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What medications are best for diabetic neuropathic pain?
TRICYCLIC ANTIDEPRESSANTS, duloxetine, pregabalin, oxycodone, and tramadol are all effective for the symptomatic treatment of painful diabetic neuropathy (strength of recommendation [SOR]: A, systematic reviews of randomized controlled trials [RCTs] and single RCTs).
Gabapentin is also effective (SOR: B, systematic review of RCTs with methodologic flaws). Studies directly comparing tricyclic antidepressants with gabapentin or duloxetine show equivalent efficacy (SOR: A, systematic reviews of RCTs and single RCTs).
The outcome evaluated in all of these studies was pain.
Evidence summary
A Cochrane review of antidepressants for neuropathic pain included 5 RCTs of tricyclic antidepressant use in patients with diabetic neuropathy. The strongest evidence of benefit was for the tricyclic antidepressants amitriptyline, imipramine, and nortriptyline1 (TABLE).
Another Cochrane review of 3 RCTs of duloxetine for treating painful diabetic neuropathy found moderately strong evidence that duloxetine 60 mg/d was more effective than placebo. A 120 mg daily dose didn’t result in significantly greater pain relief than 60 mg/d.2
TABLE
Meta-analyses of drug therapy vs placebo for diabetic neuropathic pain
| Drug and dose | Subjects (N) | Duration (wk) | Mean age (y) | Measured outcome | NNT (95% CI) | NNH (95% CI) |
|---|---|---|---|---|---|---|
| Various tricyclic antidepressants and doses1 | 177 | 3-12 | 50 | Overall effectiveness | 1.3 (1.2-1.5) | Treatment cessation: 28 (17.6-68.9) Minor adverse effects: 6 (4.2-10.7) |
| Duloxetine2 60 mg/d 120 mg/d | 655 655 | 12 | N/A | 50% pain reduction | 6.0 (5-10) 6.0 (5-10) | Treatment cessation: 17 (12-50) |
| Pregabalin 600 mg/d3 | 1425 | 5-13 | 59 | 50% pain reduction | 5 (4-6.6) | Somnolence: 8.8 (7-12)* Dizziness: 2.8 (2.5-3.2) Treatment cessation: 8.8 (6.8-12) |
| Gabapentin 1200-3600 mg/d4 | 829 | 4-12 | 58 | 50% pain reduction | 5.8 (4.3-9.0) | Any adverse effect: 6.6 (5.3-9.0)† Treatment cessation: 32 (19-100)‡ |
| Oxycodone 20-80 mg/d6 | 36 | 4 | 63 | Moderate pain relief (defined as a score of 3 on a 6-point scale) | 2.6 (N/A) | Nausea: 4 (2-219) Constipation: 4 (2-19) Treatment cessation: 7 (4-87) |
| CI, confidence interval; NA, not available; NNH, number needed to harm; NNT, number needed to treat. *Six studies of pregabalin (N=1351) reported rates of somnolence and treatment cessation, whereas only 3 studies (N=1122) reported rates of dizziness. †NNH calculated from 11 studies (N=2356) that included patients with other chronic pain diagnoses. ‡NNH calculated from 17 studies (N=3022) that included patients with other chronic pain diagnoses. | ||||||
Antiepileptics alleviate pain, but with some drawbacks
A Cochrane review of 7 RCTs of pregabalin for acute and chronic pain in adults concluded that 600 mg/d was more effective than placebo for relieving diabetic neuropathic pain. However, as many as 28% of patients discontinued treatment because of dizziness and somnolence. Lower doses—150 and 300 mg—resulted in fewer adverse effects, but less relief.3
A Cochrane review of 4 RCTs that compared gabapentin with placebo or active control found that gabapentin in daily doses >1200 mg provided pain relief superior to that of placebo.4 An independent evaluation of manufacturer-sponsored gabapentin trials reported significant methodologic flaws, including selective outcome reporting.5
Opioids also provide significant pain relief
A Cochrane review of studies of opioids for neuropathic pain identified 2 RCTs favoring oxycodone over placebo in patients with painful diabetic neuropathy. In the larger study (159 patients, mean age 59 years) subjects used a 0- to 10-point scale to evaluate pain intensity (0=none; 10=extreme). At 6 weeks, patients receiving oxycodone in doses of 10-120 mg/d had significantly lower pain scores than patients taking placebo (4.3±0.3 for oxycodone vs 5.3±0.3 for placebo; P=.002).6
An RCT that compared the benefit of tramadol at an average dose of 210 mg per day with placebo in 131 patients with diabetic neuropathy (mean age 59 years) found tramadol to be significantly better than placebo for treating pain. At 6 weeks, the mean pain scores on a scale of 0 (mild pain) to 4 (extreme pain) were 1.4±0.1 for tramadol vs 2.2±0.1 for placebo (P<.001).7
Amitriptyline, gabapentin, duloxetine show similar benefit in some studies
A meta-analysis of 2 RCTs (N=77) comparing amitriptyline (25-90 mg/d) with gabapentin (900-2400 mg/d) found no significant difference between the 2 drugs in relief of diabetic neuropathic pain (relative risk=0.99; 95% confidence interval, 0.69-1.38).8 A randomized, double-blind, crossover trial involving 58 patients with diabetic neuropathy compared duloxetine (20-60 mg/d) with amitriptyline (10-50 mg/d). After 6 weeks, 59% of patients on duloxetine and 55% of patients on amitriptyline achieved a ≥50% reduction in pain. The 4% difference between the groups was not statistically significant.9
Recommendations
The American Diabetes Association recommends tricyclic antidepressants as first-line agents, anticonvulsants as second-line treatment, and opioids as third-line therapy.10
The Diabetic Peripheral Neuropathic Pain Consensus Treatment Guidelines Advisory Boards recommend duloxetine, controlled-release oxycodone, pregabalin, and tricyclic antidepressants as first-tier agents and topical capsaicin and lidocaine as alternatives.11
The American Academy of Neurology advocates pregabalin as the first-choice treatment and states that venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, controlled-release oxycodone), and capsaicin are probably effective.12
1. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007;(4):CD005454.-
2. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy or chronic pain. Cochrane Database Syst Rev. 2009;(4):CD007115.-
3. Moore RA, Straube S, Wiffen PJ, et al. Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev. 2009;(3):CD007076.-
4. Moore RA, Wiffen PJ, Derry S, et al. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2011;(3):CD007938.-
5. Vedula SS, Bero L, Scherer RW, et al. Outcome reporting in industry-sponsored trials of gabapentin for off-label use. N Engl J Med. 2009;361:1963-1971.
6. Eisenberg E, McNicol ED, Carr DB. Opioids for neuropathic pain. Cochrane Database Syst Rev. 2006;(3):CD006146.-
7. Harati Y, Gooch C, Swenson M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology. 1998;50:1842-1846.
8. Chou R, Carson S, Chan BK. Gabapentin versus tricyclic antidepressants for diabetic neuropathy and post-herpetic neuralgia: discrepancies between direct and indirect meta-analyses of randomized controlled trials. J Gen Intern Med. 2009;24:178-188.
9. Kaur H, Hota D, Bhansali A, et al. A comparative evaluation of amitriptyline and duloxetine in painful diabetic neuropathy: a randomized, double-blind, cross-over clinical trial. Diabetes Care. 2011;34:818-822.
10. Boulton AJ, Vinik AI, Arezzo JC. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005;28:956-962.
11. Argoff CE, Backonja MM, Belgrade MJ, et al. Consensus guidelines: treatment planning and options. Diabetic peripheral neuropathic pain. Mayo Clin Proc. 2006;81(suppl):S12-S25.
12. Bril V, England J, Franklin GM, et al. Evidence-based guideline. Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76:1758-1765.
TRICYCLIC ANTIDEPRESSANTS, duloxetine, pregabalin, oxycodone, and tramadol are all effective for the symptomatic treatment of painful diabetic neuropathy (strength of recommendation [SOR]: A, systematic reviews of randomized controlled trials [RCTs] and single RCTs).
Gabapentin is also effective (SOR: B, systematic review of RCTs with methodologic flaws). Studies directly comparing tricyclic antidepressants with gabapentin or duloxetine show equivalent efficacy (SOR: A, systematic reviews of RCTs and single RCTs).
The outcome evaluated in all of these studies was pain.
Evidence summary
A Cochrane review of antidepressants for neuropathic pain included 5 RCTs of tricyclic antidepressant use in patients with diabetic neuropathy. The strongest evidence of benefit was for the tricyclic antidepressants amitriptyline, imipramine, and nortriptyline1 (TABLE).
Another Cochrane review of 3 RCTs of duloxetine for treating painful diabetic neuropathy found moderately strong evidence that duloxetine 60 mg/d was more effective than placebo. A 120 mg daily dose didn’t result in significantly greater pain relief than 60 mg/d.2
TABLE
Meta-analyses of drug therapy vs placebo for diabetic neuropathic pain
| Drug and dose | Subjects (N) | Duration (wk) | Mean age (y) | Measured outcome | NNT (95% CI) | NNH (95% CI) |
|---|---|---|---|---|---|---|
| Various tricyclic antidepressants and doses1 | 177 | 3-12 | 50 | Overall effectiveness | 1.3 (1.2-1.5) | Treatment cessation: 28 (17.6-68.9) Minor adverse effects: 6 (4.2-10.7) |
| Duloxetine2 60 mg/d 120 mg/d | 655 655 | 12 | N/A | 50% pain reduction | 6.0 (5-10) 6.0 (5-10) | Treatment cessation: 17 (12-50) |
| Pregabalin 600 mg/d3 | 1425 | 5-13 | 59 | 50% pain reduction | 5 (4-6.6) | Somnolence: 8.8 (7-12)* Dizziness: 2.8 (2.5-3.2) Treatment cessation: 8.8 (6.8-12) |
| Gabapentin 1200-3600 mg/d4 | 829 | 4-12 | 58 | 50% pain reduction | 5.8 (4.3-9.0) | Any adverse effect: 6.6 (5.3-9.0)† Treatment cessation: 32 (19-100)‡ |
| Oxycodone 20-80 mg/d6 | 36 | 4 | 63 | Moderate pain relief (defined as a score of 3 on a 6-point scale) | 2.6 (N/A) | Nausea: 4 (2-219) Constipation: 4 (2-19) Treatment cessation: 7 (4-87) |
| CI, confidence interval; NA, not available; NNH, number needed to harm; NNT, number needed to treat. *Six studies of pregabalin (N=1351) reported rates of somnolence and treatment cessation, whereas only 3 studies (N=1122) reported rates of dizziness. †NNH calculated from 11 studies (N=2356) that included patients with other chronic pain diagnoses. ‡NNH calculated from 17 studies (N=3022) that included patients with other chronic pain diagnoses. | ||||||
Antiepileptics alleviate pain, but with some drawbacks
A Cochrane review of 7 RCTs of pregabalin for acute and chronic pain in adults concluded that 600 mg/d was more effective than placebo for relieving diabetic neuropathic pain. However, as many as 28% of patients discontinued treatment because of dizziness and somnolence. Lower doses—150 and 300 mg—resulted in fewer adverse effects, but less relief.3
A Cochrane review of 4 RCTs that compared gabapentin with placebo or active control found that gabapentin in daily doses >1200 mg provided pain relief superior to that of placebo.4 An independent evaluation of manufacturer-sponsored gabapentin trials reported significant methodologic flaws, including selective outcome reporting.5
Opioids also provide significant pain relief
A Cochrane review of studies of opioids for neuropathic pain identified 2 RCTs favoring oxycodone over placebo in patients with painful diabetic neuropathy. In the larger study (159 patients, mean age 59 years) subjects used a 0- to 10-point scale to evaluate pain intensity (0=none; 10=extreme). At 6 weeks, patients receiving oxycodone in doses of 10-120 mg/d had significantly lower pain scores than patients taking placebo (4.3±0.3 for oxycodone vs 5.3±0.3 for placebo; P=.002).6
An RCT that compared the benefit of tramadol at an average dose of 210 mg per day with placebo in 131 patients with diabetic neuropathy (mean age 59 years) found tramadol to be significantly better than placebo for treating pain. At 6 weeks, the mean pain scores on a scale of 0 (mild pain) to 4 (extreme pain) were 1.4±0.1 for tramadol vs 2.2±0.1 for placebo (P<.001).7
Amitriptyline, gabapentin, duloxetine show similar benefit in some studies
A meta-analysis of 2 RCTs (N=77) comparing amitriptyline (25-90 mg/d) with gabapentin (900-2400 mg/d) found no significant difference between the 2 drugs in relief of diabetic neuropathic pain (relative risk=0.99; 95% confidence interval, 0.69-1.38).8 A randomized, double-blind, crossover trial involving 58 patients with diabetic neuropathy compared duloxetine (20-60 mg/d) with amitriptyline (10-50 mg/d). After 6 weeks, 59% of patients on duloxetine and 55% of patients on amitriptyline achieved a ≥50% reduction in pain. The 4% difference between the groups was not statistically significant.9
Recommendations
The American Diabetes Association recommends tricyclic antidepressants as first-line agents, anticonvulsants as second-line treatment, and opioids as third-line therapy.10
The Diabetic Peripheral Neuropathic Pain Consensus Treatment Guidelines Advisory Boards recommend duloxetine, controlled-release oxycodone, pregabalin, and tricyclic antidepressants as first-tier agents and topical capsaicin and lidocaine as alternatives.11
The American Academy of Neurology advocates pregabalin as the first-choice treatment and states that venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, controlled-release oxycodone), and capsaicin are probably effective.12
TRICYCLIC ANTIDEPRESSANTS, duloxetine, pregabalin, oxycodone, and tramadol are all effective for the symptomatic treatment of painful diabetic neuropathy (strength of recommendation [SOR]: A, systematic reviews of randomized controlled trials [RCTs] and single RCTs).
Gabapentin is also effective (SOR: B, systematic review of RCTs with methodologic flaws). Studies directly comparing tricyclic antidepressants with gabapentin or duloxetine show equivalent efficacy (SOR: A, systematic reviews of RCTs and single RCTs).
The outcome evaluated in all of these studies was pain.
Evidence summary
A Cochrane review of antidepressants for neuropathic pain included 5 RCTs of tricyclic antidepressant use in patients with diabetic neuropathy. The strongest evidence of benefit was for the tricyclic antidepressants amitriptyline, imipramine, and nortriptyline1 (TABLE).
Another Cochrane review of 3 RCTs of duloxetine for treating painful diabetic neuropathy found moderately strong evidence that duloxetine 60 mg/d was more effective than placebo. A 120 mg daily dose didn’t result in significantly greater pain relief than 60 mg/d.2
TABLE
Meta-analyses of drug therapy vs placebo for diabetic neuropathic pain
| Drug and dose | Subjects (N) | Duration (wk) | Mean age (y) | Measured outcome | NNT (95% CI) | NNH (95% CI) |
|---|---|---|---|---|---|---|
| Various tricyclic antidepressants and doses1 | 177 | 3-12 | 50 | Overall effectiveness | 1.3 (1.2-1.5) | Treatment cessation: 28 (17.6-68.9) Minor adverse effects: 6 (4.2-10.7) |
| Duloxetine2 60 mg/d 120 mg/d | 655 655 | 12 | N/A | 50% pain reduction | 6.0 (5-10) 6.0 (5-10) | Treatment cessation: 17 (12-50) |
| Pregabalin 600 mg/d3 | 1425 | 5-13 | 59 | 50% pain reduction | 5 (4-6.6) | Somnolence: 8.8 (7-12)* Dizziness: 2.8 (2.5-3.2) Treatment cessation: 8.8 (6.8-12) |
| Gabapentin 1200-3600 mg/d4 | 829 | 4-12 | 58 | 50% pain reduction | 5.8 (4.3-9.0) | Any adverse effect: 6.6 (5.3-9.0)† Treatment cessation: 32 (19-100)‡ |
| Oxycodone 20-80 mg/d6 | 36 | 4 | 63 | Moderate pain relief (defined as a score of 3 on a 6-point scale) | 2.6 (N/A) | Nausea: 4 (2-219) Constipation: 4 (2-19) Treatment cessation: 7 (4-87) |
| CI, confidence interval; NA, not available; NNH, number needed to harm; NNT, number needed to treat. *Six studies of pregabalin (N=1351) reported rates of somnolence and treatment cessation, whereas only 3 studies (N=1122) reported rates of dizziness. †NNH calculated from 11 studies (N=2356) that included patients with other chronic pain diagnoses. ‡NNH calculated from 17 studies (N=3022) that included patients with other chronic pain diagnoses. | ||||||
Antiepileptics alleviate pain, but with some drawbacks
A Cochrane review of 7 RCTs of pregabalin for acute and chronic pain in adults concluded that 600 mg/d was more effective than placebo for relieving diabetic neuropathic pain. However, as many as 28% of patients discontinued treatment because of dizziness and somnolence. Lower doses—150 and 300 mg—resulted in fewer adverse effects, but less relief.3
A Cochrane review of 4 RCTs that compared gabapentin with placebo or active control found that gabapentin in daily doses >1200 mg provided pain relief superior to that of placebo.4 An independent evaluation of manufacturer-sponsored gabapentin trials reported significant methodologic flaws, including selective outcome reporting.5
Opioids also provide significant pain relief
A Cochrane review of studies of opioids for neuropathic pain identified 2 RCTs favoring oxycodone over placebo in patients with painful diabetic neuropathy. In the larger study (159 patients, mean age 59 years) subjects used a 0- to 10-point scale to evaluate pain intensity (0=none; 10=extreme). At 6 weeks, patients receiving oxycodone in doses of 10-120 mg/d had significantly lower pain scores than patients taking placebo (4.3±0.3 for oxycodone vs 5.3±0.3 for placebo; P=.002).6
An RCT that compared the benefit of tramadol at an average dose of 210 mg per day with placebo in 131 patients with diabetic neuropathy (mean age 59 years) found tramadol to be significantly better than placebo for treating pain. At 6 weeks, the mean pain scores on a scale of 0 (mild pain) to 4 (extreme pain) were 1.4±0.1 for tramadol vs 2.2±0.1 for placebo (P<.001).7
Amitriptyline, gabapentin, duloxetine show similar benefit in some studies
A meta-analysis of 2 RCTs (N=77) comparing amitriptyline (25-90 mg/d) with gabapentin (900-2400 mg/d) found no significant difference between the 2 drugs in relief of diabetic neuropathic pain (relative risk=0.99; 95% confidence interval, 0.69-1.38).8 A randomized, double-blind, crossover trial involving 58 patients with diabetic neuropathy compared duloxetine (20-60 mg/d) with amitriptyline (10-50 mg/d). After 6 weeks, 59% of patients on duloxetine and 55% of patients on amitriptyline achieved a ≥50% reduction in pain. The 4% difference between the groups was not statistically significant.9
Recommendations
The American Diabetes Association recommends tricyclic antidepressants as first-line agents, anticonvulsants as second-line treatment, and opioids as third-line therapy.10
The Diabetic Peripheral Neuropathic Pain Consensus Treatment Guidelines Advisory Boards recommend duloxetine, controlled-release oxycodone, pregabalin, and tricyclic antidepressants as first-tier agents and topical capsaicin and lidocaine as alternatives.11
The American Academy of Neurology advocates pregabalin as the first-choice treatment and states that venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulfate, tramadol, controlled-release oxycodone), and capsaicin are probably effective.12
1. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007;(4):CD005454.-
2. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy or chronic pain. Cochrane Database Syst Rev. 2009;(4):CD007115.-
3. Moore RA, Straube S, Wiffen PJ, et al. Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev. 2009;(3):CD007076.-
4. Moore RA, Wiffen PJ, Derry S, et al. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2011;(3):CD007938.-
5. Vedula SS, Bero L, Scherer RW, et al. Outcome reporting in industry-sponsored trials of gabapentin for off-label use. N Engl J Med. 2009;361:1963-1971.
6. Eisenberg E, McNicol ED, Carr DB. Opioids for neuropathic pain. Cochrane Database Syst Rev. 2006;(3):CD006146.-
7. Harati Y, Gooch C, Swenson M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology. 1998;50:1842-1846.
8. Chou R, Carson S, Chan BK. Gabapentin versus tricyclic antidepressants for diabetic neuropathy and post-herpetic neuralgia: discrepancies between direct and indirect meta-analyses of randomized controlled trials. J Gen Intern Med. 2009;24:178-188.
9. Kaur H, Hota D, Bhansali A, et al. A comparative evaluation of amitriptyline and duloxetine in painful diabetic neuropathy: a randomized, double-blind, cross-over clinical trial. Diabetes Care. 2011;34:818-822.
10. Boulton AJ, Vinik AI, Arezzo JC. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005;28:956-962.
11. Argoff CE, Backonja MM, Belgrade MJ, et al. Consensus guidelines: treatment planning and options. Diabetic peripheral neuropathic pain. Mayo Clin Proc. 2006;81(suppl):S12-S25.
12. Bril V, England J, Franklin GM, et al. Evidence-based guideline. Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76:1758-1765.
1. Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. Cochrane Database Syst Rev. 2007;(4):CD005454.-
2. Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy or chronic pain. Cochrane Database Syst Rev. 2009;(4):CD007115.-
3. Moore RA, Straube S, Wiffen PJ, et al. Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev. 2009;(3):CD007076.-
4. Moore RA, Wiffen PJ, Derry S, et al. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev. 2011;(3):CD007938.-
5. Vedula SS, Bero L, Scherer RW, et al. Outcome reporting in industry-sponsored trials of gabapentin for off-label use. N Engl J Med. 2009;361:1963-1971.
6. Eisenberg E, McNicol ED, Carr DB. Opioids for neuropathic pain. Cochrane Database Syst Rev. 2006;(3):CD006146.-
7. Harati Y, Gooch C, Swenson M, et al. Double-blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology. 1998;50:1842-1846.
8. Chou R, Carson S, Chan BK. Gabapentin versus tricyclic antidepressants for diabetic neuropathy and post-herpetic neuralgia: discrepancies between direct and indirect meta-analyses of randomized controlled trials. J Gen Intern Med. 2009;24:178-188.
9. Kaur H, Hota D, Bhansali A, et al. A comparative evaluation of amitriptyline and duloxetine in painful diabetic neuropathy: a randomized, double-blind, cross-over clinical trial. Diabetes Care. 2011;34:818-822.
10. Boulton AJ, Vinik AI, Arezzo JC. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005;28:956-962.
11. Argoff CE, Backonja MM, Belgrade MJ, et al. Consensus guidelines: treatment planning and options. Diabetic peripheral neuropathic pain. Mayo Clin Proc. 2006;81(suppl):S12-S25.
12. Bril V, England J, Franklin GM, et al. Evidence-based guideline. Treatment of painful diabetic neuropathy: report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine and the American Academy of Physical Medicine and Rehabilitation. Neurology. 2011;76:1758-1765.
Evidence-based answers from the Family Physicians Inquiries Network
What risk factors contribute to C difficile diarrhea?
CERTAIN ANTIBIOTICS AND USING 3 OR MORE ANTIBIOTICS AT ONE TIME are associated with Clostridium difficile-associated diarrhea (CDAD) (strength of recommendation [SOR]: B, 1 heterogeneous systematic review and several good-quality cohort studies).
Hospital risk factors include proximity to other patients with C difficile and longer length of stay (SOR: B, several good-quality cohort studies).
Patient risk factors include advanced age and comorbid conditions (SOR: B, several good-quality cohort studies).
Acid suppression medication is also a risk factor for CDAD (SOR: B, 1 heterogeneous systematic review and 2 good-quality cohort studies).
Evidence summary
One systematic review found increased risk of CDAD in patients taking cephalosporins, penicillin, or clindamycin (TABLE 1).1 A subsequent retrospective cohort investigation of 5619 patients during a CDAD epidemic in Quebec, Canada reported that quinolone antibiotics were most strongly associated with CDAD, whereas other antibiotics posed an intermediate risk.2
A prospective cohort study of 101,796 admissions over a 5-year period at a tertiary medical center defined a group of high-risk antibiotics before starting research.3 They included fluoroquinolones, cephalosporins, intravenous β-lactam/β-lactamase inhibitors, macrolides, clindamycin, and carbapenems. All other antibiotics were considered low risk. High-risk antibiotics were associated with a 3-fold increase in CDAD compared with low-risk drugs (odds ratio [OR]=3.37; 95% confidence interval [CI], 2.64-4.31); number needed to harm [NNH]= 10).3
TABLE 1
Medications associated with C difficile diarrhea
| Medication | Reported ratio* (95% CI) | NNH† |
|---|---|---|
| Antibiotics | ||
| β-Lactam/β-lactamase inhibitor, intraveneous2 | aHR=1.88 (1.35-2.63) | 25 |
| Cephalosporins1 | RR=2.07 (1.06-6.62) | 21 |
| Cephalosporins, first generation2 | aHR=1.78 (1.28-2.46) | 28 |
| Cephalosporins, second generation2 | aHR=1.89 (1.45-2.46) | 25 |
| Cephalosporins, third generation2 | aHR=1.56 (1.15-2.12) | 39 |
| Clindamycin1 | OR=4.22 (2.11-8.45) | 8 |
| Clindamycin2 | aHR=1.77 (1.06-2.96) | 28 |
| Macrolides2 | aHR=1.65 (1.15-2.39) | 33 |
| Penicillins1 | RR=3.62 (1.28-8.42) | 9 |
| Quinolones2 | aHR=3.44 (2.65-4.47) | 10 |
| Acid suppression medication | ||
| Histamine2-receptor antagonist3 | aOR=1.53 (1.12-2.10) | 41 |
| Proton-pump inhibitor daily3 | aOR=1.74 (1.29-2.18) | 30 |
| Proton-pump inhibitor more often than daily3 | aOR=2.36 (1.79-3.11) | 17 |
| aHR, adjusted hazard ratio; aOR, adjusted odds ratio; CI, confidence interval; NNH, number needed to harm; OR, odds ratio; RR, risk ratio. *Because the incidence of C difficile diarrhea is low, each reported adjusted hazard ratio or risk ratio is approximately equal to the odds ratio used to calculate number needed to harm. †Assuming an event rate of 5%. | ||
The number of antibiotics is a factor
The number of antibiotics used also may influence the risk of CDAD. A retrospective cohort of 2859 patients from a community hospital found that an increased number of antibiotics was a risk factor for CDAD (OR=1.49; 95% CI, 1.23-1.81; NNH=44).4 Another retrospective cohort study of 1187 inpatients at a Montreal hospital found 3 or more antibiotics increased the risk (adjusted OR=2.1; 95% CI, 1.3-3.4; NNH=20).5
Hospital risks: Proximity to an infected patient, length of stay
A prospective cohort of 252 patients and a retrospective cohort of 1187 patients show that recent hospitalization puts patients at risk for CDAD (TABLE 2).5,6 Several retrospective cohort studies have shown that patients in close proximity to a C difficile-positive patient in the hospital (roommate, neighbor, or subsequent tenant) are at risk for CDAD.4,7
Length of hospitalization is also a risk factor.2 A retrospective cohort study of 2859 patients found that patients with CDAD had spent more time in the hospital—a mean of 19 days compared with 8 days for patients without diarrhea (P<.001).4 A prospective cohort study of 101,796 admissions reported that the mean length of stay was 15 days (range=8.0-26.0) for CDAD patients compared with 5 days (range=3.0-8.0) for patients without CDAD (P<.001).3
TABLE 2
Hospital risk factors for C difficile diarrhea
| Hospital factor | Reported ratio* (95% CI) | NNH† |
|---|---|---|
| Length of stay 4-7 vs 1-3 days2 | HR=4.69 (2.14-10.28) | 6 |
| Length of stay 8-14 vs 1-3 days2 | HR=5.11 (2.34-11.18) | 6 |
| Length of stay >15 vs 1-3 days2 | HR=3.55 (1.53-7.24) | 10 |
| Any proximity to CDAD-positive patients4 | RR=3.34 (2.00-5.57) | 10 |
| Admission within previous 3 months5 | OR=3.0 (1.5-6.0) | 11 |
| Admission within previous 30 days6 | OR= 2.6 (1.13-5.7) | 14 |
| CDAD-positive patient in adjacent bed7 | OR=2.34 (1.56-3.51) | 17 |
| Occupying bed of previous CDAD-positive patient7 | OR-2.33 (1.54-3.52) | 17 |
| CDAD, Clostridium difficile-associated diarrhea; CI, confidence interval; HR, hazard ratio; NNH, number needed to harm; OR, odds ratio; RR, relative risk. *Because the incidence of C difficile diarrhea is low, each reported hazard ratio or risk ratio is approximately equal to the odds ratio, which was used to calculate number needed to harm. †Assuming an event rate of 5%. | ||
Patient risk factors: Age and comorbid disease
Two cohort studies found that CDAD patients were about 10 years older than patients without CDAD.3,8 Among 535 patients in Jerusalem, patients positive for C difficile toxin had a mean age of 76±20 years compared with 66±26 years in toxin-negative patients (P<.001).8 In the previously mentioned study of 101,796 patients, the average age for patients with CDAD was 65.4±16.9 years compared with 56.5±19.9 years for patients without CDAD (P<.001).3
The patients in this study also showed significant associations between CDAD and comorbid conditions, including myocardial infarction, heart failure, chronic pulmonary disease, peripheral vascular disease, complicated diabetes, fluid and electrolyte disorders, chronic renal failure, cancer, coagulopathy, and methicillin-resistant Staphylococcus aureus infection.3
Acid suppression therapy is another risk
A systematic review that included a total of 2948 patients in 12 studies (cross-sectional, case-control, and cohort) evaluated acid suppression therapy and found an association between CDAD and use of histamine2-receptor antagonists (H2RAs) (OR=1.48; 95% CI, 1.06-2.06; NNH=45) and between CDAD and proton-pump inhibitors (PPIs) (OR=2.05; 95% CI, 1.47-2.85; NNH=21).9 Significant heterogeneity among the studies limited the interpretation of results, however.
The prospective cohort study of 101,796 patients also reported an increased risk of CDAD with H2RAs and PPIs.3 The risk of CDAD rose with progression from no acid suppression to H2RA use to daily PPI use to more frequent PPI use.3 Another cohort study of 1187 patients found an association between PPIs and CDAD (adjusted OR=2.1; 95% CI, 1.2-3.5).5
Using a score to gauge risk
Researchers studying a cohort of 54,226 patients developed a risk score using clinical characteristics associated with CDAD.10 The patients were older than 18 years, hospitalized longer than 48 hours, and had received broad spectrum antibiotics (intravenous glycopeptides, fluoroquinolones, penicillins, cephalosporins, or carbapenems). When the researchers tested their clinical risk index on a validation cohort of 13,002 patients, they found that increasing scores were significantly associated with increasing risk for C difficile colitis (OR=3.31; 95% CI, 2.61-4.91; area under the receiver operating characteristic curve=0.712).10
Recommendations
Clinical practice guidelines by the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America recommend minimizing the frequency and duration of antibiotics and the total number of antibiotics used.11 They also suggest private rooms, chlorine cleaning products, and contact precautions (gloves, hand hygiene, and disposable thermometers) to reduce risk.
The authors of the guidelines propose antimicrobial stewardship programs based on the local epidemiology of C difficile strains, including restricted use of cephalosporins and clindamycin, except for surgical prophylaxis.
1. Thomas C, Stevenson M, Riley TV. Antibiotics and hospital-acquired Clostridium difficile-associated diarrhea: a systematic review. J Antimicrob Chemother. 2003;51:1339-1350.
2. Pepin J, Saheb N, Coulombe M, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associate diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis. 2005;41:1254-1260.
3. Howell MD, Novack V, Grgurich P, et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med. 2010;170:784-790.
4. Chang VT, Nelson K. The role of physical proximity in nosocomial diarrhea. Clin Infect Dis. 2000;31:717-722.
5. Dial S, Alrsadi K, Manoukian C, et al. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ. 2004;171:33-38.
6. Kyne L, Sougioultzis S, McFarland LV, et al. Underlying disease severity as a major risk factor for nosocomial Clostridium difficile diarrhea. Infect Control Hosp Epidemiol. 2002;23:653-659.
7. Howitt JR, Grace JW, Schaefer MG, et al. Clostridium difficile-positive stools: a retrospective identification of risk factors. Am J Infect Control. 2008;36:488-491.
8. Raveh D, Rabinowitz B, Breuer GS, et al. Risk factors for Clostridium difficile toxin-positive nosocomial diarrhea. Int J Antimicrob Agents. 2006;28:231-237.
9. Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk of enteric infection in patients taking acid suppression. Am J Gastroenterol. 2007;102:2047-2056.
10. Garey KW, Dao-Tran TK, Jiang ZD, et al. A clinical risk index for Clostridium difficile infection in hospitalized patients receiving broad-spectrum antibiotics. J Hosp Infect. 2008;70:142-147.
11. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31:431-455.
CERTAIN ANTIBIOTICS AND USING 3 OR MORE ANTIBIOTICS AT ONE TIME are associated with Clostridium difficile-associated diarrhea (CDAD) (strength of recommendation [SOR]: B, 1 heterogeneous systematic review and several good-quality cohort studies).
Hospital risk factors include proximity to other patients with C difficile and longer length of stay (SOR: B, several good-quality cohort studies).
Patient risk factors include advanced age and comorbid conditions (SOR: B, several good-quality cohort studies).
Acid suppression medication is also a risk factor for CDAD (SOR: B, 1 heterogeneous systematic review and 2 good-quality cohort studies).
Evidence summary
One systematic review found increased risk of CDAD in patients taking cephalosporins, penicillin, or clindamycin (TABLE 1).1 A subsequent retrospective cohort investigation of 5619 patients during a CDAD epidemic in Quebec, Canada reported that quinolone antibiotics were most strongly associated with CDAD, whereas other antibiotics posed an intermediate risk.2
A prospective cohort study of 101,796 admissions over a 5-year period at a tertiary medical center defined a group of high-risk antibiotics before starting research.3 They included fluoroquinolones, cephalosporins, intravenous β-lactam/β-lactamase inhibitors, macrolides, clindamycin, and carbapenems. All other antibiotics were considered low risk. High-risk antibiotics were associated with a 3-fold increase in CDAD compared with low-risk drugs (odds ratio [OR]=3.37; 95% confidence interval [CI], 2.64-4.31); number needed to harm [NNH]= 10).3
TABLE 1
Medications associated with C difficile diarrhea
| Medication | Reported ratio* (95% CI) | NNH† |
|---|---|---|
| Antibiotics | ||
| β-Lactam/β-lactamase inhibitor, intraveneous2 | aHR=1.88 (1.35-2.63) | 25 |
| Cephalosporins1 | RR=2.07 (1.06-6.62) | 21 |
| Cephalosporins, first generation2 | aHR=1.78 (1.28-2.46) | 28 |
| Cephalosporins, second generation2 | aHR=1.89 (1.45-2.46) | 25 |
| Cephalosporins, third generation2 | aHR=1.56 (1.15-2.12) | 39 |
| Clindamycin1 | OR=4.22 (2.11-8.45) | 8 |
| Clindamycin2 | aHR=1.77 (1.06-2.96) | 28 |
| Macrolides2 | aHR=1.65 (1.15-2.39) | 33 |
| Penicillins1 | RR=3.62 (1.28-8.42) | 9 |
| Quinolones2 | aHR=3.44 (2.65-4.47) | 10 |
| Acid suppression medication | ||
| Histamine2-receptor antagonist3 | aOR=1.53 (1.12-2.10) | 41 |
| Proton-pump inhibitor daily3 | aOR=1.74 (1.29-2.18) | 30 |
| Proton-pump inhibitor more often than daily3 | aOR=2.36 (1.79-3.11) | 17 |
| aHR, adjusted hazard ratio; aOR, adjusted odds ratio; CI, confidence interval; NNH, number needed to harm; OR, odds ratio; RR, risk ratio. *Because the incidence of C difficile diarrhea is low, each reported adjusted hazard ratio or risk ratio is approximately equal to the odds ratio used to calculate number needed to harm. †Assuming an event rate of 5%. | ||
The number of antibiotics is a factor
The number of antibiotics used also may influence the risk of CDAD. A retrospective cohort of 2859 patients from a community hospital found that an increased number of antibiotics was a risk factor for CDAD (OR=1.49; 95% CI, 1.23-1.81; NNH=44).4 Another retrospective cohort study of 1187 inpatients at a Montreal hospital found 3 or more antibiotics increased the risk (adjusted OR=2.1; 95% CI, 1.3-3.4; NNH=20).5
Hospital risks: Proximity to an infected patient, length of stay
A prospective cohort of 252 patients and a retrospective cohort of 1187 patients show that recent hospitalization puts patients at risk for CDAD (TABLE 2).5,6 Several retrospective cohort studies have shown that patients in close proximity to a C difficile-positive patient in the hospital (roommate, neighbor, or subsequent tenant) are at risk for CDAD.4,7
Length of hospitalization is also a risk factor.2 A retrospective cohort study of 2859 patients found that patients with CDAD had spent more time in the hospital—a mean of 19 days compared with 8 days for patients without diarrhea (P<.001).4 A prospective cohort study of 101,796 admissions reported that the mean length of stay was 15 days (range=8.0-26.0) for CDAD patients compared with 5 days (range=3.0-8.0) for patients without CDAD (P<.001).3
TABLE 2
Hospital risk factors for C difficile diarrhea
| Hospital factor | Reported ratio* (95% CI) | NNH† |
|---|---|---|
| Length of stay 4-7 vs 1-3 days2 | HR=4.69 (2.14-10.28) | 6 |
| Length of stay 8-14 vs 1-3 days2 | HR=5.11 (2.34-11.18) | 6 |
| Length of stay >15 vs 1-3 days2 | HR=3.55 (1.53-7.24) | 10 |
| Any proximity to CDAD-positive patients4 | RR=3.34 (2.00-5.57) | 10 |
| Admission within previous 3 months5 | OR=3.0 (1.5-6.0) | 11 |
| Admission within previous 30 days6 | OR= 2.6 (1.13-5.7) | 14 |
| CDAD-positive patient in adjacent bed7 | OR=2.34 (1.56-3.51) | 17 |
| Occupying bed of previous CDAD-positive patient7 | OR-2.33 (1.54-3.52) | 17 |
| CDAD, Clostridium difficile-associated diarrhea; CI, confidence interval; HR, hazard ratio; NNH, number needed to harm; OR, odds ratio; RR, relative risk. *Because the incidence of C difficile diarrhea is low, each reported hazard ratio or risk ratio is approximately equal to the odds ratio, which was used to calculate number needed to harm. †Assuming an event rate of 5%. | ||
Patient risk factors: Age and comorbid disease
Two cohort studies found that CDAD patients were about 10 years older than patients without CDAD.3,8 Among 535 patients in Jerusalem, patients positive for C difficile toxin had a mean age of 76±20 years compared with 66±26 years in toxin-negative patients (P<.001).8 In the previously mentioned study of 101,796 patients, the average age for patients with CDAD was 65.4±16.9 years compared with 56.5±19.9 years for patients without CDAD (P<.001).3
The patients in this study also showed significant associations between CDAD and comorbid conditions, including myocardial infarction, heart failure, chronic pulmonary disease, peripheral vascular disease, complicated diabetes, fluid and electrolyte disorders, chronic renal failure, cancer, coagulopathy, and methicillin-resistant Staphylococcus aureus infection.3
Acid suppression therapy is another risk
A systematic review that included a total of 2948 patients in 12 studies (cross-sectional, case-control, and cohort) evaluated acid suppression therapy and found an association between CDAD and use of histamine2-receptor antagonists (H2RAs) (OR=1.48; 95% CI, 1.06-2.06; NNH=45) and between CDAD and proton-pump inhibitors (PPIs) (OR=2.05; 95% CI, 1.47-2.85; NNH=21).9 Significant heterogeneity among the studies limited the interpretation of results, however.
The prospective cohort study of 101,796 patients also reported an increased risk of CDAD with H2RAs and PPIs.3 The risk of CDAD rose with progression from no acid suppression to H2RA use to daily PPI use to more frequent PPI use.3 Another cohort study of 1187 patients found an association between PPIs and CDAD (adjusted OR=2.1; 95% CI, 1.2-3.5).5
Using a score to gauge risk
Researchers studying a cohort of 54,226 patients developed a risk score using clinical characteristics associated with CDAD.10 The patients were older than 18 years, hospitalized longer than 48 hours, and had received broad spectrum antibiotics (intravenous glycopeptides, fluoroquinolones, penicillins, cephalosporins, or carbapenems). When the researchers tested their clinical risk index on a validation cohort of 13,002 patients, they found that increasing scores were significantly associated with increasing risk for C difficile colitis (OR=3.31; 95% CI, 2.61-4.91; area under the receiver operating characteristic curve=0.712).10
Recommendations
Clinical practice guidelines by the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America recommend minimizing the frequency and duration of antibiotics and the total number of antibiotics used.11 They also suggest private rooms, chlorine cleaning products, and contact precautions (gloves, hand hygiene, and disposable thermometers) to reduce risk.
The authors of the guidelines propose antimicrobial stewardship programs based on the local epidemiology of C difficile strains, including restricted use of cephalosporins and clindamycin, except for surgical prophylaxis.
CERTAIN ANTIBIOTICS AND USING 3 OR MORE ANTIBIOTICS AT ONE TIME are associated with Clostridium difficile-associated diarrhea (CDAD) (strength of recommendation [SOR]: B, 1 heterogeneous systematic review and several good-quality cohort studies).
Hospital risk factors include proximity to other patients with C difficile and longer length of stay (SOR: B, several good-quality cohort studies).
Patient risk factors include advanced age and comorbid conditions (SOR: B, several good-quality cohort studies).
Acid suppression medication is also a risk factor for CDAD (SOR: B, 1 heterogeneous systematic review and 2 good-quality cohort studies).
Evidence summary
One systematic review found increased risk of CDAD in patients taking cephalosporins, penicillin, or clindamycin (TABLE 1).1 A subsequent retrospective cohort investigation of 5619 patients during a CDAD epidemic in Quebec, Canada reported that quinolone antibiotics were most strongly associated with CDAD, whereas other antibiotics posed an intermediate risk.2
A prospective cohort study of 101,796 admissions over a 5-year period at a tertiary medical center defined a group of high-risk antibiotics before starting research.3 They included fluoroquinolones, cephalosporins, intravenous β-lactam/β-lactamase inhibitors, macrolides, clindamycin, and carbapenems. All other antibiotics were considered low risk. High-risk antibiotics were associated with a 3-fold increase in CDAD compared with low-risk drugs (odds ratio [OR]=3.37; 95% confidence interval [CI], 2.64-4.31); number needed to harm [NNH]= 10).3
TABLE 1
Medications associated with C difficile diarrhea
| Medication | Reported ratio* (95% CI) | NNH† |
|---|---|---|
| Antibiotics | ||
| β-Lactam/β-lactamase inhibitor, intraveneous2 | aHR=1.88 (1.35-2.63) | 25 |
| Cephalosporins1 | RR=2.07 (1.06-6.62) | 21 |
| Cephalosporins, first generation2 | aHR=1.78 (1.28-2.46) | 28 |
| Cephalosporins, second generation2 | aHR=1.89 (1.45-2.46) | 25 |
| Cephalosporins, third generation2 | aHR=1.56 (1.15-2.12) | 39 |
| Clindamycin1 | OR=4.22 (2.11-8.45) | 8 |
| Clindamycin2 | aHR=1.77 (1.06-2.96) | 28 |
| Macrolides2 | aHR=1.65 (1.15-2.39) | 33 |
| Penicillins1 | RR=3.62 (1.28-8.42) | 9 |
| Quinolones2 | aHR=3.44 (2.65-4.47) | 10 |
| Acid suppression medication | ||
| Histamine2-receptor antagonist3 | aOR=1.53 (1.12-2.10) | 41 |
| Proton-pump inhibitor daily3 | aOR=1.74 (1.29-2.18) | 30 |
| Proton-pump inhibitor more often than daily3 | aOR=2.36 (1.79-3.11) | 17 |
| aHR, adjusted hazard ratio; aOR, adjusted odds ratio; CI, confidence interval; NNH, number needed to harm; OR, odds ratio; RR, risk ratio. *Because the incidence of C difficile diarrhea is low, each reported adjusted hazard ratio or risk ratio is approximately equal to the odds ratio used to calculate number needed to harm. †Assuming an event rate of 5%. | ||
The number of antibiotics is a factor
The number of antibiotics used also may influence the risk of CDAD. A retrospective cohort of 2859 patients from a community hospital found that an increased number of antibiotics was a risk factor for CDAD (OR=1.49; 95% CI, 1.23-1.81; NNH=44).4 Another retrospective cohort study of 1187 inpatients at a Montreal hospital found 3 or more antibiotics increased the risk (adjusted OR=2.1; 95% CI, 1.3-3.4; NNH=20).5
Hospital risks: Proximity to an infected patient, length of stay
A prospective cohort of 252 patients and a retrospective cohort of 1187 patients show that recent hospitalization puts patients at risk for CDAD (TABLE 2).5,6 Several retrospective cohort studies have shown that patients in close proximity to a C difficile-positive patient in the hospital (roommate, neighbor, or subsequent tenant) are at risk for CDAD.4,7
Length of hospitalization is also a risk factor.2 A retrospective cohort study of 2859 patients found that patients with CDAD had spent more time in the hospital—a mean of 19 days compared with 8 days for patients without diarrhea (P<.001).4 A prospective cohort study of 101,796 admissions reported that the mean length of stay was 15 days (range=8.0-26.0) for CDAD patients compared with 5 days (range=3.0-8.0) for patients without CDAD (P<.001).3
TABLE 2
Hospital risk factors for C difficile diarrhea
| Hospital factor | Reported ratio* (95% CI) | NNH† |
|---|---|---|
| Length of stay 4-7 vs 1-3 days2 | HR=4.69 (2.14-10.28) | 6 |
| Length of stay 8-14 vs 1-3 days2 | HR=5.11 (2.34-11.18) | 6 |
| Length of stay >15 vs 1-3 days2 | HR=3.55 (1.53-7.24) | 10 |
| Any proximity to CDAD-positive patients4 | RR=3.34 (2.00-5.57) | 10 |
| Admission within previous 3 months5 | OR=3.0 (1.5-6.0) | 11 |
| Admission within previous 30 days6 | OR= 2.6 (1.13-5.7) | 14 |
| CDAD-positive patient in adjacent bed7 | OR=2.34 (1.56-3.51) | 17 |
| Occupying bed of previous CDAD-positive patient7 | OR-2.33 (1.54-3.52) | 17 |
| CDAD, Clostridium difficile-associated diarrhea; CI, confidence interval; HR, hazard ratio; NNH, number needed to harm; OR, odds ratio; RR, relative risk. *Because the incidence of C difficile diarrhea is low, each reported hazard ratio or risk ratio is approximately equal to the odds ratio, which was used to calculate number needed to harm. †Assuming an event rate of 5%. | ||
Patient risk factors: Age and comorbid disease
Two cohort studies found that CDAD patients were about 10 years older than patients without CDAD.3,8 Among 535 patients in Jerusalem, patients positive for C difficile toxin had a mean age of 76±20 years compared with 66±26 years in toxin-negative patients (P<.001).8 In the previously mentioned study of 101,796 patients, the average age for patients with CDAD was 65.4±16.9 years compared with 56.5±19.9 years for patients without CDAD (P<.001).3
The patients in this study also showed significant associations between CDAD and comorbid conditions, including myocardial infarction, heart failure, chronic pulmonary disease, peripheral vascular disease, complicated diabetes, fluid and electrolyte disorders, chronic renal failure, cancer, coagulopathy, and methicillin-resistant Staphylococcus aureus infection.3
Acid suppression therapy is another risk
A systematic review that included a total of 2948 patients in 12 studies (cross-sectional, case-control, and cohort) evaluated acid suppression therapy and found an association between CDAD and use of histamine2-receptor antagonists (H2RAs) (OR=1.48; 95% CI, 1.06-2.06; NNH=45) and between CDAD and proton-pump inhibitors (PPIs) (OR=2.05; 95% CI, 1.47-2.85; NNH=21).9 Significant heterogeneity among the studies limited the interpretation of results, however.
The prospective cohort study of 101,796 patients also reported an increased risk of CDAD with H2RAs and PPIs.3 The risk of CDAD rose with progression from no acid suppression to H2RA use to daily PPI use to more frequent PPI use.3 Another cohort study of 1187 patients found an association between PPIs and CDAD (adjusted OR=2.1; 95% CI, 1.2-3.5).5
Using a score to gauge risk
Researchers studying a cohort of 54,226 patients developed a risk score using clinical characteristics associated with CDAD.10 The patients were older than 18 years, hospitalized longer than 48 hours, and had received broad spectrum antibiotics (intravenous glycopeptides, fluoroquinolones, penicillins, cephalosporins, or carbapenems). When the researchers tested their clinical risk index on a validation cohort of 13,002 patients, they found that increasing scores were significantly associated with increasing risk for C difficile colitis (OR=3.31; 95% CI, 2.61-4.91; area under the receiver operating characteristic curve=0.712).10
Recommendations
Clinical practice guidelines by the Society for Healthcare Epidemiology of America and the Infectious Diseases Society of America recommend minimizing the frequency and duration of antibiotics and the total number of antibiotics used.11 They also suggest private rooms, chlorine cleaning products, and contact precautions (gloves, hand hygiene, and disposable thermometers) to reduce risk.
The authors of the guidelines propose antimicrobial stewardship programs based on the local epidemiology of C difficile strains, including restricted use of cephalosporins and clindamycin, except for surgical prophylaxis.
1. Thomas C, Stevenson M, Riley TV. Antibiotics and hospital-acquired Clostridium difficile-associated diarrhea: a systematic review. J Antimicrob Chemother. 2003;51:1339-1350.
2. Pepin J, Saheb N, Coulombe M, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associate diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis. 2005;41:1254-1260.
3. Howell MD, Novack V, Grgurich P, et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med. 2010;170:784-790.
4. Chang VT, Nelson K. The role of physical proximity in nosocomial diarrhea. Clin Infect Dis. 2000;31:717-722.
5. Dial S, Alrsadi K, Manoukian C, et al. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ. 2004;171:33-38.
6. Kyne L, Sougioultzis S, McFarland LV, et al. Underlying disease severity as a major risk factor for nosocomial Clostridium difficile diarrhea. Infect Control Hosp Epidemiol. 2002;23:653-659.
7. Howitt JR, Grace JW, Schaefer MG, et al. Clostridium difficile-positive stools: a retrospective identification of risk factors. Am J Infect Control. 2008;36:488-491.
8. Raveh D, Rabinowitz B, Breuer GS, et al. Risk factors for Clostridium difficile toxin-positive nosocomial diarrhea. Int J Antimicrob Agents. 2006;28:231-237.
9. Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk of enteric infection in patients taking acid suppression. Am J Gastroenterol. 2007;102:2047-2056.
10. Garey KW, Dao-Tran TK, Jiang ZD, et al. A clinical risk index for Clostridium difficile infection in hospitalized patients receiving broad-spectrum antibiotics. J Hosp Infect. 2008;70:142-147.
11. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31:431-455.
1. Thomas C, Stevenson M, Riley TV. Antibiotics and hospital-acquired Clostridium difficile-associated diarrhea: a systematic review. J Antimicrob Chemother. 2003;51:1339-1350.
2. Pepin J, Saheb N, Coulombe M, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile-associate diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis. 2005;41:1254-1260.
3. Howell MD, Novack V, Grgurich P, et al. Iatrogenic gastric acid suppression and the risk of nosocomial Clostridium difficile infection. Arch Intern Med. 2010;170:784-790.
4. Chang VT, Nelson K. The role of physical proximity in nosocomial diarrhea. Clin Infect Dis. 2000;31:717-722.
5. Dial S, Alrsadi K, Manoukian C, et al. Risk of Clostridium difficile diarrhea among hospital inpatients prescribed proton pump inhibitors: cohort and case-control studies. CMAJ. 2004;171:33-38.
6. Kyne L, Sougioultzis S, McFarland LV, et al. Underlying disease severity as a major risk factor for nosocomial Clostridium difficile diarrhea. Infect Control Hosp Epidemiol. 2002;23:653-659.
7. Howitt JR, Grace JW, Schaefer MG, et al. Clostridium difficile-positive stools: a retrospective identification of risk factors. Am J Infect Control. 2008;36:488-491.
8. Raveh D, Rabinowitz B, Breuer GS, et al. Risk factors for Clostridium difficile toxin-positive nosocomial diarrhea. Int J Antimicrob Agents. 2006;28:231-237.
9. Leonard J, Marshall JK, Moayyedi P. Systematic review of the risk of enteric infection in patients taking acid suppression. Am J Gastroenterol. 2007;102:2047-2056.
10. Garey KW, Dao-Tran TK, Jiang ZD, et al. A clinical risk index for Clostridium difficile infection in hospitalized patients receiving broad-spectrum antibiotics. J Hosp Infect. 2008;70:142-147.
11. Cohen SH, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31:431-455.
Evidence-based answers from the Family Physicians Inquiries Network
What is the role of prokinetic agents for constipation?
Erythromycin has a limited role in treating pediatric patients (strength of recommendation [SOR]: B, limited-quality, patient-oriented evidence). Tegaserod and cisapride are the only prokinetic agents available for constipated adults (SOR: A, consistent, good-quality, patient-oriented evidence for tegaserod; SOR: B, for cisapride), but cardiovascular risk restricts prescribing of both medications.
Evidence summary
Prokinetic agents promote transit of intestinal contents by increasing the frequency or strength of small intestine contractions. Available prokinetics include erythromycin and metoclopramide. Metoclopramide has been tested only for upper gastrointestinal mobility. The only randomized controlled trials (RCTs) of erythromycin for constipation have been conducted in children. Cisapride and tegaserod have been withdrawn from general use because of adverse side effects. The TABLE summarizes the available data.
TABLE
Prokinetics for constipation: What the research tells us
| DRUG | DESIGN (N) | DOSE | OUTCOME | NNT |
|---|---|---|---|---|
| Erythromycin estolate1 | Crossover children (14) | 20 mg/kg/day divided qid | †Constipation and laxative use | 10 |
| Cisapride5 | RCT adults (69) | 5-10 mg tid | ü Spontaneous BM † Abdominal pain | 4 |
| Cisapride6 | RCT adults (82) | 5-10 mg tid | Abdominal pain and constipation, drug=placebo | N/A |
| Tegaserod7 | RCT adults (1348) | 2 mg or 6 mg bid | † Constipation ü Spontaneous BM | 6 (2 mg) 5 (6 mg) |
| Tegaserod8 | RCT adults (1264) | 2 mg or 6 mg bid | † Constipation and abdominal pain | 11 (2 mg) 7 (6 mg) |
| Renzapride11 | Pilot study adults (17) | Escalating dose: 2 mg daily to 2 mg bid | † Abdominal pain and bloating | Not enough information to calculate |
| Renzapride12 | Parallel group adults (48) | 1, 2, or 4 mg daily | ü Colonic transit; stool form and ease of passage, drug=placebo | N/A |
| BM, bowel movement; N/A, not available; NNT, number needed to treat; RCT, randomized controlled trial. | ||||
Pediatric constipation: Erythromycin helps; watch dosage
A small RCT of 14 children between 4 and 13 years of age showed that erythromycin improved symptoms of constipation and decreased laxative use (number needed to treat [NNT]=10).1 Two RCTs in neonates demonstrated that erythromycin shortened intestinal transit time and improved feeding tolerance.2,3
The erythromycin dose used in these studies was lower than the dosage for antibiotic purposes; no adverse effects were reported. However, cardiac arrhythmias and death have occurred when erythromycin is given to adults and children at the usual antibiotic doses.4
Adult constipation: The options are limited
One RCT of cisapride for constipation showed that it improved symptoms,5 whereas another demonstrated no significant difference between cisapride and placebo in constipation-predominant irritable bowel syndrome.6 Reports of fatal arrhythmias have prompted restrictions on the use of the drug.
In 2 RCTs of tegaserod for constipation, patients exhibited improved abdominal symptoms and increased spontaneous bowel movements (NNT=6 for 2 mg and 5 for 6 mg in the first study; NNT=11 for 2 mg and 7 for 6 mg in the second study).7,8 A pooled analysis of RCTs of tegaserod revealed an increase in cardiovascular events, prompting withdrawal of the drug from the market (number needed to harm=1000).9 Tegaserod is available only for emergency and investigational use.
Renzapride, a newer prokinetic similar to cisapride, is under investigation. It is one tenth the strength of cisapride and carries a lower potential risk of cardiac complications.10 Two small placebo-controlled trials demonstrated improved abdominal pain and stool consistency, but only 1 showed statistically significant results compared with placebo.11,12
Recommendations
The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition states that the benefits of cisapride do not outweigh the risks.13 The American College of Gastroenterology’s Chronic Constipation Task Force states that tegaserod effectively treats chronic constipation.14 Neither guideline includes recommendations regarding other prokinetic agents.
1. Bellomo-Brandao MA, Collares EF, da-Costa-Pinto EA. Use of erythromycin for the treatment of severe chronic constipation in children. Braz J Med Biol Res. 2003;36:1391-1396.
2. Costalos C, Gounaris A, Varhalama E, et al. Erythromycin as a prokinetic agent in preterm infants. J Pediatr Gastroenterol Nutr. 2002;34:23-25.
3. Costalos C, Gavrili V, Skouteri V, et al. The effect of low-dose erythromycin on whole gastrointestinal transit time of preterm infants. Early Hum Dev. 2001;65:91-96.
4. Ray WA, Murray KT, Meredith S, et al. Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med. 2004;351:1089-1096.
5. Van Outryve M, Milo R, Toussaint J, et al. “Prokinetic” treatment of constipation-predominant irritable bowel syndrome: a placebo-controlled study of cisapride. J Clin Gastroenterol. 1991;13:49-57.
6. Ziegenhagen DJ, Kruis W. Cisapride treatment of constipation-predominant irritable bowel syndrome is not superior to placebo. J Gastroenterol Hepatol. 2004;19:744-749.
7. Johanson JF, Wald A, Tougas G, et al. Effect of tegaserod in chronic constipation: a randomized, double-blind, controlled trial. Clin Gastroenterol Hepatol. 2004;2:796-805.
8. Kamm MA, Müller-Lissner S, Talley NJ, et al. Tegaserod for the treatment of chronic constipation: a randomized, double-blind, placebo-controlled multinational study. Am J Gastroenterol. 2005;100:362-372.
9. US Food and Drug Administration, Center for Drug Evaluation and Research. FDA Public Health Advisory: tegaserod maleate. March 30, 2007. Available at: www.fda.gov/cder/drug/advisory/tegaserod.htm. Accessed November 17, 2007.
10. Galligan JJ, Vanner S. Basic and clinical pharmacology of new motility promoting agents. Neurogastroenterol Motil. 2005;17:643-653.
11. Tack J, Middleton SJ, Horne MC, et al. Pilot study of the efficacy of renzapride on gastrointestinal motility and symptoms in patients with constipation-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2006;23:1655-1665.
12. Camilleri M, McKinzie S, Fox J, et al. Effect of renzapride on transit in constipation-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol. 2004;2:895-904.
13. North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Evaluation and treatment of constipation in children: summary of updated recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2006;43:405-407.
14. American College of Gastroenterology Chronic Constipation Task Force. An evidence-based approach to the management of chronic constipation in North America. Am J Gastroenterol. 2005;100(suppl 1):S1-S4.
Erythromycin has a limited role in treating pediatric patients (strength of recommendation [SOR]: B, limited-quality, patient-oriented evidence). Tegaserod and cisapride are the only prokinetic agents available for constipated adults (SOR: A, consistent, good-quality, patient-oriented evidence for tegaserod; SOR: B, for cisapride), but cardiovascular risk restricts prescribing of both medications.
Evidence summary
Prokinetic agents promote transit of intestinal contents by increasing the frequency or strength of small intestine contractions. Available prokinetics include erythromycin and metoclopramide. Metoclopramide has been tested only for upper gastrointestinal mobility. The only randomized controlled trials (RCTs) of erythromycin for constipation have been conducted in children. Cisapride and tegaserod have been withdrawn from general use because of adverse side effects. The TABLE summarizes the available data.
TABLE
Prokinetics for constipation: What the research tells us
| DRUG | DESIGN (N) | DOSE | OUTCOME | NNT |
|---|---|---|---|---|
| Erythromycin estolate1 | Crossover children (14) | 20 mg/kg/day divided qid | †Constipation and laxative use | 10 |
| Cisapride5 | RCT adults (69) | 5-10 mg tid | ü Spontaneous BM † Abdominal pain | 4 |
| Cisapride6 | RCT adults (82) | 5-10 mg tid | Abdominal pain and constipation, drug=placebo | N/A |
| Tegaserod7 | RCT adults (1348) | 2 mg or 6 mg bid | † Constipation ü Spontaneous BM | 6 (2 mg) 5 (6 mg) |
| Tegaserod8 | RCT adults (1264) | 2 mg or 6 mg bid | † Constipation and abdominal pain | 11 (2 mg) 7 (6 mg) |
| Renzapride11 | Pilot study adults (17) | Escalating dose: 2 mg daily to 2 mg bid | † Abdominal pain and bloating | Not enough information to calculate |
| Renzapride12 | Parallel group adults (48) | 1, 2, or 4 mg daily | ü Colonic transit; stool form and ease of passage, drug=placebo | N/A |
| BM, bowel movement; N/A, not available; NNT, number needed to treat; RCT, randomized controlled trial. | ||||
Pediatric constipation: Erythromycin helps; watch dosage
A small RCT of 14 children between 4 and 13 years of age showed that erythromycin improved symptoms of constipation and decreased laxative use (number needed to treat [NNT]=10).1 Two RCTs in neonates demonstrated that erythromycin shortened intestinal transit time and improved feeding tolerance.2,3
The erythromycin dose used in these studies was lower than the dosage for antibiotic purposes; no adverse effects were reported. However, cardiac arrhythmias and death have occurred when erythromycin is given to adults and children at the usual antibiotic doses.4
Adult constipation: The options are limited
One RCT of cisapride for constipation showed that it improved symptoms,5 whereas another demonstrated no significant difference between cisapride and placebo in constipation-predominant irritable bowel syndrome.6 Reports of fatal arrhythmias have prompted restrictions on the use of the drug.
In 2 RCTs of tegaserod for constipation, patients exhibited improved abdominal symptoms and increased spontaneous bowel movements (NNT=6 for 2 mg and 5 for 6 mg in the first study; NNT=11 for 2 mg and 7 for 6 mg in the second study).7,8 A pooled analysis of RCTs of tegaserod revealed an increase in cardiovascular events, prompting withdrawal of the drug from the market (number needed to harm=1000).9 Tegaserod is available only for emergency and investigational use.
Renzapride, a newer prokinetic similar to cisapride, is under investigation. It is one tenth the strength of cisapride and carries a lower potential risk of cardiac complications.10 Two small placebo-controlled trials demonstrated improved abdominal pain and stool consistency, but only 1 showed statistically significant results compared with placebo.11,12
Recommendations
The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition states that the benefits of cisapride do not outweigh the risks.13 The American College of Gastroenterology’s Chronic Constipation Task Force states that tegaserod effectively treats chronic constipation.14 Neither guideline includes recommendations regarding other prokinetic agents.
Erythromycin has a limited role in treating pediatric patients (strength of recommendation [SOR]: B, limited-quality, patient-oriented evidence). Tegaserod and cisapride are the only prokinetic agents available for constipated adults (SOR: A, consistent, good-quality, patient-oriented evidence for tegaserod; SOR: B, for cisapride), but cardiovascular risk restricts prescribing of both medications.
Evidence summary
Prokinetic agents promote transit of intestinal contents by increasing the frequency or strength of small intestine contractions. Available prokinetics include erythromycin and metoclopramide. Metoclopramide has been tested only for upper gastrointestinal mobility. The only randomized controlled trials (RCTs) of erythromycin for constipation have been conducted in children. Cisapride and tegaserod have been withdrawn from general use because of adverse side effects. The TABLE summarizes the available data.
TABLE
Prokinetics for constipation: What the research tells us
| DRUG | DESIGN (N) | DOSE | OUTCOME | NNT |
|---|---|---|---|---|
| Erythromycin estolate1 | Crossover children (14) | 20 mg/kg/day divided qid | †Constipation and laxative use | 10 |
| Cisapride5 | RCT adults (69) | 5-10 mg tid | ü Spontaneous BM † Abdominal pain | 4 |
| Cisapride6 | RCT adults (82) | 5-10 mg tid | Abdominal pain and constipation, drug=placebo | N/A |
| Tegaserod7 | RCT adults (1348) | 2 mg or 6 mg bid | † Constipation ü Spontaneous BM | 6 (2 mg) 5 (6 mg) |
| Tegaserod8 | RCT adults (1264) | 2 mg or 6 mg bid | † Constipation and abdominal pain | 11 (2 mg) 7 (6 mg) |
| Renzapride11 | Pilot study adults (17) | Escalating dose: 2 mg daily to 2 mg bid | † Abdominal pain and bloating | Not enough information to calculate |
| Renzapride12 | Parallel group adults (48) | 1, 2, or 4 mg daily | ü Colonic transit; stool form and ease of passage, drug=placebo | N/A |
| BM, bowel movement; N/A, not available; NNT, number needed to treat; RCT, randomized controlled trial. | ||||
Pediatric constipation: Erythromycin helps; watch dosage
A small RCT of 14 children between 4 and 13 years of age showed that erythromycin improved symptoms of constipation and decreased laxative use (number needed to treat [NNT]=10).1 Two RCTs in neonates demonstrated that erythromycin shortened intestinal transit time and improved feeding tolerance.2,3
The erythromycin dose used in these studies was lower than the dosage for antibiotic purposes; no adverse effects were reported. However, cardiac arrhythmias and death have occurred when erythromycin is given to adults and children at the usual antibiotic doses.4
Adult constipation: The options are limited
One RCT of cisapride for constipation showed that it improved symptoms,5 whereas another demonstrated no significant difference between cisapride and placebo in constipation-predominant irritable bowel syndrome.6 Reports of fatal arrhythmias have prompted restrictions on the use of the drug.
In 2 RCTs of tegaserod for constipation, patients exhibited improved abdominal symptoms and increased spontaneous bowel movements (NNT=6 for 2 mg and 5 for 6 mg in the first study; NNT=11 for 2 mg and 7 for 6 mg in the second study).7,8 A pooled analysis of RCTs of tegaserod revealed an increase in cardiovascular events, prompting withdrawal of the drug from the market (number needed to harm=1000).9 Tegaserod is available only for emergency and investigational use.
Renzapride, a newer prokinetic similar to cisapride, is under investigation. It is one tenth the strength of cisapride and carries a lower potential risk of cardiac complications.10 Two small placebo-controlled trials demonstrated improved abdominal pain and stool consistency, but only 1 showed statistically significant results compared with placebo.11,12
Recommendations
The North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition states that the benefits of cisapride do not outweigh the risks.13 The American College of Gastroenterology’s Chronic Constipation Task Force states that tegaserod effectively treats chronic constipation.14 Neither guideline includes recommendations regarding other prokinetic agents.
1. Bellomo-Brandao MA, Collares EF, da-Costa-Pinto EA. Use of erythromycin for the treatment of severe chronic constipation in children. Braz J Med Biol Res. 2003;36:1391-1396.
2. Costalos C, Gounaris A, Varhalama E, et al. Erythromycin as a prokinetic agent in preterm infants. J Pediatr Gastroenterol Nutr. 2002;34:23-25.
3. Costalos C, Gavrili V, Skouteri V, et al. The effect of low-dose erythromycin on whole gastrointestinal transit time of preterm infants. Early Hum Dev. 2001;65:91-96.
4. Ray WA, Murray KT, Meredith S, et al. Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med. 2004;351:1089-1096.
5. Van Outryve M, Milo R, Toussaint J, et al. “Prokinetic” treatment of constipation-predominant irritable bowel syndrome: a placebo-controlled study of cisapride. J Clin Gastroenterol. 1991;13:49-57.
6. Ziegenhagen DJ, Kruis W. Cisapride treatment of constipation-predominant irritable bowel syndrome is not superior to placebo. J Gastroenterol Hepatol. 2004;19:744-749.
7. Johanson JF, Wald A, Tougas G, et al. Effect of tegaserod in chronic constipation: a randomized, double-blind, controlled trial. Clin Gastroenterol Hepatol. 2004;2:796-805.
8. Kamm MA, Müller-Lissner S, Talley NJ, et al. Tegaserod for the treatment of chronic constipation: a randomized, double-blind, placebo-controlled multinational study. Am J Gastroenterol. 2005;100:362-372.
9. US Food and Drug Administration, Center for Drug Evaluation and Research. FDA Public Health Advisory: tegaserod maleate. March 30, 2007. Available at: www.fda.gov/cder/drug/advisory/tegaserod.htm. Accessed November 17, 2007.
10. Galligan JJ, Vanner S. Basic and clinical pharmacology of new motility promoting agents. Neurogastroenterol Motil. 2005;17:643-653.
11. Tack J, Middleton SJ, Horne MC, et al. Pilot study of the efficacy of renzapride on gastrointestinal motility and symptoms in patients with constipation-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2006;23:1655-1665.
12. Camilleri M, McKinzie S, Fox J, et al. Effect of renzapride on transit in constipation-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol. 2004;2:895-904.
13. North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Evaluation and treatment of constipation in children: summary of updated recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2006;43:405-407.
14. American College of Gastroenterology Chronic Constipation Task Force. An evidence-based approach to the management of chronic constipation in North America. Am J Gastroenterol. 2005;100(suppl 1):S1-S4.
1. Bellomo-Brandao MA, Collares EF, da-Costa-Pinto EA. Use of erythromycin for the treatment of severe chronic constipation in children. Braz J Med Biol Res. 2003;36:1391-1396.
2. Costalos C, Gounaris A, Varhalama E, et al. Erythromycin as a prokinetic agent in preterm infants. J Pediatr Gastroenterol Nutr. 2002;34:23-25.
3. Costalos C, Gavrili V, Skouteri V, et al. The effect of low-dose erythromycin on whole gastrointestinal transit time of preterm infants. Early Hum Dev. 2001;65:91-96.
4. Ray WA, Murray KT, Meredith S, et al. Oral erythromycin and the risk of sudden death from cardiac causes. N Engl J Med. 2004;351:1089-1096.
5. Van Outryve M, Milo R, Toussaint J, et al. “Prokinetic” treatment of constipation-predominant irritable bowel syndrome: a placebo-controlled study of cisapride. J Clin Gastroenterol. 1991;13:49-57.
6. Ziegenhagen DJ, Kruis W. Cisapride treatment of constipation-predominant irritable bowel syndrome is not superior to placebo. J Gastroenterol Hepatol. 2004;19:744-749.
7. Johanson JF, Wald A, Tougas G, et al. Effect of tegaserod in chronic constipation: a randomized, double-blind, controlled trial. Clin Gastroenterol Hepatol. 2004;2:796-805.
8. Kamm MA, Müller-Lissner S, Talley NJ, et al. Tegaserod for the treatment of chronic constipation: a randomized, double-blind, placebo-controlled multinational study. Am J Gastroenterol. 2005;100:362-372.
9. US Food and Drug Administration, Center for Drug Evaluation and Research. FDA Public Health Advisory: tegaserod maleate. March 30, 2007. Available at: www.fda.gov/cder/drug/advisory/tegaserod.htm. Accessed November 17, 2007.
10. Galligan JJ, Vanner S. Basic and clinical pharmacology of new motility promoting agents. Neurogastroenterol Motil. 2005;17:643-653.
11. Tack J, Middleton SJ, Horne MC, et al. Pilot study of the efficacy of renzapride on gastrointestinal motility and symptoms in patients with constipation-predominant irritable bowel syndrome. Aliment Pharmacol Ther. 2006;23:1655-1665.
12. Camilleri M, McKinzie S, Fox J, et al. Effect of renzapride on transit in constipation-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol. 2004;2:895-904.
13. North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Evaluation and treatment of constipation in children: summary of updated recommendations of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr. 2006;43:405-407.
14. American College of Gastroenterology Chronic Constipation Task Force. An evidence-based approach to the management of chronic constipation in North America. Am J Gastroenterol. 2005;100(suppl 1):S1-S4.
Evidence-based answers from the Family Physicians Inquiries Network