Susan Meadows, MLS

Evidence summary

Patients with acute DVT have traditionally been treated with immobilization and bed rest, combined with anticoagulation, for days. This approach is motivated by fear of dislodging an unstable thrombus and causing a pulmonary embolism (PE) and by the belief that inactivity relieves local pain and swelling. On the other hand, bed rest promotes stasis, an element in Virchow’s triad.

Early ambulation doesn’t raise risk of PE
We performed a structured literature review, which found 6 RCTs and 3 cohort studies that address this problem. All 6 RCTs included patients with acute DVT but without life-threatening conditions.^1-6 They assessed various outcomes, including incidence of new PE, change in leg circumference, leg pain, patient well-being, and progression of DVT.

The studies consistently found that early ambulation, along with compression, is safe when compared with bed rest ( TABLE ). Although the sample size of all the RCTs was small, the RCTs showed consistent trends in favor of ambulation and compression.

A prospective cohort study of new PE in patients treated with ambulation and compression plus anticoagulation found that the incidence of PE was significantly lower than historical incidence rates in patients managed with bed rest.⁷

Another study using the RIETE registry, a Spanish registry of consecutively enrolled patients with objectively confirmed acute DVT or PE, found no significant difference in occurrence of new PE between immobilized and mobilized patients.⁸ Patients with DVT who were immobilized were generally sicker, more likely to have PaO₂ <60, and more likely to have received lower doses of low-molecular-weight heparin (LMWH) compared with the group that walked (P<.005).

TABLE
Early ambulation and compression: What RCTs show

Does ambulation affect thrombus propagation?
A multicenter RCT showed that thrombus progression occurred more often in patients who were treated with bed rest compared with patients treated with ambulation and compression (P<.01).²

Another RCT revealed a similar trend, though the difference didn’t reach statistical significance because of small sample size.⁴ The clinical importance of these phlebographic studies isn’t clear.

Is it the walking, or compression, that works?
RCTs have shown that ambulation with leg compression, compared with bed rest without compression, can effectively decrease leg swelling and pain^1,2,4 The difference was detectable 2 years after DVT.⁷

In contrast, RCTs in which both ambulating and resting patients received compression therapy showed no significant difference in leg circumference at 1 or 6 months.³ This finding suggests that the benefit on local symptoms may result from compression rather than ambulation.

Reduced mortality? Evidence is weak
Estimates of the possible effect on mortality of ambulation compared with bed rest are based on cohort studies. A cohort study in which 691 patients were kept walking with compression therapy reported a mortality rate of 0.2%.⁹ In another cohort, the mortality rate was also 0.2%, and all deaths occurred in patients older than 70 years.¹⁰

This rate is lower than rates reported in the historic literature, which typically are 1% among patients treated with unfractionated heparin and bed rest.^9,10 A retrospective, multicenter cohort of 1647 patients treated with unfractionated heparin and bed rest in different German hospitals reported a rate of fatal PE of 2.33%.¹¹

Data from the RIETE registry indicated that overall mortality was significantly higher in immobilized patients with a PE (3.6% vs 0.5% in mobile patients; P=.01).⁸ Notably, immobilized patients with a PE were more likely to be hypoxic and also tended to receive lower doses of LMWH. No differences were found in outcomes for patients with DVT.

Recommendations

The American College of Chest Physicians (ACCP) doesn’t recommend bed rest in its guidelines for treating acute venous thromboembolism, but rather ambulation as tolerated after starting anticoagulation. Patients who are not hemodynamically stable should be stabilized first.

The ACCP also recommends wearing an elastic compression stocking with a pressure of 30 to 40 mm Hg at the ankle for 2 years after an episode of DVT and a course of intermittent pneumatic compression for patients with severe edema of the leg resulting from post-thrombotic syndrome.¹²

A joint guideline from the American College of Physicians and the American Academy of Family Physicians doesn’t make recommendations about ambulation for therapy of DVT and PE.¹³

Evidence summary

Patients with acute DVT have traditionally been treated with immobilization and bed rest, combined with anticoagulation, for days. This approach is motivated by fear of dislodging an unstable thrombus and causing a pulmonary embolism (PE) and by the belief that inactivity relieves local pain and swelling. On the other hand, bed rest promotes stasis, an element in Virchow’s triad.

Early ambulation doesn’t raise risk of PE
We performed a structured literature review, which found 6 RCTs and 3 cohort studies that address this problem. All 6 RCTs included patients with acute DVT but without life-threatening conditions.^1-6 They assessed various outcomes, including incidence of new PE, change in leg circumference, leg pain, patient well-being, and progression of DVT.

The studies consistently found that early ambulation, along with compression, is safe when compared with bed rest ( TABLE ). Although the sample size of all the RCTs was small, the RCTs showed consistent trends in favor of ambulation and compression.

A prospective cohort study of new PE in patients treated with ambulation and compression plus anticoagulation found that the incidence of PE was significantly lower than historical incidence rates in patients managed with bed rest.⁷

Another study using the RIETE registry, a Spanish registry of consecutively enrolled patients with objectively confirmed acute DVT or PE, found no significant difference in occurrence of new PE between immobilized and mobilized patients.⁸ Patients with DVT who were immobilized were generally sicker, more likely to have PaO₂ <60, and more likely to have received lower doses of low-molecular-weight heparin (LMWH) compared with the group that walked (P<.005).

TABLE
Early ambulation and compression: What RCTs show

Does ambulation affect thrombus propagation?
A multicenter RCT showed that thrombus progression occurred more often in patients who were treated with bed rest compared with patients treated with ambulation and compression (P<.01).²

Another RCT revealed a similar trend, though the difference didn’t reach statistical significance because of small sample size.⁴ The clinical importance of these phlebographic studies isn’t clear.

Is it the walking, or compression, that works?
RCTs have shown that ambulation with leg compression, compared with bed rest without compression, can effectively decrease leg swelling and pain^1,2,4 The difference was detectable 2 years after DVT.⁷

In contrast, RCTs in which both ambulating and resting patients received compression therapy showed no significant difference in leg circumference at 1 or 6 months.³ This finding suggests that the benefit on local symptoms may result from compression rather than ambulation.

Reduced mortality? Evidence is weak
Estimates of the possible effect on mortality of ambulation compared with bed rest are based on cohort studies. A cohort study in which 691 patients were kept walking with compression therapy reported a mortality rate of 0.2%.⁹ In another cohort, the mortality rate was also 0.2%, and all deaths occurred in patients older than 70 years.¹⁰

This rate is lower than rates reported in the historic literature, which typically are 1% among patients treated with unfractionated heparin and bed rest.^9,10 A retrospective, multicenter cohort of 1647 patients treated with unfractionated heparin and bed rest in different German hospitals reported a rate of fatal PE of 2.33%.¹¹

Data from the RIETE registry indicated that overall mortality was significantly higher in immobilized patients with a PE (3.6% vs 0.5% in mobile patients; P=.01).⁸ Notably, immobilized patients with a PE were more likely to be hypoxic and also tended to receive lower doses of LMWH. No differences were found in outcomes for patients with DVT.

Recommendations

The American College of Chest Physicians (ACCP) doesn’t recommend bed rest in its guidelines for treating acute venous thromboembolism, but rather ambulation as tolerated after starting anticoagulation. Patients who are not hemodynamically stable should be stabilized first.

The ACCP also recommends wearing an elastic compression stocking with a pressure of 30 to 40 mm Hg at the ankle for 2 years after an episode of DVT and a course of intermittent pneumatic compression for patients with severe edema of the leg resulting from post-thrombotic syndrome.¹²

A joint guideline from the American College of Physicians and the American Academy of Family Physicians doesn’t make recommendations about ambulation for therapy of DVT and PE.¹³

Evidence summary

Patients with acute DVT have traditionally been treated with immobilization and bed rest, combined with anticoagulation, for days. This approach is motivated by fear of dislodging an unstable thrombus and causing a pulmonary embolism (PE) and by the belief that inactivity relieves local pain and swelling. On the other hand, bed rest promotes stasis, an element in Virchow’s triad.

Early ambulation doesn’t raise risk of PE
We performed a structured literature review, which found 6 RCTs and 3 cohort studies that address this problem. All 6 RCTs included patients with acute DVT but without life-threatening conditions.^1-6 They assessed various outcomes, including incidence of new PE, change in leg circumference, leg pain, patient well-being, and progression of DVT.

The studies consistently found that early ambulation, along with compression, is safe when compared with bed rest ( TABLE ). Although the sample size of all the RCTs was small, the RCTs showed consistent trends in favor of ambulation and compression.

A prospective cohort study of new PE in patients treated with ambulation and compression plus anticoagulation found that the incidence of PE was significantly lower than historical incidence rates in patients managed with bed rest.⁷

Another study using the RIETE registry, a Spanish registry of consecutively enrolled patients with objectively confirmed acute DVT or PE, found no significant difference in occurrence of new PE between immobilized and mobilized patients.⁸ Patients with DVT who were immobilized were generally sicker, more likely to have PaO₂ <60, and more likely to have received lower doses of low-molecular-weight heparin (LMWH) compared with the group that walked (P<.005).

TABLE
Early ambulation and compression: What RCTs show

Does ambulation affect thrombus propagation?
A multicenter RCT showed that thrombus progression occurred more often in patients who were treated with bed rest compared with patients treated with ambulation and compression (P<.01).²

Another RCT revealed a similar trend, though the difference didn’t reach statistical significance because of small sample size.⁴ The clinical importance of these phlebographic studies isn’t clear.

Is it the walking, or compression, that works?
RCTs have shown that ambulation with leg compression, compared with bed rest without compression, can effectively decrease leg swelling and pain^1,2,4 The difference was detectable 2 years after DVT.⁷

In contrast, RCTs in which both ambulating and resting patients received compression therapy showed no significant difference in leg circumference at 1 or 6 months.³ This finding suggests that the benefit on local symptoms may result from compression rather than ambulation.

Reduced mortality? Evidence is weak
Estimates of the possible effect on mortality of ambulation compared with bed rest are based on cohort studies. A cohort study in which 691 patients were kept walking with compression therapy reported a mortality rate of 0.2%.⁹ In another cohort, the mortality rate was also 0.2%, and all deaths occurred in patients older than 70 years.¹⁰

This rate is lower than rates reported in the historic literature, which typically are 1% among patients treated with unfractionated heparin and bed rest.^9,10 A retrospective, multicenter cohort of 1647 patients treated with unfractionated heparin and bed rest in different German hospitals reported a rate of fatal PE of 2.33%.¹¹

Data from the RIETE registry indicated that overall mortality was significantly higher in immobilized patients with a PE (3.6% vs 0.5% in mobile patients; P=.01).⁸ Notably, immobilized patients with a PE were more likely to be hypoxic and also tended to receive lower doses of LMWH. No differences were found in outcomes for patients with DVT.

Recommendations

The American College of Chest Physicians (ACCP) doesn’t recommend bed rest in its guidelines for treating acute venous thromboembolism, but rather ambulation as tolerated after starting anticoagulation. Patients who are not hemodynamically stable should be stabilized first.

The ACCP also recommends wearing an elastic compression stocking with a pressure of 30 to 40 mm Hg at the ankle for 2 years after an episode of DVT and a course of intermittent pneumatic compression for patients with severe edema of the leg resulting from post-thrombotic syndrome.¹²

A joint guideline from the American College of Physicians and the American Academy of Family Physicians doesn’t make recommendations about ambulation for therapy of DVT and PE.¹³

Evidence summary

A Cochrane review⁴ (6 randomized controlled trials, N=1689, mean duration 5.8 weeks) assessed the efficacy and safety of acetaminophen in the management of osteoarthritis, comparing it with placebo and NSAIDs. Acetaminophen was superior to placebo in pain reduction and global assessment (number needed to treat [NNT]=2) with a similar safety profile. NSAIDs were better than acetaminophen in pain reduction, patient (NNT=6) and physician global assessment (NNT=17), but no better for functional improvement. Compared with nonselective NSAIDs, acetaminophen led to fewer withdrawals (number needed to harm [NNH]=20) and fewer GI adverse events (NNH=9), but there was no statistical difference when compared with COX-2 selective NSAIDs.

Another Cochrane review⁵ (26 randomized controlled trials) found that rofecoxib (Vioxx) was more effective than placebo (NNT=5), and equally effective with other NSAIDs in the management of osteoarthritis. They reported fewer GI adverse events (endoscopically observed gastric erosion and ulcers) with rofecoxib than with other NSAIDs—naproxen (Naprosyn), ibuprofen (Motrin), diclofenac (Cataflam), nabumetone (Relafen), diclofenac/misoprostol (Arthrotec), and nimesulide. However, the withdrawal rate due to adverse events and the increase in blood pressure and edema were significantly greater with rofecoxib than placebo at 6 weeks.

Two Cochrane reviews^6-7 confirmed the efficacy of celecoxib (Celebrex) and rofecoxib in treating of rheumatoid arthritis. One review included 2 RCTs (N=8734) with a placebo arm (8 weeks) and naproxen arm (9 months).⁷ The rofecoxib groups (25 mg, 50 mg) had more responders than the placebo group (NNT=8 and 6 respectively). Compared with naproxen (1 g), no difference was seen in efficacy in the OMERACT outcomes (Outcome Measures for Rheumatoid Arthritis Clinical Trials), but all combined GI adverse events (perforation, ulcer, obstruction, bleeding, and all episodes of GI bleeding) were significantly reduced at 9 months (NNH=20). The withdrawals were the same in the 3 groups. Compared with placebo, the rofecoxib groups had similar incidence of elevated blood pressure and edema (NNH=50 and 100, respectively). Compared with the naproxen group, no difference was seen in renal adverse events, but total cardiovascular thrombotic events (NNH=200) and nonfatal MI (NNH=300) increased at 9 months in the 50 mg rofecoxib group.

Similar cardiovascular adverse events were reported in the APPROVE trial.⁹ In this study, patients taking rofecoxib 25 mg daily for 18 months had increased total thrombotic events (MI, stroke, peripheral arterial and venous thrombosis, and pulmonary embolism) when compared with placebo (NNH=63). A recent study also raised the same concern of increased cardiovascular adverse events with celecoxib.¹⁰ This study demonstrated an increase risk of cardiovascular events (combined death, myocardial infarction, stroke, and heart failure) for patients taking celecoxib 200 mg twice a day (NNH=77) or 400 mg twice a day (NNH=42).

Many patients taking low-dose aspirin for cardioprotection also frequently require treatment of pain and inflammation with a NSAID. Even low-dose aspirin (75 mg/d) is known to be associated with increased GI toxicity (ulcers and hemorrhages).¹¹ A recent double-blind, randomized placebo-controlled trial found that 12 weeks of treatment with a combination of low-dose aspirin and a COX-2 selective NSAID (rofecoxib) had more than twice the incidence of endoscopically confirmed gastric and duodenal ulcers, compared with aspirin alone, and no difference with a nonselective NSAID.¹² This has raised the safety concern of concomitant use of a COX-2 selective NSAID with low-dose aspirin.

TABLE 1
Prediction of serious gastrointestinal bleeding

Recommendations from others

The American Pain Society recommends that for patients with osteoarthritis, acetaminophen is the drug of choice for mild pain.¹³ For moderate to severe pain and or inflammation, a COX-2 selective NSAID is the first choice, unless the patient is at significant risk for hypertension or renal disorder. For patients with active rheumatoid arthritis and moderate to severe pain with or without inflammation, a COX-2 selective NSAID should be used concomitantly with a disease-modifying antirheumatic drug (DMARD), unless contraindicated by existing uncontrolled hypertension and renal disease. It further recommends that for a person who is at risk for a cardiovascular event, an aspirin (75–160 mg/d), should be given along with a COX-2 selective NSAID.

The American College of Rheumatology recommends that a COX-2 selective NSAID should be considered for a person with osteoarthritis and pain not relieved by an adequate dose of acetaminophen (not to exceed 4 g/d).^14,15 The COX-2 selective NSAID is particularly advantageous for those who have higher risk factors for adverse GI events (TABLE 2). For a person with rheumatoid arthritis, in addition to DMARDs, NSAIDs (salicylates, nonselective NSAID, or COX-2 selective NSAID) should be used to reduce joint pain and swelling and improve joint function. Patients with additional risks for cardiovascular events should be cautioned about use of a COX-2 selective NSAID.

A recent AHRQ report on managing osteoarthritis underscores the importance of physician-patient partnership and patient’s self management of osteoarthritis, and recommends acetaminophen (up to 4 g/day) as the drug of choice.¹⁶ It further cautions the injudicious use of NSAIDs because of its greater GI toxicity when compared with acetaminophen, and its higher medical costs.

TABLE 2
Risk factors for upper gastrointestinal adverse events

Evidence summary

A Cochrane review⁴ (6 randomized controlled trials, N=1689, mean duration 5.8 weeks) assessed the efficacy and safety of acetaminophen in the management of osteoarthritis, comparing it with placebo and NSAIDs. Acetaminophen was superior to placebo in pain reduction and global assessment (number needed to treat [NNT]=2) with a similar safety profile. NSAIDs were better than acetaminophen in pain reduction, patient (NNT=6) and physician global assessment (NNT=17), but no better for functional improvement. Compared with nonselective NSAIDs, acetaminophen led to fewer withdrawals (number needed to harm [NNH]=20) and fewer GI adverse events (NNH=9), but there was no statistical difference when compared with COX-2 selective NSAIDs.

Another Cochrane review⁵ (26 randomized controlled trials) found that rofecoxib (Vioxx) was more effective than placebo (NNT=5), and equally effective with other NSAIDs in the management of osteoarthritis. They reported fewer GI adverse events (endoscopically observed gastric erosion and ulcers) with rofecoxib than with other NSAIDs—naproxen (Naprosyn), ibuprofen (Motrin), diclofenac (Cataflam), nabumetone (Relafen), diclofenac/misoprostol (Arthrotec), and nimesulide. However, the withdrawal rate due to adverse events and the increase in blood pressure and edema were significantly greater with rofecoxib than placebo at 6 weeks.

Two Cochrane reviews^6-7 confirmed the efficacy of celecoxib (Celebrex) and rofecoxib in treating of rheumatoid arthritis. One review included 2 RCTs (N=8734) with a placebo arm (8 weeks) and naproxen arm (9 months).⁷ The rofecoxib groups (25 mg, 50 mg) had more responders than the placebo group (NNT=8 and 6 respectively). Compared with naproxen (1 g), no difference was seen in efficacy in the OMERACT outcomes (Outcome Measures for Rheumatoid Arthritis Clinical Trials), but all combined GI adverse events (perforation, ulcer, obstruction, bleeding, and all episodes of GI bleeding) were significantly reduced at 9 months (NNH=20). The withdrawals were the same in the 3 groups. Compared with placebo, the rofecoxib groups had similar incidence of elevated blood pressure and edema (NNH=50 and 100, respectively). Compared with the naproxen group, no difference was seen in renal adverse events, but total cardiovascular thrombotic events (NNH=200) and nonfatal MI (NNH=300) increased at 9 months in the 50 mg rofecoxib group.

Similar cardiovascular adverse events were reported in the APPROVE trial.⁹ In this study, patients taking rofecoxib 25 mg daily for 18 months had increased total thrombotic events (MI, stroke, peripheral arterial and venous thrombosis, and pulmonary embolism) when compared with placebo (NNH=63). A recent study also raised the same concern of increased cardiovascular adverse events with celecoxib.¹⁰ This study demonstrated an increase risk of cardiovascular events (combined death, myocardial infarction, stroke, and heart failure) for patients taking celecoxib 200 mg twice a day (NNH=77) or 400 mg twice a day (NNH=42).

Many patients taking low-dose aspirin for cardioprotection also frequently require treatment of pain and inflammation with a NSAID. Even low-dose aspirin (75 mg/d) is known to be associated with increased GI toxicity (ulcers and hemorrhages).¹¹ A recent double-blind, randomized placebo-controlled trial found that 12 weeks of treatment with a combination of low-dose aspirin and a COX-2 selective NSAID (rofecoxib) had more than twice the incidence of endoscopically confirmed gastric and duodenal ulcers, compared with aspirin alone, and no difference with a nonselective NSAID.¹² This has raised the safety concern of concomitant use of a COX-2 selective NSAID with low-dose aspirin.

TABLE 1
Prediction of serious gastrointestinal bleeding

Recommendations from others

The American Pain Society recommends that for patients with osteoarthritis, acetaminophen is the drug of choice for mild pain.¹³ For moderate to severe pain and or inflammation, a COX-2 selective NSAID is the first choice, unless the patient is at significant risk for hypertension or renal disorder. For patients with active rheumatoid arthritis and moderate to severe pain with or without inflammation, a COX-2 selective NSAID should be used concomitantly with a disease-modifying antirheumatic drug (DMARD), unless contraindicated by existing uncontrolled hypertension and renal disease. It further recommends that for a person who is at risk for a cardiovascular event, an aspirin (75–160 mg/d), should be given along with a COX-2 selective NSAID.

The American College of Rheumatology recommends that a COX-2 selective NSAID should be considered for a person with osteoarthritis and pain not relieved by an adequate dose of acetaminophen (not to exceed 4 g/d).^14,15 The COX-2 selective NSAID is particularly advantageous for those who have higher risk factors for adverse GI events (TABLE 2). For a person with rheumatoid arthritis, in addition to DMARDs, NSAIDs (salicylates, nonselective NSAID, or COX-2 selective NSAID) should be used to reduce joint pain and swelling and improve joint function. Patients with additional risks for cardiovascular events should be cautioned about use of a COX-2 selective NSAID.

A recent AHRQ report on managing osteoarthritis underscores the importance of physician-patient partnership and patient’s self management of osteoarthritis, and recommends acetaminophen (up to 4 g/day) as the drug of choice.¹⁶ It further cautions the injudicious use of NSAIDs because of its greater GI toxicity when compared with acetaminophen, and its higher medical costs.

TABLE 2
Risk factors for upper gastrointestinal adverse events

Evidence summary

A Cochrane review⁴ (6 randomized controlled trials, N=1689, mean duration 5.8 weeks) assessed the efficacy and safety of acetaminophen in the management of osteoarthritis, comparing it with placebo and NSAIDs. Acetaminophen was superior to placebo in pain reduction and global assessment (number needed to treat [NNT]=2) with a similar safety profile. NSAIDs were better than acetaminophen in pain reduction, patient (NNT=6) and physician global assessment (NNT=17), but no better for functional improvement. Compared with nonselective NSAIDs, acetaminophen led to fewer withdrawals (number needed to harm [NNH]=20) and fewer GI adverse events (NNH=9), but there was no statistical difference when compared with COX-2 selective NSAIDs.

Another Cochrane review⁵ (26 randomized controlled trials) found that rofecoxib (Vioxx) was more effective than placebo (NNT=5), and equally effective with other NSAIDs in the management of osteoarthritis. They reported fewer GI adverse events (endoscopically observed gastric erosion and ulcers) with rofecoxib than with other NSAIDs—naproxen (Naprosyn), ibuprofen (Motrin), diclofenac (Cataflam), nabumetone (Relafen), diclofenac/misoprostol (Arthrotec), and nimesulide. However, the withdrawal rate due to adverse events and the increase in blood pressure and edema were significantly greater with rofecoxib than placebo at 6 weeks.

Two Cochrane reviews^6-7 confirmed the efficacy of celecoxib (Celebrex) and rofecoxib in treating of rheumatoid arthritis. One review included 2 RCTs (N=8734) with a placebo arm (8 weeks) and naproxen arm (9 months).⁷ The rofecoxib groups (25 mg, 50 mg) had more responders than the placebo group (NNT=8 and 6 respectively). Compared with naproxen (1 g), no difference was seen in efficacy in the OMERACT outcomes (Outcome Measures for Rheumatoid Arthritis Clinical Trials), but all combined GI adverse events (perforation, ulcer, obstruction, bleeding, and all episodes of GI bleeding) were significantly reduced at 9 months (NNH=20). The withdrawals were the same in the 3 groups. Compared with placebo, the rofecoxib groups had similar incidence of elevated blood pressure and edema (NNH=50 and 100, respectively). Compared with the naproxen group, no difference was seen in renal adverse events, but total cardiovascular thrombotic events (NNH=200) and nonfatal MI (NNH=300) increased at 9 months in the 50 mg rofecoxib group.

Similar cardiovascular adverse events were reported in the APPROVE trial.⁹ In this study, patients taking rofecoxib 25 mg daily for 18 months had increased total thrombotic events (MI, stroke, peripheral arterial and venous thrombosis, and pulmonary embolism) when compared with placebo (NNH=63). A recent study also raised the same concern of increased cardiovascular adverse events with celecoxib.¹⁰ This study demonstrated an increase risk of cardiovascular events (combined death, myocardial infarction, stroke, and heart failure) for patients taking celecoxib 200 mg twice a day (NNH=77) or 400 mg twice a day (NNH=42).

Many patients taking low-dose aspirin for cardioprotection also frequently require treatment of pain and inflammation with a NSAID. Even low-dose aspirin (75 mg/d) is known to be associated with increased GI toxicity (ulcers and hemorrhages).¹¹ A recent double-blind, randomized placebo-controlled trial found that 12 weeks of treatment with a combination of low-dose aspirin and a COX-2 selective NSAID (rofecoxib) had more than twice the incidence of endoscopically confirmed gastric and duodenal ulcers, compared with aspirin alone, and no difference with a nonselective NSAID.¹² This has raised the safety concern of concomitant use of a COX-2 selective NSAID with low-dose aspirin.

TABLE 1
Prediction of serious gastrointestinal bleeding

Recommendations from others

The American Pain Society recommends that for patients with osteoarthritis, acetaminophen is the drug of choice for mild pain.¹³ For moderate to severe pain and or inflammation, a COX-2 selective NSAID is the first choice, unless the patient is at significant risk for hypertension or renal disorder. For patients with active rheumatoid arthritis and moderate to severe pain with or without inflammation, a COX-2 selective NSAID should be used concomitantly with a disease-modifying antirheumatic drug (DMARD), unless contraindicated by existing uncontrolled hypertension and renal disease. It further recommends that for a person who is at risk for a cardiovascular event, an aspirin (75–160 mg/d), should be given along with a COX-2 selective NSAID.

The American College of Rheumatology recommends that a COX-2 selective NSAID should be considered for a person with osteoarthritis and pain not relieved by an adequate dose of acetaminophen (not to exceed 4 g/d).^14,15 The COX-2 selective NSAID is particularly advantageous for those who have higher risk factors for adverse GI events (TABLE 2). For a person with rheumatoid arthritis, in addition to DMARDs, NSAIDs (salicylates, nonselective NSAID, or COX-2 selective NSAID) should be used to reduce joint pain and swelling and improve joint function. Patients with additional risks for cardiovascular events should be cautioned about use of a COX-2 selective NSAID.

A recent AHRQ report on managing osteoarthritis underscores the importance of physician-patient partnership and patient’s self management of osteoarthritis, and recommends acetaminophen (up to 4 g/day) as the drug of choice.¹⁶ It further cautions the injudicious use of NSAIDs because of its greater GI toxicity when compared with acetaminophen, and its higher medical costs.

TABLE 2
Risk factors for upper gastrointestinal adverse events

Evidence summary

Two randomized controlled trials have compared the efficacy of oral metronidazole and oral vancomycin for treatment of CDAD.^1,2 Both studies demonstrated statistically equivalent cure rates exceeding 90%, with relapse rates of 10% to 20% for each drug. These small trials lacked the power to detect small but potentially significant differences in treatment response.

No published data exist indicating that vancomycin is more effective than metronidazole in any clinical setting. A dose-range study showed that 125 mg of oral vancomycin 4 times a day is as effective as higher doses.³ Patients who cannot take medication by mouth should receive intravenous metronidazole, 500 mg 4 times per day. Unlike vancomycin, metronidazole achieves potentially effective concentrations in the intestinal lumen following intravenous administration.⁴

Treatment of first recurrences of infection with metronidazole or vancomycin produces response rates similar to treatment of initial infections.⁵ A minority of patients suffers multiple relapses of infection, and there are few data to guide therapy in this setting.

A randomized, double-blinded, placebocontrolled study evaluated the impact of adding the probiotic agent Saccharomyces boulardii. to either metronidazole or vancomycin.⁶ For persons with recurrent infection, addition of S boulardii. led to a 30% decrease in the absolute risk of relapse (64% relapse vs 34%; number needed to treat=3; P.<.05). There was also a nonsignificant trend toward reduced recurrences in the treatment of primary infections. The 2 minor side effects noted with this treatment were dry mouth (number needed to harm [NNH]=11) and constipation (NNH=9). S boulardii. capsules are available from health food stores and via the Internet. Several published case series describe various additional approaches to therapy of recurrent CDAD (Table).

TABLE
Medical treatment of C difficile–.associated diarrhea

Recommendations from others

The American College of Gastroenterology and the American College of Physicians treatment guidelines for CDAD both call for treatment with oral metronidazole 250 mg 4 times daily or 500 mg 3 times daily.^7,8 The American College of Gastroenterology recommends vancomycin (125 mg orally 4 times daily) when there is an intolerance or confirmed resistance to metronidazole, failure of response, when the patient is pregnant, breast feeding, or under 10 years of age, critically ill from colitis, or when the diarrhea could be related to Staphylococcus aureus.. In milder cases, treatment may involve only discontinuation of antibiotics and supportive therapy with observation. Opiates and antispasmodics should be avoided. These guidelines do not recommend any treatment over another for therapy of multiple recurrences.

Evidence summary

Two randomized controlled trials have compared the efficacy of oral metronidazole and oral vancomycin for treatment of CDAD.^1,2 Both studies demonstrated statistically equivalent cure rates exceeding 90%, with relapse rates of 10% to 20% for each drug. These small trials lacked the power to detect small but potentially significant differences in treatment response.

No published data exist indicating that vancomycin is more effective than metronidazole in any clinical setting. A dose-range study showed that 125 mg of oral vancomycin 4 times a day is as effective as higher doses.³ Patients who cannot take medication by mouth should receive intravenous metronidazole, 500 mg 4 times per day. Unlike vancomycin, metronidazole achieves potentially effective concentrations in the intestinal lumen following intravenous administration.⁴

Treatment of first recurrences of infection with metronidazole or vancomycin produces response rates similar to treatment of initial infections.⁵ A minority of patients suffers multiple relapses of infection, and there are few data to guide therapy in this setting.

A randomized, double-blinded, placebocontrolled study evaluated the impact of adding the probiotic agent Saccharomyces boulardii. to either metronidazole or vancomycin.⁶ For persons with recurrent infection, addition of S boulardii. led to a 30% decrease in the absolute risk of relapse (64% relapse vs 34%; number needed to treat=3; P.<.05). There was also a nonsignificant trend toward reduced recurrences in the treatment of primary infections. The 2 minor side effects noted with this treatment were dry mouth (number needed to harm [NNH]=11) and constipation (NNH=9). S boulardii. capsules are available from health food stores and via the Internet. Several published case series describe various additional approaches to therapy of recurrent CDAD (Table).

TABLE
Medical treatment of C difficile–.associated diarrhea

Recommendations from others

The American College of Gastroenterology and the American College of Physicians treatment guidelines for CDAD both call for treatment with oral metronidazole 250 mg 4 times daily or 500 mg 3 times daily.^7,8 The American College of Gastroenterology recommends vancomycin (125 mg orally 4 times daily) when there is an intolerance or confirmed resistance to metronidazole, failure of response, when the patient is pregnant, breast feeding, or under 10 years of age, critically ill from colitis, or when the diarrhea could be related to Staphylococcus aureus.. In milder cases, treatment may involve only discontinuation of antibiotics and supportive therapy with observation. Opiates and antispasmodics should be avoided. These guidelines do not recommend any treatment over another for therapy of multiple recurrences.

Evidence summary

Two randomized controlled trials have compared the efficacy of oral metronidazole and oral vancomycin for treatment of CDAD.^1,2 Both studies demonstrated statistically equivalent cure rates exceeding 90%, with relapse rates of 10% to 20% for each drug. These small trials lacked the power to detect small but potentially significant differences in treatment response.

No published data exist indicating that vancomycin is more effective than metronidazole in any clinical setting. A dose-range study showed that 125 mg of oral vancomycin 4 times a day is as effective as higher doses.³ Patients who cannot take medication by mouth should receive intravenous metronidazole, 500 mg 4 times per day. Unlike vancomycin, metronidazole achieves potentially effective concentrations in the intestinal lumen following intravenous administration.⁴

Treatment of first recurrences of infection with metronidazole or vancomycin produces response rates similar to treatment of initial infections.⁵ A minority of patients suffers multiple relapses of infection, and there are few data to guide therapy in this setting.

A randomized, double-blinded, placebocontrolled study evaluated the impact of adding the probiotic agent Saccharomyces boulardii. to either metronidazole or vancomycin.⁶ For persons with recurrent infection, addition of S boulardii. led to a 30% decrease in the absolute risk of relapse (64% relapse vs 34%; number needed to treat=3; P.<.05). There was also a nonsignificant trend toward reduced recurrences in the treatment of primary infections. The 2 minor side effects noted with this treatment were dry mouth (number needed to harm [NNH]=11) and constipation (NNH=9). S boulardii. capsules are available from health food stores and via the Internet. Several published case series describe various additional approaches to therapy of recurrent CDAD (Table).

TABLE
Medical treatment of C difficile–.associated diarrhea

Recommendations from others

The American College of Gastroenterology and the American College of Physicians treatment guidelines for CDAD both call for treatment with oral metronidazole 250 mg 4 times daily or 500 mg 3 times daily.^7,8 The American College of Gastroenterology recommends vancomycin (125 mg orally 4 times daily) when there is an intolerance or confirmed resistance to metronidazole, failure of response, when the patient is pregnant, breast feeding, or under 10 years of age, critically ill from colitis, or when the diarrhea could be related to Staphylococcus aureus.. In milder cases, treatment may involve only discontinuation of antibiotics and supportive therapy with observation. Opiates and antispasmodics should be avoided. These guidelines do not recommend any treatment over another for therapy of multiple recurrences.

Evidence summary

Observational studies have shown at least a 10- to 12-fold increase in urinary tract infections (UTIs) in uncircumcised male infants compared with their circumcised counterparts.¹ The number of male infants that need to be circumcised to prevent 1 UTI is estimated to be between 44 and 100.^2,3 The only randomized controlled trial of circumcision for UTI prevention was not during the neonatal period (average age was 30 months) and focused on secondary prevention.⁴ It demonstrated a statistically significant decrease in the rate of bacteriuria. The long-term effect on UTI incidence, renal scarring, and subsequent complications such as hypertension and end-stage renal disease is unknown.

Evidence from case series supports the protective effect of circumcision on the rates of penile cancer. A review of 592 cases of penile cancer revealed that none of those affected had been circumcised in infancy.⁵ In another series of 89 men with penile cancer, only 2 had been circumcised in infancy, while 87 were uncircumcised.⁶ Since HPV is thought to be a major etiologic agent in both penile cancer and cervical cancer, investigators studied the link between circumcision status and cervical cancer. In a meta-analysis of 7 case-control studies, penile HPV was detected 2.7 times more often in uncircumcised men after controlling for confounders.⁷ In this same meta-analysis, monogamous female partners of high-risk circumcised men (men with more than 6 lifetime partners) had a lower risk of cervical cancer than women whose high-risk partner was uncircumcised (adjusted odds ratio=0.42; 95% confidence interval [CI], 0.23–0.79).⁷

The evidence that circumcision prevents most sexually transmitted diseases is not very strong, with the exception of HIV and genital ulcer disease. Most of these studies are from sub-Saharan Africa, where rates of HIV infection are extremely high. A meta-analysis of 15 observational studies in Africa, with adjustment for potential confounding factors, found that circumcision decreased the risk of acquiring HIV by more than half (relative risk [RR]=0.42; 95% CI, 0.34–0.54).⁸ A more recent prospective study from India showed a strong protective effect of circumcision against HIV infection (RR=0.15; 95% CI, 0.04–0.62).⁹ This study found no protective effect of circumcision against herpes, syphilis, or gonorrhea, suggesting a biological rather than a behavioral explanation for the protective effect of circumcision against HIV.

A conservative estimate of the post-neonatal childhood circumcision rate for purely medical reasons is 2% to 5%; estimates go as high as 7% to 10%.¹⁰ The most common medical indication for circumcision is phimosis, followed by recurrent balanitis and paraphimosis. Circumcision may also be protective against genital dermatoses; a case-control study found an age-adjusted odds ratio of 3.2 (95% CI, 2.3–4.6) for penile skin diseases in uncircumcised men compared with circumcised men.¹¹

Recommendations from others

Circumcision rates vary widely worldwide, with strong cultural and religious preferences. Most major organizations have cautiously neutral opinions on circumcision, stating that medical benefits are not large enough to justify routine neonatal circumcision. The American Academy of Pediatrics Task Force on Circumcision recommends parents “should be given accurate and unbiased information” and that “parents should determine what is in the best interest of the child.”¹² The American Medical Association, American College of Obstetrics and Gynecology, and the American Academy of Family Physicians all use similar statements.^13-15

Evidence summary

Observational studies have shown at least a 10- to 12-fold increase in urinary tract infections (UTIs) in uncircumcised male infants compared with their circumcised counterparts.¹ The number of male infants that need to be circumcised to prevent 1 UTI is estimated to be between 44 and 100.^2,3 The only randomized controlled trial of circumcision for UTI prevention was not during the neonatal period (average age was 30 months) and focused on secondary prevention.⁴ It demonstrated a statistically significant decrease in the rate of bacteriuria. The long-term effect on UTI incidence, renal scarring, and subsequent complications such as hypertension and end-stage renal disease is unknown.

Evidence from case series supports the protective effect of circumcision on the rates of penile cancer. A review of 592 cases of penile cancer revealed that none of those affected had been circumcised in infancy.⁵ In another series of 89 men with penile cancer, only 2 had been circumcised in infancy, while 87 were uncircumcised.⁶ Since HPV is thought to be a major etiologic agent in both penile cancer and cervical cancer, investigators studied the link between circumcision status and cervical cancer. In a meta-analysis of 7 case-control studies, penile HPV was detected 2.7 times more often in uncircumcised men after controlling for confounders.⁷ In this same meta-analysis, monogamous female partners of high-risk circumcised men (men with more than 6 lifetime partners) had a lower risk of cervical cancer than women whose high-risk partner was uncircumcised (adjusted odds ratio=0.42; 95% confidence interval [CI], 0.23–0.79).⁷

The evidence that circumcision prevents most sexually transmitted diseases is not very strong, with the exception of HIV and genital ulcer disease. Most of these studies are from sub-Saharan Africa, where rates of HIV infection are extremely high. A meta-analysis of 15 observational studies in Africa, with adjustment for potential confounding factors, found that circumcision decreased the risk of acquiring HIV by more than half (relative risk [RR]=0.42; 95% CI, 0.34–0.54).⁸ A more recent prospective study from India showed a strong protective effect of circumcision against HIV infection (RR=0.15; 95% CI, 0.04–0.62).⁹ This study found no protective effect of circumcision against herpes, syphilis, or gonorrhea, suggesting a biological rather than a behavioral explanation for the protective effect of circumcision against HIV.

A conservative estimate of the post-neonatal childhood circumcision rate for purely medical reasons is 2% to 5%; estimates go as high as 7% to 10%.¹⁰ The most common medical indication for circumcision is phimosis, followed by recurrent balanitis and paraphimosis. Circumcision may also be protective against genital dermatoses; a case-control study found an age-adjusted odds ratio of 3.2 (95% CI, 2.3–4.6) for penile skin diseases in uncircumcised men compared with circumcised men.¹¹

Recommendations from others

Circumcision rates vary widely worldwide, with strong cultural and religious preferences. Most major organizations have cautiously neutral opinions on circumcision, stating that medical benefits are not large enough to justify routine neonatal circumcision. The American Academy of Pediatrics Task Force on Circumcision recommends parents “should be given accurate and unbiased information” and that “parents should determine what is in the best interest of the child.”¹² The American Medical Association, American College of Obstetrics and Gynecology, and the American Academy of Family Physicians all use similar statements.^13-15

Evidence summary

Observational studies have shown at least a 10- to 12-fold increase in urinary tract infections (UTIs) in uncircumcised male infants compared with their circumcised counterparts.¹ The number of male infants that need to be circumcised to prevent 1 UTI is estimated to be between 44 and 100.^2,3 The only randomized controlled trial of circumcision for UTI prevention was not during the neonatal period (average age was 30 months) and focused on secondary prevention.⁴ It demonstrated a statistically significant decrease in the rate of bacteriuria. The long-term effect on UTI incidence, renal scarring, and subsequent complications such as hypertension and end-stage renal disease is unknown.

Evidence from case series supports the protective effect of circumcision on the rates of penile cancer. A review of 592 cases of penile cancer revealed that none of those affected had been circumcised in infancy.⁵ In another series of 89 men with penile cancer, only 2 had been circumcised in infancy, while 87 were uncircumcised.⁶ Since HPV is thought to be a major etiologic agent in both penile cancer and cervical cancer, investigators studied the link between circumcision status and cervical cancer. In a meta-analysis of 7 case-control studies, penile HPV was detected 2.7 times more often in uncircumcised men after controlling for confounders.⁷ In this same meta-analysis, monogamous female partners of high-risk circumcised men (men with more than 6 lifetime partners) had a lower risk of cervical cancer than women whose high-risk partner was uncircumcised (adjusted odds ratio=0.42; 95% confidence interval [CI], 0.23–0.79).⁷

The evidence that circumcision prevents most sexually transmitted diseases is not very strong, with the exception of HIV and genital ulcer disease. Most of these studies are from sub-Saharan Africa, where rates of HIV infection are extremely high. A meta-analysis of 15 observational studies in Africa, with adjustment for potential confounding factors, found that circumcision decreased the risk of acquiring HIV by more than half (relative risk [RR]=0.42; 95% CI, 0.34–0.54).⁸ A more recent prospective study from India showed a strong protective effect of circumcision against HIV infection (RR=0.15; 95% CI, 0.04–0.62).⁹ This study found no protective effect of circumcision against herpes, syphilis, or gonorrhea, suggesting a biological rather than a behavioral explanation for the protective effect of circumcision against HIV.

A conservative estimate of the post-neonatal childhood circumcision rate for purely medical reasons is 2% to 5%; estimates go as high as 7% to 10%.¹⁰ The most common medical indication for circumcision is phimosis, followed by recurrent balanitis and paraphimosis. Circumcision may also be protective against genital dermatoses; a case-control study found an age-adjusted odds ratio of 3.2 (95% CI, 2.3–4.6) for penile skin diseases in uncircumcised men compared with circumcised men.¹¹

Recommendations from others

Circumcision rates vary widely worldwide, with strong cultural and religious preferences. Most major organizations have cautiously neutral opinions on circumcision, stating that medical benefits are not large enough to justify routine neonatal circumcision. The American Academy of Pediatrics Task Force on Circumcision recommends parents “should be given accurate and unbiased information” and that “parents should determine what is in the best interest of the child.”¹² The American Medical Association, American College of Obstetrics and Gynecology, and the American Academy of Family Physicians all use similar statements.^13-15

Evidence summary

Cold sores, or herpes labialis, are caused by HSV. Recurrent lesions progress quickly through several stages (prodrome, erythema, papule, vesicle, ulcer, crust, residual swelling, healed).¹ Because of the rapid development of the vesicle stage (<12 hours) and the rapid decrease in detectable virus after 48 hours, studies of antiviral therapy empirically require early treatment within the first several hours of signs or symptoms of a recurrence. For this reason, there are no controlled trials of oral medications given later than 12 hours after the onset of recurrent symptoms.

Although limited, the clearest indication of appropriate timing for HSV 1 treatment with acyclovir comes from a well-designed, double-blinded RCT of 174 adults with a history of culture confirmed HSV labialis who initiated self-treatment with acyclovir 400 mg or placebo 5 times a day for 5 days. Patients were asked to defer treatment until the next episode if they awoke with the lesion or first noticed them in the vesicle or ulcer stage. Ninety-seven percent of the patients started treatment within 1 hour of signs/symptoms of a recurrence. Of the 174 patients, 90 had lesions in the prodrome or erythema stage at the start of treatment and 84 had lesions in the papule or vesicle stage.

Overall, acyclovir did not effect lesion progression, size, or healing time to loss of hard crust or normal skin. However, the mean duration of pain for all patients significantly decreased (2.5 days vs 3.8 days for placebo, P=.01). For the subgroup of patients who started acyclovir treatment in the prodrome or erythema stage, the mean duration of pain significantly decreased (2.5 days vs 3.9 days for placebo, P=.02), as did healing time to loss of crust (5.8 days vs 7.9 days for placebo, P=.03). Among those who started acyclovir in the papular stage, the trend was toward drug benefit, but this was not statistically significant (mean pain duration: 2.5 vs. 3.6, P=.36; mean healing time to loss of crust: 8.0 vs. 7.2, P=.52).² This evidence supports early (prodrome or erythema stage) but not late (macule, papule, vesicle, or crusted stage) treatment of HSV 1 with oral acyclovir.

Topical application of 5% acyclovir cream significantly decreases clinician-assessed duration of the episode and duration of patient-reported pain, based on 2 double-blind, multicenter RCTs that used a vehicle control. In these trials, 686 and 699 patients self-initiated treatment 5 times a day for 4 days beginning within 1 hour of the onset of a recurrent lesion. In the first study, the mean clinician-assessed duration of the episode with topical acyclovir was 4.3 vs 4.8 days for placebo (hazard ratio [HR]=1.23; 95% confidence interval [CI], 1.06–1.44), and the mean duration of patient-assessed pain was 2.9 vs 3.2 days (HR=1.20; 95% CI, 1.03–1.40). The second study showed a mean clinician-assessed duration with topical acyclovir of 4.6 vs 5.2 days for control (HR=1.24; 95% CI, 1.06–1.44), and the mean duration of patient-assessed pain was 3.1 vs 3.5 days (HR=1.21; 95% CI, 1.04–1.40). Benefits were seen regardless of whether treatment was initiated early (prodrome or erythema stage) or late (macule, papule, vesicle or crusted stage).³

Recent studies of valacyclovir (the L-valine ester of acyclovir, which has 3 to 5 times greater bioavailability) offer the most promise for effective self-initiated treatment of recurrent herpes labialis. In a report of 2 well-designed, multicenter RCTs, valacyclovir at the FDA-approved dosage of 2 g twice daily for 1 day at the onset of symptoms (before visible signs of a cold sore) significantly decreased the mean duration of the lesion and time to lesion healing. In the first study (n=603), episode duration was decreased by 1.1 days (5.0 days vs 6.1 days for placebo; 95% CI, –1.6 to –0.6) and in the second study (n=605) by 1.0 day (5.3 vs 6.3 days for placebo; 95% CI, –1.0 to –0.5). In the first study, the time to lesion healing was decreased by 1.3 days (4.8 vs 6.1 days for placebo; 95% CI, –1.9 to –0.7) and in the second study by 1.2 days (5.1 vs. 6.4 days; 95% CI, –1.8 to –0.7). There also was a trend towards preventing the development of lesions, but this was not statistically significant.⁴

Recommendations from others

The BMJ Clinical Evidence Guideline reiterates that no trials compare early vs late treatment, so no firm conclusions about the efficacy of delayed treatment can be drawn.⁵ UpToDate reports that HSV 1 studies take into account that acyclovir acts only during active viral replication, which largely precedes symptoms, and thus suggest that it has little effect if begun after the appearance of lesions.⁶

Evidence summary

Cold sores, or herpes labialis, are caused by HSV. Recurrent lesions progress quickly through several stages (prodrome, erythema, papule, vesicle, ulcer, crust, residual swelling, healed).¹ Because of the rapid development of the vesicle stage (<12 hours) and the rapid decrease in detectable virus after 48 hours, studies of antiviral therapy empirically require early treatment within the first several hours of signs or symptoms of a recurrence. For this reason, there are no controlled trials of oral medications given later than 12 hours after the onset of recurrent symptoms.

Although limited, the clearest indication of appropriate timing for HSV 1 treatment with acyclovir comes from a well-designed, double-blinded RCT of 174 adults with a history of culture confirmed HSV labialis who initiated self-treatment with acyclovir 400 mg or placebo 5 times a day for 5 days. Patients were asked to defer treatment until the next episode if they awoke with the lesion or first noticed them in the vesicle or ulcer stage. Ninety-seven percent of the patients started treatment within 1 hour of signs/symptoms of a recurrence. Of the 174 patients, 90 had lesions in the prodrome or erythema stage at the start of treatment and 84 had lesions in the papule or vesicle stage.

Overall, acyclovir did not effect lesion progression, size, or healing time to loss of hard crust or normal skin. However, the mean duration of pain for all patients significantly decreased (2.5 days vs 3.8 days for placebo, P=.01). For the subgroup of patients who started acyclovir treatment in the prodrome or erythema stage, the mean duration of pain significantly decreased (2.5 days vs 3.9 days for placebo, P=.02), as did healing time to loss of crust (5.8 days vs 7.9 days for placebo, P=.03). Among those who started acyclovir in the papular stage, the trend was toward drug benefit, but this was not statistically significant (mean pain duration: 2.5 vs. 3.6, P=.36; mean healing time to loss of crust: 8.0 vs. 7.2, P=.52).² This evidence supports early (prodrome or erythema stage) but not late (macule, papule, vesicle, or crusted stage) treatment of HSV 1 with oral acyclovir.

Topical application of 5% acyclovir cream significantly decreases clinician-assessed duration of the episode and duration of patient-reported pain, based on 2 double-blind, multicenter RCTs that used a vehicle control. In these trials, 686 and 699 patients self-initiated treatment 5 times a day for 4 days beginning within 1 hour of the onset of a recurrent lesion. In the first study, the mean clinician-assessed duration of the episode with topical acyclovir was 4.3 vs 4.8 days for placebo (hazard ratio [HR]=1.23; 95% confidence interval [CI], 1.06–1.44), and the mean duration of patient-assessed pain was 2.9 vs 3.2 days (HR=1.20; 95% CI, 1.03–1.40). The second study showed a mean clinician-assessed duration with topical acyclovir of 4.6 vs 5.2 days for control (HR=1.24; 95% CI, 1.06–1.44), and the mean duration of patient-assessed pain was 3.1 vs 3.5 days (HR=1.21; 95% CI, 1.04–1.40). Benefits were seen regardless of whether treatment was initiated early (prodrome or erythema stage) or late (macule, papule, vesicle or crusted stage).³

Recent studies of valacyclovir (the L-valine ester of acyclovir, which has 3 to 5 times greater bioavailability) offer the most promise for effective self-initiated treatment of recurrent herpes labialis. In a report of 2 well-designed, multicenter RCTs, valacyclovir at the FDA-approved dosage of 2 g twice daily for 1 day at the onset of symptoms (before visible signs of a cold sore) significantly decreased the mean duration of the lesion and time to lesion healing. In the first study (n=603), episode duration was decreased by 1.1 days (5.0 days vs 6.1 days for placebo; 95% CI, –1.6 to –0.6) and in the second study (n=605) by 1.0 day (5.3 vs 6.3 days for placebo; 95% CI, –1.0 to –0.5). In the first study, the time to lesion healing was decreased by 1.3 days (4.8 vs 6.1 days for placebo; 95% CI, –1.9 to –0.7) and in the second study by 1.2 days (5.1 vs. 6.4 days; 95% CI, –1.8 to –0.7). There also was a trend towards preventing the development of lesions, but this was not statistically significant.⁴

Recommendations from others

The BMJ Clinical Evidence Guideline reiterates that no trials compare early vs late treatment, so no firm conclusions about the efficacy of delayed treatment can be drawn.⁵ UpToDate reports that HSV 1 studies take into account that acyclovir acts only during active viral replication, which largely precedes symptoms, and thus suggest that it has little effect if begun after the appearance of lesions.⁶

Evidence summary

Cold sores, or herpes labialis, are caused by HSV. Recurrent lesions progress quickly through several stages (prodrome, erythema, papule, vesicle, ulcer, crust, residual swelling, healed).¹ Because of the rapid development of the vesicle stage (<12 hours) and the rapid decrease in detectable virus after 48 hours, studies of antiviral therapy empirically require early treatment within the first several hours of signs or symptoms of a recurrence. For this reason, there are no controlled trials of oral medications given later than 12 hours after the onset of recurrent symptoms.

Although limited, the clearest indication of appropriate timing for HSV 1 treatment with acyclovir comes from a well-designed, double-blinded RCT of 174 adults with a history of culture confirmed HSV labialis who initiated self-treatment with acyclovir 400 mg or placebo 5 times a day for 5 days. Patients were asked to defer treatment until the next episode if they awoke with the lesion or first noticed them in the vesicle or ulcer stage. Ninety-seven percent of the patients started treatment within 1 hour of signs/symptoms of a recurrence. Of the 174 patients, 90 had lesions in the prodrome or erythema stage at the start of treatment and 84 had lesions in the papule or vesicle stage.

Overall, acyclovir did not effect lesion progression, size, or healing time to loss of hard crust or normal skin. However, the mean duration of pain for all patients significantly decreased (2.5 days vs 3.8 days for placebo, P=.01). For the subgroup of patients who started acyclovir treatment in the prodrome or erythema stage, the mean duration of pain significantly decreased (2.5 days vs 3.9 days for placebo, P=.02), as did healing time to loss of crust (5.8 days vs 7.9 days for placebo, P=.03). Among those who started acyclovir in the papular stage, the trend was toward drug benefit, but this was not statistically significant (mean pain duration: 2.5 vs. 3.6, P=.36; mean healing time to loss of crust: 8.0 vs. 7.2, P=.52).² This evidence supports early (prodrome or erythema stage) but not late (macule, papule, vesicle, or crusted stage) treatment of HSV 1 with oral acyclovir.

Topical application of 5% acyclovir cream significantly decreases clinician-assessed duration of the episode and duration of patient-reported pain, based on 2 double-blind, multicenter RCTs that used a vehicle control. In these trials, 686 and 699 patients self-initiated treatment 5 times a day for 4 days beginning within 1 hour of the onset of a recurrent lesion. In the first study, the mean clinician-assessed duration of the episode with topical acyclovir was 4.3 vs 4.8 days for placebo (hazard ratio [HR]=1.23; 95% confidence interval [CI], 1.06–1.44), and the mean duration of patient-assessed pain was 2.9 vs 3.2 days (HR=1.20; 95% CI, 1.03–1.40). The second study showed a mean clinician-assessed duration with topical acyclovir of 4.6 vs 5.2 days for control (HR=1.24; 95% CI, 1.06–1.44), and the mean duration of patient-assessed pain was 3.1 vs 3.5 days (HR=1.21; 95% CI, 1.04–1.40). Benefits were seen regardless of whether treatment was initiated early (prodrome or erythema stage) or late (macule, papule, vesicle or crusted stage).³

Recent studies of valacyclovir (the L-valine ester of acyclovir, which has 3 to 5 times greater bioavailability) offer the most promise for effective self-initiated treatment of recurrent herpes labialis. In a report of 2 well-designed, multicenter RCTs, valacyclovir at the FDA-approved dosage of 2 g twice daily for 1 day at the onset of symptoms (before visible signs of a cold sore) significantly decreased the mean duration of the lesion and time to lesion healing. In the first study (n=603), episode duration was decreased by 1.1 days (5.0 days vs 6.1 days for placebo; 95% CI, –1.6 to –0.6) and in the second study (n=605) by 1.0 day (5.3 vs 6.3 days for placebo; 95% CI, –1.0 to –0.5). In the first study, the time to lesion healing was decreased by 1.3 days (4.8 vs 6.1 days for placebo; 95% CI, –1.9 to –0.7) and in the second study by 1.2 days (5.1 vs. 6.4 days; 95% CI, –1.8 to –0.7). There also was a trend towards preventing the development of lesions, but this was not statistically significant.⁴

Recommendations from others

The BMJ Clinical Evidence Guideline reiterates that no trials compare early vs late treatment, so no firm conclusions about the efficacy of delayed treatment can be drawn.⁵ UpToDate reports that HSV 1 studies take into account that acyclovir acts only during active viral replication, which largely precedes symptoms, and thus suggest that it has little effect if begun after the appearance of lesions.⁶

Evidence summary

The accuracy of physical examination findings for meniscal injury varies widely among meta-analyses. In a meta-analysis of 13 studies, no physical examination test—including assessment for joint effusion, McMurray test, joint line tenderness, or the Apley compression test—yielded clinically significant positive or negative likelihood ratios for a meniscal tear ( Table ). The McMurray test performed best, but at 9% to 11% pretest probability of JFP_1104_CI.final 10/18/04 11:06 AM Page 918 meniscal lesions, based on prevalence estimates among primary care/specialist populations,² the posttest probability of a positive exam is still <30%.

A meta-analysis of 4 studies by Jackson compared the utility of the McMurray test and joint line tenderness.³ For detecting meniscal tears, the McMurray test had a clinically and statistically significant positive likelihood ratio of 17.33, corresponding to a posttest probability of nearly 61%. Negative likelihood ratios for the McMurray test and joint line tenderness (0.5 and 0.8) were not clinically significant, indicating that absence of the McMurray sign or joint line tenderness alone is of little benefit in ruling out meniscal injury.

In another meta-analysis including 9 studies of meniscal injury diagnosis,⁴ individual tests for joint line tenderness, joint effusion, the medial-lateral grind test, and the McMurray test failed to yield statistically significant likelihood ratios for the presence or absence of meniscal tears ( Table footnotes). Positive and negative likelihood ratios for aggregate physical examination were 2.7 (95% confidence interval [CI], 1.4–5.1) and 0.4 (95% CI, 0.2–0.7), which are statistically, but not clinically, significant values for ruling meniscal lesions in or out.

Jackson’s meta-analysis also calculated the posttest probability of injury for a composite meniscal examination. Based on the positive likelihood ratio of 3.1 (95% CI, 0.54–5.7) and negative likelihood ratio of 0.19 (95% CI, 0.11–0.77), the posttest probability of a medial meniscal tear was 17% in the setting of composite physical exam findings and 1% in the absence of physical exam findings. For a lateral meniscal tear, based on the positive likelihood ratio of 11 (95% CI, 1.8–20.2), and negative likelihood ratio of 0.13 (95% CI, 0.0–0.25), the posttest probability of injury with a positive exam was 41% and with a negative exam 0.8%.

Authors of all meta-analyses noted the lack of standardization in physical examination maneuvers (especially the McMurray test)⁵ and, in some cases, no specification of how physical examination tests were performed. Authors analyzed the utility of the aggregate and composite knee examinations without specifying what constituted such an exam. No study included in the meta-analyses used control subjects without meniscal pathology, and few studies were blinded. Lack of blinding may have introduced verification bias; use of specialty patients in all studies made referral bias likely. Studies were heterogeneous and results were associated with wide confidence intervals, introducing an element of random error into the processes of combining and interpreting data.

TABLE
Physical exams for meniscal tear

Recommendations from others

The American Academy of Orthopaedic Surgeons’ clinical guideline on the evaluation and treatment of knee injuries lists the following findings as associated with a meniscal tear: delayed swelling of the knee, twisting injury, painful popping and catching, effusion, joint line tenderness, positive McMurray’s test, and negative radiography.⁶ The guideline fails to list the strength and type of supporting evidence for these associations.

The American College of Radiology’s Appropriateness Criteria for Acute Trauma to the Knee states that decision rules for meniscal tears and other soft tissue injuries to the knee are being investigated, but it fails to mention specific evaluation strategies for meniscal tears.⁷

Evidence summary

The accuracy of physical examination findings for meniscal injury varies widely among meta-analyses. In a meta-analysis of 13 studies, no physical examination test—including assessment for joint effusion, McMurray test, joint line tenderness, or the Apley compression test—yielded clinically significant positive or negative likelihood ratios for a meniscal tear ( Table ). The McMurray test performed best, but at 9% to 11% pretest probability of JFP_1104_CI.final 10/18/04 11:06 AM Page 918 meniscal lesions, based on prevalence estimates among primary care/specialist populations,² the posttest probability of a positive exam is still <30%.

A meta-analysis of 4 studies by Jackson compared the utility of the McMurray test and joint line tenderness.³ For detecting meniscal tears, the McMurray test had a clinically and statistically significant positive likelihood ratio of 17.33, corresponding to a posttest probability of nearly 61%. Negative likelihood ratios for the McMurray test and joint line tenderness (0.5 and 0.8) were not clinically significant, indicating that absence of the McMurray sign or joint line tenderness alone is of little benefit in ruling out meniscal injury.

In another meta-analysis including 9 studies of meniscal injury diagnosis,⁴ individual tests for joint line tenderness, joint effusion, the medial-lateral grind test, and the McMurray test failed to yield statistically significant likelihood ratios for the presence or absence of meniscal tears ( Table footnotes). Positive and negative likelihood ratios for aggregate physical examination were 2.7 (95% confidence interval [CI], 1.4–5.1) and 0.4 (95% CI, 0.2–0.7), which are statistically, but not clinically, significant values for ruling meniscal lesions in or out.

Jackson’s meta-analysis also calculated the posttest probability of injury for a composite meniscal examination. Based on the positive likelihood ratio of 3.1 (95% CI, 0.54–5.7) and negative likelihood ratio of 0.19 (95% CI, 0.11–0.77), the posttest probability of a medial meniscal tear was 17% in the setting of composite physical exam findings and 1% in the absence of physical exam findings. For a lateral meniscal tear, based on the positive likelihood ratio of 11 (95% CI, 1.8–20.2), and negative likelihood ratio of 0.13 (95% CI, 0.0–0.25), the posttest probability of injury with a positive exam was 41% and with a negative exam 0.8%.

Authors of all meta-analyses noted the lack of standardization in physical examination maneuvers (especially the McMurray test)⁵ and, in some cases, no specification of how physical examination tests were performed. Authors analyzed the utility of the aggregate and composite knee examinations without specifying what constituted such an exam. No study included in the meta-analyses used control subjects without meniscal pathology, and few studies were blinded. Lack of blinding may have introduced verification bias; use of specialty patients in all studies made referral bias likely. Studies were heterogeneous and results were associated with wide confidence intervals, introducing an element of random error into the processes of combining and interpreting data.

TABLE
Physical exams for meniscal tear

Recommendations from others

The American Academy of Orthopaedic Surgeons’ clinical guideline on the evaluation and treatment of knee injuries lists the following findings as associated with a meniscal tear: delayed swelling of the knee, twisting injury, painful popping and catching, effusion, joint line tenderness, positive McMurray’s test, and negative radiography.⁶ The guideline fails to list the strength and type of supporting evidence for these associations.

The American College of Radiology’s Appropriateness Criteria for Acute Trauma to the Knee states that decision rules for meniscal tears and other soft tissue injuries to the knee are being investigated, but it fails to mention specific evaluation strategies for meniscal tears.⁷

Evidence summary

The accuracy of physical examination findings for meniscal injury varies widely among meta-analyses. In a meta-analysis of 13 studies, no physical examination test—including assessment for joint effusion, McMurray test, joint line tenderness, or the Apley compression test—yielded clinically significant positive or negative likelihood ratios for a meniscal tear ( Table ). The McMurray test performed best, but at 9% to 11% pretest probability of JFP_1104_CI.final 10/18/04 11:06 AM Page 918 meniscal lesions, based on prevalence estimates among primary care/specialist populations,² the posttest probability of a positive exam is still <30%.

A meta-analysis of 4 studies by Jackson compared the utility of the McMurray test and joint line tenderness.³ For detecting meniscal tears, the McMurray test had a clinically and statistically significant positive likelihood ratio of 17.33, corresponding to a posttest probability of nearly 61%. Negative likelihood ratios for the McMurray test and joint line tenderness (0.5 and 0.8) were not clinically significant, indicating that absence of the McMurray sign or joint line tenderness alone is of little benefit in ruling out meniscal injury.

In another meta-analysis including 9 studies of meniscal injury diagnosis,⁴ individual tests for joint line tenderness, joint effusion, the medial-lateral grind test, and the McMurray test failed to yield statistically significant likelihood ratios for the presence or absence of meniscal tears ( Table footnotes). Positive and negative likelihood ratios for aggregate physical examination were 2.7 (95% confidence interval [CI], 1.4–5.1) and 0.4 (95% CI, 0.2–0.7), which are statistically, but not clinically, significant values for ruling meniscal lesions in or out.

Jackson’s meta-analysis also calculated the posttest probability of injury for a composite meniscal examination. Based on the positive likelihood ratio of 3.1 (95% CI, 0.54–5.7) and negative likelihood ratio of 0.19 (95% CI, 0.11–0.77), the posttest probability of a medial meniscal tear was 17% in the setting of composite physical exam findings and 1% in the absence of physical exam findings. For a lateral meniscal tear, based on the positive likelihood ratio of 11 (95% CI, 1.8–20.2), and negative likelihood ratio of 0.13 (95% CI, 0.0–0.25), the posttest probability of injury with a positive exam was 41% and with a negative exam 0.8%.

Authors of all meta-analyses noted the lack of standardization in physical examination maneuvers (especially the McMurray test)⁵ and, in some cases, no specification of how physical examination tests were performed. Authors analyzed the utility of the aggregate and composite knee examinations without specifying what constituted such an exam. No study included in the meta-analyses used control subjects without meniscal pathology, and few studies were blinded. Lack of blinding may have introduced verification bias; use of specialty patients in all studies made referral bias likely. Studies were heterogeneous and results were associated with wide confidence intervals, introducing an element of random error into the processes of combining and interpreting data.

TABLE
Physical exams for meniscal tear

Recommendations from others

The American Academy of Orthopaedic Surgeons’ clinical guideline on the evaluation and treatment of knee injuries lists the following findings as associated with a meniscal tear: delayed swelling of the knee, twisting injury, painful popping and catching, effusion, joint line tenderness, positive McMurray’s test, and negative radiography.⁶ The guideline fails to list the strength and type of supporting evidence for these associations.

The American College of Radiology’s Appropriateness Criteria for Acute Trauma to the Knee states that decision rules for meniscal tears and other soft tissue injuries to the knee are being investigated, but it fails to mention specific evaluation strategies for meniscal tears.⁷

Evidence summary

Clinical guidelines for osteoarthritis recommend acetaminophen as first-line therapy followed by an NSAID or cyclooxygenase-2 (COX-2) inhibitor, and many patients are treated with combination therapy.

Several small randomized controlled trials have compared the individual efficacy of NSAIDs and acetaminophen in osteoarthritis and have found that both provide more pain relief than placebo.^1-3There is a trend toward improved pain relief with NSAIDs compared with acetaminophen in the initial treatment period; however, few long-term studies of efficacy have been reported. One randomized controlled trial comparing 750 mg/d naproxen (Aleve, Naprosyn) with 2600 mg/d acetaminophen for 2 years found similar pain relief for both medications and a dropout rate of 65% in both groups.² Similar numbers of persons taking acetaminophen or naproxen dropped out because of adverse effects (20%) or lack of efficacy (19%), and no difference was seen in functional improvement between the 2 groups.

A 6-week randomized double-blind crossover trial of 227 patients comparing 75 mg diclofenac and 200 mg misoprostol (Arthrotec) with acetaminophen 4 g/d found the diclofenac-misoprostol combination provided more pain control than acetaminophen alone. Adverse events were slightly more common in the diclofenac group (54% vs 46%; P=.046).⁴

The COX-2 inhibitors rofecoxib (Vioxx) and celecoxib (Celebrex) have been shown to provide equal pain relief compared with naproxen for patients with osteoarthritis.⁵ One industry-sponsored randomized trial found rofecoxib superior to celecoxib, and both superior to acetaminophen in treatment of osteoarthritis pain.⁶ There was no difference in the incidence of side effects among the 3 medications. Thirty percent of patients taking 4 g/d acetaminophen discontinued the study because of lack of efficacy, compared with 20% of those taking either celecoxib or rofecoxib.⁶

Few studies have evaluated the safety or efficacy of the combination of NSAIDs and acetaminophen in osteoarthritis. One double-blind, double-dummy crossover trial of 18 patients with osteoarthritis of the hip compared naproxen at doses of 500 mg and 1000 mg, with and without 4 g/d of acetaminophen, and 1500 mg/d of naproxen alone over 5 one-week trial periods.⁷Adding acetaminophen improved patient-reported pain scores compared with naproxen alone. Higher doses of naproxen alone provided less pain relief than a lower dose of naproxen combined with acetaminophen. GI side effects increased with the increase in naproxen dose, but were unaffected by the addition of acetaminophen. Functional ability was not affected during this short study. A similar study by the same researchers of patients with rheumatoid arthritis found similar results.⁷

One randomized, double-blind, crossover trial compared single doses of tolmetin (Tolectin, 100, 150, 200 mg) and acetaminophen (400 mg) alone and in combination with placebo in the control of experimentally induced pain (thermal and electrical stimulation). Acetaminophen alone did not differ from placebo in pain control; however, the combinations of acetaminophen with tolmetin provided similar pain relief to higher doses of tolmetin alone.⁸ No studies have evaluated the efficacy or safety of acetaminophen combined with rofecoxib or celecoxib.

Regarding the risks of combining acetaminophen with NSAIDs, 1 nested case-control study based on the entire enrollment panel of the British National Health Service characterized the risk of upper GI side effects among persons taking NSAIDs or acetaminophen alone or in combination. The study evaluated medications in use at the time of an upper GI bleed, controlling for age, sex, and concomitant medications (corticosteroids, H₂ receptor antagonists, omeprazole, anticoagulants, and others) and excluding patients with varices, alcohol-related disorders, liver disease, and cancer; no attempt was made to control other comorbidities. The relative risk of upper GI perforation or bleeding for patients taking 2g/d acetaminophen or high-dose NSAIDs was 2.4 (95% confidence interval [CI], 1.7–3.5) and 3.6 (95% CI, 2.9–4.3), respectively. Concomitant use of an NSAID with 2 g/d of acetaminophen showed a relative risk of upper GI perforation or bleed of 16.6 (95% CI, 11.0–24.9). Acetaminophen doses <2 g/d conferred no additional risk for serious upper GI side effects.⁹

A systematic review of selective COX-2 inhibitors vs naproxen found fewer endoscopically detected ulcers in patients taking celecoxib but no difference in serious gastrointestinal bleeds.⁵ A meta-analysis of randomized controlled trials found a higher incidence of serious thrombotic cardiovascular events among patients taking COX-2 inhibitors compared with naprosyn.¹⁰ The safety profile of rofecoxib and celecoxib in the long-term treatment of pain is not fully understood at this time.

Recommendations from others

The American College of Rheumatology (ACR) recommends acetaminophen up to 4 g/d as a first-line pharmacologic treatment for osteoarthritis of the hip and knee, and advises NSAIDs be used at the lowest effective dose if they are necessary for pain control.¹¹ The ACR does not specifically comment on combining NSAID and acetaminophen use. The American Academy of Orthopaedic Surgeons recommends initial use of an NSAID or acetaminophen, but does not comment on the combination of NSAIDs and acetaminophen.¹²

Evidence summary

Clinical guidelines for osteoarthritis recommend acetaminophen as first-line therapy followed by an NSAID or cyclooxygenase-2 (COX-2) inhibitor, and many patients are treated with combination therapy.

Several small randomized controlled trials have compared the individual efficacy of NSAIDs and acetaminophen in osteoarthritis and have found that both provide more pain relief than placebo.^1-3There is a trend toward improved pain relief with NSAIDs compared with acetaminophen in the initial treatment period; however, few long-term studies of efficacy have been reported. One randomized controlled trial comparing 750 mg/d naproxen (Aleve, Naprosyn) with 2600 mg/d acetaminophen for 2 years found similar pain relief for both medications and a dropout rate of 65% in both groups.² Similar numbers of persons taking acetaminophen or naproxen dropped out because of adverse effects (20%) or lack of efficacy (19%), and no difference was seen in functional improvement between the 2 groups.

A 6-week randomized double-blind crossover trial of 227 patients comparing 75 mg diclofenac and 200 mg misoprostol (Arthrotec) with acetaminophen 4 g/d found the diclofenac-misoprostol combination provided more pain control than acetaminophen alone. Adverse events were slightly more common in the diclofenac group (54% vs 46%; P=.046).⁴

The COX-2 inhibitors rofecoxib (Vioxx) and celecoxib (Celebrex) have been shown to provide equal pain relief compared with naproxen for patients with osteoarthritis.⁵ One industry-sponsored randomized trial found rofecoxib superior to celecoxib, and both superior to acetaminophen in treatment of osteoarthritis pain.⁶ There was no difference in the incidence of side effects among the 3 medications. Thirty percent of patients taking 4 g/d acetaminophen discontinued the study because of lack of efficacy, compared with 20% of those taking either celecoxib or rofecoxib.⁶

Few studies have evaluated the safety or efficacy of the combination of NSAIDs and acetaminophen in osteoarthritis. One double-blind, double-dummy crossover trial of 18 patients with osteoarthritis of the hip compared naproxen at doses of 500 mg and 1000 mg, with and without 4 g/d of acetaminophen, and 1500 mg/d of naproxen alone over 5 one-week trial periods.⁷Adding acetaminophen improved patient-reported pain scores compared with naproxen alone. Higher doses of naproxen alone provided less pain relief than a lower dose of naproxen combined with acetaminophen. GI side effects increased with the increase in naproxen dose, but were unaffected by the addition of acetaminophen. Functional ability was not affected during this short study. A similar study by the same researchers of patients with rheumatoid arthritis found similar results.⁷

One randomized, double-blind, crossover trial compared single doses of tolmetin (Tolectin, 100, 150, 200 mg) and acetaminophen (400 mg) alone and in combination with placebo in the control of experimentally induced pain (thermal and electrical stimulation). Acetaminophen alone did not differ from placebo in pain control; however, the combinations of acetaminophen with tolmetin provided similar pain relief to higher doses of tolmetin alone.⁸ No studies have evaluated the efficacy or safety of acetaminophen combined with rofecoxib or celecoxib.

Regarding the risks of combining acetaminophen with NSAIDs, 1 nested case-control study based on the entire enrollment panel of the British National Health Service characterized the risk of upper GI side effects among persons taking NSAIDs or acetaminophen alone or in combination. The study evaluated medications in use at the time of an upper GI bleed, controlling for age, sex, and concomitant medications (corticosteroids, H₂ receptor antagonists, omeprazole, anticoagulants, and others) and excluding patients with varices, alcohol-related disorders, liver disease, and cancer; no attempt was made to control other comorbidities. The relative risk of upper GI perforation or bleeding for patients taking 2g/d acetaminophen or high-dose NSAIDs was 2.4 (95% confidence interval [CI], 1.7–3.5) and 3.6 (95% CI, 2.9–4.3), respectively. Concomitant use of an NSAID with 2 g/d of acetaminophen showed a relative risk of upper GI perforation or bleed of 16.6 (95% CI, 11.0–24.9). Acetaminophen doses <2 g/d conferred no additional risk for serious upper GI side effects.⁹

A systematic review of selective COX-2 inhibitors vs naproxen found fewer endoscopically detected ulcers in patients taking celecoxib but no difference in serious gastrointestinal bleeds.⁵ A meta-analysis of randomized controlled trials found a higher incidence of serious thrombotic cardiovascular events among patients taking COX-2 inhibitors compared with naprosyn.¹⁰ The safety profile of rofecoxib and celecoxib in the long-term treatment of pain is not fully understood at this time.

Recommendations from others

The American College of Rheumatology (ACR) recommends acetaminophen up to 4 g/d as a first-line pharmacologic treatment for osteoarthritis of the hip and knee, and advises NSAIDs be used at the lowest effective dose if they are necessary for pain control.¹¹ The ACR does not specifically comment on combining NSAID and acetaminophen use. The American Academy of Orthopaedic Surgeons recommends initial use of an NSAID or acetaminophen, but does not comment on the combination of NSAIDs and acetaminophen.¹²

Evidence summary

Clinical guidelines for osteoarthritis recommend acetaminophen as first-line therapy followed by an NSAID or cyclooxygenase-2 (COX-2) inhibitor, and many patients are treated with combination therapy.

Several small randomized controlled trials have compared the individual efficacy of NSAIDs and acetaminophen in osteoarthritis and have found that both provide more pain relief than placebo.^1-3There is a trend toward improved pain relief with NSAIDs compared with acetaminophen in the initial treatment period; however, few long-term studies of efficacy have been reported. One randomized controlled trial comparing 750 mg/d naproxen (Aleve, Naprosyn) with 2600 mg/d acetaminophen for 2 years found similar pain relief for both medications and a dropout rate of 65% in both groups.² Similar numbers of persons taking acetaminophen or naproxen dropped out because of adverse effects (20%) or lack of efficacy (19%), and no difference was seen in functional improvement between the 2 groups.

A 6-week randomized double-blind crossover trial of 227 patients comparing 75 mg diclofenac and 200 mg misoprostol (Arthrotec) with acetaminophen 4 g/d found the diclofenac-misoprostol combination provided more pain control than acetaminophen alone. Adverse events were slightly more common in the diclofenac group (54% vs 46%; P=.046).⁴

The COX-2 inhibitors rofecoxib (Vioxx) and celecoxib (Celebrex) have been shown to provide equal pain relief compared with naproxen for patients with osteoarthritis.⁵ One industry-sponsored randomized trial found rofecoxib superior to celecoxib, and both superior to acetaminophen in treatment of osteoarthritis pain.⁶ There was no difference in the incidence of side effects among the 3 medications. Thirty percent of patients taking 4 g/d acetaminophen discontinued the study because of lack of efficacy, compared with 20% of those taking either celecoxib or rofecoxib.⁶

Few studies have evaluated the safety or efficacy of the combination of NSAIDs and acetaminophen in osteoarthritis. One double-blind, double-dummy crossover trial of 18 patients with osteoarthritis of the hip compared naproxen at doses of 500 mg and 1000 mg, with and without 4 g/d of acetaminophen, and 1500 mg/d of naproxen alone over 5 one-week trial periods.⁷Adding acetaminophen improved patient-reported pain scores compared with naproxen alone. Higher doses of naproxen alone provided less pain relief than a lower dose of naproxen combined with acetaminophen. GI side effects increased with the increase in naproxen dose, but were unaffected by the addition of acetaminophen. Functional ability was not affected during this short study. A similar study by the same researchers of patients with rheumatoid arthritis found similar results.⁷

One randomized, double-blind, crossover trial compared single doses of tolmetin (Tolectin, 100, 150, 200 mg) and acetaminophen (400 mg) alone and in combination with placebo in the control of experimentally induced pain (thermal and electrical stimulation). Acetaminophen alone did not differ from placebo in pain control; however, the combinations of acetaminophen with tolmetin provided similar pain relief to higher doses of tolmetin alone.⁸ No studies have evaluated the efficacy or safety of acetaminophen combined with rofecoxib or celecoxib.

Regarding the risks of combining acetaminophen with NSAIDs, 1 nested case-control study based on the entire enrollment panel of the British National Health Service characterized the risk of upper GI side effects among persons taking NSAIDs or acetaminophen alone or in combination. The study evaluated medications in use at the time of an upper GI bleed, controlling for age, sex, and concomitant medications (corticosteroids, H₂ receptor antagonists, omeprazole, anticoagulants, and others) and excluding patients with varices, alcohol-related disorders, liver disease, and cancer; no attempt was made to control other comorbidities. The relative risk of upper GI perforation or bleeding for patients taking 2g/d acetaminophen or high-dose NSAIDs was 2.4 (95% confidence interval [CI], 1.7–3.5) and 3.6 (95% CI, 2.9–4.3), respectively. Concomitant use of an NSAID with 2 g/d of acetaminophen showed a relative risk of upper GI perforation or bleed of 16.6 (95% CI, 11.0–24.9). Acetaminophen doses <2 g/d conferred no additional risk for serious upper GI side effects.⁹

A systematic review of selective COX-2 inhibitors vs naproxen found fewer endoscopically detected ulcers in patients taking celecoxib but no difference in serious gastrointestinal bleeds.⁵ A meta-analysis of randomized controlled trials found a higher incidence of serious thrombotic cardiovascular events among patients taking COX-2 inhibitors compared with naprosyn.¹⁰ The safety profile of rofecoxib and celecoxib in the long-term treatment of pain is not fully understood at this time.

Recommendations from others

The American College of Rheumatology (ACR) recommends acetaminophen up to 4 g/d as a first-line pharmacologic treatment for osteoarthritis of the hip and knee, and advises NSAIDs be used at the lowest effective dose if they are necessary for pain control.¹¹ The ACR does not specifically comment on combining NSAID and acetaminophen use. The American Academy of Orthopaedic Surgeons recommends initial use of an NSAID or acetaminophen, but does not comment on the combination of NSAIDs and acetaminophen.¹²

Evidence summary

Multiple case-control studies have identified risk factors for SIDS, which are presented along (with odds ratios) in Table 1.^1-6 None of these case-control studies found apnea of prematurity to be a risk factor for SIDS.

A prospective cohort study of 1079 infants monitored for cardiorespiratory events, the Collaborative Home Infant Monitor Evaluation (CHIME) study, demonstrated that prior to 43 weeks postconceptional age, preterm infants had a statistically significant greater risk of extreme events (apnea or bradycardia longer than 30 seconds) compared with healthy term infants (Table 2). After 43 weeks postconceptional age, there were no differences in incidence of apnea or bradycardia, comparing preterm and term infants. Neither preterm infants nor infants with apnea, bradycardia, or apparent life-threatening events had increased incidences of SIDS.⁷

Significant financial costs are associated with home monitoring. The average monthly cost is $300 to $400, not including physician fees. This would lead to an estimated annual cost of $24 million dollars if every infant <1500 grams in the United States were monitored.⁸

The psychological costs of home apnea monitoring have also been studied. One hundred and four parents of monitored and unmonitored infants were enrolled in a questionnaire study to determine emotional distress and family functioning. As is common among families in the postpartum period, all experienced increased stress. But parents of monitored infants, compared with parents of unmonitored infants, had an increased incidence of subjective depression (number needed to harm [NNH]=7) and hostility (NNH=12) at 2 weeks postpartum. Interestingly, at 1-year follow-up interviews, 83% of parents who had consistently used the monitor reported feeling more secure for having used it and 69% believed that monitor use had been helpful.⁹

Recommendations from others

The American Academy of Pediatrics (AAP) acknowledges that no established predictive or precursor relationship exists between prolonged apnea and SIDS, stating that the “prevention of SIDS is not an acceptable indication for home cardiorespiratory monitoring.” They issue a weak recommendation that home cardiorespiratory monitoring may be necessary for recurrent apnea, recurrent bradycardia, hypoxemia, chronic lung disease, and technology-dependent infants. Finally, they state that monitoring should be discontinued at 43 weeks postconceptional age or after cessation of extreme cardiorespiratory events, whichever occurs last. The AAP recommends proven practices such as supine sleeping position, a safe sleeping environment, and elimination of prenatal and postnatal exposure to tobacco smoke to decrease the risk of SIDS.⁸

TABLE 1
Risk factors for SIDS

Evidence summary

Multiple case-control studies have identified risk factors for SIDS, which are presented along (with odds ratios) in Table 1.^1-6 None of these case-control studies found apnea of prematurity to be a risk factor for SIDS.

A prospective cohort study of 1079 infants monitored for cardiorespiratory events, the Collaborative Home Infant Monitor Evaluation (CHIME) study, demonstrated that prior to 43 weeks postconceptional age, preterm infants had a statistically significant greater risk of extreme events (apnea or bradycardia longer than 30 seconds) compared with healthy term infants (Table 2). After 43 weeks postconceptional age, there were no differences in incidence of apnea or bradycardia, comparing preterm and term infants. Neither preterm infants nor infants with apnea, bradycardia, or apparent life-threatening events had increased incidences of SIDS.⁷

Significant financial costs are associated with home monitoring. The average monthly cost is $300 to $400, not including physician fees. This would lead to an estimated annual cost of $24 million dollars if every infant <1500 grams in the United States were monitored.⁸

The psychological costs of home apnea monitoring have also been studied. One hundred and four parents of monitored and unmonitored infants were enrolled in a questionnaire study to determine emotional distress and family functioning. As is common among families in the postpartum period, all experienced increased stress. But parents of monitored infants, compared with parents of unmonitored infants, had an increased incidence of subjective depression (number needed to harm [NNH]=7) and hostility (NNH=12) at 2 weeks postpartum. Interestingly, at 1-year follow-up interviews, 83% of parents who had consistently used the monitor reported feeling more secure for having used it and 69% believed that monitor use had been helpful.⁹

Recommendations from others

The American Academy of Pediatrics (AAP) acknowledges that no established predictive or precursor relationship exists between prolonged apnea and SIDS, stating that the “prevention of SIDS is not an acceptable indication for home cardiorespiratory monitoring.” They issue a weak recommendation that home cardiorespiratory monitoring may be necessary for recurrent apnea, recurrent bradycardia, hypoxemia, chronic lung disease, and technology-dependent infants. Finally, they state that monitoring should be discontinued at 43 weeks postconceptional age or after cessation of extreme cardiorespiratory events, whichever occurs last. The AAP recommends proven practices such as supine sleeping position, a safe sleeping environment, and elimination of prenatal and postnatal exposure to tobacco smoke to decrease the risk of SIDS.⁸

TABLE 1
Risk factors for SIDS

Evidence summary

Multiple case-control studies have identified risk factors for SIDS, which are presented along (with odds ratios) in Table 1.^1-6 None of these case-control studies found apnea of prematurity to be a risk factor for SIDS.

A prospective cohort study of 1079 infants monitored for cardiorespiratory events, the Collaborative Home Infant Monitor Evaluation (CHIME) study, demonstrated that prior to 43 weeks postconceptional age, preterm infants had a statistically significant greater risk of extreme events (apnea or bradycardia longer than 30 seconds) compared with healthy term infants (Table 2). After 43 weeks postconceptional age, there were no differences in incidence of apnea or bradycardia, comparing preterm and term infants. Neither preterm infants nor infants with apnea, bradycardia, or apparent life-threatening events had increased incidences of SIDS.⁷

Significant financial costs are associated with home monitoring. The average monthly cost is $300 to $400, not including physician fees. This would lead to an estimated annual cost of $24 million dollars if every infant <1500 grams in the United States were monitored.⁸

The psychological costs of home apnea monitoring have also been studied. One hundred and four parents of monitored and unmonitored infants were enrolled in a questionnaire study to determine emotional distress and family functioning. As is common among families in the postpartum period, all experienced increased stress. But parents of monitored infants, compared with parents of unmonitored infants, had an increased incidence of subjective depression (number needed to harm [NNH]=7) and hostility (NNH=12) at 2 weeks postpartum. Interestingly, at 1-year follow-up interviews, 83% of parents who had consistently used the monitor reported feeling more secure for having used it and 69% believed that monitor use had been helpful.⁹

Recommendations from others

The American Academy of Pediatrics (AAP) acknowledges that no established predictive or precursor relationship exists between prolonged apnea and SIDS, stating that the “prevention of SIDS is not an acceptable indication for home cardiorespiratory monitoring.” They issue a weak recommendation that home cardiorespiratory monitoring may be necessary for recurrent apnea, recurrent bradycardia, hypoxemia, chronic lung disease, and technology-dependent infants. Finally, they state that monitoring should be discontinued at 43 weeks postconceptional age or after cessation of extreme cardiorespiratory events, whichever occurs last. The AAP recommends proven practices such as supine sleeping position, a safe sleeping environment, and elimination of prenatal and postnatal exposure to tobacco smoke to decrease the risk of SIDS.⁸

TABLE 1
Risk factors for SIDS

Evidence summary

Postherpetic neuralgia is defined as pain that persists more than 1 month following onset of herpes zoster. The annual incidence of herpes zoster in population-based studies ranges from 1/1000 to 2/1000.^1,3 Among adults aged >60 years, the annual incidence increases to 3.6/1000 for men and 5.6/1000 for women.¹

In a prospective study performed in a primary care setting in Iceland, all cases of herpes zoster and postherpetic neuralgia occurring over 4.5 years in a population of 100,000 were identified, and all cases of postherpetic neuralgia were followed for up to 7.6 years. Few patients (4%) received antiviral medication.

In this study, postherpetic neuralgia followed herpes zoster in 2% of patients under age 40, 21% between the ages of 40 and 60, and in 40% of those over age 60.^1,2 Subjects self-described pain as none, mild, moderate, or severe. Patients aged >60 years had the worst prognosis: 18% still had mild pain at 3 months and 6% had moderate or severe pain. At 1 year, 8% had mild pain and 2% had moderate pain. No patients had severe pain after 12 months.^1,2

Among the 14 patients with pain persisting >12 months, 7 had complete resolution of pain, 5 had persisting pain that either improved or remained mild, 1 had ongoing moderate pain at 7 years, and 1 was lost to follow-up.² (See Table.) Although postherpetic neuralgia can recur after resolution,⁴ no recurrence of pain was found among 183 randomly selected patients who had had resolution by 1 year.²

These results are similar to those found in an analysis of a retrospective cohort drawn from a large general practice network database,⁵ as well as other population-based studies.^6,7 The prognosis is better than that reported in the placebo arms of trials of acute herpes zoster treatment.⁴ Patients in such trials are more likely to have severe disease than those seen in primary care settings.

TABLE
Risk of postherpetic neuralgia by age

Recommendations from others

A British guideline states that 5% of herpes zoster patients have postherpetic neuralgia 1 year after shingles.⁸ A review in the New England Journal of Medicine states that 48% of herpes zoster patients aged >70 years have postherpetic neuralgia at 1 year.⁹ This prevalence comes from a retrospective cohort study that combined patients presenting to a referral center with herpes zoster or postherpetic neuralgia into a single cohort, thus overestimating the prevalence of postherpetic neuralgia and providing a less reliable prognosis.¹⁰

Evidence summary

Postherpetic neuralgia is defined as pain that persists more than 1 month following onset of herpes zoster. The annual incidence of herpes zoster in population-based studies ranges from 1/1000 to 2/1000.^1,3 Among adults aged >60 years, the annual incidence increases to 3.6/1000 for men and 5.6/1000 for women.¹

In a prospective study performed in a primary care setting in Iceland, all cases of herpes zoster and postherpetic neuralgia occurring over 4.5 years in a population of 100,000 were identified, and all cases of postherpetic neuralgia were followed for up to 7.6 years. Few patients (4%) received antiviral medication.

In this study, postherpetic neuralgia followed herpes zoster in 2% of patients under age 40, 21% between the ages of 40 and 60, and in 40% of those over age 60.^1,2 Subjects self-described pain as none, mild, moderate, or severe. Patients aged >60 years had the worst prognosis: 18% still had mild pain at 3 months and 6% had moderate or severe pain. At 1 year, 8% had mild pain and 2% had moderate pain. No patients had severe pain after 12 months.^1,2

Among the 14 patients with pain persisting >12 months, 7 had complete resolution of pain, 5 had persisting pain that either improved or remained mild, 1 had ongoing moderate pain at 7 years, and 1 was lost to follow-up.² (See Table.) Although postherpetic neuralgia can recur after resolution,⁴ no recurrence of pain was found among 183 randomly selected patients who had had resolution by 1 year.²

These results are similar to those found in an analysis of a retrospective cohort drawn from a large general practice network database,⁵ as well as other population-based studies.^6,7 The prognosis is better than that reported in the placebo arms of trials of acute herpes zoster treatment.⁴ Patients in such trials are more likely to have severe disease than those seen in primary care settings.

TABLE
Risk of postherpetic neuralgia by age

Recommendations from others

A British guideline states that 5% of herpes zoster patients have postherpetic neuralgia 1 year after shingles.⁸ A review in the New England Journal of Medicine states that 48% of herpes zoster patients aged >70 years have postherpetic neuralgia at 1 year.⁹ This prevalence comes from a retrospective cohort study that combined patients presenting to a referral center with herpes zoster or postherpetic neuralgia into a single cohort, thus overestimating the prevalence of postherpetic neuralgia and providing a less reliable prognosis.¹⁰

Evidence summary

Postherpetic neuralgia is defined as pain that persists more than 1 month following onset of herpes zoster. The annual incidence of herpes zoster in population-based studies ranges from 1/1000 to 2/1000.^1,3 Among adults aged >60 years, the annual incidence increases to 3.6/1000 for men and 5.6/1000 for women.¹

In a prospective study performed in a primary care setting in Iceland, all cases of herpes zoster and postherpetic neuralgia occurring over 4.5 years in a population of 100,000 were identified, and all cases of postherpetic neuralgia were followed for up to 7.6 years. Few patients (4%) received antiviral medication.

In this study, postherpetic neuralgia followed herpes zoster in 2% of patients under age 40, 21% between the ages of 40 and 60, and in 40% of those over age 60.^1,2 Subjects self-described pain as none, mild, moderate, or severe. Patients aged >60 years had the worst prognosis: 18% still had mild pain at 3 months and 6% had moderate or severe pain. At 1 year, 8% had mild pain and 2% had moderate pain. No patients had severe pain after 12 months.^1,2

Among the 14 patients with pain persisting >12 months, 7 had complete resolution of pain, 5 had persisting pain that either improved or remained mild, 1 had ongoing moderate pain at 7 years, and 1 was lost to follow-up.² (See Table.) Although postherpetic neuralgia can recur after resolution,⁴ no recurrence of pain was found among 183 randomly selected patients who had had resolution by 1 year.²

These results are similar to those found in an analysis of a retrospective cohort drawn from a large general practice network database,⁵ as well as other population-based studies.^6,7 The prognosis is better than that reported in the placebo arms of trials of acute herpes zoster treatment.⁴ Patients in such trials are more likely to have severe disease than those seen in primary care settings.

TABLE
Risk of postherpetic neuralgia by age

Recommendations from others

A British guideline states that 5% of herpes zoster patients have postherpetic neuralgia 1 year after shingles.⁸ A review in the New England Journal of Medicine states that 48% of herpes zoster patients aged >70 years have postherpetic neuralgia at 1 year.⁹ This prevalence comes from a retrospective cohort study that combined patients presenting to a referral center with herpes zoster or postherpetic neuralgia into a single cohort, thus overestimating the prevalence of postherpetic neuralgia and providing a less reliable prognosis.¹⁰

Evidence summary

Bell’s palsy is a lower motor neuron disease of the facial nerve characterized by a transient paralysis. Healing is occasionally incomplete, resulting in residual nerve dysfunction, including partial palsy and motor synkinesis (involuntary movement accompanying a voluntary one) and autonomic synkinesis (involuntary lacrimation after a voluntary muscle movement). Bell’s palsy is associated with significant edema and ischemia of the facial nerve as it passes through its bony canal.

Herpes simplex reactivation has been shown to be associated with a large proportion of cases.

Corticosteroids are the most studied form of therapy for Bell’s palsy (Table). Early work in England culminated in 1971 with a well-performed study demonstrating lower rates of incomplete recovery with prednisolone compared with corticotrophin.¹ A potentially definitive randomized controlled trial in 1970 was stopped prematurely because of investigators’ subjective impression that prednisone markedly reduced postauricular pain.² Subsequently, the highest-quality study had few patients (n=51) and reported no difference in outcomes between patients receiving 10 days of oral prednisone plus vitamins and those receiving vitamins alone.³

One open randomized controlled trial demonstrated shorter mean recovery times with intramuscular methylcobalamin (1.95 weeks) and methylcobalamin plus prednisone (2.0 weeks) compared with prednisone alone (9.6 weeks).⁴ Another trial of 239 patients showed improved rates of autonomic synkinesis after treatment with 16 days of prednisone compared with placebo.⁵

A randomized, controlled trial of children 2 to 6 years of age found no significant differences in short-term recovery after treatment with methylprednisolone compared with untreated controls.⁶ Eventually, all these children recovered normal facial nerve function within 12 months.

Two randomized controlled trials have assessed the efficacy of acyclovir for treatment of Bell’s palsy. One trial compared prednisone with acyclovir and found patients treated with prednisone had better complete recovery rates, 93.6% versus 77.7% (absolute risk reduction [ARR]=15.9%, 95% confidence interval [CI]=2.8%–29%], number needed to treat [NNT]=7).⁷

Another study demonstrated that the combination of prednisone and acyclovir had greater complete recovery rates compared with prednisone alone (92% vs. 76%, ARR=16%, 95% CI=1.7%–30.3%, NNT=7).⁸

Overall, the data suggest corticosteroid therapy may provide a small clinical benefit in adult patients with Bell’s palsy. In many of these studies, patients who had contraindications to steroid therapy (peptic ulcer disease, uncontrolled diabetes, hypertension, or immunosuppression) were excluded.

If no contraindications to steroids exist, it is resonable to initiate treatment with corticosteroids for an adult patient with new-onset Bell’s palsy. Most studies have started patients on steroids within 10 days of onset of symptoms.

TABLE
Therapies for Bell’s palsy

Recommendations from others

A practice parameter from the American Academy of Neurology states that steroids are safe and probably effective (SOR: B), whereas acyclovir is safe and possibly effective (SOR: C).⁹ Systematic reviews from the Cochrane Database report that available evidence from randomized controlled trials does not show significant benefit from treating Bell’s palsy with corticosteroids and that clinical trials on acyclovir are inconclusive and therefore cannot be used to make recommendations regarding its use.^10,11

PATIENT INFORMATION

What is Bell’s palsy?

Weakness and slumping on one side of the face are common features of this condition in which the nerve controlling the face has been injured. Other symptoms are:

• Inability to move affected side of the face
• Drooping mouth, unblinking eye
• Numbness
• Twitching of facial muscles
• Taste disturbance
• Increased sensitivity to sound.

Symptoms usually start suddenly. Pain behind the ear may be felt hours to days before other symptoms appear. People between ages 30 and 60 years are most likely to be affected, but this disorder can happen at any age.

Any sudden weakness of the face also suggests the possibility of stroke—a serious emergency. You should contact your physician immediately.

Possible causes

The most common cause of Bell’s palsy is an infection of the facial nerve by the herpes simplex virus. Your doctor will also ask about possible recent trauma to the face and will check for swelling of facial tissues or a mass pressing on the facial nerve.

What to expect

In many cases, the symptoms of Bell’s palsy go away in about 3 weeks without treatment, and the face regains its normal appearance. A good sign that this will happen is if the weakness or other symptoms begin to resolve after 1 week.

In other cases, symptoms may take several months to disappear. Lasting effects are possible, though rare.

Treatments your doctor may prescribe

If a viral infection is the likely cause of your symptoms, your doctor may have you take acyclovir (Zovirax), famciclovir (Famvir), or another antiviral medication to speed your recovery. These antiviral medications are taken as pills, usually a few times a day for 10 days.

A steroid (prednisone, for example) may also help to reduce swelling that could be pressing on the facial nerve. This medication is also administered as a pill over 1 to 2 weeks.

If you cannot blink, and dryness of the eye is one of your symptoms, your doctor will ask you to use moisturizing eye drops to protect the eye from damage while you recover.

Evidence summary

Bell’s palsy is a lower motor neuron disease of the facial nerve characterized by a transient paralysis. Healing is occasionally incomplete, resulting in residual nerve dysfunction, including partial palsy and motor synkinesis (involuntary movement accompanying a voluntary one) and autonomic synkinesis (involuntary lacrimation after a voluntary muscle movement). Bell’s palsy is associated with significant edema and ischemia of the facial nerve as it passes through its bony canal.

Herpes simplex reactivation has been shown to be associated with a large proportion of cases.

Corticosteroids are the most studied form of therapy for Bell’s palsy (Table). Early work in England culminated in 1971 with a well-performed study demonstrating lower rates of incomplete recovery with prednisolone compared with corticotrophin.¹ A potentially definitive randomized controlled trial in 1970 was stopped prematurely because of investigators’ subjective impression that prednisone markedly reduced postauricular pain.² Subsequently, the highest-quality study had few patients (n=51) and reported no difference in outcomes between patients receiving 10 days of oral prednisone plus vitamins and those receiving vitamins alone.³

One open randomized controlled trial demonstrated shorter mean recovery times with intramuscular methylcobalamin (1.95 weeks) and methylcobalamin plus prednisone (2.0 weeks) compared with prednisone alone (9.6 weeks).⁴ Another trial of 239 patients showed improved rates of autonomic synkinesis after treatment with 16 days of prednisone compared with placebo.⁵

A randomized, controlled trial of children 2 to 6 years of age found no significant differences in short-term recovery after treatment with methylprednisolone compared with untreated controls.⁶ Eventually, all these children recovered normal facial nerve function within 12 months.

Two randomized controlled trials have assessed the efficacy of acyclovir for treatment of Bell’s palsy. One trial compared prednisone with acyclovir and found patients treated with prednisone had better complete recovery rates, 93.6% versus 77.7% (absolute risk reduction [ARR]=15.9%, 95% confidence interval [CI]=2.8%–29%], number needed to treat [NNT]=7).⁷

Another study demonstrated that the combination of prednisone and acyclovir had greater complete recovery rates compared with prednisone alone (92% vs. 76%, ARR=16%, 95% CI=1.7%–30.3%, NNT=7).⁸

Overall, the data suggest corticosteroid therapy may provide a small clinical benefit in adult patients with Bell’s palsy. In many of these studies, patients who had contraindications to steroid therapy (peptic ulcer disease, uncontrolled diabetes, hypertension, or immunosuppression) were excluded.

If no contraindications to steroids exist, it is resonable to initiate treatment with corticosteroids for an adult patient with new-onset Bell’s palsy. Most studies have started patients on steroids within 10 days of onset of symptoms.

TABLE
Therapies for Bell’s palsy

Recommendations from others

A practice parameter from the American Academy of Neurology states that steroids are safe and probably effective (SOR: B), whereas acyclovir is safe and possibly effective (SOR: C).⁹ Systematic reviews from the Cochrane Database report that available evidence from randomized controlled trials does not show significant benefit from treating Bell’s palsy with corticosteroids and that clinical trials on acyclovir are inconclusive and therefore cannot be used to make recommendations regarding its use.^10,11

PATIENT INFORMATION

What is Bell’s palsy?

Weakness and slumping on one side of the face are common features of this condition in which the nerve controlling the face has been injured. Other symptoms are:

• Inability to move affected side of the face
• Drooping mouth, unblinking eye
• Numbness
• Twitching of facial muscles
• Taste disturbance
• Increased sensitivity to sound.

Symptoms usually start suddenly. Pain behind the ear may be felt hours to days before other symptoms appear. People between ages 30 and 60 years are most likely to be affected, but this disorder can happen at any age.

Any sudden weakness of the face also suggests the possibility of stroke—a serious emergency. You should contact your physician immediately.

Possible causes

The most common cause of Bell’s palsy is an infection of the facial nerve by the herpes simplex virus. Your doctor will also ask about possible recent trauma to the face and will check for swelling of facial tissues or a mass pressing on the facial nerve.

What to expect

In many cases, the symptoms of Bell’s palsy go away in about 3 weeks without treatment, and the face regains its normal appearance. A good sign that this will happen is if the weakness or other symptoms begin to resolve after 1 week.

In other cases, symptoms may take several months to disappear. Lasting effects are possible, though rare.

Treatments your doctor may prescribe

If a viral infection is the likely cause of your symptoms, your doctor may have you take acyclovir (Zovirax), famciclovir (Famvir), or another antiviral medication to speed your recovery. These antiviral medications are taken as pills, usually a few times a day for 10 days.

A steroid (prednisone, for example) may also help to reduce swelling that could be pressing on the facial nerve. This medication is also administered as a pill over 1 to 2 weeks.

If you cannot blink, and dryness of the eye is one of your symptoms, your doctor will ask you to use moisturizing eye drops to protect the eye from damage while you recover.

Evidence summary

Bell’s palsy is a lower motor neuron disease of the facial nerve characterized by a transient paralysis. Healing is occasionally incomplete, resulting in residual nerve dysfunction, including partial palsy and motor synkinesis (involuntary movement accompanying a voluntary one) and autonomic synkinesis (involuntary lacrimation after a voluntary muscle movement). Bell’s palsy is associated with significant edema and ischemia of the facial nerve as it passes through its bony canal.

Herpes simplex reactivation has been shown to be associated with a large proportion of cases.

Corticosteroids are the most studied form of therapy for Bell’s palsy (Table). Early work in England culminated in 1971 with a well-performed study demonstrating lower rates of incomplete recovery with prednisolone compared with corticotrophin.¹ A potentially definitive randomized controlled trial in 1970 was stopped prematurely because of investigators’ subjective impression that prednisone markedly reduced postauricular pain.² Subsequently, the highest-quality study had few patients (n=51) and reported no difference in outcomes between patients receiving 10 days of oral prednisone plus vitamins and those receiving vitamins alone.³

One open randomized controlled trial demonstrated shorter mean recovery times with intramuscular methylcobalamin (1.95 weeks) and methylcobalamin plus prednisone (2.0 weeks) compared with prednisone alone (9.6 weeks).⁴ Another trial of 239 patients showed improved rates of autonomic synkinesis after treatment with 16 days of prednisone compared with placebo.⁵

A randomized, controlled trial of children 2 to 6 years of age found no significant differences in short-term recovery after treatment with methylprednisolone compared with untreated controls.⁶ Eventually, all these children recovered normal facial nerve function within 12 months.

Two randomized controlled trials have assessed the efficacy of acyclovir for treatment of Bell’s palsy. One trial compared prednisone with acyclovir and found patients treated with prednisone had better complete recovery rates, 93.6% versus 77.7% (absolute risk reduction [ARR]=15.9%, 95% confidence interval [CI]=2.8%–29%], number needed to treat [NNT]=7).⁷

Another study demonstrated that the combination of prednisone and acyclovir had greater complete recovery rates compared with prednisone alone (92% vs. 76%, ARR=16%, 95% CI=1.7%–30.3%, NNT=7).⁸

Overall, the data suggest corticosteroid therapy may provide a small clinical benefit in adult patients with Bell’s palsy. In many of these studies, patients who had contraindications to steroid therapy (peptic ulcer disease, uncontrolled diabetes, hypertension, or immunosuppression) were excluded.

If no contraindications to steroids exist, it is resonable to initiate treatment with corticosteroids for an adult patient with new-onset Bell’s palsy. Most studies have started patients on steroids within 10 days of onset of symptoms.

TABLE
Therapies for Bell’s palsy

Recommendations from others

A practice parameter from the American Academy of Neurology states that steroids are safe and probably effective (SOR: B), whereas acyclovir is safe and possibly effective (SOR: C).⁹ Systematic reviews from the Cochrane Database report that available evidence from randomized controlled trials does not show significant benefit from treating Bell’s palsy with corticosteroids and that clinical trials on acyclovir are inconclusive and therefore cannot be used to make recommendations regarding its use.^10,11

PATIENT INFORMATION

What is Bell’s palsy?

Weakness and slumping on one side of the face are common features of this condition in which the nerve controlling the face has been injured. Other symptoms are:

• Inability to move affected side of the face
• Drooping mouth, unblinking eye
• Numbness
• Twitching of facial muscles
• Taste disturbance
• Increased sensitivity to sound.

Symptoms usually start suddenly. Pain behind the ear may be felt hours to days before other symptoms appear. People between ages 30 and 60 years are most likely to be affected, but this disorder can happen at any age.

Any sudden weakness of the face also suggests the possibility of stroke—a serious emergency. You should contact your physician immediately.

Possible causes

The most common cause of Bell’s palsy is an infection of the facial nerve by the herpes simplex virus. Your doctor will also ask about possible recent trauma to the face and will check for swelling of facial tissues or a mass pressing on the facial nerve.

What to expect

In many cases, the symptoms of Bell’s palsy go away in about 3 weeks without treatment, and the face regains its normal appearance. A good sign that this will happen is if the weakness or other symptoms begin to resolve after 1 week.

In other cases, symptoms may take several months to disappear. Lasting effects are possible, though rare.

Treatments your doctor may prescribe

If a viral infection is the likely cause of your symptoms, your doctor may have you take acyclovir (Zovirax), famciclovir (Famvir), or another antiviral medication to speed your recovery. These antiviral medications are taken as pills, usually a few times a day for 10 days.

A steroid (prednisone, for example) may also help to reduce swelling that could be pressing on the facial nerve. This medication is also administered as a pill over 1 to 2 weeks.

If you cannot blink, and dryness of the eye is one of your symptoms, your doctor will ask you to use moisturizing eye drops to protect the eye from damage while you recover.