Clinical Inquiries

EVIDENCE SUMMARY

A 28-week RCT compared the effects of placebo, allopurinol (300 mg/d), and febuxostat (80 mg, 120 mg, and 240 mg) on serum uric acid levels (sUA) and gout attacks in 1067 patients with gout and hyperuricemia (94% male, 78% white, 18 to 85 years of age with mean age ranging from 51 to 54 years ± 12 years in each group).¹ Patients also received prophylaxis with either colchicine or naproxen during the first 8 weeks of the study.

During Weeks 1 through 8, investigators found no statistically significant differences in the percentage of patients requiring treatment for gout attacks between the febuxostat 80 mg, allopurinol, and placebo groups (28%, 23%, and 20%, respectively). During Weeks 8 through 28, no statistically significant differences in gout attack rates occurred between the allopurinol and febuxostat groups, although the study didn’t report specific attack rates for this period.

Both allopurinol and all doses of febuxostat reduced sUA to <6 mg/dL more effectively than placebo; more patients treated with febuxostat than allopurinol achieved a uric acid level of less than <6 mg/dL.

Another RCT of 762 mostly white, male patients (mean age 52 years) with gout and sUA >8 mg/dL—35% of whom had renal impairment, defined as creatinine clearance <80 mL/min/1.73m²—also concluded that febuxostat and allopurinol are equally effective in reducing gout attacks (incidence of gout flares during Weeks 9 to 52 was 64% with both febuxostat 80 mg and allopurinol 300 mg).² The percentage of patients with sUA <6 mg/dL at the last 3 monthly visits was 53% in the febuxostat 80 mg group compared with 21% in the allopurinol 300 mg group (P<.001; number needed to treat [NNT]=4]).

One significant limitation of both RCTs was the fixed dose of allopurinol (300 mg/d). US Food and Drug Administration-approved dosing for allopurinol allows for titration to a maximum of 800 mg/d to achieve serum uric acid <6 mg/dL.

Pegloticase is an intravenously administered, recombinant form of uricase, the natural enzyme that converts uric acid to more soluble allantoin. Two RCTs compared pegloticase with placebo in a total of 212 patients with gout (mean age 54 to 59 years; 70% to 90% male) intolerant or refractory to allopurinol (defined as baseline sUA of ≥8 mg/dL and at least one of the following: ≥3 self-reported gout flares during the previous 18 months, ≥1 tophi, or gouty arthropathy.

These trials found that treatment with 8 mg of pegloticase every 2 weeks for 6 months initially increased gout flares during Months 1 to 3 (75% with pegloticase, 53% with placebo; P=.02; number needed to harm [NNH]=5) but then decreased the incidence of acute gout attacks during Months 4 to 6 (41% with pegloticase, 67% with placebo; P=.007; NNT=4).3 In addition, pegloticase resulted in statistically significant improvements in QOL measured at the final visit using the Health Assessment Questionnaire (HAQ) pain scale, the HAQ-Disability Index, and the 36-item Short Form Health Survey.

Colchicine plus probenecid or allopurinol reduces gout attacks

One small, low-quality RCT (N=38) found that colchicine 0.5 mg administered 3 times daily effectively prevented gout attacks when administered concomitantly with probenecid initiated to lower urate (gout attacks per month in colchicine and placebo-treated patients, respectively, were 0.19±0.05 and 0.48±0.12; P<.05).⁴

Another RCT that compared allopurinol with and without colchicine showed that coadministration of colchicine 0.6 mg twice daily reduced gout attacks: 33% of patients treated with colchicine experienced a gout flare compared with 77% of placebo-treated patients (P=.008; NNT=3 over 6 months).⁵

We identified no RCTs that evaluated the uricosuric agent probenecid and no studies that assessed the use of nonsteroidal anti-inflammatory drugs (NSAIDs) to prevent recurrent gout attacks.

RECOMMENDATIONS

Eight weeks of treatment with either allopurinol or febuxostat reduces the frequency of gout attacks equally.The American College of Rheumatology (ACR) guidelines on managing gout recommend allopurinol or febuxostat as first-line pharmacologic urate-lowering therapy, with a goal of reducing sUA to <6 mg/dL. They recommend probenecid as an alternative if contraindications exist or the patient is intolerant to allopurinol and febuxostat.⁶ The guidelines note that allopurinol doses may exceed 300 mg/d, even in patients with chronic kidney disease.

The ACR recommends anti-inflammatory prophylaxis with colchicine or NSAIDs upon initiation of urate-lowering therapy. Anti-inflammatory prophylaxis should be continued as long as clinical evidence of continuing gout disease exists and until the sUA target has been acheived.7

EVIDENCE SUMMARY

A 28-week RCT compared the effects of placebo, allopurinol (300 mg/d), and febuxostat (80 mg, 120 mg, and 240 mg) on serum uric acid levels (sUA) and gout attacks in 1067 patients with gout and hyperuricemia (94% male, 78% white, 18 to 85 years of age with mean age ranging from 51 to 54 years ± 12 years in each group).¹ Patients also received prophylaxis with either colchicine or naproxen during the first 8 weeks of the study.

During Weeks 1 through 8, investigators found no statistically significant differences in the percentage of patients requiring treatment for gout attacks between the febuxostat 80 mg, allopurinol, and placebo groups (28%, 23%, and 20%, respectively). During Weeks 8 through 28, no statistically significant differences in gout attack rates occurred between the allopurinol and febuxostat groups, although the study didn’t report specific attack rates for this period.

Both allopurinol and all doses of febuxostat reduced sUA to <6 mg/dL more effectively than placebo; more patients treated with febuxostat than allopurinol achieved a uric acid level of less than <6 mg/dL.

Another RCT of 762 mostly white, male patients (mean age 52 years) with gout and sUA >8 mg/dL—35% of whom had renal impairment, defined as creatinine clearance <80 mL/min/1.73m²—also concluded that febuxostat and allopurinol are equally effective in reducing gout attacks (incidence of gout flares during Weeks 9 to 52 was 64% with both febuxostat 80 mg and allopurinol 300 mg).² The percentage of patients with sUA <6 mg/dL at the last 3 monthly visits was 53% in the febuxostat 80 mg group compared with 21% in the allopurinol 300 mg group (P<.001; number needed to treat [NNT]=4]).

One significant limitation of both RCTs was the fixed dose of allopurinol (300 mg/d). US Food and Drug Administration-approved dosing for allopurinol allows for titration to a maximum of 800 mg/d to achieve serum uric acid <6 mg/dL.

Pegloticase is an intravenously administered, recombinant form of uricase, the natural enzyme that converts uric acid to more soluble allantoin. Two RCTs compared pegloticase with placebo in a total of 212 patients with gout (mean age 54 to 59 years; 70% to 90% male) intolerant or refractory to allopurinol (defined as baseline sUA of ≥8 mg/dL and at least one of the following: ≥3 self-reported gout flares during the previous 18 months, ≥1 tophi, or gouty arthropathy.

These trials found that treatment with 8 mg of pegloticase every 2 weeks for 6 months initially increased gout flares during Months 1 to 3 (75% with pegloticase, 53% with placebo; P=.02; number needed to harm [NNH]=5) but then decreased the incidence of acute gout attacks during Months 4 to 6 (41% with pegloticase, 67% with placebo; P=.007; NNT=4).3 In addition, pegloticase resulted in statistically significant improvements in QOL measured at the final visit using the Health Assessment Questionnaire (HAQ) pain scale, the HAQ-Disability Index, and the 36-item Short Form Health Survey.

Colchicine plus probenecid or allopurinol reduces gout attacks

One small, low-quality RCT (N=38) found that colchicine 0.5 mg administered 3 times daily effectively prevented gout attacks when administered concomitantly with probenecid initiated to lower urate (gout attacks per month in colchicine and placebo-treated patients, respectively, were 0.19±0.05 and 0.48±0.12; P<.05).⁴

Another RCT that compared allopurinol with and without colchicine showed that coadministration of colchicine 0.6 mg twice daily reduced gout attacks: 33% of patients treated with colchicine experienced a gout flare compared with 77% of placebo-treated patients (P=.008; NNT=3 over 6 months).⁵

We identified no RCTs that evaluated the uricosuric agent probenecid and no studies that assessed the use of nonsteroidal anti-inflammatory drugs (NSAIDs) to prevent recurrent gout attacks.

RECOMMENDATIONS

Eight weeks of treatment with either allopurinol or febuxostat reduces the frequency of gout attacks equally.The American College of Rheumatology (ACR) guidelines on managing gout recommend allopurinol or febuxostat as first-line pharmacologic urate-lowering therapy, with a goal of reducing sUA to <6 mg/dL. They recommend probenecid as an alternative if contraindications exist or the patient is intolerant to allopurinol and febuxostat.⁶ The guidelines note that allopurinol doses may exceed 300 mg/d, even in patients with chronic kidney disease.

The ACR recommends anti-inflammatory prophylaxis with colchicine or NSAIDs upon initiation of urate-lowering therapy. Anti-inflammatory prophylaxis should be continued as long as clinical evidence of continuing gout disease exists and until the sUA target has been acheived.7

EVIDENCE SUMMARY

A 28-week RCT compared the effects of placebo, allopurinol (300 mg/d), and febuxostat (80 mg, 120 mg, and 240 mg) on serum uric acid levels (sUA) and gout attacks in 1067 patients with gout and hyperuricemia (94% male, 78% white, 18 to 85 years of age with mean age ranging from 51 to 54 years ± 12 years in each group).¹ Patients also received prophylaxis with either colchicine or naproxen during the first 8 weeks of the study.

During Weeks 1 through 8, investigators found no statistically significant differences in the percentage of patients requiring treatment for gout attacks between the febuxostat 80 mg, allopurinol, and placebo groups (28%, 23%, and 20%, respectively). During Weeks 8 through 28, no statistically significant differences in gout attack rates occurred between the allopurinol and febuxostat groups, although the study didn’t report specific attack rates for this period.

Both allopurinol and all doses of febuxostat reduced sUA to <6 mg/dL more effectively than placebo; more patients treated with febuxostat than allopurinol achieved a uric acid level of less than <6 mg/dL.

Another RCT of 762 mostly white, male patients (mean age 52 years) with gout and sUA >8 mg/dL—35% of whom had renal impairment, defined as creatinine clearance <80 mL/min/1.73m²—also concluded that febuxostat and allopurinol are equally effective in reducing gout attacks (incidence of gout flares during Weeks 9 to 52 was 64% with both febuxostat 80 mg and allopurinol 300 mg).² The percentage of patients with sUA <6 mg/dL at the last 3 monthly visits was 53% in the febuxostat 80 mg group compared with 21% in the allopurinol 300 mg group (P<.001; number needed to treat [NNT]=4]).

One significant limitation of both RCTs was the fixed dose of allopurinol (300 mg/d). US Food and Drug Administration-approved dosing for allopurinol allows for titration to a maximum of 800 mg/d to achieve serum uric acid <6 mg/dL.

Pegloticase is an intravenously administered, recombinant form of uricase, the natural enzyme that converts uric acid to more soluble allantoin. Two RCTs compared pegloticase with placebo in a total of 212 patients with gout (mean age 54 to 59 years; 70% to 90% male) intolerant or refractory to allopurinol (defined as baseline sUA of ≥8 mg/dL and at least one of the following: ≥3 self-reported gout flares during the previous 18 months, ≥1 tophi, or gouty arthropathy.

These trials found that treatment with 8 mg of pegloticase every 2 weeks for 6 months initially increased gout flares during Months 1 to 3 (75% with pegloticase, 53% with placebo; P=.02; number needed to harm [NNH]=5) but then decreased the incidence of acute gout attacks during Months 4 to 6 (41% with pegloticase, 67% with placebo; P=.007; NNT=4).3 In addition, pegloticase resulted in statistically significant improvements in QOL measured at the final visit using the Health Assessment Questionnaire (HAQ) pain scale, the HAQ-Disability Index, and the 36-item Short Form Health Survey.

Colchicine plus probenecid or allopurinol reduces gout attacks

One small, low-quality RCT (N=38) found that colchicine 0.5 mg administered 3 times daily effectively prevented gout attacks when administered concomitantly with probenecid initiated to lower urate (gout attacks per month in colchicine and placebo-treated patients, respectively, were 0.19±0.05 and 0.48±0.12; P<.05).⁴

Another RCT that compared allopurinol with and without colchicine showed that coadministration of colchicine 0.6 mg twice daily reduced gout attacks: 33% of patients treated with colchicine experienced a gout flare compared with 77% of placebo-treated patients (P=.008; NNT=3 over 6 months).⁵

We identified no RCTs that evaluated the uricosuric agent probenecid and no studies that assessed the use of nonsteroidal anti-inflammatory drugs (NSAIDs) to prevent recurrent gout attacks.

RECOMMENDATIONS

Eight weeks of treatment with either allopurinol or febuxostat reduces the frequency of gout attacks equally.The American College of Rheumatology (ACR) guidelines on managing gout recommend allopurinol or febuxostat as first-line pharmacologic urate-lowering therapy, with a goal of reducing sUA to <6 mg/dL. They recommend probenecid as an alternative if contraindications exist or the patient is intolerant to allopurinol and febuxostat.⁶ The guidelines note that allopurinol doses may exceed 300 mg/d, even in patients with chronic kidney disease.

The ACR recommends anti-inflammatory prophylaxis with colchicine or NSAIDs upon initiation of urate-lowering therapy. Anti-inflammatory prophylaxis should be continued as long as clinical evidence of continuing gout disease exists and until the sUA target has been acheived.7

EVIDENCE SUMMARY

A systematic review by the Agency for Healthcare Research and Quality of adult female outpatients with SUI examined the effectiveness of PFMT, electrical stimulation, magnetic stimulation, and vaginal cones compared with no active treatment or sham treatment to produce continence (90% to 100% symptom reduction) or improve symptoms (at least 50% patient-reported symptom reduction).¹ The TABLE summarizes the results.¹ Investigators also assessed improvement in patient-reported QOL.

Pelvic floor muscle training improves continence, quality of life

A meta-analysis of 10 RCTs demonstrated that PFMT produced continence more often than placebo, and a meta-analysis of 6 RCTs found that PFMT improved SUI symptoms.¹ PFMT regimens ranged in duration from 8 weeks to 6 months, including unsupervised treatment (8 to 12 repetitions, 3 to 10 times a day) and supervised treatment (as long as an hour, as often as 3 times a week).¹

Both unsupervised and supervised PFMT produced similar results. One RCT evaluating QOL measures found that PFMT improved activity and reduced psychological impact (number needed to treat [NNT]=1; 95% confidence interval [CI], 1-2).¹

A meta-analysis of 7 RCTs found that intravaginal electrical stimulation increased continence compared with sham treatment.1 A meta-analysis of 8 RCTs found that intravaginal electrical stimulation also improved SUI symptoms.¹ All of the trials used electrical stimulation at frequencies between 4 and 50 Hz for 15 to 20 minutes, 1 to 3 times daily for 4 to 15 weeks.

Pelvic floor muscle training increases urinary continence and improves symptoms of stress urinary incontinence and quality of life.

Percutaneous electrical stimulation improves symptoms

A meta-analysis of 3 RCTs found that percutaneous electrical stimulation improved SUI symptoms compared with no active treatment. Four RCTs found that electrical stimulation improved QOL, although a meta-analysis couldn’t be performed because of clinical heterogeneity.¹

A meta-analysis of 3 RCTs found that magnetic stimulation at frequencies of 10 to 18.5 Hz given over 1 to 8 weeks didn’t increase continence. A meta-analysis of an additional 3 RCTs concluded that magnetic stimulation improved continence, but the individual studies reported conflicting results and were heterogenous.¹

Two RCTs evaluating QOL scores found conflicting results. One study found a mean difference of 3.9 points on the 100-point Incontinence Quality of Life Questionnaire (95% CI, 2.08-5.72; minimal clinically important difference rated 2-5 points).¹

Vaginal cones are ineffective and not well-tolerated

Two RCTs found that vaginal cones didn’t improve continence or QOL compared with no treatment. Investigators reported high discontinuation rates and adverse effects with the cones, which weighed 20 to 70 g and were worn for 20 minutes a day for as long as 24 weeks.¹

RECOMMENDATIONS

The National Institute for Health and Care Excellence recommends PFMT comprising at least 8 contractions 3 times daily for at least 3 months as first-line therapy for women with SUI.² They don’t recommend electrical stimulation or intravaginal devices for women who can actively contract their pelvic floor muscles. The American College of Obstetricians and Gynecologists recommends PFMT as first-line therapy for women with SUI and states that PFMT is more effective than electrical stimulation or vaginal cones.³

EVIDENCE SUMMARY

A systematic review by the Agency for Healthcare Research and Quality of adult female outpatients with SUI examined the effectiveness of PFMT, electrical stimulation, magnetic stimulation, and vaginal cones compared with no active treatment or sham treatment to produce continence (90% to 100% symptom reduction) or improve symptoms (at least 50% patient-reported symptom reduction).¹ The TABLE summarizes the results.¹ Investigators also assessed improvement in patient-reported QOL.

Pelvic floor muscle training improves continence, quality of life

A meta-analysis of 10 RCTs demonstrated that PFMT produced continence more often than placebo, and a meta-analysis of 6 RCTs found that PFMT improved SUI symptoms.¹ PFMT regimens ranged in duration from 8 weeks to 6 months, including unsupervised treatment (8 to 12 repetitions, 3 to 10 times a day) and supervised treatment (as long as an hour, as often as 3 times a week).¹

Both unsupervised and supervised PFMT produced similar results. One RCT evaluating QOL measures found that PFMT improved activity and reduced psychological impact (number needed to treat [NNT]=1; 95% confidence interval [CI], 1-2).¹

A meta-analysis of 7 RCTs found that intravaginal electrical stimulation increased continence compared with sham treatment.1 A meta-analysis of 8 RCTs found that intravaginal electrical stimulation also improved SUI symptoms.¹ All of the trials used electrical stimulation at frequencies between 4 and 50 Hz for 15 to 20 minutes, 1 to 3 times daily for 4 to 15 weeks.

Pelvic floor muscle training increases urinary continence and improves symptoms of stress urinary incontinence and quality of life.

Percutaneous electrical stimulation improves symptoms

A meta-analysis of 3 RCTs found that percutaneous electrical stimulation improved SUI symptoms compared with no active treatment. Four RCTs found that electrical stimulation improved QOL, although a meta-analysis couldn’t be performed because of clinical heterogeneity.¹

A meta-analysis of 3 RCTs found that magnetic stimulation at frequencies of 10 to 18.5 Hz given over 1 to 8 weeks didn’t increase continence. A meta-analysis of an additional 3 RCTs concluded that magnetic stimulation improved continence, but the individual studies reported conflicting results and were heterogenous.¹

Two RCTs evaluating QOL scores found conflicting results. One study found a mean difference of 3.9 points on the 100-point Incontinence Quality of Life Questionnaire (95% CI, 2.08-5.72; minimal clinically important difference rated 2-5 points).¹

Vaginal cones are ineffective and not well-tolerated

Two RCTs found that vaginal cones didn’t improve continence or QOL compared with no treatment. Investigators reported high discontinuation rates and adverse effects with the cones, which weighed 20 to 70 g and were worn for 20 minutes a day for as long as 24 weeks.¹

RECOMMENDATIONS

The National Institute for Health and Care Excellence recommends PFMT comprising at least 8 contractions 3 times daily for at least 3 months as first-line therapy for women with SUI.² They don’t recommend electrical stimulation or intravaginal devices for women who can actively contract their pelvic floor muscles. The American College of Obstetricians and Gynecologists recommends PFMT as first-line therapy for women with SUI and states that PFMT is more effective than electrical stimulation or vaginal cones.³

EVIDENCE SUMMARY

A systematic review by the Agency for Healthcare Research and Quality of adult female outpatients with SUI examined the effectiveness of PFMT, electrical stimulation, magnetic stimulation, and vaginal cones compared with no active treatment or sham treatment to produce continence (90% to 100% symptom reduction) or improve symptoms (at least 50% patient-reported symptom reduction).¹ The TABLE summarizes the results.¹ Investigators also assessed improvement in patient-reported QOL.

Pelvic floor muscle training improves continence, quality of life

A meta-analysis of 10 RCTs demonstrated that PFMT produced continence more often than placebo, and a meta-analysis of 6 RCTs found that PFMT improved SUI symptoms.¹ PFMT regimens ranged in duration from 8 weeks to 6 months, including unsupervised treatment (8 to 12 repetitions, 3 to 10 times a day) and supervised treatment (as long as an hour, as often as 3 times a week).¹

Both unsupervised and supervised PFMT produced similar results. One RCT evaluating QOL measures found that PFMT improved activity and reduced psychological impact (number needed to treat [NNT]=1; 95% confidence interval [CI], 1-2).¹

A meta-analysis of 7 RCTs found that intravaginal electrical stimulation increased continence compared with sham treatment.1 A meta-analysis of 8 RCTs found that intravaginal electrical stimulation also improved SUI symptoms.¹ All of the trials used electrical stimulation at frequencies between 4 and 50 Hz for 15 to 20 minutes, 1 to 3 times daily for 4 to 15 weeks.

Pelvic floor muscle training increases urinary continence and improves symptoms of stress urinary incontinence and quality of life.

Percutaneous electrical stimulation improves symptoms

A meta-analysis of 3 RCTs found that percutaneous electrical stimulation improved SUI symptoms compared with no active treatment. Four RCTs found that electrical stimulation improved QOL, although a meta-analysis couldn’t be performed because of clinical heterogeneity.¹

A meta-analysis of 3 RCTs found that magnetic stimulation at frequencies of 10 to 18.5 Hz given over 1 to 8 weeks didn’t increase continence. A meta-analysis of an additional 3 RCTs concluded that magnetic stimulation improved continence, but the individual studies reported conflicting results and were heterogenous.¹

Two RCTs evaluating QOL scores found conflicting results. One study found a mean difference of 3.9 points on the 100-point Incontinence Quality of Life Questionnaire (95% CI, 2.08-5.72; minimal clinically important difference rated 2-5 points).¹

Vaginal cones are ineffective and not well-tolerated

Two RCTs found that vaginal cones didn’t improve continence or QOL compared with no treatment. Investigators reported high discontinuation rates and adverse effects with the cones, which weighed 20 to 70 g and were worn for 20 minutes a day for as long as 24 weeks.¹

RECOMMENDATIONS

The National Institute for Health and Care Excellence recommends PFMT comprising at least 8 contractions 3 times daily for at least 3 months as first-line therapy for women with SUI.² They don’t recommend electrical stimulation or intravaginal devices for women who can actively contract their pelvic floor muscles. The American College of Obstetricians and Gynecologists recommends PFMT as first-line therapy for women with SUI and states that PFMT is more effective than electrical stimulation or vaginal cones.³

EVIDENCE SUMMARY

The COMM—originally designed to detect recent aberrant drug-related behaviors in pain center patients—was validated by a cross-sectional study involving 238 primary care patients who had been prescribed an opioid within the previous 12 months.¹

The study authors defined aberrant drug-related behaviors as meeting the criteria for prescription drug use disorder in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). High COMM scores significantly predicted this diagnosis (P<.001). A COMM cutoff score >13 yielded a sensitivity of 77% and a specificity of 77% (positive predictive value=0.30; negative predictive value=0.96).

Development of the COMM. The authors of the COMM developed questions by expert consensus for use in a population of patients in a pain center. They established the validity of the questions by correlating COMM results from a cohort of pain center patients with 2 previously validated instruments: The Marlowe-Crowne Social Desirability Scale and the Aberrant Drug Behavior Index. They also tested COMM’s validity for monitoring changes in aberrant drug-related behaviors in a second cohort (sensitivity=94%; specificity=73%).² They later cross-validated COMM with another group of 226 patients treated at pain management clinics, achieving similar results.³

The ABC was developed based on literature review and validated against the PDUQ and clinician judgment of opioid misuse. Scores on the ABC differed significantly between patients who were discontinued from opioid therapy (based on urine toxicology, for example) and patients who weren’t (P=.021).⁴

The authors of the POMI determined sensitivity and specificity by comparing the POMI with DSM-IV diagnostic criteria for opiate addiction. One weakness of this index is that it is based on a small, homogenous sample.⁵

Items in the PDUQ were based on a literature review and extracts from the charts of patients with chronic pain.⁶

Additional reviews

Two systematic reviews of screening tools used to predict aberrant behaviors in pain center populations included several studies with methodologic limitations.^7,8

RECOMMENDATIONS

A guideline from the American Pain Society based on a systematic review concluded that the most predictive factor for aberrant drug-related behaviors is a personal or family history of drug or alcohol abuse.^9,10 In 2009, APS and American Academy of Pain Medicine developed guidelines to assist in selecting, risk-stratifying, and monitoring patients on chronic pain medication.^9,10 The American Society of Interventional Pain Physicians recommends evaluation of misuse risk, but considers screening tools an optional measure during initial assessment for opioid prescribing.¹¹

EVIDENCE SUMMARY

The COMM—originally designed to detect recent aberrant drug-related behaviors in pain center patients—was validated by a cross-sectional study involving 238 primary care patients who had been prescribed an opioid within the previous 12 months.¹

The study authors defined aberrant drug-related behaviors as meeting the criteria for prescription drug use disorder in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). High COMM scores significantly predicted this diagnosis (P<.001). A COMM cutoff score >13 yielded a sensitivity of 77% and a specificity of 77% (positive predictive value=0.30; negative predictive value=0.96).

Development of the COMM. The authors of the COMM developed questions by expert consensus for use in a population of patients in a pain center. They established the validity of the questions by correlating COMM results from a cohort of pain center patients with 2 previously validated instruments: The Marlowe-Crowne Social Desirability Scale and the Aberrant Drug Behavior Index. They also tested COMM’s validity for monitoring changes in aberrant drug-related behaviors in a second cohort (sensitivity=94%; specificity=73%).² They later cross-validated COMM with another group of 226 patients treated at pain management clinics, achieving similar results.³

The ABC was developed based on literature review and validated against the PDUQ and clinician judgment of opioid misuse. Scores on the ABC differed significantly between patients who were discontinued from opioid therapy (based on urine toxicology, for example) and patients who weren’t (P=.021).⁴

The authors of the POMI determined sensitivity and specificity by comparing the POMI with DSM-IV diagnostic criteria for opiate addiction. One weakness of this index is that it is based on a small, homogenous sample.⁵

Items in the PDUQ were based on a literature review and extracts from the charts of patients with chronic pain.⁶

Additional reviews

Two systematic reviews of screening tools used to predict aberrant behaviors in pain center populations included several studies with methodologic limitations.^7,8

RECOMMENDATIONS

A guideline from the American Pain Society based on a systematic review concluded that the most predictive factor for aberrant drug-related behaviors is a personal or family history of drug or alcohol abuse.^9,10 In 2009, APS and American Academy of Pain Medicine developed guidelines to assist in selecting, risk-stratifying, and monitoring patients on chronic pain medication.^9,10 The American Society of Interventional Pain Physicians recommends evaluation of misuse risk, but considers screening tools an optional measure during initial assessment for opioid prescribing.¹¹

EVIDENCE SUMMARY

The COMM—originally designed to detect recent aberrant drug-related behaviors in pain center patients—was validated by a cross-sectional study involving 238 primary care patients who had been prescribed an opioid within the previous 12 months.¹

The study authors defined aberrant drug-related behaviors as meeting the criteria for prescription drug use disorder in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). High COMM scores significantly predicted this diagnosis (P<.001). A COMM cutoff score >13 yielded a sensitivity of 77% and a specificity of 77% (positive predictive value=0.30; negative predictive value=0.96).

Development of the COMM. The authors of the COMM developed questions by expert consensus for use in a population of patients in a pain center. They established the validity of the questions by correlating COMM results from a cohort of pain center patients with 2 previously validated instruments: The Marlowe-Crowne Social Desirability Scale and the Aberrant Drug Behavior Index. They also tested COMM’s validity for monitoring changes in aberrant drug-related behaviors in a second cohort (sensitivity=94%; specificity=73%).² They later cross-validated COMM with another group of 226 patients treated at pain management clinics, achieving similar results.³

The ABC was developed based on literature review and validated against the PDUQ and clinician judgment of opioid misuse. Scores on the ABC differed significantly between patients who were discontinued from opioid therapy (based on urine toxicology, for example) and patients who weren’t (P=.021).⁴

The authors of the POMI determined sensitivity and specificity by comparing the POMI with DSM-IV diagnostic criteria for opiate addiction. One weakness of this index is that it is based on a small, homogenous sample.⁵

Items in the PDUQ were based on a literature review and extracts from the charts of patients with chronic pain.⁶

Additional reviews

Two systematic reviews of screening tools used to predict aberrant behaviors in pain center populations included several studies with methodologic limitations.^7,8

RECOMMENDATIONS

A guideline from the American Pain Society based on a systematic review concluded that the most predictive factor for aberrant drug-related behaviors is a personal or family history of drug or alcohol abuse.^9,10 In 2009, APS and American Academy of Pain Medicine developed guidelines to assist in selecting, risk-stratifying, and monitoring patients on chronic pain medication.^9,10 The American Society of Interventional Pain Physicians recommends evaluation of misuse risk, but considers screening tools an optional measure during initial assessment for opioid prescribing.¹¹

EVIDENCE SUMMARY

Troponin I and T proteins are specific to cardiac myocytes and, unlike CK-MB, aren’t elevated by damage to skeletal muscle.

Measuring troponin levels increased the number of patients diagnosed with AMI

A multinational prospective cohort study of patients with suspected ACS (N=10,719) found that measuring troponin levels in addition to CK-MB levels improved the diagnosis of AMI.¹ Investigators used elevation of any biomarker (CK, CK-MB, or troponin I or T) above the upper limit of normal as their diagnostic criterion. They found that measuring troponin increased the number of patients diagnosed with AMI by 10.4% over patients diagnosed using CK and CK-MB levels. Elevated troponin levels were associated with an inpatient mortality rate 1.5 to 3 times higher, regardless of the patient’s CK-MB status.

Troponin levels are more sensitive and specific than CK-MB

A prospective cohort study of 718 patients with suspected AMI calculated the area under curve (AUC) of the receiver operator curve—a measure of diagnostic accuracy in which an AUC value of 1 indicates 100% sensitivity and specificity—for troponin and CK-MB levels at initial presentation.² Two independent cardiologists reviewed all available medical records and made the final diagnosis. The AUCs for troponin levels ranged from 0.94 to 0.96 compared with 0.88 for CK-MB.

A prospective study of 1852 patients with suspected ACS from 3 trial populations evaluated the prognostic value of increased troponin levels vs CK-MB levels at initial presentation, compared with a reference group with normal troponin and CK-MB levels.³ Patients with isolated troponin elevation had an increased odds of MI or death at 24 hours (odds ratio [OR]=5.2; 95% confidence interval [CI], 2.2-11.9) and 30 days (OR=2.1; 95% CI, 1.4-3.0), whereas patients with isolated CK-MB elevations didn't. At 30 days, patients with isolated CK-MB elevations equaled the reference group odds for MI and death (OR=1.0; 95% CI, 0.6-1.6).

Serial troponin assessment boosts diagnostic sensitivity

A prospective cohort study found that serial measurements of troponin increased the diagnostic sensitivity for AMI.⁴ Investigators evaluated 1818 consecutive patients with new onset chest pain in 3 German chest-pain units with troponin levels on admission and at 3 and 6 hours later. The gold standard was diagnosis of AMI by 2 independent cardiologists. Troponin measurement produced an AUC of 0.96 at admission, increasing to 0.98 and 0.99 at 3 and 6 hours after admission, respectively.

RECOMMENDATIONS

The American College of Cardiology and American Heart Association recommend measuring biomarkers of cardiac injury in all patients who present with chest discomfort consistent with ACS.⁵ A cardiac-specific troponin is the preferred marker and should be measured in all patients. If troponin is not available, CK-MB is the best alternative. Cardiac biomarkers should be repeated 6 to 9 hours after presentation and, in patients with a high clinical suspicion of AMI, at 12 to 24 hours.^6,7

EVIDENCE SUMMARY

Troponin I and T proteins are specific to cardiac myocytes and, unlike CK-MB, aren’t elevated by damage to skeletal muscle.

Measuring troponin levels increased the number of patients diagnosed with AMI

A multinational prospective cohort study of patients with suspected ACS (N=10,719) found that measuring troponin levels in addition to CK-MB levels improved the diagnosis of AMI.¹ Investigators used elevation of any biomarker (CK, CK-MB, or troponin I or T) above the upper limit of normal as their diagnostic criterion. They found that measuring troponin increased the number of patients diagnosed with AMI by 10.4% over patients diagnosed using CK and CK-MB levels. Elevated troponin levels were associated with an inpatient mortality rate 1.5 to 3 times higher, regardless of the patient’s CK-MB status.

Troponin levels are more sensitive and specific than CK-MB

A prospective cohort study of 718 patients with suspected AMI calculated the area under curve (AUC) of the receiver operator curve—a measure of diagnostic accuracy in which an AUC value of 1 indicates 100% sensitivity and specificity—for troponin and CK-MB levels at initial presentation.² Two independent cardiologists reviewed all available medical records and made the final diagnosis. The AUCs for troponin levels ranged from 0.94 to 0.96 compared with 0.88 for CK-MB.

A prospective study of 1852 patients with suspected ACS from 3 trial populations evaluated the prognostic value of increased troponin levels vs CK-MB levels at initial presentation, compared with a reference group with normal troponin and CK-MB levels.³ Patients with isolated troponin elevation had an increased odds of MI or death at 24 hours (odds ratio [OR]=5.2; 95% confidence interval [CI], 2.2-11.9) and 30 days (OR=2.1; 95% CI, 1.4-3.0), whereas patients with isolated CK-MB elevations didn't. At 30 days, patients with isolated CK-MB elevations equaled the reference group odds for MI and death (OR=1.0; 95% CI, 0.6-1.6).

Serial troponin assessment boosts diagnostic sensitivity

A prospective cohort study found that serial measurements of troponin increased the diagnostic sensitivity for AMI.⁴ Investigators evaluated 1818 consecutive patients with new onset chest pain in 3 German chest-pain units with troponin levels on admission and at 3 and 6 hours later. The gold standard was diagnosis of AMI by 2 independent cardiologists. Troponin measurement produced an AUC of 0.96 at admission, increasing to 0.98 and 0.99 at 3 and 6 hours after admission, respectively.

RECOMMENDATIONS

The American College of Cardiology and American Heart Association recommend measuring biomarkers of cardiac injury in all patients who present with chest discomfort consistent with ACS.⁵ A cardiac-specific troponin is the preferred marker and should be measured in all patients. If troponin is not available, CK-MB is the best alternative. Cardiac biomarkers should be repeated 6 to 9 hours after presentation and, in patients with a high clinical suspicion of AMI, at 12 to 24 hours.^6,7

EVIDENCE SUMMARY

Troponin I and T proteins are specific to cardiac myocytes and, unlike CK-MB, aren’t elevated by damage to skeletal muscle.

Measuring troponin levels increased the number of patients diagnosed with AMI

A multinational prospective cohort study of patients with suspected ACS (N=10,719) found that measuring troponin levels in addition to CK-MB levels improved the diagnosis of AMI.¹ Investigators used elevation of any biomarker (CK, CK-MB, or troponin I or T) above the upper limit of normal as their diagnostic criterion. They found that measuring troponin increased the number of patients diagnosed with AMI by 10.4% over patients diagnosed using CK and CK-MB levels. Elevated troponin levels were associated with an inpatient mortality rate 1.5 to 3 times higher, regardless of the patient’s CK-MB status.

Troponin levels are more sensitive and specific than CK-MB

A prospective cohort study of 718 patients with suspected AMI calculated the area under curve (AUC) of the receiver operator curve—a measure of diagnostic accuracy in which an AUC value of 1 indicates 100% sensitivity and specificity—for troponin and CK-MB levels at initial presentation.² Two independent cardiologists reviewed all available medical records and made the final diagnosis. The AUCs for troponin levels ranged from 0.94 to 0.96 compared with 0.88 for CK-MB.

A prospective study of 1852 patients with suspected ACS from 3 trial populations evaluated the prognostic value of increased troponin levels vs CK-MB levels at initial presentation, compared with a reference group with normal troponin and CK-MB levels.³ Patients with isolated troponin elevation had an increased odds of MI or death at 24 hours (odds ratio [OR]=5.2; 95% confidence interval [CI], 2.2-11.9) and 30 days (OR=2.1; 95% CI, 1.4-3.0), whereas patients with isolated CK-MB elevations didn't. At 30 days, patients with isolated CK-MB elevations equaled the reference group odds for MI and death (OR=1.0; 95% CI, 0.6-1.6).

Serial troponin assessment boosts diagnostic sensitivity

A prospective cohort study found that serial measurements of troponin increased the diagnostic sensitivity for AMI.⁴ Investigators evaluated 1818 consecutive patients with new onset chest pain in 3 German chest-pain units with troponin levels on admission and at 3 and 6 hours later. The gold standard was diagnosis of AMI by 2 independent cardiologists. Troponin measurement produced an AUC of 0.96 at admission, increasing to 0.98 and 0.99 at 3 and 6 hours after admission, respectively.

RECOMMENDATIONS

The American College of Cardiology and American Heart Association recommend measuring biomarkers of cardiac injury in all patients who present with chest discomfort consistent with ACS.⁵ A cardiac-specific troponin is the preferred marker and should be measured in all patients. If troponin is not available, CK-MB is the best alternative. Cardiac biomarkers should be repeated 6 to 9 hours after presentation and, in patients with a high clinical suspicion of AMI, at 12 to 24 hours.^6,7

EVIDENCE SUMMARY

A systematic review and meta-analysis of the effectiveness of oral and topical nucleoside antiviral agents to prevent recurrent HSL in immunocompetent people found 11 RCTs with a total of 1250 patients that compared an active drug against placebo.¹ The medications were topical 5% acyclovir, topical 1% penciclovir, and oral acyclovir, valacyclovir, or famciclovir in various doses. The primary outcome was recurrence of herpes simplex virus type 1 lesions during the treatment period. The relative risk (RR) of recurrence ranged from 0.22 to 1.22. Pooled results found a benefit favoring antiviral agents (RR of recurrence=0.70; 95% confidence interval [CI], 0.55-0.89).

Seven of the trials looked at acyclovir (5 oral, 2 topical). A subgroup analysis demonstrated that oral acyclovir (800-1000 mg/d) was more effective than placebo (RR=0.51; 95% CI, 0.29-0.88), whereas topical acyclovir wasn’t. Oral valacyclovir (2 studies; 500 mg/d for 4 months) also reduced recurrence (RR=0.65; 95% CI, 0.43-0.91). The authors of the meta-analysis noted that although 9 studies favored the use of an antiviral drug, only 4 showed statistically significant differences when compared with placebo, and none of them had a low risk of bias. They concluded that the review supported using oral acyclovir and valacyclovir to prevent recurrent HSL.¹

Oral antivirals produce variable treatment results

Three RCTs evaluated oral antiviral medications against placebo to treat recurrent HSL, with mixed results. The largest RCT found that valacyclovir (2000 mg twice in 24 hours, with or without an additional 1000 mg twice in another 24 hours) modestly but significantly reduced both healing time and duration of pain (by 0.5-0.8 day).² The second RCT showed that a higher, single dose of famciclovir (1500 mg) reduced healing time (by 1.8 days) and pain duration (by 1.2 days) and that a smaller, repeated dose (750 mg twice in 24 hours) reduced healing time alone (by 2.2 days).³

The third RCT demonstrated that acyclovir (400 mg 5 times a day for 5 days) reduced pain duration (by 0.9 day) but didn’t shorten healing time. If acyclovir was started during the prodrome, it decreased the time to disappearance of the lesion’s hard crust (2.1 days’ less time; P=.03), but the clinical significance of this finding is unclear.⁴

Topical treatment shows modest success

Two trials demonstrated that topical acyclovir (5% cream) modestly improved healing time and duration of pain (by as much as half a day). Patients in the first trial (paired RCTs reported together) began treatment within an hour of prodromal symptoms or signs, applying the medication 5 times daily for 4 days.⁵

Topical acyclovir, penciclovir, and docosanol modestly decrease healing time and pain duration—typically by less than a day—and require multiple doses per day.Patients in the second trial used ME-609 cream (5% acyclovir plus 1% hydrocortisone), 5% acyclovir cream, or placebo, all applied 5 times daily for 5 days.⁶ Although the cream with acyclovir and hydrocortisone showed a slight benefit compared with placebo (lessening healing time by 0.8 day and pain duration by 1 day), it didn’t improve healing more than acyclovir alone. Other topical agents (penciclovir 1%; docosanol 10%) produced results similar to topical acyclovir.^7,8

RECOMMENDATIONS

No national guidelines on this topic exist. An online resource notes that most patients don’t require treatment for mild self-limited HSL.⁹ For patients with prodromal symptoms, the authors recommend episodic oral antiviral therapy. Patients who have no prodome but multiple painful or disfiguring lesions may choose to use chronic suppressive therapy with an oral antiviral drug.

EVIDENCE SUMMARY

A systematic review and meta-analysis of the effectiveness of oral and topical nucleoside antiviral agents to prevent recurrent HSL in immunocompetent people found 11 RCTs with a total of 1250 patients that compared an active drug against placebo.¹ The medications were topical 5% acyclovir, topical 1% penciclovir, and oral acyclovir, valacyclovir, or famciclovir in various doses. The primary outcome was recurrence of herpes simplex virus type 1 lesions during the treatment period. The relative risk (RR) of recurrence ranged from 0.22 to 1.22. Pooled results found a benefit favoring antiviral agents (RR of recurrence=0.70; 95% confidence interval [CI], 0.55-0.89).

Seven of the trials looked at acyclovir (5 oral, 2 topical). A subgroup analysis demonstrated that oral acyclovir (800-1000 mg/d) was more effective than placebo (RR=0.51; 95% CI, 0.29-0.88), whereas topical acyclovir wasn’t. Oral valacyclovir (2 studies; 500 mg/d for 4 months) also reduced recurrence (RR=0.65; 95% CI, 0.43-0.91). The authors of the meta-analysis noted that although 9 studies favored the use of an antiviral drug, only 4 showed statistically significant differences when compared with placebo, and none of them had a low risk of bias. They concluded that the review supported using oral acyclovir and valacyclovir to prevent recurrent HSL.¹

Oral antivirals produce variable treatment results

Three RCTs evaluated oral antiviral medications against placebo to treat recurrent HSL, with mixed results. The largest RCT found that valacyclovir (2000 mg twice in 24 hours, with or without an additional 1000 mg twice in another 24 hours) modestly but significantly reduced both healing time and duration of pain (by 0.5-0.8 day).² The second RCT showed that a higher, single dose of famciclovir (1500 mg) reduced healing time (by 1.8 days) and pain duration (by 1.2 days) and that a smaller, repeated dose (750 mg twice in 24 hours) reduced healing time alone (by 2.2 days).³

The third RCT demonstrated that acyclovir (400 mg 5 times a day for 5 days) reduced pain duration (by 0.9 day) but didn’t shorten healing time. If acyclovir was started during the prodrome, it decreased the time to disappearance of the lesion’s hard crust (2.1 days’ less time; P=.03), but the clinical significance of this finding is unclear.⁴

Topical treatment shows modest success

Two trials demonstrated that topical acyclovir (5% cream) modestly improved healing time and duration of pain (by as much as half a day). Patients in the first trial (paired RCTs reported together) began treatment within an hour of prodromal symptoms or signs, applying the medication 5 times daily for 4 days.⁵

Topical acyclovir, penciclovir, and docosanol modestly decrease healing time and pain duration—typically by less than a day—and require multiple doses per day.Patients in the second trial used ME-609 cream (5% acyclovir plus 1% hydrocortisone), 5% acyclovir cream, or placebo, all applied 5 times daily for 5 days.⁶ Although the cream with acyclovir and hydrocortisone showed a slight benefit compared with placebo (lessening healing time by 0.8 day and pain duration by 1 day), it didn’t improve healing more than acyclovir alone. Other topical agents (penciclovir 1%; docosanol 10%) produced results similar to topical acyclovir.^7,8

RECOMMENDATIONS

No national guidelines on this topic exist. An online resource notes that most patients don’t require treatment for mild self-limited HSL.⁹ For patients with prodromal symptoms, the authors recommend episodic oral antiviral therapy. Patients who have no prodome but multiple painful or disfiguring lesions may choose to use chronic suppressive therapy with an oral antiviral drug.

EVIDENCE SUMMARY

A systematic review and meta-analysis of the effectiveness of oral and topical nucleoside antiviral agents to prevent recurrent HSL in immunocompetent people found 11 RCTs with a total of 1250 patients that compared an active drug against placebo.¹ The medications were topical 5% acyclovir, topical 1% penciclovir, and oral acyclovir, valacyclovir, or famciclovir in various doses. The primary outcome was recurrence of herpes simplex virus type 1 lesions during the treatment period. The relative risk (RR) of recurrence ranged from 0.22 to 1.22. Pooled results found a benefit favoring antiviral agents (RR of recurrence=0.70; 95% confidence interval [CI], 0.55-0.89).

Seven of the trials looked at acyclovir (5 oral, 2 topical). A subgroup analysis demonstrated that oral acyclovir (800-1000 mg/d) was more effective than placebo (RR=0.51; 95% CI, 0.29-0.88), whereas topical acyclovir wasn’t. Oral valacyclovir (2 studies; 500 mg/d for 4 months) also reduced recurrence (RR=0.65; 95% CI, 0.43-0.91). The authors of the meta-analysis noted that although 9 studies favored the use of an antiviral drug, only 4 showed statistically significant differences when compared with placebo, and none of them had a low risk of bias. They concluded that the review supported using oral acyclovir and valacyclovir to prevent recurrent HSL.¹

Oral antivirals produce variable treatment results

Three RCTs evaluated oral antiviral medications against placebo to treat recurrent HSL, with mixed results. The largest RCT found that valacyclovir (2000 mg twice in 24 hours, with or without an additional 1000 mg twice in another 24 hours) modestly but significantly reduced both healing time and duration of pain (by 0.5-0.8 day).² The second RCT showed that a higher, single dose of famciclovir (1500 mg) reduced healing time (by 1.8 days) and pain duration (by 1.2 days) and that a smaller, repeated dose (750 mg twice in 24 hours) reduced healing time alone (by 2.2 days).³

The third RCT demonstrated that acyclovir (400 mg 5 times a day for 5 days) reduced pain duration (by 0.9 day) but didn’t shorten healing time. If acyclovir was started during the prodrome, it decreased the time to disappearance of the lesion’s hard crust (2.1 days’ less time; P=.03), but the clinical significance of this finding is unclear.⁴

Topical treatment shows modest success

Two trials demonstrated that topical acyclovir (5% cream) modestly improved healing time and duration of pain (by as much as half a day). Patients in the first trial (paired RCTs reported together) began treatment within an hour of prodromal symptoms or signs, applying the medication 5 times daily for 4 days.⁵

Topical acyclovir, penciclovir, and docosanol modestly decrease healing time and pain duration—typically by less than a day—and require multiple doses per day.Patients in the second trial used ME-609 cream (5% acyclovir plus 1% hydrocortisone), 5% acyclovir cream, or placebo, all applied 5 times daily for 5 days.⁶ Although the cream with acyclovir and hydrocortisone showed a slight benefit compared with placebo (lessening healing time by 0.8 day and pain duration by 1 day), it didn’t improve healing more than acyclovir alone. Other topical agents (penciclovir 1%; docosanol 10%) produced results similar to topical acyclovir.^7,8

RECOMMENDATIONS

No national guidelines on this topic exist. An online resource notes that most patients don’t require treatment for mild self-limited HSL.⁹ For patients with prodromal symptoms, the authors recommend episodic oral antiviral therapy. Patients who have no prodome but multiple painful or disfiguring lesions may choose to use chronic suppressive therapy with an oral antiviral drug.

EVIDENCE SUMMARY

Because no randomized controlled trials have evaluated the efficacy of UTI treatment in lactating women, recommendations are extrapolated from studies in other populations and case reports.

Antibiotics: Comparable and effective

A 2010 Cochrane review examined 21 good-quality randomized trials that compared the effectiveness of TMP-SMX, β-lactam antibiotics, nitrofurantoin, and fluoroquinolones for uncomplicated UTIs in 6016 women.¹ The authors found no significant differences in short-term symptom cure rates: all antibiotics were very effective. Seven studies reported mixed (clinical and bacteriologic) cure rates.

Symptom cure rates for patients followed for as long as 2 weeks ranged from 78% to 95%; longer-term (as long as 8 weeks) symptom cure rates ranged from 82% to 91%. The review suggested that TMP-SMX may be slightly more likely to cause a rash than other antibiotics.¹

Antibiotic concentrations in breast milk

In a case series, TMP/SMX, 160/800 mg, given to 50 lactating women 2 times (40 women) or 3 times (10 women) daily resulted in an average breast milk concentration of 2 μg/mL of TMP and 4.6 μg/mL of SMX, corresponding to respective doses of 0.3 and 0.7 mg/kg/d for infants taking 150 mL breast milk/kg/d.² The authors state that this dose is safe for infants without G6PD deficiency. The study included only women with UTIs or other infections requiring antibiotic treatment.

A case series of 4 lactating mothers who received a single 100-mg oral dose of nitrofurantoin found that peak breast milk concentration occurred 4 hours later and averaged 2.4 μg/mL (standard deviation=1.7-3.2 μg/mL).³ The authors calculated a mean concentration over 12 hours of 1.3 μg nitrofurantoin/mL breast milk. This level would correspond to an estimated dose of 0.2 mg/kg/d for an infant consuming 150 mL/kg/d of breast milk whose mother takes 100 mg nitrofurantoin twice daily, much lower than the recommended pediatric dose of 5 to 7 mg/kg/d.

Data from a case series and a case report suggest the amount of ciprofloxacin transferred to breastfed infants is low. In the case series, researchers gave 10 lactating women 3 oral doses of ciprofloxacin, 750 mg, at 12-hour intervals and then measured ciprofloxacin levels in breast milk.⁴ The highest levels occurred 2 hours after the third dose and averaged 3.79 μg/mL. Average levels fell gradually to 0.02 μg/mL 24 hours after the third dose. Assuming a milk intake of 150 mL/kg/d, a breastfed infant would consume approximately 0.3 mg/kg/d, much lower than the 10 to 40 mg/kg/d dose recommended for treating sick infants.

A case report of a woman who took oral ciprofloxacin 500 mg/d for 10 days noted a breast milk ciprofloxacin concentration of 0.98 mg/L at 10.7 hours after the last dose.⁵ Ofloxacin, norfloxacin, and levofloxacin have been associated with lower milk concentrations than ciprofloxacin.⁶

Adverse effects

In a cohort study of 838 women from a program for pregnant and lactating women exposed to drugs and other substances, 2 of 12 mothers taking TMP/SMX reported poor feeding in their infants.⁷

The same program received reports of infants with diarrhea from mothers taking amoxicillin (3 of 25 infants), nitrofurantoin (2 of 6 infants), and cephalexin (2 of 7 infants), but no reports of other adverse effects. Another study demonstrated that nitrofurantoin is actively transported into the mother’s milk, making hemolytic anemia a possibility in G6PD-deficient infants.³

Data from a case series and a case report suggest the amount of ciprofloxacin transferred to breastfed infants is low.Studies indicate that adverse effects of fluoroquinolones in children are similar to those in adults despite a contraindication in children because of reports of arthropathy in young animals. One case of pseudomembranous colitis in a breastfeeding infant and 2 cases of green teeth in neonates have been reported with ciprofloxacin use.^6,8,9

RECOMMENDATIONS

The Infectious Disease Society of America recommends nitrofurantoin, TMP/SMX, or fosfomycin for first-line treatment of uncomplicated UTIs in women, although fosfomycin appears to be inferior to other standard short-course antibiotics based on FDA data. Fluoroquinolones and β-lactams are recommended alternative treatments.¹⁰

The American Academy of Pediatrics’ Committee on Drugs says that TMP/SMX (unless G6PD deficiency is present), amoxicillin, nitrofurantoin, ciprofloxacin, and ofloxacin usually are compatible with breastfeeding.¹¹

EVIDENCE SUMMARY

Because no randomized controlled trials have evaluated the efficacy of UTI treatment in lactating women, recommendations are extrapolated from studies in other populations and case reports.

Antibiotics: Comparable and effective

A 2010 Cochrane review examined 21 good-quality randomized trials that compared the effectiveness of TMP-SMX, β-lactam antibiotics, nitrofurantoin, and fluoroquinolones for uncomplicated UTIs in 6016 women.¹ The authors found no significant differences in short-term symptom cure rates: all antibiotics were very effective. Seven studies reported mixed (clinical and bacteriologic) cure rates.

Symptom cure rates for patients followed for as long as 2 weeks ranged from 78% to 95%; longer-term (as long as 8 weeks) symptom cure rates ranged from 82% to 91%. The review suggested that TMP-SMX may be slightly more likely to cause a rash than other antibiotics.¹

Antibiotic concentrations in breast milk

In a case series, TMP/SMX, 160/800 mg, given to 50 lactating women 2 times (40 women) or 3 times (10 women) daily resulted in an average breast milk concentration of 2 μg/mL of TMP and 4.6 μg/mL of SMX, corresponding to respective doses of 0.3 and 0.7 mg/kg/d for infants taking 150 mL breast milk/kg/d.² The authors state that this dose is safe for infants without G6PD deficiency. The study included only women with UTIs or other infections requiring antibiotic treatment.

A case series of 4 lactating mothers who received a single 100-mg oral dose of nitrofurantoin found that peak breast milk concentration occurred 4 hours later and averaged 2.4 μg/mL (standard deviation=1.7-3.2 μg/mL).³ The authors calculated a mean concentration over 12 hours of 1.3 μg nitrofurantoin/mL breast milk. This level would correspond to an estimated dose of 0.2 mg/kg/d for an infant consuming 150 mL/kg/d of breast milk whose mother takes 100 mg nitrofurantoin twice daily, much lower than the recommended pediatric dose of 5 to 7 mg/kg/d.

Data from a case series and a case report suggest the amount of ciprofloxacin transferred to breastfed infants is low. In the case series, researchers gave 10 lactating women 3 oral doses of ciprofloxacin, 750 mg, at 12-hour intervals and then measured ciprofloxacin levels in breast milk.⁴ The highest levels occurred 2 hours after the third dose and averaged 3.79 μg/mL. Average levels fell gradually to 0.02 μg/mL 24 hours after the third dose. Assuming a milk intake of 150 mL/kg/d, a breastfed infant would consume approximately 0.3 mg/kg/d, much lower than the 10 to 40 mg/kg/d dose recommended for treating sick infants.

A case report of a woman who took oral ciprofloxacin 500 mg/d for 10 days noted a breast milk ciprofloxacin concentration of 0.98 mg/L at 10.7 hours after the last dose.⁵ Ofloxacin, norfloxacin, and levofloxacin have been associated with lower milk concentrations than ciprofloxacin.⁶

Adverse effects

In a cohort study of 838 women from a program for pregnant and lactating women exposed to drugs and other substances, 2 of 12 mothers taking TMP/SMX reported poor feeding in their infants.⁷

The same program received reports of infants with diarrhea from mothers taking amoxicillin (3 of 25 infants), nitrofurantoin (2 of 6 infants), and cephalexin (2 of 7 infants), but no reports of other adverse effects. Another study demonstrated that nitrofurantoin is actively transported into the mother’s milk, making hemolytic anemia a possibility in G6PD-deficient infants.³

Data from a case series and a case report suggest the amount of ciprofloxacin transferred to breastfed infants is low.Studies indicate that adverse effects of fluoroquinolones in children are similar to those in adults despite a contraindication in children because of reports of arthropathy in young animals. One case of pseudomembranous colitis in a breastfeeding infant and 2 cases of green teeth in neonates have been reported with ciprofloxacin use.^6,8,9

RECOMMENDATIONS

The Infectious Disease Society of America recommends nitrofurantoin, TMP/SMX, or fosfomycin for first-line treatment of uncomplicated UTIs in women, although fosfomycin appears to be inferior to other standard short-course antibiotics based on FDA data. Fluoroquinolones and β-lactams are recommended alternative treatments.¹⁰

The American Academy of Pediatrics’ Committee on Drugs says that TMP/SMX (unless G6PD deficiency is present), amoxicillin, nitrofurantoin, ciprofloxacin, and ofloxacin usually are compatible with breastfeeding.¹¹

EVIDENCE SUMMARY

Because no randomized controlled trials have evaluated the efficacy of UTI treatment in lactating women, recommendations are extrapolated from studies in other populations and case reports.

Antibiotics: Comparable and effective

A 2010 Cochrane review examined 21 good-quality randomized trials that compared the effectiveness of TMP-SMX, β-lactam antibiotics, nitrofurantoin, and fluoroquinolones for uncomplicated UTIs in 6016 women.¹ The authors found no significant differences in short-term symptom cure rates: all antibiotics were very effective. Seven studies reported mixed (clinical and bacteriologic) cure rates.

Symptom cure rates for patients followed for as long as 2 weeks ranged from 78% to 95%; longer-term (as long as 8 weeks) symptom cure rates ranged from 82% to 91%. The review suggested that TMP-SMX may be slightly more likely to cause a rash than other antibiotics.¹

Antibiotic concentrations in breast milk

In a case series, TMP/SMX, 160/800 mg, given to 50 lactating women 2 times (40 women) or 3 times (10 women) daily resulted in an average breast milk concentration of 2 μg/mL of TMP and 4.6 μg/mL of SMX, corresponding to respective doses of 0.3 and 0.7 mg/kg/d for infants taking 150 mL breast milk/kg/d.² The authors state that this dose is safe for infants without G6PD deficiency. The study included only women with UTIs or other infections requiring antibiotic treatment.

A case series of 4 lactating mothers who received a single 100-mg oral dose of nitrofurantoin found that peak breast milk concentration occurred 4 hours later and averaged 2.4 μg/mL (standard deviation=1.7-3.2 μg/mL).³ The authors calculated a mean concentration over 12 hours of 1.3 μg nitrofurantoin/mL breast milk. This level would correspond to an estimated dose of 0.2 mg/kg/d for an infant consuming 150 mL/kg/d of breast milk whose mother takes 100 mg nitrofurantoin twice daily, much lower than the recommended pediatric dose of 5 to 7 mg/kg/d.

Data from a case series and a case report suggest the amount of ciprofloxacin transferred to breastfed infants is low. In the case series, researchers gave 10 lactating women 3 oral doses of ciprofloxacin, 750 mg, at 12-hour intervals and then measured ciprofloxacin levels in breast milk.⁴ The highest levels occurred 2 hours after the third dose and averaged 3.79 μg/mL. Average levels fell gradually to 0.02 μg/mL 24 hours after the third dose. Assuming a milk intake of 150 mL/kg/d, a breastfed infant would consume approximately 0.3 mg/kg/d, much lower than the 10 to 40 mg/kg/d dose recommended for treating sick infants.

A case report of a woman who took oral ciprofloxacin 500 mg/d for 10 days noted a breast milk ciprofloxacin concentration of 0.98 mg/L at 10.7 hours after the last dose.⁵ Ofloxacin, norfloxacin, and levofloxacin have been associated with lower milk concentrations than ciprofloxacin.⁶

Adverse effects

In a cohort study of 838 women from a program for pregnant and lactating women exposed to drugs and other substances, 2 of 12 mothers taking TMP/SMX reported poor feeding in their infants.⁷

The same program received reports of infants with diarrhea from mothers taking amoxicillin (3 of 25 infants), nitrofurantoin (2 of 6 infants), and cephalexin (2 of 7 infants), but no reports of other adverse effects. Another study demonstrated that nitrofurantoin is actively transported into the mother’s milk, making hemolytic anemia a possibility in G6PD-deficient infants.³

Data from a case series and a case report suggest the amount of ciprofloxacin transferred to breastfed infants is low.Studies indicate that adverse effects of fluoroquinolones in children are similar to those in adults despite a contraindication in children because of reports of arthropathy in young animals. One case of pseudomembranous colitis in a breastfeeding infant and 2 cases of green teeth in neonates have been reported with ciprofloxacin use.^6,8,9

RECOMMENDATIONS

The Infectious Disease Society of America recommends nitrofurantoin, TMP/SMX, or fosfomycin for first-line treatment of uncomplicated UTIs in women, although fosfomycin appears to be inferior to other standard short-course antibiotics based on FDA data. Fluoroquinolones and β-lactams are recommended alternative treatments.¹⁰

The American Academy of Pediatrics’ Committee on Drugs says that TMP/SMX (unless G6PD deficiency is present), amoxicillin, nitrofurantoin, ciprofloxacin, and ofloxacin usually are compatible with breastfeeding.¹¹

EVIDENCE SUMMARY

This summary updates the 2007 Clinical Inquiry, “What is the best approach to goiter for euthyroid patients?”¹

Initial evaluation of palpable goiter with a normal thyrotropin

In the United States, MNG is generally nonendemic and unrelated to iodine deficiency, as distinguished from endemic goiter caused by iodine deficiency in other parts of the world.

Our structured search of the literature found no randomized trials or prospective cohort studies comparing diagnostic approaches. The American Association of Clinical Endocrinologists’ (AACE) 2010 guidelines and American Thyroid Association (ATA) guidelines recommend ultrasound for all MNG.^2,3 The AACE guidelines recommend thyroid scintigraphy when clinicians suspect retrosternal MNG.²

Ultrasound findings can change management, avoid biopsy

In a retrospective analysis of 223 patients with nodular thyroid disease, thyroid ultrasound altered clinical management of 63% of patients with abnormal thyroid exams.⁴ A single center retrospective cohort study of 650 FNA biopsies identified 4 morphologic patterns on ultrasound that predicted benign cytology with 100% specificity. The authors concluded that using ultrasound pattern to determine which patients require FNA could have obviated more than 60% of thyroid biopsies.⁵

Thyroid hormone suppression therapy risks hyperthyroidis

A systematic review of 9 RCTs of 18-month or shorter duration found that thyroid hormone suppression therapy reduced benign thyroid nodule volume (relative risk=1.88 compared with placebo or no treatment; 95% confidence interval [CI], 1.18-3.01; P=.008). The number needed to treat was 8 to reduce volume by >50% (risk difference=0.13; 95% CI, 0.06-0.19; P=.0003).⁶ However, thyroid hormone suppression therapy risks inducing hyperthyroidism and is not routinely recommended by the AACE or the ATA.^2,3

Thyroidectomy is the definitive therapy for MNG. A narrative review of 15 mostly retrospective cohort studies demonstrated MNG recurrence rates of 0% to 0.3% after total thyroidectomy, with follow-up intervals of 4.8 to 30 years.⁷

AACE consensus opinion recommends thyroidectomy for compressive symptoms, progressive growth, or when ultrasound or FNA results indicate thyroid cancer.²

A retrospective cohort study of 462 thyroidectomies for MNG found incidental thyroid carcinomas in 8.9% (41 patients). Risk factors included neck irradiation (odds ratio [OR]=21.64; 95% CI, 3.28-143), parenchymal calcifications on imaging (OR=2.30; 95% CI, 0.85-6.23), and family history of thyroid disease (OR=8.2; 95% CI, 2.15-29.87). Living in a goiter-endemic area was protective (OR=0.24; 95% CI, 0.07-0.83).⁸

Experts recommend ultrasound evaluation of nontoxic multinodular goiters followed by fine-needle aspiration of suspicious nodules.

Follow-up of patients with initial benign evaluation

Consensus opinion regarding follow-up of MNG is based on observational studies of the natural history of the condition. Benign MNG rarely progresses to malignancy. A review of 6 cohort studies, including 1265 patients with untreated nontoxic MNG who were followed for 60 to 130 months from 1990 to 2007, yielded an annual incidence range of 1.3 to 3.7 new cases of thyroid carcinoma per 1000 patients.⁹

Some goiters are more likely to enlarge. A retrospective cohort study of 488 patients treated surgically for MNG identified risk factors for enlargement: African American (OR=3.3; 95% CI, 2.0-5.4), age >40 years (OR=2.1; 95% CI, 1.2-3.8), and body mass index >30 (OR=2.5; 95% CI, 1.5-4.0).¹⁰

RECOMMENDATIONS

The AACE and the ATA recommend that patients with MNG with benign nodules have a repeat examination, TSH, and ultrasound in 6 to 18 months. Follow-up of stable nodules can then be done in 3 to 5 years.

An enlarging nodule requires repeat FNA.² If palpation or ultrasound reveal evidence of nodule growth (more than a 50% change in volume or a 20% increase in at least 2 nodule dimensions, with a minimal increase of 2 mm in solid nodules or the solid portion of mixed cystic-solid nodules), the AACE and ATA recommend FNA, preferably with ultrasound guidance.³ Low TSH suggests autonomous nodules and the ATA recommends radionuclide scanning with FNA of hypofunctioning nodules with suspicious US features.³

EVIDENCE SUMMARY

This summary updates the 2007 Clinical Inquiry, “What is the best approach to goiter for euthyroid patients?”¹

Initial evaluation of palpable goiter with a normal thyrotropin

In the United States, MNG is generally nonendemic and unrelated to iodine deficiency, as distinguished from endemic goiter caused by iodine deficiency in other parts of the world.

Our structured search of the literature found no randomized trials or prospective cohort studies comparing diagnostic approaches. The American Association of Clinical Endocrinologists’ (AACE) 2010 guidelines and American Thyroid Association (ATA) guidelines recommend ultrasound for all MNG.^2,3 The AACE guidelines recommend thyroid scintigraphy when clinicians suspect retrosternal MNG.²

Ultrasound findings can change management, avoid biopsy

In a retrospective analysis of 223 patients with nodular thyroid disease, thyroid ultrasound altered clinical management of 63% of patients with abnormal thyroid exams.⁴ A single center retrospective cohort study of 650 FNA biopsies identified 4 morphologic patterns on ultrasound that predicted benign cytology with 100% specificity. The authors concluded that using ultrasound pattern to determine which patients require FNA could have obviated more than 60% of thyroid biopsies.⁵

Thyroid hormone suppression therapy risks hyperthyroidis

A systematic review of 9 RCTs of 18-month or shorter duration found that thyroid hormone suppression therapy reduced benign thyroid nodule volume (relative risk=1.88 compared with placebo or no treatment; 95% confidence interval [CI], 1.18-3.01; P=.008). The number needed to treat was 8 to reduce volume by >50% (risk difference=0.13; 95% CI, 0.06-0.19; P=.0003).⁶ However, thyroid hormone suppression therapy risks inducing hyperthyroidism and is not routinely recommended by the AACE or the ATA.^2,3

Thyroidectomy is the definitive therapy for MNG. A narrative review of 15 mostly retrospective cohort studies demonstrated MNG recurrence rates of 0% to 0.3% after total thyroidectomy, with follow-up intervals of 4.8 to 30 years.⁷

AACE consensus opinion recommends thyroidectomy for compressive symptoms, progressive growth, or when ultrasound or FNA results indicate thyroid cancer.²

A retrospective cohort study of 462 thyroidectomies for MNG found incidental thyroid carcinomas in 8.9% (41 patients). Risk factors included neck irradiation (odds ratio [OR]=21.64; 95% CI, 3.28-143), parenchymal calcifications on imaging (OR=2.30; 95% CI, 0.85-6.23), and family history of thyroid disease (OR=8.2; 95% CI, 2.15-29.87). Living in a goiter-endemic area was protective (OR=0.24; 95% CI, 0.07-0.83).⁸

Experts recommend ultrasound evaluation of nontoxic multinodular goiters followed by fine-needle aspiration of suspicious nodules.

Follow-up of patients with initial benign evaluation

Consensus opinion regarding follow-up of MNG is based on observational studies of the natural history of the condition. Benign MNG rarely progresses to malignancy. A review of 6 cohort studies, including 1265 patients with untreated nontoxic MNG who were followed for 60 to 130 months from 1990 to 2007, yielded an annual incidence range of 1.3 to 3.7 new cases of thyroid carcinoma per 1000 patients.⁹

Some goiters are more likely to enlarge. A retrospective cohort study of 488 patients treated surgically for MNG identified risk factors for enlargement: African American (OR=3.3; 95% CI, 2.0-5.4), age >40 years (OR=2.1; 95% CI, 1.2-3.8), and body mass index >30 (OR=2.5; 95% CI, 1.5-4.0).¹⁰

RECOMMENDATIONS

The AACE and the ATA recommend that patients with MNG with benign nodules have a repeat examination, TSH, and ultrasound in 6 to 18 months. Follow-up of stable nodules can then be done in 3 to 5 years.

An enlarging nodule requires repeat FNA.² If palpation or ultrasound reveal evidence of nodule growth (more than a 50% change in volume or a 20% increase in at least 2 nodule dimensions, with a minimal increase of 2 mm in solid nodules or the solid portion of mixed cystic-solid nodules), the AACE and ATA recommend FNA, preferably with ultrasound guidance.³ Low TSH suggests autonomous nodules and the ATA recommends radionuclide scanning with FNA of hypofunctioning nodules with suspicious US features.³

EVIDENCE SUMMARY

This summary updates the 2007 Clinical Inquiry, “What is the best approach to goiter for euthyroid patients?”¹

Initial evaluation of palpable goiter with a normal thyrotropin

In the United States, MNG is generally nonendemic and unrelated to iodine deficiency, as distinguished from endemic goiter caused by iodine deficiency in other parts of the world.

Our structured search of the literature found no randomized trials or prospective cohort studies comparing diagnostic approaches. The American Association of Clinical Endocrinologists’ (AACE) 2010 guidelines and American Thyroid Association (ATA) guidelines recommend ultrasound for all MNG.^2,3 The AACE guidelines recommend thyroid scintigraphy when clinicians suspect retrosternal MNG.²

Ultrasound findings can change management, avoid biopsy

In a retrospective analysis of 223 patients with nodular thyroid disease, thyroid ultrasound altered clinical management of 63% of patients with abnormal thyroid exams.⁴ A single center retrospective cohort study of 650 FNA biopsies identified 4 morphologic patterns on ultrasound that predicted benign cytology with 100% specificity. The authors concluded that using ultrasound pattern to determine which patients require FNA could have obviated more than 60% of thyroid biopsies.⁵

Thyroid hormone suppression therapy risks hyperthyroidis

A systematic review of 9 RCTs of 18-month or shorter duration found that thyroid hormone suppression therapy reduced benign thyroid nodule volume (relative risk=1.88 compared with placebo or no treatment; 95% confidence interval [CI], 1.18-3.01; P=.008). The number needed to treat was 8 to reduce volume by >50% (risk difference=0.13; 95% CI, 0.06-0.19; P=.0003).⁶ However, thyroid hormone suppression therapy risks inducing hyperthyroidism and is not routinely recommended by the AACE or the ATA.^2,3

Thyroidectomy is the definitive therapy for MNG. A narrative review of 15 mostly retrospective cohort studies demonstrated MNG recurrence rates of 0% to 0.3% after total thyroidectomy, with follow-up intervals of 4.8 to 30 years.⁷

AACE consensus opinion recommends thyroidectomy for compressive symptoms, progressive growth, or when ultrasound or FNA results indicate thyroid cancer.²

A retrospective cohort study of 462 thyroidectomies for MNG found incidental thyroid carcinomas in 8.9% (41 patients). Risk factors included neck irradiation (odds ratio [OR]=21.64; 95% CI, 3.28-143), parenchymal calcifications on imaging (OR=2.30; 95% CI, 0.85-6.23), and family history of thyroid disease (OR=8.2; 95% CI, 2.15-29.87). Living in a goiter-endemic area was protective (OR=0.24; 95% CI, 0.07-0.83).⁸

Experts recommend ultrasound evaluation of nontoxic multinodular goiters followed by fine-needle aspiration of suspicious nodules.

Follow-up of patients with initial benign evaluation

Consensus opinion regarding follow-up of MNG is based on observational studies of the natural history of the condition. Benign MNG rarely progresses to malignancy. A review of 6 cohort studies, including 1265 patients with untreated nontoxic MNG who were followed for 60 to 130 months from 1990 to 2007, yielded an annual incidence range of 1.3 to 3.7 new cases of thyroid carcinoma per 1000 patients.⁹

Some goiters are more likely to enlarge. A retrospective cohort study of 488 patients treated surgically for MNG identified risk factors for enlargement: African American (OR=3.3; 95% CI, 2.0-5.4), age >40 years (OR=2.1; 95% CI, 1.2-3.8), and body mass index >30 (OR=2.5; 95% CI, 1.5-4.0).¹⁰

RECOMMENDATIONS

The AACE and the ATA recommend that patients with MNG with benign nodules have a repeat examination, TSH, and ultrasound in 6 to 18 months. Follow-up of stable nodules can then be done in 3 to 5 years.

An enlarging nodule requires repeat FNA.² If palpation or ultrasound reveal evidence of nodule growth (more than a 50% change in volume or a 20% increase in at least 2 nodule dimensions, with a minimal increase of 2 mm in solid nodules or the solid portion of mixed cystic-solid nodules), the AACE and ATA recommend FNA, preferably with ultrasound guidance.³ Low TSH suggests autonomous nodules and the ATA recommends radionuclide scanning with FNA of hypofunctioning nodules with suspicious US features.³