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How should you evaluate a toddler for speech delay?
USE A BRIEF SCREENING TOOL to assess children for speech and language delay at every preventive visit. If a delay in speech is identified, evaluate the child for potentially treatable causes, starting with a history and physical examination and a formal audiogram. Additional tests and referral to appropriate specialists may be indicated (strength of recommendation [SOR]: C, expert opinion).
Speech and language therapy improves phonological delays and vocabulary difficulties in young children (SOR: A, systematic review of randomized controlled trials [RCTs]). However, no studies have evaluated long-term outcomes or looked for adverse effects from speech and language screening or interventions.
Evidence summary
Although no studies identify the optimal age or frequency of screening,1 the American Academy of Pediatrics (AAP) recommends surveillance for developmental delays (including speech and language delay [SLD]) at every preventive visit and additional developmental screening at 9, 18, 24, and 30 months.2
No single standardized tool exists to screen for SLDs; no research compares the tools against each other or offers clear evidence of how sensitive they are.1 Commonly used brief screening tools include Ages and Stages Parent Questionnaire (ASQ) (1-66 months of age), Denver Developmental Screen II (1-66 months), Early Language Milestone Scale (1-36 months), Clinical Adaptive Test/ Clinical Linguistic and Auditory Milestone Scale (<24 months), Infant Developmental Inventory and Child Development Review (1-66 months), and the Fluharty Preschool Speech and Language Screening Tests (3-5 years).
When a child screens positive for speech and language delay
When an SLD is recognized, experts recommend a history and physical examination to evaluate for common causes (TABLE). A detailed history should focus on family, social, and environmental aspects affecting speech. A comprehensive physical examination should evaluate the child’s interaction with the examiner and family members, pronunciation of sounds and words, and include a careful examination of the face, external ears and tympanic membranes, nose, palate, teeth, tongue, and neck.3,4
Experts recommend full audiologic assessment and vision testing for all children with SLD and an electroencephalogram or chromosomal studies if appropriate. When no cause for the SLD is found, experts recommend consulting a speech pathologist. Consultation with an audiologist, psychologist, neurologist, occupational therapist, or social worker also may be helpful.1-4
TABLE
Common causes of speech and language delays
| Autism |
| Bilingualism |
| Cerebral palsy |
| Elective mutism |
| Expressive language disorder (developmental expressive aphasia) |
| Hearing loss |
| Maturation delay (developmental language delay) |
| Mental retardation |
| Psychosocial deprivation |
| Receptive aphasia |
| Source: Leung A, et al. Am Fam Physician. 1999.4 |
How effective are speech and language interventions?
A systematic review of 14 RCTs evaluated speech and language therapy interventions ranging from 3 to 6 months’ duration in pre-school children. Investigators reported significant improvements in speech and language outcomes, including articulation, phonation and syntax, and expressive and receptive language with the interventions. Individual studies were limited by small size, heterogeneity, and varied measures of short-term outcomes.1
A Cochrane meta-analysis of 25 RCTs (N=1539 children, of whom 986 were <5 years) found that speech and language therapy produced similar improvements for preschool and elementary school children. Therapy improved phonological delays significantly (standard mean difference [SMD]=0.44; 95% confidence interval [CI], 0.01-0.86), and vocabulary difficulties even more (SMD=0.89; 95% CI, 0.21-1.56). However, in this review, therapy didn’t significantly affect receptive speech difficulties (SMD=?0.04; 95% CI, ?0.64 to 0.56).
The analysis didn’t evaluate whether specific age groups would respond better to therapy.5 No studies evaluated long-term effectiveness or possible harms associated with screening or intervention.4
Recommendations
The AAP Council on Children with Disabilities, Section on Developmental Behavioral Pediatrics recommends general developmental surveillance at every well-child visit for children from birth through 3 years of age and more formal screening tests at the 9-, 18-, and 30-month visits. The AAP doesn’t recommend a specific screening test, however.2
The US Preventive Services Task Force found insufficient evidence that brief formal screening instruments accurately identify pre-school children who would benefit from further evaluation and intervention, but found fair evidence that interventions improve speech in the short term.6
1. Nelson HD, Nygren P, Walker M, et al. Screening for speech and language delay in preschool children: systematic evidence review for the US Preventive Services Task Force. Pediatrics. 2006;117:e298-e319.
2. Council on Children with Disabilities, Section on Developmental Behavioral Pediatrics; Bright Futures Steering Committee; Medical Home Initiatives for Children with Special Needs Project Advisory Committee. Identifying infants and young children with developmental disorders in the medical home: an algorithm for developmental surveillance and screening. Pediatrics. 2006;118:405-420.
3. Feldman HM. Evaluation and management of language and speech disorders in preschool children. Pediatr Rev. 2005;26:131-142.
4. Leung A, Kao CP. Evaluation and management of the child with speech delay. Am Fam Physician. 1999;59:3121-3128, 3135.
5. Law J, Garrett Z, Nye C. Speech and language therapy interventions for children with primary speech and language delay or disorder. Cochrane Database Syst Rev. 2003;(3):CD004110.-
6. US Preventive Services Task Force. Screening for speech and language delay in preschool children: recommendation statement. Pediatrics. 2006;117:497-501.
USE A BRIEF SCREENING TOOL to assess children for speech and language delay at every preventive visit. If a delay in speech is identified, evaluate the child for potentially treatable causes, starting with a history and physical examination and a formal audiogram. Additional tests and referral to appropriate specialists may be indicated (strength of recommendation [SOR]: C, expert opinion).
Speech and language therapy improves phonological delays and vocabulary difficulties in young children (SOR: A, systematic review of randomized controlled trials [RCTs]). However, no studies have evaluated long-term outcomes or looked for adverse effects from speech and language screening or interventions.
Evidence summary
Although no studies identify the optimal age or frequency of screening,1 the American Academy of Pediatrics (AAP) recommends surveillance for developmental delays (including speech and language delay [SLD]) at every preventive visit and additional developmental screening at 9, 18, 24, and 30 months.2
No single standardized tool exists to screen for SLDs; no research compares the tools against each other or offers clear evidence of how sensitive they are.1 Commonly used brief screening tools include Ages and Stages Parent Questionnaire (ASQ) (1-66 months of age), Denver Developmental Screen II (1-66 months), Early Language Milestone Scale (1-36 months), Clinical Adaptive Test/ Clinical Linguistic and Auditory Milestone Scale (<24 months), Infant Developmental Inventory and Child Development Review (1-66 months), and the Fluharty Preschool Speech and Language Screening Tests (3-5 years).
When a child screens positive for speech and language delay
When an SLD is recognized, experts recommend a history and physical examination to evaluate for common causes (TABLE). A detailed history should focus on family, social, and environmental aspects affecting speech. A comprehensive physical examination should evaluate the child’s interaction with the examiner and family members, pronunciation of sounds and words, and include a careful examination of the face, external ears and tympanic membranes, nose, palate, teeth, tongue, and neck.3,4
Experts recommend full audiologic assessment and vision testing for all children with SLD and an electroencephalogram or chromosomal studies if appropriate. When no cause for the SLD is found, experts recommend consulting a speech pathologist. Consultation with an audiologist, psychologist, neurologist, occupational therapist, or social worker also may be helpful.1-4
TABLE
Common causes of speech and language delays
| Autism |
| Bilingualism |
| Cerebral palsy |
| Elective mutism |
| Expressive language disorder (developmental expressive aphasia) |
| Hearing loss |
| Maturation delay (developmental language delay) |
| Mental retardation |
| Psychosocial deprivation |
| Receptive aphasia |
| Source: Leung A, et al. Am Fam Physician. 1999.4 |
How effective are speech and language interventions?
A systematic review of 14 RCTs evaluated speech and language therapy interventions ranging from 3 to 6 months’ duration in pre-school children. Investigators reported significant improvements in speech and language outcomes, including articulation, phonation and syntax, and expressive and receptive language with the interventions. Individual studies were limited by small size, heterogeneity, and varied measures of short-term outcomes.1
A Cochrane meta-analysis of 25 RCTs (N=1539 children, of whom 986 were <5 years) found that speech and language therapy produced similar improvements for preschool and elementary school children. Therapy improved phonological delays significantly (standard mean difference [SMD]=0.44; 95% confidence interval [CI], 0.01-0.86), and vocabulary difficulties even more (SMD=0.89; 95% CI, 0.21-1.56). However, in this review, therapy didn’t significantly affect receptive speech difficulties (SMD=?0.04; 95% CI, ?0.64 to 0.56).
The analysis didn’t evaluate whether specific age groups would respond better to therapy.5 No studies evaluated long-term effectiveness or possible harms associated with screening or intervention.4
Recommendations
The AAP Council on Children with Disabilities, Section on Developmental Behavioral Pediatrics recommends general developmental surveillance at every well-child visit for children from birth through 3 years of age and more formal screening tests at the 9-, 18-, and 30-month visits. The AAP doesn’t recommend a specific screening test, however.2
The US Preventive Services Task Force found insufficient evidence that brief formal screening instruments accurately identify pre-school children who would benefit from further evaluation and intervention, but found fair evidence that interventions improve speech in the short term.6
USE A BRIEF SCREENING TOOL to assess children for speech and language delay at every preventive visit. If a delay in speech is identified, evaluate the child for potentially treatable causes, starting with a history and physical examination and a formal audiogram. Additional tests and referral to appropriate specialists may be indicated (strength of recommendation [SOR]: C, expert opinion).
Speech and language therapy improves phonological delays and vocabulary difficulties in young children (SOR: A, systematic review of randomized controlled trials [RCTs]). However, no studies have evaluated long-term outcomes or looked for adverse effects from speech and language screening or interventions.
Evidence summary
Although no studies identify the optimal age or frequency of screening,1 the American Academy of Pediatrics (AAP) recommends surveillance for developmental delays (including speech and language delay [SLD]) at every preventive visit and additional developmental screening at 9, 18, 24, and 30 months.2
No single standardized tool exists to screen for SLDs; no research compares the tools against each other or offers clear evidence of how sensitive they are.1 Commonly used brief screening tools include Ages and Stages Parent Questionnaire (ASQ) (1-66 months of age), Denver Developmental Screen II (1-66 months), Early Language Milestone Scale (1-36 months), Clinical Adaptive Test/ Clinical Linguistic and Auditory Milestone Scale (<24 months), Infant Developmental Inventory and Child Development Review (1-66 months), and the Fluharty Preschool Speech and Language Screening Tests (3-5 years).
When a child screens positive for speech and language delay
When an SLD is recognized, experts recommend a history and physical examination to evaluate for common causes (TABLE). A detailed history should focus on family, social, and environmental aspects affecting speech. A comprehensive physical examination should evaluate the child’s interaction with the examiner and family members, pronunciation of sounds and words, and include a careful examination of the face, external ears and tympanic membranes, nose, palate, teeth, tongue, and neck.3,4
Experts recommend full audiologic assessment and vision testing for all children with SLD and an electroencephalogram or chromosomal studies if appropriate. When no cause for the SLD is found, experts recommend consulting a speech pathologist. Consultation with an audiologist, psychologist, neurologist, occupational therapist, or social worker also may be helpful.1-4
TABLE
Common causes of speech and language delays
| Autism |
| Bilingualism |
| Cerebral palsy |
| Elective mutism |
| Expressive language disorder (developmental expressive aphasia) |
| Hearing loss |
| Maturation delay (developmental language delay) |
| Mental retardation |
| Psychosocial deprivation |
| Receptive aphasia |
| Source: Leung A, et al. Am Fam Physician. 1999.4 |
How effective are speech and language interventions?
A systematic review of 14 RCTs evaluated speech and language therapy interventions ranging from 3 to 6 months’ duration in pre-school children. Investigators reported significant improvements in speech and language outcomes, including articulation, phonation and syntax, and expressive and receptive language with the interventions. Individual studies were limited by small size, heterogeneity, and varied measures of short-term outcomes.1
A Cochrane meta-analysis of 25 RCTs (N=1539 children, of whom 986 were <5 years) found that speech and language therapy produced similar improvements for preschool and elementary school children. Therapy improved phonological delays significantly (standard mean difference [SMD]=0.44; 95% confidence interval [CI], 0.01-0.86), and vocabulary difficulties even more (SMD=0.89; 95% CI, 0.21-1.56). However, in this review, therapy didn’t significantly affect receptive speech difficulties (SMD=?0.04; 95% CI, ?0.64 to 0.56).
The analysis didn’t evaluate whether specific age groups would respond better to therapy.5 No studies evaluated long-term effectiveness or possible harms associated with screening or intervention.4
Recommendations
The AAP Council on Children with Disabilities, Section on Developmental Behavioral Pediatrics recommends general developmental surveillance at every well-child visit for children from birth through 3 years of age and more formal screening tests at the 9-, 18-, and 30-month visits. The AAP doesn’t recommend a specific screening test, however.2
The US Preventive Services Task Force found insufficient evidence that brief formal screening instruments accurately identify pre-school children who would benefit from further evaluation and intervention, but found fair evidence that interventions improve speech in the short term.6
1. Nelson HD, Nygren P, Walker M, et al. Screening for speech and language delay in preschool children: systematic evidence review for the US Preventive Services Task Force. Pediatrics. 2006;117:e298-e319.
2. Council on Children with Disabilities, Section on Developmental Behavioral Pediatrics; Bright Futures Steering Committee; Medical Home Initiatives for Children with Special Needs Project Advisory Committee. Identifying infants and young children with developmental disorders in the medical home: an algorithm for developmental surveillance and screening. Pediatrics. 2006;118:405-420.
3. Feldman HM. Evaluation and management of language and speech disorders in preschool children. Pediatr Rev. 2005;26:131-142.
4. Leung A, Kao CP. Evaluation and management of the child with speech delay. Am Fam Physician. 1999;59:3121-3128, 3135.
5. Law J, Garrett Z, Nye C. Speech and language therapy interventions for children with primary speech and language delay or disorder. Cochrane Database Syst Rev. 2003;(3):CD004110.-
6. US Preventive Services Task Force. Screening for speech and language delay in preschool children: recommendation statement. Pediatrics. 2006;117:497-501.
1. Nelson HD, Nygren P, Walker M, et al. Screening for speech and language delay in preschool children: systematic evidence review for the US Preventive Services Task Force. Pediatrics. 2006;117:e298-e319.
2. Council on Children with Disabilities, Section on Developmental Behavioral Pediatrics; Bright Futures Steering Committee; Medical Home Initiatives for Children with Special Needs Project Advisory Committee. Identifying infants and young children with developmental disorders in the medical home: an algorithm for developmental surveillance and screening. Pediatrics. 2006;118:405-420.
3. Feldman HM. Evaluation and management of language and speech disorders in preschool children. Pediatr Rev. 2005;26:131-142.
4. Leung A, Kao CP. Evaluation and management of the child with speech delay. Am Fam Physician. 1999;59:3121-3128, 3135.
5. Law J, Garrett Z, Nye C. Speech and language therapy interventions for children with primary speech and language delay or disorder. Cochrane Database Syst Rev. 2003;(3):CD004110.-
6. US Preventive Services Task Force. Screening for speech and language delay in preschool children: recommendation statement. Pediatrics. 2006;117:497-501.
Evidence-based answers from the Family Physicians Inquiries Network
What is the prognosis for patients with chronic urticaria?
THE PROGNOSIS FOR CHRONIC URTICARIA IN PRIMARY CARE IS UNKNOWN; studies in dermatology clinics in multiple countries report complete resolution in approximately one-third of patients with idiopathic chronic urticaria over 1 to 5 years and partial improvement in another third. Patients younger than 30 years with more severe symptoms, or symptoms with physical causes, fared less well (strength of recommendation: B, cohort studies).
Evidence summary
A prospective cohort study of 220 patients from an outpatient dermatology center in Amsterdam investigated the natural course of chronic urticaria and angioedema.1 Researchers categorized patients according to subtypes: idiopathic urticaria-angioedema, idiopathic urticaria, idiopathic angioedema, physical and idiopathic urticaria, and physical urticaria only.
The duration of symptoms at enrollment wasn’t reported. Therapy wasn’t controlled and was composed of oral antihistamines, steroids, and other drugs.
One year after enrollment, 35% of patients had complete resolution of symptoms. Resolution rates ranged from a high of 59.6% in patients with idiopathic urticaria-angioedema to a low of 16.4% in patients who had urticaria with a physical cause.
A study finds 1-year control or improvement in chronic urticaria
Another prospective cohort study from an outpatient dermatology center in Brazil evaluated 125 patients with chronic urticaria-angioedema.2 Participants were predominantly adults 20 to 40 years of age, with a mean duration of symptoms of 45 months.
Most patients had idiopathic disease (78%), but some had parasitic and skin infections, medication sensitivities, thyroid disease, and other problems that could contribute to skin hyperreactivity. Therapeutic interventions for underlying conditions or angioedema-urticaria weren’t controlled or reported.
One year after presentation, 58.4% of patients had symptoms “under control,” 31.7% were improved, and 8.9% were unchanged. One patient’s symptoms worsened.
Urticaria is less severe in patients older than 30 years
A prospective cohort study followed 62 patients with urticaria caused by cold from a tertiary referral center in Greece.3 The mean age at presentation was 42 years and the mean duration of symptoms was 10 years. The study followed patients for a mean of 9 years. Therapeutic interventions weren’t controlled or reported
Overall, 29% of patients experienced resolution of symptoms, 41.9% noted improvement, and 29% experienced worsening of symptoms. The mean time to resolution was 5.6 years. The study also found that chronic urticaria was less severe if patients developed the condition after 30 years of age.
Worst prognosis found in patients with cold-related urticaria
A retrospective cohort study identified 544 cases of chronic urticaria and angioedema in 22 years of records from a tertiary referral center in the Netherlands.4 The mean age at presentation was 35 years; patients had been symptomatic an average of 5 years. All patients were sent a questionnaire to fill out; 372 questionnaires were returned.
At 5 years after presentation, symptoms resolved in 29% of patients; at 10 years, the number of resolved cases increased to 44%. Patients with cold-related urticaria had the worst prognosis.
Zafirlukast has no effect
An RCT with a study group of 137 patients (mean age 41 years) compared the effectiveness of zafirlukast vs placebo for treating chronic urticaria symptoms. Zafirlukast showed no significant benefit over placebo; symptoms resolved or improved in 41.3% of all patients after 12 weeks.5
Recommendations
Habif’s Clinical Dermatology states that chronic urticaria:
- may last for months or years
- may be subject to lengthy and often un-rewarding evaluation
- resolves spontaneously in most cases.6
1. Kozel MM, Mekkes JR, Bossuyt PM, et al. Natural course of physical and chronic urticaria and angioedema in 220 patients. J Am Acad Dermatol. 2001;45:387-391.
2. Silvares MR, Coelho KI, Dalben I, et al. Sociodemographic and clinical characteristics, causal factors and evolution of a group of patients with chronic urticaria-angioedema. Sao Paulo Med J. 2007;125:281-285.
3. Katsarou-Katsari A, Makris M, Lagogianni E, et al. Clinical features and natural history of acquired cold urticaria in a tertiary referral hospital: a 10-year prospective study. J Eur Acad Dermatol Venereol. 2008;22:1405-1411.
4. van der Valk PG, Moret G, Kiemeney LA. The natural history of chronic urticaria and angioedema in patients visiting a tertiary referral centre. Br J Dermatol. 2003;146:110-113.
5. Reimers A, Pichler C, Helbing A, et al. Zafirlukast has no beneficial effects in the treatment of chronic urticaria. Clin Exp Allergy. 2002;32:1763-1768.
6. Habif TP. Urticaria and angioedema. Clinical Dermatology: A Color Guide to Diagnosis and Therapy. 4th ed. New York: Mosby; 2004:129–161.
THE PROGNOSIS FOR CHRONIC URTICARIA IN PRIMARY CARE IS UNKNOWN; studies in dermatology clinics in multiple countries report complete resolution in approximately one-third of patients with idiopathic chronic urticaria over 1 to 5 years and partial improvement in another third. Patients younger than 30 years with more severe symptoms, or symptoms with physical causes, fared less well (strength of recommendation: B, cohort studies).
Evidence summary
A prospective cohort study of 220 patients from an outpatient dermatology center in Amsterdam investigated the natural course of chronic urticaria and angioedema.1 Researchers categorized patients according to subtypes: idiopathic urticaria-angioedema, idiopathic urticaria, idiopathic angioedema, physical and idiopathic urticaria, and physical urticaria only.
The duration of symptoms at enrollment wasn’t reported. Therapy wasn’t controlled and was composed of oral antihistamines, steroids, and other drugs.
One year after enrollment, 35% of patients had complete resolution of symptoms. Resolution rates ranged from a high of 59.6% in patients with idiopathic urticaria-angioedema to a low of 16.4% in patients who had urticaria with a physical cause.
A study finds 1-year control or improvement in chronic urticaria
Another prospective cohort study from an outpatient dermatology center in Brazil evaluated 125 patients with chronic urticaria-angioedema.2 Participants were predominantly adults 20 to 40 years of age, with a mean duration of symptoms of 45 months.
Most patients had idiopathic disease (78%), but some had parasitic and skin infections, medication sensitivities, thyroid disease, and other problems that could contribute to skin hyperreactivity. Therapeutic interventions for underlying conditions or angioedema-urticaria weren’t controlled or reported.
One year after presentation, 58.4% of patients had symptoms “under control,” 31.7% were improved, and 8.9% were unchanged. One patient’s symptoms worsened.
Urticaria is less severe in patients older than 30 years
A prospective cohort study followed 62 patients with urticaria caused by cold from a tertiary referral center in Greece.3 The mean age at presentation was 42 years and the mean duration of symptoms was 10 years. The study followed patients for a mean of 9 years. Therapeutic interventions weren’t controlled or reported
Overall, 29% of patients experienced resolution of symptoms, 41.9% noted improvement, and 29% experienced worsening of symptoms. The mean time to resolution was 5.6 years. The study also found that chronic urticaria was less severe if patients developed the condition after 30 years of age.
Worst prognosis found in patients with cold-related urticaria
A retrospective cohort study identified 544 cases of chronic urticaria and angioedema in 22 years of records from a tertiary referral center in the Netherlands.4 The mean age at presentation was 35 years; patients had been symptomatic an average of 5 years. All patients were sent a questionnaire to fill out; 372 questionnaires were returned.
At 5 years after presentation, symptoms resolved in 29% of patients; at 10 years, the number of resolved cases increased to 44%. Patients with cold-related urticaria had the worst prognosis.
Zafirlukast has no effect
An RCT with a study group of 137 patients (mean age 41 years) compared the effectiveness of zafirlukast vs placebo for treating chronic urticaria symptoms. Zafirlukast showed no significant benefit over placebo; symptoms resolved or improved in 41.3% of all patients after 12 weeks.5
Recommendations
Habif’s Clinical Dermatology states that chronic urticaria:
- may last for months or years
- may be subject to lengthy and often un-rewarding evaluation
- resolves spontaneously in most cases.6
THE PROGNOSIS FOR CHRONIC URTICARIA IN PRIMARY CARE IS UNKNOWN; studies in dermatology clinics in multiple countries report complete resolution in approximately one-third of patients with idiopathic chronic urticaria over 1 to 5 years and partial improvement in another third. Patients younger than 30 years with more severe symptoms, or symptoms with physical causes, fared less well (strength of recommendation: B, cohort studies).
Evidence summary
A prospective cohort study of 220 patients from an outpatient dermatology center in Amsterdam investigated the natural course of chronic urticaria and angioedema.1 Researchers categorized patients according to subtypes: idiopathic urticaria-angioedema, idiopathic urticaria, idiopathic angioedema, physical and idiopathic urticaria, and physical urticaria only.
The duration of symptoms at enrollment wasn’t reported. Therapy wasn’t controlled and was composed of oral antihistamines, steroids, and other drugs.
One year after enrollment, 35% of patients had complete resolution of symptoms. Resolution rates ranged from a high of 59.6% in patients with idiopathic urticaria-angioedema to a low of 16.4% in patients who had urticaria with a physical cause.
A study finds 1-year control or improvement in chronic urticaria
Another prospective cohort study from an outpatient dermatology center in Brazil evaluated 125 patients with chronic urticaria-angioedema.2 Participants were predominantly adults 20 to 40 years of age, with a mean duration of symptoms of 45 months.
Most patients had idiopathic disease (78%), but some had parasitic and skin infections, medication sensitivities, thyroid disease, and other problems that could contribute to skin hyperreactivity. Therapeutic interventions for underlying conditions or angioedema-urticaria weren’t controlled or reported.
One year after presentation, 58.4% of patients had symptoms “under control,” 31.7% were improved, and 8.9% were unchanged. One patient’s symptoms worsened.
Urticaria is less severe in patients older than 30 years
A prospective cohort study followed 62 patients with urticaria caused by cold from a tertiary referral center in Greece.3 The mean age at presentation was 42 years and the mean duration of symptoms was 10 years. The study followed patients for a mean of 9 years. Therapeutic interventions weren’t controlled or reported
Overall, 29% of patients experienced resolution of symptoms, 41.9% noted improvement, and 29% experienced worsening of symptoms. The mean time to resolution was 5.6 years. The study also found that chronic urticaria was less severe if patients developed the condition after 30 years of age.
Worst prognosis found in patients with cold-related urticaria
A retrospective cohort study identified 544 cases of chronic urticaria and angioedema in 22 years of records from a tertiary referral center in the Netherlands.4 The mean age at presentation was 35 years; patients had been symptomatic an average of 5 years. All patients were sent a questionnaire to fill out; 372 questionnaires were returned.
At 5 years after presentation, symptoms resolved in 29% of patients; at 10 years, the number of resolved cases increased to 44%. Patients with cold-related urticaria had the worst prognosis.
Zafirlukast has no effect
An RCT with a study group of 137 patients (mean age 41 years) compared the effectiveness of zafirlukast vs placebo for treating chronic urticaria symptoms. Zafirlukast showed no significant benefit over placebo; symptoms resolved or improved in 41.3% of all patients after 12 weeks.5
Recommendations
Habif’s Clinical Dermatology states that chronic urticaria:
- may last for months or years
- may be subject to lengthy and often un-rewarding evaluation
- resolves spontaneously in most cases.6
1. Kozel MM, Mekkes JR, Bossuyt PM, et al. Natural course of physical and chronic urticaria and angioedema in 220 patients. J Am Acad Dermatol. 2001;45:387-391.
2. Silvares MR, Coelho KI, Dalben I, et al. Sociodemographic and clinical characteristics, causal factors and evolution of a group of patients with chronic urticaria-angioedema. Sao Paulo Med J. 2007;125:281-285.
3. Katsarou-Katsari A, Makris M, Lagogianni E, et al. Clinical features and natural history of acquired cold urticaria in a tertiary referral hospital: a 10-year prospective study. J Eur Acad Dermatol Venereol. 2008;22:1405-1411.
4. van der Valk PG, Moret G, Kiemeney LA. The natural history of chronic urticaria and angioedema in patients visiting a tertiary referral centre. Br J Dermatol. 2003;146:110-113.
5. Reimers A, Pichler C, Helbing A, et al. Zafirlukast has no beneficial effects in the treatment of chronic urticaria. Clin Exp Allergy. 2002;32:1763-1768.
6. Habif TP. Urticaria and angioedema. Clinical Dermatology: A Color Guide to Diagnosis and Therapy. 4th ed. New York: Mosby; 2004:129–161.
1. Kozel MM, Mekkes JR, Bossuyt PM, et al. Natural course of physical and chronic urticaria and angioedema in 220 patients. J Am Acad Dermatol. 2001;45:387-391.
2. Silvares MR, Coelho KI, Dalben I, et al. Sociodemographic and clinical characteristics, causal factors and evolution of a group of patients with chronic urticaria-angioedema. Sao Paulo Med J. 2007;125:281-285.
3. Katsarou-Katsari A, Makris M, Lagogianni E, et al. Clinical features and natural history of acquired cold urticaria in a tertiary referral hospital: a 10-year prospective study. J Eur Acad Dermatol Venereol. 2008;22:1405-1411.
4. van der Valk PG, Moret G, Kiemeney LA. The natural history of chronic urticaria and angioedema in patients visiting a tertiary referral centre. Br J Dermatol. 2003;146:110-113.
5. Reimers A, Pichler C, Helbing A, et al. Zafirlukast has no beneficial effects in the treatment of chronic urticaria. Clin Exp Allergy. 2002;32:1763-1768.
6. Habif TP. Urticaria and angioedema. Clinical Dermatology: A Color Guide to Diagnosis and Therapy. 4th ed. New York: Mosby; 2004:129–161.
Evidence-based answers from the Family Physicians Inquiries Network
What is the best way to treat Morton’s neuroma?
NO SINGLE TREATMENT HAS BEEN IDENTIFIED in the literature. That said, a protocol of stepped care that showed good results in an uncontrolled trial seems reasonable: patient education and foot-wear or insole changes, followed by corticosteroid injections and, finally, surgery (strength of recommendation [SOR]: C, case series).
Injecting sclerosing alcohol depends on the provider’s access to and comfort with ultrasound, but the evidence is insufficient to recommend it routinely (SOR: C, case series).
Evidence summary
Options for treating Morton’s neuroma include changing shoe type, using insoles or metatarsal pads, taking nonsteroidal anti-inflammatory drugs (NSAIDs), giving corticosteroid or sclerosing alcohol injections, and surgically excising or transposing the offending nerve.1-3
Different conservative measures produce similar results
A small randomized prospective study of 23 patients compared reduction in neuroma pain using supinatory or pronatory insoles.4 No explicit inclusion or exclusion criteria other than clinical diagnosis were mentioned. Neither participants nor evaluators were blind to intervention allocations.
Two patients (13%) dropped out at 1 month. At 12 months, pain reduction in the supination and pronation insole groups was 50% and 45%, respectively (not significant).
Injections improve symptoms with minimal adverse effects
A prospective randomized study of 82 patients compared steroid injections alone with shoe modifications.5 Primary outcomes were patient satisfaction (presence or absence of pain), amount of pain, and return of pain.
Steroid injections yielded better patient satisfaction compared with shoe modifications alone at 1 and 6 months. Twenty-three percent of shoe-modification patients achieved complete satisfaction at 1 month, compared with 50% of injection patients (P<.01; number needed to treat [NNT]=3.7). At 6 months, the results were 28.6% satisfaction with shoe modification and 73.5% satisfaction with injection (P<.001; NNT=2.3).
The difference disappeared at 1 year (63% satisfaction with shoe modification compared with 82% satisfaction with injection; P>.05), although patients were allowed to cross over at 6 months. No complications occurred. The study was limited by a high rate of crossover from the shoe modification to the injection group at 6 months, elimination of dropouts from the final analysis, and lack of intent-to-treat analysis.
Another technique uses the sclerosing effects of alcohol6 delivered by multiple ultrasound-guided injections over time.7,8 Improvement of symptoms with no long-term adverse events were reported in several case series, although in each study a small number of patients reported localized pain at the site of injection.6-10 The TABLE summarizes injection studies.5-11
TABLE
How injection therapies for Morton’s neuroma compare
| Study | Injection materials | Type of study | Number of cases | Average follow-up, (mo) | Average number of injections | Results |
|---|---|---|---|---|---|---|
| Greenfield 19849 | Steroid | Retrospective case series | 67 | 24 | 3 | 80% complete relief |
| Saygi 20055 | Steroid | Prospective quasirandomized injection vs footwear modification | 82 | 12 | 2-3 | 82% vs 63% complete or partial pain relief in 2 groups, respectively |
| Markovic 200811 | Steroid* | Prospective case series | 39 | 9 | 1 | 38% complete satisfaction and 28% satisfaction with minor reservations |
| Dockery 19996 | Alcohol | Prospective case series | 100 | 13 | 5.5 | 89% resolution or improved symptoms |
| Fanucci 20048 | Alcohol* | Prospective case series | 40 | 10 | 4 | 90% resolution or improved symptoms |
| Hughes 20077 | Alcohol* | Prospective case series | 101 | 21.1 | 4.1 | 94% resolution or improved symptoms |
| Mozena 200710 | Alcohol | Retrospective case series | 42 | 11 | 3-7 | 61% resolution or improved symptoms. Patients with ≥5 injections (74%) were more likely to respond (P=.0072) |
| *Ultrasound guided. | ||||||
Surgery: Consider cost and risk of complications
Most surgical studies enrolled patients who had initially failed conservative treatments. Costs and risks of complications must be weighed, including infection, scar sensitivity, residual pain, sensory deficits, and other wound-related morbidities.
Technique varies considerably among surgeons.12 A Cochrane systematic review of 3 randomized controlled trials comprising 121 patients concluded that, at most, very limited evidence exists that transposition of the transected plantar digital nerve may yield better long-term results than standard resection.3
In a retrospective case series, 82 patients with primary Morton’s neuroma were treated by a single surgeon and a single technique (dorsal incision and nerve transection).13 All patients had failed conservative management with orthotics, shoe modification, and NSAIDs (lidocaine injections were used only to pinpoint neuroma location). Sixty-six (81%) returned for follow-up.
Average follow-up evaluation was 5.8 years. Of the patients who were followed, 85% rated overall satisfaction as excellent or good.
Stepped care gets results
A prospective case series enrolled 115 subjects out of 340 consecutive patients who presented to a private orthopedic clinic with a diagnosis of Morton’s neuroma.1 The authors assessed a 3-stage protocol of stepped care, progressing to the next stage if improvement was inadequate after 3 months: Stage I comprised patient education, footwear modifications, and a metatarsal pad placed proximal to the involved nerve; stage II, injection of steroids with local anesthetic or local anesthetic alone; and stage III, surgery.
Of 57 patients treated only with footwear modifications, 47 (41%) improved and required no further treatment. Twenty-seven (47%) of the 58 patients who received injections improved and required no further treatment. Of the 24 patients who advanced to stage III, 96% improved with surgery.
Recommendations
No consensus exists regarding definitive treatment of Morton’s neuroma. The American College of Occupational and Environmental Medicine recommends excision of the neuroma if nonsurgical treatment fails.14
A 2003 Cochrane systematic review of 107 studies found insufficient evidence to assess efficacy of surgical and nonsurgical interventions.3 Stepped care has been adopted by many third-party payers who require conservative care before reimbursing for injections, and treatment with injections before reimbursing for surgery.
1. Bennett GL, Graham CE, Mauldin DM. Morton’s interdigital neuroma: a comprehensive treatment protocol. Foot Ankle Int. 1995;16:760-763.
2. Wu KK. Morton’s neuroma and metatarsalgia. Curr Opin Rheumatol. 2000;12:131-142.
3. Thomson CE, Gibson JN, Martin D. Interventions for the treatment of Morton’s neuroma. Cochrane Database Syst Rev. 2004;(3):CD003118.-
4. Kilmartin TE, Wallace WA. Effect of pronation and supination orthosis on Morton’s neuroma and lower extremity function. Foot Ankle Int. 1994;15:256-262.
5. Saygi B, Yildirim Y, Saygi EK, et al. Morton’s neuroma: comparative results of two conservative methods. Foot Ankle Int. 2005;26:556-559.
6. Dockery GL. The treatment of intermetatarsal neuromas with 4% alcohol sclerosing injections. J Foot Ankle Surg. 1999;38:403-408.
7. Hughes RJ, Ali K, Jones H, et al. Treatment of Morton’s neuroma with alcohol injection under sonographic guidance: follow-up of 101 cases. Am J Roentgenol. 2007;188:1535-1539.
8. Fanucci E, Masala S, Fabiano S, et al. Treatment of intermetatarsal Morton’s neuroma with alcohol injection under US guide: 10-month follow-up. Eur Radiol. 2004;14:514-518.
9. Greenfield J, Rea J, Jr, Ilfeld FW. Morton’s interdigital neuroma: indications for treatment by local injections versus surgery. Clin Orthop Relat Res. 1984;185:142-144.
10. Mozena JD, Clifford JT. Efficacy of chemical neurolysis for the treatment of interdigital nerve compression of the foot: a retrospective study. J Am Podiatr Med Assoc. 2007;97:203-206.
11. Markovic M, Crichton K, Read JW, et al. Effectiveness of ultrasound-guided corticosteroid injection in the treatment of Morton’s neuroma. Foot Ankle Int. 2008;29:483-487.
12. Hassouna H, Singh D. Morton’s metatarsalgia: pathogenesis, aetiology and current management. Acta Orthop Belg. 2005;71:646-655.
13. Coughlin MJ, Pinsonneault T. Operative treatment of interdigital neuroma: a long-term follow-up study. J Bone Joint Surg Am. 2001;83-A:1321-1328.
14. Clinical Practice Guideline Forefoot Disorders Panel, Thomas JL, Blitch EL, IV, Chaney DM, et al. Diagnosis and treatment of forefoot disorders. Section 3. Morton’s intermetatarsal neuroma. J Foot Ankle Surg. 2009;48:251-256.Available at: . Accessed July 5, 2010.
NO SINGLE TREATMENT HAS BEEN IDENTIFIED in the literature. That said, a protocol of stepped care that showed good results in an uncontrolled trial seems reasonable: patient education and foot-wear or insole changes, followed by corticosteroid injections and, finally, surgery (strength of recommendation [SOR]: C, case series).
Injecting sclerosing alcohol depends on the provider’s access to and comfort with ultrasound, but the evidence is insufficient to recommend it routinely (SOR: C, case series).
Evidence summary
Options for treating Morton’s neuroma include changing shoe type, using insoles or metatarsal pads, taking nonsteroidal anti-inflammatory drugs (NSAIDs), giving corticosteroid or sclerosing alcohol injections, and surgically excising or transposing the offending nerve.1-3
Different conservative measures produce similar results
A small randomized prospective study of 23 patients compared reduction in neuroma pain using supinatory or pronatory insoles.4 No explicit inclusion or exclusion criteria other than clinical diagnosis were mentioned. Neither participants nor evaluators were blind to intervention allocations.
Two patients (13%) dropped out at 1 month. At 12 months, pain reduction in the supination and pronation insole groups was 50% and 45%, respectively (not significant).
Injections improve symptoms with minimal adverse effects
A prospective randomized study of 82 patients compared steroid injections alone with shoe modifications.5 Primary outcomes were patient satisfaction (presence or absence of pain), amount of pain, and return of pain.
Steroid injections yielded better patient satisfaction compared with shoe modifications alone at 1 and 6 months. Twenty-three percent of shoe-modification patients achieved complete satisfaction at 1 month, compared with 50% of injection patients (P<.01; number needed to treat [NNT]=3.7). At 6 months, the results were 28.6% satisfaction with shoe modification and 73.5% satisfaction with injection (P<.001; NNT=2.3).
The difference disappeared at 1 year (63% satisfaction with shoe modification compared with 82% satisfaction with injection; P>.05), although patients were allowed to cross over at 6 months. No complications occurred. The study was limited by a high rate of crossover from the shoe modification to the injection group at 6 months, elimination of dropouts from the final analysis, and lack of intent-to-treat analysis.
Another technique uses the sclerosing effects of alcohol6 delivered by multiple ultrasound-guided injections over time.7,8 Improvement of symptoms with no long-term adverse events were reported in several case series, although in each study a small number of patients reported localized pain at the site of injection.6-10 The TABLE summarizes injection studies.5-11
TABLE
How injection therapies for Morton’s neuroma compare
| Study | Injection materials | Type of study | Number of cases | Average follow-up, (mo) | Average number of injections | Results |
|---|---|---|---|---|---|---|
| Greenfield 19849 | Steroid | Retrospective case series | 67 | 24 | 3 | 80% complete relief |
| Saygi 20055 | Steroid | Prospective quasirandomized injection vs footwear modification | 82 | 12 | 2-3 | 82% vs 63% complete or partial pain relief in 2 groups, respectively |
| Markovic 200811 | Steroid* | Prospective case series | 39 | 9 | 1 | 38% complete satisfaction and 28% satisfaction with minor reservations |
| Dockery 19996 | Alcohol | Prospective case series | 100 | 13 | 5.5 | 89% resolution or improved symptoms |
| Fanucci 20048 | Alcohol* | Prospective case series | 40 | 10 | 4 | 90% resolution or improved symptoms |
| Hughes 20077 | Alcohol* | Prospective case series | 101 | 21.1 | 4.1 | 94% resolution or improved symptoms |
| Mozena 200710 | Alcohol | Retrospective case series | 42 | 11 | 3-7 | 61% resolution or improved symptoms. Patients with ≥5 injections (74%) were more likely to respond (P=.0072) |
| *Ultrasound guided. | ||||||
Surgery: Consider cost and risk of complications
Most surgical studies enrolled patients who had initially failed conservative treatments. Costs and risks of complications must be weighed, including infection, scar sensitivity, residual pain, sensory deficits, and other wound-related morbidities.
Technique varies considerably among surgeons.12 A Cochrane systematic review of 3 randomized controlled trials comprising 121 patients concluded that, at most, very limited evidence exists that transposition of the transected plantar digital nerve may yield better long-term results than standard resection.3
In a retrospective case series, 82 patients with primary Morton’s neuroma were treated by a single surgeon and a single technique (dorsal incision and nerve transection).13 All patients had failed conservative management with orthotics, shoe modification, and NSAIDs (lidocaine injections were used only to pinpoint neuroma location). Sixty-six (81%) returned for follow-up.
Average follow-up evaluation was 5.8 years. Of the patients who were followed, 85% rated overall satisfaction as excellent or good.
Stepped care gets results
A prospective case series enrolled 115 subjects out of 340 consecutive patients who presented to a private orthopedic clinic with a diagnosis of Morton’s neuroma.1 The authors assessed a 3-stage protocol of stepped care, progressing to the next stage if improvement was inadequate after 3 months: Stage I comprised patient education, footwear modifications, and a metatarsal pad placed proximal to the involved nerve; stage II, injection of steroids with local anesthetic or local anesthetic alone; and stage III, surgery.
Of 57 patients treated only with footwear modifications, 47 (41%) improved and required no further treatment. Twenty-seven (47%) of the 58 patients who received injections improved and required no further treatment. Of the 24 patients who advanced to stage III, 96% improved with surgery.
Recommendations
No consensus exists regarding definitive treatment of Morton’s neuroma. The American College of Occupational and Environmental Medicine recommends excision of the neuroma if nonsurgical treatment fails.14
A 2003 Cochrane systematic review of 107 studies found insufficient evidence to assess efficacy of surgical and nonsurgical interventions.3 Stepped care has been adopted by many third-party payers who require conservative care before reimbursing for injections, and treatment with injections before reimbursing for surgery.
NO SINGLE TREATMENT HAS BEEN IDENTIFIED in the literature. That said, a protocol of stepped care that showed good results in an uncontrolled trial seems reasonable: patient education and foot-wear or insole changes, followed by corticosteroid injections and, finally, surgery (strength of recommendation [SOR]: C, case series).
Injecting sclerosing alcohol depends on the provider’s access to and comfort with ultrasound, but the evidence is insufficient to recommend it routinely (SOR: C, case series).
Evidence summary
Options for treating Morton’s neuroma include changing shoe type, using insoles or metatarsal pads, taking nonsteroidal anti-inflammatory drugs (NSAIDs), giving corticosteroid or sclerosing alcohol injections, and surgically excising or transposing the offending nerve.1-3
Different conservative measures produce similar results
A small randomized prospective study of 23 patients compared reduction in neuroma pain using supinatory or pronatory insoles.4 No explicit inclusion or exclusion criteria other than clinical diagnosis were mentioned. Neither participants nor evaluators were blind to intervention allocations.
Two patients (13%) dropped out at 1 month. At 12 months, pain reduction in the supination and pronation insole groups was 50% and 45%, respectively (not significant).
Injections improve symptoms with minimal adverse effects
A prospective randomized study of 82 patients compared steroid injections alone with shoe modifications.5 Primary outcomes were patient satisfaction (presence or absence of pain), amount of pain, and return of pain.
Steroid injections yielded better patient satisfaction compared with shoe modifications alone at 1 and 6 months. Twenty-three percent of shoe-modification patients achieved complete satisfaction at 1 month, compared with 50% of injection patients (P<.01; number needed to treat [NNT]=3.7). At 6 months, the results were 28.6% satisfaction with shoe modification and 73.5% satisfaction with injection (P<.001; NNT=2.3).
The difference disappeared at 1 year (63% satisfaction with shoe modification compared with 82% satisfaction with injection; P>.05), although patients were allowed to cross over at 6 months. No complications occurred. The study was limited by a high rate of crossover from the shoe modification to the injection group at 6 months, elimination of dropouts from the final analysis, and lack of intent-to-treat analysis.
Another technique uses the sclerosing effects of alcohol6 delivered by multiple ultrasound-guided injections over time.7,8 Improvement of symptoms with no long-term adverse events were reported in several case series, although in each study a small number of patients reported localized pain at the site of injection.6-10 The TABLE summarizes injection studies.5-11
TABLE
How injection therapies for Morton’s neuroma compare
| Study | Injection materials | Type of study | Number of cases | Average follow-up, (mo) | Average number of injections | Results |
|---|---|---|---|---|---|---|
| Greenfield 19849 | Steroid | Retrospective case series | 67 | 24 | 3 | 80% complete relief |
| Saygi 20055 | Steroid | Prospective quasirandomized injection vs footwear modification | 82 | 12 | 2-3 | 82% vs 63% complete or partial pain relief in 2 groups, respectively |
| Markovic 200811 | Steroid* | Prospective case series | 39 | 9 | 1 | 38% complete satisfaction and 28% satisfaction with minor reservations |
| Dockery 19996 | Alcohol | Prospective case series | 100 | 13 | 5.5 | 89% resolution or improved symptoms |
| Fanucci 20048 | Alcohol* | Prospective case series | 40 | 10 | 4 | 90% resolution or improved symptoms |
| Hughes 20077 | Alcohol* | Prospective case series | 101 | 21.1 | 4.1 | 94% resolution or improved symptoms |
| Mozena 200710 | Alcohol | Retrospective case series | 42 | 11 | 3-7 | 61% resolution or improved symptoms. Patients with ≥5 injections (74%) were more likely to respond (P=.0072) |
| *Ultrasound guided. | ||||||
Surgery: Consider cost and risk of complications
Most surgical studies enrolled patients who had initially failed conservative treatments. Costs and risks of complications must be weighed, including infection, scar sensitivity, residual pain, sensory deficits, and other wound-related morbidities.
Technique varies considerably among surgeons.12 A Cochrane systematic review of 3 randomized controlled trials comprising 121 patients concluded that, at most, very limited evidence exists that transposition of the transected plantar digital nerve may yield better long-term results than standard resection.3
In a retrospective case series, 82 patients with primary Morton’s neuroma were treated by a single surgeon and a single technique (dorsal incision and nerve transection).13 All patients had failed conservative management with orthotics, shoe modification, and NSAIDs (lidocaine injections were used only to pinpoint neuroma location). Sixty-six (81%) returned for follow-up.
Average follow-up evaluation was 5.8 years. Of the patients who were followed, 85% rated overall satisfaction as excellent or good.
Stepped care gets results
A prospective case series enrolled 115 subjects out of 340 consecutive patients who presented to a private orthopedic clinic with a diagnosis of Morton’s neuroma.1 The authors assessed a 3-stage protocol of stepped care, progressing to the next stage if improvement was inadequate after 3 months: Stage I comprised patient education, footwear modifications, and a metatarsal pad placed proximal to the involved nerve; stage II, injection of steroids with local anesthetic or local anesthetic alone; and stage III, surgery.
Of 57 patients treated only with footwear modifications, 47 (41%) improved and required no further treatment. Twenty-seven (47%) of the 58 patients who received injections improved and required no further treatment. Of the 24 patients who advanced to stage III, 96% improved with surgery.
Recommendations
No consensus exists regarding definitive treatment of Morton’s neuroma. The American College of Occupational and Environmental Medicine recommends excision of the neuroma if nonsurgical treatment fails.14
A 2003 Cochrane systematic review of 107 studies found insufficient evidence to assess efficacy of surgical and nonsurgical interventions.3 Stepped care has been adopted by many third-party payers who require conservative care before reimbursing for injections, and treatment with injections before reimbursing for surgery.
1. Bennett GL, Graham CE, Mauldin DM. Morton’s interdigital neuroma: a comprehensive treatment protocol. Foot Ankle Int. 1995;16:760-763.
2. Wu KK. Morton’s neuroma and metatarsalgia. Curr Opin Rheumatol. 2000;12:131-142.
3. Thomson CE, Gibson JN, Martin D. Interventions for the treatment of Morton’s neuroma. Cochrane Database Syst Rev. 2004;(3):CD003118.-
4. Kilmartin TE, Wallace WA. Effect of pronation and supination orthosis on Morton’s neuroma and lower extremity function. Foot Ankle Int. 1994;15:256-262.
5. Saygi B, Yildirim Y, Saygi EK, et al. Morton’s neuroma: comparative results of two conservative methods. Foot Ankle Int. 2005;26:556-559.
6. Dockery GL. The treatment of intermetatarsal neuromas with 4% alcohol sclerosing injections. J Foot Ankle Surg. 1999;38:403-408.
7. Hughes RJ, Ali K, Jones H, et al. Treatment of Morton’s neuroma with alcohol injection under sonographic guidance: follow-up of 101 cases. Am J Roentgenol. 2007;188:1535-1539.
8. Fanucci E, Masala S, Fabiano S, et al. Treatment of intermetatarsal Morton’s neuroma with alcohol injection under US guide: 10-month follow-up. Eur Radiol. 2004;14:514-518.
9. Greenfield J, Rea J, Jr, Ilfeld FW. Morton’s interdigital neuroma: indications for treatment by local injections versus surgery. Clin Orthop Relat Res. 1984;185:142-144.
10. Mozena JD, Clifford JT. Efficacy of chemical neurolysis for the treatment of interdigital nerve compression of the foot: a retrospective study. J Am Podiatr Med Assoc. 2007;97:203-206.
11. Markovic M, Crichton K, Read JW, et al. Effectiveness of ultrasound-guided corticosteroid injection in the treatment of Morton’s neuroma. Foot Ankle Int. 2008;29:483-487.
12. Hassouna H, Singh D. Morton’s metatarsalgia: pathogenesis, aetiology and current management. Acta Orthop Belg. 2005;71:646-655.
13. Coughlin MJ, Pinsonneault T. Operative treatment of interdigital neuroma: a long-term follow-up study. J Bone Joint Surg Am. 2001;83-A:1321-1328.
14. Clinical Practice Guideline Forefoot Disorders Panel, Thomas JL, Blitch EL, IV, Chaney DM, et al. Diagnosis and treatment of forefoot disorders. Section 3. Morton’s intermetatarsal neuroma. J Foot Ankle Surg. 2009;48:251-256.Available at: . Accessed July 5, 2010.
1. Bennett GL, Graham CE, Mauldin DM. Morton’s interdigital neuroma: a comprehensive treatment protocol. Foot Ankle Int. 1995;16:760-763.
2. Wu KK. Morton’s neuroma and metatarsalgia. Curr Opin Rheumatol. 2000;12:131-142.
3. Thomson CE, Gibson JN, Martin D. Interventions for the treatment of Morton’s neuroma. Cochrane Database Syst Rev. 2004;(3):CD003118.-
4. Kilmartin TE, Wallace WA. Effect of pronation and supination orthosis on Morton’s neuroma and lower extremity function. Foot Ankle Int. 1994;15:256-262.
5. Saygi B, Yildirim Y, Saygi EK, et al. Morton’s neuroma: comparative results of two conservative methods. Foot Ankle Int. 2005;26:556-559.
6. Dockery GL. The treatment of intermetatarsal neuromas with 4% alcohol sclerosing injections. J Foot Ankle Surg. 1999;38:403-408.
7. Hughes RJ, Ali K, Jones H, et al. Treatment of Morton’s neuroma with alcohol injection under sonographic guidance: follow-up of 101 cases. Am J Roentgenol. 2007;188:1535-1539.
8. Fanucci E, Masala S, Fabiano S, et al. Treatment of intermetatarsal Morton’s neuroma with alcohol injection under US guide: 10-month follow-up. Eur Radiol. 2004;14:514-518.
9. Greenfield J, Rea J, Jr, Ilfeld FW. Morton’s interdigital neuroma: indications for treatment by local injections versus surgery. Clin Orthop Relat Res. 1984;185:142-144.
10. Mozena JD, Clifford JT. Efficacy of chemical neurolysis for the treatment of interdigital nerve compression of the foot: a retrospective study. J Am Podiatr Med Assoc. 2007;97:203-206.
11. Markovic M, Crichton K, Read JW, et al. Effectiveness of ultrasound-guided corticosteroid injection in the treatment of Morton’s neuroma. Foot Ankle Int. 2008;29:483-487.
12. Hassouna H, Singh D. Morton’s metatarsalgia: pathogenesis, aetiology and current management. Acta Orthop Belg. 2005;71:646-655.
13. Coughlin MJ, Pinsonneault T. Operative treatment of interdigital neuroma: a long-term follow-up study. J Bone Joint Surg Am. 2001;83-A:1321-1328.
14. Clinical Practice Guideline Forefoot Disorders Panel, Thomas JL, Blitch EL, IV, Chaney DM, et al. Diagnosis and treatment of forefoot disorders. Section 3. Morton’s intermetatarsal neuroma. J Foot Ankle Surg. 2009;48:251-256.Available at: . Accessed July 5, 2010.
Evidence-based answers from the Family Physicians Inquiries Network
Does turmeric relieve inflammatory conditions?
YES, but data aren’t plentiful. Limited evidence suggests that turmeric and its active compound, curcumin, are effective for rheumatoid arthritis and other inflammatory conditions (strength of recommendation [SOR]: C, primarily low-quality cohort studies with small patient numbers).
Curcumin has shown limited benefit for patients with psoriasis, inflammatory bowel disease (IBS), inflammatory eye diseases, familial adenomatous polyposis, and kidney transplantation (SOR: B, small, short randomized controlled trials [RCTs]).
No evidence indicates that curcumin helps patients with human immunodeficiency virus (HIV) (SOR: B, single RCT)
Evidence summary
Although extensive in vitro and animal studies have analyzed the effect of curcumin on inflammation and inflammatory mediators (including inhibition of lipoxygenase, cyclooxygenase-2, leukotrienes, thromboxane, prostaglandins, and tumor necrosis factor),1 few human studies have looked at patient-oriented outcomes.
Rheumatoid arthritis. One very small (N=18) double-blind crossover study showed a statistically significant improvement in morning stiffness, walking time, and joint swelling in rheumatoid arthritis patients taking curcumin.2
Psoriasis. A cohort study demonstrated that curcumin applied topically in a gel formulation to patients with psoriasis resulted in either resolution or reduction in psoriatic plaques after 8 weeks of treatment.3
IBS. Two studies have found curcumin to have a positive effect on patients with IBS. A cohort study (N=10) of patients with ulcerative colitis or Crohn’s disease demonstrated symptomatic improvement (more formed stools, less frequent bowel movements, and less abdominal pain and cramping) after consuming curcumin for 2 and 3 months, respectively.4 A randomized, double-blind, multicenter trial (N=89) showed that 6 months of daily curcumin improved the clinical activity index and maintained remission in patients with ulcerative colitis.5
Inflammatory eye diseases. A cohort study of 32 patients found that curcumin was as effective as corticosteroids for chronic anterior uveitis (as demonstrated by improved vision, decreased keratic precipitates, and a break of synechiae assessed by slit lamp examination).6 Another small cohort study (N=5) by the same authors showed that curcumin reduced or resolved inflammatory orbital pseudotumor (as evidenced by reduced ocular swelling, normal ocular movements, and absence of diplopia).7
Familial adenomatous polyposis. A small cohort study (N=5) demonstrated a decrease in size and number of adenomas in patients with familial adenomatous polyposis after a mean of 6 months of treatment with curcumin, although patients received quercetin concurrently during the treatment period.8
Kidney transplantation. A cohort study followed 43 dialysis-dependent cadaver kidney recipients who had taken curcumin for 1 month. Investigators observed reduced acute rejection and neurotoxicity over the course of 6 months.9
HIV. Curcumin didn’t reduce viral load or improve CD4 counts in 40 HIV patients in the single study identified in a Cochrane Review.10
Dosage and adverse effects.
Dosing varied across the studies reviewed in this Clinical Inquiry, but generally was 500 to 1000 mg, 1 to 3 times daily. Curcumin doses as high as 12,000 mg daily have been given in experimental settings without significant adverse events. Minor gastrointestinal side effects, including nausea and diarrhea, have been reported.11
Recommendations
The National Center for Complementary and Alternative Medicine of the National Institutes of Health states that little reliable evidence exists to support the use of turmeric for any health condition because few clinical trials have been conducted. Preliminary findings from animal and laboratory studies suggest that curcumin may have anti-inflammatory and anticancer properties, but these findings have not been confirmed in people.12
1. Chainani-Wu N. Safety and anti-inflammatory activity of curcumin: a component of turmeric (Curcuma longa). J Altern Complement Med. 2003;9:161-168.
2. Deodhar SD, Sethi R, Srimal RC. Preliminary studies on antirheumatic activity of curcumin (diferuloyl methane). Indian J Med Res. 1980;71:632-634.
3. Heng MC, Song MK, Harker J, et al. Drug-induced suppression of phosphorylase kinase activity correlates with resolution of psoriasis as assessed by clinical, histological, and immunohistochemical parameters. Br J Dermatol. 2000;143:937-949.
4. Holt PR, Katz S, Kirshoff R. Curcumin therapy in inflammatory bowel disease: a pilot study. Dig Dis Sci. 2005;50:2191-2193.
5. Hanai H, Iida T, Takeuchi K, et al. Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol. 2006;4:1502-1506.
6. Lal B, Kapoor AK, Asthana OP, et al. Efficacy of curcumin in the management of chronic anterior uveitis. Phytother Res. 1999;13:318-322.
7. Lal B, Kapoor AK, Agrawal PK, et al. Role of curcumin in idiopathic inflammatory orbital pseudotumours. Phytother Res. 2000;14:443-447.
8. Cruz-Correa M, Shoskes DA, Sanchez P, et al. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clin Gastroenterol Hepatol. 2006;4:1035-1038.
9. Shoskes D, Lapierre C, Cruz-Correa M, et al. Beneficial effects of the bioflavonoids curcumin and quercetin on early function in cadaveric renal transplantation: a randomized placebo controlled trial. Transplantation. 2005;80:1556-1559.
10. Liu JP, Manheimer E, Yang M. Herbal medicines for treating HIV infection and AIDS. Cochrane Database Syst Rev. 2005;(3):CD003937.
11. Hsu CH, Cheng AL. Clinical studies with curcumin. Adv Exp Med Biol. 2007;595:471-480.
12. National Center for Complementary and Alternative Medicine Herbs at a glance: turmeric. Updated August 12, 2010. Available at: http://nccam.nih.gov/health/turmeric/. Accessed October 11, 2010.
YES, but data aren’t plentiful. Limited evidence suggests that turmeric and its active compound, curcumin, are effective for rheumatoid arthritis and other inflammatory conditions (strength of recommendation [SOR]: C, primarily low-quality cohort studies with small patient numbers).
Curcumin has shown limited benefit for patients with psoriasis, inflammatory bowel disease (IBS), inflammatory eye diseases, familial adenomatous polyposis, and kidney transplantation (SOR: B, small, short randomized controlled trials [RCTs]).
No evidence indicates that curcumin helps patients with human immunodeficiency virus (HIV) (SOR: B, single RCT)
Evidence summary
Although extensive in vitro and animal studies have analyzed the effect of curcumin on inflammation and inflammatory mediators (including inhibition of lipoxygenase, cyclooxygenase-2, leukotrienes, thromboxane, prostaglandins, and tumor necrosis factor),1 few human studies have looked at patient-oriented outcomes.
Rheumatoid arthritis. One very small (N=18) double-blind crossover study showed a statistically significant improvement in morning stiffness, walking time, and joint swelling in rheumatoid arthritis patients taking curcumin.2
Psoriasis. A cohort study demonstrated that curcumin applied topically in a gel formulation to patients with psoriasis resulted in either resolution or reduction in psoriatic plaques after 8 weeks of treatment.3
IBS. Two studies have found curcumin to have a positive effect on patients with IBS. A cohort study (N=10) of patients with ulcerative colitis or Crohn’s disease demonstrated symptomatic improvement (more formed stools, less frequent bowel movements, and less abdominal pain and cramping) after consuming curcumin for 2 and 3 months, respectively.4 A randomized, double-blind, multicenter trial (N=89) showed that 6 months of daily curcumin improved the clinical activity index and maintained remission in patients with ulcerative colitis.5
Inflammatory eye diseases. A cohort study of 32 patients found that curcumin was as effective as corticosteroids for chronic anterior uveitis (as demonstrated by improved vision, decreased keratic precipitates, and a break of synechiae assessed by slit lamp examination).6 Another small cohort study (N=5) by the same authors showed that curcumin reduced or resolved inflammatory orbital pseudotumor (as evidenced by reduced ocular swelling, normal ocular movements, and absence of diplopia).7
Familial adenomatous polyposis. A small cohort study (N=5) demonstrated a decrease in size and number of adenomas in patients with familial adenomatous polyposis after a mean of 6 months of treatment with curcumin, although patients received quercetin concurrently during the treatment period.8
Kidney transplantation. A cohort study followed 43 dialysis-dependent cadaver kidney recipients who had taken curcumin for 1 month. Investigators observed reduced acute rejection and neurotoxicity over the course of 6 months.9
HIV. Curcumin didn’t reduce viral load or improve CD4 counts in 40 HIV patients in the single study identified in a Cochrane Review.10
Dosage and adverse effects.
Dosing varied across the studies reviewed in this Clinical Inquiry, but generally was 500 to 1000 mg, 1 to 3 times daily. Curcumin doses as high as 12,000 mg daily have been given in experimental settings without significant adverse events. Minor gastrointestinal side effects, including nausea and diarrhea, have been reported.11
Recommendations
The National Center for Complementary and Alternative Medicine of the National Institutes of Health states that little reliable evidence exists to support the use of turmeric for any health condition because few clinical trials have been conducted. Preliminary findings from animal and laboratory studies suggest that curcumin may have anti-inflammatory and anticancer properties, but these findings have not been confirmed in people.12
YES, but data aren’t plentiful. Limited evidence suggests that turmeric and its active compound, curcumin, are effective for rheumatoid arthritis and other inflammatory conditions (strength of recommendation [SOR]: C, primarily low-quality cohort studies with small patient numbers).
Curcumin has shown limited benefit for patients with psoriasis, inflammatory bowel disease (IBS), inflammatory eye diseases, familial adenomatous polyposis, and kidney transplantation (SOR: B, small, short randomized controlled trials [RCTs]).
No evidence indicates that curcumin helps patients with human immunodeficiency virus (HIV) (SOR: B, single RCT)
Evidence summary
Although extensive in vitro and animal studies have analyzed the effect of curcumin on inflammation and inflammatory mediators (including inhibition of lipoxygenase, cyclooxygenase-2, leukotrienes, thromboxane, prostaglandins, and tumor necrosis factor),1 few human studies have looked at patient-oriented outcomes.
Rheumatoid arthritis. One very small (N=18) double-blind crossover study showed a statistically significant improvement in morning stiffness, walking time, and joint swelling in rheumatoid arthritis patients taking curcumin.2
Psoriasis. A cohort study demonstrated that curcumin applied topically in a gel formulation to patients with psoriasis resulted in either resolution or reduction in psoriatic plaques after 8 weeks of treatment.3
IBS. Two studies have found curcumin to have a positive effect on patients with IBS. A cohort study (N=10) of patients with ulcerative colitis or Crohn’s disease demonstrated symptomatic improvement (more formed stools, less frequent bowel movements, and less abdominal pain and cramping) after consuming curcumin for 2 and 3 months, respectively.4 A randomized, double-blind, multicenter trial (N=89) showed that 6 months of daily curcumin improved the clinical activity index and maintained remission in patients with ulcerative colitis.5
Inflammatory eye diseases. A cohort study of 32 patients found that curcumin was as effective as corticosteroids for chronic anterior uveitis (as demonstrated by improved vision, decreased keratic precipitates, and a break of synechiae assessed by slit lamp examination).6 Another small cohort study (N=5) by the same authors showed that curcumin reduced or resolved inflammatory orbital pseudotumor (as evidenced by reduced ocular swelling, normal ocular movements, and absence of diplopia).7
Familial adenomatous polyposis. A small cohort study (N=5) demonstrated a decrease in size and number of adenomas in patients with familial adenomatous polyposis after a mean of 6 months of treatment with curcumin, although patients received quercetin concurrently during the treatment period.8
Kidney transplantation. A cohort study followed 43 dialysis-dependent cadaver kidney recipients who had taken curcumin for 1 month. Investigators observed reduced acute rejection and neurotoxicity over the course of 6 months.9
HIV. Curcumin didn’t reduce viral load or improve CD4 counts in 40 HIV patients in the single study identified in a Cochrane Review.10
Dosage and adverse effects.
Dosing varied across the studies reviewed in this Clinical Inquiry, but generally was 500 to 1000 mg, 1 to 3 times daily. Curcumin doses as high as 12,000 mg daily have been given in experimental settings without significant adverse events. Minor gastrointestinal side effects, including nausea and diarrhea, have been reported.11
Recommendations
The National Center for Complementary and Alternative Medicine of the National Institutes of Health states that little reliable evidence exists to support the use of turmeric for any health condition because few clinical trials have been conducted. Preliminary findings from animal and laboratory studies suggest that curcumin may have anti-inflammatory and anticancer properties, but these findings have not been confirmed in people.12
1. Chainani-Wu N. Safety and anti-inflammatory activity of curcumin: a component of turmeric (Curcuma longa). J Altern Complement Med. 2003;9:161-168.
2. Deodhar SD, Sethi R, Srimal RC. Preliminary studies on antirheumatic activity of curcumin (diferuloyl methane). Indian J Med Res. 1980;71:632-634.
3. Heng MC, Song MK, Harker J, et al. Drug-induced suppression of phosphorylase kinase activity correlates with resolution of psoriasis as assessed by clinical, histological, and immunohistochemical parameters. Br J Dermatol. 2000;143:937-949.
4. Holt PR, Katz S, Kirshoff R. Curcumin therapy in inflammatory bowel disease: a pilot study. Dig Dis Sci. 2005;50:2191-2193.
5. Hanai H, Iida T, Takeuchi K, et al. Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol. 2006;4:1502-1506.
6. Lal B, Kapoor AK, Asthana OP, et al. Efficacy of curcumin in the management of chronic anterior uveitis. Phytother Res. 1999;13:318-322.
7. Lal B, Kapoor AK, Agrawal PK, et al. Role of curcumin in idiopathic inflammatory orbital pseudotumours. Phytother Res. 2000;14:443-447.
8. Cruz-Correa M, Shoskes DA, Sanchez P, et al. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clin Gastroenterol Hepatol. 2006;4:1035-1038.
9. Shoskes D, Lapierre C, Cruz-Correa M, et al. Beneficial effects of the bioflavonoids curcumin and quercetin on early function in cadaveric renal transplantation: a randomized placebo controlled trial. Transplantation. 2005;80:1556-1559.
10. Liu JP, Manheimer E, Yang M. Herbal medicines for treating HIV infection and AIDS. Cochrane Database Syst Rev. 2005;(3):CD003937.
11. Hsu CH, Cheng AL. Clinical studies with curcumin. Adv Exp Med Biol. 2007;595:471-480.
12. National Center for Complementary and Alternative Medicine Herbs at a glance: turmeric. Updated August 12, 2010. Available at: http://nccam.nih.gov/health/turmeric/. Accessed October 11, 2010.
1. Chainani-Wu N. Safety and anti-inflammatory activity of curcumin: a component of turmeric (Curcuma longa). J Altern Complement Med. 2003;9:161-168.
2. Deodhar SD, Sethi R, Srimal RC. Preliminary studies on antirheumatic activity of curcumin (diferuloyl methane). Indian J Med Res. 1980;71:632-634.
3. Heng MC, Song MK, Harker J, et al. Drug-induced suppression of phosphorylase kinase activity correlates with resolution of psoriasis as assessed by clinical, histological, and immunohistochemical parameters. Br J Dermatol. 2000;143:937-949.
4. Holt PR, Katz S, Kirshoff R. Curcumin therapy in inflammatory bowel disease: a pilot study. Dig Dis Sci. 2005;50:2191-2193.
5. Hanai H, Iida T, Takeuchi K, et al. Curcumin maintenance therapy for ulcerative colitis: randomized, multicenter, double-blind, placebo-controlled trial. Clin Gastroenterol Hepatol. 2006;4:1502-1506.
6. Lal B, Kapoor AK, Asthana OP, et al. Efficacy of curcumin in the management of chronic anterior uveitis. Phytother Res. 1999;13:318-322.
7. Lal B, Kapoor AK, Agrawal PK, et al. Role of curcumin in idiopathic inflammatory orbital pseudotumours. Phytother Res. 2000;14:443-447.
8. Cruz-Correa M, Shoskes DA, Sanchez P, et al. Combination treatment with curcumin and quercetin of adenomas in familial adenomatous polyposis. Clin Gastroenterol Hepatol. 2006;4:1035-1038.
9. Shoskes D, Lapierre C, Cruz-Correa M, et al. Beneficial effects of the bioflavonoids curcumin and quercetin on early function in cadaveric renal transplantation: a randomized placebo controlled trial. Transplantation. 2005;80:1556-1559.
10. Liu JP, Manheimer E, Yang M. Herbal medicines for treating HIV infection and AIDS. Cochrane Database Syst Rev. 2005;(3):CD003937.
11. Hsu CH, Cheng AL. Clinical studies with curcumin. Adv Exp Med Biol. 2007;595:471-480.
12. National Center for Complementary and Alternative Medicine Herbs at a glance: turmeric. Updated August 12, 2010. Available at: http://nccam.nih.gov/health/turmeric/. Accessed October 11, 2010.
Evidence-based answers from the Family Physicians Inquiries Network
How best to diagnose asthma in infants and toddlers?
NO RELIABLE WAY EXISTS TO DIAGNOSE ASTHMA IN INFANTS AND TODDLERS. Recurrent wheezing, especially apart from colds, combined with physician-diagnosed eczema or atopic dermatitis, eosinophilia, and a parental history of asthma, increase the probability of a subsequent asthma diagnosis in the absence of other causes (strength of recommendation: B, 2 good-quality cohort studies).
Evidence summary
Wheezing in children is common and the differential diagnosis is broad. The many potential causes include upper respiratory infection, asthma, cystic fibrosis, foreign body aspiration, vascular ring, tracheomalacia, primary immunodeficiency, and congenital heart disease.1
Outpatient primary care cohort studies estimate that about half of children wheeze before they reach school age. Only one-third of children who wheeze during the first 3 years of life, however, continue to wheeze into later childhood and young adulthood.2-4
These findings have led some experts to suggest that not all wheezing in children is asthma and that asthma exists in variant forms.5-7 Variant wheezing patterns include transient early wheezing, which seems to be most prevalent in the first 3 years of life; wheezing without atopy, which occurs most often at 3 to 6 years of age; and wheezing with immunoglobulin E-associated atopy, which gradually increases in prevalence from birth and dominates in the over-6 age group. It is children in this last group whom we generally consider to have asthma.
Objective measures of lung function are challenging to perform in young children. Clinical signs and symptoms thus suggest the diagnosis of asthma.
Atopy, rhinitis, and eczema most often accompany persistent wheezing
Primary care cohort studies provide the best available evidence on which findings in infants and toddlers most likely predict persistent airway disease in childhood. A whole-population cohort study followed nearly all children born on the Isle of Wight from January 1989 through February 1990 to evaluate the natural history of childhood wheezing and to study associated risk factors.8 Children were seen at birth and at 1, 2, 4, and 10 years of age.
Findings most associated with current wheezing (within the last year) in 10-year-olds were atopy (odds ratio [OR]=4.38; 95% confidence interval [CI], 3.07-6.25), rhinitis (OR=3.72; 95% CI, 2.21-6.27), and eczema (OR=3.04; 95% CI, 2.05-4.51).8
An index to predict asthma
Since 1980, the Tucson Children’s Respiratory Study has followed 1246 healthy newborns seen by pediatricians affiliated with a large HMO in Tucson, Arizona. Questionnaires about parental asthma history and prenatal smoking history were obtained at enrollment. Childhood wheezing and its frequency, as well as physician-diagnosed allergies or asthma, were assessed at ages 2 and 3. If the child had wheezed in the past year, then the child was considered to be an “early wheezer.” If the frequency was 3 or more on a 5-point scale, then the child was considered to be an “early frequent wheezer.” Questionnaires were re-administered at ages 6, 8, 11, and 13. Three episodes of wheezing within the past year or a physician diagnosis of asthma with symptoms in the past year was considered “active asthma.” Blood specimens for eosinophils were obtained at age 10.
Using these data, the researchers developed stringent and loose criteria (TABLE 1) and odds ratios (TABLES 2 and 3) for childhood factors most predictive of an asthma diagnosis at an older age. The findings of the study may help clinicians care for wheezing infants and toddlers.9
TABLE 1
A clinical index of asthma risk9*
| Major criteria | Minor criteria |
|---|---|
| Parental asthma (history of physician diagnosis of asthma in a parent) | Allergic rhinitis (physician diagnosis of allergic rhinitis as reported in questionnaires at ages 2 or 3 y) |
| Eczema (physician diagnosis of atopic dermatitis as reported in questionnaires at ages 2 or 3 y) | Wheezing apart from colds |
| Eosinophilia (≥4%) | |
| *Stringent index for predicting asthma: Child has early, frequent wheezing plus at least 1 of the 2 major criteria or 2 of the 3 minor criteria. Loose index for predicting asthma: Child has early wheezing plus at least 1 of the 2 major criteria or 2 of the 3 minor criteria. | |
TABLE 2
Likelihood of active asthma predicted by stringent index9
| Active asthma | OR (95% CI) | Sensitivity, % (95% CI) | Specificity, % (95% CI) | PPV, % (95% CI) | NPV, % (95% CI) |
|---|---|---|---|---|---|
| At 6 y | 9.8 (5.6-17.2) | 27.5 (24.6-30.4) | 96.3 (95.1-97.5) | 47.5 (44.3-50.7) | 91.6 (89.8-93.4) |
| At 8 y | 5.8 (2.9-11.2) | 16.3 (13.7-18.9) | 96.7 (95.4-98.0) | 43.6 (40.1-47.1) | 88.2 (85.9-90.5) |
| At 11 y | 4.3 (2.4-7.8) | 15 (12.6-17.4) | 96.1 (94.8-97.4) | 42.0 (38.7-45.3) | 85.6 (83.3-87.9) |
| At 13 y | 5.7 (2.8-11.6) | 14.8 (12.1-17.5) | 97.0 (95.7-98.3) | 51.5 (47.7-55.3) | 84.2 (81.4-87.0) |
| CI, confidence interval; NPV, negative predictive value; OR, odds ratio; PPV, positive predictive value. | |||||
TABLE 3
Likelihood of active asthma predicted by loose index9
| Active asthma | OR (95% CI) | Sensitivity, % (95% CI) | Specificity, % (95% CI) | PPV, % (95% CI) | NPV, % (95% CI) |
|---|---|---|---|---|---|
| At 6 y | 5.5 (3.5-8.4) | 56.6 (53.3-59.9) | 80.8 (78.3-83.3) | 26.2 (23.4-29.0) | 93.9 (92.4-95.4) |
| At 8 y | 4.4 (2.8-6.8) | 50.5 (47.0-54.0) | 81.1 (78.3-83.9) | 29.4 (26.2-32.6) | 91.3 (89.3-93.3) |
| At 11 y | 2.6 (1.8-3.8) | 40.1 (36.8-43.4) | 79.6 (76.9-82.3) | 27.1 (24.1-30.1) | 87.5 (85.3-89.7) |
| At 13 y | 3.0 (1.9-4.6) | 39.3 (35.5-43.1) | 82.1 (79.1-85.1) | 31.7 (28.1-35.3) | 86.5 (83.9-89.1) |
| CI, confidence interval; NPV, negative predictive value; OR, odds ratio; PPV, positive predictive value. | |||||
Recommendations
A European and United States expert panel guide to the diagnosis and treatment of asthma in childhood, PRACTALL, states that “asthma should be suspected in any infant with recurrent wheezing and cough episodes. Frequently, diagnosis is possible only through long-term follow-up, consideration of the extensive differential diagnoses, and by observing the child’s response to bronchodilator and/or anti-inflammatory treatment.”10
The National Asthma Education and Prevention Program’s Expert Panel Report 3 (EPR-3) notes that diagnostic evaluation for asthma in children 0 to 4 years of age should include history, symptoms, physical examination, and assessment of quality of life.1
1. National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program. Expert panel report 3 (EPR-3): guidelines for the diagnosis and management of asthma. NIH publication 07-4051. Bethesda, Md: National Heart, Lung, and Blood Institute; 2007. Available at: www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm. Accessed June 20, 2008.
2. Martinez FD, Wright AL, Taussig LM, et al. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med. 1995;332:133-138.
3. Sears MR, Greene JM, Willan AR, et al. A longitudinal, population-based cohort study of childhood asthma followed to adulthood. N Engl J Med. 2003;349:1414-1422.
4. Jenkins MA, Hopper JL, Bowes G, et al. Factors in childhood as predictors of asthma in adult life. BMJ. 1994;309:90-93.
5. Rusconi F, Galassi C, Corbo GM, et al. Risk factors for early, persistent, and late-onset wheezing in young children. SIDRIA Collaborative Group. Am J Respir Crit Care Med. 1999;167:1617-1622.
6. Stein RT, Martinez FD. Asthma phenotypes in childhood: lessons from an epidemiologic approach. Paediatr Respir Rev. 2004;5:155-161.
7. Stein RT, Holberg CJ, Morgan WJ, et al. Peak flow variability, methacholine responsiveness and atopy as markers for detecting different wheezing phenotypes in childhood. Thorax. 1997;52:946-952.
8. Arshad SH, Kurukulaaratchy RJ, Fenn M, et al. Early life risk factors for current wheeze, asthma, and bronchial hyper-responsiveness at 10 years of age. Chest. 2005;127:502-508.
9. Castro-Rodriguez JA, Holberg CJ, Wright AL, et al. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med. 2000;162:1403-1406.
10. Bacharier LB, Boner A, Carlsen KH, et al. Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report. Allergy. 2008;63:5-34.
NO RELIABLE WAY EXISTS TO DIAGNOSE ASTHMA IN INFANTS AND TODDLERS. Recurrent wheezing, especially apart from colds, combined with physician-diagnosed eczema or atopic dermatitis, eosinophilia, and a parental history of asthma, increase the probability of a subsequent asthma diagnosis in the absence of other causes (strength of recommendation: B, 2 good-quality cohort studies).
Evidence summary
Wheezing in children is common and the differential diagnosis is broad. The many potential causes include upper respiratory infection, asthma, cystic fibrosis, foreign body aspiration, vascular ring, tracheomalacia, primary immunodeficiency, and congenital heart disease.1
Outpatient primary care cohort studies estimate that about half of children wheeze before they reach school age. Only one-third of children who wheeze during the first 3 years of life, however, continue to wheeze into later childhood and young adulthood.2-4
These findings have led some experts to suggest that not all wheezing in children is asthma and that asthma exists in variant forms.5-7 Variant wheezing patterns include transient early wheezing, which seems to be most prevalent in the first 3 years of life; wheezing without atopy, which occurs most often at 3 to 6 years of age; and wheezing with immunoglobulin E-associated atopy, which gradually increases in prevalence from birth and dominates in the over-6 age group. It is children in this last group whom we generally consider to have asthma.
Objective measures of lung function are challenging to perform in young children. Clinical signs and symptoms thus suggest the diagnosis of asthma.
Atopy, rhinitis, and eczema most often accompany persistent wheezing
Primary care cohort studies provide the best available evidence on which findings in infants and toddlers most likely predict persistent airway disease in childhood. A whole-population cohort study followed nearly all children born on the Isle of Wight from January 1989 through February 1990 to evaluate the natural history of childhood wheezing and to study associated risk factors.8 Children were seen at birth and at 1, 2, 4, and 10 years of age.
Findings most associated with current wheezing (within the last year) in 10-year-olds were atopy (odds ratio [OR]=4.38; 95% confidence interval [CI], 3.07-6.25), rhinitis (OR=3.72; 95% CI, 2.21-6.27), and eczema (OR=3.04; 95% CI, 2.05-4.51).8
An index to predict asthma
Since 1980, the Tucson Children’s Respiratory Study has followed 1246 healthy newborns seen by pediatricians affiliated with a large HMO in Tucson, Arizona. Questionnaires about parental asthma history and prenatal smoking history were obtained at enrollment. Childhood wheezing and its frequency, as well as physician-diagnosed allergies or asthma, were assessed at ages 2 and 3. If the child had wheezed in the past year, then the child was considered to be an “early wheezer.” If the frequency was 3 or more on a 5-point scale, then the child was considered to be an “early frequent wheezer.” Questionnaires were re-administered at ages 6, 8, 11, and 13. Three episodes of wheezing within the past year or a physician diagnosis of asthma with symptoms in the past year was considered “active asthma.” Blood specimens for eosinophils were obtained at age 10.
Using these data, the researchers developed stringent and loose criteria (TABLE 1) and odds ratios (TABLES 2 and 3) for childhood factors most predictive of an asthma diagnosis at an older age. The findings of the study may help clinicians care for wheezing infants and toddlers.9
TABLE 1
A clinical index of asthma risk9*
| Major criteria | Minor criteria |
|---|---|
| Parental asthma (history of physician diagnosis of asthma in a parent) | Allergic rhinitis (physician diagnosis of allergic rhinitis as reported in questionnaires at ages 2 or 3 y) |
| Eczema (physician diagnosis of atopic dermatitis as reported in questionnaires at ages 2 or 3 y) | Wheezing apart from colds |
| Eosinophilia (≥4%) | |
| *Stringent index for predicting asthma: Child has early, frequent wheezing plus at least 1 of the 2 major criteria or 2 of the 3 minor criteria. Loose index for predicting asthma: Child has early wheezing plus at least 1 of the 2 major criteria or 2 of the 3 minor criteria. | |
TABLE 2
Likelihood of active asthma predicted by stringent index9
| Active asthma | OR (95% CI) | Sensitivity, % (95% CI) | Specificity, % (95% CI) | PPV, % (95% CI) | NPV, % (95% CI) |
|---|---|---|---|---|---|
| At 6 y | 9.8 (5.6-17.2) | 27.5 (24.6-30.4) | 96.3 (95.1-97.5) | 47.5 (44.3-50.7) | 91.6 (89.8-93.4) |
| At 8 y | 5.8 (2.9-11.2) | 16.3 (13.7-18.9) | 96.7 (95.4-98.0) | 43.6 (40.1-47.1) | 88.2 (85.9-90.5) |
| At 11 y | 4.3 (2.4-7.8) | 15 (12.6-17.4) | 96.1 (94.8-97.4) | 42.0 (38.7-45.3) | 85.6 (83.3-87.9) |
| At 13 y | 5.7 (2.8-11.6) | 14.8 (12.1-17.5) | 97.0 (95.7-98.3) | 51.5 (47.7-55.3) | 84.2 (81.4-87.0) |
| CI, confidence interval; NPV, negative predictive value; OR, odds ratio; PPV, positive predictive value. | |||||
TABLE 3
Likelihood of active asthma predicted by loose index9
| Active asthma | OR (95% CI) | Sensitivity, % (95% CI) | Specificity, % (95% CI) | PPV, % (95% CI) | NPV, % (95% CI) |
|---|---|---|---|---|---|
| At 6 y | 5.5 (3.5-8.4) | 56.6 (53.3-59.9) | 80.8 (78.3-83.3) | 26.2 (23.4-29.0) | 93.9 (92.4-95.4) |
| At 8 y | 4.4 (2.8-6.8) | 50.5 (47.0-54.0) | 81.1 (78.3-83.9) | 29.4 (26.2-32.6) | 91.3 (89.3-93.3) |
| At 11 y | 2.6 (1.8-3.8) | 40.1 (36.8-43.4) | 79.6 (76.9-82.3) | 27.1 (24.1-30.1) | 87.5 (85.3-89.7) |
| At 13 y | 3.0 (1.9-4.6) | 39.3 (35.5-43.1) | 82.1 (79.1-85.1) | 31.7 (28.1-35.3) | 86.5 (83.9-89.1) |
| CI, confidence interval; NPV, negative predictive value; OR, odds ratio; PPV, positive predictive value. | |||||
Recommendations
A European and United States expert panel guide to the diagnosis and treatment of asthma in childhood, PRACTALL, states that “asthma should be suspected in any infant with recurrent wheezing and cough episodes. Frequently, diagnosis is possible only through long-term follow-up, consideration of the extensive differential diagnoses, and by observing the child’s response to bronchodilator and/or anti-inflammatory treatment.”10
The National Asthma Education and Prevention Program’s Expert Panel Report 3 (EPR-3) notes that diagnostic evaluation for asthma in children 0 to 4 years of age should include history, symptoms, physical examination, and assessment of quality of life.1
NO RELIABLE WAY EXISTS TO DIAGNOSE ASTHMA IN INFANTS AND TODDLERS. Recurrent wheezing, especially apart from colds, combined with physician-diagnosed eczema or atopic dermatitis, eosinophilia, and a parental history of asthma, increase the probability of a subsequent asthma diagnosis in the absence of other causes (strength of recommendation: B, 2 good-quality cohort studies).
Evidence summary
Wheezing in children is common and the differential diagnosis is broad. The many potential causes include upper respiratory infection, asthma, cystic fibrosis, foreign body aspiration, vascular ring, tracheomalacia, primary immunodeficiency, and congenital heart disease.1
Outpatient primary care cohort studies estimate that about half of children wheeze before they reach school age. Only one-third of children who wheeze during the first 3 years of life, however, continue to wheeze into later childhood and young adulthood.2-4
These findings have led some experts to suggest that not all wheezing in children is asthma and that asthma exists in variant forms.5-7 Variant wheezing patterns include transient early wheezing, which seems to be most prevalent in the first 3 years of life; wheezing without atopy, which occurs most often at 3 to 6 years of age; and wheezing with immunoglobulin E-associated atopy, which gradually increases in prevalence from birth and dominates in the over-6 age group. It is children in this last group whom we generally consider to have asthma.
Objective measures of lung function are challenging to perform in young children. Clinical signs and symptoms thus suggest the diagnosis of asthma.
Atopy, rhinitis, and eczema most often accompany persistent wheezing
Primary care cohort studies provide the best available evidence on which findings in infants and toddlers most likely predict persistent airway disease in childhood. A whole-population cohort study followed nearly all children born on the Isle of Wight from January 1989 through February 1990 to evaluate the natural history of childhood wheezing and to study associated risk factors.8 Children were seen at birth and at 1, 2, 4, and 10 years of age.
Findings most associated with current wheezing (within the last year) in 10-year-olds were atopy (odds ratio [OR]=4.38; 95% confidence interval [CI], 3.07-6.25), rhinitis (OR=3.72; 95% CI, 2.21-6.27), and eczema (OR=3.04; 95% CI, 2.05-4.51).8
An index to predict asthma
Since 1980, the Tucson Children’s Respiratory Study has followed 1246 healthy newborns seen by pediatricians affiliated with a large HMO in Tucson, Arizona. Questionnaires about parental asthma history and prenatal smoking history were obtained at enrollment. Childhood wheezing and its frequency, as well as physician-diagnosed allergies or asthma, were assessed at ages 2 and 3. If the child had wheezed in the past year, then the child was considered to be an “early wheezer.” If the frequency was 3 or more on a 5-point scale, then the child was considered to be an “early frequent wheezer.” Questionnaires were re-administered at ages 6, 8, 11, and 13. Three episodes of wheezing within the past year or a physician diagnosis of asthma with symptoms in the past year was considered “active asthma.” Blood specimens for eosinophils were obtained at age 10.
Using these data, the researchers developed stringent and loose criteria (TABLE 1) and odds ratios (TABLES 2 and 3) for childhood factors most predictive of an asthma diagnosis at an older age. The findings of the study may help clinicians care for wheezing infants and toddlers.9
TABLE 1
A clinical index of asthma risk9*
| Major criteria | Minor criteria |
|---|---|
| Parental asthma (history of physician diagnosis of asthma in a parent) | Allergic rhinitis (physician diagnosis of allergic rhinitis as reported in questionnaires at ages 2 or 3 y) |
| Eczema (physician diagnosis of atopic dermatitis as reported in questionnaires at ages 2 or 3 y) | Wheezing apart from colds |
| Eosinophilia (≥4%) | |
| *Stringent index for predicting asthma: Child has early, frequent wheezing plus at least 1 of the 2 major criteria or 2 of the 3 minor criteria. Loose index for predicting asthma: Child has early wheezing plus at least 1 of the 2 major criteria or 2 of the 3 minor criteria. | |
TABLE 2
Likelihood of active asthma predicted by stringent index9
| Active asthma | OR (95% CI) | Sensitivity, % (95% CI) | Specificity, % (95% CI) | PPV, % (95% CI) | NPV, % (95% CI) |
|---|---|---|---|---|---|
| At 6 y | 9.8 (5.6-17.2) | 27.5 (24.6-30.4) | 96.3 (95.1-97.5) | 47.5 (44.3-50.7) | 91.6 (89.8-93.4) |
| At 8 y | 5.8 (2.9-11.2) | 16.3 (13.7-18.9) | 96.7 (95.4-98.0) | 43.6 (40.1-47.1) | 88.2 (85.9-90.5) |
| At 11 y | 4.3 (2.4-7.8) | 15 (12.6-17.4) | 96.1 (94.8-97.4) | 42.0 (38.7-45.3) | 85.6 (83.3-87.9) |
| At 13 y | 5.7 (2.8-11.6) | 14.8 (12.1-17.5) | 97.0 (95.7-98.3) | 51.5 (47.7-55.3) | 84.2 (81.4-87.0) |
| CI, confidence interval; NPV, negative predictive value; OR, odds ratio; PPV, positive predictive value. | |||||
TABLE 3
Likelihood of active asthma predicted by loose index9
| Active asthma | OR (95% CI) | Sensitivity, % (95% CI) | Specificity, % (95% CI) | PPV, % (95% CI) | NPV, % (95% CI) |
|---|---|---|---|---|---|
| At 6 y | 5.5 (3.5-8.4) | 56.6 (53.3-59.9) | 80.8 (78.3-83.3) | 26.2 (23.4-29.0) | 93.9 (92.4-95.4) |
| At 8 y | 4.4 (2.8-6.8) | 50.5 (47.0-54.0) | 81.1 (78.3-83.9) | 29.4 (26.2-32.6) | 91.3 (89.3-93.3) |
| At 11 y | 2.6 (1.8-3.8) | 40.1 (36.8-43.4) | 79.6 (76.9-82.3) | 27.1 (24.1-30.1) | 87.5 (85.3-89.7) |
| At 13 y | 3.0 (1.9-4.6) | 39.3 (35.5-43.1) | 82.1 (79.1-85.1) | 31.7 (28.1-35.3) | 86.5 (83.9-89.1) |
| CI, confidence interval; NPV, negative predictive value; OR, odds ratio; PPV, positive predictive value. | |||||
Recommendations
A European and United States expert panel guide to the diagnosis and treatment of asthma in childhood, PRACTALL, states that “asthma should be suspected in any infant with recurrent wheezing and cough episodes. Frequently, diagnosis is possible only through long-term follow-up, consideration of the extensive differential diagnoses, and by observing the child’s response to bronchodilator and/or anti-inflammatory treatment.”10
The National Asthma Education and Prevention Program’s Expert Panel Report 3 (EPR-3) notes that diagnostic evaluation for asthma in children 0 to 4 years of age should include history, symptoms, physical examination, and assessment of quality of life.1
1. National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program. Expert panel report 3 (EPR-3): guidelines for the diagnosis and management of asthma. NIH publication 07-4051. Bethesda, Md: National Heart, Lung, and Blood Institute; 2007. Available at: www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm. Accessed June 20, 2008.
2. Martinez FD, Wright AL, Taussig LM, et al. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med. 1995;332:133-138.
3. Sears MR, Greene JM, Willan AR, et al. A longitudinal, population-based cohort study of childhood asthma followed to adulthood. N Engl J Med. 2003;349:1414-1422.
4. Jenkins MA, Hopper JL, Bowes G, et al. Factors in childhood as predictors of asthma in adult life. BMJ. 1994;309:90-93.
5. Rusconi F, Galassi C, Corbo GM, et al. Risk factors for early, persistent, and late-onset wheezing in young children. SIDRIA Collaborative Group. Am J Respir Crit Care Med. 1999;167:1617-1622.
6. Stein RT, Martinez FD. Asthma phenotypes in childhood: lessons from an epidemiologic approach. Paediatr Respir Rev. 2004;5:155-161.
7. Stein RT, Holberg CJ, Morgan WJ, et al. Peak flow variability, methacholine responsiveness and atopy as markers for detecting different wheezing phenotypes in childhood. Thorax. 1997;52:946-952.
8. Arshad SH, Kurukulaaratchy RJ, Fenn M, et al. Early life risk factors for current wheeze, asthma, and bronchial hyper-responsiveness at 10 years of age. Chest. 2005;127:502-508.
9. Castro-Rodriguez JA, Holberg CJ, Wright AL, et al. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med. 2000;162:1403-1406.
10. Bacharier LB, Boner A, Carlsen KH, et al. Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report. Allergy. 2008;63:5-34.
1. National Heart, Lung, and Blood Institute, National Asthma Education and Prevention Program. Expert panel report 3 (EPR-3): guidelines for the diagnosis and management of asthma. NIH publication 07-4051. Bethesda, Md: National Heart, Lung, and Blood Institute; 2007. Available at: www.nhlbi.nih.gov/guidelines/asthma/asthgdln.htm. Accessed June 20, 2008.
2. Martinez FD, Wright AL, Taussig LM, et al. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med. 1995;332:133-138.
3. Sears MR, Greene JM, Willan AR, et al. A longitudinal, population-based cohort study of childhood asthma followed to adulthood. N Engl J Med. 2003;349:1414-1422.
4. Jenkins MA, Hopper JL, Bowes G, et al. Factors in childhood as predictors of asthma in adult life. BMJ. 1994;309:90-93.
5. Rusconi F, Galassi C, Corbo GM, et al. Risk factors for early, persistent, and late-onset wheezing in young children. SIDRIA Collaborative Group. Am J Respir Crit Care Med. 1999;167:1617-1622.
6. Stein RT, Martinez FD. Asthma phenotypes in childhood: lessons from an epidemiologic approach. Paediatr Respir Rev. 2004;5:155-161.
7. Stein RT, Holberg CJ, Morgan WJ, et al. Peak flow variability, methacholine responsiveness and atopy as markers for detecting different wheezing phenotypes in childhood. Thorax. 1997;52:946-952.
8. Arshad SH, Kurukulaaratchy RJ, Fenn M, et al. Early life risk factors for current wheeze, asthma, and bronchial hyper-responsiveness at 10 years of age. Chest. 2005;127:502-508.
9. Castro-Rodriguez JA, Holberg CJ, Wright AL, et al. A clinical index to define risk of asthma in young children with recurrent wheezing. Am J Respir Crit Care Med. 2000;162:1403-1406.
10. Bacharier LB, Boner A, Carlsen KH, et al. Diagnosis and treatment of asthma in childhood: a PRACTALL consensus report. Allergy. 2008;63:5-34.
Evidence-based answers from the Family Physicians Inquiries Network
Which nutritional therapies are safe and effective for depression?
ST. JOHN’S WORT is effective for short-term relief of mild to moderate depression (strength of recommendation [SOR]: A; 1 systematic review). Its safety profile is superior to older antidepressants; data comparing it with newer antidepressants (such as selective serotonin reuptake inhibitors) are limited (SOR: A, 1 systematic review).
A small but statistically significant clinical benefit has been demonstrated for saffron, lavender, borage, dan zhi xiao yao (SOR: B, 1 systematic review and 3 randomized controlled trials), folate (SOR: A, 1 systematic review), and S-adenosylmethionine (SAMe) (SOR: A, 1 meta-analysis and 1 systematic review). Most trials of these preparations were short and small, limiting the ability to detect adverse effects.
Tryptophan (SOR: A, 1 systematic review) and 5-hydroxytryptophan (5-HTP) (SOR: A, 1 systematic review) have demonstrated superiority over placebo in alleviating symptoms of depression, but concerns exist about their safety.
N-3 long-chain polyunsaturated fatty acids (n-3 PUFAs) and omega-3 fatty acids don’t appear effective in treating major depressive disorder (SOR: A, 1 systematic review.)
Evidence summary
TABLE W1 summarizes study results and recommendations for nutritional therapies for depression.1-16
St. John’s wort works as well as standard antidepressants
A recent Cochrane review suggested that St. John’s wort is more effective than placebo in patients with mild to moderate depression and as effective as standard antidepressants.1
Other supplements also have benefits
A systematic review of 4 small randomized controlled trials (RCTs) suggested that saffron (30 mg) is superior to placebo in treating short-term depression (6 weeks). Treatment and outcomes were equivalent to fluoxetine and imipramine.2 A later RCT yielded results consistent with the systematic review.3
Combined lavender tincture (60 drops per day) and imipramine were more effective than imipramine alone in 1 small RCT.4
Borage, a traditional Persian medicine, was superior to placebo in reducing depressive symptoms in 1 small RCT.2
Dan zhi xiao yao, a traditional Chinese medicine, was as effective as the tricyclic anti-depressant maprotiline in 1 small RCT.2
Three RCTs suggested that folate may be used to supplement conventional treatments for depression, but it isn’t clear whether this would help patients with normal folate levels.5
A meta-analysis of 13 controlled clinical trials and a later systematic review of 11 articles including 2 RCTs concluded that SAMe is more effective than placebo and as efficacious as tricyclic antidepressants in treating major depression in adults. However, further trials are needed to answer questions about absorption, mechanism of action, and bioavailability.6,7
Tryptophan’s benefit comes with risk
In a Cochrane review of 2 RCTs, tryptophan and 5-HTP were superior to placebo in alleviating symptoms of depression. However, some published case reports have linked tryptophan use to potentially fatal eosinophilia-myalgia syndrome.8
No clear evidence for inositol or n-3 PUFAs
A Cochrane review of 4 small double-blind RCTs investigating inositol as a nutritional supplement in depression treatment failed to find clear evidence of therapeutic benefit.9
Three RCTs demonstrated significantly higher red blood cell membrane levels of n-3 PUFAs in nondepressed patients compared with depressed patients.10 However, a systematic review of 12 RCTs failed to demonstrate any benefit of n-3 PUFA supplementation over placebo in treating depressed mood.11 The authors concluded that larger trials are needed to demonstrate efficacy because of marked heterogeneity among the RCTs.
Safety issues. A recent Cochrane review found fewer adverse effects for St. John’s wort than tricyclic antidepressants.1 The most common adverse reactions were sensitivity to light, skin symptoms, gastrointestinal symptoms, and agitation. Data comparing St. John’s wort with newer antidepressants are lacking.
St. John’s wort does have pharmacokinetic interactions and should not be taken concurrently with other antidepressants, immunosuppressants, anti-HIV drugs, cou-marin-type anticoagulants, or certain antineoplastic agents.17
Reviews of meta-analyses, case reports, population studies, RCTs, and other literature have reported virtually no adverse effects for PUFAs; 18 trials investigating saffron, lavender, borage, dan zhi xiao yao, folate, SAMe, and inositol also reported no safety concerns. However, the size and duration of these studies limit their ability to detect significant problems.2,5,6,9 As previously noted, concerns exist regarding an association between tryptophan and eosinophilia-myalgia syndrome.8
Recommendations
The World Federation of Societies of Biological Psychiatry doesn’t recommend St. John’s wort for moderate to severe depression, but suggests it can be considered for treating mild to moderate depressive episodes provided the prescriber considers potential pharmacokinetic interactions with other medications and understands possible variations in purity and potency of extracts.19 The Federation also states that St. John’s wort is an alternative for patients reluctant to take traditional antidepressants.
TABLE W1
What the studies say about nutritional therapies for depression
| Supplement | Study type | Number of subjects | Comparison group | Outcome measure | Results | Conclusion | SOR |
|---|---|---|---|---|---|---|---|
| Borage (Echium amoenum) | 1 small RCT | 352,16 | Placebo | HAM-D | Improved HAM-D scores significantly at week 4 (borage 18. 3±3. 9 vs placebo 21. 9±3. 9; t=2. 51; P=. 02); no significant difference at Week 62,16 | Superior to placebo in reducing symptoms of depression | B |
| Dan zhi xiao yao | 1 small RCT | 632 | Maprotiline | HAM-D, SDS, SAS, scale for traditional Chinese medicine syndrome and symptom differentiation | 87% depression reduction (dan zhi xiao yao) vs 84% depression reduction (maprotiline) | As effective as maprotiline in treating depression | B |
| Folate | Cochrane review of 3 RCTs | 2475 | Studies 1 and 2: folate vs folate + other treatment (Study 1: low folate levels; Study 2: normal folate levels) Study 3: folate vs trazodone (normal folate levels) | HAM-D | Superior to placebo (NNT=5, defined as 50% reduction in HAM-D); comparable to trazodone (RR=0. 97; 95% CI, 0. 14-2. 01)7 | May have role as supplement to other treatments for depression Efficacy unclear in patients with normal folate levels | A |
| Inositol | Cochrane review of 4 RCTs | 1419 | Studies 1-3: placebo plus conventional antidepressants Study 4: placebo only | HAM-D, MADRS | Pooled estimate of effect of all 3 studies (SMD= -0. 08; 95% CI, -0. 45 to 0. 30) | No clear evidence of therapeutic benefit | A |
| Lavender (Lavandula angustifolia) | 1 small RCT | 454 | Imipramine | HAM-D | Imipramine plus lavender showed significant effect compared with imipramine alone (f=26. 87; Df=3. 01; P<. 0001) | Synergistic effect suggested when used with imipramine | B |
| n-3 long-chain polyunsaturated fatty acids | Systematic review including 3 RCTs; 10 meta-analysis of 12 RCTs11 | 10210 103211 | Various comparison groups included | Serum SFAs, MUFAs, PUFAs; RBC membrane levels n-3 PUFAs2 HAM-D, BDI3 | Systematic review:10 Study 1: n=30; ES=3. 61 Study 2: n=24; ES=1. 2 Study 3: n=48; ES=2. 43 Meta-analysis:11 Pooled ES=0. 13; 95% CI, 0. 01-0. 25 | Significantly higher RBC membrane levels of n-3 PUFAs in nondepressed vs depressed patients10 No significant effect for supplementation11 Larger trials with adequate power needed2,3 | A |
| S-adenosyl-methionine (SAMe) | Meta-analysis of 13 RCTs,6 systematic review including 2 RCTs7 | 3996 787 | Placebo and conventional antidepressants | HAM-D | NNT=2. 5 for HAM-D decrease of >25%; 6 NNT=6. 25 for HAM-D decrease of >50%6 | May have role in treatment of major depression Further trials are needed to address unanswered questions about absorption, mechanism of action, and bioavailability7 | A |
| Saffron (Crocus sativus) | Systematic review of 4 small RCTs, 1 later RCT | 3012 4013 4014 4015 403 | Imipramine12 Placebo13,15 Fluoxetine5,14 | HAM-D | Systematic review: Study 1: imipramine and saffron equally efficacious (f=2. 91; P=. 09)12 Study 2: Improved HAM-D scores: -12. 20±4. 67 (saffron) vs -5. 10±4. 71 (placebo) (P<. 0001)13 Study 3: Improved HAM-D scores: saffron petal -12. 00±4. 10; fluoxetine -13. 50±4. 91; difference between 2 treatments not significant (P=. 27)14 Study 4: Improved HAM-D scores: -14. 01±5. 53 (saffron petal) vs -5. 05±4. 63 (placebo) (P<. 0001)15 Study 5:5 NNT=10 | Efficacy of extract and petal suggested to treat mild to moderate depression Large-scale trials are warranted | B |
| St. John’s wort (Hypericum perforatum L. ) | Cochrane review of 29 RCTs | 54891 | SSRIs, tri/tetracyclic antidepressants, placebo | Responder rate ratio | St. John’s wort vs placebo: 9 larger trials: RR=1. 28; 95% CI, 1. 10-1. 491 9 smaller trials: RR=1. 87; 95% CI, 1. 22-2. 871 St. John’s wort vs SSRIs: 12 trials: RR=1. 00; 95% CI, 0. 90-1. 111 St. John’s wort vs tricyclics: 5 trials: RR=1. 02; 95% CI, 0. 90-1. 151 | Effective for treating mild to moderate depression | A |
| Tryptophan and 5-hydroxy-tryptophan (5-HTP) | Cochrane review of 2 RCTs | 648 | Placebo | HAM-D | NNT=2. 78 vs placebo (OR=4. 1; 95% CI, 1. 28-13. 15 | Superior to placebo Insufficient evidence regarding safety | A |
| BDI, Beck Depression Inventory; CI, confidence interval; DF, degrees of freedom; ES, effect size; F, F statistic; HAM-D, Hamilton Depression Rating Scale; MADRS, Mont-gomery-Asberg Depression Rating Scale; MUFAs, monounsaturated fatty acids; n-3 PUFAs, n-3 long-chain polyunsaturated fatty acids; NNT, number needed to treat; OR, odds ratio; PUFAs, polyunsaturated fatty acids; RBC, red blood cell; RCT, randomized controlled trial; RR, relative risk; SAS, self-rating anxiety scale; SDS, self-rating depression scale; SFAs, saturated fatty acids; SMD, standard weighted mean difference; SOR, strength of recommendation; SSRI, selective serotonin reuptake inhibitor. | |||||||
1. Linde K, Bemer MM, Kriston L. St. John’s wort for major depression. Cochrane Database Syst Rev. 2008;(4):CD000448.-
2. Sarris J. Herbal medicines in the treatment of psychiatric disorders: a systematic review. Phytother Res. 2007;21:703-716.
3. Akhondzadeh Basti A, Moshiri E, Noorbala AA, et al. Comparison of petal of Crocus sativus L. and fluoxetine in the treatment of depressed outpatients. Prog Neuropsychopharmacol Biol Psychiatry. 2006;31:439-442.
4. Akhondzadeh S, Kashani L, Fotouhi A, et al. Comparison of Lavandula angustifolia Mill. tincture and imipramine in the treatment of mild to moderate depression. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:123-127.
5. Taylor MJ, Carney S, Geddes J, et al. Folate for depressive disorders. Cochrane Database Syst Rev. 2003;(2):CD003390.-
6. Bressa GM. S-adenosyl-l-methionine (SAMe) as antidepres-sant. Acta Neurol Scand Suppl. 1994;154:7-14.
7. Williams AL, Girard C, Jui D, et al. S-adenosylmethionine (SAMe) as treatment for depression. Clin Invest Med. 2005;28:132-139.
8. Shaw K, Turner J, Del Mar C. Tryptophan and 5-hydroxy-tryptophan for depression. Cochrane Database Syst Rev. 2002;(1):CD003198.-
9. Taylor MJ, Wilder H, Bhagwager Z, et al. Inositol for depressive disorders. Cochrane Database Syst Rev. 2004;(2):CD004049.-
10. Williams AL, Katz D, Ali A, et al. Do essential fatty acids have a role in the treatment of depression? J Affect Disord. 2006;93:117-123.
11. Appleton KM, Hayward RC, Gunnell D, et al. Effects of n-3 longchain polyunsaturated fatty acids on depressed mood. Am J Clin Nutr. 2006;84:1308-1316.
12. Akhondzadeh S, Fallah-Pour H, Afkham K, et al. Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression. BMC Complement Altern Med. 2004;4:12.-
13. Akhondzadeh S, Tahmacebi-Pour N, Noorbala AA, et al. Crocus sativus L. in the treatment of mild to moderate depression. Phytother Res. 2005;19:148-151.
14. Noorbala AA, Akhondzadeh S, Tahmacebi-Pour N, et al. Hydro-alcoholic extract of Crocus sativus L. versus fluoxetine in the treatment of mild to moderate depression. J Ethnopharmacol. 2005;97:281-284.
15. Moshiri E, Basti AA, Noorbala AA, et al. Crocus sativus L. (petal) in the treatment of mild-to-moderate depression. Phytomedicine. 2006;13:607-611.
16. Sayyah M, Sahhah M, Kamalinejad M. A preliminary randomized double blind clinical trial on the efficacy of aqueous extract of Echium amoenum in the treatment of mild to moderate major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:166-169.
17. Schulz V Safety of St. John’s wort extract compared to synthetic antidepressants. Phytomedicine. 2006;13:199-204.
18. Lee S, Gura KM, Kim S, et al. Current clinical applications of ome-ga-6 and omega-3 fatty acids. Nutr Clin Pract. 2006;21:323-341.
19. Bauer M, Bschor T, Pfennig A, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders in primary care. World J Biol Psychiatry. 2007;8:67-104.
ST. JOHN’S WORT is effective for short-term relief of mild to moderate depression (strength of recommendation [SOR]: A; 1 systematic review). Its safety profile is superior to older antidepressants; data comparing it with newer antidepressants (such as selective serotonin reuptake inhibitors) are limited (SOR: A, 1 systematic review).
A small but statistically significant clinical benefit has been demonstrated for saffron, lavender, borage, dan zhi xiao yao (SOR: B, 1 systematic review and 3 randomized controlled trials), folate (SOR: A, 1 systematic review), and S-adenosylmethionine (SAMe) (SOR: A, 1 meta-analysis and 1 systematic review). Most trials of these preparations were short and small, limiting the ability to detect adverse effects.
Tryptophan (SOR: A, 1 systematic review) and 5-hydroxytryptophan (5-HTP) (SOR: A, 1 systematic review) have demonstrated superiority over placebo in alleviating symptoms of depression, but concerns exist about their safety.
N-3 long-chain polyunsaturated fatty acids (n-3 PUFAs) and omega-3 fatty acids don’t appear effective in treating major depressive disorder (SOR: A, 1 systematic review.)
Evidence summary
TABLE W1 summarizes study results and recommendations for nutritional therapies for depression.1-16
St. John’s wort works as well as standard antidepressants
A recent Cochrane review suggested that St. John’s wort is more effective than placebo in patients with mild to moderate depression and as effective as standard antidepressants.1
Other supplements also have benefits
A systematic review of 4 small randomized controlled trials (RCTs) suggested that saffron (30 mg) is superior to placebo in treating short-term depression (6 weeks). Treatment and outcomes were equivalent to fluoxetine and imipramine.2 A later RCT yielded results consistent with the systematic review.3
Combined lavender tincture (60 drops per day) and imipramine were more effective than imipramine alone in 1 small RCT.4
Borage, a traditional Persian medicine, was superior to placebo in reducing depressive symptoms in 1 small RCT.2
Dan zhi xiao yao, a traditional Chinese medicine, was as effective as the tricyclic anti-depressant maprotiline in 1 small RCT.2
Three RCTs suggested that folate may be used to supplement conventional treatments for depression, but it isn’t clear whether this would help patients with normal folate levels.5
A meta-analysis of 13 controlled clinical trials and a later systematic review of 11 articles including 2 RCTs concluded that SAMe is more effective than placebo and as efficacious as tricyclic antidepressants in treating major depression in adults. However, further trials are needed to answer questions about absorption, mechanism of action, and bioavailability.6,7
Tryptophan’s benefit comes with risk
In a Cochrane review of 2 RCTs, tryptophan and 5-HTP were superior to placebo in alleviating symptoms of depression. However, some published case reports have linked tryptophan use to potentially fatal eosinophilia-myalgia syndrome.8
No clear evidence for inositol or n-3 PUFAs
A Cochrane review of 4 small double-blind RCTs investigating inositol as a nutritional supplement in depression treatment failed to find clear evidence of therapeutic benefit.9
Three RCTs demonstrated significantly higher red blood cell membrane levels of n-3 PUFAs in nondepressed patients compared with depressed patients.10 However, a systematic review of 12 RCTs failed to demonstrate any benefit of n-3 PUFA supplementation over placebo in treating depressed mood.11 The authors concluded that larger trials are needed to demonstrate efficacy because of marked heterogeneity among the RCTs.
Safety issues. A recent Cochrane review found fewer adverse effects for St. John’s wort than tricyclic antidepressants.1 The most common adverse reactions were sensitivity to light, skin symptoms, gastrointestinal symptoms, and agitation. Data comparing St. John’s wort with newer antidepressants are lacking.
St. John’s wort does have pharmacokinetic interactions and should not be taken concurrently with other antidepressants, immunosuppressants, anti-HIV drugs, cou-marin-type anticoagulants, or certain antineoplastic agents.17
Reviews of meta-analyses, case reports, population studies, RCTs, and other literature have reported virtually no adverse effects for PUFAs; 18 trials investigating saffron, lavender, borage, dan zhi xiao yao, folate, SAMe, and inositol also reported no safety concerns. However, the size and duration of these studies limit their ability to detect significant problems.2,5,6,9 As previously noted, concerns exist regarding an association between tryptophan and eosinophilia-myalgia syndrome.8
Recommendations
The World Federation of Societies of Biological Psychiatry doesn’t recommend St. John’s wort for moderate to severe depression, but suggests it can be considered for treating mild to moderate depressive episodes provided the prescriber considers potential pharmacokinetic interactions with other medications and understands possible variations in purity and potency of extracts.19 The Federation also states that St. John’s wort is an alternative for patients reluctant to take traditional antidepressants.
TABLE W1
What the studies say about nutritional therapies for depression
| Supplement | Study type | Number of subjects | Comparison group | Outcome measure | Results | Conclusion | SOR |
|---|---|---|---|---|---|---|---|
| Borage (Echium amoenum) | 1 small RCT | 352,16 | Placebo | HAM-D | Improved HAM-D scores significantly at week 4 (borage 18. 3±3. 9 vs placebo 21. 9±3. 9; t=2. 51; P=. 02); no significant difference at Week 62,16 | Superior to placebo in reducing symptoms of depression | B |
| Dan zhi xiao yao | 1 small RCT | 632 | Maprotiline | HAM-D, SDS, SAS, scale for traditional Chinese medicine syndrome and symptom differentiation | 87% depression reduction (dan zhi xiao yao) vs 84% depression reduction (maprotiline) | As effective as maprotiline in treating depression | B |
| Folate | Cochrane review of 3 RCTs | 2475 | Studies 1 and 2: folate vs folate + other treatment (Study 1: low folate levels; Study 2: normal folate levels) Study 3: folate vs trazodone (normal folate levels) | HAM-D | Superior to placebo (NNT=5, defined as 50% reduction in HAM-D); comparable to trazodone (RR=0. 97; 95% CI, 0. 14-2. 01)7 | May have role as supplement to other treatments for depression Efficacy unclear in patients with normal folate levels | A |
| Inositol | Cochrane review of 4 RCTs | 1419 | Studies 1-3: placebo plus conventional antidepressants Study 4: placebo only | HAM-D, MADRS | Pooled estimate of effect of all 3 studies (SMD= -0. 08; 95% CI, -0. 45 to 0. 30) | No clear evidence of therapeutic benefit | A |
| Lavender (Lavandula angustifolia) | 1 small RCT | 454 | Imipramine | HAM-D | Imipramine plus lavender showed significant effect compared with imipramine alone (f=26. 87; Df=3. 01; P<. 0001) | Synergistic effect suggested when used with imipramine | B |
| n-3 long-chain polyunsaturated fatty acids | Systematic review including 3 RCTs; 10 meta-analysis of 12 RCTs11 | 10210 103211 | Various comparison groups included | Serum SFAs, MUFAs, PUFAs; RBC membrane levels n-3 PUFAs2 HAM-D, BDI3 | Systematic review:10 Study 1: n=30; ES=3. 61 Study 2: n=24; ES=1. 2 Study 3: n=48; ES=2. 43 Meta-analysis:11 Pooled ES=0. 13; 95% CI, 0. 01-0. 25 | Significantly higher RBC membrane levels of n-3 PUFAs in nondepressed vs depressed patients10 No significant effect for supplementation11 Larger trials with adequate power needed2,3 | A |
| S-adenosyl-methionine (SAMe) | Meta-analysis of 13 RCTs,6 systematic review including 2 RCTs7 | 3996 787 | Placebo and conventional antidepressants | HAM-D | NNT=2. 5 for HAM-D decrease of >25%; 6 NNT=6. 25 for HAM-D decrease of >50%6 | May have role in treatment of major depression Further trials are needed to address unanswered questions about absorption, mechanism of action, and bioavailability7 | A |
| Saffron (Crocus sativus) | Systematic review of 4 small RCTs, 1 later RCT | 3012 4013 4014 4015 403 | Imipramine12 Placebo13,15 Fluoxetine5,14 | HAM-D | Systematic review: Study 1: imipramine and saffron equally efficacious (f=2. 91; P=. 09)12 Study 2: Improved HAM-D scores: -12. 20±4. 67 (saffron) vs -5. 10±4. 71 (placebo) (P<. 0001)13 Study 3: Improved HAM-D scores: saffron petal -12. 00±4. 10; fluoxetine -13. 50±4. 91; difference between 2 treatments not significant (P=. 27)14 Study 4: Improved HAM-D scores: -14. 01±5. 53 (saffron petal) vs -5. 05±4. 63 (placebo) (P<. 0001)15 Study 5:5 NNT=10 | Efficacy of extract and petal suggested to treat mild to moderate depression Large-scale trials are warranted | B |
| St. John’s wort (Hypericum perforatum L. ) | Cochrane review of 29 RCTs | 54891 | SSRIs, tri/tetracyclic antidepressants, placebo | Responder rate ratio | St. John’s wort vs placebo: 9 larger trials: RR=1. 28; 95% CI, 1. 10-1. 491 9 smaller trials: RR=1. 87; 95% CI, 1. 22-2. 871 St. John’s wort vs SSRIs: 12 trials: RR=1. 00; 95% CI, 0. 90-1. 111 St. John’s wort vs tricyclics: 5 trials: RR=1. 02; 95% CI, 0. 90-1. 151 | Effective for treating mild to moderate depression | A |
| Tryptophan and 5-hydroxy-tryptophan (5-HTP) | Cochrane review of 2 RCTs | 648 | Placebo | HAM-D | NNT=2. 78 vs placebo (OR=4. 1; 95% CI, 1. 28-13. 15 | Superior to placebo Insufficient evidence regarding safety | A |
| BDI, Beck Depression Inventory; CI, confidence interval; DF, degrees of freedom; ES, effect size; F, F statistic; HAM-D, Hamilton Depression Rating Scale; MADRS, Mont-gomery-Asberg Depression Rating Scale; MUFAs, monounsaturated fatty acids; n-3 PUFAs, n-3 long-chain polyunsaturated fatty acids; NNT, number needed to treat; OR, odds ratio; PUFAs, polyunsaturated fatty acids; RBC, red blood cell; RCT, randomized controlled trial; RR, relative risk; SAS, self-rating anxiety scale; SDS, self-rating depression scale; SFAs, saturated fatty acids; SMD, standard weighted mean difference; SOR, strength of recommendation; SSRI, selective serotonin reuptake inhibitor. | |||||||
ST. JOHN’S WORT is effective for short-term relief of mild to moderate depression (strength of recommendation [SOR]: A; 1 systematic review). Its safety profile is superior to older antidepressants; data comparing it with newer antidepressants (such as selective serotonin reuptake inhibitors) are limited (SOR: A, 1 systematic review).
A small but statistically significant clinical benefit has been demonstrated for saffron, lavender, borage, dan zhi xiao yao (SOR: B, 1 systematic review and 3 randomized controlled trials), folate (SOR: A, 1 systematic review), and S-adenosylmethionine (SAMe) (SOR: A, 1 meta-analysis and 1 systematic review). Most trials of these preparations were short and small, limiting the ability to detect adverse effects.
Tryptophan (SOR: A, 1 systematic review) and 5-hydroxytryptophan (5-HTP) (SOR: A, 1 systematic review) have demonstrated superiority over placebo in alleviating symptoms of depression, but concerns exist about their safety.
N-3 long-chain polyunsaturated fatty acids (n-3 PUFAs) and omega-3 fatty acids don’t appear effective in treating major depressive disorder (SOR: A, 1 systematic review.)
Evidence summary
TABLE W1 summarizes study results and recommendations for nutritional therapies for depression.1-16
St. John’s wort works as well as standard antidepressants
A recent Cochrane review suggested that St. John’s wort is more effective than placebo in patients with mild to moderate depression and as effective as standard antidepressants.1
Other supplements also have benefits
A systematic review of 4 small randomized controlled trials (RCTs) suggested that saffron (30 mg) is superior to placebo in treating short-term depression (6 weeks). Treatment and outcomes were equivalent to fluoxetine and imipramine.2 A later RCT yielded results consistent with the systematic review.3
Combined lavender tincture (60 drops per day) and imipramine were more effective than imipramine alone in 1 small RCT.4
Borage, a traditional Persian medicine, was superior to placebo in reducing depressive symptoms in 1 small RCT.2
Dan zhi xiao yao, a traditional Chinese medicine, was as effective as the tricyclic anti-depressant maprotiline in 1 small RCT.2
Three RCTs suggested that folate may be used to supplement conventional treatments for depression, but it isn’t clear whether this would help patients with normal folate levels.5
A meta-analysis of 13 controlled clinical trials and a later systematic review of 11 articles including 2 RCTs concluded that SAMe is more effective than placebo and as efficacious as tricyclic antidepressants in treating major depression in adults. However, further trials are needed to answer questions about absorption, mechanism of action, and bioavailability.6,7
Tryptophan’s benefit comes with risk
In a Cochrane review of 2 RCTs, tryptophan and 5-HTP were superior to placebo in alleviating symptoms of depression. However, some published case reports have linked tryptophan use to potentially fatal eosinophilia-myalgia syndrome.8
No clear evidence for inositol or n-3 PUFAs
A Cochrane review of 4 small double-blind RCTs investigating inositol as a nutritional supplement in depression treatment failed to find clear evidence of therapeutic benefit.9
Three RCTs demonstrated significantly higher red blood cell membrane levels of n-3 PUFAs in nondepressed patients compared with depressed patients.10 However, a systematic review of 12 RCTs failed to demonstrate any benefit of n-3 PUFA supplementation over placebo in treating depressed mood.11 The authors concluded that larger trials are needed to demonstrate efficacy because of marked heterogeneity among the RCTs.
Safety issues. A recent Cochrane review found fewer adverse effects for St. John’s wort than tricyclic antidepressants.1 The most common adverse reactions were sensitivity to light, skin symptoms, gastrointestinal symptoms, and agitation. Data comparing St. John’s wort with newer antidepressants are lacking.
St. John’s wort does have pharmacokinetic interactions and should not be taken concurrently with other antidepressants, immunosuppressants, anti-HIV drugs, cou-marin-type anticoagulants, or certain antineoplastic agents.17
Reviews of meta-analyses, case reports, population studies, RCTs, and other literature have reported virtually no adverse effects for PUFAs; 18 trials investigating saffron, lavender, borage, dan zhi xiao yao, folate, SAMe, and inositol also reported no safety concerns. However, the size and duration of these studies limit their ability to detect significant problems.2,5,6,9 As previously noted, concerns exist regarding an association between tryptophan and eosinophilia-myalgia syndrome.8
Recommendations
The World Federation of Societies of Biological Psychiatry doesn’t recommend St. John’s wort for moderate to severe depression, but suggests it can be considered for treating mild to moderate depressive episodes provided the prescriber considers potential pharmacokinetic interactions with other medications and understands possible variations in purity and potency of extracts.19 The Federation also states that St. John’s wort is an alternative for patients reluctant to take traditional antidepressants.
TABLE W1
What the studies say about nutritional therapies for depression
| Supplement | Study type | Number of subjects | Comparison group | Outcome measure | Results | Conclusion | SOR |
|---|---|---|---|---|---|---|---|
| Borage (Echium amoenum) | 1 small RCT | 352,16 | Placebo | HAM-D | Improved HAM-D scores significantly at week 4 (borage 18. 3±3. 9 vs placebo 21. 9±3. 9; t=2. 51; P=. 02); no significant difference at Week 62,16 | Superior to placebo in reducing symptoms of depression | B |
| Dan zhi xiao yao | 1 small RCT | 632 | Maprotiline | HAM-D, SDS, SAS, scale for traditional Chinese medicine syndrome and symptom differentiation | 87% depression reduction (dan zhi xiao yao) vs 84% depression reduction (maprotiline) | As effective as maprotiline in treating depression | B |
| Folate | Cochrane review of 3 RCTs | 2475 | Studies 1 and 2: folate vs folate + other treatment (Study 1: low folate levels; Study 2: normal folate levels) Study 3: folate vs trazodone (normal folate levels) | HAM-D | Superior to placebo (NNT=5, defined as 50% reduction in HAM-D); comparable to trazodone (RR=0. 97; 95% CI, 0. 14-2. 01)7 | May have role as supplement to other treatments for depression Efficacy unclear in patients with normal folate levels | A |
| Inositol | Cochrane review of 4 RCTs | 1419 | Studies 1-3: placebo plus conventional antidepressants Study 4: placebo only | HAM-D, MADRS | Pooled estimate of effect of all 3 studies (SMD= -0. 08; 95% CI, -0. 45 to 0. 30) | No clear evidence of therapeutic benefit | A |
| Lavender (Lavandula angustifolia) | 1 small RCT | 454 | Imipramine | HAM-D | Imipramine plus lavender showed significant effect compared with imipramine alone (f=26. 87; Df=3. 01; P<. 0001) | Synergistic effect suggested when used with imipramine | B |
| n-3 long-chain polyunsaturated fatty acids | Systematic review including 3 RCTs; 10 meta-analysis of 12 RCTs11 | 10210 103211 | Various comparison groups included | Serum SFAs, MUFAs, PUFAs; RBC membrane levels n-3 PUFAs2 HAM-D, BDI3 | Systematic review:10 Study 1: n=30; ES=3. 61 Study 2: n=24; ES=1. 2 Study 3: n=48; ES=2. 43 Meta-analysis:11 Pooled ES=0. 13; 95% CI, 0. 01-0. 25 | Significantly higher RBC membrane levels of n-3 PUFAs in nondepressed vs depressed patients10 No significant effect for supplementation11 Larger trials with adequate power needed2,3 | A |
| S-adenosyl-methionine (SAMe) | Meta-analysis of 13 RCTs,6 systematic review including 2 RCTs7 | 3996 787 | Placebo and conventional antidepressants | HAM-D | NNT=2. 5 for HAM-D decrease of >25%; 6 NNT=6. 25 for HAM-D decrease of >50%6 | May have role in treatment of major depression Further trials are needed to address unanswered questions about absorption, mechanism of action, and bioavailability7 | A |
| Saffron (Crocus sativus) | Systematic review of 4 small RCTs, 1 later RCT | 3012 4013 4014 4015 403 | Imipramine12 Placebo13,15 Fluoxetine5,14 | HAM-D | Systematic review: Study 1: imipramine and saffron equally efficacious (f=2. 91; P=. 09)12 Study 2: Improved HAM-D scores: -12. 20±4. 67 (saffron) vs -5. 10±4. 71 (placebo) (P<. 0001)13 Study 3: Improved HAM-D scores: saffron petal -12. 00±4. 10; fluoxetine -13. 50±4. 91; difference between 2 treatments not significant (P=. 27)14 Study 4: Improved HAM-D scores: -14. 01±5. 53 (saffron petal) vs -5. 05±4. 63 (placebo) (P<. 0001)15 Study 5:5 NNT=10 | Efficacy of extract and petal suggested to treat mild to moderate depression Large-scale trials are warranted | B |
| St. John’s wort (Hypericum perforatum L. ) | Cochrane review of 29 RCTs | 54891 | SSRIs, tri/tetracyclic antidepressants, placebo | Responder rate ratio | St. John’s wort vs placebo: 9 larger trials: RR=1. 28; 95% CI, 1. 10-1. 491 9 smaller trials: RR=1. 87; 95% CI, 1. 22-2. 871 St. John’s wort vs SSRIs: 12 trials: RR=1. 00; 95% CI, 0. 90-1. 111 St. John’s wort vs tricyclics: 5 trials: RR=1. 02; 95% CI, 0. 90-1. 151 | Effective for treating mild to moderate depression | A |
| Tryptophan and 5-hydroxy-tryptophan (5-HTP) | Cochrane review of 2 RCTs | 648 | Placebo | HAM-D | NNT=2. 78 vs placebo (OR=4. 1; 95% CI, 1. 28-13. 15 | Superior to placebo Insufficient evidence regarding safety | A |
| BDI, Beck Depression Inventory; CI, confidence interval; DF, degrees of freedom; ES, effect size; F, F statistic; HAM-D, Hamilton Depression Rating Scale; MADRS, Mont-gomery-Asberg Depression Rating Scale; MUFAs, monounsaturated fatty acids; n-3 PUFAs, n-3 long-chain polyunsaturated fatty acids; NNT, number needed to treat; OR, odds ratio; PUFAs, polyunsaturated fatty acids; RBC, red blood cell; RCT, randomized controlled trial; RR, relative risk; SAS, self-rating anxiety scale; SDS, self-rating depression scale; SFAs, saturated fatty acids; SMD, standard weighted mean difference; SOR, strength of recommendation; SSRI, selective serotonin reuptake inhibitor. | |||||||
1. Linde K, Bemer MM, Kriston L. St. John’s wort for major depression. Cochrane Database Syst Rev. 2008;(4):CD000448.-
2. Sarris J. Herbal medicines in the treatment of psychiatric disorders: a systematic review. Phytother Res. 2007;21:703-716.
3. Akhondzadeh Basti A, Moshiri E, Noorbala AA, et al. Comparison of petal of Crocus sativus L. and fluoxetine in the treatment of depressed outpatients. Prog Neuropsychopharmacol Biol Psychiatry. 2006;31:439-442.
4. Akhondzadeh S, Kashani L, Fotouhi A, et al. Comparison of Lavandula angustifolia Mill. tincture and imipramine in the treatment of mild to moderate depression. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:123-127.
5. Taylor MJ, Carney S, Geddes J, et al. Folate for depressive disorders. Cochrane Database Syst Rev. 2003;(2):CD003390.-
6. Bressa GM. S-adenosyl-l-methionine (SAMe) as antidepres-sant. Acta Neurol Scand Suppl. 1994;154:7-14.
7. Williams AL, Girard C, Jui D, et al. S-adenosylmethionine (SAMe) as treatment for depression. Clin Invest Med. 2005;28:132-139.
8. Shaw K, Turner J, Del Mar C. Tryptophan and 5-hydroxy-tryptophan for depression. Cochrane Database Syst Rev. 2002;(1):CD003198.-
9. Taylor MJ, Wilder H, Bhagwager Z, et al. Inositol for depressive disorders. Cochrane Database Syst Rev. 2004;(2):CD004049.-
10. Williams AL, Katz D, Ali A, et al. Do essential fatty acids have a role in the treatment of depression? J Affect Disord. 2006;93:117-123.
11. Appleton KM, Hayward RC, Gunnell D, et al. Effects of n-3 longchain polyunsaturated fatty acids on depressed mood. Am J Clin Nutr. 2006;84:1308-1316.
12. Akhondzadeh S, Fallah-Pour H, Afkham K, et al. Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression. BMC Complement Altern Med. 2004;4:12.-
13. Akhondzadeh S, Tahmacebi-Pour N, Noorbala AA, et al. Crocus sativus L. in the treatment of mild to moderate depression. Phytother Res. 2005;19:148-151.
14. Noorbala AA, Akhondzadeh S, Tahmacebi-Pour N, et al. Hydro-alcoholic extract of Crocus sativus L. versus fluoxetine in the treatment of mild to moderate depression. J Ethnopharmacol. 2005;97:281-284.
15. Moshiri E, Basti AA, Noorbala AA, et al. Crocus sativus L. (petal) in the treatment of mild-to-moderate depression. Phytomedicine. 2006;13:607-611.
16. Sayyah M, Sahhah M, Kamalinejad M. A preliminary randomized double blind clinical trial on the efficacy of aqueous extract of Echium amoenum in the treatment of mild to moderate major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:166-169.
17. Schulz V Safety of St. John’s wort extract compared to synthetic antidepressants. Phytomedicine. 2006;13:199-204.
18. Lee S, Gura KM, Kim S, et al. Current clinical applications of ome-ga-6 and omega-3 fatty acids. Nutr Clin Pract. 2006;21:323-341.
19. Bauer M, Bschor T, Pfennig A, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders in primary care. World J Biol Psychiatry. 2007;8:67-104.
1. Linde K, Bemer MM, Kriston L. St. John’s wort for major depression. Cochrane Database Syst Rev. 2008;(4):CD000448.-
2. Sarris J. Herbal medicines in the treatment of psychiatric disorders: a systematic review. Phytother Res. 2007;21:703-716.
3. Akhondzadeh Basti A, Moshiri E, Noorbala AA, et al. Comparison of petal of Crocus sativus L. and fluoxetine in the treatment of depressed outpatients. Prog Neuropsychopharmacol Biol Psychiatry. 2006;31:439-442.
4. Akhondzadeh S, Kashani L, Fotouhi A, et al. Comparison of Lavandula angustifolia Mill. tincture and imipramine in the treatment of mild to moderate depression. Prog Neuropsychopharmacol Biol Psychiatry. 2003;27:123-127.
5. Taylor MJ, Carney S, Geddes J, et al. Folate for depressive disorders. Cochrane Database Syst Rev. 2003;(2):CD003390.-
6. Bressa GM. S-adenosyl-l-methionine (SAMe) as antidepres-sant. Acta Neurol Scand Suppl. 1994;154:7-14.
7. Williams AL, Girard C, Jui D, et al. S-adenosylmethionine (SAMe) as treatment for depression. Clin Invest Med. 2005;28:132-139.
8. Shaw K, Turner J, Del Mar C. Tryptophan and 5-hydroxy-tryptophan for depression. Cochrane Database Syst Rev. 2002;(1):CD003198.-
9. Taylor MJ, Wilder H, Bhagwager Z, et al. Inositol for depressive disorders. Cochrane Database Syst Rev. 2004;(2):CD004049.-
10. Williams AL, Katz D, Ali A, et al. Do essential fatty acids have a role in the treatment of depression? J Affect Disord. 2006;93:117-123.
11. Appleton KM, Hayward RC, Gunnell D, et al. Effects of n-3 longchain polyunsaturated fatty acids on depressed mood. Am J Clin Nutr. 2006;84:1308-1316.
12. Akhondzadeh S, Fallah-Pour H, Afkham K, et al. Comparison of Crocus sativus L. and imipramine in the treatment of mild to moderate depression. BMC Complement Altern Med. 2004;4:12.-
13. Akhondzadeh S, Tahmacebi-Pour N, Noorbala AA, et al. Crocus sativus L. in the treatment of mild to moderate depression. Phytother Res. 2005;19:148-151.
14. Noorbala AA, Akhondzadeh S, Tahmacebi-Pour N, et al. Hydro-alcoholic extract of Crocus sativus L. versus fluoxetine in the treatment of mild to moderate depression. J Ethnopharmacol. 2005;97:281-284.
15. Moshiri E, Basti AA, Noorbala AA, et al. Crocus sativus L. (petal) in the treatment of mild-to-moderate depression. Phytomedicine. 2006;13:607-611.
16. Sayyah M, Sahhah M, Kamalinejad M. A preliminary randomized double blind clinical trial on the efficacy of aqueous extract of Echium amoenum in the treatment of mild to moderate major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2006;30:166-169.
17. Schulz V Safety of St. John’s wort extract compared to synthetic antidepressants. Phytomedicine. 2006;13:199-204.
18. Lee S, Gura KM, Kim S, et al. Current clinical applications of ome-ga-6 and omega-3 fatty acids. Nutr Clin Pract. 2006;21:323-341.
19. Bauer M, Bschor T, Pfennig A, et al. World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for biological treatment of unipolar depressive disorders in primary care. World J Biol Psychiatry. 2007;8:67-104.
Evidence-based answers from the Family Physicians Inquiries Network
What is the most effective treatment for acne rosacea?
TOPICAL METRONIDAZOLE AND AZELAIC ACID are equally effective for the papulopustular lesions of acne rosacea, although metronidazole is better tolerated. Oral doxycycline, tetracycline, and metronidazole are also effective, but not enough evidence exists to determine whether one is more effective than another or more effective than topical therapy (strength of recommendation [SOR]: A, systematic review and individual randomized controlled trials [RCTs]).
Some evidence supports a benefit for topical sodium sulfacetamide with sulfur, and benzoyl peroxide (SOR: B, small single RCTs).
Pulsed-light and laser therapy may improve the erythema and telangiectasias associated with acne rosacea (SOR: C, case series).
All patients with acne rosacea should use sunscreen and emollients, and avoid skin irritants (SOR: C, expert opinion).
Evidence summary
A Cochrane systematic review found that topical metronidazole and azelaic acid are both more effective than placebo for patients with papulopustular lesions of acne rosacea (TABLE). The authors noted that the studies were generally weak because of poor methodology and reporting, small sample sizes, and lack of quality-of-life measures (only 2 RCTs evaluated patient assessment of treatment effectiveness).1
Another systematic review reported small case series suggesting possible effectiveness with topical tretinoin (43 cases), oral clindamycin (43 cases), oral erythromycin (13 cases), and topical tacrolimus (3 cases).2
TABLE
Papulopustular acne rosacea: Doctors assess treatment efficacy in placebo-controlled trials1,2
| Primary intervention | Number of trials | Number of patients | Physician assessment of improvement vs placebo |
|---|---|---|---|
| Topical metronidazole | 9 | 488 | OR=7.01 (95% CI, 2.5-20) |
| Topical azelaic acid | 4 | 778 | OR=2.23 (95% CI, 1.66-3.00) |
| Topical benzoyl peroxide | 1 | 58 | OR=3.17 (95% CI, 1.08-9.31) |
| Topical sodium sulfacetamide with sulfur | 1 | 94 | 90%-98% vs 58%-68% improved (P<.01) |
| Oral doxycycline | 2 | 577 | 9.5 and 11.8 fewer lesions with doxycycline vs 4.3 and 5.9 fewer lesions with placebo (P<.001 for both RCTs) |
| Oral tetracycline | 3 | 152 | OR=6.06 (95% CI, 2.96-12.4) |
| Oral metronidazole | 1 | 27 | OR=13.75 (95% CI, 2.05-92.04) |
| CI, confidence interval; OR, odds ratio; RCTs, randomized controlled trials. | |||
Oral metronidazole and tetracycline also work
The Cochrane systematic review also found that oral metronidazole and tetracycline were more effective than placebo for papulopustular lesions.1 A subsequent systematic review found that anti-inflammatory doses of oral doxycycline (20-40 mg daily) were effective.3,4
Evidence for other oral drugs is limited or inconclusive
Limited supporting evidence exists for oral macrolides, isotretinoin, and spironolactone.1,2 Three small placebo-controlled RCTs found insignificant or inconclusive benefits for ampicillin, oral clarithromycin plus omeprazole, and oral rilmenidine (a centrally acting, sympatholytic antihypertensive.)1
Many studies, little difference in drug effects
A large number of studies have compared the effectiveness of one treatment against another, but only one comparison demonstrated a statistically significant benefit. Two RCTs enrolling 104 patients found that oral doxycycline (40 mg daily) in combination with topical metronidazole reduced the number of lesions more than topical metronidazole alone (4 and 7 fewer lesions; P<.01 for both studies). It is unclear whether the reduction is clinically significant.3,5
Other comparisons that found no significant difference in effectiveness included:
- 3 RCTs (N=491) that compared topical metronidazole with topical azelaic acid1,2
- 1 RCT (N=72) that compared once-daily with twice-daily topical azelaic acid6
- 1 RCT (N=43) that compared topical metronidazole with topical permethrin1
- 1 RCT (N=40) that compared oral metronidazole with oral tetracycline1
- 1 RCT (N=91) that compared oral doxycycline 100 mg daily with 40 mg daily4
- 1 open trial (N=67) that compared oral doxycycline with oral azithromycin.7
Not all therapies were equally well-tolerated, however. Topical metronidazole produced fewer adverse events than topical azelaic acid (odds ratio=4.56; 95% confidence interval, 2.07-10.03).1 Doxycycline dosed at 40 mg daily produced fewer gastrointestinal adverse effects than 100 mg daily (5% vs 26%; P value not given).4
Therapy for erythema and telangiectasia
A systematic review described multiple small case series that reported improvements in erythema and telangiectasias with pulsed-light therapy (188 cases) and laser therapy (82 cases).2 Another case series with 17 patients reported improvements with photodynamic therapy with red ight.8
General skin care measures
A case series reported improved symptom scores among 20 patients using twice-daily metronidazole gel when they added moisturizing lotion to one side of their face.9 Expert opinion recommends using sunscreen and protective emollients and avoiding triggers that cause flushing, such as certain foods, beverages, and cosmetics.1,2
Recommendations
The American Acne and Rosacea Society guidelines state that good evidence supports 3 topical treatments—metronidazole, azelaic acid, and sulfacetamide/sulfur—as well as anti-inflammatory doses of oral doxycycline.
The guidelines also list other topical and oral antibiotic treatments, but cite low-quality evidence for their efficacy and concerns about the emergence of antibiotic resistance. They advise appropriate skin care, including gentle cleansers, moisturizers, and sun protection.10
1. van Zuuren EJ, Graber MA, Hollis S, et al. Interventions for rosacea. Cochrane Database Syst Rev. 2005;(3):CD003262.-
2. Pelle MT, Crawford GH, James WD. Rosacea: II. Therapy. J Am Acad Dermatol. 2004;51:499-512.
3. Conde JF, Yelverton CB, Balkrishnan R, et al. Managing rosacea: a review of the use of metronidazole alone and in combination with oral antibiotics. J Drugs Dermatol. 2007;6:495-498.
4. Del Rosso JQ, Schlessinger J, Werschler P. Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea. J Drugs Dermatol. 2008;7:573-574.
5. Fowler JF, Jr. Combined effect of anti-inflammatory dose doxycycline (40-mg doxycycline, usp monohydrate controlled-release capsules) and metronidazole topical gel 1% in the treatment of rosacea. J Drugs Dermatol. 2007;6:641-645.
6. Thiboutot DM, Fleischer AB, Jr, Del Rosso JQ, et al. Azelaic acid 15% gel once daily versus twice daily in papulopustular rosacea. J Drugs Dermatol. 2008;7:541-546.
7. Akhyani M, Ehsani AH, Ghiasi M, et al. Comparison of efficacy of azithromycin versus doxycycline in the treatment of rosacea: a randomized open clinical trial. Int J Dermatol. 2008;47:284-288.
8. Bryld LE, Jemec GB. Photodynamic therapy in a series of rosacea patients. J Eur Acad Dermatol Venereol. 2007;21:1199-1202.
9. Laquieze S, Czernielewski J, Baltas E. Beneficial use of Cetaphil moisturizing cream as part of a daily skin care regimen for individuals with rosacea. J Dermatolog Treat. 2007;18:158-162.
10. Del Rosso JQ, Baldwin H, Webster G. American Acne and Rosacea Society. American Acne and Rosacea Society rosacea medical management guidelines. J Drugs Dermatol. 2008;7:531-533.
TOPICAL METRONIDAZOLE AND AZELAIC ACID are equally effective for the papulopustular lesions of acne rosacea, although metronidazole is better tolerated. Oral doxycycline, tetracycline, and metronidazole are also effective, but not enough evidence exists to determine whether one is more effective than another or more effective than topical therapy (strength of recommendation [SOR]: A, systematic review and individual randomized controlled trials [RCTs]).
Some evidence supports a benefit for topical sodium sulfacetamide with sulfur, and benzoyl peroxide (SOR: B, small single RCTs).
Pulsed-light and laser therapy may improve the erythema and telangiectasias associated with acne rosacea (SOR: C, case series).
All patients with acne rosacea should use sunscreen and emollients, and avoid skin irritants (SOR: C, expert opinion).
Evidence summary
A Cochrane systematic review found that topical metronidazole and azelaic acid are both more effective than placebo for patients with papulopustular lesions of acne rosacea (TABLE). The authors noted that the studies were generally weak because of poor methodology and reporting, small sample sizes, and lack of quality-of-life measures (only 2 RCTs evaluated patient assessment of treatment effectiveness).1
Another systematic review reported small case series suggesting possible effectiveness with topical tretinoin (43 cases), oral clindamycin (43 cases), oral erythromycin (13 cases), and topical tacrolimus (3 cases).2
TABLE
Papulopustular acne rosacea: Doctors assess treatment efficacy in placebo-controlled trials1,2
| Primary intervention | Number of trials | Number of patients | Physician assessment of improvement vs placebo |
|---|---|---|---|
| Topical metronidazole | 9 | 488 | OR=7.01 (95% CI, 2.5-20) |
| Topical azelaic acid | 4 | 778 | OR=2.23 (95% CI, 1.66-3.00) |
| Topical benzoyl peroxide | 1 | 58 | OR=3.17 (95% CI, 1.08-9.31) |
| Topical sodium sulfacetamide with sulfur | 1 | 94 | 90%-98% vs 58%-68% improved (P<.01) |
| Oral doxycycline | 2 | 577 | 9.5 and 11.8 fewer lesions with doxycycline vs 4.3 and 5.9 fewer lesions with placebo (P<.001 for both RCTs) |
| Oral tetracycline | 3 | 152 | OR=6.06 (95% CI, 2.96-12.4) |
| Oral metronidazole | 1 | 27 | OR=13.75 (95% CI, 2.05-92.04) |
| CI, confidence interval; OR, odds ratio; RCTs, randomized controlled trials. | |||
Oral metronidazole and tetracycline also work
The Cochrane systematic review also found that oral metronidazole and tetracycline were more effective than placebo for papulopustular lesions.1 A subsequent systematic review found that anti-inflammatory doses of oral doxycycline (20-40 mg daily) were effective.3,4
Evidence for other oral drugs is limited or inconclusive
Limited supporting evidence exists for oral macrolides, isotretinoin, and spironolactone.1,2 Three small placebo-controlled RCTs found insignificant or inconclusive benefits for ampicillin, oral clarithromycin plus omeprazole, and oral rilmenidine (a centrally acting, sympatholytic antihypertensive.)1
Many studies, little difference in drug effects
A large number of studies have compared the effectiveness of one treatment against another, but only one comparison demonstrated a statistically significant benefit. Two RCTs enrolling 104 patients found that oral doxycycline (40 mg daily) in combination with topical metronidazole reduced the number of lesions more than topical metronidazole alone (4 and 7 fewer lesions; P<.01 for both studies). It is unclear whether the reduction is clinically significant.3,5
Other comparisons that found no significant difference in effectiveness included:
- 3 RCTs (N=491) that compared topical metronidazole with topical azelaic acid1,2
- 1 RCT (N=72) that compared once-daily with twice-daily topical azelaic acid6
- 1 RCT (N=43) that compared topical metronidazole with topical permethrin1
- 1 RCT (N=40) that compared oral metronidazole with oral tetracycline1
- 1 RCT (N=91) that compared oral doxycycline 100 mg daily with 40 mg daily4
- 1 open trial (N=67) that compared oral doxycycline with oral azithromycin.7
Not all therapies were equally well-tolerated, however. Topical metronidazole produced fewer adverse events than topical azelaic acid (odds ratio=4.56; 95% confidence interval, 2.07-10.03).1 Doxycycline dosed at 40 mg daily produced fewer gastrointestinal adverse effects than 100 mg daily (5% vs 26%; P value not given).4
Therapy for erythema and telangiectasia
A systematic review described multiple small case series that reported improvements in erythema and telangiectasias with pulsed-light therapy (188 cases) and laser therapy (82 cases).2 Another case series with 17 patients reported improvements with photodynamic therapy with red ight.8
General skin care measures
A case series reported improved symptom scores among 20 patients using twice-daily metronidazole gel when they added moisturizing lotion to one side of their face.9 Expert opinion recommends using sunscreen and protective emollients and avoiding triggers that cause flushing, such as certain foods, beverages, and cosmetics.1,2
Recommendations
The American Acne and Rosacea Society guidelines state that good evidence supports 3 topical treatments—metronidazole, azelaic acid, and sulfacetamide/sulfur—as well as anti-inflammatory doses of oral doxycycline.
The guidelines also list other topical and oral antibiotic treatments, but cite low-quality evidence for their efficacy and concerns about the emergence of antibiotic resistance. They advise appropriate skin care, including gentle cleansers, moisturizers, and sun protection.10
TOPICAL METRONIDAZOLE AND AZELAIC ACID are equally effective for the papulopustular lesions of acne rosacea, although metronidazole is better tolerated. Oral doxycycline, tetracycline, and metronidazole are also effective, but not enough evidence exists to determine whether one is more effective than another or more effective than topical therapy (strength of recommendation [SOR]: A, systematic review and individual randomized controlled trials [RCTs]).
Some evidence supports a benefit for topical sodium sulfacetamide with sulfur, and benzoyl peroxide (SOR: B, small single RCTs).
Pulsed-light and laser therapy may improve the erythema and telangiectasias associated with acne rosacea (SOR: C, case series).
All patients with acne rosacea should use sunscreen and emollients, and avoid skin irritants (SOR: C, expert opinion).
Evidence summary
A Cochrane systematic review found that topical metronidazole and azelaic acid are both more effective than placebo for patients with papulopustular lesions of acne rosacea (TABLE). The authors noted that the studies were generally weak because of poor methodology and reporting, small sample sizes, and lack of quality-of-life measures (only 2 RCTs evaluated patient assessment of treatment effectiveness).1
Another systematic review reported small case series suggesting possible effectiveness with topical tretinoin (43 cases), oral clindamycin (43 cases), oral erythromycin (13 cases), and topical tacrolimus (3 cases).2
TABLE
Papulopustular acne rosacea: Doctors assess treatment efficacy in placebo-controlled trials1,2
| Primary intervention | Number of trials | Number of patients | Physician assessment of improvement vs placebo |
|---|---|---|---|
| Topical metronidazole | 9 | 488 | OR=7.01 (95% CI, 2.5-20) |
| Topical azelaic acid | 4 | 778 | OR=2.23 (95% CI, 1.66-3.00) |
| Topical benzoyl peroxide | 1 | 58 | OR=3.17 (95% CI, 1.08-9.31) |
| Topical sodium sulfacetamide with sulfur | 1 | 94 | 90%-98% vs 58%-68% improved (P<.01) |
| Oral doxycycline | 2 | 577 | 9.5 and 11.8 fewer lesions with doxycycline vs 4.3 and 5.9 fewer lesions with placebo (P<.001 for both RCTs) |
| Oral tetracycline | 3 | 152 | OR=6.06 (95% CI, 2.96-12.4) |
| Oral metronidazole | 1 | 27 | OR=13.75 (95% CI, 2.05-92.04) |
| CI, confidence interval; OR, odds ratio; RCTs, randomized controlled trials. | |||
Oral metronidazole and tetracycline also work
The Cochrane systematic review also found that oral metronidazole and tetracycline were more effective than placebo for papulopustular lesions.1 A subsequent systematic review found that anti-inflammatory doses of oral doxycycline (20-40 mg daily) were effective.3,4
Evidence for other oral drugs is limited or inconclusive
Limited supporting evidence exists for oral macrolides, isotretinoin, and spironolactone.1,2 Three small placebo-controlled RCTs found insignificant or inconclusive benefits for ampicillin, oral clarithromycin plus omeprazole, and oral rilmenidine (a centrally acting, sympatholytic antihypertensive.)1
Many studies, little difference in drug effects
A large number of studies have compared the effectiveness of one treatment against another, but only one comparison demonstrated a statistically significant benefit. Two RCTs enrolling 104 patients found that oral doxycycline (40 mg daily) in combination with topical metronidazole reduced the number of lesions more than topical metronidazole alone (4 and 7 fewer lesions; P<.01 for both studies). It is unclear whether the reduction is clinically significant.3,5
Other comparisons that found no significant difference in effectiveness included:
- 3 RCTs (N=491) that compared topical metronidazole with topical azelaic acid1,2
- 1 RCT (N=72) that compared once-daily with twice-daily topical azelaic acid6
- 1 RCT (N=43) that compared topical metronidazole with topical permethrin1
- 1 RCT (N=40) that compared oral metronidazole with oral tetracycline1
- 1 RCT (N=91) that compared oral doxycycline 100 mg daily with 40 mg daily4
- 1 open trial (N=67) that compared oral doxycycline with oral azithromycin.7
Not all therapies were equally well-tolerated, however. Topical metronidazole produced fewer adverse events than topical azelaic acid (odds ratio=4.56; 95% confidence interval, 2.07-10.03).1 Doxycycline dosed at 40 mg daily produced fewer gastrointestinal adverse effects than 100 mg daily (5% vs 26%; P value not given).4
Therapy for erythema and telangiectasia
A systematic review described multiple small case series that reported improvements in erythema and telangiectasias with pulsed-light therapy (188 cases) and laser therapy (82 cases).2 Another case series with 17 patients reported improvements with photodynamic therapy with red ight.8
General skin care measures
A case series reported improved symptom scores among 20 patients using twice-daily metronidazole gel when they added moisturizing lotion to one side of their face.9 Expert opinion recommends using sunscreen and protective emollients and avoiding triggers that cause flushing, such as certain foods, beverages, and cosmetics.1,2
Recommendations
The American Acne and Rosacea Society guidelines state that good evidence supports 3 topical treatments—metronidazole, azelaic acid, and sulfacetamide/sulfur—as well as anti-inflammatory doses of oral doxycycline.
The guidelines also list other topical and oral antibiotic treatments, but cite low-quality evidence for their efficacy and concerns about the emergence of antibiotic resistance. They advise appropriate skin care, including gentle cleansers, moisturizers, and sun protection.10
1. van Zuuren EJ, Graber MA, Hollis S, et al. Interventions for rosacea. Cochrane Database Syst Rev. 2005;(3):CD003262.-
2. Pelle MT, Crawford GH, James WD. Rosacea: II. Therapy. J Am Acad Dermatol. 2004;51:499-512.
3. Conde JF, Yelverton CB, Balkrishnan R, et al. Managing rosacea: a review of the use of metronidazole alone and in combination with oral antibiotics. J Drugs Dermatol. 2007;6:495-498.
4. Del Rosso JQ, Schlessinger J, Werschler P. Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea. J Drugs Dermatol. 2008;7:573-574.
5. Fowler JF, Jr. Combined effect of anti-inflammatory dose doxycycline (40-mg doxycycline, usp monohydrate controlled-release capsules) and metronidazole topical gel 1% in the treatment of rosacea. J Drugs Dermatol. 2007;6:641-645.
6. Thiboutot DM, Fleischer AB, Jr, Del Rosso JQ, et al. Azelaic acid 15% gel once daily versus twice daily in papulopustular rosacea. J Drugs Dermatol. 2008;7:541-546.
7. Akhyani M, Ehsani AH, Ghiasi M, et al. Comparison of efficacy of azithromycin versus doxycycline in the treatment of rosacea: a randomized open clinical trial. Int J Dermatol. 2008;47:284-288.
8. Bryld LE, Jemec GB. Photodynamic therapy in a series of rosacea patients. J Eur Acad Dermatol Venereol. 2007;21:1199-1202.
9. Laquieze S, Czernielewski J, Baltas E. Beneficial use of Cetaphil moisturizing cream as part of a daily skin care regimen for individuals with rosacea. J Dermatolog Treat. 2007;18:158-162.
10. Del Rosso JQ, Baldwin H, Webster G. American Acne and Rosacea Society. American Acne and Rosacea Society rosacea medical management guidelines. J Drugs Dermatol. 2008;7:531-533.
1. van Zuuren EJ, Graber MA, Hollis S, et al. Interventions for rosacea. Cochrane Database Syst Rev. 2005;(3):CD003262.-
2. Pelle MT, Crawford GH, James WD. Rosacea: II. Therapy. J Am Acad Dermatol. 2004;51:499-512.
3. Conde JF, Yelverton CB, Balkrishnan R, et al. Managing rosacea: a review of the use of metronidazole alone and in combination with oral antibiotics. J Drugs Dermatol. 2007;6:495-498.
4. Del Rosso JQ, Schlessinger J, Werschler P. Comparison of anti-inflammatory dose doxycycline versus doxycycline 100 mg in the treatment of rosacea. J Drugs Dermatol. 2008;7:573-574.
5. Fowler JF, Jr. Combined effect of anti-inflammatory dose doxycycline (40-mg doxycycline, usp monohydrate controlled-release capsules) and metronidazole topical gel 1% in the treatment of rosacea. J Drugs Dermatol. 2007;6:641-645.
6. Thiboutot DM, Fleischer AB, Jr, Del Rosso JQ, et al. Azelaic acid 15% gel once daily versus twice daily in papulopustular rosacea. J Drugs Dermatol. 2008;7:541-546.
7. Akhyani M, Ehsani AH, Ghiasi M, et al. Comparison of efficacy of azithromycin versus doxycycline in the treatment of rosacea: a randomized open clinical trial. Int J Dermatol. 2008;47:284-288.
8. Bryld LE, Jemec GB. Photodynamic therapy in a series of rosacea patients. J Eur Acad Dermatol Venereol. 2007;21:1199-1202.
9. Laquieze S, Czernielewski J, Baltas E. Beneficial use of Cetaphil moisturizing cream as part of a daily skin care regimen for individuals with rosacea. J Dermatolog Treat. 2007;18:158-162.
10. Del Rosso JQ, Baldwin H, Webster G. American Acne and Rosacea Society. American Acne and Rosacea Society rosacea medical management guidelines. J Drugs Dermatol. 2008;7:531-533.
Evidence-based answers from the Family Physicians Inquiries Network
Which medications benefit patients with diastolic heart failure?
Aangiotensin-converting enzyme inhibitors (ACEIs), propranolol, statins, furosemide, and some angiotensin receptor blockers (ARBs) benefit patients. Medications that reduce mortality in diastolic heart failure include ACEIs (strength of recommendation [SOR]: C, 1 prospective cohort trial with matched controls), propranolol (SOR: B, 1 randomized controlled trial [RCT]), and statins (SOR: C, 1 prospective cohort trial).
Furosemide improves symptoms of heart failure and quality of life (SOR: C, 1 RCT, using cohort data).
ARBs show mixed results: candesartan decreases hospital admissions (SOR: B, 1 large RCT); losartan improves exercise duration and quality of life (SOR: B, 2 small RCTs); irbesartan doesn’t improve heart failure symptoms or other outcomes (SOR: B, 1 large RCT).
Evidence summary
Diastolic heart failure, defined as classic evidence of congestive heart failure with “preserved” or “normal” left ventricular ejection fraction (LVEF),1 is often encountered in medical practice. Unfortunately, studies that address diastolic heart failure don’t use a uniform ejection fraction to define preserved systolic function. Treatments for diastolic failure have included diuretics, ACEIs, ARBs, beta-blockers, calcium channel blockers, digoxin, and statins.
ACEIs decrease mortality
One small prospective study in France enrolled 358 subjects who were admitted for a first episode of heart failure but had ejection fractions ≥50%. Patients were separated into 2 groups based on whether or not they were prescribed an ACEI—lisinopril (32.3%), ramipril (25.6%), perindopril (23.8%), or enalapril (5.5%)—at discharge. The authors attempted to adjust for selection bias by developing a propensity score and comparing matched controls.
Patients who had been prescribed ACEIs had a 10% reduction in 5-year mortality (number needed to treat [NNT]=10).2
ARBs produce mixed outcomes
Evidence regarding outcomes with ARBs is not clear cut. Candesartan was studied in the CHARM-Preserved Trial, which enrolled 3023 patients from 618 centers in 26 countries with New York Heart Association functional class II to class IV congestive heart failure of at least 4 weeks’ duration and LVEF >40%.3 The treatment group showed a significant decrease in hospital admission for congestive heart failure (NNT=30, covariate adjusted), but no improvement in mortality.
Losartan improved exercise duration and quality of life compared with placebo or hydrochlorothiazide in 2 small RCTs totaling 60 patients.4,5
In the I-PRESERVE Trial, irbesartan didn’t improve primary or secondary outcomes, including death from any cause or hospitalization for a cardiovascular cause (P=.35), death or hospitalization from heart failure, or quality of life (P=.44).6 However, concomitant use of other medications could have been a factor because 39%, 28%, and 73% of patients in the irbesartan group and 40%, 29%, and 73% in the placebo group were taking an ACEI, spironolactone, or a beta-blocker, respectively.
Propranolol reduces mortality, but data on other beta-blockers are lacking
One prospective randomized trial of heart failure patients with LVEF ≥40% already treated with an ACEI and a diuretic, found that propranolol reduced total mortality by 35% after 1 year of therapy (absolute risk reduction=20%; NNT=5).7 Studies of other beta-blockers haven’t reported patient-oriented outcomes as an end point.
Diuretics alone outperform diuretics plus other meds
A study that randomized 150 elderly patients with symptomatic heart failure and LVEF >45% to diuretics alone (80% were given furosemide), diuretics plus irbesartan, or diuretics plus ramipril found that diuretics alone improved the quality of life score by 46% after 52 weeks and also improved symptoms of heart failure.8 No significant symptomatic or other benefit was noted with the addition of irbesartan or ramipril.
Statins are linked to lower mortality
A prospective cohort study followed 137 patients with heart failure and ejection fraction >50% for a mean of 21 months.9 After adjustment for differences in baseline clinical variables between groups, therapy with various statins (68% of patients were on atorvastatin) was associated with lower mortality (NNT=5).
Little evidence exists to support the use of calcium channel blockers, digoxin, or other vasodilators in diastolic heart failure.
Recommendations
The TABLE summarizes recommendations of the American College of Cardiology Foundation and the American Heart Association.1
TABLE
Treating the patient with heart failure and normal LVEF: Recommendations from the ACCF and AHA
| Recommendation | Level of evidence |
|---|---|
| Control systolic and diastolic hypertension | Good supportive evidence |
| Control ventricular rate in patients with atrial fibrillation | Expert opinion/limited evidence |
| Use diuretics for pulmonary congestion and peripheral edema | Expert opinion/limited evidence |
| Perform coronary revascularization if ischemia is having an adverse effect | Expert opinion/limited evidence |
| Rhythm control in patients with atrial fibrillation may be useful | Expert opinion/limited evidence |
| Beta-adrenergic blocking agents, ACEIs, angiotensin II receptor blockers, or calcium antagonists may be effective | Expert opinion/limited evidence |
| Digitalis isn’t clearly effective | Expert opinion/limited evidence |
| ACCF, American College of Cardiology Foundation; ACEIs, angiotensin-converting enzyme inhibitors; AHA, American Heart Association; LVEF, left ventricular ejection fraction. | |
| Adapted from: Hunt SA et al. J Am Coll Cardiol. 2009.1 | |
1. Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the International Society for Heart and Lung Transplantation. J Am Coll Cardiol. 2009;53:e1-e90.
2. Tribouilloy C, Rusinaru D, Leborgne L, et al. Prognostic impact of angiotensin-converting enzyme inhibitor therapy in diastolic heart failure. Am J Cardiol. 2008;101:639-644.
3. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362:777-781.
4. Little WC, Zile MR, Klein A, et al. Effect of losartan and hydrochlorothiazide on exercise tolerance in exertional hypertension and left ventricular diastolic dysfunction. Am J Cardiol. 2006;98:383-385.
5. Warner JG Jr, Metzger DC, Kitzman DW, et al. Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response to exercise. J Am Coll Cardiol. 1999;33:1567-1572.
6. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359:2456-2467.
7. Aronow WS, Ahn C, Kronzon I. Effect of propranolol versus no propranolol on total mortality plus nonfatal myocardial infarction in older patients with prior myocardial infarction, congestive heart failure, and left ventricular ejection fraction ≥40% treated with diuretics plus angiotensin-converting enzyme inhibitors. Am J Cardiol. 1997;80:207-209.
8. Yip GW, Wang M, Wang T, et al. The Hong Kong diastolic heart failure study: a randomised controlled trial of diuretics, irbesartan and ramipril on quality of life, exercise capacity, left ventricular global and regional function in heart failure with a normal ejection fraction. Heart. 2008;94:573-580.
9. Fukuta H, Sane DC, Brucks S, et al. Statin therapy may be associated with lower mortality in patients with diastolic heart failure: a preliminary report. Circulation. 2005;112:357-363.
Aangiotensin-converting enzyme inhibitors (ACEIs), propranolol, statins, furosemide, and some angiotensin receptor blockers (ARBs) benefit patients. Medications that reduce mortality in diastolic heart failure include ACEIs (strength of recommendation [SOR]: C, 1 prospective cohort trial with matched controls), propranolol (SOR: B, 1 randomized controlled trial [RCT]), and statins (SOR: C, 1 prospective cohort trial).
Furosemide improves symptoms of heart failure and quality of life (SOR: C, 1 RCT, using cohort data).
ARBs show mixed results: candesartan decreases hospital admissions (SOR: B, 1 large RCT); losartan improves exercise duration and quality of life (SOR: B, 2 small RCTs); irbesartan doesn’t improve heart failure symptoms or other outcomes (SOR: B, 1 large RCT).
Evidence summary
Diastolic heart failure, defined as classic evidence of congestive heart failure with “preserved” or “normal” left ventricular ejection fraction (LVEF),1 is often encountered in medical practice. Unfortunately, studies that address diastolic heart failure don’t use a uniform ejection fraction to define preserved systolic function. Treatments for diastolic failure have included diuretics, ACEIs, ARBs, beta-blockers, calcium channel blockers, digoxin, and statins.
ACEIs decrease mortality
One small prospective study in France enrolled 358 subjects who were admitted for a first episode of heart failure but had ejection fractions ≥50%. Patients were separated into 2 groups based on whether or not they were prescribed an ACEI—lisinopril (32.3%), ramipril (25.6%), perindopril (23.8%), or enalapril (5.5%)—at discharge. The authors attempted to adjust for selection bias by developing a propensity score and comparing matched controls.
Patients who had been prescribed ACEIs had a 10% reduction in 5-year mortality (number needed to treat [NNT]=10).2
ARBs produce mixed outcomes
Evidence regarding outcomes with ARBs is not clear cut. Candesartan was studied in the CHARM-Preserved Trial, which enrolled 3023 patients from 618 centers in 26 countries with New York Heart Association functional class II to class IV congestive heart failure of at least 4 weeks’ duration and LVEF >40%.3 The treatment group showed a significant decrease in hospital admission for congestive heart failure (NNT=30, covariate adjusted), but no improvement in mortality.
Losartan improved exercise duration and quality of life compared with placebo or hydrochlorothiazide in 2 small RCTs totaling 60 patients.4,5
In the I-PRESERVE Trial, irbesartan didn’t improve primary or secondary outcomes, including death from any cause or hospitalization for a cardiovascular cause (P=.35), death or hospitalization from heart failure, or quality of life (P=.44).6 However, concomitant use of other medications could have been a factor because 39%, 28%, and 73% of patients in the irbesartan group and 40%, 29%, and 73% in the placebo group were taking an ACEI, spironolactone, or a beta-blocker, respectively.
Propranolol reduces mortality, but data on other beta-blockers are lacking
One prospective randomized trial of heart failure patients with LVEF ≥40% already treated with an ACEI and a diuretic, found that propranolol reduced total mortality by 35% after 1 year of therapy (absolute risk reduction=20%; NNT=5).7 Studies of other beta-blockers haven’t reported patient-oriented outcomes as an end point.
Diuretics alone outperform diuretics plus other meds
A study that randomized 150 elderly patients with symptomatic heart failure and LVEF >45% to diuretics alone (80% were given furosemide), diuretics plus irbesartan, or diuretics plus ramipril found that diuretics alone improved the quality of life score by 46% after 52 weeks and also improved symptoms of heart failure.8 No significant symptomatic or other benefit was noted with the addition of irbesartan or ramipril.
Statins are linked to lower mortality
A prospective cohort study followed 137 patients with heart failure and ejection fraction >50% for a mean of 21 months.9 After adjustment for differences in baseline clinical variables between groups, therapy with various statins (68% of patients were on atorvastatin) was associated with lower mortality (NNT=5).
Little evidence exists to support the use of calcium channel blockers, digoxin, or other vasodilators in diastolic heart failure.
Recommendations
The TABLE summarizes recommendations of the American College of Cardiology Foundation and the American Heart Association.1
TABLE
Treating the patient with heart failure and normal LVEF: Recommendations from the ACCF and AHA
| Recommendation | Level of evidence |
|---|---|
| Control systolic and diastolic hypertension | Good supportive evidence |
| Control ventricular rate in patients with atrial fibrillation | Expert opinion/limited evidence |
| Use diuretics for pulmonary congestion and peripheral edema | Expert opinion/limited evidence |
| Perform coronary revascularization if ischemia is having an adverse effect | Expert opinion/limited evidence |
| Rhythm control in patients with atrial fibrillation may be useful | Expert opinion/limited evidence |
| Beta-adrenergic blocking agents, ACEIs, angiotensin II receptor blockers, or calcium antagonists may be effective | Expert opinion/limited evidence |
| Digitalis isn’t clearly effective | Expert opinion/limited evidence |
| ACCF, American College of Cardiology Foundation; ACEIs, angiotensin-converting enzyme inhibitors; AHA, American Heart Association; LVEF, left ventricular ejection fraction. | |
| Adapted from: Hunt SA et al. J Am Coll Cardiol. 2009.1 | |
Aangiotensin-converting enzyme inhibitors (ACEIs), propranolol, statins, furosemide, and some angiotensin receptor blockers (ARBs) benefit patients. Medications that reduce mortality in diastolic heart failure include ACEIs (strength of recommendation [SOR]: C, 1 prospective cohort trial with matched controls), propranolol (SOR: B, 1 randomized controlled trial [RCT]), and statins (SOR: C, 1 prospective cohort trial).
Furosemide improves symptoms of heart failure and quality of life (SOR: C, 1 RCT, using cohort data).
ARBs show mixed results: candesartan decreases hospital admissions (SOR: B, 1 large RCT); losartan improves exercise duration and quality of life (SOR: B, 2 small RCTs); irbesartan doesn’t improve heart failure symptoms or other outcomes (SOR: B, 1 large RCT).
Evidence summary
Diastolic heart failure, defined as classic evidence of congestive heart failure with “preserved” or “normal” left ventricular ejection fraction (LVEF),1 is often encountered in medical practice. Unfortunately, studies that address diastolic heart failure don’t use a uniform ejection fraction to define preserved systolic function. Treatments for diastolic failure have included diuretics, ACEIs, ARBs, beta-blockers, calcium channel blockers, digoxin, and statins.
ACEIs decrease mortality
One small prospective study in France enrolled 358 subjects who were admitted for a first episode of heart failure but had ejection fractions ≥50%. Patients were separated into 2 groups based on whether or not they were prescribed an ACEI—lisinopril (32.3%), ramipril (25.6%), perindopril (23.8%), or enalapril (5.5%)—at discharge. The authors attempted to adjust for selection bias by developing a propensity score and comparing matched controls.
Patients who had been prescribed ACEIs had a 10% reduction in 5-year mortality (number needed to treat [NNT]=10).2
ARBs produce mixed outcomes
Evidence regarding outcomes with ARBs is not clear cut. Candesartan was studied in the CHARM-Preserved Trial, which enrolled 3023 patients from 618 centers in 26 countries with New York Heart Association functional class II to class IV congestive heart failure of at least 4 weeks’ duration and LVEF >40%.3 The treatment group showed a significant decrease in hospital admission for congestive heart failure (NNT=30, covariate adjusted), but no improvement in mortality.
Losartan improved exercise duration and quality of life compared with placebo or hydrochlorothiazide in 2 small RCTs totaling 60 patients.4,5
In the I-PRESERVE Trial, irbesartan didn’t improve primary or secondary outcomes, including death from any cause or hospitalization for a cardiovascular cause (P=.35), death or hospitalization from heart failure, or quality of life (P=.44).6 However, concomitant use of other medications could have been a factor because 39%, 28%, and 73% of patients in the irbesartan group and 40%, 29%, and 73% in the placebo group were taking an ACEI, spironolactone, or a beta-blocker, respectively.
Propranolol reduces mortality, but data on other beta-blockers are lacking
One prospective randomized trial of heart failure patients with LVEF ≥40% already treated with an ACEI and a diuretic, found that propranolol reduced total mortality by 35% after 1 year of therapy (absolute risk reduction=20%; NNT=5).7 Studies of other beta-blockers haven’t reported patient-oriented outcomes as an end point.
Diuretics alone outperform diuretics plus other meds
A study that randomized 150 elderly patients with symptomatic heart failure and LVEF >45% to diuretics alone (80% were given furosemide), diuretics plus irbesartan, or diuretics plus ramipril found that diuretics alone improved the quality of life score by 46% after 52 weeks and also improved symptoms of heart failure.8 No significant symptomatic or other benefit was noted with the addition of irbesartan or ramipril.
Statins are linked to lower mortality
A prospective cohort study followed 137 patients with heart failure and ejection fraction >50% for a mean of 21 months.9 After adjustment for differences in baseline clinical variables between groups, therapy with various statins (68% of patients were on atorvastatin) was associated with lower mortality (NNT=5).
Little evidence exists to support the use of calcium channel blockers, digoxin, or other vasodilators in diastolic heart failure.
Recommendations
The TABLE summarizes recommendations of the American College of Cardiology Foundation and the American Heart Association.1
TABLE
Treating the patient with heart failure and normal LVEF: Recommendations from the ACCF and AHA
| Recommendation | Level of evidence |
|---|---|
| Control systolic and diastolic hypertension | Good supportive evidence |
| Control ventricular rate in patients with atrial fibrillation | Expert opinion/limited evidence |
| Use diuretics for pulmonary congestion and peripheral edema | Expert opinion/limited evidence |
| Perform coronary revascularization if ischemia is having an adverse effect | Expert opinion/limited evidence |
| Rhythm control in patients with atrial fibrillation may be useful | Expert opinion/limited evidence |
| Beta-adrenergic blocking agents, ACEIs, angiotensin II receptor blockers, or calcium antagonists may be effective | Expert opinion/limited evidence |
| Digitalis isn’t clearly effective | Expert opinion/limited evidence |
| ACCF, American College of Cardiology Foundation; ACEIs, angiotensin-converting enzyme inhibitors; AHA, American Heart Association; LVEF, left ventricular ejection fraction. | |
| Adapted from: Hunt SA et al. J Am Coll Cardiol. 2009.1 | |
1. Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the International Society for Heart and Lung Transplantation. J Am Coll Cardiol. 2009;53:e1-e90.
2. Tribouilloy C, Rusinaru D, Leborgne L, et al. Prognostic impact of angiotensin-converting enzyme inhibitor therapy in diastolic heart failure. Am J Cardiol. 2008;101:639-644.
3. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362:777-781.
4. Little WC, Zile MR, Klein A, et al. Effect of losartan and hydrochlorothiazide on exercise tolerance in exertional hypertension and left ventricular diastolic dysfunction. Am J Cardiol. 2006;98:383-385.
5. Warner JG Jr, Metzger DC, Kitzman DW, et al. Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response to exercise. J Am Coll Cardiol. 1999;33:1567-1572.
6. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359:2456-2467.
7. Aronow WS, Ahn C, Kronzon I. Effect of propranolol versus no propranolol on total mortality plus nonfatal myocardial infarction in older patients with prior myocardial infarction, congestive heart failure, and left ventricular ejection fraction ≥40% treated with diuretics plus angiotensin-converting enzyme inhibitors. Am J Cardiol. 1997;80:207-209.
8. Yip GW, Wang M, Wang T, et al. The Hong Kong diastolic heart failure study: a randomised controlled trial of diuretics, irbesartan and ramipril on quality of life, exercise capacity, left ventricular global and regional function in heart failure with a normal ejection fraction. Heart. 2008;94:573-580.
9. Fukuta H, Sane DC, Brucks S, et al. Statin therapy may be associated with lower mortality in patients with diastolic heart failure: a preliminary report. Circulation. 2005;112:357-363.
1. Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused update incorporated into the ACC/AHA 2005 guidelines for the diagnosis and management of heart failure in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines developed in collaboration with the International Society for Heart and Lung Transplantation. J Am Coll Cardiol. 2009;53:e1-e90.
2. Tribouilloy C, Rusinaru D, Leborgne L, et al. Prognostic impact of angiotensin-converting enzyme inhibitor therapy in diastolic heart failure. Am J Cardiol. 2008;101:639-644.
3. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362:777-781.
4. Little WC, Zile MR, Klein A, et al. Effect of losartan and hydrochlorothiazide on exercise tolerance in exertional hypertension and left ventricular diastolic dysfunction. Am J Cardiol. 2006;98:383-385.
5. Warner JG Jr, Metzger DC, Kitzman DW, et al. Losartan improves exercise tolerance in patients with diastolic dysfunction and a hypertensive response to exercise. J Am Coll Cardiol. 1999;33:1567-1572.
6. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med. 2008;359:2456-2467.
7. Aronow WS, Ahn C, Kronzon I. Effect of propranolol versus no propranolol on total mortality plus nonfatal myocardial infarction in older patients with prior myocardial infarction, congestive heart failure, and left ventricular ejection fraction ≥40% treated with diuretics plus angiotensin-converting enzyme inhibitors. Am J Cardiol. 1997;80:207-209.
8. Yip GW, Wang M, Wang T, et al. The Hong Kong diastolic heart failure study: a randomised controlled trial of diuretics, irbesartan and ramipril on quality of life, exercise capacity, left ventricular global and regional function in heart failure with a normal ejection fraction. Heart. 2008;94:573-580.
9. Fukuta H, Sane DC, Brucks S, et al. Statin therapy may be associated with lower mortality in patients with diastolic heart failure: a preliminary report. Circulation. 2005;112:357-363.
Evidence-based answers from the Family Physicians Inquiries Network
Childhood alopecia areata: What treatment works best?
IT’S UNCLEAR; there are no validated effective treatments for alopecia areata (AA). Topical immunotherapy (squaric acid dibutylester [SADBE] and diphenylcyclopropenone [DPCP]) induces the most signifi cant short-term hair regrowth in children with severe AA (strength of recommendation [SOR]: C, 4 small individual cohort studies and 1 moderately sized retrospective case review). Intralesional steroids can induce hair regrowth greater than 50% in children with limited AA (SOR: C, 1 retrospective cohort study).
Other commonly used treatments—topical and oral corticosteroids, topical cyclosporine, photodynamic therapy, and topical minoxidil—have no benefit over placebo (SOR: A, 14 randomized controlled trials [RCTs] and 3 within-patient studies).
Evidence summary
AA is a common inflammatory condition that causes hair loss and subsequent social consequences. Spontaneous remission occurs in 34% to 50% of patients within 1 year.1 Many trials of commonly used AA treatments have identified no significant patient benefits. A 2008 Cochrane review that examined 17 studies (14 RCTs and 3 within-patient studies) of AA interventions in 540 participants found no clinically significant hair regrowth (>50%) when patients were treated with topical corticosteroids, cyclosporine, minoxidil, photodynamic therapy, or oral corticosteroids.2
Documenting patient outcomes is problematic because of spontaneous resolution and frequent relapses.2 Moreover, few quality-controlled trials have studied children, and no long-term, randomized outcome trials of AA treatments exist.
Intralesional steroids and SADBE show results
In a moderately sized retrospective cohort study in Singapore (392 patients <16 years), 57% of patients experienced more than 50% improvement after 12 weeks of intralesional steroids for limited AA, and 75% showed similar improvement after 24 weeks. Of 43 children treated with anthralin, only 10 with limited AA showed more than 50% clinical improvement within 6 months.3 Fifty-four patients with extensive AA received SADBE; 74% experienced greater than 50% hair regrowth at 6 months.3
SADBE effects aren’t long-lived
A 1996 individual cohort study of 33 children (6*#8211;14 years of age) with extensive AA who were treated with SADBE once a week for a year showed a complete regrowth rate of 30.3%. Only 9% of the children maintained total or partial regrowth during long-term follow-up (mean 6 years), however.4
In another individual cohort study, 28 pediatric patients with extensive AA had mixed results with 2% SADBE used once a week for a year.5 Nine patients (32.1%) showed total or acceptable hair growth; 6 (21.4%) had diffuse regrowth but thinner than normal hair. Eighty-seven percent of patients relapsed within 6 months of discontinuing therapy.5
Studies of DPCP are too small
A 1996 small individual cohort investigation recorded a 40% response rate (90%–100% regrowth) to DPCP in 10 pediatric patients with extensive AA who were treated for an average of 8.6 months. The same study found cosmetically acceptable growth in 27% of patients (4 of 15 patients 4–15 years of age) treated for an average of 9.6 months.6
A small individual study of DPCP reported complete regrowth in 4 of 12 (33%) children with extensive AA; growth persisted at 6 months in 3 of the 4 responders.7 Another cohort study reported a 50% response rate (>80% regrowth) using DPCP in 10 patients (11–14 years of age) with extensive disease.8
Use SADBE and DPCP with caution
SADBE and DPCP are unlicensed treatments that can cause occipital and cervical lymphadenopathy, severe dermatitis (minimized by careful titration), urticaria, and hypo- or hyperpigmentation disorders (especially in racially pigmented patients). These agents shouldn’t be used during pregnancy and should be applied using gloves and aprons to avoid allergic contact dermatitis.
In light of these cautions, and handling and storage limitations, SADBE and DPCP should be reserved for patients with extensive disease (after obtaining signed informed consent). Patients should avoid ultraviolet light for 24 to 48 hours after application to avoid degradation of the medication.
Recommendations
The National Alopecia Areata Foundation and the American Academy of Dermatology recommend corticosteroids, topical minoxidil, and anthralin to treat AA.9,10
The British Association of Dermatologists’ guidelines for managing AA advise using intralesional corticosteroids for limited AA and contact immunotherapy for more extensive disease.1 They also note that intralesional corticosteroids are poorly tolerated and clinicians are reluctant to use contact immunotherapy in children.
Acknowledgements
The opinions and assertions contained herein are the private views of the author and are not to be construed as official, or as reflecting the views of the United States Air Force Medical Service or the US Air Force at large.
1. MacDonald Hull SP, Wood ML, Hutchinson PE, et al. Guidelines for the management of alopecia areata. Br J Dermatol. 2003;149:692-699.
2. Delamere FM, Sladden MJ, Dobbins HM, et al. Interventions for alopecia areata. Cochrane Database Syst Rev. 2008;(2):CD004413.-
3. Tan E, Tay YK, Giam YC. A clinical study of childhood alopecia areata in Singapore. Pediatr Dermatol. 2002;19:298-301.
4. Tosti A, Guidetti MS, Bardazzi F, et al. Long-term results of topical immunotherapy in children with alopecia totalis or alopecia universalis. J Am Acad Dermatol. 1996;35:199-201.
5. Orecchia G, Malagoli P, Santagostino L. Treatment of severe alopecia areata with squaric acid dibutylester in pediatric patients. Pediatr Dermatol. 1994;11:65-68.
6. Schuttelaar ML, Hamstra JJ, Plinck EP, et al. Alopecia areata in children: treatment with diphencyprone. Br J Dermatol. 1996;135:581-585.
7. Hull SM, Pepall L, Cunliffe WJ. Alopecia areata in children: response to treatment with diphencyprone. Br J Dermatol. 1991;125:164-168.
8. Sotiriadis D, Patsatsi A, Lazaridou E, et al. Topical immunotherapy with diphenylcyclopropenone in the treatment of chronic extensive alopecia areata. Clin Exp Dermatol. 2007;32:48-51.
9. National Alopecia Areata Foundation. Treatment recommendations. Available at: www.naaf.org/site/PageServer?pagename=about_alopecia_treatment.html. Accessed December 17, 2010.
10. American Academy of Dermatology. Alopecia areata. Available at: http://www.aad.org/public/publications/pamphlets/common_alopecia.html. Accessed December 17, 2010.
IT’S UNCLEAR; there are no validated effective treatments for alopecia areata (AA). Topical immunotherapy (squaric acid dibutylester [SADBE] and diphenylcyclopropenone [DPCP]) induces the most signifi cant short-term hair regrowth in children with severe AA (strength of recommendation [SOR]: C, 4 small individual cohort studies and 1 moderately sized retrospective case review). Intralesional steroids can induce hair regrowth greater than 50% in children with limited AA (SOR: C, 1 retrospective cohort study).
Other commonly used treatments—topical and oral corticosteroids, topical cyclosporine, photodynamic therapy, and topical minoxidil—have no benefit over placebo (SOR: A, 14 randomized controlled trials [RCTs] and 3 within-patient studies).
Evidence summary
AA is a common inflammatory condition that causes hair loss and subsequent social consequences. Spontaneous remission occurs in 34% to 50% of patients within 1 year.1 Many trials of commonly used AA treatments have identified no significant patient benefits. A 2008 Cochrane review that examined 17 studies (14 RCTs and 3 within-patient studies) of AA interventions in 540 participants found no clinically significant hair regrowth (>50%) when patients were treated with topical corticosteroids, cyclosporine, minoxidil, photodynamic therapy, or oral corticosteroids.2
Documenting patient outcomes is problematic because of spontaneous resolution and frequent relapses.2 Moreover, few quality-controlled trials have studied children, and no long-term, randomized outcome trials of AA treatments exist.
Intralesional steroids and SADBE show results
In a moderately sized retrospective cohort study in Singapore (392 patients <16 years), 57% of patients experienced more than 50% improvement after 12 weeks of intralesional steroids for limited AA, and 75% showed similar improvement after 24 weeks. Of 43 children treated with anthralin, only 10 with limited AA showed more than 50% clinical improvement within 6 months.3 Fifty-four patients with extensive AA received SADBE; 74% experienced greater than 50% hair regrowth at 6 months.3
SADBE effects aren’t long-lived
A 1996 individual cohort study of 33 children (6*#8211;14 years of age) with extensive AA who were treated with SADBE once a week for a year showed a complete regrowth rate of 30.3%. Only 9% of the children maintained total or partial regrowth during long-term follow-up (mean 6 years), however.4
In another individual cohort study, 28 pediatric patients with extensive AA had mixed results with 2% SADBE used once a week for a year.5 Nine patients (32.1%) showed total or acceptable hair growth; 6 (21.4%) had diffuse regrowth but thinner than normal hair. Eighty-seven percent of patients relapsed within 6 months of discontinuing therapy.5
Studies of DPCP are too small
A 1996 small individual cohort investigation recorded a 40% response rate (90%–100% regrowth) to DPCP in 10 pediatric patients with extensive AA who were treated for an average of 8.6 months. The same study found cosmetically acceptable growth in 27% of patients (4 of 15 patients 4–15 years of age) treated for an average of 9.6 months.6
A small individual study of DPCP reported complete regrowth in 4 of 12 (33%) children with extensive AA; growth persisted at 6 months in 3 of the 4 responders.7 Another cohort study reported a 50% response rate (>80% regrowth) using DPCP in 10 patients (11–14 years of age) with extensive disease.8
Use SADBE and DPCP with caution
SADBE and DPCP are unlicensed treatments that can cause occipital and cervical lymphadenopathy, severe dermatitis (minimized by careful titration), urticaria, and hypo- or hyperpigmentation disorders (especially in racially pigmented patients). These agents shouldn’t be used during pregnancy and should be applied using gloves and aprons to avoid allergic contact dermatitis.
In light of these cautions, and handling and storage limitations, SADBE and DPCP should be reserved for patients with extensive disease (after obtaining signed informed consent). Patients should avoid ultraviolet light for 24 to 48 hours after application to avoid degradation of the medication.
Recommendations
The National Alopecia Areata Foundation and the American Academy of Dermatology recommend corticosteroids, topical minoxidil, and anthralin to treat AA.9,10
The British Association of Dermatologists’ guidelines for managing AA advise using intralesional corticosteroids for limited AA and contact immunotherapy for more extensive disease.1 They also note that intralesional corticosteroids are poorly tolerated and clinicians are reluctant to use contact immunotherapy in children.
Acknowledgements
The opinions and assertions contained herein are the private views of the author and are not to be construed as official, or as reflecting the views of the United States Air Force Medical Service or the US Air Force at large.
IT’S UNCLEAR; there are no validated effective treatments for alopecia areata (AA). Topical immunotherapy (squaric acid dibutylester [SADBE] and diphenylcyclopropenone [DPCP]) induces the most signifi cant short-term hair regrowth in children with severe AA (strength of recommendation [SOR]: C, 4 small individual cohort studies and 1 moderately sized retrospective case review). Intralesional steroids can induce hair regrowth greater than 50% in children with limited AA (SOR: C, 1 retrospective cohort study).
Other commonly used treatments—topical and oral corticosteroids, topical cyclosporine, photodynamic therapy, and topical minoxidil—have no benefit over placebo (SOR: A, 14 randomized controlled trials [RCTs] and 3 within-patient studies).
Evidence summary
AA is a common inflammatory condition that causes hair loss and subsequent social consequences. Spontaneous remission occurs in 34% to 50% of patients within 1 year.1 Many trials of commonly used AA treatments have identified no significant patient benefits. A 2008 Cochrane review that examined 17 studies (14 RCTs and 3 within-patient studies) of AA interventions in 540 participants found no clinically significant hair regrowth (>50%) when patients were treated with topical corticosteroids, cyclosporine, minoxidil, photodynamic therapy, or oral corticosteroids.2
Documenting patient outcomes is problematic because of spontaneous resolution and frequent relapses.2 Moreover, few quality-controlled trials have studied children, and no long-term, randomized outcome trials of AA treatments exist.
Intralesional steroids and SADBE show results
In a moderately sized retrospective cohort study in Singapore (392 patients <16 years), 57% of patients experienced more than 50% improvement after 12 weeks of intralesional steroids for limited AA, and 75% showed similar improvement after 24 weeks. Of 43 children treated with anthralin, only 10 with limited AA showed more than 50% clinical improvement within 6 months.3 Fifty-four patients with extensive AA received SADBE; 74% experienced greater than 50% hair regrowth at 6 months.3
SADBE effects aren’t long-lived
A 1996 individual cohort study of 33 children (6*#8211;14 years of age) with extensive AA who were treated with SADBE once a week for a year showed a complete regrowth rate of 30.3%. Only 9% of the children maintained total or partial regrowth during long-term follow-up (mean 6 years), however.4
In another individual cohort study, 28 pediatric patients with extensive AA had mixed results with 2% SADBE used once a week for a year.5 Nine patients (32.1%) showed total or acceptable hair growth; 6 (21.4%) had diffuse regrowth but thinner than normal hair. Eighty-seven percent of patients relapsed within 6 months of discontinuing therapy.5
Studies of DPCP are too small
A 1996 small individual cohort investigation recorded a 40% response rate (90%–100% regrowth) to DPCP in 10 pediatric patients with extensive AA who were treated for an average of 8.6 months. The same study found cosmetically acceptable growth in 27% of patients (4 of 15 patients 4–15 years of age) treated for an average of 9.6 months.6
A small individual study of DPCP reported complete regrowth in 4 of 12 (33%) children with extensive AA; growth persisted at 6 months in 3 of the 4 responders.7 Another cohort study reported a 50% response rate (>80% regrowth) using DPCP in 10 patients (11–14 years of age) with extensive disease.8
Use SADBE and DPCP with caution
SADBE and DPCP are unlicensed treatments that can cause occipital and cervical lymphadenopathy, severe dermatitis (minimized by careful titration), urticaria, and hypo- or hyperpigmentation disorders (especially in racially pigmented patients). These agents shouldn’t be used during pregnancy and should be applied using gloves and aprons to avoid allergic contact dermatitis.
In light of these cautions, and handling and storage limitations, SADBE and DPCP should be reserved for patients with extensive disease (after obtaining signed informed consent). Patients should avoid ultraviolet light for 24 to 48 hours after application to avoid degradation of the medication.
Recommendations
The National Alopecia Areata Foundation and the American Academy of Dermatology recommend corticosteroids, topical minoxidil, and anthralin to treat AA.9,10
The British Association of Dermatologists’ guidelines for managing AA advise using intralesional corticosteroids for limited AA and contact immunotherapy for more extensive disease.1 They also note that intralesional corticosteroids are poorly tolerated and clinicians are reluctant to use contact immunotherapy in children.
Acknowledgements
The opinions and assertions contained herein are the private views of the author and are not to be construed as official, or as reflecting the views of the United States Air Force Medical Service or the US Air Force at large.
1. MacDonald Hull SP, Wood ML, Hutchinson PE, et al. Guidelines for the management of alopecia areata. Br J Dermatol. 2003;149:692-699.
2. Delamere FM, Sladden MJ, Dobbins HM, et al. Interventions for alopecia areata. Cochrane Database Syst Rev. 2008;(2):CD004413.-
3. Tan E, Tay YK, Giam YC. A clinical study of childhood alopecia areata in Singapore. Pediatr Dermatol. 2002;19:298-301.
4. Tosti A, Guidetti MS, Bardazzi F, et al. Long-term results of topical immunotherapy in children with alopecia totalis or alopecia universalis. J Am Acad Dermatol. 1996;35:199-201.
5. Orecchia G, Malagoli P, Santagostino L. Treatment of severe alopecia areata with squaric acid dibutylester in pediatric patients. Pediatr Dermatol. 1994;11:65-68.
6. Schuttelaar ML, Hamstra JJ, Plinck EP, et al. Alopecia areata in children: treatment with diphencyprone. Br J Dermatol. 1996;135:581-585.
7. Hull SM, Pepall L, Cunliffe WJ. Alopecia areata in children: response to treatment with diphencyprone. Br J Dermatol. 1991;125:164-168.
8. Sotiriadis D, Patsatsi A, Lazaridou E, et al. Topical immunotherapy with diphenylcyclopropenone in the treatment of chronic extensive alopecia areata. Clin Exp Dermatol. 2007;32:48-51.
9. National Alopecia Areata Foundation. Treatment recommendations. Available at: www.naaf.org/site/PageServer?pagename=about_alopecia_treatment.html. Accessed December 17, 2010.
10. American Academy of Dermatology. Alopecia areata. Available at: http://www.aad.org/public/publications/pamphlets/common_alopecia.html. Accessed December 17, 2010.
1. MacDonald Hull SP, Wood ML, Hutchinson PE, et al. Guidelines for the management of alopecia areata. Br J Dermatol. 2003;149:692-699.
2. Delamere FM, Sladden MJ, Dobbins HM, et al. Interventions for alopecia areata. Cochrane Database Syst Rev. 2008;(2):CD004413.-
3. Tan E, Tay YK, Giam YC. A clinical study of childhood alopecia areata in Singapore. Pediatr Dermatol. 2002;19:298-301.
4. Tosti A, Guidetti MS, Bardazzi F, et al. Long-term results of topical immunotherapy in children with alopecia totalis or alopecia universalis. J Am Acad Dermatol. 1996;35:199-201.
5. Orecchia G, Malagoli P, Santagostino L. Treatment of severe alopecia areata with squaric acid dibutylester in pediatric patients. Pediatr Dermatol. 1994;11:65-68.
6. Schuttelaar ML, Hamstra JJ, Plinck EP, et al. Alopecia areata in children: treatment with diphencyprone. Br J Dermatol. 1996;135:581-585.
7. Hull SM, Pepall L, Cunliffe WJ. Alopecia areata in children: response to treatment with diphencyprone. Br J Dermatol. 1991;125:164-168.
8. Sotiriadis D, Patsatsi A, Lazaridou E, et al. Topical immunotherapy with diphenylcyclopropenone in the treatment of chronic extensive alopecia areata. Clin Exp Dermatol. 2007;32:48-51.
9. National Alopecia Areata Foundation. Treatment recommendations. Available at: www.naaf.org/site/PageServer?pagename=about_alopecia_treatment.html. Accessed December 17, 2010.
10. American Academy of Dermatology. Alopecia areata. Available at: http://www.aad.org/public/publications/pamphlets/common_alopecia.html. Accessed December 17, 2010.
Evidence-based answers from the Family Physicians Inquiries Network
Is cinnamon safe and effective for treating lipid disorders?
IT’S PROBABLY SAFE, BUT ITS EFFECTIVENESS IS UNCERTAIN. Insufficient evidence exists to determine whether cinnamon improves outcomes in patients with lipid disorders. In healthy patients without hyperlipidemia, cinnamon doesn’t change lipid levels but does cause mild gastrointestinal symptoms. In patients with diabetes, the bulk of the available evidence suggests cinnamon supplementation neither improves serum lipid levels nor causes significant harm (strength of recommendation [SOR]: B, extrapolated from small randomized controlled trials [RCTs] with heterogeneous results).
Evidence summary
No large trials with patient-oriented outcomes have evaluated cinnamon as a treatment for hyperlipidemia. One small RCT compared cinnamon with turmeric in 11 healthy individuals, ages 21 to 38 years, without diabetes or hyperlipidemia.
Investigators administered 3 g cinnamon or 2.8 g turmeric daily for 4 weeks; they found no significant change in fasting lipid values. Baseline lipid levels were 155 mg/dL for total cholesterol and 139 mg/dL for triglycerides. Clinical side effects of cinnamon included transient eructation (burping or reflux), headache, and a “burning stomach” sensation.1
RCT with diabetes patients shows some positive results
Four small RCTs whose primary purpose was to investigate the effects of cinnamon supplements on blood glucose control in patients with diabetes also assessed blood lipid levels.
The first RCT studied 30 men and 30 women with type 2 diabetes, mean age 52 years. Patients had had diabetes (controlled with a sulfonylurea) for a mean of 7 years, but had no other medical conditions. Investigators randomized them into 6 groups of 10 subjects, each taking 1, 3, or 6 g of cinnamon or an equal number of placebo capsules daily for 40 days, followed by a 20-day washout period.
At 40 days, cinnamon at 3- and 6-g doses significantly reduced total cholesterol (12%-26% reduction; P<.05), low-density lipoprotein (LDL) (7%-27% reduction; P<.05), and triglycerides (23%-30% reduction; P<.05), but did not change high-density lipoprotein (HDL) levels. Cinnamon at the 1-g dose also reduced triglycerides and total cholesterol.2 Investigators didn’t mention adverse effects.
Other studies find no change in lipids, but no harm either
However, 3 subsequent RCTs with a total of 181 patients found that cinnamon didn’t improve fasting lipid profiles in patients with type 2 diabetes.
In the first study, investigators randomized 25 postmenopausal women (mean age 63 years) with type 2 diabetes (controlled on any of 3 classes of oral medication) to receive either 1.5 g cinnamon or placebo daily for 6 weeks. Mean baseline lipid levels (total cholesterol=190 mg/dL; HDL=50 mg/dL; LDL=116 mg/dL; and triglycerides=113 mg/dL) did not change significantly. Investigators didn’t mention adverse effects.3
The second RCT, involving 79 patients (mean age 63 years) with type 2 diabetes on oral therapy, also found that 3 g cinnamon daily didn’t change lipid profiles over 4 months. Baseline lipid levels were: total cholesterol=209 mg/dL; HDL=56 mg/dL; LDL=135 mg/dL; and triglycerides=170 mg/dL. Investigators reported no adverse effects.4
The third RCT evaluated the effects of cinnamon supplementation compared with placebo on lipid levels and glycosylated hemoglobin (HbA1c) for 77 individuals with type 2 diabetes. Investigators recruited subjects of any age with diabetes controlled on a stable dose of oral agents and randomized them to receive either 500 mg cinnamon or placebo twice daily.
Subjects’ mean baseline cholesterol levels were: total cholesterol=170 mg/dL; HDL= 44 mg/dL; LDL=102 mg/dL; and triglycerides=132 mg/dL. There was no difference from baseline in fasting glucose, cholesterol levels (total, HDL, or LDL), or triglycerides at monthly intervals over 3 months, nor was there any change in HbA1c from baseline to 3 months.5
Recommendations
The American Diabetes Association states that cinnamon produces no benefit for people with diabetes.6 The Mayo Clinic states that there is little evidence that cinnamon reduces cholesterol levels, and does not recommend cinnamon as a treatment for high cholesterol.7
1. Tang M, Larson-Meyer DE, Liebman M. Effect of cinnamon and turmeric on urinary oxalate excretion, plasma lipids, and plasma glucose in healthy subjects. Am J Clin Nutr. 2008;87:1262-1267.
2. Khan A, Safdar M, Ali Khan MM, et al. Cinnamon improves glucose and lipids of people with type 2 diabetes. Diabetes Care. 2003;26:3215-3218.
3. Vanschoonbeek K, Thomassen BJ, Senden JM, et al. Cinnamon supplementation does not improve glycemic control in post-menopausal type 2 diabetes patients. J Nutr. 2006;136:977-980.
4. Mang B, Wolters M, Schmitt B, et al. Effects of a cinnamon extract on plasma glucose, HbA, and serum lipid in diabetes mellitus type 2. Eur J Clin Invest. 2006;36:340-344.
5. Blevins SM, Leyva MJ, Brown J, et al. Effect of cinnamon on glucose and lipid levels in non-insulin dependent type 2 diabetes. Diabetes Care. 2007;30:2236-2237.
6. American Diabetic Association. Cinnamon has no benefit for people with diabetes. Available at: http://www.diabetes.org/news-research/research/access-diabetes-research/baker-cinnamon-has-no-benefit-for-people-with-diabetes.html. Accessed November 19, 2010.
7. Collazo-Clavell M. Diabetes treatment: can cinnamon lower blood sugar? MayoClinic.com. September 10, 2010. Available at: http://www.mayoclinic.com/health/diabetes/AN00939. Accessed October 13, 2010.
IT’S PROBABLY SAFE, BUT ITS EFFECTIVENESS IS UNCERTAIN. Insufficient evidence exists to determine whether cinnamon improves outcomes in patients with lipid disorders. In healthy patients without hyperlipidemia, cinnamon doesn’t change lipid levels but does cause mild gastrointestinal symptoms. In patients with diabetes, the bulk of the available evidence suggests cinnamon supplementation neither improves serum lipid levels nor causes significant harm (strength of recommendation [SOR]: B, extrapolated from small randomized controlled trials [RCTs] with heterogeneous results).
Evidence summary
No large trials with patient-oriented outcomes have evaluated cinnamon as a treatment for hyperlipidemia. One small RCT compared cinnamon with turmeric in 11 healthy individuals, ages 21 to 38 years, without diabetes or hyperlipidemia.
Investigators administered 3 g cinnamon or 2.8 g turmeric daily for 4 weeks; they found no significant change in fasting lipid values. Baseline lipid levels were 155 mg/dL for total cholesterol and 139 mg/dL for triglycerides. Clinical side effects of cinnamon included transient eructation (burping or reflux), headache, and a “burning stomach” sensation.1
RCT with diabetes patients shows some positive results
Four small RCTs whose primary purpose was to investigate the effects of cinnamon supplements on blood glucose control in patients with diabetes also assessed blood lipid levels.
The first RCT studied 30 men and 30 women with type 2 diabetes, mean age 52 years. Patients had had diabetes (controlled with a sulfonylurea) for a mean of 7 years, but had no other medical conditions. Investigators randomized them into 6 groups of 10 subjects, each taking 1, 3, or 6 g of cinnamon or an equal number of placebo capsules daily for 40 days, followed by a 20-day washout period.
At 40 days, cinnamon at 3- and 6-g doses significantly reduced total cholesterol (12%-26% reduction; P<.05), low-density lipoprotein (LDL) (7%-27% reduction; P<.05), and triglycerides (23%-30% reduction; P<.05), but did not change high-density lipoprotein (HDL) levels. Cinnamon at the 1-g dose also reduced triglycerides and total cholesterol.2 Investigators didn’t mention adverse effects.
Other studies find no change in lipids, but no harm either
However, 3 subsequent RCTs with a total of 181 patients found that cinnamon didn’t improve fasting lipid profiles in patients with type 2 diabetes.
In the first study, investigators randomized 25 postmenopausal women (mean age 63 years) with type 2 diabetes (controlled on any of 3 classes of oral medication) to receive either 1.5 g cinnamon or placebo daily for 6 weeks. Mean baseline lipid levels (total cholesterol=190 mg/dL; HDL=50 mg/dL; LDL=116 mg/dL; and triglycerides=113 mg/dL) did not change significantly. Investigators didn’t mention adverse effects.3
The second RCT, involving 79 patients (mean age 63 years) with type 2 diabetes on oral therapy, also found that 3 g cinnamon daily didn’t change lipid profiles over 4 months. Baseline lipid levels were: total cholesterol=209 mg/dL; HDL=56 mg/dL; LDL=135 mg/dL; and triglycerides=170 mg/dL. Investigators reported no adverse effects.4
The third RCT evaluated the effects of cinnamon supplementation compared with placebo on lipid levels and glycosylated hemoglobin (HbA1c) for 77 individuals with type 2 diabetes. Investigators recruited subjects of any age with diabetes controlled on a stable dose of oral agents and randomized them to receive either 500 mg cinnamon or placebo twice daily.
Subjects’ mean baseline cholesterol levels were: total cholesterol=170 mg/dL; HDL= 44 mg/dL; LDL=102 mg/dL; and triglycerides=132 mg/dL. There was no difference from baseline in fasting glucose, cholesterol levels (total, HDL, or LDL), or triglycerides at monthly intervals over 3 months, nor was there any change in HbA1c from baseline to 3 months.5
Recommendations
The American Diabetes Association states that cinnamon produces no benefit for people with diabetes.6 The Mayo Clinic states that there is little evidence that cinnamon reduces cholesterol levels, and does not recommend cinnamon as a treatment for high cholesterol.7
IT’S PROBABLY SAFE, BUT ITS EFFECTIVENESS IS UNCERTAIN. Insufficient evidence exists to determine whether cinnamon improves outcomes in patients with lipid disorders. In healthy patients without hyperlipidemia, cinnamon doesn’t change lipid levels but does cause mild gastrointestinal symptoms. In patients with diabetes, the bulk of the available evidence suggests cinnamon supplementation neither improves serum lipid levels nor causes significant harm (strength of recommendation [SOR]: B, extrapolated from small randomized controlled trials [RCTs] with heterogeneous results).
Evidence summary
No large trials with patient-oriented outcomes have evaluated cinnamon as a treatment for hyperlipidemia. One small RCT compared cinnamon with turmeric in 11 healthy individuals, ages 21 to 38 years, without diabetes or hyperlipidemia.
Investigators administered 3 g cinnamon or 2.8 g turmeric daily for 4 weeks; they found no significant change in fasting lipid values. Baseline lipid levels were 155 mg/dL for total cholesterol and 139 mg/dL for triglycerides. Clinical side effects of cinnamon included transient eructation (burping or reflux), headache, and a “burning stomach” sensation.1
RCT with diabetes patients shows some positive results
Four small RCTs whose primary purpose was to investigate the effects of cinnamon supplements on blood glucose control in patients with diabetes also assessed blood lipid levels.
The first RCT studied 30 men and 30 women with type 2 diabetes, mean age 52 years. Patients had had diabetes (controlled with a sulfonylurea) for a mean of 7 years, but had no other medical conditions. Investigators randomized them into 6 groups of 10 subjects, each taking 1, 3, or 6 g of cinnamon or an equal number of placebo capsules daily for 40 days, followed by a 20-day washout period.
At 40 days, cinnamon at 3- and 6-g doses significantly reduced total cholesterol (12%-26% reduction; P<.05), low-density lipoprotein (LDL) (7%-27% reduction; P<.05), and triglycerides (23%-30% reduction; P<.05), but did not change high-density lipoprotein (HDL) levels. Cinnamon at the 1-g dose also reduced triglycerides and total cholesterol.2 Investigators didn’t mention adverse effects.
Other studies find no change in lipids, but no harm either
However, 3 subsequent RCTs with a total of 181 patients found that cinnamon didn’t improve fasting lipid profiles in patients with type 2 diabetes.
In the first study, investigators randomized 25 postmenopausal women (mean age 63 years) with type 2 diabetes (controlled on any of 3 classes of oral medication) to receive either 1.5 g cinnamon or placebo daily for 6 weeks. Mean baseline lipid levels (total cholesterol=190 mg/dL; HDL=50 mg/dL; LDL=116 mg/dL; and triglycerides=113 mg/dL) did not change significantly. Investigators didn’t mention adverse effects.3
The second RCT, involving 79 patients (mean age 63 years) with type 2 diabetes on oral therapy, also found that 3 g cinnamon daily didn’t change lipid profiles over 4 months. Baseline lipid levels were: total cholesterol=209 mg/dL; HDL=56 mg/dL; LDL=135 mg/dL; and triglycerides=170 mg/dL. Investigators reported no adverse effects.4
The third RCT evaluated the effects of cinnamon supplementation compared with placebo on lipid levels and glycosylated hemoglobin (HbA1c) for 77 individuals with type 2 diabetes. Investigators recruited subjects of any age with diabetes controlled on a stable dose of oral agents and randomized them to receive either 500 mg cinnamon or placebo twice daily.
Subjects’ mean baseline cholesterol levels were: total cholesterol=170 mg/dL; HDL= 44 mg/dL; LDL=102 mg/dL; and triglycerides=132 mg/dL. There was no difference from baseline in fasting glucose, cholesterol levels (total, HDL, or LDL), or triglycerides at monthly intervals over 3 months, nor was there any change in HbA1c from baseline to 3 months.5
Recommendations
The American Diabetes Association states that cinnamon produces no benefit for people with diabetes.6 The Mayo Clinic states that there is little evidence that cinnamon reduces cholesterol levels, and does not recommend cinnamon as a treatment for high cholesterol.7
1. Tang M, Larson-Meyer DE, Liebman M. Effect of cinnamon and turmeric on urinary oxalate excretion, plasma lipids, and plasma glucose in healthy subjects. Am J Clin Nutr. 2008;87:1262-1267.
2. Khan A, Safdar M, Ali Khan MM, et al. Cinnamon improves glucose and lipids of people with type 2 diabetes. Diabetes Care. 2003;26:3215-3218.
3. Vanschoonbeek K, Thomassen BJ, Senden JM, et al. Cinnamon supplementation does not improve glycemic control in post-menopausal type 2 diabetes patients. J Nutr. 2006;136:977-980.
4. Mang B, Wolters M, Schmitt B, et al. Effects of a cinnamon extract on plasma glucose, HbA, and serum lipid in diabetes mellitus type 2. Eur J Clin Invest. 2006;36:340-344.
5. Blevins SM, Leyva MJ, Brown J, et al. Effect of cinnamon on glucose and lipid levels in non-insulin dependent type 2 diabetes. Diabetes Care. 2007;30:2236-2237.
6. American Diabetic Association. Cinnamon has no benefit for people with diabetes. Available at: http://www.diabetes.org/news-research/research/access-diabetes-research/baker-cinnamon-has-no-benefit-for-people-with-diabetes.html. Accessed November 19, 2010.
7. Collazo-Clavell M. Diabetes treatment: can cinnamon lower blood sugar? MayoClinic.com. September 10, 2010. Available at: http://www.mayoclinic.com/health/diabetes/AN00939. Accessed October 13, 2010.
1. Tang M, Larson-Meyer DE, Liebman M. Effect of cinnamon and turmeric on urinary oxalate excretion, plasma lipids, and plasma glucose in healthy subjects. Am J Clin Nutr. 2008;87:1262-1267.
2. Khan A, Safdar M, Ali Khan MM, et al. Cinnamon improves glucose and lipids of people with type 2 diabetes. Diabetes Care. 2003;26:3215-3218.
3. Vanschoonbeek K, Thomassen BJ, Senden JM, et al. Cinnamon supplementation does not improve glycemic control in post-menopausal type 2 diabetes patients. J Nutr. 2006;136:977-980.
4. Mang B, Wolters M, Schmitt B, et al. Effects of a cinnamon extract on plasma glucose, HbA, and serum lipid in diabetes mellitus type 2. Eur J Clin Invest. 2006;36:340-344.
5. Blevins SM, Leyva MJ, Brown J, et al. Effect of cinnamon on glucose and lipid levels in non-insulin dependent type 2 diabetes. Diabetes Care. 2007;30:2236-2237.
6. American Diabetic Association. Cinnamon has no benefit for people with diabetes. Available at: http://www.diabetes.org/news-research/research/access-diabetes-research/baker-cinnamon-has-no-benefit-for-people-with-diabetes.html. Accessed November 19, 2010.
7. Collazo-Clavell M. Diabetes treatment: can cinnamon lower blood sugar? MayoClinic.com. September 10, 2010. Available at: http://www.mayoclinic.com/health/diabetes/AN00939. Accessed October 13, 2010.
Evidence-based answers from the Family Physicians Inquiries Network