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When is the best time to clamp the umbilical cord after routine vaginal delivery?
SOMETIME BETWEEN 30 SECONDS AND 2 MINUTES after delivery appears to be the best interval. In term infants, delayed clamping (waiting 1 or 2 minutes or until the cord stops pulsating) improves hemoglobin and ferritin levels, but slightly increases the risk of neonatal jaundice requiring phototherapy (strength of recommendation [SOR]: A, meta-analysis).
In preterm infants less than 37 weeks of age, cord clamping between 30 and 120 seconds after delivery reduces the need for blood transfusion (number needed to treat [NNT]=4) and frequency of intraventricular hemorrhage (NNT=8) compared with clamping in less than 20 seconds (SOR: A, meta-analyses).
Evidence summary
A 2008 Cochrane meta-analysis reviewed 11 randomized controlled trials (RCTs), enrolling more than 2900 women who had term vaginal deliveries, that compared early cord clamping (ECC) with delayed cord clamping (DCC).1 All of the trials defined ECC as clamping less than 1 minute after birth. DCC was variously defined as clamping after 1 minute, after 2 minutes, or after the cord stopped pulsating.
DCC was associated with increased newborn hemoglobin values (weighted mean difference [WMD]=2.2 g/dL; 95% confidence interval [CI], 0.3-4.1) and increased mean ferritin levels that persisted for as long as 6 months (WMD=12 mcg/L; 95% CI, 4.1-20). However, significantly fewer infants who underwent ECC required phototherapy for jaundice (relative risk [RR]=0.59; 95% CI, 0.38-0.92; NNT=45).
This meta-analysis was limited by variations in the definition of DCC, the level at which newborns were held in relation to the placenta (above, below, or level with), and the use of uterotonics. These limitations also apply to the other systematic reviews discussed here.
But is hyperbilirubinemia significant?
A 2007 meta-analysis of 15 clinical trials (8 randomized and 7 nonrandomized) with 1001 term infants in the DCC group and 911 in the ECC group found results similar to the Cochrane review.2 When compared with ECC, delayed clamping at least 2 minutes after birth was associated with significantly higher hematocrit (WMD=3.7%; 95% CI, 2-4), ferritin (WMD=18 mcg/L; 95% CI, 17-19), and stored iron (WMD=20 mg; 95% CI, 8-32), as well as decreased risk of anemia (RR=0.5; 95% CI, 0.4-0.7).
Infants in the DCC group had an increased risk of asymptomatic polycythemia (RR=3.9; 95% CI, 1.0-15). Delayed clamping was also associated with an increased rate of phototherapy for hyperbilirubinemia that didn’t reach statistical significance, although the confidence interval was wide (RR=1.78; 95% CI, 0.71-4.46).
Early clamping poses risks for preterm infants
A 2008 meta-analysis (using Cochrane methodology) identified 10 RCTs enrolling 454 infants born at less than 37 weeks’ gestation.3 ECC was defined as less than 20 seconds after delivery and DCC as greater than 30 seconds (and up to 120 seconds).
The review found ECC to be inferior to DCC. Early clamping was associated with an increased risk of transfusion for anemia (3 studies, 112 patients; RR=2.1; 95% CI, 1.2-3.3; NNT=4), increased number of blood transfusions (4 studies, 170 patients; WMD=1.2; 95% CI, 0.52-1.8), and increased rate of intraventricular hemorrhage (RR=1.9; 95% CI, 1.3-2.8; NNT=8).
Recommendations
The World Health Organization (WHO) recommends against clamping the umbilical cord any earlier than is necessary to apply traction to the placenta in the active management of the third state of labor.4 (WHO estimates this would normally take around 3 minutes.) Early clamping may be required if the baby is asphyxiated and needs immediate resuscitation.
The Society of Obstetricians and Gynecologists of Canada recommends delaying cord clamping by at least 60 seconds in premature newborns (<37 weeks’ gestation) to reduce the risk of intraventricular hemorrhage and the need for transfusion.5 For term newborns, the Society advises clinicians to weigh the increased risk of neonatal jaundice against the benefit of greater iron stores on a case-by-case basis.
1. McDonald SJ, Middleton P. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes. Cochrane Database Syst Rev. 2008;(2):CD004074.-
2. Hutton EK, Hassan ES. Late vs early clamping of the umbilical cord in full-term neonates: systematic review and meta-analysis of controlled trials. JAMA. 2007;297:1241-1252.
3. Rabe H, Reynolds G, Diaz-Rossello J. A systematic review and meta-analysis of a brief delay in clamping the umbilical cord of preterm infants. Neonatology. 2008;93:138-144.
4. Abalos E. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes: RHL commentary (last revised March 2, 2009). In: The WHO Reproductive Health Library; Geneva, Switzerland: World Health Organization. Available at: http://apps.who.int/rhl/pregnancy_childbirth/childbirth/3rd_stage/cd004074_abalose_com/en/index.html. Accessed July 21, 2010.
5. Leduc D, Senikas V, Lalonde AB, et al. Active management of the third stage of labour: prevention and treatment of postpartum hemorrhage. J Obstet Gynaecol Can. 2009;31:980-993.
SOMETIME BETWEEN 30 SECONDS AND 2 MINUTES after delivery appears to be the best interval. In term infants, delayed clamping (waiting 1 or 2 minutes or until the cord stops pulsating) improves hemoglobin and ferritin levels, but slightly increases the risk of neonatal jaundice requiring phototherapy (strength of recommendation [SOR]: A, meta-analysis).
In preterm infants less than 37 weeks of age, cord clamping between 30 and 120 seconds after delivery reduces the need for blood transfusion (number needed to treat [NNT]=4) and frequency of intraventricular hemorrhage (NNT=8) compared with clamping in less than 20 seconds (SOR: A, meta-analyses).
Evidence summary
A 2008 Cochrane meta-analysis reviewed 11 randomized controlled trials (RCTs), enrolling more than 2900 women who had term vaginal deliveries, that compared early cord clamping (ECC) with delayed cord clamping (DCC).1 All of the trials defined ECC as clamping less than 1 minute after birth. DCC was variously defined as clamping after 1 minute, after 2 minutes, or after the cord stopped pulsating.
DCC was associated with increased newborn hemoglobin values (weighted mean difference [WMD]=2.2 g/dL; 95% confidence interval [CI], 0.3-4.1) and increased mean ferritin levels that persisted for as long as 6 months (WMD=12 mcg/L; 95% CI, 4.1-20). However, significantly fewer infants who underwent ECC required phototherapy for jaundice (relative risk [RR]=0.59; 95% CI, 0.38-0.92; NNT=45).
This meta-analysis was limited by variations in the definition of DCC, the level at which newborns were held in relation to the placenta (above, below, or level with), and the use of uterotonics. These limitations also apply to the other systematic reviews discussed here.
But is hyperbilirubinemia significant?
A 2007 meta-analysis of 15 clinical trials (8 randomized and 7 nonrandomized) with 1001 term infants in the DCC group and 911 in the ECC group found results similar to the Cochrane review.2 When compared with ECC, delayed clamping at least 2 minutes after birth was associated with significantly higher hematocrit (WMD=3.7%; 95% CI, 2-4), ferritin (WMD=18 mcg/L; 95% CI, 17-19), and stored iron (WMD=20 mg; 95% CI, 8-32), as well as decreased risk of anemia (RR=0.5; 95% CI, 0.4-0.7).
Infants in the DCC group had an increased risk of asymptomatic polycythemia (RR=3.9; 95% CI, 1.0-15). Delayed clamping was also associated with an increased rate of phototherapy for hyperbilirubinemia that didn’t reach statistical significance, although the confidence interval was wide (RR=1.78; 95% CI, 0.71-4.46).
Early clamping poses risks for preterm infants
A 2008 meta-analysis (using Cochrane methodology) identified 10 RCTs enrolling 454 infants born at less than 37 weeks’ gestation.3 ECC was defined as less than 20 seconds after delivery and DCC as greater than 30 seconds (and up to 120 seconds).
The review found ECC to be inferior to DCC. Early clamping was associated with an increased risk of transfusion for anemia (3 studies, 112 patients; RR=2.1; 95% CI, 1.2-3.3; NNT=4), increased number of blood transfusions (4 studies, 170 patients; WMD=1.2; 95% CI, 0.52-1.8), and increased rate of intraventricular hemorrhage (RR=1.9; 95% CI, 1.3-2.8; NNT=8).
Recommendations
The World Health Organization (WHO) recommends against clamping the umbilical cord any earlier than is necessary to apply traction to the placenta in the active management of the third state of labor.4 (WHO estimates this would normally take around 3 minutes.) Early clamping may be required if the baby is asphyxiated and needs immediate resuscitation.
The Society of Obstetricians and Gynecologists of Canada recommends delaying cord clamping by at least 60 seconds in premature newborns (<37 weeks’ gestation) to reduce the risk of intraventricular hemorrhage and the need for transfusion.5 For term newborns, the Society advises clinicians to weigh the increased risk of neonatal jaundice against the benefit of greater iron stores on a case-by-case basis.
SOMETIME BETWEEN 30 SECONDS AND 2 MINUTES after delivery appears to be the best interval. In term infants, delayed clamping (waiting 1 or 2 minutes or until the cord stops pulsating) improves hemoglobin and ferritin levels, but slightly increases the risk of neonatal jaundice requiring phototherapy (strength of recommendation [SOR]: A, meta-analysis).
In preterm infants less than 37 weeks of age, cord clamping between 30 and 120 seconds after delivery reduces the need for blood transfusion (number needed to treat [NNT]=4) and frequency of intraventricular hemorrhage (NNT=8) compared with clamping in less than 20 seconds (SOR: A, meta-analyses).
Evidence summary
A 2008 Cochrane meta-analysis reviewed 11 randomized controlled trials (RCTs), enrolling more than 2900 women who had term vaginal deliveries, that compared early cord clamping (ECC) with delayed cord clamping (DCC).1 All of the trials defined ECC as clamping less than 1 minute after birth. DCC was variously defined as clamping after 1 minute, after 2 minutes, or after the cord stopped pulsating.
DCC was associated with increased newborn hemoglobin values (weighted mean difference [WMD]=2.2 g/dL; 95% confidence interval [CI], 0.3-4.1) and increased mean ferritin levels that persisted for as long as 6 months (WMD=12 mcg/L; 95% CI, 4.1-20). However, significantly fewer infants who underwent ECC required phototherapy for jaundice (relative risk [RR]=0.59; 95% CI, 0.38-0.92; NNT=45).
This meta-analysis was limited by variations in the definition of DCC, the level at which newborns were held in relation to the placenta (above, below, or level with), and the use of uterotonics. These limitations also apply to the other systematic reviews discussed here.
But is hyperbilirubinemia significant?
A 2007 meta-analysis of 15 clinical trials (8 randomized and 7 nonrandomized) with 1001 term infants in the DCC group and 911 in the ECC group found results similar to the Cochrane review.2 When compared with ECC, delayed clamping at least 2 minutes after birth was associated with significantly higher hematocrit (WMD=3.7%; 95% CI, 2-4), ferritin (WMD=18 mcg/L; 95% CI, 17-19), and stored iron (WMD=20 mg; 95% CI, 8-32), as well as decreased risk of anemia (RR=0.5; 95% CI, 0.4-0.7).
Infants in the DCC group had an increased risk of asymptomatic polycythemia (RR=3.9; 95% CI, 1.0-15). Delayed clamping was also associated with an increased rate of phototherapy for hyperbilirubinemia that didn’t reach statistical significance, although the confidence interval was wide (RR=1.78; 95% CI, 0.71-4.46).
Early clamping poses risks for preterm infants
A 2008 meta-analysis (using Cochrane methodology) identified 10 RCTs enrolling 454 infants born at less than 37 weeks’ gestation.3 ECC was defined as less than 20 seconds after delivery and DCC as greater than 30 seconds (and up to 120 seconds).
The review found ECC to be inferior to DCC. Early clamping was associated with an increased risk of transfusion for anemia (3 studies, 112 patients; RR=2.1; 95% CI, 1.2-3.3; NNT=4), increased number of blood transfusions (4 studies, 170 patients; WMD=1.2; 95% CI, 0.52-1.8), and increased rate of intraventricular hemorrhage (RR=1.9; 95% CI, 1.3-2.8; NNT=8).
Recommendations
The World Health Organization (WHO) recommends against clamping the umbilical cord any earlier than is necessary to apply traction to the placenta in the active management of the third state of labor.4 (WHO estimates this would normally take around 3 minutes.) Early clamping may be required if the baby is asphyxiated and needs immediate resuscitation.
The Society of Obstetricians and Gynecologists of Canada recommends delaying cord clamping by at least 60 seconds in premature newborns (<37 weeks’ gestation) to reduce the risk of intraventricular hemorrhage and the need for transfusion.5 For term newborns, the Society advises clinicians to weigh the increased risk of neonatal jaundice against the benefit of greater iron stores on a case-by-case basis.
1. McDonald SJ, Middleton P. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes. Cochrane Database Syst Rev. 2008;(2):CD004074.-
2. Hutton EK, Hassan ES. Late vs early clamping of the umbilical cord in full-term neonates: systematic review and meta-analysis of controlled trials. JAMA. 2007;297:1241-1252.
3. Rabe H, Reynolds G, Diaz-Rossello J. A systematic review and meta-analysis of a brief delay in clamping the umbilical cord of preterm infants. Neonatology. 2008;93:138-144.
4. Abalos E. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes: RHL commentary (last revised March 2, 2009). In: The WHO Reproductive Health Library; Geneva, Switzerland: World Health Organization. Available at: http://apps.who.int/rhl/pregnancy_childbirth/childbirth/3rd_stage/cd004074_abalose_com/en/index.html. Accessed July 21, 2010.
5. Leduc D, Senikas V, Lalonde AB, et al. Active management of the third stage of labour: prevention and treatment of postpartum hemorrhage. J Obstet Gynaecol Can. 2009;31:980-993.
1. McDonald SJ, Middleton P. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes. Cochrane Database Syst Rev. 2008;(2):CD004074.-
2. Hutton EK, Hassan ES. Late vs early clamping of the umbilical cord in full-term neonates: systematic review and meta-analysis of controlled trials. JAMA. 2007;297:1241-1252.
3. Rabe H, Reynolds G, Diaz-Rossello J. A systematic review and meta-analysis of a brief delay in clamping the umbilical cord of preterm infants. Neonatology. 2008;93:138-144.
4. Abalos E. Effect of timing of umbilical cord clamping of term infants on maternal and neonatal outcomes: RHL commentary (last revised March 2, 2009). In: The WHO Reproductive Health Library; Geneva, Switzerland: World Health Organization. Available at: http://apps.who.int/rhl/pregnancy_childbirth/childbirth/3rd_stage/cd004074_abalose_com/en/index.html. Accessed July 21, 2010.
5. Leduc D, Senikas V, Lalonde AB, et al. Active management of the third stage of labour: prevention and treatment of postpartum hemorrhage. J Obstet Gynaecol Can. 2009;31:980-993.
Evidence-based answers from the Family Physicians Inquiries Network
What treatment works best for tennis elbow?
Topical or oral nonsteroidal anti-inflammatory medications (NSAIDs), corticosteroid injection, and acupuncture are more helpful than placebo in treating lateral epicondylitis, or tennis elbow (strength of recommendation [SOR]: B, multiple systematic reviews of randomized, controlled trials [RCTs] of limited quality and individual RCTs).
A corticosteroid injection is effective for short-term therapy—as long as 6 weeks—but produces no long-term improvement. Physiotherapy or a wait-and-see approach are superior to corticosteroid injection at 52 weeks (SOR: B, RCTs).
There’s insufficient evidence to support specific physiotherapy methods or orthoses (braces), shock wave therapy, ultrasound, or deep friction massage (SOR: B, multiple systematic reviews). Surgery may succeed in refractory cases that have failed extensive conservative measures (SOR: C, case series and expert opinion).
How about strengthening the extensor muscles?
Daniel Spogen, MD
Department of Family and Community Medicine, University of Nevada School of Medicine, Reno
Tennis elbow is one disorder that I see almost every day in my clinic or the sports medicine clinic. The age-old standard treatments are rest, ice, and NSAIDs, followed by corticosteroid injection if the condition doesn’t improve in 3 to 4 weeks. Because these remedies are all symptomatic, not curative, we should look at the mechanism of injury to help design therapy.
The extensor muscle group of the forearm is weaker than the flexor group, which puts a lot of stress on the insertion of the extensor muscles—that is, the lateral epicondyle. For this reason, I’ve been advocating exercises to strengthen the extensor muscles as a more long-term “cure” for lateral epicondylitis. When I didn’t see any mention of extensor muscle strengthening exercises in this Clinical Inquiry, I searched the database and found that insufficient data exist to recommend for or against such exercises.
I agree that rest, ergonomic activity modification, and NSAIDs are the best initial treatments for lateral epicondylitis. However, more studies of extensor muscle strengthening need to be done because this approach may be very helpful in the long term.
Evidence summary
NSAIDs: Benefits with limits
A Cochrane systematic review evaluating the efficacy of topical and oral NSAIDs to treat lateral epicondylitis found that topically applied diclofenac gel was more effective than placebo, as measured by overall patient satisfaction (relative risk [RR]=0.39; 95% confidence interval [CI], 0.23-0.66; number needed to treat [NNT]=3).1 Topical diclofenac or benzydamine gel had a significant effect on the patient’s perception of pain compared with placebo, but not beyond 4 weeks of therapy (weighted mean difference [WMD] on a 10-point scale=-1.88 points; 95% CI, –2.54 to –1.21). However, no difference was noted in functional outcomes, measured by grip or wrist extension strength.
Patients who used topical NSAIDs reported more adverse events than those using placebo, including minor skin irritation (RR=2.26; 95% CI, 1.04-4.94).1
Oral NSAIDs relieve pain, but not as much as steroids
In the same review, oral diclofenac reduced pain scores at 4 weeks compared with placebo (WMD on 100-point scale=-13.9 points; 95% CI, -23.21 to -4.59).1 Adequate studies are lacking to show a benefit of oral NSAIDs past 4 weeks. Significantly more complaints of abdominal pain occurred with oral diclofenac than placebo (RR=3.17; 95% CI, 1.35-7.41; number needed to harm [NNH]=5).1
One study that directly compared diflunisal with naproxen for lateral epicondylitis found no difference between the therapies in patients’ subjective perception of pain on a 5-point scale (RR=0.24; 95% CI, 0.03-1.89).1 When oral NSAIDs were compared with steroid injections, patients receiving an injection reported more improvement in pain than patients who took an oral NSAID (RR=3.06; 95% CI, 1.55-6.06; NNT=4).1
Corticosteroids more effective in short term than long term
A subanalysis of 4 studies in another systematic review found corticosteroid injections to be superior to other conservative treatments such as elbow supports, oral NSAIDs, and physiotherapy at 2 to 6 weeks (RR=0.50; 95% CI, 0.36-0.70).2 The positive effects weren’t maintained at 6 weeks.
In a randomized study with 3 treatment arms, 185 patients were treated with a corticosteroid injection, physiotherapy, or a wait-and-see approach (ergonomic advice, rest, and oral anti-inflammatory medication). Corticosteroid injections were significantly more effective for the patients’ main complaint at 6 weeks compared with wait-and-see (mean difference in improvement [MDI] on a 100-point scale=24; 95% CI, 14-35; NNT=2) or physiotherapy (MDI=20; 95% CI, 10-31; NNT=2).3 By contrast, at 26 and 52 weeks’ follow-up, physiotherapy was more effective than steroid injections (MDI=15; 95% CI, 5-25) but statistically equivalent to a wait-and-see approach (MDI=7; 95% CI, –4 to 17).
Physiotherapy, exercise, acupuncture bring short-term relief
In a separate RCT, physiotherapy and exercise were significantly better than a wait-and-see approach at 6 weeks for pain-free grip force, rating of pain severity, and global improvement (RR=0.5; 99% CI, 0.2-0.8; NNT=3), but by 52 weeks the outcomes were statistically equal.4
An individual RCT, cited in a Cochrane review, showed acupuncture had a very short-term benefit for pain relief compared with placebo (WMD=18.8 hours; 95% CI, 10.1-27.5).5 Another individual RCT, which was not included in the meta-analysis because of methodologic problems in the other studies, found that a short course of 10 acupuncture treatments resulted in an excellent or good outcome (as reported by participants) compared with placebo (RR=0.09; 95% CI, 0.01-0.64; NNT=4).5 No benefit was noted after 3 or 12 months.
Physiotherapy techniques, orthotics are hard to evaluate
Systematic reviews of specific physiotherapy or orthotic (bracing) treatments are hampered by the large number of treatment options available and the heterogeneity of the available studies, which prevent statistically useful evaluation.6,7
Shock wave, ultrasound, massage offer little or no benefit
In a meta-analysis of 3 trials, shock wave therapy provided no significant benefit at 4 to 6 weeks compared with placebo (WMD on a 100-point scale=-9.42; 95% CI, -20.70 to 1.86).8 Pooling 2 studies in a different systematic review showed weak evidence that ultrasound reduced pain at 13 weeks compared with placebo (standardized mean difference=–0.98; 95% CI, –1.64 to –0.33).6 Another Cochrane review found no added benefit in function from combining deep transverse friction massage with ultrasound or a placebo ointment (RR=3.3; 95% CI, 0.4-24.3).9
Recommendations
The Work Loss Data Institute recommends ice, rest, ergonomic modifications, and short-term topical or oral NSAIDs. Progressive physical or occupational therapy may follow if no improvement is seen in 2 weeks.
Splinting, acupuncture, and corticosteroid administration by injection or iontophoresis may reduce pain for as long as 2 to 6 weeks. If these conservative measures fail, surgical treatment is recommended as a last resort.10
1. Green S, Buchbinder R, Barnsley L, et al. Non-steroidal anti-inflammatory drugs (NSAIDs) for treating lateral elbow pain in adults. Cochrane Database Syst Rev. 2001;(4):CD003686.
2. Smidt N, Assendelft WJ, van der Windt DA, et al. Corticosteroid injections for lateral epicondylitis: a systemic review. Pain. 2002;96:23-40.
3. Smidt N, van der Windt DA, Assendelft WJ, et al. Corticosteroid injections, physiotherapy, or a wait-and-see policy for lateral epicondylitis: a randomised controlled trial. Lancet. 2002;359:657-662.
4. Bisset L, Beller E, Jull G, et al. Mobilisation with movement and exercise, corticosteroid injection, or wait and see for tennis elbow: randomised trial. BMJ. 2006;333:939.
5. Green S, Buchbinder R, Barnsley L, et al. Acupuncture for lateral elbow pain. Cochrane Database Syst Rev. 2002;(1):CD003527.
6. Smidt N, Assendelft WJ, Arola H, et al. Effectiveness of physiotherapy for lateral epicondylitis: a systematic review. Ann Med. 2003;35:51-62.
7. Struijs PA, Smidt N, Arola H, et al. Orthotic devices for the treatment of tennis elbow. Cochrane Database Syst Rev. 2002;(1):CD001821.
8. Buchbinder R, Green SE, Youd JM, et al. Shock wave therapy for lateral elbow pain. Cochrane Database of Syst Rev. 2005;(4):CD003524.
9. Brosseau L, Casimiro L, Milne S, et al. Deep transverse friction massage for treating tendinitis. Cochrane Database Syst Rev. 2002;(4):CD003528.
10. Chapell R, Turkelson CM, Coates V, et al. Diagnosis and Treatment of Worker-Related Musculoskeletal Disorders of the Upper Extremity. Evidence Report/Technology Assessment Number 62 (prepared by ECRI, Health Technology Assessment Group under contract no. 290-97-0020). AHRQ Publication no. 02-E038. Rockville, Md: Agency for Healthcare Research and Quality; December 2002. Available at: http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat1a.chapter.29294. Accessed June 8, 2007.
Topical or oral nonsteroidal anti-inflammatory medications (NSAIDs), corticosteroid injection, and acupuncture are more helpful than placebo in treating lateral epicondylitis, or tennis elbow (strength of recommendation [SOR]: B, multiple systematic reviews of randomized, controlled trials [RCTs] of limited quality and individual RCTs).
A corticosteroid injection is effective for short-term therapy—as long as 6 weeks—but produces no long-term improvement. Physiotherapy or a wait-and-see approach are superior to corticosteroid injection at 52 weeks (SOR: B, RCTs).
There’s insufficient evidence to support specific physiotherapy methods or orthoses (braces), shock wave therapy, ultrasound, or deep friction massage (SOR: B, multiple systematic reviews). Surgery may succeed in refractory cases that have failed extensive conservative measures (SOR: C, case series and expert opinion).
How about strengthening the extensor muscles?
Daniel Spogen, MD
Department of Family and Community Medicine, University of Nevada School of Medicine, Reno
Tennis elbow is one disorder that I see almost every day in my clinic or the sports medicine clinic. The age-old standard treatments are rest, ice, and NSAIDs, followed by corticosteroid injection if the condition doesn’t improve in 3 to 4 weeks. Because these remedies are all symptomatic, not curative, we should look at the mechanism of injury to help design therapy.
The extensor muscle group of the forearm is weaker than the flexor group, which puts a lot of stress on the insertion of the extensor muscles—that is, the lateral epicondyle. For this reason, I’ve been advocating exercises to strengthen the extensor muscles as a more long-term “cure” for lateral epicondylitis. When I didn’t see any mention of extensor muscle strengthening exercises in this Clinical Inquiry, I searched the database and found that insufficient data exist to recommend for or against such exercises.
I agree that rest, ergonomic activity modification, and NSAIDs are the best initial treatments for lateral epicondylitis. However, more studies of extensor muscle strengthening need to be done because this approach may be very helpful in the long term.
Evidence summary
NSAIDs: Benefits with limits
A Cochrane systematic review evaluating the efficacy of topical and oral NSAIDs to treat lateral epicondylitis found that topically applied diclofenac gel was more effective than placebo, as measured by overall patient satisfaction (relative risk [RR]=0.39; 95% confidence interval [CI], 0.23-0.66; number needed to treat [NNT]=3).1 Topical diclofenac or benzydamine gel had a significant effect on the patient’s perception of pain compared with placebo, but not beyond 4 weeks of therapy (weighted mean difference [WMD] on a 10-point scale=-1.88 points; 95% CI, –2.54 to –1.21). However, no difference was noted in functional outcomes, measured by grip or wrist extension strength.
Patients who used topical NSAIDs reported more adverse events than those using placebo, including minor skin irritation (RR=2.26; 95% CI, 1.04-4.94).1
Oral NSAIDs relieve pain, but not as much as steroids
In the same review, oral diclofenac reduced pain scores at 4 weeks compared with placebo (WMD on 100-point scale=-13.9 points; 95% CI, -23.21 to -4.59).1 Adequate studies are lacking to show a benefit of oral NSAIDs past 4 weeks. Significantly more complaints of abdominal pain occurred with oral diclofenac than placebo (RR=3.17; 95% CI, 1.35-7.41; number needed to harm [NNH]=5).1
One study that directly compared diflunisal with naproxen for lateral epicondylitis found no difference between the therapies in patients’ subjective perception of pain on a 5-point scale (RR=0.24; 95% CI, 0.03-1.89).1 When oral NSAIDs were compared with steroid injections, patients receiving an injection reported more improvement in pain than patients who took an oral NSAID (RR=3.06; 95% CI, 1.55-6.06; NNT=4).1
Corticosteroids more effective in short term than long term
A subanalysis of 4 studies in another systematic review found corticosteroid injections to be superior to other conservative treatments such as elbow supports, oral NSAIDs, and physiotherapy at 2 to 6 weeks (RR=0.50; 95% CI, 0.36-0.70).2 The positive effects weren’t maintained at 6 weeks.
In a randomized study with 3 treatment arms, 185 patients were treated with a corticosteroid injection, physiotherapy, or a wait-and-see approach (ergonomic advice, rest, and oral anti-inflammatory medication). Corticosteroid injections were significantly more effective for the patients’ main complaint at 6 weeks compared with wait-and-see (mean difference in improvement [MDI] on a 100-point scale=24; 95% CI, 14-35; NNT=2) or physiotherapy (MDI=20; 95% CI, 10-31; NNT=2).3 By contrast, at 26 and 52 weeks’ follow-up, physiotherapy was more effective than steroid injections (MDI=15; 95% CI, 5-25) but statistically equivalent to a wait-and-see approach (MDI=7; 95% CI, –4 to 17).
Physiotherapy, exercise, acupuncture bring short-term relief
In a separate RCT, physiotherapy and exercise were significantly better than a wait-and-see approach at 6 weeks for pain-free grip force, rating of pain severity, and global improvement (RR=0.5; 99% CI, 0.2-0.8; NNT=3), but by 52 weeks the outcomes were statistically equal.4
An individual RCT, cited in a Cochrane review, showed acupuncture had a very short-term benefit for pain relief compared with placebo (WMD=18.8 hours; 95% CI, 10.1-27.5).5 Another individual RCT, which was not included in the meta-analysis because of methodologic problems in the other studies, found that a short course of 10 acupuncture treatments resulted in an excellent or good outcome (as reported by participants) compared with placebo (RR=0.09; 95% CI, 0.01-0.64; NNT=4).5 No benefit was noted after 3 or 12 months.
Physiotherapy techniques, orthotics are hard to evaluate
Systematic reviews of specific physiotherapy or orthotic (bracing) treatments are hampered by the large number of treatment options available and the heterogeneity of the available studies, which prevent statistically useful evaluation.6,7
Shock wave, ultrasound, massage offer little or no benefit
In a meta-analysis of 3 trials, shock wave therapy provided no significant benefit at 4 to 6 weeks compared with placebo (WMD on a 100-point scale=-9.42; 95% CI, -20.70 to 1.86).8 Pooling 2 studies in a different systematic review showed weak evidence that ultrasound reduced pain at 13 weeks compared with placebo (standardized mean difference=–0.98; 95% CI, –1.64 to –0.33).6 Another Cochrane review found no added benefit in function from combining deep transverse friction massage with ultrasound or a placebo ointment (RR=3.3; 95% CI, 0.4-24.3).9
Recommendations
The Work Loss Data Institute recommends ice, rest, ergonomic modifications, and short-term topical or oral NSAIDs. Progressive physical or occupational therapy may follow if no improvement is seen in 2 weeks.
Splinting, acupuncture, and corticosteroid administration by injection or iontophoresis may reduce pain for as long as 2 to 6 weeks. If these conservative measures fail, surgical treatment is recommended as a last resort.10
Topical or oral nonsteroidal anti-inflammatory medications (NSAIDs), corticosteroid injection, and acupuncture are more helpful than placebo in treating lateral epicondylitis, or tennis elbow (strength of recommendation [SOR]: B, multiple systematic reviews of randomized, controlled trials [RCTs] of limited quality and individual RCTs).
A corticosteroid injection is effective for short-term therapy—as long as 6 weeks—but produces no long-term improvement. Physiotherapy or a wait-and-see approach are superior to corticosteroid injection at 52 weeks (SOR: B, RCTs).
There’s insufficient evidence to support specific physiotherapy methods or orthoses (braces), shock wave therapy, ultrasound, or deep friction massage (SOR: B, multiple systematic reviews). Surgery may succeed in refractory cases that have failed extensive conservative measures (SOR: C, case series and expert opinion).
How about strengthening the extensor muscles?
Daniel Spogen, MD
Department of Family and Community Medicine, University of Nevada School of Medicine, Reno
Tennis elbow is one disorder that I see almost every day in my clinic or the sports medicine clinic. The age-old standard treatments are rest, ice, and NSAIDs, followed by corticosteroid injection if the condition doesn’t improve in 3 to 4 weeks. Because these remedies are all symptomatic, not curative, we should look at the mechanism of injury to help design therapy.
The extensor muscle group of the forearm is weaker than the flexor group, which puts a lot of stress on the insertion of the extensor muscles—that is, the lateral epicondyle. For this reason, I’ve been advocating exercises to strengthen the extensor muscles as a more long-term “cure” for lateral epicondylitis. When I didn’t see any mention of extensor muscle strengthening exercises in this Clinical Inquiry, I searched the database and found that insufficient data exist to recommend for or against such exercises.
I agree that rest, ergonomic activity modification, and NSAIDs are the best initial treatments for lateral epicondylitis. However, more studies of extensor muscle strengthening need to be done because this approach may be very helpful in the long term.
Evidence summary
NSAIDs: Benefits with limits
A Cochrane systematic review evaluating the efficacy of topical and oral NSAIDs to treat lateral epicondylitis found that topically applied diclofenac gel was more effective than placebo, as measured by overall patient satisfaction (relative risk [RR]=0.39; 95% confidence interval [CI], 0.23-0.66; number needed to treat [NNT]=3).1 Topical diclofenac or benzydamine gel had a significant effect on the patient’s perception of pain compared with placebo, but not beyond 4 weeks of therapy (weighted mean difference [WMD] on a 10-point scale=-1.88 points; 95% CI, –2.54 to –1.21). However, no difference was noted in functional outcomes, measured by grip or wrist extension strength.
Patients who used topical NSAIDs reported more adverse events than those using placebo, including minor skin irritation (RR=2.26; 95% CI, 1.04-4.94).1
Oral NSAIDs relieve pain, but not as much as steroids
In the same review, oral diclofenac reduced pain scores at 4 weeks compared with placebo (WMD on 100-point scale=-13.9 points; 95% CI, -23.21 to -4.59).1 Adequate studies are lacking to show a benefit of oral NSAIDs past 4 weeks. Significantly more complaints of abdominal pain occurred with oral diclofenac than placebo (RR=3.17; 95% CI, 1.35-7.41; number needed to harm [NNH]=5).1
One study that directly compared diflunisal with naproxen for lateral epicondylitis found no difference between the therapies in patients’ subjective perception of pain on a 5-point scale (RR=0.24; 95% CI, 0.03-1.89).1 When oral NSAIDs were compared with steroid injections, patients receiving an injection reported more improvement in pain than patients who took an oral NSAID (RR=3.06; 95% CI, 1.55-6.06; NNT=4).1
Corticosteroids more effective in short term than long term
A subanalysis of 4 studies in another systematic review found corticosteroid injections to be superior to other conservative treatments such as elbow supports, oral NSAIDs, and physiotherapy at 2 to 6 weeks (RR=0.50; 95% CI, 0.36-0.70).2 The positive effects weren’t maintained at 6 weeks.
In a randomized study with 3 treatment arms, 185 patients were treated with a corticosteroid injection, physiotherapy, or a wait-and-see approach (ergonomic advice, rest, and oral anti-inflammatory medication). Corticosteroid injections were significantly more effective for the patients’ main complaint at 6 weeks compared with wait-and-see (mean difference in improvement [MDI] on a 100-point scale=24; 95% CI, 14-35; NNT=2) or physiotherapy (MDI=20; 95% CI, 10-31; NNT=2).3 By contrast, at 26 and 52 weeks’ follow-up, physiotherapy was more effective than steroid injections (MDI=15; 95% CI, 5-25) but statistically equivalent to a wait-and-see approach (MDI=7; 95% CI, –4 to 17).
Physiotherapy, exercise, acupuncture bring short-term relief
In a separate RCT, physiotherapy and exercise were significantly better than a wait-and-see approach at 6 weeks for pain-free grip force, rating of pain severity, and global improvement (RR=0.5; 99% CI, 0.2-0.8; NNT=3), but by 52 weeks the outcomes were statistically equal.4
An individual RCT, cited in a Cochrane review, showed acupuncture had a very short-term benefit for pain relief compared with placebo (WMD=18.8 hours; 95% CI, 10.1-27.5).5 Another individual RCT, which was not included in the meta-analysis because of methodologic problems in the other studies, found that a short course of 10 acupuncture treatments resulted in an excellent or good outcome (as reported by participants) compared with placebo (RR=0.09; 95% CI, 0.01-0.64; NNT=4).5 No benefit was noted after 3 or 12 months.
Physiotherapy techniques, orthotics are hard to evaluate
Systematic reviews of specific physiotherapy or orthotic (bracing) treatments are hampered by the large number of treatment options available and the heterogeneity of the available studies, which prevent statistically useful evaluation.6,7
Shock wave, ultrasound, massage offer little or no benefit
In a meta-analysis of 3 trials, shock wave therapy provided no significant benefit at 4 to 6 weeks compared with placebo (WMD on a 100-point scale=-9.42; 95% CI, -20.70 to 1.86).8 Pooling 2 studies in a different systematic review showed weak evidence that ultrasound reduced pain at 13 weeks compared with placebo (standardized mean difference=–0.98; 95% CI, –1.64 to –0.33).6 Another Cochrane review found no added benefit in function from combining deep transverse friction massage with ultrasound or a placebo ointment (RR=3.3; 95% CI, 0.4-24.3).9
Recommendations
The Work Loss Data Institute recommends ice, rest, ergonomic modifications, and short-term topical or oral NSAIDs. Progressive physical or occupational therapy may follow if no improvement is seen in 2 weeks.
Splinting, acupuncture, and corticosteroid administration by injection or iontophoresis may reduce pain for as long as 2 to 6 weeks. If these conservative measures fail, surgical treatment is recommended as a last resort.10
1. Green S, Buchbinder R, Barnsley L, et al. Non-steroidal anti-inflammatory drugs (NSAIDs) for treating lateral elbow pain in adults. Cochrane Database Syst Rev. 2001;(4):CD003686.
2. Smidt N, Assendelft WJ, van der Windt DA, et al. Corticosteroid injections for lateral epicondylitis: a systemic review. Pain. 2002;96:23-40.
3. Smidt N, van der Windt DA, Assendelft WJ, et al. Corticosteroid injections, physiotherapy, or a wait-and-see policy for lateral epicondylitis: a randomised controlled trial. Lancet. 2002;359:657-662.
4. Bisset L, Beller E, Jull G, et al. Mobilisation with movement and exercise, corticosteroid injection, or wait and see for tennis elbow: randomised trial. BMJ. 2006;333:939.
5. Green S, Buchbinder R, Barnsley L, et al. Acupuncture for lateral elbow pain. Cochrane Database Syst Rev. 2002;(1):CD003527.
6. Smidt N, Assendelft WJ, Arola H, et al. Effectiveness of physiotherapy for lateral epicondylitis: a systematic review. Ann Med. 2003;35:51-62.
7. Struijs PA, Smidt N, Arola H, et al. Orthotic devices for the treatment of tennis elbow. Cochrane Database Syst Rev. 2002;(1):CD001821.
8. Buchbinder R, Green SE, Youd JM, et al. Shock wave therapy for lateral elbow pain. Cochrane Database of Syst Rev. 2005;(4):CD003524.
9. Brosseau L, Casimiro L, Milne S, et al. Deep transverse friction massage for treating tendinitis. Cochrane Database Syst Rev. 2002;(4):CD003528.
10. Chapell R, Turkelson CM, Coates V, et al. Diagnosis and Treatment of Worker-Related Musculoskeletal Disorders of the Upper Extremity. Evidence Report/Technology Assessment Number 62 (prepared by ECRI, Health Technology Assessment Group under contract no. 290-97-0020). AHRQ Publication no. 02-E038. Rockville, Md: Agency for Healthcare Research and Quality; December 2002. Available at: http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat1a.chapter.29294. Accessed June 8, 2007.
1. Green S, Buchbinder R, Barnsley L, et al. Non-steroidal anti-inflammatory drugs (NSAIDs) for treating lateral elbow pain in adults. Cochrane Database Syst Rev. 2001;(4):CD003686.
2. Smidt N, Assendelft WJ, van der Windt DA, et al. Corticosteroid injections for lateral epicondylitis: a systemic review. Pain. 2002;96:23-40.
3. Smidt N, van der Windt DA, Assendelft WJ, et al. Corticosteroid injections, physiotherapy, or a wait-and-see policy for lateral epicondylitis: a randomised controlled trial. Lancet. 2002;359:657-662.
4. Bisset L, Beller E, Jull G, et al. Mobilisation with movement and exercise, corticosteroid injection, or wait and see for tennis elbow: randomised trial. BMJ. 2006;333:939.
5. Green S, Buchbinder R, Barnsley L, et al. Acupuncture for lateral elbow pain. Cochrane Database Syst Rev. 2002;(1):CD003527.
6. Smidt N, Assendelft WJ, Arola H, et al. Effectiveness of physiotherapy for lateral epicondylitis: a systematic review. Ann Med. 2003;35:51-62.
7. Struijs PA, Smidt N, Arola H, et al. Orthotic devices for the treatment of tennis elbow. Cochrane Database Syst Rev. 2002;(1):CD001821.
8. Buchbinder R, Green SE, Youd JM, et al. Shock wave therapy for lateral elbow pain. Cochrane Database of Syst Rev. 2005;(4):CD003524.
9. Brosseau L, Casimiro L, Milne S, et al. Deep transverse friction massage for treating tendinitis. Cochrane Database Syst Rev. 2002;(4):CD003528.
10. Chapell R, Turkelson CM, Coates V, et al. Diagnosis and Treatment of Worker-Related Musculoskeletal Disorders of the Upper Extremity. Evidence Report/Technology Assessment Number 62 (prepared by ECRI, Health Technology Assessment Group under contract no. 290-97-0020). AHRQ Publication no. 02-E038. Rockville, Md: Agency for Healthcare Research and Quality; December 2002. Available at: http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=hstat1a.chapter.29294. Accessed June 8, 2007.
Evidence-based answers from the Family Physicians Inquiries Network
What is the best therapy for superficial thrombophlebitis?
For proximal saphenous vein thrombosis, anticoagulation is more effective than venous ligation (with or without stripping) in preventing deep venous thrombosis (DVT) and pulmonary embolus (PE) (strength of recommendation [SOR]: C, qualitative systematic review of primarily case series).
For patients with superficial venous thrombophlebitis (SVTP) distal to the saphenous vein of the thigh, tenoxicam (a nonsteroidal anti-inflammatory agent [NSAID]) and low-molecular-weight heparin are similarly effective for reducing extension and subsequent DVT when administered along with compression therapy (SOR: B, 1 randomized controlled trial). Oral or topical NSAIDs, topical heparin, and topical nitroglycerin all alleviate symptoms and speed resolution of SVTP caused by infusion catheters (SOR: B, smaller, occasionally conflicting randomized trials).
Evidence summary
Superficial thrombophlebitis refers to erythema, pain, induration, and other findings of inflammation in superficial veins, usually due to infection or thrombosis. Typically, SVTP is localized problem, but some lower-extremity SVTP is associated with increased risk of DVT and PE, particularly the long saphenous vein. This review will not address thrombosis in the superficial femoral vein, a portion of the deep venous system, which requires full DVT therapy.1
Since saphenous vein thrombosis above the knee is associated with DVT and PE, 1 systematic review looked at papers comparing anticoagulation (IV heparin followed by 6 weeks to 6 months of warfarin) with surgical ligation of the saphenous vein (either alone or combined with vein stripping or with vein stripping and perforator ligation).1 The review included primarily case series with widely varying protocols. According to the authors, the data “suggests that medical management with anticoagulants is somewhat superior” to surgery for preventing DVT and PE. However, the fewest extensions of SVTP occurred when vein ligation was combined with stripping of the thrombosed vein and interruption of perforators.
In a more recent trial, patients randomized to subcutaneous heparin at 12,500 units twice daily for a week followed by 10,000 units twice daily had fewer vascular complications of proximal saphenous vein thrombosis than those receiving heparin at 5000 units twice daily (6/30 in the low-dose group and 1/30 in the high-dose group; P<.05; number needed to treat [NNT]=6).2 There were no bleeding complications in either group.
One large double-blind randomized controlled trial compared tenoxicam (an NSAID available in Canada, similar to piroxicam), enoxaparin (Lovenox), and placebo for 8 to 12 days in 427 patients with SVTP of the leg measuring 5 cm or more.3 Patients were also treated with compression hose. Patients who required immediate anticoagulation or venous ligation were excluded. Within 3 months, 35% of patients taking placebo developed an extension or recurrence of their SVTP or a DVT, compared with 16% to 17% of treated patients (NNT=6). There was no significant difference in outcome between subcutaneous enoxaparin at fixed (40 mg/d) or adjusted doses (1.5 mg/kg), or 20 mg/d oral tenoxicam. In a small randomized trial (n=40), intramuscular defibrotide provided better symptom resolution than low-dose heparin for patients with uncomplicated SVTP of the leg.4
For infusion-related SVTP, a randomized controlled trial of 120 patients found both oral and topical diclofenac effective in reducing symptoms (NNT=3), although oral diclofenac had significantly more gastrointestinal side effects (number needed to harm=3 for dyspepsia).5 Two double-blind trials of topical heparin showed it to be superior to placebo in reducing symptoms and speeding healing.6,7
In the larger study (n=126), 44% of patients treated with 1000 IU/g heparin gel 3 times a day were symptom-free at 1 week, compared with 26% on placebo (NNT=6).7 A randomized trial of infusion-related SVTP (n=100) found that 2% nitroglycerin gel eliminated pain in 50 hours vs 72 hours with topical heparin (P<.05).8 A smaller, underpowered double-blind trial of topical heparin, piroxicam gel, and placebo (22 to 24 patients in each treatment arm) failed to find efficacy with either therapy.9
Recommendation from others
For SVTP of the leg that does not include the proximal saphenous vein, Up To Date recommends compression and oral NSAIDs, noting that NSAIDs are inexpensive, help with symptom control, and appear comparable to low-molecular-weight heparin in limiting complications.10
Those with symptoms in the thigh need closer follow-up, more aggressive therapy
James L. Greenwald, MD
SUNY Upstate Medical University, Syracuse, NY
Patients with a red, swollen, painful extremity are commonly encountered in my practice. I see this among patients with venous stasis due to obesity, aging, and varicosities. I find ready access to a D-dimer blood test and a venous Doppler can help me rule out DVT. I end up treating many of these patients with both an NSAID and an antistaphylococcal antibiotic, because of the lack of certainty in differentiating superficial phlebitis from cellulitis.
Upper extremity phlebitis is less common. It can occur in a delayed fashion several days after a patient has received intravenous therapy. The characteristic on exam is a knotty, red, ropey painful structure correlating to the course of the basilic or cephalic vein.
This review is helpful to me; it reinforces that the patients I see with symptoms in the thigh need closer follow-up and more aggressive therapy with anticoagulation, no matter what the Doppler shows. I usually hold off on anticoagulating other patients until they show no improvement with a trial of the NSAIDs and compression. Topical heparin and nitroglycerin gel are therapies new to me and appear worth looking into for the patient who is not improving. In a quick search for topical heparin, I could not find a US source, and it is not used locally.
1. Sullivan V, Denk PM, Sonnad SS, Eagleton MJ, Wakefield TW. Ligation versus anticoagulation: treatment of aboveknee superficial thrombophlebitis not involving the deep venous system. J Am Coll Surg 2001;193:556-562.
2. Marchiori A, Verlato F, Sabbion P, et al. High versus low doses of unfractionated heparin for the treatment of superficial thrombophlebitis of the leg. A prospective, controlled, randomized study. Haematologica 2002;87:523-527.
3. Superficial Thrombophlebitis Treated by Enoxaparin Study Group. A pilot randomized double-blind comparison of a low-molecular-weight heparin, a nonsteroidal anti-inflammatory agent, and placebo in the treatment of superficial vein thrombosis. Arch Intern Med 2003;163:1657-1663.
4. Belcaro G. Evolution of superficial vein thrombosis treated with defibrotide: comparison with low dose subcutaneous heparin. Int J Tissue React 1990;12:319-324.
5. Becherucci A, Bagilet D, Marenghini J, Diab M, Biancardi H. [Effect of topical and oral diclofenac on superficial thrombophlebitis caused by intravenous infusion]. Med Clin (Barc) 2000;114:371-373.
6. Mehta PP, Sagar S, Kakkar VV. Treatment of superficial thrombophlebitis: a randomized, double-blind trial of heparinoid cream. Br Med J 1975;3:614-616.
7. Vilardell M, Sabat D, Arnaiz JA, et al. Topical heparin for the treatment of acute superficial phlebitis secondary to indwelling intravenous catheter. A double-blind, randomized, placebo-controlled trial. Eur J Clin Pharmacol 1999;54:917-921.
8. Almenar L, Hernandez M, Gimeno JV, Palencia M, Algarra F. [Heparionoids versus nitroglycerin in the treatment of superficial phlebitis]. Rev Clin Esp 1993;193:229-231.
9. Bergqvist D, Brunkwall J, Jensen N, Persson NH. Treatment of superficial thrombophlebitis. A comparative trial between placebo, Hirudoid cream, and piroxicam gel. Ann Chir Gynaecol 1990;79:92-96.
10. Fernandez L. Superficial phlebitis. UpToDate [online database]. Last updated September 2, 2003. Available at: www.uptodateonline.com.
For proximal saphenous vein thrombosis, anticoagulation is more effective than venous ligation (with or without stripping) in preventing deep venous thrombosis (DVT) and pulmonary embolus (PE) (strength of recommendation [SOR]: C, qualitative systematic review of primarily case series).
For patients with superficial venous thrombophlebitis (SVTP) distal to the saphenous vein of the thigh, tenoxicam (a nonsteroidal anti-inflammatory agent [NSAID]) and low-molecular-weight heparin are similarly effective for reducing extension and subsequent DVT when administered along with compression therapy (SOR: B, 1 randomized controlled trial). Oral or topical NSAIDs, topical heparin, and topical nitroglycerin all alleviate symptoms and speed resolution of SVTP caused by infusion catheters (SOR: B, smaller, occasionally conflicting randomized trials).
Evidence summary
Superficial thrombophlebitis refers to erythema, pain, induration, and other findings of inflammation in superficial veins, usually due to infection or thrombosis. Typically, SVTP is localized problem, but some lower-extremity SVTP is associated with increased risk of DVT and PE, particularly the long saphenous vein. This review will not address thrombosis in the superficial femoral vein, a portion of the deep venous system, which requires full DVT therapy.1
Since saphenous vein thrombosis above the knee is associated with DVT and PE, 1 systematic review looked at papers comparing anticoagulation (IV heparin followed by 6 weeks to 6 months of warfarin) with surgical ligation of the saphenous vein (either alone or combined with vein stripping or with vein stripping and perforator ligation).1 The review included primarily case series with widely varying protocols. According to the authors, the data “suggests that medical management with anticoagulants is somewhat superior” to surgery for preventing DVT and PE. However, the fewest extensions of SVTP occurred when vein ligation was combined with stripping of the thrombosed vein and interruption of perforators.
In a more recent trial, patients randomized to subcutaneous heparin at 12,500 units twice daily for a week followed by 10,000 units twice daily had fewer vascular complications of proximal saphenous vein thrombosis than those receiving heparin at 5000 units twice daily (6/30 in the low-dose group and 1/30 in the high-dose group; P<.05; number needed to treat [NNT]=6).2 There were no bleeding complications in either group.
One large double-blind randomized controlled trial compared tenoxicam (an NSAID available in Canada, similar to piroxicam), enoxaparin (Lovenox), and placebo for 8 to 12 days in 427 patients with SVTP of the leg measuring 5 cm or more.3 Patients were also treated with compression hose. Patients who required immediate anticoagulation or venous ligation were excluded. Within 3 months, 35% of patients taking placebo developed an extension or recurrence of their SVTP or a DVT, compared with 16% to 17% of treated patients (NNT=6). There was no significant difference in outcome between subcutaneous enoxaparin at fixed (40 mg/d) or adjusted doses (1.5 mg/kg), or 20 mg/d oral tenoxicam. In a small randomized trial (n=40), intramuscular defibrotide provided better symptom resolution than low-dose heparin for patients with uncomplicated SVTP of the leg.4
For infusion-related SVTP, a randomized controlled trial of 120 patients found both oral and topical diclofenac effective in reducing symptoms (NNT=3), although oral diclofenac had significantly more gastrointestinal side effects (number needed to harm=3 for dyspepsia).5 Two double-blind trials of topical heparin showed it to be superior to placebo in reducing symptoms and speeding healing.6,7
In the larger study (n=126), 44% of patients treated with 1000 IU/g heparin gel 3 times a day were symptom-free at 1 week, compared with 26% on placebo (NNT=6).7 A randomized trial of infusion-related SVTP (n=100) found that 2% nitroglycerin gel eliminated pain in 50 hours vs 72 hours with topical heparin (P<.05).8 A smaller, underpowered double-blind trial of topical heparin, piroxicam gel, and placebo (22 to 24 patients in each treatment arm) failed to find efficacy with either therapy.9
Recommendation from others
For SVTP of the leg that does not include the proximal saphenous vein, Up To Date recommends compression and oral NSAIDs, noting that NSAIDs are inexpensive, help with symptom control, and appear comparable to low-molecular-weight heparin in limiting complications.10
Those with symptoms in the thigh need closer follow-up, more aggressive therapy
James L. Greenwald, MD
SUNY Upstate Medical University, Syracuse, NY
Patients with a red, swollen, painful extremity are commonly encountered in my practice. I see this among patients with venous stasis due to obesity, aging, and varicosities. I find ready access to a D-dimer blood test and a venous Doppler can help me rule out DVT. I end up treating many of these patients with both an NSAID and an antistaphylococcal antibiotic, because of the lack of certainty in differentiating superficial phlebitis from cellulitis.
Upper extremity phlebitis is less common. It can occur in a delayed fashion several days after a patient has received intravenous therapy. The characteristic on exam is a knotty, red, ropey painful structure correlating to the course of the basilic or cephalic vein.
This review is helpful to me; it reinforces that the patients I see with symptoms in the thigh need closer follow-up and more aggressive therapy with anticoagulation, no matter what the Doppler shows. I usually hold off on anticoagulating other patients until they show no improvement with a trial of the NSAIDs and compression. Topical heparin and nitroglycerin gel are therapies new to me and appear worth looking into for the patient who is not improving. In a quick search for topical heparin, I could not find a US source, and it is not used locally.
For proximal saphenous vein thrombosis, anticoagulation is more effective than venous ligation (with or without stripping) in preventing deep venous thrombosis (DVT) and pulmonary embolus (PE) (strength of recommendation [SOR]: C, qualitative systematic review of primarily case series).
For patients with superficial venous thrombophlebitis (SVTP) distal to the saphenous vein of the thigh, tenoxicam (a nonsteroidal anti-inflammatory agent [NSAID]) and low-molecular-weight heparin are similarly effective for reducing extension and subsequent DVT when administered along with compression therapy (SOR: B, 1 randomized controlled trial). Oral or topical NSAIDs, topical heparin, and topical nitroglycerin all alleviate symptoms and speed resolution of SVTP caused by infusion catheters (SOR: B, smaller, occasionally conflicting randomized trials).
Evidence summary
Superficial thrombophlebitis refers to erythema, pain, induration, and other findings of inflammation in superficial veins, usually due to infection or thrombosis. Typically, SVTP is localized problem, but some lower-extremity SVTP is associated with increased risk of DVT and PE, particularly the long saphenous vein. This review will not address thrombosis in the superficial femoral vein, a portion of the deep venous system, which requires full DVT therapy.1
Since saphenous vein thrombosis above the knee is associated with DVT and PE, 1 systematic review looked at papers comparing anticoagulation (IV heparin followed by 6 weeks to 6 months of warfarin) with surgical ligation of the saphenous vein (either alone or combined with vein stripping or with vein stripping and perforator ligation).1 The review included primarily case series with widely varying protocols. According to the authors, the data “suggests that medical management with anticoagulants is somewhat superior” to surgery for preventing DVT and PE. However, the fewest extensions of SVTP occurred when vein ligation was combined with stripping of the thrombosed vein and interruption of perforators.
In a more recent trial, patients randomized to subcutaneous heparin at 12,500 units twice daily for a week followed by 10,000 units twice daily had fewer vascular complications of proximal saphenous vein thrombosis than those receiving heparin at 5000 units twice daily (6/30 in the low-dose group and 1/30 in the high-dose group; P<.05; number needed to treat [NNT]=6).2 There were no bleeding complications in either group.
One large double-blind randomized controlled trial compared tenoxicam (an NSAID available in Canada, similar to piroxicam), enoxaparin (Lovenox), and placebo for 8 to 12 days in 427 patients with SVTP of the leg measuring 5 cm or more.3 Patients were also treated with compression hose. Patients who required immediate anticoagulation or venous ligation were excluded. Within 3 months, 35% of patients taking placebo developed an extension or recurrence of their SVTP or a DVT, compared with 16% to 17% of treated patients (NNT=6). There was no significant difference in outcome between subcutaneous enoxaparin at fixed (40 mg/d) or adjusted doses (1.5 mg/kg), or 20 mg/d oral tenoxicam. In a small randomized trial (n=40), intramuscular defibrotide provided better symptom resolution than low-dose heparin for patients with uncomplicated SVTP of the leg.4
For infusion-related SVTP, a randomized controlled trial of 120 patients found both oral and topical diclofenac effective in reducing symptoms (NNT=3), although oral diclofenac had significantly more gastrointestinal side effects (number needed to harm=3 for dyspepsia).5 Two double-blind trials of topical heparin showed it to be superior to placebo in reducing symptoms and speeding healing.6,7
In the larger study (n=126), 44% of patients treated with 1000 IU/g heparin gel 3 times a day were symptom-free at 1 week, compared with 26% on placebo (NNT=6).7 A randomized trial of infusion-related SVTP (n=100) found that 2% nitroglycerin gel eliminated pain in 50 hours vs 72 hours with topical heparin (P<.05).8 A smaller, underpowered double-blind trial of topical heparin, piroxicam gel, and placebo (22 to 24 patients in each treatment arm) failed to find efficacy with either therapy.9
Recommendation from others
For SVTP of the leg that does not include the proximal saphenous vein, Up To Date recommends compression and oral NSAIDs, noting that NSAIDs are inexpensive, help with symptom control, and appear comparable to low-molecular-weight heparin in limiting complications.10
Those with symptoms in the thigh need closer follow-up, more aggressive therapy
James L. Greenwald, MD
SUNY Upstate Medical University, Syracuse, NY
Patients with a red, swollen, painful extremity are commonly encountered in my practice. I see this among patients with venous stasis due to obesity, aging, and varicosities. I find ready access to a D-dimer blood test and a venous Doppler can help me rule out DVT. I end up treating many of these patients with both an NSAID and an antistaphylococcal antibiotic, because of the lack of certainty in differentiating superficial phlebitis from cellulitis.
Upper extremity phlebitis is less common. It can occur in a delayed fashion several days after a patient has received intravenous therapy. The characteristic on exam is a knotty, red, ropey painful structure correlating to the course of the basilic or cephalic vein.
This review is helpful to me; it reinforces that the patients I see with symptoms in the thigh need closer follow-up and more aggressive therapy with anticoagulation, no matter what the Doppler shows. I usually hold off on anticoagulating other patients until they show no improvement with a trial of the NSAIDs and compression. Topical heparin and nitroglycerin gel are therapies new to me and appear worth looking into for the patient who is not improving. In a quick search for topical heparin, I could not find a US source, and it is not used locally.
1. Sullivan V, Denk PM, Sonnad SS, Eagleton MJ, Wakefield TW. Ligation versus anticoagulation: treatment of aboveknee superficial thrombophlebitis not involving the deep venous system. J Am Coll Surg 2001;193:556-562.
2. Marchiori A, Verlato F, Sabbion P, et al. High versus low doses of unfractionated heparin for the treatment of superficial thrombophlebitis of the leg. A prospective, controlled, randomized study. Haematologica 2002;87:523-527.
3. Superficial Thrombophlebitis Treated by Enoxaparin Study Group. A pilot randomized double-blind comparison of a low-molecular-weight heparin, a nonsteroidal anti-inflammatory agent, and placebo in the treatment of superficial vein thrombosis. Arch Intern Med 2003;163:1657-1663.
4. Belcaro G. Evolution of superficial vein thrombosis treated with defibrotide: comparison with low dose subcutaneous heparin. Int J Tissue React 1990;12:319-324.
5. Becherucci A, Bagilet D, Marenghini J, Diab M, Biancardi H. [Effect of topical and oral diclofenac on superficial thrombophlebitis caused by intravenous infusion]. Med Clin (Barc) 2000;114:371-373.
6. Mehta PP, Sagar S, Kakkar VV. Treatment of superficial thrombophlebitis: a randomized, double-blind trial of heparinoid cream. Br Med J 1975;3:614-616.
7. Vilardell M, Sabat D, Arnaiz JA, et al. Topical heparin for the treatment of acute superficial phlebitis secondary to indwelling intravenous catheter. A double-blind, randomized, placebo-controlled trial. Eur J Clin Pharmacol 1999;54:917-921.
8. Almenar L, Hernandez M, Gimeno JV, Palencia M, Algarra F. [Heparionoids versus nitroglycerin in the treatment of superficial phlebitis]. Rev Clin Esp 1993;193:229-231.
9. Bergqvist D, Brunkwall J, Jensen N, Persson NH. Treatment of superficial thrombophlebitis. A comparative trial between placebo, Hirudoid cream, and piroxicam gel. Ann Chir Gynaecol 1990;79:92-96.
10. Fernandez L. Superficial phlebitis. UpToDate [online database]. Last updated September 2, 2003. Available at: www.uptodateonline.com.
1. Sullivan V, Denk PM, Sonnad SS, Eagleton MJ, Wakefield TW. Ligation versus anticoagulation: treatment of aboveknee superficial thrombophlebitis not involving the deep venous system. J Am Coll Surg 2001;193:556-562.
2. Marchiori A, Verlato F, Sabbion P, et al. High versus low doses of unfractionated heparin for the treatment of superficial thrombophlebitis of the leg. A prospective, controlled, randomized study. Haematologica 2002;87:523-527.
3. Superficial Thrombophlebitis Treated by Enoxaparin Study Group. A pilot randomized double-blind comparison of a low-molecular-weight heparin, a nonsteroidal anti-inflammatory agent, and placebo in the treatment of superficial vein thrombosis. Arch Intern Med 2003;163:1657-1663.
4. Belcaro G. Evolution of superficial vein thrombosis treated with defibrotide: comparison with low dose subcutaneous heparin. Int J Tissue React 1990;12:319-324.
5. Becherucci A, Bagilet D, Marenghini J, Diab M, Biancardi H. [Effect of topical and oral diclofenac on superficial thrombophlebitis caused by intravenous infusion]. Med Clin (Barc) 2000;114:371-373.
6. Mehta PP, Sagar S, Kakkar VV. Treatment of superficial thrombophlebitis: a randomized, double-blind trial of heparinoid cream. Br Med J 1975;3:614-616.
7. Vilardell M, Sabat D, Arnaiz JA, et al. Topical heparin for the treatment of acute superficial phlebitis secondary to indwelling intravenous catheter. A double-blind, randomized, placebo-controlled trial. Eur J Clin Pharmacol 1999;54:917-921.
8. Almenar L, Hernandez M, Gimeno JV, Palencia M, Algarra F. [Heparionoids versus nitroglycerin in the treatment of superficial phlebitis]. Rev Clin Esp 1993;193:229-231.
9. Bergqvist D, Brunkwall J, Jensen N, Persson NH. Treatment of superficial thrombophlebitis. A comparative trial between placebo, Hirudoid cream, and piroxicam gel. Ann Chir Gynaecol 1990;79:92-96.
10. Fernandez L. Superficial phlebitis. UpToDate [online database]. Last updated September 2, 2003. Available at: www.uptodateonline.com.
Evidence-based answers from the Family Physicians Inquiries Network
What medications are effective for treating symptoms of premenstrual syndrome (PMS)?
EVIDENCE-BASED ANSWER
Vitamin B6 (50–100 mg/d) and elemental calcium (1200 mg/d) are safe, inexpensive, and moderately effective (Table) (grade of recommendation: B). Selective serotonin reuptake inhibitors (SSRIs) and some other antidepressants are more effective, but are also more costly and more likely to cause side effects or treatment dropout (grade of recommendation: A). Antidepressant dosing only during the luteal phase may be effective and more tolerable (grade of recommendation: B). Alprazolam (generally 0.25–0.5 mg 3 times a day during luteal phase) may be effective for treating mood or anxiety symptoms (grade of recommendation: B). Hormonal therapies (oral contraceptives, gonadotropin-releasing hormone agonists, danazol, estrogen) lack convincing evidence of efficacy and cause many side effects; progesterone is no more beneficial than placebo (grade of recommendation: B). There is no convincing evidence of benefit from diuretics, magnesium, beta-blockers, or lithium (grade of recommendation: C).
TABLE
Agents for treating symptoms of premenstrual syndrome
| Medication | Sample drug and dose | Adverse effects | Benefit |
|---|---|---|---|
| Vitamin B61 | 50–100 mg/d | Peripheral neuropathy | OR = 2.32 (95% CI 1.95–2.54) |
| Elemental | 1200 mg/d calcium2 | Same as placebo | NNT = 6 for 50% symptom reduction |
| SSRIs3 | Fluoxetine 20 mg/d | Insomnia, headache, nausea, dizziness | NNT = 4–11 |
| Benzodiazepines4 | Alprazolam 0.25–0.5 mg tid/qid in luteal phase | Habituation | NNT = 3 for 50% symptom reduction |
| GnRH agonists5 | Danazol 200–400 mg/d | Hypoestrogenic Androgenic | Benefit unclear Benefit unclear |
| GnRH, gonadotropin-releasing hormone; NNT, number needed to treat; SSRIs, selective serotonin reuptake inhibitors. | |||
Evidence summary
Pooled results of 9, generally poor-quality studies of Vitamin B6 show some benefit.1 Doses higher than 100 mg/d may cause peripheral neuropathy. Three small studies in the 1980s suggested possible benefit of Vitamin E; however, these studies have not been further replicated. One well-designed, randomized controlled trial of calcium therapy showed > 50% decrease in symptom complex scores after 3 months in more than half of subjects taking 1200 mg/d supplemental elemental calcium (NNT=6).2
Among SSRIs, fluoxetine (20 mg/d) is well-studied and effective.3 Other SSRIs, including sertraline, paroxetine, fluvoxamine, and venlafaxine, and clomipramine (a tricyclic with serotonin reuptake inhibitor activity), also show benefit but are less well studied. Luteal phase-only dosing may be equally or more effective than continuous dosing for some SSRIs. Benzodiazepines have shown mixed results in treating PMS, and overall their benefit appears smaller than that of SSRIs.4 Luteal phase-only dosing theoretically reduces the risk of benzodiazepine withdrawal or dependence, but published data are rare.
Gonadotropin-releasing hormone agonists may be effective, but troublesome anti-estrogenic side effects limit their utility. Estrogen and progesterone “add-back” therapy to counter side effects further complicates this approach. The gonadotropin inhibitor danazol has a high treatment dropout rate at higher doses (200–400 mg/d continuously), but can be effective in individuals who are able to tolerate it3,5 ; however, danazol is expensive and causes significant androgenic side effects. Lower-dose danazol (200 mg/d luteal phase only) is better tolerated but ineffective.6 A meta-analysis of progesterone found no evidence to support its efficacy.7 Oral contraceptives are ineffective for global symptoms, and may actually cause PMS symptoms in some women.
Recommendations from others
The American College of Obstetricians and Gynecologists recommend that patients with mild to moderate PMS should receive supportive, lifestyle, and dietary interventions. For severe PMS, SSRIs are the initial drug of choice. Alprazolam may be useful when these interventions are ineffective. Consider oral contraceptives for primarily physical symptoms and reserve gonadotropin-releasing hormone for severe cases unresponsive to other treatments.8
Clinical Commentary by Peter Danis, MD, at http://www.fpin.org.
1. Wyatt KM, Dimmock PW, Jones PW, Shaughn O’Brien PM. BMJ 1999;318:1375-81.
2. Thys-Jacobs S, Starkey P, Bernstein D, Tian J. Am J Obstet Gynecol 1998;179:444-52.
3. Wyatt K. Clinical Evidence 2002;7:1739-57.
4. Freeman EW, Rickels K, Sondheimer SJ, Polansky M. JAMA 1995;274:51-7.
5. Watts JF, Butt WR, Logan Edwards R. Br J Obstet Gynaecol 1987;94:30-4.
6. O’Brien PM, Abukhalil IE. Am J Obstet Gynecol 1999;180:18-23.
7. Wyatt K, Dimmock P, Jones P, Obhrai M, O’Brien S. BMJ 2001;323:776-80.
8. ACOG. Premenstrual Syndrome. ACOG Practice Bulletin No. 15. Washington, DC: ACOG; April 2000.
EVIDENCE-BASED ANSWER
Vitamin B6 (50–100 mg/d) and elemental calcium (1200 mg/d) are safe, inexpensive, and moderately effective (Table) (grade of recommendation: B). Selective serotonin reuptake inhibitors (SSRIs) and some other antidepressants are more effective, but are also more costly and more likely to cause side effects or treatment dropout (grade of recommendation: A). Antidepressant dosing only during the luteal phase may be effective and more tolerable (grade of recommendation: B). Alprazolam (generally 0.25–0.5 mg 3 times a day during luteal phase) may be effective for treating mood or anxiety symptoms (grade of recommendation: B). Hormonal therapies (oral contraceptives, gonadotropin-releasing hormone agonists, danazol, estrogen) lack convincing evidence of efficacy and cause many side effects; progesterone is no more beneficial than placebo (grade of recommendation: B). There is no convincing evidence of benefit from diuretics, magnesium, beta-blockers, or lithium (grade of recommendation: C).
TABLE
Agents for treating symptoms of premenstrual syndrome
| Medication | Sample drug and dose | Adverse effects | Benefit |
|---|---|---|---|
| Vitamin B61 | 50–100 mg/d | Peripheral neuropathy | OR = 2.32 (95% CI 1.95–2.54) |
| Elemental | 1200 mg/d calcium2 | Same as placebo | NNT = 6 for 50% symptom reduction |
| SSRIs3 | Fluoxetine 20 mg/d | Insomnia, headache, nausea, dizziness | NNT = 4–11 |
| Benzodiazepines4 | Alprazolam 0.25–0.5 mg tid/qid in luteal phase | Habituation | NNT = 3 for 50% symptom reduction |
| GnRH agonists5 | Danazol 200–400 mg/d | Hypoestrogenic Androgenic | Benefit unclear Benefit unclear |
| GnRH, gonadotropin-releasing hormone; NNT, number needed to treat; SSRIs, selective serotonin reuptake inhibitors. | |||
Evidence summary
Pooled results of 9, generally poor-quality studies of Vitamin B6 show some benefit.1 Doses higher than 100 mg/d may cause peripheral neuropathy. Three small studies in the 1980s suggested possible benefit of Vitamin E; however, these studies have not been further replicated. One well-designed, randomized controlled trial of calcium therapy showed > 50% decrease in symptom complex scores after 3 months in more than half of subjects taking 1200 mg/d supplemental elemental calcium (NNT=6).2
Among SSRIs, fluoxetine (20 mg/d) is well-studied and effective.3 Other SSRIs, including sertraline, paroxetine, fluvoxamine, and venlafaxine, and clomipramine (a tricyclic with serotonin reuptake inhibitor activity), also show benefit but are less well studied. Luteal phase-only dosing may be equally or more effective than continuous dosing for some SSRIs. Benzodiazepines have shown mixed results in treating PMS, and overall their benefit appears smaller than that of SSRIs.4 Luteal phase-only dosing theoretically reduces the risk of benzodiazepine withdrawal or dependence, but published data are rare.
Gonadotropin-releasing hormone agonists may be effective, but troublesome anti-estrogenic side effects limit their utility. Estrogen and progesterone “add-back” therapy to counter side effects further complicates this approach. The gonadotropin inhibitor danazol has a high treatment dropout rate at higher doses (200–400 mg/d continuously), but can be effective in individuals who are able to tolerate it3,5 ; however, danazol is expensive and causes significant androgenic side effects. Lower-dose danazol (200 mg/d luteal phase only) is better tolerated but ineffective.6 A meta-analysis of progesterone found no evidence to support its efficacy.7 Oral contraceptives are ineffective for global symptoms, and may actually cause PMS symptoms in some women.
Recommendations from others
The American College of Obstetricians and Gynecologists recommend that patients with mild to moderate PMS should receive supportive, lifestyle, and dietary interventions. For severe PMS, SSRIs are the initial drug of choice. Alprazolam may be useful when these interventions are ineffective. Consider oral contraceptives for primarily physical symptoms and reserve gonadotropin-releasing hormone for severe cases unresponsive to other treatments.8
Clinical Commentary by Peter Danis, MD, at http://www.fpin.org.
EVIDENCE-BASED ANSWER
Vitamin B6 (50–100 mg/d) and elemental calcium (1200 mg/d) are safe, inexpensive, and moderately effective (Table) (grade of recommendation: B). Selective serotonin reuptake inhibitors (SSRIs) and some other antidepressants are more effective, but are also more costly and more likely to cause side effects or treatment dropout (grade of recommendation: A). Antidepressant dosing only during the luteal phase may be effective and more tolerable (grade of recommendation: B). Alprazolam (generally 0.25–0.5 mg 3 times a day during luteal phase) may be effective for treating mood or anxiety symptoms (grade of recommendation: B). Hormonal therapies (oral contraceptives, gonadotropin-releasing hormone agonists, danazol, estrogen) lack convincing evidence of efficacy and cause many side effects; progesterone is no more beneficial than placebo (grade of recommendation: B). There is no convincing evidence of benefit from diuretics, magnesium, beta-blockers, or lithium (grade of recommendation: C).
TABLE
Agents for treating symptoms of premenstrual syndrome
| Medication | Sample drug and dose | Adverse effects | Benefit |
|---|---|---|---|
| Vitamin B61 | 50–100 mg/d | Peripheral neuropathy | OR = 2.32 (95% CI 1.95–2.54) |
| Elemental | 1200 mg/d calcium2 | Same as placebo | NNT = 6 for 50% symptom reduction |
| SSRIs3 | Fluoxetine 20 mg/d | Insomnia, headache, nausea, dizziness | NNT = 4–11 |
| Benzodiazepines4 | Alprazolam 0.25–0.5 mg tid/qid in luteal phase | Habituation | NNT = 3 for 50% symptom reduction |
| GnRH agonists5 | Danazol 200–400 mg/d | Hypoestrogenic Androgenic | Benefit unclear Benefit unclear |
| GnRH, gonadotropin-releasing hormone; NNT, number needed to treat; SSRIs, selective serotonin reuptake inhibitors. | |||
Evidence summary
Pooled results of 9, generally poor-quality studies of Vitamin B6 show some benefit.1 Doses higher than 100 mg/d may cause peripheral neuropathy. Three small studies in the 1980s suggested possible benefit of Vitamin E; however, these studies have not been further replicated. One well-designed, randomized controlled trial of calcium therapy showed > 50% decrease in symptom complex scores after 3 months in more than half of subjects taking 1200 mg/d supplemental elemental calcium (NNT=6).2
Among SSRIs, fluoxetine (20 mg/d) is well-studied and effective.3 Other SSRIs, including sertraline, paroxetine, fluvoxamine, and venlafaxine, and clomipramine (a tricyclic with serotonin reuptake inhibitor activity), also show benefit but are less well studied. Luteal phase-only dosing may be equally or more effective than continuous dosing for some SSRIs. Benzodiazepines have shown mixed results in treating PMS, and overall their benefit appears smaller than that of SSRIs.4 Luteal phase-only dosing theoretically reduces the risk of benzodiazepine withdrawal or dependence, but published data are rare.
Gonadotropin-releasing hormone agonists may be effective, but troublesome anti-estrogenic side effects limit their utility. Estrogen and progesterone “add-back” therapy to counter side effects further complicates this approach. The gonadotropin inhibitor danazol has a high treatment dropout rate at higher doses (200–400 mg/d continuously), but can be effective in individuals who are able to tolerate it3,5 ; however, danazol is expensive and causes significant androgenic side effects. Lower-dose danazol (200 mg/d luteal phase only) is better tolerated but ineffective.6 A meta-analysis of progesterone found no evidence to support its efficacy.7 Oral contraceptives are ineffective for global symptoms, and may actually cause PMS symptoms in some women.
Recommendations from others
The American College of Obstetricians and Gynecologists recommend that patients with mild to moderate PMS should receive supportive, lifestyle, and dietary interventions. For severe PMS, SSRIs are the initial drug of choice. Alprazolam may be useful when these interventions are ineffective. Consider oral contraceptives for primarily physical symptoms and reserve gonadotropin-releasing hormone for severe cases unresponsive to other treatments.8
Clinical Commentary by Peter Danis, MD, at http://www.fpin.org.
1. Wyatt KM, Dimmock PW, Jones PW, Shaughn O’Brien PM. BMJ 1999;318:1375-81.
2. Thys-Jacobs S, Starkey P, Bernstein D, Tian J. Am J Obstet Gynecol 1998;179:444-52.
3. Wyatt K. Clinical Evidence 2002;7:1739-57.
4. Freeman EW, Rickels K, Sondheimer SJ, Polansky M. JAMA 1995;274:51-7.
5. Watts JF, Butt WR, Logan Edwards R. Br J Obstet Gynaecol 1987;94:30-4.
6. O’Brien PM, Abukhalil IE. Am J Obstet Gynecol 1999;180:18-23.
7. Wyatt K, Dimmock P, Jones P, Obhrai M, O’Brien S. BMJ 2001;323:776-80.
8. ACOG. Premenstrual Syndrome. ACOG Practice Bulletin No. 15. Washington, DC: ACOG; April 2000.
1. Wyatt KM, Dimmock PW, Jones PW, Shaughn O’Brien PM. BMJ 1999;318:1375-81.
2. Thys-Jacobs S, Starkey P, Bernstein D, Tian J. Am J Obstet Gynecol 1998;179:444-52.
3. Wyatt K. Clinical Evidence 2002;7:1739-57.
4. Freeman EW, Rickels K, Sondheimer SJ, Polansky M. JAMA 1995;274:51-7.
5. Watts JF, Butt WR, Logan Edwards R. Br J Obstet Gynaecol 1987;94:30-4.
6. O’Brien PM, Abukhalil IE. Am J Obstet Gynecol 1999;180:18-23.
7. Wyatt K, Dimmock P, Jones P, Obhrai M, O’Brien S. BMJ 2001;323:776-80.
8. ACOG. Premenstrual Syndrome. ACOG Practice Bulletin No. 15. Washington, DC: ACOG; April 2000.
Evidence-based answers from the Family Physicians Inquiries Network