The majority of children with obstructive sleep apnea (OSA) who took oral montelukast showed reductions in their apnea-hypopnea index (AHI) scores, according to the results of a randomized, double-blind placebo-controlled study. Typically, OSA in children is treated with adenotonsillectomy, explained Leila Kheirandish-Gozal, MD, director of clinical sleep research at the University of Chicago, and her colleagues. However, in this study, children were given either montelukast or placebo for 16 weeks and then participated in an overnight polysomnographic study. Seventy-one percent of the patients who took montelukast had fewer AHI events per hour of total sleep time at the end of the study. To learn more, see Family Practice News: http://www.mdedge.com/familypracticenews/article/116479/pulmonology/pediatric-osa-improved-oral-montelukast.

The majority of children with obstructive sleep apnea (OSA) who took oral montelukast showed reductions in their apnea-hypopnea index (AHI) scores, according to the results of a randomized, double-blind placebo-controlled study. Typically, OSA in children is treated with adenotonsillectomy, explained Leila Kheirandish-Gozal, MD, director of clinical sleep research at the University of Chicago, and her colleagues. However, in this study, children were given either montelukast or placebo for 16 weeks and then participated in an overnight polysomnographic study. Seventy-one percent of the patients who took montelukast had fewer AHI events per hour of total sleep time at the end of the study. To learn more, see Family Practice News: http://www.mdedge.com/familypracticenews/article/116479/pulmonology/pediatric-osa-improved-oral-montelukast.

The majority of children with obstructive sleep apnea (OSA) who took oral montelukast showed reductions in their apnea-hypopnea index (AHI) scores, according to the results of a randomized, double-blind placebo-controlled study. Typically, OSA in children is treated with adenotonsillectomy, explained Leila Kheirandish-Gozal, MD, director of clinical sleep research at the University of Chicago, and her colleagues. However, in this study, children were given either montelukast or placebo for 16 weeks and then participated in an overnight polysomnographic study. Seventy-one percent of the patients who took montelukast had fewer AHI events per hour of total sleep time at the end of the study. To learn more, see Family Practice News: http://www.mdedge.com/familypracticenews/article/116479/pulmonology/pediatric-osa-improved-oral-montelukast.

Researchers found that men, but not women, who had achieved sustained virologic response (SVR) after treatment for hepatitis C virus (HCV) had a small but significant weight gain, according to a single-center retrospective study. Liver fat also increased significantly in men after SVR was achieved, according to noninvasive assessments. The researchers believe that social, and not biochemical or mechanistic, reasons may be behind the weight gain and increased hepatic steatosis. A video interview with one of the researchers can be seen at Family Practice News: http://www.mdedge.com/familypracticenews/article/118172/obesity/video-dont-be-surprised-weight-gain-men-after-hcv-cure.

Researchers found that men, but not women, who had achieved sustained virologic response (SVR) after treatment for hepatitis C virus (HCV) had a small but significant weight gain, according to a single-center retrospective study. Liver fat also increased significantly in men after SVR was achieved, according to noninvasive assessments. The researchers believe that social, and not biochemical or mechanistic, reasons may be behind the weight gain and increased hepatic steatosis. A video interview with one of the researchers can be seen at Family Practice News: http://www.mdedge.com/familypracticenews/article/118172/obesity/video-dont-be-surprised-weight-gain-men-after-hcv-cure.

Researchers found that men, but not women, who had achieved sustained virologic response (SVR) after treatment for hepatitis C virus (HCV) had a small but significant weight gain, according to a single-center retrospective study. Liver fat also increased significantly in men after SVR was achieved, according to noninvasive assessments. The researchers believe that social, and not biochemical or mechanistic, reasons may be behind the weight gain and increased hepatic steatosis. A video interview with one of the researchers can be seen at Family Practice News: http://www.mdedge.com/familypracticenews/article/118172/obesity/video-dont-be-surprised-weight-gain-men-after-hcv-cure.

Results of a new 40,000-patient Swedish observational study provide the strongest evidence to date suggesting a causal relationship between bariatric surgery and reduced risk of heart failure, according to Johan Sundström, MD. The study, which included patients drawn from 2 large Swedish national registries, demonstrated that bariatric surgery was associated with a 46% reduction in the incidence of heart failure during a median 4.1 years of follow-up, compared with an intensive lifestyle modification program for weight loss.  

“A great way of studying causality is to take away the exposure and note what happens to the outcome. If there’s a causal link, then if you take away the risk factor—in this case, obesity—the disease should go away,” Dr. Sundström explained. Further details and a video interview are available at Cardiology News: http://www.mdedge.com/ecardiologynews/article/118204/heart-failure/video-bariatric-surgery-may-protect-against-heart?channel=224.

Results of a new 40,000-patient Swedish observational study provide the strongest evidence to date suggesting a causal relationship between bariatric surgery and reduced risk of heart failure, according to Johan Sundström, MD. The study, which included patients drawn from 2 large Swedish national registries, demonstrated that bariatric surgery was associated with a 46% reduction in the incidence of heart failure during a median 4.1 years of follow-up, compared with an intensive lifestyle modification program for weight loss.  

“A great way of studying causality is to take away the exposure and note what happens to the outcome. If there’s a causal link, then if you take away the risk factor—in this case, obesity—the disease should go away,” Dr. Sundström explained. Further details and a video interview are available at Cardiology News: http://www.mdedge.com/ecardiologynews/article/118204/heart-failure/video-bariatric-surgery-may-protect-against-heart?channel=224.

Results of a new 40,000-patient Swedish observational study provide the strongest evidence to date suggesting a causal relationship between bariatric surgery and reduced risk of heart failure, according to Johan Sundström, MD. The study, which included patients drawn from 2 large Swedish national registries, demonstrated that bariatric surgery was associated with a 46% reduction in the incidence of heart failure during a median 4.1 years of follow-up, compared with an intensive lifestyle modification program for weight loss.  

“A great way of studying causality is to take away the exposure and note what happens to the outcome. If there’s a causal link, then if you take away the risk factor—in this case, obesity—the disease should go away,” Dr. Sundström explained. Further details and a video interview are available at Cardiology News: http://www.mdedge.com/ecardiologynews/article/118204/heart-failure/video-bariatric-surgery-may-protect-against-heart?channel=224.

Temporary interruption of oral anticoagulation for stroke prevention in patients with atrial fibrillation occurs often and is associated with substantially increased risk of both cardioembolic events and all-cause mortality, according to a new prespecified secondary analysis of the ENGAGE-AF TIMI 48 trial.

The analysis showed that many of these treatment interruptions occur in response to nonserious adverse events such as minor bleeding, planned dental procedures, or simply because of patient wishes. The new ENGAGE-AF TIMI 48 findings may encourage physicians and patients to think twice before interrupting anticoagulant therapy for such reasons. More on the findings of this analysis can be found at Cardiology News: http://www.mdedge.com/ecardiologynews/article/116905/arrhythmias-ep/interrupting-oral-anticoagulation-af-carries-high.

Temporary interruption of oral anticoagulation for stroke prevention in patients with atrial fibrillation occurs often and is associated with substantially increased risk of both cardioembolic events and all-cause mortality, according to a new prespecified secondary analysis of the ENGAGE-AF TIMI 48 trial.

The analysis showed that many of these treatment interruptions occur in response to nonserious adverse events such as minor bleeding, planned dental procedures, or simply because of patient wishes. The new ENGAGE-AF TIMI 48 findings may encourage physicians and patients to think twice before interrupting anticoagulant therapy for such reasons. More on the findings of this analysis can be found at Cardiology News: http://www.mdedge.com/ecardiologynews/article/116905/arrhythmias-ep/interrupting-oral-anticoagulation-af-carries-high.

Temporary interruption of oral anticoagulation for stroke prevention in patients with atrial fibrillation occurs often and is associated with substantially increased risk of both cardioembolic events and all-cause mortality, according to a new prespecified secondary analysis of the ENGAGE-AF TIMI 48 trial.

The analysis showed that many of these treatment interruptions occur in response to nonserious adverse events such as minor bleeding, planned dental procedures, or simply because of patient wishes. The new ENGAGE-AF TIMI 48 findings may encourage physicians and patients to think twice before interrupting anticoagulant therapy for such reasons. More on the findings of this analysis can be found at Cardiology News: http://www.mdedge.com/ecardiologynews/article/116905/arrhythmias-ep/interrupting-oral-anticoagulation-af-carries-high.

In part 1 of our review on preventing postcesarean infection, we critically evaluated methods of skin preparation and administration of prophylactic antibiotics. In part 2, we address preoperative cleansing of the vagina with an antiseptic solution, preoperative bathing with an antiseptic solution, methods of placental extraction, closure of the deep subcutaneous layer of the abdomen, and closure of the skin.

Related article:
Preventing infection after cesarean delivery: Evidence-based guidance

CASE: Should vaginal cleansing be performed prior to cesarean delivery?

An 18-year-old primigravid woman at 41 weeks’ gestation has been in labor for 16 hours, and now has an arrest of descent at 0 station. An intrauterine pressure catheter and scalp electrode have been in place for the same length of time. The patient has had 9 internal examinations during the period of membrane rupture. As you are preparing to scrub the patient’s abdomen, the third-year medical student asks, “When I was on the Gynecology Service, I saw the doctors wash the vagina with an antiseptic solution before they performed a vaginal hysterectomy. Should we also do that before we operate on this patient?”

Preoperative vaginal cleansing

A preoperative antiseptic vaginal scrub is often used as an additional step to help reduce postcesarean infection.

Does cleansing the vagina with povidone-iodine before surgery further reduce the risk of endometritis and wound infection?

Multiple studies have sought to determine if cleansing the vagina with an antiseptic solution further reduces the incidence of postcesarean infection beyond what can be achieved with systemic antibiotic prophylaxis. These studies typically have focused on 3 specific outcomes: endometritis, wound (surgical site) infection, and febrile morbidity. The term febrile morbidity is defined as a temperature ≥100.4°F (38°C) on any 2 postoperative days excluding the first 24 hours. However, many patients who meet the standard definition of febrile morbidity may not have a proven infection and will not require treatment with antibiotics. The more precise measures of outcome are distinctly symptomatic infections, such as endometritis and wound infection, although, as noted in the review of published studies below, some authors continue to use the term febrile morbidity as one measure of postoperative complications.

In a randomized, placebo-controlled trial (RCT) of 308 women having a nonemergent cesarean delivery, Starr and colleagues reported a decreased incidence of postoperative endometritis in women who received a 30-second vaginal scrub with povidone-iodine compared with women who received only an abdominal scrub (7.0% vs 14.5%, P<.05).¹ The groups did not differ in the frequency of wound infection (0.7% vs 1.2%, P = .4) or febrile morbidity (23.9% vs 28.3%, P = .4).¹

In another RCT, Haas and colleagues found that preoperative vaginal cleansing with povidone-iodine compared with an abdominal scrub alone was associated with a decreased incidence of a composite measure of postoperative morbidity (6.5% vs 11.7%; relative risk [RR], 0.55; 95% confidence interval [CI], 0.26–1.11; P = .11).² The postoperative composite included fever, endometritis, sepsis, readmission, and wound infection.

Subsequently, Asghania and associates conducted a double-blind, nonrandomized study of 568 women having cesarean delivery who received an abdominal scrub plus a 30-second vaginal scrub with povidone-iodine or received an abdominal scrub alone.³ They documented a decreased incidence of postoperative endometritis in the women who received the combined scrub (1.4% vs 2.5%; P = .03, adjusted odds ratio [AOR], 0.03; 95% CI, 0.008–0.7). The authors observed no significant difference in febrile morbidity (4.9% vs 6.0%; P = .73) or wound infection (3.5% vs 3.2%; P = .5).³

Yildirim and colleagues conducted an RCT comparing rates of infection in 334 women who received an abdominal scrub plus vaginal cleansing with povidone-iodine and 336 patients who had only a standard abdominal scrub.⁴ They documented a decreased incidence of endometritis in women who received the vaginal scrub (6.9% vs 11.6%; P = .04; RR for infection in the control group, 1.69; 95% CI, 1.03–2.76.) The authors found no difference in febrile morbidity (16.5% vs 18.2%; P = .61) or wound infection (1.8% vs 2.7%; P = .60). Of note, in excluding from the analysis women who had ruptured membranes or who were in labor, the investigators found no differences in outcome, indicating that the greatest impact of vaginal cleansing was in the highest risk patients.

In 2014, Haas and associates published a Cochrane review evaluating the effectiveness of preoperative vaginal cleansing with povidone-iodine.⁵ The authors reviewed 7 studies that analyzed outcomes in 2,635 women. They concluded that vaginal preparation with povidone-iodine at the time of cesarean delivery significantly decreased postoperative endometritis when compared with the control group (4.3% vs 8.3%; RR, 0.45; 95% CI, 0.25–0.81). They also noted that the most profound impact of vaginal cleansing was in women who were in labor before delivery (7.4% vs 13.0%; RR, 0.56; 95% CI, 0.34–0.95) and in women with ruptured membranes at the time of delivery (4.3% vs 17.9%; RR, 0.24; 95% CI, 0.10–0.55). The authors did not find a significant difference in postoperative wound infection or frequency of fever in women who received the vaginal scrub.

Related article:
STOP using instruments to assist with delivery of the head at cesarean

A notable exception to the beneficial outcomes reported above was the study by Reid et al.⁶ These authors randomly assigned 247 women having cesarean delivery to an abdominal scrub plus vaginal scrub with povidone-iodine and assigned 251 women to only an abdominal scrub. The authors were unable to document any significant difference between the groups with respect to frequency of fever, endometritis, and wound infection.

Other methods of vaginal preparation also have been studied. For example, Pitt and colleagues conducted a double-blind RCT of 224 women having cesarean delivery and compared preoperative metronidazole vaginal gel with placebo.⁷ Most of the patients in this trial also received systemic antibiotic prophylaxis after the umbilical cord was clamped. The authors demonstrated a decreased incidence of postcesarean endometritis in women who received the intravaginal antibiotic gel (7% vs 17%; RR, 0.42; 95% CI, 0.19–0.92). There was no difference in febrile morbidity (13% vs 19%; P = .28) or wound infection (4% vs 3%, P = .50).

What the evidence says

Consider vaginal preparation with povidone-iodine at the time of cesarean delivery to reduce the risk of postpartum endometritis. Do not expect this intervention to significantly reduce the frequency of wound infection. Vaginal cleansing is of most benefit to women who have ruptured membranes or are in labor at the time of delivery (Level I Evidence, Level A Recommendation; TABLE). Whether vaginal preparation with chlorhexidine with 4% alcohol would have the same beneficial effect has not been studied in a systematic manner.

Placenta extraction, closure techniques

Evidence suggests that employing certain intraoperative approaches helps reduce the incidence of postcesarean infection.

What other measures help prevent infection following cesarean surgery?

One other measure known to decrease the risk of postcesarean endometritis is removing the placenta by exerting traction on the umbilical cord rather than extracting it manually. In one of the first descriptions of this intervention, Lasley and associates showed that, in high-risk patients who also received intravenous antibiotic prophylaxis after cord clamping, the rate of postoperative endometritis was 15% in the group that had spontaneous delivery of the placenta compared with 27% in women who had manual extraction (RR, 0.6; 95% CI, 0.3–0.9; P = .02).⁸ A recent Cochrane review that included multiple subsequent reports confirmed this observation (Level I Evidence, Level A Recommendation; TABLE, page 2).⁹

Abdominal wall closure. Two other interventions are valuable in decreasing the frequency of deep and superficial wound infection. In patients whose subcutaneous layer is >2 cm thick, closure of the deep subcutaneous tissue significantly reduces the risk of wound seroma, hematoma, and infection.¹⁰ In addition, closure of the skin edges with a subcuticular suture, as opposed to surgical staples, significantly reduces the frequency of superficial wound complications (Level I Evidence, Level A Recommendation; TABLE, page 2).¹¹ Poliglecaprone 25, polyglactin 910, and polyglycolic acid suture, 3-0 or 4-0 gauge, are excellent suture choices for this closure.

Related article:
Does one particular cesarean technique confer better maternal and neonatal outcomes?

CASE
Planned cesarean delivery: Is preoperative antiseptic bathing warranted?

A 33-year-old woman (G2P1001) at 39 weeks’ gestation is scheduled for a repeat low transverse cesarean delivery. In addition to planning to implement the measures discussed above, her clinician is considering whether to recommend that the patient bathe with an antiseptic solution, such as chlorhexidine, the day before the procedure.

Preoperative antiseptic bathing

The concept of bathing with an antiseptic solution before surgery to prevent surgical site infections (SSIs) has been considered for many years. Intuitively, if the body’s resident and transient skin flora are decreased preoperatively with whole-body antiseptic washing, then the overall pathogen burden should be decreased and the risk of SSI also should be reduced. Historically, chlorhexidine preparations have been used as preoperative antiseptic solutions because they are so effective in reducing colony counts of skin flora, especially staphylococci.¹² Although preoperative antiseptic washing definitely reduces the concentration of skin bacteria, the data regarding reduction in SSI are inconsistent. Of particular note, there are no studies investigating the impact of preoperative antiseptic bathing in women having cesarean delivery.

Does preop bathing with an antiseptic reduce infection risk?

One of the first studies evaluating preoperative antiseptic washing was published by Cruse and Foord in 1980.¹³ In this 10-year prospective investigation, the authors demonstrated that patients who underwent preoperative washing with a hexachlorophene solution had fewer SSIs compared with those who washed with a nonmedicated soap and those who did not wash at all. Subsequent studies by Brady et al in 1990,¹⁴ Wilcox et al in 2003,¹⁵ and Colling et al in 2015¹⁶ all showed a decrease in the rate of SSIs with preoperative antiseptic washing, and the authors strongly supported this intervention. However, care must be taken when interpreting the results of these cohort investigations because in some cases antiseptic washing was not the only preoperative intervention. Thus, it is difficult to ascertain the true benefit of antiseptic washing alone.^14,15 Moreover, in one study, preoperative antiseptic washing did not decrease the overall incidence of SSIs, just those caused by Staphylococcus aureus and methicillin-resistant S aureus (MRSA).¹⁶

Authors of 3 recent reviews have assessed the relationship between preoperative antiseptic washing and SSIs. Webster and Osborne analyzed 7 RCTs in a Cochrane review.¹⁷ All trials used 4% chlorhexidine gluconate as the antiseptic, and they included a total of 10,157 patients. The authors concluded that bathing with chlorhexidine did not significantly reduce SSIs compared with either placebo (RR, 0.91; 95% CI, 0.8–1.04) or bar soap (RR, 1.02; 95% CI, 0.57–1.84). Three additional studies in this review compared chlorhexidine bathing with no washing. One study showed a significant reduction of SSIs after the patients bathed with chlorhexidine (RR, 0.36; 95% CI, 0.17–0.79); the other 2 studies demonstrated no significant difference in outcome.

Kamel and colleagues conducted a recent systematic review that included 20 randomized and nonrandomized studies (n = 9,520); while the authors concluded that showering with an antiseptic solution reduced skin flora, they could not confirm that it produced a significant reduction in infection.¹⁸ Finally, in a meta-analysis that included 16 randomized and nonrandomized studies with 17,932 patients, Chlebicki and associates concluded that there was no significant reduction in SSIs with whole-body bathing with chlorhexidine compared with bathing with soap or placebo or with no bathing (RR, 0.90; 95% CI, 0.77–1.05; P = .19).¹⁹ A recent report from the World Health Organization confirmed these observations, although the report did not specifically focus on patients who had had a cesarean delivery.²⁰

What the evidence says

Although chlorhexidine bathing reduces skin flora, especially in the number of staphylococcal species, this effect does not necessarily translate into a reduction of SSIs. Therefore, we recommend against routine chlorhexidine bathing before cesarean delivery, although we acknowledge that there is no apparent harm associated with this practice, assuming that the patient is not allergic to the medicated soap (Level II Evidence, Level C Recommendation; TABLE, page 2).

Did you read Part 1 of this series?

Preventing infection after cesarean delivery: Evidence-based guidance, Part 1

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In part 1 of our review on preventing postcesarean infection, we critically evaluated methods of skin preparation and administration of prophylactic antibiotics. In part 2, we address preoperative cleansing of the vagina with an antiseptic solution, preoperative bathing with an antiseptic solution, methods of placental extraction, closure of the deep subcutaneous layer of the abdomen, and closure of the skin.

Related article:
Preventing infection after cesarean delivery: Evidence-based guidance

CASE: Should vaginal cleansing be performed prior to cesarean delivery?

An 18-year-old primigravid woman at 41 weeks’ gestation has been in labor for 16 hours, and now has an arrest of descent at 0 station. An intrauterine pressure catheter and scalp electrode have been in place for the same length of time. The patient has had 9 internal examinations during the period of membrane rupture. As you are preparing to scrub the patient’s abdomen, the third-year medical student asks, “When I was on the Gynecology Service, I saw the doctors wash the vagina with an antiseptic solution before they performed a vaginal hysterectomy. Should we also do that before we operate on this patient?”

Preoperative vaginal cleansing

A preoperative antiseptic vaginal scrub is often used as an additional step to help reduce postcesarean infection.

Does cleansing the vagina with povidone-iodine before surgery further reduce the risk of endometritis and wound infection?

Multiple studies have sought to determine if cleansing the vagina with an antiseptic solution further reduces the incidence of postcesarean infection beyond what can be achieved with systemic antibiotic prophylaxis. These studies typically have focused on 3 specific outcomes: endometritis, wound (surgical site) infection, and febrile morbidity. The term febrile morbidity is defined as a temperature ≥100.4°F (38°C) on any 2 postoperative days excluding the first 24 hours. However, many patients who meet the standard definition of febrile morbidity may not have a proven infection and will not require treatment with antibiotics. The more precise measures of outcome are distinctly symptomatic infections, such as endometritis and wound infection, although, as noted in the review of published studies below, some authors continue to use the term febrile morbidity as one measure of postoperative complications.

In a randomized, placebo-controlled trial (RCT) of 308 women having a nonemergent cesarean delivery, Starr and colleagues reported a decreased incidence of postoperative endometritis in women who received a 30-second vaginal scrub with povidone-iodine compared with women who received only an abdominal scrub (7.0% vs 14.5%, P<.05).¹ The groups did not differ in the frequency of wound infection (0.7% vs 1.2%, P = .4) or febrile morbidity (23.9% vs 28.3%, P = .4).¹

In another RCT, Haas and colleagues found that preoperative vaginal cleansing with povidone-iodine compared with an abdominal scrub alone was associated with a decreased incidence of a composite measure of postoperative morbidity (6.5% vs 11.7%; relative risk [RR], 0.55; 95% confidence interval [CI], 0.26–1.11; P = .11).² The postoperative composite included fever, endometritis, sepsis, readmission, and wound infection.

Subsequently, Asghania and associates conducted a double-blind, nonrandomized study of 568 women having cesarean delivery who received an abdominal scrub plus a 30-second vaginal scrub with povidone-iodine or received an abdominal scrub alone.³ They documented a decreased incidence of postoperative endometritis in the women who received the combined scrub (1.4% vs 2.5%; P = .03, adjusted odds ratio [AOR], 0.03; 95% CI, 0.008–0.7). The authors observed no significant difference in febrile morbidity (4.9% vs 6.0%; P = .73) or wound infection (3.5% vs 3.2%; P = .5).³

Yildirim and colleagues conducted an RCT comparing rates of infection in 334 women who received an abdominal scrub plus vaginal cleansing with povidone-iodine and 336 patients who had only a standard abdominal scrub.⁴ They documented a decreased incidence of endometritis in women who received the vaginal scrub (6.9% vs 11.6%; P = .04; RR for infection in the control group, 1.69; 95% CI, 1.03–2.76.) The authors found no difference in febrile morbidity (16.5% vs 18.2%; P = .61) or wound infection (1.8% vs 2.7%; P = .60). Of note, in excluding from the analysis women who had ruptured membranes or who were in labor, the investigators found no differences in outcome, indicating that the greatest impact of vaginal cleansing was in the highest risk patients.

In 2014, Haas and associates published a Cochrane review evaluating the effectiveness of preoperative vaginal cleansing with povidone-iodine.⁵ The authors reviewed 7 studies that analyzed outcomes in 2,635 women. They concluded that vaginal preparation with povidone-iodine at the time of cesarean delivery significantly decreased postoperative endometritis when compared with the control group (4.3% vs 8.3%; RR, 0.45; 95% CI, 0.25–0.81). They also noted that the most profound impact of vaginal cleansing was in women who were in labor before delivery (7.4% vs 13.0%; RR, 0.56; 95% CI, 0.34–0.95) and in women with ruptured membranes at the time of delivery (4.3% vs 17.9%; RR, 0.24; 95% CI, 0.10–0.55). The authors did not find a significant difference in postoperative wound infection or frequency of fever in women who received the vaginal scrub.

Related article:
STOP using instruments to assist with delivery of the head at cesarean

A notable exception to the beneficial outcomes reported above was the study by Reid et al.⁶ These authors randomly assigned 247 women having cesarean delivery to an abdominal scrub plus vaginal scrub with povidone-iodine and assigned 251 women to only an abdominal scrub. The authors were unable to document any significant difference between the groups with respect to frequency of fever, endometritis, and wound infection.

Other methods of vaginal preparation also have been studied. For example, Pitt and colleagues conducted a double-blind RCT of 224 women having cesarean delivery and compared preoperative metronidazole vaginal gel with placebo.⁷ Most of the patients in this trial also received systemic antibiotic prophylaxis after the umbilical cord was clamped. The authors demonstrated a decreased incidence of postcesarean endometritis in women who received the intravaginal antibiotic gel (7% vs 17%; RR, 0.42; 95% CI, 0.19–0.92). There was no difference in febrile morbidity (13% vs 19%; P = .28) or wound infection (4% vs 3%, P = .50).

What the evidence says

Consider vaginal preparation with povidone-iodine at the time of cesarean delivery to reduce the risk of postpartum endometritis. Do not expect this intervention to significantly reduce the frequency of wound infection. Vaginal cleansing is of most benefit to women who have ruptured membranes or are in labor at the time of delivery (Level I Evidence, Level A Recommendation; TABLE). Whether vaginal preparation with chlorhexidine with 4% alcohol would have the same beneficial effect has not been studied in a systematic manner.

Placenta extraction, closure techniques

Evidence suggests that employing certain intraoperative approaches helps reduce the incidence of postcesarean infection.

What other measures help prevent infection following cesarean surgery?

One other measure known to decrease the risk of postcesarean endometritis is removing the placenta by exerting traction on the umbilical cord rather than extracting it manually. In one of the first descriptions of this intervention, Lasley and associates showed that, in high-risk patients who also received intravenous antibiotic prophylaxis after cord clamping, the rate of postoperative endometritis was 15% in the group that had spontaneous delivery of the placenta compared with 27% in women who had manual extraction (RR, 0.6; 95% CI, 0.3–0.9; P = .02).⁸ A recent Cochrane review that included multiple subsequent reports confirmed this observation (Level I Evidence, Level A Recommendation; TABLE, page 2).⁹

Abdominal wall closure. Two other interventions are valuable in decreasing the frequency of deep and superficial wound infection. In patients whose subcutaneous layer is >2 cm thick, closure of the deep subcutaneous tissue significantly reduces the risk of wound seroma, hematoma, and infection.¹⁰ In addition, closure of the skin edges with a subcuticular suture, as opposed to surgical staples, significantly reduces the frequency of superficial wound complications (Level I Evidence, Level A Recommendation; TABLE, page 2).¹¹ Poliglecaprone 25, polyglactin 910, and polyglycolic acid suture, 3-0 or 4-0 gauge, are excellent suture choices for this closure.

Related article:
Does one particular cesarean technique confer better maternal and neonatal outcomes?

CASE
Planned cesarean delivery: Is preoperative antiseptic bathing warranted?

A 33-year-old woman (G2P1001) at 39 weeks’ gestation is scheduled for a repeat low transverse cesarean delivery. In addition to planning to implement the measures discussed above, her clinician is considering whether to recommend that the patient bathe with an antiseptic solution, such as chlorhexidine, the day before the procedure.

Preoperative antiseptic bathing

The concept of bathing with an antiseptic solution before surgery to prevent surgical site infections (SSIs) has been considered for many years. Intuitively, if the body’s resident and transient skin flora are decreased preoperatively with whole-body antiseptic washing, then the overall pathogen burden should be decreased and the risk of SSI also should be reduced. Historically, chlorhexidine preparations have been used as preoperative antiseptic solutions because they are so effective in reducing colony counts of skin flora, especially staphylococci.¹² Although preoperative antiseptic washing definitely reduces the concentration of skin bacteria, the data regarding reduction in SSI are inconsistent. Of particular note, there are no studies investigating the impact of preoperative antiseptic bathing in women having cesarean delivery.

Does preop bathing with an antiseptic reduce infection risk?

One of the first studies evaluating preoperative antiseptic washing was published by Cruse and Foord in 1980.¹³ In this 10-year prospective investigation, the authors demonstrated that patients who underwent preoperative washing with a hexachlorophene solution had fewer SSIs compared with those who washed with a nonmedicated soap and those who did not wash at all. Subsequent studies by Brady et al in 1990,¹⁴ Wilcox et al in 2003,¹⁵ and Colling et al in 2015¹⁶ all showed a decrease in the rate of SSIs with preoperative antiseptic washing, and the authors strongly supported this intervention. However, care must be taken when interpreting the results of these cohort investigations because in some cases antiseptic washing was not the only preoperative intervention. Thus, it is difficult to ascertain the true benefit of antiseptic washing alone.^14,15 Moreover, in one study, preoperative antiseptic washing did not decrease the overall incidence of SSIs, just those caused by Staphylococcus aureus and methicillin-resistant S aureus (MRSA).¹⁶

Authors of 3 recent reviews have assessed the relationship between preoperative antiseptic washing and SSIs. Webster and Osborne analyzed 7 RCTs in a Cochrane review.¹⁷ All trials used 4% chlorhexidine gluconate as the antiseptic, and they included a total of 10,157 patients. The authors concluded that bathing with chlorhexidine did not significantly reduce SSIs compared with either placebo (RR, 0.91; 95% CI, 0.8–1.04) or bar soap (RR, 1.02; 95% CI, 0.57–1.84). Three additional studies in this review compared chlorhexidine bathing with no washing. One study showed a significant reduction of SSIs after the patients bathed with chlorhexidine (RR, 0.36; 95% CI, 0.17–0.79); the other 2 studies demonstrated no significant difference in outcome.

Kamel and colleagues conducted a recent systematic review that included 20 randomized and nonrandomized studies (n = 9,520); while the authors concluded that showering with an antiseptic solution reduced skin flora, they could not confirm that it produced a significant reduction in infection.¹⁸ Finally, in a meta-analysis that included 16 randomized and nonrandomized studies with 17,932 patients, Chlebicki and associates concluded that there was no significant reduction in SSIs with whole-body bathing with chlorhexidine compared with bathing with soap or placebo or with no bathing (RR, 0.90; 95% CI, 0.77–1.05; P = .19).¹⁹ A recent report from the World Health Organization confirmed these observations, although the report did not specifically focus on patients who had had a cesarean delivery.²⁰

What the evidence says

Although chlorhexidine bathing reduces skin flora, especially in the number of staphylococcal species, this effect does not necessarily translate into a reduction of SSIs. Therefore, we recommend against routine chlorhexidine bathing before cesarean delivery, although we acknowledge that there is no apparent harm associated with this practice, assuming that the patient is not allergic to the medicated soap (Level II Evidence, Level C Recommendation; TABLE, page 2).

Did you read Part 1 of this series?

Preventing infection after cesarean delivery: Evidence-based guidance, Part 1

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

In part 1 of our review on preventing postcesarean infection, we critically evaluated methods of skin preparation and administration of prophylactic antibiotics. In part 2, we address preoperative cleansing of the vagina with an antiseptic solution, preoperative bathing with an antiseptic solution, methods of placental extraction, closure of the deep subcutaneous layer of the abdomen, and closure of the skin.

Related article:
Preventing infection after cesarean delivery: Evidence-based guidance

CASE: Should vaginal cleansing be performed prior to cesarean delivery?

An 18-year-old primigravid woman at 41 weeks’ gestation has been in labor for 16 hours, and now has an arrest of descent at 0 station. An intrauterine pressure catheter and scalp electrode have been in place for the same length of time. The patient has had 9 internal examinations during the period of membrane rupture. As you are preparing to scrub the patient’s abdomen, the third-year medical student asks, “When I was on the Gynecology Service, I saw the doctors wash the vagina with an antiseptic solution before they performed a vaginal hysterectomy. Should we also do that before we operate on this patient?”

Preoperative vaginal cleansing

A preoperative antiseptic vaginal scrub is often used as an additional step to help reduce postcesarean infection.

Does cleansing the vagina with povidone-iodine before surgery further reduce the risk of endometritis and wound infection?

Multiple studies have sought to determine if cleansing the vagina with an antiseptic solution further reduces the incidence of postcesarean infection beyond what can be achieved with systemic antibiotic prophylaxis. These studies typically have focused on 3 specific outcomes: endometritis, wound (surgical site) infection, and febrile morbidity. The term febrile morbidity is defined as a temperature ≥100.4°F (38°C) on any 2 postoperative days excluding the first 24 hours. However, many patients who meet the standard definition of febrile morbidity may not have a proven infection and will not require treatment with antibiotics. The more precise measures of outcome are distinctly symptomatic infections, such as endometritis and wound infection, although, as noted in the review of published studies below, some authors continue to use the term febrile morbidity as one measure of postoperative complications.

In a randomized, placebo-controlled trial (RCT) of 308 women having a nonemergent cesarean delivery, Starr and colleagues reported a decreased incidence of postoperative endometritis in women who received a 30-second vaginal scrub with povidone-iodine compared with women who received only an abdominal scrub (7.0% vs 14.5%, P<.05).¹ The groups did not differ in the frequency of wound infection (0.7% vs 1.2%, P = .4) or febrile morbidity (23.9% vs 28.3%, P = .4).¹

In another RCT, Haas and colleagues found that preoperative vaginal cleansing with povidone-iodine compared with an abdominal scrub alone was associated with a decreased incidence of a composite measure of postoperative morbidity (6.5% vs 11.7%; relative risk [RR], 0.55; 95% confidence interval [CI], 0.26–1.11; P = .11).² The postoperative composite included fever, endometritis, sepsis, readmission, and wound infection.

Subsequently, Asghania and associates conducted a double-blind, nonrandomized study of 568 women having cesarean delivery who received an abdominal scrub plus a 30-second vaginal scrub with povidone-iodine or received an abdominal scrub alone.³ They documented a decreased incidence of postoperative endometritis in the women who received the combined scrub (1.4% vs 2.5%; P = .03, adjusted odds ratio [AOR], 0.03; 95% CI, 0.008–0.7). The authors observed no significant difference in febrile morbidity (4.9% vs 6.0%; P = .73) or wound infection (3.5% vs 3.2%; P = .5).³

Yildirim and colleagues conducted an RCT comparing rates of infection in 334 women who received an abdominal scrub plus vaginal cleansing with povidone-iodine and 336 patients who had only a standard abdominal scrub.⁴ They documented a decreased incidence of endometritis in women who received the vaginal scrub (6.9% vs 11.6%; P = .04; RR for infection in the control group, 1.69; 95% CI, 1.03–2.76.) The authors found no difference in febrile morbidity (16.5% vs 18.2%; P = .61) or wound infection (1.8% vs 2.7%; P = .60). Of note, in excluding from the analysis women who had ruptured membranes or who were in labor, the investigators found no differences in outcome, indicating that the greatest impact of vaginal cleansing was in the highest risk patients.

In 2014, Haas and associates published a Cochrane review evaluating the effectiveness of preoperative vaginal cleansing with povidone-iodine.⁵ The authors reviewed 7 studies that analyzed outcomes in 2,635 women. They concluded that vaginal preparation with povidone-iodine at the time of cesarean delivery significantly decreased postoperative endometritis when compared with the control group (4.3% vs 8.3%; RR, 0.45; 95% CI, 0.25–0.81). They also noted that the most profound impact of vaginal cleansing was in women who were in labor before delivery (7.4% vs 13.0%; RR, 0.56; 95% CI, 0.34–0.95) and in women with ruptured membranes at the time of delivery (4.3% vs 17.9%; RR, 0.24; 95% CI, 0.10–0.55). The authors did not find a significant difference in postoperative wound infection or frequency of fever in women who received the vaginal scrub.

Related article:
STOP using instruments to assist with delivery of the head at cesarean

A notable exception to the beneficial outcomes reported above was the study by Reid et al.⁶ These authors randomly assigned 247 women having cesarean delivery to an abdominal scrub plus vaginal scrub with povidone-iodine and assigned 251 women to only an abdominal scrub. The authors were unable to document any significant difference between the groups with respect to frequency of fever, endometritis, and wound infection.

Other methods of vaginal preparation also have been studied. For example, Pitt and colleagues conducted a double-blind RCT of 224 women having cesarean delivery and compared preoperative metronidazole vaginal gel with placebo.⁷ Most of the patients in this trial also received systemic antibiotic prophylaxis after the umbilical cord was clamped. The authors demonstrated a decreased incidence of postcesarean endometritis in women who received the intravaginal antibiotic gel (7% vs 17%; RR, 0.42; 95% CI, 0.19–0.92). There was no difference in febrile morbidity (13% vs 19%; P = .28) or wound infection (4% vs 3%, P = .50).

What the evidence says

Consider vaginal preparation with povidone-iodine at the time of cesarean delivery to reduce the risk of postpartum endometritis. Do not expect this intervention to significantly reduce the frequency of wound infection. Vaginal cleansing is of most benefit to women who have ruptured membranes or are in labor at the time of delivery (Level I Evidence, Level A Recommendation; TABLE). Whether vaginal preparation with chlorhexidine with 4% alcohol would have the same beneficial effect has not been studied in a systematic manner.

Placenta extraction, closure techniques

Evidence suggests that employing certain intraoperative approaches helps reduce the incidence of postcesarean infection.

What other measures help prevent infection following cesarean surgery?

One other measure known to decrease the risk of postcesarean endometritis is removing the placenta by exerting traction on the umbilical cord rather than extracting it manually. In one of the first descriptions of this intervention, Lasley and associates showed that, in high-risk patients who also received intravenous antibiotic prophylaxis after cord clamping, the rate of postoperative endometritis was 15% in the group that had spontaneous delivery of the placenta compared with 27% in women who had manual extraction (RR, 0.6; 95% CI, 0.3–0.9; P = .02).⁸ A recent Cochrane review that included multiple subsequent reports confirmed this observation (Level I Evidence, Level A Recommendation; TABLE, page 2).⁹

Abdominal wall closure. Two other interventions are valuable in decreasing the frequency of deep and superficial wound infection. In patients whose subcutaneous layer is >2 cm thick, closure of the deep subcutaneous tissue significantly reduces the risk of wound seroma, hematoma, and infection.¹⁰ In addition, closure of the skin edges with a subcuticular suture, as opposed to surgical staples, significantly reduces the frequency of superficial wound complications (Level I Evidence, Level A Recommendation; TABLE, page 2).¹¹ Poliglecaprone 25, polyglactin 910, and polyglycolic acid suture, 3-0 or 4-0 gauge, are excellent suture choices for this closure.

Related article:
Does one particular cesarean technique confer better maternal and neonatal outcomes?

CASE
Planned cesarean delivery: Is preoperative antiseptic bathing warranted?

A 33-year-old woman (G2P1001) at 39 weeks’ gestation is scheduled for a repeat low transverse cesarean delivery. In addition to planning to implement the measures discussed above, her clinician is considering whether to recommend that the patient bathe with an antiseptic solution, such as chlorhexidine, the day before the procedure.

Preoperative antiseptic bathing

The concept of bathing with an antiseptic solution before surgery to prevent surgical site infections (SSIs) has been considered for many years. Intuitively, if the body’s resident and transient skin flora are decreased preoperatively with whole-body antiseptic washing, then the overall pathogen burden should be decreased and the risk of SSI also should be reduced. Historically, chlorhexidine preparations have been used as preoperative antiseptic solutions because they are so effective in reducing colony counts of skin flora, especially staphylococci.¹² Although preoperative antiseptic washing definitely reduces the concentration of skin bacteria, the data regarding reduction in SSI are inconsistent. Of particular note, there are no studies investigating the impact of preoperative antiseptic bathing in women having cesarean delivery.

Does preop bathing with an antiseptic reduce infection risk?

One of the first studies evaluating preoperative antiseptic washing was published by Cruse and Foord in 1980.¹³ In this 10-year prospective investigation, the authors demonstrated that patients who underwent preoperative washing with a hexachlorophene solution had fewer SSIs compared with those who washed with a nonmedicated soap and those who did not wash at all. Subsequent studies by Brady et al in 1990,¹⁴ Wilcox et al in 2003,¹⁵ and Colling et al in 2015¹⁶ all showed a decrease in the rate of SSIs with preoperative antiseptic washing, and the authors strongly supported this intervention. However, care must be taken when interpreting the results of these cohort investigations because in some cases antiseptic washing was not the only preoperative intervention. Thus, it is difficult to ascertain the true benefit of antiseptic washing alone.^14,15 Moreover, in one study, preoperative antiseptic washing did not decrease the overall incidence of SSIs, just those caused by Staphylococcus aureus and methicillin-resistant S aureus (MRSA).¹⁶

Authors of 3 recent reviews have assessed the relationship between preoperative antiseptic washing and SSIs. Webster and Osborne analyzed 7 RCTs in a Cochrane review.¹⁷ All trials used 4% chlorhexidine gluconate as the antiseptic, and they included a total of 10,157 patients. The authors concluded that bathing with chlorhexidine did not significantly reduce SSIs compared with either placebo (RR, 0.91; 95% CI, 0.8–1.04) or bar soap (RR, 1.02; 95% CI, 0.57–1.84). Three additional studies in this review compared chlorhexidine bathing with no washing. One study showed a significant reduction of SSIs after the patients bathed with chlorhexidine (RR, 0.36; 95% CI, 0.17–0.79); the other 2 studies demonstrated no significant difference in outcome.

Kamel and colleagues conducted a recent systematic review that included 20 randomized and nonrandomized studies (n = 9,520); while the authors concluded that showering with an antiseptic solution reduced skin flora, they could not confirm that it produced a significant reduction in infection.¹⁸ Finally, in a meta-analysis that included 16 randomized and nonrandomized studies with 17,932 patients, Chlebicki and associates concluded that there was no significant reduction in SSIs with whole-body bathing with chlorhexidine compared with bathing with soap or placebo or with no bathing (RR, 0.90; 95% CI, 0.77–1.05; P = .19).¹⁹ A recent report from the World Health Organization confirmed these observations, although the report did not specifically focus on patients who had had a cesarean delivery.²⁰

What the evidence says

Although chlorhexidine bathing reduces skin flora, especially in the number of staphylococcal species, this effect does not necessarily translate into a reduction of SSIs. Therefore, we recommend against routine chlorhexidine bathing before cesarean delivery, although we acknowledge that there is no apparent harm associated with this practice, assuming that the patient is not allergic to the medicated soap (Level II Evidence, Level C Recommendation; TABLE, page 2).

Did you read Part 1 of this series?

Preventing infection after cesarean delivery: Evidence-based guidance, Part 1

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

An experimental biological agent, GP2015, demonstrated equivalent efficacy and comparable safety to etanercept for moderate to severe plaque psoriasis in a manufacturer-sponsored study, according to a report published online in the British Journal of Dermatology.

These findings should contribute to the confirmation of GP2015 as an etanercept (Enbrel) biosimilar for this patient population. Proposed biosimilars such as GP2015 are follow-on versions of authorized biological products, and regulatory authorities require that they demonstrate similarity with a large body of physiochemical and clinical data before they can be confirmed as biosimilars, said Christopher Griffiths, MD, of the Dermatology Centre, Salford Royal Hospital, University of Manchester (England), and his associates.

To contribute such data, Dr. Griffiths and his associates studied the efficacy and safety of GP2015 compared with etanercept, a tumor necrosis factor blocker, in the 2-year EGALITY trial. They assessed 531 adults at 74 medical centers in 11 European countries and South Africa, all of whom had active but stable chronic plaque psoriasis affecting 10% or more of their body surface area and Psoriasis Area and Severity Index (PASI) scores of 10 or more.

The study participants were randomly assigned in approximately equal numbers in a double-blind fashion to self administer GP2015 or etanercept subcutaneously, twice weekly for 12 weeks. Those who achieved at least a 50% improvement in PASI score were then randomized to continue the same treatment once weekly or to undergo a series of three treatment “switches” between GP2015 and etanercept at 6-week intervals until week 30. During an extension phase of the study, participants could then continue to receive the same treatment they had ended on, until week 52.

The primary efficacy endpoint – the percentage of patients who showed at least a 75% improvement from baseline in PASI score (PASI 75) at 12 weeks – was 73.4% with GP2015 and 75.7% with etanercept, which demonstrated therapeutic equivalence. A secondary efficacy end point – mean change in PASI score from baseline to week 12 – also was similar between the two study drugs. In all treatment groups, both PASI mean scores and change in PASI scores over time were comparable between the two study groups, regardless of switching between the two agents. In addition, in all groups, PASI 75 and PASI 90 scores increased gradually over time until week 30, and then remained stable through week 52, the investigators said (Br J Dermatol. 2016. doi: 10.1111/bjd.15152).

The proportion of patients with at least one treatment-emergent adverse event was similar in the GP2015 and etanercept groups who did not switch agents (59.8% and 57.3%, respectively), and was also similar among those who did switch agents between GP2015 (61%) and etanercept (59.4%).

The rates of serious adverse events and of adverse events that led to withdrawal from the study were similar across all treatment groups. Immunogenicity of GP2015 was similar to etanercept.

However, the rate of “adverse events of special interest” – those referred to in special warnings and precautions on the etanercept label – was markedly higher for continued GP2015 than for continued etanercept (11.0% vs. 4.7%) and for switched GP2015 than for switched etanercept (11.0% vs. 5.2%). One patient who took etanercept throughout the trial developed malignant melanoma.

The results of the study “confirm biosimilarity that was established with all previous analytical comparisons to the reference product in that equivalent efficacy was demonstrated as well as similar safety and immunogenicity of GP2015” with etanercept, “in a highly sensitive, generally immune-competent population,” the authors concluded.

The study was funded by Hexal AG, a Sandoz company, which was involved in the study design, data collection and analysis, and manuscript preparation. Dr. Griffiths reported ties to AbbVie, BMS. Galderma, Janssen, Leo-Pharma, Lilly, MSD, Novartis, Pfizer, Regeneron, Roche, Sandoz, and UCB Pharma, and his associates reported ties to numerous industry sources.

An experimental biological agent, GP2015, demonstrated equivalent efficacy and comparable safety to etanercept for moderate to severe plaque psoriasis in a manufacturer-sponsored study, according to a report published online in the British Journal of Dermatology.

These findings should contribute to the confirmation of GP2015 as an etanercept (Enbrel) biosimilar for this patient population. Proposed biosimilars such as GP2015 are follow-on versions of authorized biological products, and regulatory authorities require that they demonstrate similarity with a large body of physiochemical and clinical data before they can be confirmed as biosimilars, said Christopher Griffiths, MD, of the Dermatology Centre, Salford Royal Hospital, University of Manchester (England), and his associates.

To contribute such data, Dr. Griffiths and his associates studied the efficacy and safety of GP2015 compared with etanercept, a tumor necrosis factor blocker, in the 2-year EGALITY trial. They assessed 531 adults at 74 medical centers in 11 European countries and South Africa, all of whom had active but stable chronic plaque psoriasis affecting 10% or more of their body surface area and Psoriasis Area and Severity Index (PASI) scores of 10 or more.

The study participants were randomly assigned in approximately equal numbers in a double-blind fashion to self administer GP2015 or etanercept subcutaneously, twice weekly for 12 weeks. Those who achieved at least a 50% improvement in PASI score were then randomized to continue the same treatment once weekly or to undergo a series of three treatment “switches” between GP2015 and etanercept at 6-week intervals until week 30. During an extension phase of the study, participants could then continue to receive the same treatment they had ended on, until week 52.

The primary efficacy endpoint – the percentage of patients who showed at least a 75% improvement from baseline in PASI score (PASI 75) at 12 weeks – was 73.4% with GP2015 and 75.7% with etanercept, which demonstrated therapeutic equivalence. A secondary efficacy end point – mean change in PASI score from baseline to week 12 – also was similar between the two study drugs. In all treatment groups, both PASI mean scores and change in PASI scores over time were comparable between the two study groups, regardless of switching between the two agents. In addition, in all groups, PASI 75 and PASI 90 scores increased gradually over time until week 30, and then remained stable through week 52, the investigators said (Br J Dermatol. 2016. doi: 10.1111/bjd.15152).

The proportion of patients with at least one treatment-emergent adverse event was similar in the GP2015 and etanercept groups who did not switch agents (59.8% and 57.3%, respectively), and was also similar among those who did switch agents between GP2015 (61%) and etanercept (59.4%).

The rates of serious adverse events and of adverse events that led to withdrawal from the study were similar across all treatment groups. Immunogenicity of GP2015 was similar to etanercept.

However, the rate of “adverse events of special interest” – those referred to in special warnings and precautions on the etanercept label – was markedly higher for continued GP2015 than for continued etanercept (11.0% vs. 4.7%) and for switched GP2015 than for switched etanercept (11.0% vs. 5.2%). One patient who took etanercept throughout the trial developed malignant melanoma.

The results of the study “confirm biosimilarity that was established with all previous analytical comparisons to the reference product in that equivalent efficacy was demonstrated as well as similar safety and immunogenicity of GP2015” with etanercept, “in a highly sensitive, generally immune-competent population,” the authors concluded.

The study was funded by Hexal AG, a Sandoz company, which was involved in the study design, data collection and analysis, and manuscript preparation. Dr. Griffiths reported ties to AbbVie, BMS. Galderma, Janssen, Leo-Pharma, Lilly, MSD, Novartis, Pfizer, Regeneron, Roche, Sandoz, and UCB Pharma, and his associates reported ties to numerous industry sources.

An experimental biological agent, GP2015, demonstrated equivalent efficacy and comparable safety to etanercept for moderate to severe plaque psoriasis in a manufacturer-sponsored study, according to a report published online in the British Journal of Dermatology.

These findings should contribute to the confirmation of GP2015 as an etanercept (Enbrel) biosimilar for this patient population. Proposed biosimilars such as GP2015 are follow-on versions of authorized biological products, and regulatory authorities require that they demonstrate similarity with a large body of physiochemical and clinical data before they can be confirmed as biosimilars, said Christopher Griffiths, MD, of the Dermatology Centre, Salford Royal Hospital, University of Manchester (England), and his associates.

To contribute such data, Dr. Griffiths and his associates studied the efficacy and safety of GP2015 compared with etanercept, a tumor necrosis factor blocker, in the 2-year EGALITY trial. They assessed 531 adults at 74 medical centers in 11 European countries and South Africa, all of whom had active but stable chronic plaque psoriasis affecting 10% or more of their body surface area and Psoriasis Area and Severity Index (PASI) scores of 10 or more.

The study participants were randomly assigned in approximately equal numbers in a double-blind fashion to self administer GP2015 or etanercept subcutaneously, twice weekly for 12 weeks. Those who achieved at least a 50% improvement in PASI score were then randomized to continue the same treatment once weekly or to undergo a series of three treatment “switches” between GP2015 and etanercept at 6-week intervals until week 30. During an extension phase of the study, participants could then continue to receive the same treatment they had ended on, until week 52.

The primary efficacy endpoint – the percentage of patients who showed at least a 75% improvement from baseline in PASI score (PASI 75) at 12 weeks – was 73.4% with GP2015 and 75.7% with etanercept, which demonstrated therapeutic equivalence. A secondary efficacy end point – mean change in PASI score from baseline to week 12 – also was similar between the two study drugs. In all treatment groups, both PASI mean scores and change in PASI scores over time were comparable between the two study groups, regardless of switching between the two agents. In addition, in all groups, PASI 75 and PASI 90 scores increased gradually over time until week 30, and then remained stable through week 52, the investigators said (Br J Dermatol. 2016. doi: 10.1111/bjd.15152).

The proportion of patients with at least one treatment-emergent adverse event was similar in the GP2015 and etanercept groups who did not switch agents (59.8% and 57.3%, respectively), and was also similar among those who did switch agents between GP2015 (61%) and etanercept (59.4%).

The rates of serious adverse events and of adverse events that led to withdrawal from the study were similar across all treatment groups. Immunogenicity of GP2015 was similar to etanercept.

However, the rate of “adverse events of special interest” – those referred to in special warnings and precautions on the etanercept label – was markedly higher for continued GP2015 than for continued etanercept (11.0% vs. 4.7%) and for switched GP2015 than for switched etanercept (11.0% vs. 5.2%). One patient who took etanercept throughout the trial developed malignant melanoma.

The results of the study “confirm biosimilarity that was established with all previous analytical comparisons to the reference product in that equivalent efficacy was demonstrated as well as similar safety and immunogenicity of GP2015” with etanercept, “in a highly sensitive, generally immune-competent population,” the authors concluded.

The study was funded by Hexal AG, a Sandoz company, which was involved in the study design, data collection and analysis, and manuscript preparation. Dr. Griffiths reported ties to AbbVie, BMS. Galderma, Janssen, Leo-Pharma, Lilly, MSD, Novartis, Pfizer, Regeneron, Roche, Sandoz, and UCB Pharma, and his associates reported ties to numerous industry sources.

Fear of potential pain caused by insertion of an intrauterine device (IUD) prevents some women from using this highly effective and safe contraceptive method. Recently, investigators conducted a randomized, placebo-controlled trial to assess whether vaginal lidocaine gel administered shortly before IUD placement was associated with a decrease from baseline in patient-reported pain scores.¹

In this blinded trial, Rapkinand colleagues randomly assigned nulliparous women presenting for IUD placement (either the copper T380A IUD or the 52-mg levonorgestrel-releasing IUD) at faculty and resident clinics at a US urban academic center to place 4 mL of 2% lidocaine gel or placebo gel vaginally (using an applicator) 5 to 15 minutes prior to IUD placement.¹ A 100-mm visual analog scale (VAS) was used to assess pain at each step of the procedure, including at baseline (before speculum insertion), after speculum placement, tenaculum placement, uterine sound, IUD insertion, and 5 minutes after speculum removal.

Among the 58 evaluable participants, the mean age was 23 years in the lidocaine group and 24 years in the placebo group; more than 80% of the women were white.

The study’s primary outcome was change in pain experience from baseline to IUD insertion. Pain was measured on a VAS from 0 mm (no pain) to 100 mm (worst pain in my life). Secondary outcomes included patient acceptability of gel self-insertion, physician-reported ease of IUD insertion, and need for pain medication for up to 7 days after IUD insertion.

Related article:
Liletta gets a new inserter: Steps for successful placement

What the investigators found

The mean change in pain scores with IUD placement was 61 mm for the lidocaine group and 69 mm for the placebo group (P = .06). Thus, no difference in the primary outcome was found between the 2 groups. However, women who received the lidocaine gel treatment experiencedsignificantly less pain with tenaculum placement than those who received placebo gel (32 mm vs 56 mm; P = .02), and they were substantially less likely to require cervical dilation (3.3% vs 34.5%; P = .002), an often painful procedure.

Related article:
Does the injection of ketorolac prior to IUD placement reduce pain?
 

Patient acceptability and satisfaction. Five minutes after the IUD placement procedure, approximately two-thirds of women in both groups indicated that they experienced an acceptable level of discomfort, and more than three-quarters indicated that they were satisfied with the placement procedure. Fully 67% of the lidocaine group and 68% of the placebo group indicated definitely or probably yes when asked if the level of discomfort they experienced was acceptable, with 27% and 21%, respectively, responding as neutral. When asked if getting the IUD was worth the level of discomfort experienced, 73% of the lidocaine group and 82% of the placebo group responded “yes,” while 23% and 18%, respectively, were unsure.

Pearls for practice

As this study showed, self-administered lidocaine vaginal gel did not alter the primary outcome (pain with IUD placement), but the reduced need for cervical dilation is a promising finding and warrants additional study.

Tip. Interestingly, the placebo-treated women experienced pain intensity with cervical tenaculum placement similar to that associated with IUD placement. This finding illuminates the fact that IUD placement is not the only action that can produce pain. For this reason, I use a finer, single-tooth tenaculum designed for use with sonohysterograms (Goldstein Grasp Cervical Stabilizer).² This instrument appears to cause less pain and bleeding than conventional tenacula.

Related article:
How to identify and localize IUDs on ultrasound
 

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Fear of potential pain caused by insertion of an intrauterine device (IUD) prevents some women from using this highly effective and safe contraceptive method. Recently, investigators conducted a randomized, placebo-controlled trial to assess whether vaginal lidocaine gel administered shortly before IUD placement was associated with a decrease from baseline in patient-reported pain scores.¹

In this blinded trial, Rapkinand colleagues randomly assigned nulliparous women presenting for IUD placement (either the copper T380A IUD or the 52-mg levonorgestrel-releasing IUD) at faculty and resident clinics at a US urban academic center to place 4 mL of 2% lidocaine gel or placebo gel vaginally (using an applicator) 5 to 15 minutes prior to IUD placement.¹ A 100-mm visual analog scale (VAS) was used to assess pain at each step of the procedure, including at baseline (before speculum insertion), after speculum placement, tenaculum placement, uterine sound, IUD insertion, and 5 minutes after speculum removal.

Among the 58 evaluable participants, the mean age was 23 years in the lidocaine group and 24 years in the placebo group; more than 80% of the women were white.

The study’s primary outcome was change in pain experience from baseline to IUD insertion. Pain was measured on a VAS from 0 mm (no pain) to 100 mm (worst pain in my life). Secondary outcomes included patient acceptability of gel self-insertion, physician-reported ease of IUD insertion, and need for pain medication for up to 7 days after IUD insertion.

Related article:
Liletta gets a new inserter: Steps for successful placement

What the investigators found

The mean change in pain scores with IUD placement was 61 mm for the lidocaine group and 69 mm for the placebo group (P = .06). Thus, no difference in the primary outcome was found between the 2 groups. However, women who received the lidocaine gel treatment experiencedsignificantly less pain with tenaculum placement than those who received placebo gel (32 mm vs 56 mm; P = .02), and they were substantially less likely to require cervical dilation (3.3% vs 34.5%; P = .002), an often painful procedure.

Related article:
Does the injection of ketorolac prior to IUD placement reduce pain?
 

Patient acceptability and satisfaction. Five minutes after the IUD placement procedure, approximately two-thirds of women in both groups indicated that they experienced an acceptable level of discomfort, and more than three-quarters indicated that they were satisfied with the placement procedure. Fully 67% of the lidocaine group and 68% of the placebo group indicated definitely or probably yes when asked if the level of discomfort they experienced was acceptable, with 27% and 21%, respectively, responding as neutral. When asked if getting the IUD was worth the level of discomfort experienced, 73% of the lidocaine group and 82% of the placebo group responded “yes,” while 23% and 18%, respectively, were unsure.

Pearls for practice

As this study showed, self-administered lidocaine vaginal gel did not alter the primary outcome (pain with IUD placement), but the reduced need for cervical dilation is a promising finding and warrants additional study.

Tip. Interestingly, the placebo-treated women experienced pain intensity with cervical tenaculum placement similar to that associated with IUD placement. This finding illuminates the fact that IUD placement is not the only action that can produce pain. For this reason, I use a finer, single-tooth tenaculum designed for use with sonohysterograms (Goldstein Grasp Cervical Stabilizer).² This instrument appears to cause less pain and bleeding than conventional tenacula.

Related article:
How to identify and localize IUDs on ultrasound
 

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Fear of potential pain caused by insertion of an intrauterine device (IUD) prevents some women from using this highly effective and safe contraceptive method. Recently, investigators conducted a randomized, placebo-controlled trial to assess whether vaginal lidocaine gel administered shortly before IUD placement was associated with a decrease from baseline in patient-reported pain scores.¹

In this blinded trial, Rapkinand colleagues randomly assigned nulliparous women presenting for IUD placement (either the copper T380A IUD or the 52-mg levonorgestrel-releasing IUD) at faculty and resident clinics at a US urban academic center to place 4 mL of 2% lidocaine gel or placebo gel vaginally (using an applicator) 5 to 15 minutes prior to IUD placement.¹ A 100-mm visual analog scale (VAS) was used to assess pain at each step of the procedure, including at baseline (before speculum insertion), after speculum placement, tenaculum placement, uterine sound, IUD insertion, and 5 minutes after speculum removal.

Among the 58 evaluable participants, the mean age was 23 years in the lidocaine group and 24 years in the placebo group; more than 80% of the women were white.

The study’s primary outcome was change in pain experience from baseline to IUD insertion. Pain was measured on a VAS from 0 mm (no pain) to 100 mm (worst pain in my life). Secondary outcomes included patient acceptability of gel self-insertion, physician-reported ease of IUD insertion, and need for pain medication for up to 7 days after IUD insertion.

Related article:
Liletta gets a new inserter: Steps for successful placement

What the investigators found

The mean change in pain scores with IUD placement was 61 mm for the lidocaine group and 69 mm for the placebo group (P = .06). Thus, no difference in the primary outcome was found between the 2 groups. However, women who received the lidocaine gel treatment experiencedsignificantly less pain with tenaculum placement than those who received placebo gel (32 mm vs 56 mm; P = .02), and they were substantially less likely to require cervical dilation (3.3% vs 34.5%; P = .002), an often painful procedure.

Related article:
Does the injection of ketorolac prior to IUD placement reduce pain?
 

Patient acceptability and satisfaction. Five minutes after the IUD placement procedure, approximately two-thirds of women in both groups indicated that they experienced an acceptable level of discomfort, and more than three-quarters indicated that they were satisfied with the placement procedure. Fully 67% of the lidocaine group and 68% of the placebo group indicated definitely or probably yes when asked if the level of discomfort they experienced was acceptable, with 27% and 21%, respectively, responding as neutral. When asked if getting the IUD was worth the level of discomfort experienced, 73% of the lidocaine group and 82% of the placebo group responded “yes,” while 23% and 18%, respectively, were unsure.

Pearls for practice

As this study showed, self-administered lidocaine vaginal gel did not alter the primary outcome (pain with IUD placement), but the reduced need for cervical dilation is a promising finding and warrants additional study.

Tip. Interestingly, the placebo-treated women experienced pain intensity with cervical tenaculum placement similar to that associated with IUD placement. This finding illuminates the fact that IUD placement is not the only action that can produce pain. For this reason, I use a finer, single-tooth tenaculum designed for use with sonohysterograms (Goldstein Grasp Cervical Stabilizer).² This instrument appears to cause less pain and bleeding than conventional tenacula.

Related article:
How to identify and localize IUDs on ultrasound
 

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WASHINGTON – Women with systemic lupus erythematosus are nine times more likely to develop early-onset preeclampsia during a first pregnancy than are women without the disease, according a study of two Swedish national population-based registries.

The risk of preeclampsia occurring before 34 weeks’ gestation declined with subsequent pregnancies, but it remained significantly elevated above the background risk, Julia F. Simard, ScD, said at the annual meeting of the American College of Rheumatology.

copyright Sohel_Parvez_Haque/Thinkstock

[email protected]

On Twitter @alz_gal

WASHINGTON – Women with systemic lupus erythematosus are nine times more likely to develop early-onset preeclampsia during a first pregnancy than are women without the disease, according a study of two Swedish national population-based registries.

The risk of preeclampsia occurring before 34 weeks’ gestation declined with subsequent pregnancies, but it remained significantly elevated above the background risk, Julia F. Simard, ScD, said at the annual meeting of the American College of Rheumatology.

copyright Sohel_Parvez_Haque/Thinkstock

[email protected]

On Twitter @alz_gal

WASHINGTON – Women with systemic lupus erythematosus are nine times more likely to develop early-onset preeclampsia during a first pregnancy than are women without the disease, according a study of two Swedish national population-based registries.

The risk of preeclampsia occurring before 34 weeks’ gestation declined with subsequent pregnancies, but it remained significantly elevated above the background risk, Julia F. Simard, ScD, said at the annual meeting of the American College of Rheumatology.

copyright Sohel_Parvez_Haque/Thinkstock

[email protected]

On Twitter @alz_gal

Children whose fathers have a positive emotional response to parenting and provide a sense of security early on are less likely to exhibit behavioral problems at age 9, a cohort study of more than 13,000 children shows. However, the researchers found no association between behavioral problems and paternal involvement with child care and household tasks.

The researchers used data from the Avon Longitudinal Study of Parents and Children, a birth cohort study of children in southwest England that is also known as Children of the 90s. In this study, the children’s fathers completed questionnaires at 8 weeks (37 questions) and 8 months (21 questions) after the birth. They were asked to rate their level of agreement with 58 statements related to several issues, including direct care, household tasks, attitudes about parenting, and relationships with the child. The mothers were interviewed at child age 9 (N = 6,898) and 11 (N = 6,328) to determine the presence or absence of behavioral problems, which were measured via the total difficulties score of the Strengths and Difficulties Questionnaire.

Previous studies have tended toward the assumption that paternal involvement with the child is unidimensional, which might explain why other studies have not found a clear association with behavioral problems. This study is the first to look at paternal involvement as multidimensional, reported Charles Opondo, PhD, of the University of Oxford (England), and his colleagues (BMJ Open. 2016;6:e012034. doi: 10.1136/bmjopen-2016-012034).

The questions for fathers related to emotional response to the childhood, how often fathers participated in domestic and child care activity, and feelings of security about their paternal role.

Children of fathers who scored high on questions about emotional response were less likely to have behavioral problems at age 9 (odds ratio, 0.86; 95% confidence interval, 0.79-0.94; P = .001), as were children of fathers who scored high on their sense of security (OR, 0.87; 95% CI, 0.79-0.96; P = .006). The same patterns were true at age 11.

The impact of paternal involvement on mothers could be an important factor. “There is evidence that fathers’ involvement can also alleviate the impact of factors such as maternal depression, which are known to increase children’s risk of behavioral problems,” the researchers wrote.

Meanwhile, Dr. Opondo and his colleagues found no significant relationship between behavioral problems, and time spent in domestic and child care activity at either age.

“The findings of this research study suggest that it is psychological and emotional aspects of paternal involvement in a child’s infancy that are most powerful in influencing later child behavior and not the amount of time that fathers are engaged in child care or domestic tasks in the household,” Dr. Opondo and his colleagues said.

The researchers cited several limitations. The study was observational, for example, and could be subject to unobserved confounders. In addition, the study relied on self-reporting, which can produce bias.

The Policy Research Program in the Department of Health, England, funded the study. The authors reported having no financial disclosures.

[email protected]

Children whose fathers have a positive emotional response to parenting and provide a sense of security early on are less likely to exhibit behavioral problems at age 9, a cohort study of more than 13,000 children shows. However, the researchers found no association between behavioral problems and paternal involvement with child care and household tasks.

The researchers used data from the Avon Longitudinal Study of Parents and Children, a birth cohort study of children in southwest England that is also known as Children of the 90s. In this study, the children’s fathers completed questionnaires at 8 weeks (37 questions) and 8 months (21 questions) after the birth. They were asked to rate their level of agreement with 58 statements related to several issues, including direct care, household tasks, attitudes about parenting, and relationships with the child. The mothers were interviewed at child age 9 (N = 6,898) and 11 (N = 6,328) to determine the presence or absence of behavioral problems, which were measured via the total difficulties score of the Strengths and Difficulties Questionnaire.

Previous studies have tended toward the assumption that paternal involvement with the child is unidimensional, which might explain why other studies have not found a clear association with behavioral problems. This study is the first to look at paternal involvement as multidimensional, reported Charles Opondo, PhD, of the University of Oxford (England), and his colleagues (BMJ Open. 2016;6:e012034. doi: 10.1136/bmjopen-2016-012034).

The questions for fathers related to emotional response to the childhood, how often fathers participated in domestic and child care activity, and feelings of security about their paternal role.

Children of fathers who scored high on questions about emotional response were less likely to have behavioral problems at age 9 (odds ratio, 0.86; 95% confidence interval, 0.79-0.94; P = .001), as were children of fathers who scored high on their sense of security (OR, 0.87; 95% CI, 0.79-0.96; P = .006). The same patterns were true at age 11.

The impact of paternal involvement on mothers could be an important factor. “There is evidence that fathers’ involvement can also alleviate the impact of factors such as maternal depression, which are known to increase children’s risk of behavioral problems,” the researchers wrote.

Meanwhile, Dr. Opondo and his colleagues found no significant relationship between behavioral problems, and time spent in domestic and child care activity at either age.

“The findings of this research study suggest that it is psychological and emotional aspects of paternal involvement in a child’s infancy that are most powerful in influencing later child behavior and not the amount of time that fathers are engaged in child care or domestic tasks in the household,” Dr. Opondo and his colleagues said.

The researchers cited several limitations. The study was observational, for example, and could be subject to unobserved confounders. In addition, the study relied on self-reporting, which can produce bias.

The Policy Research Program in the Department of Health, England, funded the study. The authors reported having no financial disclosures.

[email protected]

Children whose fathers have a positive emotional response to parenting and provide a sense of security early on are less likely to exhibit behavioral problems at age 9, a cohort study of more than 13,000 children shows. However, the researchers found no association between behavioral problems and paternal involvement with child care and household tasks.

The researchers used data from the Avon Longitudinal Study of Parents and Children, a birth cohort study of children in southwest England that is also known as Children of the 90s. In this study, the children’s fathers completed questionnaires at 8 weeks (37 questions) and 8 months (21 questions) after the birth. They were asked to rate their level of agreement with 58 statements related to several issues, including direct care, household tasks, attitudes about parenting, and relationships with the child. The mothers were interviewed at child age 9 (N = 6,898) and 11 (N = 6,328) to determine the presence or absence of behavioral problems, which were measured via the total difficulties score of the Strengths and Difficulties Questionnaire.

Previous studies have tended toward the assumption that paternal involvement with the child is unidimensional, which might explain why other studies have not found a clear association with behavioral problems. This study is the first to look at paternal involvement as multidimensional, reported Charles Opondo, PhD, of the University of Oxford (England), and his colleagues (BMJ Open. 2016;6:e012034. doi: 10.1136/bmjopen-2016-012034).

The questions for fathers related to emotional response to the childhood, how often fathers participated in domestic and child care activity, and feelings of security about their paternal role.

Children of fathers who scored high on questions about emotional response were less likely to have behavioral problems at age 9 (odds ratio, 0.86; 95% confidence interval, 0.79-0.94; P = .001), as were children of fathers who scored high on their sense of security (OR, 0.87; 95% CI, 0.79-0.96; P = .006). The same patterns were true at age 11.

The impact of paternal involvement on mothers could be an important factor. “There is evidence that fathers’ involvement can also alleviate the impact of factors such as maternal depression, which are known to increase children’s risk of behavioral problems,” the researchers wrote.

Meanwhile, Dr. Opondo and his colleagues found no significant relationship between behavioral problems, and time spent in domestic and child care activity at either age.

“The findings of this research study suggest that it is psychological and emotional aspects of paternal involvement in a child’s infancy that are most powerful in influencing later child behavior and not the amount of time that fathers are engaged in child care or domestic tasks in the household,” Dr. Opondo and his colleagues said.

The researchers cited several limitations. The study was observational, for example, and could be subject to unobserved confounders. In addition, the study relied on self-reporting, which can produce bias.

The Policy Research Program in the Department of Health, England, funded the study. The authors reported having no financial disclosures.

[email protected]

Opioid Abuse-Deterrent Formulations

The meaning of the term abuse-deterrent is often misunderstood to mean abuse-proof. The FDA defines abuse-deterrent properties as those properties expected to meaningfully deter abuse even if they do not fully prevent abuse. Abuse-deterrent properties make certain types of abuse, such as crushing in order to snort or dissolving in order to inject, more difficult or less rewarding. However, this does not mean that the product is impossible to abuse or that these properties will necessarily prevent addiction, overdose, or death.

Of note, currently marketed abuse-deterrent formulation technologies do not effectively deter one of the most common forms of opioid abuse—simply swallowing a number of intact tablets or capsules. Abuse-deterrent opioids do not reduce the risk for opioid addiction, and they carry the same warnings about the risk for addiction as do conventional opioids.

Abuse and Misuse Data

The FDA is encouraging pharmaceutical industry efforts to develop pain medicines that are more difficult to abuse and to prioritize the need for data and study methods that will help evaluate the impact of abuse-deterrent opioids on misuse and abuse in the community. To collect this important information, the FDA requires that all companies that have brand-name opioids with labeling describing abuse-deterrent properties conduct postmarketing studies to determine the impact of abuse-deterrent formulation technologies in the real world. Each company is given a time line to which they must adhere. These types of studies take several years to conduct and analyze. Data collected will include the amount prescribed for each product; adverse events related to the use, abuse, and misuse of the products; and epidemiologic data on the rates of abuse and misuse and their consequences (addiction, overdose, and death). These studies should allow the FDA to assess the impact in the community, if any, attributable to the abuse-deterrent properties.

The science of abuse deterrence is relatively new, and both the formulation technologies and the analytical, clinical, and statistical methods for evaluating those technologies ar

Key Points for Practitioners

The FDA’s work to facilitate the safe use of opioids is taking place within a larger policy framework aimed at addressing opioid abuse while ensuring appropriate access to pain treatment. The FDA has undertaken several efforts helpful to clinicians. The FDA’s Extended-Release and Long-Acting Opioid Analgesics Risk Evaluation and Mitigation Strategy (ER/LA REMS) Program is required for all companies who make these products. The program’s goal is to reduce serious adverse outcomes of inappropriate prescribing, misuse, and abuse of ER/LA opioid analgesics while maintaining patient access to pain medications. Adverse outcomes of concern include addiction, unintentional overdose, and death.

As part of the REMS, all ER/LA opioid analgesic pharmaceutical companies must provide education for prescribers of their medications through accredited continuing education activities that are supported by independent educational grants. Companies must also provide information that prescribers can use when counseling patients about the risks and benefits associated with ER/LA opioid analgesic use.

The FDA has developed core messages that are communicated to prescribers in the Blueprint for Prescriber Education. The Blueprint is directed to prescribers of ER/LA opioid analgesics but also may be relevant for other health care professionals (eg, pharmacists). Companies involved in the ER/LA Opioid Analgesics REMS Program have collaborated to implement a single shared REMS. This group provides a list of REMS-compliant continuing education activities, which can be found at http://www.er-la-opioidrems.com.

It is important for practitioners to understand that all currently approved abuse-deterrent opioid products still can be abused, and as scheduled controlled substances, they are addictive. The abuse-deterrent properties are expected to deter but do not wholly prevent abuse. Because in the end opioid medications must be able to deliver the opioid to the patient, there probably always will be potential for abuse of these products. Consequently, practitioners should counsel their patients on the following:

• Keep medicines in a secure location out of the reach and out of sight of children and pets. Put away medicines after every use. Accidental exposure to medicine in the home is a major source of unintentional poisonings in the U.S.
• If medicines are no longer needed, dispose of them properly. Disposing of all unused opioid analgesics reduces access to these medications by family members and household guests seeking opioids for abuse.
• The FDA recommends returning most prescription medications through a local or U.S. Drug Enforcement Administration (DEA)-sponsored take-back program or DEA-authorized collector. For opioid analgesics, the FDA recommends immediate removal from the home by flushing them down the toilet or sink.

Opioids Action Plan

In February 2016, FDA Commissioner Robert Califf (then the deputy commissioner for medical products and tobacco) announced the FDA Opioids Action Plan. The plan focuses on policies aimed at reversing the opioid epidemic while still providing patients in pain access to effective pain relief. The FDA actions include:

• Convening an expert advisory committee before approving any new drug application for an opioid that does not have abuse-deterrent properties;
• Consulting with the Pediatric Advisory Committee about a framework for pediatric opioid labeling before any new labeling is approved;
• Updating the REMS requirements for ER/LA opioid analgesics after considering the advisory committee’s recommendations from a meeting held in May 2016 and reviewing existing requirements;
• Improving access to naloxone (by facilitating the development of an over-the-counter version of naloxone, which is currently available only by prescription, thereby making it more accessible to treat opioid overdose), and medication-assisted treatment options for patients with opioid use disorders; and
• Supporting better pain management options, including alternative, nonaddictive treatments for pain.

The FDA is conducting research on pain measurements for conditions such as chronic low back pain, osteoarthritis, diabetic neuropathy, postherpetic neuralgia, and fibromyalgia. The FDA is also working to support the development of nonopioid options for these patients.

Consistent with the plan, in March 2016, the FDA announced that it was requiring changes to the labeling on immediate-release opioids, including additional warnings and safety information that incorporate elements similar to the ER/LA opioid analgesics labeling. Furthermore, among other steps, the FDA has contracted with the National Academy of Medicine to provide advice on how to incorporate current evidence about the public health impact of opioid use (for patients who are prescribed opioids as well as for nonpatients) into regulatory activities concerning opioids.

The FDA shares the responsibility of keeping patients safe. Working with the health care community and federal and state partners to help reduce opioid misuse and abuse and improve appropriate opioid prescribing while ensuring that patients in pain continue to have appropriate access to opioid analgesics is a top priority for the FDA and part of the targeted approach of the HHS focused on prevention, treatment, and intervention.

Opioid Abuse-Deterrent Formulations

The meaning of the term abuse-deterrent is often misunderstood to mean abuse-proof. The FDA defines abuse-deterrent properties as those properties expected to meaningfully deter abuse even if they do not fully prevent abuse. Abuse-deterrent properties make certain types of abuse, such as crushing in order to snort or dissolving in order to inject, more difficult or less rewarding. However, this does not mean that the product is impossible to abuse or that these properties will necessarily prevent addiction, overdose, or death.

Of note, currently marketed abuse-deterrent formulation technologies do not effectively deter one of the most common forms of opioid abuse—simply swallowing a number of intact tablets or capsules. Abuse-deterrent opioids do not reduce the risk for opioid addiction, and they carry the same warnings about the risk for addiction as do conventional opioids.

Abuse and Misuse Data

The FDA is encouraging pharmaceutical industry efforts to develop pain medicines that are more difficult to abuse and to prioritize the need for data and study methods that will help evaluate the impact of abuse-deterrent opioids on misuse and abuse in the community. To collect this important information, the FDA requires that all companies that have brand-name opioids with labeling describing abuse-deterrent properties conduct postmarketing studies to determine the impact of abuse-deterrent formulation technologies in the real world. Each company is given a time line to which they must adhere. These types of studies take several years to conduct and analyze. Data collected will include the amount prescribed for each product; adverse events related to the use, abuse, and misuse of the products; and epidemiologic data on the rates of abuse and misuse and their consequences (addiction, overdose, and death). These studies should allow the FDA to assess the impact in the community, if any, attributable to the abuse-deterrent properties.

The science of abuse deterrence is relatively new, and both the formulation technologies and the analytical, clinical, and statistical methods for evaluating those technologies ar

Key Points for Practitioners

The FDA’s work to facilitate the safe use of opioids is taking place within a larger policy framework aimed at addressing opioid abuse while ensuring appropriate access to pain treatment. The FDA has undertaken several efforts helpful to clinicians. The FDA’s Extended-Release and Long-Acting Opioid Analgesics Risk Evaluation and Mitigation Strategy (ER/LA REMS) Program is required for all companies who make these products. The program’s goal is to reduce serious adverse outcomes of inappropriate prescribing, misuse, and abuse of ER/LA opioid analgesics while maintaining patient access to pain medications. Adverse outcomes of concern include addiction, unintentional overdose, and death.

As part of the REMS, all ER/LA opioid analgesic pharmaceutical companies must provide education for prescribers of their medications through accredited continuing education activities that are supported by independent educational grants. Companies must also provide information that prescribers can use when counseling patients about the risks and benefits associated with ER/LA opioid analgesic use.

The FDA has developed core messages that are communicated to prescribers in the Blueprint for Prescriber Education. The Blueprint is directed to prescribers of ER/LA opioid analgesics but also may be relevant for other health care professionals (eg, pharmacists). Companies involved in the ER/LA Opioid Analgesics REMS Program have collaborated to implement a single shared REMS. This group provides a list of REMS-compliant continuing education activities, which can be found at http://www.er-la-opioidrems.com.

It is important for practitioners to understand that all currently approved abuse-deterrent opioid products still can be abused, and as scheduled controlled substances, they are addictive. The abuse-deterrent properties are expected to deter but do not wholly prevent abuse. Because in the end opioid medications must be able to deliver the opioid to the patient, there probably always will be potential for abuse of these products. Consequently, practitioners should counsel their patients on the following:

• Keep medicines in a secure location out of the reach and out of sight of children and pets. Put away medicines after every use. Accidental exposure to medicine in the home is a major source of unintentional poisonings in the U.S.
• If medicines are no longer needed, dispose of them properly. Disposing of all unused opioid analgesics reduces access to these medications by family members and household guests seeking opioids for abuse.
• The FDA recommends returning most prescription medications through a local or U.S. Drug Enforcement Administration (DEA)-sponsored take-back program or DEA-authorized collector. For opioid analgesics, the FDA recommends immediate removal from the home by flushing them down the toilet or sink.

Opioids Action Plan

In February 2016, FDA Commissioner Robert Califf (then the deputy commissioner for medical products and tobacco) announced the FDA Opioids Action Plan. The plan focuses on policies aimed at reversing the opioid epidemic while still providing patients in pain access to effective pain relief. The FDA actions include:

• Convening an expert advisory committee before approving any new drug application for an opioid that does not have abuse-deterrent properties;
• Consulting with the Pediatric Advisory Committee about a framework for pediatric opioid labeling before any new labeling is approved;
• Updating the REMS requirements for ER/LA opioid analgesics after considering the advisory committee’s recommendations from a meeting held in May 2016 and reviewing existing requirements;
• Improving access to naloxone (by facilitating the development of an over-the-counter version of naloxone, which is currently available only by prescription, thereby making it more accessible to treat opioid overdose), and medication-assisted treatment options for patients with opioid use disorders; and
• Supporting better pain management options, including alternative, nonaddictive treatments for pain.

The FDA is conducting research on pain measurements for conditions such as chronic low back pain, osteoarthritis, diabetic neuropathy, postherpetic neuralgia, and fibromyalgia. The FDA is also working to support the development of nonopioid options for these patients.

Consistent with the plan, in March 2016, the FDA announced that it was requiring changes to the labeling on immediate-release opioids, including additional warnings and safety information that incorporate elements similar to the ER/LA opioid analgesics labeling. Furthermore, among other steps, the FDA has contracted with the National Academy of Medicine to provide advice on how to incorporate current evidence about the public health impact of opioid use (for patients who are prescribed opioids as well as for nonpatients) into regulatory activities concerning opioids.

The FDA shares the responsibility of keeping patients safe. Working with the health care community and federal and state partners to help reduce opioid misuse and abuse and improve appropriate opioid prescribing while ensuring that patients in pain continue to have appropriate access to opioid analgesics is a top priority for the FDA and part of the targeted approach of the HHS focused on prevention, treatment, and intervention.

Opioid Abuse-Deterrent Formulations

The meaning of the term abuse-deterrent is often misunderstood to mean abuse-proof. The FDA defines abuse-deterrent properties as those properties expected to meaningfully deter abuse even if they do not fully prevent abuse. Abuse-deterrent properties make certain types of abuse, such as crushing in order to snort or dissolving in order to inject, more difficult or less rewarding. However, this does not mean that the product is impossible to abuse or that these properties will necessarily prevent addiction, overdose, or death.

Of note, currently marketed abuse-deterrent formulation technologies do not effectively deter one of the most common forms of opioid abuse—simply swallowing a number of intact tablets or capsules. Abuse-deterrent opioids do not reduce the risk for opioid addiction, and they carry the same warnings about the risk for addiction as do conventional opioids.

Abuse and Misuse Data

The FDA is encouraging pharmaceutical industry efforts to develop pain medicines that are more difficult to abuse and to prioritize the need for data and study methods that will help evaluate the impact of abuse-deterrent opioids on misuse and abuse in the community. To collect this important information, the FDA requires that all companies that have brand-name opioids with labeling describing abuse-deterrent properties conduct postmarketing studies to determine the impact of abuse-deterrent formulation technologies in the real world. Each company is given a time line to which they must adhere. These types of studies take several years to conduct and analyze. Data collected will include the amount prescribed for each product; adverse events related to the use, abuse, and misuse of the products; and epidemiologic data on the rates of abuse and misuse and their consequences (addiction, overdose, and death). These studies should allow the FDA to assess the impact in the community, if any, attributable to the abuse-deterrent properties.

The science of abuse deterrence is relatively new, and both the formulation technologies and the analytical, clinical, and statistical methods for evaluating those technologies ar

Key Points for Practitioners

The FDA’s work to facilitate the safe use of opioids is taking place within a larger policy framework aimed at addressing opioid abuse while ensuring appropriate access to pain treatment. The FDA has undertaken several efforts helpful to clinicians. The FDA’s Extended-Release and Long-Acting Opioid Analgesics Risk Evaluation and Mitigation Strategy (ER/LA REMS) Program is required for all companies who make these products. The program’s goal is to reduce serious adverse outcomes of inappropriate prescribing, misuse, and abuse of ER/LA opioid analgesics while maintaining patient access to pain medications. Adverse outcomes of concern include addiction, unintentional overdose, and death.

As part of the REMS, all ER/LA opioid analgesic pharmaceutical companies must provide education for prescribers of their medications through accredited continuing education activities that are supported by independent educational grants. Companies must also provide information that prescribers can use when counseling patients about the risks and benefits associated with ER/LA opioid analgesic use.

The FDA has developed core messages that are communicated to prescribers in the Blueprint for Prescriber Education. The Blueprint is directed to prescribers of ER/LA opioid analgesics but also may be relevant for other health care professionals (eg, pharmacists). Companies involved in the ER/LA Opioid Analgesics REMS Program have collaborated to implement a single shared REMS. This group provides a list of REMS-compliant continuing education activities, which can be found at http://www.er-la-opioidrems.com.

It is important for practitioners to understand that all currently approved abuse-deterrent opioid products still can be abused, and as scheduled controlled substances, they are addictive. The abuse-deterrent properties are expected to deter but do not wholly prevent abuse. Because in the end opioid medications must be able to deliver the opioid to the patient, there probably always will be potential for abuse of these products. Consequently, practitioners should counsel their patients on the following:

• Keep medicines in a secure location out of the reach and out of sight of children and pets. Put away medicines after every use. Accidental exposure to medicine in the home is a major source of unintentional poisonings in the U.S.
• If medicines are no longer needed, dispose of them properly. Disposing of all unused opioid analgesics reduces access to these medications by family members and household guests seeking opioids for abuse.
• The FDA recommends returning most prescription medications through a local or U.S. Drug Enforcement Administration (DEA)-sponsored take-back program or DEA-authorized collector. For opioid analgesics, the FDA recommends immediate removal from the home by flushing them down the toilet or sink.

Opioids Action Plan

In February 2016, FDA Commissioner Robert Califf (then the deputy commissioner for medical products and tobacco) announced the FDA Opioids Action Plan. The plan focuses on policies aimed at reversing the opioid epidemic while still providing patients in pain access to effective pain relief. The FDA actions include:

• Convening an expert advisory committee before approving any new drug application for an opioid that does not have abuse-deterrent properties;
• Consulting with the Pediatric Advisory Committee about a framework for pediatric opioid labeling before any new labeling is approved;
• Updating the REMS requirements for ER/LA opioid analgesics after considering the advisory committee’s recommendations from a meeting held in May 2016 and reviewing existing requirements;
• Improving access to naloxone (by facilitating the development of an over-the-counter version of naloxone, which is currently available only by prescription, thereby making it more accessible to treat opioid overdose), and medication-assisted treatment options for patients with opioid use disorders; and
• Supporting better pain management options, including alternative, nonaddictive treatments for pain.

The FDA is conducting research on pain measurements for conditions such as chronic low back pain, osteoarthritis, diabetic neuropathy, postherpetic neuralgia, and fibromyalgia. The FDA is also working to support the development of nonopioid options for these patients.

Consistent with the plan, in March 2016, the FDA announced that it was requiring changes to the labeling on immediate-release opioids, including additional warnings and safety information that incorporate elements similar to the ER/LA opioid analgesics labeling. Furthermore, among other steps, the FDA has contracted with the National Academy of Medicine to provide advice on how to incorporate current evidence about the public health impact of opioid use (for patients who are prescribed opioids as well as for nonpatients) into regulatory activities concerning opioids.

The FDA shares the responsibility of keeping patients safe. Working with the health care community and federal and state partners to help reduce opioid misuse and abuse and improve appropriate opioid prescribing while ensuring that patients in pain continue to have appropriate access to opioid analgesics is a top priority for the FDA and part of the targeted approach of the HHS focused on prevention, treatment, and intervention.