patients received 60 drops 3 times daily vs 52 patients who received a higher-dose placebo.

The report gives the outcomes of the low-dose arm only. Two-thirds of the participants were women; all were Caucasian. Patients in the treatment and placebo groups were similar in terms of recurrent disease, prior use of medication for the common cold, smoking, and alcohol and caffeine consumption. All had a negative Group A beta-hemolytic strep test.

Inclusion criteria. Patients included men and women 18 to 55 years of age; able to provide written informed consent; with 2 major cold symptoms (nasal discharge, sore throat) and at least 1 minor cold symptom (nasal congestion, sneezing, scratchy throat, hoarseness, cough, headaches, muscle aches, or fever) or presence of 1 major cold symptom and at least 3 minor cold symptoms; duration of symptoms 24 to 48 hours.

Exclusion criteria were any acute ear, nose, throat and respiratory tract disease other than the common cold; positive rapid strep test; 6 or more episodes of recurrent tonsillitis, sinusitis, or otitis within the past 12 months or any chronic ear, nose, throat or respiratory tract disease; treatment with antibiotics, glucocorticoids, or antihistamine drugs during the 4 weeks prior to enrollment in the trial; treatment with cold medications that might impair the trial results (eg, decongestants, local anesthetics); and use of cough or pain relief medications, or any other treatment for the common cold within 7 days prior to enrollment in the trial.

Treatment regimen. Patients were assigned to take 30 drops of either the study herbal preparation or 30 drops of placebo 3 times daily, at least 30 minutes before or after a meal, from day 1 continuing to day 10. The investigational drug and placebo were supplied by Dr. Willmar Schwabe GmbH & Co. (Karlsruhe, Germany). The investigational medication is a preparation of the roots of P sidoides, extraction solution: ethanol 11% (1:8-10) (wt/wt). The placebo was matched for color, smell, taste, and viscosity. Paracetamol (acetaminophen) tablets were allowed for all patients for fever greater than 39°C.

Primary endpoint. Severity of cold symptoms was evaluated using the Cold Intensity Score (CIS), a validated scale derived from the sum of scores for 10 cold-related symptoms (nasal drainage, sore throat, nasal congestion, sneezing, scratchy throat, hoarseness, cough, headaches, muscle aches, and fever) on a scale of 0 to 4, where 0=not present and 4=very severe, to a maximum of 40 points. At baseline, the mean total CIS was comparable in both treatment and placebo groups (17.8±4.0 vs 16.9±3.4). From baseline to day 5, the mean total CIS decreased by 10.4±3.0 in the treatment group vs 5.6±4.3 in the placebo group (P<.0001).

Secondary endpoints. The number of patients achieving clinical cure (defined by CIS ≤1) by day 10 was significantly higher in the treatment group (78.8% vs 31.4%, P<.0001). The mean duration of days absent from work was significantly lower in the treatment group (6.9±1.8 vs 8.2±2.1, P<.0003), as was number of days with less than 100% usual activity level (7.1±1.5 vs 8.7±1.3, P<.0001). Data for both the primary and secondary endpoints were evaluated according to an intention-to-treat analysis. Both the intervention and placebo sides each had 4 patients that became ineligible after initial randomization. No patients were lost to follow-up.

Safety and tolerability. Patients in the low-dose arm experienced 3 nonserious adverse events, and 1 experienced mild epistaxis. Two additional patients (1 in the treatment and 1 in the placebo group) experienced moderate to severe tracheitis, not attributable to the study medication. Tolerability was rated slightly better in the treatment than placebo group on day 5. Forty-nine of 52 patients (94%) in the treatment group rated the preparation as good or very good tolerability vs 42 of 51 patients (82%) in the placebo group.

WHAT’S NEW?: A first

This is the first study that demonstrates the efficacy and safety of P sidoides in the treatment of the common cold. More importantly, this degree of improvement in cold symptoms is dramatically better than other common OTC treatments, including vitamin C, echinacea, and zinc preparations.

CAVEATS: How is this different from other cold remedies?

Patients are already spending a lot on cold remedies; this study suggests money would be better spent on having a ready supply of Pelargonium in the medicine cabinet, and it appears to be safe.

Other initially promising complementary and alternative therapies, such as zinc, echinacea, and vitamin C, have not been shown to be effective with more vigorous evaluation. We recognize that this is only 1 clinical trial, and the results may not be replicated in future trials. However, we are impressed by the effect size—twice the size as that seen for placebo, with a reduction in half of total cold symptom severity over 5 days and a reduction of missed time from work by more than a full day on average over placebo.

In vitro studies suggest a physiologic mechanism that is consistent with the study outcomes.

Similar findings are reported for symptom reduction in acute bronchitis.

Safety

There were no significant adverse events in this study, which is consistent with the findings of the studies of acute bronchitis.^12-14P sidoides has been widely used in Germany since the 1980s, with an annual sale value in 2002 of $55 million or 4.1 million packages.

The Uppsala Monitoring Centre, in conjunction with the World Health Organization international pharmacovigilance program, received 34 case reports between 2002 and 2006 of allergic reactions to ethanolic herbal extract of Pelargonium root, 2 of which involved life-threatening circulatory collapse requiring emergency medical attention. Given the extremely rare occurrence of these events we believe the minimal risk is acceptable. The others involved rash and pruritus.

Also of note: contact dermatitis to Pelargonium houseplants has been reported. As a result, product information will be added to product packaging, warning of common reactions of gastrointestinal complaints (gastric pain, heartburn, nausea, and diarrhea) as well as the potential for serious allergic reaction. In addition, since some of the active compounds are plant coumarins, there is a theoretical risk of interaction with warfarin and aspirin but no serious bleeding events have been reported.¹⁶

It is also recommended that individuals with renal or hepatic disease or women who are pregnant or breastfeeding avoid use of this preparation, as safety studies have not been performed.

Other study design issues

A few other issues struck us as important when assessing the validity of this study. For example, 1 of the authors appears to be an employee of the pharmaceutical company that manufactures the preparation, raising the conflict of interest issue.

We were also curious about why the results of the high-dose arm were not reported in this manuscript. Could there have been a higher rate of adverse events in the high-dose arm? Knowing how many patients were ineligible or excluded, and the efficacy or safety in the high-dose arm would give us more confidence in the findings, but we decided that these were not necessarily fatal flaws.

Bottom line

Despite the above caveats, this was a well-designed randomized controlled trial that suggests that P sidoides is impressively efficacious in decreasing the duration and severity of the common cold. In the final analysis, we think that these findings justify recommending this to our patients.

CHALLENGES TO IMPLEMENTATION: 2-day window

The medication was started within 48 hours of the onset of symptoms. We generally see patients seeking treatment for the common cold well after the first 2 days. The efficacy of Pelargonium is no doubt less when started later in the course of the illness. Colds resolve spontaneously, so to get the benefit of this treatment, it likely must be started early.

Our conclusion is that patients could be advised to purchase the medication to have on hand at home at the start of the cold season.

Availability of the drug

P sidoides is available in the US under the brand name Umcka Coldcare.

The preparation used in the study is marketed in Europe by ISO-Arzneimittel¹⁷ under the name Umckaloabo, which is a combination of the Zulu words for lung symptoms and breast pain.¹⁸

Our Internet search on the term “Pelargonium sidoides” failed to yield a distributor of the German preparation used in the study that would be available in the United States. However, a different manufacturer, Nature’s Way, distributes a number of similar preparations containing extract of the root of P sidoides under the name Umcka Coldcare. Umcka Cold-care appears to be readily available for purchase, both on-line and through local health food stores, for less than $20 per 4-oz (120-mL) bottle. A different retailer, African Red Tea, offers syrup, 1:10 ethanolic extract for $29.95 for 100-mL bottle.¹⁹ Like the German preparation, these formulations are delivered by dropper.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 39-year-old, otherwise healthy woman presents to your clinic with a sore throat, nasal congestion, and dry cough she’s had since yesterday. She wants an antibiotic, but your evaluation reveals an uncomplicated viral upper respiratory infection—a common cold. You would like to provide her with an alternative treatment, but you are aware of the lack of evidence for clear benefit of zinc lozenges, echinacea, and vitamin C. Is there any other medication that might benefit this patient?

Yes. Pelargonium sidoides, a species of South African geranium used for centuries in Zulu medicine,² shows promise as an herbal remedy for respiratory infections. Two randomized trials show that extracts of P sidoides improve symptoms of acute bronchitis which, like the common cold, is usually caused by a virus.^3-5

There is a plausible biological mechanism of action. In vitro studies show that Pelargonium extract induces the interferon system and up-regulates cytokines important in protecting host cells from viral infection.⁶

BACKGROUND: $17 billion dollar cold

Our patients want more relief from cold symptoms and are clearly willing to pay for it. Americans spend approximately $2.9 billion annually on over-the-counter (OTC) cold preparations and $1.1 billion on unnecessary antibiotics.⁷ The term “common cold” refers to a collection of symptoms, including sore throat, rhinorrhea, nasal congestion, cough, low-grade fever, and malaise, usually self-limited and lasting 10 to 14 days, caused by a number of viruses, most commonly by a rhinovirus.⁸ According to the 2005 National Ambulatory Medical Care Survey, the common cold is the third most common diagnosis in physicians’ offices behind only hypertension and well-infant/child visits.⁹ A 2001 US telephone survey determined that approximately 500 million episodes of non-influenza viral infection occur annually, resulting in direct costs of $17 billion for physician services and medications and approximately 200 million missed days of work.⁷

CLINICAL CONTEXT: Evidence proves most cold remedies don’t work

Although colds are common and result in annoying symptoms and missed work, much of the money spent on remedies is wasted. A truly effective treatment would be valuable to our patients.

Despite brisk sales, evidence for the efficacy of various cold remedies is inconclusive and contradictory. We found 6 Cochrane reviews of cold treatments, including antitussives, antihistamines, decongestants, vitamin C, echinacea, and zinc lozenges. With the exception of pseudoephedrine for nasal symptoms, the evidence that any product improves symptoms or decreases the duration of the cold is not encouraging.

Cough medications. The 2004 Cochrane Review of OTC medications for cough¹⁰ found no consistent evidence that any of them work. Codeine was no more effective than placebo for reducing cough symptoms. Three efficacy studies of dextromethorphan for cough showed either no difference or small but possibly clinically insignificant improvement in cough over placebo. One study of guaifenesin showed benefit over placebo in reducing cough frequency; another one showed no benefit over placebo.

Vitamin C, echinacea. Three Cochrane reviews found no conclusive evidence of benefit over placebo for either vitamin C¹¹ or echinacea¹² in treating the common cold.

Zinc. A new panel has been convened by the Cochrane group to reassess the effectiveness of zinc, but a 1999 Cochrane review¹³ found no benefit for zinc over placebo.

Antihistamines are not effective for relieving cold symptoms.¹⁴

Pseudoephedrine is the only medication with good-quality evidence for effectiveness, but only for reducing nasal symptoms.¹⁵ The authors concluded that patients may be encouraged to continue pseudoephedrine for up to 5 days if found to be effective with the first dose. Nasal congestion and discharge, however, are only 2 of the many irritating symptoms of a cold.

You can be a “REALITY CHECKER”

Bernard Ewigman, MD, MSPH

If you are in full-time clinical practice, a medical director of a practice, or otherwise directly involved in decision-making about adopting new practices, join our team of “reality checkers.”

Just email me at [email protected]

STUDY SUMMARY: Duration and severity of symptoms are reduced

This was a multicenter, prospective, double-blind, placebo-controlled randomized trial to evaluate the effectiveness of a liquid herbal preparation from the roots of Pelargonium sidoides for decreasing the duration and severity of symptoms of the common cold.

Patient characteristics. Patients were recruited from 8 outpatient departments in Ukraine between December 2003 and May 2004. Two hundred and seven (207) patients were eligible. The number of ineligible and excluded patients was not stated. These 207 patients were randomized into 1 of 4 groups:

• 52 received 30 drops 3 times daily vs 51 patients who received placebo
• 52 patients received 60 drops 3 times daily vs 52 patients who received a higher-dose placebo.

The report gives the outcomes of the low-dose arm only. Two-thirds of the participants were women; all were Caucasian. Patients in the treatment and placebo groups were similar in terms of recurrent disease, prior use of medication for the common cold, smoking, and alcohol and caffeine consumption. All had a negative Group A beta-hemolytic strep test.

Inclusion criteria. Patients included men and women 18 to 55 years of age; able to provide written informed consent; with 2 major cold symptoms (nasal discharge, sore throat) and at least 1 minor cold symptom (nasal congestion, sneezing, scratchy throat, hoarseness, cough, headaches, muscle aches, or fever) or presence of 1 major cold symptom and at least 3 minor cold symptoms; duration of symptoms 24 to 48 hours.

Exclusion criteria were any acute ear, nose, throat and respiratory tract disease other than the common cold; positive rapid strep test; 6 or more episodes of recurrent tonsillitis, sinusitis, or otitis within the past 12 months or any chronic ear, nose, throat or respiratory tract disease; treatment with antibiotics, glucocorticoids, or antihistamine drugs during the 4 weeks prior to enrollment in the trial; treatment with cold medications that might impair the trial results (eg, decongestants, local anesthetics); and use of cough or pain relief medications, or any other treatment for the common cold within 7 days prior to enrollment in the trial.

Treatment regimen. Patients were assigned to take 30 drops of either the study herbal preparation or 30 drops of placebo 3 times daily, at least 30 minutes before or after a meal, from day 1 continuing to day 10. The investigational drug and placebo were supplied by Dr. Willmar Schwabe GmbH & Co. (Karlsruhe, Germany). The investigational medication is a preparation of the roots of P sidoides, extraction solution: ethanol 11% (1:8-10) (wt/wt). The placebo was matched for color, smell, taste, and viscosity. Paracetamol (acetaminophen) tablets were allowed for all patients for fever greater than 39°C.

Primary endpoint. Severity of cold symptoms was evaluated using the Cold Intensity Score (CIS), a validated scale derived from the sum of scores for 10 cold-related symptoms (nasal drainage, sore throat, nasal congestion, sneezing, scratchy throat, hoarseness, cough, headaches, muscle aches, and fever) on a scale of 0 to 4, where 0=not present and 4=very severe, to a maximum of 40 points. At baseline, the mean total CIS was comparable in both treatment and placebo groups (17.8±4.0 vs 16.9±3.4). From baseline to day 5, the mean total CIS decreased by 10.4±3.0 in the treatment group vs 5.6±4.3 in the placebo group (P<.0001).

Secondary endpoints. The number of patients achieving clinical cure (defined by CIS ≤1) by day 10 was significantly higher in the treatment group (78.8% vs 31.4%, P<.0001). The mean duration of days absent from work was significantly lower in the treatment group (6.9±1.8 vs 8.2±2.1, P<.0003), as was number of days with less than 100% usual activity level (7.1±1.5 vs 8.7±1.3, P<.0001). Data for both the primary and secondary endpoints were evaluated according to an intention-to-treat analysis. Both the intervention and placebo sides each had 4 patients that became ineligible after initial randomization. No patients were lost to follow-up.

Safety and tolerability. Patients in the low-dose arm experienced 3 nonserious adverse events, and 1 experienced mild epistaxis. Two additional patients (1 in the treatment and 1 in the placebo group) experienced moderate to severe tracheitis, not attributable to the study medication. Tolerability was rated slightly better in the treatment than placebo group on day 5. Forty-nine of 52 patients (94%) in the treatment group rated the preparation as good or very good tolerability vs 42 of 51 patients (82%) in the placebo group.

WHAT’S NEW?: A first

This is the first study that demonstrates the efficacy and safety of P sidoides in the treatment of the common cold. More importantly, this degree of improvement in cold symptoms is dramatically better than other common OTC treatments, including vitamin C, echinacea, and zinc preparations.

CAVEATS: How is this different from other cold remedies?

Patients are already spending a lot on cold remedies; this study suggests money would be better spent on having a ready supply of Pelargonium in the medicine cabinet, and it appears to be safe.

Other initially promising complementary and alternative therapies, such as zinc, echinacea, and vitamin C, have not been shown to be effective with more vigorous evaluation. We recognize that this is only 1 clinical trial, and the results may not be replicated in future trials. However, we are impressed by the effect size—twice the size as that seen for placebo, with a reduction in half of total cold symptom severity over 5 days and a reduction of missed time from work by more than a full day on average over placebo.

In vitro studies suggest a physiologic mechanism that is consistent with the study outcomes.

Similar findings are reported for symptom reduction in acute bronchitis.

Safety

There were no significant adverse events in this study, which is consistent with the findings of the studies of acute bronchitis.^12-14P sidoides has been widely used in Germany since the 1980s, with an annual sale value in 2002 of $55 million or 4.1 million packages.

The Uppsala Monitoring Centre, in conjunction with the World Health Organization international pharmacovigilance program, received 34 case reports between 2002 and 2006 of allergic reactions to ethanolic herbal extract of Pelargonium root, 2 of which involved life-threatening circulatory collapse requiring emergency medical attention. Given the extremely rare occurrence of these events we believe the minimal risk is acceptable. The others involved rash and pruritus.

Also of note: contact dermatitis to Pelargonium houseplants has been reported. As a result, product information will be added to product packaging, warning of common reactions of gastrointestinal complaints (gastric pain, heartburn, nausea, and diarrhea) as well as the potential for serious allergic reaction. In addition, since some of the active compounds are plant coumarins, there is a theoretical risk of interaction with warfarin and aspirin but no serious bleeding events have been reported.¹⁶

It is also recommended that individuals with renal or hepatic disease or women who are pregnant or breastfeeding avoid use of this preparation, as safety studies have not been performed.

Other study design issues

A few other issues struck us as important when assessing the validity of this study. For example, 1 of the authors appears to be an employee of the pharmaceutical company that manufactures the preparation, raising the conflict of interest issue.

We were also curious about why the results of the high-dose arm were not reported in this manuscript. Could there have been a higher rate of adverse events in the high-dose arm? Knowing how many patients were ineligible or excluded, and the efficacy or safety in the high-dose arm would give us more confidence in the findings, but we decided that these were not necessarily fatal flaws.

Bottom line

Despite the above caveats, this was a well-designed randomized controlled trial that suggests that P sidoides is impressively efficacious in decreasing the duration and severity of the common cold. In the final analysis, we think that these findings justify recommending this to our patients.

CHALLENGES TO IMPLEMENTATION: 2-day window

The medication was started within 48 hours of the onset of symptoms. We generally see patients seeking treatment for the common cold well after the first 2 days. The efficacy of Pelargonium is no doubt less when started later in the course of the illness. Colds resolve spontaneously, so to get the benefit of this treatment, it likely must be started early.

Our conclusion is that patients could be advised to purchase the medication to have on hand at home at the start of the cold season.

Availability of the drug

P sidoides is available in the US under the brand name Umcka Coldcare.

The preparation used in the study is marketed in Europe by ISO-Arzneimittel¹⁷ under the name Umckaloabo, which is a combination of the Zulu words for lung symptoms and breast pain.¹⁸

Our Internet search on the term “Pelargonium sidoides” failed to yield a distributor of the German preparation used in the study that would be available in the United States. However, a different manufacturer, Nature’s Way, distributes a number of similar preparations containing extract of the root of P sidoides under the name Umcka Coldcare. Umcka Cold-care appears to be readily available for purchase, both on-line and through local health food stores, for less than $20 per 4-oz (120-mL) bottle. A different retailer, African Red Tea, offers syrup, 1:10 ethanolic extract for $29.95 for 100-mL bottle.¹⁹ Like the German preparation, these formulations are delivered by dropper.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

ILLUSTRATIVE CASE

A 39-year-old, otherwise healthy woman presents to your clinic with a sore throat, nasal congestion, and dry cough she’s had since yesterday. She wants an antibiotic, but your evaluation reveals an uncomplicated viral upper respiratory infection—a common cold. You would like to provide her with an alternative treatment, but you are aware of the lack of evidence for clear benefit of zinc lozenges, echinacea, and vitamin C. Is there any other medication that might benefit this patient?

Yes. Pelargonium sidoides, a species of South African geranium used for centuries in Zulu medicine,² shows promise as an herbal remedy for respiratory infections. Two randomized trials show that extracts of P sidoides improve symptoms of acute bronchitis which, like the common cold, is usually caused by a virus.^3-5

There is a plausible biological mechanism of action. In vitro studies show that Pelargonium extract induces the interferon system and up-regulates cytokines important in protecting host cells from viral infection.⁶

BACKGROUND: $17 billion dollar cold

Our patients want more relief from cold symptoms and are clearly willing to pay for it. Americans spend approximately $2.9 billion annually on over-the-counter (OTC) cold preparations and $1.1 billion on unnecessary antibiotics.⁷ The term “common cold” refers to a collection of symptoms, including sore throat, rhinorrhea, nasal congestion, cough, low-grade fever, and malaise, usually self-limited and lasting 10 to 14 days, caused by a number of viruses, most commonly by a rhinovirus.⁸ According to the 2005 National Ambulatory Medical Care Survey, the common cold is the third most common diagnosis in physicians’ offices behind only hypertension and well-infant/child visits.⁹ A 2001 US telephone survey determined that approximately 500 million episodes of non-influenza viral infection occur annually, resulting in direct costs of $17 billion for physician services and medications and approximately 200 million missed days of work.⁷

CLINICAL CONTEXT: Evidence proves most cold remedies don’t work

Although colds are common and result in annoying symptoms and missed work, much of the money spent on remedies is wasted. A truly effective treatment would be valuable to our patients.

Despite brisk sales, evidence for the efficacy of various cold remedies is inconclusive and contradictory. We found 6 Cochrane reviews of cold treatments, including antitussives, antihistamines, decongestants, vitamin C, echinacea, and zinc lozenges. With the exception of pseudoephedrine for nasal symptoms, the evidence that any product improves symptoms or decreases the duration of the cold is not encouraging.

Cough medications. The 2004 Cochrane Review of OTC medications for cough¹⁰ found no consistent evidence that any of them work. Codeine was no more effective than placebo for reducing cough symptoms. Three efficacy studies of dextromethorphan for cough showed either no difference or small but possibly clinically insignificant improvement in cough over placebo. One study of guaifenesin showed benefit over placebo in reducing cough frequency; another one showed no benefit over placebo.

Vitamin C, echinacea. Three Cochrane reviews found no conclusive evidence of benefit over placebo for either vitamin C¹¹ or echinacea¹² in treating the common cold.

Zinc. A new panel has been convened by the Cochrane group to reassess the effectiveness of zinc, but a 1999 Cochrane review¹³ found no benefit for zinc over placebo.

Antihistamines are not effective for relieving cold symptoms.¹⁴

Pseudoephedrine is the only medication with good-quality evidence for effectiveness, but only for reducing nasal symptoms.¹⁵ The authors concluded that patients may be encouraged to continue pseudoephedrine for up to 5 days if found to be effective with the first dose. Nasal congestion and discharge, however, are only 2 of the many irritating symptoms of a cold.

You can be a “REALITY CHECKER”

Bernard Ewigman, MD, MSPH

If you are in full-time clinical practice, a medical director of a practice, or otherwise directly involved in decision-making about adopting new practices, join our team of “reality checkers.”

Just email me at [email protected]

STUDY SUMMARY: Duration and severity of symptoms are reduced

This was a multicenter, prospective, double-blind, placebo-controlled randomized trial to evaluate the effectiveness of a liquid herbal preparation from the roots of Pelargonium sidoides for decreasing the duration and severity of symptoms of the common cold.

Patient characteristics. Patients were recruited from 8 outpatient departments in Ukraine between December 2003 and May 2004. Two hundred and seven (207) patients were eligible. The number of ineligible and excluded patients was not stated. These 207 patients were randomized into 1 of 4 groups:

• 52 received 30 drops 3 times daily vs 51 patients who received placebo
• 52 patients received 60 drops 3 times daily vs 52 patients who received a higher-dose placebo.

The report gives the outcomes of the low-dose arm only. Two-thirds of the participants were women; all were Caucasian. Patients in the treatment and placebo groups were similar in terms of recurrent disease, prior use of medication for the common cold, smoking, and alcohol and caffeine consumption. All had a negative Group A beta-hemolytic strep test.

Inclusion criteria. Patients included men and women 18 to 55 years of age; able to provide written informed consent; with 2 major cold symptoms (nasal discharge, sore throat) and at least 1 minor cold symptom (nasal congestion, sneezing, scratchy throat, hoarseness, cough, headaches, muscle aches, or fever) or presence of 1 major cold symptom and at least 3 minor cold symptoms; duration of symptoms 24 to 48 hours.

Exclusion criteria were any acute ear, nose, throat and respiratory tract disease other than the common cold; positive rapid strep test; 6 or more episodes of recurrent tonsillitis, sinusitis, or otitis within the past 12 months or any chronic ear, nose, throat or respiratory tract disease; treatment with antibiotics, glucocorticoids, or antihistamine drugs during the 4 weeks prior to enrollment in the trial; treatment with cold medications that might impair the trial results (eg, decongestants, local anesthetics); and use of cough or pain relief medications, or any other treatment for the common cold within 7 days prior to enrollment in the trial.

Treatment regimen. Patients were assigned to take 30 drops of either the study herbal preparation or 30 drops of placebo 3 times daily, at least 30 minutes before or after a meal, from day 1 continuing to day 10. The investigational drug and placebo were supplied by Dr. Willmar Schwabe GmbH & Co. (Karlsruhe, Germany). The investigational medication is a preparation of the roots of P sidoides, extraction solution: ethanol 11% (1:8-10) (wt/wt). The placebo was matched for color, smell, taste, and viscosity. Paracetamol (acetaminophen) tablets were allowed for all patients for fever greater than 39°C.

Primary endpoint. Severity of cold symptoms was evaluated using the Cold Intensity Score (CIS), a validated scale derived from the sum of scores for 10 cold-related symptoms (nasal drainage, sore throat, nasal congestion, sneezing, scratchy throat, hoarseness, cough, headaches, muscle aches, and fever) on a scale of 0 to 4, where 0=not present and 4=very severe, to a maximum of 40 points. At baseline, the mean total CIS was comparable in both treatment and placebo groups (17.8±4.0 vs 16.9±3.4). From baseline to day 5, the mean total CIS decreased by 10.4±3.0 in the treatment group vs 5.6±4.3 in the placebo group (P<.0001).

Secondary endpoints. The number of patients achieving clinical cure (defined by CIS ≤1) by day 10 was significantly higher in the treatment group (78.8% vs 31.4%, P<.0001). The mean duration of days absent from work was significantly lower in the treatment group (6.9±1.8 vs 8.2±2.1, P<.0003), as was number of days with less than 100% usual activity level (7.1±1.5 vs 8.7±1.3, P<.0001). Data for both the primary and secondary endpoints were evaluated according to an intention-to-treat analysis. Both the intervention and placebo sides each had 4 patients that became ineligible after initial randomization. No patients were lost to follow-up.

Safety and tolerability. Patients in the low-dose arm experienced 3 nonserious adverse events, and 1 experienced mild epistaxis. Two additional patients (1 in the treatment and 1 in the placebo group) experienced moderate to severe tracheitis, not attributable to the study medication. Tolerability was rated slightly better in the treatment than placebo group on day 5. Forty-nine of 52 patients (94%) in the treatment group rated the preparation as good or very good tolerability vs 42 of 51 patients (82%) in the placebo group.

WHAT’S NEW?: A first

This is the first study that demonstrates the efficacy and safety of P sidoides in the treatment of the common cold. More importantly, this degree of improvement in cold symptoms is dramatically better than other common OTC treatments, including vitamin C, echinacea, and zinc preparations.

CAVEATS: How is this different from other cold remedies?

Patients are already spending a lot on cold remedies; this study suggests money would be better spent on having a ready supply of Pelargonium in the medicine cabinet, and it appears to be safe.

Other initially promising complementary and alternative therapies, such as zinc, echinacea, and vitamin C, have not been shown to be effective with more vigorous evaluation. We recognize that this is only 1 clinical trial, and the results may not be replicated in future trials. However, we are impressed by the effect size—twice the size as that seen for placebo, with a reduction in half of total cold symptom severity over 5 days and a reduction of missed time from work by more than a full day on average over placebo.

In vitro studies suggest a physiologic mechanism that is consistent with the study outcomes.

Similar findings are reported for symptom reduction in acute bronchitis.

Safety

There were no significant adverse events in this study, which is consistent with the findings of the studies of acute bronchitis.^12-14P sidoides has been widely used in Germany since the 1980s, with an annual sale value in 2002 of $55 million or 4.1 million packages.

The Uppsala Monitoring Centre, in conjunction with the World Health Organization international pharmacovigilance program, received 34 case reports between 2002 and 2006 of allergic reactions to ethanolic herbal extract of Pelargonium root, 2 of which involved life-threatening circulatory collapse requiring emergency medical attention. Given the extremely rare occurrence of these events we believe the minimal risk is acceptable. The others involved rash and pruritus.

Also of note: contact dermatitis to Pelargonium houseplants has been reported. As a result, product information will be added to product packaging, warning of common reactions of gastrointestinal complaints (gastric pain, heartburn, nausea, and diarrhea) as well as the potential for serious allergic reaction. In addition, since some of the active compounds are plant coumarins, there is a theoretical risk of interaction with warfarin and aspirin but no serious bleeding events have been reported.¹⁶

It is also recommended that individuals with renal or hepatic disease or women who are pregnant or breastfeeding avoid use of this preparation, as safety studies have not been performed.

Other study design issues

A few other issues struck us as important when assessing the validity of this study. For example, 1 of the authors appears to be an employee of the pharmaceutical company that manufactures the preparation, raising the conflict of interest issue.

We were also curious about why the results of the high-dose arm were not reported in this manuscript. Could there have been a higher rate of adverse events in the high-dose arm? Knowing how many patients were ineligible or excluded, and the efficacy or safety in the high-dose arm would give us more confidence in the findings, but we decided that these were not necessarily fatal flaws.

Bottom line

Despite the above caveats, this was a well-designed randomized controlled trial that suggests that P sidoides is impressively efficacious in decreasing the duration and severity of the common cold. In the final analysis, we think that these findings justify recommending this to our patients.

CHALLENGES TO IMPLEMENTATION: 2-day window

The medication was started within 48 hours of the onset of symptoms. We generally see patients seeking treatment for the common cold well after the first 2 days. The efficacy of Pelargonium is no doubt less when started later in the course of the illness. Colds resolve spontaneously, so to get the benefit of this treatment, it likely must be started early.

Our conclusion is that patients could be advised to purchase the medication to have on hand at home at the start of the cold season.

Availability of the drug

P sidoides is available in the US under the brand name Umcka Coldcare.

The preparation used in the study is marketed in Europe by ISO-Arzneimittel¹⁷ under the name Umckaloabo, which is a combination of the Zulu words for lung symptoms and breast pain.¹⁸

Our Internet search on the term “Pelargonium sidoides” failed to yield a distributor of the German preparation used in the study that would be available in the United States. However, a different manufacturer, Nature’s Way, distributes a number of similar preparations containing extract of the root of P sidoides under the name Umcka Coldcare. Umcka Cold-care appears to be readily available for purchase, both on-line and through local health food stores, for less than $20 per 4-oz (120-mL) bottle. A different retailer, African Red Tea, offers syrup, 1:10 ethanolic extract for $29.95 for 100-mL bottle.¹⁹ Like the German preparation, these formulations are delivered by dropper.

PURLs methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature (PURL) Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at www.jfponline.com/purls.

Illustrative Case

A 75-year-old woman comes to see you 1 month after she had surgery to repair a hip fracture. She was diagnosed with osteoporosis 3 years prior to the hip fracture and is currently taking calcium and vitamin D. She tried taking an oral bisphosphonate but couldn’t tolerate the gastrointestinal side effects. What treatment can you recommend to reduce her risk of sustaining another fracture?

Background: First fracture heightens risk

Patients with a prior hip fracture have 2.5 times the risk of a new fracture compared to age-matched persons without a previous hip fracture.² Women who have hip fractures are 3 times more likely to die in the first 6 months after the fracture than women of the same age and health status without fractures.³ Ten million people in the US have osteoporosis and 300,000 per year suffer hip fracture.⁴

Guidelines from the National Osteoporosis Foundation (NOF) and the Institute for Clinical Systems Improvement (ICSI) include these recommendations for hip fracture patients: discuss adequacy of total calcium and vitamin D intake; address home safety and falls prevention; and encourage specific exercises for muscle strength. They also recommend treating all patients with a prior hip or vertebral fracture with an antiresorptive agent. Options include oral bisphosphonates (alendronate, ibandronate, or risedronate), calcitonin intranasal spray or subcutaneous calcitonin, hormone therapy, parathyroid hormone, and raloxifene.^5,6

Clinical context: Are we doing our best?

Most patients with hip fracture are not properly evaluated or treated for osteoporosis. A 2002 study of 500 hip fracture patients treated at 4 Midwestern health systems found that only 12% to 24% of patients had a DXA (dual-energy x-ray absorptiometry) scan either before or after hip fracture, 5% to 27% of the patients received documented advice to take adequate calcium and vitamin D, and 5% to 37% received a prescription for any antiresorptive medication (bisphosphonate [2% to 10%], estrogen, calcitonin, or raloxifene).⁷

Bisphosphonates are effective but compliance is poor

Bisphosphonates are effective in preventing recurrence of hip fracture. One cohort study that included over 35,000 women over age 45 who had received a bisphosphonate prescription showed that patients who are adherent to treatment have a 44.5% relative risk reduction over 2 years and an absolute risk reduction of 0.8%, for an NNT of 125.

However, compliance with oral bisphosphonate therapy is poor; only 20% of the women in this study persisted with the therapy for 24 months.⁸ Patients must take these medications first thing in the morning with 8 ounces of water and then remain upright for 30 to 60 minutes before eating or drinking. Gastrointestinal side effects, including dyspepsia, nausea, and reflux disease, occur in about 25% of patients, and there is a small risk of developing gastric or duodenal ulcers.

Study summary

The HORIZON Recurrent Fracture Trial was an international, randomized, double blind, placebo-controlled trial of 2127 patients with a recent hip fracture.

• The primary endpoint was a new clinical fracture.
• Secondary endpoints included the change in bone mineral density in the non-fractured hip, new vertebral and hip fractures, and pre-specified safety endpoints, including death.

Patients. Women and men age 50 or older who had undergone a surgical repair of a minimal trauma hip fracture in the previous 90 days were eligible for the study. Ninety-one percent of the patients were white, 76% were female, and the mean age was 74.5 years. Forty-one percent of patients had a T score at the femoral neck of –2.5 or less at baseline (meeting diagnostic criteria for osteoporosis).

Method. Patients were randomized to receive either intravenous zoledronic acid 5 mg or placebo within 90 days of surgical repair of a hip fracture and yearly thereafter for the duration of the study. Patients with serum 25-hydroxyvitamin D levels <15 ng/mL received a loading dose of vitamin D (50,000–125,000 IU) 14 days before the first dose of the study drug. All patients were given daily calcium (1000–1500 mg) and vitamin D (800–1200 IU) supplements. Simultaneous treatment with nasal calcitonin, selective estrogen-receptor modulators, hormone replacement, tobolone, and external hip protectors was permitted “at the discretion of the investigators,” and 10.5% of the study patients did receive one of these other osteoporosis therapies.

Patients were followed for up to 5 years. Bone mineral density was tested by DXA at the hip and femoral neck at baseline and then annually. The median follow-up time was 1.9 years; 71.3% of patients completing the trial, and 3% of patients were lost to follow-up.

Results. The patients assigned to zoledronic acid had a 5.3% absolute risk reduction for new clinical fractures, yielding an NNT of 19 over 2 years to prevent one new clinical fracture ( TABLE 1 ). Bone mineral density of the contralateral hip increased in the zoledronic acid group by 2.6% after 1 year, 4.7% after 2 years, and 5.5% after 3 years and declined in the placebo group by 1.0%, 0.7%, and 0.9% respectively.

There was a 3.7% absolute risk reduction of death, with an NNT of 27 for 2 years to prevent one death.

Adverse events that were more common in the zoledronic acid group included fever (8.7% vs 3.1%) and musculoskeletal pain (3.1% vs. 1.2%). There were no reported cases of jaw osteonecrosis in either group and no statistically significant delay in the healing of fractures with zoledronic acid. Both groups had similar rates of renal and cardiovascular events, including atrial fibrillation and stroke.

Novartis provided funding for the study. An independent data and safety monitoring board oversaw the conduct and safety of the study and recommended that it be stopped early after having surpassed the pre-specified efficacy boundaries. Independent statisticians confirmed the data analysis that was performed by the sponsor.¹

TABLE 1
The HORIZON study: Rates of fracture and death were lower in the zoledronic group compared to placebo¹

What’s new: The adherence advantage

The obvious advantage of zoledronic acid over other bisphosphonates is the high level of adherence that is possible under the controlled environment of a once yearly infusion administered under medical supervision. Considering the low rates of adherence to oral bisphosphonates, this is a significant medical advance.

This study shows that a yearly infusion of zoledronic acid is highly effective in preventing subsequent clinical fractures in patients who have recently suffered a hip fracture. It is the first randomized-controlled trial of a bisphosphonate for secondary prevention in patients with recent hip fracture, regardless of their bone mineral density status.

In a previous 3-year randomized controlled trial of 5mg zoledronic acid once yearly vs placebo for postmenopausal women with osteoporosis, the risk of vertebral fractures was reduced by 70% (3.3% vs 10.9% placebo) and the risk of hip fracture was reduced by 41% (1.4% vs 2.5% placebo).⁹

The NNT of 19 for 2 years to prevent one clinical fracture and NNT of 27 for 2 years to prevent one death strikes us as a good bargain compared to many modern medical interventions. Are these results too good to be true? We don’t think so.

No serious design flaws

This was a well done trial with no serious flaws in design. The number of deaths, however, was relatively small, so the NNT may be as high as 50 by our rough calculations. As a “worst case” for the benefit, however, this still seems worthwhile.

Caveats

Patients with uncorrected hypocalcemia or creatinine clearance <35 mL/min should not take bisphosphonates, including zoledronic acid. Although this study did not show any evidence of an increased risk of atrial fibrillation or report any cases of osteonecrosis of the jaw, providers should monitor patients for these potential adverse events.

Challenges to implementation: $1200 per dose

The FDA approved Reclast (zoledronic acid 5 mg) as a once-yearly treatment for postmenopausal osteoporosis and Paget’s disease in August 2007. (Zometa is the brand name for zoledronic acid 4 mg that is indicated for multiple myeloma, bone metastasis, and hypercalcemia of malignancy.) Medicare and most insurance plans will reimburse Reclast infusion for these FDA-approved indications when billed by a provider using a CPT code. It is administered intravenously over 15-minutes and there are no risks beyond those associated with local infiltration.

The greatest barrier to implementing this practice for solo physicians or small group practices will likely be the up front expense of buying the drug; one dose is approximately $1200. Patients can be referred to larger practices or hospitals with the capital to have zoledronic acid on hand and the capability of providing the infusion.

The cost is comparable to the annual cost of oral bisphosphonates and less than the cost of the other IV bisphosphonate (ibandronate), which is administered every 3 months ( TABLE 2 ).

TABLE 2
Bisphosphonates for osteoporosis: Routes, dosage, and cost

PURLS methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at here.

Illustrative Case

A 75-year-old woman comes to see you 1 month after she had surgery to repair a hip fracture. She was diagnosed with osteoporosis 3 years prior to the hip fracture and is currently taking calcium and vitamin D. She tried taking an oral bisphosphonate but couldn’t tolerate the gastrointestinal side effects. What treatment can you recommend to reduce her risk of sustaining another fracture?

Background: First fracture heightens risk

Patients with a prior hip fracture have 2.5 times the risk of a new fracture compared to age-matched persons without a previous hip fracture.² Women who have hip fractures are 3 times more likely to die in the first 6 months after the fracture than women of the same age and health status without fractures.³ Ten million people in the US have osteoporosis and 300,000 per year suffer hip fracture.⁴

Guidelines from the National Osteoporosis Foundation (NOF) and the Institute for Clinical Systems Improvement (ICSI) include these recommendations for hip fracture patients: discuss adequacy of total calcium and vitamin D intake; address home safety and falls prevention; and encourage specific exercises for muscle strength. They also recommend treating all patients with a prior hip or vertebral fracture with an antiresorptive agent. Options include oral bisphosphonates (alendronate, ibandronate, or risedronate), calcitonin intranasal spray or subcutaneous calcitonin, hormone therapy, parathyroid hormone, and raloxifene.^5,6

Clinical context: Are we doing our best?

Most patients with hip fracture are not properly evaluated or treated for osteoporosis. A 2002 study of 500 hip fracture patients treated at 4 Midwestern health systems found that only 12% to 24% of patients had a DXA (dual-energy x-ray absorptiometry) scan either before or after hip fracture, 5% to 27% of the patients received documented advice to take adequate calcium and vitamin D, and 5% to 37% received a prescription for any antiresorptive medication (bisphosphonate [2% to 10%], estrogen, calcitonin, or raloxifene).⁷

Bisphosphonates are effective but compliance is poor

Bisphosphonates are effective in preventing recurrence of hip fracture. One cohort study that included over 35,000 women over age 45 who had received a bisphosphonate prescription showed that patients who are adherent to treatment have a 44.5% relative risk reduction over 2 years and an absolute risk reduction of 0.8%, for an NNT of 125.

However, compliance with oral bisphosphonate therapy is poor; only 20% of the women in this study persisted with the therapy for 24 months.⁸ Patients must take these medications first thing in the morning with 8 ounces of water and then remain upright for 30 to 60 minutes before eating or drinking. Gastrointestinal side effects, including dyspepsia, nausea, and reflux disease, occur in about 25% of patients, and there is a small risk of developing gastric or duodenal ulcers.

Study summary

The HORIZON Recurrent Fracture Trial was an international, randomized, double blind, placebo-controlled trial of 2127 patients with a recent hip fracture.

• The primary endpoint was a new clinical fracture.
• Secondary endpoints included the change in bone mineral density in the non-fractured hip, new vertebral and hip fractures, and pre-specified safety endpoints, including death.

Patients. Women and men age 50 or older who had undergone a surgical repair of a minimal trauma hip fracture in the previous 90 days were eligible for the study. Ninety-one percent of the patients were white, 76% were female, and the mean age was 74.5 years. Forty-one percent of patients had a T score at the femoral neck of –2.5 or less at baseline (meeting diagnostic criteria for osteoporosis).

Method. Patients were randomized to receive either intravenous zoledronic acid 5 mg or placebo within 90 days of surgical repair of a hip fracture and yearly thereafter for the duration of the study. Patients with serum 25-hydroxyvitamin D levels <15 ng/mL received a loading dose of vitamin D (50,000–125,000 IU) 14 days before the first dose of the study drug. All patients were given daily calcium (1000–1500 mg) and vitamin D (800–1200 IU) supplements. Simultaneous treatment with nasal calcitonin, selective estrogen-receptor modulators, hormone replacement, tobolone, and external hip protectors was permitted “at the discretion of the investigators,” and 10.5% of the study patients did receive one of these other osteoporosis therapies.

Patients were followed for up to 5 years. Bone mineral density was tested by DXA at the hip and femoral neck at baseline and then annually. The median follow-up time was 1.9 years; 71.3% of patients completing the trial, and 3% of patients were lost to follow-up.

Results. The patients assigned to zoledronic acid had a 5.3% absolute risk reduction for new clinical fractures, yielding an NNT of 19 over 2 years to prevent one new clinical fracture ( TABLE 1 ). Bone mineral density of the contralateral hip increased in the zoledronic acid group by 2.6% after 1 year, 4.7% after 2 years, and 5.5% after 3 years and declined in the placebo group by 1.0%, 0.7%, and 0.9% respectively.

There was a 3.7% absolute risk reduction of death, with an NNT of 27 for 2 years to prevent one death.

Adverse events that were more common in the zoledronic acid group included fever (8.7% vs 3.1%) and musculoskeletal pain (3.1% vs. 1.2%). There were no reported cases of jaw osteonecrosis in either group and no statistically significant delay in the healing of fractures with zoledronic acid. Both groups had similar rates of renal and cardiovascular events, including atrial fibrillation and stroke.

Novartis provided funding for the study. An independent data and safety monitoring board oversaw the conduct and safety of the study and recommended that it be stopped early after having surpassed the pre-specified efficacy boundaries. Independent statisticians confirmed the data analysis that was performed by the sponsor.¹

TABLE 1
The HORIZON study: Rates of fracture and death were lower in the zoledronic group compared to placebo¹

What’s new: The adherence advantage

The obvious advantage of zoledronic acid over other bisphosphonates is the high level of adherence that is possible under the controlled environment of a once yearly infusion administered under medical supervision. Considering the low rates of adherence to oral bisphosphonates, this is a significant medical advance.

This study shows that a yearly infusion of zoledronic acid is highly effective in preventing subsequent clinical fractures in patients who have recently suffered a hip fracture. It is the first randomized-controlled trial of a bisphosphonate for secondary prevention in patients with recent hip fracture, regardless of their bone mineral density status.

In a previous 3-year randomized controlled trial of 5mg zoledronic acid once yearly vs placebo for postmenopausal women with osteoporosis, the risk of vertebral fractures was reduced by 70% (3.3% vs 10.9% placebo) and the risk of hip fracture was reduced by 41% (1.4% vs 2.5% placebo).⁹

The NNT of 19 for 2 years to prevent one clinical fracture and NNT of 27 for 2 years to prevent one death strikes us as a good bargain compared to many modern medical interventions. Are these results too good to be true? We don’t think so.

No serious design flaws

This was a well done trial with no serious flaws in design. The number of deaths, however, was relatively small, so the NNT may be as high as 50 by our rough calculations. As a “worst case” for the benefit, however, this still seems worthwhile.

Caveats

Patients with uncorrected hypocalcemia or creatinine clearance <35 mL/min should not take bisphosphonates, including zoledronic acid. Although this study did not show any evidence of an increased risk of atrial fibrillation or report any cases of osteonecrosis of the jaw, providers should monitor patients for these potential adverse events.

Challenges to implementation: $1200 per dose

The FDA approved Reclast (zoledronic acid 5 mg) as a once-yearly treatment for postmenopausal osteoporosis and Paget’s disease in August 2007. (Zometa is the brand name for zoledronic acid 4 mg that is indicated for multiple myeloma, bone metastasis, and hypercalcemia of malignancy.) Medicare and most insurance plans will reimburse Reclast infusion for these FDA-approved indications when billed by a provider using a CPT code. It is administered intravenously over 15-minutes and there are no risks beyond those associated with local infiltration.

The greatest barrier to implementing this practice for solo physicians or small group practices will likely be the up front expense of buying the drug; one dose is approximately $1200. Patients can be referred to larger practices or hospitals with the capital to have zoledronic acid on hand and the capability of providing the infusion.

The cost is comparable to the annual cost of oral bisphosphonates and less than the cost of the other IV bisphosphonate (ibandronate), which is administered every 3 months ( TABLE 2 ).

TABLE 2
Bisphosphonates for osteoporosis: Routes, dosage, and cost

PURLS methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at here.

Illustrative Case

A 75-year-old woman comes to see you 1 month after she had surgery to repair a hip fracture. She was diagnosed with osteoporosis 3 years prior to the hip fracture and is currently taking calcium and vitamin D. She tried taking an oral bisphosphonate but couldn’t tolerate the gastrointestinal side effects. What treatment can you recommend to reduce her risk of sustaining another fracture?

Background: First fracture heightens risk

Patients with a prior hip fracture have 2.5 times the risk of a new fracture compared to age-matched persons without a previous hip fracture.² Women who have hip fractures are 3 times more likely to die in the first 6 months after the fracture than women of the same age and health status without fractures.³ Ten million people in the US have osteoporosis and 300,000 per year suffer hip fracture.⁴

Guidelines from the National Osteoporosis Foundation (NOF) and the Institute for Clinical Systems Improvement (ICSI) include these recommendations for hip fracture patients: discuss adequacy of total calcium and vitamin D intake; address home safety and falls prevention; and encourage specific exercises for muscle strength. They also recommend treating all patients with a prior hip or vertebral fracture with an antiresorptive agent. Options include oral bisphosphonates (alendronate, ibandronate, or risedronate), calcitonin intranasal spray or subcutaneous calcitonin, hormone therapy, parathyroid hormone, and raloxifene.^5,6

Clinical context: Are we doing our best?

Most patients with hip fracture are not properly evaluated or treated for osteoporosis. A 2002 study of 500 hip fracture patients treated at 4 Midwestern health systems found that only 12% to 24% of patients had a DXA (dual-energy x-ray absorptiometry) scan either before or after hip fracture, 5% to 27% of the patients received documented advice to take adequate calcium and vitamin D, and 5% to 37% received a prescription for any antiresorptive medication (bisphosphonate [2% to 10%], estrogen, calcitonin, or raloxifene).⁷

Bisphosphonates are effective but compliance is poor

Bisphosphonates are effective in preventing recurrence of hip fracture. One cohort study that included over 35,000 women over age 45 who had received a bisphosphonate prescription showed that patients who are adherent to treatment have a 44.5% relative risk reduction over 2 years and an absolute risk reduction of 0.8%, for an NNT of 125.

However, compliance with oral bisphosphonate therapy is poor; only 20% of the women in this study persisted with the therapy for 24 months.⁸ Patients must take these medications first thing in the morning with 8 ounces of water and then remain upright for 30 to 60 minutes before eating or drinking. Gastrointestinal side effects, including dyspepsia, nausea, and reflux disease, occur in about 25% of patients, and there is a small risk of developing gastric or duodenal ulcers.

Study summary

The HORIZON Recurrent Fracture Trial was an international, randomized, double blind, placebo-controlled trial of 2127 patients with a recent hip fracture.

• The primary endpoint was a new clinical fracture.
• Secondary endpoints included the change in bone mineral density in the non-fractured hip, new vertebral and hip fractures, and pre-specified safety endpoints, including death.

Patients. Women and men age 50 or older who had undergone a surgical repair of a minimal trauma hip fracture in the previous 90 days were eligible for the study. Ninety-one percent of the patients were white, 76% were female, and the mean age was 74.5 years. Forty-one percent of patients had a T score at the femoral neck of –2.5 or less at baseline (meeting diagnostic criteria for osteoporosis).

Method. Patients were randomized to receive either intravenous zoledronic acid 5 mg or placebo within 90 days of surgical repair of a hip fracture and yearly thereafter for the duration of the study. Patients with serum 25-hydroxyvitamin D levels <15 ng/mL received a loading dose of vitamin D (50,000–125,000 IU) 14 days before the first dose of the study drug. All patients were given daily calcium (1000–1500 mg) and vitamin D (800–1200 IU) supplements. Simultaneous treatment with nasal calcitonin, selective estrogen-receptor modulators, hormone replacement, tobolone, and external hip protectors was permitted “at the discretion of the investigators,” and 10.5% of the study patients did receive one of these other osteoporosis therapies.

Patients were followed for up to 5 years. Bone mineral density was tested by DXA at the hip and femoral neck at baseline and then annually. The median follow-up time was 1.9 years; 71.3% of patients completing the trial, and 3% of patients were lost to follow-up.

Results. The patients assigned to zoledronic acid had a 5.3% absolute risk reduction for new clinical fractures, yielding an NNT of 19 over 2 years to prevent one new clinical fracture ( TABLE 1 ). Bone mineral density of the contralateral hip increased in the zoledronic acid group by 2.6% after 1 year, 4.7% after 2 years, and 5.5% after 3 years and declined in the placebo group by 1.0%, 0.7%, and 0.9% respectively.

There was a 3.7% absolute risk reduction of death, with an NNT of 27 for 2 years to prevent one death.

Adverse events that were more common in the zoledronic acid group included fever (8.7% vs 3.1%) and musculoskeletal pain (3.1% vs. 1.2%). There were no reported cases of jaw osteonecrosis in either group and no statistically significant delay in the healing of fractures with zoledronic acid. Both groups had similar rates of renal and cardiovascular events, including atrial fibrillation and stroke.

Novartis provided funding for the study. An independent data and safety monitoring board oversaw the conduct and safety of the study and recommended that it be stopped early after having surpassed the pre-specified efficacy boundaries. Independent statisticians confirmed the data analysis that was performed by the sponsor.¹

TABLE 1
The HORIZON study: Rates of fracture and death were lower in the zoledronic group compared to placebo¹

What’s new: The adherence advantage

The obvious advantage of zoledronic acid over other bisphosphonates is the high level of adherence that is possible under the controlled environment of a once yearly infusion administered under medical supervision. Considering the low rates of adherence to oral bisphosphonates, this is a significant medical advance.

This study shows that a yearly infusion of zoledronic acid is highly effective in preventing subsequent clinical fractures in patients who have recently suffered a hip fracture. It is the first randomized-controlled trial of a bisphosphonate for secondary prevention in patients with recent hip fracture, regardless of their bone mineral density status.

In a previous 3-year randomized controlled trial of 5mg zoledronic acid once yearly vs placebo for postmenopausal women with osteoporosis, the risk of vertebral fractures was reduced by 70% (3.3% vs 10.9% placebo) and the risk of hip fracture was reduced by 41% (1.4% vs 2.5% placebo).⁹

The NNT of 19 for 2 years to prevent one clinical fracture and NNT of 27 for 2 years to prevent one death strikes us as a good bargain compared to many modern medical interventions. Are these results too good to be true? We don’t think so.

No serious design flaws

This was a well done trial with no serious flaws in design. The number of deaths, however, was relatively small, so the NNT may be as high as 50 by our rough calculations. As a “worst case” for the benefit, however, this still seems worthwhile.

Caveats

Patients with uncorrected hypocalcemia or creatinine clearance <35 mL/min should not take bisphosphonates, including zoledronic acid. Although this study did not show any evidence of an increased risk of atrial fibrillation or report any cases of osteonecrosis of the jaw, providers should monitor patients for these potential adverse events.

Challenges to implementation: $1200 per dose

The FDA approved Reclast (zoledronic acid 5 mg) as a once-yearly treatment for postmenopausal osteoporosis and Paget’s disease in August 2007. (Zometa is the brand name for zoledronic acid 4 mg that is indicated for multiple myeloma, bone metastasis, and hypercalcemia of malignancy.) Medicare and most insurance plans will reimburse Reclast infusion for these FDA-approved indications when billed by a provider using a CPT code. It is administered intravenously over 15-minutes and there are no risks beyond those associated with local infiltration.

The greatest barrier to implementing this practice for solo physicians or small group practices will likely be the up front expense of buying the drug; one dose is approximately $1200. Patients can be referred to larger practices or hospitals with the capital to have zoledronic acid on hand and the capability of providing the infusion.

The cost is comparable to the annual cost of oral bisphosphonates and less than the cost of the other IV bisphosphonate (ibandronate), which is administered every 3 months ( TABLE 2 ).

TABLE 2
Bisphosphonates for osteoporosis: Routes, dosage, and cost

PURLS methodology

This study was selected and evaluated using FPIN’s Priority Updates from the Research Literature Surveillance System methodology. The criteria and findings leading to the selection of this study as a PURL can be accessed at here.

Frank is a high school history teacher who reads The Wall Street Journal and The New York Times every morning. So I was a bit taken aback when, just as we stepped onto the court for Sunday morning doubles last month, he asked, “Say John, can you call in a Z-Pak to Walgreens for me today?” Being a typical nice-guy family doc, I said with only slight hesitation, “Why sure, Frank. Which Walgreens?”

Because I’d recently written an editorial about the overuse of antibiotics for respiratory infections,¹ I felt obliged to lay on a few facts about the dubious value of antibiotics for acute bronchitis, the illness he clearly had, judging from the hacking cough.

“You know, Frank,” I said, “you’ll probably get better just as fast without the Z-Pak.”

To which he replied, “The Walgreens on the corner of Lake Park and 55th.”

Okay, I didn’t win that round. But I have been keeping score for the last 2 weeks. I am batting .800 at the office; 4 of the last 5 patients with a variety of upper respiratory infections have walked out of the office without an antibiotic prescription. In the spirit of full disclosure, however, I should tell you that one patient was pregnant and another gentleman said that his symptoms were already clearing up since he made the appointment for a cough lasting 2 weeks. I could not resist pulling out the pad, however, for a woman with mild depression, hypertension, and chronic back pain (which was flaring), who complained that she’d “been blowing green stuff out of [her] nose for the past three days” and wanted an antibiotic.

Just say no

The science, of course, does not back up this practice and is the reason for the “just say no to antibiotics for acute respiratory infections” campaign being waged by the Centers for Disease Control and Prevention. For years we’ve known that viral upper respiratory infections do not respond to antibiotics. Research during the past 5 years has demonstrated repeatedly and convincingly that acute sinusitis, acute bronchitis, and most cases of pharyngitis and otitis media resolve as rapidly or nearly as rapidly without antibiotics, as well.

Why is this so? These syndromes, too, are predominately viral in origin, and even those caused by bacterial infection resolve nearly as rapidly without an antibiotic. For example, the duration of strep pharyngitis is shortened by only 1 to 2 days with antibiotic treatment, and complications of strep pharyngitis are now rare in the US. It’s reasonable to treat mildly symptomatic cases with supportive care; in fact, that’s the official, evidence-based recommendation in the Netherlands. Nonetheless, despite strong evidence of the limited effectiveness of antibiotics for acute respiratory infections, a recent study shows that 65% of upper respiratory infections, 78% of acute bronchitis, 65% of acute pharyngitis, and 81% of acute sinusitis episodes in primary care are treated with an antibiotic.²

Techniques for turning the tide

How are we to improve our prescribing for acute respiratory infections? First, it’s important to put 1 simple fact on the table: Most acute respiratory infections do not resolve in 1 week. The sad truth is that most acute respiratory infections for which patients consult a physician run their course in 10 to 21 days. Knowing this fact allows me to tell patients who present during the first week of illness that I am not at all surprised they are not yet well.

Next, I tell patients they do not need an antibiotic and that they will recover as rapidly without one. Sometimes this does the trick. For patients who insist that they need an antibiotic, the “wait and see” prescription reduces antibiotic use by about 50%.³ In this approach, one gives the patient a prescription but tells him to fill it only if symptoms do not improve in the next few days.

Two studies published recently in the Annals of Family Medicine provide new evidence for additional approaches. A study of patients’ expectations for treatment of their sore throat revealed that patients’ main purpose in consulting a physician was not to obtain a prescription but to find out the cause of the sore throat and to get pain relief.⁴ This suggests that aggressive treatment of throat pain might satisfy many patients more than a worthless antibiotic that might cause diarrhea and other adverse effects.

In the second study, researchers performed a secondary analysis of data from an earlier randomized controlled trial and attempted to identify clinical features of acute sinusitis that might predict a good response to antibiotic treatment.⁵ In the original randomized clinical trial, patients treated with amoxicillin did not improve more rapidly than those treated with placebo.⁶ In the recent analysis, the investigators found that even the classic symptoms of purulent nasal discharge and facial pain did not predict which patient would improve more rapidly with an antibiotic. This study prompted me to reflect on the futility of giving any patient with sinusitis symptoms an antibiotic, save for those who appear significantly ill or who are at risk for complications. But change comes slowly.

Yesterday I was driving home from Sunday tennis doubles with Frank, my friend who’d requested the Z-Pak, and a fellow player Jerry. We were shooting the breeze when the topic of the high cost of health care came up. After my short treatise on the waste we create with over-testing and over-treatment, Frank piped up, “You know, John, I don’t think that Z-Pak did me any good.”

I had not won the first round with Frank, but I had sowed the seeds of doubt.

Frank is a high school history teacher who reads The Wall Street Journal and The New York Times every morning. So I was a bit taken aback when, just as we stepped onto the court for Sunday morning doubles last month, he asked, “Say John, can you call in a Z-Pak to Walgreens for me today?” Being a typical nice-guy family doc, I said with only slight hesitation, “Why sure, Frank. Which Walgreens?”

Because I’d recently written an editorial about the overuse of antibiotics for respiratory infections,¹ I felt obliged to lay on a few facts about the dubious value of antibiotics for acute bronchitis, the illness he clearly had, judging from the hacking cough.

“You know, Frank,” I said, “you’ll probably get better just as fast without the Z-Pak.”

To which he replied, “The Walgreens on the corner of Lake Park and 55th.”

Okay, I didn’t win that round. But I have been keeping score for the last 2 weeks. I am batting .800 at the office; 4 of the last 5 patients with a variety of upper respiratory infections have walked out of the office without an antibiotic prescription. In the spirit of full disclosure, however, I should tell you that one patient was pregnant and another gentleman said that his symptoms were already clearing up since he made the appointment for a cough lasting 2 weeks. I could not resist pulling out the pad, however, for a woman with mild depression, hypertension, and chronic back pain (which was flaring), who complained that she’d “been blowing green stuff out of [her] nose for the past three days” and wanted an antibiotic.

Just say no

The science, of course, does not back up this practice and is the reason for the “just say no to antibiotics for acute respiratory infections” campaign being waged by the Centers for Disease Control and Prevention. For years we’ve known that viral upper respiratory infections do not respond to antibiotics. Research during the past 5 years has demonstrated repeatedly and convincingly that acute sinusitis, acute bronchitis, and most cases of pharyngitis and otitis media resolve as rapidly or nearly as rapidly without antibiotics, as well.

Why is this so? These syndromes, too, are predominately viral in origin, and even those caused by bacterial infection resolve nearly as rapidly without an antibiotic. For example, the duration of strep pharyngitis is shortened by only 1 to 2 days with antibiotic treatment, and complications of strep pharyngitis are now rare in the US. It’s reasonable to treat mildly symptomatic cases with supportive care; in fact, that’s the official, evidence-based recommendation in the Netherlands. Nonetheless, despite strong evidence of the limited effectiveness of antibiotics for acute respiratory infections, a recent study shows that 65% of upper respiratory infections, 78% of acute bronchitis, 65% of acute pharyngitis, and 81% of acute sinusitis episodes in primary care are treated with an antibiotic.²

Techniques for turning the tide

How are we to improve our prescribing for acute respiratory infections? First, it’s important to put 1 simple fact on the table: Most acute respiratory infections do not resolve in 1 week. The sad truth is that most acute respiratory infections for which patients consult a physician run their course in 10 to 21 days. Knowing this fact allows me to tell patients who present during the first week of illness that I am not at all surprised they are not yet well.

Next, I tell patients they do not need an antibiotic and that they will recover as rapidly without one. Sometimes this does the trick. For patients who insist that they need an antibiotic, the “wait and see” prescription reduces antibiotic use by about 50%.³ In this approach, one gives the patient a prescription but tells him to fill it only if symptoms do not improve in the next few days.

Two studies published recently in the Annals of Family Medicine provide new evidence for additional approaches. A study of patients’ expectations for treatment of their sore throat revealed that patients’ main purpose in consulting a physician was not to obtain a prescription but to find out the cause of the sore throat and to get pain relief.⁴ This suggests that aggressive treatment of throat pain might satisfy many patients more than a worthless antibiotic that might cause diarrhea and other adverse effects.

In the second study, researchers performed a secondary analysis of data from an earlier randomized controlled trial and attempted to identify clinical features of acute sinusitis that might predict a good response to antibiotic treatment.⁵ In the original randomized clinical trial, patients treated with amoxicillin did not improve more rapidly than those treated with placebo.⁶ In the recent analysis, the investigators found that even the classic symptoms of purulent nasal discharge and facial pain did not predict which patient would improve more rapidly with an antibiotic. This study prompted me to reflect on the futility of giving any patient with sinusitis symptoms an antibiotic, save for those who appear significantly ill or who are at risk for complications. But change comes slowly.

Yesterday I was driving home from Sunday tennis doubles with Frank, my friend who’d requested the Z-Pak, and a fellow player Jerry. We were shooting the breeze when the topic of the high cost of health care came up. After my short treatise on the waste we create with over-testing and over-treatment, Frank piped up, “You know, John, I don’t think that Z-Pak did me any good.”

I had not won the first round with Frank, but I had sowed the seeds of doubt.

Frank is a high school history teacher who reads The Wall Street Journal and The New York Times every morning. So I was a bit taken aback when, just as we stepped onto the court for Sunday morning doubles last month, he asked, “Say John, can you call in a Z-Pak to Walgreens for me today?” Being a typical nice-guy family doc, I said with only slight hesitation, “Why sure, Frank. Which Walgreens?”

Because I’d recently written an editorial about the overuse of antibiotics for respiratory infections,¹ I felt obliged to lay on a few facts about the dubious value of antibiotics for acute bronchitis, the illness he clearly had, judging from the hacking cough.

“You know, Frank,” I said, “you’ll probably get better just as fast without the Z-Pak.”

To which he replied, “The Walgreens on the corner of Lake Park and 55th.”

Okay, I didn’t win that round. But I have been keeping score for the last 2 weeks. I am batting .800 at the office; 4 of the last 5 patients with a variety of upper respiratory infections have walked out of the office without an antibiotic prescription. In the spirit of full disclosure, however, I should tell you that one patient was pregnant and another gentleman said that his symptoms were already clearing up since he made the appointment for a cough lasting 2 weeks. I could not resist pulling out the pad, however, for a woman with mild depression, hypertension, and chronic back pain (which was flaring), who complained that she’d “been blowing green stuff out of [her] nose for the past three days” and wanted an antibiotic.

Just say no

The science, of course, does not back up this practice and is the reason for the “just say no to antibiotics for acute respiratory infections” campaign being waged by the Centers for Disease Control and Prevention. For years we’ve known that viral upper respiratory infections do not respond to antibiotics. Research during the past 5 years has demonstrated repeatedly and convincingly that acute sinusitis, acute bronchitis, and most cases of pharyngitis and otitis media resolve as rapidly or nearly as rapidly without antibiotics, as well.

Why is this so? These syndromes, too, are predominately viral in origin, and even those caused by bacterial infection resolve nearly as rapidly without an antibiotic. For example, the duration of strep pharyngitis is shortened by only 1 to 2 days with antibiotic treatment, and complications of strep pharyngitis are now rare in the US. It’s reasonable to treat mildly symptomatic cases with supportive care; in fact, that’s the official, evidence-based recommendation in the Netherlands. Nonetheless, despite strong evidence of the limited effectiveness of antibiotics for acute respiratory infections, a recent study shows that 65% of upper respiratory infections, 78% of acute bronchitis, 65% of acute pharyngitis, and 81% of acute sinusitis episodes in primary care are treated with an antibiotic.²

Techniques for turning the tide

How are we to improve our prescribing for acute respiratory infections? First, it’s important to put 1 simple fact on the table: Most acute respiratory infections do not resolve in 1 week. The sad truth is that most acute respiratory infections for which patients consult a physician run their course in 10 to 21 days. Knowing this fact allows me to tell patients who present during the first week of illness that I am not at all surprised they are not yet well.

Next, I tell patients they do not need an antibiotic and that they will recover as rapidly without one. Sometimes this does the trick. For patients who insist that they need an antibiotic, the “wait and see” prescription reduces antibiotic use by about 50%.³ In this approach, one gives the patient a prescription but tells him to fill it only if symptoms do not improve in the next few days.

Two studies published recently in the Annals of Family Medicine provide new evidence for additional approaches. A study of patients’ expectations for treatment of their sore throat revealed that patients’ main purpose in consulting a physician was not to obtain a prescription but to find out the cause of the sore throat and to get pain relief.⁴ This suggests that aggressive treatment of throat pain might satisfy many patients more than a worthless antibiotic that might cause diarrhea and other adverse effects.

In the second study, researchers performed a secondary analysis of data from an earlier randomized controlled trial and attempted to identify clinical features of acute sinusitis that might predict a good response to antibiotic treatment.⁵ In the original randomized clinical trial, patients treated with amoxicillin did not improve more rapidly than those treated with placebo.⁶ In the recent analysis, the investigators found that even the classic symptoms of purulent nasal discharge and facial pain did not predict which patient would improve more rapidly with an antibiotic. This study prompted me to reflect on the futility of giving any patient with sinusitis symptoms an antibiotic, save for those who appear significantly ill or who are at risk for complications. But change comes slowly.

Yesterday I was driving home from Sunday tennis doubles with Frank, my friend who’d requested the Z-Pak, and a fellow player Jerry. We were shooting the breeze when the topic of the high cost of health care came up. After my short treatise on the waste we create with over-testing and over-treatment, Frank piped up, “You know, John, I don’t think that Z-Pak did me any good.”

I had not won the first round with Frank, but I had sowed the seeds of doubt.

In 1998 the British Journal of General Practice published a study by W. Stalman¹ entitled “The end of antibiotic treatment in adults with acute sinusitis-like complaints in general practice?” In this Dutch randomized trial, doxycycline was no more effective than placebo for clinically diagnosed acute sinusitis. Stallman’s trial was unique, because the diagnosis of acute sinusitis was based on clinical findings rather than xrays, computed tomography (CT) scans, or sinus puncture and culture—the gold standard for diagnosing bacterial sinusitis. He based the diagnosis on clinical findings because that is how we practice in family medicine. We rarely use x-rays and CT scans to diagnose sinusitis. X-ray findings are not all that accurate,² and CT scans are expensive, not immediately available, and should be reserved for difficult cases.

Since Stallman’s study, 2 more randomized placebo-controlled trials of antibiotic treatment for sinusitis-like symptoms in general practice— one of amoxicillin and the other of amoxicillin-clavulanate—found no benefit.^3,4 Even for patients with “x-ray confirmed” acute sinusitis in general practice, a randomized trial showed no benefit for amoxicillin.⁵

In this issue of The journal of family practice, Merenstein et al⁶ report the results of a similar randomized trial of clinically diagnosed sinusitis in primary care, showing once again that antibiotics are not very effective for treating sinusitislike symptoms, even for patients who have had symptoms for at least 7 days. At 14 days follow-up, 32 (48%) of the amoxicillin group vs 25 (37%) of the placebo group were cured, a nonsignificant difference. Even assuming that this 11% absolute difference was statistically significant—which might have occurred with a larger study—the number needed to treat would be 9. That is a lot of unnecessary antibiotic prescribing. Most readers of JFP will be familiar with the reason for the disappointing outcome of Merenstein’s and others sinusitis antibiotic treatment trials in primary care. That is, most cases of clinically diagnosed acute sinusitis are caused by viruses and do not respond to antibiotics. Furthermore, there is no reliable way clinically to distinguish viral from bacterial sinus infection; there is too much overlap in symptoms.

We now have 5 good placebo-controlled randomized trials of antibiotic treatment of clinically diagnosed acute sinusitis, all with negative results. This approaches “A” level of evidence. Is it time we “just say no” to treating sinusitis-like complaints with antibiotics? Was Stalman right? Is this the end of the story? Not quite, in my opinion.

For the most part, I agree that being stingy with antibiotics for patients with sinusitis-like complaints is a good thing, especially patients with mild symptoms. Most patients will have viral infections and will recover as quickly with symptomatic treatment. But we know that some patients we see do have acute bacterial sinusitis and will benefit from an antibiotic. We just don’t know who they are. On average, patients with acute sinusitis and air-fluid levels on CT scan improve more quickly with antibiotics.⁷ This point brings me back to the Merenstein study. The investigators noted that, despite similar cure rates at 14 days, the amoxicillin group improved more rapidly, and the time to complete improvement for those who fully recovered by 14 days was 8.1 days for the amoxicillin group and 10.7 days for the placebo group. This suggests to me there are “antibiotic responsive” cases buried in the group of patients in this study. I can’t get too excited about this, however, because patients’ average symptom severity ratings at 3, 7, and 14 days were not significantly different in the amoxicillin and placebo groups (as noted in Merenstein’s Table 2) Nonetheless, it is not yet time to give up the search for identifying “antibiotic responsive” acute sinusitis.

Here is another piece of evidence to support this assertion. Hansen found that patients with a clinical diagnosis of acute sinusitis who had significant facial pain did benefit from penicillin.⁸ As soon as 3 days after treatment started, pain was significantly diminished in the penicillin treated group compared with placebo.

What we really need is a reliable, easy, and inexpensive point-of-care test to distinguish viral from bacterial sinusitis—the “strep screen” for acute sinusitis. That test is the Holy Grail of acute sinusitis treatment. CT scans are too expensive, and plain x-rays and sinus transillumination are not accurate enough.² The Europeans have had limited success with C-reactive protein, but the predictive value is not terrific. I expect that a clever microbiologist will eventually discover the right test. Then we can target antibiotic treatment to those who will really benefit.

In the meantime, I recommend following the CDC principles of appropriate antibiotic use for acute rhinosinusitis.⁹ Temporize at least a week for those who are not that ill, treat pain, and do not hesitate to use an antibiotic for those with more severe, classical symptoms of acute bacterial sinusitis—maxillary pain and purulent (not green or yellow) nasal discharge. Despite concerns about antibiotic resistance, amoxicillin is still a good initial choice, reserving broad-spectrum antibiotics for resistant cases. JFP has published 3 “Clinical Inquires” that nicely summarize the current scientific evidence for diagnosis and treatment of acute sinusitis.^10,11,12

In 1998 the British Journal of General Practice published a study by W. Stalman¹ entitled “The end of antibiotic treatment in adults with acute sinusitis-like complaints in general practice?” In this Dutch randomized trial, doxycycline was no more effective than placebo for clinically diagnosed acute sinusitis. Stallman’s trial was unique, because the diagnosis of acute sinusitis was based on clinical findings rather than xrays, computed tomography (CT) scans, or sinus puncture and culture—the gold standard for diagnosing bacterial sinusitis. He based the diagnosis on clinical findings because that is how we practice in family medicine. We rarely use x-rays and CT scans to diagnose sinusitis. X-ray findings are not all that accurate,² and CT scans are expensive, not immediately available, and should be reserved for difficult cases.

Since Stallman’s study, 2 more randomized placebo-controlled trials of antibiotic treatment for sinusitis-like symptoms in general practice— one of amoxicillin and the other of amoxicillin-clavulanate—found no benefit.^3,4 Even for patients with “x-ray confirmed” acute sinusitis in general practice, a randomized trial showed no benefit for amoxicillin.⁵

In this issue of The journal of family practice, Merenstein et al⁶ report the results of a similar randomized trial of clinically diagnosed sinusitis in primary care, showing once again that antibiotics are not very effective for treating sinusitislike symptoms, even for patients who have had symptoms for at least 7 days. At 14 days follow-up, 32 (48%) of the amoxicillin group vs 25 (37%) of the placebo group were cured, a nonsignificant difference. Even assuming that this 11% absolute difference was statistically significant—which might have occurred with a larger study—the number needed to treat would be 9. That is a lot of unnecessary antibiotic prescribing. Most readers of JFP will be familiar with the reason for the disappointing outcome of Merenstein’s and others sinusitis antibiotic treatment trials in primary care. That is, most cases of clinically diagnosed acute sinusitis are caused by viruses and do not respond to antibiotics. Furthermore, there is no reliable way clinically to distinguish viral from bacterial sinus infection; there is too much overlap in symptoms.

We now have 5 good placebo-controlled randomized trials of antibiotic treatment of clinically diagnosed acute sinusitis, all with negative results. This approaches “A” level of evidence. Is it time we “just say no” to treating sinusitis-like complaints with antibiotics? Was Stalman right? Is this the end of the story? Not quite, in my opinion.

For the most part, I agree that being stingy with antibiotics for patients with sinusitis-like complaints is a good thing, especially patients with mild symptoms. Most patients will have viral infections and will recover as quickly with symptomatic treatment. But we know that some patients we see do have acute bacterial sinusitis and will benefit from an antibiotic. We just don’t know who they are. On average, patients with acute sinusitis and air-fluid levels on CT scan improve more quickly with antibiotics.⁷ This point brings me back to the Merenstein study. The investigators noted that, despite similar cure rates at 14 days, the amoxicillin group improved more rapidly, and the time to complete improvement for those who fully recovered by 14 days was 8.1 days for the amoxicillin group and 10.7 days for the placebo group. This suggests to me there are “antibiotic responsive” cases buried in the group of patients in this study. I can’t get too excited about this, however, because patients’ average symptom severity ratings at 3, 7, and 14 days were not significantly different in the amoxicillin and placebo groups (as noted in Merenstein’s Table 2) Nonetheless, it is not yet time to give up the search for identifying “antibiotic responsive” acute sinusitis.

Here is another piece of evidence to support this assertion. Hansen found that patients with a clinical diagnosis of acute sinusitis who had significant facial pain did benefit from penicillin.⁸ As soon as 3 days after treatment started, pain was significantly diminished in the penicillin treated group compared with placebo.

What we really need is a reliable, easy, and inexpensive point-of-care test to distinguish viral from bacterial sinusitis—the “strep screen” for acute sinusitis. That test is the Holy Grail of acute sinusitis treatment. CT scans are too expensive, and plain x-rays and sinus transillumination are not accurate enough.² The Europeans have had limited success with C-reactive protein, but the predictive value is not terrific. I expect that a clever microbiologist will eventually discover the right test. Then we can target antibiotic treatment to those who will really benefit.

In the meantime, I recommend following the CDC principles of appropriate antibiotic use for acute rhinosinusitis.⁹ Temporize at least a week for those who are not that ill, treat pain, and do not hesitate to use an antibiotic for those with more severe, classical symptoms of acute bacterial sinusitis—maxillary pain and purulent (not green or yellow) nasal discharge. Despite concerns about antibiotic resistance, amoxicillin is still a good initial choice, reserving broad-spectrum antibiotics for resistant cases. JFP has published 3 “Clinical Inquires” that nicely summarize the current scientific evidence for diagnosis and treatment of acute sinusitis.^10,11,12

In 1998 the British Journal of General Practice published a study by W. Stalman¹ entitled “The end of antibiotic treatment in adults with acute sinusitis-like complaints in general practice?” In this Dutch randomized trial, doxycycline was no more effective than placebo for clinically diagnosed acute sinusitis. Stallman’s trial was unique, because the diagnosis of acute sinusitis was based on clinical findings rather than xrays, computed tomography (CT) scans, or sinus puncture and culture—the gold standard for diagnosing bacterial sinusitis. He based the diagnosis on clinical findings because that is how we practice in family medicine. We rarely use x-rays and CT scans to diagnose sinusitis. X-ray findings are not all that accurate,² and CT scans are expensive, not immediately available, and should be reserved for difficult cases.