Kristen DeSanto, MSLS, MS, RD

Evidence summary

Naltrexone is comparable to amitriptyline for diabetic neuropathy pain

A 2021 randomized, double-blind, active-comparator, crossover clinical trial conducted in India examined the efficacy of low-dose naltrexone vs standard-of-care amitriptyline in patients (N = 67) with painful diabetic neuropathy. Participants were adults (ages 18 to 75 years) with painful diabetic neuropathy who had been on a stable dose of nonopioid pain medication for at least 1 month.¹

Patients were randomly assigned to start receiving naltrexone 2 mg (n = 33) or amitriptyline 10 mg (n = 34). They received their starting medication for 6 weeks (with follow-up every 2 weeks), then completed a 2-week washout period, and then switched to the other study medication for 6 weeks (same follow-up schedule). If patients reported < 20% pain reduction on the Visual Analog Scale (VAS; 0-100 scoring system with 0 = no pain and 100 = worst pain) at a follow-up visit, their medication dose was titrated up, to a maximum of 4 mg of naltrexone or 25 to 50 mg of amitriptyline.¹

The primary outcome of interest was the mean change in VAS pain score following 6 weeks of treatment. There was no statistically different change from baseline VAS pain score between the amitriptyline and nal­trexone groups (mean difference [MD] = 1.6; 95% CI, –0.9 to 4.2; P = 0.21). These findings were consistent across the secondary endpoints (Likert 5-point pain scale and McGill Pain Questionnaire scores). There was no statistically significant difference in Hamilton Depression Rating Scale scores (13 in the naltrexone group vs 11 in the amitriptyline group; P = .81), no reports of decreased sleep quality in either group, and no significant difference in Patients’ Global Impression of Change scores at 6-week evaluation.¹

The naltrexone cohort experienced 8 adverse events (most commonly, mild diarrhea), while the amitriptyline cohort experienced 52 adverse events (most commonly, somnolence) (P < .001). The limitations of the study include the lack of a placebo arm and a relatively small sample size.¹

Greater reduction in pain scores with naltrexone

A 2022 retrospective cohort study evaluated the effectiveness of naltrexone for patients treated at a single outpatient integrative pain management practice in Alaska between 2014 and 2019. The exposure group (n = 36) included patients who had completed at least a 2-month continuous regimen of oral naltrexone 4.5 mg. Controls (n = 42) were selected from the remaining practice population receiving standard care and were primarily matched by diagnosis code, followed by gender, then age +/– 5 years. Patients were divided into subgroups for inflammatory and neuropathic pain.²

The primary outcome measured was the mean change in VAS score or numeric rating score (NRS; both used a 1-10 rating system), which was assessed during a patient’s appointment from initiation of treatment to the most recent visit or at the termination of therapy (intervention interquartile range, 12-14 months). There was no statistically significant difference in VAS/NRS between the low-dose naltrexone and control groups at baseline (6.09 vs 6.38; P = .454). The low-dose naltrexone group experienced a greater reduction in VAS/NRS pain scores compared to the control group (–37.8% vs –4.3%; P < .001).²

Compared with control patients in each group, patients in the inflammatory pain subgroup and the neuropathic pain subgroup who received low-dose naltrexone reported reductions in pain scores of 32% (P < .001) and 44% (P = .048), respectively. There was no statistically significant difference in mean change in VAS/NRS scores between the inflammatory and neuropathic subgroups (P = .763). A multivariate linear regression analysis did not identify significant variables other than low-dose naltrexone that correlated with pain improvement. The number needed to treat to observe a ≥ 50% reduction in pain scores was 3.2.²

Continue to: Limitations for this study...

Limitations for this study include its small sample size and open-label design.²

Low-dose naltrexone is effective for fibromyalgia pain

A 2020 single-blind prospective dose-­response study utilized the up-and-down method to identify effective naltrexone dose for patients in a Danish university hospital pain clinic. Patients were White women ages 18 to 60 years (N = 25) who had a diagnosis of fibromyalgia unresponsive to traditional pharmacologic treatment. All patients received treatment with low-dose naltrexone (ranging from 0.75 mg to 6.0 mg) but were blinded to dose.³

Studies show that low-dose naltrexone has some effectiveness in a variety of pain conditions—including diabetic neuropathy and fibromyalgia—with few adverse effects.

Patients were evaluated for improvement in fibromyalgia symptoms using the Patient Global Impression of Improvement (PGI-I) scale—which ranges from 1 (very much improved) to 7 (very much worse), with 4 being “no change”—at baseline and after 2 to 3 weeks of treatment with low-dose naltrexone. A patient was considered a responder if they scored 1 to 3 on the follow-up PGI-I scale or if they experienced a > 30% pain reduction on the VAS. If a patient did not respond to their dose, the next patient began treatment at a dose 0.75 mg higher than the previous patient’s ending dose. If a patient did respond to low-dose naltrexone treatment, the next patient’s starting dose was 0.75 mg less than the previous patient’s. Eleven of 25 patients were considered responders.³

The primary outcomes were effective dose for 50% of fibromyalgia patients (3.88 mg; 95% CI, 3.39-4.35) and effective dose for 95% of fibromyalgia patients (5.4 mg; 95% CI, 4.66-6.13). Secondary outcomes were fibromyalgia symptoms as evaluated on the Fibromyalgia Impact Questionnaire Revised. Five of the 11 responders reported a > 30% improvement in tenderness and 8 of the 11 responders reported a > 30% decrease in waking unrefreshed.³

Limitations of the study include the short time period of treatment before response was assessed and the decision to use low test ­doses, which may have hindered detection of effective doses > 6 mg in fibromyalgia.³

Editor’s takeaway

Low-dose naltrexone, a less-often-used form of pain management, is a welcome option. Studies show some effectiveness in a variety of pain conditions with few adverse effects. The small number of studies, the small sample sizes, and the limited follow-up duration should encourage more investigation into how to best use this intervention.

Evidence summary

Naltrexone is comparable to amitriptyline for diabetic neuropathy pain

A 2021 randomized, double-blind, active-comparator, crossover clinical trial conducted in India examined the efficacy of low-dose naltrexone vs standard-of-care amitriptyline in patients (N = 67) with painful diabetic neuropathy. Participants were adults (ages 18 to 75 years) with painful diabetic neuropathy who had been on a stable dose of nonopioid pain medication for at least 1 month.¹

Patients were randomly assigned to start receiving naltrexone 2 mg (n = 33) or amitriptyline 10 mg (n = 34). They received their starting medication for 6 weeks (with follow-up every 2 weeks), then completed a 2-week washout period, and then switched to the other study medication for 6 weeks (same follow-up schedule). If patients reported < 20% pain reduction on the Visual Analog Scale (VAS; 0-100 scoring system with 0 = no pain and 100 = worst pain) at a follow-up visit, their medication dose was titrated up, to a maximum of 4 mg of naltrexone or 25 to 50 mg of amitriptyline.¹

The primary outcome of interest was the mean change in VAS pain score following 6 weeks of treatment. There was no statistically different change from baseline VAS pain score between the amitriptyline and nal­trexone groups (mean difference [MD] = 1.6; 95% CI, –0.9 to 4.2; P = 0.21). These findings were consistent across the secondary endpoints (Likert 5-point pain scale and McGill Pain Questionnaire scores). There was no statistically significant difference in Hamilton Depression Rating Scale scores (13 in the naltrexone group vs 11 in the amitriptyline group; P = .81), no reports of decreased sleep quality in either group, and no significant difference in Patients’ Global Impression of Change scores at 6-week evaluation.¹

The naltrexone cohort experienced 8 adverse events (most commonly, mild diarrhea), while the amitriptyline cohort experienced 52 adverse events (most commonly, somnolence) (P < .001). The limitations of the study include the lack of a placebo arm and a relatively small sample size.¹

Greater reduction in pain scores with naltrexone

A 2022 retrospective cohort study evaluated the effectiveness of naltrexone for patients treated at a single outpatient integrative pain management practice in Alaska between 2014 and 2019. The exposure group (n = 36) included patients who had completed at least a 2-month continuous regimen of oral naltrexone 4.5 mg. Controls (n = 42) were selected from the remaining practice population receiving standard care and were primarily matched by diagnosis code, followed by gender, then age +/– 5 years. Patients were divided into subgroups for inflammatory and neuropathic pain.²

The primary outcome measured was the mean change in VAS score or numeric rating score (NRS; both used a 1-10 rating system), which was assessed during a patient’s appointment from initiation of treatment to the most recent visit or at the termination of therapy (intervention interquartile range, 12-14 months). There was no statistically significant difference in VAS/NRS between the low-dose naltrexone and control groups at baseline (6.09 vs 6.38; P = .454). The low-dose naltrexone group experienced a greater reduction in VAS/NRS pain scores compared to the control group (–37.8% vs –4.3%; P < .001).²

Compared with control patients in each group, patients in the inflammatory pain subgroup and the neuropathic pain subgroup who received low-dose naltrexone reported reductions in pain scores of 32% (P < .001) and 44% (P = .048), respectively. There was no statistically significant difference in mean change in VAS/NRS scores between the inflammatory and neuropathic subgroups (P = .763). A multivariate linear regression analysis did not identify significant variables other than low-dose naltrexone that correlated with pain improvement. The number needed to treat to observe a ≥ 50% reduction in pain scores was 3.2.²

Continue to: Limitations for this study...

Limitations for this study include its small sample size and open-label design.²

Low-dose naltrexone is effective for fibromyalgia pain

A 2020 single-blind prospective dose-­response study utilized the up-and-down method to identify effective naltrexone dose for patients in a Danish university hospital pain clinic. Patients were White women ages 18 to 60 years (N = 25) who had a diagnosis of fibromyalgia unresponsive to traditional pharmacologic treatment. All patients received treatment with low-dose naltrexone (ranging from 0.75 mg to 6.0 mg) but were blinded to dose.³

Studies show that low-dose naltrexone has some effectiveness in a variety of pain conditions—including diabetic neuropathy and fibromyalgia—with few adverse effects.

Patients were evaluated for improvement in fibromyalgia symptoms using the Patient Global Impression of Improvement (PGI-I) scale—which ranges from 1 (very much improved) to 7 (very much worse), with 4 being “no change”—at baseline and after 2 to 3 weeks of treatment with low-dose naltrexone. A patient was considered a responder if they scored 1 to 3 on the follow-up PGI-I scale or if they experienced a > 30% pain reduction on the VAS. If a patient did not respond to their dose, the next patient began treatment at a dose 0.75 mg higher than the previous patient’s ending dose. If a patient did respond to low-dose naltrexone treatment, the next patient’s starting dose was 0.75 mg less than the previous patient’s. Eleven of 25 patients were considered responders.³

The primary outcomes were effective dose for 50% of fibromyalgia patients (3.88 mg; 95% CI, 3.39-4.35) and effective dose for 95% of fibromyalgia patients (5.4 mg; 95% CI, 4.66-6.13). Secondary outcomes were fibromyalgia symptoms as evaluated on the Fibromyalgia Impact Questionnaire Revised. Five of the 11 responders reported a > 30% improvement in tenderness and 8 of the 11 responders reported a > 30% decrease in waking unrefreshed.³

Limitations of the study include the short time period of treatment before response was assessed and the decision to use low test ­doses, which may have hindered detection of effective doses > 6 mg in fibromyalgia.³

Editor’s takeaway

Low-dose naltrexone, a less-often-used form of pain management, is a welcome option. Studies show some effectiveness in a variety of pain conditions with few adverse effects. The small number of studies, the small sample sizes, and the limited follow-up duration should encourage more investigation into how to best use this intervention.

Evidence summary

Naltrexone is comparable to amitriptyline for diabetic neuropathy pain

A 2021 randomized, double-blind, active-comparator, crossover clinical trial conducted in India examined the efficacy of low-dose naltrexone vs standard-of-care amitriptyline in patients (N = 67) with painful diabetic neuropathy. Participants were adults (ages 18 to 75 years) with painful diabetic neuropathy who had been on a stable dose of nonopioid pain medication for at least 1 month.¹

Patients were randomly assigned to start receiving naltrexone 2 mg (n = 33) or amitriptyline 10 mg (n = 34). They received their starting medication for 6 weeks (with follow-up every 2 weeks), then completed a 2-week washout period, and then switched to the other study medication for 6 weeks (same follow-up schedule). If patients reported < 20% pain reduction on the Visual Analog Scale (VAS; 0-100 scoring system with 0 = no pain and 100 = worst pain) at a follow-up visit, their medication dose was titrated up, to a maximum of 4 mg of naltrexone or 25 to 50 mg of amitriptyline.¹

The primary outcome of interest was the mean change in VAS pain score following 6 weeks of treatment. There was no statistically different change from baseline VAS pain score between the amitriptyline and nal­trexone groups (mean difference [MD] = 1.6; 95% CI, –0.9 to 4.2; P = 0.21). These findings were consistent across the secondary endpoints (Likert 5-point pain scale and McGill Pain Questionnaire scores). There was no statistically significant difference in Hamilton Depression Rating Scale scores (13 in the naltrexone group vs 11 in the amitriptyline group; P = .81), no reports of decreased sleep quality in either group, and no significant difference in Patients’ Global Impression of Change scores at 6-week evaluation.¹

The naltrexone cohort experienced 8 adverse events (most commonly, mild diarrhea), while the amitriptyline cohort experienced 52 adverse events (most commonly, somnolence) (P < .001). The limitations of the study include the lack of a placebo arm and a relatively small sample size.¹

Greater reduction in pain scores with naltrexone

A 2022 retrospective cohort study evaluated the effectiveness of naltrexone for patients treated at a single outpatient integrative pain management practice in Alaska between 2014 and 2019. The exposure group (n = 36) included patients who had completed at least a 2-month continuous regimen of oral naltrexone 4.5 mg. Controls (n = 42) were selected from the remaining practice population receiving standard care and were primarily matched by diagnosis code, followed by gender, then age +/– 5 years. Patients were divided into subgroups for inflammatory and neuropathic pain.²

The primary outcome measured was the mean change in VAS score or numeric rating score (NRS; both used a 1-10 rating system), which was assessed during a patient’s appointment from initiation of treatment to the most recent visit or at the termination of therapy (intervention interquartile range, 12-14 months). There was no statistically significant difference in VAS/NRS between the low-dose naltrexone and control groups at baseline (6.09 vs 6.38; P = .454). The low-dose naltrexone group experienced a greater reduction in VAS/NRS pain scores compared to the control group (–37.8% vs –4.3%; P < .001).²

Compared with control patients in each group, patients in the inflammatory pain subgroup and the neuropathic pain subgroup who received low-dose naltrexone reported reductions in pain scores of 32% (P < .001) and 44% (P = .048), respectively. There was no statistically significant difference in mean change in VAS/NRS scores between the inflammatory and neuropathic subgroups (P = .763). A multivariate linear regression analysis did not identify significant variables other than low-dose naltrexone that correlated with pain improvement. The number needed to treat to observe a ≥ 50% reduction in pain scores was 3.2.²

Continue to: Limitations for this study...

Limitations for this study include its small sample size and open-label design.²

Low-dose naltrexone is effective for fibromyalgia pain

A 2020 single-blind prospective dose-­response study utilized the up-and-down method to identify effective naltrexone dose for patients in a Danish university hospital pain clinic. Patients were White women ages 18 to 60 years (N = 25) who had a diagnosis of fibromyalgia unresponsive to traditional pharmacologic treatment. All patients received treatment with low-dose naltrexone (ranging from 0.75 mg to 6.0 mg) but were blinded to dose.³

Studies show that low-dose naltrexone has some effectiveness in a variety of pain conditions—including diabetic neuropathy and fibromyalgia—with few adverse effects.

Patients were evaluated for improvement in fibromyalgia symptoms using the Patient Global Impression of Improvement (PGI-I) scale—which ranges from 1 (very much improved) to 7 (very much worse), with 4 being “no change”—at baseline and after 2 to 3 weeks of treatment with low-dose naltrexone. A patient was considered a responder if they scored 1 to 3 on the follow-up PGI-I scale or if they experienced a > 30% pain reduction on the VAS. If a patient did not respond to their dose, the next patient began treatment at a dose 0.75 mg higher than the previous patient’s ending dose. If a patient did respond to low-dose naltrexone treatment, the next patient’s starting dose was 0.75 mg less than the previous patient’s. Eleven of 25 patients were considered responders.³

The primary outcomes were effective dose for 50% of fibromyalgia patients (3.88 mg; 95% CI, 3.39-4.35) and effective dose for 95% of fibromyalgia patients (5.4 mg; 95% CI, 4.66-6.13). Secondary outcomes were fibromyalgia symptoms as evaluated on the Fibromyalgia Impact Questionnaire Revised. Five of the 11 responders reported a > 30% improvement in tenderness and 8 of the 11 responders reported a > 30% decrease in waking unrefreshed.³

Limitations of the study include the short time period of treatment before response was assessed and the decision to use low test ­doses, which may have hindered detection of effective doses > 6 mg in fibromyalgia.³

Editor’s takeaway

Low-dose naltrexone, a less-often-used form of pain management, is a welcome option. Studies show some effectiveness in a variety of pain conditions with few adverse effects. The small number of studies, the small sample sizes, and the limited follow-up duration should encourage more investigation into how to best use this intervention.

Evidence summary

Multiple analyses suggest HRT worsens rather than improves cognition

A 2017 Cochrane review of 22 randomized, double-blind studies compared use of HRT (estrogen only or combination estrogen + progesterone therapies) with placebo in postmenopausal women (N = 43,637). Age ranges varied, but the average age in most studies was > 60 years. Treatment duration was at least 1 year. Various outcomes were assessed across these 22 studies, including cardiovascular disease, bone health, and cognition.¹

Cognitive outcomes were assessed with the Mini-Mental Status Exam in 5 of the trials (N = 12,789). Data were not combined due to heterogeneity. The authors found no significant difference in cognitive scores between the treatment and control groups in any of these 5 studies.¹

In the largest included study, the Women’s Health Initiative (WHI) Memory Study (N = 10,739), participants were older than 65 years. Among those receiving estrogen-only HRT, there were no statistically significant differences compared to those receiving placebo. However, healthy postmenopausal women taking combination HRT had an increased risk for “probable dementia” compared to those taking placebo (relative risk [RR] = 1.97; 95% CI, 1.16-3.33). When researchers looked exclusively at women taking HRT, the risk for dementia increased from 9 in 1000 to 18 in 1000 (95% CI, 11-30) after 4 years of HRT use. This results in a number needed to harm of 4 to 50 patients.¹

Two notable limitations of this evidence are that the average age of this population was > 60 years and 80% of the participants were White.¹

A 2021 meta-analysis of 23 RCTs (N = 13,683) studied the effect of HRT on global cognitive function as well as specific cognitive domains including memory, executive function, attention, and language. Mean patient age in the studies varied from 48 to 81 years. Nine of these studies were also included in the previously discussed Cochrane review.²

There was a statistically significant but small decrease in overall global cognition (10 trials; N = 12,115; standardized mean difference [SMD] = –0.04; 95% CI, –0.08 to –0.01) in those receiving HRT compared to placebo. This effect was slightly more pronounced among those who initiated HRT at age > 60 years (8 trials; N = 11,914; SMD = –0.05; 95% CI, –0.08 to –0.01) and among patients with HRT duration > 6 months (7 trials; N = 11,828; SMD = –0.05; 95% CI, –0.08 to –0.01). There were no significant differences in specific cognitive domains.²

In a 2017 follow-up to the WHI trial, researchers analyzed data on long-term cognitive effects in women previously treated with HRT. There were 2 cohorts: participants who initiated HRT at a younger age (50-54; N = 1376) and those who initiated HRT later in life (age 65-79; N = 2880). Cognitive outcomes were assessed using the Telephone Interview for Cognitive Status-modified, with interviews conducted annually beginning 6 to 7 years after HRT was stopped.³

The investigators found no significant change in composite cognitive function in the younger HRT-treated group compared to placebo (estrogen alone: mean deviation [MD] = 0.014; 95% CI, –0.097 to 0.126; estrogen + progesterone: MD = –0.047; 95% CI, –0.134 to 0.04), or in the group who initiated HRT at an older age (estrogen alone: MD = –0.099; 95% CI, –0.202 to 0.004; estrogen + progesterone: MD = –0.022; 95% CI, –0.099 to 0.055). The authors state that although the data did not reach significance, this study also found a trend toward decreases in global cognitive function in the older age group.³

Editor’s takeaway

Abundant, consistent evidence with long-term follow-up shows postmenopausal HRT does not reduce cognitive decline. In fact, it appears to increase cognitive decline slightly. Renewed interest in postmenopausal HRT to alleviate menopausal symptoms should balance the risks and benefits to the individual patient.

Evidence summary

Multiple analyses suggest HRT worsens rather than improves cognition

A 2017 Cochrane review of 22 randomized, double-blind studies compared use of HRT (estrogen only or combination estrogen + progesterone therapies) with placebo in postmenopausal women (N = 43,637). Age ranges varied, but the average age in most studies was > 60 years. Treatment duration was at least 1 year. Various outcomes were assessed across these 22 studies, including cardiovascular disease, bone health, and cognition.¹

Cognitive outcomes were assessed with the Mini-Mental Status Exam in 5 of the trials (N = 12,789). Data were not combined due to heterogeneity. The authors found no significant difference in cognitive scores between the treatment and control groups in any of these 5 studies.¹

In the largest included study, the Women’s Health Initiative (WHI) Memory Study (N = 10,739), participants were older than 65 years. Among those receiving estrogen-only HRT, there were no statistically significant differences compared to those receiving placebo. However, healthy postmenopausal women taking combination HRT had an increased risk for “probable dementia” compared to those taking placebo (relative risk [RR] = 1.97; 95% CI, 1.16-3.33). When researchers looked exclusively at women taking HRT, the risk for dementia increased from 9 in 1000 to 18 in 1000 (95% CI, 11-30) after 4 years of HRT use. This results in a number needed to harm of 4 to 50 patients.¹

Two notable limitations of this evidence are that the average age of this population was > 60 years and 80% of the participants were White.¹

A 2021 meta-analysis of 23 RCTs (N = 13,683) studied the effect of HRT on global cognitive function as well as specific cognitive domains including memory, executive function, attention, and language. Mean patient age in the studies varied from 48 to 81 years. Nine of these studies were also included in the previously discussed Cochrane review.²

There was a statistically significant but small decrease in overall global cognition (10 trials; N = 12,115; standardized mean difference [SMD] = –0.04; 95% CI, –0.08 to –0.01) in those receiving HRT compared to placebo. This effect was slightly more pronounced among those who initiated HRT at age > 60 years (8 trials; N = 11,914; SMD = –0.05; 95% CI, –0.08 to –0.01) and among patients with HRT duration > 6 months (7 trials; N = 11,828; SMD = –0.05; 95% CI, –0.08 to –0.01). There were no significant differences in specific cognitive domains.²

In a 2017 follow-up to the WHI trial, researchers analyzed data on long-term cognitive effects in women previously treated with HRT. There were 2 cohorts: participants who initiated HRT at a younger age (50-54; N = 1376) and those who initiated HRT later in life (age 65-79; N = 2880). Cognitive outcomes were assessed using the Telephone Interview for Cognitive Status-modified, with interviews conducted annually beginning 6 to 7 years after HRT was stopped.³

The investigators found no significant change in composite cognitive function in the younger HRT-treated group compared to placebo (estrogen alone: mean deviation [MD] = 0.014; 95% CI, –0.097 to 0.126; estrogen + progesterone: MD = –0.047; 95% CI, –0.134 to 0.04), or in the group who initiated HRT at an older age (estrogen alone: MD = –0.099; 95% CI, –0.202 to 0.004; estrogen + progesterone: MD = –0.022; 95% CI, –0.099 to 0.055). The authors state that although the data did not reach significance, this study also found a trend toward decreases in global cognitive function in the older age group.³

Editor’s takeaway

Abundant, consistent evidence with long-term follow-up shows postmenopausal HRT does not reduce cognitive decline. In fact, it appears to increase cognitive decline slightly. Renewed interest in postmenopausal HRT to alleviate menopausal symptoms should balance the risks and benefits to the individual patient.

Evidence summary

Multiple analyses suggest HRT worsens rather than improves cognition

A 2017 Cochrane review of 22 randomized, double-blind studies compared use of HRT (estrogen only or combination estrogen + progesterone therapies) with placebo in postmenopausal women (N = 43,637). Age ranges varied, but the average age in most studies was > 60 years. Treatment duration was at least 1 year. Various outcomes were assessed across these 22 studies, including cardiovascular disease, bone health, and cognition.¹

Cognitive outcomes were assessed with the Mini-Mental Status Exam in 5 of the trials (N = 12,789). Data were not combined due to heterogeneity. The authors found no significant difference in cognitive scores between the treatment and control groups in any of these 5 studies.¹

In the largest included study, the Women’s Health Initiative (WHI) Memory Study (N = 10,739), participants were older than 65 years. Among those receiving estrogen-only HRT, there were no statistically significant differences compared to those receiving placebo. However, healthy postmenopausal women taking combination HRT had an increased risk for “probable dementia” compared to those taking placebo (relative risk [RR] = 1.97; 95% CI, 1.16-3.33). When researchers looked exclusively at women taking HRT, the risk for dementia increased from 9 in 1000 to 18 in 1000 (95% CI, 11-30) after 4 years of HRT use. This results in a number needed to harm of 4 to 50 patients.¹

Two notable limitations of this evidence are that the average age of this population was > 60 years and 80% of the participants were White.¹

A 2021 meta-analysis of 23 RCTs (N = 13,683) studied the effect of HRT on global cognitive function as well as specific cognitive domains including memory, executive function, attention, and language. Mean patient age in the studies varied from 48 to 81 years. Nine of these studies were also included in the previously discussed Cochrane review.²

There was a statistically significant but small decrease in overall global cognition (10 trials; N = 12,115; standardized mean difference [SMD] = –0.04; 95% CI, –0.08 to –0.01) in those receiving HRT compared to placebo. This effect was slightly more pronounced among those who initiated HRT at age > 60 years (8 trials; N = 11,914; SMD = –0.05; 95% CI, –0.08 to –0.01) and among patients with HRT duration > 6 months (7 trials; N = 11,828; SMD = –0.05; 95% CI, –0.08 to –0.01). There were no significant differences in specific cognitive domains.²

In a 2017 follow-up to the WHI trial, researchers analyzed data on long-term cognitive effects in women previously treated with HRT. There were 2 cohorts: participants who initiated HRT at a younger age (50-54; N = 1376) and those who initiated HRT later in life (age 65-79; N = 2880). Cognitive outcomes were assessed using the Telephone Interview for Cognitive Status-modified, with interviews conducted annually beginning 6 to 7 years after HRT was stopped.³

The investigators found no significant change in composite cognitive function in the younger HRT-treated group compared to placebo (estrogen alone: mean deviation [MD] = 0.014; 95% CI, –0.097 to 0.126; estrogen + progesterone: MD = –0.047; 95% CI, –0.134 to 0.04), or in the group who initiated HRT at an older age (estrogen alone: MD = –0.099; 95% CI, –0.202 to 0.004; estrogen + progesterone: MD = –0.022; 95% CI, –0.099 to 0.055). The authors state that although the data did not reach significance, this study also found a trend toward decreases in global cognitive function in the older age group.³

Editor’s takeaway

Abundant, consistent evidence with long-term follow-up shows postmenopausal HRT does not reduce cognitive decline. In fact, it appears to increase cognitive decline slightly. Renewed interest in postmenopausal HRT to alleviate menopausal symptoms should balance the risks and benefits to the individual patient.

Most interventions resulted in at least modest improvements in sleep

A randomized controlled trial (RCT) of 279 newborn infants and their mothers evaluated developmentally appropriate sleep interventions.¹ Mothers were given guidance on bedtime sleep routines, including starting the routine 30 to 45 minutes before bedtime, choosing age-appropriate calming bedtime activities, not using feeding as the last step before bedtime, and offering the child choices with their routine. Mothers were also given guidance on sleep location and behaviors, including recommendations on the best bedtime (between 7 and 8 pm), avoidance of a stimulating environment, and transition of the infant to their own room by age 3 months. To address nighttime awakenings, the researchers advised not waking the infant routinely to feed, allowing the infant some time to self-soothe after waking at night, and keeping nighttime interactions with the child boring.

These interventions were compared to a control group that received instructions on crib safety, sudden infant death syndrome prevention, and other sleep safety recommendations. Infant nocturnal sleep duration was determined by maternal report using the Brief Infant Sleep Questionnaire (BISQ). After 40 weeks, infants in the intervention group demonstrated longer sleep duration than did those in the control group (624.6 ± 67.6 minutes vs 602.9 ± 76.1 minutes; P = .01).¹

An RCT of 82 infants (ages 2-4 months) and their mothers evaluated the effect of behavioral sleep interventions on maternal and infant sleep.² Parents were offered either a 90-minute class and take-home booklet about behavioral sleep interventions or a 30-minute training on general infant safety with an accompanying pamphlet.

The behavioral interventions booklet included instructions on differentiating day and night routines for baby, avoiding digital devices and television in the evenings, playing more active games in the morning, dimming lights and reducing house noises in the afternoon, and having a consistent nighttime routine with consistent bedtime and sleep space. Participants completed an infant sleep diary prior to the intervention and repeated the sleep diary 8 weeks after the intervention. The infants whose mothers received the education on behavioral sleep interventions demonstrated an increase in nighttime sleep duration when compared to the control group (7.4 to 8.8 hours vs 7.3 to 7.5 hours; ANCOVA P < .001).

An RCT of 235 families with infants ages 6 to 8 months evaluated the effect of 45 minutes of nurse-provided education regarding normal infant sleep, effects of inadequate sleep, setting limits around infant sleep, importance of daytime routines, and negative sleep associations combined with a booklet and weekly phone follow-ups.³ This intervention was compared to routine infant education. At age 6 weeks, infants were monitored for 48 hours with actigraphy and the mothers completed a sleep diary to correlate activities. There was no difference in average nightly waking (2 nightly wakes; risk difference = –0.2%; 95% CI, –1.32 to 0.91).

The low cost and risk of these behavioral interventions to improve infants’ sleep make them worthwhile.

An RCT of 268 families with infants (ages 2-3 weeks) evaluated the effect of 45 minutes of nurse-provided education on behavioral sleep interventions including the cyclical nature of infant sleep, environmental factors that influence sleep, and parent-independent sleep cues (eg, leaving a settling infant alone for 5 minutes before responding) combined with written information.⁴ This was compared to infants receiving standard care without parental sleep intervention education. Participants recorded sleep diaries for 7 days when their infant reached age 6 weeks and again at age 12 weeks. At both 6 weeks and 12 weeks, there was a significant increase in infant nocturnal sleep time in the intervention group vs the control group (mean difference [MD] at 6 weeks = 0.5 hours; 95% CI, 0.32 to 0.69 vs MD at 12 weeks = 0.64 hours; 95% CI, 0.19 to 0.89).

A nonrandomized controlled trial with 84 mothers and infants (ages 0-6 months) evaluated the effectiveness of a multifaceted intervention involving brief focused negotiation by pediatricians, motivational counseling by a health educator, and group parenting workshops, compared to mother–infant pairs receiving standard care.⁵ Parents completed the BISQ at 0 and 6 months to assess nocturnal sleep duration. At 6 months, the intervention group had a significantly higher increase in infant nocturnal sleep duration compared to the control group (mean increase = 1.9 vs 1.3 hours; P = .05).

In a prospective cohort study involving 79 infants (ages 3-24 months) with parent- or pediatrician-reported day and night sleep problems, parents were given education on the promotion of nighttime sleep by gradually reducing contact with the infant over several nights and only leaving the room after the infant fell asleep or allowing the child to self-soothe for 1-3 minutes.⁶ The intervention was performed over 3 weeks, with in-person follow-up performed on Day 15 and phone follow-up on Days 8 and 21. Infants in this study demonstrated an increase in the average hours of total night sleep from 10.2 to 10.5 hours (P < .001).

Editor’s takeaway

Providing behavioral recommendations to parents about infant sleep routines improves sleep duration. This increased sleep duration, and the supporting evidence, is modest, but the low cost and risk of these interventions make them worthwhile.

Most interventions resulted in at least modest improvements in sleep

A randomized controlled trial (RCT) of 279 newborn infants and their mothers evaluated developmentally appropriate sleep interventions.¹ Mothers were given guidance on bedtime sleep routines, including starting the routine 30 to 45 minutes before bedtime, choosing age-appropriate calming bedtime activities, not using feeding as the last step before bedtime, and offering the child choices with their routine. Mothers were also given guidance on sleep location and behaviors, including recommendations on the best bedtime (between 7 and 8 pm), avoidance of a stimulating environment, and transition of the infant to their own room by age 3 months. To address nighttime awakenings, the researchers advised not waking the infant routinely to feed, allowing the infant some time to self-soothe after waking at night, and keeping nighttime interactions with the child boring.

These interventions were compared to a control group that received instructions on crib safety, sudden infant death syndrome prevention, and other sleep safety recommendations. Infant nocturnal sleep duration was determined by maternal report using the Brief Infant Sleep Questionnaire (BISQ). After 40 weeks, infants in the intervention group demonstrated longer sleep duration than did those in the control group (624.6 ± 67.6 minutes vs 602.9 ± 76.1 minutes; P = .01).¹

An RCT of 82 infants (ages 2-4 months) and their mothers evaluated the effect of behavioral sleep interventions on maternal and infant sleep.² Parents were offered either a 90-minute class and take-home booklet about behavioral sleep interventions or a 30-minute training on general infant safety with an accompanying pamphlet.

The behavioral interventions booklet included instructions on differentiating day and night routines for baby, avoiding digital devices and television in the evenings, playing more active games in the morning, dimming lights and reducing house noises in the afternoon, and having a consistent nighttime routine with consistent bedtime and sleep space. Participants completed an infant sleep diary prior to the intervention and repeated the sleep diary 8 weeks after the intervention. The infants whose mothers received the education on behavioral sleep interventions demonstrated an increase in nighttime sleep duration when compared to the control group (7.4 to 8.8 hours vs 7.3 to 7.5 hours; ANCOVA P < .001).

An RCT of 235 families with infants ages 6 to 8 months evaluated the effect of 45 minutes of nurse-provided education regarding normal infant sleep, effects of inadequate sleep, setting limits around infant sleep, importance of daytime routines, and negative sleep associations combined with a booklet and weekly phone follow-ups.³ This intervention was compared to routine infant education. At age 6 weeks, infants were monitored for 48 hours with actigraphy and the mothers completed a sleep diary to correlate activities. There was no difference in average nightly waking (2 nightly wakes; risk difference = –0.2%; 95% CI, –1.32 to 0.91).

The low cost and risk of these behavioral interventions to improve infants’ sleep make them worthwhile.

An RCT of 268 families with infants (ages 2-3 weeks) evaluated the effect of 45 minutes of nurse-provided education on behavioral sleep interventions including the cyclical nature of infant sleep, environmental factors that influence sleep, and parent-independent sleep cues (eg, leaving a settling infant alone for 5 minutes before responding) combined with written information.⁴ This was compared to infants receiving standard care without parental sleep intervention education. Participants recorded sleep diaries for 7 days when their infant reached age 6 weeks and again at age 12 weeks. At both 6 weeks and 12 weeks, there was a significant increase in infant nocturnal sleep time in the intervention group vs the control group (mean difference [MD] at 6 weeks = 0.5 hours; 95% CI, 0.32 to 0.69 vs MD at 12 weeks = 0.64 hours; 95% CI, 0.19 to 0.89).

A nonrandomized controlled trial with 84 mothers and infants (ages 0-6 months) evaluated the effectiveness of a multifaceted intervention involving brief focused negotiation by pediatricians, motivational counseling by a health educator, and group parenting workshops, compared to mother–infant pairs receiving standard care.⁵ Parents completed the BISQ at 0 and 6 months to assess nocturnal sleep duration. At 6 months, the intervention group had a significantly higher increase in infant nocturnal sleep duration compared to the control group (mean increase = 1.9 vs 1.3 hours; P = .05).

In a prospective cohort study involving 79 infants (ages 3-24 months) with parent- or pediatrician-reported day and night sleep problems, parents were given education on the promotion of nighttime sleep by gradually reducing contact with the infant over several nights and only leaving the room after the infant fell asleep or allowing the child to self-soothe for 1-3 minutes.⁶ The intervention was performed over 3 weeks, with in-person follow-up performed on Day 15 and phone follow-up on Days 8 and 21. Infants in this study demonstrated an increase in the average hours of total night sleep from 10.2 to 10.5 hours (P < .001).

Editor’s takeaway

Providing behavioral recommendations to parents about infant sleep routines improves sleep duration. This increased sleep duration, and the supporting evidence, is modest, but the low cost and risk of these interventions make them worthwhile.

Most interventions resulted in at least modest improvements in sleep

A randomized controlled trial (RCT) of 279 newborn infants and their mothers evaluated developmentally appropriate sleep interventions.¹ Mothers were given guidance on bedtime sleep routines, including starting the routine 30 to 45 minutes before bedtime, choosing age-appropriate calming bedtime activities, not using feeding as the last step before bedtime, and offering the child choices with their routine. Mothers were also given guidance on sleep location and behaviors, including recommendations on the best bedtime (between 7 and 8 pm), avoidance of a stimulating environment, and transition of the infant to their own room by age 3 months. To address nighttime awakenings, the researchers advised not waking the infant routinely to feed, allowing the infant some time to self-soothe after waking at night, and keeping nighttime interactions with the child boring.

These interventions were compared to a control group that received instructions on crib safety, sudden infant death syndrome prevention, and other sleep safety recommendations. Infant nocturnal sleep duration was determined by maternal report using the Brief Infant Sleep Questionnaire (BISQ). After 40 weeks, infants in the intervention group demonstrated longer sleep duration than did those in the control group (624.6 ± 67.6 minutes vs 602.9 ± 76.1 minutes; P = .01).¹

An RCT of 82 infants (ages 2-4 months) and their mothers evaluated the effect of behavioral sleep interventions on maternal and infant sleep.² Parents were offered either a 90-minute class and take-home booklet about behavioral sleep interventions or a 30-minute training on general infant safety with an accompanying pamphlet.

The behavioral interventions booklet included instructions on differentiating day and night routines for baby, avoiding digital devices and television in the evenings, playing more active games in the morning, dimming lights and reducing house noises in the afternoon, and having a consistent nighttime routine with consistent bedtime and sleep space. Participants completed an infant sleep diary prior to the intervention and repeated the sleep diary 8 weeks after the intervention. The infants whose mothers received the education on behavioral sleep interventions demonstrated an increase in nighttime sleep duration when compared to the control group (7.4 to 8.8 hours vs 7.3 to 7.5 hours; ANCOVA P < .001).

An RCT of 235 families with infants ages 6 to 8 months evaluated the effect of 45 minutes of nurse-provided education regarding normal infant sleep, effects of inadequate sleep, setting limits around infant sleep, importance of daytime routines, and negative sleep associations combined with a booklet and weekly phone follow-ups.³ This intervention was compared to routine infant education. At age 6 weeks, infants were monitored for 48 hours with actigraphy and the mothers completed a sleep diary to correlate activities. There was no difference in average nightly waking (2 nightly wakes; risk difference = –0.2%; 95% CI, –1.32 to 0.91).

The low cost and risk of these behavioral interventions to improve infants’ sleep make them worthwhile.

An RCT of 268 families with infants (ages 2-3 weeks) evaluated the effect of 45 minutes of nurse-provided education on behavioral sleep interventions including the cyclical nature of infant sleep, environmental factors that influence sleep, and parent-independent sleep cues (eg, leaving a settling infant alone for 5 minutes before responding) combined with written information.⁴ This was compared to infants receiving standard care without parental sleep intervention education. Participants recorded sleep diaries for 7 days when their infant reached age 6 weeks and again at age 12 weeks. At both 6 weeks and 12 weeks, there was a significant increase in infant nocturnal sleep time in the intervention group vs the control group (mean difference [MD] at 6 weeks = 0.5 hours; 95% CI, 0.32 to 0.69 vs MD at 12 weeks = 0.64 hours; 95% CI, 0.19 to 0.89).

A nonrandomized controlled trial with 84 mothers and infants (ages 0-6 months) evaluated the effectiveness of a multifaceted intervention involving brief focused negotiation by pediatricians, motivational counseling by a health educator, and group parenting workshops, compared to mother–infant pairs receiving standard care.⁵ Parents completed the BISQ at 0 and 6 months to assess nocturnal sleep duration. At 6 months, the intervention group had a significantly higher increase in infant nocturnal sleep duration compared to the control group (mean increase = 1.9 vs 1.3 hours; P = .05).

In a prospective cohort study involving 79 infants (ages 3-24 months) with parent- or pediatrician-reported day and night sleep problems, parents were given education on the promotion of nighttime sleep by gradually reducing contact with the infant over several nights and only leaving the room after the infant fell asleep or allowing the child to self-soothe for 1-3 minutes.⁶ The intervention was performed over 3 weeks, with in-person follow-up performed on Day 15 and phone follow-up on Days 8 and 21. Infants in this study demonstrated an increase in the average hours of total night sleep from 10.2 to 10.5 hours (P < .001).

Editor’s takeaway

Providing behavioral recommendations to parents about infant sleep routines improves sleep duration. This increased sleep duration, and the supporting evidence, is modest, but the low cost and risk of these interventions make them worthwhile.

Evidence summary

Depression symptoms improved with any of 4 antipsychotics

A 2021 systematic review of 16 RCTs (N = 3649) assessed data from trials that used an atypical antipsychotic—either aripiprazole, quetiapine, olanzapine, or risperidone—as augmentation therapy to an antidepressant vs placebo.¹ Study participants included adults ages 18 to 65 who experienced an episode of depression and did not respond adequately to at least 1 optimally dosed antidepressant. In most studies, ­treatment-resistant depression (TRD) was defined as the failure of at least 1 major class of antidepressants. Trial lengths ranged from 4 to 12 weeks.

Six RCTs evaluated the effectiveness of augmentation with aripiprazole (2-20 mg/d) in patients with unipolar depression, with 5 trials demonstrating greater improvement in clinical symptoms with aripiprazole compared to placebo. Augmentation with quetiapine (150-300 mg/d) was evaluated in 5 trials, with all trials showing improvement in depression symptoms; however, in 1 trial the difference in remission rates was not significant, and in another trial significant improvement was seen only at a quetia-pine dose of 300 mg/d. Two trials examining olanzapine found that patients receiving fluoxetine plus olanzapine augmentation demonstrated greater improvement in depression symptoms than did those receiving either agent alone. Three trials examined augmentation with risperidone (0.5-3 mg/d); in all 3, risperidone demonstrated significant improvement in depression symptoms and remission rates compared to placebo.¹

This systematic review was limited by small sample size and heterogeneity of antipsychotic dosages in the RCTs included, as well as the lack of a standardized and globally accepted definition of TRD.

Augmentation reduced symptom severity, but dropout rates were high

A 2019 Cochrane review of 10 RCTs (N = 2731) compared 5 strategies, including augmenting treatment with an antipsychotic vs continuing antidepressant monotherapy.² Participants were adults ages 18 to 74 with unipolar depression who had not responded to a minimum of 4 weeks of antidepressant treatment at a recommended dose. The primary outcome was depressive symptom severity, as measured by the Montgomery-Asberg Depression Rating Scale (MADRS; range of 0-60) or the Hamilton Depression Rating Scale (HAM-D; range, 0-52).

Compared with continued antidepressant monotherapy, symptom severity was reduced when current treatment was augmented with cariprazine 1-4.5 mg/d (1 trial; N = 808; mean difference [MD] on MADRS = –1.5; 95% CI, –2.7 to –0.25; high-quality evidence); quetiapine 150-300 mg/d (3 trials; N = 977; standardized MD = –0.32; 95% CI, –0.46 to –0.18; high-quality evidence); ziprasidone 40-160 mg/d (2 trials; N = 199; MD on HAM-D = –2.7; 95% CI, –4.5 to –0.93; ­moderate-quality evidence); or olanzapine 5-20 mg/d (1 trial; N = 20; MD on MADRS = –12; 95% CI, –22 to –2.4; low-quality evidence). One trial did not show a significant difference on the HAM-D for olanzapine (1 trial; N = 20; MD = –7.9; 95% CI, –17 to 0.96; low-quality evidence).²

Dropout rates, which were most commonly secondary to adverse effects, ranged from 10% to 39% in the groups augmented with an antipsychotic and from 12% to 23% in the comparison groups.² This systematic review was limited by the small number of studies included in the various comparisons.

Antipsychotic augmentation was effective but came with adverse effects

A 2017 RCT (N = 1522) examined the effectiveness of augmenting an antidepressant with aripiprazole in patients with TRD.³ Participants were adults (mean age, 54.4 years; 85% men) at 35 US Veterans Health Administration (VA) medical centers who had a diagnosis of nonpsychotic major depressive disorder that was unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration.

Continue to: Patients were randomly...

Patients were randomly assigned to 1 of 3 different treatment groups, which included switching to a different antidepressant (bupropion sustained release 150-500 mg/d); augmenting current treatment with bupropion; or augmenting with an atypical antipsychotic (aripiprazole 2-15 mg/d) for 12 to 36 weeks. The primary outcome was remission rate at 12 weeks, which was defined as a score ≤ 5 on the Quick Inventory of Depressive Symptomatology–Clinician Rated (QIDS-C; range, 0-27) at 2 consecutive visits. The secondary outcome, symptom response to treatment, was defined as ≥ 50% reduction on QIDS-C score.

Adjunctive antipsychotic medications more effectively treat resistant depression than increasing antidepressant dosage, switching to a different antidepressant, or adding another antidepressant.

The augment-aripiprazole group (N = 146) exceeded the switch group (N = 114) in remission rate (absolute remission rates = 28.9% vs 22.3%; relative risk [RR] = 1.3; 95% CI, 1.1-1.6; number needed to treat [NNT] = 15), but had similar remission rates to the augment-bupropion group (N = 136; absolute remission rate = 26.9%; RR = 1.1; 95% CI, 0.88-1.3). Symptom response in the augment-aripiprazole group (74.3%) was higher than in either the switch group (62.4%; RR = 1.19; 95% CI, 1.09-1.29; NNT = 8) or the augment-bupropion group (65.6%; RR = 1.13; 95% CI, 1.0-1.2; NNT = 11). There was no difference noted in response rate between the switch group and the augment-bupropion group (RR = 1.05; 95% CI, 0.96-1.15).³

The adverse events that occurred more often in the augment-aripiprazole group than in the other groups included weight gain ≥ 7% (25% at 36 weeks) and extrapyramidal symptoms (19%).³ Limitations of the study included the evaluation of only 1 antipsychotic and 1 antidepressant, the dropout rate (only 75% of patients completed the 12-week follow-up), and the homogeneity of the patient population (older, male, veterans), all of which may limit the effect size.

Editor’s takeaway

Multiple trials show that adjunctive antipsychotic medications such as aripiprazole and quetiapine more effectively treat resistant depression than adding a placebo, increasing antidepressant dosage, switching to a different antidepressant, or adding another antidepressant. However, while primary care physicians should be comfortable with this option, the magnitude of difference between these options was modest, and adverse effects were common. All options can still be reasonably considered.

Evidence summary

Depression symptoms improved with any of 4 antipsychotics

A 2021 systematic review of 16 RCTs (N = 3649) assessed data from trials that used an atypical antipsychotic—either aripiprazole, quetiapine, olanzapine, or risperidone—as augmentation therapy to an antidepressant vs placebo.¹ Study participants included adults ages 18 to 65 who experienced an episode of depression and did not respond adequately to at least 1 optimally dosed antidepressant. In most studies, ­treatment-resistant depression (TRD) was defined as the failure of at least 1 major class of antidepressants. Trial lengths ranged from 4 to 12 weeks.

Six RCTs evaluated the effectiveness of augmentation with aripiprazole (2-20 mg/d) in patients with unipolar depression, with 5 trials demonstrating greater improvement in clinical symptoms with aripiprazole compared to placebo. Augmentation with quetiapine (150-300 mg/d) was evaluated in 5 trials, with all trials showing improvement in depression symptoms; however, in 1 trial the difference in remission rates was not significant, and in another trial significant improvement was seen only at a quetia-pine dose of 300 mg/d. Two trials examining olanzapine found that patients receiving fluoxetine plus olanzapine augmentation demonstrated greater improvement in depression symptoms than did those receiving either agent alone. Three trials examined augmentation with risperidone (0.5-3 mg/d); in all 3, risperidone demonstrated significant improvement in depression symptoms and remission rates compared to placebo.¹

This systematic review was limited by small sample size and heterogeneity of antipsychotic dosages in the RCTs included, as well as the lack of a standardized and globally accepted definition of TRD.

Augmentation reduced symptom severity, but dropout rates were high

A 2019 Cochrane review of 10 RCTs (N = 2731) compared 5 strategies, including augmenting treatment with an antipsychotic vs continuing antidepressant monotherapy.² Participants were adults ages 18 to 74 with unipolar depression who had not responded to a minimum of 4 weeks of antidepressant treatment at a recommended dose. The primary outcome was depressive symptom severity, as measured by the Montgomery-Asberg Depression Rating Scale (MADRS; range of 0-60) or the Hamilton Depression Rating Scale (HAM-D; range, 0-52).

Compared with continued antidepressant monotherapy, symptom severity was reduced when current treatment was augmented with cariprazine 1-4.5 mg/d (1 trial; N = 808; mean difference [MD] on MADRS = –1.5; 95% CI, –2.7 to –0.25; high-quality evidence); quetiapine 150-300 mg/d (3 trials; N = 977; standardized MD = –0.32; 95% CI, –0.46 to –0.18; high-quality evidence); ziprasidone 40-160 mg/d (2 trials; N = 199; MD on HAM-D = –2.7; 95% CI, –4.5 to –0.93; ­moderate-quality evidence); or olanzapine 5-20 mg/d (1 trial; N = 20; MD on MADRS = –12; 95% CI, –22 to –2.4; low-quality evidence). One trial did not show a significant difference on the HAM-D for olanzapine (1 trial; N = 20; MD = –7.9; 95% CI, –17 to 0.96; low-quality evidence).²

Dropout rates, which were most commonly secondary to adverse effects, ranged from 10% to 39% in the groups augmented with an antipsychotic and from 12% to 23% in the comparison groups.² This systematic review was limited by the small number of studies included in the various comparisons.

Antipsychotic augmentation was effective but came with adverse effects

A 2017 RCT (N = 1522) examined the effectiveness of augmenting an antidepressant with aripiprazole in patients with TRD.³ Participants were adults (mean age, 54.4 years; 85% men) at 35 US Veterans Health Administration (VA) medical centers who had a diagnosis of nonpsychotic major depressive disorder that was unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration.

Continue to: Patients were randomly...

Patients were randomly assigned to 1 of 3 different treatment groups, which included switching to a different antidepressant (bupropion sustained release 150-500 mg/d); augmenting current treatment with bupropion; or augmenting with an atypical antipsychotic (aripiprazole 2-15 mg/d) for 12 to 36 weeks. The primary outcome was remission rate at 12 weeks, which was defined as a score ≤ 5 on the Quick Inventory of Depressive Symptomatology–Clinician Rated (QIDS-C; range, 0-27) at 2 consecutive visits. The secondary outcome, symptom response to treatment, was defined as ≥ 50% reduction on QIDS-C score.

Adjunctive antipsychotic medications more effectively treat resistant depression than increasing antidepressant dosage, switching to a different antidepressant, or adding another antidepressant.

The augment-aripiprazole group (N = 146) exceeded the switch group (N = 114) in remission rate (absolute remission rates = 28.9% vs 22.3%; relative risk [RR] = 1.3; 95% CI, 1.1-1.6; number needed to treat [NNT] = 15), but had similar remission rates to the augment-bupropion group (N = 136; absolute remission rate = 26.9%; RR = 1.1; 95% CI, 0.88-1.3). Symptom response in the augment-aripiprazole group (74.3%) was higher than in either the switch group (62.4%; RR = 1.19; 95% CI, 1.09-1.29; NNT = 8) or the augment-bupropion group (65.6%; RR = 1.13; 95% CI, 1.0-1.2; NNT = 11). There was no difference noted in response rate between the switch group and the augment-bupropion group (RR = 1.05; 95% CI, 0.96-1.15).³

The adverse events that occurred more often in the augment-aripiprazole group than in the other groups included weight gain ≥ 7% (25% at 36 weeks) and extrapyramidal symptoms (19%).³ Limitations of the study included the evaluation of only 1 antipsychotic and 1 antidepressant, the dropout rate (only 75% of patients completed the 12-week follow-up), and the homogeneity of the patient population (older, male, veterans), all of which may limit the effect size.

Editor’s takeaway

Multiple trials show that adjunctive antipsychotic medications such as aripiprazole and quetiapine more effectively treat resistant depression than adding a placebo, increasing antidepressant dosage, switching to a different antidepressant, or adding another antidepressant. However, while primary care physicians should be comfortable with this option, the magnitude of difference between these options was modest, and adverse effects were common. All options can still be reasonably considered.

Evidence summary

Depression symptoms improved with any of 4 antipsychotics

A 2021 systematic review of 16 RCTs (N = 3649) assessed data from trials that used an atypical antipsychotic—either aripiprazole, quetiapine, olanzapine, or risperidone—as augmentation therapy to an antidepressant vs placebo.¹ Study participants included adults ages 18 to 65 who experienced an episode of depression and did not respond adequately to at least 1 optimally dosed antidepressant. In most studies, ­treatment-resistant depression (TRD) was defined as the failure of at least 1 major class of antidepressants. Trial lengths ranged from 4 to 12 weeks.

Six RCTs evaluated the effectiveness of augmentation with aripiprazole (2-20 mg/d) in patients with unipolar depression, with 5 trials demonstrating greater improvement in clinical symptoms with aripiprazole compared to placebo. Augmentation with quetiapine (150-300 mg/d) was evaluated in 5 trials, with all trials showing improvement in depression symptoms; however, in 1 trial the difference in remission rates was not significant, and in another trial significant improvement was seen only at a quetia-pine dose of 300 mg/d. Two trials examining olanzapine found that patients receiving fluoxetine plus olanzapine augmentation demonstrated greater improvement in depression symptoms than did those receiving either agent alone. Three trials examined augmentation with risperidone (0.5-3 mg/d); in all 3, risperidone demonstrated significant improvement in depression symptoms and remission rates compared to placebo.¹

This systematic review was limited by small sample size and heterogeneity of antipsychotic dosages in the RCTs included, as well as the lack of a standardized and globally accepted definition of TRD.

Augmentation reduced symptom severity, but dropout rates were high

A 2019 Cochrane review of 10 RCTs (N = 2731) compared 5 strategies, including augmenting treatment with an antipsychotic vs continuing antidepressant monotherapy.² Participants were adults ages 18 to 74 with unipolar depression who had not responded to a minimum of 4 weeks of antidepressant treatment at a recommended dose. The primary outcome was depressive symptom severity, as measured by the Montgomery-Asberg Depression Rating Scale (MADRS; range of 0-60) or the Hamilton Depression Rating Scale (HAM-D; range, 0-52).

Compared with continued antidepressant monotherapy, symptom severity was reduced when current treatment was augmented with cariprazine 1-4.5 mg/d (1 trial; N = 808; mean difference [MD] on MADRS = –1.5; 95% CI, –2.7 to –0.25; high-quality evidence); quetiapine 150-300 mg/d (3 trials; N = 977; standardized MD = –0.32; 95% CI, –0.46 to –0.18; high-quality evidence); ziprasidone 40-160 mg/d (2 trials; N = 199; MD on HAM-D = –2.7; 95% CI, –4.5 to –0.93; ­moderate-quality evidence); or olanzapine 5-20 mg/d (1 trial; N = 20; MD on MADRS = –12; 95% CI, –22 to –2.4; low-quality evidence). One trial did not show a significant difference on the HAM-D for olanzapine (1 trial; N = 20; MD = –7.9; 95% CI, –17 to 0.96; low-quality evidence).²

Dropout rates, which were most commonly secondary to adverse effects, ranged from 10% to 39% in the groups augmented with an antipsychotic and from 12% to 23% in the comparison groups.² This systematic review was limited by the small number of studies included in the various comparisons.

Antipsychotic augmentation was effective but came with adverse effects

A 2017 RCT (N = 1522) examined the effectiveness of augmenting an antidepressant with aripiprazole in patients with TRD.³ Participants were adults (mean age, 54.4 years; 85% men) at 35 US Veterans Health Administration (VA) medical centers who had a diagnosis of nonpsychotic major depressive disorder that was unresponsive to at least 1 antidepressant course meeting minimal standards for treatment dose and duration.

Continue to: Patients were randomly...

Patients were randomly assigned to 1 of 3 different treatment groups, which included switching to a different antidepressant (bupropion sustained release 150-500 mg/d); augmenting current treatment with bupropion; or augmenting with an atypical antipsychotic (aripiprazole 2-15 mg/d) for 12 to 36 weeks. The primary outcome was remission rate at 12 weeks, which was defined as a score ≤ 5 on the Quick Inventory of Depressive Symptomatology–Clinician Rated (QIDS-C; range, 0-27) at 2 consecutive visits. The secondary outcome, symptom response to treatment, was defined as ≥ 50% reduction on QIDS-C score.

Adjunctive antipsychotic medications more effectively treat resistant depression than increasing antidepressant dosage, switching to a different antidepressant, or adding another antidepressant.

The augment-aripiprazole group (N = 146) exceeded the switch group (N = 114) in remission rate (absolute remission rates = 28.9% vs 22.3%; relative risk [RR] = 1.3; 95% CI, 1.1-1.6; number needed to treat [NNT] = 15), but had similar remission rates to the augment-bupropion group (N = 136; absolute remission rate = 26.9%; RR = 1.1; 95% CI, 0.88-1.3). Symptom response in the augment-aripiprazole group (74.3%) was higher than in either the switch group (62.4%; RR = 1.19; 95% CI, 1.09-1.29; NNT = 8) or the augment-bupropion group (65.6%; RR = 1.13; 95% CI, 1.0-1.2; NNT = 11). There was no difference noted in response rate between the switch group and the augment-bupropion group (RR = 1.05; 95% CI, 0.96-1.15).³

The adverse events that occurred more often in the augment-aripiprazole group than in the other groups included weight gain ≥ 7% (25% at 36 weeks) and extrapyramidal symptoms (19%).³ Limitations of the study included the evaluation of only 1 antipsychotic and 1 antidepressant, the dropout rate (only 75% of patients completed the 12-week follow-up), and the homogeneity of the patient population (older, male, veterans), all of which may limit the effect size.

Editor’s takeaway

Multiple trials show that adjunctive antipsychotic medications such as aripiprazole and quetiapine more effectively treat resistant depression than adding a placebo, increasing antidepressant dosage, switching to a different antidepressant, or adding another antidepressant. However, while primary care physicians should be comfortable with this option, the magnitude of difference between these options was modest, and adverse effects were common. All options can still be reasonably considered.

EVIDENCE SUMMARY

A 2017 meta-analysis of 4 RCTs (869 patients) evaluated the effectiveness of prescribing spironolactone for patients with resistant hypertension, defined as above-goal blood pressure (BP) despite treatment with at least 3 BP-lowering drugs (at least 1 of which was a diuretic).¹ All 4 trials compared spironolactone 25 to 50 mg/d with placebo. Follow-up periods ranged from 8 to 16 weeks. The primary outcomes were systolic and diastolic BPs, which were evaluated in the office, at home, or with an ambulatory monitor.

Spironolactone markedly lowers systolic and diastolic BP

A statistically significant reduction in SBP occurred in the spironolactone group compared with the placebo group (weighted mean difference [WMD] = −16.7 mm Hg; 95% confidence interval [CI], −27.5 to −5.8 mm Hg). DBP also decreased (WMD = −6.11 mm Hg; 95% CI, −9.34 to −2.88 mm Hg).

Because significant heterogeneity was found in the initial pooled results (I² = 96% for SBP; I² = 85% for DBP), investigators performed an analysis that excluded a single study with a small sample size. The re-analysis continued to show significant reductions in SBP and DBP for spironolactone compared with placebo (SBP: WMD = −10.8 mm Hg; 95% CI, −13.16 to −8.43 mm Hg; DBP: WMD = −4.62 mm Hg; 95% CI, −6.05 to −3.2 mm Hg; I² = 35%), confirming that the excluded trial was the source of heterogeneity in the initial analysis and that spironolactone continued to significantly lower BP for the treatment group compared with controls.

Add-on treatment with spironolactone also reduces BP

A 2016 meta-analysis of 5 RCTs with a total of 553 patients examined the effectiveness of add-on treatment with spironolactone (25-50 mg/d) for patients with resistant hypertension, defined as failure to achieve BP < 140/90 mm Hg despite treatment with 3 or more BP-lowering drugs, including one diuretic.² Spironolactone was compared with placebo in 4 trials and with ramipril in the remaining study. The follow-up periods were 8 to 16 weeks. Researchers separated BP outcomes into 24-hour ambulatory systolic/diastolic BPs and office systolic/diastolic BPs.

The 24-hour ambulatory BPs were significantly lower in the spironolactone group compared with the control group (24-hour SBP: WMD = −10.5 mm Hg; 95% CI, −12.3 to −8.71 mm Hg; 24-hour DBP: WMD = −4.09 mm Hg; 95% CI, −5.28 to −2.91 mm Hg). No significant heterogeneity was noted in these analyses.

Office-based BPs also were markedly reduced in spironolactone groups compared with controls (office SBP: WMD = −17 mm Hg; 95% CI, −25 to −8.95 mm Hg); office DBP: WMD = −6.18 mm Hg; 95% CI, −9.3 to −3.05 mm Hg). Because the office-based BP data showed significant heterogeneity (I² = 94% for SBP and 84.2% for DBP), 2 studies determined to be of lower quality caused by lack of detailed methodology were excluded from analysis, yielding continued statistically significant reductions in SBP (WMD = −11.7 mm Hg; 95% CI, −14.4 to −8.95 mm Hg) and DBP (WMD = −4.07 mm Hg; 95% CI, −5.6 to −2.54 mm Hg) compared with controls. Heterogeneity also decreased when the 2 studies were excluded (I² = 21% for SBP and I² = 59% for DBP).

How spironolactone compares with alternative drugs

A 2017 meta-analysis of 5 RCTs with 662 patients evaluated the effectiveness of spironolactone (25-50 mg/d) on resistant hypertension in patients taking 3 medications compared with a control group—placebo in 3 trials, placebo or bisoprolol (5-10 mg) in 1 trial, and an alternative treatment (candesartan 8 mg, atenolol 100 mg, or alpha methyldopa 750 mg) in 1 trial.³ Follow-up periods ranged from 4 to 16 weeks. Researchers evaluated changes in office and 24-hour ambulatory or home BP and completed separate analyses of pooled data for spironolactone compared with placebo groups, and spironolactone compared with alternative treatment groups.

Continue to: Investigators found a statistically significant...

Investigators found a statistically significant reduction in office SBP and DBP among patients taking spironolactone compared with control groups (SBP: WMD = −15.7 mm Hg; 95% CI, −20.5 to −11 mm Hg; DBP: WMD = −6.21 mm Hg; 95% CI, −8.33 to −4.1 mm Hg). A significant decrease also occurred in 24-hour ambulatory home SBP and DBP (SBP: MD = −8.7 mm Hg; 95% CI, −8.79 to −8.62 mm Hg; DBP: WMD = −4.12 mm Hg; 95% CI, −4.48 to −3.75 mm Hg).

Spironolactone reduces systolic blood pressure by 11 to 17 mm Hg and diastolic blood pressure by up to 6 mm Hg in patients with resistant hypertension taking 3 or more medications.

Patients treated with spironolactone showed a marked decrease in home SBP compared with alternative drug groups (WMD = −4.5 mm Hg; 95% CI, −4.63 to −4.37 mm Hg), but alternative drugs reduced home DBP significantly more than spironolactone (WMD = 0.6 mm Hg; 95% CI, 0.55-0.65 mm Hg). Marked heterogeneity was found in these analyses, and the authors also noted that reductions in SBP are more clinically relevant than decreases in DBP.

RECOMMENDATIONS

The 2017 American Heart Association/American College of Cardiology evidence-based guideline recommends considering adding a mineralocorticoid receptor agonist to treatment regimens for resistant hypertension when: office BP remains ≥ 130/80 mm Hg; the patient is prescribed at least 3 antihypertensive agents at optimal doses including a diuretic; pseudoresistance (nonadherence, inaccurate measurements) is excluded; reversible lifestyle factors have been addressed; substances that interfere with BP treatment (such as nonsteroidal anti-inflammatory drugs and oral contraceptive pills) are excluded; and screening for secondary causes of hypertension is complete.⁴

The United Kingdom’s National Institute for Health and Care Excellence (NICE) evidence-based guideline recommends considering spironolactone 25 mg/d to treat resistant hypertension if the patient’s potassium level is 4.5 mmol/L or lower and BP is higher than 140/90 mm Hg despite treatment with an optimal or best-tolerated dose of an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker plus a calcium-channel blocker and diuretic.⁵

Editor’s takeaway

The evidence from multiple RCTs convincingly shows the effectiveness of spironolactone. Despite the SOR of C because of a disease-oriented outcome, we do treat to blood pressure goals, and therefore, spironolactone is a good option.

EVIDENCE SUMMARY

A 2017 meta-analysis of 4 RCTs (869 patients) evaluated the effectiveness of prescribing spironolactone for patients with resistant hypertension, defined as above-goal blood pressure (BP) despite treatment with at least 3 BP-lowering drugs (at least 1 of which was a diuretic).¹ All 4 trials compared spironolactone 25 to 50 mg/d with placebo. Follow-up periods ranged from 8 to 16 weeks. The primary outcomes were systolic and diastolic BPs, which were evaluated in the office, at home, or with an ambulatory monitor.

Spironolactone markedly lowers systolic and diastolic BP

A statistically significant reduction in SBP occurred in the spironolactone group compared with the placebo group (weighted mean difference [WMD] = −16.7 mm Hg; 95% confidence interval [CI], −27.5 to −5.8 mm Hg). DBP also decreased (WMD = −6.11 mm Hg; 95% CI, −9.34 to −2.88 mm Hg).

Because significant heterogeneity was found in the initial pooled results (I² = 96% for SBP; I² = 85% for DBP), investigators performed an analysis that excluded a single study with a small sample size. The re-analysis continued to show significant reductions in SBP and DBP for spironolactone compared with placebo (SBP: WMD = −10.8 mm Hg; 95% CI, −13.16 to −8.43 mm Hg; DBP: WMD = −4.62 mm Hg; 95% CI, −6.05 to −3.2 mm Hg; I² = 35%), confirming that the excluded trial was the source of heterogeneity in the initial analysis and that spironolactone continued to significantly lower BP for the treatment group compared with controls.

Add-on treatment with spironolactone also reduces BP

A 2016 meta-analysis of 5 RCTs with a total of 553 patients examined the effectiveness of add-on treatment with spironolactone (25-50 mg/d) for patients with resistant hypertension, defined as failure to achieve BP < 140/90 mm Hg despite treatment with 3 or more BP-lowering drugs, including one diuretic.² Spironolactone was compared with placebo in 4 trials and with ramipril in the remaining study. The follow-up periods were 8 to 16 weeks. Researchers separated BP outcomes into 24-hour ambulatory systolic/diastolic BPs and office systolic/diastolic BPs.

The 24-hour ambulatory BPs were significantly lower in the spironolactone group compared with the control group (24-hour SBP: WMD = −10.5 mm Hg; 95% CI, −12.3 to −8.71 mm Hg; 24-hour DBP: WMD = −4.09 mm Hg; 95% CI, −5.28 to −2.91 mm Hg). No significant heterogeneity was noted in these analyses.

Office-based BPs also were markedly reduced in spironolactone groups compared with controls (office SBP: WMD = −17 mm Hg; 95% CI, −25 to −8.95 mm Hg); office DBP: WMD = −6.18 mm Hg; 95% CI, −9.3 to −3.05 mm Hg). Because the office-based BP data showed significant heterogeneity (I² = 94% for SBP and 84.2% for DBP), 2 studies determined to be of lower quality caused by lack of detailed methodology were excluded from analysis, yielding continued statistically significant reductions in SBP (WMD = −11.7 mm Hg; 95% CI, −14.4 to −8.95 mm Hg) and DBP (WMD = −4.07 mm Hg; 95% CI, −5.6 to −2.54 mm Hg) compared with controls. Heterogeneity also decreased when the 2 studies were excluded (I² = 21% for SBP and I² = 59% for DBP).

How spironolactone compares with alternative drugs

A 2017 meta-analysis of 5 RCTs with 662 patients evaluated the effectiveness of spironolactone (25-50 mg/d) on resistant hypertension in patients taking 3 medications compared with a control group—placebo in 3 trials, placebo or bisoprolol (5-10 mg) in 1 trial, and an alternative treatment (candesartan 8 mg, atenolol 100 mg, or alpha methyldopa 750 mg) in 1 trial.³ Follow-up periods ranged from 4 to 16 weeks. Researchers evaluated changes in office and 24-hour ambulatory or home BP and completed separate analyses of pooled data for spironolactone compared with placebo groups, and spironolactone compared with alternative treatment groups.

Continue to: Investigators found a statistically significant...

Investigators found a statistically significant reduction in office SBP and DBP among patients taking spironolactone compared with control groups (SBP: WMD = −15.7 mm Hg; 95% CI, −20.5 to −11 mm Hg; DBP: WMD = −6.21 mm Hg; 95% CI, −8.33 to −4.1 mm Hg). A significant decrease also occurred in 24-hour ambulatory home SBP and DBP (SBP: MD = −8.7 mm Hg; 95% CI, −8.79 to −8.62 mm Hg; DBP: WMD = −4.12 mm Hg; 95% CI, −4.48 to −3.75 mm Hg).

Spironolactone reduces systolic blood pressure by 11 to 17 mm Hg and diastolic blood pressure by up to 6 mm Hg in patients with resistant hypertension taking 3 or more medications.

Patients treated with spironolactone showed a marked decrease in home SBP compared with alternative drug groups (WMD = −4.5 mm Hg; 95% CI, −4.63 to −4.37 mm Hg), but alternative drugs reduced home DBP significantly more than spironolactone (WMD = 0.6 mm Hg; 95% CI, 0.55-0.65 mm Hg). Marked heterogeneity was found in these analyses, and the authors also noted that reductions in SBP are more clinically relevant than decreases in DBP.

RECOMMENDATIONS

The 2017 American Heart Association/American College of Cardiology evidence-based guideline recommends considering adding a mineralocorticoid receptor agonist to treatment regimens for resistant hypertension when: office BP remains ≥ 130/80 mm Hg; the patient is prescribed at least 3 antihypertensive agents at optimal doses including a diuretic; pseudoresistance (nonadherence, inaccurate measurements) is excluded; reversible lifestyle factors have been addressed; substances that interfere with BP treatment (such as nonsteroidal anti-inflammatory drugs and oral contraceptive pills) are excluded; and screening for secondary causes of hypertension is complete.⁴

The United Kingdom’s National Institute for Health and Care Excellence (NICE) evidence-based guideline recommends considering spironolactone 25 mg/d to treat resistant hypertension if the patient’s potassium level is 4.5 mmol/L or lower and BP is higher than 140/90 mm Hg despite treatment with an optimal or best-tolerated dose of an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker plus a calcium-channel blocker and diuretic.⁵

Editor’s takeaway

The evidence from multiple RCTs convincingly shows the effectiveness of spironolactone. Despite the SOR of C because of a disease-oriented outcome, we do treat to blood pressure goals, and therefore, spironolactone is a good option.

EVIDENCE SUMMARY

A 2017 meta-analysis of 4 RCTs (869 patients) evaluated the effectiveness of prescribing spironolactone for patients with resistant hypertension, defined as above-goal blood pressure (BP) despite treatment with at least 3 BP-lowering drugs (at least 1 of which was a diuretic).¹ All 4 trials compared spironolactone 25 to 50 mg/d with placebo. Follow-up periods ranged from 8 to 16 weeks. The primary outcomes were systolic and diastolic BPs, which were evaluated in the office, at home, or with an ambulatory monitor.

Spironolactone markedly lowers systolic and diastolic BP

A statistically significant reduction in SBP occurred in the spironolactone group compared with the placebo group (weighted mean difference [WMD] = −16.7 mm Hg; 95% confidence interval [CI], −27.5 to −5.8 mm Hg). DBP also decreased (WMD = −6.11 mm Hg; 95% CI, −9.34 to −2.88 mm Hg).

Because significant heterogeneity was found in the initial pooled results (I² = 96% for SBP; I² = 85% for DBP), investigators performed an analysis that excluded a single study with a small sample size. The re-analysis continued to show significant reductions in SBP and DBP for spironolactone compared with placebo (SBP: WMD = −10.8 mm Hg; 95% CI, −13.16 to −8.43 mm Hg; DBP: WMD = −4.62 mm Hg; 95% CI, −6.05 to −3.2 mm Hg; I² = 35%), confirming that the excluded trial was the source of heterogeneity in the initial analysis and that spironolactone continued to significantly lower BP for the treatment group compared with controls.

Add-on treatment with spironolactone also reduces BP

A 2016 meta-analysis of 5 RCTs with a total of 553 patients examined the effectiveness of add-on treatment with spironolactone (25-50 mg/d) for patients with resistant hypertension, defined as failure to achieve BP < 140/90 mm Hg despite treatment with 3 or more BP-lowering drugs, including one diuretic.² Spironolactone was compared with placebo in 4 trials and with ramipril in the remaining study. The follow-up periods were 8 to 16 weeks. Researchers separated BP outcomes into 24-hour ambulatory systolic/diastolic BPs and office systolic/diastolic BPs.

The 24-hour ambulatory BPs were significantly lower in the spironolactone group compared with the control group (24-hour SBP: WMD = −10.5 mm Hg; 95% CI, −12.3 to −8.71 mm Hg; 24-hour DBP: WMD = −4.09 mm Hg; 95% CI, −5.28 to −2.91 mm Hg). No significant heterogeneity was noted in these analyses.

Office-based BPs also were markedly reduced in spironolactone groups compared with controls (office SBP: WMD = −17 mm Hg; 95% CI, −25 to −8.95 mm Hg); office DBP: WMD = −6.18 mm Hg; 95% CI, −9.3 to −3.05 mm Hg). Because the office-based BP data showed significant heterogeneity (I² = 94% for SBP and 84.2% for DBP), 2 studies determined to be of lower quality caused by lack of detailed methodology were excluded from analysis, yielding continued statistically significant reductions in SBP (WMD = −11.7 mm Hg; 95% CI, −14.4 to −8.95 mm Hg) and DBP (WMD = −4.07 mm Hg; 95% CI, −5.6 to −2.54 mm Hg) compared with controls. Heterogeneity also decreased when the 2 studies were excluded (I² = 21% for SBP and I² = 59% for DBP).

How spironolactone compares with alternative drugs

A 2017 meta-analysis of 5 RCTs with 662 patients evaluated the effectiveness of spironolactone (25-50 mg/d) on resistant hypertension in patients taking 3 medications compared with a control group—placebo in 3 trials, placebo or bisoprolol (5-10 mg) in 1 trial, and an alternative treatment (candesartan 8 mg, atenolol 100 mg, or alpha methyldopa 750 mg) in 1 trial.³ Follow-up periods ranged from 4 to 16 weeks. Researchers evaluated changes in office and 24-hour ambulatory or home BP and completed separate analyses of pooled data for spironolactone compared with placebo groups, and spironolactone compared with alternative treatment groups.

Continue to: Investigators found a statistically significant...

Investigators found a statistically significant reduction in office SBP and DBP among patients taking spironolactone compared with control groups (SBP: WMD = −15.7 mm Hg; 95% CI, −20.5 to −11 mm Hg; DBP: WMD = −6.21 mm Hg; 95% CI, −8.33 to −4.1 mm Hg). A significant decrease also occurred in 24-hour ambulatory home SBP and DBP (SBP: MD = −8.7 mm Hg; 95% CI, −8.79 to −8.62 mm Hg; DBP: WMD = −4.12 mm Hg; 95% CI, −4.48 to −3.75 mm Hg).

Spironolactone reduces systolic blood pressure by 11 to 17 mm Hg and diastolic blood pressure by up to 6 mm Hg in patients with resistant hypertension taking 3 or more medications.

Patients treated with spironolactone showed a marked decrease in home SBP compared with alternative drug groups (WMD = −4.5 mm Hg; 95% CI, −4.63 to −4.37 mm Hg), but alternative drugs reduced home DBP significantly more than spironolactone (WMD = 0.6 mm Hg; 95% CI, 0.55-0.65 mm Hg). Marked heterogeneity was found in these analyses, and the authors also noted that reductions in SBP are more clinically relevant than decreases in DBP.

RECOMMENDATIONS

The 2017 American Heart Association/American College of Cardiology evidence-based guideline recommends considering adding a mineralocorticoid receptor agonist to treatment regimens for resistant hypertension when: office BP remains ≥ 130/80 mm Hg; the patient is prescribed at least 3 antihypertensive agents at optimal doses including a diuretic; pseudoresistance (nonadherence, inaccurate measurements) is excluded; reversible lifestyle factors have been addressed; substances that interfere with BP treatment (such as nonsteroidal anti-inflammatory drugs and oral contraceptive pills) are excluded; and screening for secondary causes of hypertension is complete.⁴

The United Kingdom’s National Institute for Health and Care Excellence (NICE) evidence-based guideline recommends considering spironolactone 25 mg/d to treat resistant hypertension if the patient’s potassium level is 4.5 mmol/L or lower and BP is higher than 140/90 mm Hg despite treatment with an optimal or best-tolerated dose of an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker plus a calcium-channel blocker and diuretic.⁵

Editor’s takeaway

The evidence from multiple RCTs convincingly shows the effectiveness of spironolactone. Despite the SOR of C because of a disease-oriented outcome, we do treat to blood pressure goals, and therefore, spironolactone is a good option.

EVIDENCE SUMMARY

A 2017 meta-analysis of 16 RCTs examined the risk of cardiovascular events in 7540 adult patients taking PPIs for GERD (mean ages 45-55 years).¹ The primary outcome was cardiovascular events—including acute myocardial infarction, myocardial ischemia, angina pectoris, cardiac failure, and coronary artery stenosis—and cardiac disorders.

Analysis of pooled data found that PPI use was associated with a 70% increase in cardiovascular risk (relative risk [RR] = 1.7; 95% confidence interval [CI], 1.13-2.56; number needed to harm [NNH] = 241) when compared with controls (placebo, H₂ blocker, or surgery). A subgroup analysis found that PPI use for longer than 8 weeks was associated with an even higher risk of adverse cardiovascular events (6 trials, 2296 patients; RR = 2.33; 95% CI, 1.33-4.08; NNH = 67) when compared with controls. The meta-analysis wasn’t limited by heterogeneity (I² = 0).

C difficile infection risk is higherfor PPI users

A 2016 meta-analysis of 23 observational studies (19 case-control, 4 retrospective cohort; 186,033 patients) examined the risk of hospital-acquired C difficile infections in adults prescribed PPI for any indication.² PPI exposure varied from use at time of diagnosis or hospitalization to any use within 90 days. Of the 23 studies, 16 reported sufficient data to calculate the mean age for the patients which was 69.9 years.

The risk of C difficile infection was found to be higher with PPI use than no use (pooled odds ratio [OR] = 1.81; 95% CI, 1.52-2.14). Although a significant association was found across a large group, the results were limited by considerable heterogeneity (I² = 82%).

Risk of community-acquired pneumonia also increases with PPI use

A 2015 systematic review and meta-analysis of 33 trials (18 case-control, 10 cohort, 4 RCTs, and 1 case-crossover study) examined the risk of CAP in adult patients prescribed PPI for any indication for durations ranging from less than 1 month to > 6 months.³ The systematic review was distilled to 26 studies because of overlapping study populations. These 26 studies included 226,769 cases of CAP among 6,351,656 patients. The primary outcome was development of CAP, the secondary outcome was hospitalization for CAP.

PPI use, compared with no use, was associated with an increased risk of developing CAP (pooled OR = 1.49; 95% CI, 1.16-1.92) and an increased risk of hospitalization for CAP (pooled OR = 1.61; 95% CI, 1.12-2.31).

Extrapolation from studies on all adults suggests a significant link between proton pump inhibitors and higher risk of cardiovascular events— especially with treatment > 8 weeks.

In a subgroup analysis for age, patients older than 65 years were also found to have an increased risk of developing CAP with PPI use (11 trials, total number of patients not provided; OR = 1.33; 95% CI, 1.13-1.58). Despite the significant associations of PPI use with risk revealed in the primary, secondary, and subgroup analyses, the results were limited by marked heterogeneity, with an I² > 99%.

Continue to: Hip and vertebral fracture risks associated with PPIs

A 2011 systematic review and meta-analysis investigated the risk of fracture in adult patients taking PPIs for any indication.⁴ The analysis included 10 observational studies (4 cohort, 6 case-control) with a total of 223,210 fracture cases. The authors examined the incidence of hip, vertebral, and wrist or forearm fractures.

No significant association was found between PPI use and wrist or forearm fracture (3 studies; pooled OR = 1.09; 95% CI, 0.95-1.24). A modest association was noted between PPI use and both hip fractures (9 trials; OR = 1.25; 95% CI, 1.14-1.37) and vertebral fractures (4 trials; OR = 1.5; 95% CI, 1.32-1.72).

Subgroup analysis didn’t reveal evidence of an effect of duration of PPI use on fracture. Investigators didn’t conduct subgroup analysis of different patient ages. Final results were limited by significant heterogeneity with an I² of 86%.

RECOMMENDATIONS

A 2015 American Geriatrics Society Beers Criteria update recommends limiting PPI use because of increased risk of C difficile infections and fractures. It also recommends against using PPIs for longer than 8 weeks except for high-risk patients (such as patients taking oral corticosteroids or chronic nonsteroidal anti-inflammatory drug users), patients with Barrett’s esophagitis, or patients who need maintenance after failure of a drug discontinuation trial or H₂ blockers (quality of evidence, high; SOR, strong).⁵

Editor’s takeaway: Despite limited evidence specific to patients over age 65, or perhaps because the majority of the studied populations were younger, increased caution should be exercised in the use of PPIs.

EVIDENCE SUMMARY

A 2017 meta-analysis of 16 RCTs examined the risk of cardiovascular events in 7540 adult patients taking PPIs for GERD (mean ages 45-55 years).¹ The primary outcome was cardiovascular events—including acute myocardial infarction, myocardial ischemia, angina pectoris, cardiac failure, and coronary artery stenosis—and cardiac disorders.

Analysis of pooled data found that PPI use was associated with a 70% increase in cardiovascular risk (relative risk [RR] = 1.7; 95% confidence interval [CI], 1.13-2.56; number needed to harm [NNH] = 241) when compared with controls (placebo, H₂ blocker, or surgery). A subgroup analysis found that PPI use for longer than 8 weeks was associated with an even higher risk of adverse cardiovascular events (6 trials, 2296 patients; RR = 2.33; 95% CI, 1.33-4.08; NNH = 67) when compared with controls. The meta-analysis wasn’t limited by heterogeneity (I² = 0).

C difficile infection risk is higherfor PPI users

A 2016 meta-analysis of 23 observational studies (19 case-control, 4 retrospective cohort; 186,033 patients) examined the risk of hospital-acquired C difficile infections in adults prescribed PPI for any indication.² PPI exposure varied from use at time of diagnosis or hospitalization to any use within 90 days. Of the 23 studies, 16 reported sufficient data to calculate the mean age for the patients which was 69.9 years.

The risk of C difficile infection was found to be higher with PPI use than no use (pooled odds ratio [OR] = 1.81; 95% CI, 1.52-2.14). Although a significant association was found across a large group, the results were limited by considerable heterogeneity (I² = 82%).

Risk of community-acquired pneumonia also increases with PPI use

A 2015 systematic review and meta-analysis of 33 trials (18 case-control, 10 cohort, 4 RCTs, and 1 case-crossover study) examined the risk of CAP in adult patients prescribed PPI for any indication for durations ranging from less than 1 month to > 6 months.³ The systematic review was distilled to 26 studies because of overlapping study populations. These 26 studies included 226,769 cases of CAP among 6,351,656 patients. The primary outcome was development of CAP, the secondary outcome was hospitalization for CAP.

PPI use, compared with no use, was associated with an increased risk of developing CAP (pooled OR = 1.49; 95% CI, 1.16-1.92) and an increased risk of hospitalization for CAP (pooled OR = 1.61; 95% CI, 1.12-2.31).

Extrapolation from studies on all adults suggests a significant link between proton pump inhibitors and higher risk of cardiovascular events— especially with treatment > 8 weeks.

In a subgroup analysis for age, patients older than 65 years were also found to have an increased risk of developing CAP with PPI use (11 trials, total number of patients not provided; OR = 1.33; 95% CI, 1.13-1.58). Despite the significant associations of PPI use with risk revealed in the primary, secondary, and subgroup analyses, the results were limited by marked heterogeneity, with an I² > 99%.

Continue to: Hip and vertebral fracture risks associated with PPIs

A 2011 systematic review and meta-analysis investigated the risk of fracture in adult patients taking PPIs for any indication.⁴ The analysis included 10 observational studies (4 cohort, 6 case-control) with a total of 223,210 fracture cases. The authors examined the incidence of hip, vertebral, and wrist or forearm fractures.

No significant association was found between PPI use and wrist or forearm fracture (3 studies; pooled OR = 1.09; 95% CI, 0.95-1.24). A modest association was noted between PPI use and both hip fractures (9 trials; OR = 1.25; 95% CI, 1.14-1.37) and vertebral fractures (4 trials; OR = 1.5; 95% CI, 1.32-1.72).

Subgroup analysis didn’t reveal evidence of an effect of duration of PPI use on fracture. Investigators didn’t conduct subgroup analysis of different patient ages. Final results were limited by significant heterogeneity with an I² of 86%.

RECOMMENDATIONS

A 2015 American Geriatrics Society Beers Criteria update recommends limiting PPI use because of increased risk of C difficile infections and fractures. It also recommends against using PPIs for longer than 8 weeks except for high-risk patients (such as patients taking oral corticosteroids or chronic nonsteroidal anti-inflammatory drug users), patients with Barrett’s esophagitis, or patients who need maintenance after failure of a drug discontinuation trial or H₂ blockers (quality of evidence, high; SOR, strong).⁵

Editor’s takeaway: Despite limited evidence specific to patients over age 65, or perhaps because the majority of the studied populations were younger, increased caution should be exercised in the use of PPIs.

EVIDENCE SUMMARY

A 2017 meta-analysis of 16 RCTs examined the risk of cardiovascular events in 7540 adult patients taking PPIs for GERD (mean ages 45-55 years).¹ The primary outcome was cardiovascular events—including acute myocardial infarction, myocardial ischemia, angina pectoris, cardiac failure, and coronary artery stenosis—and cardiac disorders.

Analysis of pooled data found that PPI use was associated with a 70% increase in cardiovascular risk (relative risk [RR] = 1.7; 95% confidence interval [CI], 1.13-2.56; number needed to harm [NNH] = 241) when compared with controls (placebo, H₂ blocker, or surgery). A subgroup analysis found that PPI use for longer than 8 weeks was associated with an even higher risk of adverse cardiovascular events (6 trials, 2296 patients; RR = 2.33; 95% CI, 1.33-4.08; NNH = 67) when compared with controls. The meta-analysis wasn’t limited by heterogeneity (I² = 0).

C difficile infection risk is higherfor PPI users

A 2016 meta-analysis of 23 observational studies (19 case-control, 4 retrospective cohort; 186,033 patients) examined the risk of hospital-acquired C difficile infections in adults prescribed PPI for any indication.² PPI exposure varied from use at time of diagnosis or hospitalization to any use within 90 days. Of the 23 studies, 16 reported sufficient data to calculate the mean age for the patients which was 69.9 years.

The risk of C difficile infection was found to be higher with PPI use than no use (pooled odds ratio [OR] = 1.81; 95% CI, 1.52-2.14). Although a significant association was found across a large group, the results were limited by considerable heterogeneity (I² = 82%).

Risk of community-acquired pneumonia also increases with PPI use

A 2015 systematic review and meta-analysis of 33 trials (18 case-control, 10 cohort, 4 RCTs, and 1 case-crossover study) examined the risk of CAP in adult patients prescribed PPI for any indication for durations ranging from less than 1 month to > 6 months.³ The systematic review was distilled to 26 studies because of overlapping study populations. These 26 studies included 226,769 cases of CAP among 6,351,656 patients. The primary outcome was development of CAP, the secondary outcome was hospitalization for CAP.

PPI use, compared with no use, was associated with an increased risk of developing CAP (pooled OR = 1.49; 95% CI, 1.16-1.92) and an increased risk of hospitalization for CAP (pooled OR = 1.61; 95% CI, 1.12-2.31).

Extrapolation from studies on all adults suggests a significant link between proton pump inhibitors and higher risk of cardiovascular events— especially with treatment > 8 weeks.

In a subgroup analysis for age, patients older than 65 years were also found to have an increased risk of developing CAP with PPI use (11 trials, total number of patients not provided; OR = 1.33; 95% CI, 1.13-1.58). Despite the significant associations of PPI use with risk revealed in the primary, secondary, and subgroup analyses, the results were limited by marked heterogeneity, with an I² > 99%.

Continue to: Hip and vertebral fracture risks associated with PPIs

A 2011 systematic review and meta-analysis investigated the risk of fracture in adult patients taking PPIs for any indication.⁴ The analysis included 10 observational studies (4 cohort, 6 case-control) with a total of 223,210 fracture cases. The authors examined the incidence of hip, vertebral, and wrist or forearm fractures.

No significant association was found between PPI use and wrist or forearm fracture (3 studies; pooled OR = 1.09; 95% CI, 0.95-1.24). A modest association was noted between PPI use and both hip fractures (9 trials; OR = 1.25; 95% CI, 1.14-1.37) and vertebral fractures (4 trials; OR = 1.5; 95% CI, 1.32-1.72).

Subgroup analysis didn’t reveal evidence of an effect of duration of PPI use on fracture. Investigators didn’t conduct subgroup analysis of different patient ages. Final results were limited by significant heterogeneity with an I² of 86%.

RECOMMENDATIONS

A 2015 American Geriatrics Society Beers Criteria update recommends limiting PPI use because of increased risk of C difficile infections and fractures. It also recommends against using PPIs for longer than 8 weeks except for high-risk patients (such as patients taking oral corticosteroids or chronic nonsteroidal anti-inflammatory drug users), patients with Barrett’s esophagitis, or patients who need maintenance after failure of a drug discontinuation trial or H₂ blockers (quality of evidence, high; SOR, strong).⁵

Editor’s takeaway: Despite limited evidence specific to patients over age 65, or perhaps because the majority of the studied populations were younger, increased caution should be exercised in the use of PPIs.

EVIDENCE SUMMARY

A Cochrane review of 16 RCTs (2144 patients) compared pain relief and return to function with oral NSAIDs and other oral analgesics (acetaminophen, opioids, or opioids plus acetaminophen) in patients who had suffered a soft tissue injury within the past 48 hours.¹ No differences between NSAIDs and acetaminophen were seen in pain relief at fewer than 24 hours on a 100-point visual analog scale (VAS) (4 trials; 359 patients; mean difference [MD]=1.56; 95% confidence interval [CI], -3.9 to 7.0). Nor were differences observed in return to function at 7 days (3 trials, 386 patients; risk ratio [RR]=0.99; 95% CI, 0.90-1.09).

No differences in pain relief between NSAIDs and oral opioids were seen at fewer than 24 hours (2 trials, 757 patients; MD=-0.02; 95% CI, -3.71 to 3.68) nor at days 4 to 6 (one trial, 706 patients; MD=-2.9; 95% CI, -6.06 to 0.26). Compared with NSAIDs, opioids showed a small increase in return to function at 7 days (2 trials, 749 patients; RR=1.13; 95% CI, 1.03-1.25), but the combination of acetaminophen and opioids didn’t show a difference (one trial, 89 patients; RR= 1.28; 95% CI, 0.90-1.81).

Adverse gastrointestinal events (not defined) were no different between NSAIDs and acetaminophen (7 trials, 627 patients; RR=1.76; 95% CI, 0.99-3.14) and occurred less often with NSAIDs than with oral opioids (2 trials, 769 patients; RR=0.51; 95% CI, 0.37-0.69). Overall, the authors concluded that low-quality evidence consistently showed NSAIDs were at least equal to other oral analgesics in efficacy of pain relief and return to function.

Naproxen vs oxycodone: The opioid has more adverse effects

A double-blind, noninferiority, randomized trial (published after the Cochrane review search date) compared the effects of treatment with a single dose of oxycodone with a single dose of naproxen in 150 adult emergency department (ED) patients in a tertiary care academic center who had acute soft tissue injury and pain scores between 3 and 7 (on a 1-to-10 scale).² Injuries included sprains, strains, contusions, low-back injury, and intervertebral disk problems. The authors didn’t clearly define “acute” with regard to time from injury.

Patients were randomized and given a single dose of oxycodone 10 mg or naproxen 250 mg with water. Pain scores and adverse effects were reassessed at 30 minutes and 60 minutes after administration, and a follow-up phone call was placed at 24 hours to evaluate further need for analgesics and adverse effects.

Baseline pain scores before medication administration were similar in the 2 groups (6.21 for the oxycodone group, 6 for the naproxen group). No difference in pain scores between oxycodone and naproxen was seen at 30 minutes (4.5 vs 4.4; P=.76) or 60 minutes (2.5 vs 2.6; P=.45). The number of patients who required more analgesics within 24 hours after administration didn’t differ significantly between the oxycodone group and the naproxen group (12 patients vs 5 patients; P=.07).

The study evaluated adverse effects, including nausea, vomiting, dizziness, drowsiness, pruritus, and epigastric pain. Overall, 22% of patients (33) from both groups combined experienced at least one adverse effect. The oxycodone group reported more adverse effects overall (36% vs 8%; RR=4.5; 95% CI, 2.0-10.2;). Ten patients experienced nausea, 6 vomiting, 4 dizziness, 3 drowsiness, and 2 pruritis. In the naproxen group, 4 patients experienced nausea; no other adverse effects were reported.

A double-blind RCT in a university hospital ED in Hong Kong compared patients older than 16 years with “isolated painful limb injury” after trauma who received combinations of analgesics or placebo.³ Patients were recruited during typical work-week hours (Monday to Friday, 9 am to 5 pm) and randomized into 4 groups: acetaminophen 1 g plus placebo (66 patients), placebo plus indomethacin 25 mg (71 patients), placebo plus diclofenac 25 mg (69 patients), or acetaminophen 1 g plus diclofenac 25 mg (94 patients).

Each patient was given the group’s designated combination of analgesics in the ED and asked to rate pain on a 0-to-100 visual analog pain scale (VAPS) at 0, 30, 60, 90, and 120 minutes after administration. Patients then left the ED with a 3-day course of their analgesic combination and were instructed to take the medication 4 times daily on the first day and 3 times daily thereafter. Patients recorded pain scores on the VAPS 3 times daily after discharge and at follow-up 5 to 8 days after initial presentation. Intention-to-treat analysis was done for patients lost to follow-up. A change in VAPS of 13 was considered clinically significant.

NSAIDs are at least as effective as opioids and acetaminophen in relieving pain from acute musculoskeletal injury.

All groups started with similar pain scores (30 at rest and 70 with activity) and didn’t achieve clinically significant pain relief within the first hour (mean change in VAPS <13). At 90 minutes, all groups achieved a mean change in VAPS >13, with no statistically significant difference between the groups. Adverse effects were rare (7% total), and none were severe (no gastrointestinal hemorrhage or renal damage).

Outside the ED, the acetaminophen-diclofenac combination group showed the greatest pain score reduction at every time point at rest and with activity, but none of the reductions were statistically or clinically significant (results presented graphically). No difference was found between the groups in number of patients who completed the course of analgesics, took additional analgesia, tried Chinese medicine, or returned to the ED within 30 days.

Limitations to the study included that the medication dosages may be much lower than typical dosages given in the United States and therefore lack applicability. The study also didn’t include a true placebo arm.

EVIDENCE SUMMARY

A Cochrane review of 16 RCTs (2144 patients) compared pain relief and return to function with oral NSAIDs and other oral analgesics (acetaminophen, opioids, or opioids plus acetaminophen) in patients who had suffered a soft tissue injury within the past 48 hours.¹ No differences between NSAIDs and acetaminophen were seen in pain relief at fewer than 24 hours on a 100-point visual analog scale (VAS) (4 trials; 359 patients; mean difference [MD]=1.56; 95% confidence interval [CI], -3.9 to 7.0). Nor were differences observed in return to function at 7 days (3 trials, 386 patients; risk ratio [RR]=0.99; 95% CI, 0.90-1.09).

No differences in pain relief between NSAIDs and oral opioids were seen at fewer than 24 hours (2 trials, 757 patients; MD=-0.02; 95% CI, -3.71 to 3.68) nor at days 4 to 6 (one trial, 706 patients; MD=-2.9; 95% CI, -6.06 to 0.26). Compared with NSAIDs, opioids showed a small increase in return to function at 7 days (2 trials, 749 patients; RR=1.13; 95% CI, 1.03-1.25), but the combination of acetaminophen and opioids didn’t show a difference (one trial, 89 patients; RR= 1.28; 95% CI, 0.90-1.81).

Adverse gastrointestinal events (not defined) were no different between NSAIDs and acetaminophen (7 trials, 627 patients; RR=1.76; 95% CI, 0.99-3.14) and occurred less often with NSAIDs than with oral opioids (2 trials, 769 patients; RR=0.51; 95% CI, 0.37-0.69). Overall, the authors concluded that low-quality evidence consistently showed NSAIDs were at least equal to other oral analgesics in efficacy of pain relief and return to function.

Naproxen vs oxycodone: The opioid has more adverse effects

A double-blind, noninferiority, randomized trial (published after the Cochrane review search date) compared the effects of treatment with a single dose of oxycodone with a single dose of naproxen in 150 adult emergency department (ED) patients in a tertiary care academic center who had acute soft tissue injury and pain scores between 3 and 7 (on a 1-to-10 scale).² Injuries included sprains, strains, contusions, low-back injury, and intervertebral disk problems. The authors didn’t clearly define “acute” with regard to time from injury.

Patients were randomized and given a single dose of oxycodone 10 mg or naproxen 250 mg with water. Pain scores and adverse effects were reassessed at 30 minutes and 60 minutes after administration, and a follow-up phone call was placed at 24 hours to evaluate further need for analgesics and adverse effects.

Baseline pain scores before medication administration were similar in the 2 groups (6.21 for the oxycodone group, 6 for the naproxen group). No difference in pain scores between oxycodone and naproxen was seen at 30 minutes (4.5 vs 4.4; P=.76) or 60 minutes (2.5 vs 2.6; P=.45). The number of patients who required more analgesics within 24 hours after administration didn’t differ significantly between the oxycodone group and the naproxen group (12 patients vs 5 patients; P=.07).

The study evaluated adverse effects, including nausea, vomiting, dizziness, drowsiness, pruritus, and epigastric pain. Overall, 22% of patients (33) from both groups combined experienced at least one adverse effect. The oxycodone group reported more adverse effects overall (36% vs 8%; RR=4.5; 95% CI, 2.0-10.2;). Ten patients experienced nausea, 6 vomiting, 4 dizziness, 3 drowsiness, and 2 pruritis. In the naproxen group, 4 patients experienced nausea; no other adverse effects were reported.

A double-blind RCT in a university hospital ED in Hong Kong compared patients older than 16 years with “isolated painful limb injury” after trauma who received combinations of analgesics or placebo.³ Patients were recruited during typical work-week hours (Monday to Friday, 9 am to 5 pm) and randomized into 4 groups: acetaminophen 1 g plus placebo (66 patients), placebo plus indomethacin 25 mg (71 patients), placebo plus diclofenac 25 mg (69 patients), or acetaminophen 1 g plus diclofenac 25 mg (94 patients).

Each patient was given the group’s designated combination of analgesics in the ED and asked to rate pain on a 0-to-100 visual analog pain scale (VAPS) at 0, 30, 60, 90, and 120 minutes after administration. Patients then left the ED with a 3-day course of their analgesic combination and were instructed to take the medication 4 times daily on the first day and 3 times daily thereafter. Patients recorded pain scores on the VAPS 3 times daily after discharge and at follow-up 5 to 8 days after initial presentation. Intention-to-treat analysis was done for patients lost to follow-up. A change in VAPS of 13 was considered clinically significant.

NSAIDs are at least as effective as opioids and acetaminophen in relieving pain from acute musculoskeletal injury.

All groups started with similar pain scores (30 at rest and 70 with activity) and didn’t achieve clinically significant pain relief within the first hour (mean change in VAPS <13). At 90 minutes, all groups achieved a mean change in VAPS >13, with no statistically significant difference between the groups. Adverse effects were rare (7% total), and none were severe (no gastrointestinal hemorrhage or renal damage).

Outside the ED, the acetaminophen-diclofenac combination group showed the greatest pain score reduction at every time point at rest and with activity, but none of the reductions were statistically or clinically significant (results presented graphically). No difference was found between the groups in number of patients who completed the course of analgesics, took additional analgesia, tried Chinese medicine, or returned to the ED within 30 days.

Limitations to the study included that the medication dosages may be much lower than typical dosages given in the United States and therefore lack applicability. The study also didn’t include a true placebo arm.

EVIDENCE SUMMARY

A Cochrane review of 16 RCTs (2144 patients) compared pain relief and return to function with oral NSAIDs and other oral analgesics (acetaminophen, opioids, or opioids plus acetaminophen) in patients who had suffered a soft tissue injury within the past 48 hours.¹ No differences between NSAIDs and acetaminophen were seen in pain relief at fewer than 24 hours on a 100-point visual analog scale (VAS) (4 trials; 359 patients; mean difference [MD]=1.56; 95% confidence interval [CI], -3.9 to 7.0). Nor were differences observed in return to function at 7 days (3 trials, 386 patients; risk ratio [RR]=0.99; 95% CI, 0.90-1.09).

No differences in pain relief between NSAIDs and oral opioids were seen at fewer than 24 hours (2 trials, 757 patients; MD=-0.02; 95% CI, -3.71 to 3.68) nor at days 4 to 6 (one trial, 706 patients; MD=-2.9; 95% CI, -6.06 to 0.26). Compared with NSAIDs, opioids showed a small increase in return to function at 7 days (2 trials, 749 patients; RR=1.13; 95% CI, 1.03-1.25), but the combination of acetaminophen and opioids didn’t show a difference (one trial, 89 patients; RR= 1.28; 95% CI, 0.90-1.81).

Adverse gastrointestinal events (not defined) were no different between NSAIDs and acetaminophen (7 trials, 627 patients; RR=1.76; 95% CI, 0.99-3.14) and occurred less often with NSAIDs than with oral opioids (2 trials, 769 patients; RR=0.51; 95% CI, 0.37-0.69). Overall, the authors concluded that low-quality evidence consistently showed NSAIDs were at least equal to other oral analgesics in efficacy of pain relief and return to function.

Naproxen vs oxycodone: The opioid has more adverse effects

A double-blind, noninferiority, randomized trial (published after the Cochrane review search date) compared the effects of treatment with a single dose of oxycodone with a single dose of naproxen in 150 adult emergency department (ED) patients in a tertiary care academic center who had acute soft tissue injury and pain scores between 3 and 7 (on a 1-to-10 scale).² Injuries included sprains, strains, contusions, low-back injury, and intervertebral disk problems. The authors didn’t clearly define “acute” with regard to time from injury.

Patients were randomized and given a single dose of oxycodone 10 mg or naproxen 250 mg with water. Pain scores and adverse effects were reassessed at 30 minutes and 60 minutes after administration, and a follow-up phone call was placed at 24 hours to evaluate further need for analgesics and adverse effects.

Baseline pain scores before medication administration were similar in the 2 groups (6.21 for the oxycodone group, 6 for the naproxen group). No difference in pain scores between oxycodone and naproxen was seen at 30 minutes (4.5 vs 4.4; P=.76) or 60 minutes (2.5 vs 2.6; P=.45). The number of patients who required more analgesics within 24 hours after administration didn’t differ significantly between the oxycodone group and the naproxen group (12 patients vs 5 patients; P=.07).

The study evaluated adverse effects, including nausea, vomiting, dizziness, drowsiness, pruritus, and epigastric pain. Overall, 22% of patients (33) from both groups combined experienced at least one adverse effect. The oxycodone group reported more adverse effects overall (36% vs 8%; RR=4.5; 95% CI, 2.0-10.2;). Ten patients experienced nausea, 6 vomiting, 4 dizziness, 3 drowsiness, and 2 pruritis. In the naproxen group, 4 patients experienced nausea; no other adverse effects were reported.

A double-blind RCT in a university hospital ED in Hong Kong compared patients older than 16 years with “isolated painful limb injury” after trauma who received combinations of analgesics or placebo.³ Patients were recruited during typical work-week hours (Monday to Friday, 9 am to 5 pm) and randomized into 4 groups: acetaminophen 1 g plus placebo (66 patients), placebo plus indomethacin 25 mg (71 patients), placebo plus diclofenac 25 mg (69 patients), or acetaminophen 1 g plus diclofenac 25 mg (94 patients).

Each patient was given the group’s designated combination of analgesics in the ED and asked to rate pain on a 0-to-100 visual analog pain scale (VAPS) at 0, 30, 60, 90, and 120 minutes after administration. Patients then left the ED with a 3-day course of their analgesic combination and were instructed to take the medication 4 times daily on the first day and 3 times daily thereafter. Patients recorded pain scores on the VAPS 3 times daily after discharge and at follow-up 5 to 8 days after initial presentation. Intention-to-treat analysis was done for patients lost to follow-up. A change in VAPS of 13 was considered clinically significant.

NSAIDs are at least as effective as opioids and acetaminophen in relieving pain from acute musculoskeletal injury.

All groups started with similar pain scores (30 at rest and 70 with activity) and didn’t achieve clinically significant pain relief within the first hour (mean change in VAPS <13). At 90 minutes, all groups achieved a mean change in VAPS >13, with no statistically significant difference between the groups. Adverse effects were rare (7% total), and none were severe (no gastrointestinal hemorrhage or renal damage).

Outside the ED, the acetaminophen-diclofenac combination group showed the greatest pain score reduction at every time point at rest and with activity, but none of the reductions were statistically or clinically significant (results presented graphically). No difference was found between the groups in number of patients who completed the course of analgesics, took additional analgesia, tried Chinese medicine, or returned to the ED within 30 days.

Limitations to the study included that the medication dosages may be much lower than typical dosages given in the United States and therefore lack applicability. The study also didn’t include a true placebo arm.