Clinical Inquiries

Evidence summary

One RCT that compared the levonorgestrel IUD (Mirena) with oral contraceptives in 200 nulliparous women 18 to 25 years of age found the IUD to have equivalent safety and efficacy to OCPs.¹ Moreover, the IUD group experienced a significant decrease in bleeding, with a number needed to treat of 4 (P=.001).

Neither group reported any pregnancies or pelvic inflammatory disease at one year. The overall discontinuation rate at one year was 20% for IUDs and 27% for OCPs (P=not significant [NS]).¹ Multiple studies show no unintended pregnancies with the IUD.^1-3

Study of adolescents finds low complication rate
A prospective cohort study of 179 adolescents 10 to 19 years of age found that the overall incidence of complications with the levonorgestrel IUD was relatively low, with removal rates of 8/179 (4.5%) each for pain and abnormal vaginal bleeding. The cumulative incidence of expulsion was estimated at 8.3% (95% confidence interval [CI], 4.2%-14.3%). No cases of uterine perforation were identified, and the one-year continuation rate was 85% (95% CI, 77%-90%).² Other studies haven’t evaluated adolescents as a separate group.

IUDs are also well tolerated in an older cohort
A cohort study of 113 nulliparous women 16 to 30 years of age found insertion of a copper or levonorgestrel IUD to be well tolerated; no perforations were observed. At one year, 65 women (58%) still had their original IUD, 15 (13%) had had it removed, 6 (5%) had experienced expulsion, and 27 (24%) were lost to follow-up.³

Abdominal and back pain can be a problem
An RCT of 200 nulliparous women 18 to 25 years of age found that levonorgestrel IUDs were associated with more abdominal and back pain at 12 months than OCPs (54.7% of women with IUDs had pain vs 40% of women with OCPs; number needed to harm=7; P=.007). Pain was the leading cause of discontinuation in the IUD group (6 women with IUDs stopped using them vs no OCP users; P=.012).¹

No difference in IUD complications in nulliparous vs parous women
A retrospective cohort study compared 129 nulliparous women with 332 parous women 17 to 52 years of age who had either copper or levonorgestrel IUDs. The researchers found no differences between the 2 groups in rates of perforation, pelvic inflammatory disease, ectopic pregnancy, or expulsion.⁴

Fertility after IUD removal: An encouraging picture
No studies have evaluated fertility after IUD use exclusively in adolescents. A prospective cohort study of 558 nulliparous women ages 18 to 40 years who stopped using a barrier method, copper IUD, or OCP in order to conceive found the quickest return to fertility among women who used the barrier method. The main outcome, percent of women who delivered within 12 months of discontinuation, was highest in the barrier method cohort and lowest in the OCP cohort (54% vs 32%; P=.002). The difference in delivery rates between the IUD and OCP groups at 12 months wasn’t statistically significant (39% vs 32%). By 18 months after cessation of contraception, the delivery rates in all 3 groups were similar (76%, 67%, and 70% for barrier, OCP, and IUD use, respectively).⁵

A retrospective cohort study that compared 36 nulliparous women with 83 parous women 18 to 41 years of age who were trying to conceive after removal of the GyneFix (copper) IUD found no statistical difference in pregnancy rates for age or duration of IUD use. Among women younger than 30 years, nulliparous women conceived earlier than parous women; cumulative pregnancy rates after 12 months were 100% for nulliparous and 80% for parous women (P=.007). No ectopic pregnancies were observed.⁶

Recommendations

The United Kingdom’s National Institute for Health and Clinical Excellence states that IUD use isn’t contraindicated in nulliparous women of any age, and that women of all ages may use IUDs. The Institute also states that no specific restrictions limit the use of copper or levonorgestrel IUDs by adolescents.

All women at risk for sexually transmitted infections may need to be tested before insertion. No evidence exists for a delay in return to fertility after removal or expulsion of an IUD.⁷

Evidence summary

One RCT that compared the levonorgestrel IUD (Mirena) with oral contraceptives in 200 nulliparous women 18 to 25 years of age found the IUD to have equivalent safety and efficacy to OCPs.¹ Moreover, the IUD group experienced a significant decrease in bleeding, with a number needed to treat of 4 (P=.001).

Neither group reported any pregnancies or pelvic inflammatory disease at one year. The overall discontinuation rate at one year was 20% for IUDs and 27% for OCPs (P=not significant [NS]).¹ Multiple studies show no unintended pregnancies with the IUD.^1-3

Study of adolescents finds low complication rate
A prospective cohort study of 179 adolescents 10 to 19 years of age found that the overall incidence of complications with the levonorgestrel IUD was relatively low, with removal rates of 8/179 (4.5%) each for pain and abnormal vaginal bleeding. The cumulative incidence of expulsion was estimated at 8.3% (95% confidence interval [CI], 4.2%-14.3%). No cases of uterine perforation were identified, and the one-year continuation rate was 85% (95% CI, 77%-90%).² Other studies haven’t evaluated adolescents as a separate group.

IUDs are also well tolerated in an older cohort
A cohort study of 113 nulliparous women 16 to 30 years of age found insertion of a copper or levonorgestrel IUD to be well tolerated; no perforations were observed. At one year, 65 women (58%) still had their original IUD, 15 (13%) had had it removed, 6 (5%) had experienced expulsion, and 27 (24%) were lost to follow-up.³

Abdominal and back pain can be a problem
An RCT of 200 nulliparous women 18 to 25 years of age found that levonorgestrel IUDs were associated with more abdominal and back pain at 12 months than OCPs (54.7% of women with IUDs had pain vs 40% of women with OCPs; number needed to harm=7; P=.007). Pain was the leading cause of discontinuation in the IUD group (6 women with IUDs stopped using them vs no OCP users; P=.012).¹

No difference in IUD complications in nulliparous vs parous women
A retrospective cohort study compared 129 nulliparous women with 332 parous women 17 to 52 years of age who had either copper or levonorgestrel IUDs. The researchers found no differences between the 2 groups in rates of perforation, pelvic inflammatory disease, ectopic pregnancy, or expulsion.⁴

Fertility after IUD removal: An encouraging picture
No studies have evaluated fertility after IUD use exclusively in adolescents. A prospective cohort study of 558 nulliparous women ages 18 to 40 years who stopped using a barrier method, copper IUD, or OCP in order to conceive found the quickest return to fertility among women who used the barrier method. The main outcome, percent of women who delivered within 12 months of discontinuation, was highest in the barrier method cohort and lowest in the OCP cohort (54% vs 32%; P=.002). The difference in delivery rates between the IUD and OCP groups at 12 months wasn’t statistically significant (39% vs 32%). By 18 months after cessation of contraception, the delivery rates in all 3 groups were similar (76%, 67%, and 70% for barrier, OCP, and IUD use, respectively).⁵

A retrospective cohort study that compared 36 nulliparous women with 83 parous women 18 to 41 years of age who were trying to conceive after removal of the GyneFix (copper) IUD found no statistical difference in pregnancy rates for age or duration of IUD use. Among women younger than 30 years, nulliparous women conceived earlier than parous women; cumulative pregnancy rates after 12 months were 100% for nulliparous and 80% for parous women (P=.007). No ectopic pregnancies were observed.⁶

Recommendations

The United Kingdom’s National Institute for Health and Clinical Excellence states that IUD use isn’t contraindicated in nulliparous women of any age, and that women of all ages may use IUDs. The Institute also states that no specific restrictions limit the use of copper or levonorgestrel IUDs by adolescents.

All women at risk for sexually transmitted infections may need to be tested before insertion. No evidence exists for a delay in return to fertility after removal or expulsion of an IUD.⁷

Evidence summary

One RCT that compared the levonorgestrel IUD (Mirena) with oral contraceptives in 200 nulliparous women 18 to 25 years of age found the IUD to have equivalent safety and efficacy to OCPs.¹ Moreover, the IUD group experienced a significant decrease in bleeding, with a number needed to treat of 4 (P=.001).

Neither group reported any pregnancies or pelvic inflammatory disease at one year. The overall discontinuation rate at one year was 20% for IUDs and 27% for OCPs (P=not significant [NS]).¹ Multiple studies show no unintended pregnancies with the IUD.^1-3

Study of adolescents finds low complication rate
A prospective cohort study of 179 adolescents 10 to 19 years of age found that the overall incidence of complications with the levonorgestrel IUD was relatively low, with removal rates of 8/179 (4.5%) each for pain and abnormal vaginal bleeding. The cumulative incidence of expulsion was estimated at 8.3% (95% confidence interval [CI], 4.2%-14.3%). No cases of uterine perforation were identified, and the one-year continuation rate was 85% (95% CI, 77%-90%).² Other studies haven’t evaluated adolescents as a separate group.

IUDs are also well tolerated in an older cohort
A cohort study of 113 nulliparous women 16 to 30 years of age found insertion of a copper or levonorgestrel IUD to be well tolerated; no perforations were observed. At one year, 65 women (58%) still had their original IUD, 15 (13%) had had it removed, 6 (5%) had experienced expulsion, and 27 (24%) were lost to follow-up.³

Abdominal and back pain can be a problem
An RCT of 200 nulliparous women 18 to 25 years of age found that levonorgestrel IUDs were associated with more abdominal and back pain at 12 months than OCPs (54.7% of women with IUDs had pain vs 40% of women with OCPs; number needed to harm=7; P=.007). Pain was the leading cause of discontinuation in the IUD group (6 women with IUDs stopped using them vs no OCP users; P=.012).¹

No difference in IUD complications in nulliparous vs parous women
A retrospective cohort study compared 129 nulliparous women with 332 parous women 17 to 52 years of age who had either copper or levonorgestrel IUDs. The researchers found no differences between the 2 groups in rates of perforation, pelvic inflammatory disease, ectopic pregnancy, or expulsion.⁴

Fertility after IUD removal: An encouraging picture
No studies have evaluated fertility after IUD use exclusively in adolescents. A prospective cohort study of 558 nulliparous women ages 18 to 40 years who stopped using a barrier method, copper IUD, or OCP in order to conceive found the quickest return to fertility among women who used the barrier method. The main outcome, percent of women who delivered within 12 months of discontinuation, was highest in the barrier method cohort and lowest in the OCP cohort (54% vs 32%; P=.002). The difference in delivery rates between the IUD and OCP groups at 12 months wasn’t statistically significant (39% vs 32%). By 18 months after cessation of contraception, the delivery rates in all 3 groups were similar (76%, 67%, and 70% for barrier, OCP, and IUD use, respectively).⁵

A retrospective cohort study that compared 36 nulliparous women with 83 parous women 18 to 41 years of age who were trying to conceive after removal of the GyneFix (copper) IUD found no statistical difference in pregnancy rates for age or duration of IUD use. Among women younger than 30 years, nulliparous women conceived earlier than parous women; cumulative pregnancy rates after 12 months were 100% for nulliparous and 80% for parous women (P=.007). No ectopic pregnancies were observed.⁶

Recommendations

The United Kingdom’s National Institute for Health and Clinical Excellence states that IUD use isn’t contraindicated in nulliparous women of any age, and that women of all ages may use IUDs. The Institute also states that no specific restrictions limit the use of copper or levonorgestrel IUDs by adolescents.

All women at risk for sexually transmitted infections may need to be tested before insertion. No evidence exists for a delay in return to fertility after removal or expulsion of an IUD.⁷

Evidence summary

A bite by the black widow spider (Latrodectus mactans) is painful but rarely fatal. No deaths have resulted from more than 40,000 reported bites in the United States.¹ Envenomation may cause latrodectism, a syndrome characterized by widespread, sustained muscle spasms. Victims also may have significant hypertension, autonomic and central nervous system dysfunction, and abdominal pain severe enough to be mistaken for an acute abdomen.² Our literature search didn’t find any RCTs comparing the efficacy of general symptomatic treatment with administration of specific antivenin against black widow spider bites.

Relief with opioids, benzodiazepines, but not with calcium gluconate
A retrospective case series that evaluated 163 patients who had been bitten by a black widow spider found that IV opioids and benzodiazepines (most often diazepam) relieved symptoms in most patients. Black widow–specific antivenin improved severe symptoms, albeit at the risk of causing allergic complications (antivenin contains whole immunoglobulin G from horses).³

Patients were 8 months to 88 years old (average age 31.6 years); 99 (61%) were male. Investigators reviewed their medical records and categorized symptom severity as mild (asymptomatic or local pain only, 9%), moderate (muscle or abdominal pain with normal vital signs, 37%), or severe (generalized back, chest, or abdominal pain; nausea, headache, and abnormal vital signs, 54%). Physicians treated moderate or severe symptoms with IV opioids (49 patients), IV opioids in combination with benzodiazepines (44 patients), or IV antivenin (58 patients). (Treatment was not specified for 12 patients.)

Treatment relieved pain in 55% of patients taking opioids alone and 70% using both opioids and benzodiazepines. All 58 patients who received antivenin reported complete symptom resolution after an average of 31±27 minutes. Of 24 patients with moderate or severe symptoms who initially received calcium gluconate (mean dose 1400 mg) alone or with a muscle relaxant, 96% continued to have symptoms requiring further treatment. (Numbers add up to more than 163 because some patients received multiple types of treatment.)

Benefits of antivenin come at a price
In this study, antivenin administration shortened total symptom duration (9±23 hours with antivenin compared with 22±25 hours without; P<.05) and reduced the need for hospitalization (number needed to treat with antivenin=3, no comparative statistics supplied).³ However, antivenin complications triggered 80% of the hospital admissions associated with its use (total complication rate 9%, number needed to harm=11). Antivenin caused 4 cases of generalized urticarial reactions. A patient who had asthma and multiple drug allergies died from severe bronchospasm when physicians gave him undiluted IV antivenin.

Supportive care and antivenin show similar results in a small study
A second retrospective case series found no difference in length of hospitalization or long-term outcomes in 14 patients, 6 of whom were treated with supportive care (methocarbamol and calcium gluconate) and 8 with antivenin.⁴ The study didn’t include patients treated in the emergency department and didn’t categorize severity of symptoms, however.

Is antivenin ineffective?
Additional information on horse serum antivenin comes from studies of Australian redback spider bites. An RCT of 126 patients treated with either IV or IM antivenin for moderate to severe symptoms of redback latrodectism found statistically equal clinical relief of pain at 2 hours (63% vs 53%, respectively; 95% confidence interval, -8% to 26%).⁵ However, investigators measured serum antivenin levels in a random sample of 20 patients and found that IV administration of antivenin produced a measurable level, while IM administration did not. In light of the fact that IV and IM administration were associated with equal pain relief and that the IM route didn’t produce a measurable serum level, the investigators raised the possibility that the antivenin might not be an effective treatment.⁶

A case series in which Australian physicians treated 1972 redback spider bite victims with antivenin reported delayed serum reactions in 1.7% and anaphylaxis in 0.5%.⁷

Recommendations

A wilderness medicine text recommends admitting all symptomatic children, pregnant women, and patients with hypertension to the hospital after a black widow spider bite.² The authors commented that severe pain and muscle spasm usually respond to IV narcotics or benzodiazepines.

They noted that Latrodectus antivenin may prevent systemic sequelae and should be used in pregnant women and patients with respiratory arrest, seizures, or uncontrolled hypertension. For patients with less severe symptoms, the authors recommend weighing the value of antivenin against the risks of acute hypersensitivity and delayed serum sickness. They reported that redback antivenin is effective in 94% of patients in Australia and that Australian data show anaphylaxis rates of 0.5% to 1%.

Evidence summary

A bite by the black widow spider (Latrodectus mactans) is painful but rarely fatal. No deaths have resulted from more than 40,000 reported bites in the United States.¹ Envenomation may cause latrodectism, a syndrome characterized by widespread, sustained muscle spasms. Victims also may have significant hypertension, autonomic and central nervous system dysfunction, and abdominal pain severe enough to be mistaken for an acute abdomen.² Our literature search didn’t find any RCTs comparing the efficacy of general symptomatic treatment with administration of specific antivenin against black widow spider bites.

Relief with opioids, benzodiazepines, but not with calcium gluconate
A retrospective case series that evaluated 163 patients who had been bitten by a black widow spider found that IV opioids and benzodiazepines (most often diazepam) relieved symptoms in most patients. Black widow–specific antivenin improved severe symptoms, albeit at the risk of causing allergic complications (antivenin contains whole immunoglobulin G from horses).³

Patients were 8 months to 88 years old (average age 31.6 years); 99 (61%) were male. Investigators reviewed their medical records and categorized symptom severity as mild (asymptomatic or local pain only, 9%), moderate (muscle or abdominal pain with normal vital signs, 37%), or severe (generalized back, chest, or abdominal pain; nausea, headache, and abnormal vital signs, 54%). Physicians treated moderate or severe symptoms with IV opioids (49 patients), IV opioids in combination with benzodiazepines (44 patients), or IV antivenin (58 patients). (Treatment was not specified for 12 patients.)

Treatment relieved pain in 55% of patients taking opioids alone and 70% using both opioids and benzodiazepines. All 58 patients who received antivenin reported complete symptom resolution after an average of 31±27 minutes. Of 24 patients with moderate or severe symptoms who initially received calcium gluconate (mean dose 1400 mg) alone or with a muscle relaxant, 96% continued to have symptoms requiring further treatment. (Numbers add up to more than 163 because some patients received multiple types of treatment.)

Benefits of antivenin come at a price
In this study, antivenin administration shortened total symptom duration (9±23 hours with antivenin compared with 22±25 hours without; P<.05) and reduced the need for hospitalization (number needed to treat with antivenin=3, no comparative statistics supplied).³ However, antivenin complications triggered 80% of the hospital admissions associated with its use (total complication rate 9%, number needed to harm=11). Antivenin caused 4 cases of generalized urticarial reactions. A patient who had asthma and multiple drug allergies died from severe bronchospasm when physicians gave him undiluted IV antivenin.

Supportive care and antivenin show similar results in a small study
A second retrospective case series found no difference in length of hospitalization or long-term outcomes in 14 patients, 6 of whom were treated with supportive care (methocarbamol and calcium gluconate) and 8 with antivenin.⁴ The study didn’t include patients treated in the emergency department and didn’t categorize severity of symptoms, however.

Is antivenin ineffective?
Additional information on horse serum antivenin comes from studies of Australian redback spider bites. An RCT of 126 patients treated with either IV or IM antivenin for moderate to severe symptoms of redback latrodectism found statistically equal clinical relief of pain at 2 hours (63% vs 53%, respectively; 95% confidence interval, -8% to 26%).⁵ However, investigators measured serum antivenin levels in a random sample of 20 patients and found that IV administration of antivenin produced a measurable level, while IM administration did not. In light of the fact that IV and IM administration were associated with equal pain relief and that the IM route didn’t produce a measurable serum level, the investigators raised the possibility that the antivenin might not be an effective treatment.⁶

A case series in which Australian physicians treated 1972 redback spider bite victims with antivenin reported delayed serum reactions in 1.7% and anaphylaxis in 0.5%.⁷

Recommendations

A wilderness medicine text recommends admitting all symptomatic children, pregnant women, and patients with hypertension to the hospital after a black widow spider bite.² The authors commented that severe pain and muscle spasm usually respond to IV narcotics or benzodiazepines.

They noted that Latrodectus antivenin may prevent systemic sequelae and should be used in pregnant women and patients with respiratory arrest, seizures, or uncontrolled hypertension. For patients with less severe symptoms, the authors recommend weighing the value of antivenin against the risks of acute hypersensitivity and delayed serum sickness. They reported that redback antivenin is effective in 94% of patients in Australia and that Australian data show anaphylaxis rates of 0.5% to 1%.

Evidence summary

A bite by the black widow spider (Latrodectus mactans) is painful but rarely fatal. No deaths have resulted from more than 40,000 reported bites in the United States.¹ Envenomation may cause latrodectism, a syndrome characterized by widespread, sustained muscle spasms. Victims also may have significant hypertension, autonomic and central nervous system dysfunction, and abdominal pain severe enough to be mistaken for an acute abdomen.² Our literature search didn’t find any RCTs comparing the efficacy of general symptomatic treatment with administration of specific antivenin against black widow spider bites.

Relief with opioids, benzodiazepines, but not with calcium gluconate
A retrospective case series that evaluated 163 patients who had been bitten by a black widow spider found that IV opioids and benzodiazepines (most often diazepam) relieved symptoms in most patients. Black widow–specific antivenin improved severe symptoms, albeit at the risk of causing allergic complications (antivenin contains whole immunoglobulin G from horses).³

Patients were 8 months to 88 years old (average age 31.6 years); 99 (61%) were male. Investigators reviewed their medical records and categorized symptom severity as mild (asymptomatic or local pain only, 9%), moderate (muscle or abdominal pain with normal vital signs, 37%), or severe (generalized back, chest, or abdominal pain; nausea, headache, and abnormal vital signs, 54%). Physicians treated moderate or severe symptoms with IV opioids (49 patients), IV opioids in combination with benzodiazepines (44 patients), or IV antivenin (58 patients). (Treatment was not specified for 12 patients.)

Treatment relieved pain in 55% of patients taking opioids alone and 70% using both opioids and benzodiazepines. All 58 patients who received antivenin reported complete symptom resolution after an average of 31±27 minutes. Of 24 patients with moderate or severe symptoms who initially received calcium gluconate (mean dose 1400 mg) alone or with a muscle relaxant, 96% continued to have symptoms requiring further treatment. (Numbers add up to more than 163 because some patients received multiple types of treatment.)

Benefits of antivenin come at a price
In this study, antivenin administration shortened total symptom duration (9±23 hours with antivenin compared with 22±25 hours without; P<.05) and reduced the need for hospitalization (number needed to treat with antivenin=3, no comparative statistics supplied).³ However, antivenin complications triggered 80% of the hospital admissions associated with its use (total complication rate 9%, number needed to harm=11). Antivenin caused 4 cases of generalized urticarial reactions. A patient who had asthma and multiple drug allergies died from severe bronchospasm when physicians gave him undiluted IV antivenin.

Supportive care and antivenin show similar results in a small study
A second retrospective case series found no difference in length of hospitalization or long-term outcomes in 14 patients, 6 of whom were treated with supportive care (methocarbamol and calcium gluconate) and 8 with antivenin.⁴ The study didn’t include patients treated in the emergency department and didn’t categorize severity of symptoms, however.

Is antivenin ineffective?
Additional information on horse serum antivenin comes from studies of Australian redback spider bites. An RCT of 126 patients treated with either IV or IM antivenin for moderate to severe symptoms of redback latrodectism found statistically equal clinical relief of pain at 2 hours (63% vs 53%, respectively; 95% confidence interval, -8% to 26%).⁵ However, investigators measured serum antivenin levels in a random sample of 20 patients and found that IV administration of antivenin produced a measurable level, while IM administration did not. In light of the fact that IV and IM administration were associated with equal pain relief and that the IM route didn’t produce a measurable serum level, the investigators raised the possibility that the antivenin might not be an effective treatment.⁶

A case series in which Australian physicians treated 1972 redback spider bite victims with antivenin reported delayed serum reactions in 1.7% and anaphylaxis in 0.5%.⁷

Recommendations

A wilderness medicine text recommends admitting all symptomatic children, pregnant women, and patients with hypertension to the hospital after a black widow spider bite.² The authors commented that severe pain and muscle spasm usually respond to IV narcotics or benzodiazepines.

They noted that Latrodectus antivenin may prevent systemic sequelae and should be used in pregnant women and patients with respiratory arrest, seizures, or uncontrolled hypertension. For patients with less severe symptoms, the authors recommend weighing the value of antivenin against the risks of acute hypersensitivity and delayed serum sickness. They reported that redback antivenin is effective in 94% of patients in Australia and that Australian data show anaphylaxis rates of 0.5% to 1%.

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

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

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

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

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

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

Evidence summary

In a randomized, double-blind study, 58 patients with heel cracks applied one of 2 emollients twice daily.¹ After 4 weeks of treatment, both groups reported improved scores for pain, appearance, and dryness (using a clinical xerosis score) and also skin scaling and desquamation (using a D-Squame score). Both groups reported improvement, but investigators didn’t say in the research abstract whether it was statistically or clinically significant.

In plain or soapy water, foot soaks seem to help
To compare foot soaks in plain and soapy water, a prospective cohort study enrolled 15 leprosy patients who had callosities and heel cracks.² Investigators graded the severity of the callosities and cracks clinically and photographically on a 0 to 4 scale (0=no cracks or calluses; 4=deep cracks and thick calluses). Each day, patients soaked one foot in plain water and the other in soapy water for 20 minutes, debrided both feet with a clay tool, and covered the soles with petrolatum.

By Day 7, both groups improved by more than one clinical grade. Soap soaks appeared to raise scores more than plain water, but the investigators reported no statistical comparisons. The study was limited by its size, lack of controls, and inability to generalize results to patients without leprosy.

Salicylic acid cream also brings improvement
One case-control study of 2 women found that 6% salicylic acid controlled-release cream improved hyperkeratosis, heel cracks, and pain after one or 2 weeks. The women treated one foot and used the other as a control.³ The investigator was blinded as to which foot was treated and used photographs to evaluate improvement over time. This study was limited by its size and short duration.

Tissue adhesive keeps it together
A case series involving 10 people with 14 heel cracks suggests that Super Glue may reduce pain and speed closure.⁴ Patients applied 2 to 3 drops of glue along the length of each crack and held the edges together for 60 seconds. After 5 to 7 days, 12 of the 14 cracks remained closed and pain free. Investigators then instructed patients to begin mechanical debridement.

Recommendations

Expert recommendations for treating heel cracks include the use of keratolytics, emulsifying ointments, silver nitrate, and 10% glycerol in sorbolene cream, along with treatment of any underlying conditions.^5-7 The New Zealand Dermatological Society recommends proper fitting shoes and daily moisturizers to prevent skin cracks. To treat cracks, the Society recommends keratolytics, debridement, strapping or heel cups to redistribute the weight on the heel, and tissue glue.⁸

Evidence summary

In a randomized, double-blind study, 58 patients with heel cracks applied one of 2 emollients twice daily.¹ After 4 weeks of treatment, both groups reported improved scores for pain, appearance, and dryness (using a clinical xerosis score) and also skin scaling and desquamation (using a D-Squame score). Both groups reported improvement, but investigators didn’t say in the research abstract whether it was statistically or clinically significant.

In plain or soapy water, foot soaks seem to help
To compare foot soaks in plain and soapy water, a prospective cohort study enrolled 15 leprosy patients who had callosities and heel cracks.² Investigators graded the severity of the callosities and cracks clinically and photographically on a 0 to 4 scale (0=no cracks or calluses; 4=deep cracks and thick calluses). Each day, patients soaked one foot in plain water and the other in soapy water for 20 minutes, debrided both feet with a clay tool, and covered the soles with petrolatum.

By Day 7, both groups improved by more than one clinical grade. Soap soaks appeared to raise scores more than plain water, but the investigators reported no statistical comparisons. The study was limited by its size, lack of controls, and inability to generalize results to patients without leprosy.

Salicylic acid cream also brings improvement
One case-control study of 2 women found that 6% salicylic acid controlled-release cream improved hyperkeratosis, heel cracks, and pain after one or 2 weeks. The women treated one foot and used the other as a control.³ The investigator was blinded as to which foot was treated and used photographs to evaluate improvement over time. This study was limited by its size and short duration.

Tissue adhesive keeps it together
A case series involving 10 people with 14 heel cracks suggests that Super Glue may reduce pain and speed closure.⁴ Patients applied 2 to 3 drops of glue along the length of each crack and held the edges together for 60 seconds. After 5 to 7 days, 12 of the 14 cracks remained closed and pain free. Investigators then instructed patients to begin mechanical debridement.

Recommendations

Expert recommendations for treating heel cracks include the use of keratolytics, emulsifying ointments, silver nitrate, and 10% glycerol in sorbolene cream, along with treatment of any underlying conditions.^5-7 The New Zealand Dermatological Society recommends proper fitting shoes and daily moisturizers to prevent skin cracks. To treat cracks, the Society recommends keratolytics, debridement, strapping or heel cups to redistribute the weight on the heel, and tissue glue.⁸

Evidence summary

In a randomized, double-blind study, 58 patients with heel cracks applied one of 2 emollients twice daily.¹ After 4 weeks of treatment, both groups reported improved scores for pain, appearance, and dryness (using a clinical xerosis score) and also skin scaling and desquamation (using a D-Squame score). Both groups reported improvement, but investigators didn’t say in the research abstract whether it was statistically or clinically significant.

In plain or soapy water, foot soaks seem to help
To compare foot soaks in plain and soapy water, a prospective cohort study enrolled 15 leprosy patients who had callosities and heel cracks.² Investigators graded the severity of the callosities and cracks clinically and photographically on a 0 to 4 scale (0=no cracks or calluses; 4=deep cracks and thick calluses). Each day, patients soaked one foot in plain water and the other in soapy water for 20 minutes, debrided both feet with a clay tool, and covered the soles with petrolatum.

By Day 7, both groups improved by more than one clinical grade. Soap soaks appeared to raise scores more than plain water, but the investigators reported no statistical comparisons. The study was limited by its size, lack of controls, and inability to generalize results to patients without leprosy.

Salicylic acid cream also brings improvement
One case-control study of 2 women found that 6% salicylic acid controlled-release cream improved hyperkeratosis, heel cracks, and pain after one or 2 weeks. The women treated one foot and used the other as a control.³ The investigator was blinded as to which foot was treated and used photographs to evaluate improvement over time. This study was limited by its size and short duration.

Tissue adhesive keeps it together
A case series involving 10 people with 14 heel cracks suggests that Super Glue may reduce pain and speed closure.⁴ Patients applied 2 to 3 drops of glue along the length of each crack and held the edges together for 60 seconds. After 5 to 7 days, 12 of the 14 cracks remained closed and pain free. Investigators then instructed patients to begin mechanical debridement.

Recommendations

Expert recommendations for treating heel cracks include the use of keratolytics, emulsifying ointments, silver nitrate, and 10% glycerol in sorbolene cream, along with treatment of any underlying conditions.^5-7 The New Zealand Dermatological Society recommends proper fitting shoes and daily moisturizers to prevent skin cracks. To treat cracks, the Society recommends keratolytics, debridement, strapping or heel cups to redistribute the weight on the heel, and tissue glue.⁸

Evidence summary

A systematic review of 4 RCTs with a total of 356 patients found that antibiotic therapy reduced mortality more than placebo in moderately to severely ill hospitalized patients with COPD. Short-term mortality (7 days after treatment to 18 months after hospital discharge) decreased by 77% with antibiotic use in acute exacerbations of COPD (number needed to treat [NNT]=8; 95% confidence interval [CI], 6-17).

This same Cochrane review and a meta-analysis of 4 hospital-based trials with 321 patients evaluated failure to improve, deterioration, or death during the study period.^1,2 The results favored treatment with antibiotics over placebo (NNT=3; 95% CI, 3-5).

Don’t wait to give antibiotics
A large retrospective cohort study of 84,621 hospitalized patients compared outcomes in patients given antibiotics for acute exacerbations of COPD during their first 2 days in the hospital with patients treated later or not at all.³ Outcomes assessed included need for later ventilation and readmission within 30 days for acute exacerbations of COPD.

The study included patients 40 years or older with a principal diagnosis, based on ICD 9 codes, of acute exacerbation of COPD, emphysema, or respiratory failure paired with a secondary diagnosis of COPD with acute exacerbation or emphysema. Patients who had been admitted directly to the intensive care unit were excluded, as were patients with other bacterial infections, such as pneumonia or cellulitis, for which they might receive antibiotics.

Early administration of antibiotics delayed the need for subsequent ventilation when compared with no antibiotics or antibiotics given later (1.07% vs 1.80%; P<.001; NNT=137). Giving antibiotics early also lowered readmission rates for acute exacerbations of COPD (7.91% vs 8.79%; P<.001; NNT=114), improved mortality rates (1.04% vs 1.59%; P<.001; NNT=182), and decreased treatment failure (9.77% vs 11.75%; P<.001; NNT=51).

Recommendations

The recommendations of the Global Initiative for Chronic Obstructive Lung Disease (GOLD), updated in 2008, call for antibiotics to be given to patients with 2 or more of the cardinal symptoms of acute exacerbations of COPD (shortness of breath, increased sputum production, and sputum purulence). Patients with severe exacerbations who require a ventilator should also receive antibiotics.⁴

The Primary Care Consensus Guidelines from 2004, consistent with the GOLD recommendations, state that a newer macrolide, extended-spectrum cephalosporin, or doxycycline is appropriate for moderately severe exacerbations. High-dose amoxicillin/clavulanate or a respiratory fluoroquinolone should be given for severe exacerbations.⁵

Evidence summary

A systematic review of 4 RCTs with a total of 356 patients found that antibiotic therapy reduced mortality more than placebo in moderately to severely ill hospitalized patients with COPD. Short-term mortality (7 days after treatment to 18 months after hospital discharge) decreased by 77% with antibiotic use in acute exacerbations of COPD (number needed to treat [NNT]=8; 95% confidence interval [CI], 6-17).

This same Cochrane review and a meta-analysis of 4 hospital-based trials with 321 patients evaluated failure to improve, deterioration, or death during the study period.^1,2 The results favored treatment with antibiotics over placebo (NNT=3; 95% CI, 3-5).

Don’t wait to give antibiotics
A large retrospective cohort study of 84,621 hospitalized patients compared outcomes in patients given antibiotics for acute exacerbations of COPD during their first 2 days in the hospital with patients treated later or not at all.³ Outcomes assessed included need for later ventilation and readmission within 30 days for acute exacerbations of COPD.

The study included patients 40 years or older with a principal diagnosis, based on ICD 9 codes, of acute exacerbation of COPD, emphysema, or respiratory failure paired with a secondary diagnosis of COPD with acute exacerbation or emphysema. Patients who had been admitted directly to the intensive care unit were excluded, as were patients with other bacterial infections, such as pneumonia or cellulitis, for which they might receive antibiotics.

Early administration of antibiotics delayed the need for subsequent ventilation when compared with no antibiotics or antibiotics given later (1.07% vs 1.80%; P<.001; NNT=137). Giving antibiotics early also lowered readmission rates for acute exacerbations of COPD (7.91% vs 8.79%; P<.001; NNT=114), improved mortality rates (1.04% vs 1.59%; P<.001; NNT=182), and decreased treatment failure (9.77% vs 11.75%; P<.001; NNT=51).

Recommendations

The recommendations of the Global Initiative for Chronic Obstructive Lung Disease (GOLD), updated in 2008, call for antibiotics to be given to patients with 2 or more of the cardinal symptoms of acute exacerbations of COPD (shortness of breath, increased sputum production, and sputum purulence). Patients with severe exacerbations who require a ventilator should also receive antibiotics.⁴

The Primary Care Consensus Guidelines from 2004, consistent with the GOLD recommendations, state that a newer macrolide, extended-spectrum cephalosporin, or doxycycline is appropriate for moderately severe exacerbations. High-dose amoxicillin/clavulanate or a respiratory fluoroquinolone should be given for severe exacerbations.⁵

Evidence summary

A systematic review of 4 RCTs with a total of 356 patients found that antibiotic therapy reduced mortality more than placebo in moderately to severely ill hospitalized patients with COPD. Short-term mortality (7 days after treatment to 18 months after hospital discharge) decreased by 77% with antibiotic use in acute exacerbations of COPD (number needed to treat [NNT]=8; 95% confidence interval [CI], 6-17).

This same Cochrane review and a meta-analysis of 4 hospital-based trials with 321 patients evaluated failure to improve, deterioration, or death during the study period.^1,2 The results favored treatment with antibiotics over placebo (NNT=3; 95% CI, 3-5).

Don’t wait to give antibiotics
A large retrospective cohort study of 84,621 hospitalized patients compared outcomes in patients given antibiotics for acute exacerbations of COPD during their first 2 days in the hospital with patients treated later or not at all.³ Outcomes assessed included need for later ventilation and readmission within 30 days for acute exacerbations of COPD.

The study included patients 40 years or older with a principal diagnosis, based on ICD 9 codes, of acute exacerbation of COPD, emphysema, or respiratory failure paired with a secondary diagnosis of COPD with acute exacerbation or emphysema. Patients who had been admitted directly to the intensive care unit were excluded, as were patients with other bacterial infections, such as pneumonia or cellulitis, for which they might receive antibiotics.

Early administration of antibiotics delayed the need for subsequent ventilation when compared with no antibiotics or antibiotics given later (1.07% vs 1.80%; P<.001; NNT=137). Giving antibiotics early also lowered readmission rates for acute exacerbations of COPD (7.91% vs 8.79%; P<.001; NNT=114), improved mortality rates (1.04% vs 1.59%; P<.001; NNT=182), and decreased treatment failure (9.77% vs 11.75%; P<.001; NNT=51).

Recommendations

The recommendations of the Global Initiative for Chronic Obstructive Lung Disease (GOLD), updated in 2008, call for antibiotics to be given to patients with 2 or more of the cardinal symptoms of acute exacerbations of COPD (shortness of breath, increased sputum production, and sputum purulence). Patients with severe exacerbations who require a ventilator should also receive antibiotics.⁴

The Primary Care Consensus Guidelines from 2004, consistent with the GOLD recommendations, state that a newer macrolide, extended-spectrum cephalosporin, or doxycycline is appropriate for moderately severe exacerbations. High-dose amoxicillin/clavulanate or a respiratory fluoroquinolone should be given for severe exacerbations.⁵

Evidence summary

The most commonly measured outcomes in allergic rhinitis and conjunctivitis trials are symptom scales, which are neither standardized nor clinically validated. Almost all the studies discussed here calculated outcomes as a percentage change from baseline symptom scores but didn’t provide absolute values, so it isn’t clear whether statistical differences are clinically relevant.

Steroids provide more relief of nasal symptoms
A meta-analysis of 21 randomized placebo-controlled trials (total 2821 patients, average age mid-30s) that compared changes in TNSS with intranasal steroids and oral antihistamines among adults with seasonal allergic rhinitis found that steroids reduced TNSS more than antihistamines.¹ Most of the patients had had moderate to severe symptoms for several years.

Investigators calculated percent changes from baseline in mean TNSS, which typically included sneezing, itching, congestion, and rhinorrhea, each usually scored on a scale of 0 to 3.¹ Individual RCTs compared one of 3 intranasal steroids (fluticasone, triamcinolone, or budesonide) and one of 3 oral antihistamines (cetirizine, loratadine, or fexofenadine) with placebo; no studies compared medications within classes against each other.¹

On individual symptom scores, intranasal steroids reduced sneezing, itching, congestion, and rhinorrhea more than placebo by more than 20%. Both intranasal steroids and oral antihistamines decreased itching and rhinorrhea a similar amount, but antihistamines reduced congestion by only 5% to 10% more than placebo.¹

This meta-analysis included only studies reporting TNSS as an outcome, and individual studies used varying TNSS scales. Investigators attributed heterogeneity in the studies to intraclass differences between medications.¹

Two drug company-sponsored RCTs (1616 patients combined, average age 30s, moderate to severe allergic rhinitis) published before the meta-analysis also demonstrated that the intranasal steroid fluticasone propionate modestly reduced TNSS compared with the oral antihistamine fexofenadine (1 point vs 1.3 on a scale of 0 to 12).² TABLE 1 summarizes the results of studies comparing intranasal steroids and oral antihistamines to reduce nasal symptoms.

TABLE 1
Intranasal steroids vs oral antihistamines for nasal symptom relief

Results for eye symptoms are mixed
A meta-analysis of 11 RCTs (1317 patients, average age 32) showed no significant difference in relief of eye symptoms between oral antihistamines (dexchlorpheniramine, terfenadine, and loratadine) and intranasal steroids (budesonide, beclomethasone, fluticasone, and triamcinolone) in patients with seasonal allergies, as measured by various symptom scores.³

Three other studies indicated that intranasal steroids (triamcinolone, fluticasone) relieved eye symptoms more effectively than oral antihistamines (loratadine, fexofenadine) based on mean reductions in TNSS, Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), and Total Ocular Symptom Score (TOSS).^4-6 Of these scoring systems, only the RQLQ has been clinically validated.⁷

One additional study (including 2 RCTs) showed conflicting results.² TABLE 2 summarizes the results of studies comparing intranasal steroids and oral antihistamines to relieve eye symptoms.

TABLE 2
How intranasal steroids compare with oral antihistamines for reducing eye symptoms

Antihistamines cost less than steroids and are available OTC
Oral antihistamines are less expensive than intranasal steroids and are available over the counter. The cost of antihistamines ranges from $5.70 to $21.99 for a month of treatment, whereas the cost of intranasal steroids for the same period varies from $60.99 to $149.99.⁸

In the studies reviewed here, the 2 interventions showed similar harms, including sore throat, epistaxis, and headache.^2,4-6

Recommendations

The American Academy of Allergy, Asthma and Immunology’s 2010 guidelines conclude that intranasal steroids are first-line treatment for allergic rhinitis. If the patient prefers, use oral antihistamines.⁹

The Joint Task Force on Practice Parameters for Allergy and Immunology also recommends intranasal steroids as the most effective medication class for treating allergic rhinitis; no drug within the class is preferable to another. Daily administration is more effective than administration as needed, although the latter is an option. For treating ocular symptoms, intranasal corticosteroids and oral antihistamines work equally well.¹⁰

Evidence summary

The most commonly measured outcomes in allergic rhinitis and conjunctivitis trials are symptom scales, which are neither standardized nor clinically validated. Almost all the studies discussed here calculated outcomes as a percentage change from baseline symptom scores but didn’t provide absolute values, so it isn’t clear whether statistical differences are clinically relevant.

Steroids provide more relief of nasal symptoms
A meta-analysis of 21 randomized placebo-controlled trials (total 2821 patients, average age mid-30s) that compared changes in TNSS with intranasal steroids and oral antihistamines among adults with seasonal allergic rhinitis found that steroids reduced TNSS more than antihistamines.¹ Most of the patients had had moderate to severe symptoms for several years.

Investigators calculated percent changes from baseline in mean TNSS, which typically included sneezing, itching, congestion, and rhinorrhea, each usually scored on a scale of 0 to 3.¹ Individual RCTs compared one of 3 intranasal steroids (fluticasone, triamcinolone, or budesonide) and one of 3 oral antihistamines (cetirizine, loratadine, or fexofenadine) with placebo; no studies compared medications within classes against each other.¹

On individual symptom scores, intranasal steroids reduced sneezing, itching, congestion, and rhinorrhea more than placebo by more than 20%. Both intranasal steroids and oral antihistamines decreased itching and rhinorrhea a similar amount, but antihistamines reduced congestion by only 5% to 10% more than placebo.¹

This meta-analysis included only studies reporting TNSS as an outcome, and individual studies used varying TNSS scales. Investigators attributed heterogeneity in the studies to intraclass differences between medications.¹

Two drug company-sponsored RCTs (1616 patients combined, average age 30s, moderate to severe allergic rhinitis) published before the meta-analysis also demonstrated that the intranasal steroid fluticasone propionate modestly reduced TNSS compared with the oral antihistamine fexofenadine (1 point vs 1.3 on a scale of 0 to 12).² TABLE 1 summarizes the results of studies comparing intranasal steroids and oral antihistamines to reduce nasal symptoms.

TABLE 1
Intranasal steroids vs oral antihistamines for nasal symptom relief

Results for eye symptoms are mixed
A meta-analysis of 11 RCTs (1317 patients, average age 32) showed no significant difference in relief of eye symptoms between oral antihistamines (dexchlorpheniramine, terfenadine, and loratadine) and intranasal steroids (budesonide, beclomethasone, fluticasone, and triamcinolone) in patients with seasonal allergies, as measured by various symptom scores.³

Three other studies indicated that intranasal steroids (triamcinolone, fluticasone) relieved eye symptoms more effectively than oral antihistamines (loratadine, fexofenadine) based on mean reductions in TNSS, Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), and Total Ocular Symptom Score (TOSS).^4-6 Of these scoring systems, only the RQLQ has been clinically validated.⁷

One additional study (including 2 RCTs) showed conflicting results.² TABLE 2 summarizes the results of studies comparing intranasal steroids and oral antihistamines to relieve eye symptoms.

TABLE 2
How intranasal steroids compare with oral antihistamines for reducing eye symptoms

Antihistamines cost less than steroids and are available OTC
Oral antihistamines are less expensive than intranasal steroids and are available over the counter. The cost of antihistamines ranges from $5.70 to $21.99 for a month of treatment, whereas the cost of intranasal steroids for the same period varies from $60.99 to $149.99.⁸

In the studies reviewed here, the 2 interventions showed similar harms, including sore throat, epistaxis, and headache.^2,4-6

Recommendations

The American Academy of Allergy, Asthma and Immunology’s 2010 guidelines conclude that intranasal steroids are first-line treatment for allergic rhinitis. If the patient prefers, use oral antihistamines.⁹

The Joint Task Force on Practice Parameters for Allergy and Immunology also recommends intranasal steroids as the most effective medication class for treating allergic rhinitis; no drug within the class is preferable to another. Daily administration is more effective than administration as needed, although the latter is an option. For treating ocular symptoms, intranasal corticosteroids and oral antihistamines work equally well.¹⁰

Evidence summary

The most commonly measured outcomes in allergic rhinitis and conjunctivitis trials are symptom scales, which are neither standardized nor clinically validated. Almost all the studies discussed here calculated outcomes as a percentage change from baseline symptom scores but didn’t provide absolute values, so it isn’t clear whether statistical differences are clinically relevant.

Steroids provide more relief of nasal symptoms
A meta-analysis of 21 randomized placebo-controlled trials (total 2821 patients, average age mid-30s) that compared changes in TNSS with intranasal steroids and oral antihistamines among adults with seasonal allergic rhinitis found that steroids reduced TNSS more than antihistamines.¹ Most of the patients had had moderate to severe symptoms for several years.

Investigators calculated percent changes from baseline in mean TNSS, which typically included sneezing, itching, congestion, and rhinorrhea, each usually scored on a scale of 0 to 3.¹ Individual RCTs compared one of 3 intranasal steroids (fluticasone, triamcinolone, or budesonide) and one of 3 oral antihistamines (cetirizine, loratadine, or fexofenadine) with placebo; no studies compared medications within classes against each other.¹

On individual symptom scores, intranasal steroids reduced sneezing, itching, congestion, and rhinorrhea more than placebo by more than 20%. Both intranasal steroids and oral antihistamines decreased itching and rhinorrhea a similar amount, but antihistamines reduced congestion by only 5% to 10% more than placebo.¹

This meta-analysis included only studies reporting TNSS as an outcome, and individual studies used varying TNSS scales. Investigators attributed heterogeneity in the studies to intraclass differences between medications.¹

Two drug company-sponsored RCTs (1616 patients combined, average age 30s, moderate to severe allergic rhinitis) published before the meta-analysis also demonstrated that the intranasal steroid fluticasone propionate modestly reduced TNSS compared with the oral antihistamine fexofenadine (1 point vs 1.3 on a scale of 0 to 12).² TABLE 1 summarizes the results of studies comparing intranasal steroids and oral antihistamines to reduce nasal symptoms.

TABLE 1
Intranasal steroids vs oral antihistamines for nasal symptom relief

Results for eye symptoms are mixed
A meta-analysis of 11 RCTs (1317 patients, average age 32) showed no significant difference in relief of eye symptoms between oral antihistamines (dexchlorpheniramine, terfenadine, and loratadine) and intranasal steroids (budesonide, beclomethasone, fluticasone, and triamcinolone) in patients with seasonal allergies, as measured by various symptom scores.³

Three other studies indicated that intranasal steroids (triamcinolone, fluticasone) relieved eye symptoms more effectively than oral antihistamines (loratadine, fexofenadine) based on mean reductions in TNSS, Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ), and Total Ocular Symptom Score (TOSS).^4-6 Of these scoring systems, only the RQLQ has been clinically validated.⁷

One additional study (including 2 RCTs) showed conflicting results.² TABLE 2 summarizes the results of studies comparing intranasal steroids and oral antihistamines to relieve eye symptoms.

TABLE 2
How intranasal steroids compare with oral antihistamines for reducing eye symptoms

Antihistamines cost less than steroids and are available OTC
Oral antihistamines are less expensive than intranasal steroids and are available over the counter. The cost of antihistamines ranges from $5.70 to $21.99 for a month of treatment, whereas the cost of intranasal steroids for the same period varies from $60.99 to $149.99.⁸

In the studies reviewed here, the 2 interventions showed similar harms, including sore throat, epistaxis, and headache.^2,4-6

Recommendations

The American Academy of Allergy, Asthma and Immunology’s 2010 guidelines conclude that intranasal steroids are first-line treatment for allergic rhinitis. If the patient prefers, use oral antihistamines.⁹

The Joint Task Force on Practice Parameters for Allergy and Immunology also recommends intranasal steroids as the most effective medication class for treating allergic rhinitis; no drug within the class is preferable to another. Daily administration is more effective than administration as needed, although the latter is an option. For treating ocular symptoms, intranasal corticosteroids and oral antihistamines work equally well.¹⁰